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Gary Nulls Anti-Aging Protocol for Nursing Homes: Nutrients Scientifically Proven to be Beneficial to Cognition and the Overall

Body

Prepared by: Gary Null, Ph.D., and Doug Henderson, Esq.

Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved

PROTOCOL DISCLAIMER:
The attached protocol is not in any way to be construed as a prescription to cure the condition, but as a suggested nutritional component only. This protocol was initially requested by a physician from Gary Null & Associates for a specific patient, for whose condition this protocol is to be employed under the physicians directions. Firstly, patients diagnosis, treatment, and medications must be considered in determining if any of the suggested vitamins, minerals, foods, and herbs in contraindicated. Special considerations should be given to pregnant and nursing mothers. Secondly, the attached protocol must be implemented in gradual steps. Begin with low doses of one or two items of the protocols suggested items to determine the patients acceptance and tolerance. Once it is determined that the patient has adapted, the dosage should be increased in gradual steps.

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Gary Nulls Anti-Aging Protocol for Nursing Homes: Nutrients Scientifically Proven to be Beneficial to Cognition and the Overall Body............................................................... 1 PROTOCOL DISCLAIMER:......................................................................................... 2 Nursing Home Intervention Study: Introduction ............................................................ 5 NURSING HOMES, DYING FROM NEGLECT 16 References .............................. 6 INFECTION 76 Studies............................................................................................. 10 ANTIDEPRESSANTS 109 Studies........................................................................... 32 THE HIGH COST OF MEDICAL CARE 49 Studies............................................... 65 MALNUTRITION 30 Studies ................................................................................... 80 MEDICAL ERRORS & ADVERSE DRUG REACTIONS 76 Studies.................... 89 NURSING HOME PROTOCOL................................................................................ 112 Vitamin B1 120 Studies........................................................................................... 202 Vitamin B12 64 Studies........................................................................................... 217 Pantothenic Acid (B5) 47 Studies............................................................................ 222 Calcium Carbonate - 86 Studies ................................................................................. 226 Magnesium 68 Studies........................................................................................... 233 Ginkgo Biloba 33 Studies ........................................................................................ 237 L-Phenylalanine 33 Studies ..................................................................................... 240 L-Glutathione 67 Studies ......................................................................................... 243 L-Taurine 94 Studies ............................................................................................... 249 Choline Bitartrate 63 Studies................................................................................... 265 Inositol 56 Studies ................................................................................................... 273 L- Carnitine 93 Studies ............................................................................................ 277 L-Cysteine 50 Studies.............................................................................................. 287 Blue Cohosh Root 2 Studies .................................................................................... 292 Siberian Ginseng Root 40 Studies ........................................................................... 292 Rosemary Leaves 17 Studies ................................................................................... 295 Apsartic Acid 21 Studies ......................................................................................... 296 L-Glutamine 58 Studies ........................................................................................... 298 L-Tyrosine 53 Studies.............................................................................................. 302 Linoleic Acid 56 Studies.......................................................................................... 306 Linolenic Acid 10 Studies........................................................................................ 311 Caprylic Acid - 9 Studies............................................................................................ 312 Glycerophosphorylcholine 11 Studies ..................................................................... 312 Phosphatidylserine 13 Studies ................................................................................. 314 Pregenolone -23 Studies ............................................................................................. 315 Benfotiamine 32 Studies.......................................................................................... 317 SUPER ANTIOXIDANTS ......................................................................................... 320 Vitamin A 41 STUDIES .......................................................................................... 320 Vitamin C 51 STUDIES ......................................................................................... 323 Vitamin E - 78 Studies............................................................................................ 327 Vitamin B6 - 28 STUDIES........................................................................................ 335 Magnesium - 86 Studies .......................................................................................... 338 Zinc 50 STUDIES.................................................................................................... 349 Selenium 50 STUDIES............................................................................................ 356 Copper 60 Studies.................................................................................................... 362 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 3

Quercetin 20 STUDIES ........................................................................................... 368 Astaxanthin 20 STUDIES........................................................................................ 370 L-Carnosine - 28 Studies ......................................................................................... 374 Lycopene 50 Studies........................................................................................... 377 Rosemary Leaf Powder - 20 STUDIES...................................................................... 380 Tocotrienols 40 STUDIES....................................................................................... 383 Raspberry Leaf Powder - 10 Studies ......................................................................... 388 Citrus Bioflavonoids 11 STUDIES.......................................................................... 389 Rutin 16 STUDIES .................................................................................................. 391 Billberry - 17 Studies............................................................................................... 392 Red Wine Concentrate 14 STUDIES....................................................................... 396 Grape Skin Extract 48 STUDIES ............................................................................ 398 China Green Tea Leaf Powder - 100 Studies ............................................................ 402 Reduced L-Glutathione - 13 CITATIONS ................................................................. 423 L-Cysteine 22 STUDIES ......................................................................................... 425 Coenzyme Q10 43 STUDIES .................................................................................. 429 N-Acetylcysteine (NAC) - 40 STUDIES.................................................................... 434 Alpha Lipoic Acid 20 STUDIES ............................................................................. 443 Superroxide Dismutase 51 STUDIES...................................................................... 446 Taurine ........................................................................................................................ 450 Pycnogenol 20 STUDIES ........................................................................................ 454 Licorice Root 21 STUDIES..................................................................................... 458 BroccolI Stem - 26 STUDIES .................................................................................. 460 Lutein - 21 STUDIES ................................................................................................ 462 Cabbage Leaf 10 STUDIES..................................................................................... 464 Carrot Root - 11 STUDIES......................................................................................... 466 Milk Thistle Leaf - 27 STUDIES ............................................................................... 467 Bromelain 49 STUDIES .......................................................................................... 473 Nutrients That Have Demonstrated The Ability To Slow Down the Rate at Which We Age.............................................................................................................................. 477 Acetyl-L-Carnitine - 49 ABSTRACTS ..................................................................... 477 Alpha Lipoic Acid - 70 ABSTRACTS ....................................................................... 503 Mixed Tocopherols - 398 Studies............................................................................... 547 Glycerylphosphorylcholine 4 Studies...................................................................... 596 Carnosine - 47 ABSTRACTS................................................................................... 598 Magnesium - 570 CITATIONS .................................................................................. 621 Quercetin - 30 ABSTRACTS ..................................................................................... 718 L-Carnosine - 15 Studies ........................................................................................... 737 Cayenne 267 Studies................................................................................................ 739 Phosphatidylserine 19 Studies ................................................................................. 741 Ginkgo Biloba Leaf Powder 25 Studies .................................................................. 743 Linoleic Acid 29 Studies.......................................................................................... 745 Inositol 6 Studies ..................................................................................................... 748

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Nursing Home Intervention Study: Introduction

The current health status of many of the individuals living in nursing homes is directly related to their nutritional intake. Numerous studies have concluded that these individuals suffer from multiple nutritional deficiencies. From the Clinton Administration Report on the Quality of Nursing Homes: "The report concludes that the private Joint Commission on accreditation of Healthcare Organizations (JCAHO) survey process was not effective in protecting the health and safety of nursing home residents". Also, the office of the Health Care Financing Administration stated that "Five and a half years seems a long time for Clinton to discover that hundreds of people are still dying from malnutrition, dehydration, sepsis from bedsores and even physical abuse while in nursing homes". The problems of malnutrition and dehydration are due in particular to the institutional food provided by vendors who have used RDAs which have been shown to be, A) both insufficient and, B) grossly inadequate for people who have compromised immune systems and multiple nutritional deficiencies. This proposal carefully examines the scientific literature which cites the actual therapeutic dosages in relation to the category of illnesses that the majority of people in nursing homes fall into. We conclude, after reviewing thousands of scientific articles and using data from test groups of 300 individuals, most of whom are in senior citizen age groups, that nutrition and exercise, as presented in this proposed protocol, played a key role in the health and well-being of the senior citizens. In January of 1997 I enrolled 300 people into a "Reverse the Aging Process Study" whicCreated by dhendersonh would last for 18 months. 18 months later 65 people completed the study. 235 people became controls. This was not a double blind study. It was an observation of changes in their blood chemistry, weight, physical dimensions, physical appearance, memory, energy levels, sleep patterns, bowel movements, night time urination, muscle strength, digestion, olfactory senses, visual senses, tactile senses, skin texture, hair texture and stress levels. This was a lifestyle modification study. 52% of participants had lower cholesterol and tryglyceride levels. 68% of participants had increased DHEA levels. 78% of participants had a significant improvement in their fat / muscle ratio. 90% of participants had an increase in bowel movements. 92% of participants had a decreased need for sleep. 95% of participants had increased energy levels, and stress levels were lowered by 97%. In addition, numerical diaries had been kept by the participants reflecting subjective data. This data cited improvements that affected the participants in their overall quality of life.

Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved

We can also conclude that this protocol would benefit the vast majority of people in nursing homes and hospices. The following is not a theoretical model, it is an actual model. Harry Biele, a 90 year old man who just 10 years ago had chronic sinusitis, asthma, arthritis, enlarged prostate, a pre-cancerous lower bowel and main coronary artery blockage is now a marathoner living life to its fullest. His cardiologist has taken away all medication like beta blockers, and his general practitioner has taken away his inhalers for asthma. He is not an exception. Harry is the example of someone who has taken positive action toward his own health. He improved his nutrition by applying a protocol similar to this one. Exercise became part of Harrys daily ritual. He now appears to be closer to 70 than 90. All senior citizens and baby boomers can improve their health. This is the scientific literature that justifies the use of recommended supplements in this protocol. Applying this protocol can play an important role in anyones life. Gary Null Ph.D.

NURSING HOMES, DYING FROM NEGLECT 16 References


The term nursing home implies two things: one, that nurses are taking care of the elderly and, two, that, instead of an institution, people are living in a home. Three separate reports that took over ten years to complete show us that neither assumption is correct. During President Clintons term in office, The Clinton Administration Report on the Quality of Nursing Homes was prepared. The five and one-half year report concluded that "The private Joint Commission on accreditation of Healthcare Organizations (JCAHO) survey process was not effective in protecting the health and safety of nursing home residents." Also, the office of the Health Care Financing Administration analyzed the report and stated that "Five and a half years seems a long time to discover that hundreds of people are still dying from malnutrition, dehydration, sepsis from bedsores and even physical abuse while in nursing homes". (1) Congressman Waxman sponsored a report published in 2001 called "Abuse of Residents is a Major Problem in U.S. Nursing Homes." The report found that one third - 5,283 of the nations 17,000 nursing homes - were cited for an abuse violation in the two-year period studied, January 1999 - January 2001. (2) The major findings of the report were: 1. There were more than 9,000 abuse violations during the two-year period. 2. Ten-percent of nursing homes had physical harm violations to residents. 3. Over 40-percent, or 3,800 abuse violations, were only discovered after a formal complaint was filed, usually by concerned family members. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 6

4. Many verbal abuse violations were reported. 5. There were reports of sexual abuse. The third report was an exhaustive study of nurse-to-patient ratios in nursing homes. Although mandated by Congress in 1990, the study was not begun until 1998. (3) The report found that dangerously understaffed nursing homes lead to neglect, abuse, overuse of medications, and overuse of physical restraints. About the report, a spokesperson for The National Citizens Coalition for Nursing Home Reform said, "They compiled two reports of three volumes each thoroughly documenting the number of hours of care residents must receive from nurses and nursing assistants to avoid painful, even dangerous, conditions such as bedsores and infections. Yet it took the Department of Health and Human Services and Secretary Tommy Thompson only four months to dismiss the report as insufficient." (4) The main categories of abuse in nursing homes that cause harm in the elderly are: 1. Overuse of medication and side effects of medication 2. Overuse of physical restraints 3. Malnutrition, dehydration, and nutrient deficiency 1. OVERUSE OF MEDICATION AND SIDE EFFECTS OF MEDICATION A 2003 study surveyed drug use in the elderly population. Dr. Robert Epstein, chief medical officer of Medco Health Solutions Inc. (a unit of Merck & Co.), conducted the study on drug trends. (5) Medco oversees drug benefit plans for more than 60 million Americans, including 6.3 million senior citizens who received more than 160 million prescriptions. Data analysis showed that the average senior receives 25 prescriptions annually. A total of 7.9 million medication alerts were triggered in the group of 6.3 seniors. When compared with 1999 statistics, twice as many medication alerts occurred in 2003. About 2.2 million of those alerts indicated excessive dosages unsuitable for senior citizens and about 2.4 million indicated clinically inappropriate drugs for the elderly. In a "snapshot" survey of 818 residents of residential care facilities for the elderly, 94% were receiving at least one medication at the time of the interview. The average intake of medications was five per resident; the authors noted that many of these drugs were given without a documented diagnosis justifying their use. (6) Lets also look at the irony of lack of proper pain medication for patients that really need it. In one study, the authors concluded that older patients suffering pain were more likely to go untreated. In this study pain management was evaluated in a group of 13,625 cancer patients aged 65 or over living in nursing homes. Overall, almost 30% or 4,003 patients reported pain. More than 25% or (1,000) patients with pain received absolutely no pain relief medication. Another 16% received a World Health Organization (WHO) level one drug (mild pain reliever); 32% received a WHO level two drug (moderate pain reliever); and only 26% received adequate pain-relieving morphine for their cancer pain. (7)

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2. OVERUSE OF RESTRAINTS Study after study concludes that physical restraints are a preventable cause of death. (8,9) Nursing home administrators argue that they must use physical restraints to prevent falls. In fact, they cause more injury and death because people naturally fight against such imprisonment. Studies show that the use of restraints carries a higher mortality rate and economic burden than no restraints. (10,11,12) In one study a mortality rate of 1 in every 1,000 nursing home deaths was found to be due to physical restraints, including bedrails. (13) In these studies, descriptions of frail, elderly people suffocated between the mattress and bed rails, being hung by bed restraints, and with heads crushed between bed rails gives graphic testament to their dangers. It appears that drugs are used to "restrain" nursing home residents as much as physical restraints. Sarah Green-Burger, in her 2000 review, reminds us that nursing home resident-rights include freedom from physical and chemical restraints. She says drug "restraints" are known to decrease appetite and impede eating. There is also provision for reasonable accommodation of individual needs, which should assure a healthy diet and a suitable environment conducive to eating. 3. MALNUTRITION, DEHYDRATION, AND NUTRIENT DEFICIENCY According to Green-Burger studies on nursing home populations, conducted over the last ten years, show that from 35% to 85% of U.S. nursing home residents are malnourished. (14) This can be directly measured by a simple weight scale; 30% to 50% of residents are substandard in bodyweight. These findings directly contravene specific components of The Nursing Home Reform Act of 1987 (NHRA) to prevent both malnutrition and dehydration. They also mean that nursing homes are failing our elderly on many levels. In order for such abuse to exist there is no proper assessment of residents, no individualized care, improper physician supervision, insufficient nursing staff, and little attention to quality of life care and service. The law specifically mandates that nursing homes must meet residents nutrition and hydration needs. But according to GreenBurger " the level of malnutrition and dehydration in some American nursing homes is similar to that found in many poverty-stricken developing countries where inadequate food intake is compounded by repeated infections." The Green-Burger study goes on to emphasize the seriousness of malnutrition and dehydration, which can result in repeated infections (including urinary tract infections and pneumonia), pressure ulcers, anemia, hypotension, confusion and impaired cognition, decreased wound healing, and hip fractures. Beyond physical signs and symptoms nutritionally-impaired residents become weak, fatigued, bedridden, apathetic, and depressed. Often residents are transferred to hospital for acute illness, and if malnourished or dehydrated, we know that they suffer increased morbidity and require longer lengths of stay. Green Burger states that compared with well-nourished hospitalized nursing home residents, they have a five-fold increase in mortality in the hospital.

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Green-Burger identifies four key issues that need to be addressed for the prevention and treatment of malnutrition and dehydration: 1) inadequate staffing, 2) poor environment, 3) insufficient data collection, and 4) lack of enforcement. We would add a fifth: improved nutritional intake in the form of healthier diets and nutrient supplements. TIP OF THE ICEBERG While conditions in many nursing homes appear very serious, there is evidence that what we know is only the tip of the iceberg. In fact, deaths caused by malnutrition, dehydration, and physical restraints are rarely recorded on death certificates. Even though 1 in 5 people die in nursing homes, the autopsy rate is only 0.8%. (15) Thus, we have no way of knowing the true causes of death. Dr. Steven Miles, professor of Geriatric Medicine at the University of Minnesota, in an in-depth study found many barriers to researching accidental deaths in nursing homes. (16) He found that adverse drug reactions or the late consequences of falls may go unrecognized as the cause of death. A substantial barrier was found to be nursing home staff who conceal some accidental deaths. Dr. Miles reports on one anecdotal series where attempts were made to cover up four out of eight lethal accidents. Miles says, obviously, "The success of these efforts cannot be known since successful efforts will not be countable." In a review of 17 nursing home deaths, Dr. Miles found that in 8 of 17 there was an effort to conceal the fact that a death was caused by asphyxiation by bedrails or physical vest restraints. REFERENCES: 1. http://www.hhs.gov/asl/testify/t980728b.html 2. CNN Washington senate briefing, Abuse of Residents is a Major Problem in U.S. Nursing Homes - live coverage July 30, 2001. 3. Report to Congress: Appropriateness of Minimum Nurse Staffing Ratios In Nursing Homes. Phase II Final Report. December 24, 2001. 4. Press Release. Consumer Group Criticizes Thompson Letter Dismissing Report on Dangerous Staffing Levels in Nursing Homes. The National Citizens Coalition for Nursing Home Reform. March 22, 2002. 5. Overmedication of U.S. Seniors. Reuters Health, May 21, 2003. 6. Williams BR, et al. Medication use in residential care facilities for the elderly. Ann Pharmacother. 1999 Feb;33(2):149-55. 7. Bernabei R, et al. Management of pain in elderly patients with cancer. SAGE Study Group. Systematic Assessment of Geriatric Drug Use via Epidemiology. JAMA 1998 Jun 17;279(23):1877-82. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 9

8. Miles SH, Irvine P. Deaths caused by physical restraints. Gerontologist. 1992 Dec;32(6):762-6. 9. Annas GJ. The Last Resort: The Use of Physical Restraints in Medical Emergencies. N Engl J Med. 1999 Oct 28;341(18):1408-12. 10. Robinson BE. Death by destruction of will. Lest we forget. Arch Intern Med. 1995 Nov.13;155(20):2250-1. 11. Capezuti E. et al. The relationship between physical restraint removal and falls and injuries among nursing home residents. J Gerontol A Biol Sci Med Sci. 1998 Jan;53(1):M47-52. 12. Phillips CD, Hawes C, Fries BE. Reducing the use of physical restraints in nursing homes: will it increase costs? Am J Public Health. 1993 Mar;83(3):342-8. 13. Parker K., et al. Deaths caused by bedrails. J Am Geriatr Soc. 1997 Jul;45(7):797802. 14. Green-Burger S, Kayser-Jones J, Prince-Bell J. Malnutrition and Dehydration in Nursing Homes: Key Issues in Prevention and Treatment. National Citizens' Coalition for Nursing Home Reform. June 2000. http://www.cmwf.org/programs/elders/burger_mal_386.asp 15. Katz PR, Seidel G. Nursing home autopsies. Survey of physician attitudes and practice patterns. Arch Pathol Lab Med. 1990 Feb;114(2):145-7. 16. Miles SH. Concealing accidental nursing home deaths. HEC Forum. 2002 Sep;14(3):224-34.

INFECTION 76 Studies
1. Notice to Readers: Fourth Decennial International Conference on Nosocomial and Healthcare-Associated Infections.
MMWR, February 25, 2000 / 49(07);138.

This article reports that every year in the U.S., approximately 2,000,000 patients develop hospital-acquired infections and 88,000 die from them. The cost of hospital-acquired infections has been estimated at $4.6 billion. These estimates are conservative, because

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they do not take into account nosocomial infections occurring in patients in nursing homes, outpatient clinics, dialysis centers and other health care centers.

2. Mortality associated with nosocomial infections: analysis of multiple causeof-death data.


White MC. J Clin Epidemiol 1993 Jan;46(1):95-100. This article emphasizes that hospital-acquired infections are among the 10 leading cause of death in the U.S.

3. The nationwide nosocomial infection rate. A new need for vital statistics.
Haley RW, Culver DH, White JW, Morgan WM, Emori TG. Am J Epidemiol 1985 Feb;121(2):159-67. The results of this study indicate that in 1985, the incidence of hospital-acquired infections in the U.S. was 5.7 per 100 patients. Extrapolation of these data to the 6,449 acute-care hospitals revealed that every year, in the U.S., approximately 2 million infections occur in hospitalized patients. However, after adjustment for accuracy of detection methods, trend toward a nationwide increase in infection rates, and number of infections in nursing home patients, the estimated number of yearly nosocomial infections increased to 4 millions. The authors emphasizes that these data greatly exceed previous evaluations, and call for correct statistics to properly address the problem.

4. Trends in infectious disease hospitalizations in the United States, 1980-1994. Simonsen L, Conn LA, Pinner RW, Teutsch S. Arch Intern Med 1998 Sep 28;158(17):1923-8. The results of this study show that from 1980 to 1994, mortality rates in individuals hospitalized for infectious disease doubled, from 1.9% to 4.0%.

5. Trends in infectious diseases mortality in the Unites States. Pinner RW, et al. JAMA 1996 Jan 17;275(3):189-93. The results of this study show that from 1980 to 1992, death due to infectious diseases in the U.S. increased 58%, from 41 to 65 deaths per 100,000 population. Of note, death due to infectious diseases increased 6.3 times in individuals aged 25- to 44-years-old, from 6 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 11

to 38 deaths per 100,000 population. These data indicate that despite previsions of a decline in rates of infectious diseases in the U.S., mortality rates from infectious diseases have actually been progressively increasing in recent years.

6. Nosocomial bloodstream infections. Secular trends in rates, mortality, and contribution to total hospital deaths. Pittet D, Wenzel RP. Arch Intern Med 1995 Jun 12;155(11):1177-84. The results of this study show that the incidence of hospital-acquired bloodstream infections increased threefold in the period from 1980 to 1992, from a rate of 6.7 to 18.4 infections per 1,000 discharges. Population-attributable risk of death from this complication also rose during this period, from 3.55 to 6.22 deaths per 1,000 discharges.

7. Nosocomial enterococci resistant to vancomycin--United States, 1989-1993. MMWR Morb Mortal Wkly Rep 1993 Aug 6;42(30):597-9. This article reports that from 1989 to 1993, the rate of enterococci responsible for hospital-acquired infections that acquired resistance to the antibiotic vancomycin increased by more than 20 folds. The majority of these bacteria are resistant to all available antibiotics. In the intensive care units, the percentage of vancomycin-resistant enterococci strains increased from 0.4% in 1989 to 13.6% in 1993.

8. Emerging and reemerging microbial threats. Nosocomial fungal infections. Henderson VJ, Hirvela ER. Arch Surg 1996 Mar;131(3):330-7. This article shows that the rate of fungal hospital-acquired infections increased steadily in the past 25 years, from a rate of 2.0 infections per 1000 discharges to as high as 6.6 infections per 1000 discharges.

9. Hospital-acquired candidemia. The attributable mortality and excess length of stay. Wey SB, Mori M, Pfaller MA, Woolson RF, Wenzel RP. Arch Intern Med 1988 Dec;148(12):2642-5. The results of this study show that from 1977 to 1984, the incidence of hospital-acquired bloodstream infections caused by Candida species in the U.S. tripled. Patients with fungemia have a 3-fold increased risk of dying, compared to uninfected, closely matched Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 12

patients. Hospital length of stay in patients who survived the bloodstream infection was 70 days, as compared to 40 days in matched controls. Candida infections were responsible for 10% of all bloodstream infections.

10. Secular trends in the epidemiology of nosocomial fungal infections in the United States, 1980-1990. National Nosocomial Infections Surveillance System. Beck-Sague C, Jarvis WR. J Infect Dis 1993 May;167(5):1247-51. This article reports on the increase in the incidence of hospital-acquired fungal infections in U.S. hospitals, as determined by evaluation of data submitted to the National Nosocomial Infections Surveillance System. The rate of this complication increased from 2.0 per 1000 discharges in 1980 to 3.8 per 1000 discharges in 1990, an almost two-fold increase. Candida species accounted for three-quarters of infections. Patients with a central intravascular catheter had a 3-fold increased risk of developing a fungal bloodstream infection, compared to those without it. Thirty percent of patients with hospital-acquired fungemia died, compared to 17% of those with bloodstream infections due to other microorganisms.

11. Accuracy of reporting nosocomial infections in intensive-care-unit patients to the National Nosocomial Infections Surveillance System: a pilot study. Emori TG, et al. Infect Control Hosp Epidemiol 1998 May;19(5):308-16. The results of this study indicate that the National Nosocomial Infections Surveillance (NNIS) System is not a reliable indicator of the true incidence of nosocomial infections in hospital settings. This system was instituted under the sponsorship of the Centers for Disease Control (CDC) to monitor rates of hospital-acquired infections through voluntarily reporting of this complication by participating hospitals. The accuracy of the system in reflecting the rate of nosocomial infections was evaluated by reviewing the charts of 1,136 patients admitted to the intensive care units of 9 hospitals. There were 611 reports of hospital-acquired infections submitted to the NNIS system for this cohort. However, when some trained epidemiologists evaluated retrospectively the charts of the patients, they identified 340 extra infections that had not been previously reported. These data indicate that the voluntary system of reporting of hospital-acquired infections is significantly underestimating the true incidence of nosocomial infections in U.S. hospitals, and, as a consequence, all studies that utilize data from the NNIS system are misrepresenting the real magnitude of the problem.

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Influence of nosocomial infection on mortality rate in an intensive care unit. Bueno-Cavanillas A, et al. Crit Care Med 1994 Jan;22(1):55-60. The results of this study show that patients who develop hospital-acquired infections have a twofold increased risk of death, compared to uninfected patients. The increased risk of death persists even after adjustment for several confounding factors, and is particularly high in younger patients with less severe disease.

12. A survey of nosocomial infections and their influence on hospital mortality rates. Dinkel RH, Lebok U. J Hosp Infect 1994 Dec;28(4):297-304. The results of this study show that even after controlling for possible confounders, patients who develop a hospital-acquired infection have a two-fold increased risk of death, compared to patients without this complication. The risk of death increases by three-folds in patients hospitalized for trauma who develop a hospital-acquired infection.

13. Nosocomial infections in elderly patients in the United States, 1986-1990. National Nosocomial Infections Surveillance System. Emori TG, et al. Am J Med 1991 Sep 16;91(3B):289S-293S. This study reports that from 1986 to 1990, 89 hospitals submitted to the National Nosocomial Infections Surveillance (NNIS) system a total of 101,479 reports of hospitalacquired infections occurring in 75,398 adult patients. In 12% of the infections the patients died. In 54% of elderly patients that died an in 59% of younger patients that died the infection was judged to be related to their death. Bloodstream infections and pneumonias were associated with the highest mortality rates.

14. The impact of surgical-site infections in the 1990s: attributable mortality, excess length of hospitalization, and extra costs. Kirkland KB, Briggs JP, Trivette SL, Wilkinson WE, Sexton DJ. Infect Control Hosp Epidemiol 1999 Nov;20(11):725-30. The results of this study, conducted on 255 pairs of matched surgical patients with and without surgical site infection, indicate that infected patients have a 2.2-fold increased risk of dying, a 60% increased risk of being admitted to an intensive care unit, and a twofold increased hospital length of stay, compared to uninfected patients. In addition, patients who survive a surgical site infection are approximately 6 times more likely to be Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 14

readmitted to the hospital in the 30-days following discharge, compared to uninfected patients. The study estimated that, after the inclusion of the second hospital admission, each surgical site infection was associated with an excess hospital stay of 12 days and with an excess cost of $5,038 per patient. The authors highlight that the implementation of measures designed to reduce the rates of surgical site infections will likely result in a significant reduction of infection-related morbidity, mortality and health care costs.

15. Nosocomial infections in surgical patients in the United States, January 1986-June 1992. National Nosocomial Infections Surveillance (NNIS) System. Horan TC, Culver DH, Gaynes RP, Jarvis WR, Edwards JR, Reid CR. Infect Control Hosp Epidemiol 1993 Feb;14(2):73-80. This study reports that from 1986 to 1992, 106 hospitals reported to the National Nosocomial Infections Surveillance System a total of 59,351 hospital-acquired infections occurring in 48,168 surgical patients. The probability that these infections were related to the death of the patients ranged from 22% for urinary tract infections, to 90% for organ/space surgical site infections.

16. Infection in surgical patients: effects on mortality, hospitalization, and postdischarge care. DiPiro JT, Martindale RG, Bakst A, Vacani PF, Watson P, Miller MT. Am J Health Syst Pharm 1998 Apr 15;55(8):777-81. The results of this study show that 12% of patients who undergo moderate to high-risk surgical procedures develop hospital-acquired infections. Mortality rates in infected patients are 14.5%, as compared to 1.8% in uninfected patients. In addition, hospital length of stay more than triples in infected versus uninfected patients (14 days vs. 4 days), and so does the number of patients who require health care assistance after hospital discharge (24% of infected patients versus 7% of uninfected ones).

17. Nosocomial infection, indices of intrinsic infection risk, and in-hospital mortality in general surgery. Delgado-Rodriguez M, et al. J Hosp Infect 1999 Mar;41(3):203-11. The results of this study show that patients who develop a surgical site infection or a bloodstream infection have a 4.5-fold and 17.3-fold increased risk of dying, respectively, compared to uninfected patients.

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18. Nosocomial infection in surgery wards: a controlled study of increased duration of hospital stays and direct cost of hospitalization. Vegas AA, Jodra VM, Garcia ML. Eur J Epidemiol 1993 Sep;9(5):504-10. The results of this study show that hospital-length of stay increases by an average of 14 days in patients who develop hospital-acquired wound infections. The study was conducted on a sample of patients from a general and digestive surgical ward, to assess the effect that hospital-acquired infections had on the length of their hospital stay. Infected and uninfected patients were matched for age, diagnosis, surgical procedure, and, when possible, underlying conditions, elective or emergency surgery, and invasive devises. Length of hospital stay increased by l2.6 days in patients who developed superficial wound infection, compared to those without infection. Wound infections, either superficial or deep, and other infections were associated with an extra 14.3 and 7.3 days of hospital stay, respectively.

19. Selected aspects of the socioeconomic impact of nosocomial infections: morbidity, mortality, cost, and prevention. Jarvis WR. Infect Control Hosp Epidemiol 1996 Aug;17(8):552-7. This study shows that in the U.S., every year, approximately 2 million infections occur in hospital patients, leading to substantial increase in morbidity, mortality, and health care costs. Hospital length of stay increases by 1 to 4 days in patients who contract urinary tract infections, by 7-8 days in those with surgical site infections, by 7 to 21 days in those with bloodstream infections, and by 7 to 30 days in those with pneumonia. Costs associated with these infections have been estimated at $550-$600 for each urinary tract infection, $2,700 for each surgical site infection, $3,000 to $40,000 for each bloodstream infection, and $5,000 for each pneumonia.

20. Nosocomial pneumonia and mortality among patients in intensive care units. Fagon JY, Chastre J, Vuagnat A, Trouillet JL, Novara A, Gibert C. JAMA 1996 Mar 20;275(11):866-9. The results of this study show that 16.6% of patients admitted to an intensive care unit in France develop hospital-acquired pneumonia. The study, conducted on 1978 consecutive patients, also showed that patients who developed pneumonia while in the hospital had a twofold increased rate of death, compared to those without pneumonia, and this increase was unrelated to the severity of underlying diseases.

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21. Hospital-acquired pneumonia. Attributable mortality and morbidity. Leu HS, Kaiser DL, Mori M, Woolson RF, Wenzel RP. Am J Epidemiol 1989 Jun;129(6):1258-67. The results of this study show that 30% of patients who develop hospital-acquired pneumonia die. In one third of patients the infection is judged to be directly responsible for the death of the patient.

22. Nosocomial pneumonia in ventilated patients: a cohort study evaluating attributable mortality and hospital stay. Fagon JY, Chastre J, Hance AJ, Montravers P, Novara A, Gibert C. Am J Med 1993 Mar;94(3):281-8. The results of this study show that the development of hospital-acquired pneumonia is associated with a two-fold increased risk of death in mechanically ventilated patients, and with a significant prolongation of hospital length of stay, from a median of 21 days to a median of 34 days. The increase in death rates is independent from underlying diseases.

23. Guidelines for Prevention of Nosocomial Pneumonia. MMWR January 03, 1997 / 46(RR-1);1-79. This article reports that pneumonia accounts for 15% of all hospital-acquired infections (HAIs), and is the second most frequent HAI after urinary tract infections. The incidence of nosocomial pneumonia has been estimated at approximately 6 per 1000 hospitalized patients, and is significantly higher in university hospitals, compared to non-teaching hospitals. Reported mortality rates range from 20% to 50%, and in 30% to 33% of cases the death is directly attributed to the infection contracted in the hospital. Conservative estimates place the total costs of this complication at $1.2 billion per year. Bacteria responsible for the infections are found everywhere in the hospital and are frequently spread from patient to patient through contaminated hands of health care workers. The risk of spreading the infection could be considerably reduced by adhesion to simple handwashing practices. However, doctors rarely comply with this practice, and as a consequence the use of gloves has been promoted in order to reduce cross-contamination. Unfortunately, transmission of infection has been reported even with use of gloves, and is attributable to either breaks in the glove, or to the omission by health care workers to change their gloves between contacts with different patients.

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24. Hand washing. A modest measure with big effects. Handwashing Liaison Group. BMJ 1999;318:686-686 ( 13 March ). This article highlights that hand washing, a simple preventive measure effective in reducing the spread of in-hospital infections, is frequently disregarded as such by health care workers, who often fail to perform it. The incidence of in-hospital infections is significantly high, with an estimated 9% of patients acquiring an infection while being in the hospital. Hands are an important vehicle of transfer of pathogenic bacteria from one patient to the other. The majority of physicians, however, fail to decontaminate their hands after contact with patients. One study documented hand washing in only 9% of physicians, and another documented senior physicians washing their hands only twice during a 21-hour ward shift. Failure of physicians to recognize the risks associated with non-compliance reflects a system of belief that is deeply ingrained and of difficult solution. The authors emphasize how physicians need to recognize that hand contamination is an important mean of transfer of pathogenic bacteria before hand washing practices can be integrated as part of normal duty care.

25. Current guidelines for the treatment and prevention of nosocomial infections. Bergogne-Berezin E. Drugs 1999 Jul;58(1):51-67. This article highlights that in the U.S., 5% to 10% of patients admitted to the hospital develop a hospital-acquired infection. The incidence of this complication is particularly high in the intensive care units, where it occurs in as many as 28% of patients. There are preventive measures that could reduce the incidence of hospital-acquired infections, and they include improvement in nursing practices, decreased rates of antibiotic prescribing, and shortened hospital stay. These measures could significantly lower health care costs and infection-related morbidity and mortality.

26. Nosocomial Hepatitis B Virus Infection Associated with Reusable Fingerstick Blood Sampling Devices -- Ohio and New York City, 1996. MMWR. March 14, 1997 / 46(10);217-221. This article reports on two outbreaks of hepatitis B virus infection that occurred in diabetic patients from an Ohio nursing home and a New York City hospital. In both instances, an epidemiologic investigation revealed that patients became infected because the health-care personnel did not change fingerstick devices for blood-glucose monitoring between patients.

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27. Nosocomial transmission of hepatitis B virus associated with the use of a springloaded finger-stick device. Polish LB, et al. N Engl J Med 1992 Mar 12;326(11):721-5. This article reports on the case of 26 diabetic patients who developed hepatitis B virus infection in a California hospital. Epidemiologic investigation revealed that the virus was spread from one infected patient to the others due to nursing practices of utilizing the same blood glucose monitoring fingerstick device for several patients.

28. Hospital infection rates in England out of control. News. Kmietowicz, Z. BMJ 2000;320:534 ( 26 February ). This letter explains that in England, every year, at least 100,000 patients develop hospital-acquired infections and 5,000 of them die from the complication. Hospitalacquired infections affect approximately 1 every 10 hospitalized patients, for an annual cost of 1bn ($1.6 billion). Very little effort is put in the prevention of infections, as shown by the scant participation of clinicians and hospital chief executives to the problem. In some areas, for example, 1 infection control nurse is in charge of 1,000 beds, and only 1 of 5 hospitals surveyed has the minimum number of infection control doctors recommended by the Royal College of Pathologists -1 physician per 1,000 beds. These resources are obviously insufficient to guarantee an effective control of the spread of pathogens among hospitalized patients, a negligence that results not only in excess length of hospital stay and health care costs, but also in significant morbidity and mortality.

29. Nosocomial bloodstream infection in critically ill patients. Excess length of stay, extra costs, and attributable mortality. Pittet D, Tarara D, Wenzel RP. JAMA 1994 May 25;271(20):1598-601. The results of this study show that patients who develop hospital-acquired bloodstream infections have an over three-fold increased risk of dying and an almost two-fold increase in hospital length of stay, compared to uninfected ones. The study was conducted on 86 pairs of patients from a surgical intensive care unit (SICU), with and without bloodstream infection, who were matched for age, sex, length of hospital stay and number of discharge diagnoses. Fifty percent of patients with bloodstream infection died, compared to 15% of those without this complication. In addition, patients who survived the infection spent an additional 24 days in the hospital and an additional 8 days in the SICU, compared to controls (54 vs. 30 days and 15 vs. 7 days, respectively). Health care costs attributable to the bloodstream infection were estimated at $40,000 per patient.

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30. Microbiological factors influencing the outcome of nosocomial bloodstream infections: a 6-year validated, population-based model. Pittet D, Li N, Woolson RF, Wenzel RP. Clin Infect Dis 1997 Jun;24(6):1068-78. This study reports that, between 1986 and 1991, a total of 1745 patients developed hospital-acquired bloodstream infections in a 900-bed tertiary care hospital, and 35% of them died from this complication.

31. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. Brun-Buisson C, et al. JAMA 1995 Sep 27;274(12):968-74. The results of this study, conducted on 11,828 consecutive patients admitted during a two-month period to 170 intensive care units in France, show that overall, 9.0% of patients developed signs of severe bloodstream infection and 56% of them died in the 4 weeks following the infection.

32. The Second National Prevalence Survey of infection in hospitals--overview of the results. Emmerson AM, Enstone JE, Griffin M, Kelsey MC, Smyth ET. J Hosp Infect 1996 Mar;32(3):175-90. The results of this study, conducted on over 37,000 patients from 157 hospitals in the UK and Ireland, show that nosocomial infections (infections acquired in the hospital) occur in 9% of patients, and are more frequent in teaching hospital, compared to non-teaching ones.

33. Epidemiology of infection in ICUs. Spencer RC. Intensive Care Med 1994 Nov;20 Suppl 4:S2-6. This study reports the results of the European Prevalence of Infection in Intensive Care Study (EPIC), the largest study on Intensive Care Unit (ICU)-related infections in Western Europe, that was conducted on a cohort of 10,038 patients admitted to 1417 adult ICUs from 17 countries. Overall, 21% of ICU patients developed a minimum of one Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 20

hospital-acquired infection. Pneumonia was the most frequent infection (47% of cases), followed by other lower respiratory tract infections (18%), urinary tract infections (18%), and bloodstream infections (12%).

34. The impact of nosocomial infections on patient outcomes following cardiac surgery. Kollef MH, Sharpless L, Vlasnik J, Pasque C, Murphy D, Fraser VJ. Chest 1997 Sep;112(3):666-75. This study evaluated the frequency of hospital-acquired infections in a cohort of 605 consecutive patients admitted for cardiac surgery. After the surgery, 22% of patients developed at least one hospital-acquired infection. The risk of this complication was associated with the duration of mechanical ventilation and urinary tract catheterization, and with the initiation of empiric antibiotic therapy after surgery. Infected patients had a two-fold increased risk of dying, compared to uninfected ones.

35. The impact of nosocomial infections on patient outcomes following cardiac surgery. Kollef MH, Sharpless L, Vlasnik J, Pasque C, Murphy D, Fraser VJ. Chest 1997 Sep;112(3):666-75. The results of this study, conducted on a sample population of 605 patients who underwent cardiac surgery in an U.S. hospital, show that approximately 22% of patients developed at least one hospital-acquired infection. Infected patients had a 4-fold increased risk of dying, compared to uninfected ones. In addition, hospital length of stay in patients who survived was two times greater in infected versus uninfected patients (20 days versus 9.7 days). These data indicate that hospital-acquired infections are associated with significant mortality, increased length of stay, and health care costs.

36. Epidemiology of Nosocomial Infection and Resistant Organisms in Patients Admitted for the First Time to an Acute Rehabilitation Unit. Mylotte JM, Graham R, Kahler L, Young L, Goodnough S. Clin Infect Dis 2000 Mar;30(3):425-432. The results of this study indicate that 16.5% of patients admitted to an acute rehabilitation center develop at least one hospital-acquired infection. Urinary tract infections, surgical site infections, Clostridrium difficile diarrhea and bloodstream infections accounted for 30%, 17%, 15% and 13% of the infections, respectively.

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37. Incidence of hospital-acquired infections associated with caesarean section. Henderson E, Love EJ. J Hosp Infect 1995 Apr;29(4):245-55. This study, conducted on a cohort of 1335 women who underwent caesarean section in a Canadian teaching hospital, shows that the rate of hospital-acquired infections in women delivered by primary and secondary caesarean section, was 42.1% and 46.1%, respectively. Women delivered by primary section had significantly higher incidence of deep wound infections, endometritis and bacteraemia, compared to those delivered by secondary section. Hospital-acquired infections resulted in increased length of hospital stay.

38. Post-discharge surveillance and infection rates in obstetric patients. Couto RC, Pedrosa TM, Nogueira JM, Gomes DL, Neto MF, Rezende NA. Int J Gynaecol Obstet 1998 Jun;61(3):227-31. The results of this study show that women who deliver by Cesarean section have an almost 50-fold increased risk of developing hospital-acquired surgical site infections, compared to women who deliver by the vaginal route. The study evaluated the incidence of this complication in 2431 women who delivered vaginally and 2032 women who delivered by Cesarean section, by monitoring patients during their hospital stay and up to 30 days after hospital discharge. While the incidence of hospital-acquired surgical site infections detected during hospital stay was 1.6% in women who underwent Cesarean section, this rate increased to 9.6% when cases detected by post-discharge surveillance were included. By comparison, rates of infections in women who delivered by the vaginal route were significantly lower, occurring in only 0.2% of cases. These findings indicate that unless data collected after hospital discharge are included in the estimates of the incidence of surgical site infections after Cesarean delivery, the true prevalence of this complication can be substantially underestimated.

39. Occurrence of nosocomial bloodstream infections in six neonatal intensive care units. Brodie SB, et al. Pediatr Infect Dis J 2000 Jan;19(1):56-65. This study evaluated prospectively the incidence of hospital-acquired bloodstream infections in neonates weighing less than 1,500 g admitted to six neonatal intensive care units (NICUs). Almost 20% of neonates developed a hospital-acquired bloodstream infection, and the risk of this complication was significantly associated with use of Broviac catheters and intravenous nutrition supplements. Since these infections are associated with substantial morbidity and mortality, preventive measures are urgently needed.

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40. Nosocomial infections in pediatric intensive care units in the United States. National Nosocomial Infections Surveillance System. Richards MJ, Edwards JR, Culver DH, Gaynes RP. Pediatrics 1999 Apr;103(4):e39. The results of this study show that approximately 6% of children admitted to a pediatric intensive care unit (ICU) develop hospital-acquired infections. In the study, 6290 infections occurred in a cohort of 110,709 patients admitted to 61 pediatric ICUs, according to data collected through the National Nosocomial Infections Surveillance System -a voluntary system of reporting of hospital-acquired infections. The most common type of infection was bloodstream infection (28%), followed by pneumonia (21%), and urinary tract infection (15%). These complications were almost always associated with use of invasive devices.

41. Nosocomial infections among neonates in high-risk nurseries in the United States. National Nosocomial Infections Surveillance System. Gaynes RP, Edwards JR, Jarvis WR, Culver DH, Tolson JS, Martone WJ. Pediatrics 1996 Sep;98(3 Pt 1):357-61. This study reports data submitted by 99 hospitals participating in the National Nosocomial Infections Surveillance system, a voluntary, hospital-based, reporting system established to monitor rates of hospital-acquired infections, indicating that from 1986 to 1994, a minimum of 13,179 neonates in high-risk nurseries developed this complication. The most common hospital-acquired infections were bloodstream infections, followed by pneumonias and gastrointestinal infections.

42. Hospital-acquired morbidity on a neurology service. Shafer SQ, Brust JC, Healton EB, Mayo JB. J Natl Med Assoc 1993 Jan;85(1):31-5. This study evaluated prospectively the charts of 1317 consecutive patients admitted over a 3-year period to the neurology department of a city hospital, to determine the incidence of hospital-acquired infections in this sample population. Overall, 6.8% of patients developed at least one hospital-acquired infection, which consisted of a bloodstream infection in almost half of the cases. The authors emphasize that these data greatly exceed previously reported estimates.

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43. Surveillance of nosocomial infections in geriatric patients. Beaujean DJ, et al. J Hosp Infect 1997 Aug;36(4):275-84. The results of this study, conducted on 300 geriatric patients admitted to a medical ward of a hospital in the Netherlands, show that one third of patients developed at least one hospital-acquired infection (126 infections in 100 patients). Fifty-nine percent of the infections were urinary tract infections, and 20% were infections of the gastrointestinal tract. Seventy percent of patients with asymptomatic urinary tract infection received antibiotics. Age, dehydration, and the presence of a urinary catheter were all significant risk factors for the development of hospital-acquired infections. Hospital length of stays increased by twofold in infected versus uninfected patients.

44. Hospital-acquired pressure ulcers: risk factors and use of preventive devices. Perneger TV, Heliot C, Rae AC, Borst F, Gaspoz JM. Arch Intern Med 1998 Sep 28;158(17):1940-5. The results of this study, conducted on 2373 patients who did not have pressure ulcers upon admission to a university hospital, show that 10% of them developed this complication during their hospital stay. The study detected suboptimal use of special devices (such as mattresses, cushions, and beds) for the prevention of this complication.

45. Pressure ulcers, hospital complications, and disease severity: impact on hospital costs and length of stay. Allman RM, Goode PS, Burst N, Bartolucci AA, Thomas DR. Adv Wound Care 1999 Jan-Feb;12(1):22-30. The results of this study, conducted on a sample population of 286 patients aged 55 and older, show that those who developed pressure ulcers had, after controlling for several confounders, increased length of hospital stay (21 vs. 13 days) and increased incidence of hospital-acquired infections (46% vs. 20%) and other complications (86% vs. 43%), compared to those who did not. Hospital costs for patients with incident pressure ulcers were estimated at $29,048 compared to 13,819 in those without this ailment.

46. Epidemiology of infectious and iatrogenic nosocomial diarrhea in a cohort of general medicine patients. McFarland LV. Am J Infect Control 1995 Oct;23(5):295-305.

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The results of this study, conducted on 382 patients admitted over an 11-month period to the general medicine ward of a county hospital, show that the incidence of hospitalacquired diarrhea in this cohort was 33%. The risk of developing this complication increased with increasing patient age, length of stay, number of antibiotics and nasogastric tube feeding. Patients with hospital-acquired diarrhea had an increased risk of developing a second infection, of having a prolonged hospital length of stay, and of dying, than patients without this condition.

47. Risk factors for Clostridium difficile carriage and C. difficile-associated diarrhea in a cohort of hospitalized patients. McFarland LV, Surawicz CM, Stamm WE. J Infect Dis 1990 Sep;162(3):678-84. The results of this study show that the incidence of hospital-acquired diarrhea caused by Clostidrium difficile, as evaluated in a cohort of 399 patients, was 7.8 per 100 patients. C. difficile accounted for one fifth of all hospital-acquired diarrhea, and the risk of developing C. difficile-associated diarrhea increased by 2-3 folds in individuals using cephalosporin, penicillin, enemas, gastrointestinal stimulants, or stool softeners.

48. Nosocomial infections in the ICU: the growing importance of antibiotic-resistant pathogens. Weber DJ, Raasch R, Rutala WA. Chest 1999 Mar;115(3 Suppl):34S-41S. This study indicates that patients in intensive care units have a 5-10 fold increased risk of developing a hospital-acquired infection, compared to those admitted to other hospital units. A major contributor to the morbidity and mortality associated with this complication is the antibiotic-resistance of the pathogens involved in the infection. Measures of prevention include proper handwashing, patient isolation, proper disinfection and sterilization techniques, and judicious use of antibiotics, as demonstrated by the fact that hospitals with the highest rates of hospital-acquired infections also have the highest rates of antibiotic use.

49. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Kollef MH, Sherman G, Ward S, Fraser VJ. Chest 1999 Feb;115(2):462-74. The results of this study, conducted on 2000 patients admitted to a medical or surgical intensive care unit, show that 25% of hospitalized patients with community- or hospitalCopyright Gary Null & Associates, Inc., 2005 All Rights Reserved 25

acquired infections receive inappropriate antibiotic treatment. Mortality rates in patients receiving inadequate antibiotic treatment are 42%, compared to 17.7% in patients appropriately treated. After logistic regression analyses it was shown that inappropriate antibiotic treatment was the strongest determinant of hospital mortality for the entire (infected and uninfected) patient cohort, and resulted in a 4.3-fold increased risk of death.

50. Appropriateness of antibiotic therapy in long-term care facilities. Jones SR, Parker DF, Liebow ES, Kimbrough RC 3d, Frear RS. Am J Med 1987 Sep;83(3):499-502. This study evaluated the appropriateness of antibiotic therapy in patients of two nursing homes in Portland, Oregon, over a 3-month period. One hundred twenty infections occurred during the study period. Antibiotic treatment was judged appropriate only in 49% of cases, and inappropriate and unjustified in 42% and 9% of cases, respectively.

51. Method of physician remuneration and rates of antibiotic prescription. Hutchinson JM, Foley RN. CMAJ 1999 Apr 6;160(7):1013-7. The results of this study, conducted on 476 Canadian doctors, show that physicians who are paid for fee-for-service and those with greater volume of patients are much more likely to prescribe antibiotics, compared to doctors paid by salary and with smaller patient volume. These findings indicate that factors unrelated to medical conditions play an important role in physicians' attitude toward antibiotic prescribing.

52. Antimicrobial use for pediatric upper respiratory infections: reported practice, actual practice, and parent beliefs. Watson RL, Dowell SF, Jayaraman M, Keyserling H, Kolczak M, Schwartz B. Pediatrics 1999 Dec;104(6):1251-7. This study was conducted on a sample of 366 pediatricians and family physicians from Georgia to determine their antibiotic prescribing practices in pediatric patients with upper respiratory tract infections (URTIs). While 97% of them reported that widespread use of antibiotics was a major contributor to the development of antibiotic resistant bacterial strains, they nevertheless prescribed antibiotics in 72% of visits for URTIs. In addition, contrary to published guidelines for the management of pediatric patients with these conditions, 86% of physicians prescribed antibiotics in patients with bronchitis regardless of the duration of cough, and 42% prescribed antibiotics for the common cold. Interestingly, physicians who prescribed the most antibiotics also had the highest rates of return office visits (up to 30% more). The authors conclude that antibiotic prescribing Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 26

practices in pediatric patients with URIs often are in disagreement with published guidelines, in spite of physicians' knowledge of the role of injudicious use of antibiotics in the development of antibiotic resistance.

53. Antibiotic prescribing for children with colds, upper respiratory tract infections, and bronchitis. Nyquist AC, Gonzales R, Steiner JF, Sande M. JAMA. 1998 Mar 18;279(11):875-7. This study evaluated the rates of antibiotic prescribing in 531 children younger than 18 years diagnosed with common cold, upper respiratory tract infections (URTIs) or bronchitis. Forty-four percent of children with common cold, 46% of those with URTIs, and 75% of those with brochitis received an antibiotic prescription. Extrapolation of these data to the entire U.S. population revealed that in 1992, physicians wrote 6.5 million prescriptions for children with URTIs or common cold and 4.7 million prescriptions for children with bronchitis, despite the fact that, as emphasized in the article, antibiotic treatment is typically ineffective in these conditions. These data indicate that 21% of all antibiotic prescriptions written for children younger than 18 in 1992 (over 11 million prescriptions) are unnecessary.

64. Systematic review of the treatment of upper respiratory tract infection. Fahey T, Stocks N, and Thomas T. Arch Dis Child 1998;79:225-230 ( September ). The results of this meta-analysis, conducted on 6 randomized, placebo-controlled studies involving 1,699 children, show that antibiotic treatment does not improve clinical outcome or reduce rates of complications in children with upper respiratory tract infections. The authors conclude that there is no evidence from randomized trials supporting the use of antibiotics in the management of children with upper respiratory tract infections.

65. Outcomes After Judicious Antibiotic Use for Respiratory Tract Infections Seen in a Private Pediatric Practice. Pichichero, ME. et al. Pediatrics 2000 Apr;105(4):753-759. The results of this study show that antibiotic treatment is not routinely recommended in the management of children with respiratory tract infections without a concomitant bacterial infection. The study was conducted on a sample of 383 infants and children younger than 12 with respiratory tract infections, to evaluate the effects of a reduction of Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 27

antibiotic prescribing rates on the incidence of return office visits or subsequent bacterial infections. In the study, physicians prescribed antibiotics only when a bacterial infection was confirmed or presumed, resulting in only 23% of children receiving a prescription. Of note, more than half of the antibiotic prescriptions were written for children who were diagnosed with middle ear infections, even though current evidence (presented later in this text) indicates that antibiotics are no better than placebo in the management of this condition. Evaluation of the frequency of subsequent unscheduled return visits revealed that only 29% of children who did not receive antibiotics returned for an additional visit, compared to 44% of those treated with antibiotics. These data further support judicious use of antibiotics in children and infants with respiratory tract infections, i.e. avoidance of antibiotic treatment when there are no signs of bacterial infection. Less than 1 every 5 infants or children who present with respiratory tract infections require antibiotic treatment. Untreated children had lower rates of subsequent return office visits or bacterial infections, compared to treated children. Physicians should comply with current evidence demonstrating the safety and effectiveness of judicious antibiotic use, especially in consideration of the worldwide increase in antibiotic resistant bacteria, leading to a staggering increase in morbidity, mortality and health care costs due to untreatable infections.

66. Decreasing Antibiotic Use in Ambulatory Practice. Impact of a Multidimensional Intervention on the Treatment of Uncomplicated Acute Bronchitis in Adults. Gonzales, R. et al. JAMA 1999;281:1512-1519. The results of this study show that an intervention program consisting of office-based patient educational materials and clinician educational meetings resulted in a decline in antibiotic prescribing rates from 74% to 48% in patients with uncomplicated bronchitis. No differences in office return visits were observed in the month following the first visit, between the institutions with reduced antibiotic prescribing and those with rates of antibiotic prescribing of 80%, indicating that use of these drugs is unnecessary in the routine management of patients with uncomplicated bronchitis.

67. Antibiotic prescribing for adults with colds, upper respiratory tract infections, and bronchitis by ambulatory care physicians. Gonzales R, Steiner JF, Sande MA. JAMA 1997 Sep 17;278(11):901-4. The results of this study show that although antibiotics have been shown to be largely ineffective in treating colds, upper respiratory tract infections and bronchitis, they are nevertheless prescribed to 51%-66% of patients diagnosed with these conditions. This study demonstrates that in 1992, an estimated 12 million antibiotic prescriptions, or one fifth of all antibiotics prescriptions filled during that year, were written for patients with Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 28

colds, upper respiratory tract infections or bronchitis, despite lack of evidence of their effectiveness in the management of these ailments (more than 90% of upper respiratory infections -including bronchitis and colds- note the authors, are caused by a virus and are therefore impervious to antibiotics.) This practice has contributed to the spread of antibiotic-resistant bacteria and consequent infections in community settings.

68. Antibiotics and upper respiratory infection: do some folks think there is a cure for the common cold. Mainous AG 3d, Hueston WJ, Clark JR. J Fam Pract 1996 Apr;42(4):357-61. The results of this study show that 60% of patients who present with a complaint of common cold receive an antibiotic prescription. This practice leads to an estimated annual cost of $37.5 millions for unnecessary treatment of a condition that is not improved by antibiotic treatment.

69. Trends in antimicrobial drug prescribing among office-based physicians in the United States. McCaig LF, Hughes JM. JAMA 1995 Jan 18;273(3):214-9. The results of this study indicate that from 1980 to 1992, rates of prescribing of more expensive antibiotics with a broader antibacterial spectrum have been increasing, while prescribing of cheaper antibiotics with a narrower spectrum have been decreasing. The authors emphasize that this trend leads to an increase use of health care resources and has a potential deleterious effect on the insurgence of antibiotic resistance.

70. Factors associated with antibiotic use for acute bronchitis. Gonzales R, Barrett PH Jr, Crane LA, Steiner JF. J Gen Intern Med 1998 Aug;13(8):541-8. The results of this study show that physicians in primary care office practices prescribe antibiotics to 85% of patients with acute bronchitis. The authors could not identify clinical factors that explained the high rates of antibiotic prescribing and conclude that it seems feasible that a diagnosis of acute bronchitis is interpreted by physicians as an indication for antibiotic treatment, despite available evidence indicating the contrary.

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71. Treatment of acute bronchitis in adults. A national survey of family physicians. Oeffinger KC, Snell LM, Foster BM, Panico KG, Archer RK. J Fam Pract 1998 Jun;46(6):469-75. The results of this study show that family physicians prescribe antibiotics to 75% of nonsmoking and otherwise healthy adult patients with acute bronchitis and to 90% of smoking and otherwise healthy adult patients with acute bronchitis, despite evidence from clinical trials indicating that antibiotics are largely ineffective in the management of this condition. The authors emphasize how the increasing prevalence of antibiotic resistance calls for a change in the management of patients with acute bronchitis.

72. Antimicrobials for acute otitis media? A review from the international primary care network. Froom, J. et al. BMJ 1997;315:98-102 (12 July). This article highlights that even though there is no scientific evidence demonstrating that antibiotics are effective in the treatment of middle ear infections, this condition represent the most frequent reason for prescribing antibiotics in outpatient settings in the U.S. The seven randomized studies that evaluated the effectiveness of antibiotics in children with middle ear infection showed little or no benefits compared to placebo. The authors conclude that there is no convincing evidence in support of the use of these drugs in children with middle ear infections, and the management of this condition should therefore be reevaluated. Changing treatment practices is especially important since injudicious use of antibiotics is a major factor implicated in the development of antibiotic resistance and the consequent increase in morbidity, mortality, and health care costs associated with untreatable infections.

73. Primary care based randomised, double blind trial of amoxicillin versus placebo for acute otitis media in children aged under 2 years. Damoiseaux, Roger A M J et al. BMJ 2000;320:350-354 ( 5 February ). The results of this randomized study indicate that use of antibiotics is inappropriate not only in older children with middle ear infections but also in those aged 6 months to 2 years. In the study, 240 children under 2 years diagnosed with middle ear infection were randomly assigned to receive antibiotics or placebo. Signs of inflammation, pain and crying were no different in the group receiving antibiotics, compared to that receiving placebo. One every 7 or 8 treated children showed symptomatic improvement at day 4 of infection, but there were no improvements at day 11 or 42. The small benefits observed in a 13% of children do not justify routine antibiotic use in children of this age group with middle ear infection. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 30

74. Quantitative systematic review of randomised controlled trials comparing antibiotic with placebo for acute cough in adults. Fahey T, Stocks N, Thomas T. BMJ 1998 Mar 21;316(7135):906-10. This study is a meta-analysis of 9 randomized, placebo-controlled trials evaluating the efficacy of antibiotics in the treatment of individuals with acute cough. The results of the analysis revealed that antibiotics neither improve symptoms nor speed up recovery time in individuals with acute cough, while causing significantly more side effects compared to placebo. These data indicate that antibiotic treatment is inappropriate in individuals with acute cough.

75. National trends in the use of antibiotics by primary care physicians for adult patients with cough. Metlay JP, Stafford RS, Singer DE. Arch Intern Med 1998 Sep 14;158(16):1813-8. The results of this study show that primary care physicians' rates of antibiotic prescribing for adult patients presenting with cough increased significantly from 1980 to 1994. In particular, in 1980 an estimated 59% of patients who went to their doctor with a complaint of cough received an antibiotic prescription, as compared to 70% of patients who presented with cough in 1994. These data indicate an increasing trend of antibiotic prescribing for patients with cough, despite increasing evidence of the lack of efficacy of antibiotic treatment in this condition.

76. Outpatient visits for infectious diseases in the United States, 1980 through 1996. Armstrong GL, Pinner RW. Arch Intern Med 1999 Nov 22;159(21):2531-6. The results of this study show that every year 129 million outpatient visits, or approximately 20% of all outpatient visits to physicians are for infectious diseases. Of these, the majority (38%), are for upper respiratory tract infections, followed by middle ear infections (15.1%) and lower respiratory tract infections. These data indicate that over half of all visits for infectious diseases (approximately 68.5 million annual visits) are for upper respiratory tract infections or otitis, conditions that are typically not improved by antibiotics and for which antibiotics are first choice treatment.

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ANTIDEPRESSANTS 109 Studies

1. Trends in the prescribing of antidepressant pharmacotherapy: office-based visits, 19901995. Sclar DA. et al. Clin Ther 1998 Jul-Aug;20(4):871-84; 870. The results of this study show that the number of office visits resulting in prescription of an antidepressant drug increased from 16,534,268 in 1990 to 28,664,796 in 1995, a 73.4% increase. A diagnosis of depression was documented in 6.7% of the U.S. population in 1990, and in 7.1% in 1995, a 16.4% increase. The large increase in number of prescriptions, not matched by a similar increase in the prevalence of depression, suggests that the criteria for prescribing antidepressant medications have loosened during the study period. A variation in rates of prescribing of different class of drugs was also noticed, with a decline in use of tricyclic antidepressants (from 42% to 25%), and an increase in use of selective serotonin reuptake inhibitors (from 37% to 65%).

2. Association between selective serotonin reuptake inhibitors & upper gastrointestinal bleeding population based case-control study. de Abajo, FJ, Garca Rodrguez LA, Montero D. BMJ 1999;319:1106-1109 ( 23 October ). The results of this study show that users of the antidepressants selective serotonin reuptake inhibitors (SSRIs) have a significantly increased risk of upper gastrointestinal (GI) bleeding, compared to nonusers. The study was conducted on 1651 patients hospitalized with upper GI bleeding, and 10,000 matched controls. Use of SSRIs was associated with a 3-fold increased risk of bleeding, compared to nonuse. The incidence of this complication was estimated at 1every 8,000 prescriptions. Combined use of SSRIs and aspirin was associated with a 7-fold increased risk of GI hemorrhage, and combined use of SSRIs and non-steroidal anti-inflammatory drugs resulted in a 15.6-fold increased risk. The authors emphasize that the large increase in risk of GI hemorrhage observed in their study could have important public health implications due to the frequent use of both classes of drugs in industrialized countries.

3. Hemorrhagic syndromes related to selective serotonin reuptake inhibitor (SSRI) antidepressants. Seven case reports and review of the literature. French. Nelva A, Guy C, Tardy-Poncet B, Beyens MN, Ratrema M, Benedetti C, Ollagnier M. Rev Med Interne 2000 Feb;21(2):152-60. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 32

The results of this study suggest that intake of the antidepressants selective serotonin reuptake inhibitors is associated with an increased risk of developing hemorrhagic syndromes. This adverse effect is under-recognized and under-reported, and may be due to a decrease in concentration of platelet serotonin, leading to platelet dysfunction.

4. Antidepressant Medication Use and Breast Cancer Risk. Cotterchio M, Kreiger N, Darlington G, and Steingart A. Am J Epidemiol 2000;151:951-57. The results of this study indicate that women who take antidepressants are at significantly higher risk of developing breast cancer, compared to the general population. The association between antidepressant drugs and breast cancer first emerged from animal and epidemiological data. This case-control study, conducted to further test the hypothesis, found that users of selective serotonin reuptake inhibitors (SSRIs) and tryciclic antidepressants have a 7- and 2-fold increased risk of breast cancer, respectively, compared to nonusers. The finding of a large increase in risk of breast cancer in users of SSRIs may have public health implications owing to the high prevalence of use of this class of drugs.

5. Comparative study of fluoxetine, sibutramine, sertraline and dexfenfluramine on the morphology of serotonergic nerve terminals using serotonin immunohistochemistry. Kalia M, et al. Brain Res 2000 Mar 6;858(1):92-105. The results of this study indicate that short-term exposure to selective serotonin reuptake inhibitors (SSRIs) results in changes of rat brain cells, which resemble those induced by the recreational drug Ecstasy. SSRIs work by increasing the concentration of serotonin in the brain through inhibition of their re-uptake by brain cells. Their mode of action is similar to that of the recreational drug Ecstasy, which also increases the concentration of serotonin at the receptor site through a double action of inhibited reuptake and stimulated secretion from brain cells. While Ecstasy-induced brain damage has been well demonstrated in both animal and human studies, there are no data on the effects of SSRIs on brain cells. This study documented that, after only 4 days of intake of SSRIs, rat brain cells underwent morphological changes characterized by swelling and acquisition of a corkscrew shape, indicative of occurred damage. These findings indicate that SSRIs, the most commonly prescribed class of antidepressant drugs, cause damage in animal brain cells, after only 4 days of exposure. More studies on humans are needed, before these drugs can be considered safe.

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6. Discontinuation symptoms and psychotropic drugs Young, A. and Haddad P. Lancet 2000; 355: 1181 - 1190. This letter emphasizes that 35% to 78% of individuals who take the antidepressants selective reuptake inhibitors (SSRIs) for several months, experience, upon abrupt treatment interruption, physical and psychological symptoms such as: changes in mood, affect, appetite and sleep, dizziness, fatigue, anxiety, agitation, nausea, headache, and sensory disturbance. The symptoms are so typical that the clinical entity "SSRI discontinuation syndrome" is now widely accepted, after its existence had been negated for several years following the introduction of SSRIs on the market. Symptoms are usually mild and short-term, but occasionally can be severe and long lasting. They have often been interpreted as a sign of relapse into depression, leading to re-institution of treatment. The authors propose that all new psychotropic drugs be tested in double-blind placebo-controlled studies lasting several weeks beyond the actual drug trial, in order to properly monitor adverse reactions that may occur only upon discontinuation of treatment.

7. Hormonal markers of stress response following interruption of selective serotonin reuptake inhibitor treatment. Michelson D, et al. Psychoneuroendocrinology 2000 Feb;25(2):169-77. The results of this study show that following abrupt interruption of treatment with selective serotonin reuptake inhibitors patients develop signs of activation of a stress response, as shown by significantly increased plasma levels of IGF-1 and heart rate.

8. Antidepressant discontinuation reactions. Haddad P, Lejoyeux M, and Young A. BMJ 1998;316:1105-1106 ( 11 April ). This article reports on the frequency and nature of adverse reactions occurring upon discontinuation of antidepressant treatment. It explains that the existence of discontinuation reactions is often unrecognized by clinicians and that the extent of their occurrence is largely unknown because very few studies have ever addressed this issue. Discontinuation reactions usually start after few days of interruption of antidepressant treatment, and may consist of nausea, diarrhea, abdominal pain, insomnia, nightmares, headaches, lethargy, anxiety, and irritability. With selective serotonin-reuptake inhibitors, withdrawal is more commonly associated with symptoms such as dizziness, paraesthesia, numbness, and electric shock-like sensations. Results of a double blind placebo controlled study have shown that adverse reactions occur in 35% of patients after discontinuation of a 12-week treatment with the serotonin reuptake inhibitor paroxetine. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 34

Such reactions usually resolve within one day to three weeks, but occasionally they can be more severe and persist chronically, causing substantial morbidity.

9. Discontinuation symptoms after treatment with serotonin reuptake inhibitors a literature review. Zajecka J, et al. J Clin Psychiatry 1997 Jul;58(7):291-7. The results of this study indicate that discontinuation of selective serotonin-reuptake inhibitor therapy is associated with the development of a cluster of symptoms including dizziness, light-headedness, insomnia, fatigue, anxiety, nausea, headache, and sensory disturbance. These symptoms may last up to three weeks after interruption of treatment, and may be relieved by restarting antidepressant therapy (!).

10. Antidepressant-induced sexual dysfunction during treatment with moclobemide, paroxetine, sertraline, and venlafaxine. Kennedy SH, Eisfeld BS, Dickens SE, Bacchiochi JR, Bagby RM. J Clin Psychiatry 2000 Apr;61(4):276-81. The results of this study indicate that 30%-70% of patients who take the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline experience sexual dysfunction as a side effect of treatment. Impairment in drive and/or desire occurs more frequently in men than women, while impairment in level of arousal and orgasm is experienced at similar rates by both sexes. These data indicate that the majority of patients treated with SSRIs experience sexual dysfunction. The low rates of this complication reported in previous studies were due to underreporting and was not confirmed in subsequent trials.

11. Sexual dysfunction induced by serotonin reuptake antidepressants. Labbate LA, Grimes J, Hines A, Oleshansky MA, Arana GW. J Sex Marital Ther 1998 Jan-Mar;24(1):3-12. The results of this study show that the antidepressants selective serotonin reuptake inhibitors negatively affect sexual functios. The study was conducted on 61 individuals who took these drugs for at least two months. Both men and women experienced a significant worsening of quality of orgasm after 1 and 2 months of treatment, compared to baseline. Women reported failure to achieve an orgasm significantly more often than men, while both sexes experienced prolongation of time to orgasm induction after 1, 2, and 3 months of treatment, compared to baseline.

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12. Incidence of sexual dysfunction in healthy volunteers on fluvoxamine therapy. Nafziger AN, et al. J Clin Psychiatry 1999 Mar;60(3):187-90. The results of this study show that 35% of healthy volunteer who took the antidepressant fluvoxamine developed, after 4 weeks of treatment, sexual dysfunction.

13. Adverse reactions of selective serotonin reuptake inhibitors reports from a spontaneous reporting system. Spigset O. Drug Saf 1999 Mar;20(3):277-87. This study evaluated 1202 spontaneous reports on 1861 adverse reactions to selective serotonin reuptake inhibitors (SSRIs), and found that 22.4% of such reports consisted of neurological disturbances, 20% of psychiatric disorders, and 18% of gastrointestinal symptoms. The elderly were particularly susceptible to Parkinsonism, confusion, hallucinations, and hypotension, while younger patients experienced more frequently hematological, endocrine, and sexual dysfunction. Akathisia and aggression occurred more frequently in men than women.

14. A survey of antidepressant drug use in Parkinson's disease. Parkinson Study Group. Richard IH, et al. Neurology 1997 Oct;49(4):1168-70. The results of this study indicate that approximately 26% of patients with Parkinson's disease (PD) are given antidepressant medications, which consist, in over half of the cases, of serotonin reuptake inhibitors (SSRIs). Forty-three percent of physicians of the Parkinson Study Group showed concern that use of SSRIs might induce worsening of motor function in PD patients, and 37% of physicians had at least one patient in which they believed such aggravation occurred.

15. Prenatal exposure to fluoxetine (Prozac) produces site-specific & age-dependent alterations in brain serotonin transporters in rat progeny Evidence from autoradiographic studies. Cabrera-Vera TM, Battaglia G. J Pharmacol Exp Ther 1998 Sep;286(3):1474-81.

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The results of this study show that prenatal exposure to the selective serotonin reuptake inhibitor fluoxetine (Prozac) induces changes in the density of brain serotonin transporters in rats, which are particularly evident in regions of the limbic system, such as the hypothalamus, hippocampus and amygdala. These data indicate that fluoxetine alters brain function in rats exposed to the drug while in uterus.

16. Pregnancy outcome following first-trimester exposure to fluoxetine. Pastuszak A, Schick-Boschetto B, Zuber C, Feldkamp M, Pinelli M, Sihn S, et al. JAMA 1993 May 5;269(17):2246-8. The results of this study show that women who use the antidepressant fluoxetine (Prozac) in the first trimester of pregnancy have approximately a 2-fold increased risk of miscarriage, compared to nonusers.

17. Birth outcomes in pregnant women taking fluoxetine. Chambers CD, et al. N Engl J Med, 335(14):1010-5 1996 Oct 3. This study evaluated pregnancy outcome of women who took the antidepressant fluoxetine (a serotonin uptake inhibitor) while expecting, and compared it to that of women who did not take the drug. In infants exposed to the drug, the incidence of three or more minor anomalies was 15.5% vs. 6.5% in controls. Infants exposed to fluoxetine during the third trimester had, compared to those exposed only during the first and second trimester, reduced birth weight and length, an almost 5-fold increased risk of premature delivery, a 2.6-fold increased risk of being admitted to special-care nurseries, and an almost 9-fold increased risk of experiencing respiratory difficulties, cyanosis on feeding, and jitteriness.

18. Antidepressants and suicidal risk. Muller-Oerlinghausen B, Berghofer A. J Clin Psychiatry 1999;60 Suppl 2:94-9; discussion 111-6. This article emphasizes that selective serotonin reuptake inhibitors and other non-lithium antidepressants may increase the risk of suicide in certain patients by inducing akathisia (a condition characterized by restlessness and psychomotor agitation and associated with self-destructive impulses) and by liberating suppressed energies that may be used to act upon suicidal thoughts.

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Reexposure to fluoxetine after serious suicide attempts by three patients: the role of akathisia. Rothschild AJ. et al. J Clin Psychiatry, 52(12):491-3 1991 Dec. This article describes three cases of attempt suicide after induction of akathisia in patients on fluoxetine therapy. When re-exposed to the drug, all three patients re-developed akathisia and precipitated in suicidal thoughts, strongly suggesting a relation of causality between drug exposure and suicidal impulse.

19. Selective serotonin reuptake inhibitors: meta-analysis of efficacy and acceptability. Song F. et al. BMJ 1993 Mar 13;306(6879):683-7. This study presents the results of a meta-analysis of 63 randomized controlled studies comparing the efficacy of selective serotonin reuptake inhibitors (SSRIs) to that of tricyclic antidepressants as first line treatment for depression. The analysis revealed that SSRIs are no more effective than tryciclics in the management of depression. Dropouts rate were similar for both class of drugs, but slightly more patients reported side effects as a reason for dropping out in the tryciclic group compared to those in the SSRI group (18.8% v 15.4%). The authors concluded that "Routine use of selective serotonin reuptake inhibitors as the first line treatment of depressive illness may greatly increase cost with only questionable benefit". This study is important since it shows that SSRIs are not significantly better than classic antidepressant drugs, in spite of advertising campaigns claiming the superiority of SSRIs in the treatment of depression due to their excellent safety records. The underreporting of SSRI-related adverse reactions is also partly responsible for the vast increase in prescribing rates of these drugs.

20. Double-blind, multicenter comparison of sertraline and amitriptyline in elderly depressed patients. Cohn CK. et al. J Clin Psychiatry, 51 Suppl B():28-33 1990 Dec. In this study, 241 elderly individuals suffering from depression were randomized to receive an 8-week treatment with either amitriptyline (a tricyclic antidepressant) or sertraline (a serotonin uptake inhibitor). Over 30% of patients in the sertraline group and 35% in the amitriptyline group withdrew from the study because of drug-related side effects or laboratory abnormalities.

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The cost of antidepressant drug therapy failure: a study of antidepressant use patterns in a Medicaid population. McCombs JS, et al. J Clin Psychiatry, 51 Suppl():60-9; discussion 70-1 1990 Jun. The results of this study, conducted on a cohort of 2344 patients with major depressive disorders on antidepressant medications, show that only in 3.5% of patients the pattern of use of antidepressant was indicative of successful treatment. In 12.6 of patients, pattern of antidepressant use suggested treatment failure. In the remaining 84% of cases the efficacy of treatment could not be clearly classified.

21. The adequacy of reporting randomized, controlled trials in the evaluation of antidepressants. Streiner DL, et al. Can J Psychiatry, 43(10):1026-30 1998 Dec. This study examined the statistical and methodological validity of 69 randomized control trials that compared the efficacy of two antidepressant drugs with that of placebo. Criteria scores were defined as minimal and ideal. Zero percent of the studies met all of the ideal criteria for reporting clinical trials. Only 9 of 69 articles met the minimal criteria to be included in metaanalytical studies. These data indicate that the quality of the majority of studies on antidepressant drugs is extremely poor.

22. Hyponatremia in relation to treatment with antidepressants: A survey of reports in the World Health Organization database for spontaneous reporting of adverse drug reactions. Spigset O, et al. Pharmacotherapy 1997 Mar-Apr;17(2):348-52. The results of this study show that from 1968 to 1993, 668 cases of antidepressant-related hyponatremia were spontaneously reported to the World Health Organization. In over half of the patients, the reaction occurred within two weeks of starting antidepressant treatment.

23. Relative mortality from overdose of antidepressants. Henry JA, et al. BMJ, 310(6974):221-4 1995 Jan 28.

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This study reports on the case of 1606 deaths from antidepressant toxicity, occurring in the period from 1987 to1992. Over 80% of these deaths were associated to amitriptyline and dothiepin use.

24. Antidepressant-treated patients in ambulatory care. Mortality during a nine-year period after first treatment. Bingefors K. et al. Br J Psychiatry, 169(5):647-54 1996 Nov. The results of this study show that, in individuals over 65 years of age, treatment with antidepressant is significantly associated with increased risk of long-term mortality, especially from cardiovascular causes.

25. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Reilly, J G. et al. Lancet 2000; 355: 1048 - 1052. The results of this study show that use of psychotropic drugs is associated with a significantly increased risk of heart arrhythmias. The study was conducted on 495 psychiatric patients and 101 healthy individuals who served as control. As a marker for increased risk of arrhythmias the authors used the lengthening of the QT interval on the electrocardiogram. Eight percent of patients receiving psychiatric drugs had prolonged QT interval, which poses them at risk of cardiac arrhythmias. The risk of having an abnormal QT interval in patients taking tricyclic antidepressants and the antipsychotic drugs thioridazine, and droperidol was increased by 4.4-, 5.5-, and 6.7-folds, respectively, compared to non-users. The risk increased with increasing doses of drugs, and was increased by more than 8 times in users of very high doses. These findings may explain some cases of sudden unexplained death occurring in patients taking psychotropic drugs, as this type of death has been linked to cardiac rhythm abnormalities.

26. Relative mortality from overdose of antidepressants Henry JA, et al. BMJ 1995;310:221-224 (28 January). The results of this study show that for every million prescriptions written for antidepressant drugs, approximately 30 people die from overdose. Tricyclic drugs are associated with the highest incidence of death (34 deaths per million prescriptions), and selective serotonin reuptake inhibitors with the lowest (2 deaths per million prescription).

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27. Imipramine overdose complicated by toxic megacolon. Ross JP, et al. Am Surg, 64(3):242-4 1998 Mar. This article emphasizes that tricyclic antidepressants are responsible for approximately 20 to 25% of drug overdoses leading to hospitalization. Death occurs primarily from cardiovascular complications. Respiratory disturbances, urinary retention, constipation, and intestinal obstruction are common signs of toxicity. Less frequent complications include: pancreatitis, intestinal perforation, and gangrene of the large intestine.

28. Cardiotoxic side effects associated with tricyclic antidepressant overdose. Keis NA. AACN Clin Issues Crit Care Nurs, 3(1):226-32 1992 Feb. This article emphasizes that intake of excessive doses of tricyclic antidepressants is associated with a significant risk of cardiotoxicity, especially during the first 24 hours from the overdose.

PSYCHOTROPIC DRUGS

"Psychotropic drugs" is a term that refers to drugs that have an effect on the psychological function, including antidepressants, antipsychotics or neuroleptics, antianxiety drugs, and hallucinogens.

29. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients Reilly JG. et al. Lancet 2000; 355: 1048 - 1052. The results of this study show that use of psychotropic drugs is associated with a significantly increased risk of heart arrhythmias. The study was conducted on 495 psychiatric patients and 101 healthy individuals who served as control. As a marker for increased risk of arrhythmias the authors used the lengthening of the QT interval on the electrocardiogram. Eight percent of patients receiving psychiatric drugs had prolonged QT interval, which poses them at risk of cardiac arrhythmias. The risk of having an abnormal QT interval in patients taking tricyclic antidepressants and the antipsychotic drugs thioridazine, and droperidol was increased by 4.4-, 5.5-, and 6.7-folds, respectively, compared to non-users. The risk increased with increasing doses of drugs, and was increased by more than 8 times in users of very high doses. These findings may explain Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 41

some cases of sudden unexplained death occurring in patients taking psychotropic drugs, as this type of death has been linked to cardiac rhythm abnormalities.

30. Dopamine-antagonistic, anticholinergic, and GABAergic effects on declarative and procedural memory functions. Rammsayer TH, Rodewald S, Groh D Brain Res Cogn Brain Res. 2000 Jan;9(1):61-71. The results of this study show that the psychotropic drugs haloperidol and midazolam (a benzodiazepine used for sedation) significantly impair memory functions in healthy individuals. The study was conducted on 80 healthy volunteers who were randomly assigned to receive haloperidol, midazolam, scopolamine, or placebo. Adverse effects on immediate and delayed word recall tests were observed with all three drugs, but were more pronounced in individuals taking midazolam. All drugs provoked severe impairment on object recognition tests, and these effects were particularly strong in individuals receiving midazolam. The results of this study indicate that use of these drugs is associated with significant memory-related problems in healthy individuals.

31. A comparison of the effects of olanzapine, haloperidol and placebo on cognitive and psychomotor functions in healthy elderly volunteers. Beuzen JN, Taylor N, Wesnes K, Wood A. J Psychopharmacol (Oxf) 1999;13(2):152-8. The results of this study show that the antipsychotic drug haloperidol produces significant cognitive and psychomotor impairment in elderly individuals, and these effects don't seem to improve with treatment. The study was conducted on 14 healthy elderly individuals who were randomly assigned to receive haloperidol, olanzapine (a new antipsuchotic drug), or placebo for 4 days. On day 1 of treatment, significant impairment in attention, memory, and motor control was observed in both groups receiving antipshycotic drugs. On day 4 of treatment, the cognitive and psychomotor deficits were attenuated in patients who took olanzapine, (indicating adaptation to these side effects), but had worsened in patients taking haloperidol. These data indicate that patients taking haloperidol may be experiencing significant deterioration of cognitive and motor skills from the drug. These powerful adverse effects must be taken in consideration when prescribing haloperidol to elderly individuals, as the drug may precipitate their overall health status and may render them unsuitable for independent living. Since other antipsychotic drugs don't share the same persistency of effects, haloperidol use should be replaced with safer alternatives.

32. Effects of haloperidol and amisulpride on motor and cognitive skill learning in healthy volunteers. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 42

Peretti CS, Danion JM, Kauffmann-Muller F, Grange D, Patat A, Rosenzweig P. Psychopharmacology (Berl). 1997 Jun;131(4):329-38. The results of this study show that intake of haloperidol is associated with impaired cognitive functions in healthy individuals. The study was conducted on 60 healthy individuals who were randomized to receive haloperidol, amisulpride (a drug used in the treatment of depression and dysthymia), or placebo. Those who received haloperidol showed the greatest deficits in higher cognitive functions as evaluated through a battery of tests performed immediately after and some time after drug administration, while those who received amisulpride demonstrated cognitive slowing only at tests performed at distance from drug intake.

33. Psychomotor, Cognitive, extrapyramidal, and affective functions of healthy volunteers during treatment with an atypical (amisulpride) and a classic (haloperidol) antipsychotic. Ramaekers JG, et al. J Clin Psychopharmacol 1999 Jun;19(3):209-21. The results of this study show that haloperidol significantly impairs cognitive and motor performance in healthy individuals. The study was conducted on 21 healthy volunteer who were randomly assigned to receive the atypical neuroleptic amisulpride, the classic neuroleptic haloperidol, or placebo, for 5 consecutive days. Significant cognitive and psychomotor deficits were observed at day 5 of treatment in individuals taking amisulpride and haloperidol. Additionally, practically every individual who took haloperidol exhibited extrapiramidal symptoms ranging from akatisia (restlessness of movements, an urge to move about constantly, often associated with anxiety and agitation) to acute dystonia (sustained abnormal postures or muscle spasms), and mental disturbances. These data indicate a high rate of severe adverse effects associated with neuroleptic intake. Interestingly, several of the adverse effects of haloperidol resemble symptoms found in schizophrenic patients, thus raising the question of whether they are due to the disease or to the treatment.

34. Managing antipsychotic-induced acute and chronic akathisia. Miller CH, Fleischhacker WW. Drug Saf 2000 Jan;22(1):73-81. This article emphasizes that 5% to 37% of patients treated with antipsychotic drugs develops akathisia, a condition characterized by a feeling of restlessness accompanied by anxiety, agitation, and an urge to move about that leads patients to continuously rock while sitting or standing, to lift their feet as if marching on the spot and to cross and uncross their legs while sitting. Since currently there is no satisfactory treatment for this

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complication, the only remedy is to prevent its occurrence by reducing the intake of drugs, or switching to safer antipsychotic drugs.

35. Antipsychotic-induced life-threatening 'esophageal dyskinesia'. Horiguchi J et al. Int Clin Psychopharmacol 1999 Mar;14(2):123-7. This article describes a potentially fatal adverse reaction to antipsychotic drugs, esophageal dyskinesia, consisting of abnormal movements affecting the lower portion of the pharynx and the upper portion of the esophagus. A case of a patient who died from asphyxiation of food is reported.

36. Effects of the clozapine national registry system on incidence of deaths related to agranulocytosis. Honigfeld G. Psychiatr Serv, 47(1):52-6 1996 Jan. Clozapine is an antipsychotic drug with a high potential of inducing white blood cell suppression, and is administered only to patients whose weekly blood tests show no evidence of toxicity. From its release in 1990 until December 1994, 382 cases of agranulocytosis and 12 related deaths have been identified through a national patient registry maintained by the drug manufacturer. From results of clinical research performed prior to the release of the drug in the market, the expected number of cases of agranulocytosis and death was 995 and 149, respectively, raising the question of whether such a drug should have been approved in the first place.

37. A survey of sudden death associated with the use of antipsychotic or antidepressant drugs: 49 cases in Finland. Mehtonen OP; Aranko K; Malkonen L; Vapaatalo H. Acta Psychiatr Scand, 84(1):58-64 1991 Jul. The antipsychotic class of drugs phenothiazines causes disturbances of the cardiac rhythm, and while their use has been associated with the occurrence of sudden death, a causal link has not been clearly demonstrated. This study shows that in 46 of 49 cases of sudden death reported in users of antipsychotic or antidepressant drugs, individuals were taking therapeutic doses of phenothiazines, which consisted of the drug thioridazine in over half the cases. The high representation of this class of drugs in individuals with sudden death is indicative of a causal association.

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38. Assessment of EPS and tardive dyskinesia in clinical trials. Collaborative Working Group on Clinical Trial Evaluations. J Clin Psychiatry 1998;59 Suppl 12:23-7. This article explains that approximately 50%-75% of individuals who take conventional antipshycotic drugs develop acute extrapyramidal symptoms (EPS) such as akathisia, dystonia and parkinsonism. Although the incidence of such symptoms is less frequent with the new antipsychotic drugs, the authors still caution to use them at doses below the EPS-producing levels until more data on their long-term effects are available.

39. Extrapyramidal syndromes in neuroleptic-treated patients: prevalence, risk factors, and association with tardive dyskinesia. Muscettola G, et al. J Clin Psychopharmacol 1999 Jun;19(3):203-8. This study evaluated the prevalence of signs of extrapyramidal syndrome (EPS) (akathisia, dystonia and parkinsonism) in a cohort of 1,559 patients treated with antipsychotic drugs. EPS was present in approximately 30% of patients, with 65% of these patients presenting with signs of parkinsonism such as rigidity, tremors and slowness of movements. These data indicate a high rate of severe and disabling adverse reactions associated with neuroleptic use.

40. Intermittent neuroleptic treatment and risk for tardive dyskinesia: Curacao Extrapyramidal Syndromes Study III. van Harten PN, et al. Am J Psychiatry 1998 Apr;155(4):565-7. The results of this study, conducted on a cohort of patients with a history of antipsychotic drug use of more than 3 months, show that the incidence of tardive diskinesia increases by 3-folds in patients who had 3 or more treatment interruptions, compared to those who had 2 or less breaks in drug therapy.

41. Incidence of tardive dyskinesia in early stages of low-dose treatment with typical neuroleptics in older patients. Jeste DV, et al. Am J Psychiatry 1999 Feb;156(2):309-11. This study evaluated the incidence of tardive dyskinesia (a syndrome characterized by potentially irreversible, involuntary abnormal movements usually of the trunk and face, associated with use of antipsychotic drugs) in a cohort of 307 outpatients over 45 year of Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 45

age treated with low-dose antipsychotic drugs. In patients who had not used this type of drugs in the past, the incidence of tardive dyskinesia was 3.4% after 1 month and 6% after 2 months of use. After 1 year, the syndrome developed approximately in 25% of patients, and in 37% of those who had a history of antipsychotic drug use of over 30 days.

42. Prospective study of tardive dyskinesia in the elderly: rates and risk factors. Woerner MG, et al. Am J Psychiatry 1998 Nov;155(11):1521-8. The results of this study, conducted on a cohort of 261 patients on antipsychotic drugs, show that after 1, 2, and 3 years of cumulative treatment, 25%, 34%, and 53% of patients who started taking the drugs at age 55 or above developed tardive dyskinesia.

43. Incidence and risk factors for severe tardive dyskinesia in older patients. Caligiuri MP, et al. Br J Psychiatry 1997 Aug;171:148-53. The results of this study show that after 1, 2, and 3 years of treatment with antipsychotic drugs, the incidence of severe tardive diskinesia in middle-aged and elderly individuals is 2.5%, 12% and 23%, respectively. The authors concluded affirming, "Conventional neuroleptics may be prescribed to older patients only when necessary and at the lowest effective dosage".

44. Transient and intermittent oral dyskinesia appearing in a young woman ten days after neuroleptic treatment. Tawara Y, et al. Clin Neuropharmacol 1997 Apr;20(2):175-8. This article reports on the case of a 22-year-old woman initiated on antipsychotic drugs who developed severe extrapiramidal signs and tardive diskinesia lasting for 6 days, after only 9 days of treatment.

45. Neuroleptic drug exposure and treatment of parkinsonism in the elderly a case-control study. Avorn J, Bohn RL, Mogun H, Gurwitz JH, Monane M, Everitt D, Walker A. Am J Med 1995 Jul;99(1):48-54.

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The results of this study show that elderly patients who take antipsychotic drugs have a significant increased risk of developing symptoms of Parkinson's disease requiring initiation of pharmacological treatment. The study was conducted on a cohort of 3,512 patients aged 65 and older who received a new prescription for the treatment of Parkinson's disease and a similar number of controls without symptoms of parkinsonism. Users of neuroleptic drugs had a 5.4-fold increased risk of being treated for parkinsonism, compared to nonusers. Of note, users of neuroleptic drugs also had an over two-fold increased risk of receiving a drug with indications for idiopathic Parkinson's disease and not appropriate in individuals with drug-induced parkinsonism. The authors estimated that 37% of all prescriptions for the treatment of Parkinson's disease are due to neuroleptic drug use. In 71% of patients neuroleptic treatment was not discontinued in spite of the occurrence of parkinsonian symptoms. These data indicate that extrapyramidal symptoms of parkinsonism are a frequent complication of neuroleptic treatment. Physicians however, often fail to recognize that these symptoms are drugrelated, as shown by the high rate of inappropriate prescribing of drugs that are not indicated for drug-induced parkinsonism, resulting in inappropriate management of the condition and failure of optimization of treatment regimens.

46. Drug-induced cognition disorders in the elderly: incidence, prevention and management. Gray SL, Lai KV, Larson EB. Drug Saf 1999 Aug;21(2):101-22. This article highlights that elderly individuals are particularly at risk of developing drugrelated delirium and dementia. Although practically every drug has the potential of worsening cognitive function in the elderly, those more commonly implicated are benzodiazepines, opioids, anticholinergics, and tricyclic antidepressants. The risk is particularly high in elderly frail individuals who are taking several medications at once, such that a careful evaluation should always be conducted to exclude the possibility of drug-related cognitive impairment in this age group.

47. Increased morbidity and mortality related to asthma among asthmatic patients who use major tranquillisers. Joseph KS, et al. BMJ 1996;312:79-81 (13 January). The results of this study show that use of neuroleptic drugs in asthmatic patients with psychosis is associated with a 3.2-fold increased risk of death or near-death from asthma, compared to nonuse.

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48. Association of venous thromboembolism and clozapine. Staffan Hgg, Olav Spigset, Torbjrn G Sderstrm. Lancet 2000; 355: 1155 - 1156. The results of this study show that the antipsychotic drug clozapine is associated with a significantly increased risk of death from venous thromboembolism. The researchers evaluated cases of deep venous thrombosis and pulmonary embolism that occurred in individuals treated with clozapine, reported to the Swedish Adverse Reactions Advisory Committee from April 1989 through March 2000. Of the 12 patients who experienced venous thromboembolism, 5 died (42%). Median age of patients was 38 years. Only one had known risk factors for thromboembolism (contraceptive use). Sixty-seven percent of the cases occurred during the first 3 months of clozapine treatment. Overall, from 20,000 to 70,000 Swedish patients take clozapine, indicating that the risk of this complication is at least 1 per 2-6,000 treated patients. The actual risk, however, is likely to be higher, in view of the fact that reporting of adverse events is spontaneous (not mandatory), such that a substantial number of cases may be missed due to under-reporting.

49. Myocarditis and cardiomyopathy associated with clozapine. Jens G Kilian, Kristin Kerr, Christopher Lawrence, David S Celermajer. Lancet 1999; 354: 1841-45. The results of this study show that individuals taking the anti-psychotic drug clozapine have a 1,000-2,000-fold increased risk of death from myocarditis, compared to non-users. The study was conducted after two young, physically healthy patients died unexpectedly soon after initiation of treatment. The authors investigated the risk of adverse cardiovascular effects by searching for cases of myocarditis and cardiomyopathy in the Australian Adverse Reaction Committee register, a voluntary reporting system. They found 15 reports of myocarditis and 8 of cardiomyopathy. Six patients died, 5 from myocarditis, and 1 from cardiomyopathy. All cases of myocarditis occurred within 3 weeks of initiation of treatment, whether cardiomyopathy occurred up to 3 years after initiation of treatment. From 1993 to 1999, 8,000 patients were started on clozapine in Australia. Among these 8,000 patients, a minimum of 23 cases of myocarditis and cardiomyopathy occurred, including 6 deaths. The number of patients who suffered these complications may, however be higher, since reporting of adverse events is not mandatory. Extrapolation of this data indicates that approximately 1 in 500 young individuals who are treated with clozapine for schizophrenia will have fatal and nonfatal myocarditis in the first month of treatment. These estimates are conservative, due to likely underreporting. Since myocarditis is a very rare cause of death worldwide (approximately 4 deaths per 1,000,000 individuals), these figures represent a 1000-2000 increased risk of death from the disease in patients taking clozapine, compared to the general population. In addition, users of clozapine have a 5-fold increased risk of cardiomyopathy, compared to non-users. This article further highlights the risks associated with use of this drug, which has been found to cause potentially fatal agranulocytosis (marked decrease in the number of white blood cells) in one every 100 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 48

treated patients, and deep venous thrombosis in at least 1 in 2-6-000 patients (based on spontaneous reporting), the latter complication being fatal in over 40% of cases.

PSYCHOTROPIC DRUGS USED FOR ADULTS AND THE ELDERLY

50. Prescribing trends in psychotropic medications: primary care, psychiatry, and other medical specialties. Pincus HA, Tanielian TL, Marcus SC, Olfson M, Zarin DA, Thompson J, Magno Zito J. JAMA 1998 Feb 18;279(7):526-31. The results of this study show that in 1985, in the U.S., 32.73 million visits to officebased primary care physicians resulted in prescription of psychotropic drugs. In 1994, the number of such visits increased to 45.64 million. Psychiatrists and primary care physicians' visits for depression doubled from 1988 to 1994, and visits for stimulants more than quadrupled. In addition, of the visits for depression, those paid to psychiatrists in 1994 resulted in a higher rate of drug prescribing, compared to 1988.

51. Expenditures for psychotropic medications in the United States in 1985. Zorc JJ. et al. Am J Psychiatry 1991 May;148(5):644-7. This study shows that, in 1985, the U.S. spent $1.45 billion in psychotropic drugs for outpatients. Sixty percent of this sum ($868 million) was spent for antianxiety and sedative-hypnotic medications, 18% for antipsychotics, and 17% for antidepressants.

52. The direct economic costs of insomnia in the United States for 1995. Walsh JK, Engelhardt CL. Sleep 1999 May 1;22 Suppl 2:S386-93. The results of this study show that in 1995, the U.S. spent $13.9 billion for the treatment of insomnia.

53. Psychotropic prescribing for the elderly in office-based practice. Aparasu RR, Mort JR, Sitzman S. Clin Ther 1998 May-Jun;20(3):603-16. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 49

The results of this study show that 17% of visits by the elderly to office-based physicians result in the prescription of at least one inappropriate psychotropic drug. According to the study, in 1995, approximately 12 million visits by the elderly to their doctors resulted in prescription of a psychotropic drugs, primarily antidepressants and antianxiety drugs. In over 2 million visits, patients received a minimum of one potentially inappropriate psychotropic medication. The high rates of inappropriate prescribing, coupled with the particular susceptibility of elderly patients to experiencing drug-related adverse effects, raises concerns on the quality of care offered by physicians in ambulatory settings.

54. Determinants of psychotropic drug usage in a general intensive care unit. Stolker J. et al. Gen Hosp Psychiatry 1998 Nov;20(6):371-6. The results of this study show that 36% and 17.5% of patients admitted to a Dutch general intensive care unit receive benzodiazepines and antipsychotics, respectively.

55. Psychotropic drug use and polypharmacy in a general hospital. Salzman C. Gen Hosp Psychiatry, 3(1):1-9 1981 Mar. The results of this study show that approximately 43% of patients admitted to a general Boston teaching hospital received psychotropic drugs. Drugs were given mainly for sleep problems or to reduce anxiety. The authors found high rates of inappropriate prescribing of antipsychotic drugs, which were given to control symptoms such as nausea, pain, or agitation rather than psychosis, and of antidepressant drugs, which were given irrespective of signs of depression, or below therapeutic doses in patients with depression.

56. Psychotropic use among older residents of board and care facilities. Spore D. et al. J Am Geriatr Soc, 43(12):1403-9 1995 Dec. The results of this study, conducted on 2054 elderly residents from 410 board and care facilities in 10 states, indicate that approximately 35% of them were receiving a minimum of one psychotropic drug. Simultaneous use of 2 or more psychotropic drugs occurred in 30% of psychotropic drug users.

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57. Regulatory environment and psychotropic use in board-and-care facilities: results of a 10-state study. Spore D. et al. J Gerontol A Biol Sci Med Sci, 51(3):M131-41 1996 May. The results of this study, conducted on a sample population of 2,949 residents from 493 board-and-care facilities in 10 states, show that 41% of them were primarily or routinely being prescribed a minimum of one psychotropic drug. Twenty-one percent of residents were on antipsychotic drugs. About half of the individuals currently on psychotropic drugs did not have any psychiatric diagnosis in the previous year.

58. Psychotropic drug intake in residents newly admitted to nursing homes. Wancata J. et al. Psychopharmacology (Berl) 1997 Nov;134(2):115-20. The results of this study indicate that prescribing of psychotropic drugs to nursing home residents occurs irrespective of prior history of psychiatric conditions. The study, conducted on a cohort of 262 individuals admitted to nursing homes in Austria, show that the prevalence of use of psychotropic drugs rose from 45.5% in the 3 months before admission, to 72% in the 2 weeks after admission, to 79% during the first six months of stay.

59. Psychotropic drug use in Sydney nursing homes. Snowdon J. et al. Med J Aust, 163(2):70-2 1995 Jul 17. The results of this study, conducted on all residents of 46 nursing homes in Sydney, show that 59% of them were regularly receiving psychotropic drugs, and 7% of them were receiving them on an "as required" basis. Benzodiazepines, antipsychotics, hypnotics, antidepressants and anxiolytics were taken regularly by 32.3%, 27.4%, 26.6%, 15.6% and 8.6% of individuals, respectively.

60. A follow-up survey of psychotropic drug use in Sydney nursing homes. Snowdon J. Med J Aust 1999 Apr 5;170(7):299-301. The results of this study show that 48.5% of Sidney nursing home residents receive at least one psychotropic drug regularly, and another 4.5% "as required". Antipshychotic drugs were taken by 27.6% of residents. Anticonvulsants, who were not considered in this study as psychotropic drugs, were given to 13% of residents. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 51

61. Use of psychotropic medications for persons with mental retardation who live in Oklahoma nursing homes. Spreat S. et al. Psychiatr Serv, 49(4):510-2 1998 Apr. The results of this study, conducted on a cohort of 1,056 individuals with mental retardation living in Oklahoma nursing homes, show that 32% of them were taking antipsychotic medications, 16% were taking anxiolytic drugs, and 6% were taking antidepressants. Use of antipsychotics, a class of drugs associated with a high risk of severe complications, was not always justified by patients' clinical history. The high rates of prescribing of antipsychotic drugs make the authors question the appropriateness of placing individuals with mental retardation in nursing homes.

62. Use of psychotropic medication in Oklahoma: a statewide survey. Spreat S. et al. Am J Ment Retard, 102(1):80-5 1997 Jul. The results of this study indicate that 22.5%, 9.3%, and 5.9% of mentally retarded individuals are prescribed antipsychotic drugs, anxiolytics and antidepressant medications, respectively. Rates of prescribing for mentally retarded individuals living in institutions or intermediate care facilities are significantly higher.

63. Frequency of and determinants for psychotropic drug use in an institution for the mentally retarded. Linaker OM. Br J Psychiatry 1990 Apr;156:525-30. The results of this study, conducted on a cohort of 168 mentally retarded individuals institutionalized in Norway, show that 49% of them were receiving antipsychotic drugs. Only in a small percentage of cases the prescription of these drugs could be justified by a psychiatric diagnosis.

64. Prevalence and prediction of psychotropic drug use in California developmental centers. Stone RK. et al. Am J Ment Retard, 93(6):627-32 1989 May.

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The results of this study show that, on average, 35.4% of developmentally disabled individuals institutionalized in California are treated with psychotropic drugs, with 26.8% of them receiving antipsychotic medications. Rates of prescription of psychotropic drugs varied greatly among institutions, ranging from 13.7% to 63.6% of the individuals.

65. Withdrawal of haloperidol, thioridazine, and lorazepam in the nursing home: a controlled, double-blind study. Cohen-Mansfield J, et al. Arch Intern Med 1999 Aug 9-23;159(15):1733-40. This double-blind placebo controlled study evaluated the effect of discontinuation of treatment with haloperidol, thioridazine, and lorazepam, three psychotropic drugs commonly used to control patient behavior, in residents of a nursing home. The behavior of patients who were slowly switched to placebo did not differ from that of patients who continued taking the drugs, questioning the efficacy of these medications in managing patient agitation. The authors conclude that an attempt to discontinue the use of such drugs should be routinely performed in nursing home settings.

66. Long-stay patients with long-stay drugs. A case review; a cause for concern. Fottrell E, et al. Lancet 1976 Jan 10;1(7950):81-2. The results of this study, conducted on a cohort of 200 long-term psychiatric patients, show that approximately half of them were being prescribed unnecessary or excessive medications.

67. Clonidine impairs sustained attention and memory in Alzheimer's disease. Riekkinen Jr P, Laakso MP, Jakala P, Riekkinen P Jr. Neuroscience 1999;92(3):975-82. The results of this study indicate that clonidine at doses of 2 microg/kg significantly disrupts attention and short-term memory in approximately one-third of Alzheimer patients. The negative effects of clonidine on attention were observed only in tests that were demanding for the patients, while those requiring simpler processing remained unaffected.

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68. Psychotropic drug use and cognitive decline among older men and women. Dealberto MJ. et al. Int J Geriatr Psychiatry, 12(5):567-74 1997 May. The results of this study, conducted on a cohort of 1200 individuals without cognitive impairment at baseline, show that users of non-benzodiazepine psychotropic drugs have a 5-fold increased risk of cognitive decline compared to nonusers.

69. Benzodiazepine use and cognitive function among community-dwelling elderly. Hanlon JT, et al. Clin Pharmacol Ther 1998 Dec;64(6):684-92. The results of this study, conducted on 2765 elderly individuals living in the community and followed up for 3 years, show that current users of benzodiazepines experience significant worsening of memory function, compared to non-users. The association between benzodiazepine use and memory decline is dose-dependent, and exists with both short- and long-acting drugs.

70. Cognitive impairment in long-term benzodiazepine users. Golombok S, Moodley P, Lader M. Psychol Med 1988 May;18(2):365-74. The results of this study indicate that long-term use of benzodiazepines is associated with significant cognitive impairment, particularly for tasks involving sustained attention and visual-spatial ability.

71. Anterograde amnesia linked to benzodiazepines. Mejo SL. Nurse Pract 1992 Oct;17(10):44, 49-50. This article highlights that use of benzodiazepines is associated with disruption of longterm memory, a symptom that is often unrecognized by patients who take the drugs. The author concludes that is important that patients be fully informed on the side effects of treatment, and that the minimum possible dose be prescribed for the shortest period of time, in order to reduce the occurrence of treatment-induced adverse events.

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72. Benzodiazepine use as a cause of cognitive impairment in elderly hospital inpatients. Foy A, O'Connell D, Henry D, Kelly J, Cocking S, Halliday J. J Gerontol A Biol Sci Med Sci 1995 Mar;50(2):M99-106. The results of this study show that use of benzodiazepines significantly increases the risk of cognitive impairment in elderly individuals. The study was conducted on 418 individuals aged 59-88, with normal cognitive function upon admission to the hospital. During hospitalization, 10.8% of patients developed cognitive impairment. Patients who reported use of benzodiazepines were 3.5 times more likely to develop cognitive impairment, compared to nonusers. Overall, benzodiazepine use accounted for 30% of all cases of cognitive disruption.

73. Fatal myocardial infarction and use of psychotropic drugs in young women. Thorogood M. et al. Lancet, 340(8827):1067-8 1992 Oct 31. The results of this study show that current use of psychotropic drugs in women aged 16 to 39 is associated with a 17-fold higher incidence of fatal myocardial infarction, compared to nonuse.

74. Use of psychotropic drugs and risk of myocardial infarction: a case-control study in Finnish farmers. Penttinen J. et al. Int J Epidemiol, 25(4):760-2 1996 Aug. The results of this study, conducted on a cohort of 3172 male farmers, show that users of psychotropic drugs have a 2.5-fold increased risk of myocardial infarction, compared to nonusers. The risk of heart attack increased by 5.4-folds in users of antidepressants.

75. Psychotropic medication use and risk of epithelial ovarian cancer. Harlow BL; et al. Cancer Epidemiol Biomarkers Prev, 7(8):697-702 1998 Aug. The results of this study, conducted on cohort of 563 women with ovarian cancer and 523 controls, show that users of psychotropic drugs for 6 or more months had a 60% increased risk of invasive ovarian cancer, compared to nonusers. In women who first used psychotropic drugs before menopause for more than two years, the risk increased by almost three times.

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PSYCHOTROPIC DRUGS IN PREGNANCY

76. Psychotropic drug use during pregnancy: weighing the risks. Cohen LS. et al. J Clin Psychiatry, 59 Suppl 2():18-28 1998. This article discusses some of the risks associated with use of psychotropic drugs by pregnant women, which include malformations, neonatal toxicity, and neurological and behavioral impairment. Additionally, it emphasizes that since the safety and efficacy of these drugs in the expecting mother has never been tested, nor their use has been approved by the FDA, a careful evaluation of the risks and benefits of treatment should be conducted before psychotropic drugs are taken during pregnancy.

77. Psychotropic drug use in pregnancy and perinatal death. Laegreid L. et al. Acta Obstet Gynecol Scand, 71(6):451-7 1992 Aug. This study analyzed psychotropic drug use in a sample population of 73 mothers of dead infants and in a control cohort of mothers of surviving infants, and found that psychotropic drug use was significantly associated with perinatal death.

78. Use of psychotropic drugs and pregnancy outcome. Larivaara P; et al. J Clin Epidemiol, 49(11):1309-13 1996 Nov. The results of this study, conducted on a cohort of 7933 pregnant women and their 8030 babies, show that use of psychotropic drugs during pregnancy is significantly associated with an increased need for hospital observation. In particular, 80.8%, and 38.3% of regular and occasional psychotropic drug users required hospital observation, compared to 27.4% of nonusers. In addition, bleeding was significantly more frequent in users vs. nonusers (23% vs. 13%), and infant mean birth weight was significantly lower among regular users.

79. Neurodevelopment in late infancy after prenatal exposure to benzodiazepines--a prospective study. Laegreid L. et al. Neuropediatrics, 23(2):60-7 1992 Apr.

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This study evaluated neurodevelopment and growth in 17 children of mothers who used therapeutic doses of benzodiazepines (BZD) throughout pregnancy. Follow up was performed at 6, 10, and 18 months of age. Children exposed to BZD had slightly reduced head circumference at birth and throughout follow up, compared to children of women who were not exposed to BZD. Craniofacial abnormalities were present in 5 infants. Gross motor development was impaired at 6 and 10 months while fine motor development was impaired throughout follow up. Deviating muscle tone and movements were found more frequently in children exposed to BZD compared to controls. These data indicate that exposure to therapeutic levels of BZD during pregnancy is associated with a significantly higher risk of abnormal development in the offspring.

80. Mental development in late infancy after prenatal exposure to benzodiazepines--a prospective study. Viggedal G, Hagberg BS, Laegreid L, Aronsson M. J Child Psychol Psychiatry 1993 Mar;34(3):295-305. The results of this study show that continuous use of benzodiazepines during pregnancy is associated with significant impairment of mental development in the offspring.

81. Benzodiazepine use in pregnancy and major malformations or oral cleft: metaanalysis of cohort and case-control studies. Dolovich LR, et al. BMJ 1998;317:839-843 ( 26 September ). This article presents the results of a meta-analysis of 23 selected studies investigating whether use of benzodiazepine during the first trimester of pregnancy increases the risk of major malformations or oral cleft in the offspring. While cohort studies did not detect an increased incidence of major malformations or oral cleft, analysis of case-control studies revealed a 3-fold increase in incidence of major malformations and an 80% increase in incidence of oral cleft alone in the offspring of benzodiazepine users, compared to controls.

DRUGS, FALLS AND HIP FRACTURES

82. Injurious falls in nonambulatory nursing home residents: a comparative study of circumstances, incidence, and risk factors. Thapa PB. et al. J Am Geriatr Soc 1996 Mar;44(3):273-8. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 57

The results of this study show that ambulatory nursing home residents who take psychotropic drugs have a 2.5-fold increased risk of falls resulting in injuries, compared to those not on these drugs.

83. Psychotropic drugs and risk of recurrent falls in ambulatory nursing home residents. Thapa PB. et al. Am J Epidemiol 1995 Jul 15;142(2):202-11. The results of this study show that 36% of all recurrent falls in ambulatory nursing home residents can be attributed to psychotropic drug use.

84. Relationship between the administration of selected medications and falls in hospitalized elderly patients. Gales BJ. et al. Ann Pharmacother, 29(4):354-8 1995 Apr. The results of this study, conducted on a sample group of 100 patients aged 70 and older who fell and 100 control subjects of the same age, show that benzodiazepine use in fallers was 2.7 times more frequent that in non users. Sixty-five percent of patients who fell while taking long-acting benzodiazepines, were taking higher than recommended doses of the drug. Congestive heart failure, treatment with digoxin and use of 3 or more psychotropic drugs were all factors positively associated with an increased risk of falls.

85. Falls, injuries due to falls, and the risk of admission to a nursing home. Tinetti ME, et al. N Engl J Med 1997 Oct 30;337(18):1279-84. The results of this study, conducted on a sample group of 1103 elderly individuals living in the community, show that those who fall are at significantly increased risk of being admitted to a nursing home, compared to the remaining population. In particular, the risk of being admitted to a nursing home increases by 3 times in those with one noninjurious fall, by 5.5-times in those with multiple noninjurious falls, and by more than 10 times in those with one or more injurious fall. These data suggest that interventions aiming at reducing the incidence of falls can substantially reduce the number of admission to nursing homes.

86. Potential adverse outcomes of psychotropic and narcotic drug use in Canadian seniors. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 58

Ebly EM. et al. J Clin Epidemiol 1997 Jul;50(7):857-63. The results of this study, conducted on a large population of elderly individuals with intact cognition, show that the incidence of falls is 3 times greater in users of two or more psychotropic drugs, compared to nonuser (42.6% versus 13.9%). These data indicate that psychotropic drug-related adverse effects may significantly increase the risk of falls in elderly individuals.

87. Effects of central nervous system polypharmacy on falls liability in communitydwelling elderly. Weiner DK. et al. Gerontology 1998;44(4):217-21. The results of this study, conducted on a cohort of 305 community-dwelling elderly individuals, show that use of one psychotropic drug is associated with a 54% increased risk of falls, while use of two or more psychotropic drugs is associated with a 137% increased risk of falls. The authors conclude that the dose-response effect is indicative of a relation of causality between use of psychotropic drugs and falls.

88. Antidepressants and the risk of falls among nursing home residents. Thapa PB. et al. N Engl J Med 1998 Sep 24;339(13):875-82. The results of this study, conducted on a sample population of 2428 nursing home residents, show that use of the antidepressants tricyclics, serotonin-reuptake-inhibitors and trazodone, is associated with a 2.0-, 1.8- and 1.2-fold increased risk of falls, respectively.

89. Risk factors for falls as a cause of hip fracture in women. The Northeast Hip Fracture Study Group. Grisso JA. et al. N Engl J Med 1991 May 9;324(19):1326-31. The results of this study show that use of long-acting barbiturates in the elderly is associated with a 5.2-fold increased risk of hip fractures.

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90. Opioid analgesics and the risk of hip fracture in the elderly: codeine and propoxyphene. Shorr RI. et al. J Gerontol 1992 Jul;47(4):M111-5. The results of this study, conducted on a cohort of 4,500 elderly individuals and 24,041 matched controls, show that users of the commonly prescribed anti-pain medications codeine or propoxyphene have a 60% increased risk of hip fractures, compared to nonusers. The risk of hip fractures increases by 2.2-times in new users of the drugs, and by 2.6 times in those who take them in combination with a psychotropic drug. These findings are important, especially in consideration of the widespread prescribing of antipain medications to elderly individuals.

91. Cognitive impairment, drug use, and the risk of hip fracture in persons over 75 years old: a community-based prospective study. Guo Z. et al. Am J Epidemiol 1998 Nov 1;148(9):887-92. The results of this study, conducted on a sample group of 1,608 individuals aged 75 and older, show that those using the opioid analgesic propoxyphene have a two-fold increased risk of hip fractures, compared to nonusers. In addition, use of potassium supplements was associated with a 45% reduction in hip fracture risk.

92. Cyclic antidepressants and the risk of hip fracture. Ray WA, et al. Arch Intern Med 1991 Apr;151(4):754-6. The results of this study show that elderly individuals using tricyclic antidepressants have a 60% increased risk of hip fractures, compared to nonusers.

93. Use of selective serotonin-reuptake inhibitors of tricyclic antidepressants and risk of hip fractures in elderly people. Liu B, et al. Lancet 1998 May 2;351(9112):1303-7. The results of this study, performed on a sample group of 8,239 elderly individuals with hip fracture and five controls matched to each subject, show that use of the antidepressants selective serotonin-reuptake inhibitors, secondary-amine tricyclics and tertiary-amine tricyclics, was associated with a 2.4-, 2.2-, and 1.5-fold increased risk of

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hip fractures, respectively, compared to nonuse. New use of each class of drugs resulted in a further increase in the risk of hip fractures.

94. Benzodiazepines of long and short elimination half-life and the risk of hip fracture. Ray WA, et al. JAMA 1989 Dec 15;262(23):3303-7. The results of this study, conducted on a cohort of 4501 elderly individuals with hip fracture and 24,041 controls, show that use of long-acting benzodiazepines is associated with a 70% increased risk of hip fractures.

95. Effect of a single dose of diazepam on balance measures in older people. Cutson TM, Gray SL, Hughes MA, Carson SW, Hanlon JT. J Am Geriatr Soc 1997 Apr;45(4):435-40. The results of this study show that diazepam adversely affects balance control in elderly individuals. The researchers evaluated the effects of a single dose of diazepam on balance in 12 healthy individuals aged 65 and older. Administration of the drug was associated with prolongation of the latency time of the muscle of the lower leg in response to a sudden perturbation, and with impaired performance at neuropsychological tests of attention. These findings seem to confirm the epidemiological finding of an increased risk of falls associated with use of benzodiazepines.

96. Psychotropic drug use and the risk of hip fracture. Ray WA; Griffin MR; Schaffner W; Baugh DK; Melton LJ 3d. N Engl J Med, 316(7):363-9 1987 Feb 12. The results of this study, conducted on a cohort of 1021 elderly patients with hip fracture and 5606 controls, show that use of long-acting hypnotics-anxiolytics, tricyclic antidepressants, and antipsychotics drugs is associated with an 80%, 90%, and 2-fold increased risk of hip fractures, respectively, compared to nonuse. The risk of fractures increases with increasing doses of these drugs, thus suggesting a relation of causality between drug use and injurious falls.

97. Diuretic drug use and the risk for hip fracture. Heidrich FE, et al. Ann Intern Med 1991 Jul 1;115(1):1-6.

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The results of this study, conducted on a cohort of 462 elderly patients hospitalized for hip fractures and 462 matched controls, show that current use of thiazide diuretics is associated with a 60% increased risk of hip fractures, compared to nonuse. Use of the diuretic furosemide was associated with an almost 4-fold increased risk of fracture.

98. Psychotropics, thiazide diuretics and hip fractures in the elderly. Cumming RG. et al. Med J Aust 1993 Mar 15;158(6):414-7. The results of this study, conducted on a sample group of 209 individuals with hip fracture and 207 controls, show that use of the benzodiazepine temazepan is associated with a 3.5-fold increased risk of hip fractures, compared to nonuse. Intake of thiazide diuretics in this study was not associated with a higher risk of fractures.

99. Rheumatoid arthritis, corticosteroid therapy and hip fracture. Cooper C, et al. Ann Rheum Dis 1995 Jan;54(1):49-52. The results of this study show that patients with rheumatoid arthritis and those taking corticosteroids have a 2.0- and 2.7-fold increased risk of hip fractures, respectively, compared to patients without this condition and not using these drugs. After adjusting for functional impairment, the risk decreased in patients with RA, but remained high in those taking corticosteroids.

100. Hip fractures and fluoridation in Utah's elderly population. Danielson C, et al. JAMA 1992 Aug 12;268(6):746-8. The results of this large ecological study, conducted on all elderly individuals from three communities in Utah who presented with hip fractures over a 7-year period, show that men and women living in fluoridated areas had a 41% and 27% increased risk of hip fractures, respectively, compared to those living in areas without fluoridated water.

101. Quality of life related to fear of falling and hip fracture in older women: a time trade off study. Salkeld, G. et al. BMJ 2000;320:341-346 ( 5 February ).

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The results of this study, conducted on a sample group of 194 women aged 75 and older, show that 80% of them would rather die than lose their independence and be admitted to a nursing home after a bad hip fracture.

PSYCHOTROPIC DRUGS AND MOTOR VEHICLE ACCIDENTS

102. Psychoactive drugs and the risk of injurious motor vehicle crashes in elderly drivers. Ray WA. et al. Am J Epidemiol, 136(7):873-83 1992 Oct 1. The results of this study, conducted on a cohort of 16,262 individuals aged 65 and older, show that users of benzodiazepines have a 50% increased risk of motor vehicle crashes, compared to nonusers. Use of tricyclic antidepressants was associated with an over twofold increased risk of crashes, and the risk increased with increasing drug dosage, being 5.5-times higher in users of 125 mg or more of amitriptyline, compared to nousers.

103. Association of road-traffic accidents with benzodiazepine use. Barbone F, et al. Lancet 1998 Oct 24;352(9137):1331-6. The results of this study show that use of long half-life benzodiazepines (used to treat anxiety) and of short half-life hypnotics (zopiclone) is associated with an increased risk of motor vehicle crash in individuals aged 18 and older. The risk increases with increasing doses of benzodiazepine.

104. Benzodiazepine use among the elderly in the community. Kirby M, et al. Int J Geriatr Psychiatry 1999 Apr;14(4):280-4. The results of this study show that 17% of community-dwelling elderly individuals in Ireland take benzodiazepines, which are, in over 50% of cases, of the long-acting form. The high rate of prescription of long-acting benzodiazepines causes concern, since these drugs have been associated with an increased risk of hip fractures and motor vehicle crashes in the elderly.

ANTIPSYCHOTICS Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 63

105. Growth patterns in the developing brain detected by using continuum mechanical tensor maps. Thompson PM, Giedd JN, Woods RP, MacDonald D, Evans AC, Toga AW. Nature 2000 Mar 9;404(6774):190-3. The results of this study show that brain cells continue to grow and organize at least into puberty. The researchers scanned the brain of children at intervals of up to 4 years, from the age of 3 to 15 years. They observed waves of growth at the fiber system that relays information between the right and left side of the brain, throughout the follow-up period, with growth occurring predominantly in the frontal regions, associated with the planning of new actions, earlier in age, and subsequently in the mid- and posterior regions of the brain, where associative thinking and language are regulated. These data indicate that brain development can be affected throughout puberty, contradicting previous theories which viewed the brain as essentially organized by the time a child reach the age of 6. The effects of psychotropic drugs on the evolving brain must be carefully evaluated, since these drugs have the potential of interfering with its development.

106. A comparison of prazepam, diazepam, lorazepam and placebo in anxious outpatients in non-psychiatric private practices. Zung WW; et al. J Clin Psychiatry, 42(7):280-4 1981 Jul. The results of this double-blind, randomized, placebo controlled study, show that the anxiolytics prazepam, diazepam, lorazepam, or placebo were all effective in relieving anxiety and depression in patients predominantly depressed with anxiety, while only placebo and prazepam reduced both symptoms in patients predominantly anxious with depression. These data suggest that anxyolytics are no better than placebo in the management of patients with anxiety and depression.

107. Benzodiazepines for depression? A review of the literature. Birkenhager TK; et al. Int Clin Psychopharmacol, 10(3):181-95 1995 Sep This study shows that combination therapy with benzodiazepines and tricyclic antidepressants (TCA) for treatment of depression is not superior, beyond the first few weeks of treatment, to monotherapy with TCAs.

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108. Worsening of symptoms of multiple sclerosis associated with carbamazepine. Letter. Ramsaransing G, Zwanikken C, De Keyser J. BMJ 2000;320:1113 ( 22 April ). This article reports on the worsening of symptoms of multiple sclerosis associated with use of carbamazepine, a tricyclic drug used to treat some forms of pain, convulsions, epilepsy, and manic episodes. The case of five patients with severe aggravation of disease following initiation of treatment and with symptoms resolution after carbamazepine discontinuation is presented. In one case, the onset of new symptoms (loss of the ability to walk) was interpreted as progression of disease and the patient, rather than having carbamazepine treatment interrupted, was aggressively treated with intravenous corticosteroids without improvement. Only after being discharged from the hospital, carbamazepine was stopped and the patient resumed her ability of walking.

109. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomised multicentre study of treatment for eight weeks. Philipp M. et al. BMJ 1999;319:1534-1539 ( 11 Dec ). This double blind, placebo controlled study shows that the herbal supplement hypericum extract (St. John's Wort) (1050 mg per day) is as effective as the antidepressant imipramine (100 mg per day) in alleviating symptoms in moderately depressed patients. Furthermore while patients in the hypericum arm reported improvement in the physical scale of a quality of life questionnaire, patients in the imipramine arm did not. Patients taking hypericum experienced the same rate of adverse reactions of patients taking placebo, and less than half the rate of those taking imipramine.

THE HIGH COST OF MEDICAL CARE 49 Studies

1. Hospital expenditures in the United States and Canada. Redelmeier DA, et al. N Engl J Med 1993 Mar 18;328(11):772-8.

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The results of this study indicate that hospital costs in the U.S. are considerably higher than in Canada. In 1987, the cost of each patient' admission to an acute care hospital was 24% higher in the U.S. than in Canada, and 46% higher in California than in Ontario. Total hospital expenditures were significantly lower in Canada even though Canadian hospitals had more hospital beds (5.4 vs. 3.9 per 1000 individuals) more admissions (142 vs. 129 per 1000 individuals) and longer stays (11.2 vs. 7.2 days) than U.S hospitals. Higher administrative costs were partly responsible for the increase in hospital expenses observed in the U.S. Applying the same spending patterns of Canada would have saved to the U.S. over $30 billion in 1985 alone.

2. The cost of inappropriate admissions: a study of health benefits and resource utilization in a department of internal medicine. Eriksen BO, Kristiansen IS, Nord E, Pape JF, Almdahl SM, Hensrud A, Jaeger S. J Intern Med 1999 Oct;246(4):379-87. The results of this study show that approximately 1 every 4 patients are inappropriately admitted to the hospital. The study was conducted on 422 consecutive patients who were admitted to a teaching hospital over a 6-week period. In 102 of them (24%), the admission was judged to be inappropriate. The average cost of each inappropriate admission was estimated at $2532, significantly lower than that of appropriate admissions ($5800). Overall, unnecessary admissions accounted for 12% of the total hospital costs.

3. The costs of adverse drug events in hospitalized patients. Adverse Drug Events Prevention Study Group. Bates DW; et al. JAMA, 277(4):307-11 1997 Jan 22-29. The results of this study indicate that over a 6-month period, 190 of the 4108 admissions to a tertiary hospital occurred as a consequence of an adverse drug event (ADE). Of these, 60 were preventable. The authors estimated at $5.6 million the annual cost of all admissions for ADEs in a 700-bed teaching hospital, and at $2.8 million the cost of preventable ADEs. These data indicate that ADEs account for a substantial fraction of total hospital costs. Implementation of measures aimed at reducing the occurrence of these events would translate in significant health care savings and in reduction of patients' morbidity and mortality.

4. Involvement of HMO-based pharmacists in clinical rounds at contract hospitals. Yee DK; Veal JH; Trinh B; Bauer S; Freeman CH. Am J Health Syst Pharm, 54(6):670-3 1997 Mar 15.

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The results of this study indicate that the recommendations of a managed care pharmacist participating to clinical rounds saved, over a 14-month period, an estimated $523,907 to the hospital. These data indicate that inappropriate drug treatment is an important source of extra health care expenses in hospital settings.

5. Pharmacist participation on physician rounds and adverse drug events in the intensive care unit. Leape LL, et al. JAMA 1999 Jul 21;282(3):267-70. The results of this study, conducted in the intensive care unit of a teaching hospital, show that participation of a senior pharmacist to clinical rounds decreased the rate of preventable adverse events caused by prescription errors by 66%.

6. Impact of a pharmacist on medication discontinuation in a hospital-based geriatric clinic. Phillips SL; Carr-Lopez SM. Am J Hosp Pharm, 47(5):1075-9 1990 May. This study evaluated the effect of a pharmacist on doctors' drug prescription practices in a geriatric ambulatory care clinic. Before pharmacist intervention, 72 patients received 414 prescriptions, 246 of which were for drugs associated with adverse drug reactions in the elderly. After intervention, there was a 32% reduction in total number of prescription with a direct overall cost saving of $3872 over a six-month period.

7. Drug-related emergency department visits and hospital admissions. Prince BS; Goetz CM; Rihn TL; Olsky M. Am J Hosp Pharm, 49(7):1696-700 1992 Jul. The results of this study show that 2.9% of visits to the emergency department of a tertiary care hospital are due to drug-related problems. Twenty-four percent of these visits result in hospital admission, and the average cost of each admission is $8888.

8. Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality. Classen DC; Pestotnik SL; Evans RS; Lloyd JF; Burke JP. JAMA, 277(4):301-6 1997 Jan 22-29.

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The results of this study indicate that 2.43% of hospital admissions are complicated by adverse drug events (ADEs). ADEs are associated with a prolonged length of stay of 1.91 days, an increased cost of $2262 per event, and an almost doubled risk of death.

9. Medication errors: 1977 to 1988. Experience in medical malpractice claims. Kuehm SL; Doyle MJ. N J Med, 87(1):27-34 1990 Jan. This article shows that from 1977 to 1988, MIIENJ paid US$30,144,636 in indemnity from medical malpractice suits due to medication errors.

10. Pressure ulcers, hospital complications, and disease severity: impact on hospital costs and length of stay. Allman RM, Goode PS, Burst N, Bartolucci AA, Thomas DR. Adv Wound Care 1999 Jan-Feb;12(1):22-30. The results of this study, conducted on a sample population of 286 patients aged 55 and over, show that those who developed pressure ulcers had significantly increased length of hospital stay (21 vs. 13 days) and incidence of hospital-related infections (46% vs. 20%) and other complications (86% vs. 43%), compared to those who did not. Hospital costs for patients with incident pressure ulcers were estimated at $29,048, more than two-fold higher than the costs for patients without this ailment ($13,819).

11. Sedative-hypnotic use and increased hospital stay and costs in older people. Zisselman MH, Rovner BW, Yuen EJ, Louis DZ. J Am Geriatr Soc 1996 Nov;44(11):1371-4. The results of this study, conducted on a cohort of 856 consecutive elderly patients admitted to a tertiary care teaching hospital, show that those with sedative-hypnotic (S/H) use exceeding the Health Care Financing Administration (HCFA) guidelines had, compared to patients with S/H use within recommended values or not on these drugs, longer hospital stay (21.5 days vs 12.3 days vs 6.7 days), increased hospital costs ($29,245 vs $15,219 vs $7,516), and greater severity of illness. These data indicate that appropriate use of sedative-hypnotic drugs could reduce morbidity and substantially cut health care costs.

12. Expenditures for psychotropic medications in the United States in 1985. Zorc JJ. et al. Am J Psychiatry 1991 May;148(5):644-7. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 68

This study shows that, in 1985, the U.S. spent $1.45 billion in psychotropic drugs for outpatients. Sixty percent of this sum ($868 million) was spent for antianxiety and sedative-hypnotic medications, 18% for antipsychotics, and 17% for antidepressants.

13. The direct economic costs of insomnia in the United States for 1995. Walsh JK, Engelhardt CL. Sleep 1999 May 1;22 Suppl 2:S386-93. The results of this study show that in 1995, the U.S. spent $13.9 billion for the treatment of insomnia.

14. Reevaluation of continuous oxygen therapy after initial prescription in patients with chronic obstructive pulmonary disease. Oba Y, Salzman GA, Willsie SK. Respir Care 2000 Apr;45(4):401-6. The results of this study show that lack of reevaluation of the need of home oxygen therapy in patients with chronic obstructive pulmonary disease (COPD) costs the nation an estimated extra $106-$153 million per year. In the study, 57 patients with COPD were prescribed home oxygen therapy. Of the 55 that returned for follow-up, only 19 (35%) were properly evaluated as to the need for continuous oxygen therapy, and in approximately 60% of them, oxygen treatment was discontinued. These data indicate that the majority of patients with COPD assigned to home oxygen therapy are needlessly kept on treatment. The lack of reevaluation of patients' need for oxygen treatment goes against recommended guidelines issued by the Third Oxygen Therapy Consensus Conference, which recommend patients' reassessment within 1 to 3 months after initiation of oxygen therapy. This omission results in unnecessary discomfort for the patient and in an estimated extra health care expenses of $106 to $153 million per year in the U.S. alone.

15. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. Wolfe MM, et al. N Engl J Med. 1999 Jun 17;340(24):1888-99. Review. This article emphasizes that every year in the U.S., at least 103,000 individuals are hospitalized for serious gastrointestinal toxicity from nonsteroidal antiinflammatory drugs (NSAID) use, and an estimated 16,500 will not survive the complication. Based on these estimates, death from gastrointestinal complications of NSAIDs represents the 15th cause of death in the U.S. Unfortunately these figures are conservative since they do not take in account users of over-the-counter NSAIDs. The cost of NSAID gastrointestinal

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toxicity has been estimated at approximately $15,000 to $20,000 per hospitalization, leading to total annual health care expenses exceeding $2 billion.

16. Cost of medication-related problems at a university hospital. Schneider PJ, Gift MG, Lee YP, Rothermich EA, Sill BE. Am J Health Syst Pharm 1995 Nov 1;52(21):2415-8. This study estimated at $1.5 million the costs associated with drug-related complications in a medical center hospital during the year 1994.

17. Cost implications of malpractice and adverse events. Korin J. Hosp Formul 1993 Jan;28 Suppl 1:59-61. This study shows that each year approximately 5% of hospitalized patients develop hospital-acquired infections, for a total annual cost of $10 billion. Over three-quarters of these expenses are due to increased length of hospital stay for intravenous antibiotic therapy.

18. Notice to Readers: Fourth Decennial International Conference on Nosocomial and Healthcare-Associated Infections. MMWR, February 25, 2000 / 49(07);138. This article reports that every year in the U.S., approximately 2,000,000 patients develop hospital-acquired infections and 88,000 die from them. The cost of hospital-acquired infections has been estimated at $4.6 billion. These estimates are conservative, since they do not take into account infections occurring in patients in nursing homes, outpatient clinics, dialysis centers and other health care centers.

19. Selected aspects of the socioeconomic impact of nosocomial infections: morbidity, mortality, cost, and prevention. Jarvis WR. Infect Control Hosp Epidemiol, 17(8):552-7 1996 Aug. The results of this study indicate that every year in the U.S., approximately 2 million patients develop hospital-acquired infections (HAIs). Overall, 23.8 % to 50% of patients with hospital-acquired bloodstream infections and 14.8% to 71% of patients with hospital-acquired pneumonia die. The cost associated with each HAI is: $558 to $593 for Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 70

each urinary tract infection, $2,734 for each surgical site infection, $3,061 to $40,000 for each bloodstream infection, and $4,947 for each pneumonia.

20. Nosocomial bloodstream infection in critically ill patients. Excess length of stay, extra costs, and attributable mortality. Pittet D, Tarara D, Wenzel RP. JAMA 1994 May 25;271(20):1598-601. The results of this study show that the incidence of hospital-related bloodstream infections in the Surgical Intensive Care Unit (SICU) of a tertiary hospital is 2.67%. Mortality rates in patients with this complication are 50% versus 15% in matched controls. Length of stay in the hospital and in the SICU increases significantly in patients with bloodstream infection compared to controls (54 vs. 30 days and 15 days vs. 7 days, respectively). The cost attributable to this complication was estimated at approximately $40,000 per survivor.

21. Prolongation of hospital stay and extra costs due to hospital-acquired infection in a neonatal unit. Leroyer A, et al. J Hosp Infect 1997 Jan;35(1):37-45. The results of this study indicate that the incidence of hospital-acquired infections (HAIs) in a neonatology unit ias 5.5%. For each HAI, the mean extra length of stay per patient is 5.2 days and the mean extra cost per patient $10,440.

22. Costs of treating simple nosocomial urinary tract infection. Rutledge KA, McDonald HP Jr. Urology 1985 Jul;26(1 Suppl):24-6. The results of this study show that the annual national cost of hospital-acquired urinary tract infections is $1.8 billion (1985 values).

23. Infections in the hospitalized elderly. Gingrich D. Hosp Physician 1990 Jan;26(1):35-8. The results of this study show that hospital-acquired infections in the elderly are associated with high mortality rates and with health care costs of $4 billion per year (1990 values). Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 71

24. Otitis media-related antibiotic prescribing patterns, outcomes, and expenditures in a pediatric medicaid population Berman S; Byrns PJ; Bondy J; Smith PJ; Lezotte D. Pediatrics, 100(4):585-92 1997 Oct. This study evaluated the pattern of antibiotic prescribing in a sample population of 12,381 children with middle ear infection. This condition is the most frequent reason for prescribing antibiotics to children in the U.S., even though several studies have shown that they are no better than placebo in the management of children and infants with middle ear infections. The results of the study show that in 1991 and 1992, low-cost antibiotics accounted for 67% of the total antibiotic fills and for 21% of the total costs. High-cost antibiotics, on the other hand, accounted for 30% of the fills and for 77% of the total costs. The more expensive antibiotics had the same efficacy and were associated with a slightly higher incidence of adverse reactions compared to the less expensive ones. These data indicate that just switching choice of antibiotic in patients with middle ear infection could save almost two-thirds of the cost of antibiotic treatment without interfering with patient outcome.

25. Errors in the treatment of tuberculosis in Baltimore. Rao SN, Mookerjee AL, Obasanjo OO, Chaisson RE. Chest 2000 Mar;117(3):734-7. The results of this study show that private physicians often treat tuberculosis (TB) incorrectly, favoring the development of acquired drug resistance and multidrug resistant TB. The study was conducted on 110 patients diagnosed with TB in the city of Baltimore between 1994 and 1995. Almost 40% of patients treated by a private physician were prescribed the wrong treatment regimen, compared to 5% of those treated at the Baltimore City Health Department's Tuberculosis Clinic. Inappropriate management consisting of low-doses antibiotics and short treatment courses is an important cause of treatment failure and acquired antibiotic resistance. The authors estimated the costs of salvage of inadequate treatment at $180,000 per patient.

26. "Routine" preoperative studies. Which studies in which patients? Marcello PW, Roberts PL. Surg Clin North Am 1996 Feb;76(1):11-23 This article highlights that 60% of routine tests conducted on patients in preparation of their surgery are unnecessary and add an extra $18 billion to the annual health care bill. In addition, unnecessary tests cause harm resulting from complications associated with

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the testing procedure, or with the unnecessary treatment of patients who receive a false positive test result.

27. Unnecessary preoperative investigations: evaluation and cost analysis. Allison JG; Bromley HR. Am Surg, 62(8):686-9 1996 Aug. The results of this study indicate that two-thirds of the tests patients undergo in preparation of their surgery are unnecessary. The study evaluated prospectively the appropriateness of pre-operative testing in 60 randomly selected ambulatory surgery patients. Only one-third of tests had clinical indications and was therefore deemed appropriate. The cost of inappropriate tests was estimated at $47 to $80 per patient. The authors emphasize the need of changing obsolete practices.

28. Extraimmunization Among US Children. Feikema SM et al. JAMA 2000;283:1311-1317. The results of this study show that in the U.S., every year approximately 900,000 children aged 19-36 months (one fifth of all U.S. children in that age group) receive at least an extra immunization, leading to an excess cost of $26.5 billion. The investigators surveyed parents of 32,742 children and obtained information from 22,806 of them through their health care provider. They found that 21% of them had received at least one extra vaccination. Extra doses of vaccine, in addition to adding discomfort and stress to the baby, are associated with an increased risk of adverse reactions. The risk of adverse reactions is particularly high with extra doses of the diphtheria-tetanus vaccine, and there is evidence showing that extra doses of these vaccines can cause serious side effects. In addition extra immunizations add extra costs and labor to the health care system. This study estimated this excess cost at $26.5 billions. This estimate, however, is conservative, since it does not take in account the costs associated with vaccine handling and distribution, parent's travel time, treatment for adverse effects, or other indirect costs.

29. Cost-Utility Analysis of Screening Intervals for Diabetic Retinopathy in Patients With Type 2 Diabetes Mellitus. Vijan S; Hofer TP; Hayward RA. JAMA 2000;283:889-896. The results of this study show that screening for eye disease every other year or every three years can be as effective as screening annually to prevent blindness in patients with type 2 diabetes and no signs of eye deterioration. Current guidelines recommend yearly eye examination for diabetic patients on the basis of cost-effectiveness analyses Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 73

demonstrating an economic benefit associated with this practice. The authors of the study used a computer model to assess the costs and effectiveness of yearly versus extended screening intervals. The results of the study indicate that a high-risk diabetic patient aged 45 years with poor glycemic control is expected to gain 21 days of sight by attending screening visits annually, rather than every third year. On the other hand, a 65-year old low-risk diabetic patient with moderately well glycemic control is expected to gain 3 days of sight by undergoing screening annually, rather than every third year. Screening low-risk patients annually rather than every other year results in an additional cost of $123,580 for each year of quality life gained. These estimates show that annual eye screening produces little benefits in low-risk diabetic patients, while substantially increasing health care costs. The authors emphasize that current guidelines calling for yearly screening in patients with type 2 diabetes should be re-evaluated, and recommendations should be tailored to patients clinical status.

30. Costs of poison-related hospitalizations at an urban teaching hospital for children. Woolf A; Wieler J; Greenes D. Arch Pediatr Adolesc Med, 151(7):719-23 1997 Jul. The results of this study show that poison-related admissions to a single pediatric facility account for 0.9% of all pediatric hospital admissions and are associated with an estimated annual cost of $1 million. Acetaminophen, lead and antidepressants are the substances most frequently involved in poisoning.

31. Economic outcomes of a targeted intervention program: the costs of treating allergic rhinitis patients. Santos R, Cifaldi M, Gregory C, Seitz P. Am J Manag Care 1999 Apr;5(4 Suppl):S225-34. The results of this study, conducted on a cohort of 7,936 patients with symptoms of allergic rhinitis, show that each year one managed care provider (Lovelace Health Systems) spends approximately $2 million for the symptomatic treatment of this condition.

32. Cost effectiveness of low-molecular weight heparin versus warfarin following hip replacement surgery. Saunders ME; Grant RE. J Natl Med Assoc, 90(11):677-80 1998 Nov. This study compared the cost-efficacy of low-molecular-weight (LMW) heparin versus warfarin use for the prophylaxis of deep vein thrombosis and pulmonary embolism Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 74

following hip-replacement surgery. Use of LMW heparin was associated with a saving of $1,253 per patient and with a 0% versus 3% incidence of thrombo-embolic events, compared to warfarin. These data indicate that switching to LMW heparin could significantly cut health care costs and improve patient outcome.

33. Cost-effectiveness of routine radiation therapy following conservative surgery for early-stage breast cancer. Hayman JA; Hillner BE; Harris JR; Weeks JC. J Clin Oncol, 16(3):1022-9 1998 Mar. The results of this study show that in women aged 60 and older, radiation therapy after conservative surgery for early stage breast cancer adds nothing in terms of life expectancy while increasing the cost of therapy by $9,800 per patient.

34. Escalating costs for cancer chemotherapy. Nyman JV; Dorr RT; Hall GR. Am J Hosp Pharm, 38(8):1151-4 1981 Aug. The results of this study indicate that the annual cost of antineoplastic drugs for one hospital rose from $10,156 in 1973-1974 to $296,914 in 1979-1980, these amounts consisting of 5.74% and 16.74% of the hospital total drug budget, respectively. This increase was not justified by patient load, inflation, or amount of medication prescribed.

35. The costs of cancer care in the United States: implications for action. Schuette HL; Tucker TC; Brown ML; Potosky AL; Samuel T. Oncology (Huntingt), 9(11 Suppl):19-22 1995 Nov. This article emphasizes that the annual direct and indirect costs of cancer care are in the range of $100 billion, indicating the need to shift the costs toward more effective measures such as prevention.

36. Comprehensive discharge planning and home follow-up of hospitalized elders: a randomized clinical trial. Naylor MD, Brooten D, Campbell R, Jacobsen BS, Mezey MD, Pauly MV, Schwartz JS. JAMA 1999 Feb 17;281(7):613-20. This randomized study evaluated the outcome of a comprehensive discharge planning and home follow-up intervention program conducted by nurses from two urban hospitals Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 75

on a cohort of elderly patients at risk for hospital readmissions. Twenty-four weeks after discharge, patients in the intervention group, compared to those in the control group, showed decreased rate of hospital admissions (37% vs. 20%), decreased rate of multiple hospital readmissions (6.2% vs. 14.5%) and reduced length of hospital stay when readmitted (1.5 days vs. 4 days). Total Medicare reimbursement costs were about $0.6 million in the intervention group versus $1.2 million in the control group. These data indicate that preventive intervention in high-risk patients results in a 50% reduction in health care costs and in improved patient outcome.

37. Cost-effectiveness of colon cancer screening. Lieberman D. Am J Gastroenterol, 86(12):1789-94 1991 Dec. This study evaluated the cost-effectiveness of two different methods of colon cancer screening: sigmoidoscopy from age 50 with yearly testing for fecal occult blood (as recommended by the American Cancer Society) and colonoscopy. The cost of preventing one death from colon cancer was estimated to be $444,133 with sigmoidoscopy and $347,214 with colonoscopy.

38. Clinical and economic impact of oral ciprofloxacin as follow-up to parenteral antibiotics. Grasela TH Jr; et al. DICP, 25(7-8):857-62 1991 Jul-Aug. This study, conducted on a sample population of 766 patients initially treated with parenteral antibiotics for respiratory tract (RTI), skin or skin structure (SSS), bone or joint (BJI), and urinary tract infections (UTI) for a median of 4, 6, 6, and 7.5 days, respectively, shows that switching to oral antibiotic therapy shortened hospital stay and saved in drugs and hospitalization costs a total of $980,246.

39. Cost and morbidity associated with antibiotic prophylaxis in the ICU. Namias N; Harvill S; Ball S; McKenney MG; Salomone JP; Civetta JM. J Am Coll Surg, 188(3):225-30 1999 Mar. This study evaluated prospectively data on prophylactic antibiotic (PA) treatment in patients admitted to the Surgical Intensive Care Unit of a teaching hospital over a 19month period, to determine physicians' compliance to current guidelines recommending cessation of PA at 24 hours. In 61% of patients, PA therapy was continued beyond 24 hours. Patients receiving PA for more than 4 days had higher rates of bacteremias and

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line infections, compared to those with shorter antibiotic course. The cost of inappropriate antibiotic treatment in this patient population was estimated at $44,893.

40. Antimicrobial prophylaxis in surgical patients. Crossley K, Gardner LC. JAMA 1981 Feb 20;245(7):722-6. This study evaluated use of prophylactic antibiotics (PA) in a cohort of 1,021 surgical patients from 27 different hospitals. Only 41% of patients received PA in the four hours before surgery, and in one-third of patients PA continued for more than 72 hours. Reducing the time of PA treatment would save 18% to 50% of the total cost of perioperative antibiotic prophylaxis.

41. Surveillance of the use of antibiotic prophylaxis in surgery. Finkelstein R, Reinhertz G, Embom A. Isr J Med Sci 1996 Nov;32(11):1093-7. This study evaluated implementation of prophylactic antibiotic (PA) treatment two years after updated recommendations on its use were made available throughout the surgical wards of an Israeli hospital. In certain types of surgery, PA was prescribed systematically without indications for its use. In almost 50% of patients the first dose of PA therapy was not given at the appropriate timing; PA administration extended over the recommended 24 hours in 21% of cases and frequently consisted of unstandardized regimens. These data indicate high rates of inappropriate PA treatment. This phenomenon results in extra health care costs and contributes to the worldwide increase in antibiotic resistance.

42. Surgical infections and prophylactic antibiotics: 341 consecutive cases of gallbladder surgery in the era of laparoscopic surgery. Garcia N, Kapur S, McClane J, Davis JM. J Laparoendosc Adv Surg Tech A 1997 Jun;7(3):157-62. This study evaluated the appropriateness of prophylactic antibiotic (PA) treatment in a cohort of 341 consecutive patients admitted to the hospital for laparoscopic and open cholecystectomy. In 63.2% of cases PA was administered inappropriately. Seventy-three percent of patients received a large-spectrum antibiotic when a cheaper and narrower spectrum agent would have been adequate.

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43. Oral versus intravenous antibiotics for community acquired lower respiratory tract infection in a general hospital: open, randomised controlled trial. Chan R; Hemeryck L; O'Regan M; Clancy L; Feely J. BMJ, 310(6991):1360-2 1995 May 27. The results of this study, conducted on a cohort of 541 patients admitted to the hospital over a 1-year period for lower respiratory tract infections who had no immune system depression or severe infection, show that treatment with oral antibiotics is equally effective to intravenous antibiotic therapy as to patient clinical outcome and mortality, and is associated with reduced hospital length of stay. The authors estimated that if the 800 patients admitted every year to the hospital would be treated routinely with oral rather than intravenous antibiotics, the hospital could save approximately 176,000 pounds per year, and patients would benefit from early discharge.

44. Early transition to oral antibiotic therapy for community-acquired pneumonia: duration of therapy, clinical outcomes, and cost analysis. Omidvari K; de Boisblanc BP; Karam G; Nelson S; Haponik E; Summer W. Respir Med, 92(8):1032-9 1998 Aug. This randomized study evaluated the therapeutic efficacy and costs of conventional 7-day treatment with intravenous (IV) antibiotics for community-acquired pneumonia versus abbreviated 2-day course of IV antibiotics followed by oral antibiotics. Clinical course, cure rates and survival were similar in the two treatment groups. Oral therapy was associated with shorter hospital stay (7.3 versus 9.71 days) and reduced overall costs of care ($2953 vs. $5002 per patient).

45. Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Hoberman A, Wald ER, Hickey RW, Baskin M, Charron M, Majd M, et al. Pediatrics 1999 Jul;104(1 Pt 1):79-86. This randomized study evaluated the cost and efficacy of outpatient oral versus inpatient intravenous antibiotic therapy in the treatment of children 1 to 24 months old with febrile urinary tract infection. Oral therapy was judged to be as safe and effective as intravenous therapy, and its use was associated with an over 50% reduction in overall costs ($1473 per patient for oral therapy versus $3577 for intravenous therapy).

46. The cost of antibiotics in treating upper respiratory tract infections in a medicaid population.

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Mainous AG 3rd; Hueston WJ. Arch Fam Med, 7(1):45-9 1998 Jan-Feb. Antibiotic therapy for nonspecific upper respiratory tract infections (URIs) is nonindicated and ineffective, and increases the occurrence of antibiotic-resistant pathogens. This study evaluated antibiotic prescribing practices for URIs in a sample population of 50,000 Medicaid recipients. Antibiotics were prescribed in 60% of outpatient visits and in 48% of emergency department episodes. In 23% and 9% of the outpatient and emergency department visits, respectively, a prescription for antihistamines was filled. These data indicate that contrary to published guidelines, physicians routinely prescribe antibiotics in over 50% of patients with upper respiratory infections, resulting in significant extra health care costs and in the favoring of the spread of antibiotic-resistant bacterial strains.

47. Antibiotic administration in patients undergoing common surgical procedures in a community teaching hospital: the chaos continues. Gorecki P, Schein M, Rucinski JC, Wise L. World J Surg. 1999 May;23(5):429-32. This study evaluated the appropriateness of antibiotic treatment in a randomly selected sample of 211 patients undergoing elective (132 patients) or emergency (79 patients) surgery in a teaching hospital during 1996. Seventy-four percent of patients received inappropriate antibiotic treatment. The total cost of prolonged antibiotic treatment for this cohort was estimated at $18,533.

48. Decrease in expenditures and selected nosocomial infections following implementation of an antimicrobial-prescribing improvement program. Frank MO, Batteiger BE, Sorensen SJ, Hartstein AI, Carr JA, McComb JS, et al. Clin Perform Qual Health Care 1997 Oct-Dec;5(4):180-8 The results of this study show that implementation of an antimicrobial-prescribing improvement program in an academic medical center was associated with a substantial reduction in antibiotic use, which translated in cost savings of $390,000 in 1994 alone, compared to the costs prior to program implementation. In addition, decreased use of antimicrobial agents was associated with an over 50% reduction in the rate of several hospital-acquired infections.

49. Government orders inquiry as price of generic drugs soars. Jones, J. BMJ 1999;319:1151 ( 30 October ). Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 79

This article reports on the recent sharp increase in the price of generic drugs in UK. In 1999 for example, the price of common drugs such as amoxicillin, furosemide, and thyroxine, was 4-8 times higher than in 1998. This rise could result in extra annual health care expenses of $320 million.

MALNUTRITION 30 Studies
1. Prevalence of malnutrition in general medical patients. Bistrian BR, Blackburn GL, Vitale J, Cochran D, Naylor J. JAMA 1976 Apr 12;235(15):1567-70. This study shows that in 1976, the prevalence of malnutrition in hospitalized patients of the general wards of an urban teaching hospital, was 44% or greater. Thirty-four percent of patients had levels of lymphopenia likely to be associated with reduced cellular immunity.

2. Incidence and recognition of malnutrition in hospital. McWhirter JP, Pennington CR. BMJ 1994 Apr 9;308(6934):945-8. This 1994 study shows that 40% of patients admitted to an acute teaching hospital were malnourished, and in 78% of them nutritional status further deteriorated during hospital stay. In addition, two thirds of all patients lost weight during hospital stay.

3. In 1995 a correlation between malnutrition and poor outcome in critically ill patients still exists. Giner M, Laviano A, Meguid MM, Gleason JR. Nutrition 1996 Jan;12(1):23-9. This study shows that 43% of 129 patients admitted to the intensive care unit of a hospital, were malnourished. Length of hospital stay, complications and number of deaths were greater in malnourished compared to well-nourished patients, and malnourished patients with less severe illnesses had worse clinical outcomes than sicker, wellnourished patients. The study also showed that malnutrition in patients who underwent surgery developed mainly during their preoperative stay in general medicine wards.

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4. In-hospital malnutrition: indications of postoperative evolution. Farre Rovira R, Frasquet Pons I, Ibor Pica JF. Nutr Hosp, 13(3):130-7 1998 May-Jun. This study shows that, after admission to the hospital, the number of patients with belownormal levels of serum albumin doubles, and the number of those with below-normal levels of body weight and body mass index, triplicates. Nutritional status worsens as length of hospital stay increases.

5. Protein-energy undernutrition among elderly hospitalized patients: a prospective study. Sullivan DH, Sun S, Walls RC. JAMA 1999 Jun 2;281(21):2013-9. This study evaluated whether hospitalized patients receive adequate nutritional intake during hospital stay and whether eventual nutritional deficits translate in increased mortality rates. The results of the study, conducted on 497 elderly patients during a 4year period, showed that 21% of patients consumed less than 50% of their estimated maintenance energy requirements, and this was partly due to the fact that patients were frequently ordered to eat nothing by mouth but did not receive nutritional supplementation by other routes. Patients with low energy intake were 8 times more likely to die while being in the hospital and 3 times more likely to die within 90 days, compared to patients with normal energy intake. These findings indicate that during their hospital stay, elderly patients often receive largely inadequate nutrient intake -a practice that seems associated with a significant negative impact on their overall survival.

6. Malnutrition and clinical outcomes: the case for medical nutrition therapy. Gallagher-Allred CR, Voss AC, Finn SC, McCamish MA. J Am Diet Assoc 1996 Apr;96(4):361-6, 369. This article reports on the results of several studies conducted on over 1,327 patients, indicating that 40% to 55% of hospitalized patients are either malnourished or at risk for malnutrition, and 12% of them are severely malnourished. Postoperative complications and mortality occur 2-3 times more often, and hospital costs are 35% to 75% higher, in malnourished compared to well-nourished patients.

7. Prevalence of malnutrition in nonsurgical hospitalized patients and its association with disease complications. Naber TH, et al. Am J Clin Nutr 1997 Nov;66(5):1232-9.

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The results of this study, conducted on 155 patients admitted to the internal medicine ward of a hospital, show that the prevalence of malnutrition in this cohort, according to the Maastricht Index (which evaluates ideal weight together with prealbumin, albumin, and lymphocytes levels) was 62%. Rates of complications were 3 times higher in malnourished versus well-nourished patients.

8. The relationship between clinical assessments of nutritional status and adverse outcomes in older hospitalized medical patients. Covinsky KE, Martin GE, Beyth RJ, Justice AC, Sehgal AR, Landefeld CS. J Am Geriatr Soc 1999 May;47(5):532-8. This study evaluated the nutritional status of 369 patients aged 70 years or more admitted to a general ward of a tertiary care hospital, and found that 60% of them were well nourished, 25% were moderately malnourished, and 16% were severely malnourished. After controlling for severity of disease, presence of coexisting diseases, and functional status on admission, the researchers showed that severely malnourished patients were 2.8 times more likely to die and 3.2 times more likely to be admitted to a nursing home within a year of discharge, compared to well nourished patients.

9. Protein-energy undernutrition and the risk of mortality within six years of hospital discharge. Sullivan DH, Walls RC. J Am Coll Nutr 1998 Dec;17(6):571-8. The results of this study show that protein-energy malnutrition is the single strongest predictor of long-term mortality in elderly individuals discharged from the hospital. In the study, 322 elderly patients were followed for 6 years after being discharged from the hospital to evaluate the effects that nutritional status had on their long-term survival. Patients were defined as being at risk for malnutrition if they had serum albumin levels below 3.0 g/dL or body mass index below 19. Being at risk for malnutrition was the strongest predictor of death in the following 6 years. A diagnosis of congestive heart failure, being discharged to a health care facility, age and marital status were not as strongly associated with mortality as protein-energy malnutrition.

10. Economic impact of malnutrition: a model system for hospitalized patients. Reilly JJ Jr, Hull SF, Albert N, Waller A, Bringardener S. JPEN J Parenter Enteral Nutr 1988 Jul-Aug;12(4):371-6. This retrospective study, conducted on 771 individuals admitted to two acute care hospitals, shows that the rate of likelihood of malnutrition was 59% in medical wards and Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 82

48% in surgical wards. Rates of minor and major complications were 2.6 and 3.4 times higher, respectively, in patients with likelihood of malnutrition compared to those without it. Likelihood of malnutrition was associated with a 3.8-fold increased risk of death. Suspected malnutrition was also associated with increased length of hospital stay and increased excess average costs of $1738 to $3557 per patient. The impact of a nutritional intervention program could not be assessed, because too few patients had received it.

11. High-quality nutritional interventions reduce costs. Smith PE, Smith AE. Healthc Financ Manage 1997 Aug;51(8):66-9. This article reports on the results of a survey of 19 hospitals indicating that length of hospital stay decreases by approximately 2 days in patients who receive optimal nutritional care. The survey also revealed that only 7.5% of patients at risk for malnutrition receive optimal nutritional intervention, and this omission results in an increased cost of $1.064 per patient at risk of malnutrition.

12. Relationship of nutritional status to length of stay, hospital costs, and discharge status of patients hospitalized in the medicine service. Chima CS, Barco K, Dewitt ML, Maeda M, Teran JC, Mullen KD. J Am Diet Assoc 1997 Sep;97(9):975-8. This study, conducted on all 173 individuals admitted to three medicine units during a 1month period, shows that those who, upon admission, were classified as being at risk for malnutrition, had, compared to patients not a risk of malnutrition, higher hospital length of stay (6 days vs. 4 days), higher hospitalization costs ($6,196 vs. $4,563), and higher home health care needs, even if 91% of them received nutrition intervention during hospitalization.

13. The five-year evolution of a malnutrition treatment program in a community hospital. Brugler L, DiPrinzio MJ, Bernstein L. Jt Comm J Qual Improv 1999 Apr;25(4):191-206. This study shows that implementation of a malnutrition treatment program in a 395-bed community hospital in Delaware, resulted in reduction of average patient length of stay from 10.8 to 8.2 days, in decrease of incidence of major complications from 75.3% to 17.5%, and in reduction of 30-day hospital re-admission rates from 16.5% to 7.15.

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14. Effect of malnutrition after acute stroke on clinical outcome. Davalos A, et al. Stroke, 27(6):1028-32 1996 Jun. This study, conducted on a cohort of 104 patients with acute stroke, shows that the number of individuals with malnutrition increased from 16.3% at admission to 26.4% after a week in the hospital. Malnourished patients had increased incidence of infections and bedsores. In addition, patients with malnutrition after a week of hospitalization had a 3.5-fold increased risk of poor outcome, regardless of their age and nutritional status at admission.

15. Influence of nutritional status on clinical outcome after acute stroke. Gariballa SE, Parker SG, Taub N, Castleden CM. Am J Clin Nutr 1998 Aug;68(2):275-81. This study shows that the nutritional status of patients admitted to the hospital over a 15month study period for acute stroke, deteriorated significantly during hospital stay. Malnutrition was significantly associated with increased risk of infections and poor functional outcome, and was a strong predictor of mortality in the 3 months after the stroke.

16. Clinical significance of preoperative nutritional status in 215 noncancer patients. Warnold I, Lundholm K. Ann Surg 1984 Mar;199(3):299-305. The results of this study, conducted on 215 patients hospitalized for surgery, show that those with low nutritional status had a two-fold increase in rates of post-operative complications and in length of hospital stay, compared to those with normal nutritional status. The difference in rate of complications was particularly evident for major complications, which occurred in 31% of undernourished patients, compared to 9% of well-nourished subjects.

17. Outcomes of undernutrition in patients in the community with cancer or cardiovascular disease. Edington J, Winter PD, Coles SJ, Gale CR, Martyn CN. Proc Nutr Soc 1999 Aug;58(3):655-61. The results of this study indicate that even low levels of malnutrition are associated with significantly increased rates of morbidity and mortality in individuals with cancer or cardiovascular diseases. In the study, conducted on 10,128 individuals aged 18 and older Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 84

with a diagnosis of cancer or cardiovascular disease, those with body mass index (BMI) levels below 20 kg/m2 had higher rates of physician consultations and higher rates of death, compared to those with higher levels of BMI. Poor nutritional status was strongly associated with increased risk of hospitalization in patients with cardiovascular disease.

18. Impact of body mass index and albumin on morbidity and mortality after cardiac surgery. Engelman DT, et al. J Thorac Cardiovasc Surg 1999 Nov;118(5):866-73. The results of this study indicate that patients with albumin levels below 2.5 g/dL and body mass index below 20 kg/m2 undergoing cardiac bypass surgery have significantly higher rates of post-operative morbidity and mortality, compared to those with normal values of both parameters.

19. Nutritional status is a prognostic factor for survival in ALS patients. Desport JC, Preux PM, Truong TC, Vallat JM, Sautereau D, Couratier P. Neurology 1999 Sep 22;53(5):1059-63. The results of this study show that patients with amyotrophic lateral sclerosis (ALS) with malnutrition have a 7.7-fold increased risk of death, compared to well-nourished patients, independently of neurological scores and type of ALS. The authors recommend increased surveillance of nutritional status in patients with this disease.

20. The impact of nutritional status on the outcome of lung volume reduction surgery: a prospective study. Mazolewski P, Turner JF, Baker M, Kurtz T, Little AG. Chest 1999 Sep;116(3):693-6. The results of this study indicate that patients with end stage emphysema and with belownormal levels of body mass index (BMI) undergoing lung surgery have significantly increased post-operative morbidity and length of hospital stay, compared to patients with normal levels of BMI. This study shows that body mass index value is a good indicator of nutritional status and a simple way to screen individuals at risk of nutritional deficiencies. The authors suggest that correction of nutritional deficiencies may translate in lower rates of hospital morbidity, length of stay, and health care costs in this group of patients.

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21. Malnutrition in childhood lymphoblastic leukemia: a predictor of early mortality during the induction-to-remission phase of the treatment. Mejia-Arangure JM, et al. Arch Med Res 1999 Mar-Apr;30(2):150-3. The results of this study show that malnourished children undergoing chemotherapy for acute lymphoblastic leukemia (ALL) have a 2.6-fold increased risk of death, compared to well-nourished children. The risk of mortality increases with increased severity of nutritional deficit.

22. Disability is associated with malnutrition in institutionalized elderly people. The I.R.A. Study. Istituto di Riposo per Anziani. Romagnoni F, et al. Aging (Milano) 1999 Jun;11(3):194-9. The results of this study indicate that disability in elderly patients is strongly associated with the presence of anthropometric and plasma measurements indicative of malnutrition. This association exists independently of age, gender, and presence of coexisting illness or other confounding factors. The authors highlight the importance of correcting nutritional imbalances in the management of elderly disabled patients.

23. Body mass index and mortality among older people living in the community. Landi F, et al. J Am Geriatr Soc 1999 Sep;47(9):1072-6. The results of this study show that elderly individuals living in the community who have body mass index (BMI) levels below 22 Kg/m2 (a sign of malnutrition) have a 20% increased risk of being dependent in one or more Activities of Daily Living and a 15% increased risk of death, compared to individuals with normal BMI levels.

FOLLOWING IS A SERIES OF STUDY SHOWING THE EFFECTS OF NUTRITIONAL SUPPLEMENTATION ON MORBIDITY AND MORTALITY.

24. Dietary supplementation in elderly patients with fractured neck of the femur. Delmi M, Rapin CH, Bengoa JM, Delmas PD, Vasey H, Bonjour JP. Lancet 1990 Apr 28;335(8696):1013-6.

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The results of this study show that elderly patients hospitalized with a fracture of the neck of the femur who underwent nutritional supplementation had approximately half the rates of complications and death, compared to those who did not receive dietary supplementation. The study was conducted on 59 elderly patients who were randomly assigned to receive daily for an average of 32 days an oral nutritional supplement (27 patients), or no supplementation (32 patients). Most patients had nutritional deficiencies upon admission. Outcome was favorable in 56% of supplemented patients, compared to 13% of those not supplemented. In the supplemented group, 44% of patients experienced complications or death, compared to 87% of patients in the non-supplemented group. These differences persisted 6 months after the occurrence of the fracture. Average length of hospital stay was 24 days in the supplemented group, and 40 days in the nonsupplemented group. These findings indicate that daily oral supplementation cuts length of hospital stay and rates of complications and death by half, in elderly patients with fractured neck of the femur.

25. Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects. Chandra RK. Lancet 1992 Nov 7;340(8828):1124-7. The results of this study show that supplementation with modest physiological amounts of nutrients improves immune status and significantly reduces rates of infections in elderly individuals. The study was conducted on 96 healthy elderly subjects who were randomized to receive a nutritional supplement containing vitamins and trace elements or a placebo pill. After 12 months, immune function was improved, compared to baseline values, in individuals who had received nutritional supplementation, but not in those receiving placebo. In addition, those who received the supplement, spent considerable less time being ill from infectious diseases, compared to control subjects who received placebo (23 days versus 48 day per year). These findings indicate that a simple nutritional supplement is efficacious in improving immune status and significantly decreasing rates of infections in elderly individuals.

26. Vitamin C depletion and pressure sores in elderly patients with femoral neck fracture. Goode HF, Burns E, Walker BE. BMJ 1992 Oct 17;305(6859):925-7. The results of this study show that vitamin C concentration in elderly patients hospitalized with fractured neck of the femur who developed pressure ulcers is approximately half that of patients who did not develop this complication, indicating that vitamin C depletion may be an important factor in the etiology of pressure ulcers in the elderly.

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27. Impact of trace elements and vitamin supplementation on immunity and infections in institutionalized elderly patients: a randomized controlled trial. MIN. VIT. AOX. geriatric network. Girodon F, et al. Arch Intern Med 1999 Apr 12;159(7):748-54. The results of this double-blind, placebo-controlled study conducted on 725 institutionalized patients aged 65 and older, show that supplementation with zinc and selenium is associated with a significant reduction of the incidence of respiratory tract infections.

28. The clinical effects of vitamin C supplementation in elderly hospitalised patients with acute respiratory infections. Hunt C, Chakravorty NK, Annan G, Habibzadeh N, Schorah CJ. Int J Vitam Nutr Res 1994;64(3):212-9. The results of this randomized, double-blind, placebo controlled trial show that elderly patients admitted to the hospital for acute respiratory infections who receive daily supplementation of 200 mg of vitamin C, had significantly improved disease course, compared to those who received placebo. The positive effects of vitamin C supplementation were particularly evident in patients who were most severely ill, and who often had very low levels of the vitamin on admission.

29. Routine protein energy supplementation in adults: systematic review. Potter, J et al. BMJ 1998;317:495-501. This study reviewed 30 randomized trial conducted on 2,062 patients, evaluating the impact of routine oral and enteral nutritional supplementation on survival in adult hospitalized patients. Patients who received nutritional supplementation showed significant improvements in body weight and mid-arm muscle circumference, and had an overall 36% increased rate of survival, compared to untreated patients. These findings indicate that protein calorie supplementation improves nutritional status in adults and significantly lowers fatality rates.

30. Care of dying patients in hospital. Mills M, Davies HT, Macrae WA. BMJ 1994 Sep 3;309(6954):583-6. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 88

This study assessed the level of care received by dying patients in 13 wards of four large university hospitals in Scotland and concluded that patients basic needs before dying were left unmet: thirst remained unquenched, oral hygiene was poor, eating was not encouraged. Contact with patients by nurses and doctors was minimal and patient isolation increased as death advanced. Over half of the patients remained conscious until shortly before death.

MEDICAL ERRORS & ADVERSE DRUG REACTIONS 76 Studies


1. Epidemiology of medical error. Weingart, SN. et al. BMJ 2000;320:774-777 ( 18 March ). This article presents a review of current available information on the incidence and nature of medical errors in U.S. hospitals. Medical errors have been estimated to kill 48,00098,000 Americans each year, and to injure an additional 1 million. These data, however, are likely to significantly underestimate the real extent of the problem, since they only refer to hospital patients, and are not inclusive of errors occurring in nursing homes and other health care settings. In addition, the methods used by investigators to identify adverse medical events can significantly affect the estimates of their prevalence. In a landmark study conducted by the University of Harvard, for example, where the researchers used a stringent definition of error, it was calculated that 3.7% of hospitalized patients experienced an adverse event, which was caused by errors -and was therefore preventable- in two-thirds of cases. In another study, where errors were detected through a computerized model, the incidence of adverse drug reactions in hospitalized patients was estimated to be 1.7%. On the other hand, when Bates and colleagues determined the incidence of adverse drug reactions by reviewing patients' medical charts and by conducting interviews with physicians, they found that 6.5% of hospitalized patients developed an adverse drug reaction, and another 5.5% developed a potential adverse drug reaction; these events were found to be caused by errors in 28% of cases. Furthermore, when trained observers who visited a general surgery unit where asked to evaluate the rate of adverse events, they reported that almost 50% of patients experienced an adverse event, which was serious in 18% of cases. Little research has been conducted on the extent of medical error outside hospital settings. One study revealed that drug-related complications occur in 18% of outpatients. Another study calculated that every year treatment-related complications result in 116 million additional physicians visits, 76 million prescriptions, 17 million emergency department visits, 8 million hospital admissions, 3 million long-term care facility admissions, and 200,000 additional deaths, for a cost of $76.6 billion. These data indicate that the extent of injury caused by preventable errors occurring in health care settings is enormous, and the real dimension of the problem is largely unknown.

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2. Reporting and preventing medical mishaps: lessons from non-medical near miss reporting systems. Barach, P. and Small S. BMJ 2000;320:759-763 ( 18 March ). This article reports on some of the data that emerged from the results of two studies conducted by the Institute of Medicine showing that, every year, approximately 100,000 patients die needlessly in the hospital as a result of errors in medical management, and many more are injured. These data, already alarming, become even more preoccupying when considering that, as the article highlights, 50%-96% of adverse events are not reported. These data indicate that preventable deaths from errors in medical management have reached endemic proportions, and that the extent of the injury is largely underestimated.

3. To Err Is Human: Building a Safer Health System. Kohn L., Corrigan J., and Donaldson M., Editors; Committee on Quality of Health Care in America, Institute of Medicine. http://www.iom.edu The Institute of Medicine (IOM) committee released a report on November 29, 1999 on medical errors in U.S. hospitals. A medical error was defined as "the failure to complete a planned action as intended or the use of a wrong plan to achieve an aim". The report presented the results from two large studies revealing that medical errors occurring in the hospital kill an estimated 44,000 (based on one study) or 98,000 (based on the second study) Americans each year. These estimates do not include errors that may arise in settings other than the hospital such as outpatient clinics, retail pharmacies, nursing homes, home care, and day-surgery clinics. Even considering only the most conservative figure (44,000 deaths per year), medical errors would be the eight leading cause of death, killing more people than breast cancer, AIDS or traffic accidents. The yearly cost resulting from such errors has been estimated at approximately $9 billion. Many of these errors are avoidable, and the IOM called for a 50% reduction in errors over the next 5 years. According to the report, systems designed to ensure public safety are over a decade behind in the health care industry compared to other high-risk industries.

4. Reducing errors in medicine. Leape LL. BMJ 1999;319:136-137 ( 17 July ). This article reports on previous studies demonstrating that injuries from medical care occur in 3.7% to 6.7% of hospital admissions, and are fatal in 13.6% of cases. Over half of these injuries are preventable. From these data it is deduced that, in the U.S., more than 120,000 individuals die each year while in the hospital from errors that are Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 90

avoidable. The cost of a preventable medication error has been estimated at approximately $4,700 per event.

5. Medication-prescribing errors in a teaching hospital. A 9-year experience. Lesar TS, Lomaestro BM, Pohl H. Arch Intern Med, 157(14):1569-76 1997 Jul 28. In this study 11,186 medication-prescribing errors with a potential for adverse patient outcome were detected and averted by a staff pharmacist of a teaching hospital over a 9year period. The number of detected errors increased from 522 in the year 1987 to 2115 in 1995, with a significant increased rate of errors per order written, per admission and per patient/day.

6. Factors related to errors in medication prescribing. Lesar TS, Briceland L, Stein DS. JAMA, 277(4):312-7 1997 Jan 22-29. In this study, conducted on a 631-bed tertiary care teaching hospital, 2103 errors with a potential for adverse patient consequences were detected and averted over a 1-year period. Overall, the rate of errors was 3.99 per 1000 written orders.

7. Medication prescribing errors in a teaching hospital. Lesar TS, Briceland LL, Delcoure K, Parmalee JC, Masta-Gornic V, Pohl H. JAMA, 263(17):2329-34 1990 May 2. In this study, conducted in a tertiary care teaching hospital, researchers detected and averted a rate of 3.13 medication-prescribing errors per 1000 physicians' written orders. In 58% of cases, the errors had a potential for adverse patient consequences.

8. A look into the nature and causes of human errors in the intensive care unit. Donchin Y, Gopher D, Olin M, Badihi Y, Biesky M, Sprung CL, Pizov R, Cotev S. Crit Care Med, 23(2):294-300 1995 Feb. In this study, an estimated 1.7 errors per patient per day were detected in the intensive care unit (ICU) of a teaching hospital. For the whole ICU, an average of two severe or potentially detrimental errors occurred each day.

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9. Relationship between medication errors and adverse drug events. Bates DW, Boyle DL, Vander Vliet MB, Schneider J, Leape L. J Gen Intern Med 1995 Apr;10(4):199-205. This study evaluated the frequency of medication errors in a sample population of 379 consecutive patients admitted to an urban tertiary care hospital. On average, 0.3 medication errors per patient occurred each day, with half of these errors consisting of missing doses. About 1% of the medication errors resulted in adverse drug events.

10. A computer alert system to prevent injury from adverse drug events: development and evaluation in a community teaching hospital. Raschke RA, et al. JAMA 1998 Oct 21;280(15):1317-20. In this study, a computer alert system was used in a 650-bed university hospital to identify prescription errors with the potential of causing adverse drug events. Errors with such potential were detected at a rate of 64 per 1000 admissions and were unrecognized by physicians prior to notification in 44% of cases.

11. Improving prescribing patterns for the elderly through an online drug utilization review intervention: a system linking the physician, pharmacist, and computer. Monane M, Matthias DM, Nagle BA, Kelly MA. JAMA 1998 Oct 14;280(14):1249-52. In this study, a computer alert system was used to evaluate the appropriateness of medications prescribing in a cohort of 23,269 elderly patients. Overall, the system fired 43,007 alerts for suboptimal medication. In 56% of cases, a pharmacist was able to notify the alert to a physician. Of the notified alerts, 24% resulted in change to a more appropriate drug.

12. Inappropriate medication is a major cause of adverse drug reactions in elderly patients. Lindley CM, et al. Age Ageing 1992 Jul;21(4):294-300. This study evaluated the rate of prescribing of drugs with absolute contraindications or unnecessary, in a sample population of 416 elderly patients consecutively admitted to a teaching hospital. On admission, 11.5% of patients were receiving drugs with absolute contraindications, and 27% were receiving drugs that were unnecessary. Adverse drug reactions (ADRs) occurred in 27% of patients on medication, and half of these reactions Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 92

were due to drugs with absolute contraindications or unnecessary. ADRs were the cause of hospital admission in 6.3% of patients, and were due to inappropriate prescribing (and were therefore avoidable) in half of the cases.

13. Inappropriate medication prescribing for the elderly by office-based physicians. Aparasu RR, Fliginger SE. Ann Pharmacother 1997 Jul-Aug;31(7-8):823-9. The results of this study show that in 1992, 7.6% of individuals aged 65 and greater received at least 1 of 20 medications that should never be prescribed to the elderly, by their office-based doctor. The authors emphasize how the high rates of inappropriate prescribing by office-based doctor raises concerns on the quality of care they deliver.

14. Inappropriate drug prescriptions for elderly residents of board and care facilities. Spore DL, Mor V, Larrat P, Hawes C, Hiris J. Am J Public Health 1997 Mar;87(3):404-9. The results of this study indicate that a minimum of 20% to 25% of elderly individuals living in board and care facilities receive at least one inappropriate medication (a drug that should be entirely avoided in this age group).

15. Prescription of contraindicated and interacting drugs in elderly patients admitted to hospital. Gosney M, et al. Lancet 1984 Sep 8;2(8402):564-7. The results of this study, conducted on 573 elderly patients admitted to a teaching hospital, show that overall, 3.2% of the prescriptions they received before, during, or after hospital stay, were for drugs that were either contraindicated or that interacted adversely with other drugs. Overall, almost 24% of patients received a contraindicated or interacting drug. Approximately 84% of the inappropriate prescriptions were either preventable or probably preventable.

16. Do too many cooks spoil the broth? Multiple physician involvement in medical management of elderly patients and potentially inappropriate drug combinations. Tamblyn RM; McLeod PJ; Abrahamowicz M; Laprise R. CMAJ, 154(8):1177-84 1996 Apr 15.

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This study shows that the prevalence of a potentially inappropriate drug combination (PIDC) in a population of elderly Medicare patients ranged from 4% to 20.3%. The greater the number of physician involved in patient care, the higher the risk of PIDC.

17. A database analysis of potentially inappropriate drug use in an elderly medicaid population. Piecoro LT, Browning SR, Prince TS, Ranz TT, Scutchfield FD. Pharmacotherapy 2000 Feb;20(2):221-8. The results of this study, conducted on 64,832 elderly individuals, show that 27% of them had been prescribed at least one inappropriate medication. The rate of irrational prescribing was higher in nursing home residents (33%) than in outpatients (24%).

ADVERSE DRUG REACTIONS AND ADVERSE EVENTS

18. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. Lazarou J, Pomeranz BH, Corey PN. JAMA 1998 Apr 15;279(15):1200-5. This study analyzed 39 prospective U.S. studies to determine the incidence of serious and fatal adverse drug reactions (ADRs). Serious ADRs were defined as those requiring hospitalization or resulting in permanent damage. Only ADRs requiring hospital admission or occurring in the hospital were included in the analysis. Overall, the incidence of serious ADRs was 6.7 per 100 patients and that of fatal ADRs was 0.32 per 100 patients. Extrapolation of these data to the entire U.S. population revealed that in 1994 alone, over 2.2 million patients experienced a serious ADR and 106,000 died from this complication. These figures place ADRs between the fourth and sixth leading cause of death in the U.S. These are conservative estimates, since they don't take in consideration possible ADRs, errors in drug administration, patient non-compliance, overdose, drug abuse, therapeutic failures and injuries and deaths occurring in nursing home patients.

19. Drug-related emergency department visits and hospital admissions. Prince BS, Goetz CM, Rihn TL, Olsky M. Am J Hosp Pharm 1992 Jul;49(7):1696-700.

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This study evaluated the prevalence of different drug-related illnesses in patients visiting the emergency department or admitted to the hospital at one institution during a 4-month period. Drug-related illnesses were found to account for 3% of emergency visits and resulted in hospital admission in approximately 1/4 of cases. Of interest, adverse drug reactions were not the most common type of drug-related illnesses. Overdose or abuse accounted for 35% of drug-related complications, followed by noncompliance (28%), adverse drug reactions (28%), toxicity (8%), and drug interaction (1%).

20. The role of medication noncompliance and adverse drug reactions in hospitalizations of the elderly. Col N; Fanale JE; Kronholm P. Arch Intern Med, 150(4):841-5 1990 Apr. The results of this study, conducted on 315 elderly patients consecutively admitted to the hospital, show that in 28.2% of them, the cause of hospitalization was related to the medication they were taking, and was due to noncompliance with treatment in 11.4% of cases, and to adverse drug reactions in another 16.8%.

21. Drug-related hospital admissions. Nelson KM, et al. Pharmacotherapy 1996 Jul-Aug;16(4):701-7. The results of this study indicate that 73 (16%) of 452 consecutive admissions to a hospital were for drug-related problems. Approximately 55% were due to drug failure, 33% to adverse drug reactions and 12% to drug overdose. About half of the drug-related admissions were preventable.

22. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Singh G. Am J Med, 105(1B):31S-38S 1998 Jul 27. This study shows that each year, approximately 107,000 individuals are hospitalized for gastrointestinal (GI) complications derived from nonsteroidal anti-inflammatory drug (NSAID) use and that, among arthritis patients alone, at least 16,500 die as a consequence of NSAID use. These are conservative estimates, since they don't take into account gastrointestinal complications occurring in patients taking over-the-counter NSAIDs. If we consider that every year, in the U.S., there are over 70 million prescriptions written for NSAIDs, and over 30 billion tablets are sold over-the-counter, the number of injuries and death caused by only one type of adverse event related to NSAID use -gastrointestinal complications- reaches staggering figures. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 95

23. Incidence and types of preventable adverse events in elderly patients: population based review of medical records. Thomas, EJ. and Brennan TA. BMJ 2000;320:741-744 ( 18 March ). The results of this study show that hospitalized elderly patients have almost twice the risk of developing preventable adverse reactions, compared to younger patients. The study, conducted on 13 Utah' and 15 Colorado' hospitals, found that the incidence of adverse events leading to prolongation of hospital stay, disability or death in patients younger than 64 years of age is 2.8%, while that of patients aged 65 years or more is 5.3%. The incidence of preventable adverse events is 1.6% in younger patients and 3.0% in older ones, indicating that almost half of the adverse events that occur in hospitalized patients are preventable. Elderly patients, compared to younger ones, experience significantly higher rates of preventable adverse drug reactions, adverse events due to medical procedures, and falls. These data are likely to significantly underestimate the real incidence of adverse events in hospitalized patients, since adverse events were evaluated through medical chart documentation (where the occurrence of an adverse event is often not documented), the evaluation was performed by nurses and general practitioners (and not by specialists), their judgment of an adverse event was not always consistent, the study evaluated only adverse events that prolonged hospital stay or resulted in disability or death, and was conducted on hospitals that were not randomly selected. With this said, death due to preventable adverse events in hospitalized patients, still ranks at least as the 8th cause of mortality in the U.S.

24. Medication-related visits to the emergency department: a prospective study. Tafreshi MJ, Melby MJ, Kaback KR, Nord TC. Ann Pharmacother 1999 Dec;33(12):1252-7. The results of this study show that 28% of visits to the emergency room are related to medications. In the study, one physician and pharmacists evaluated prospectively the percentage of visits to the emergency room that were due to medications in a sample of 253 consecutive patients. In 71 patients (28.1%) the cause of the visit was due to medications, either in the form of adverse drug reaction, or of overprescribing. Over twothirds of the reactions were judged to be preventable. Cardiovascular medications were the most frequent class of drugs implicated. The cost for each preventable drug-related visit was estimated at $1444. The article emphasizes that the high rate of drug-related visits found in the study is accounted for by the study design (prospective, observational study) and by the presence of drug experts in determining the presence of treatmentcomplications.

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25. Drug Complications in Outpatients. Gandhi TK, Burstin HR, Cook EF, Puopolo AL, Haas JS, Brennan TA, Bates DW. J Gen Intern Med. 2000 Mar;15(3):149-154. The results of this study show that almost 1 out of 5 patients who take prescription drugs experience a treatment-related complication. The study was conducted on 2,248 randomly chosen patients from 11 ambulatory clinics in Massachusetts. Patient interviews and medical chart reviews were conducted to determine the frequency of drugrelated adverse reactions. Eighteen percent of patients reported complications from treatment, but only one-sixth of these adverse reactions were reported in the medical chart. Approximately 50% of patients who experienced an adverse reaction sought medical attention as a consequence of it, and 5% of them were hospitalized. These figures show that drug-related complications occur significantly more often than reported in patients' medical charts, leading to extensive utilization of the health care resources and patients' dissatisfaction with quality of care. This study is particularly important because presents rates of adverse drug reactions in outpatient settings, where most of the medications are given, and because reveals how the vast majority of adverse reactions are unreported.

26. Adverse drug events in elderly patients receiving home health services following hospital discharge. Gray SL, Mahoney JE, Blough DK. Ann Pharmacother 1999 Nov;33(11):1147-53. The results of this study show that 20% of elderly individuals who are discharged after hospitalization on medications, experience drug-related adverse effects. The study was conducted on 256 individuals aged 65 or more, who were hospitalized for medical illness and who received, upon discharge, home health nursing services. Twenty-percent of them reported at least one adverse effect from treatment, which involved the gastrointestinal system in approximately one third of cases and the central nervous system in another third. Women and individuals with low cognition were particularly at risk of experiencing treatment-related adverse events.

27. Incidence of adverse events and negligence in hospitalized patients. Results of the Harvard Medical Practice Study I. Brennan TA, et al. N Engl J Med 1991 Feb 7;324(6):370-6. This study evaluated the extent of injuries caused by medical management in a random population of over 30,000 patients hospitalized in the state of New York. Treatmentrelated injuries occurred in 3.7% of patients and were due to negligence in over a quarter of them. They led to disability lasting less than 6 months in 70% of patients, to permanent Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 97

disability in 2.6% of cases, and to death in 13.6% of cases. Extrapolation of these data for the whole state of New York showed that in 1984, medical management in the state of New York alone injured approximately 100,000 patients, with 27,000 of these injuries being due to negligence. Elderly patients were particularly at risk of adverse reactions due to negligent care. When these data were later further analyzed (Leape et al. Qual Rev Bull 1993 May;19(5):144-9.), it was shown that two-thirds of the injuries was due to errors, and was therefore potentially preventable.

28. Computerized surveillance of adverse drug reactions in hospital: implementation. Levy M, et al. Eur J Clin Pharmacol 1999 Jan;54(11):887-92. The results of this study, conducted on a sample population of 199 consecutive patients admitted to the medical ward of a hospital, indicate that adverse drug reactions (ADRs) were present in 32% of patients and were the cause of hospitalization in 9% of cases. Twenty-seven percent of ADRs were defined as serious.

29. Incidence of adverse drug events and potential adverse drug events. Implications for prevention. ADE Prevention Study Group. Bates DW, et al. JAMA 1995 Jul 5;274(1):29-34. The results of this study, conducted on 4031 hospitalized patients from 11 different units of two tertiary care hospitals, show that the incidence of adverse drug events (ADEs) and potential ADEs in this cohort was 6.5% and 5.5%, respectively. One percent of all ADE were fatal, 12% life-threatening, 30% serious, and 57% significant. Forty-two percent of the serious and life-threatening ADEs were preventable.

30. Incidence of adverse drug reactions in adult medical inpatients. Bowman L, Carlstedt BC, and Black CD. Can J Hosp Pharm 1994 Oct;47(5):209-16. This study estimated that 23.1% of patients admitted to the internal medicine ward of a hospital experience an adverse drug reaction (ADR). Length of hospital stay doubled in patients with ADR, compared to those without this complication. The severity of ADRs in this study was less than previously reported, with 10% of all ADRs judged to be severe, 53% moderate, and 36% mild.

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31. Adverse drug reaction-related hospitalizations of nursing facility patients: a 4-year study. Cooper JW. South Med J 1999 May;92(5):485-90. The results of this study indicate that one every 6-7 nursing home residents is hospitalized for adverse drug reactions (ADRs). The drugs more commonly involved in ADR-related hospitalizations are NSAIDs, psychotropic drugs (for inducing falls), digoxin and insulin. In the sample population evaluated in this study, 10% of patients experienced recurrent hospitalization for the same problem. The risk of being hospitalized increased with the number of medications that nursing home patients received.

32. Iatrogenic complications in high-risk, elderly patients. Lefevre F, Feinglass J, Potts S, Soglin L, Yarnold P, Martin GJ, Webster JR. Arch Intern Med 1992 Oct;152(10):2074-80. This study evaluated the medical records of 120 elderly patients admitted to a large university hospital for congestive heart failure, acute myocardial infarction, or pneumonia, and found that in 58.3% of them, a minimum of one iatrogenic complication occurred. The complication was judged to be potentially preventable in 35.8% of patients.

33. Adverse drug events in high risk older outpatients. Hanlon JT, et al. J Am Geriatr Soc 1997 Aug;45(8):945-8. This study evaluated the frequency of adverse drug events (ADEs) in a cohort of 167 elderly ambulatory patients taking more than 5 scheduled medications. Fifty-eight patients (35%) reported 80 ADEs that were textbook confirmed, of which 95% were predictable. Eleven percent of patients with ADEs were hospitalized, 10% required an emergency room visit and 63% a physician consultation.

34. Adverse drug events in hospitalized elderly. Gray SL, Sager M, Lestico MR, Jalaluddin M. J Gerontol A Biol Sci Med Sci 1998 Jan;53(1):M59-63. The results of this study, conducted on a cohort of 157 patients aged 70 and over consecutively admitted to the hospital, show that 14.6% of them experienced adverse drug reactions (ADRs), that were potentially preventable in half the cases. Upon Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 99

discharge, 50% of patients with ADRs experienced a decline in one or more activities of daily living, compared to 24% of patients without ADRs.

35. Adverse drug reactions in an elderly outpatient population. Schneider JK, Mion LC, Frengley JD. Am J Hosp Pharm 1992 Jan;49(1):90-6. This study, conducted on a cohort of 463 elderly outpatients, documented 107 adverse drug reactions (ADRs) that occurred in 97 (21%) individuals and caused the hospitalization of 12 of them. Attendance to a geriatric clinic, use of potentially dangerous drug combinations, and use of drugs requiring laboratory monitoring were all associated with an increased risk of experiencing ADRs.

36. Hospital characteristics associated with adverse events and substandard care. Brennan TA, et al. JAMA 1991 Jun 26;265(24):3265-9. This study evaluated 31,000 medical charts from 51 randomly selected NY hospitals, and found that the incidence of patient injuries due to medical treatment varied from 0.2% to 7.9% (mean 3.2%). Rates of adverse events were significantly higher in primary teaching hospitals (4.1%) compared to rural hospitals (1%). The percentage of adverse events due to negligence varied from 1 to 60% (mean 25%) and was significantly lower in teaching hospitals (10.7%) and significantly higher in hospital with a predominance of minority patients.

37. Physician characteristics and prescribing for elderly people in New Brunswick: relation to patient outcomes. Davidson W; Molloy DW; Bedard M. CMAJ, 152(8):1227-34 1995 Apr 15. This study examined whether mortality and morbidity rates in a community of elderly patients in New Brunswick could be associated with any physician' personal, professional, or practice characteristic. The results of the study revealed that general practitioners with higher patients' mortality rates were more likely to be males, prescribed more drugs, had larger practices, saw more patients and billed more per year compared to doctors with lower mortality rates. In addition, the study found higher rates of hip fractures in patients of doctors who prescribed more frequently antihypertensives, bronchodilators, cholesterol-lowering agents, gastrointestinal drugs and non-steroidal antiinflammatory drugs, who had larger practices, and who billed more per year.

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38. An alternative strategy for studying adverse events in medical care. Andrews LB, Stocking C, Krizek T, Gottlieb L, Krizek C, Vargish T, Siegler M. Lancet 1997 Feb 1;349(9048):309-13. This study shows that the frequency of adverse drug reactions (ADRs) reported in medical records may not be a real representation of the actual rate at which these events occur. When trained observers recorded all ADRs discussed at clinical meetings, the actual incidence of serious ADRs among a study group of 1047 patients was 17.7%. With each day of hospital stay, the risk of experiencing an adverse event increased by 6%.

39. The incident reporting system does not detect adverse drug events: a problem for quality improvement. Cullen DJ, Bates DW, Small SD, Cooper JB, Nemeskal AR, Leape LL. Jt Comm J Qual Improv 1995 Oct;21(10):541-8. The results of this study show that adverse drug events (ADEs) occurring in hospitalized patients are rarely reported to the hospital's quality assurance program. In particular, of the 55 ADEs that were detected during the study period, only 3 (6%) had been reported to the incident reporting system, even though 26 of them were serious or life threatening. Fifteen of the ADEs detected were considered preventable. These findings indicate that studies based on data gathered from voluntary reporting of adverse events may be underestimating the incidence of these complications by as much as 94%.

40. Reporting of adverse drug reactions by hospital doctors and the response to intervention. McGettigan P, Golden J, Conroy RM, Arthur N, Feely J. Br J Clin Pharmacol 1997 Jul;44(1):98-100. The results of this study indicate that in Ireland only 45% of doctors from 118 hospitals had ever reported adverse drug reactions (ADRs). When reporting cards were made readily available by placing them inside the patient admission chart and doctors were regularly reminded to report ADRs, the frequency of reports increased by 5 times over a 3-month period. However, the rate of reports declined rapidly after discontinuation of verbal reminders.

41. Underreporting of suspected adverse drug reactions to newly marketed ("black triangle") drugs in general practice: observational study.

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Martin,M, et al. BMJ 1998;317:119-120 ( 11 July ). The results of this study show that physicians report only 9% of suspected adverse reactions to newly marketed drugs to the Committee on safety of Medicines. Although the highest rate of reporting was for serious adverse drug reactions, still only 32% of serious unlabelled reactions (those that are not listed in the accompanying drug information sheet) and 11% of serious labeled reactions were submitted to the Committee. These data indicate that the large majority of serious adverse drug reactions go unreported.

42. Adverse drug reactions in a hospital general medical unit meriting notification to the Committee on Safety of Medicines. Smith CC, et al. Br J Clin Pharmacol 1996 Oct;42(4):423-9. The results of this study show that suspected adverse drug reactions (ADRs) occur in 6.8% of patients admitted to the hospital and are responsible for the hospitalization in 3/4 of cases. Only 6.3% of adverse drug reactions that, according to current guidelines, should have been notified to the Committee on Safety of Medicines had been actually submitted. The majority of unreported ADRs were for those that caused hospital admissions and involved mostly well-known complications to commonly used drugs.

43. Differences in perceived and presented adverse drug reactions in general practice. Ottervanger JP, Valkenburg HA, Grobbee DE, Stricker BH. J Clin Epidemiol 1998 Sep;51(9):795-9. This study indicates that patients experience significantly more adverse drug reactions (ADRs) than what their physicians are aware of. ADRs to sumatriptan were evaluated through a questionnaire sent to physicians and their patients. To avoid bias, no specific reactions were listed in the questionnaire. The most frequent ADRs reported by patients' physicians were: dizziness (1.7%), nausea or vomiting (1.5%) drowsiness or sedation (1.4%) and chest pain (1.3%). Patients on the other hand reported dizziness (8.1%), chest pain (7.9%), paraesthesia (11.7%), and feeling of heaviness (8%). The authors conclude that post-marketing studies that utilize data from physicians could significantly underestimate the real incidence of adverse drug reactions.

44. Postmarketing surveillance and adverse drug reactions: current perspectives and future needs.

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Brewer T, Colditz GA. JAMA 1999 Mar 3;281(9):824-9. This article illustrates how spontaneous reporting of adverse drug reactions (ADRs) is not a reliable indicator of the true occurrence of these events. Spontaneous reporting leaves potentially important ADRs undetected, since it cannot adequately assess the incidence of events occurring separated in time from treatment initiation, or consisting of symptoms occurring also in individuals not exposed to the drug.

45. Age and sex distribution of suspected adverse drug reactions to newly marketed drugs in general practice in England: analysis of 48 cohort studies. Martin RM, Biswas PN, Freemantle SN, Pearce GL, Mann RD. Br J Clin Pharmacol 1998 Nov;46(5):505-11. The results of this study, conducted on a cohort of over 510,000 patients, show that women have a 60% increased risk of developing an adverse drug reactions compared to men. Interestingly, the majority of clinical trials are conducted on men.

46. Adverse drug events in hospitalized patients. A comparison of doctors, nurses and patients as sources of reports. van den Bemt PM, et al. Eur J Clin Pharmacol 1999 Apr;55(2):155-8. The results of this study, conducted on a sample population of 620 hospitalized patients, indicate that adverse drug events (ADEs) occur in 29% of patients. Serious ADEs comprised 26% of all ADEs reported by doctors, and were detected three-times as frequently by doctors than by their patients. Adverse reactions to new drugs, on the other hand, were reported more frequently by patients than by their doctors.

47. Retrospective analysis of the frequency and recognition of adverse drug reactions by means of automatically recorded laboratory signals. Tegeder I, et al. Br J Clin Pharmacol 1999 May;47(5):557-564. This study evaluated retrospectively the incidence of adverse drug reactions in hospitalized patients through an automatic system (ALS) that fired signals every time laboratory results revealed abnormalities potentially indicative of an adverse drug reaction (ADR). Eighteen of 98 signals that were alerted were considered as probable ADRs after reviewing laboratory results and patients' charts. In two-thirds of the cases,

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the attending physician was not aware that an adverse drug reaction had occurred, even though 80% of the reactions were considered predictable.

48. The nosocomial component of medical care. A prospective study on the amount, spectrum and costs of medical disturbances in a department of infectious diseases. Jorup-Ronstrom C, Britton S. Scand J Infect Dis Suppl 1982;36:150-6. The results of this study, conducted on a cohort of 1271 patients admitted to the infectious disease department of a hospital, show that 11% of the admissions were due to complications to previous medical treatment while 27% of patients developed adverse reactions during hospitalization. Overall, the cost for medical care-related adverse events accounted for 17% of the total department costs.

49. Visits to office-based physicians in the United States for medication-related morbidity. Aparasu RR. J Am Pharm Assoc (Wash) 1999 May-Jun;39(3):332-7. This study indicates that in 1995, approximately 2 million outpatients visits occurred because of medication side effects, and the majority of these visits resulted in a scheduled follow-up visit. The drugs most frequently involved were hormones and synthetic substitutes (13%), followed by antibiotics (11.5%) and cardiovascular drugs (9%). These data indicate that adverse drug reactions leading to consultation of an office-based physician result in significant utilization of health care resources.

50. Adverse reactions to antibiotic drugs: the present scope of the problem in outpatient care and possibilities for improvement. Hemminki E. Int J Health Serv 1981;11(2):283-301. This article shows that in 1974, in the U.S., physicians wrote an average of 1 antibiotic prescription for each inhabitant. Antibiotic-related adverse drug reactions (ADRs) and serious ADRs, occurred in 7.6% and 1.4% of the population, respectively. If antibiotics had been prescribed only when necessary, two-thirds of ADRs would have been prevented; if the drug of choice had been prescribed, 37% of ADRs would have been prevented. If the antibiotic of choice had been prescribed only when necessary, four fifth of all ADRs would have been avoided.

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51. Errors in the treatment of tuberculosis in Baltimore. Rao SN, Mookerjee AL, Obasanjo OO, Chaisson RE. Chest 2000 Mar;117(3):734-7. The results of this study show that private physicians often treat tuberculosis (TB) incorrectly, favoring the development of acquired drug resistance and multidrug resistant TB. The study was conducted on 110 patients diagnosed with TB in the city of Baltimore between 1994 and 1995. Almost 40% of patients treated by private physicians were prescribed the wrong treatment regimen, compared to 5% of those treated at the Baltimore City Health Department's Tuberculosis Clinic. Inappropriate management consisting of low-doses antibiotics and short treatment courses is an important cause of treatment failure and acquired antibiotic resistance. The authors estimated the costs of salvage of inadequate treatment at $180,000 per patient.

52. Complications of care in a medical intensive care unit. Rubins HB, Moskowitz MA. J Gen Intern Med 1990 Mar-Apr;5(2):104-9. The results of this study indicate that 14% of patients admitted to a medical intensive care unit of a teaching hospital develop a complication from treatment. Patients with complications tend to be older and more severely ill, and have longer hospital stay and higher mortality rates, compared to those with uncomplicated course (67% vs. 27%). The authors conclude that since mortality rates in these patients exceeded significantly the expected mortality rate of 46%, it is conceivable that complications of care in the MICU independently contribute to in-hospital mortality.

53. Acute renal failure: clinical outcome and causes of death. Barretti P; Soares VA. Ren Fail, 19(2):253-7 1997 Mar. This study shows that the incidence of acute renal failure (ARF) in hospitalized patients is 4.9/1000 patients. Over 46% of patients who develop ARF die. Nephrotoxic drugs are the main cause of ARF in 21% of cases.

54. Incidence and characteristics of preventable iatrogenic cardiac arrests. Bedell SE, et al. JAMA 1991 Jun 5;265(21):2815-20.

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The results of this study, conducted on all patients hospitalized during a one-year period at Boston's Beth Israel Hospital, show that 28 (14%) of the 203 cardiac arrests suffered by patients had a iatrogenic cause (e.g. medications, medical procedures, or failure to detect warning signs). Sixty-one percent of patients with iatrogenic cardiac arrest died. Approximately 10% of all arrests were due to preventable physicians' errors (lack of attention to patients' history, to findings of physical examination, and to laboratory results).

55. Iatrogenic congestive heart failure in older adults: clinical course and prognosis. Rich MW, et al. J Am Geriatr Soc 1996 Jun;44(6):638-43. This study shows that in 7% of patients aged 70 years or older hospitalized with heart failure the cause is iatrogenic, e.g. the heart failure is induced by medications, by excessive administration of fluids or by a complication of a medical procedure. In this study, in-hospital and one-year mortality rates in patients with iatrogenic heart failure were 32% and 68%, respectively, compared to 9% and 39% in noniatrogenic patients. Iatrogenic vs. noniatrogenic heart failure was associated with a 2.5-fold higher risk of death.

56. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem. Page J, Henry D. Arch Intern Med 2000 Mar 27;160(6):777-84. The results of this study indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) are an important cause of hospitalization for congestive heart failure (CHF) in individuals with or without a history of heart disease. The study was conducted on 365 patients hospitalized for heart failure and 658 controls. Individuals who used NSAIDs in the previous week had a 2-fold increased risk of hospitalization for CHF, compared to nonusers. In patients with a history of heart disease, use of NSAIDs was associated with a 10-fold increased risk of hospitalization for CHF. The risk increased with increasing doses of NSAIDs taken in the previous week, and was greater with NSAIDs of long versus short half-life. The authors concluded that NSAIDs could account for approximately 20% of hospitalizations for congestive heart failure. Heart failure affects approximately 4.6 million Americans and this condition represent the most common hospital discharge diagnosis among patients older than 65 years. If this association is casual, as the dose-response relation suggests, cardiovascular morbidity due to NSAIDs would surpass gastro-intestinal NSAID-related morbidity, which alone is responsible for a minimum of 105,000 hospitalizations and 16,500 deaths occurring each year in the U.S. The economic and health consequences of these findings are staggering.

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57. Hospitalizations with adverse events caused by digitalis therapy among elderly Medicare beneficiaries. Warren JL, McBean AM, Hass SL, Babish JD. Arch Intern Med 1994 Jul 11;154(13):1482-7. This study indicates that in 1987, more than 3 million Medicare recipients were taking digitalis. During a seven-year study period, among this cohort, 202,011 patients were hospitalized because of adverse reactions to digitalis. This means that, every year, for every 1,000 individuals taking digitalis, 8.53 are hospitalized for adverse drug reactions to the drug.

58. Contribution of adverse drug reaction to admission rates in an acute psychiatric ward. Hermesh H, et al. Acta Psychiatr Scand 1985 Jul;72(1):104-10. The results of this study show that 7.5% of all admission to an acute psychiatric ward, are due to adverse drug reactions. The elderly are particularly at risk of experiencing drugrelated complications.

59. Adverse drug reactions (ADRs) in patients with HIV infection. A prospective study. Gonzalez-Martin G, et al. Int J Clin Pharmacol Ther 1999 Jan;37(1):34-40. In this study, the frequency of adverse drug reactions (ADRs) evaluated in a cohort of 50 ambulatory patients with HIV infection was 32%. In 18.5% of patients ADRs were severe and in 70.4% moderate. Trimethroprim-sulfamethoxazole and zidovudine were the most frequent cause of ADRs. Withdrawal of the responsible drug was required in 50% of cases.

60. Survey of drug-related deaths in Victoria. Coleridge J; Cameron PA; Drummer OH; McNeil JJ. Med J Aust, 157(7):459-62 1992 Oct 5. This study evaluated the cause of death in a sample of 231 drug-related deaths reported in Victoria. The primary cause of death was attributed to heroin and morphine in 35% of cases and to prescription drugs in 47% of cases. Tricyclic antidepressants and benzodiazepines were responsible for 14% and 6.5% of deaths, respectively. The mode of death was unclear in most cases and could have been other than suicide. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 107

61. The manner of death among fatalities where dextropropoxyphene caused or contributed to death. Jonasson B; Jonasson U; Saldeen T. Forensic Sci Int, 96(2-3):181-7 1998 Sep 28. In this study, blood sample analyses from 23,691 deceased individuals were evaluated for presence of dextropropoxyphene (DXP), one of the most frequently prescribed painmedication in Sweden. DXP was found in 1782 samples (7.5%) and was the cause of death in 54% of these cases.

62. Deaths related to iodinated contrast media reported spontaneously to the U.S. Food and Drug Administration, 1978-1994 Effect of the availability of low-osmolality contrast media. Spring DB; Bettmann MA; Barkan HE. Radiology, 204(2):333-7 1997 Aug. This study evaluated the number of iodinated contrast medium-related deaths reported to the U.S. Food and Drug Administration Spontaneous Reporting System from 1967 to 1994. Over a thousand deaths were reported during that period, 855 of which occurred after 1978. There was a 42% increase in deaths each year from 1987 to 1994 mostly associated with use of nonionic contrast media.

63. Reports of 355 transfusion-associated deaths: 1976 through 1985. Sazama K. Transfusion, 30(7):583-90 1990 Sep. This study describes 256 blood transfusion-related deaths reported to the Food and Drug Administration from 1976 to 1985. Fifty-one percent of these deaths were due to transfusion of incompatible blood products.

64. Autologous donation error rates in Canada. Goldman M, Remy-Prince S, Trepanier A, Decary F. Transfusion 1997 May;37(5):523-7. This study shows that although use of autologous blood transfusions should eliminate certain risks associated with transfusions, the possibility of errors, mainly clerical, is still high, with a detected rate of 1 error for every 149 units transfused.

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65. Wristband identification error reporting in 712 hospitals. A College of American Pathologists' Q-Probes study of quality issues in transfusion practice. Renner SW, Howanitz PJ, Bachner P. Arch Pathol Lab Med 1993 Jun;117(6):573-7. Wristband identification of patients is essential to prevent incompatible blood transfusions. This study detected wristband identification errors in 2.2% of patients from 712 hospitals. Absent wristband was the error most frequently encountered, followed by multiple wristbands with different information, incomplete, erroneous and illegible data, and patient wearing another patient' wristband.

ADVERSE DRUG REACTIONS AND ERRORS IN CHILDREN

66. Drug utilization and reported adverse reactions in hospitalized children. Mitchell AA, Goldman P, Shapiro S, Slone D. Am J Epidemiol 1979 Aug;110(2):196-204. This study estimated the frequency of adverse clinical events in a cohort of 1669 hospitalized children at 45.7%. Approximately 17% of the adverse events were drugrelated.

67. A prospective study of adverse drug reactions as a cause of admission to a paediatric hospital. Martinez-Mir I, et al. Br J Clin Pharmacol 1996 Sep;42(3):319-24. The results of this study indicate that 4.3% of 512 consecutive hospital admissions of children 1 to 24 months old were probably drug-related. Respiratory drugs, antibiotics, drugs active on the central nervous system and dermatological drugs were the agents most frequently involved.

68. A prospective study of adverse drug reactions in hospitalized children. Martinez-Mir I, Garcia-Lopez M, Palop V, Ferrer JM, Rubio E, Morales-Olivas FJ. Br J Clin Pharmacol 1999 Jun;47(6):681-8.

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The results of this study, conducted on a cohort of 512 consecutive pediatric patients 1 to 24 months old admitted to the medical ward of a hospital, show that the incidence of adverse drug reactions (ADRs) in this study group was 16.6%. Girls had a 66% higher risk of ADRs. Antibiotics and vaccines were the most frequent cause of ADRs (41.5%).

69. Adverse drug reactions (ADRs) in hospitalized pediatric patients. A prospective study. Gonzalez-Martin G, Caroca CM, Paris E.Int J Clin Pharmacol Ther 1998 Oct;36(10):530-3. The results of this study show that 13.7% of children admitted to the hospital develop an adverse drug reaction (ADR). Ninety-three percent of the ADRs were dose-dependent. Twenty-eight percent were severe and 51% were moderate. Causality assessment determined that 54% of ADRs were probable and 32% possible.

70. Medication errors in paediatric practice: insights from a continuous quality improvement approach. Wilson DG; et al. Eur J Pediatr, 157(9):769-74 1998 Sep. In this prospective study, a multidisciplinary committee evaluated over a 2-year period the incidence of medication errors in pediatric patients. The committee detected 411 errors that occurred in 682 children. Sixty-eight percent of errors were averted prior to drug administration, 24 errors with potential for serious patient adverse reactions were not detected in advance and caused overt clinical consequences in 4 cases.

71. Errors by paediatric residents in calculating drug doses. Rowe C; Koren T; Koren G. Arch Dis Child, 79(1):56-8 1998 Jul. This article shows that a significant number of physicians specializing in childcare prescribe the wrong dose of medication to infants and children. This finding is important, since inappropriate dosage in this age group may be associated with significant morbidity and mortality. Approximately 10% of residents who participated in this study committed a 10-fold dosage error, which may be life threatening.

72. Prevalence of feeding tube placement errors & associated risk factors in children. Ellett ML; Maahs J; Forsee S. MCN Am J Matern Child Nurs, 23(5):234-9 1998 Sep-Oct. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 110

The results of this study, conducted on a cohort of 201 hospitalized children who had an enteral tube inserted, show that in approximately 14% of them the feeding tube was misplaced (e.g. the tip of the tube was in the esophagus and in the intestine when it was meant to be in the stomach, or in the esophagus and stomach when it was meant to be in the intestine).

SURGICAL COMPLICATIONS

73. The nature of adverse events in hospitalized patients. Results of the Harvard Medical Practice Study II. Leape LL, et al. N Engl J Med 1991 Feb 7;324(6):377-84. This study analyzed the medical records of 30,195 randomly selected in-hospital patients and found that the incidence of patient injuries due to medical treatment was 3.7%. Fortyeight percent of events were due to surgical procedures, 19% to drug-related complications, 14% to wound infections, and 13% due to technical complications.

74. Proportion of hospital deaths associated with adverse events. Garcia-Martin M, et al. J Clin Epidemiol 1997 Dec;50(12):1319-26. This study shows that 56% of hospital deaths secondary to adverse events are due to surgical complications and 22% are due to hospital-related infections.

75. The incidence and nature of surgical adverse events in Colorado and Utah in 1992. Gawande AA, Thomas EJ, Zinner MJ, Brennan TA. Surgery 1999 Jul;126(1):66-75. This study evaluated the medical records of 15,000 patients hospitalized in Utah and Colorado, and found that the incidence of surgical adverse events in this cohort was 3.0%. Fifty-four percent of surgical adverse events were preventable and this type of complication accounted for 12.2% of all hospital deaths occurring in Utah and Colorado.

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76. Are in-hospital deaths and long stay markers for errors in surgery? Troeng T; Janzon L. Qual Assur Health Care, 2(2):149-59 1990. In this study, surgical errors were found in the care of 23% of patients who died in the hospital during a 1-year study period, in 10% of those who had a long hospital stay, and in 3% of those referred to other departments.

NURSING HOME PROTOCOL


THE SOLUTION The problems of malnutrition and dehydration are due in particular to the institutional food provided by vendors who have used RDAs which have been shown to be: a) insufficient and b) grossly inadequate for people who have compromised immune systems and multiple nutritional deficiencies. We offer a detailed examination of the scientific literature citing actual therapeutic dosages in relation to the category of illnesses that affect a nursing home population. We conclude, after reviewing thousands of scientific articles and using data from test groups of 300 individuals, most of whom are in senior citizen age groups, that nutrition and exercise, as presented in this proposed protocol, play a key role in the health and well-being of senior citizens. 7 In January, 1997, 300 seniors were enrolled in a "Reverse the Aging Process Study" that ran for 18 months. Sixty-five people completed the study; 235 became controls. This was a lifestyle modification study that measured changes in blood chemistry, weight, physical dimensions, physical appearance, memory, energy levels, sleep patterns, bowel movements, night time urination, muscle strength, digestion, olfactory senses, visual senses, tactile senses, skin texture, hair texture, and stress levels. The results of the study showed that of the 65 participants that completed the study: 1. 52% had lower cholesterol and triglyceride levels 2. 68% had increased DHEA levels 3. 78% had a significant improvement in their fat to muscle ratio 4. 90% had an increase in bowel movements 5. 92% had a decreased need for sleep 6. 95% had increased energy levels 7. 97% had lowered stress levels Additional data from numerical diaries kept by participants reflected subjective data, citing improvements in overall quality of life. We propose that this protocol would benefit the vast majority of people in Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 112

nursing homes and hospices. We offer the anecdotal case history of Harry Biele as an example of our protocol. Harry is a 90 year-old man who just 10 years ago had chronic sinusitis, asthma, arthritis, enlarged prostate, a precancerous lower bowel and main coronary artery blockage. He is now a marathoner living life to its fullest. His cardiologist has taken him off his heart medication, including beta blockers, and his general practitioner has taken him off his asthma inhalers. He is not an exception. Harry is an example of someone who has taken positive action toward his own health. He improved his nutrition by applying a protocol similar to this one. Exercise became part of Harrys daily ritual. He now appears to be closer to 70 than 90. NURSING HOME INTERVENTION PROTOCOL

The nursing home intervention protocol consists of a) diet, b) supplementation, c) exercise. DIET 1. Intake of animal protein should be reduced (1 x week) and consumption of cold-water fish should be increased (3 x week). 2. Additional protein should be derived from whole grains, legumes and seeds. If needed a protein powder supplement may be used. 3. The diet should provide 40-50 grams of fiber a day. 4. At least one (preferably 3) serving of a cruciferous vegetable should be provided daily: Brussell sprouts, broccoli, cabbage, or cauliflower. 5. 1-2 glasses of dark green leafy vegetable juices/day. The juice should also include 1inch length of ginger, aloe concentrate and protein powder (optional). 6. 1/2-1 gallon of water ingested/day. 7. Caffeine, soda, white sugar, and refined white flour products should be reduced to a minimum. For optimal results, they should be eliminated completely. 8. Olive oil should be used for cooking purposes. 9. Supplements should be taken with meals in divided doses where noted. Following the description of the supplement protocol there are detailed peer review journal articles of human studies and trials demonstrating the efficacy and suggested dosages of vitamins, nutrients, and herbs.

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Vitamins, Nutrients & Herbal Supplements 9 SEE TABLES Physical Exercise It is no secret anymore: exercise is a very important element in the overall health of people of all ages. However, as we age our tendons shrink and our muscle mass decreases. So in order to keep the body as youthful as possible, muscle mass needs to be retained, and if possible, increased. Tendons need to be stretched. So as we get older we actually need more exercise and longer stretching. All forms of exercise should be preceded with a thorough stretching routine. Stretching will elongate and strengthen the tendons and get the muscles warmed up and ready for movement. Senior citizens in general will take a longer time to warm up. Some exercises that are recommended for senior citizens are: fast walking, low impact aerobics, weight lifting, Yoga (for stretching), treadmill and the stair climbing machine. All exercises that are not too impacting on the joints are beneficial. We learned in our Reversing the Aging Process Study that most of the participants and 100% of the controls were not exercising properly. They were not doing enough exercise and not exercising with enough intensity. Our exercise protocol is modified specifically for senior citizens: a) Build up gradually to 45 minutes/day of aerobic activity. b) Take the pulse during a workout to maintain the target heart rate. A heart rate monitor is very useful and can be purchased at any local sports store. Generally, the target heart rate is determined by taking 220, subtracting your age (this is the maximal heart rate), and then multiplying the result by 50%-60%. Therefore, an 81 year-old person would have a rate of 220 minus 81 times 50%-60%, or 70 to 83 beats per minute. After a few months of training, increase to 70% of the maximal heart rate. c) As well as aerobic exercise, do weight training 3 times per week. Vitamins, Nutrients & Herbal Supplements Suggested Dosages Dosages Based on PeerReview Journal Articles** B Complex 50 mg 10-200 mg B6 25-75 mg 50-200 mg Folic Acid 400 mcg 2.5-35 mg B12 100 mcg 1,000 mcg-3 mg Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 114

Choline 500 mg 500 mg-16,000 mg Vitamin E 400-800 IU 30-4,800 mg L-Methionine 500 mg 2,000-10,000 mg Vitamin C 2,000-15,000 mg 30-17,000 mg Silybum Marianum 50 mg 140-600 mg Garlic 500 mg 4xday 3,000-10,000 mg Evening Primrose Oil 500 mg 2xday 3,000-6,000 mg Fish oil lipids 1,000 mg 2,600-24,000 mg Ginkgo Biloba 60-120 mg 50-600 mg Lecithin/Choline 5 gm 0.500 gm-16 gm N-Acetyl Cysteine 500-1,000 mg 300 mg-42,000 mg DHEA 25 mg 30-500 mg DMAE 200 mg Phosphatidyl serine 200 mg 3xday 50-800 mg Acetyl L-Carnitine 500 mg 2xday 1,000-3,000 mg Co-enzyme Q-10 100-300 mg 30-390 mg Calcium/Magnesium 800-1,400 mg 1,000-1,400 mg (Ca++) Niacin 100-500 mg 500-3,000 mg Glutathione 500-1,000 mg 2,500-5,000 mg Curcumine 250 mg 500 mg Alpha Lipoic Acid 200 mg 100-600 mg Melatonin 5 mg 0.3-75 mg Pregnenolone 10 mg 70 mg (based on 70 kg male) Precursors to growth Hormone Arginine 1,000 mg 4,000-35,000 mg Ornithine 1,000 mg 10,000-18,000 mg Glutamine 1,000 mg 1,500-4,000 mg TMG-Betaine 500 mg 6,000-20,000 mg Linoleic acid (Conjugated FA) 500 mg Herbs for Cleansing Apple pectin 25-50 mg 8,500-20,000 mg Bee Pollen 25-50 mg Burdock root 25-50 mg Chrysanthemum 25-50 mg Dandelion root 25-50 mg Hibiscus 25-50 mg Kelp 25-50 mg Oregano 25-50 mg Peppermint 25-50 mg Enteric-coated capsules Psyllium 25-50 mg 3,400-15,000 mg Red clover 25-50 mg 100 mg (Coumarin) Vitamin and Mineral Indexes Nutrients Recommended Adult Intake Source of Recommended Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 115

Intake Therapeutic Intake Range based on Peer-Review Journals** Vitamin A 5,000 IU USRDA* Vitamin D 400 IU USRDA Vitamin E 30 IU USRDA 30-2,800mg 12 Vitamin C 60 mg RDA* 30-17,000mg Thiamin (B1) 1.5 mg USRDA 10-200mg Riboflavin (B2) 1.7 mg USRDA 10-400mg Niacin (B3) (nicotinamide) 20 mg USRDA 500-3,000mg Pyridoxine (B6) 2.0 mg RDA 50-200mg Folacin 0.4 mg USRDA .02mg-35mg Folic acid Biotin 0.3 mg USRDA Pantothenic acid (B5) 10 mg USRDA Calcium 1,200 mg RDA 1,000-1,400mg Phosphorus 1,200 mg RDA Magnesium 400 mg USRDA Iron 18 mg USRDA Zinc 15 mg USRDA Copper 3 mg ESAADDI* Fluoride 4 mg ESAADDI Iodine 0.15 mg USRDA Selenium 0.2 mg ESAADDI *RDA-Recommended Dietary Allowances; USRDA-United States Recommended Daily Allowances; ESAADDI-Estimated Safe and Adequate Daily Dietary Intakes. Shils, et al. 1994. Modern Nutrition in Health and Disease, Eighth Edition Volume 2. Lea & Febiger, p. 1582. **The therapeutic doses are based on Peer-Review Journals with a focus on human trials and studies. These articles are cited within the proposal. Please refer to the Reference Section for details. All senior citizens and baby boomers can improve their health. This is the scientific literature that justifies the use of recommended supplements in this protocol. Applying this protocol can play an important role in anyones life. Peer-Review Journal References for Vitamins, Nutrients and Herbs B-Complex B1 Alzheimer's disease Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 116

Gold M, Hauser RA, Chen MF. Plasma thiamine deficiency associated with Alzheimer's disease but not Parkinson's disease. Metab Brain Dis. 1998 Mar;13(1):43-53. Mimori, Y. et al. 1966. Thiamine therapy in Alzheimer's disease. Metab Brain Disease, 11(1), Mar., 89-94. Dose: 100mg/day, 12 weeks Cardiovascular/Coronary Heart Disease Ito M, Tanabe Y, Suzuki K, Kumakura M, Aizawa Y. Shoshin beriberi with vasospastic angina pectoris possible mechanism of mid-ventricular obstruction: possible mechanism of mid-ventricular obstruction. Circ J. 2002Nov;66(11):1070-2. Shimon, I. et al. 1995. Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving longterm Furosemide therapy. Am J Med, 98(5), 485-490. Dose: 200mg day Freye and Hartung, E. 1982. The Potential use of thiamine in patients with cardiac insufficiency. Acta Vitamino Enzymol, 4(4), 285-290. Dose: 50mg/kg Epilepsy Naito E, Ito M, Yokota I, Saijo T, Chen S, Maehara M, Kuroda Y. Concomitant administration of sodium dichloroacetate and thiamine in west syndrome caused by thiamine-responsive pyruvate dehydrogenase complex deficiency. J Neurol Sci. 1999 Dec 1;171(1):56-9. Botez, M. I. et al. 1993. Thiamine and folate treatment of chronic epileptic patients: A controlled study with the Wechsler IQ scale. Epilepsy Res, 16(2), Oct., 157-163. Fatigue Heap LC, Peters TJ, Wessely S. Vitamin B status in patients with chronic fatigue syndrome. J R Soc Med. 1999 Apr;92(4):183-5. Suzuki, M. and Itokawa, Y. 1996. Effects of thiamine supplementation on exercise-induced fatigue, Metabolic Pr Brain Dis., 11(1), Mar., 95-106. Febrile Lymphadenopathy Lonsdale D. Recurrent febrile lymphadenopathy treated with large doses of vitamin B1: report of two cases. Dev Pharmacol Ther. 1980;1(4):254-64. Lonsdale, D. 1980. Recurrent febrile lymphadenopathy treated with large doses of vitamin B1: Report of two cases. Dev Pharmacol Ther., 1(4), 254264.

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General Hinze-Selch D, Weber MM, Zimmermann U, Pollmacher T. Thiamine treatment in psychiatry and neurology. Fortschr Neurol Psychiatr. 2000 Mar;68(3):113-20. Meador, K. J. et al. 1993. Evidence for a clinical cholinergic effect of highdose thiamine. Ann Neurol, 34(5), Nov., 724-726. Smidt, L. J. et al. 1991. Influence of thiamin supplementation on the health and general well-being of an elderly Irish population with marginal thiamin deficiency. J Gereontology, 46(1), Jan., M16-22. Dose: 10mg/day Lactic Acidosis McComsey GA, Lederman MM. High doses of riboflavin and thiamine may help in secondary prevention of hyperlactatemia. AIDS Read. 2002 May;12(5):222-4. Klein, G. et al. 1990. [Life-threatening lactic acidosis during total parenteral nutrition. Successful therapy with thiamine]. Dtsch Med Wochenschr, 115(7), Feb., 254-256. Dose: 400mg Liver Disease Levy S, Herve C, Delacoux E, Erlinger S. Thiamine deficiency in hepatitis C virus and alcohol-related liver diseases. Dig Dis Sci. 2002 Mar;47(3):543-8. 15 Hassan, R. et al. 1991. Effect of thiamine on glucose utilization in hepatic cirrhosis. J Gastroenterology Hepatology, 6(1), Jan.-Feb., 59-60. Dose: 50 mg/day for 30 days Rossouw, J. E. et al. 1978. Red blood cell transketolase activity and the effect of thiamine supplementation in patients with chronic liver disease. Scandinavian J Gastroenterology, 13(2), 133-138. Dose: 200 mg/day Seasonal Ataxia Nishimune T, Watanabe Y, Okazaki H, Akai H. Thiamin is decomposed due to Anaphe spp. entomophagy in seasonal ataxia patients in Nigeria. J Nutr. 2000 Jun;130(6):1625-8. Adamolekun, B. et al. 1994. A double-blind, placebo-controlled study of the efficacy of thiamine hydrochloride in a seasonal ataxia in Nigerians. Neurology, 44(3 Pt 1), Mar., 549-551.

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Surgical Stress Vinogradov, V. V. et al. 1981. [Thiamine prevention of the corticosteroid reaction after surgery]. Probl Endokrinol, 27(3), May-June, 11-16. Dose: IV administration of 0.12 g one day and 1.5-2 hours prior to surgery B2 Congenital Methaemoglobinaemia Svecova D, Bohmer D. Congenital and acquired methemoglobinemia and its therapy. Cas Lek Cesk. 1998 Mar 23;137(6):168-70. Hirano, M. et al. 1981. Congenital methaemoglobinaemia due to NADH methaemoglobin reductase deficiency: Successful treatment with oral riboflavin. British J Haematology, 47(3), Mar., 353-359. Dose: 120 mg/day Depression Tolmunen T, Voutilainen S, Hintikka J, Rissanen T, Tanskanen A, Viinamaki H, Kaplan GA, Salonen JT. Dietary folate and depressive symptoms are associated in middle-aged Finnish men. J Nutr. 2003 Oct;133(10):3233-6. Bell, I. R. et al. 1992. Brief communication. Vitamin B1, B2, and B6 augmentation of tricyclic antidepressant treatment in geriatric depression with cognitive dysfunction. J Am Coll Nutr., 11(2), Apr., 159-163. Dose: 10mg B1, B2 and B6 each with antidepressants Migraine Mauskop A. Alternative therapies in headache. Is there a role? Med Clin North Am. 2001 Jul;85(4):1077-84. Schoenen, J. et al. 1994. High-dose riboflavin as a prophylactic treatment of migraine: Results of an open pilot study. Cephalalgia, 14(5), Oct., 328-329. Dose: 400mg for at least 3 months Sickle Cell Disease Ajayi OA, George BO, Ipadeola T. Clinical trial of riboflavin in sickle cell disease. East Afr Med J. 1993 Jul;70(7):418-21. Ajayi, O. A. et al. 1993. Clinical trial of riboflavin in sickle cell disease. East African Med J, 70(7), 418-421. Dose: 5mg 2x/day for 8 weeks B6 Anemia Shoolingin-Jordan PM, Al-Daihan S, Alexeev D, Baxter RL, Bottomley SS, Kahari ID, Roy I, Sarwar M, Sawyer L, Wang SF. 5-Aminolevulinic acid synthase: mechanism, mutations and medicine. Biochim Biophys Acta. 2003 Apr 11;1647(1-2):361-6. Toriyama, T. et al. 1993. Effects of high-dose vitamin B6 therapy on Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 119

microcytic and hypochromic anemia in hemodialysis patients. Nippon Jinzo Gakkai Shi 35(8), Aug., 975-980. Dose: 180mg for 20 weeks Asthma Gaby AR. Intravenous nutrient therapy: the "Myers' cocktail". Altern Med Rev. 2002 Oct;7(5):389-403. Ubbink JB, van der Merwe A, Delport R, Allen RH, Stabler SP, Riezler R, Vermaak WJ. The effect of a subnormal vitamin B-6 status on homocysteine metabolism. J Clin Invest. 1996 Jul 1;98(1):177-84. Collipp, P. J. et al. 1975. Pyridoxine treatment of childhood bronchial asthma. Ann Allergy 35(2), Aug., 93-97.Dose: 200mg/day Cardiovascular/Coronary Heart Disease Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteinelowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA. 2002 Aug 28;288(8):973-9. Van den Berg, M. et al. 1994. Combined vitamin B6 plus folic acid therapy in young patients with arteriosclerosis and hyperhomocysteinemia. J Vascular Surg. 20(6), Dec., 933-940. Dose: 250mg for 6 weeks Ellis, J. M. and McCully, K. S. 1995. Prevention of myocardial infarction by vitamin B6. Res Commun Mol Pathol Pharmac 89(2) Aug., 208-220. Carpal Tunnel Syndrome Holm G, Moody LE. Carpal tunnel syndrome: current theory, treatment, and the use of B6. J Am Acad Nurse Pract. 2003 Jan;15(1):18-22. Ellis, J. et al. 1979. Clinical results of a cross-over treatment with pyridoxine and placebo of the Carpal Tunnel Syndrome. Am J Clin Nutr 32(10), Oct., 2040-2046. Dose: 100mg/day Kasdan, M. L. and Janes, C. 1987. Carpal Tunnel Syndrome and vitamin B6. Plastic Reconstructive Surgery 79(3), Mar., 456-462. Dose: 100mg/day Stransky, M. et al. 1989. Treatment of Carpal Tunnel Syndrome with vitamin Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 120

B6: A double-blind study. Southern Med J 82(7), July, 841-842. Ellis, J. M. 1987. Treatment of Carpal Tunnel Syndrome with vitamin B6. Southern Med J 80(7), July, 882-884. Dose: 100mg to 200mg/day for 12 weeks Guzman, F. J. L. et al. 1989. Carpal Tunnel Syndrome and vitamin B6. Klin Wochenschr, 67(1), Jan. 4, 38-41. Dose: 150mg/day for 3 months Ellis, J. et al. 1981. Therapy with vitamin B6 with and without surgery for treatment of patients having the Idiopathic Carpal Tunnel Syndrome. Res Commun Pathol Pharmacol 33(2) Aug., 331-344. Diabetes Okada M, Shibuya M, Yamamoto E, Murakami Y. Effect of diabetes on vitamin B6 requirement in experimental animals. Diabetes Obes Metab. 1999 Jul;1(4):221-5. Bennink, H. J. and Schreurs, W. H. 1975. Improvement of oral glucose tolerance in gestational diabetes by pyridoxine. Br Med J 3(5974), 13-15. Immune Function Grimble RF. Effect of antioxidative vitamins on immune function with clinical applications. Int J Vitam Nutr Res. 1997;67(5):312-20. Casciato, D. A. et al. 1984. Immunologic abnormalities in hemodialysis patients: Improvement after pyridoxine therapy. Nephron 38(1), 9-16. Dose: 50mg/day for 3-5 weeks Primary Hyperoxaluria van Woerden CS, Groothoff JW, Wanders RJ, Davin JC, Wijburg FA. Primary hyperoxaluria type 1 in The Netherlands: prevalence and outcome. Nephrol Dial Transplant. 2003 Feb;18(2):273-9. Milliner, D. S. et al. 1994. Results of long-term treatment with orthophosphate and pyridoxine in patients with primary hyperoxaluria. NEJM. 331(23), Dec. 8, 1553-1558. B12 Anemia de Lonlay P, Fenneteau O, Touati G, Mignot C, Billette de Villemeur T, Rabier D, Blanche S, Ogier de Baulny H, Saudubray JM. Hematologic manifestations of inborn errors of metabolism. Arch Pediatr. 2002 Aug;9(8):822-35. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 121

Samson, D. et al. 1977. Reversal of ineffective erythropoiesis in pernicious anaemia following vitamin B12 therapy. Br J Haematology 35(2), Feb., 217224. Kafetz, K. 1985. Immunoglobulin deficiency responding to vitamin B12 in two elderly patients with megaloblastic anaemia. Postgrad Med J 61(722), Dec., 1065-1056. Kubota, K. et al. 1987. Restoration of decreased suppressor cells by vitamin B12 therapy in a patient with pernicious anemia. Am J Hematol 24(2), Feb., 221-223. Kubota, K. et al. 1992. Restoration of abnormally high CD4/CD8 ratio and low natural killer cell activity by vitamin B12 therapy in a patient with postgastrectomy megaloblastic anemia. Internal Med 31(1), Jan., 125-126. Apthae Wray, D. et al. 1975. Recurrent aphthae: Treatment with vitamin B12, folic acid, and iron. British Med J 2(5969), May 31, 490-493. Bronchial Squamous Metaplasia Heimburger, D. C> et al. 1988. Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin B12. Report of a preliminary randomized, double-blind intervention trial. JAMA 259(10), Mar. 11, 1525-1530. Dose: 500mcg for 4 months Dementia Serot JM, Christmann D, Dubost T, Bene MC, Faure GC. CSF-folate levels are decreased in late-onset AD patients. J Neural Transm. 2001;108(1):93-9. Regland, B. et al. 1991. Vitamin B12-induced reduction of platelet monoamine oxidase activity in patients with dementia and pernicious anaemia. Eur Arch Psychiatry Clin Neurosci 240(4-5), 288-291. General Tschop M, Folwaczny C, Schindlbeck N, Loeschke K. Megaloblastic anemia due to inadequate nutrition. Dtsch Med Wochenschr. 1997 Jun 20;122(25-26):820-4. Newbold, H. L. 1989. Vitamin B-12: Placebo or neglected therapeutic tool? Med Hypothesis, 28(3), May, 155-164. Hepatitis Mathe G, Morette C, Hallard M, Pontiggia P, Blanquet D, Hage F. Viral and 20 immunologic follow up of 4 to 9 years of AIDS treatments by quadruple Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 122

combinations of virostatics including integrase inhibitors applied in short sequences differing by drug rotation. Acta Pharmacol Sin. 2002 Jan;23(1):1-15. Iwarson, S. and Lindberg, J. 1977. Coenzyme-B12 therapy in acute viral hepatitis. Scandinavian J Infectious Dis 9(2), 157-158. Komar, I. V. 1982. [Use of vitamin B12 in the combined therapy of viral hepatitis]. Vopr Pitan (1), Feb., 26-29. Dose: 100mcg every other day Imerslund-Grasbeck Syndrome Salameh, M. M. et al. 1991. Reversal of severe neurological abnormalities after vitamin B12 replacement in the Imerslund-Grasbeck Syndrome. J Neurology 238(6), Sept., 349-350. Methylmalonic Acidemia Gordon, B. A. and Carson, R. A. 1976. Methylmalonic acidemia controlled with oral administration of vitamin B12. Canadian Med Assoc J 115(3), Aug. 7, 233-236. Dose: Continuous intramuscular supplements in doses of 1 mg on alternate days followed by 15 mg/day taken orally Multiple Sclerosis Kira, J. et al. 1994. Vitamin B12 metabolism and massive-dose methyl vitamin B12 therapy in Japanese patients with multiple sclerosis. Internal Med 33(2), Feb., 82-86. Dose: 60mg/day for 6 months Sleep Honma, K. et al. 1992. Effects of vitamin B12 on plasma melatonin rhythm in humans: Increased light sensitivity phase-advances the Circadian Clock? Experentia 48(4), Aug. 15, 716-720. Dose: 3mg/day Ohta, T. et al. 1991. Treatment of persistent sleep-wake schedule disorders in adolescents with methylcobalamin (vitamin B12). Sleep 14(5), Oct., 414418. Dose: 3,000mcg/day Okawa, M. et al. 1990. Vitamin B12 treatment for sleep-wake rhythm disorders. Sleep 13(1), Feb., 15-23. Dose: 1.5 mg /day tid Vitiligo Montes, L. F. et al. 1992. Folic acid and vitamin B12 in vitiligo: A nutritional approach. Cutis 50(1), July, 39-42. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 123

Choline/Lecithin Head Injury Dempsey RJ, Raghavendra Rao VL. Cytidinediphosphocholine treatment to decrease traumatic brain injury-induced hippocampal neuronal death, cortical contusion volume, and neurological dysfunction in rats. J Neurosurg. 2003 Apr;98(4):867-73. Levin, H. S. 1991. Treatment of postconcussional symptoms with CDPcholine. J Neurol Sci 103 Suppl, July, S39-S42. Dose: 1 gm of CDP-choline Maldonado, V. C. et al. 1991. Effects of CDP-choline on the recovery of patients with head injury. J. Neurol Sci 103 Suppl, July, S15-S18. Hemiplegia Hazama T, Hasegawa T, Ueda S, Sakuma A. Evaluation of the effect of CDPcholine on poststroke hemiplegia employing a double-blind controlled trial. Assessed by a new rating scale for recovery in hemiplegia. Int J Neurosci. 1980;11(3):211-25. Hazama, T. et al. 1980. Evaluation of the effect of CDP-choline on poststroke hemiplegia employing a double-blind controlled trial. Assessed by a rating scale for recovery in hemiplegia. Int J Neurosci 11(3), 211-215. Dose: ranging from 250-1000 mg over an 8 week period Hepatic Steatosis Oliveira CP, da Costa Gayotto LC, Tatai C, Della Bina BI, Janiszewski M, Lima ES, Abdalla DS, Lopasso FP, Laurindo FR, Laudanna AA. Oxidative stress in the pathogenesis of nonalcoholic fatty liver disease, in rats fed with a cholinedeficient diet. J Cell Mol Med. 2002 Jul-Sep;6(3):399-406. Buchman, A. L. et al. 1995. Choline deficiency: A cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Hepatology 22(5), Nov., 1399-1403. Dose: 1-4 g choline chloride over a period of 4 weeks Neurological Function Uteshev VV, Meyer EM, Papke RL. Regulation of neuronal function by choline and 4OH-GTS-21 through alpha 7 nicotinic receptors. J Neurophysiol. 2003 Apr;89(4):1797-806. Epub 2002 Dec 04 Fernandez, R. L. 1983. Efficacy and safety of oral CDP-choline. Drug surveillance study in 2817 cases. Arzeimittelforschung 33(7A), 1073-1080. Dose: 6 ml/day mean dose of CDP-choline

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Seizures Yang Y, Liu Z, Cermak JM, Tandon P, Sarkisian MR, Stafstrom CE, Neill JC, Blusztajn JK, Holmes GL. Protective effects of prenatal choline supplementation on seizure-induced memory impairment. J Neurosci. 2000 Nov 15;20(22):RC109. McNamara, J. O. et al. 1980. Effects of oral choline on human complex partial seizures. Neurology 30(12), 1334-1336. Dose: 12-16 g/day Stroke Rao AM, Hatcher JF, Dempsey RJ. CDP-choline: neuroprotection in transient forebrain ischemia of gerbils. J Neurosci Res. 1999 Dec 1;58(5):697-705. Tazaki, Y. et al. 1988. Treatment of acute cerebral infarction with a choline precursor in a multicenter double-blind placebo-controlled study. Stroke 19(2), Feb., 211-216. Dose: 1000 mg iv CDP-choline/day for 14 days Tardive Dyskinesia Tammenmaa IA, McGrath JJ, Sailas E, Soares-Weiser K. Cholinergic medication for neuroleptic-induced tardive dyskinesia. Cochrane Database Syst Rev. 2002;(3):CD000207. Gelenberg, A. J. et al. 1979. Choline and lecithin in the treatment of tardive dyskinesia: Preliminary results from a pilot study. Am J Psychiatry 136(6), June, 772-776. Growdon, . H. et al. 1977. Oral choline administration to patients with tardive dyskinesia. NEJM 297(10), Sept. 8, 524-527. Arranz, J. and Ganoza, G. 1983. Treatment of chronic dyskinesia with CDPcholine. Arzneimittelforschung 33(&a), 1071-1073. Dose: 500-1200 mg CDP-choline/day Nasrallah, H. A. et al. 1984. Variable clinical response to choline in tardive dyskinesia. Psychol Med 14(3), Aug., 697-700. Folic acid Anemia Agarwal KN, Gomber S, Bisht H, Som M. Anemia prophylaxis in adolescent school girls by weekly or daily iron-folate supplementation. Indian Pediatr. 2003 Apr;40(4):296-301.

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Rahpael, J. C. et al. 1975. [Myelopathy and macrocytic anemia associated with a folate deficiency. Cure by folic acid]. Ann Med Interne 126(5), May, 339-348. Arthritis Endresen GK, Husby G. Folate supplementation during methotrexate treatment of patients with rheumatoid arthritis. An update and proposals for guidelines. Scand J Rheumatol. 2001;30(3):129-34. Morgan, S. L. et al. 1994. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebocontrolled trial. Annals Intern Med 121(11), Dec. 1, 833-841. Dose: 5mg or 27.5 mg at weekly doses Morgan, S. L. et al. 1990. The effect of folic acid supplementation on the toxicity of lowdose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 33(1), Jan., 9-18. Dose: 1mg folic acid/day Flynn, M. A. et al. 1994. The effect of folate and cobalamin on osteoarthritic hands. J American Colle Nutr 13(4), Aug., 351-356. Dose: 6400mcg folate/day Cancer Bajetta E, Celio L, Buzzoni R, Ferrari L, Marchiano A, Martinetti A, Longarini R, Becerra C, Ilardi C, John W. Phase II study of pemetrexed disodium (Alimta) administered with oral folic acid in patients with advanced gastric cancer. Ann Oncol. 2003 Oct;14(10):1543-8. Saito, M. et al. 1994. Chemoprevention effects on bronchial squamous metaplasia by folate and vitamin B12 in heavy smokers. Chest 106(2), Aug., 496-499. Jennings, E. 1995. Folic acid as a cancer-preventing agent. Med Hypotheses 45(3), Sept., 297-303. Cardiovascular/Coronary Heart Disease Das UN. Folic acid says NO to vascular diseases. Nutrition. 2003 Jul-Aug;19(78):686-92. Landgren, F. et al. 1995. Plasma homocysteine in acute myocardial infarction: Homocysteine-lowering effect of folic acid. J Intern Med 237(4), Apr., 381-388. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 126

Dose: 2.5mg or 10mg over a 6 week period van den Berg, M. et al. 1994. Combined vitamin B6 plus folic acid therapy in young patients with arteriosclerosis and hyperhomocysteinemia. J Vascular Surgery 20(6), Dec., 933-940. Dose: 5mg folic acid/day Morrison, H. I. et al. 1996. Serum folate and risk of fatal coronary heart disease. JAMA 275(24), June 26, 1893-1896. Wilcken, D. E. et al. 1988. Folic acid lowers elevated plasma homocysteine in chronic renal insufficiency: Possible implications for prevention of vascular disease. Metabolism 37(7), July, 697-701. Dose: 5mg folic acid/day for average of 15 days Arnadottir, M. et al. 1993. The effect of high-dose pyridoxine and folic acid supplementation on serum lipid and plasma homocysteine concentrations in dialysis patients. Clinical J Nephrol 40(4), Oct., 236-240. Dose: 5mg/day Cervical Dysplasia Thomson SW, Heimburger DC, Cornwell PE, Turner ME, Sauberlich HE, Fox LM, 25 Butterworth CE. Correlates of total plasma homocysteine: folic acid, copper, and cervical dysplasia. Nutrition. 2000 Jun;16(6):411-6. Butterworth, Jr. C. E. 1982. Improvement of cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr, 35(1) Jan., 73-82. Dose: 10mg folic acid/day for 3 months Fragile X Syndrome Strom CM, Brusca RM, Pizzi WJ. Double-blind, placebo-controlled crossover study of folinic acid (Leucovorin for the treatment of fragile X syndrome. Am J Med Genet. 1992 Nov 15;44(5):676-82. Brown, W. T. et al. Folic acid therapy in the Fragile X Syndrome. Am. J Med Genetics 17(1), Jan., 289-297. Hagerman, R. J. et al. 1986. Oral folic acid versus placebo in the treatment of males with the Fragile X Syndrome. Am. J Med Genetics 23(1-2), Jan.Feb., 241-262. Dose: 10mg/day Lejeune, J. et al. 1984. [Trial of folic acid treatment in Fragile X Syndrome] Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 127

Ann Genet 27(4), 230-232. Dose: 0.5 mg/kg per day of folic acid Gingival Health Munoz CA, Kiger RD, Stephens JA, Kim J, Wilson AC. Effects of a nutritional supplement on periodontal status. Compend Contin Educ Dent. 2001 May;22(5):425-8, 430, 432 passim; quiz 440. Vogel, R. I. et al. 1976. The effect of folic acid on gingival health. J Periodontology 47(11), Nov., 667-668. Dose: 4mg/day for 30 days Homocystinuria Ashfield-Watt PA, Moat SJ, Doshi SN, McDowell IF. Folate, homocysteine, endothelial function and cardiovascular disease. What is the link? Biomed Pharmacother. 2001 Oct;55(8):425-33. Takenaka, T. et al. 1993. [Effect of folic acid for treatment of homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency]. Rinsho Shinkeigaku 33(11), Nov., 1140-1145. Dose: 400mcg/day of folic acid over approx 70 days Kidney Damage Manns B, Hyndman E, Burgess E, Parsons H, Schaefer J, Snyder F, Scott-Douglas N. Oral vitamin B(12) and high-dose folic acid in hemodialysis patients with hyper-homocyst(e)inemia. Kidney Int. 2001 Mar;59(3):1103-9. Chauveau, P. et al. 1996. Long-term folic acid (but not pyridoxine) supplementation lowers elevated plasma homocysteine level in chronic renal failure. Miner Electrolyte Metab 22(1-3), 106-109. Dose: 10mg/day folate for 3 months Lithium Prophylaxis McKeon P, Shelley R, O'Regan S, O'Broin J. Serum and red cell folate and affective morbidity in lithium prophylaxis. Acta Psychiatr Scand. 1991 Mar;83(3):199-201. Coppen, A. et al. 1986. Folic acid enhances lithium prophylaxis. J Affective Disorders 10(1), Jan.-Feb., 9-13. Dose: 200mcg/day folic acid Multiple Sclerosis Bottiglieri T. Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 128

1996 Dec;54(12):382-90. Kanevskaia, S. A. et al. 1990. [Folic acid in the combined treatment of patients with disseminated sclerosis and chronic gastritis] Vrach Delo (4), Apr. 96-97. Dose: 200-300mcg/day Zinc Absorption Tavares E, Carreras O, Gomez-Tubio A, Murillo D, Murillo ML. Effects of folic acid and amino acids supplementation on zinc intestinal absorption in the progeny of ethanol-treated rats. J Physiol Biochem. 2000 Sep;56(3):247-56. Milne, D. B. et al. 1984. Effect of oral folic acid supplements on zinc, copper, and iron absorption and excretion. Am J Clin Nutr 39(4), Apr., 535539. Dose: 400mcg folic acid every other day for 16 weeks Niacin General Talpur N, Echard BW, Yasmin T, Bagchi D, Preuss HG. Effects of niacin-bound chromium, Maitake mushroom fraction SX and (-)-hydroxycitric acid on the metabolic syndrome in aged diabetic Zucker fatty rats. Mol Cell Biochem. 2003 Oct;252(1-2):369-77. Chojnowska-Jezierska, J,. and Adamska-Dyniewska, H. 1998. Efficacy and safety of one-year treatment with slow-release nicotinic acid. Monitoring of drug concentration in serum. Int J Clin Pharmacol Ther, 36(6), Jun., 326332. Dose: 1.5 g/d (2 months), and subsequently 2-3 g/d (10 months), on average 2.13 g/d. During the treatment with 2.0 g/d dose. Hoogerbrugge, N. et al. 1998. The additional effects of acipimox to simvastatin in the treatment of combined hyperlipidaemia. J Intern Med, 243(5) May, 151-156. Dose: Acipimox in a daily dose of 3 X 250 mg for 12 weeks. Brown, B. G. et al. 1998. Lipid altering or antioxidant vitamins for patients with coronary disease and very low HDL cholesterol? The HDLAtherosclerosis Treatment Study Design. Can J Cardiol, Suppl A, Apr. 14, 6A-13A. Chojnowska-Jezierska, J. and Adamska-Dyniewska, H. 1997. [Prolonged treatment with slow release nicotinic acid in patients with type II Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 129

hyperlipidemia]. Pol Arch Med Wewn, 98(11) Nov., 391-399 Dose: one-year therapy with slow-release nicotinic acid McKenney, J.M. et al. 1998. A randomized trial of the effects of atorvastatin and niacin in patients with combined hyperlipidemia or isolated hypertriglyceridemia. Collaborative Atorvastatin Study Group. Am J Med, 104(2) Feb., 137-143 Dose: immediate-release niacin 1 g 3x/day for 12 weeks Brown, B. G. et al. 1998. Use of niacin, statins, and resins in patients with combined hyperlipidemia. Am J Cardiol, 81(4A) Feb. 26, 52B-59B Fagerberg, B. et al. 1998. Mortality rates in treated hypertensive men with additional risk factors are high but can be reduced: a randomized intervention study. Am J Hypertens, 11(1 Pt 1) Jan., 14-22. Kukharchuk, V. V. et al. 1997. [The effect of long-term Enduracin monotherapy on the clinical and biochemical status of patients with ischemic heart disease]. Ter Arkh, 69(9), 41-45 Dose: enduracin in a dose 1500 mg/day. Brown, B. G. et al. 1997. Moderate dose, three-drug therapy with niacin, lovastatin, and colestipol to reduce low-density lipoprotein cholesterol <100 mg/dl in patients with hyperlipidemia and coronary artery disease. Am J Cardiol, 80(2) Jul. 15, 111-115. Dose: initial 12-month phase, regular niacin 500 mg qid alternated with a polygel controlled-release formula. Gardner, S. F. et al. 1997. Combination of low-dose niacin and pravastatin improves the lipid profile in diabetic patients without compromising glycemic control. Ann Pharmacother, 31(6) Jun., 677-682 Dose: low-dose niacin (1.5 g/d) over a 14 week period. Vitamin C Aging Parle M, Dhingra D. Ascorbic Acid: a promising memory-enhancer in mice. J Pharmacol Sci. 2003 Oct;93(2):129-35. Phillips, C. L. et al. 1994. Effects of ascorbic acid on proliferation and collagen synthesis in relation to the donor age of human dermal fibroblasts. J Invest Dermatol 103(2) Aug., 228-232. Postaire, E. et al. 1995. Increase of singlet oxygen protection of erythrocytes by Vitamin E, Vitamin C and Beta Carotene intakes. Biochem Mol Biol Int, 35(2), Feb., 371-375. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 130

Dose: 30mg/day Vitamin C Okamoto, K et al. 1992. [The relationship between dietary ascorbic acid intake and serum lipid concentration in the aged.] Nippon Ronen Igakkai Zasshi 29(12), Dec., 908-911. Cheraskin, E. 1994. Chronologic versus biologic age. J Advancement Med 7(1), Spring, 31-41. Dose: 100mg-200mg/day Vitamin C Cheraskin, E. 1993. Vitamin C, cancer and aging. Age 16, 55-58. Delafuente, J. C. et al. 1986. Immunologic modulation by vitamin C in elderly. Int J Immunopharmacol 8(2), 205-211. Alcohol Toxicity Sivaram AG, Suresh MV, Indira M. Combined effect of ascorbic acid and selenium supplementation on alcohol-induced oxidative stress in guinea pigs. Comp Biochem Physiol C Toxicol Pharmacol. 2003 Mar;134(3):397-401 Susick, R. L. and Zannoni, V. G. 1987. Effect of ascorbic acid on the consequences of acute alcohol consumption in humans. Clin Pharmacol Ther, 41(5), May, 502-509. Dose: 0.95gm/kg body weight over 2.5 hours for 2 weeks Wickramasinghe, S. N. and Hasan, R. 1994. In vivo effects of Vitamin C on the cytotoxicity of post-ethanol serum. Biochem Pharmacol, 48(3), Aug. 3, 621-624. Dose: 1gm/day for 3 days Chen, M. F. et al. 1990. Effect of ascorbic acid on plasma alcohol clearance. J Am Coll Nutr, 9(3), June, 185-189. Arthritis Jensen NH. Reduced pain from osteoarthritis in hip joint or knee joint during treatment with calcium ascorbate. A randomized, placebocontrolled cross-over trial in general practice. Ugeskr Laeger. 2003 Jun 16;165(25):2563-6.s Oldroyd, K. G. and Dawes, P. T. 1985. Clinically significant vitamin C deficiency in rheumatoid arthritis. British J Rheumatology 24(4) Nov, 362363. Davis, R. H. et al. 1990. Vitamin C influence of localized adjuvant arthritis. J American Podiatry Med Assoc 80(8) Aug, 414-418. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 131

Dose: 150mg/kg of subcutaneous Vitamin C for 20 days Asthma Kongerud J, Crissman K, Hatch G, Alexis N. Ascorbic acid is decreased in induced sputum of mild asthmatics. Inhal Toxicol. 2003 Feb;15(2):101-9. Hatch, G. E. 1995. Asthma, inhaled oxidants, and dietary antioxidants. American J Clin Nutr 61(3 Suppl), Mar, 625S-630S. Anderson, R. et al. 1980. The effect of ascorbate on cellular humoral immunity in asthmatic children. South African Med J 58(24) Dec 13, 974977. Dose: 1g ascorbic single daily dose for a 6-month period Anah, C. O. et al. 1980. High dose ascorbic acid in Nigerian asthmatics. Trop Geogr Med 32(2) June, 132-137. Dose: 1g of ascorbic acid daily Rozanov, E. M. et al. 1987. [Vitamin PP and C allowances and their correction in the treatment of bronchial asthma patients.] Vopr Pitan (6):214, Nov-Dec, 21-24. Dose: 275-300 mg of Vitamin C Cancer Drisko JA, Chapman J, Hunter VJ. The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer. J Am Coll Nutr. 2003 Apr;22(2):118-23. Block, G. et al. 1991. Epidemiologic evidence regarding vitamin C and cancer. Am J Clin Nutr 54(6 Suppl) Dec., 1310S-1314S. Herrero, R. et al. A case-control study of nutrient status and invasive cervical cancer: I. Dietary indicators. Am J Epi 134(11), Dec. 1, 1335-1346. Stahelin, H. B. et al. Plasma antioxidant vitamins and subsequent cancer mortality in the 12-year follow-up of the prospective based study. Am J Epi 133(8), Apr. 15, 766-775. Knekt, P et al. 1991. Dietary antioxidants and the risk of lung cancer. Am J Epi 134(5), Sept. 1, 471-479. Trizna, Z. et al. 1991. Effects of N-acetyl-L-cysteine and ascorbic acid on mutagen-induced chromosomal sensitivity in patients with head and neck cancers. Am J Surgery 162(4), Oct., 294-298. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 132

Ferraroni, M et al. 1994. Selected micronutrient intake and the risk of colorectal cancer. British J Cancer 70(6), Dec., 1150-1155. Shibata, A. et al. 1992. Intake of vegetables, fruits, beta-carotene, vitamin C and vitamin supplements and cancer incidence among the elderly: A prospective study. British J Cancer 66(4) Oct., 673-679. Bussey, H. J. et al. A randomized trial of ascorbic acid in polyposis coli. Cancer 50(7) Oct. 1, 1434-1439. Dose: 3g/day of ascorbic acid for 9 months Fontham, E. T. et al. 1988. Dietary vitamins A and C and lung cancer risk in Louisiana. Cancer 62(10), Nov. 15, 2267-2273. Park, C. H. et al. 1980. Growth suppression of human leukemic cells in vitro by L-ascorbic acid. Cancer Res 40(4), 1062-1065. Kaugars, G. et al. 1993. Serum and tissue antioxidant levels in supplemented patients with premalignant oral lesions (meeting abstract). FASEB J 7(4), A519. Dose: 1000mg Vitamin C for 9 months Sobala, G. M. et al. 1989. Ascorbic acid in the human stomach. Gastroenterology 97(2) Aug., 357-363. Paganelli, G. M. et al. 1992. Effect of vitamin A, C, and E supplementation on rectal cell proliferation in patients with colorectal adenomas. J National Cancer Inst. 84(1) Jan. 1, 47-51. Brock, K. E. et al. Nutrients in diet and plasma and risk of in situ cervical cancer. J National Cancer Inst. 80(8) June 15, 580-585. Potter, J. D. and McMichael, A. J. 1986. Diet and cancer of the colon and rectum: A case-control study. J National Cancer Inst. 76(4) Apr., 557-569. Moffat, L. et al. 1983. High dose ascorbate therapy and cancer. NFCR Cancer Res Assoc Symp. (2), 243-256. Dose: 2.5 g Vitamin C 4x/day Kaugars, G. et al. 1993. The role of antioxidants in the treatment of oral leukoplakia. CCPC-93: Second Int Cancer Chemo Prevention Conf. Berlin, Germany, Apr. 28-30, 65. Dose: 1000mg/day of ascorbic acid for 9 months Greco, A. M. et al. 1982. Study of blood vitamin C in lung and bladder cancer patients before and after treatment with ascorbic acid: A preliminary report. Acta Vitaminol Enzymol 4(1-2), 155-162. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 133

Dose: 5g/day Glatthaar, B. E. et al. The role of ascorbic acid in carcinogenesis. Adv Exp Med Biol 206, 357-377. Chen, L H. et al. 1988. Vitamin C, vitamin E and cancer. Anticancer Res 8(4), July-Aug., 739-748. Garcia-Alejo Hernandez, R. et al. 1989. [Radioprotective effect of ascorbic acid on oral structures in patients with cancer of the head and neck]. Av odontoestomatol 5(7), Sept., 469-472. La Vecchia, C. et al. Selected micronutrient intake and the risk of gastric cancer. Cancer Epidemiol Biomarkers Prev. 3(5) July-Aug., 393-398. Dyke, G. W. et al. Effect of vitamin C supplementation on gastric mucosal DNA damage. Carcinogenesis 15(2), 291-295. Slattery, M. L. et al. 1990. Dietary vitamins A, C, and E and selenium as risk factors for cervical cancer. Epidemiology 1(1), Jan., 8-15. Reed, P. I. et al. 1991. Effect of ascorbic acid on the intragastric environment in patients at increased risk of developing gastric cancer. IARC Sci Publ. (105), 139-142. Nomura, A. M. et al. 1991. Dietary factors in cancer of the lower urinary tract. Int. J Cancer 48(2), May 10, 199-205. Verreault, R. et al. 1989. A case-control study of diet and invasive cervical cancer. Int J Cancer 43(6), June 15, 1050-1054. Cameron, E. 1982. Vitamin C and cancer: An overview. Int J Vitamin Nutr Res Suppl 23, 115-127. Murata,, A. et al. 1982. Prolongation of survival times of terminal cancer patients by administration of large doses of ascorbate. Int J Vitamin Nutr Res Suppl 23, 103-113. Waddell, . R. and Germer, R. E. 1980. Indomethacin and ascorbate inhibit desmoid tumors. J Surg Oncol 15(1), 85-90. Ghosh, J and Das, S. 1995. Evaluation of vitamin A and C status in normal and malignant conditions and their possible role in cancer prevention. Japanese J Cancer Res 76(12) Dec., 1174-1178. Cameron, E. and Campbell, A. 1991. Innovation vs. quality control: An 'Unpublishable' clinical trial on supplemental ascorbate in incurable Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 134

cancer. Med Hyp 36(3), Nov., 185-189. Jaffey, M. Vitamin C and cancer: Examination of the value of eleven trial results using broad inductive reasoning. Med Hyp 8(1), 49-84. Dose: 10g/day Vitamin C Campbell, A. et al. 1991. Reticulum cell sarcoma: Two complete spontaneous' regressions in response to high-dose ascorbic acid therapy. A report on subsequent progress. Oncology 48(6), 495-497. Kaminski, M. and Boal, R. 1992. An effect of ascorbate acid on delayedonset muscle soreness. Pain 50(3), Sept., 317-321. Raushenbakh, M. O. et al. [Effect of ascorbic acid on formation and leukemogenic activity of p-hydroxyphenyllactic acid]. Probl Gematol Pereliv Krovi 27(7), 3-6. Dose: 8g/day over 8-10 days before chemotherapy Stahelin, H. B. 1989. [Vitamins and cancer: Results of a Basel study]. Soz Praventivmed 34(2), 75-77. Gorozhanskaia. E. G. et al. [The role of ascorbic acid in the combined preoperative preparation of cancer patients]. Vopr Onkol 35(4), 436-441. Dose: 1.5g/day of ascorbic acid for 7 days. Baikova, V. N. et al. 1982. [The effect of large doses of ascorbic acid on tyrosine metabolism and hemoblastosis course in children]. Vopr Onkol 28(9), 28-34. Dose: 100mg/kg/day. Yuan, J. M. et al. 1995. Diet and breast cancer in Shanghai and Tianjin, China. British J Cancer 71, 1353-1358. Howe, G. R. et al. 1990. Dietary factors and the risk of breast cancer: Combined analysis of 12 case-controlled studies. J National Cancer Inst. 82, 561-569. VanEenwyk, J. 1993. The role of vitamins in the development of cervical cancer. The Nutrition Report. 11(1), Jan., 1-8. Amburgey, C. F. et al. 1993. Undernutrition as a risk factor for cervical intraepithelial neoplasia: A case control analysis. Nutrition and Cancer 20(1), 51-60. Cardiovascular/Coronary Heart Disease Mak S, Newton GE. Vitamin C augments the inotropic response to Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 135

dobutamine in humans with normal left ventricular function. Circulation. 2001 Feb 13;103(6):826-30. Salonen, J. T. et al. 1991. Effects of antioxidant supplementation on platelet function: A randomized pair-matched, placebo-controlled, double-blind trial in men with low antioxidant status. Am J Clin Nutr. 53(5), May, 1222-1229. Dose: 600mg of ascorbic acid/day. Trout, D. L. 1991. Vitamin C and cardiovascular risk factors. Am J Clin Nutr 53(1 Suppl), Jan., 322S-325S. 34 Sisto, T. et al. 1995. Pretreatment with antioxidants and allopurinol diminishes cardiac onset events in coronary artery bypass grafting. Ann Thorac Surg 59(6) June, 1519-1523. Khaw, K. T. and Woodhouse, P. 1988. Interrelation of vitamin C, infection, haemostatic factors and cardiovascular disease. British Med J 310(6994), June 17, 1559-1563. Dose: 60mg. Brox, A. G. et al. 1988. Treatment of idiopathic thrombocytopenic purpura with ascorbate. British J Haematology 70(3) Nov., 341-344. Singh, R. B. et al. 1995. Effect of antioxidant-rich foods on plasma ascorbic acid, cardiac enzyme, and lipid peroxide levels in patients hospitalized with acute myocardial infarction. J Am Dietetic Assoc. 95(7), July, 775-780. Singh, R. B. et al. 1994. Plasma levels of antioxidant vitamins and oxidative stress in patients with acute myocardial infarction. Acta Cardiol 49(5), 441452. Riemersma. R. A. et al. 1989. Low plasma vitamins E and C. Increased risk of angina in Scottish men. Annals NY Academy Sci. 570, 291-295. Gey, K. F. et al. 1987. Relationship of plasma level of vitamin C to mortality from ischemic heart disease. Annals NY Academy Sci. 498, 110-123. Cordova, C, et al. 1982. Influence of ascorbic acid on platelet aggregation in vitro and in vivo. Atherosclerosis 41(1), Jan., 15-19. Dose: 2g of ascorbic acid. Bordia, A. K. 1980. The effect of vitamin C on blood lipids, fibrinolytic activity and platelet adhesiveness in patients with coronary artery disease. Atherosclerosis 35(2), Feb., 181-187. Dose: 2g/day Vitamin C. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 136

Li, C. C. 1990. [Changes on creatine phosphokinase and malondialdehyde in the serum and clinical use of large doses of vitamin C following open heart surgery]. Chung Hua Wai Ko Tsa Chih 28(1) Jan., 16-17, 60-61. Dose: 250mg/kg Vitamin C prior to heart surgery. Bordia, A. and Verma, S. K. 1985. Effect of vitamin C on platelet adhesiveness and platelet aggregation in coronary artery disease patients. Clinical Cardiology 8(10) Oct.., 552-554. Dose: 1g and 1 g every 8 hours over 10 days. Yoshioka, M. et al. 1984. Inverse association of serum ascorbic acid level and blood pressure or rate of hypertension in male adults aged 30-39 years. Int J Vitamin Nutr Res. 54(4), 343-347. Simon, J. A. 1992. Vitamin C and cardiovascular disease: A review. J Am Coll Nutr. 11(2) Apr., 107-125. Mostafa, S. et al. 1989. Beneficial effects of vitamin C on risk factors of cardiovascular diseases. J Egyptian Public health Assoc. 64(1-2), 123-133. Dose: 500mg/day of Vitamin C. Fujimura, I. et al. [Correlation between hypercholesterolemia and vitamin C deficient diet]. Rev Hosp Clin Fac Med Sao Paulo 46(1), Jan.-Feb., 14-18. Dobson, H. M. et al. 1984. The effect of ascorbic acid on the seasonal variations in serum cholesterol levels. Scottish Med J 29(3) July, 176-182. Dose: 1g of ascorbic acid for 2 months. Gey, K. F. et al. [Essential antioxidants in cardiovascular diseases-Lessons for Europe]. Ther Umsch 51(7) July, 475-482. Dingchao, H. et al. 1994. The protective effects of high-dose ascorbic acid on myocardium against reperfusion injury after cardiopulmonary bypass. Thorac Cardiovasc Surg 42(5) Oct., 276-278. Dose: 250 mg/kg. Cataracts Serum ascorbic acid and other correlates of self-reported cataract among older Americans. Simon JA, Hudes ES. Serum ascorbic acid and other correlates of selfreported cataract among older Americans. J Clin Epidemiol. 1999 Dec;52(12):1207-11. Jacques, P. F. and Chylack Jr., L. T. Epidemiologic evidence of a role for the antioxidant vitamins and carotenoids in cataract prevention. Am J Clin Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 137

Nutr 53(1 Suppl) Jan., 352S-355S. Robertson, J. M. et al. 1991. A possible role for vitamins C and E in cataract prevention. Am J Clin Nutr. 53(1 Suppl), Jan., 346S-351S. Jacques, P. F. et al. 1988. Antioxidant status in persons with and without senile cataract. Arch Ophthalmol 106(3)m Mar., 337-340. Gerster, H. 1989. Antioxidant vitamins in cataract prevention. Z Ernahrungswiss. 28(1), Mar., 56-75. Cervical Dysplasia Ho GY, Palan PR, Basu J, Romney SL, Kadish AS, Mikhail M, Wassertheil-Smoller S, Runowicz C, Burk RD. Viral characteristics of human papillomavirus infection and antioxidant levels as risk factors for cervical dysplasia. Int J Cancer. 1998 Nov 23;78(5):594-9. Wassertheil-Smoller, S. et al. 1981. Dietary Vitamin C and uterine cervical Dysplasia. Am J Epi, 114(5), No., 714-724. Romney, S. L. et al. 1985. Plasma Vitamin C and uterine cervical dysplasia. Am J Obstetrics Gynecology, 151(7), Apr. 1, 976-980. Common Cold Van Straten M, Josling P. Preventing the common cold with a vitamin C supplement: a double-blind, placebo-controlled survey. Adv Ther. 2002 MayJun;19(3):151-9. Hemila, H. 1994. Does Vitamin C alleviate the symptoms of the common cold?-A review of current evidence. Scandanavian J Infect Dis, 26(1), 1-6. Dose: 1g Vitamin C. Diabetes Krawczuk-Rybak M, Peczynska J, Urban M. Usefulness of antioxidant vitamin supplementation in children and adolescents with newly diagnosed diabetes mellitus type. Endokrynol Diabetol Chor Przemiany Materii Wieku Rozw. 1999;5(1):11-20. Johnson, C. S. and Yen, M. F. 1994. Megadose of vitamin C delays insulin response to a glucose challenge in normoglycemic adults. Am J Clin Nutr 60(5), Nov., 735-738. Dose: 2g/day for 2 weeks. Paolisso, G. et al. 1994. Plasma vitamin C affects glucose homeostasis in healthy subjects and in non-insulin-dependent diabetics. Am J Physiol Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 138

266(2 Pt 1), Feb., E261-268. Davie, S. J. et al. Effect of vitamin C on glycosylation of proteins. Diabetes 41(2), Feb., 167-173. Dose: 1g/day of Vitamin C for 3 months. Vinson, J. A. et al. 1989. In vitro and in vivo reduction of erythrocyte sorbitol by ascorbic acid. Diabetes 38(8), Aug., 1036-1041. Dose: 500mg/day for 2 weeks. Yue, D. K. et al. 1990. Abnormalities of ascorbic acid metabolism and diabetic control: Differences between diabetic patients and diabetic rats. Diabetes Res Clin Pract. 9(3) July, 239-244. Kodama, M. et al. 1993. Diabetes mellitus is controlled by vitamin C treatment. In vivo 7(6A), Nov.-Dec., 535-350. Cunningham, J. J. et al. 1994. Vitamin C: An aldose reductase inhibitor that normalizes erythrocyte sorbitol in insulin-dependent diabetes mellitus. J Am Coll Nutr. 13(4), Aug., 344-350. Dose: 100-600mg/day of Vitamin C for 58 days. Cunningham, J. J. et al. Reduced mononuclear leukocyte ascorbic acid content in adults with insulin-dependent diabetes mellitus consuming adequate dietary vitamin C. Metabolism 40, 146-149. Fatigue Thompson D, Williams C, McGregor SJ, Nicholas CW, McArdle F, Jackson MJ, Powell JR. Prolonged vitamin C supplementation and recovery from demanding exercise. Int J Sport Nutr Exerc Metab. 2001 Dec;11(4):466-81. Cheraskin, E. et al. 1976. Daily Vitamin C consumption and fatigability. J Am Geriatric Soc., 24(3), 136-137. Glaucoma Filina AA, Sporova NA. Effect of lipoic acid on tyrosine metabolism in patients with open-angle glaucoma. Vestn Oftalmol. 1991 May-Jun;107(3):19-21. Jampel, H. D. 1990. Ascorbic acid is cytotoxic to dividing human Tenon's capsule fibroblasts: A possible contributing factor in glaucoma filtration surgery success. Arch Ophthalmol. 108(9) Sept., 1323-1325. Glutathione Deficiency Lenton KJ, Sane AT, Therriault H, Cantin AM, Payette H, Wagner JR. Vitamin C augments lymphocyte glutathione in subjects with ascorbate deficiency. Am J Clin Nutr. 2003 Jan;77(1):189-95.

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Jain, A. et al. 1994. Effect of ascorbate or N-acetylcysteine treatment in a patient with hereditary glutathione synthetase deficiency. J Pediatrics, 124(2), Feb., 229-233. Dose: 0.7 mmol/kg/day for 1-2 weeks. Herpes Hovi T, Hirvimies A, Stenvik M, Vuola E, Pippuri R. Topical treatment of recurrent mucocutaneous herpes with ascorbic acid-containing solution. Antiviral Res. 1995 Jun;27(3):263-70. Fitzherbert, J. 1979. Genital herpes and zinc. Med J Aust, 1, 399. Dose: 250mg Vitamin C 2x/day Terezhalmy, G. T. et al. 1978. The use of water-soluble bioflavonoidascorbic acid complex in the treatment of recurrent herpes labialis. Oral Surgery, 45, 56-62. Dose: 200mg Vitamin C for 3-5 times/day for 3 days beginning after onset of symptoms. Immune enhancement Heuser G, Vojdani A. Enhancement of natural killer cell activity and T and B cell function by buffered vitamin C in patients exposed to toxic chemicals: the role of protein kinase-C. Immunopharmacol Immunotoxicol. 1997 Aug;19(3):291-312. Anderson, R. et al. 1980. The effects of increasing weekly doses of ascorbate on certain cellular and humoral immune functions in normal volunteers. Am J Clin Nutr. 33(1) Jan., 71-76. Dose: 2-3g/day. Penn, N. D. et al. 1991. The effect of dietary supplementation with vitamins A, C and E on cell-mediated immune function in elderly long-stay patients: A randomized controlled trial. Age Ageing 20(3) May, 169-174. Kodama, M. et al. 1994. Autoimmune disease and allergy are controlled by vitamin C treatment. In vivo 8(2), Nar.-Apr., 251-257. Delafuente, J. C. et al. 1986. Immunologic modulation by vitamin C in the elderly. Int J Immunopharmacol 8(2), 205-211. Dose: 2g/day for 3 weeks. Menopause Vihtamaki T, Parantainen J, Koivisto AM, Metsa-Ketela T, Tuimala R. Oral Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 140

ascorbic acid increases plasma oestradiol during postmenopausal hormone replacement therapy. Maturitas. 2002 Jun 25;42(2):129-35. Horoschak, A. 1959. Nocturnal leg cramps, easy bruisability and epistaxis in menopausal patients: Treated with Hesperidin and ascorbic acid. Delaware State Med J. 19-22. Dose: 200mg of Vitamin C following each meal and at bedtime for 2 weeks plus another 100mg of both 4x/day for 4 weeks. Neutrophil Dysfunction Demertzis S, Scherer M, Langer F, Dwenger A, Hausen B, Schafers HJ. Ascorbic acid for amelioration of reperfusion injury in a lung autotransplantation model in sheep. Ann Thorac Surg. 2000 Nov;70(5):1684-9. Rebora, A. et al. 1980. Neutrophil dysfunction and repeated infections: Influence of levamisole and ascorbic avid. British J Dermatology, 102(1), Jan., 49-56. Levy, R. and Schlaeffer, F. 1993. Successful treatment of a patient with recurrent furunculosis by Vitamin C: Improvement of clinical course and of impaired neutrophil functions. Int J Dermatology, 32(11), Nov., 832-834. Dose: 500mg/day of Vitamin C for 30 days. Obesity Harnroongroj T, Jintaridhi P, Vudhivai N, Pongpaew P, Tungtrongchitr R, Phonrat B, Changbumrung S, Schelp FP. B vitamins, vitamin C and hematological measurements in overweight and obese Thais in Bangkok. J Med Assoc Thai. 2002 Jan;85(1):17-25. Naylor, G. J. et al. 1985. A double blind placebo controlled trial of ascorbic acid in obesity. Nutr Health, 4(1), 25-28. Dose: 3g/day for 6 weeks. Paget's Disease Basu TK, Smethurst M, Gillett MB, Donaldson D, Jordan SJ, Williams DC, Hicklin JA. Acta Vitaminol Enzymol. 1978;32(1-4):45-9. Ascorbic acid therapy for the relief of bone pain in Paget's disease. Smethurst, M. et al. 1981. Combined therapy with ascorbic acid and calcitonin for the relief of bone pain in Paget's disease. Acta Vitaminol Enzymol, 3(1), 8-11.

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Pancreatitis Shishlov VI. The status of ascorbate oxidation-reduction system of blood in patients with chronic pancreatitis throughout parenteral nutrition. Klin Khir. 1999;(10):7-9. Bonham MJ, Abu-Zidan FM, Simovic MO, Sluis KB, Wilkinson A, Winterbourn CC, Windsor JA. Early ascorbic acid depletion is related to the severity of acute pancreatitis. Br J Surg. 1999 Oct;86(10):1296-301. Scott, P. et al. 1993. Vitamin C status in patients with acute pancreatitis. British J Surgery, 80(6), June, 750-754. Parkinson's disease Martin A, Youdim K, Szprengiel A, Shukitt-Hale B, Joseph J. Roles of vitamins E and C on neurodegenerative diseases and cognitive performance. Nutr Rev. 2002 Oct;60(10 Pt 1):308-26. Fahn, S. 1992. A pilot trial of high-dose alpha-tocopherol and ascorbate in early Parkinson's disease. Annals Neurology 32 Suppl., S128-S132. Reilly, D. K. et al. 1983. On-off effects in Parkinson's disease: A controlled investigation of ascorbic acid therapy. Advanc Neurol 37, 51-60. Linazasoro, G. and Gorospe, A. [Treatment of complicated Parkinson disease with a solution of levodopa-carbidopa and ascorbic acid]. Neurologia 10(6) June-July, 220-223. Yapa, S. C. 1992. Detection of subclinical ascorbate deficiency in early Parkinson's Disease. Public Health 106(5) Sept., 393-395. Periodontal Disease Lowe G, Woodward M, Rumley A, Morrison C, Tunstall-Pedoe H, Stephen K. Total tooth loss and prevalent cardiovascular disease in men and women: possible roles of citrus fruit consumption, vitamin C, and inflammatory and thrombotic variables. J Clin Epidemiol. 2003 Jul;56(7):694-700. Leggott, P. J. et al. 1991. Effects of ascorbic acid depletion and supplementation of periodontal health and subgingival microflora in humans. J Dental Res, 70(12), Dec., 1531-1536. Leggott, P. J. et al. 1986. The effect of controlled ascorbic acid depletion and supplementation on periodontal health. J Periodonotal, 57(8), Aug., 480-485. Respiration Kelly Y, Sacker A, Marmot M. Nutrition and respiratory health in adults: 41 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 142

findings from the health survey for Scotland. Eur Respir J. 2003 Apr;21(4):66471. Lee MH, Shiau SY. Increase of dietary vitamin C improves haemocyte respiratory burst response and growth of juvenile grass shrimp, Penaeus monodon, fed with high dietary copper. Fish Shellfish Immunol. 2003 Apr;14(4):305-15. Peters, E. M. et al. 1993. Vitamin C supplementation reduces the incidence of postrace symptoms of upper-respiratory-tract infection in ultramarathon runners. Am J Clin Nutr. (2) Feb., 170-174. Dose: 600mg/day Vitamin C. Mohsenin, V. 1987. Effect of vitamin C on NO2-induced airway hyperresponsiveness in normal subjects: A randomized double-blind experiment. Am Rev Resp Dis 136(6), Dec., 1408-1411. Dose: 500mg 4x/day of ascorbic acid for 3 days. Bucca, C. et al. 1990. Effect of vitamin C on histamine bronchial responsiveness of patients with allergic rhinitis. Ann Allergy 65(4), Oct., 311-314. Dose: 2g of Vitamin C. Bucca, C. et al. 1989. Effects of vitamin C on airway responsiveness to inhaled histamine in heavy smokers. European Respir J 2(3), Mar., 229-233. Dose: 2g of Vitamin C. Schizophrenia Rachkauskas GS. The efficacy of enterosorption and a combination of antioxidants in schizophrenics. Lik Sprava. 1998 Jun;(4):122-4. Sandyk, R. and Kanofsky, J. D. 1993. Vitamin C in the treatment of schizophrenia. Int J Neuroscience, 68(1-2), Jan., 67-71. Sickle Cell Anemia Jaja SI, Ikotun AR, Gbenebitse S, Temiye EO. Blood pressure, hematologic and erythrocyte fragility changes in children suffering from sickle cell anemia following ascorbic acid supplementation. J Trop Pediatr. 2002 Dec;48(6):366-70. 42 Jain, S. K. et al. 1985. Reduced levels of plasma ascorbic acid (Vitamin C) in sickle cell disease patients: Its possible role in the oxidant damage to sickle cells in vivo. Clin Chim Acta, 149(2-3), July 15, 257-161. Smoking Cessation Dietrich M, Block G, Hudes M, Morrow JD, Norkus EP, Traber MG, Cross CE, Packer L. Antioxidant supplementation decreases lipid peroxidation biomarker F(2)-isoprostanes in plasma of smokers. Cancer Epidemiol Biomarkers Prev. 2002 Jan;11(1):7-13. Levin, E. D. et al. 1993. Clinical trials using ascorbic acid aerosal to aid smoking cessation. Drug Alcohol Depend, 33(3), Oct., 211-223. Stroke Kurl S, Tuomainen TP, Laukkanen JA, Nyyssonen K, Lakka T, Sivenius J, Salonen JT. Plasma vitamin C modifies the association between hypertension and risk of stroke. Stroke. 2002 Jun;33(6):1568-73. Gale, C. R. et al. 1995. Vitamin C and risk of death from stroke and coronary Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 143

heart disease in cohort of elderly people. British Med J 310(6994) June 17, 1563-1566. Tetanus Jahan, J. K. et al. 1985. Effect of ascorbic acid in the treatment of tetanus. Bangladesh Med Res Council Bull, 10(1), June, 24-28. Dose: 1000 mg/day iv Wound healing Jagetia GC, Rajanikant GK, Rao SK. Evaluation of the effect of ascorbic acid treatment on wound healing in mice exposed to different doses of fractionated gamma radiation. Radiat Res. 2003 Mar;159(3):371-80. Ringsdorf Jr., W. M. and Cheraskin, E. 1982. Vitamin C and human wound healing. Oral Surg Med Oral Pathol 53(3) Mar., 231-236. Dose: 500-3000mg/day. Goode, H. F. et al. 1992. Vitamin C depletion and pressure sores in elderly patients with femoral neck fractures. British Med J 305(6859) Oct. 17, 925927. Vitamin E 43 Abetalipoproteinemia Chowers I, Banin E, Merin S, Cooper M, Granot E. Long-term assessment of combined vitamin A and E treatment for the prevention of retinal degeneration in abetalipoproteinaemia and hypobetalipoproteinaemia patients. Eye. 2001 Aug;15(Pt 4):525-30. Illingworth, D. R. et al. 1980. Abetalipoprotein. Report of two cases and review of therapy. Arch Neurol 37(10), Oct., 659-662. Bishara, S. et al. 1982. Combined Vitamin A and therapy prevents retinal electrophysiological deterioration in abetalipoprotein. British J Ophthalmology 66(12), Dec., 767-770. Muller, D. P. et al. 1983. Vitamin E and neurological function: Abetalipoproteinaemia and other disorders of fat absorption. Ciba Found Symp 101, 106-121. Hegele, R. A. and Angel, A. 1985. Arrest of neuropathy and myopathy in abetalipoproteinemia with high-dose Vitamin E therapy. Canadian Med Assoc J 132(1), Jan., 1, 41-44. Dose: 3200mg/day over 7 years. Aging Polidori MC. Antioxidant micronutrients in the prevention of age-related diseases. J Postgrad Med. 2003 Jul-Sep;49(3):229-35. Courtiere, A. et al. 1989. [Lipid peroxidation in aged patients. Influence of an antioxidant combination (vitamin C-vitamin E-rutin)]. Therapie 44(1) Jan.-Feb., 13-17. Alzheimer's disease Sano M. Noncholinergic treatment options for Alzheimer's disease. J Clin Psychiatry. 2003;64 Suppl 9:23-8. Klatte ET, Scharre DW, Nagaraja HN, Davis RA, Beversdorf DQ. Combination therapy of donepezil and vitamin E in Alzheimer disease. Alzheimer Dis Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 144

Assoc Disord. 2003 Apr-Jun;17(2):113-6. Adams, Jr., J. D. et al. 1991. Alzheimer's and Parkinson's Disease. Brain levels of glutathione, glutathione disulfide, and Vitamin E. Mol Chem Neuropathol. 14(3), June, 213-226. Anemia 44 Juan-Salles C, Prats N, Resendes A, Domingo M, Hilton D, Ruiz JM, Garner MM, Valls X, Marco AJ. Anemia, myopathy, and pansteatitis in vitamin Edeficient captive marmosets (Callithrix spp.). Vet Pathol. 2003 Sep;40(5):540-7. Ono, K. 1985. Effects of large dose of Vitamin E supplementation on anemia in hemodialysis patients. Nephron, 40(4), 440-445. Dose: 600mg/day for 30 days. Arthritis Can C, Cinar MG, Kosay S, Evinc A. Vascular endothelial dysfunction associated with elevated serum homocysteine levels in rat adjuvant arthritis: effect of vitamin E administration. Life Sci. 2002 Jun 14;71(4):401-10. Honkanen, V. E. et al. 1990. Serum cholesterol and Vitamins A and E in juvenile chronic arthritis. Clin Exp Pheumatol 8(2), Mar.-Apr., 187-191. Honkanen, V. E. et al. 1989. Vitamins A and E, retinol binding protein and zinc in Rheumatoid Arthritis. Clin Exp Pheumatol 7(5), Sept.-Oct., 465-469. Ataxia Roubertie A, Biolsi B, Rivier F, Humbertclaude V, Cheminal R, Echenne B. Ataxia with vitamin E deficiency and severe dystonia: report of a case. Brain Dev. 2003 Sep;25(6):442-5. Rayner, R. J. et al. 1993. Isolated Vitamin E deficiency and progressive ataxia. Arch Dis Child 69(5), Nov., 602-603. Brain injury Ikeda Y, Mochizuki Y, Nakamura Y, Dohi K, Matsumoto H, Jimbo H, Hayashi M, Matsumoto K, Yoshikawa T, Murase H, Sato K. Protective effect of a novel vitamin E derivative on experimental traumatic brain edema in rats-preliminary study. Acta Neurochir Suppl. 2000;76:343-5. Dzandzhgava, T. G. and Shakarishvili, R. R. 1991. [Effect of alphatocopherol and selenium on the activity of antioxidant enzymes and level of lipid peroxidation products in erythrocytes of patients with cerebral ischemia]. Vopr Med Khim 37(5), Sept.-Oct. 79-82. Cancer Neuzil J. Vitamin E succinate and cancer treatment: a vitamin E prototype for selective antitumour activity. Br J Cancer. 2003 Nov 17;89(10):1822-6. 45 Zu K, Ip C. Synergy between selenium and vitamin E in apoptosis induction is associated with activation of distinctive initiator caspases in human prostate cancer cells. Cancer Res. 2003 Oct 15;63(20):6988-95. Kneky, P. et al. 1991. Vitamin E and cancer prevention. Am J Clin Nutr 53(1 Suppl), Jan., 283S-286S. Kneky, R. et al. 1988. Serum Vitamin E and risk of cancer among Finnish men during a 10-year follow-up. Am J Epidemiology 127(1), Jan., 28-41. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 145

Knekt, P. et al. 1991. Dietary antioxidants and the risk of lung cancer. Am J Epidemiology 134(5), Sept. 1, 471-479. Garewal, H. S. and Schantz, S. 1995. Emerging role of beta-carotene and antioxidant nutrients in prevention of oral cancer. Arch Otalaryngol Head Neck Surg 121(2), Feb., 141-144. Wald, N. J. et al. 1984. Plasma retinol, beta-carotene and Vitamin E levels in relation to the future risk of breast cancer. British J Cancer 49(3), Mar., 321324. Wald, N. J. et al. 1987. Serum Vitamin E and subsequent risk of cancer. British J Cancer 56(1), July, 69-72. Salonen, J. T. et al. 1985. Risk of cancer in relation to serum concentrations of selenium and Vitamins A and E: Matched case-control analysis of prospective data. British Med J 290(6466), Feb. 9, 417-420. London, R. S. et al. 1981. Endocrine parameters and alpha-tocopherol therapy of patients with mammary dysplasia. Cancer Res 41(9 Pt 2), Sept., 3811-3813. Dose: 600 units/day. Taylor, P. R. et al. 1994. Prevention of esophageal cancer: The nutrition intervention trials in Linxian, China: Linxian nutrition intervention trials study group. Cancer Res. 54(7 Suppl), April 1, 2029s-2031s. Dose: 30-60IU/day for 5.25 years. Bostick, R. M. et al. 1993. Reduced risk of colon cancer with high intake of Vitamin E: The Iowa Women's Health Study. Cancer Res 53(18), Sept. 15, 4230-4237. Zheng, W. et al. 1993. Serum micronutrients and the subsequent risk of oral and pharyngeal cancer. Cancer Res 53(4) Feb. 15, 795-798. Menkes, M. J. 1986. Vitamin A, E, Selenium and risk of lung cancer. Dissertation Abstracts Int. 46(11), 3807. 46 Longnecker, M. P. et al. 1992. Serum alpha-tocopherol concentration in relation to subsequent colorectal cancer: Pooled data from five cohorts. J National Cancer Inst. 84(6), Mar. 18, 430-435. Menkes, M. S. et al. 1986. Serum beta-carotene, Vitamins A and E, selenium, and the risk of lung cancer. NEJM 315(20), Nov. 13, 1250-1254. Wei, Q. et al. 1993. Vitamin supplementation has a protective effect on basal cell carcinoma. Am Soc Preventive Oncology, 17th Annual Meeting, Mar. 20-23, Tuscon, AR. Does: greater than 100 IU/day. Knekt, P. 1993. Vitamin E and smoking and the risk of lung cancer. Annals NY Acad Sci. 686, May 28, 280-287. London, S. J. et al. 1992. Carotenoids, retinol, and Vitamin E and risk of proliferative benign breast disease and breast cancer. Cancer Causes Control 3(6), Nov., 503-512. Benner, S. F. et al. 1994. Reduction in oral mucosa micronuclei frequency following alpha-tocopherol treatment of oral leukoplakia. Cancer Epidemiol Biomarkers Prev. 3(1), Jan.-Feb., 73-76. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 146

Dose: 400 IU. de Vries, N. and Snow, G. B. 1990. Relationships of Vitamins A and E and beta-carotene serum levels to head and neck cancer patients with and without second primary tumors. Eur Arch Otorhinolaryngol 247(6), 368-370. Garewal, H. 1982. Chemoprevention of oral cancer: Beta-carotene and Vitamin E in leukoplakia. European J Cell Biology 28(1), Aug., 92-97. Knekt, P. et al. 1988. Serum Vitamin E, serum selenium and the risk of gastrointestinal cancer. Int J Cancer 42(6), Dec. 15, 846-850. Knekt, P. 1988. Serum Vitamin E level and risk of female cancers. Int J Epidemiology 17(2), June, 281-286. Prasad, K. N. and Edwards-Prasad, J. 1992. Vitamin E and cancer prevention: Recent advances and future potentials. J Am College Nutr. 11(5), Oct. 487-500. Torun, M. et al. 1995. Serum Vitamin E level in patients with breast cancer. J Clin Pharm Ther., 20(3), June, 173-178. Lockwood, K. et al. ?. Apparent partial remission of breast cancer in 'high risk' patients supplemented with nutritional antioxidants, essential fatty acids and coenzyme Q10. Mol Aspects Med., 15(Suppl), 231-240. Dose: 2500 IU. Palan, R. R. et al. 1991. Plasma levels of antioxidant beta-carotene and alpha-tocopherol in uterine cervix dysplasias and cancer. Nutr Cancer 15(1), 13-20. LeGardeur, B. Y. et al. 1990. A case-control study of serum Vitamins A, E, and C in lung cancer patients. Nutr Cancer 14(2), 133-140. Wadleigh, R. et al. 1990. Vitamin E in the treatment of chemotherapyinduced mucosisitis. Proceedings Annual Meeting Am Soc Clin Oncologists 9, A1237. Dose: 400 mg/ml applied to lesions for 1 week. Dimery, I. et al. 1992. Reduction in toxicity of high dose 13-CIS-Retinoic acid (13-CRA) with alpha-tocopherol. Proc Annual Meeting Am Soc Clin Oncologists 11, A399. Dose: 800, 1200, 1600, 2000 IU/day 4 week cycle. Sukolinskii, V. N. and Morozkina, T. S. 1989. [Prevention of postoperative complications in patients with stomach cancer using an antioxidant complex]. Vopr Onkol 35 (10), 1242-1245. Gorozhanskaia, E. G. et al. 1995. [The role of alpha-tocopherol and retinol in correcting disorders of lipid peroxidation in patients with malignant liver neoplasms]. Vopr Onkol 41(1), 47-51. Dose: 600 mg for 7 days prior to surgery. Cardiovascular/Coronary heart disease Salonen, J. T. et al. 1991. Effects of antioxidant supplementation on platelet function: A randomized pair-matched, placebo-controlled, double-blind trial in men with low antioxidant status. Am J Clin Nutr 53(5) May, 1222-1229. Dose: 300 mg/day for 5 months. Bellizz, M. C. et al. 1994. Vitamin E and coronary heart disease: The Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 147

European paradox. Eur J Clin Nutr. 48(11), Nov., 822-831. Dose: 1 capsule of palmvitee/day for 30 days. Tan, D. T. et al. 1991. Effect of a palm-oil-vitamin E concentrate on the serum and lipoprotein lipids in humans. Am J Clin Nutr. 53(4 Suppl), Apr. 1027S-1030S. Qureshi, A. A. et al. 1991. Lowering of serum cholesterol in hypercholesterolemic humans by tocopherols (Palmvitee). Am J Clin Nutr. 53(4 Suppl), Apr. 1021S-1026S. Dose: 200 mg palmvitee capsules/day or 200mg gamma-tocotrienol/day for 4 weeks. 48 Paolisso, G. et al. 1995. Chronic intake of pharmacological doses of Vitamin E might be useful in the therapy of elderly patients with coronary heart disease. Am J Clin Nutr. 61(4), Apr., 848-852. Dose: 900 mg/day for 4 months. Brown, K. M. et al. 1994. Vitamin E supplementation suppresses indexes of lipid peroxidation and platelet counts in blood of smokers and nonsmokers but plasma lipoprotein concentrations remain unchanged. Am J Clin Nutr. 60(3), Sept., 383-387. Dose: 280 mg/day for 10 weeks. Steiner, M. et al. 1995. Vitamin E plus aspirin compared with aspirin alone in patients with transient ischemic attacks. Am J Clin Nutr 62(6 Suppl), Dec., 1381S-1384S. Dose: 400 IU/day for up to 2 years. Chan, A. C. et al. 1986. Transitory stimulation of human platelet 12lipoxygenase by Vitamin E supplementation . Am J Clin Nutr. 44(2), Aug., 278-282. 400 IU/day of either D- or DL- alpha-tocopherol for 4 weeks. Guetta, V. et al. 1995. Effect of combined 17 beta-estradiol and Vitamin E on low-density lipoprotein oxidation in postmenopausal women. Am J Clin Cardiology 75(17), June 15, 1274-1276. Knekt, P. et al. 1994. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiology. 139(12), June 15, 11801189. Sisto, T. et al. 1995. Pretreatment with antioxidants and Allopurinol diminishes cardiac onset events in coronary artery bypass grafting. Ann Thorac Surg, 59(6), June, 1519-1523. Princen, H. M. et al. 1992. Supplementation with Vitamin E but not betacarotene in vivo protects low density lipoprotein from lipid peroxidation in vitro: Effect of cigarette smoking. Arteriosclerosis Thrombosis 12(5), May, 554-562. Dose: 100 IU/day of DL-alpha-tocopherol. Reaven, P. D. and Witzum, J. L. 1993. Comparisons of supplementation of RRR-alpha-tocopherol and racemic alpha-tocopherol in humans. Effects on lipid levels and lipoprotein susceptibility to oxidation. Arterioscler Thromb 13 (4), Apr., 601-608. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 148

Reaven, P. D. et al. 1993. Effect of dietary antioxidant combinations in humans: Protection of LDL by vitamin E but not by beta-carotene. Arterioscler Thromb 13(4), Apr., 590-600. 49 Kritchevsky, S. B. et al. Dietary antioxidants and carotid artery wall thickness: The ARIC study. Atherosclerosis risk in communities study. Circulation 92(8), Oct. 15, 2142-2150. Jialal, I. and Grundy, S. M. 1993. Effect of combined supplementation with alpha-tocopherol, ascorbate, and beta-carotene on low-density lipoprotein oxidation. Circulation 88(6), Dec., 2780-2786. Dose: 800 IU/day. Luoma, P. V. et al. 1995. High serum alpha-tocopherol, albumin, selenium and cholesterol, and low mortality from coronary heart disease in Northern Finland. J Internal Med 237(1), Jan., 49-54. Haglund, O. et al. 1991. The effects of fish oil on triglycerides, cholesterol, fibrinogen and malondialehyde in humans supplemented with Vitamin E. J Nutr. 121(2), Feb., 165-169. Hodis, H. N. et al. 1995. Serial coronary angiographic evidence that antioxidant Vitamin intake reduces progression of coronary artery atherosclerosis. JAMA 273(23), June 21, 1849-1854. Dose: 100 IU/day or more. Fuenmayor, A. J. et al. Vitamin E and ventricular fibrillation threshold in myocardial ischemia. Japanese Circulation J 53(10), Oct., 1229-1232. Riemersma, R. A. et al. 1991. Risk of angina pectoris and plasma concentrations of Vitamins A, C, and E and Carotene. Lancet 337(8732), Jan. 5, 1-5. Kardinaal, A. F. et al. Antioxidants in adipose tissue and risk of myocardial infarction: The EURAMIC study. Lancet 342(8884), Dec. 4, 1379-1384. Rimm, E. B. et al. 1993. Vitamin E consumption and the risk of coronary heart disease in men. NEJM 328(20), May 20, 1450-1456. Dose: 60 IU/day or more. Stampfer, M. J. et al. 1993. Vitamin E consumption and the risk of coronary disease in women. NEJM 328(20), May 20, 1444-1449. Singh, R. B. et al. 1994. Diet, antioxidant vitamins, oxidative stress and risk of coronary artery disease: The Peerzada prospective study. Acta Cardiol 49(5), 453-467. Knight, J. A. et al. 1993. The effect of Vitamins C and E on lipid peroxidation in stored erythrocytes. Ann Clin Lab Sci 23(1), Jan.-Feb., 51-56. Postaire, E. et al. 1995. Increase of singlet oxygen protection of erythrocytes by Vitamin E, Vitamin C, and beta-carotene intakes. Biochem Mol Biol Int 35(2) Feb., 371-374. 50 Dose: 15 mg/day for 15 days. Kleijnen, J. et al. 1989. Vitamin E and cardiovascular disease. European J Clin Pharmacol 37(6), 541-544. Gey, K. F. 1989. Inverse correlation of Vitamin E and ischemic heart Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 149

disease. Int J Vitamin Nutr Res Suppl 30, 224-231. Dmoszynska-Giannopoulou, A. et al. 1987. Alpha-tocopherol: Effect of sulphinpyrazone and alpha-tocopherol on platelet activation and function in haemodialysed patients. Int Urol Nephrol 22(6), 561-566. Cloarec, M. J. et al. Alpha-tocopherol: Effect on plasma lipoproteins in hypercholesterolemic patients. Israeli J Med Sci 23(8), Aug., 869-872. Dose: 500 IU/day for 3 months. Rifici, V. A. and Khachadurian, A. K. 1993. Dietary supplementation with Vitamins C and E inhibits in vitro oxidation of lipoproteins. J Am Coll Nutr 12(6), Dec., 631-637. Dose: 800 IU/day. Lenzhofer, R. et al. 1983. Acute cardian toxicity in patients after Doxorubucin treatment and the effect of combined tocopherol and Nifedipine pretreatment. J Cancer Res Clin Oncol 106(2), 143-147. Yukawa, S. et al. 1992. Prevention of aortic calcification in patients on hemodialysis by long-term administration of Vitamin E. J Nutr Sci Vitaminol. Spec No:187-90. Dose: 600 mg/day for 2 weeks. Gey, K. F. et al. 1994. [Essential antioxidants on cardiovascular diseasesLessons for Europe]. Ther Unsch 51(7), July, 475-482. Dose: 100 mg/day. Steiner, M. 1993. Effect of alpha-tocopherol administration on platelet function in man. Thromb Haemost 49(2), Apr. 28, 73-77. Dose: 400-1200 IU/day over 6 weeks. Cataracts Mathew JP, Thomas VC, Thomas I. Selenite cataract and its attenuation by vitamin E in Wistar rats. Indian J Ophthalmol. 2003 Jun;51(2):161-70. Jacques, P. F. et al. 1988. Antioxidants status in persons with and without senile cataract. Arch Ophthalmol 106(3), Mar., 337-340. 51 Knekt, P. et al. 1992. Serum antioxidant Vitamins and risk of cataract. British Med J 305(6866), Dec. 5, 1392-1394. Robertson, J. M. et al. 1989. Vitamin E intake and risk of cataracts in humans. Ann NY Acad Sci 570, 372-382. Cystic Fibrosis Winklhofer-Roob BM, Rock E, Ribalta J, Shmerling DH, Roob JM. Effects of vitamin E and carotenoid status on oxidative stress in health and disease. Evidence obtained from human intervention studies. Mol Aspects Med. 2003 Dec;24(6):391-402. Sitrin, M. D. et al. 1987. Vitamin E deficiency and neurologic disease in adults with cystic fibrosis. Annals Int Med, 107(1), July, 51-54. Sung, J. H. et al. 1980. Axonal dystrophy in the gracile nucleus in congenital biliary atresia and cystic fibrosis (mucoviscidosis): Beneficial effect of Vitamin E therapy. J Neuropathol Exp Neurol, 39(5), Sept., 584-597. Cynamon, H. A. et al. 1988. Effect of Vitamin E deficiency on neurologic function in patients with cystic fibrosis. J Pediatrics, 113(4), Oct., 637-640. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 150

Elias, E. et al. 1981. Association of spinocerebellar disorders with cystic fibrosis or chronic childhood cholestasis and very low serum Vitamin E. Lancet, 2(8259), Dec. 12, 1319-1321. James. D. R. et al. 1991. Increased susceptibility to peroxide-induced haemolysis with normal Vitamin E concentrations in cystic fibrosis. Clin Chim Acta, 204(1-3), Dec. 31, 279-290. Diabetes Hirnerova E, Krahulec B, Strbova L, Stecova A, Dekret J, Hajovska A. Effect of vitamin E therapy on progression of diabetic nephropathy. Vnitr Lek. 2003 Jul;49(7):529-34. Ruffini I, Belcaro G, Cesarone MR, Geroulakos G, Di Renzo A, Milani M, Coen L, Ricci A, Brandolini R, Dugall M, Pomante P, Cornelli U, Acerbi G, Corsi M, Griffin M, Ippolito E, Bavera P. Evaluation of the local effects of vitamin E (EMousse) on free radicals in diabetic microangiopathy: a randomized, controlled trial. Angiology. 2003 Jul-Aug;54(4):415-21. Colette, C. et al. 1988. Platelet function in Type I diabetes: Effects of supplementation with large doses of Vitamin E. Am J Clin Nutr 47(2), Feb., 256-261. Dose: 1 gm/day for 35 days. Paolisso, G. et al. Pharmacologic doses of Vitamin E improve insulin action in healthy subjects and non-insulin-dependent diabetic patients. Am J Clin Nutr 57(5), May, 650-656. Dose: 900 mg/day for 4 months. Salonen, J. T. et al. 1995. Increased risk of non-insulin dependent Diabetes Mellitus at low plasma Vitamin E concentrations: A four year follow-up study in men. British Med J 311(7013), Oct. 28, 1124-1127. Karpen, C. W. et al. 1984. Interrelation of platelet Vitamin E and thromboxane synthesis in type I Diabetes Mellitus. Diabetes, 33(3), Mar., 239-243. Watanabe, J. et al. 1984. Effect of Vitamin E on platelet aggregation in Diabetes Mellitus. Thromb Haemost, 51(3), July 29, 3130316. Karpen, C. W. et al. 1985. Production of 12-hydroyeicosatetraenoic acid and Vitamin E status in platelets from type I human diabetic subjects. Diabetes 34(6), June, 526-531. Caballero, B. 1993. Vitamin E improves the action of insulin. Nutr Rev, 51(11), Nov., 339-340. Kunisaki, M. et al. 1990. Effects of Vitamin E administration on platelet function in Diabetes Mellitus. Diabetes Res, 14(1), May, 37-42. Dose: 600 mg/day. Dmoszynska-Giannopoulou, A. et al. 1989. [Effect of Vitamin E on the function of blood platelets in patients with Diabetes Mellitus], Pol Tyg Lek, 44(21-22), May 22-29, 496-498. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 151

Dose: 1000 mg/day. Dzhavad-zade, M. D. et al. 1992. [Disorders of pulmonary hemodynamics in patients with Diabetic Nephroangiopathy and its correction with antioxidants], Probl Endokrinol, 38(2), Mar.-Apr., 20-22. Dose: 8 mcg/kg/day for 2 weeks. Mamedgasanov, R. M. and Rakhmani, S. A. [Dynamics of lipid peroxidation in patients with noninsulin-dependent Diabetes Mellitus], Probl Endokrinol, 35(1), Jan.-Feb., 19-21. Balabolkin, M. I. et al. 1994. [Effect of high doses of tocopherol on the process of lipid peroxidation and insulin secretion in patients with noninsulindependent Diabetes Mellitus], Probl Endokrinol, 40(3), May-June, 10-12. Dose: 600-1200 mg/day. Kuznetsov, N. S. et al. 1993. [The use of antioxidants (alpha-tocopherol acetate) in the treatment of Diabetes Mellitus], Probl Endokrinol, 39(2), Mar.-Apr., 9-11. Dose: 300 mg/day. Watanabe, J. et al. 1984. Effect of Vitamin E in platelet aggregation in Diabetes Mellitus. Tohoku J Exp Med, 143(2), June, 161-169. Splavskii, O. I. 1982. [Effectiveness of Vitamin E in the combined therapy of the hepatobiliary system lesions in Diabetes Mellitus]. Vopr Pitan, (6), Nov.Dec., 36-39. Gerster, H. et al. 1993. Prevention of platelet dysfunction by Vitamin E in diabetic athersclerosis. Z Ernahrungswiss 32(4), Dec., 243-261. Disseminated Granuloma Anulare Burg G. Disseminated granuloma anulare: therapy with vitamin E topically. Dermatology. 1992;184(4):308-9. Goldstein RK, Zillikens D, Miller K, Elsner P, Burg G. Local treatment of disseminated granuloma anulare with a vitamin E emulsion. Hautarzt. 1991 Mar;42(3):176-8. Epilepsy Oztas B, Kilic S, Dural E, Ispir T. Influence of antioxidants on the blood-brain barrier permeability during epileptic seizures. J Neurosci Res. 2001 Nov 15;66(4):674-8. Ogunmekan, A. O. and Hwang, P. A. 1989. A randomized, double-blind, placebo-controlled, clinical trial of D-alpha-tocopherol acetate (Vitamin E), as Add-on therapy, for epilepsy in children. Epilepsia, 30(1), Jan.-Feb., 8489. Kovalenko, V. M. et al. 1984. [Alpha-tocopherol in the complex treatment of Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 152

several forms of epilepsy]. Zh Nevropatol Psikhiatr, 84(6), 892-897. Dose: 600 mg/day Megrabian, A. A. et al. 1986. [Use of lithium carbonate and Vitamin E in the complex treatment of epileptics]. Zh Nevropatol Psikhiatr, 86(9), 1407-1410. Gastrointestinal Disease Taylor PR, Qiao YL, Abnet CC, Dawsey SM, Yang CS, Gunter EW, Wang W, Blot WJ, Dong ZW, Mark SD. Prospective study of serum vitamin E levels and esophageal and gastric cancers. J Natl Cancer Inst. 2003 Sep 17;95(18):1414-6. Beno, I. et al. 1994. The activity of Cu/Zn-superoxide dismutase and catalase of gastric mucosa in chronic gastritis, and the effect of alphatocopherol. Bratisl Lek Listy, 95(1), Jan., 9-14. Feher, J. and Pronai, L. 1993. [Role of free radical scavengers in gastrointestinal diseases], Orv Hetil, 34(13), Mar. 28, 693-696. General Bidoli E, Bosetti C, La Vecchia C, Levi F, Parpinel M, Talamini R, Negri E, Maso LD, Franceschi S. Micronutrients and laryngeal cancer risk in Italy and Switzerland: a case-control study. Cancer Causes Control. 2003 Jun;14(5):477-84 Johnson KA, Bernard MA, Funderburg K. Vitamin nutrition in older adults. Clin Geriatr Med. 2002 Nov;18(4):773-99. Wartanowicz, W. et al. 1984. The effect of alpha-tocopherol and ascorbic acid on the serum lipid peroxide level in elderly people. Anna Nutr Metab, 28(3), 186-191. Dose: 200 mg/day for 4 months. Regnault, C. et al. 1993. Influence of beta carotene,, Vitamin E, and Vitamin C on endogenous antioxidant defenses in erythrocytes. Ann Pharmacother, 27(11), Nov., 1349-1350. Denzlinger, C. et al. 1995. Modulation of the endogenous leukotriene production by fish oil and Vitamin E. J Lipid Mediat Cell Signal, 11(2), Mar., 119-132. Dose: 800 IU/day. Hearing loss Joachims HZ, Segal J, Golz A, Netzer A, Goldenberg D. Antioxidants in treatment of idiopathic sudden hearing loss. Otol Neurotol. 2003 Jul;24(4):5725. Romeo, G. 1985. The therapeutic effect of Vitamins a and E in neurosensory hearing loss. Acta Vitaminol Enzymol, 7 Suppl, 85-92. Romeo, G. and Giorgetti, M. 1985. [Therapeutic effects of Vitamin A associated with Vitamin E in perceptual hearing loss], Acta Vitaminol Enzymol, 7(1-2), 139-143. Hemodialysis Badiou S, Cristol JP, Morena M, Bosc JY, Carbonneau MA, Dupuy AM, Descomps B, Canaud B. Vitamin E supplementation increases LDL resistance to ex Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 153

vivo oxidation in hemodialysis patients. Int J Vitam Nutr Res. 2003 Jul;73(4):2906. Giardini, O. et al. 1984. Effects of alpha-tocopherol administration on red blood cell membrane lipid peroxidation in hemodialysis patients. Clin Nephrol, 21(3), Mar., 174-177. Hemolysis Usberti M, Gerardi G, Micheli A, Tira P, Bufano G, Gaggia P, Movilli E, Cancarini GC, De Marinis S, D'Avolio G, Broccoli R, Manganoni A, Albertin A, Di Lorenzo D. Effects of a vitamin E-bonded membrane and of glutathione on anemia and erythropoietin requirements in hemodialysis patients. J Nephrol. 2002 Sep-Oct;15(5):558-64. Prussick, R. et al. 1992. The protective effect of Vitamin E on the hemolysis associated with dapsone treatment in patients with dermatitis herpetiformis. Arch Dermatol, 128(2)Feb., 210-213. Dose: 800 IU/day for 4 weeks. Hafez, M, et al. 1986. Improved erythrocyte survival with combined vitamin E and selenium therapy in children with glucose-6-phosphate dehydrogenase deficiency and mild chronic hemolysis. J Pediatrics, 108(4), Apr., 558-561. Dose: 800 IU/day for 2 months. Corash, L. et al. 1980. Reduced chronic hemolysis during high-dose Vitamin E administration in Mediterranean-type glucose-6-phosphate dehydrogenase deficiency. New England J Med, 303(8), Aug. 12, 416-420. Yalcin, A. S. et al. 1989. The effect of Vitamin E therapy on plasma and erythrocyte lipid peroxidation in chronic hemodialysis patients. Clin Chim Acta, 185(1), Oct. 31, 109-112. Dose: 300 mg/day for 1 month. Hepatitis Xu M, Hou J, Wu Y, Ling Y. Study on the modulation of the inflammatory response in mouse hepatic vasculitis with sodium selenite and vitamin E antioxidants. Zhonghua Bing Li Xue Za Zhi. 2000 Aug;29(4):279-83. Han, Y. C. 1993. [Study of anti-lipid peroxidation of Vitamin E in human body]. Chung Hua Yu Fang I Hsueh Tsa Chih, 27(3), May, 132-134. Dose: 200 mg/day after 10 days. Immune enhancement Ortuno J, Esteban MA, Meseguer J. High dietary intake of alpha-tocopherol acetate enhances the non-specific immune response of gilthead seabream (Sparus aurata L.). Fish Shellfish Immunol. 2000 May;10(4):293-307. Meydani, S. N. et al. 1990. Vitamin E supplementation enhances cellmediated immunity in healthy elderly subjects. Am J Clin Nutr, 52(3), Sept., 557-563. Dose: 800 mg/day for 30 days. Kowdley, K. V. et al. 1992. Vitamin E deficiency and impaired cellular Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 154

immunity related to intestinal fat malabsorption. Gastroenterology 102(6), June, 2139-2142. Penn, N. D. et al. 1991. The effect of dietary supplementation with Vitamins A, C and E on cell-mediated immune function in elderly long-stay patients: A randomized controlled trial. Age Ageing, 20(3), May, 169-174. Taccone-Gallucci, M. et al. 1986. Vitamin E supplementation in hemodialysis patients: Effects on peripheral blood mononuclear cells lipid peroxidation and immune response. Clin Nephrol, 25(2), Feb., 81-86. Gaidova, O. S. et al. 1990. [The immunomodulating properties of Vitamin E in surgery involving artificial circulation], Grud serdechnososudistaia Khir, (12), Dec., 30-33. Dose: 40 mg/kg 3.5 hours prior to open heart surgery. Kidney disease/Damage Saran R, Novak JE, Desai A, Abdulhayoglu E, Warren JS, Bustami R, Handelman GJ, Barbato D, Weitzel W, D'Alecy LG, Rajagopalan S. Impact of vitamin E on plasma asymmetric dimethylarginine (ADMA) in chronic kidney disease (CKD): a pilot study. Nephrol Dial Transplant. 2003 Nov;18(11):2415-20. Bilenko, M. V. et al. 1983. [Use of antioxidants to prevent damage during acute ischemia and reperfusion of the kidneys], Biull Eksp Biol Med, 96(9), Sept., 8-11. Leg cramps Roca AO, Jarjoura D, Blend D, Cugino A, Rutecki GW, Nuchikat PS, Whittier FC. Dialysis leg cramps. Efficacy of quinine versus vitamin E. ASAIO J. 1992 JulSep;38(3):M481-5. Roca, A. O. et al. 1992. Dialysis leg cramps: Efficacy of quinine versus Vitamin E. ASAIO J, 38(3), July-Sept., M481-485. Dose: 400 IU/day. Mucositis Lopez I, Goudou C, Ribrag V, Sauvage C, Hazebroucq G, Dreyfus F. Treatment of mucositis with vitamin E during administration of neutropenic antineoplastic agents. Ann Med Interne (Paris). 1994;145(6):405-8. Wadleigh, R. G. et al. 1992. Vitamin E in the treatment of chemotherapyinduced Mucositis. Am J Med. 92(5) May, 481-484. Myotonic dystrophy Backman E, Henriksson KG. Effect of sodium selenite and vitamin E treatment in myotonic dystrophy. J Intern Med. 1990 Dec;228(6):577-81. Orndahl, G. et al. 1986. Myotonic dystrophy treated with selenium and Vitamin E. Acta Med Scand, 219(4), 407-414. Dose: 600 mg Vitamin E. Neurological function Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 155

Yargicoglu P, Yaras N, Agar A, Gumuslu S, Bilmen S, Ozkaya G. The effect of vitamin E on stress-induced changes in visual evoked potentials (VEPs) in rats exposed to different experimental stress models. Acta Ophthalmol Scand. 2003 Apr;81(2):181-7. Muller, D. P. et al. 1983. Vitamin E and neurological function. Lancet 1(8318), Jan. 29, 225-228. Muller, D. P. 1986. Vitamin E-Its role in neurological function. Postgraduate Med J, 62(724), Feb., 107-112. Lloyd, B. W. and Dubowitz, V. 1992. Progressive neurological disorders associated with obstructive jaundice and Vitamin E deficiency. Neuropediactrics, 13(3), Aug., 155-157. Davidai, G. et al. 1986. Hypovitaminosis E induced neuropathy in exocrine pancreatic failure. Arch Dis Child, 61(9), Sept., 901-903. Palmucci, L. et al. 1988. Neuropathy secondary to Vitamin E deficiency in acquired in acquired intestinal malabsorption. Italian J Neurol Sci, 9(6), Dec., 599-602. Neutrophil Hou J, Wu Y, Ling Y. Modulation of the inflammatory response through complement-neutrophil activation feedback mechanism with selenium and vitamin E. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2000 Dec;22(6):580-4. Chai, J. et al. 1995. [Protective effects of Vitamin E on impaired neutrophil phagocytic function in patients with severe burn]. Chung Hua Cheng Hsing Shao Shang Wai Ko Tsa Chih, 11(1), Jan., 32-35. Osteoarthritis Kaiki G, Tsuji H, Yonezawa T, Sekido H, Takano T, Yamashita S, Hirano N, Sano A. Osteoarthrosis induced by intra-articular hydrogen peroxide injection and running load. J Orthop Res. 1990 Sep;8(5):731-40. Blankenhorn, G. 1986. [Clinical effectiveness of Spondyvit (vitamin E) in activated arthroses: A multicenter placebo-controlled double-blind study], Z Orthop, 124(3), May-June, 340-343. Dose: 400 IU/day for 6 weeks. Scherak, O. et al. 1990. [High dose Vitamin E therapy in patients with activated arthrosis], Z Rheumatol, 49(6), Nov.-Dec., 369-373. Dose: 400 IU/day for 3 weeks. Machtey, I. and Ouaknine, L. 1978. Tocopherol in osteoarthritis: A Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 156

controlled pilot study. J Am Geriatric Soc, 26(7), July, 328-330. Dose: 600 mg/day for 10 days. Parkinson's disease Fariss MW, Zhang JG. Vitamin E therapy in Parkinson's disease. Toxicology. 2003 Jul 15;189(1-2):129-46. Fahn, S. 1992. A pilot trial of high-dose alpha-tocopherol and ascorbate in early Parkinson's disease. Ann Neurol, 32(Suppl), S128-S132. Dexter, D. T. et al. 1994. Nigrostriatal function in Vitamin E deficiency: Clinical, experimental, and positron emission tomographic studies. Ann Neurol, 35(3), Mar., 298-303. Peripheral neuropathy Lagueny A. Metabolic and nutritional neuropathies. Rev Prat. 2000 Apr 1;50(7):731-5. Traber, M. G. et al. 1987. Lack of tocopherol in peripheral nerves of vitamin E-deficient patients with peripheral neuropathy. NEJM, 317(5), July 30, 262265. Physical Performance Asha Devi S, Prathima S, Subramanyam MV. Dietary vitamin E and physical exercise: I. Altered endurance capacity and plasma lipid profile in ageing rats. Exp Gerontol. 2003 Mar;38(3):285-90. Simon-Schnass, I. and Pabst, H. 1988. Influence of Vitamin E on physical performance. Int J Vitam Nutr Res, 58(1), 49-54. Dose: 2x200 mg dl-alpha-tocopherol acetate for 10 weeks. Pulmonary health Wang S, Sun NN, Zhang J, Watson RR, Witten ML. Immunomodulatory effects of high-dose alpha-tocopherol acetate on mice subjected to sidestream cigarette smoke. Toxicology. 2002 Jun 14;175(1-3):235-45. Mohsenin, V. 1991. 1991. Lipid peroxidation and antielastase activity in the lung under oxidant stress: Role of antioxidant defenses. J Appl Physiology, 70(4), Apr., 1456-1462. Respiration Rocksen D, Ekstrand-Hammarstrom B, Johansson L, Bucht A. Vitamin E reduces transendothelial migration of neutrophils and prevents lung injury in endotoxin-induced airway inflammation. Am J Respir Cell Mol Biol. 2003 Feb;28(2):199-207. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 157

Richards, G. et al. 1990. Investigations of the effects of oral administration of Vitamin E and beta-carotene on the chemiluminescence responses and the frequency of sister chromatid exchanges in circulating leukocytes from cigarette smokers. Am Rev Respiratory Dis, 142(3), Sept., 648-654. Dose: 900 IU for 6 weeks. Skopinska-Rozewska, E. et al. 1987. The effect of Vitamin E treatment on the incidence of OKT+4 lymphocytes in the peripheral blood of children with chronic respiratory tract infections. Archives Immunol Ther Exp, 35(2), 207-210. Short Bowel Syndrome Tanyel MC, Mancano LD. Neurologic findings in vitamin E deficiency. Am Fam Physician. 1997 Jan;55(1):197-201. Howard, L. et al. 1982. Reversible neurological symptoms caused by Vitamin E deficiency in a patient with short bowel syndrome. Am J Clin Nutr, 36(6), Dec., 1243-1249. Traber, M. G. et al. 1994. Efficacy of water-soluble Vitamin E in the treatment of Vitamin E malabsorption in short-bowel syndrome. Am J Clin Nutr, 59(6), June, 1270-1274. Smoking Dyer AR, Elliott P, Stamler J, Chan Q, Ueshima H, Zhou BF; INTERMAP Research Group. Dietary intake in male and female smokers, ex-smokers, and never smokers: the INTERMAP study. J Hum Hypertens. 2003 Sep;17(9):641-54. Pacht, E. R. et al. 1986. Deficiency of Vitamin E in the alveolar fluid of cigarette smokers: Influence on alveolar macrophage cytotoxicity. J Clin Invest 77(3), Mar., 789-796. Hoshino, E. et al. 1990. Vitamin E suppresses increased lipid peroxidation in cigarette smokers. J Parenteral Enteral Nutr, 14(3), May-June, 300-305. Dose: 800 mg/day for 2 weeks. Spinocerebeller dysfunction Brin, M. F. et al. 1985. Blind loop syndrome, Vitamin E malabsorption, and spinocerebellar degeneration. Neurology, 35(3), Mar., 338-342. Spondylosis Mahmud, Z. and Ali, S. M. 1992. Role of Vitamin A and E in spondylosis. Bangladesh Med Res Counc Bull, 18(1), Apr., 47-59. Dose: 100 mg/day for 3 weeks. Steatorrhoea Rovner AJ, Schall JI, Jawad AF, Piccoli DA, Stallings VA, Mulberg AE, Zemel BS. Rethinking growth failure in Alagille syndrome: the role of dietary intake Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 158

and steatorrhea. J Pediatr Gastroenterol Nutr. 2002 Oct;35(4):495-502. Evans, D. J. et al. 1995. Symptomatic Vitamin E deficiency diagnosed after histological recognition of myometrial lipofuscinosis. Lancet 346(8974), Aug. 26, 545-546. Stress Banerjee AK, Mandal A, Chanda D, Chakraborti S. Oxidant, antioxidant and physical exercise. Mol Cell Biochem. 2003 Nov;253(1-2):307-12. Micheletta F, Natoli S, Misuraca M, Sbarigia E, Diczfalusy U, Iuliano L. Vitamin E Supplementation in Patients With Carotid Atherosclerosis. Reversal of Altered Oxidative Stress Status in Plasma But Not in Plaque. Arterioscler Thromb Vasc Biol. 2003 Oct 30. Meydani, M. et al. 1992. Vitamin E requirement in relation to dietary fish oil and oxidative stress in elderly. EXS, 62, 411-418. Rokitzki, L. et al. 1994. Alpha-tocopherol supplementation in racing cyclists during extreme endurance training. Int J Sport Nutr, 4(3), Sept., 253-264. Hartmann, A. et al. 1995. Vitamin E prevents exercise-induced DNA damage. Mutation Res, 346(4), Apr., 195-202. Dose: 1200 mg/day for 14 days. Tardive Dyskinesia Michael N, Sourgens H, Arolt V, Erfurth A. Severe tardive dyskinesia in affective disorders: treatment with vitamin E and C. Neuropsychobiology. 2002;46 Suppl 1:28-30. Egan, M. F. et al. 1992. Treatment of Tardive Dyskinesia with Vitamin E. Am J Psychiatry, 149(6), June, 773-777. Dose: 1600 IU/day for 6 weeks. Elkashef, A. M. et al. 1990. Vitamin E in the treatment of Tardive Dyskinesia. Am J Psychiatry 147(4), Apr., 505-506. Dabiri, L. M. et al. 1994. Effectiveness of Vitamin E for treatment of longterm Tardive Dyskinesia. Am J Psychiatry, 151(6), June, 925-926. Adler, L. A. et al. 1993. Vitamin E treatment of Tardive Dyskinesia. Am J Psychiatry, 150(9), Sept., 1405-1407. Dose: 1600 IU/day for 8-12 weeks. Bischot, L. et al. 1993. Vitamin E in extrapyramidal disorders. Pharm World Sci 15(4), Aug. 20, 1993, 146-150. Dose: 1600 IU/day. Adler, L. A. et al. 1993. Vitamin E in Tardive Dyskinesia: Time course of effect after placebo substitution. Psychopharmacol Bull, 29(3), 371-374. Lohr, J. B. et al. 1988. Vitamin E in the treatment of Tardive Dyskinesia: The possible involvement of free radical mechanisms. Schizophrenia Bull, 14(2), 291-296.

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Thyroid Dysfunction Mano T, Iwase K, Hayashi R, Hayakawa N, Uchimura K, Makino M, Nagata M, Sawai Y, Oda N, Hamada M, Aono T, Nakai A, Nagasaka A, Itoh M. Vitamin E and coenzyme Q concentrations in the thyroid tissues of patients with various thyroid disorders. Am J Med Sci. 1998 Apr;315(4):230-2. Venditti P, De Leo T, Di Meo S. Vitamin E administration attenuates the triiodothyronine-induced modification of heart electrical activity in the rat. J Exp Biol. 1997 Mar;200 ( Pt 5):909-14. Krishnamurthy, S. and Prasanna, D. 1984. Serum Vitamin E and lipid peroxides in malnutrition, hyper and hypothyroidism. Acta Vitaminol Exzymol, 6(1), 17-21. Danis, I. et al. 1990. [Vitamin E and malondialdehyde in the blood serum of thyrotoxicosis patients]. Probl Endokrinol, 36(5), Sept.-Oct. 21-24. Tuberculosis Plit ML, Theron AJ, Fickl H, van Rensburg CE, Pendel S, Anderson R. Influence of antimicrobial chemotherapy and smoking status on the plasma concentrations of vitamin C, vitamin E, beta-carotene, acute phase reactants, iron and lipid peroxides in patients with pulmonary tuberculosis. Int J Tuberc Lung Dis. 1998 Jul;2(7):590-6. Gur'eva, I. G. et al. [Antioxidants-Effective pathogenic agents in the combined therapy of Pulmonary Tuberculosis]. Ter Arkh 59(7), 72-74. Ulcerative colitis Sato K, Kanazawa A, Ota N, Nakamura T, Fujimoto K. Dietary supplementation of catechins and alpha-tocopherol accelerates the healing of trinitrobenzene sulfonic acid-induced ulcerative colitis in rats. J Nutr Sci Vitaminol (Tokyo). 1998 Dec;44(6):769-78. Bennet, J. D. 1986. Use of alpha-tocopherylquinone in the treatment of ulcerative colitis. Gut, 27(6), June, 695-697. Dose: 3 gm/day. Vitiligo Potapenko AY, Kyagova AA. The application of antioxidants in investigations and optimization of photochemotherapy. Membr Cell Biol. 1998;12(2):269-78. Koshevenko, I. 1989. [Alpha-tocopherol in the combined treatment of Vitiligo]. Vestn Dermatol Venerol, (10), 70-72. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 160

Wound healing Susaman N, Yalcin S, Ilhan N, Ozercan IH, Kaygusuz I, Karlidag T, Gok U. The effect of vitamin E on histopathologic healing and lipid peroxidation levels in experimentally induced traumatic tympanic membrane perforations. Kulak Burun Bogaz Ihtis Derg. 2003 Mar;10(3):87-92. Haberal, M. et al. 1988. The effects of Vitamin E on immune regulations after thermal injury. Burns Incl Therm Injuries, 14(5) Oct., 388-393. Yellow Nail Syndrome Tosti A, Piraccini BM, Iorizzo M. Systemic itraconazole in the yellow nail syndrome. Br J Dermatol. 2002 Jun;146(6):1064-7. Williams, H. C. et al. 1991. Successful use of topical Vitamin E solution in the treatment of nail changes in Yellow Nail Syndrome. Arch Dermatol, 127(7), July, 1023-1028. Omega fatty acids Arthritis Rennie KL, Hughes J, Lang R, Jebb SA. Nutritional management of rheumatoid arthritis: a review of the evidence. J Hum Nutr Diet. 2003 Apr;16(2):97-109. 64 Kremer, J. M. 1991. Clinical studies of Omega-3 fatty acid supplementation in patients who have Rheumatoid arthritis. Rheum Dis Clin North Am, 17(2) May, 391-402. Geusens, P. et al. 1994. Long-term effect of Omega-3 fatty acid supplementation in active Rheumatoid Arthritis. A 12-month, double-blind, controlled study. Arthritis Rheum 37(6), June, 824-829. Dose: 2.6 gm/day for 12 months. Cancer Dewailly E, Mulvad G, Sloth Pedersen H, Hansen JC, Behrendt N, Hart Hansen JP. Inuit are protected against prostate cancer. Cancer Epidemiol Biomarkers Prev. 2003 Sep;12(9):926-7. Kemen, M. et al. 1995 Early postoperative enteral nutrition with arginineomega3 fatty acids and ribonucleic acid-supplemented diet versus placebo in cancer patients: An immunologic evaluation of impact. Crit Care med 23(4), Apr., 652-659. Anti, M. et al. 1992. Effect of omega-3 fatty acids on rectal mucosal cell proliferation in subjects at risk for colon cancer. Gastroenterology, 103(3) Sept., 883-891. Dose: 4 g EPA, 3.6 g DHA for 12 weeks. Cardiovascular/Coronary heart disease Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 161

Lee KW, Lip GY. The role of omega-3 fatty acids in the secondary prevention of cardiovascular disease. QJM. 2003 Jul;96(7):465-80. Levine, P. H. et al. 1989. Dietary supplementation with Omega-3 fatty acids prolongs platelet survival in hyperlipidemic patients with atherosclerosis. Arch Intern Med 149(5) May, 1113-1116. Illingworth, D. R. et al. 1984. Inhibition of low density lipoprotein synthesis by dietary omega-3 fatty acids in humans. Arteriosclerosis. Arch Intern Med, 4(3), May-June, 270-275. Dose: 24 gm/day for 4 weeks. Harris, W. S. et al. 1984. Dietary omega-3 fatty acids prevent carbohydrateinduced hypertriglyceridemia. Metabolism, 33(11), Nov., 1016-1019. d'Ivernois, C. et al. [Potential value of omega-3 polyunsaturated fatty acids in the prevention of atherosclerosis and cardiovascular diseases], Arch Mal Coeur Vaiss, 85(6), June, 899-904. 65 Lox, C. D. 1990. The effects of dietary marine fish oils (Omega-3 fatty acids) on coagulation profiles in men. Gen Pharmacol, 21(2), 241-246. Dose: 900 mg over a period of 30 days. Engler, M. B. 1994. Vascular effects of omega-3 fatty acids: Possible therapeutic mechanisms in cardiovascular disease. J Cardiovascular Nurs, 8(3) Apr., 53-67. Lungershausen, Y. K. et al. 1994. Reduction of blood pressure and plasma triglycerides by omega-3 fatty acids in treated hypertensives. J Hypertension, 12(9), Sept., 1041-1045. Diabetes Christopher CL, Mathuram LN, Genitta G, Cyrus I, Jaya Sundar S. Omega-3 polyunsaturated fatty acids inhibit the accumulation of PAS-positive material in the myocardium of STZ-diabetic wistar rats. Int J Cardiol. 2003 Apr;88(2-3):183-90. Landgraf-Leurs, M. M. et al. 1990. Pilot study on omega-3 fatty acids in type I Diabetes Mellitus. Diabetes, 39(3), Mar., 369-375. Dose: 5.4 gm EPA, 2.3 gm DHA. Popp-Snijders, C. et al. 1987. Dietary supplementation of omega-3 polyunsaturated fatty acids improves insulin sensitivity in non-insulindependent diabetes. Diabetes Res, 4(3), Mar., 141-147. Dose: EPA and DHA 3 gm for 8 weeks. Evening Primrose Oil Arthritis Belch JJ, Hill A. Evening primrose oil and borage oil in rheumatologic conditions. Am J Clin Nutr. 2000 Jan;71(1 Suppl):352S-6S. Jantti, J. et al. 1989. Evening primrose oil in rheumatoid arthritis: Changes in serum lipids and fatty acids. Ann Rheum Disease, 48(2), Feb., 1240127. Dose: 20 ml evening primrose oil (EPO) containing 9% of gamma-linolenic Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 162

acid for 12 weeks. Brzeski, M. et al. 1991. Evening primrose oil in patients with rheumatoid arthritis and side-effects of non-steroidal anti-inflammatory drugs. British J Rhheumatology, 30(5), Oct., 370-372. Dose: 6 gm/day 66 Eczema Ashcroft DM, Po AL. Herbal remedies: issues in licensing and economic evaluation. Pharmacoeconomics. 1999 Oct;16(4):321-8. Schlin-Karrila, M. et al. Evening primrose oil in the treatment of atopic eczema: Effect on clinical status, plasma phospholipid fatty acids and circulating blood prostaglandins. British J Dermatology, 117(1), July, 11-19. Biagi, P. L. et al. 1988. A long-term study on the use of evening primrose oil (Efamol) in atopic children. Drugs Exp Clin Res, 14(4), 285-290. Diabetes Uccella, R. et al. [Action of evening primrose oil on cardiovascular risk factors in insulin-dependent diabetics]. Clin Ter, 129(5), June 15, 381-388. Dose: 3 gm/day. Schlin-Karrila, M. et al. Evening primrose oil in the treatment of atopic eczema: Effect on clinical status, plasma phospholipid fatty acids and circulating blood prostaglandins. British J Dermatology, 117(1), July, 11-19. Biagi, P. L. et al. 1988. A long-term study on the use of evening primrose oil (Efamol) in atopic children. Drugs Exp Clin Res, 14(4), 285-290. Diabetes Uccella, R. et al. [Action of evening primrose oil on cardiovascular risk factors in insulin-dependent diabetics]. Clin Ter, 129(5), June 15, 381-388. Dose: 3 gm/day. Takahashi, R. et al. 1993. Evening primrose oil and fish oil in non-insulindependentdiabetes. Prostaglandins Leukot Essent Fatt Acids, 49(2), Aug., 569-571. Dose: 4gm/day for 4 weeks. DMAE Hemiballismus-hemichorea Jameson, H. D. et al. 1977. Hemiballismus-hemichorea treated with dimethylaminoethanol. Dis Nerv Syst 38(11) Nov., 931-932 Phosphatidyl serine Alzheimer's disease Shea TB. Phospholipids alter tau conformation, phosphorylation, Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 163

proteolysis, and association with microtubules: implication for tau function under normal and degenerative conditions. J Neurosci Res. 1997 Oct 1;50(1):114-22. Heiss, W. D. et al. 1994. Long-term effects of phosphatidylserine, pyritinol, and cognitive training in Alzheimer's Disease. A neuropsychological, EEG, and PET investigation. Dementia, 5(2), Mar.-Apr., 88-98. Dose: 400 mg/day. Engel, R. R. et al. 1992. Double-blind cross-over study of phosphatidylserine vs. placebo in patients with early dementia of the Alzheimer type. Eur Neuropsychopharmacol 2(2), June, 1992, 149-155. Dose: 300 mg/day for 8 weeks. Crook, T. et al. 1992. Effects of phosphatidylserine in Alzheimer's disease. Psychopharmacol Bull, 28(1), 61-66. Dose: 100 mg/day for 12 weeks. Brain Function Mitoma J, Kasama T, Furuya S, Hirabayashi Y. Occurrence of an unusual phospholipid, phosphatidyl-L-threonine, in cultured hippocampal neurons. Exogenous L-serine is required for the synthesis of neuronal phosphatidyl-L-serine and sphingolipids. J Biol Chem. 1998 Jul 31;273(31):19363-6. Lombardi, G. F. 1989. [Pharmacological treatment with phosphatidyl serine of 40 ambulatory patients with senile dementia syndrome]. Minerva Med 80(6), June, 599-602. Crook, T. H. et al. 1991. Effects of phosphatidylserine in the age-associated memory impairment. Neurology 41(5), May, 644-649. Dose: 100 mg for 12 weeks. Delwaide, P. J. et al. 1986. Double-blind randomized controlled study of phosphatidylserine in senile demented patients. Acta Neurol Scand, 73(2) Feb., 136-140. Dose: 3x100 mg. Maggioni, M. et al. (1990). Effects of phosphatidylserine therapy in geriatric patients with depressive disorders. Acta Psychiatr Scand, 81(3), Mar., 265270. Dose: 300 mg/day for 30 days. Cenacchi, T. t al. 1993. Cognitive decline in elderly: A double-blind, placebo-controlled multicenter study on efficacy of phosphatidylserine administration. Aging 5(2), Apr., 123-133. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 164

Dose: 300 mg/day Sakai, M. et al. 1996. Pharmacological effect of phosphatidylserine enzymatically synthesized from soybean lecithin on brain functions in rodents. J Nutr Sci Vitaminol 42(1), Feb., 47-54. Dose: 300 mg/day. Epilepsy Loeb, C. et al. 1987. Preliminary evaluation of the effect of GABA and phosphatidylserine in epileptic patients. Epilepsy Res, 1(3), May, 209-212. Parkinson's disease Finfgeld, E. W. et al. 1989. Double-blind study with phosphatidylserine (PS) in Parkinsonian patients with senile dementia of Alzheimer's type. Prog Clin Biol Res, 1235-1246. Schizophrenia Tachik, K. H. et al. 1986. Phosphatidyleserine inhibition of monoamine oxidase in platelets of schizophrenics. Biol Psychiatry 21(1), Jan., 59-68. Stress Sohi KK, Mittal N, Hundal MK, Khanduja KL. Gallic acid, an antioxidant, exhibits antiapoptotic potential in normal human lymphocytes: A Bcl-2 independent mechanism. J Nutr Sci Vitaminol (Tokyo). 2003 Aug;49(4):221-7. Monteleone, P. et al. 1992. Blunting by chronic phosphatidylserine administration of the stress-induced activation of the hypothalamopituitaryadrenal axis in healthy men. European J Clin Pharmacol 42(4), 385-388. Dose: 800 mg/day for 10 days. Monteleone, P. et al. 1990. Effects of phosphatidylserine on the neuroendocrine response to physical stress in humans. Neuroendocrinology, 52(3), 243-248. Dose: 50 and 75 mg/day. Calcium Calcium Pancreatitis Kaur, N. et al. 1996. Chronic calcific pancreatitis associated with osteomalacia and secondary hyperparathyroidism. Indian J Gastroenterology 15(4) Oct., 147-148. Calcium absorption

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Harvey, J. A. et al. 1990. Superior calcium absorption from calcium citrate than calcium carbonate using external forearm counting. J Am Coll Nutr, 9(6), Dec., 583-587. Cancer Kim JA, Kang YS, Lee YS. Role of Ca2+-activated Cl- channels in the mechanism of apoptosis induced by cyclosporin A in a human hepatoma cell line. Biochem Biophys Res Commun. 2003 Sep 19;309(2):291-7. Duris, I. et al. Calcium chemoprevention in colorectal cancer. Hepatogastroenterology, 43(7), Jan.-Feb., 152-154. Dental health Krall EA, Wehler C, Garcia RI, Harris SS, Dawson-Hughes B. Calcium and vitamin D supplements reduce tooth loss in the elderly. Am J Med. 2001 Oct 15;111(6):452-6. Gupta, S. K. et al. 1994. Reversal of clinical and dental fluorosis. Indian Pediatr, Apr., 439-443. Dose: 250 mg/day for 44 days. Hip fracture Dawson-Hughes B. Calcium and protein in bone health. Proc Nutr Soc. 2003 May;62(2):505-9. Meunier, P. 1996. Prevention of hip fractures by correcting calcium and Vitamin D insufficiencies in elderly people. Scand J Rheumatology, 103(Suppl), 75-78. Dose: 1.2 gm/day for a 3 year study. Hypertension Liao XD, Tang AH, Chen Q, Jin HJ, Wu CH, Chen LY, Wang SQ. Role of Ca2+ signaling in initiation of stretch-induced apoptosis in neonatal heart cells. Biochem Biophys Res Commun. 2003 Oct 17;310(2):405-11. Wimalawansa, S. J. 1993. Antihypertensive effects of oral calcium supplementation may be mediated through the potent vasodilator CGRP. Am J Hypertension, 6(12), Dec., 996-1002. Dose: 1.4 gm/day. Osteoporosis Koo WW, Warren L. Calcium and bone health in infants. Neonatal Netw. 2003 Sep-Oct;22(5):23-37. Adachi, J. D. et al. 1996. Vitamin D and calcium in the prevention of corticosteroid induced osteoporosis: A 3 year follow-up. J Rheumatology 23(6), June, 995-1000. Dose:1000 mg/day. Leyes-Vence, M. et al. 1996. Transient osteoporosis of the hip. Presentation of a case and literature review. Acta Orthop Belg, 62(1), Mar., 56-59. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 166

Prince, R. et al. 1995. The effects of calcium supplementation (milk powder of tablets) and exercise on bone density in postmodern women. J Bone Mineral Res 10(7), July, 1068-1075. Dose: 1 gm/night over a period of 2 years. Haines, C. J. et al. 1995. Calcium supplementation and bone mineral density in postmenopausal women using estrogen replacement therapy. Bone 16(5), may, 529-531. Warady, B. D. 1994. Effects of nutritional supplementation and bone mineral status of children with Rheumatic diseases receiving corticosteroid therapy. J Rheumatology, 21(3), mar., 530-535. Vestibulitis Metts JF. Vulvodynia and vulvar vestibulitis: challenges in diagnosis and management. Am Fam Physician. 1999 Mar 15;59(6):1547-56, 1561-2. Solomons, C. C. et al. 1991. Calcium citrate of vulvar vestibulitis. A case report. J Reproductive Med, 36(12), Dec., 879-882. Magnesium Gastrointestinal Problems Witham CL, Stull CL. Metabolic responses of chronically starved horses to refeeding with three isoenergetic diets. J Am Vet Med Assoc. 1998 Mar 1;212(5):691-6. Zartarian M, Perez JP, Gelas B, Thomas JL. Comparative study of the shortterm acceptability and tolerance of a new oral formulation of magnesium (TX 1341) and a reference magnesium. J Gynecol Obstet Biol Reprod (Paris). 1997;26(2):182-6. Sue, Y. J. et al. 1994. Efficacy of magnesium citrate cathartic in pediatric toxic ingestions. Ann Emerg Med, 24(4), Oct., 709-712. Acetyl L-Carnitine Aging Scapagnini G, Ravagna A, Bella R, Colombrita C, Pennisi G, Calvani M, Alkon D, Calabrese V. Long-term ethanol administration enhances age-dependent modulation of redox state in brain and peripheral organs of rat: protection by acetyl carnitine. Int J Tissue React. 2002;24(3):89-96. Cipolli, C. and Chiari, G. 1990. [Effects of L-acetylcarnitine on mental deterioration in the aged: Initial results]. Clin Ter, 132(6Suppl), Mar. 31, 479510. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 167

Dose: 1500 mg/day. Salvioli, G. and Neri, M. 1994. L-acetylcarnitine treatment of mental decline in the elderly. Drugs Exp Clin Res, 20(4), 169-176. Dose: 1500 mg/day for 90 days. Bella, R. et al. 1990. Effect of acetyle-L-carnitine on geriatric patients suffering from dysthymic disorders. Int J Clin Pharmacol Res, 10(6), 355360. Dose: 3 gm/day for 30-60 days. Passeri, M. et al. 1990. Acetyl-L-carnitine in the treatment of mildly demented elderly patients. Int J Clin Pharmacol Res, 101(1-2), 75-79. Dose: 2 gm/day for 3 months. Franceschi, C. et al. 1990. Immunological parameters in aging: Studies on natural immunomodulatory substances. Int J Clin Pharmacology Res 10(12), 53-57. Alcoholism Calabrese V, Scapagnini G, Latteri S, Colombrita C, Ravagna A, Catalano C, Pennisi G, Calvani M, Butterfield DA. Long-term ethanol administration enhances age-dependent modulation of redox state in different brain regions in the rat: protection by acetyl carnitine. Int J Tissue React. 2002;24(3):97-104. Tempesta, E. et al. 1990. Role of acetyl-L-carnitine in the treatment of cognitive deficit in chronic alcoholism. Int J Clin Pharmacology Res, 10(12), 101-107. Alzheimer's disease Bianchetti A, Rozzini R, Trabucchi M. Effects of acetyl-L-carnitine in Alzheimer's disease patients unresponsive to acetylcholinesterase inhibitors. Curr Med Res Opin. 2003;19(4):350-3. Sano, M. et al. 1992. Double-blind parallel design pilot study of acetyl levocarnitine in patients with Alzheimer's disease. Arch Neurol, 49(11), Nov., 1137-1141. Dose: 2.5 gm/day for 3 months. Spagnoli, A. et al. 1991. Long-term acetyl-L-carnitine treatment in Alzheimer's disease. Neurology, 41(11), Nov., 1726-1732. Rai, G. et al. 1990. Double-blind, placebo controlled study of acetyl-Lcarnitine in patients with Alzheimer's dementia. Curr Med Res Opin, 11(10), 638-647. Dose: 2 gm/day for 24 weeks. Parnetti, L. et al. 1992. Pharmacokinetics of IV and oral acetyl-L-carnitine in a multiple dose regimen in patients with senile dementia of Alzheimer type. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 168

European J Clin Pharmacology, 42(1), 89-93. Pettegrew, J. W. et al. 1995. Clinical and neurochemical effects of acetyl-Lcarnitine in Alzheimer's disease. Neurobiol Aging, 16(1), Jan.-Feb., 1-4. Amenorrhea Genazzani, A. D. et al. 1991. Acetyl-L-carnitine as possible drug in the treatment of hypothalamic amenorrhea. Acta Obstet Gynecol Scand, 70(6), 487-492. Dose: 2 gm/day for 6 months. Cardiovascular/Coronary heart disease Adembri, C. et al. 1994. Ischemia-reperfusion of human skeletal muscle during aortoiliac surgery: Effects of acetylcarnitine. Histol Histopathol, 9(4), Oct., 683-690. Dose:3 mg/day iv prior to surgery. Dementia Kidd PM. A review of nutrients and botanicals in the integrative management of cognitive dysfunction. Altern Med Rev. 1999 Jun;4(3):144-61. Sinforiani, E. et al. 1990. Neuropsychological changes in demented patients treated with acetyl-L-carnitine. Int J Clin Pharmacology Res 10(1-2), 69-74. Bonavita, E. 1986. Study of the efficacy and tolerability of L-acetylcarnitine therapy in the senile brain. Int J Clin Pharmacol Ther Toxicol, 24(9), Sept., 511-516. Dose: 1,000 mg/day. Depression Pettegrew JW, Levine J, Gershon S, Stanley JA, Servan-Schreiber D, Panchalingam K, McClure RJ. 31P-MRS study of acetyl-L-carnitine treatment in geriatric depression: preliminary results. Bipolar Disord. 2002 Feb;4(1):61-6. Garzya, G. et al. 1990. Evaluation of the effects of L-acetylcarnitine on senile patients suffering from depression. Drugs Exp Clin Res, 16(2), 101-16. Dose: 1,500 mg/day. Neurological function Tafti M, Petit B, Chollet D, Neidhart E, de Bilbao F, Kiss JZ, Wood PA, Franken P. Deficiency in short-chain fatty acid beta-oxidation affects theta oscillations during sleep. Nat Genet. 2003 Jul;34(3):320-5. De Grandis D, Minardi C. Acetyl-L-carnitine (levacecarnine) in the treatment of diabetic neuropathy. A long-term, randomised, double-blind, placebocontrolled study. Drugs R D. 2002;3(4):223-31.

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Mezzina, C. et al. 1992. Idiopathic facial paralysis: New therapeutic prospects with acetyl-L-carnitine. Int J Clin Pharmacology Res, 12(5-6), 299-304. Dose: 3 gm/day for 14 days. Mazzocchio, R. et al. 1990. Enhancement of recurrent inhibition by intravenous administration of L-acetylcarnitine in spastic patients. J Neurol Neurosurg Psychiatry, 53(4), Apr., 321-326. Parkinson's disease Beal MF. Bioenergetic approaches for neuroprotection in Parkinson's disease. Ann Neurol. 2003;53 Suppl 3:S39-47; discussion S47-8. Kidd PM. Parkinson's disease as multifactorial oxidative neurodegeneration: implications for integrative management. Altern Med Rev. 2000 Dec;5(6):502-29. Puca, F. M. et al. 1990. Clinical pharmodynamics of acetyl-L-carnitine in patients with Parkinson's disease. Int J Clin Pharmacol Res, 10(1-2), 139143. Dose: 1 or 2 gm/day for 7 days. Stroke Lolic MM, Fiskum G, Rosenthal RE. Neuroprotective effects of acetyl-Lcarnitine after stroke in rats. Ann Emerg Med. 1997 Jun;29(6):758-65. Arrigo, A. et al. 1990. Effects of acetyl-L-carnitine on reaction times in patients with cerebrovascular insufficiency. Int J Clin Pharmacol Res, 10(12), 133-137. Postiglione, A. et al. 1990. Cerebral blood flow in patients with chronic cerebrovascular disease: Effect of acetyl-L-carnitine. Int J Clin Pharmacology Res, 10(1-2), 129-132. Dose: 1.5 gm iv. Rosadini, G. et al. 1990. Acute effects of acetyl-L-carnitine on regional cerebral blood flow in patients with brain ischaemia. Int J Clin Pharmacol Res, 10(1-2), 123-128. Dose: 1,500 mg iv. Postiglione, A. et al. 1991. Effect of acute administration of L-acetyl carnitine on cerebral blood flow in patients with chronic cerebral infarct. Pharmacology Res.23(3), Apr., 241-246. Dose: 1.5 gm iv. Co-enzyme Q-10 Cancer Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 170

Palan PR, Mikhail MS, Shaban DW, Romney SL. Plasma concentrations of coenzyme Q10 and tocopherols in cervical intraepithelial neoplasia and cervical cancer. Eur J Cancer Prev. 2003 Aug;12(4):321-6. Drisko JA, Chapman J, Hunter VJ. The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer. J Am Coll Nutr. 2003 Apr;22(2):118-23. Lockwood, K. et al. 1995. Progress therapy on breast cancer with Vitamin Q10 and the regression of metastases. Biochem Biophys Res Commun, 212(1), July 6, 172-177. Dose: 390 mg/day for 3-5 years. Lockwood, K. et al. 1994. Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q10, Biochem Biophys Res Commun, 199(3), Mar. 30, 1504-1508. Dose: 390 mg/day after 1 month tumor no longer palpable, after 2 months mammagrophy indicated no tumor. Tsubaki, K. et al. 1984. [Investigation of the preventive effect of CoQ10 against the side-effects of anthracycline antineoplastic agents], Gan To Kagaku Ryoho, 11(7) July, 1420-1427. Dose: 1 mg/kg/day iv. Okuma, K. et al. 1983. [Protective effect of coenzyme Q10 in cardiotoxicity induced by adriamycin], Gan To Kagaku Ryoho, 11(3), Mar., 502-508. Cardiovascular/Coronary heart disease Kamikawa, T. et al. 1985. Effects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris. Am J Cardiology, 56(4), Aug. 1, 1985, 247251. Dose: 150 mg/day for 4 weeks. Tanaka, J. et al. 1983. Coenzyme Q10: The prophylactic effect on low cardiac output following cardiac valve replacement. Annals Thoraci Surg. 33(2), Feb., 145-151. Dose: 30-60 mg/day orally for 6 days. 76 Chello, M. et al. 1994. Protection by Coenzyme Q10 from myocardial reperfusion injury during coronary artery bypass grafting. Annals Thoracic Surg. 58(5), Nov., 1427-1432. Dose:150 mg/day for 7 days before surgery. Chen, Y. F. et al. 1994. Effectiveness of coenzyme Q10 in myocardial preservation during hypothermic cardioplegic arrest. J Thoracic Cardiovascular Surg. 107(1), Jan., 242-247.

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Greenberg, S. M. and Frishman, W. H. 1988. Coenzyme Q10: A new drug for myocardial ischemia? Med Clin North America, 72(1), Jan., 243-258. Nishikawa, Y. et al. 1989. Long-term coenzyme Q10 therapy for a mitochondrial encephalomyopathy with cytochrome C oxidase deficiency: A 31P NMR study. Neurology, 39(3), Mar., 399-403. Ogasahara, S. et al. 1985. Improvement of abnormal pyruvate metabolism and cardia conduction defect with coenzyme Q10 in Kearns-Sayre syndrome, Neurology, 35(3), Mar., 372-373. Dose: 60-120 mg/day for 3 months. Folkers, K. et al. 1992. Therapy with coenzyme Q10 of patients in heart failure who are eligible of ineligible for a transplant. Biochem Biophys Res Commun, 182(1) Jan. 15, 247-253. Sunamori, M. et al. 1991. Clinical experience of coenzyme Q10 to enhance intraoperative myocardial protection in coronary artery revascularization, Cardiovasc Drugs Ther, 5 Suppl 2, Mar., 297-300. Dose: pretreatment with 5mg/kg iv. Baggio, E. et al. 1993. Italian multicenter study of the safety and efficacy of coenzyme Q10 as adjunctive therapy in heart failure (interim analysis). The CoQ10 drug surveillance investigators. Clin Investigations, 71(8 Suppl), S145-149. Dose: 50-100 mg/day for 3 months. Langsjoen, P. H. et al. 1993. Isolated diastolic dysfunction of the myocardium and its response to CoQ10 treatment. Clin Investigations, 71(8 Suppl), S140-144. Morisco, C. et al. 1993. Effect of coenzyme Q10 therapy in patients with congestive heart failure: A long-term multicenter randomized study. Clin Investigations, 71(8 Suppl), S134-146. Dose: 2 mg/kg/day for 1 year. Lampertico, M. and Conis, S. 1993. Italian multicenter study on the efficacy and safety of coenzyme Q10 as adjuvant therapy in heart failure. Clin Investigations, 71(8 Suppl), S129-S133. Dose: 50 mg/day for 4 weeks. Mortensen, S. A. 1993. Perspectives on therapy of cardiovascular diseases with coenzyme Q10 (Ubiquinonq). Clin Investigations, 71(8 Suppl), S116S123. Mortensen, S. A. et al. 1985. Long-term coenzyme Q10 therapy: A major advance in the management of resistant myocardial failure. Drugs Exp Clin Res, 11(8), 581-593. Dose: 100 mg/day. Langsjoen. P. H. et al. 1985. Effective treatment with coenzyme Q10 of patients with chronic myocardial disease. Drugs Exp Clin Res, 11(8), 577Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 172

579. Oda, T. 1985. Effect of coenzyme Q10 on stress-induced cardiac dysfunction in paediatric patients with mitral valve prolapse: A study by stress echocardiography. Drugs Exp Clin Res, 11(8), 557-576. Dose: 3-3.4 mg/day. Suzuki, H. et al. 1984. Cardiac performance and coenzyme Q10 levels in thyroid disorders. Endocrinol Japan, 31(6), Dec., 755-761. Kato, T. et al. 1990. Reduction in blood viscosity by treatment with coenzyme Q10 in patients with ischemic heart disease. Int J Clin Pharmacol Ther Toxicol, 28(3), Mar., 123-126. Dose: 60 mg/day for 2 months. Manzoli, U. et al. 1990. Coenzyme Q10 in dilated cardiomyopathy. Int J Tissue React 12(3), 173-178. Dose: 100 mg/day orally. Langsjoen, P. H. et al. 1990. A six-year clinical study of therapy of cardiomyopathy with coenzyme Q10. Int J Tissue React, 12(3), 168-171. Langsjoen, P. H. et al. 1990. Pronounced increase of survival of patients with cardiomyopathy when treated with coenzyme Q10 and conventional therapy. Int J Tissue React, 12(3), 163-168. Diabetes Watts GF, Playford DA, Croft KD, Ward NC, Mori TA, Burke V. Coenzyme Q(10) improves endothelial dysfunction of the brachial artery in Type II diabetes mellitus. Diabetologia. 2002 Mar;45(3):420-6. Suzuki, Y. et al. 1995. A case of Diabetic amyotrophy associated with 3243 mitochondrial tRNA(leu: UUR) Mutation and successful therapy with coenzyme Q10, Endocr J, 42(2), Apr., 141-145. Immune enhancement Folkers, K. et al. 1993. The activities of coenzyme Q10 and vitamin B6 for immune responses. Biochem Biophys Res Commun, 193(1), May 28, 88-92. Lung disease Gazdik F, Gvozdjakova A, Nadvornikova R, Repicka L, Jahnova E, Kucharska J, Pijak MR, Gazdikova K. Decreased levels of coenzyme Q(10) in patients with bronchial asthma. Allergy. 2002 Sep;57(9):811-4. Fujimoto, S. et al. 1993. Effects of coenzyme Q10 administration on pulmonary function and exercise performance in patients with chronic lung diseases. Clin Investigations, 71(8 Suppl), S126-S166. Dose: 90 mg/day for 8 weeks. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 173

Muscular Injury Folkers, K. and Simonsen, R. 1995. Two successful double-blind trials with coenzyme Q10 (vitamin Q10) on muscular dystrophies and neurogenic atrophies. Biochim Biophys Acta, 127(1), May 24, 281-286. Glutathione Aging Cruz R, Almaguer Melian W, Bergado Rosado JA. Glutathione in cognitive function and neurodegeneration. Rev Neurol. 2003 May 1-15;36(9):877-86. Julius, M. et al. 1994. Glutathione and morbidity in a community-based sample of elderly. J Clin Epi, 47(9), Sept., 1021-1026. Cancer Kaufmann Y, Kornbluth J, Feng Z, Fahr M, Schaefer RF, Klimberg VS. Effect of glutamine on the initiation and promotion phases of DMBA-induced mammary tumor development. JPEN J Parenter Enteral Nutr. 2003 NovDec;27(6):411-8. Flagg, E. W. et al. 1994. Dietary glutathione intake and the risk of oral and pharyngeal cancer. Am J Epi, 139(5), Mar. 1, 453-465. Cascinu, S. et al. 1995. Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: A randomized double-blind placebo-controlled trial. J Clin Oncology, 13(1), Jan., 26-32. Bowman, A. et al. 1994. Effect of adding glutathione (GSH) to cisplatin (CDDP) in the treatment of stage I-IV ovarian cancer. British J Cancer, 71(Suppl 24), 14. Dose: 3 gm/m2 for 21 days. Spatti, G. B. et al. 1990. Cisplatin with minimal hydration and glutathione protection in the treatment of ovarian carcinoma. Anticancer Res, 10(5B), 1425-1456. Dose: 2.5-5 gm in 100-200 ml of normal saline over 15 minutes iv. Dalhoff, K. et al. 1992. Glutathione treatment of hepatocellular carcinoma. Liver, 12(5), Oct., 341-343. Dose: 5 gm/day. Trickler, D. et al. 1993. Inhibition of oral carcinogenesis by glutathione. Nutr Cancer, 20(2), 139-144. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 174

Smyth, J. et al. 1995. Glutathione improves the therapeutic index of cisplatin and quality of life for patients with ovarian cancer. Proceedings Annual Meeting Am Soc Clin Oncologists, 14, A761. Cataracts Reddy VN, Giblin FJ, Lin LR, Dang L, Unakar NJ, Musch DC, Boyle DL, Takemoto LJ, Ho YS, Knoernschild T, Juenemann A, Lutjen-Drecoll E. Glutathione peroxidase-1 deficiency leads to increased nuclear light scattering, membrane damage, and cataract formation in gene-knockout mice. Invest Ophthalmol Vis Sci. 2001 Dec;42(13):3247-55. Sternberg Jr., P. 1993. Protection of retinal pigment epithelium from oxidative injury by glutathione and precursors. Invest Ophthalmol Vis Sci, 34(13), Dec., 3661-3668. Gastric injury Yajima N, Hiraishi H, Yamaguchi N, Ishida M, Shimada T, Terano A. Monochloramine-induced cytolysis to cultured rat gastric mucosal cells: role of glutathione and iron in protection and injury. J Lab Clin Med. 1999 Oct;134(4):372-7. Loguericio, C. et al. 1953. Glutathione prevents ethanol induced gastric mucosal damage and depletion of sulfydryl compounds in humans. Gut, 34(2), Feb., 161-165. Liver damage Grattagliano I, Lauterburg BH, Portincasa P, Caruso ML, Vendemiale G, Valentini AM, Palmieri VO, Palasciano G. Mitochondrial glutathione content determines the rate of liver regeneration after partial hepatectomy in euand hypothyroid rats. J Hepatol. 2003 Oct;39(4):571-9. Nardi, E. A. et al. 1991. [High-dose reduced glutathione in the therapy of alcoholic hepatopathy]. Clin Ter, 136(1), Jan. 15, 47-51. Dentico, P. et al. 1995. [Glutathione in the treatment of chronic fatty liver diseases], Recenti Prog Med, 86(7-8), July-Aug., 290-293. N-Acetyl-Cysteine Adult respiratory distress syndrome Davreux CJ, Soric I, Nathens AB, Watson RW, McGilvray ID, Suntres ZE, Shek PN, Rotstein OD. N-acetyl cysteine attenuates acute lung injury in the rat. Shock. 1997 Dec;8(6):432-8. Laurent, T. et al. 1996. Oxidant-antioxidant balance in granulocytes during ARDS. Effect of N-acetylcysteine. Chest, 109(1), Jan., 163-166. Bernard, G. R. 1990. Potential of N-acetylcysteine as treatment for the Adult Respiratory Distress Syndrome. European Resp J Suppl, 11 Oct., 496sCopyright Gary Null & Associates, Inc., 2005 All Rights Reserved 175

498s. Cardiovascuar/Coronary heart disease Reinhart, K. et al. 1995. N-acetylcysteine preserves oxygen consumption and gastric mucosal pH during hyperoxic ventilation. Am J Resp Critical Care Med, 151(3 Pt 1), Mar., 773-779. Dose: 150 mg/kg-1. Boesgaard, S. et al. 1992. Preventive administration of intravenous Nacetylcysteine and development of tolerance to isosorbide dinitrate in patients with angina pectoris. Circulatio, 85(1), Jan., 143-149. Dose: 2 gm NAC over 15 minutes iv. Horowitz, J. D. et al. 1993. Potentiation of the cardiovascular effects of nitroglycerin by N-acetylcysteine. Circulation, 68(6), Dec., 1247-1253. Dose: 100 mg/kg of NAC iv. Arstall, M. A. et al. 1995. N-acetylcysteine in combination with nitroglycerin and streptokinase for the treatment of evolving acute myocardial infarction. Safety and biochemical effects. Circulation, 92(10), Nov. 15, 2855-2862. Dose: 15 gm iv NAC. Boesgaard, S. et al. 1994. Altered peripheral vasodilator profile of nitroglycerin during long-term infusion of N-acetylcysteine. J Am Coll Cardiology, 23(1), Jan., 163-169. Dose: 2 gm iv NAC followed by 5 mg/kg per hour on human veins. Spies, C. et al. 1996. [Effect of prophylactically administered Nacetylcysteine on clinical indicators for tissue oxygenation during hyperoxic ventilation in cardiac risk patients], Anaesthesist, 45(4), Apr., 343-350. Dose: 150 mg/kg NAC. Horowitz, J. D. et al. 1990. Nitroglycerine/N-acetylecysteine in the management of unstable angina pectoris. European Heart J, 9(Suppl A) Jan., 95-100. Dose: 5 gm 6 hourly iv. Svendsen, J. H. et al. 1989. N-acetylcysteine modifies the acute effects of isosorbide-5-mononitrate in angina pectoris patients. Pharmacol, 13(2), Feb., 320-323. Andersen, L. W. et al. 1995. The role of N-acetylcysteine administration on the oxidative response of neutrophils during cardiopulmonary bypass. Perfusion, 10(1), 21-26. Dose: bolus of 100 mg/kg of NAC followed by a continuous infusion of 20 mg/kg. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 176

Chronic Bronchitis Jaber R. Respiratory and allergic diseases: from upper respiratory tract infections to asthma. Prim Care. 2002 Jun;29(2):231-61. Rasmussen, J. B. and Glennow, C. 1988. Reduction in days of illness after long-term treatment with N-acetylcysteine controlled-release tablets in patients with chronic bronchitis. European Respir J, 1(4), Apr., 351-355. Dose: 300 mg bid. 82 Gerards, H. H. and Vits, U. 1991. [Therapy of bronchitis. Successful singledosage treatment with N-acetylcysteine, results of an administration surveillance study in 3,076 patients]. Fortschr Med, 109(34), Nov. 30, 707710. Dose: 600 mg/kg. Boner, A. L. et al. 1984. A combination of cefuroxine and N-acetyl-cysteine for the treatment of maxillary sinusitis in children with respiratory allergy. Int J Clin Pharmacol Ther Toxicol, 22(9), Sept, 511-514. Dose: 15-25 mg/kg/day over a 10 day period. Santagelo, G. et al. 1985. A combination of Cefuroxime and N-acetylcysteine for the treatment of lower respiratory tract infections in children. Int J Clin Pharmacol Ther Toxicol, 23(5), May, 279-281. General Simkeviciene V, Straukas J, Uleckiene S. N-acetil-l-cysteine and 2-amino-2thiiazoline N-acetyl-l-cysteinate as a possible cancer chemopreventive agents in murine models. Acta Biol Hung. 2002;53(3):293-8. Smilkstein, M. J. et al. 1991. Acetaminophen overdose: A 48-hour intravenous N-acetylcysteine treatment protocol. Annals Emergency Med., 20(10), Oct., 1058-1063. Dose: (12) 70 mg/kg dose every 4 hours and a loading dose of 140mg/kg. Lund, M. E. et al. 1984. Treatment of acute methylmercury ingestion by hemodialysis with N-acetylcysteine (Mucomyst) infusion and 2,3dimercaptopropane sulfonate. J Toxicol Clin Yoxicol, 22(1), July, 31-49. Jensen, T. et al. 1988. Effect of oral N-acetylcyteine administration on human blood neutrophil and monocyte function. APMIS, 96(1), Jan., 62-67. Dose: 400 mg oral dose. De Groote, J. and Van Steenbergen, W. 1995. Paracetamol intoxication and N-acetyl-cysteine treatment. Acta Gastroenterol Belg, 58(3-4), May-Aug., 326-334. Todisco, T. et al. 1985. Effect of N-acetylcysteine in subjects with slow pulmonary mucociliary clearance. European J Respir Diseases Suppl, 139, 136-141. Dose: 0.6 gm/day. 83 Beckett, G. J. et al. 1990. Intravenous N-acetylcysteine, hepatoxicity and Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 177

plasma glutathione S-transferase in patients with Paracetamol overdosage. Hum Exp Toxicol, 9(3) May, 183-186. Brahm, J. et al. 1992. [Paracetamol overdose: A new form of suicide in Chile and the value of N-acetylcysteine administration]. Rev Med Chil, 120(4), Apr., 427-499. Glutathione deficiency Boulares AH, Contreras FJ, Espinoza LA, Smulson ME. Roles of oxidative stress and glutathione depletion in JP-8 jet fuel-induced apoptosis in rat lung epithelial cells. Toxicol Appl Pharmacol. 2002 Apr 15;180(2):92-9. Jan, A. et al. 1994. Effect of ascorbate or N-acetylcysteine treatment in a patient with hereditary glutathione synthetase deficiency. J Pediatrics, 124(2), Feb., 229-233. Martensson, J. et al. 1989. A therapeutic trial with N-acetylcysteine in subjects with hereditary glutathione synthetase deficiency (5oxoprolinuria), J Inherist Metab Dis, 12(2), 120-130. Dose: 15 mg/kg/day. Hepatitis Neri S, Ierna D, Antoci S, Campanile E, D'Amico RA, Noto R. Association of alpha-interferon and acetyl cysteine in patients with chronic C hepatitis. Panminerva Med. 2000 Sep;42(3):187-92. Hepatitis viral load correlates to glutathione levels. Posit Health News. 1998 Fall;(No 17):14-5. Hansen, R. M. et al. 1991. Gold induced hepatitis and pure red cell aplasia. Complete recovery after corticosteroid and N-acetylcysteine therapy. J Pheumatology, 18(8), Aug., 1251-1253. Liver damage Neal R, Matthews RH, Lutz P, Ercal N. Antioxidant role of N-acetyl cysteine isomers following high dose irradiation. Free Radic Biol Med. 2003 Mar 15;34(6):689-95. Bromley, P. N. et al. 1995. Effects of intraoperative N-acetylcysteine on orthotopic liver transplantation. British J Anaesth, 75(3), Sept., 352-354. Oh, T. E. and Shenfield, G. M. 1980. Intravenous N-acetylcysteine for Paracetamol poisoning. Med J Australia, 1(13), June 28, 664-665. Lung damage Rahman Q, Abidi P, Afaq F, Schiffmann D, Mossman BT, Kamp DW, Athar M. Glutathione redox system in oxidative lung injury. Crit Rev Toxicol. 1999 Nov;29(6):543-68. Meyer, A. et al. 1995. Intravenous N-acetylcysteine and lung glutathione of patients with pulmonary fibrosis and normals. Am J Respiratory Crit Care Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 178

Med, 152(3), Sept., 1055-1060. Dose: 1.8 gm. Suter, P. M. et al. 1994. N-acetylcysteine enhances recovery from acute lung injury in man. A randomized, double-blind, placebo-controlled clinical study. Chest, 105(1), Jan., 190-194. Dose: 40 mg/kg/day iv over a period of 72 hours. Eklund, A. et al. 1988. Oral N-acetylcysteine reduces selected humoral markers of inflammatory cell activity in BAL fluid from healthy smokers: Correlation to effects on cellular variables. European Respir J, 1(9), Oct., 832-838. Dose: 200 mg tid over an 8 week period. Linden, M. et al. 1988. Effects of oral N-acetylecysteine on cell content and macrophage function in bronchoalveolar lavage from healthy smokers. European Respiratory J, 1(7), July, 645-650. Dose: 200 mg tid over an 8 week period. Muscle fatigue Khawli FA, Reid MB. N-acetylcysteine depresses contractile function and inhibits fatigue of diaphragm in vitro. J Appl Physiol. 1994 Jul;77(1):317-24. Reid, M. B. et al. 1994. N-acetylcysteine inhibits muscle fatigue in humans. J Clin Investigations, 94(6), Dec., 2468-2474. Dose: pretreatment with 150 mg/kg. Sjogren's Syndrome Walters, M. T. et al. 1986. A double-blind, cross-over, study of oral Nacetylcysteine in Sjogren's syndrome. Scandanavian J Pheumatol Suppl, 61, 253-258. Alpha Lipoic acid Diabetes Gouty S, Regalia J, Cai F, Helke CJ. Alpha-Lipoic acid treatment prevents the diabetes-induced attenuation of the afferent limb of the baroreceptor reflex in rats. Auton Neurosci. 2003 Oct 31;108(1-2):32-44. Kahler, W. et al. 1993. Diabetes Mellitus-A free radical-associated disease. Results of adjuvant supplementation. Z. Gesante Inn Med, 48(5), May, 223232. Dose: 600 mg/day for 3 months. Jacob, S. et al. 1995. Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid. Arzneimittelforschung, 45(8), Aug., 872-874. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 179

Dose: 1000 mg. Ziegler, D. et al. 1995. Treatment of symptomatic diabetic peripheral neuropathy with anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial. Diabetologia, 38(12), Dec., 1425-1433. Dose: 600 mg/day over a 3 week period. Klein, W. 1975. [Treatment of diabetic neuropathy with oral alpha-lipoic acid]. MMW Munch Med Wochenschr, 117(22), May 30, 957-958. Dose: 2x50 mg or 2x100 mg/day. General Andreassen OA, Ferrante RJ, Dedeoglu A, Beal MF. Lipoic acid improves survival in transgenic mouse models of Huntington's disease. Neuroreport. 2001 Oct 29;12(15):3371-3. Mottley C, Mason RP. Sulfur-centered radical formation from the antioxidant dihydrolipoic acid. J Biol Chem. 2001 Nov 16;276(46):42677-83. Epub 2001 Sep 06 Barbirolli, B. et al. 1995. Lipoic (thiotic) acid increases brain energy availability and skeletal muscle performance as shown by an in vivo 31PMRS in a patient with mitochondrial cytopathy. J Neurology, 242(7), July, 472-477. Dose: 600 mg/day for 1 month. Glaucoma Head KA. Natural therapies for ocular disorders, part two: cataracts and glaucoma. Altern Med Rev. 2001 Apr;6(2):141-66. Filina, A. A. et al. 1995. Lipoic acid as a means of metabolic therapy of open-angle glaucoma. Vestn Oftalmol, 111(4), Oct.-Dec., 6-8. Dose: 0.15 gm/day for 1 month. DHEA Aging Kamel HK. Sarcopenia and aging. Nutr Rev. 2003 May;61(5 Pt 1):157-67. Ponholzer A, Plas E, Schatzl G, Jungwirth A, Madersbacher S; Austrian Society of Urology. Association of DHEA-S and estradiol serum levels to symptoms of aging men. Aging Male. 2002 Dec;5(4):233-8. Yen, S. S. et al. 1995. Replacement of DHEA in aging men and women. Potential remedial effects. Ann NY Acad Sci, 774, Dec. 29, 128-142. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 180

Alzheimer's disease Leowattana W. DHEA(S): the fountain of youth. J Med Assoc Thai. 2001 Oct;84 Suppl 2:S605-12. Hillen T, Lun A, Reischies FM, Borchelt M, Steinhagen-Thiessen E, Schaub RT. DHEA-S plasma levels and incidence of Alzheimer's disease. Biol Psychiatry. 2000 Jan 15;47(2):161-3. Yanase, T. et al. 1996. Serum dehyfroepiandrosterone (DHEA) and DHEAsulfate (DHEA-S) in Alzheimer's Disease and in cerebrovascular dementia. Endocr J, 43(1), Feb., 119-123. Cognitive function Harris DS, Wolkowitz OM, Reus VI. Movement disorder, memory, psychiatric symptoms and serum DHEA levels in schizophrenic and schizoaffective patients. World J Biol Psychiatry. 2001 Apr;2(2):99-102. Friess, E. et al. 1995. DHEA administration increases rapid eye movement sleep and EEG power in the Sigma frequency range. Am J Physiol, 268(1 Pt 1), Jan., E107-13. Dose: 500 mg oral dose. 87 Depression Goodyer IM, Herbert J, Tamplin A. Psychoendocrine antecedents of persistent first-episode major depression in adolescents: a community-based longitudinal enquiry. Psychol Med. 2003 May;33(4):601-10. Wolkowitz, O. M. et al. 1997. Dehydroepiandrosterone (DHEA) treatment of depression. Biol Psychiatry, 41(3), Feb. 1, 311-318. Dose: 30-90 mg/day for 4 weeks. General Netherton C, Goodyer I, Tamplin A, Herbert J. Salivary cortisol and dehydroepiandrosterone in relation to puberty and gender. Psychoneuroendocrinology. 2004 Feb;29(2):125-40. Khorram, O. 1996. DHEA: A hormone with multiple effects. Curr Opin Obstet Gynecol, 8(5), Oct., 351-354. Lupus Chang DM, Lan JL, Lin HY, Luo SF. Dehydroepiandrosterone treatment of women with mild-to-moderate systemic lupus erythematosus: a multicenter randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002 Nov;46(11):2924-7. Van Vollenhoven, R. F. and McGuire, J. L. 1996. Studies of dehydroepiandrosterone (DHEA) as a therapeutic agent in systemic lupus erythematosus. Ann Med Interne, 147(4), 290-296.

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Melatonin Cancer Sainz RM, Mayo JC, Rodriguez C, Tan DX, Lopez-Burillo S, Reiter RJ. Melatonin and cell death: differential actions on apoptosis in normal and cancer cells. Cell Mol Life Sci. 2003 Jul;60(7):1407-26. Lissoni, P. et al. 1992. Biological and clinical results of a neuroimmunotherapy with interleukin-2 and the pineal hormone melatonin as a first line treatment in advanced non-small cell lung cancer. British J Cancer, 66(1), July, 155-158. Dose: 10 mg/day. Lissoni, P. et al. 1995. Modulation of cancer endocrine therapy by melatonin: A phase II study of Taxoifen plus melatonin in metastatic breast cancer patients progressing under Tamoxifen alone. British J Cancer, 71(4), Apr., 854-856. Dose: 20 mg/day. Neri, B. et al. 1994. Modulation of human lymphoblastoid interferon activity by melatonin in metastatic renal cell carcinoma: A phase II study. Cancer, 73(12), June 15, 3015-3019. Dose: 10 mg/day. Lissoni, P. et al 1994. A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer, 73(3), Feb 1, 699-701. Lissoni, P. et al. 1989. Endocrine and immune effects of melatonin therapy in metastic cancer patients. European J Cancer Clin Oncol, 25(5), May, 789795. Dose: 20 mg/day intramuscular, followed with 10mg/day in patients experiencing remission. Viviani, S. et al. 1990. Preliminary studies on melatonin in the treatment of Myelodysplastic Syndromes following cancer chemotherapy. J Pineal Res, 8(4), 347-354. Dose: 20 mg/day. Gonzalez, R. et al. 1991. Melatonin therapy of advanced human malignant melanoma. Melanoma Res, 1(4), Nov.-Dec., 237-243. Dose: daily oral dose of 5 mg/m2 to 700mg/m2 after 5 weeks. Lissoni, P. et al. 1991. Clinical results with pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies. Oncology, 48(6), 448-450. Dose: 20 mg/day followed with 10mg/day orally. Jet Lag Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 182

Beaumont M, Batejat D, Pierard C, Van Beers P, Denis JB, Coste O, Doireau P, Chauffard F, French J, Lagarde D. CAFFEINE OR MELATONIN EFFECTS ON SLEEP AND SLEEPINESS AFTER RAPID EASTWARD TRANSMERIDIAN TRAVEL. J Appl Physiol. 2003 Sep 5. Petri, K. et al. 1989. Effect of melatonin of jet lag after long haul flights. BMJ, 298(6675), Mar. 18, 705-707. Dose: 5 mg 3 days prior to flight. Petrie, K. et al. A double-blind trial of melatonin as a treatment for jet lag in internatinal cabin crew. Biological Psychiatry, 33(7), Apr. 1, 526-530. Dose: 5 mg 3 days prior to flight. Sleep Turk J. Melatonin supplementation for severe and intractable sleep disturbance in young people with genetically determined developmental disabilities: short review and commentary. J Med Genet. 2003 Nov;40(11):7936. Palm, L. et al. 1991. Correction of non-24-hour sleep/wake cycle by melatonin in a blind retarded boy. Ann Neurol, 29(3), Mar., 336-339. Zhdanova, I. V. et al. 1995. Sleep-inducing effects of low doses of melatonin ingested in the evening. Clin Pharmacol Therapy, 57(5), 552-558. Dose: 0.3 or 1.0 mg at 6, 8 or 9PM. Dahlitz, M. et al. 1991. Delayed sleep phase syndrome response to melatonin. Lancet, 337(8750), May 11, 1121-1124. Dose: 5 mg for 4 weeks. Garfinkel, D. et al. 1995. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet, 346(8974), Aug. 26, 541-544. Dose: 2 mg/night for 3 weeks. Etzioni, A. et al. 1996. Melatonin replacement corrects sleep disturbances in a child with pineal tumor. Neurology, 46(1), Jan, 261-263. Dose: 3 mg/night for 2 weeks. MacFarlane, J. G. et al. 1991. The effects of exogenous melatonin on the total sleep time and daytime alertness of chronic insomniacs: A preliminary study. Biological Psychiatry, 30(4), Aug. 15, 371-376. Dose: 75 mg per os/night. Folkard, S. et al. 1993. Can melatonin improve shift workers' tolerance of the night shift? Some preliminary findings. Chronobiol Int, 10(5), Oct., 315320. Dose: 5 mg/night. Jan, J. E. et al. 1994. The treatment of sleep disorders with melatonin. Dev Med Child Neurol, 36(2), Feb., 970107. Dose: 2-10 mg.

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Waldhauser, F. et al. 1990. Sleep laboratory investigations on hypnotic properties of melatonin. Psychopharmacology, 100(2), 222-226. Tzischinsky, O. and Lavie, P. 1994. Melatonin possesses time-dependent hypnotic effects. Sleep, 17(7), Oct., 638-645. Dose: 5 mg. Haimov, I. et al. 1995. Melatonin replacement therapy of elderly insomniacs. Sleep, 18(7), Sept., 598-603. Dose: 2 mg/night for 7 consecutive days. 1 mg of sustained-release. Vision Scher J, Wankiewicz E, Brown GM, Fujieda H. MT(1) melatonin receptor in the human retina: expression and localization. Invest Ophthalmol Vis Sci. 2002 Mar;43(3):889-97. Samples, J. R. et al. 1988. Effect of melatonin on intraocular pressure. Current Eye Res 7(7), July, 649-653. Pregnenolone Kamei H, Noda Y, Nabeshima T, Yamada K. Effects of sigma receptor ligands on psychiatric disorders. Nihon Shinkei Seishin Yakurigaku Zasshi. 2003 Oct;23(5):187-96. Araneo, B. A. et al. 1995. Dehydroepiandrosterone reduces progressive dermal ischemia caused by thermal&127;&127;&127;&127;&127;&127;&127;&127;&127; injury. J Surg Res, 59(2) Aug., 250-262 Dose: Subcutaneous administration of DHEA at approximately 1 mg/kg/day achieved optimal protection against the&127; development of progressive dermal ischemia. Arginine Cancer Bonafe M, Ceccarelli C, Farabegoli F, Santini D, Taffurelli M, Barbi C, Marzi E, Trapassi C, Storci G, Olivieri F, Franceschi C. Retention of the p53 codon 72 arginine allele is associated with a reduction of disease-free and overall survival in arginine/proline heterozygous breast cancer patients. Clin Cancer Res. 2003 Oct 15;9(13):4860-4. Brittenden, J. et al. 1994. L-arginine stimulates host defenses in patients with breast cancer. Surgery, 115(2), Feb., 205-212. Dose: 30 gm/day for 3 days. Cardiovascuar/Coronary heart disease Tousoulis D, Davies GJ, Tentolouris C, Crake T, Goumas G, Stefanadis C, Toutouzas P. Effects of L-arginine on flow mediated dilatation induced by Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 184

atrial pacing in diseased epicardial coronary arteries. Heart. 2003 May;89(5):531-4. Rector, T. S. et al. 1996. Randomized, double-blind, placebo controlled study of supplemental oral L-arginine in patients with heart failure. Circulation, 93(12), June 15, 2135-2141. Dose: 5.6 to 12.6 gm/day over 6 weeks. Koifman, B. et al. 1995. Improvement of cardiac performance by intravenous infusion of L-arginine in patients with moderate congestive heart failure. J Am Coll Cardiol, 26(5), Nov. 1, 1251-1256. Dose: 20 gm iv. Clarkson, P. et al. 1996. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Investigation, 97(8), Apr. 15, 1989-1994. Dose: 7 gm 3x/day over 4 weeks. McCaffrey, M. J. et al. 1995. Effect of L-arginine infusion on infants with persistent pulmonary hypertension on the newborn. Biol Neonate, 6794), 240-243. Dose: 500 mg/kg infused over 30 minutes. Hishikawa, K. et al. 1992. L-arginine as a antihypertensive agent. J Cardiovascular Pharmacol, 20(suppl 12), S196-S197. Kilbourn, R. G. et al. 1995. NG-methyl-L-arginine, an inhibitor of nitric oxide synthase, reverses interleukin-2-induced hypotension. Crit Care Med, 23(6), June, 1018-1024. Dose: 12 mg/kg followed by 4mg/kg every 4 hours. General Huang ZH, Lin HW, Li Z, Feng HM, Sun YG, Zhang QG. L-arginine decreases P-selectin expression in traumatic shock. Di Yi Jun Yi Da Xue Xue Bao. 2003 Aug;23(8):777-80. Pittari, A. M. et al. 1993. Therapy with arginine chlorohydrate in children with short constitutional stature. Minerva Pediatr, 45(1-2), Jan.-Feb., 61-65. Dose: 4 gm/day. Hepatitis Rizzo, S. 1986. Clinical trial with arginine tidiacicate in symptomatic chronic persistent hepatitis. Int J Clin Pharmacol Res, 6(3), 225-230. Dose: 80 ml of 10% L-arginine HCL daily per os over 6 months. Pain Harima, A. et al. 1991. Analgesic effect of L-arginine in patients with persistent pain. European Neuropsychopharmacol, 1(4), Dec., 529-533. Dose: iv 10% solution, 300ml (30g)/patient over a 60-70 minute period. Wound healimg Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 185

Lu, S. L. 1993. Effect of arginine supplementation on T-lymphocyte function in burn patients. Chung Hua Cheng Hsing Shao Shang Wai Ko Tsa Chih, 9(5), Sept., 368-371. Ornithine Aging Virgili M, Necchi D, Scherini E, Contestabile A. Increase of the ornithine decarboxylase/polyamine system and transglutaminase upregulation in the spinal cord of aged rats. Neurosci Lett. 2001 Aug 17;309(1):62-6. Brocker, P. et al. 1994. A two-centre, randomized, double-blind trial or ornithine oxoglutarate in 194 elderly, ambulatory, convalescent subjects, Age Ageing, 23(4), July, 303-306. Dose: 10 gm/day for 2 months. Cancer Sandgren S, Belting M. Suramin selectively inhibits carcinoma cell growth that is dependent on extracellular polyamines. Anticancer Res. 2003 MarApr;23(2B):1223-8. Dunzendorfer, U. 1981. Alpha-difluoromethyornithine (alpha DFMO) and phenoxybenzamine hydrochloride in the treatment of chronic nonsuppurative prostatitis. Arzneimittelforschung, 31(2), 382-385. Dose: 18 gm/day over 1 month. Alberts, D. S. et al. 1996. Positive randomized, double blinded, placebo controlled study of topical difluoromethyl ornithine (DFMO) in the chemoprevention of skin cancer. Proc Annual Meeting Am Soc Clin Oncology, 15, A342. Dose: 10% w/w topical solution of DFMO applied for 6 months. Encephalopathy Nicolaides P, Liebsch D, Dale N, Leonard J, Surtees R. Neurological outcome of patients with ornithine carbamoyltransferase deficiency. Arch Dis Child. 2002 Jan;86(1):54-6. Herlong, H. F. et al. 1980. The use of ornithine salts of branched-chain ketoacids in portal-systemic encephalopathy. Ann Intern Med, 93(4), Oct., 545-550. Dose: 34 mmol/day over 7-10 days. Surgical Trauma Yin L. Effects on the normalization of amino acids in metabolic support for trauma surgical patients Zhonghua Wai Ke Za Zhi. 1992 Nov;30(11):659-62, 699. Wernerman, J. et al. 1989. Glutamine and ornithine-alpha-ketoglutarate but not branched-chain amino acids reduce the loss of muscle glutamine after surgical trauma. Metabolism, 38(8 Suppl 1), Aug., 63-66. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 186

Glutamine Cancer Todorova VK, Harms SA, Luo S, Kaufmann Y, Babb KB, Klimberg VS. Oral glutamine (AES-14) supplementation inhibits PI-3k/Akt signaling in experimental breast cancer. JPEN J Parenter Enteral Nutr. 2003 NovDec;27(6):404-10. 94 Skubitz, K. M. and Anderson, P. M. 1996. Oral glutamine to prevent chemotherapy induced stomatitis: A pilot study. J Lab Clin Med, 127(2), Feb., 223-228. Dose: 4 gm swish and swallow. Cardiovascuar/Coronary heart disease Khogali SE, Pringle SD, Weryk BV, Rennie MJ. Is glutamine beneficial in ischemic heart disease? Nutrition. 2002 Feb;18(2):123-6. Svedjeholm, R. et al. 1995. Glutamate and high-dose glucose-insulinpotassium (GIK) in the treatment of severe cardiac failure after cardiac operations. Ann Thirac Surg, 59(2 Suppl), Feb., S23-S30. General Zhu M, Tang D, Zhao X, Cao J, Wei J, Chen Y, Xiao L, Sun Q. Impact of glutamine of gut permeability and clinical prognosis on the aging patients undergoing gastric-intestinal operation. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2000 Oct;22(5):425-7. Castell, L. M. et al. 1996. Does glutamine have a role in reducing infections in athletes? Eur J Appl Physiol, 73(5), 488-490. Liver damage Dhar A, Kujath S, Van Way CW 3rd. Glutamine administration during total parenteral nutrition protects liver adenosine nucleotides during and after subsequent hemorrhagic shock. JPEN J Parenter Enteral Nutr. 2003 JulAug;27(4):246-51. Santagati, G. et al. 1978. [Glutamic acid gamma-ethyl ester in high doses in the treatment of high blood ammonia levels in severe hepatic failure]. Minerva Med, 69(20), Apr. 28, 1367-1374. Neurotoxicity Hasegawa K, Mizutani Y, Kuramoto H, Nagao S, Masuyama H, Hongo A, Kodama J, Yoshinouchi M, Hiramatsu Y, Kudo T, Okuda H. The effect of L-Glutamine and Shakuyaku-Kanzo-to for paclitaxel-induced myalgia/arthralgia. Gan To Kagaku Ryoho. 2002 Apr;29(4):569-74. Cooper AJ. Role of glutamine in cerebral nitrogen metabolism and ammonia neurotoxicity. Ment Retard Dev Disabil Res Rev. 2001;7(4):280-6. 95 Jackson, D. V. et al. 1988. Amelioration of vincristine neurotoxicity by glutamic acid. Am J Med. 84(6), June, 1016-1022. Dose: 1,500 mg/day. Short Bowel Syndrome Wilmore DW. Indications for specific therapy in the rehabilitation of Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 187

patients with the short-bowel syndrome. Best Pract Res Clin Gastroenterol. 2003 Dec;17(6):895-906. Byrne, T. A. et al. 1995. A new treatment for patients with short-bowel syndrome. Growth hormone, glutamine, and a modified diet. Annals Surg, 222(3), Sept., 243-254. Tinnitus Ehrenberger, K. and Brix, R. 1983. Glutamic acid and glutamic acid diethylester in tinnitus treatment. Acta Otolaryngol, 95(5-6), May-June, 599605. Wound injury MacKay D, Miller AL. Nutritional support for wound healing. Altern Med Rev. 2003 Nov;8(4):359-377. Yan, R. et al. 1995. Early enteral feeding and supplement of glutamine prevent occurence of stress ulcer following severe thermal injury. Chung Hua Cheng Hsing Shao Shang Wai Ko Tsa Chih, 11(3), May, 189-192. L-Methionine Hepatitis Gazarian KG, Gening LV, Gazarian TG. L-Homoserine: a novel excreted metabolic marker of hepatitis B abnormally produced in liver from methionine. Med Hypotheses. 2002 Apr;58(4):279-83. Cho MK, Kim SG. Enhanced expression of rat hepatic microsomal epoxide hydrolase by methylthiazole in conjunction with liver injury. Toxicology. 2000 May 5;146(2-3):111-22. Windsor, J. A. and Wynne-Jones, G. 1988. Halothane hepatitis and prompt resolution with methionine therapy: Case report. New Zealand Med J 101(851), Aug. 10, 502-503. 96 Neuropathy Tan SV, Guiloff RJ. Hypothesis on the pathogenesis of vacuolar myelopathy, dementia, and peripheral neuropathy in AIDS. J Neurol Neurosurg Psychiatry. 1998 Jul;65(1):23-8. Stacy, C. B. et al. 1992. Methionine in the treatment of nitrous-oxideinduced neuropathy and myeloneuropathy. J Neurol, 239(7), Aug., 401-403. Paracetamol Poisoning Wallace KP, Center SA, Hickford FH, Warner KL, Smith S. S-adenosyl-Lmethionine (SAMe) for the treatment of acetaminophen toxicity in a dog. J Am Anim Hosp Assoc. 2002 May-Jun;38(3):246-54. Vale, J. A. et al. 1981. Treatment of acetaminophen poisoning. The use of oral methionine. Arch Intern Med, 141(3 Spec No), Feb. 23, 394-396. Crome, P. et al. 1976. Oral methionine in the treatment of severe Paracetamol (Acetaminophen) overdose. Lancet, 2(7990), Oct. 6, 829-830. Dose: 2-5 gm every 4 hours up to a total of 10g beginning within 10 hours of overdose. Breen, K. J. et al. 1982. Paracetamol self-poisoning: Diagnosis, management, and outcome. Med J Australia, 1(2), Jan. 23, 77-79. Trimethyl glycine Betaine Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 188

Dry Mouth Soderling, E. et al. 1998. Betaine-containing toothpaste relieves subjective symptoms of dry mouth. Acta Odontol Scand, 56(2) Apr., 65-69 Dose: Betaine-containing toothpaste. Homocystinuria Montero Brens C, Dalmau Serra J, Cabello Tomas ML, Garcia Gomez AM, Rodes Monegal M, Vilaseca Busca A. Homocystinuria: effectiveness of the treatment with pyridoxine, folic acid, and betaine. An Esp Pediatr. 1993 Jul;39(1):37-41. Wilcken, D. E. et al. 1985. Homocystinuria due to cystathionine betasynthase deficiency--the effects of betaine treatment in pyridoxineresponsive patients. Metabolism, 34(12) Dec., 1115-1121 Dose: Betaine (trimethylglycine) 6 g/d. 97 Wendel, U. and Bremer, H. J. 1984. Betaine in the treatment of homocystinuria die to 5,10-methylenetetrahydrofolate reductase deficiency. Europ J Pediatrics 142(2), June, 147-150. Dose: 15-20 gm/day. Aloe Cardiovascular/Coronary Heart Disease Agarwal, O. P. 1985. Prevention of atheromaous heart disease. Angiology, 36(8), Aug., 485-492. Constipation Odes, H. A. and Madar, Z. 1991. A double-blind trial of a celandin, Aloe vera and psyllium laxative preparation in adult patients with constipation. Digestion, 49(2), 65-71. Diabetes Abdullah KM, Abdullah A, Johnson ML, Bilski JJ, Petry K, Redmer DA, Reynolds LP, Grazul-Bilska AT. Effects of Aloe vera on gap junctional intercellular communication and proliferation of human diabetic and nondiabetic skin fibroblasts. J Altern Complement Med. 2003 Oct;9(5):711-8. Ghannam, N. et al. 1986. The antidiabetic activity of aloes: Preliminary clinical and experimental observations. Hormone Res, 24(4), 288-294. Dose: 1/2 tsp/day for 4-14 weeks. Ghannam, N. et al. 1986. The antidiabetic activity of aloes. Hormone Res, 24, 288-294. Dose: 1/2 tsp 4x/day for 14 weeks. Skin Damage Strickland FM, Pelley RP, Kripke ML. Prevention of ultraviolet radiationinduced suppression of contact and delayed hypersensitivity by Aloe barbadensis gel extract. J Invest Dermatol. 1994 Feb;102(2):197-204. Syed, T. A. et al. 1996. Management of psoriasis with aloe vera extract in a hydrophilic cream: A placebo-controlled, double-blind study. Trop Med Int Health, 1(4), Aug., 505-509. Dose: 0.5% Aloe vera extract in a hydrophilic cream. 98 Wound Healing Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 189

Muller MJ, Hollyoak MA, Moaveni Z, Brown TL, Herndon DN, Heggers JP. Retardation of wound healing by silver sulfadiazine is reversed by Aloe vera and nystatin. Burns. 2003 Dec;29(8):834-6. Fulton Jr., J. E. The stimulation of postdermabrasion wound healing with stabilized aloe vera gel-polyethylene oxide dressing. J Dermatol Surg Oncology, 16(5), may, 460-467. Dose: stabilized Aloe vera. Visuthiokosol, V. et al. 1995. Effect of aloe vera gel to healing of burn wound a clinical and histologic study. J Med Assoc Thailand, 78(8), Aug., 403-409. Dose: Aloe vera gel. Apple Pectin Acute Intestinal Infections Potievskii, E. G. et al. 1994. [Experimental and clinical studies of the effect of pectin on the causative agents of acute intestinal infections]. Zh Mikrobiol Epidemiol Immunobiol, Suppl 1 Aug., 106-109 Dose: 5% pectin solution. Diarrhea Potievskii EG, Shavakhabov ShSh, Bondarenko VM, Ashubaeva ZD. Experimental and clinical studies of the effect of pectin on the causative agents of acute intestinal infections. Zh Mikrobiol Epidemiol Immunobiol. 1994 Aug-Sep;Suppl 1:106-9. de la Motte, S. et al. 1997. [Double-blind comparison of an apple pectinchamomile extract preparation with placebo in children with diarrhea]. Arzneimittelforschung, 47(11) Nov., 1247-1249 Dose: Apple pectin and chamomille. Hypercholesterolemia Biesenbach, G. et al. 1993. [The lipid lowering effect of a new guar-pectin fiber mixture in type II diabetic patients with hypercholesterolemia]. Leber Magen Darm, 23(5) Sept., 204. Dose: 1 package of 17 gm with about 5.9 gm water-soluble fiber) dissolved in 250 ml water for the next 9 weeks: during the first 3 weeks 2 portions per 99 day, the next 3 weeks twice 1/2 portion and the last 3 weeks one 1/2 portion daily. The fiber mixture had to been consumed 30 minutes before taking a main meal. Pirich, C. et al. 1992. [Lowering cholesterol with Anticholest--a high fiber guar-apple pectin drink]. Wien Klin Wochenschr, 104(11):314-316. Dose: (group 1) at dosages of 1 cup (17 gm) every second day, or (group 2) of 1 cup a day or (group 3) of 2 cups a day. Hyperlipidemia Biesenbach G, Grafinger P, Janko P, Kaiser W, Stuby U, Moser E. The lipid lowering effect of a new guar-pectin fiber mixture in type II diabetic patients with hypercholesterolemia. Leber Magen Darm. 1993 Sep;23(5):204, 207-9. Grudeva-Popova, J. and Sirakova, I. 1998. Effect of pectin on some Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 190

electrolytes and trace elements in patients with hyperlipoproteinemia. Folia Med (Plovdiv), 40(1):41-45 Dose: 15 gm/day high-esterified pectin for 3 months. Grudeva-Popova, J. et al. 1997. Application of soluble dietary fibres in treatment of hyperlipoproteinemias. Folia Med (Plovdiv), 39(1), 39-43. Satiety Tiwary, C. M. et al. 1997. Effect of pectin on satiety in healthy US Army adults. J Am Coll Nutr, 16(5) Oct., 423-428 Dose: 5, 10, 15, 20g Bee Pollen Climacteric Symptoms Szanto, E. et al. 1994. [Placebo-controlled study of melbrosia in treatment of climacteric symptoms]. Wien Med Wochenschr, 144(7):130-133. Memory Function Iversen, T. et al. 1997. The effect of Nao Li Su on memory functions and blood chemistry in elderly people. J Ethnopharmacol, 56(2) Apr., 109-116. Memory Function 100 Iarosh, A. A. 1990. [Changes in the immunological reactivity of patients with disseminated sclerosis treated by prednisolone and the preparation Proper-Myl]. Syringomyelia Ludianskii, E. A. 1991. [The use of apiotherapy and radon baths in treating syringomyelia]. Zh Nevropatol Psikhiatr Im S Korsakova, 91(3), 102-103. Chrysanthemum Lee JS, Kim HJ, Lee YS. A new anti-HIV flavonoid glucuronide from Chrysanthemum morifolium. Planta Med. 2003 Sep;69(9):859-61. Urzua A, Mendoza L. Antibacterial activity of fresh flower heads of Chrysantemum coronarium. Fitoterapia. 2003 Sep;74(6):606-8. Yu, X. Y. 1993. [A prospective clinical study on reversion of 200 precancerous patients with hua-sheng-ping]. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih 13(3) Mar., 147-149 Zhou , Y. L. 1987. [Chrysanthemum morifolium in the treatment of hypertension]. Chung Hsi I Chieh Ho Tsa Chih, 7(1) Jan., 18-20. Cruciferous vegetables Cancer Jackson SJ, Singletary KW. Sulforaphane: a naturally occurring mammary carcinoma mitotic inhibitor which disrupts tubulin polymerization. Carcinogenesis. 2003 Oct 24. Yuan, &127; J. M. et al. 1998. Cruciferous vegetables in relation to renal cell carcinoma. Int J Cancer, 77(2) Jul. 17, 211-216. Rosen, C. A. 1998. &127;Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg, 118(6) Jun., 810-815. &127;&127;&127;Dose: oral indole-3-carbinol and had a minimum follow-up of 8 months and a mean follow-up of 14.6 months. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 191

DeMarini, D. M. et al. 1997. Pilot study of free and conjugated urinary mutagenicity during consumption of pan-fried meats: possible modulation by cruciferous vegetables, glutathione S-transferase-M1, and Nacetyltransferase2. Mutat Res, 381(1) Nov. 19, 83-96. 101 Dose: Ingestion of cruciferous vegetables. Witte, J. S. et al. 1996. Relation of vegetable, fruit, and grain consumption to colorectal adenomatous&127; polyps. Am J Epidemiol, 144(11) Dec. 1, 1015-1025. Steinmetz, K. A. and&127; Potter, J. D. 1996. Vegetables, fruit, and cancer prevention: a review. J Am Diet Assoc, 96(10) Oct, &127;1027-1039. General Nagle CM, Purdie DM, Webb PM, Green A, Harvey PW, Bain CJ. Dietary influences on survival after ovarian cancer. Int J Cancer. 2003 Aug 20;106(2):264-9. Michnovicz, J. J. et al. 1997. Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol&127; treatment in humans. J Natl Cancer Inst, 89(10) May 21, 718-723. Dose: Oral ingestion of 13C (6-7 mg/kg/day. Men received for &127;1 week, women received for 2 months. Chen, L. et al. 1996. Decrease of plasma and urinary oxidative metabolites of acetaminophen after consumption of watercress by human volunteers. Clin Pharmacol Ther, 60(6) Dec., 651-660. Dose: Watercress homogenates (50 gm). Smokers Caicoya M. Lung cancer and vegetable consumption in Asturias, Spain. A case control study. Med Clin (Barc). 2002 Jul 13;119(6):206-10. Seow A, Poh WT, Teh M, Eng P, Wang YT, Tan WC, Chia KS, Yu MC, Lee HP. Diet, reproductive factors and lung cancer risk among Chinese women in Singapore: evidence for a protective effect of soy in nonsmokers. Int J Cancer. 2002 Jan 20;97(3):365-71. Hecht SS, Chung FL, Richie JP Jr, Akerkar SA, Borukhova A, Skowronski L, Carmella SG. Effects of watercress consumption on metabolism of a tobacco-specific lung carcinogen in smokers. Cancer Epidemiol Biomarkers Prev. 1995 Dec;4(8):877-84. Taioli, E. et al. 1997. Effects of indole-3-carbinol on the metabolism of 4(methylnitrosamino)-1-(3-pyridyl)-1-butanone in smokers. Cancer Epidemiol Biomarkers Prev, 6(7) Jul., 517-522. Dose: 400 mg of I3C on 5 consecutive days and maintained constant smoking habits during this period. 102 Curcumine (Turmeric) Anti-inflammatory Effects Ammon HP, Safayhi H, Mack T, Sabieraj J. Mechanism of antiinflammatory actions of curcumine and boswellic acids. J Ethnopharmacol. 1993 Mar;38(23):113-9. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 192

Satoskar, R. R. et al. 1986. Evaluation of anti-inflammatory property of curcumin (Diferuloyl Methane) in patients with postoperative inflammation. Int J Clin Pharmacol Ther Toxicol, 24(12), Dec., 651-654. Cancer Zhang H, Yang L, Liu S, Ren L. Study on active constituents of traditional Chinese medicine reversing multidrug resistance of tumor cells in vitro. Zhong Yao Cai. 2001 Sep;24(9):655-7. Polasa, K. et al. 1992. Effect of turmeric on urinary mutagens in smokers. Mutagenesis, 7(2), Mar., 107-109. Kuttan, R. et al. 1987. Turmeric and curcumin as topical agents in cancer therapy. Tumori, 73(1), Feb. 28, 29-31. Cardiovascular/Coronary Heart Disease Ammon HP, Safayhi H, Mack T, Sabieraj J. Mechanism of antiinflammatory actions of curcumine and boswellic acids. J Ethnopharmacol. 1993 Mar;38(23):113-9. Soni, K. B. and Kuttan, R. 1992. Effect of oral curcumin administration on serum peroxides and cholesterol levels in human volunteers. Indian J Physiol Pharmacol, 36(4), Oct., 273-275. Dose: 500 mg/day for 7 days. Dandelion Root Chronic Colitis Chakurski, I. et al.&127; 1981. [Treatment of chronic colitis with an herbal combination of Taraxacum officinale, Hipericum perforatum, Melissa officinaliss, Calendula officinalis and Foeniculum vulgare]. Vutr Boles, 20(6), 51-54. Garlic 103 Cancer Das S. Garlic - A Natural Source of Cancer Preventive Compounds. Asian Pac J Cancer Prev. 2002;3(4):305-311. You, W. C. et al. 1989. Allium vegetables and reduced risk of stomach cancer. J National Cancer Inst, 81(2), Jan. 18, 162-164. Cardiovascular/Coronary Heart Disease Li G, Shi Z, Jia H, Ju J, Wang X, Xia Z, Qin L, Ge C, Xu Y, Cheng L, Chen P, Yuan G. A clinical investigation on garlicin injectio for treatment of unstable angina pectoris and its actions on plasma endothelin and blood sugar levels. J Tradit Chin Med. 2000 Dec;20(4):243-6. Bordia A, Verma SK, Srivastava KC. Effect of garlic on platelet aggregation in humans: a study in healthy subjects and patients with coronary artery disease. Prostaglandins Leukot Essent Fatty Acids. 1996 Sep;55(3):201-5. Gadkari, J. V. and Joshi, V. D. 1991. Effect of ingestion of raw garlic on serum cholesterol level, clotting time and fibrinolytic activity in normal subjects. J Postgrad Med, 37(3), July, 128-131. Dose: 10 gm/day for 2 months. Bordia, A. 1981. Effect of garlic on blood lipids in patients with coronary heart disease. Am J Clin Nutr, 34(10), Oct., 2100-2103. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 193

Jain, A. K. et al. 1993. Can garlic reduce levels of serum lipids? A controlled clinical study. Am J Med, 94(6), June, 632-635. Dose: 300 mg 3x/day. Warhafsky, S. et al. 1993. Effect of garlic on total serum cholesterol. A meta-analysis. Annals Int Med, 119(7 Pt 1), Oct. 1, 599-605. Vorberg, G. and Schneider, B. 1990. Therapy with garlic: Results of a placebo-controlled, double-blind study. British J Clin Pract Symp Suppl, 69, Aug., 7-11. Dose: 900 mg garlic powder for 4 months. Auer, W. et al. 1990. Hypertension and hyperlipidaemia: Garlic helps in mild cases. British J Clin Pract Symp Suppl, 69, Aug., 3-6. McMahon, F. G. and Vargas, R. 1993. Can garlic lower blood pressure? A pilot study. Pharmacotherapy, 13(4), July-Aug., 406-407. 104 Dose: 1.3% allicin at 2400mg. Ali, M. and Thomson, M. 1995. Consumption of a garlic clove a day could be beneficial in preventing thrombosis. Prostaglandins Leukot Essent Fatty Acids, 53(3), Sept., 211-212. Dose: 1 fresh clove of garlic/day for 16 weeks. Kieswetter, H. et al. 1993. Effect of garlic on platelet aggregation in patients with increased risk of juvenile ischaemic attack. European J Pharmacology, 45(333-336. Dose: 800 mg powdered garlic over 4 weeks. Silagy, C. A. and Neil, A. W. 1994. A meta-analysis of this effect of garlic on blood pressure. J Hypertension, 12, 463-468. Dose: 600-900 mg/day of dried garlic powder for 12 weeks. Hepatopulmonary Syndrome Abrams GA, Fallon MB. Treatment of hepatopulmonary syndrome with Allium sativum L. (garlic): a pilot trial. J Clin Gastroenterol. 1998 Oct;27(3):2325. Caldwell, S. H. et al. 1992. Ancient remedies revisited: Does Allium Sativum palliate the hepatopulmonary syndrome? J Clin Gastroenterology, 15(3), Oct., 248-250. Meningitis Shen J, Davis LE, Wallace JM, Cai Y, Lawson LD. Enhanced diallyl trisulfide has in vitro synergy with amphotericin B against Cryptococcus neoformans. Planta Med. 1996 Oct;62(5):415-8. Davis LE, Shen J, Royer RE. In vitro synergism of concentrated Allium sativum extract and amphotericin B against Cryptococcus neoformans. Planta Med. 1994 Dec;60(6):546-9. Davis, L. E. et al. 1990. Anitfungal activity in human cerebrospinal fluid and plasma after intravenous administration of Allium Sativum. Antimicrob Agents Chemother, 34(4), Apr., 651-653. Gingko Biloba Aging Topic B, Tani E, Tsiakitzis K, Kourounakis PN, Dere E, Hasenohrl RU, Hacker R, Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 194

105 Mattern CM, Huston JP. Enhanced maze performance and reduced oxidative stress by combined extracts of zingiber officinale and ginkgo biloba in the aged rat. Neurobiol Aging. 2002 Jan-Feb;23(1):135-43. Taillandier, J. et al. 1986. [Treatment of cerebral aging disorders with Ginko Biloba extract. A longitudinal multicenter double-blind drug vs. placebo study]. Presse Med, 15(31), Sept. 25, 1583-1587. Allard, M. 1986. [Treatment of the disorders of aging with Ginko Biloba extract. From pharmacology to clinical medicine]. Presse Med, 15(31), Sept. 25, 1540, 1545. Anti-Clastogenic Effects Emerit, I. et al. 1995. Clastogenic factors in the plasma of Chernobyl accident recovery workers: Anticlastogenic effect of Gingko Biloba extract. Radiat Res, 144(2), Nov., 198-205. Dose: 120 mg/day for 2 months. Brain Function/ Injury Siddique MS, Eddeb F, Mantle D, Mendelow AD. Extracts of Ginkgo biloba and Panax ginseng protect brain proteins from free radical induced oxidative damage in vitro. Acta Neurochir Suppl. 2000;76:87-90. Hofferberth, B. 1989. [The effect of Ginko Biloba extract on neurophysiological and psychometric measurement results in patients with psychotic organic brain syndrome. A double-blind study against placebo]. Arzneimittelforschung, 39(8), Aug., 918-922. Dose: 120 mg/day for 8 weeks. Hopfenmuller, W. 1994. [Evidence for a therapeutic effect of Ginko Biloba special extract. Meta-analysis of 11 clinical studies in patients with cerebrovascular insufficiency in old age]. Arzneimittelforschung, 44(9), Sept., 1005-1013. Dose: 150 mg/day. Gessner, B. et al. 1985. Study of the long-term action of a Ginkgo Biloba extract on vigilance and mental performance as determined by means of quantitative pharmaco-EEg and psychometric measurements. Arzneimittelforschung, 35(9), 1459-1465. Dose: 120 mg/day Kleijnen, J. and Knipschild, P. 1992. Ginkgo Biloba for cerebral insufficiency. British J Clin Pharmacology, 34(4), Oct., 352-358. 106 Dose: 120 mg/day for 4-6 weeks. Allain, H. et al 1993. Effect of two doses of Ginkgo Biloba extract (EGb 761) on the dual coding test in elderly subjects. Clin Ther, 15(3), may-June, 549558. Dose: 320 or 600 mg. Rai, G. S. et al. 1991. A double-blind, placebo controlled study of Gingko Biloba extract ('tanakan') in elderly outpatients with mild to moderate memory impairment. Curr Med Res Opin, 12(6), 350-355. Dose: 120 mg/day at 12 and 24 weeks. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 195

Grassel, E. 1992. [Effect of Ginkgo-biloba extract on mental performance: Double-blind study using computerized measurement conditions in patients with cerebral insufficiency]. Fortschr Med, 110(5), Feb. 20, 73-76. Eckmann, F. 1990. [Cerebral insufficiency-Treatment with Gingko-biloba extract. Time of onset of effect in a double-blind study with 60 inpatients]. Fortschr Med, 108(29), Oct. 10, 557-560. Dose: 160 mg/day. Gerhardt, G. et al. 1990. [Drug therapy of disorders of cerebral performance: Randomized comparative study of dihydroergotoxine and Ginkgo Biloba extract]. Fortschr Med, 108(19), June 30, 384-388. Subhan, Z. and Hindmarch, I. 1984. The psychopharmacological effects of Ginkgo Biloba extract in normal healthy volunteers. Int J Clin Pharmacology Res, 4(2), 89-93. Dose: 120, 240, or 600 mg/day. Raabe, A. et al. 1991. [Therapeutic follow-up using automatic perimetry in chronic cerebroretinal ischemia in elderly patients. prospective doubleblind study with graduated dose Ginkgo Biloba treatment (EGb 761), Klin Monatsbl Augenheilkd, 199(6), Dec., 432-438. Dose: 160 mg/day for 4 weeks. Lebuisson, D. A. et al. 1986. [Treatment of senile macular degeneration with Ginkgo Biloba extract. A preliminary double-blind drug vs. placebo study]. Presse Med, 15(31), Sept. 25, 1556-1558. Funfgeld, E. W. 1989. A natural and broad spectrum nootropic substance for treatment of SDAT-the Ginkgo Biloba extract. Prog Clin Biol Res, 317, 1247-1260. Cardiovascular/Coronary Heart Disease Mahady GB. Ginkgo biloba for the prevention and treatment of 107 cardiovascular disease: a review of the literature. J Cardiovasc Nurs. 2002 Jul;16(4):21-32. Schneider, B. 1992. [Ginkgo biloba extract in peripheral arterial diseases. Meat-analysis of controlled clinical studies]. Arzneimittelforschung, 42(4), Apr., 428-436. Jung, F. et al. 1990. Effect of Ginkgo Biloba on fluidity of blood and peripheral microcirculation in volunteers. Arzneimittelforschung, 40(5), May, 589-593. Bauer, U. 1984. 6-month double-blind randomised clinical trial of Ginkgo Biloba extract versus placebo in two parallel groups in patients suffering from peripheral arterial insufficiency. Arzneimittelforschung, 34(6), 716-720. Schaffler, K. and Reeh, P. W. 1985. [Double blind study of the hypoxia protective effect of a standardized Ginkgo Biloba preparation after repeated administration in healthy subjects]. Arzneimittelforschung, 35(8), 12831286. Witte, S. et al. 1992. [Improvement of hemorheology with Ginkgo Biloba extract. Decreasing a cardiovascular risk factor]. Fortschr Med, 110(13), May 10m 247-250. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 196

Dose: 240 mg/day for 12 weeks. Koltringer, P. et al. 1993. [Hemorheologic effects of Ginkgo Biloba extract EFb 671. Dose-dependent effect of EGb 761 on microcirculation and visoelasticity of blood]. Fortschr Med, 111(10), Apr. 10, 170-172. Dose: single injection of 50, 100, 150, 200 mg. Bauer, U. 1986. [Ginkgo Biloba extract in the treatment of arteriopathy of the lower extremities. A 65-week trial]. Presse Med, 15(31), Sept. 25, 15461549. Koltringer, P. et al. 1989. [Microcirculation in parenteral Ginkgo Biloba extract therapy]. Wien Klin Wochenschr, 101(6), Mar. 17, 198-200. Claudication Pittler MH, Ernst E. Ginkgo biloba extract for the treatment of intermittent claudication: a meta-analysis of randomized trials. Am J Med. 2000 Mar;108(4):276-81. Erns, E. 1996. [Ginkgo Biloba in treatment of intermittent claudication. A systematic research based on controlled studies in the literature]. Fortschr Med, 114(8), Mar. 20, 85-87. Drabaek, H. et al. 1986. [The effect of Ginkgo Biloba extract in patients with intermittent claudication]. Ugeskr Laeger, 158(27), July 1, 3928-3931. 108 Dose: 120 mg/day for 3 months. Diabetes Fitzl G, Welt K, Wassilew G, Clemens N, Penka K, Mukke N. The influence of hypoxia on the myocardium of experimentally diabetic rats with and without protection by Ginkgo biloba extract. III: Ultrastructural investigations on mitochondria. Exp Toxicol Pathol. 2001 Feb;52(6):557-68. Lanthony, P. and Cosson, J. P. 1988. [The course of color vision in early diabetic retinopathy treated with Ginkgo Biloba extract. A preliminary double-blind versus placebo study]. J Fr Ophtalmol, 11(10), 671-674. Edema Westman J, Drieu K, Sharma HS. Antioxidant compounds EGB-761 and BN520 21 attenuate heat shock protein (HSP 72 kD) response, edema and cell changes following hyperthermic brain injury. An experimental study using immunohistochemistry in the rat. Amino Acids. 2000;19(1):339-50. Lagrue, G. et al. [Idiopathic cyclic edema. The role of capillary hyperpermeability and its correction by Ginkgo Biloba extract]. Presse Med, 15(31), Sept. 25, 1550-1553. General Schulz V. Ginkgo extract or cholinesterase inhibitors in patients with dementia: what clinical trials and guidelines fail to consider. Phytomedicine. 2003;10 Suppl 4:74-9. Lagrue, G. et al. 1986. [Recurrent shock with monoclonal gammopathy. Treatment in the acute and chronic phases with oral and parenteral Ginkgo Biloba extract]. Presse Med, 15(31), Sept. 25, 1554-1555. Hearing Loss Hoffman, F. et al. 1994. [Ginkgo extract EGb 761 )tenobin)/HAES versus Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 197

Naftidrofuryl (Dusodril)/HAES. A randomized study of therapy of sudden deafness]. Laryngorhinootologie, 73(3), Mar., 149-152. Dubreuil, C. 1986. [Therapeutic trial in acute cochlear deafness. A comparative study of Ginkgo Biloba extract and Nicergoline]. Presse Med, 15(31), Sept. 25, 1559-1561. Hepatitis 109 Li, W. et al. [Preliminary study of early fibrosis of chronic hepatitis B treated with Ginkgo Biloba composita]. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih, 15(10) Oct., 593-595. Neuropathy Yoshikawa T, Naito Y, Kondo M. Ginkgo biloba leaf extract: review of biological actions and clinical applications. Antioxid Redox Signal. 1999 Winter;1(4):469-80. Koltringer, P. et al. 1989. [Ginkgo Biloba extract and folic acid in the therapy of changes caused by autonomic neuropathy]. Acta Med Austriaca, 16(2), 35-37. Dose; 87.5 mg for 4 days. Tinnitus Morgenstern C, Biermann E. The efficacy of Ginkgo special extract EGb 761 in patients with tinnitus. Int J Clin Pharmacol Ther. 2002 May;40(5):188-97. Meyer, B. 1986. [Multicenter randomized double-blind drug vs. placebo study of the treatment of Tinnitus with Ginkgo Biloba extract]. Presse med, 15(31), Sept. 25, 1562-1564. Vertigo Cesarani A, Meloni F, Alpini D, Barozzi S, Verderio L, Boscani PF. Ginkgo biloba (EGb 761) in the treatment of equilibrium disorders. Adv Ther. 1998 SepOct;15(5):291-304. Haguenaauer, J. P. et al. 1986. [Treatment of equilibrium disorders with Ginkgo Biloba extract. A multicenter double-blind drug vs. placebo study]. Presse Med, 15(310, Sept. 25, 1569-1572. Hibiscus Renal Stone Disease Kirdpon, S. et al. 1994. Changes in urinary chemical composition in healthy volunteers after consuming roselle (Hibiscus sabdariffa Linn.) juice. J Med Assoc Thai, 77(6) Jun., 314-321. Dose: Roselle juice consumption, 16 gm/day. Peppermint 110 General Hiki N, Kurosaka H, Tatsutomi Y, Shimoyama S, Tsuji E, Kojima J, Shimizu N, Ono H, Hirooka T, Noguchi C, Mafune K, Kaminishi M. Peppermint oil reduces gastric spasm during upper endoscopy: a randomized, double-blind, double-dummy controlled trial. Gastrointest Endosc. 2003 Apr;57(4):475-82. Spirling LI, Daniels IR. Botanical perspectives on health peppermint: more than just an after-dinner mint. J R Soc Health. 2001 Mar;121(1):62-3. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 198

Gobel, H. et al. 1994. Effect of peppermint and eucalyptus oil preparations on neurophysiological and experimental algesimetric headache parameters. Cephalalgia, 14(3), June, 228-234. Irritable Bowel Syndrome Gaby AR. Treatment with enteric-coated peppermint oil reduced smallintestinal bacterial overgrowth in a patient with irritable bowel syndrome. Altern Med Rev. 2003 Feb;8(1):3. Logan AC, Beaulne TM. The treatment of small intestinal bacterial overgrowth with enteric-coated peppermint oil: a case report. Altern Med Rev. 2002 Oct;7(5):410-7. Treating irritable bowel syndrome with peppermint oil. British Med J, Oct. 6, 835-836. Dose: Peppermint oil in enteric-coated capsules. Ulcers Meyer, J. et al. 1945. Action of oil of peppermint on the secretion and motility of the stomach in man. Arch Int Med, 56,88-97. Psyllium Jenkins DJ, Kendall CW, Marchie A, Jenkins AL, Connelly PW, Jones PJ, Vuksan V. The Garden of Eden--plant based diets, the genetic drive to conserve cholesterol and its implications for heart disease in the 21st century. Comp Biochem Physiol A Mol Integr Physiol. 2003 Sep;136(1):141-51 Sierra M, Garcia JJ, Fernandez N, Diez MJ, Calle AP. Therapeutic effects of psyllium in type 2 diabetic patients. Eur J Clin Nutr. 2002 Sep;56(9):830-42. 111 Zumarraga, L. et al. 1997. Absence of gaseous symptoms during ingestion of commercial fibre preparations. Aliment Pharmacol Ther, 11(6) Dec., 1067-1072. Dose: Psyllium 3.4 gm. McRorie, J. W. et al. 1998. Psyllium is superior to docusate sodium for treatment of chronic constipation. Aliment Pharmacol Ther, 12(5) May, 491497. Dose: Psyllium (5.1 gm b.d.). Moran, S. et al. 1997. [Effects of fiber administration in the prevention of gallstones in obese patients on a reducing diet. A clinical trial]. Rev Gastroenterol Mex, 62(4) Oct., 266-272. Dose: Psyllium 15 gm. Rigaud, D. et al. 1998. Effect of psyllium on gastric emptying, hunger feeling and food intake in normal volunteers: a double blind study. Eur J Clin Nutr, 52(4) Apr., 239-245. Dose: Psyllium 7.4 gm. Segawa, K. et al. 1998. Cholesterol-lowering effects of psyllium seed associated with urea metabolism. Biol Pharm Bull, 21(2) Feb., &127;184187. Davidson, M. H. et al. 1998. Long-term effects of consuming foods containing psyllium seed husk on serum lipids in subjects with hypercholesterolemia. Am J Clin Nutr, 67(3) Mar., 367-376. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 199

Dose: Psyllium seed 0, 3.4, 6.8, or 10.2 gm for 24 weeks. Washington, N. et al. 1998. Moderation of lactulose-induced diarrhea by psyllium: Effects on motility and fermentation. Am J Clin Nutr, 67(2) Feb., 317-321. Dose: Psyllium 3.5 gm 3x/day. Olson, B. H. et al. 1997. Psyllium-enriched cereals lower blood total cholesterol and LDL cholesterol, but not HDL cholesterol, in hypercholesterolemic adults: results of a meta-analysis. J Nutr, 127(10) Oct., 1973-1980. Dose: 3 gm soluble fiber/day. Red Clover Cancer 112 Rock E, DeMichele A. Nutritional approaches to late toxicities of adjuvant chemotherapy in breast cancer survivors. J Nutr. 2003 Nov;133(11 Suppl 1):3785S-3793S. Katz AE. Flavonoid and botanical approaches to prostate health. J Altern Complement Med. 2002 Dec;8(6):813-21. Jarred RA, Keikha M, Dowling C, McPherson SJ, Clare AM, Husband AJ, Pedersen JS, Frydenberg M, Risbridger GP. Induction of apoptosis in low to moderate-grade human prostate carcinoma by red clover-derived dietary isoflavones. Cancer Epidemiol Biomarkers Prev. 2002 Dec;11(12):1689-96. Marshal, M. E. et al. 1987. Treatment of metastatic renal cell carcinoma with coumarin (1,2-benzopyrone) and cimetide: A pilot study. J Clin Oncology, 5f(6), June, 862-866. Dose:100 mg/day coumarin. Silybum Marianum (Milk Thistle) Alcohol Abuse Jacobs BP, Dennehy C, Ramirez G, Sapp J, Lawrence VA. Milk thistle for the treatment of liver disease: a systematic review and meta-analysis. Am J Med. 2002 Oct 15;113(6):506-15. Fintelmann, V. 1970. [Zur therapie der fettleber mit silymarin]. Therapiewoche, 20, 1055. Cirrhosis Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver diseases. Drugs. 2001;61(14):2035-63. Ferenci, P. et al. 1989. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol,&127; 9(1) Jul., 105-113. Dose:140 mg silymarin 3x/day. Diabetes Savickiene N, Dagilyte A, Lukosius A, Zitkevicius V. Importance of biologically active components and plants in the prevention of complications of diabetes mellitus. Medicina (Kaunas). 2002;38(10):970-5. 113 Velussi, M. 1997 et al. Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 200

and malondialdehyde levels in cirrhotic diabetic patients. J Hepatol, 26(4) Apr., 871-879. Dose: 600 mg silymarin/day. Zhang. J. Q. et al. 1993. [Effects of silybin on red blood cell sorbitol and nerve conduction velocity in diabetic patients]. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih, 13(12) Dec., 725-726. Dose: Silybin 231 mg/day for 4 weeks. Geller, L. I. et al. 1993. [Treatment of fatty hepatosis in diabetics]. Probl Endokrinol (Mosk), 39(5) Sept., 20-22. Drug Abuse Carrescia, O. et al. 1980. Silymarin in the prevention of hepatic damage by psychopharmacologic drugs. Experimental premises and clinical evaluation. Clin Ter, 95, 157. Hepatitis Giese LA. Milk thistle and the treatment of hepatitis. Gastroenterol Nurs. 2001 Mar-Apr;24(2):95-7. Buzzelli, G. et al. 1993. A pilot study on the liver protective effect of silybinphosphatidylcholine complex (IdB1016) in chronic active hepatitis. Int J Clin Pharmacol Ther Toxicol, 31(9), Sept., 456-460. Dose: 240 mg silybin bid. Liver damage Schumann J, Prockl J, Kiemer AK, Vollmar AM, Bang R, Tiegs G. Silibinin protects mice from T cell-dependent liver injury. J Hepatol. 2003 Sep;39(3):333-40. Bromley, P. N. et al. 1995. Effects of intraoperative N-acetylcysteine on orthotopic liver transplantation. British J Anaesth, 75(3), Sept., 352-354. Oh, T. E. and Shenfield, G. M. 1980. Intravenous N-acetylcysteine for Paracetamol poisoning. Med J Australia, 1(13), June 28, 664-665. Lung damage Meyer, A. et al. 1995. Intravenous N-acetylcysteine and lung glutathione of patients with pulmonary fibrosis and normals. Am J Respiratory Crit Care Med, 152(3), Sept., 10551060. 114 Dose: 1.8 gm. Suter, P. M. et al. 1994. N-acetylcysteine enhances recovery from acute lung injury in man. A randomized, double-blind, placebo-controlled clinical study. Chest, 105(1), Jan., 190194. Dose: 40 mg/kg/day iv over a period of 72 hours. Eklund, A. et al. 1988. Oral N-acetylcysteine reduces selected humoral markers of inflammatory cell activity in BAL fluid from healthy smokers: Correlation to effects on cellular variables. European Respir J, 1(9), Oct., 832-838. Dose: 200 mg tid over an 8 week period. Linden, M. et al. 1988. Effects of oral N-acetylecysteine on cell content and macrophage function in bronchoalveolar lavage from healthy smokers. European Respiratory J, 1(7), Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 201

July, 645-650. Dose: 200 mg tid over an 8 week period. Muscle fatigue Reid, M. B. et al. 1994. N-acetylcysteine inhibits muscle fatigue in humans. J Clin Investigations, 94(6), Dec., 2468-2474. Dose: pretreatment with 150 mg/kg. Sjogren's Syndrome Walters, M. T. et al. 1986. A double-blind, cross-over, study of oral N-acetylcysteine in Sjogren's syndrome. Scandanavian J Pheumatol Suppl, 61, 253-258. 115

Vitamin B1 120 Studies


1. J Neurol Neurosurg Psychiatry. 2003 May;74(5):674-6. Reversible acute axonal polyneuropathy associated with Wernicke-Korsakoff syndrome: impaired physiological nerve conduction due to thiamine deficiency? Ishibashi S, Yokota T, Shiojiri T, Matunaga T, Tanaka H, Nishina K, Hirota H, Inaba A, Yamada M, Kanda T, Mizusawa H. Japan 2. J Clin Pharm Ther. 2003 Feb;28(1):47-51. Effect of intravenous infusions of thiamine on the disposition kinetics of thiamine and its pyrophosphate. Drewe J, Delco F, Kissel T, Beglinger C. Switzerland

3. Ke ZJ, DeGiorgio LA, Volpe BT et al. Reversal of thiamine deficiency-induced neurodegeneration. J Neuropathol Exp Neurol 2003 Feb;62(2):195-207. 4. Anti-obesity effects of a mixture of thiamin, arginine, caffeine, and citric acid in noninsulin dependent diabetic KK mice. Muroyama K, Murosaki S, Yamamoto Y, Odaka H, Chung HC, Miyoshi M. J Nutr Sci Vitaminol (Tokyo). 2003 Feb;49(1):56-63. PMID: 12882397

5. Anaesthesiol Reanim. 2003;28(1):13-20. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 202

Can alcoholic withdrawal delirium be prevented? Hensel M, Kox WJ. 6. Cardiology. 2003;99(4):177-81. Dietary intake of various nutrients in older patients with congestive heart failure. Gorelik O, Almoznino-Sarafian D, Feder I, Wachsman O, Alon I, Litvinjuk V, Roshovsky M, Modai D, Cohen N.

7. Eur J Clin Nutr. 2002 Dec;56(12):1162-8. Changes in the intake of vitamins and minerals by men and women with hyperlipidemia and overweight during dietetic treatment. Grzybek A, Klosiewicz-Latoszek L, Targosz U. 8. Psychiatr Genet. 2002 Dec;12(4):217-24. Individual susceptibility to Wernicke-Korsakoff syndrome and alcoholism-induced cognitive deficit: impaired thiamine utilization found in alcoholics and alcohol abusers. Heap LC, Pratt OE, Ward RJ, Waller S, Thomson AD, Shaw GK, Peters TJ. 9. Alcohol Alcohol. 2002 Nov-Dec;37(6):513-21. The Royal College of Physicians report on alcohol: guidelines for managing Wernicke's encephalopathy in the accident and Emergency Department Thomson AD, Cook CC, Touquet R, Henry JA; Royal College of Physicians, London. 10. Bras Cardiol. 2002 Nov;79(5):454. Thiamin, selenium, and copper levels in patients with idiopathic dilated cardiomyopathy taking diuretics. da Cunha S, Albanesi Filho FM, da Cunha Bastos VL, Antelo DS, Souza MM. 11. Circ J. 2002 Nov;66(11):1070-2. Shoshin beriberi with vasospastic angina pectoris possible mechanism of mid-ventricular obstruction: possible mechanism of mid-ventricular obstruction. Ito M, Tanabe Y, Suzuki K, Kumakura M, Aizawa Y. Japan 12. Mol Genet. 2002 Nov 1;11(23):2951-60. Targeted disruption of Slc19a2, the gene encoding the high-affinity thiamin transporter Thtr-1, causes diabetes mellitus, sensorineural deafness and megaloblastosis in mice. Oishi K, Hofmann S, Diaz GA, Brown T, Manwani D, Ng L, Young R, Vlassara H, Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 203

Ioannou YA, Forrest D, Gelb BD. 13. Biochim Biophys Acta. 2002 Oct 9;1588(1):79-84. Thiamine-responsive pyruvate dehydrogenase deficiency in two patients caused by a point mutation (F205L and L216F) within the thiamine pyrophosphate binding region. Naito E, Ito M, Yokota I, Saijo T, Matsuda J, Ogawa Y, Kitamura S, Takada E, Horii Y, Kuroda Y. 14. Nutr Rev. 2002 Sep;60(9):277-80. Acute versus marginal deficiencies of nutrients. Carpenter KJ.. 15. Ann Neurol. 2002 Aug;52(2):195-204. Cofactors of mitochondrial enzymes attenuate copper-induced death in vitro and in vivo. Sheline CT, Choi EH, Kim-Han JS, Dugan LL, Choi DW. 16. AIDS Read. 2002 May;12(5):222-4. High doses of riboflavin and thiamine may help in secondary prevention of hyperlactatemia. McComsey GA, Lederman MM. 17. Med Sci Monit. 2002 May;8(5):CR357-63. Alcohol consumption and the risk of colorectal cancer at low levels of micronutrient intake. Jedrychowski W, Steindorf K, Popiela T, Wahrendorf J, Tobiasz-Adamczyk B, Kulig J, Penar A.

18. Neurochem Int. 2002 May;40(6):493-504 Interactions of oxidative stress with thiamine homeostasis promote neurodegeneration. Gibson GE, Zhang H. 19. Obstet Gynecol. 2002 May;99(5 Pt 2):875-7. Hyperemesis gravidarum complicated by Wernicke's encephalopathy. Spruill SC, Kuller JA. 20. Proc Nutr Soc. 2002 May;61(2):251-7. Meeting the challenges of micronutrient deficiencies in emergency-affected populations. Weise Prinzo Z, de Benoist B. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 204

21. Dig Dis Sci. 2002 Mar;47(3):543-8. Thiamine deficiency in hepatitis C virus and alcohol-related liver diseases. Levy S, Herve C, Delacoux E, Erlinger S. 22. Int J Geriatr Psychiatry. 2002 Feb;17(2):189-92. Using thiamine to reduce post-ECT confusion. Linton CR, Reynolds MT, Warner NJ. 23. J Am Coll Nutr. 2002 Feb;21(1):33-7. Vitamin profile of 563 gravidas during trimesters of pregnancy. Baker H, DeAngelis B, Holland B, Gittens-Williams L, Barrett T Jr.. 24. Gastric Cancer. 2002;5(2):77-82. Reduced thiamine (vitamin B1) levels following gastrectomy for gastric cancer. Iwase K, Higaki J, Yoon HE, Mikata S, Miyazaki M, Kamiike W. 25. J Nutr Health Aging. 2002;6(4):237-42. Dietary intake analysis in institutionalized elderly: a focus on nutrient density. Dror Y, Berner YN, Stern F, Polyak Z. 26. J Nutr Health Aging. 2002;6(1):75-7. Reduced serum concentrations of riboflavine and ascorbic acid, and blood thiamine pyrophosphate and pyridoxal-5-phosphate in geriatric patients with and without pressure sores. Selvaag E, Bohmer T, Benkestock K. 27. Medicina (B Aires). 2002;62(4):331-4. Acute cardiovascular beriberi (shoshin-beriberi). Lopez Gaston OD, Malvino ER, McLoughlin D, Osatnik J, Chavez Zambrano MA, Pino C. 28. Rocz Panstw Zakl Hig. 2002;53(3):243-52. Changes in vitamins intake in overweight and obese adults after low-energy diets Pachocka L, Klosiewicz-Latoszek L. 29. Sci Total Environ. 2001 Dec 17;281(1-3):177-82. Lead poisoning in Indian silver refiners. Tandon SK, Chatterjee M, Bhargava A, Shukla V, Bihari V.

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30. Am J Clin Nutr. 2001 Dec;74(6):808-13. Postpartum thiamine deficiency in a Karen displaced population. McGready R, Simpson JA, Cho T, Dubowitz L, Changbumrung S, Bohm V, Munger RG, Sauberlich HE, White NJ, Nosten F. 31. J Nutr Sci Vitaminol (Tokyo). 2001 Dec;47(6):385-6. Cooperation of divalent ions and thiamin diphosphate in regulation of the function of pig heart pyruvate dehydrogenase complex. Czerniecki J, Czygier M. 32. Mech Ageing Dev. 2001 Dec;123(1):21-7. Co-culture with astrocytes or microglia protects metabolically impaired neurons. Park LC, Zhang H, Gibson GE. 33. Psychiatry Res. 2001 Nov 5;108(1):49-55. Serial MRI and (1)H-MRS of Wernicke's encephalopathy: report of a case with remarkable cerebellar lesions on MRI. Murata T, Fujito T, Kimura H, Omori M, Itoh H, Wada Y. 34. Am J Kidney Dis. 2001 Nov;38(5):941-7. Thiamine deficiency and unexplained encephalopathy in hemodialysis and peritoneal dialysis patients. Hung SC, Hung SH, Tarng DC, Yang WC, Chen TW, Huang TP. 35. Aust N Z J Obstet Gynaecol. 2001 Nov;41(4):453-6. Wernicke's encephalopathy due to hyperemesis gravidarum: an under-recognised condition. Togay-Isikay C, Yigit A, Mutluer N. 36. Harefuah. 2001 Nov;140(11):1062-7, 1117. Micronutrient (vitamins and minerals) supplementation for the elderly, suggested by a special committee nominated by Ministry of Health Dror Y, Stern F, Berner YN, Kaufmann NA, Berry E, Maaravi Y, Altman H, Cohen A, Leventhal A, Kaluski DN. 37. Surgery. 2001 Nov;130(5):851-8. Thiamine reverses hyperglycemia-induced dysfunction in cultured endothelial cells. Ascher E, Gade PV, Hingorani A, Puthukkeril S, Kallakuri S, Scheinman M, Jacob T.

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38. J Hum Nutr Diet. 2001 Oct;14(5):365-70. Riboflavin deficiency in cystic fibrosis: three case reports. McCabe H. 39. Am J Physiol Cell Physiol. 2001 Sep;281(3):C786-92. Mechanism of thiamine uptake by human jejunal brush-border membrane vesicles. Dudeja PK, Tyagi S, Kavilaveettil RJ, Gill R, Said HM.

40. J Neurol Neurosurg Psychiatry. 2001 Sep;71(3):357-62. Postgastrectomy polyneuropathy with thiamine deficiency. Koike H, Misu K, Hattori N, Ito S, Ichimura M, Ito H, Hirayama M, Nagamatsu M, Sasaki I, Sobue G. 41. Wei Sheng Yan Jiu. 2001 Sep;30(5):273-5. Effect of multi-micronutrient on heat adaptation and its probable mechanism. Guo J, Zhao F, Qiu L, Li X.

42. Eur J Biochem. 2001 Aug;268(15):4177-82. The effect of thiamine supplementation on tumour proliferation. A metabolic control analysis study. Comin-Anduix B, Boren J, Martinez S, Moro C, Centelles JJ, Trebukhina R, Petushok N, Lee WN, Boros LG, Cascante M.

43. Life Sci. 2001 Jul 27;69(10):1181-91. Characteristics of depressive behavior induced by feeding thiamine-deficient diet in mice. Nakagawasai O, Tadano T, Hozumi S, Taniguchi R, Tan-No K, Esashi A, Niijima F, Kisara K.

44. Am J Ophthalmol. 2001 Jul;132(1):19-26. Use of vitamin supplements and cataract: the Blue Mountains Eye Study. Kuzniarz M, Mitchell P, Cumming RG, Flood VM. 45. Am J Physiol Gastrointest Liver Physiol. 2001 Jul;281(1):G144-50. Mechanism of thiamine uptake by human colonocytes: studies with cultured colonic

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epithelial cell line NCM460. Said HM, Ortiz A, Subramanian VS, Neufeld EJ, Moyer MP, Dudeja PK. 46. Eur J Pharmacol. 2001 Jun 15;421(3):157-64. B vitamins induce an antinociceptive effect in the acetic acid and formaldehyde models of nociception in mice. Franca DS, Souza AL, Almeida KR, Dolabella SS, Martinelli C, Coelho MM.

47. Br J Nutr. 2001 Jun;85(6):741-8. Vitamin B intake and status in healthy Havanan men, 2 years after the Cuban neuropathy epidemic. Arnaud J, Fleites-Mestre P, Chassagne M, Verdura T, Garcia Garcia I, HernandezFernandez T, Gautier H, Favier A, Perez-Cristia R, Barnouin J. France/Cuba

48. Int J STD AIDS. 2001 Jun;12(6):407-9. Severe lactic acidosis and thiamine administration in an HIV-infected patient on HAART. Arici C, Tebaldi A, Quinzan GP, Maggiolo F, Ripamonti D, Suter F.

49. Aquat Toxicol. 2001 May;52(3-4):229-39. The use of thiamine and thiamine antagonists to investigate the etiology of early mortality syndrome in lake trout (Salvelinus namaycush). Fitzsimons JD, Vandenbyllaardt L, Brown SB.

50. Mt Sinai J Med. 2001 May;68(3):216-8. Wernicke's encephalopathy in a non-alcoholic man: case report and brief review. Munir A, Hussain SA, Sondhi D, Ameh J, Rosner F.

51. J Biochem (Tokyo). 2001 Apr;129(4):543-9. Suppression of the accumulation of triosephosphates and increased formation of methylglyoxal in human red blood cells during hyperglycaemia by thiamine in vitro. Thornalley PJ, Jahan I, Ng R.

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52. Nutrition. 2001 Apr;17(4):351-2. Severe metabolic acidosis and heart failure due to thiamine deficiency. Ozawa H, Homma Y, Arisawa H, Fukuuchi F, Handa S.

53. Am J Gastroenterol. 2001 Mar;96(3):864-8. Thiamine treatment of chronic hepatitis B infection. Wallace AE, Weeks WB. 54. Public Health. 2001 Mar;115(2):133-8. Relationships between dietary intake and cognitive function level in Korean elderly people. Lee L, Kang SA, Lee HO, Lee BH, Park JS, Kim JH, Jung IK, Park YJ, Lee JE. 55. Rev Med Liege. 2001 Mar;56(3):155-8. Shoshin beriberi: myth or reality? Masset C, Lancellotti P, Nkoghe D. 56. Ukr Biokhim Zh. 2001 Mar-Apr;73(2):51-6. Interaction of rat brain thiamine kinase with thiamine and its derivatives Pylypchuk Siu, Parkhomenko IuM, Protasova ZS, Vovk AI, Donchenko HV. 57. Brain Research. 2001 Feb 16;892(1):218-27. Glucose induced IEG expression in the thiamin-deficient rat brain. Zimitat C, Nixon PF. Australia 58. Can J Neurol Sci. 2001 Feb;28(1):89-92. Wernickes encephalopathy following gastroplasty for morbid obesity. Toth C, Voll C.

59. Alcohol Clin Exp Res. 2001 Jan;25(1):112-6. Thiamin treatment and working memory function of alcohol-dependent people: preliminary findings. Ambrose ML, Bowden SC, Whelan G. 60. Ann Nutr Metab. 2001;45(4):175-80. Nutritional disorders among workers in North China during national turmoil. Lee BY, Thurmon TF.

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61. Behav Neurol. 2001-2002;13(3-4):89-94. Wernicke-Korsakoff syndrome following small bowel obstruction. Deb S, Law-Min R, Fearnley D. 62. Blood Cells Mol Dis. 2001 Jan-Feb;27(1):135-8. Thiamine-responsive megaloblastic anemia syndrome: a disorder of high-affinity thiamine transport. Neufeld EJ, Fleming JC, Tartaglini E, Steinkamp MP. 63. Br J Nutr. 2001 Jan;85(1):49-58. Longitudinal vitamin and homocysteine levels in normal pregnancy. Cikot RJ, Steegers-Theunissen RP, Thomas CM, de Boo TM, Merkus HM, Steegers EA. 64. J Int Med Res. 2001 Jan-Feb;29(1):37-40. Cardiac beriberi among illegal mainland Chinese immigrants. Chen KT, Chiou ST, Chang YC, Pan WH, Twu SJ. China

65. Rev Environ Health. 2001 Jul-Sep;16(3):213-22. Risk of colorectal cancer from alcohol consumption at lower vitamin intakes. A hospitalbased case-control study in Poland. Jedrychowski W, Steindorf K, Popiela T, Wahrendorf J, Tobiasz-Adamczyk B, Kulig J, Penar A. Poland

66. J Am Coll Cardiol. 2001 Jun 1;37(7):1765-74. Chronic heart failure and micronutrients. Witte KK, Clark AL, Cleland JG. UK

67. Molecular mechanisms of thiamine utilization. Singleton CK, Martin PR. USA

68. J Clin Anesth. 2001 May;13(3):230-8. Early recognition of acute cardiovascular beriberi by interpretation of hemodynamics Gabrielli A, Caruso L, Stacpoole PW. USA.. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 210

69. Behav Brain Res. 2001 Mar 15;119(2):167-77. Aging potentiates the acute and chronic neurological symptoms of pyrithiamine-induced thiamine deficiency in the rodent. Pitkin SR, Savage LM. USA

70. Clin Nephrol. 2001 Mar;55(3):248-53. Central and extrapontine myelinolysis in a patient in spite of a careful correction of hyponatremia. Leens C, Mukendi R, Foret F, Hacourt A, Devuyst O, Colin IM. Belgium

71. J Am Med Dir Assoc. 2001 Mar-Apr;2(2):71-5. Wernicke's Encephalopathy: The Subacute Setting as Safety Net. Buxbaum RC, Yurkofsky M. USA

72. Pediatr Radiol. 2001 Mar;31(3):167-8. Wernicke's encephalopathy in a child: case report and MR findings. Coe M, Carfagnini F, Tani G, Ambrosetto P. Italy

73. Am J Kidney Dis. 2001 Feb;37(2):427-30. Chorea induced by thiamine deficiency in hemodialysis patients. Hung SC, Hung SH, Tarng DC, Yang WC, Huang TP. China

74. J Magn Reson Imaging. 2001 Feb;13(2):163-6. In vivo and in vitro proton NMR spectroscopic studies of thiamine-deficient rat brains. Lee H, Holburn GE, Price RR. USA

75. Ann Fr Anesth Reanim. 2001 Jan;20(1):40-3. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 211

Postoperative encephalopathies: thiamine deficiency, an unrecognized etiology S, Andrianjatovo JJ, Dubau B, Winnock S, Maurette P. France

76. Ann Hematol. 1999 Feb;78(2):105-7. Downbeat nystagmus caused by thiamine deficiency: an unusual presentation of CNS localization of large cell anaplastic CD 30-positive non-Hodgkin's lymphoma. Mulder AH, Raemaekers JM, Boerman RH, Mattijssen V. Netherlands

77. Fortschr Neurol Psychiatr. 2000 Mar;68(3):113-20. Thiamine treatment in psychiatry and neurology Hinze-Selch D, Weber MM, Zimmermann U, Pollmacher T. Garmany

78. Eur J Paediatr Neurol. 2000;4(3):115-7. Outcome of thiamine treatment in a child with Leigh disease due to thiamine-responsive pyruvate dehydrogenase deficiency. Di Rocco M, Lamba LD, Minniti G, Caruso U, Naito E. Italy ANIMAL RESEARCH 79. Brain Res Bull. 2000 Jan 1;51(1):47-55. Immunohistochemical estimation of rat brain somatostatin on avoidance learning impairment induced by thiamine deficiency. Nakagawasai O, Tadano T, Niijima F, Tan-No K, Kisara K. Japan. 80. Ann Vasc Surg. 2000 Jan;14(1):37-43. Thiamine (Vitamin B1) protects against glucose- and insulin-mediated proliferation of human infragenicular arterial smooth muscle cells. Avena R, Arora S, Carmody BJ, Cosby K, Sidawy AN. USA

81. Acta Haematol. 2000;102(3):157-9. Graft failure of autologous peripheral blood stem cell transplantation due to acute Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 212

metabolic acidosis associated with total parenteral nutrition in a patient with relapsed breast cancer. Sawada M, Tsurumi H, Hara T, Goto H, Yamada T, Oyama M, Moriwaki H. Japan. 82. Nihon Arukoru Yakubutsu Igakkai Zasshi. 2000 Feb;35(1):19-27. Alcohol intake and nutrition. Itokawa Y. Japan

83. Presse Med. 2000 Feb 12;29(5):240-1. Right heart failure caused by thiamine deficiency (cardiac beriberi)] Akpan T, Peschard S, Brinkane AH, Bergheul S, Leroy-Terquem E, Levy R. France

84. J Neurochem. 2000 Jan;74(1):114-24. Metabolic impairment elicits brain cell type-selective changes in oxidative stress and cell death in culture. Park LC, Calingasan NY, Uchida K, Zhang H, Gibson GE. USA

85. J Nutr Health Aging. 2000;4(2):69-71. Diuretic use: a risk for subclinical thiamine deficiency in elderly patients. Suter PM, Haller J, Hany A, Vetter W. Switzerland

86. Neurol Neurochir Pol. 2000;34 Suppl 8:59-66. Disturbances of glucose metabolism in epilepsy and other neurodegenerative diseases Szutowicz A, Jankowska A, Tomaszewicz M. Poland

87. No To Shinkei. 2000 Jan;52(1):59-63. A case of Wernicke-Korsakoff syndrome with dramatic improvement in consciousness immediately after intravenous infusion of thiamine Kikuchi A, Chida K, Misu T, Okita N, Nomura H, Konno H, Takase S, Takeda A, Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 213

Itoyama Y. Japan

88. Acta Neuropathol (Berl). 1999 Dec;98(6):614-21. Changes in serotonergic neurons in the brain of pyrithiamine-induced acute thiaminedeficient mice. Matsushita H, Takeuchi Y, Kosaka K, Fushiki S, Kawata M, Sawada T. Japan

89. Clin Nutr. 1999 Dec;18(6):375-8. Thiamin deficiency in HIV-positive patients: evaluation by erythrocyte transketolase activity and thiamin pyrophosphate effect. Muri RM, Von Overbeck J, Furrer J, Ballmer PE. Switzerland.

90. Endocr J. 1999 Dec;46(6):787-93. Gestational thyrotoxicosis with acute Wernicke encephalopathy: a case report. Ohmori N, Tushima T, Sekine Y, Sato K, Shibagaki Y, Ijuchi S, Akano K. Japan. 91. Am Fam Physician. 1999 Oct 1;60(5):1468-76. Management of the hyperosmolar hyperglycemic syndrome. Matz R. USA.. 92. Eur J Anaesthesiol. 1999 Oct;16(10):733-5. Thiamine for the treatment of nucleoside analogue-induced severe lactic acidosis. Schramm C, Wanitschke R, Galle PR. Germany

93. Nippon Rinsho. 1999 Oct;57(10):2362-5. Diabetes and vitamin levels Tamai H. Japan

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94. Acta Neurol Belg. 1999 Sep;99(3):198-201. Acute axonal polyneuropathy in chronic alcoholism and malnutrition. Vandenbulcke M, Janssens J. Belgium

95. J Lab Clin Med. 1999 Sep;134(3):238-43. Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers. Rieck J, Halkin H, Almog S, Seligman H, Lubetsky A, Olchovsky D, Ezra D. Isreal

96. J Neuropathol Exp Neurol. 1999 Sep;58(9):946-58. Oxidative stress is associated with region-specific neuronal death during thiamine deficiency. Calingasan NY, Chun WJ, Park LC, Uchida K, Gibson GE. USA.

97. Metab Brain Dis. 1999 Sep;14(3):137-48. The relationship between thiamine deficiency and performance of a learning task in rats. Terasawa M, Nakahara T, Tsukada N, Sugawara A, Itokawa Y. Japan

98. Public Health Nutr. 1999 Sep;2(3A):403-9. The effects of nutrients on mood. Benton D, Donohoe RT. UK

99. Neurosci Lett. 1999 Aug 13;271(1):33-6. Cerebrospinal fluid levels of thiamine in patients with Parkinson's disease. Jimenez-Jimenez FJ, Molina JA, Hernanz A, Fernandez-Vivancos E, de Bustos F,Barcenilla B, Gomez-Escalonilla C, Zurdo M, Berbel A, Villanueva C. Spain

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Reversible MRI abnormalities in an unusual paediatric presentation of Wernicke's encephalopathy. Sparacia G, Banco A, Lagalla R. Italy 101. Ambrose, ML, Bowden SC, Whelan G. Thiamin treatment and working memory function of alcohol-dependent people: preliminary findings. Alcohol Clin Exp Res. 2001;25(1):112-116. 102. Antoon AY, Donovan DK. Burn Injuries. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. Philadelphia, Pa: W.B. Saunders Company; 2000:287-294. 103. Bell I, Edman J, Morrow F, et al. Brief communication. Vitamin B1, B2, and B6 augmentation of tricyclic antidepressant treatment in geriatric depression with cognitive dysfunction. J Am Coll Nutr. 1992;11:159-163. 104. Boros LG, Brandes JL, Lee W-N P, et al. Thiamine supplementation to cancer patients: a double-edged sword. Anticancer Res. 1998;18:595602. 105. Cumming RG, Mitchell P, Smith W. Diet and cataract: the Blue Mountains Eye Study. Ophthalmology. 2000;107(3):450-456. 106. De-Souza DA, Greene LJ. Pharmacological nutrition after burn injury. J Nutr. 1998;128:797-803. 107. Jacques PF, Chylack LT Jr, Hankinson SE, et al. Long-term nutrient intake and early age-related nuclear lens opacities. Arch Ophthalmol. 2001;119(7):1009-1019. 108. Kelly GS. Nutritional and botanical interventions to assist with the adaptation to stress. Alt Med Rev. 1999;4(4):249-265. 109. Kirschmann GJ, Kirschmann JD. Nutrition Almanac. 4th ed. New York: McGrawHill;1996:80-83. 110. Kuzniarz M, Mitchell P, Cumming RG, Flood VM. Use of vitamin supplements and cataract: the Blue Mountains Eye Study. Am J Ophthalmol. 2001;132(1):19-26. 111. Leslie D, Gheorghiade M. Is there a role for thiamine supplementation in the management of heart failure? Am Heart J. 1996;131:12481250. 112. Lindberg MC, Oyler RA. Wernick's encephalopathy. Am Fam Physician. 1990;41:12051209.

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1. Araki A, et al. 1993. Plasma homocysteine concentrations in Japanese patients with non-insulin-dependent diabetes mellitus: effect of parenteral methylcobalamin treatment. Atherosclerosis 103(2):149-57. 2. Berlin R, et al. 1978. Vitamin B12 body stores during oral and parenteral treatment of pernicious anaemia. Acta Med Scand 204(1-2):81-4. 3. Bernard MA, et al. 1998. The effect of vitamin B12 deficiency on older veterans and its relationship to health [see comments]. J Am Geriatr Soc 46(10):1199-206. 4. Freeman AG. 1992. Cyanocobalamin-a case for withdrawal: discussion paper. J R Soc Med 85:686-7. 5. Honma K, et al. 1992. Effects of vitamin B12 on plasma melatonin rhythm in humans: increased light sensitivity phase-advances the circadian clock? Experientia 48:716-20. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 217

6. Houston DK, et al. Age-related hearing loss, vitamin B-12, and folate in elderly women. Am J Clin Nutr 69:564-71. 7. Kaji R, et al. 1998. Effect of ultra high-dose methylcobalamin on compound muscle action potentials in amyotrophic lateral sclerosis: a double-blind controlled study. Muscle Nerve 21:1775-8. 8. Kamgar-Parsi B, et al. 1983. Successful treatment of human non-24-hour sleep-wake syndrome. Sleep 6:257-64. 9. Kuzminski AM, et al. 1998. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 92:1191-98. 10. Mayer G, et al. 1996. Effects of vitamin B12 on performance and circadian rhythm in normal subjects. Neuropsychopharm 15:456-464. 11. Parnetti L, et al. 1992. Platelet MAO-B activity and vitamin B12 in old age dementias. Mol Chem Neuropathol 16(1-2):23-32. 12. Salom IL, et al. Effect of cimetidine on the absorption of vitamin B12. 1982. Scand J Gastroenterol 17(1):129-31. 13. Shane B, et al. 1985. Vitamin B12--folate interrelationships. Ann Rev Nutr 5:115-41. 14. van Asselt DZ, et al. 1998. Role of cobalamin intake and atrophic gastritis in mild cobalamin deficiency in older Dutch subjects [see comments]. Am J Clin Nutr 68(2):32834. 15. Watanabe T, et al. 1994. Ultra-high dose methylcobalamin promotes nerve regeneration in experimental acrylamide neuropathy. J Neurol Sci 122:140-3 16. Yamazaki K, et al. 1994. Methylcobalamin (methyl-B12) promotes regeneration of motor nerve terminals degenerating in anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mouse. Neurosci Lett 170:195-7. 17. Shane B. Folic acid, vitamin B-12, and vitamin B-6. In: Stipanuk M, ed. Biochemical and Physiological Aspects of Human Nutrition. Philadelphia: W.B. Saunders Co.; 2000:483-518. 18. Baik HW, Russell RM. Vitamin B12 deficiency in the elderly. Annu Rev Nutr. 1999;19:357-377. (PubMed) 19. Herbert V. Vitamin B-12. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington D.C.: ILSI Press; 1996:191-205.

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33. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002;346(7):476-483. (PubMed) 34. Hutto BR. Folate and cobalamin in psychiatric illness. Compr Psychiatry. 1997;38(6):305-314. (PubMed) 35. Penninx BW, Guralnik JM, Ferrucci L, Fried LP, Allen RH, Stabler SP. Vitamin B(12) deficiency and depression in physically disabled older women: epidemiologic evidence from the Women's Health and Aging Study. Am J Psychiatry. 2000;157(5):715721. (PubMed) 36. Hadded EH, et al. 1999. Dietary intake and biochemical, hematologic, and immune status of vegans compared with nonvegetarians. Am J Clin Nutr 70(3 Suppl):586S-93S. 37. Hall CA, et al. 1986. Methionine synthetase activity of human lymphocytes both replete in and depleted of vitamin B12. J Lab Clin Med 108:325-31. 38. Tamura J, et al. 1999. Immunomodulation by vitamin B12: augmentation of CD8+ T lymphocytes and natural killer (NK) cell activityin vitamin B12-deficient patients by methyl-B12 tratment. Clin Exp Immunol 116:28-32. 39. Tang AM, et al. 1997. Low serum vitamin B-12 concentrations are associated with faster human immunodeficiency virus type 1 (HIV-1) disease progression. J Nutr 127:345-51. 41. Adachi S, et al. 2000. Enteral vitamin B12 supplements reverse postgastrectomy B12 deficiency. Ann Surg 232:199-201. 42. Akaike A, et al. 1993. Protective effects of a vitamin B12 analog, methylcobalamin, against glutamate cytotoxicity in cultured cortical neurons. Eur J Pharm 241:1-6. 43. Aytemir K, et al. 2000. Assessment of autonomic nervous system functions in patients with vitamin B12 deficiency by power spectral analysis of heart rate variability. Pacing Clin Electrophysiol 23:975-78. 44. Baik HW, et al. 1999. Vitamin B12 deficiency in the elderly. Annu Rev Nutr 19:35777. 45. Eastley R, et al. 2000. Vitamin B12 deficiency in dementia and cognitive impairment: the effects of treatment on neuropshychological function. Int J Geriatr Psychiatry 15:22633. 46. Fenech M. 1999. Micronucleus frequency in human lymphocytes is related to plasma vitamin B12 and homocysteine. Muta Res 428:299-304. 47. Freeman AG. 1992. Cyanocobalamina case for withdrawal: discussion paper. J Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 220

Royal Soc Med 85:686-7. 48. Haddad EH, et al. 1999. Dietary intake and biochemical, hematologic and immune status of vegans compared with nonvegetarians. Am J Clin Nutr 70(3 suppl):586S-93S. 49. Kaptan K, et al. 2000. Helicobacter pyloriis it a novel causative agent in vitamin B12 deficiency? Arch Intern Med 160(9):1349-53. 50. Kikuchi M, et al. 1997. Protective effects of methylcobalamin, a vitamin B12 analog, against glutamate-induced neurotoxicity in retinal cell culture. Invest Ophthal Vis Sci 38:848-54. 51. Kuwabara S, et al. 1999. Intravenous methylcobalamin treatment for uremic and diabetic neuropathy in chronic hemodialysis patients. Intern Med 38:472-5. 52. Laine L, et al. 2000. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 14:651-68. 53. Lederle FA. Oral cobalamin for pernicious anemia: back from the verge of extinction. J Am Geratr Soc 46:1125-27. 54. Lindeman RD, et al. 2000. Serum vitamin B12, C and folate concentrations in the New Mexico elder health surve: correlations with cognitive and affective functions. J Am Coll Nutr 19:68-76. 55. Mayer G, et al. 1996. Effects of vitamin B12 on performance and circadian rhythm in normal subjects. Neuropsychopharm 15:456-64. 56. Meins W, et al. 2000. Subnormal serum vitamin B12 and behavioural and psychological symptoms in Alzheimers disease. Int J Geriatr Psychiatry 15:415-18. 57. Moelby L, et al. 2000. Relationahip between methylmalonic acid and cobalamin in uremia. Kindey Int 57:265-73. 58. Pongstaporn W, et al. 1999. Hematological parameters, ferritin and vitamin B12 in vegetarians. J Med Assoc Thai 82:304-11. 59. Silver H. 2000. Vitamin B12 levels are low in hospitalized psychiatric patients. Isr J Psychiatry Relat Sci 37:41-45. 60. Sponne IE, et al. 2000. Inhibition of vitamin B12 metabolism by OH-cobalamin clactam in rat oligodendrocytes in culture: a model for studying neuropathy due to vitamin B12 deficiency. Neurosci Lett 288:191-4. 61. Tamura J, et al. 1999. Immunomodulation by vitamin B12: augmentation of CD8+ T lymphocytes and natural killer (NK) cell activity in vitamin B12-deficient patients by Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 221

methyl-B12 treatment. Clin Exp Immunol 116:28-32. 62. Temple ME, et al. 2000. Homocysteine as a risk factor for atherosclerosis. Ann Pharmacother 34:57-65. 63. Watanabe T, et al. 1994. Ultra-high dose methylcogalamin promotes nerve regeneration in experimental acrylamide neuropathy. J Neurol Sci 122:140-43. 64. Yagihashi S, et al. 1982. In vivo effect of methylcobalamin on the periopheral nerve structure in streptozotocin diabetic rats. Horm Metab Res 14:10-13.

Pantothenic Acid (B5) 47 Studies


1. Effects of ethanol and pantothenic acid on brain acetylcholine synthesis. Rivera-Calimlim L, Hartley D, Osterhout D. Department of Pharmacology, University of Rochester, School of Medicine and Dentistry, NY 14642. Br J Pharmacol. 1988 Sep;95(1):77-82. 2. Pantothenic acid transport and metabolism in the central nervous system. Spector R. Am J Physiol. 1986 Feb;250(2 Pt 2):R292-7. Vitamins and lipid metabolism. 3. Fidanza A, Audisio M. Acta Vitaminol Enzymol. 1982;4(1-2):105-14. 4. Pantothenic acid protects jurkat cells against ultraviolet light-induced apoptosis. Slyshenkov VS, Piwocka K, Sikora E, Wojtczak L. Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland. Free Radic Biol Med. 2001 Jun 1;30(11):1303-10. 5. Mitochondrial, but not peroxisomal, beta-oxidation of fatty acids is conserved in coenzyme A-deficient rat liver.

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Youssef JA, Song WO, Badr MZ. Division of Pharmacology, University of MissouriKansas City 64108, USA. Mol Cell Biochem. 1997 Oct;175(1-2):37-42. 6. Amelioration of adverse effects of valproic acid on ketogenesis and liver coenzyme A metabolism by cotreatment with pantothenate and carnitine in developing mice: possible clinical significance. Thurston JH, Hauhart RE. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110. Pediatr Res. 1992 Apr;31(4 Pt 1):419-23. 7. Pantothenic acid and its derivatives protect Ehrlich ascites tumor cells against lipid peroxidation. Slyshenkov VS, Rakowska M, Moiseenok AG, Wojtczak L. Nencki Institute of Experimental Biology, Warsaw, Poland. Free Radic Biol Med. 1995 Dec;19(6):767-72. Erratum in:Free Radic Biol Med 1996;20(3):493. 8. Topical use of dexpanthenol in skin disorders. Ebner F, Heller A, Rippke F, Tausch I. Technical University of Munich, Allershausen, Germany. fritz.ebner@t-online.de Am J Clin Dermatol. 2002;3(6):427-33. 9. Topical corticosteroid therapy for acute radiation dermatitis: a prospective, randomized, double-blind study. 10. Tahiliani AG, Beinlich CJ. Pantothenic acid in health and disease. Vitam Horm. 1991;46:165-228. 11. Bender DA. Optimum nutrition: thiamin, biotin and pantothenate. Proc Nutr Soc. 1999;58(2):427-433. 12. Hodges RE, Ohlson MA, Bean WB. Pantothenic acid deficiency in man. J Clin Invest. 1958;37:1642-1657. 13. Fry PC, Fox HM, Tao HG. Metabolic response to a pantothenic acid deficient diet in humans. J Nutr Sci Vitaminol (Tokyo). 1976;22(4):339-346.

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14. Plesofsky-Vig N. Pantothenic acid. In: Filer LJ, ed. Present Knowledge in Nutrition. 7th ed. Washington D.C.: ILSI Press; 1996. 15. Food and Nutrition Board, Institute of Medicine. Pantothenic acid. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: National Academy Press; 1998:357-373. 16. Weimann BI, Hermann D. Studies on wound healing: effects of calcium Dpantothenate on the migration, proliferation and protein synthesis of human dermal fibroblasts in culture. Int J Vitam Nutr Res. 1999;69(2):113-119. 17. Gaddi A, Descovich GC, Noseda G, et al. Controlled evaluation of pantethine, a natural hypolipidemic compound, in patients with different forms of hyperlipoproteinemia. Atherosclerosis. 1984;50(1):73-83. 18. Coronel F, Tornero F, Torrente J, et al. Treatment of hyperlipemia in diabetic patients on dialysis with a physiological substance. Am J Nephrol. 1991;11(1):32-36. 19. Said HM, Ortiz A, McCloud E, Dyer D, Moyer MP, Rubin S. Biotin uptake by human colonic epithelial NCM460 cells: a carrier-mediated process shared with pantothenic acid. Am J Physiol. 1998;275(5 Pt 1):C1365-1371. 21. Effect of pantothenic acid and ascorbic acid supplementation on human skin wound healing process. A double-blind, prospective and randomized trial. Vaxman F, Olender S, Lambert A, Nisand G, Aprahamian M, Bruch JF, Didier E, Volkmar P, Grenier JF. INSERM U 61, Hospices Civils, Strasbourg, France. Eur Surg Res. 1995;27(3):158-66. 23. Role of pantothenic and ascorbic acid in wound healing processes: in vitro study on fibroblasts. Lacroix B, Didier E, Grenier JF. INSERM Unite 61-Service de Chirurgie B, Hopital Civil, Strasbourg. Int J Vitam Nutr Res. 1988;58(4):407-13. 24. Effects of supplemental pantothenic acid on wound healing: experimental study in rabbit. Aprahamian M, Dentinger A, Stock-Damge C, Kouassi JC, Grenier JF. Am J Clin Nutr. 1985 Mar;41(3):578-89.

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25. A new drug combination for treating polyneuropathy 26. Munchener Medizinische Wochenschrift (Germany), 1997, 139/12 (34-37) 27. [Therapeutic efficacy of pantothenic acid preparations in ischemic heart disease patients] Vopr Pitan (USSR) Mar-Apr 1987, (2) p15-7 28. Vitamins and immunity: II. Influence of L-carnitine on the immune system. Acta Vitaminol Enzymol (ITALY) 1982, 4 (1-2) p135-40 29. Adding vitamins to the mix: skin care products that can benefit the skin [press release]. American Academy of Dermatology; March 11, 2000. 30. Antoon AY, Donovan DK. Burn Injuries. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. Philadelphia, Pa: W.B. Saunders Company; 2000:287-294. 31. Aprahamian M, Dentinger A, Stock-Damge C, Kouassi JC, Grenier JF. Effects of supplemental pantothenic acid on wound healing: experimental study in rabbit. Am J Clin Nutr. 1985;41(3):578-89. 32. Arsenio L, Bodria P, Magnati G, Strata A, Trovato R.. Effectiveness of long-term treatment with pantethine in patients with dyslipidemia. Clin Ther. 1986;8:537545. 33. Bertolini S, Donati C, Elicio N, et al. Lipoprotein changes induced by pantethine in hyperlipoproteinemic patients: adults and children. Int J Clin Pharmacol Ther Toxicol. 1986;24:630637. 34. Coronel F, Tornero F, Torrente J, et al. Treatment of hyperlipemia in diabetic patients on dialysis with a physiological substance. Am J Nephrol. 1991;11:3236. 35. De-Souza DA, Greene LJ. Pharmacological nutrition after burn injury. J Nutr. 1998;128:797-803. 36. Gaddi A, Descovich GC, Noseda G, et al. Controlled evaluation of pantethine, a natural hypolipidemic compound in patients with different forms of hyperlipoproteinemia. Atherosclerosis. 1984;50:7383. 37. General Practitioner Research Group. Calcium pantothenate in arthritic conditions. A report from the General Practitioner Research Group. Practitioner. 1980;224(1340):208211. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 225

38. Hoeg JM. Pharmacologic and surgical treatment of dyslipidemic children and adolescents. Ann NY Acad Sci. 1991;623:275-284. 39. Kelly GS. Nutritional and botanical interventions to assist with the adaptation to stress. [Review]. Altern Med Rev. 1999 Aug;4(4):249-265. 40. Kirschmann GJ, Kirschmann JD. Nutrition Almanac. 4th ed. New York: McGrawHill;1996:115-118. 41. Lacroix B, Didier E, Grenier JF. Role of pantothenic and ascorbic acid in wound healing processes: in vitro study on fibroblasts. Int J Vitam Nutr Res. 1988;58(4):407413. 42. McCarty MF. Inhibition of acetyl-CoA carboxylase by cystamine may mediate the hypotriglyceridemic activity of pantethine. Med Hypotheses. 2001;56(3):314-317. 43. Meyer NA, Muller MJ, Herndon DN. Nutrient support of the healing wound. New Horizons. 1994;2(2):202-214. 44. Naruta E, Buko V. Hypolipidemic effect of pantothenic acid derivatives in mice with hypothalamic obesity induced by aurothioglucose. Exp Toxicol Pathol. 2001;53(5):393398. 45. Weimann BI, Hermann D. Studies on wound healing: effects of calcium Dpantothenate on the migration, proliferation and protein synthesis of human dermal fibroblasts in culture. Int J Vitam Nutr Res. 1999;69(2):113-119. 46. Brenner A. The effects of megadoses of selected B complex vitamins on children with hyperkinesis: controlled studies with long-term follow-up. J Learn Disabil. 1982 May;15(5):258-64. No abstract available. PMID: 7086283 47. American Diet Inadequate in Vitamin B5. Availability of vitamin B6 and pantothenate in an average American diet in man. Tarr JB. Tamura T. Stokstad EL. American Journal of Clinical Nutrition. 34(7):1328-37, 1981 Jul.

Calcium Carbonate - 86 Studies


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3. Holt, P.R. et al Modulation of Abnormal Colonic Epithelial Cell Proliferation and Differentiation by Low-fat Dairy Foods. AM. J. CLIN. NUTR. 1998, 68 (3) 648-655. 4. Calcium for Hypertension. J.A.M.A. 1998, 280 (12) 1074-9. 5. Clark, S. More Effort Needed to Halt Osteoporotic Bone Loss. LANCET 1998, 351 (9112) 1335. 6. Macready, N. Vitamins Associated With Lower Colon-Cancer Risk. The Lancet 1997, 350 (9089) 1452. 7. Dawson-Hughes, B et al. Effect of Calcium and Vitamin D Supplementation on Bone Density in Men and Women 65 Years of Age or Older. N. ENGL. J. MED. 1997, 337 (10) 670-6. 8. Allender PS, Cutler JA, Follmann D, Cappuccio FP, Pryer J, Elliott P. Dietary calcium and blood pressure: a meta-analysis of randomized clinical trials. Ann Intern Med. 1996;124(9):825-831. 9. O'sullivan AJ, Lawson JA, Chan M, Kelly JJ. Body composition and energy metabolism in chronic renal insufficiency. Am J Kidney Dis. 2002 Feb;39(2):369-375. 10. Appel L, Moore T, Obarzonek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med. 1997;336:1117-1124. 11. Baeksgaard L, Andersen KP, and Hyldstrup L. Calcium and vitamin D supplementation increases spinal BMD in healthy, postmenopausal women. Osteoporos Int. 1998;8:255-260. 12. Balfour JA, Wiseman LR. Moxifloxacin. Drugs. 1999;57(3):363-374. 13. Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the prevention of colorectal adenomas. N Eng J Med. 1999;340:101-107. 14. Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000;23(9):1227-1231. 15. Bendich A. The potential for dietary supplements to reduce premenstrual syndrome (PMS) symptoms [review]. J Am Coll Nutr. 2000;19(1);3-12. 16. Blanch J, Pros A. Calcium as a treatment of osteoporosis. Drugs Today. 1999;35:631639.

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17. Bonithon-Kopp C, Kronborg O, Giacosa A, Rath U, Faivre J. Calcium and fibre supplementation in prevention of colorectal adenoma recurrence: a randomised intervention trial. European Cancer Prevention Organisation Study Group. Lancet. 2000;356:1300-1306. 18. Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med. 2002;346(2):77-84. 19. Bostick RM, Fosdick L, Grandits GA, Grambsch P, Gross M, Louis TA. Effect of calcium supplementation on serum cholesterol and blood pressure. Arch Fam Med. 2000;9:31-39. 20. Brouwers JR. Drug interactions with quinolone antibacterials. Drug Safety. 1992;7(4):268-281. 21. Bryant RJ, Cadogan J, Weaver CM. The new dietary reference intakes for calcium: implications for osteoporosis. J Am Coll Nutr. 1999;18:406S-412S. 22. Burgess E, Lewanczuk R, Bolli P, et al. Recommendations on potassium, magnesium and calcium. CMAJ. 1999;160:S35-S45. 23. Campbell NR, Hasinoff BB. Iron supplements: a common cause of drug interactions. Br J Clin Pharmacol. 1991;31(3):251-255. 24. Cardona PD. Drug-food interactions [in Spanish]. Nutr Hosp. 1999;14(suppl 2):129S140S. 25. Chan JM, Stampfer MJ, Ma J, Gann PH, Gaziano JM, Giovannucci EL. Dairy products, calcium, and prostate cancer risk in the Physicians' Health Study. Am J Clin Nutr. 2001;74(4):549-554. 26. Coburn JW, Mischel MG, Goodman WG, Salusky IB. Calcium citrate markedly enhances aluminum absorption from aluminum hydroxide. Am J Kidney Dis. 1991;17(6):708-711. 27. Consensus Opinion. The role of calcium in peri- and postmenopausal women: consensus opinion of the North American Menopause Society. Menopause. 2001;8:8495. 28. Davies KM, Heaney RP, Recker RR, et al. Calcium intake and body weight. J Clin Endocrinol Metab. 2000;85(12):4635-4638. 29. Garland CF, Garland FC, Gorham ED. Calcium and vitamin D: their potential roles in colon and breast cancer prevention. Ann NY Acad Sci. 1999;889:107-119.

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30. Gugler R, Allgayer H. Effects on antacids on the clinical pharmacokinetics of drugs. An update. Clin Pharmacokinet. 1990;18(3): 210-219. 31. Gulson BL, Mizon KJ, Palmer Jm, Korsch MJ, Taylor AJ. Contribution of lead from calcium supplements to blood lead. Environ Health Perspect. 2001;109(3):283-288. 32. Haft JJ, Habbab MA. Treatment of atrial arrhythmias. Effectiveness of verapamil when preceeded by calcium infusion. Arch Intern Med. 1986; 146(6):1085-1089. 33. Hardman JG, Gilman AG, Limbird LE, eds. Goodman and Gilman's Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996:839874. 34. Hathcock JN. Metabolic mechanisms of drug-nutrient interactions. Fed Proc. 1985;44(1):124-129. 35. Heaney RP. Lead in calcium supplements: cause for alarm or celebration [editorial]? JAMA. 2000;284(11):1432-1433. 36. Heaney RP, Dowell SD, Bierman J, Hale CA, Bendich A. Absorbability and cost effectiveness in calcium supplementation. J Am Coll Nutr. 2001;20(3):239-246. 37. Heller HJ, Stewart A, Haynes S, Pak CYC. Pharmacokinetics of calcium absorption from two commercial calcium supplements. J Clin Pharmacol. 1999;39:1151-1154. 38. Hermensen K. Diet, blood pressure and hypertension. Br J Nutr. 2000;83(Suppl 1):S113-S119. 39. Hines Burnham T, et al, eds. Drug Facts and Comparisons. St. Louis, MO:Facts and Comparisons; 2000. 40. Holt PR. Dairy foods and prevention of colon cancer: human studies. J Am Coll Nutr. 1999;18(suppl 5):379S-391S. 41. Institute of Medicine. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press; 1997. 42. Iso H, Stampfer MJ, Manson JE, et al. Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women. Stroke. 1999;30(9):1772-1779. 43. Jnne PA, Mayer RJ. Chemoprevention of colorectal cancer. N Engl J Med. 2000;342(26):1960-1968.

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44. Joint National Committee. Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Arch Int Med. 1997;157:2413-2446. 45. Kampman E, Slattery ML, Caan B, Potter JD. Calcium, vitamin D, sunshine exposure, dairy products and colon cancer risk (United States). Cancer Causes Control. 2000:11:459-466. 46. Kara M, Hasinoff BB, McKay DW, et al. Clinical and chemical interactions between iron preparations and ciprofloxacin. Br J Clin Pharmacol. 1991;31(3):257-261. 47. Kirch W, Schfer-Korting M, Axthelm T, et al. Interaction of atenolol with furosemide and calcium and aluminum salts. Clin Pharm Ther. 1981;30(4):429-435. 48. Kirschmann GJ, Kirschmann JD, eds. Nutrition Almanac. 4th ed. New York: McGraw-Hill; 1996. 49. Krall EA, Wehler C, Garcia RI, et al. Calcium and vitamin D supplements reduce tooth loss in the elderly. Am J Med. 2001 Oct 15;111(6):452-456. 50. Krauss RM, Eckel RH, Howard B, et al. AHA dietary guidelines. Revision 2000: A statement for healthcare professionals from the Nutrition Committee of the American Heart Association. Circulation. 2000;102:2284-2299. 51. Leppla D, Browne R, Hill K, Pak C. Effect of amiloride with or without hydrochlorothiazide on urinary calcium and saturation of calcium salts. J Clin Endocrinol Metab. 1983;57(5):920-924. 52. Li RC, Lo KN, Lam JS, et al. Effects of order of magnesium exposure on the postantibiotic effect and bactericidal activity of ciprofloxacin. J Chemother. 1999;11(4):243-247. 53. Lin Y-C, Lyle RM, McCabe LD, et al. Dairy calcium is related to changes in body composition during a two-year exercise intervention in young women. J Am Coll Nutr. 2000;19(6):754-760. 54. Lobo RA, Roy S, Shoupe D, et al. Estrogen and progestin effects on urinary calcium and calciotropic hormones in surgically-induced postmenopausal women. Horm Metab Res. 1985;17(7):370-373. 55. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med. 1990;112(5):352-364. 56. Mazariegos-Ramos E, Guerrero-Romero F, Rodriquez-Moran M, Lazcano-Burciago G,

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57. Paniagua R, Amato D. Consumption of soft drinks with phosphoric acid as a risk factor for the development of hypocalcemia in children: a case-control study. J Pediatr. 1995;126(6):940-942. 58. McCarron D, Reusser M. Finding Consensus in the Dietary Calcium-Blood Pressure Debate. J Am Coll Nutr. 1999;18:398S-405S. 59. NAMS Consensus. Consensus Opinion: the role of calcium in peri-and postmenopausal women: consensus opinion of The North American Menopause Society. Menopause. 2001;8(20):84-95. 60. Nieves JW, Komar L, Cosman F, Lindsay R. Caclium potentiates the effect of estrogen and calcitonin on bone mass: review and analysis. Am J Clin Nutr. 1998;67(1):18-24. 61. NIH Consensus Development Panel. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285(6):785-795. 62. Nolan CR, DeGoes JJ, Alfrey AC. Aluminum and lead absorption from dietary sources in women ingesting calcium citrate. South Med J. 1994;8(9):894-898. 63. Nutrients and Nutritional Agents. In: Kastrup EK, Hines Burnham T, Short RM, et al, eds. Drug Facts and Comparisons. St. Louis, Mo: Facts and Comparisons; 2000:4-5. 64. Peacock M, Liu G, Carey M, et al. Effect of calcium or 25OH vitamin D3 supplementation on bone loss at the hip in men and women over the age of 60. J Clin Endocrinol Metabol. 2000;85(9):3011-3019. 65. Petti S, Cairella G, Tarsitani G. Nutritional variables related to gingival health in adolescent girls. Community Dent Oral Epidemiol. 2000 Dec;28(6):407-413. 66. Physicians' Desk Reference. 55th ed. Montvale, NJ: Medical Economics Co., Inc; 2000:1418-1422. 67. Pietinen P, Malila N, Virtanen M, et al. Diet and risk of colorectal cancer in a cohort of Finnish men. Cancer Causes Control. 1999;10:387-396. 68. Potter JD. Nutrition and colorectal cancer. Cancer Causes Control. 1996;7:127-146. 69. Reid IR, Veale AG, France JT. Glucocorticoid osteoporosis. J Asthma. 1994;31(1):718. 69. Ross EA, Szabo NJ, Tebbett IR. Lead content of calcium supplements. JAMA. 2000;284(11):1425-1429.

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70. Ruml LA, Sakhaee K, Peterson R, et al. The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study. Am J Ther. 1999;6:303-311. 71. Sacks FM, Svetkey LP, Volmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet. N Engl J Med. 2001;344:3-10. 72. Sakhaee K, Bhuket T, Adams-Huet B, Rao DS. Meta-analysis of calcium bioavailability: a comparison of calcium citrate with calcium carbonate. Am J Ther. 1999;6:313-321. 73. Sakhaee K, Nicar M, Glass K, Zerwekh J, Pak C. Reduction in intestinal calcium absorption by hydrochlorothiazide in postmenopausal osteoporosis. J Clin Endocrinol Metab. 1984;59(6):1037-1043. 74. Schneider M, Valentine S, Clarke GM, Newman MA, Peacock J. Acute renal failure in cardiac surgical patients, potentiated by gentamicin and calcium. Anaesth Intens Care. 1996;24(6):647-650. 75. Shils ME, Olson JA, Shike M, Ross AC. Modern Nutrition in Health and Disease. 9th ed. Baltimore, Md: Williams & Wilkins; 1999:169192, A127A128. 76. Sonnenblick M, Abraham AS, Meshulam Z, Eylath U. Correlation between manifestations of digoxin toxicity and serum digoxin, calcium, potassium, and magnesium concentrations and arterial pH. BMJ. 1983;286(6371):1089-1091. 77. Stier CT Jr, Itskovitz HD. Renal calcium metabolism and diuretics. Ann Rev Pharmacol Toxicol. 1986;26:101-116. 78. Thatcher TD, Fischer PR, Pettifor JM, et al. A comparison of calcium, vitamin D, or both for nutritional rickets in Nigerian children. N Engl J Med. 1999;341:563-568. 79. Thys-Jacobs S. Micronutrients and the premenstrual syndrome: the case for calcium. J Am Coll Nutr. 2000;19(2):220-227. 80. Thys-Jacobs S, Starkey P, Bernstein D, Tian J. Calcium carbonate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Premenstrual Syndrome Study Group. Am J Obstet Gynecol. 1998;179:444452. 81. Torkos S. Drug-nutrient interactions: a focus on cholesterol-lowering agents. Int J Integrative Med. 2000;2(3):9-13. 82. van den Elzen HJ, Wladimiroff JW, Overbeek TE, Morris CD, Grobbee DE. Calcium metabolism, calcium supplementation and hypertensive disorders of pregnancy. Eur J Obstet Gynecol Reprod Biol. 1995;59(1):5-16. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 232

83. Weiss AT, Lewis BS, Halon DA, Hasin Y, Gotsman MS. The use of calcium with verapamil in the management of supraventricular tachyarrhythmias. Int J Cardiol. 1983;4(3):275-284. 84. Wyshak G, Frisch RE. Carbonated beverages, dietary calcium, the dietary calcium/phosphorus ratio, and bone fractures in girls and boys. J Adolesc Health. 1994;15(3):210-215. 85. Zemel MB, Shi H, Greer B, Dirienzo D, Zemel PC. Regulation of adiposity by dietary calcium. FASEB. 2000;14:1132-1138. 86.Thys-Jacobs,S.et al. Calcium for Hypertension. AMER. J .OBSTET. GYNECOL. 1998, 179 (2) 444-52.

Magnesium 68 Studies
1. Rude RK. Magnesium deficiency: a cause of heterogeneous disease in humans. J Bone Miner Res. 1998 Apr;13(4):749-58. 2. Cohen JS. High-dose oral magnesium in the treatment of chronic, intractable erythromelalgia. Ann Pharmacother. 2002 Feb;36(2):255-60. 3. Iseri LT, French JH. Magnesium: natures physiologic calcium blocker. Am Heart J. 1984 Jul;108(1):18893. 4. Leppert J, Myrdal U, Hedner T, Edvinsson L, Tracz Z, Ringqvist I. Effect of magnesium sulfate infusion on circulating levels of noradrenaline and neuropeptide-Ylike immunoreactivity in patients with primary Raynauds phenomenon. Angiology. 1994 Jul;45(7):637-45. 5. Rogers SA. Tired or Toxic? A Blueprint for Health. Syracuse, NY: Prestige Publishing; 1990. 6. Altura BM, Altura BT. Magnesium in cardiovascular biology. Scientific American Science & Medicine. May/June 1995:28-37. 7. Altura BM, Altura BT. Role of magnesium in the pathogenesis of hypertension updated: relationship to its actions on cardiac, vascular smooth muscle, and endothelial cells. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis, and Management. 2nd ed. New York, NY: Raven Press; 1995. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 233

8. Motoyama T, Sano H, Fukuzaki H. Oral magnesium supplementation in patients with essential hypertension. Hypertension. 1989 Mar;13(3):22732. 9. Widman L, Wester PO, Stegmayr BK, Wirell M. The dosedependent reduction in blood pressure through administration of magnesium. A double-blind placebo-controlled crossover study. Am J Hypertens. 1993 Jan;6(1):41-5. 10. Sanjuliani AF, de Abreu Fagundes VG, Francischetti EA. Effects of magnesium on blood pressure and intracellular ion levels of Brazilian hypertensive patients. Int J Cardiol. 1996 Oct 11;56(2):177-83. 11. Itoh K, Kawasaka T, Nakamura M. The effects of high oral magnesium supplementation on blood pressure, serum lipids and related variables in apparently healthy Japanese subjects. Br J Nutr. 1997 Nov;78(5):737-50. 12. Kawano Y, Matsuoka H, Takishita S, Omae T. Effects of magnesium supplementation in hypertensive patients: assessment by office, home, and ambulatory blood pressures. Hypertension. 1998 Aug;32(2):2605. 13. Dyckner T, Wester PO. Effect of magnesium on blood pressure. Br Med J (Clin Res Ed). 1983 Jun 11;286(6381):1847-9. 14. Witteman JC, Grobbee DE, Derkx FH, Bouillon R, de Bruijn AM, Hofman A. Reduction of blood pressure with oral mag- nesium supplementation in women with mild to moderate hypertension. Am J Clin Nutr. 1994 Jul;60(1):129-35. 15. Seelig MS, Rosanoff A. The Magnesium Factor. New York, NY: Avery Publishers; 2003. 16. Johnson S. The multifaceted and widespread pathology of magnesium deficiency. Med Hypotheses. 2001 Feb;56(2):16370. 17. Galan P, Preziosi P, Durlach V, et al. Dietary magnesium intake in a French adult popula- tion. In: Theophanides T, Anastassopoulou J. Magnesium: Current Status and New Developments: Theoretical, Biological, and Medical Aspects. 1st ed. Dordrecht, Netherlands: Kluwer Academic Publishers; 1997. 18. Healy DP, Dansereau RJ, Dunn AB, Clendening CE, Mounts AW, Deepe GS Jr. Reduced tetracycline bioavailability caused by magnesium aluminum silicate in liquid formulations of bismuth subsalicylate. Ann Pharmacother. 1997;31:1460-1464. 19. June CH, Thompson CB, Kennedy MS, Loughran TP Jr, Deeg HJ. Correlation of hypomagnesemia with the onset of cyclosporine-associated hypertension in marrow transplant patients. Transplantation. 1986;41:47-51.

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20. Lajer H, Daugaard G. Cisplatin and hypomagnesemia. Cancer Treat Rev. 1999;25:4758. 21. Nanji AA, Denegri JF. Hypomagnesemia associated with gentamicin therapy. Drug Intell Clin Pharm. 1984;18:596-598. 22. Quamme GA. Renal magnesium handling: new insights in understanding old problems. Kidney Int. 1997;52:1180-1195. 23. Rivlin RS. Magnesium deficiency and alcohol intake: mechanisms, clinical significance and possible relation to cancer development (a review). J Am Coll Nutr. 1994;13:416-423. 24. Rob PM, Lebeau A, Nobiling R, et al. Magnesium metabolism: basic aspects and implications of ciclosporine [sic] toxicity in rats. Nephron. 1996;72:59-66. 25. Sadowski DC. Drug interactions with antacids. Mechanisms and clinical significance. Drug Saf. 1994;11:395-407. 26.Schaafsma G. Bioavailability of calcium and magnesium. Eur J Clin Nutr. 1997;51(Suppl 1):S13-S16. 27. Spencer H, Norris C, Williams D. Inhibitory effects of zinc on magnesium balance and magnesium absorption in man. J Am Coll Nutr. 1994;13:479-484.
28. Food Nutrition Board, Natl Acad Sci., Chapter3.1997.

29. Pao E.M, Mickle S.J. (1981) Food Technology35:58 30. Lakshmanan F.L., Rao R.B., Kim W.W., Kelsay J.L. (1984). Am J Clin Nutr.40:1380 31. Morgan K.J., Stampley G.L. (1988). Magnesium, 7:225 32. Morgan K.J., Stampley G.L., Zabik M.E., Fischer D.R. (I 985), J Am Coll Nutr.4: 195 33. Abdulla M., Behbehani A., Dashti H. (I 989) ed Itokawa Y., and Durlach J., Magnesium in Health and Disease, Publ. J. Libbey, London: III. 34. Pennington J.A., Young B.E. (1991). J Am Diet Assoc 91:179183. 35. Schmidt C.L.A., Greenberg D.M., Physiol Rev, 15: 297. 36. Hathaway F.W., Home Economics Research Report #19, Agricultural Research Service, Washington D.C., 1962.

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37. Seelig M. S. (1964). Am 3 Clin Nutr 14:342. 38. Irwin M.I., Feeley R.M. (1967) Am J Clin Nutr,20:816. 39. Spiller G.A., Jensen C.D., Whittam J.H. (1988). FASEBJ.,2:A1099. 40. Seelig M.S. (1980). Magnesium Deficiency in the pathogenesis of disease. Early Roots of Cardiovascular, Skeletal, and Renal Abnormalities. Pub] Plenum Press, NY, pp 41. Karppannen H. (1990). Magnesium Bulletin 12:80-86. 42. Simonen H. (1991). Calcif Tiss Res (Suppl) 49:S8. 43. Seelig M.S. (1990). Magnesium Res 3:197. 44. Weaver K. (1986).Magnesium 5:191200. 45. Hwang DL, Yen CF, Nadler JL (1992). Am J Hypertens 5:700. 46. Seelig M.S. (1993). J Am Coll Nutr 12:442- 458. 47. Seelig M.S. (1994). J Am Coll Nutr 12:429. 48. Farago, M., Szabo, C., Dora, E., et al (1991). J Cerebr Blood Flow Metab 11:161. 49. Gormican A, Catli, E [1971] Nutr Metab 13:364-377. 50. Whyte K.F., Addis G.J., Whitesmith R., Reid J.L. (1987). Clin Sci 72:135. 51. Resnick L.M. (1992). Am J Med 93(2A): 11S20S. 52. Barbagallo M., Novo S., Licata G., Resnick L.M. (1993). Intl Angiol 12:365370. 53. Rueddel H., Baehr M., Schaechinger H., Schmieder R., Ising G. (1989). Magnesium Bulletin 11:9398. 54. Parlier R., Hioco D., LeBlanc R. (I 963). Rev Franc Endocr Clin, 4:93.31 55. Leichsenring J.M., Norris L.M., Lamison S.A. (1951) J Nutr 45:477. 56. Briscoe A.M., Ragan C. (1966). Am J Clin Nutr, 19:296. 57. Lichton, J (1989). Magnesium 8:117. 58. Fatemi S, Ryzen E, Flores J, Endres DB, Rude RK (1991). J Clin Endocrinol Metab 73:1067. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 236

59. Kimura M., Nagai, K, Itokawa, Y. (1989). In Magnesium in Health and Disease. eds Itokawa Y, Durlach J, Publ J. Libbey, London: 63. 60. Wang, R., Flink, E.B., Dyckner, T. et al. (1985): Magnesium depletion as a cause of refractory potassium repletion Arch. Intern. Med. 145, 1686. 61. Hasselbach, W., Makinose, M. (1961): Die Calciumpumpe des Muskels und ihre Abhngigkeit von der ATP-Spaltung Biochem. Z. 333, 518. 62. Achenbach, C., Daying, H., Schweikart, P. et al. (1991): Unterschiedliche Effekte von Mg, Ca, Mn und Nifedipin auf den Na/Ca-Austausch whrend des Aktionspotentials der Herzmuskelzelle. Int. Symposium Edinburgh New approaches in the Pathophysiology and Treatment of Cardiovascular Disease. 63. Dyckner T., Wester, P.O. (1979): Ventricular extrasystoles and intracellular electrolytes before and after potassium and magnesium infusions in patients on diuretic treatment Am. Heart J. 97, 12. 64. Schroll, A. (1981): Optimierte Magnesium-Substitution bei extrakorporaler Zirkulation Mg. Bull. 3, 163. 65. Schroll, A. (1986): Magnesium in open heart surgery: its role in ischemia and arrhythmia Internat. Symposium on Anaesthesia for Cardiac Patients, Mnchen. 66. Wischnik, A., Schroll A., Kollmer, W.E. et al. (1982): Magnesium-aspartat als Kardioprotektivum und Adjuvans bei Tokolyse mit Betamimetika Z. Geburtsh. und Perinat. 186, 326. 67. Borman, B. von, Scheld, H.H., Kling, D. et al. (1983): Concentrations of cations in the tissue of papillary muscle under different modes of supplementation 5th Annual Meeting of the Society of Cardiovascular Anesthesiologists, San Diego. 68. Kahles, H., Riegger, A.J.G., Kromer, E.P. et al. (1991): Wirkungen von hochdosiertem Magnesium-aspartat wahrend Koronarangioplastie Deutscher Ansthesiekongre Mannheim.

Ginkgo Biloba 33 Studies


1. Antagonistic effects of extract from leaves of Ginkgo biloba on glutamate neurotoxicity. Zhu L Wu J Liao H Gao J Zhao XN Zhang ZX Acta Pharmacol Sin 1997 JUL;18(4):344 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 237

Zhu L, Nanjing Univ, Sch Med, Nanjing 210093, PEOPLES R CHINA 2. Attenuation of salicylate-induced tinnitus by Ginkgo biloba extract in rats. Jastreboff PJ Zhou ST Jastreboff MM Kwapisz U Gryczynska U Audiol Neuro Otol 1997 JUL-AUG;2(4):197-212 Jastreboff PJ, Univ Maryland, Sch Med, Dept Surg, Tinnitus & Hyperacusis Ctr, 10 S Pine St, Mstf Bldg, RM 436, Baltimore,MD 21201 USA 3. Phospholipid breakdown and choline release under hypoxic conditions: Inhibition by bilobalide, a constituent of Ginkgo biloba. Klein J Chatterjee SS Loffelholz K Brain Res 1997 MAY 2;755(2):347-350 Klein J, Univ Mainz, Dept Pharmacol, Obere Zahlbacher Str 67, D 55101 Mainz, GERMANY 4. Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multiinfarct dementia (Reprinted f rom Pharmacopsychiat, vol 29, pg 47-56, 1996). Kanowski S Herrmann WM Stephan K Wierich W Horr R Phytomedicine 1997 MAR;4(1):3-13 Kanowski S, Free Univ Berlin, Klinikum Benjamin Franklin, ABT Gerontopsychiat, Dept Gerontopsychiat, D 14050 Berlin, GERMANY 5. Effect of Ginkgo biloba extract (EGb 761) on the vasospastic response of mouse cutaneous arterioles to platelet activation. Stucker O Pons C Duverger JP Drieu K DArbigny P Int J Microcirc Clin Exp 1997 MAR-APR;17(2):61-66 Stucker O, Cerom, 155 Rue Faubourg St Denis, F 75010 Paris, FRANCE 6. Agnoli, A., J. R. Rapin, V. Scapagnini, and W. V. Weitbrecht (eds.). 1985. Effects of Ginkgo Biloba Extract on Organic Cerebral Impairment. London: John Libbey Eurotext, Ltd. 7. Bauer, U. 1984. Six-month Double-blind Randomized Clinical Trial of Ginkgo Biloba Extracts Versus Placebo in Two Parallel Groups in Patients Suffering from Peripheral Arterial Insufficiency. Arzneim-Forsch. 34: 716-721. 8. Boralle, N., P. Braquet and O. R. Gottlieb. 1988. Chemical Composition of Ginkgo. In P. Braquet (ed.) 1988. Op. cit. Pp. 9-25. 9. Braquet, P. 1985. BN 52021 and related compounds: A new series of highly specific PAF-Acether receptor antagonists isolated from Ginkgo biloba. Blood Vessels. 16: 559572. 10. Braquet, P. (ed.) 1988. Ginkgolides-Chemistry, Biology, Pharmacology and Clinical Perspectives. Vol. I. Barcelona, Spain: J. R. Prous. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 238

11. Chatterjee, S. S. 1985. Effects of Ginkgo Biloba Extract on Cerebral Metabolic Processes. In A. Agnoli, J. R. Rapin, V. Scapagnini, and W. V. Weitbrecht (eds.) 1985. Op. cit. Pp. 5-15. 12. Chung, K. F. and P. J. Barnes. 1988. Clinical Perspectives of PAF-Acether Antagonists. In P. Braquet (ed.) 1988. Op. cit. Pp. 333-344. 13. Claussen, C. F. 1988. Diagnostic and Practical Value of Craniocopography in Vertiginous Syndromes. In E. W. Funfgeld (ed.) 1988. Op. cit. pp. 251-259. 14. Cory, E. J., M. C. Kang, M. C. Desai, A. K. Ghosh, and I. N. Houpis. 1988. Total Synthesis of Ginkgolide B. J. Am. Chem. Soc. 110: 649-651. 15. DeFeudis, F. V. 1991. Ginkgo biloba Extract (EGb 761): Pharmacological Activities and Clinical Applications. Amsterdam: Elsevier. 16. Drieu, K. 1985. Multiplicity of effects of Ginkgo Biloba Extract: Current status and new trends. In A. Agnoli, J.R. Rapin, V. Scapagini, and W. V. Weitbrecht (eds.). Op. cit. Pp. 63-68. 17. Drieu, K. 1988. Preparation and Definition of Ginkgo Biloba. Extract. In E. W. Funfgeld (ed.) 1988. Op. cit. pp. 32-36. 18. Funfgeld, E. W. (ed.) 1988. Rokan (Ginkgo biloba), Recent Results in Pharmacology, and Clinic. Berlin: Springer-Verlag. 19. Hindmarch, I. 1988. Activity of Ginkgo Biloba Extract on Short-term Memory. In E. W. Funfgeld (ed.) 1988. Op. cit. Pp. 321-326. 20. Huh, H. and E. J. Staba. 1992. The Botany and Chemistry of Ginkgo biloba L. Journal of Herbs, Spices & Medicinal Plants. 1(1/2):91-124. 21. Kleijnen, J. and P. Knipschild. 1992. Ginkgo biloba for cerebral insufficiency. Br. J. Clin. Pharmac. 34:352-358. 22. Leung, A. 1990. Personal communication, Feb. 13. 23. Li, H. L. 1956. A Horticultural and Botanical History of Ginkgo. Morris Arb. Bull. 7:3-12. 24. Liberti, L. (ed.) 1988. Ginkgo. The Lawrence Review of Natural Products. Feb. 1988. 25. Meyer, B. 1988. A Multicenter Randomized Double-Blind Study of Ginkgo Biloba Extract Versus Placebo in the Treatment of Tinnitus. In E. W. Funfgeld (ed.) 1988. Op. cit. Pp. 245-250.

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26. Michel, P. F. and D. Hosford. 1988. Ginkgo Biloba: From "Living Fossil" to Modern Therapeutic Agent. In P. Braquet (ed.) 1988. Op. cit. pp.1-8. 27. Nakanishi, K. 1988. Ginkgolides - Isolation and Structural Studies Carried out in the Mid-1960s. In P. Braquet (ed.) 1988. Op. cit. pp. 27-36. 28. Pincemail, J. and C. Deby. 1988. The Antiradical Properties of Ginkgo Biloba Extract. In E. W. Funfgeld (ed.) 1988. Op. cit. pp. 71-182. 29. Schaffler, V. K. and P. W. Reeh. 1985. Double-blind Study of the Hypoxia-protective Effect of a Standardized Ginkgo Biloba Preparation after Repeated Administration in Healthy Volunteers. Arzneim-Forsch. 35: 1283-1286. 30. Stalleicken, D. and P. Ihm. 1989. Observation of the Course of Cognitive Deficits. Results of a Multicenter Study Involving Psychological Test Operations. Neurologie Psychiatrie. Special Issue 1: 64-69. 31. Vorberg, G. 1985. Ginkgo Biloba Extract (GBE): A Long-term Study of Chronic Cerebral Insufficiency in Geriatric Patients. Clinical Trials Journal 22:149-157. 32. Warburton, D. M. 1988. Clinical Psychopharmacology of Ginkgo Biloba Extract. In E. W. Funfgeld (ed.) 1988. Op. cit. pp. 327-345. 33. Weiss, R. F. 1989. Herbal Medicine. Beaconsfeld, England: Beaconsfield Publishers Ltd.

L-Phenylalanine 33 Studies
1. Plasma tryptophan and five other amino acids in depressed and normal subjects. Archives of General Psychiatry 38(6):642-646, 1981 2. Trace amine deficit in depressive illness: the phenylalanine connexion. Acta Psychiatrica Scandinavica 61(Suppl. 280):29-39, 1980 3. Phenylalanine levels in endogenous psychoses. Psychiatrie, Neurologie und Medizinische Psychologie 32(10):631-633, 1980 4. Evaluation of the relative potency of individual competing amino acids to tryptophan transport in endogenously depressed patients. Psychiatry Research 3(2):141-150, 1980 5. Amino acids in mental illness. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 240

Biological psychiatry today. Vol. B Amsterdam, Elsevier/North Holland, 1979, p1581-4 6. Depression, pregnancy and phenylalanine. Neuropisiquiatria (Buenos Aires) 8(1):60-64, 1977 7. Theoretical and therapeutic potential of indoleamine precursors in affective disorders. Neuropsychobiology (Basel) 3(4):199-233, 1977 8. Phenylethylamine and glucose in true depression. Journal of Orthomolecular Psychiatry (Regina) 5(3):199-202, 1976 9. Therapeutic action of D-phenylalanine in Parkinson's disease. Arzneimittel-Forschung (Aulendorf) 26(4):577-579, 1976 10. Effects of D-phenylalanine on clinical picture and phenethylaminuria in depression. Biological Psychiatry 10(2):235-239, 1975 11. Phenylalanine for endogenous depression. Joof Orthomolecular Psychiatry (Regina) 3(2):80-81, 1974 12. Antoniou C, Katsambas A. Guidelines for the treatment of vitiligo. Drugs. 1992;43(4):490-498. 13. Bugard P, Bremer HJ, Buhrdel P, et al. Rationale for the German recommendations for phenylalanine level control in phenylketonuria 1997. Eur J Pediatr. 1999;158:4654. 14. Burkhart CG, Burkhart CN. Phenylalanine with UVA for the treatment of vitiligo needs more testing for possible side effects. J Am Acad Dermatol. 1999;40(6 Pt 1):1015. 15. Camacho F, Mazuecos J. Treatment of vitiligo with oral and topical phenylalanine: 6 years of experience. Arch Dermatol. 1999;135(2):216-217. 16. Cejudo-Ferragud E, Nacher A, Polache A, Ceros-Fortea T, Merino M, Casabo VG. Evidence of competitive inhibition for the intestinal absorption of baclofen by phenylalanine. Int J Pharmaceutics. 1996;132:63-69. 17. Cormane RH, Siddiqui AH, Westerhof W, Schutgens RB. Phenylalanine and UVA light for the treatment of vitiligo. Arch Dermatol Res. 1985;277(2):126-130. 18. Fugh-Berman A, Cott JM. Dietary supplements and natural products as psychotherapeutic agents. Psychomatic Med. 1999;61:712-728. 19. Kovacs SO. Vitiligo. J Am Acad Dermatol. 1998 May;38(5 Pt 1):647-666.

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20. Meyers S. Use of neurotransmitter precursors for treatment of depression. Alt Med Rev. 2000;5(1):64-71. 21. Pietz J. Neurological aspects of adult phenylketonuria. Curr Opin Neurol. 1998;11:679688. 22. Pietz J, Dunckelmann R, Rupp A, et al. Neurological outcome in adult patients with early-treated phenylketonuria. Eur J Pediatr. 1998;157:824830. 23. Rezvani I. Defects in metabolism of amino acids; Phenylalanine. In: Behrman RE, Kliefman RM, and Jenson HB, eds. Nelson Textbook of Pediatrics. 16th ed. Philadelphia, PA: W.B. Saunders Company; 2000: 344-346. 24. Russell AL, McCarty MF. DL-phenylalanine markedly potentiates opiate analgesia an example of nutrient pharmaceutical up-regulation of the endogenous analgesia system. Med Hypotheses. 2000;55(4):283-288. 25. Sabelli HC, Fawcett J, Gusovsky F, et al. Clinical studies on the phenylethylamine hypothesis of affective disorder: urine and blood phenylacetic acid and phenylalanine dietary supplements. J Clin Psychiatry. 1986;47:66-70. 26. Schallreuter KU, Zschiesche M, Moore J, et al. In vivo evidence for compromised phenylalalanine metabolism in vitiligo. Biochem Biophys Res Commun. 1998;243(2):395399. 27. Schulpis CH, Antoniou C, Michas T, Strarigos J. Phenylalanine plus ultraviolet light: preliminary report of a promising treatment for childhood vitiligo. Pediat Dermatol. 1989;6(4):332-335. 28. Shils ME, Olson JA, Shike M, Ross AC. Modern Nutrition in Health and Disease. 9th ed. Baltimore, Md: Williams & Wilkins; 1999(41):1010. 29. Siddiqui AH, Stolk LM, Bhaggoe R, et al. L-phenylalanine and UVA irradiation in the treatment of vitiligo. Dermatology. 1994;188(3):215-218. 30. Start K. Treating phenylketonuria by a phenylalanine-free diet. Prof Care Mother Child. 1998;8:109110. 31. Walsh NE, Ramamurthy S, Schoenfeld L, Hoffman J. Analgesic effectiveness of Dphenylalanine in chronic pain patients. Arch Phys Med Rehabil. 1986;67(7):436-439. 32. Werbach MR. Nutritional Influences on Illness. 2nd ed. Tarzana, Calif: Third Line Press; 1993:159160, 384, 434, 494495, 506, 580, 613614, 636.

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33. Woodward WR, Olanow CW, Beckner RM, et al. The effect of L-dopa infusions with and without phenylalanine challenges in parkinsonian patients: Plasma and ventricular CSF L-dopa levels and clinical responses. Neurol. 1993;43:1704-1708.

L-Glutathione 67 Studies
1. Medical Hypotheses (1999) 53(4): 347-349 - 1999 Harcourt Publishers Ltd. - Article No. mehy. 1998.0780 Competition For Glutathione Precursors Between The Immune System And The Skeletal Muscle: Pathogenesis Of Chronic Fatigue Syndrome G. Bounous1, J Molson2 2. Anticancer Research 15: 2643-2650, 1995 The Use of a Whey Protein Concentrate in the Treatment of Patients with metastatic Carcinoma: A Phase I-II Clinical Study RENEE S. KENNEDY1, GEORGE P. KONOK1, GUSTAVO BOUNOUS2, SYLVAIN BARUCHEL3 and TIMOTHY D.G. LEE4 3. Clin Invest Med, 16: 204-209, 1993 Whey Proteins As A Food Supplement In HIV-Seropositive Individuals G. Bounous, S. Baruchel, J. Falutz, P. Gold 4. Clin Invest Med, 14: 296-309, 1991 The Biological Activity Of Undenatured Dietary Whey Proteins: Role Of Glutathione. G. Bounous, P. Gold 5. Cancer Letters, 57: 91-94, 1991 Whey Proteins In Cancer Prevention G. Bounous*, G. Batist** and P. Gold*** 6. Tumor Biol 11: 129-136, 1990 Dietary Milk Proteins Inhibit the Development of Dimethylhydrazine-Induced Malignancy R. Papenburga, G. Bounousa, D. Fleiszera, P. Goldb 7. Clin Invest Med, 12: 343-349, 1989 The Influence Of Dietary Whey Protein On Tissue Glutathione And The Diseases Of Aging Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 243

Gustavo Bounous, Francine Gervais,Victor Amer, Gerald Batist, and Phil Gold. 8. Clin Invest Med, 12: 154-61, 1989 Immunoenhancing Property Of Dietary Whey Protein In Mice: Role Of Glutathione G. Bounous, G. Batist, P. Gold 9. Clinical and Investigative Medicine, Vol. 11,.No. 4,.pp 271-278,. 1988. The Immunoenhancing Property Of Dietary Whey Protein Concentrate Gustavo Bounous, Patricia A.L. Kongshavn, and Phil Gold. 10. Clin Inv Med, 11: 213-217, 1988 Dietary Whey Protein Inhibits the Development of Dimethylhydrazine-Induced Malignancy G. Bounous, R. Papenburg, P.A.L Kongshavn, P. Gold, and D. Fleiszer. 11. J. Nutr. 115: 1409-1417, 1985 Mechanism Of Altered B-Cell Response Induced By Changes In Dietary Protein Type In Mice G. Bounous, N. Shenouda,* P.A.L. Kongshavn and D.G. Osmond* 12. J. Nutr. 115: 1403-1408, 1985. Differential Effect of Dietary Protein Type on the B-Cell and T-Cell Immune Responses in Mice Gustavo Bounous and Patricia A.L. Kongshavn. 13. J. Nutr. 113: 1415-1421, 1983 Influence Of Dietary Protein Type On The Immune System Of Mice G. Bounous, L. Ltourneau and P.A.L. Kongshavn. 14. Minerva Dietol Gastroenterol 35(4): 241-5, 1989 Changes in Biliary Secretory Immunoglobulins A in Mice Fed Whey Proteins Costantino AM, Balzola F, Bounous G. 15. Oxidative Stress, Cell Activation and Viral infection C. Pasquier et al. (eds) 1994 Birkhuser Verlag Basel/Switzerland Place For An Antioxidant Therapy In Human Immunodeficiency Virus (HIV) Infection 16, J. Nutr. 112:1747-1755, 1982. - Reprinted from The Journal of Nutrition Vol. 112, no. 9, September 1982 The American Institute of Nutrition 1982 Influence Of Dietary Proteins On The Immune System Of Mice. 17. The Journal of Infectious Diseases, 144: 281, 1981 Influence Of Dietary Lactalbumin Hydrolysate On The Immune System Of Mice And Resistance To Salmonellosis Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 244

G. Bounous, M.M. Stevenson*, P.A.L. Kongshavn. 18. Journal of Applied Physiology, 87: 1381-1385, 1999 The Effect Of Supplementation With A Cysteine Donor On Muscular Performance LC Lands, MD, PhD*, VL Grey, PhD, AA Smountas, BSc. 19. Accepted for publication in Chest Treatment Of Obstructive Airway Disease With A Cysteine Donor Protein Supplement: A Case Report Bryce Lothian, MD, Vijaylaxmi Grey, PhD, R. John Kimoff, MD, Larry Lands, MD, PhD. 20. PR514 Treatment Of Chronic Hepatitis Using Whey Protein (Non-Heated) A. Watanabe, K. Higuchi, K. Okada, Y. Shimizu, Y. Kondo* and H. Kohri. 21. Anticancer Research 20: 4785-4792, 2000. Whey Protein Concentrate (WPC) and Glutathione Modulation in Cancer Treatment Gustavo Bounous, M.D. 22. Accepted for publication in Nutrition and Cancer, Vol 38, Issue #2 Enhancing Effect of Patented Whey Protein Isolate (IMMUNOCAL) on the Cytotoxicity of Anti-cancer Drug Wayne Y. Tsai, Wen-Huei Chang, Ching-Hsein Chen, and Fung-Jou Lu Department of Biochemistry, College of Medicine National Taiwan University, Taipei, Taiwan, R.O.C. 23. Oxidative Stress in Cancer, AIDS, and Neurodegenerative Diseases Luc Montagnier et al., (Ed.) Marcel Dekker Inc., New York: 447-461, 1998 Nutriceutical Modulation Of Glutathione With A Humanized Native Milk Serum Protein Isolate, Immunocal: Application In AIDS And Cancer. S. Baruchel, G. Viau, R. Olivier, G. Bounous, M.A. Wainberg. 24. Anderson ME, Luo JL. Glutathione therapy: from prodrugs to genes. Semin Liver Dis. 1998; 18:415-424. 25. Aw TW, Wierzbicka G, Jones DP. Oral glutathione increases tissue glutathione in vivo. Chem Biol Interact. 1991; 80:89-97. 26. Bains JS, Shaw CA. Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death. Brain Res Brain Res Rev. 1997; 25:335-358.

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40. Hayes JD, McLellan LI. Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defence against oxidative stress. Free Rad Res. 1999; 31:273300. 41. Hayes JD, Strange RC. Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology. 2000; 61:154-166. 42. Hercbergs A, Brok-Simoni F, Holtzman F, et al. Erythrocyte glutathione and tumor response to chemotherapy. Lancet. 1992; 339:1074-1076. 43. Holroyd KJ, Buhl R, Borok Z, et al. Correction of glutathione deficiency in the lower respiratory tract of HIV seropositive individuals by glutathione aerosol treatment. Thorax. 1993; 48:985-989. 44. Hwang C, Sinskey AJ, Lodish HF. Oxidized redox state of glutathione in the endoplasmic reticulum. Science. 1992; 257:1496-1502. 45. Janaky R, Ogita K, Pasqualotta BA, et al. Glutathione and signal transduction in the mammalian CNS. J Neurochem. 1999; 73:889-902. 46. Lash LH, Hagen TM, Jones DP. Exogenous glutathione protects intestinal epithelial cells from oxidative injury. Proc Natl Acad Sci USA. 1986; 83:4641-4645. 47.Lenzi A, Culasso F, Gandini L, et al. Placebo-controlled, double-blind, cross-over trial of glutathione therapy in male infertility. Hum Reprod. 1993; 8:1657-1662. 48. Lenzi A, Picardo M, Gandini L, et al. Glutathione treatment of dyspermia: effect on the lipoperoxidation process. Hum Reprod. 1994; 9:2044-2050. 49. Loguercio C, Di Pierro M. The role of glutathione in the gastrointestinal tract: a review. Ital J Gastroenterol Hepatol. 1999; 31:401-407. 50. Lyons J, Rauh-Pfeiffer A, Yu YM, et al. Blood glutathione synthesis rates in healthy adults receiving a sulfur amino acid-free diet. Proc Natl Acad Sci USA. 2000; 97:50715076. 51. Martensson J, Jain A, Meister A. Glutathione is required for intestinal function. Proc Natl Acad Sci USA. 1990; 87:1715-1719. 52. Meister A. On the antioxidant effects of ascorbic acid and glutathionine. Biochem Pharmacol. 1992; 44:1905-1915. 53. Murphy ME, Scholich H, Sies H. Protection by glutathione and other thiol compounds against the loss of protein thiols and tocopherol homologs during microsomal lipid peroxidation. Eur J Biochem. 1992; 210:139-146.

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54. Rahman I, MacNee W: Regulation of redox glutathione levels and gene transcription in lung inflammation: therapeutic approaches. Free Radic Biol Med 2000, 28:1405-1420. 55. Nagasawa HT, Cohen JF, Holleschau AM, Rathbun WB. Augmentation of human and rat lenticular glutathione in vitro by prodrugs of gamma-L-glutamyl-L-cysteine. J Med Chem. 1996; 39:1676-1681. 56. Novi AM. Regression of aflatoxin B1-induced hepatocellular carcinomas by reduced glutathione. Science. 1981; 212:541-542. 57. Ohinataab Y, Yamasobac T, Schachta J, Millera JM. Glutathione limits noise-induced hearing loss. Hear Res. 2000; 146:28-34. 58. Palamara AT, Perno C-F, Ciriolo MR, et al. Evidence for antiviral activity of glutathione: in vitro inhibition of herpes simplex virus type 1 replication. Antiviral Res. 1995; 27:237-253. 59. Paolisso G, Giugliano D, Pizza G, et al. Glutathione infusion potentiates glucoseinduced insulin secretion in aged patients with impaired glucose tolerance. Diabetes Care. 1992; 15:1-7. 60. Roum JH, Borok Z, McElvaney NG, et al. Glutathione aerosol suppresses lung epithelial surface inflammatory cell-derived oxidants in cystic fibrosis. J Appl Physiol. 1999; 87:438-443. 61. Samiec PS, Drews-Botsch C, Flagg EW, et al. Glutathione in human plasma: decline in association with aging, age-related macular degeneration, and diabetes. Free Radic Biol Med. 1998; 24:699-704. 62. Schmidinger M, Budinsky AC, Wenzel C, et al. Glutathione in the prevention of cisplatin induced toxicities. A prospectively randomized pilot trial in patients with head and neck cancer and non small cell lung cancer. Wien Klin Wochenschr. 2000; 112:617623. 63. Shaw CA, ed. Glutathione in the Nervous System. London: Taylor and Francis; 1998. 64. Sies H. Glutathione and its role in cellular functions. Free Rad Biol Med. 1999; 27:916-921. 65. Smyth JF, Bowman A, Perren T, et al. Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of a double-blind, randomized trial. Ann Oncol. 1997; 8:569-573.

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L-Taurine 94 Studies
1. Arzneimittelforschung. 1993 Mar;43(3):308-12. Effects on heart membranes after taurine treatment in rabbits with congestive heart failure. Elizarova EP, Orlova TR, Medvedeva NV. 2. Jpn Circ J. 1992 Jan;56(1):95-9. Usefulness of taurine in chronic congestive heart failure and its prospective application. Azuma J, Sawamura A, Awata N. Third Department of Internal Medicine, Osaka University Medical School, Japan. 3. Kardiologiia. 1991 Jun;31(6):77-80. (Animal Study) [Use of taurine in the treatment of experimental congestive heart failure] [Article in Russian] Orlova TsR, Elizarova EP, Ryff IM, Fetisova NI, Mit'kina LI. 4. Am Heart J. 1986 Dec;112(6):1278-84. (Animal Study) Beneficial effect of taurine in rabbits with chronic congestive heart failure. Takihara K, Azuma J, Awata N, Ohta H, Hamaguchi T, Sawamura A, Tanaka Y, Kishimoto S, Sperelakis N. 5. Clin Cardiol. 1985 May;8(5):276-82. Therapeutic effect of taurine in congestive heart failure: a double-blind crossover trial. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 249

Azuma J, Sawamura A, Awata N, Ohta H, Hamaguchi T, Harada H, Takihara K, Hasegawa H, Yamagami T, Ishiyama T, et al. 6. Res Commun Chem Pathol Pharmacol. 1984 Aug;45(2):261-70. (Animal Study) Beneficial effect of taurine on congestive heart failure induced by chronic aortic regurgitation in rabbits. Azuma J, Takihara K, Awata N, Ohta H, Sawamura A, Harada H, Kishimoto S. 7. Clin Ther. 1983;5(4):398-408. Therapy of congestive heart failure with orally administered taurine. Azuma J, Hasegawa H, Sawamura A, Awata N, Ogura K, Harada H, Yamamura Y, Kishimoto S. 8. Physiol Chem Phys. 1977;9(3):259-63. (Animal Study) A relation between myocardial taurine contest and pulmonary wedge pressure in dogs with heart failure. Newman WH, Frangakis CJ, Grosso DS, Bressler R. 9. Amino Acids. 2002;23(4):381-93. Treatment of hypertension with oral taurine: experimental and clinical studies. Militante JD, Lombardini JB. Department of Pharmacology, Texas Tech University Health Sciences Center, Lubbock, Texas, USA. 10. Poult Sci. 2001 Nov;80(11):1607-18. (Animal Study) Taurine, cardiopulmonary hemodynamics, and pulmonary hypertension syndrome in broilers. Ruiz-Feria CA, Wideman RF Jr. Department of Poultry Science, University of Arkansas, Fayetteville 72701, USA. cruizfe@hotmail.com 11. Amino Acids. 2000;19(3-4):643-65. (Animal Study)

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Effects of high salt diets and taurine on the development of hypertension in the strokeprone spontaneously hypertensive rat. Dawson R Jr, Liu S, Jung B, Messina S, Eppler B. Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville 32610, USA. dawson@cop.health.ufl.edu 12. Amino Acids. 2000;19(3-4):643-65. (Animal Study) Effects of high salt diets and taurine on the development of hypertension in the strokeprone spontaneously hypertensive rat. Dawson R Jr, Liu S, Jung B, Messina S, Eppler B. Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville 32610, USA. dawson@cop.health.ufl.edu 13. Hypertens Res. 2000 May;23(3):277-84. Oral taurine supplementation prevents the development of ethanol-induced hypertension in rats. Harada H, Kitazaki K, Tsujino T, Watari Y, Iwata S, Nonaka H, Hayashi T, Takeshita T, Morimoto K, Yokoyama M. First Department of Internal Medicine, Kobe University School of Medicine, Japan. 14. Can J Physiol Pharmacol. 1999 Oct;77(10):749-54. (Animal Study) Taurine attenuates hypertension and improves insulin sensitivity in the fructose-fed rat, an animal model of insulin resistance. Anuradha CV, Balakrishnan SD. Department of Biochemistry, Annamalai University, Annamalai Nagar, Tamil Nadu, India. 15. Poult Sci. 1999 Nov;78(11):1627-33. (Animal Study) Plasma taurine levels in broilers with pulmonary hypertension syndrome induced by unilateral pulmonary artery occlusion. Ruiz-Feria CA, Beers KW, Kidd MT, Wideman RF Jr.

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Department of Poultry Science, University of Arkansas, Fayetteville 72701, USA. cruizfe@comp.uark.edu 16. J Hypertens. 1994 Jun;12(6):653-61. (Animal Study) Taurine amplifies renal kallikrein and prevents salt-induced hypertension in Dahl rats. Ideishi M, Miura S, Sakai T, Sasaguri M, Misumi Y, Arakawa K. Department of Internal Medicine, Fukuoka University School of Medicine, Japan. 17. Cardiovasc Res. 1988 May;22(5):351-8. (Animal Study) Retardation of the development of hypertension in DOCA salt rats by taurine supplement. Inoue A, Takahashi H, Lee LC, Sasaki S, Kohno Y, Takeda K, Yoshimura M, Nakagawa M. 2nd Department of Medicine, Kyoto Prefectural University of Medicine, Japan. 18. Hypertension. 1987 Oct;10(4):383-9. Inhibition of hypertension and salt intake by oral taurine treatment in hypertensive rats. Abe M, Shibata K, Matsuda T, Furukawa T. Department of Pharmacology, School of Medicine, Fukuoka University, Japan. 19. Jpn Heart J. 1983 Jan;24(1):91-102. Decrease of urinary taurine in essential hypertension. Kohashi N, Katori R. 20. Amino Acids. 2002;22(1):27-38. Taurine modulates kallikrein activity and glucose metabolism in insulin resistant rats. Nandhini AT, Anuradha CV. Department of Biochemistry, Faculty of Science, Annamalai University, Tamil Nadu, India. 21. Drug Chem Toxicol. 2001 Nov;24(4):429-37.

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Protective role of vitamin E, 2-deoxy-D-glucose, and taurine on perchloroethylene induced alterations in ATPases. Ebrahim AS, Babu E, Thirunavukkarasu C, Sakthisekaran D. Department of Medical Biochemistry, Dr. ALM Post-Graduate Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai 600113, India. 22. Diabetes. 2003 Feb;52(2):499-505. (Animal Study) Comparative trial of N-acetyl-cysteine, taurine, and oxerutin on skin and kidney damage in long-term experimental diabetes. Odetti P, Pesce C, Traverso N, Menini S, Maineri EP, Cosso L, Valentini S, Patriarca S, Cottalasso D, Marinari UM, Pronzato MA. Department of Internal Medicine, University of Genova, Italy. 23. Diabetes Metab Res Rev. 2001 Sep-Oct;17(5):330-46. The role of taurine in diabetes and the development of diabetic complications. Hansen SH. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Denmark. shhansen@rh.dk 24. Cardiovasc Res. 2000 Jun;46(3):393-402. The role of taurine in the pathogenesis of the cardiomyopathy of insulin-dependent diabetes mellitus. Militante JD, Lombardini JB, Schaffer SW. Department of Pharmacology, Texas Tech University, Health Sciences Center, Lubbock 79430, USA. 25. Adv Exp Med Biol. 2000;483:497-501. (Animal Study) Taurine fluxes in insulin dependent diabetes mellitus and rehydration in streptozotocin treated rats. Rose SJ, Bushi M, Nagra I, Davies WE. Department of Paediatrics, Heartlands Hospital, Birmingham, England.

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26. Am J Clin Nutr. 2000 Jan;71(1):54-8. (Animal Study) Taurine improves insulin sensitivity in the Otsuka Long-Evans Tokushima Fatty rat, a model of spontaneous type 2 diabetes. Nakaya Y, Minami A, Harada N, Sakamoto S, Niwa Y, Ohnaka M. Department of Nutrition, Tokushima University, School of Medicine, Tokushima, Japan. nakaya@nutr.med.tokushima-u.ac.jp 27. Adv Exp Med Biol. 1998;442:163-8. (Animal Study) Effects of taurine supplementation on lipid peroxidation, blood glucose and blood lipid metabolism in streptozotocin-induced diabetic rats. You JS, Chang KJ. Department of Food Nutrition, Inha University, Inchon, Korea. 28. Eur J Pharmacol. 1996 May 6;303(1-2):47-53. (Animal Study) Restoration of endothelium-dependent relaxation in both hypercholesterolemia and diabetes by chronic taurine. Kamata K, Sugiura M, Kojima S, Kasuya Y. Department of Physiology and Morphology, Hoshi University, Tokyo, Japan. 29. Am J Physiol. 1995 Sep;269(3 Pt 2):F429-38. (Animal Study) Taurine ameliorates chronic streptozocin-induced diabetic nephropathy in rats. Trachtman H, Futterweit S, Maesaka J, Ma C, Valderrama E, Fuchs A, Tarectecan AA, Rao PS, Sturman JA, Boles TH, et al. Department of Pediatrics, Schneider Children's Hospital, Long Island Jewish Medical Center, Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA. 30. Biochem Biophys Res Commun. 1993 Mar 15;191(2):759-65. (Animal Study) Taurine prevents glucose-induced lipid peroxidation and increased collagen production in cultured rat mesangial cells. Trachtman H, Futterweit S, Bienkowski RS. Division of Nephrology, Schneider Children's Hospital, New Hyde Park, NY 11042. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 254

31. Biochem Med Metab Biol. 1990 Feb;43(1):1-9. (Animal Study) Supplemental taurine in diabetic rats: effects on plasma glucose and triglycerides. Goodman HO, Shihabi ZK. Department of Pediatrics, Bowman Gray School of Medicine, Winston-Salem, North Carolina 27103. 32. Probl Endokrinol (Mosk). 1987 Mar-Apr;33(2):63-6. [Effect of taurine on the functional status of the insular apparatus and adrenal cortex of the rat with experimental diabetes] [Article in Russian] Mizina TIu, Dokshina GA. 33. Psychopharmacology (Berl). 1989;98(3):316-20. (Animal Study) Effect of ICV taurine on the impairment of learning, convulsions and death caused by hypoxia. Malcangio M, Bartolini A, Ghelardini C, Bennardini F, Malmberg-Aiello P, Franconi F, Giotti A. Department of Preclinical and Clinical Pharmacology, University of Florence, Firenze, Italy. 34. Eur J Pharmacol. 1986 Jan 21;120(2):235-9. Protective effect of taurine against decline of cardiac slow action potentials during hypoxia. Sawamura A, Sperelakis N, Azuma J. 35. The protective effects of taurine on hypoxia (performed in the absence of glucose) and on reoxygenation (in the presence of glucose) in guinea-pig heart. Franconi F, Stendardi I, Failli P, Matucci R, Baccaro C, Montorsi L, Bandinelli R, Giotti A. 36. Indian J Exp Biol. 2002 Oct;40(10):1169-72. Antiatherogenic effect of taurine in high fat diet fed rats.

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Sethupathy S, Elanchezhiyan C, Vasudevan K, Rajagopal G. Division of Biochemistry, Rajah Muthiah Medical College, Annamalai University, Annamalai Nagar 608 002, India. drsethupathy@rediffmail.com 37. J Nutr Sci Vitaminol (Tokyo). 1995 Dec;41(6):627-34. Effects of taurine on depletion of erythrocyte membrane Na-K ATPase activity due to ozone exposure or cholesterol enrichment. Qi B, Yamagami T, Naruse Y, Sokejima S, Kagamimori S. Department of Community Health and Preventive Medicine, Toyama Medical and Pharmaceutical University, Japan. 38. Adv Exp Med Biol. 2003;526:515-25. (Animal Study) Prevention of epileptic seizures by taurine. El Idrissi A, Messing J, Scalia J, Trenkner E. New York State Institute for Basic Research in Developmental Disabilities and The Center for Developmental Neuroscience, The City University of New York, Staten Island, NY 10314, USA. 39. Amino Acids. 1999;16(2):133-47. (Animal Study) Kainic acid (KA)-induced seizures in Sprague-Dawley rats and the effect of dietary taurine (TAU) supplementation or deficiency. Eppler B, Patterson TA, Zhou W, Millard WJ, Dawson R Jr. Department of Pharmacodynamics, University of Florida, Gainesville, USA. 40. Yakubutsu Seishin Kodo. 1991 Aug;11(4):257-60. (Animal Study) [Drug-induced seizures in taurine-deficient mice] [Article in Japanese] Shimada C, Tanaka S, Sano M, Araki H. Research and Development Center, Fuso Pharmaceutical Industries, Ltd., Osaka, Japan. 41. Neuropharmacology. 1987 Dec;26(12):1721-5.

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Higher susceptibility of taurine-deficient rats to seizures induced by 4-aminopyridine. Pasantes-Morales H, Arzate ME, Quesada O, Huxtable RJ. Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico, D.F. 42. Med Hypotheses. 1985 Dec;18(4):411-5. Could supplementary dietary tryptophan and taurine prevent epileptic seizures? Maurizi CP. 43. J Neurosci Res. 1981;6(4):465-74. Effect of taurine on seizures induced by 4-aminopyridine. Pasantes-Morales H, Arzate ME. 44. J Neural Transm. 1980;48(4):311-6. (Animal Study) Taurine selectivity antagonizes L-kynurenine-produced seizures in mice. Lapin IP. 45. Can J Physiol Pharmacol. 1978 Jun;56(3):497-500. (Animal Study) The effect of taurine on kindled seizures in the rat. Burnham WM, Albright P, Racine RJ. 46. Epilepsia. 1975 Jun;16(2):229-34. Effects of taurine on kindled amygdaloid seizures in rats, cats, and photosensitive baboons. Wada JA, Osawa T, Wake A, Corcoran ME. 47. Neural Plast. 2000;7(4):245-59. (Animal Study) Improvement of impaired memory in mice by taurine. Vohra BP, Hui X. Department of Biotechnology, School of Life Sciences, Sun-Yat-Sen University, Guangzhou, China-510 275. Vohra001@tc.umn.edu

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48. Environ Res. 2000 Jan;82(1):7-17. Effects of taurine on ozone-induced memory deficits and lipid peroxidation levels in brains of young, mature, and old rats. Rivas-Arancibia S, Dorado-Martinez C, Borgonio-Perez G, Hiriart-Urdanivia M, Verdugo-Diaz L, Duran-Vazquez A, Colin-Baranque L, Avila-Costa MR. Departamento de Fisiologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Mexico. 49. Arch Dis Child. 1992 Sep;67(9):1082-5. Effect of taurine supplementation on fat and energy absorption in cystic fibrosis. De Curtis M, Santamaria F, Ercolini P, Vittoria L, De Ritis G, Garofalo V, Ciccimarra F. Department of Paediatrics, 2nd School of Medicine, University of Naples, Italy. 50. Am J Dis Child. 1991 Dec;145(12):1401-4. Taurine decreases fecal fatty acid and sterol excretion in cystic fibrosis. A randomized double-blind trial. Smith LJ, Lacaille F, Lepage G, Ronco N, Lamarre A, Roy CC. Department of Pediatrics, Hopital Ste-Justine, Montreal, Quebec, Canada. 51. Klin Padiatr. 1991 Jan-Feb;203(1):28-32. [Taurine supplementation in cystic fibrosis (CF): effect on vitamin E absorption kinetics] [Article in German] Skopnik H, Kusenbach G, Bergt U, Friedrichs F, Stuhlsatz H, Dohmen H, Heimann G. Kinderklinik, RWTH Aachen. 52. Acta Univ Carol [Med] (Praha). 1990;36(1-4):152-6. Effect of taurine supplements on growth, fat absorption and bile acid on cystic fibrosis. Carrasco S, Codoceo R, Prieto G, Lama R, Polanco I. Department of Pediatrics, Children's Hospital La Paz, Autonoma University, Madrid, Spain. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 258

53. Biochem Cell Biol. 1988 Jul;66(7):702-6. Taurine uptake by normal and cystic fibrosis fibroblasts. Thompson GN. Department of Chemical Pathology, Adelaide Children's Hospital, North Adelaide, Australia. 54. J Pediatr Gastroenterol Nutr. 1988 Mar-Apr;7(2):214-9. Excessive fecal taurine loss predisposes to taurine deficiency in cystic fibrosis. Thompson GN. Department of Chemical Pathology, Adelaide Children's Hospital, South Australia. 55. Scand J Gastroenterol Suppl. 1988;143:151-6. Effect of taurine supplementation on fat and bile acid absorption in patients with cystic fibrosis. Colombo C, Arlati S, Curcio L, Maiavacca R, Garatti M, Ronchi M, Corbetta C, Giunta A. Dept. of Pediatrics, University of Milan, Italy. 56. Am J Clin Nutr. 1987 Oct;46(4):606-13. Protein metabolism in cystic fibrosis: responses to malnutrition and taurine supplementation. Thompson GN, Tomas FM. Department of Chemical Pathology, Adelaide Children's Hospital, South Australia. 57. Pediatrics. 1987 Oct;80(4):517-23. Taurine improves the absorption of a fat meal in patients with cystic fibrosis. Belli DC, Levy E, Darling P, Leroy C, Lepage G, Giguere R, Roy CC. Department of Pediatrics, Hopital Ste-Justine, Montreal, Quebec, Canada. 58. Pediatr Res. 1985 Jun;19(6):578-82.

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Effect of taurine supplements on fat absorption in cystic fibrosis. Darling PB, Lepage G, Leroy C, Masson P, Roy CC. 59. Invest Ophthalmol Vis Sci. 2002 Feb;43(2):425-33. (Animal Study) Osmoregulatory alterations in taurine uptake by cultured human and bovine lens epithelial cells. Cammarata PR, Schafer G, Chen SW, Guo Z, Reeves RE. Department of Pathology and Anatomy, Division of Cell Biology and Genetics, University of North Texas Health Science Center at Fort Worth and the North Texas Eye Research Institute, Fort Worth, Texas 76107, USA. pcammara@hsc.unt.edu 60. Zhonghua Yan Ke Za Zhi. 2000 Jul;36(4):272-4, 17. (Animal Study) [An experimental research of taurine on H2O2-induced bovine lens epithelial cell apoptosis] [Article in Chinese] Chen F, Chen C. Beijing Institute of Ophthalmology, Beijing 100005, China. 61. Invest Ophthalmol Vis Sci. 1999 Mar;40(3):680-8. (Animal Study) Effect of dietary taurine supplementation on GSH and NAD(P)-redox status, lipid peroxidation, and energy metabolism in diabetic precataractous lens. Obrosova IG, Stevens MJ. Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, USA. 62. Free Radic Res. 1998 Sep;29(3):189-95. (Animal Study) Oxidative stress to rat lens in vitro: protection by taurine. Devamanoharan PS, Ali AH, Varma SD. Department of Ophthalmology, University of Maryland, Baltimore 21201, USA. 63. Mol Cell Biochem. 1997 Dec;177(1-2):245-50.

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Prevention of lens protein glycation by taurine. Devamanoharan PS, Ali AH, Varma SD. Department of Ophthalmology, University of Maryland School of Medicine, Baltimore 21201, USA. 64. Invest Ophthalmol Vis Sci. 1993 Jul;34(8):2512-7. Hypertonic stress increases NaK ATPase, taurine, and myoinositol in human lens and retinal pigment epithelial cultures. Yokoyama T, Lin LR, Chakrapani B, Reddy VN. Eye Research Institute, Oakland University, Rochester, Michigan. 65. Neurochem Res. 1986 Apr;11(4):535-42. (Animal Study) Taurine and other free amino acids in the retina, vitreous, lens, iris-ciliary body, and cornea of the rat eye. Heinamaki AA, Muhonen AS, Piha RS. 66. Exp Eye Res. 1983 Oct;37(4):379-84. Distribution of taurine in the crystalline lens of vertebrate species and in cataractogenesis. Gupta K, Mathur RL. Cardiac Lesions 67. Can J Neurol Sci. 1980 Nov;7(4):435-40. (Animal Study) Taurine decreases lesion severity in the hearts of cardiomyopathic hamsters. Azari J, Brumbaugh P, Barbeau A, Huxtable R. 68. Gen Pharmacol. 1998 Apr;30(4):451-63. Review of some actions of taurine on ion channels of cardiac muscle cells and others. Satoh H, Sperelakis N. Department of Pharmacology, Nara Medical University, Japan. 69. Arzneimittelforschung 1998 Apr;48(4):360-4 (Animal Study) Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 261

Protective effects of taurine against reperfusion-induced arrhythmias in isolated ischemic rat heart. Chahine R, Feng J Laboratory of Physiology, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon. 70. Ann Acad Med Stetin. 1997;43:129-42. (Animal Study) [Taurine as a regulator of fluid-electrolyte balance and arterial pressure] [Article in Polish] Ciechanowska B. Z Katedry Chorob Dzieci Pomorskiej Akademii Medycznej w Szczecinie, Szczecin. 71. Am J Vet Res. 1992 Feb;53(2):237-41. (Animal Study) Myocardial taurine concentrations in cats with cardiac disease and in healthy cats fed taurine-modified diets. Fox PR, Sturman JA. Department of Medicine, Animal Medical Center, New York, NY 10021. 72. Eur J Pharmacol. 1986 May 13;124(1-2):129-33. (Animal Study) Positive inotropic effect of some taurine-related compounds on guinea-pig ventricular strips perfused with low calcium medium. Franconi F, Failli P, Stendardi I, Matucci R, Bennardini F, Baccaro C, Giotti A. 73. Proc Soc Exp Biol Med. 1984 Oct;177(1):143-50. (Animal Study) Taurine in hearts and bodies of embryonic through early postpartum CF1 mice. Quilligan CJ, Hilton FK, Hilton MA. 74. Eur J Pharmacol. 1984 Feb 17;98(2):269-73. (Animal Study) TAG antagonises the central cardiovascular effects of taurine. Bousquet P, Feldman J, Bloch R, Schwartz J. 75. Res Commun Chem Pathol Pharmacol. 1984 Feb;43(2):343-6. (Animal Study)

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Further evidence of the antiarrhythmic efficacy of taurine in the rat heart. Hernandez J, Artillo S, Serrano MI, Serrano JS.

76. The role of taurine in developing rat retina Ophtalmologie (France), 1995, 9/3 (283-286)

77. Supplemental taurine in diabetic rats: Effects on plasma glucose and triglycerides BIOCHEM. MED. METAB. BIOL. (USA), 1990, 43/1 (1-9+8) 78. Taurine deficiency retinopathy in the cat J. SMALL ANIM. PRACT. (ENGLAND), 1980, 21/10 (521-534) 79. Taurine: A therapeutic agent in experimental kidney disease Amino Acids (Austria), 1996, 11/1 (1-13) 80. Effects of taurine and guanidinoethane sulfonate on toxicity of the pyrrolizidine alkaloid monocrotaline Biochemical Pharmacology (USA), 1996, 51/3 (321-329) 81. Fish oil and other nutritional adjuvants for treatment of congestive heart failure Medical Hypotheses (United Kingdom), 1996, 46/4 (400-406) 82. Usefulness of TAURINE in chronic congestive heart failure and its prospective application. Jpn Circ J (JAPAN) Jan 1992, 56 (1) p95-9 83. Platelet TAURINE in patients with arterial hypertension, myocardial failure or infarction.

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Acta Med Scand Suppl (SWEDEN) 1980, 642 p79-84 84. Physiological and experimental regulation of TAURINE content in the heart. Fed Proc (UNITED STATES) Jul 1980, 39 (9) p2685-90 85. A relation between myocardial TAURINE contest and pulmonary wedge pressure in dogs with heart failure. Physiol Chem Phys (UNITED STATES) 1977, 9 (3) p259-63 86. Adrenergic stimulation of TAURINE transport by the heart. Science (UNITED STATES) Oct 28 1977, 198 (4315) p409-11 87. Taurine and serine supplementation modulates the metabolic response to tumor necrosis factor alpha in rats fed a low protein diet J. NUTR. (USA), 1992, 122/7 (1369-1375) 88. Taurine deficiency after intensive chemotherapy and/or radiation Am J Clin Nutr; 55(3):708-11 1992 89. Effect of glutaurine and its derivatives and their combinations with radiation protective substances upon irradiated mice Acta Radiol Oncol Radiat Phys Biol; 20(5):319-324 1981 90. [Effect of mixed gamma-neutron irradiation on taurine penetration through cellular membranes of rat peripheral blood leukocytes] Res. Inst. Biology and Biophysics, V. V. Kuibyshev Tomsk State Univ., Tomsk, USSR 91. [Sources of taurine hyperexcretion in irradiated rats] Radiobiologiia; 20(3):455-459 1980 92. [Taurine and sh-group content in the platelets of irradiated rats]

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Radiobiologiia; 18(2):271-274 93. Prophylactic effects of taurine and diltiazem, alone or combined, on reperfusion arrhythmias in rats Acta Pharmacologica Sinica (China), 1996, 17/2 (122-124) 94. The antiarrhythmic effects of taurine alone and in combination with magnesium sulfate on ischemia/reperfusion arrhythmia Chinese Pharmacological Bulletin (China), 1994, 10/5 (358-362)

Choline Bitartrate 63 Studies


1. Blusztajn, J.K. Choline, a vital amine. Science. 1998; volume 281: pages 794-795. 2. Zeisel, S.H. Choline and phosphatidylcholine. In Shils, M. et al. Eds. Nutrition in Health and Disease, 9th Edition. Baltimore: Williams & Wilkins, 1999: pages 513-523. 3. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press, 1998: pages 390-422. 4. Zeisel, S.H. Choline: an essential nutrient for humans. Nutrition. 2000; volume 16: pages 669-671. 5. Jacob, R.A. et al. Folate nutriture alters choline status of women and men fed low choline diets. Journal of Nutrition. 1999; volume 129: pages 712-717. 6. Zeisel, S.H. & Blusztajn, J.K. Choline and human nutrition. Annual Review of Nutrition. 1994; volume 14: pages 269-296. 7. Gerhard, G.T. & Duell, P.B. Homocysteine and atherosclerosis. Current Opinion in Lipidology. 1999; volume 10: pages 417-428. 8. Lundberg, P. et al. 1H NMR determination of urinary betaine in patients with premature vascular disease and mild hyperhomocysteinemia. Clinical Chemistry. 1995; volume 41: pages 275-283. 9. Blom, H. Determinants of plasma homocysteine. American Journal of Clinical Nutrition. 1998; volume 68: pages 919-921. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 265

10. Whitehouse, P.J. The cholinergic deficit in Alzheimer's disease. Journal of Clinical Psychiatry. 1998; volume 59 (supplement 13): pages 19-22. 11. Higgins, J.P. & Flicker, L. Lecithin for dementia and cognitive impairment. Cochrane Database of Systematic Reviews. 2000. 2:CD001015. 12. Zeisel SH, Mar MH, Howe JC, Holden JM. Concentrations of choline-containing compounds and betaine in common foods. J Nutr. 2003;133(5):1302-1307. 13. Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001. 14. Dietary precursors and brain neurotransmitter formation. Fernstrom JD. Annu Rev Med (UNITED STATES) 1981, 32 p413-25 15. Behavioral effects of dietary neurotransmitter precursors: Basic and clinical aspects Young SN. Neuroscience and Biobehavioral Reviews (USA), 1996, 20/2 (313 323) 16. Precursor control of neurotransmitter synthesis. Wurtman RJ, Hefti F, Melamed E. Pharmacol Rev. 1980 Dec;32(4):315-35. 17. Nutrition 4. Choline and human nutrition Zeisel SH, Blusztajn JK. ANNU. REV. NUTR. (USA), 1994, 14:269-296 18. Choline may be an essential nutrient in malnourished patients with cirrhosis Chawla RK, Wolf DC, Kutner MH, Bonkovsky HL. GASTROENTEROLOGY (USA), 1989, 97/6 (1514-1520) 19. Male rats fed methyl and folate deficient diets with or without niacin develop hepatic carcinomas associated with decreased tissue NAD concentrations and altered poly(ADP ribose) polymerase activity Henning SM, Swendseid ME, Coulson WF. Journal of Nutrition (USA), 1997, 127/1 (30 36) 20. Habituation of exploratory activity in mice: effects of combinations of piracetam and choline on memory processes. Platel A, Jalfre M, Pawelec C, Roux S, Porsolt RD. Pharmacol Biochem Behav (UNITED STATES) Aug 1984, 21 (2) p209-12 21. Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats. Bartus RT, Dean RL 3rd, Sherman KA, Friedman E, Beer B. Neurobiol Aging (UNITED STATES) Summer 1981, 2 (2) p105-11 22. Verbal and visual memory improve after choline supplementation in long-term total parenteral nutrition: a pilot study.

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Buchman AL, Sohel M, Brown M, Jenden DJ, Ahn C, Roch M, Brawley TL. Division of Gastroenterology and Hepatology, Northwestern University, Chicago, Illinois 60611, USA. a-buchman@nwu.edu JPEN J Parenter Enteral Nutr. 2001 Jan-Feb;25(1):30-5.

23. Dietary precursors and brain neurotransmitter formation. Annu Rev Med (UNITED STATES) 1981, 32 p413-25 24. Choline and human nutrition ANNU. REV. NUTR. (USA), 1994, 14/- (269-296) 25. Choline may be an essential nutrient in malnourished patients with cirrhosis GASTROENTEROLOGY (USA), 1989, 97/6 (1514-1520)

26. Behavioral effects of dietary neurotransmitter precursors: Basic and clinical aspects Neuroscience and Biobehavioral Reviews (USA), 1996, 20/2 (313-323) 27. Habituation of exploratory activity in mice: effects of combinations of piracetam and choline on memory processes. Pharmacol Biochem Behav (UNITED STATES) Aug 1984, 21 (2) p209-12 28. Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats. Neurobiol Aging (UNITED STATES) Summer 1981, 2 (2) p105-11 29. Male rats fed methyl- and folate-deficient diets with or without niacin develop hepatic carcinomas associated with decreased tissue NAD concentrations and altered poly(ADPribose) polymerase activity Journal of Nutrition (USA), 1997, 127/1 (30-36)

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30. Choline and cholinergic neurons. Blusztajn JK, Wurtman RJ. Science. 1983 Aug 12;221(4611):614-20. 31. Free choline and choline metabolites in rat brain and body fluids: sensitive determination and implications for choline supply to the brain. Klein J, Gonzalez R, Koppen A, Loffelholz K. Department of Pharmacology, University of Mainz, Germany. Neurochem Int. 1993 Mar;22(3):293-300. 32. Brain acetylcholine: control by dietary choline. Cohen EL, Wurtman RJ. Science. 1976 Feb 13;191(4227):561-2. 33. Neurochemical effects of choline supplementation. Wecker L. Can J Physiol Pharmacol. 1986 Mar;64(3):329-33. 34. Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study. Cohen BM, Renshaw PF, Stoll AL, Wurtman RJ, Yurgelun-Todd D, Babb SM. Brain Imaging Center, McLean Hospital, Belmont, MA 02178, USA. JAMA. 1995 Sep 20;274(11):902-7. 35. Metabolic imprinting of choline by its availability during gestation: implications for memory and attentional processing across the lifespan. Meck WH, Williams CL. Department of Psychological and Brain Sciences, Duke University, 9 Flowers Drive, Box 90086, 27708-0086, Durham, NC, USA Neurosci Biobehav Rev. 2003 Jun;27(4):385-99. 36. Choline supplementation reduces urinary carnitine excretion in humans. Dodson WL, Sachan DS. Department of Nutrition, University of Tennessee, Knoxville 37996-1900, USA. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 268

Am J Clin Nutr. 1996 Jun;63(6):904-10. Comment in: Am J Clin Nutr. 1997 Feb;65(2):574-5. 37. J Nutr. 2003 Jan;133(1):84-9. Carnitine and choline supplementation with exercise alter carnitine profiles, biochemical markers of fat metabolism and serum leptin concentration in healthy women. Hongu N, Sachan DS. Department of Nutrition and Agricultural Experiment Station, The University of Tennessee, Knoxville, TN 379961900, USA. 38. 1_ J Nutr Biochem. 1992 Jun;3(6):3135. Effects of orally administered cytidine 5'diphosphate choline on brain phospholipid content. Lopez GCoviella I, Agut J, Ortiz JA, Wurtman RJ. 39. Arch Neurol. 1996 May;53(5):4418. Citicoline improves verbal memory in aging. Spiers PA, Myers D, Hochanadel GS, Lieberman HR, Wurtman RJ. 40. Methods Find Exp Clin Pharmacol. 1997 Apr;19(3):20110. Citicoline improves memory performance in elderly subjects. Alvarez XA, Laredo M, Corzo D, FernandezNovoa L, Mouzo R, Perea JE, Daniele D, Cacabelos R. 41. Psychopharmacology (Berl). 2002 May;161(3):24854. Epub 2002 Mar 22. Chronic citicoline increases phosphodiesters in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy study. Babb SM, Wald LL, Cohen BM, Villafuerte RA, Gruber SA, YurgelunTodd DA, Renshaw PF. 42. Clin Ter. 1991 Jun 30;137(6):40313. [Citicoline in the treatment of cognitive and behavioral disorders in pathologic senile decline] Di Trapani G, Fioravanti M. 43. Prog Neuropsychopharmacol Biol Psychiatry. 2003 Jun;27(4):7117.

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Dietary cytidine (5')diphosphocholine supplementation protects against development of memory deficits in aging rats. Teather LA, Wurtman RJ. 44. Arzneimittelforschung. 1993 Aug;43(8):8228. Effects of cytidine diphosphate choline on rats with memory deficits. Petkov VD, Kehayov RA, Mosharrof AH, Petkov VV, Getova D, Lazarova MB, Vaglenova J. 45. Minerva Med. 1990 Jun;81(6):46570. [Effect of CDPcholine on senile mental deterioration. Multicenter experience on 237 cases] Serra F, Diaspri GP, Gasbarrini A, Giancane S, Rimondi A, Tame MR, Sakellaridis E, Bernardi M, Gasbarrini G. 46. Naturforsch [C]. 2003 MarApr;58(34):27781. Effect of CDPcholine on hippocampal acetylcholinesterase and Na+,K(+)ATPase in adult and aged rats. Plataras C, Angelogianni P, Tsakiris S. 47. Methods Find Exp Clin Pharmacol. 1994 Apr;16(3):2118. Effects of CDPcholine on cognition and cerebral hemodynamics in patients with Alzheimer's disease. Caamano J, Gomez MJ, Franco A, Cacabelos R. 48. Methods Find Exp Clin Pharmacol. 1999 Nov;21(9):63344. Doubleblind placebocontrolled study with citicoline in APOE genotyped Alzheimer's disease patients. Effects on cognitive performance, brain bioelectrical activity and cerebral perfusion. Alvarez XA, Mouzo R, Pichel V, Perez P, Laredo M, FernandezNovoa L, Corzo L, Zas R, Alcaraz M, Secades JJ, Lozano R, Cacabelos R. 49. Ann N Y Acad Sci. 1996 Jan 17;777:399403.

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Therapeutic effects of CDPcholine in Alzheimer's disease. Cognition, brain mapping, cerebrovascular hemodynamics, and immune factors. Cacabelos R, Caamano J, Gomez MJ, FernandezNovoa L, FrancoMaside A, Alvarez XA. 50. Methods Find Exp Clin Pharmacol. 1994 May;16(4):27984. CDPcholine induced blood histamine changes in Alzheimer's disease. FernandezNovoa L, Alvarez XA, FrancoMaside A, Caamano J, Cacabelos R. 51. J Neurosurg. 2003 Apr;98(4):86773. Cytidinediphosphocholine treatment to decrease traumatic brain injury induced hippocampal neuronal death, cortical contusion volume, and neurological dysfunction in rats. Dempsey RJ, Raghavendra Rao VL. 52. J Neurol Sci. 1991 Jul;103 Suppl:S158. Effects of CDPcholine on the recovery of patients with head injury. Calatayud Maldonado V, Calatayud Perez JB, Aso Escario J. 53. J Mol Neurosci. 2003 Feb;20(1):5360. CDPcholine prevents glutamatemediated cell death in cerebellar granule neurons. Mir C, Clotet J, Aledo R, Durany N, Argemi J, Lozano R, CervosNavarro J, Casals N. 54. J Neurochem. 2002 Jan;80(1):1223. Citicoline: neuroprotective mechanisms in cerebral ischemia. Adibhatla RM, Hatcher JF, Dempsey RJ. 55. J Neurosci Res. 1999 Dec 1;58(5):697705. CDPcholine: neuroprotection in transient forebrain ischemia of gerbils. Rao AM, Hatcher JF, Dempsey RJ. 56. Folia Neuropathol. 2001;39(3):1415.

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CDPcholine, but not cytidine, protects hippocampal CA1 neurones in the gerbil following transient forebrain ischaemia. Grieb P, Gadamski R, Wojda R, Janisz M. 57. Stroke. 2002 Dec;33(12):28507. Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials. Davalos A, Castillo J, AlvarezSabin J, Secades JJ, Mercadal J, Lopez S, Cobo E, Warach S, Sherman D, Clark WM, Lozano R. 58. Rev Neurol. 2001 May 115;32(9):81821. [Neuroprotection in acute ischemic stroke. Practicability of guidelines for treatment] 59. Ann Neurol. 2000 Nov;48(5):71322. Effect of citicoline on ischemic lesions as measured by diffusion weighted magnetic resonance imaging. Citicoline 010 Investigators. Warach S, Pettigrew LC, Dashe JF, Pullicino P, Lefkowitz DM, Sabounjian L, Harnett K, Schwiderski U, Gammans R. 60. Neurology. 1997 Sep;49(3):6718. A randomized dose response trial of citicoline in acute ischemic stroke patients. Citicoline Stroke Study Group. Clark WM, Warach SJ, Pettigrew LC, Gammans RE, Sabounjian LA. 61. Arch Physiol Biochem. 2001 Apr;109(2):1617. Ischemic brain injury caused by interrupted versus uninterrupted occlusion in hypotensive rats with subarachnoid hemorrhage: neuroprotective effects of citicoline. Alkan T, Kahveci N, Goren B, Korfali E, Ozluk K. 62. J Neurosci Res. 2002 Jan 15;67(2):1438. Pharmacodynamics of citicoline relevant to the treatment of glaucoma. Grieb P, Rejdak R. 63. Ophthalmology. 1999 Jun;106(6):112634. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 272

Cytidine5'diphosphocholine (citicoline) improves retinal and cortical responses in patients with glaucoma. Parisi V, Manni G, Colacino G, Bucci MG.

Inositol 56 Studies
1. Benjamin, J. et al. 1995. Double-blind, placebo-controlled, crossover trial of inositol treatment of panic disorder. Am J Psychiatry 52: 1084-1086. 2. Fux, M. et al. 1996. Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry 153(9): 1219-1221. 3. Levine, J et al. 1997. Controlled trials of inositol in psychiatry. Eur Neuropsychopharmacol 7(2): 147-155. 4. Mishori, et al. 1999. Combination of inositol and serotonin reuptake inhibitors in the treatment of depression. Biol Psychiatry 45: 270-273. 5. Palatnik, A. et al. 2001. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol 21(3): 335-339. 6. Fux M, Levine J, Aviv A, Belmaker RH. Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry. 1996 Sep;153(9):1219-21. 7. High-dose peripheral inositol raises brain inositol levels and reverses behavioral effects of inositol depletion by lithium. Pharmacol Biochem Behav 1994 Oct;49(2):341-3. Agam G, Shapiro Y, Bersudsky Y, Kofman O, Belmaker RH. Laboratory of Biochemistry, Soroka Medical Center, Beer-Sheva, Israel. 8. Inositol treatment in psychiatry. Psychopharmacol Bull 1995;31(1):167-75. Benjamin J, Agam G, Levine J, Bersudsky Y, Kofman O, Belmaker RH. Division of Psychiatry, Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel. 9. Barak Y, Levine J, Glassman A, et al. Inositol treatment of Alzheimer's disease: a double blind, cross-over placebo controlled trial. Prog Neuropsychopharmacol Biol Psychiatry. 1996; 20:729-735. 10. Benjamin J, Levine J, Fox M, et al. Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder. Am J Psychiatry. 1995; 152:1084-1086. 11. Cohen RA, MacGregory LC, Spokes KC, et al. Effect of myo-inositol on renal Na-KATPase in experimental diabetes. Metabol. 1990; 39:1026-1032. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 273

12. Colodny L, Hoffman RL. Inositol-clinical applications for exogenous use. Altern Med Rev. 1998; 3:432-447. 13. Downes CP. The cellular functions of myo-inositol. Biochem Soc Trans. 1989; 17:259-268. 14. Einat H, Belmaker RH, Kopilov M, et al. Rat brain monomines after acute and chronic myo-inositol treatment. Eur Neuropsychopharmacol. 1999; 10:27-30. 15. Einat H, Karbovski H, Korik J, et al. Inositol reduces depressive-like behaviors in two different models of depression. Psychopharmacology. 1999; 144:158-162. 16. Fox M, Levine J, Aviv A, Belmaker RH. Inositol treatment of obsessive-compulsive disorder. Am J Psychiat. 1996; 153:1219-1221. 17. Holub BJ. Metabolism and function of myo-inositol and inositol phospholipids. Annu Rev Nutr. 1986; 6:563-597. 18. Holub BJ. The cellular forms and functions of the inositol phospholipids and their metabolic derivates. Nutr Rev. 1987; 45:65-71. 19. Khandelwal M, Reece EA, Wu YK, Borenstein M. Dietary myo-inositol therapy in hyperglycemic-induced embryopathy. Teratology. 1998; 57:79-84. 20. Larner J, Allan G, Kessler C, et al. Phosphoinositol glycan derived mediators and insulin resistance. Prospects for diagnosis and therapy. J Basic Clin Physiol Pharmacol. 1998; 9:127-137. 21. Levine J. Controlled trials of inositol in psychiatry. Eur Neuropsychopharmacol. 1997; 7:147-155. 22. Levine J, Aviram A, Holan A, et al. Inositol treatment of action, J Neural Transm. 1997; 104:307-310. 23. Levine J, Barak Y, Gonzalues M, et al. Double-blind, controlled-trial of inositol treatment of depression. Am J Psychiatry. 1995; 152:792-794. 24. Levine J, Goldberger I, Rapaport A, et al. CSF inositol in schizophrenia and highdose inositol treatment of schizophrenic. Eur Neuropsychopharmacol. 1994; 4:487-490. 25. Levine J, Kurtzman L, Rapoport A, et al. CSF inositol does not predict antidepressant response to inositol. J Neural Transm. 1996; 103:1457-1462. 26. Nestler JE, Jakabowicz DJ, Reamer P, et al. Ovulatory and metabolic effects of Dchiro-inositol in the polycystic overary syndrome. N Engl J Med. 1999; 340:1314-1320.

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27. Seedat S, Stein DJ. Inositol augmentation of serotonin reuptake inhibitors in treatment-refractory obsessive-compulsive disorder: an open trial. Int Clin Psychopharmacol. 1999; 14:353-356. 28. 1. Belmaker, R. H. et al. 1995. Manipulation of inositol-linked second messenger systems as a therapeutic strategy in psychiatry. Adv Biochem Psychopharmacol 49: 6784. 29. Hooper, N. 1997. Glycosyl-phosphatidylinositol anchored membrane enzymes. Clin Chim Acta 266(1): 3-12. 31. Levine, J. 1997. Controlled trials of inositol in psychiatry. Eur europsychopharmacol 7(2): 147-155. 32. Levine, J. et al. 1995. Double-blind, controlled trial of inositol treatment of depression. Am J Psychiatry 152(5): 792-794. 33. Benjamin, J. et al. 1995a. Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder. Am J Psychiatry 152(7): 1084-1086. 34. Benjamin, J. et al. 1995b. Inositol treatment in psychiatry. Psychopharmacol Bull 31(1): 167-175. 35. Gelber et al. 2001. Effect of inositol on bulimia nervosa and binge eating. Int J Eat Disord. 29(3):345-8. 36. Palatnik, A. et al., 2001. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol 21(3): 335-339. 37. Fux, M. et al. 1996. Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry 153(9): 1219-1221. 38. Levine, J. et al. 1999. Combination of inositol and serotonin reuptake inhibitors in the treatment of depression. Biol Psychiatry 45(3): 270-273.

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39. Chengappa et al. 2000. Inositol as an add-on treatment for bipolar depression. Bipolar Disord. 2(1):47-55. 40. Rahman, S. and R. S. Neuman. 1993. Myo-inositol reduces serotonin (5-HT2) receptor induced homologous and heterologous desensitization. Brain Res 631(2): 349351. 41. Greist, J. H. et al. 1995. Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive disorder. A meta-analysis. Arch Gen Psychiatry 52(1): 53-60. 42. Hefez, A. et al. 1987. Long-term effects of extreme situational stress on sleep and dreaming. Am J Psychiatry 144(3): 344-347. 43. Friedman CA, et al. 2000. Relationship between serum inositol concentration and development of retinopathy of prematurity: a prospective study. J Pediatr Ophthalmol Strabismus Mar-Apr;37(2): 79-86. 44. Greene, N. D. and A. J. Copp. 1997. Inositol prevents folate-resistant neural tube defects in the mouse. Nat Med 3(1): 60-66. 45. Reece, E. A. et al. 1997. Dietary intake of myo-inositol and neural tube defects in offspring of diabetic rats. Am J Obstet Gynecol 176(3): 536-539. 46. Khandelwal, M. et al. 1998. Dietary myo-inositol therapy in hyperglycemia-induced embryopathy. Teratology 57(2): 79-84. 47. Colodny, L. and R. L. Hoffman. 1998. Inositol--clinical applications for exogenous use. Altern Med Rev 3(6): 432-447. 48. Gill, D. L. et al. 1989. Calcium signalling mechanisms in endoplasmic reticulum activated by inositol 1,4,5-trisphosphate and GTP. Cell Calcium 10(5):363-374. 49. Graf, E. and J. W. Eaton. 1993. Suppression of colonic cancer by dietary phytic acid. Nutr Cancer 19(1): 11-19. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 276

50. Graf, E. et al. 1987. Phytic acid. A natural antioxidant. J Biol Chem 262(24): 116471150. 51. Zhou, J. R. and J. W. Erdman. 1995. Phytic acid in health and disease. Crit Rev Food Sci Nutr 35(6): 495-508. 52. Carey et al. 2004. Single photon emission computed tomography (SPECT) in obsessive-compulsive disorder before and after treatment with inositol. Metab Brain Dis. 19(1-2):125-34. 53. Brink CB et al. 2004. Effects of myo-inositol versus fluoxetine and imipramine pretreatments on serotonin 5HT2A and muscarinic acetylcholine receptors in human neuroblastoma cells. Metab Brain Dis. 19(1-2):51-70. 54. Cai, F. et al. 1990. Preliminary report of efficacy of diabetic polyneuropathy treated with large dose inositol. Hua Xi Yi Ke Da Xue Xue Bao 21(2): 201-203. 55. Barak, Y. et al. 1996. Inositol treatment of Alzheimer's disease: A double blind, crossover placebo controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 20(4): 729-735. 56. Nemets et al. 2002. Myo-inositol has no beneficial effect on premenstrual dysphoric disorder. World J Biol Psychiatry. 3(3):147-9.

L- Carnitine 93 Studies

1. Li B, Lloyd ML, Gudjonsson H, et al. The effect of enteral carnitine administration in humans. Am J Clin Nutr 1992;55:838-845. 2. Harper P, Elwin CE, Cederblad G. Pharmacokinetics of intravenous and oral bolus doses of L-carnitine in healthy subjects. Eur J Clin Pharmacol 1988;35:555-562. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 277

3. Sahajwalla CG, Helton ED, Purich ED, et al. Multiple-dose pharmacokinetics and bioequivalence of L-carnitine 330-mg tablet versus 1-g chewable tablet versus enteral solution in healthy adult male volunteers. J Pharm Sci 1995;84:627-633. 4. Bach AC, Schirardin H, Sihr MO, Storck D. Free and total camitine in human serum after oral ingestion of L-carnitine. Diabete Metab 1983;9:121-124. 5. Rebouche CJ, Chenard CA. Metabolic fate of dietary carnitine in human adults: identification and quantification of urinary and fecal metabolites. J Nutr 1991;121:539546. 6. Baker H, Frank O, DeAngelis B, Baker ER. Absorption and excretion of L-carnitine during single or multiple dosings in humans. Int J Vitam Nutr Res 1993;63:22-26. 7. Jogl G, Hsiao YS, Tong L. Structure and function of carnitine acyltransferases. Ann N Y Acad Sci 2004;1033:17-29. 8. Fukao T, Lopaschuk GD, Mitchell GA. Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry. Prostaglandins Leukot Essent Fatty Acids 2004;70:243-251. 9. Platell C, Kong SE, McCauley R, Hall JC. Branched-chain amino acids. J Gastroenterol Hepatol 2000; 15:706-717. 10. Stanley CA. Carnitine deficiency disorders in children. Ann N Y Acad Sci 2004; 1033:42-51. 11. Evangeliou A, Vlassopoulos D. Carnitine metabolism and deficit--when supplementation is necessary? Curr Pharm Biotechnol 2003;4:211-219. 12. Cruciani RA, Dvorkin E, Homel P, et al. L-carnitine supplementation for the treatment of fatigue and depressed mood in cancer patients with carnitine deficiency: a preliminary analysis. Ann N Y Acad Sci 2004;1033:168-176. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 278

13. Korkina MB, Korchak GM, Medvedev DI. Clinico-experimental substantiation of the use of carnitine and cobalamin in the treatment of anorexia nervosa. Zh Nevropatol Psikhiatr Im S S Korsakova 1989;89:82-87. [Article in Russian] 14. Korkina MV, Korchak GM, Kareva MA. Effects of carnitine and cobamamide on the dynamics of mental work capacity in patients with anorexia nervosa. Zh Nevropatol Psikhiatr Im S S Korsakova 1992;92:99-102. [Article in Russian] 15. Giordano C, Perrotti G. Clinical studies of the effects of treatment with a combination of carnitine and cobamamide in infantile anorexia. Clin Ter 1979;88:51-60. [Article in Italian] 16. Swart I, Rossouw J, Loots JM, Kruger MC. The effect of L-carnitine supplementation on plasma carnitine levels and various performance parameters of male marathon athletes. Nutr Res 1997;17:405-414. 17. Vecchiet L, Di Lisa F, Pieralisi G, et al. Influence of L-carnitine administration on maximal physical exercise. Eur J Appl Physiol Occup Physiol 1990;61:486-490. 18. Volek JS, Kraemer WJ, Rubin MR, et al. L-carnitine L-tartrate supplementation favorably affects markers of recovery from exercise stress. Am J Physiol Endocrinol Metab 2002;282:E474-E482. 19. Vukovich MD, Costill DL, Fink WJ. Carnitine supplementation: effect on muscle carnitine and glycogen content during exercise. Med Sci Sports Exerc 1994;26:11221129. 20. Cooper MB, Jones DA, Edwards RH, et al. The effect of marathon running on carnitine metabolism and on some aspects of muscle mitochondrial activities and antioxidant mechanisms. J Sports Sci 1986;4:79-87.

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30. Corbucci GG, Lettieri B. Cardiogenic shock and L-carnitine: clinical data and therapeutic perspectives. Int J Clin Pharmacol Res 1991;11:283-293. 31. Corbucci GG, Loche F. L-carnitine in cardiogenic shock therapy: pharmacodynamic aspects and clinical data. Int J Clin Pharmacol Res 1993; 13:87-91. 32. Rizos I. Three-year survival of patients with heart failure caused by dilated cardiomyopathy and L-carnitine administration. Am Heart J 2000; 139: S120-S123. 33. Gurlek A, Tutar E, Akcil E, et al. The effects of L-carnitine treatment on left ventricular function and erythrocyte superoxide dismutase activity in patients with ischemic cardiomyopathy. Eur J Heart Fail 2000;2:189-193. 34. Davini P, Bigalli A, Lamanna F, Boem A. Controlled study on L-carnitine therapeutic efficacy in post-infarction. Drugs Exp Clin Res 1992;18:355-365. 35. De Pasquale B, Righetti G, Menotti A. L-carnitine for the treatment of acute myocardial infarct. Cardiologia 1990;35:591-596. [Article in Italian] 36. Singh RB, Niaz MA, Agarwal P, et al. A randomised, double-blind, placebocontrolled trial of L-carnitine in suspected acute myocardial infarction. Postgrad Med J 1996;72:45-50. 37. Iliceto S, Scrutinio D, Bruzzi P, et al. Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: the L-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) Trial. J Am Coll Cardiol 1995;26:380-387. 38. Stefanutti C, Vivenzio A, Lucani G, et al. Effect of L-carnitine on plasma lipoprotein fatty acids pattern in patients with primary hyperlipoproteinemia. Clin Ter 1998;149:115119.

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49. Selimoglu MA, Yagci RV. Plasma and liver carnitine levels of children with chronic hepatitis B. J Clin Gastroenterol 2004;38:130-133. 50. DaVanzo WJ, Ullian ME. L-carnitine administration reverses acute mental status changes in a chronic hemodialysis patient with hepatitis C infection. Clin Nephrol 2002;57:402-405. 51. Malaguarnera M, Pistone G, Astuto M, et al. L-carnitine in the treatment of mild or moderate hepatic encephalopathy. Dig Dis 2003;21:271-275. 52. Moretti S, Alesse E, Di Marzio L, et al. Effect of L-carnitine on human immunodeficiency virus-1 infection-associated apoptosis: a pilot study. Blood 1998;91:3817-3824. 53. De Simone C, Tzantzoglou S, Famularo G, et al. High dose L-carnitine improves immunologic and metabolic parameters in AIDS patients. Immunopharmacol Immunotoxicol 1993;15:1-12. 54. Moretti S, Famularo G, Marcellini S, et al. L-carnitine reduces lymphocyte apoptosis and oxidant stress in HIV-1-infected subjects treated with zidovudine and didanosine. Antioxid Redox Signal 2002;4:391-403. 55. Benvenga S, Ruggeri RM, Russo A, et al. Usefulness of L-carnitine, a naturally occurring peripheral antagonist of thyroid hormone action, in iatrogenic hyperthyroidism: a randomized, double-blind, placebo-controlled clinical trial. J Clin Endocrinol Metab 2001;86:3579-3594. 56. Costa M, Canale D, Filicori M, et al. L-carnitine in idiopathic asthenozoospermia: a multicenter study. Italian Study Group on Carnitine and Male Infertility. Andrologia 1994;26:155-159. 57. Vitali G, Parente R, Melotti C. Carnitine supplementation in human idiopathic asthenospermia: clinical results. Drugs Exp Clin Res 1995;21:157-159. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 283

58. Lenzi A, Lombardo F, Sgro P, et al. Use of carnitine therapy in selected cases of male factor infertility: a double-blind crossover trial. Fertil Steril 2003;79:292-300. 59. Lenzi A, Sgro P, Salacone P, et al. A placebo-controlled double-blind randomized trial of the use of combined L-carnitine and L-acetyl-camitine treatment in men with asthenozoospermia. Fertil Steril 2004;81:1578-1584. 60. Gunal AI, Celiker H, Donder E, Gunal SY. The effect of L-carnitine on insulin resistance in hemodialysed patients with chronic renal failure. J Nephrol 1999;12:38-40. 61. Vesela E, Racek J, Trefil L, et al. Effect of L-carnitine supplementation in hemodialysis patients. Nephron 2001;88:218-223. 62. Matsumoto Y, Amano I, Hirose S, et al. Effects of L-carnitine supplementation on renal anemia in poor responders to erythropoietin. Blood Purif 2001;19:24-32. 63. Elisaf M, Bairaktari E, Katopodis K, et al. Effect of L-carnitine supplementation on lipid parameters in hemodialysis patients. Am J Nephrol 1998;18:416-421. 64. Romagnoli GF, Naso A, Carraro G, Lidestri V. Beneficial effects of L-carnitine in dialysis patients with impaired left ventricular function: an observational study. Curr Med Res Opin 2002;18:172-175. 65. Golper TA, Goral S, Becker BN, Langman CB. L-carnitine treatment of anemia. Am J Kidney Dis 2003;41:S27-S34. 66. Kurz C, Arbeiter K, Obermair A, et al. L-carnitine-betamethasone combination therapy versus betamethasone therapy alone in prevention of respiratory distress syndrome. Z Geburtshilfe Perinatol 1993;197:215-219. [Article in German] 67. O'Donnell J, Finer NN, Rich W, et al. Role of L-carnitine in apnea of prematurity: a randomized, controlled trial. Pediatrics 2002;109:622-626.

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68. Whitfield J, Smith T, Sollohub H, et al. Clinical effects of L-carnitine supplementation on apnea and growth in very low birth weight infants. Pediatrics 2003;111:477-482. 69. Iafolla AK, Browning IB 3rd, Roe CR. Familial infantile apnea and immature beta oxidation. Pediatr Pulmonol 1995;20:167-171. 70. Villani RG, Gannon J, Self M, Rich PA. L-Carnitine supplementation combined with aerobic training does not promote weight loss in moderately obese women. Int J Sport Nutr Exerc Metab 2000;10:199-207. 71. Johnston CS, Solomon RE, Cone C. Vitamin C depletion is associated with alterations in blood histamine and plasma free carnitine in adults. J Am Coil Nutr 1996;15:586-591. 72. Ha TY, Otsuka M, Arakawa N. The effect of graded doses of ascorbic acid on the tissue carnitine and plasma lipid concentrations. J Nutr Sci Vitaminol (Tokyo) 1990;36:227-234. 73. Otsuka M, Matsuzawa M, Ha TY, Arakawa N. Contribution of a high dose of Lascorbic acid to carnitine synthesis in guinea pigs fed high-fat diets. J Nutr Sci Vitaminol (Tokyo) 1999;45:163-171. 74. Triggs WJ, Roe CR, Rhead WJ, et al. Neuropsychiatric manifestations of defect in mitochondrial beta oxidation response to riboflavin. J Neurol Neurosurg Psychiatry 1992;55:209-211. 75. Podlepa EM, Gessler NN, Bykhovskii Via. The effect of methylation on the carnitine synthesis. Prikl Biokhim Mikrobiol 1990;26:179-183. [Article in Russian] 76. Dodson WL, Sachan DS. Choline supplementation reduces urinary carnitine excretion in humans. Am J Clin Nutr 1996;63:904-910.

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77. Hug G, McGraw CA, Bates SR, Landrigan EA. Reduction of serum carnitine concentrations during anticonvulsant therapy with phenobarbital, valproic acid, phenytoin, and carbamazepine in children. J Pediatr 1991;119:799-802. 78. Melegh B, Pap M, Molnar D, et al. Carnitine administration ameliorates the changes in energy metabolism caused by short-term pivampicillin medication. Eur J Pediatr 1997;156:795-799. 79. Herink J. Enhancing effect of L-carnitine on some abnormal signs induced by pentylenetetrazol. Acta Medica (Hradec Kralove) 1996;39:63-66. 80. Lissoni P, Galli MA, Tancini G, Barni S. Prevention by L-carnitine of interleukin-2 related cardiac toxicity during cancer immunotherapy. Tumori 1993;79:202-204. 81. Kawasaki N, Lee JD, Shimizu H, Ueda T. Long-term L-carnitine treatment prolongs the survival in rats with adriamycin-induced heart failure. J Card Fail 1996;2:293-299. 82. Semino-Mora MC, Leon-Monzon ME, Dalakas MC. Effect of L-carnitine on the zidovudine-induced destruction of human myotubes. Part I: L-carnitine prevents the myotoxicity of AZT in vitro. Lab Invest 1994;71:102-112. 83. Georgala S, Schulpis KH, Georgala C, Michas T. L-carnitine supplementation in patients with cystic ache on isotretinoin therapy. J Eur Acad Dermatol Venereol 1999; 13:205-209. 84. Kuntzer T, Reichmann H, Bogousslavsky J, Regli F. Emetine-induced myopathy and carnitine deficiency. J Neurol 1990;237:495-496. 85. Sekas G, Paul HS. Hyperammonemia and carnitine deficiency in a patient receiving sulfadiazine and pyrimethamine. Am J Med 1993;95:112-113.

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L-Cysteine 50 Studies
1. Neurosci Lett. 2003 Jul 31;346(1-2):97-100. L-cysteine sulphinate, endogenous sulphur-containing amino acid, inhibits rat brain kynurenic acid production via selective interference with kynurenine aminotransferase II. Kocki T, Luchowski P, Luchowska E, Wielosz M, Turski WA, Urbanska EM. Department of Pharmacology and Toxicology, Medical University, Jaczewskiego 8, 20-090 Lublin, Poland. 2. Biochem Biophys Res Commun. 2003 May 23;305(1):94-100. L-cysteine administration prevents liver fibrosis by suppressing hepatic stellate cell proliferation and Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 287

activation. Horie T, Sakaida I, Yokoya F, Nakajo M, Sonaka I, Okita K. Pharmaceuticals Research Laboratories, Ajinomoto Co, Inc, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki 210-8681, Japan. 3. Russ J Immunol. 2002 Apr;7(1):48-56. Up-regulation of interferon-gamma production by reduced glutathione, anthocyane and L-cysteine treatment in children with allergic asthma and recurrent respiratory diseases. Chernyshov VP, Omelchenko LI, Treusch G, Vodyanik MA, Pochinok TV, Gumenyuk ME, Zelinsky GM. Institute of Pediatrics, Obstetrics and Gynecology, Academy of Medical Sciences, Kiev, Ukraine. chernyshov@ukr.net 4. Proc Nutr Soc. 2000 Nov;59(4):595-600. Glutathione and immune function. Droge W, Breitkreutz R. Department of Immunochemistry, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. W.Droege@dkfz-heidelberg.de 5. Toxicol Appl Pharmacol. 2000 Oct 1;168(1):72-8. gamma-Glutamyl transpeptidase and L-cysteine regulate methylmercury uptake by HepG2 cells, a human hepatoma cell line. Wang W, Clarkson TW, Ballatori N. Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, New York 14642, USA. 6. Amino Acids. 2000;18(4):319-27. Polyamines and thiols in the cytoprotective effect of L-cysteine and L-methionine on carbon tetrachloride-induced hepatotoxicity. Chen W, Kennedy DO, Kojima A, Matsui-Yuasa I. Department of Food and Nutrition, Faculty of Human Life Science, Osaka City University, Osaka, Japan. 7. Z Naturforsch [C]. 2000 Mar-Apr;55(3-4):271-7. Protective effect of L-cysteine and glutathione on rat brain Na+,K+-ATPase inhibition induced by free radicals. Tsakiris S, Angelogianni P, Schulpis KH, Behrakis P. Department of Experimental Physiology, University of Athens, Medical School, Greece. stsakir@cc.uoa.gr 8. Comp Biochem Physiol B Biochem Mol Biol. 1997 Feb;116(2):223-6. L-cysteine metabolism in guinea pig and rat tissues. Wrobel M, Ubuka T, Yao WB, Abe T. Department of Biochemistry, Okayama University Medical School, Japan. 9. Elevated hepatic gamma-glutamylcysteine synthetase activity and abnormal sulfate levels in liver and muscle tissue may explain abnormal cysteine and glutathione levels in SIV-infected rhesus macaques. Gross A, Hack V, Stahl-Hennig C, Droge W. AIDS Res Hum Retroviruses. 1996 Nov 20;12(17):1639-41. 10. Biochem Pharmacol. 1996 May 3;51(9):1111-6. Maintenance of hepatic glutathione homeostasis and prevention of acetaminophen-induced cataract in mice by L-cysteine prodrugs. Rathbun WB, Killen CE, Holleschau AM, Nagasawa HT. Department of Ophthalmology, University of Minnesota, Minneapolis, USA.

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22. J Biol Chem. 1984 May 10;259(9):5606-11. Free radical metabolites of L-cysteine oxidation. Harman LS, Mottley C, Mason RP. 23. Preventing Hypoglycemia Anti-Aging News, January 1982 Vo.2, No. 1 pg 6-7 24. Hum Genet. 1979;50(1):51-7. Chromosomal breakage in Crohn's disease: anticlastogenic effect of D-penicillamine and L-cysteine. Emerit I, Emerit J, Levy A, Keck M. 25. Annu Rev Plant Biol. 2002;53:159-82. Phytochelatins and metallothioneins: roles in heavy metal detoxification and homeostasis. Cobbett C, Goldsbrough P. Department of Genetics, University of Melbourne, Parkville, Australia 3052. ccobbett@unimelb.edu.au 26. J Biol Chem. 2001 Jun 15;276(24):20817-20. Epub 2001 Apr 19. A new pathway for heavy metal detoxification in animals. Phytochelatin synthase is required for cadmium tolerance in Caenorhabditis elegans. Vatamaniuk OK, Bucher EA, Ward JT, Rea PA. Department of Biology, Plant Science Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6018, USA. 27. Biol Trace Elem Res. 2000 Jul;76(1):19-30. Study of the effect of the administration of Cd(II), cysteine, methionine, and Cd(II) together with cysteine or methionine on the conversion of xanthine dehydrogenase into xanthine oxidase. Esteves AC, Felcman J. Department of Chemistry, Pontificia Universidade Catolica do Rio de Janeiro, Rio de Janeiro, Brazil. 28. Altern Med Rev. 1998 Aug;3(4):262-70. Cysteine metabolism and metal toxicity. Quig D. Doctor's Data, Inc., West Chicago, IL, USA. dquig@doctorsdata.com 29. J Nutr. 1987 Jun;117(6):1003-10. Pharmacologic role of cysteine in ameliorating or exacerbating mineral toxicities. Baker DH, Czarnecki-Maulden GL. 30. J Infect Dis. 2000 Sep;182 Suppl 1:S81-4. Regulation of cysteine-rich intestinal protein, a zinc finger protein, by mediators of the immune response. Cousins RJ, Lanningham-Foster L. Food Science and Human Nutrition Department, Center for Nutritional Sciences, University of Florida, Gainesville, FL 32611-0370, USA. 31. Am J Med. 1991 Sep 30;91(3C):140S-144S. Modulation of lymphocyte functions and immune responses by cysteine and cysteine derivatives. Droge W, Eck HP, Gmunder H, Mihm S. Division of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, F.R.G. 32. Salim AS. Sulfhydryl-containing agents in the treatment of gastric bleeding induced by nonsteroidal anti-inflammatory drugs. Can J Surgery 1993;36:5358.

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33. Droge W, Eck HP, Gander H, Mihm S. Modulation of lymphocyte functions and immune responses by cysteine and cysteine derivatives. Am J Med 1991;91(suppl 3C):140S44S. 34. Umbach, JA & Gundersen CB Evidence that cysteine string proteins regulate an early step in the Ca++-dependent secretion of transmitter at Drosophila neuromuscular junctions.. J. Neuroscience 1997; 17: 7203-7209. 35. Coppola,T & Gundersen, CB Widespread expression of human cysteine string proteins.. FEBS Letters 1996; 391: 269-272. 36. Kohan,SA, Pescatori,M, Brecha,N, Mastrogiacomo,A, Umbach,JA & Gundersen, CB Cysteine string protein immunoreactivity in the nervous system and adrenal gland of the rat.. J. Neuroscience 1995; 15: 6230-6238. 37.Gundersen, CB, Mastrogiacomo,A, & Umbach, JA Cysteine string proteins as templates for membrane fusion: models of synaptic vesicle exocytosis.. J. Theoretical Biology 1995; 172: 269-277. 38. Mastrogiacomo,A & Gundersen, CB The nucleotide and deduced amino acid sequence of a rat cysteine string protein.. Mol. Brain Research 1995; 28: 12-18. 39. Mastrogiacomo,A., Parsons,S.M., Zampighi,G.A., Jenden,D.J. Umbach, J.A. & Gundersen, C.B. Cysteine string proteins: a potential link between synaptic vesicles and presynaptic calcium channels.. Science 1994; 263: 981-982. 40. Gundersen,CB, Mastrogiacomo,A, Faull, K, & Umbach, JA Extensive lipidation of a Torpedo cysteine string protein.. J. Biol. Chem. 1994; 269: 19197-19199. 41. Umbach,JA, Zinsmaier,KE, Eberle,KK, Buchner,E, Benzer, S & Gundersen CB Presynaptic dysfunction in Drosophila csp mutants.. Neuron 1994; 13: 899-907. 42.Gundersen, C.B. and J.A. Umbach Suppression cloning of the cDNA for a candidate subunit of a presynaptic calcium channel.. Neuron 1992; 9: 527-537. 43. Anderson R, Lukey PT, Theron AJ, Dippenaar U. Ascorbate and cysteine-mediated selective neutralization of extracellular oxidants during N-formyl peptide activation of human phagocytes. Agents Actions. 1987;20:77-86. 44. Anderson R, Theron AJ, Ras GJ. Regulation by the antioxidants ascorbate, cysteine, and dapsone of the increased extracellular and intracellular generation of reactive oxidants by activated phagocytes from cigarette smokers. Am Rev Respir Dis. 1987; 135:1027-1032 45. Asper R, Schmucki O. Cystinuric therapy by ascorbic acid. Urol Int. 1982;37:91-109.

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46. Campbell NR, Reade PC, Radden BG. Effect of cysteine on the survival of mice with transplanted malignant lymphoma. Nature. 1974;251:158-159. 47. Csako G. False-positive results for ketone with the drug mensa and other freesulfhydryl compounds. Clin Chem. 1987;33(2 pt 1):289-292. 48. Fettman MJ, Valerius KD, Ogilvie GK. Effects of dietary cysteine on blood sulfur amino acid, glutathione, and malondialdehyde concentrations in cats. Am J Vet Res. 1999;60:328-333. 49. Oeriu S, Vachitu E. The effect of the administration of compounds which contain sulfhydryl groups on the survival rate of mice, rats and guinea pigs. Journ Geront. 1965;20;47. 50. Stipanuk MH. Homocysteine, cysteine and taurine. In: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. Ninth edition. Baltimore, MD: Williams & Wilkins; 1999:543-558.

Blue Cohosh Root 2 Studies


1. Castleman M. The Healing Herbs. New York: Bantam Books, 1991, 1203. 2. Foster S. Herbal Renaissance. Salt Lake City: Gibbs-Smith Publisher, 1993, 4850.

Siberian Ginseng Root 40 Studies


1. Blumenthal M, ed. The Complete German Commission E Monographs. Boston, Mass: Integrative Medicine Communications; 1998:124-125. 2. Bucci LR. Selected herbals and human exercise performance. Am J Clin Nutr. 2000;72(suppl):624S-636S. 3. Fugh-Berman A. Herb-drug interactions. Lancet. 2000;355:134-138. 4. Glatthaar-Saalmuller B, Sacher F, Esperester A. Antiviral activity of an extract derived from roots of Eleutherococcus senticosus. Antiviral Res. 2001;50(3):223-8. 5. Gyllenhaal C, Merritt SL, Peterson SD, Block KI, Gochenour T. Efficacy and safety of herbal stimulants and sedatives in sleep disorders. Sleep Med Rev. 2000;4(2):229-251.

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6. Harkey MR, Henderson GL, Gershwin ME, Stern JS, Hackman RM. Variability in commercial ginseng products: an analysis of 25 preparations. Am J Clin Nutr. 2001;73:1101-1106. 7. Kelly GS. Nutritional and botanical interventions to assist with the adaptation to stress. Alt Med Rev. 1999;4(4):249-265. 8. Koren G, Randor S, Martin S, Danneman D. Maternal ginseng use associated with neonatal androgenization [letter]. JAMA. 1990;264(22):2866. 9. McRae S. Elevated serum digoxin levels in a patient taking digoxin and Siberian ginseng. Can Med Assoc J. 1996;155:293295. 10. Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med. 1998;158(20):22002211. 11. Newall CA, Anderson LA, Phillipson JD. Herbal Medicines: A Guide for Health Care Professionals. London, England: The Pharmaceutical Press; 1996:141-144. 12. Ott BR, Owens NJ. Complementary and alternative medicines for Alzheimer's disease. J Geriatr Psychiatry Neurol. 1998;11:163-173. 13. Pizzorno JE, Murray MT, eds. Textbook of Natural Medicine. New York, NY: Churchill-Livingstone; 1999:433-434;531-532;713-717;1385-1386. 14. Sinclair S. Male infertility: nutritional and environmental considerations. Alt Med Rev. 2000;5(1):28-38. 15. Vogler BK, Pittler MH, Ernst E. The efficacy of ginseng. A systematic review of randomized clinical trials. Eur J Clin Pharmacol. 1999;55:567-575. 16. White L, Mavor S. Kids, Herbs, Health. Loveland, Colo: Interweave Press; 1998:22, 40. 17. Williams M. Immuno-protection against herpes simplex type II infection by eleutherococcus root extract. Int J Alt Comp Med. 1995;13:9-12. 18. Winther K, Ranlov C, Rein E, Mehlsen J. Russian root (Siberian ginseng) improves cognitive functions in middle-aged people, whereas Ginkgo biloba seems effective only in the elderly. J Neurol Sci. 1997;150:S90. 19. Wong AHC, Smith M, Boon HS. Herbal remedies in psychiatric practice. Arch Gen Psychiatry. 1998;55:1033-1044. 20. Awang, D.V.C. 1991a. Maternal Use of Ginseng and Neonatal Androgenization. JAMA, April 10, 265(14):1828. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 293

21. Awang, D.V.C. 1991b. Maternal Use of Ginseng and Neonatal Androgenization. JAMA, July 17, 266(3):363. 22. Blumenthal, M., T. Hall, R. Rister, B Steinhoff (eds.), S. Klein, R. Rister (trans.). 1996. The German Commission E Monographs. Austin, Texas: American Botanical Council. 23. Baranov, A.I. 1979. "On a Technical English Name for Eleutherococcus" Taxon 28:586-587. 24. Duke, J. A. and E.S. Ayensu. 1985. Medicinal Plants of China. 2 vols. Algonac, MI: Reference Publications. 25. Farnsworth, N.R., A. D. Kinghorn, D.D. Soejarto and D. P. Waller. 1985. "Siberian Ginseng (Eleutherococcus senticosus): Current Status as an Adaptogen" pp. 155-215. In H. Wagner, H.Hikino and N.R. Farnsworth (eds.). Economic and Medicinal Plant Research. Vol. 1. Orlando, FL: Academic Press. 26. Foster, S. and C. X. Yue. 1992. Herbal Emmissaries: Bringing Chinese Herbs to the West. Rochester, Vt: Healing Arts Press. 27. Fulder, S. 1980. "The Drug That Builds Russians" New Sci. 21:576-579. 28. Halstead, BW. and L.L. Hood. 1984. Eleutherococcus senticosus Siberian Ginseng: An Introduction to the Concept of Adaptogenic Medicine. Long Beach, CA: Oriental Healing Arts Institute. 29. Hu, S.Y. 1979. (letter to S. Foster) p. 44 In S. Foster. "Ginseng: Are You Confused: A Look at Controversy in the Herb World" Well-Being No. 46: 43-50 (October, 1979). 30. Hu, S.Y. 1980. "Eleutherococcus vs. Acanthopanax. " Journ. Arn. Arb. 61: 107-111. 31. Hu, S.Y. 1980b. An Enumeration of Chinese Materia Medica. Hong Kong: The Chinese University Press. 32. Koren, G. S. Randor, S. Martin, and D. Danneman. 1990. Maternal Use of Ginseng and Neonatal Androgenization. JAMA, Dec. 12, 264(22):2866. 33. Lucas R. 1973. Eleuthero (Siberian Ginseng) Health Herb of Russia. Spokane WA: R&M Books. 34. McCaleb, R. 1988. "Dr. I.I. Brekhman (interview)." HerbalGram 16:11-12. 35. Ohwi, J. 1965. Flora of Japan. Washington, D.C.: Smithsonian Institution.

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36. Pharmacopeia Committee of the Ministry of Health. 1985. Pharmacopeia of the People's Republic of China (Zhong Hua Ren Min Gong He Guo Yao, Dian, Ti Bu). Part 1. Beijing: People's Health Publishing House and Chemical Industry Publishing House. 37. Poyarkova, A.I. 1973. Eleutherococcus pp. 16-23. In B.K. Shishkin. Flora of the U.S.S.R. (1950) Translated from Russian. Jerusalem: Israel Program for Scientific Translations. 38. Soejarto, D.D. and N. R. Farnsworth. 1978. "The Correct Name for Siberian Ginseng" Bot. Mus. Leafl., Harv. Univ. 26 (9-10): 339-341. 39. Wagner, H. and A. Proksch. 1985. "Immunostimulatory Drugs of Fungi and Higher Plants" pp. 111- 153. In H. Wagner, H. Hikino and N.R. Farnsworth (eds.). Economic and Medicinal Plant Research. Vol. 1. Orlando, FL: Academic Press. 40. Waller, D. P., A. M. Martin, N. R. Farnsworth, and D.V.C. Awang. 1992. Lack of Androgenicity of Siberian ginseng. JAMA, May 6, 267(17):2329.

Rosemary Leaves 17 Studies


1. Masuda T et al. J Agric Food Chem 2002;50(21):5863-5869 2. al-Sereiti MR et al. Indian J Exp Biol 1999; 37(2):124-130 3. Saen-Lopez R et al. J Chromatogr A 2002953(1-2):251-256 4. Lee KG, Shibamoto T. J Agric Food Chem 2002; 50(17):4947-4952 5. Torre J et al. J Chromatogr A 2001;919(2):305-311 6. Slamenova D et al. Cancer Lett 2002;177(2):145-153 7. Zhu BT et al. Carcinogenesis 1998:19(10):1821-1827 8. Calabrese V et al. Int J Tissue React 2000;22(1):5-13

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9. Calabrese V et al. Int J Tissue React 2001;23(2):51-58 10. Debersac P et al. Food Chem Toxicol 2001:39(9):907-918 11. Halaoui M et al. J Ethnopharmacol 2000; 71(3):465-472 12. Int J Tissue React. 2000;22(1):5-13. 13. Biochemical studies of a natural antioxidant isolated from rosemary and its application in cosmetic dermatology. Calabrese V, Scapagnini G, Catalano C, Dinotta F, Geraci D, Morganti P. Department of Biochemistry, Faculty of Medicine, University of Catania, Italy. Calabrese@mbox.Unict.it. 14. Zhu BT, Loder DP, Cai MX, Ho CT, Huang MT, Conney AH. Dietary administration of an extract from rosemary leaves enhances the liver microsomal metabolism of endogenous estrogens and decreases their uterotropic action in CD-1 mice. Carcinogenesis. 1998 Oct;19(10):1821-7 15. Inoue K, Takano H, Shiga A, Fujita Y, Makino H, Yanagisawa R, Ichinose T, Kato Y, Yamada T, Yoshikawa T. Effects of volatile constituents of a rosemary extract on allergic airway inflammation related to house dust mite allergen in mice. Int J Mol Med. 2005 Aug;16(2):315-9. 16. Hsu S. Green tea and the skin. J Am Acad Dermatol. 2005 Jun;52(6):1049-59. 17. Samman S, Sandstrom B, Toft MB, Bukhave K, Jensen M, Sorensen SS, Hansen M. Green tea or rosemary extract added to foods reduces nonheme-iron absorption. Am J Clin Nutr. 2001 Mar;73(3):607-12.

Apsartic Acid 21 Studies


1. H G Pandya, S C Coley, I D Wilkinson, and P D Griffiths. Magnetic resonance spectroscopic abnormalities in sporadic and variant Creutzfeldt-Jakob disease. Clin Radiol, 58(2):148-53, February 2003. 2. D Galanaud, D Dormont, D Grabli, P Charles, J J Hauw, C Lubetzki, J P Brandel, C Marsault, and P J Cozzone. MR spectroscopic pulvinar sign in a case of variant Creutzfeldt-Jakob disease. J Neuroradiol, 29(4):285-7, December 2002. 3. Oncol Rep. 2006 Jan;15(1):113-7. Inhibition of proliferative and invasive capacities of breast cancer cells by arginine-glycine-aspartic acid peptide in vitro. Yang W, Meng L, Wang H, Chen R, Wang R, Ma X, Xu G, Zhou J, Wang S, Lu Y, Ma D. Cancer Biology Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 296

Research Center, Tongji Hospital, Tongji Medical School, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.. 4. Appl Microbiol. 1972 April; 23(4): 758764. Effect of L-Aspartic Acid and LGlutamic Acid on Production of L-Proline. Jyoji Kato, Masahiko Kisumi, and Ichiro Chibata. Department of Applied Biochemistry, Chemical Research Laboratory, Tanabe Seiyaku Co., Ltd., Kashimacho, Higashiyodogawa-ku, Osaka, Japan. Bac P, Pages N, Herrenknecht CLA, Teste JF. Magnes Res. 1995; 8:37-45.

5. de Haan A, van Doorn JE, Westra HG. Effects of potassium + magnesium aspartate on muscle metabolism and force development during short static exercise. Int J Sports Med. 1985; 6:44-49. 6. Hagan RD, Upton SJ, Duncan JJ, et al. Absence of effect of potassium- magnesium aspartate on physiologic responses to prolonged work in aerobically trained men. Int J Sports Med. 1982; 3:177-181. 7. Hicks JT. Treatment of fatigue in general practice: a double-blind study. Clinical Medicine. 1964; 71:85-90. 8. Maughan RJ, Sadler DJ. The effects of oral administration of salts of aspartic acid on the metabolic response to prolonged exhausting exercise in man. Int J Sports Med. 1983; 4:119-123.

9. Trudeau F, Murphy R. Effects of potassium-aspartate salt administration on glycogen use in the rat during a swimming stress. Physiol Behav. 1993; 54:7-12.

10. Tuttle JL, Potteiger JA, Evans BW, Ozmun JC. Effects of acute potassiummagnesium aspartate supplementation on ammonia concentrations during and after resistance training. Int J Sport Nutr. 1995; 5:102-109. 11. I . H. Koyuncuoglu and others, "The antagonizing effect of aspartic acid on the brain levels of monoamines and free amino acids during the development of tolerance to and physical dependence on morphine", Psychopharmacology, vol. 54, 1977, pp. 187 - 191. 12. H. Koyuncuoglu and M. Gungor, "Effect of nialamaide and reserpine on brain free amino acids of rats dependent on and withdrawn from morphine", Drug Research ,vol. 25, 1975, pp. 1762 - 1766.

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13. H. Koyuncuoglu and others, "The antagonizing effect of aspartic acid on morphine withdrawal and levallorphan-precipitated abstinence syndrome signs and on associated changes in brain levels of free amino acids in the rat", Psychopharmacology ,vol. 62, 1979, pp. 89 - 95. 14. L. Eroglu and H. Koyuncuoglu, "The effect of aspartic acid on the intensity of physical dependence in morphine dependent mice", Polish Journal of Pharmacology ,vol. 31 , 1979, pp. 83 - 88. 15. E. Genc, L. Eroglu and H. Koyuncuoglu, "Further hints on morphine - aspartic acid interaction", Medical Bulletin of Istanbul University, vol. 11, 1978, pp. 137 - 141. 16. H. Koyuncuoglu, L. Eroglu and T. Altug, "Effects of aspartic acid, asparagine and/or L-asparaginase on forced swimming-induced immobility, analgesia and decrease in rectal temperature in rats", Experientia ,vol. 38, 1982, pp. 117 - 118. 17. H. Koyuncuoglu and E. Genc, "The antagonizing effect of aspartic acid on morphine physical dependence in mice: its relation to brain biogenic monoamines and cAMP", Medical Bulletin of Istanbul University ,vol. 12, 1979, pp. 27 - 36. 18. H. Koyuncuoglu and others, "Mutual effects of morphine and aspartic acid on brain levels in mice", Psychopharmacology ,vol. 52, 1977, pp. 181 - 184. 19. H. Koyuncuoglu and others, "The antagonistic effects of aspartic acid on some effects of morphine on rats", European Journal of Pharmacology ,vol. 27, 1974, pp. 148 - 150. 20. H. Koyuncuoglu and others, "The relationship between morphine, aspartic acid and L-asparaginase in rats", European Journal of Pharmacology ,vol. 60, 1979, pp. 369 - 372. 21. H. Koyuncuoglu and others, "Antagonizing effect of aspartic acid on the development of physical dependence on and tolerance to morphine in the rat", Drug Research ,vol. 27, 1977, pp. 1676 - 1679.

L-Glutamine 58 Studies
1. Tischler, ME et al. J Biol Chem 1982; 257:1613-21 2. Jepson, MM et al. Am J. Physiol 1988; 255 3. Maclennan, PA et al. FEBS, Letters 1987; 215:187-191 4. Max, SR et al. Med Sci Sports Exerc 1990; 22:325-330 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 298

5. Stehle, P. et al. Lancet 1989; 231-233 6. Hammarquist, F. et al. Ann Surgery 1989; 209:455-61 7. Werneman, J. et al. Metabolism 1989;(suppl 1):63-66 8. Werneman, J. et al. Lancet 1990; 335:701-3 9.Cerra, FB et al. Ann Surgery 1984; 199:288-91 10. Bonau, RA et al. Surgery 1987; 101:400-7 11. Bonau, RA et al. JPEN 1984; 8:622-27 12. Vinnars, E. et al. Ann Surgery 1975; 163:665-70 13. Carli, F. et al. Clin Sci 1990; 78:6231-8 14. Askanazi, J. et al. Ann Surgery 1980; 192:78-85 15. Furst, P. et al. In Clinical Nutrition 1981; 10-17 16. Muhlbacher, F. et al. Am J Physiol 1984; 14 17. Rennie, MJ et al. Clin Sci 1981; 61:627-39 18. Vinnars, E. et al. JPEN 1990; 14:1258-9 19. Wernerman, J. et al. Clin Nutr 1987; 6(suppl):33 20. Rennie, MJ et al. Lancet 1986; ii:1008-12 21. Furst, P. Proc. 6th Congr. ESPEN, Milan 1984; 21-53 22. Bulus, N. et al. Metabolism 1989; 38(8, suppl 1):1-15 23. Stryer, L. Biochemistry (3rd edition) 1988 24. Shabert, J., MD et al. The Ultimate Nutrient: Glutamine, 1994 25. Cooper, K. Anti-Oxidant Revolution, 1994 26.Lowe, DK et al. Glutamine-Enriched Parenteral Nutrition Is Safe in Normal Humans, Surg Forum 40 1989; 9-11

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27. Ziegler, TR et al. Safety and Metabolic Effects of L-Glutamine Administration in Hunians, JPEN 14 1990; 137S-146S 28. Emery, AEH et al. Antenatal Diagnosis and Amino Acid Composition of Amniotic Fluid, Lancet I 1970: 1307-1308 29. Hawkins, RA Hyperammenomia Does Not Impair Brain Function in the Absence of Net Glutamine Synthesis, Biochem J 277 1991: 697-703 30. Gant, C., MD Interview on Ammonia Clearance and Liver Dysfunction, April 5, 1995. 31. Souba WW. Glutamine Physiology, Biochemistry, and Nutrition in Critical Illness. Austin, TX: R.G. Landes Co.; 1992. 32. Askanazi J, Carpenter YA, Michelsen CB, et al. Muscle and plasma amino acids following injury: Influence of intercurrent infection. Ann Surg 1980;192:78-85. 33. O'Dwyer ST, Smith RJ, Hwang TL, Wilmore DW. Maintenance of small bowel mucosa with glutamine-enriched parenteral nutrition. J Parent Enteral Nutr 1989;13:579585. 34. Hwang TL, O'Dwyer ST, Smith RJ, et al. Preservation of small bowel mucosa using glutamine-enriched parenteral nutrition. Surg Forum 1987;38:56. 35. Li J, Langkamp-Henken B, Suzuki K, Stahlgren LH. Glutamine prevents parenteral nutrition-induced increases in intestinal permeability. J Parent Enteral Nutr 1994;18:303307. 36. Barber AE, Jones WG, Minei JP, et al. Glutamine or fiber supplementation of a defined formula diet. Impact on bacterial translocation, tissue composition, and response to endotoxin. J Parent Enteral Nutr 1990;14:335-343. 37. Khan J, Iiboshi Y, Cui L, et al. Alanyl-glutamine-supplemented parenteral nutrition increased luminal mucus gel and decreased permeability in the rat small intestine. J Parent Enteral Nutr 1999;23:24-31. 38. Kanuchi O, Iwanaga T, Mitsuyama K. Germinated barley foodstuff feeding. A novel neutraceutical therapeutic strategy for ulcerative colitis. Digestion 2001;63:60-67. 39. Slotwinski R, Pertkiewicz M, Lech G, Szczygiel B. Cellular immunity changes after total parenteral nutrition enriched with glutamine in patients with sepsis and malnutrition. Pol Merkuriusz Lek 2000;8:405-408. [Article in Polish] 40. O'Flaherty L, Bouchier-Hayes DJ. Immunonutrition and surgical practice. Proc Nutr Soc 1999;58:831-837. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 300

41. Jian ZM, Cao JD, Zhu XG, et al. The impact of alanyl-glutamine on clinical safety, nitrogen balance, intestinal permeability, and clinical outcome in postoperative patients; a randomized, double-blind, controlled study of 120 patients. J Parenter Enteral Nutr 1999;23:S62-S66. 42. Barbosa E, Moreira EA, Goes JE, Faintuch J. Pilot study with a glutaminesupplemented enteral formula in critically ill infants. Rev Hosp Clin Fac Med Sao Paulo 1999;54:21-24. 43. Castell LM, Poortmans JR, Newsholme EA. Does glutamine have a role in reducing infections in athletes? Eur J Appl Physiol Occup Physiol 1996;73:488-490. 44. Shabert JK, Wilmore DW. Glutamine deficiency as a cause of human immunodeficiency virus wasting. Med Hypotheses 1996;46:252-256. 45. Noyer CM, Simon D, Borczuk A, et al. A double-blind placebo-controlled pilot study of glutamine therapy for abnormal intestinal permeability in patients with AIDS. Am J Gastroenterol 1998;93:972-975. 46. Clark RH, Feleke G, Din M, et al. Nutritional treatment for acquired immunodeficiency virus-associated wasting using beta-hydroxy beta-methylbutyrate, glutamine, and arginine: a randomized, double-blind, placebo-controlled study. J Parenter Enteral Nutr 2000;24:133-139. 47. Klimberg VS, McClellan JL. Glutamine, cancer, and its therapy. Am J Surg 1996;172:418-424. 48. Ollenschlager G, Simmel A, Roth E. Availability of glutamine from peptides and acetylglutamine for human tumor-cell cultures. Metabolism 1989;38:S40-S42. 49. Moyer MP, Armstrong A, Aust JB, et al. Effects of gastrin, glutamine, and somatostatin on the in vitro growth of normal and malignant human gastric mucosal cells. Arch Surg 1986;121:285-288. 50. Fahr MJ, Kombluth J, Blossom S, et al. Harry M. Vars Research Award. Glutamine enhances immunoregulation of tumor growth. J Parenter Enteral Nutr 1994;18:471-476. 51. van der Hulst RR, yon Meyenfeldt MF, Deutz NE, Soeters PB. Glutamine extraction by the gut is reduced in patients with depleted gastrointestinal cancer. Ann Surg 1997;225:112-121. 52. Daniele B, Perrone F, Gallo C, et al. Oral glutamine in the prevention of fluorouracil induced intestinal toxicity: a double blind, placebo controlled, randomised trial. Gut 2001;48:28-33.

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53. Yoshida S, Matsui M, Shirouzu Y, et al. Effects of glutamine supplements and radiochemotherapy on systemic immune and gut barrier function in patients with advanced esophageal cancer. Ann Surg 1998;227:485-491. 54. Anderson PM, Ramsay NK, Shu XO, et al. Effect of low-dose oral glutamine on painful stomatitis during bone marrow transplantation. Bone Marrow Transplant 1998;22:339-344. 55. Brown SA, Goringe A, Fegan C, et al. Parenteral glutamine protects hepatic function during bone marrow transplantation. Bone Marrow Transplant 1998;22:281-284. 56. Ziegler TR, Bye RK, Persinger RL. Effects of glutamine supplementation on circulating lymphocytes after bone marrow transplantation: a pilot study. Am J Med Sci 1998;315:4-10. 57. Coghlin Dickson TM, Wong RM, Offrin RS, et al. Effect of oral glutamine supplementation during bone marrow transplantation. J Parenter Enteral Nutr 2000;24:61-66. 58. Schloerb PR, Skikne BS. Oral and parenteral glutamine in bone marrow transplantation: a randomized, double-blind study. J Parenteral Enteral Nutr 1999;23:117122.

L-Tyrosine 53 Studies
1. Kearns LR, Phillips MC, Ness-Abramof R, et al: Update on parenteral amino acids. Nutr Clin Pract 16:219-225, 2002 2. Moller N, Meek S, Bigelow M, et al: The kidney is an important site for in vivo phenylalanine-to-tyrosine conversion in adult humans: A metabolic role of the kidney. Proc Natl Acad Sei USA 97:1242-1246, 2000 3. Panel on Macronutrients, Subcommittees on Upper Reference Levels of Nutrients and Interpretation and Uses of Dietary Reference Intakes, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes: Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). Food and Nutrition Board, Institute of Medicine, National Academy Press, Washington DC, 2002 4. Basile-Filho A, El-Khoury AE, Beaumier L, et al: Continuous 24-h L-[1-^sup 13^C] phenylalanine and L-[3, 3-^sup 2^H^sub 2^] tyrosine oral-tracer studies at an intermediate phenylalanine intake to estimate requirements in adults. Am J CHn Nutr 65:473-488, 1998 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 302

5. Im HA, Meyer PD, Stegink LD: N-acetyl-L-tyrosine as a tyrosine source during total parenteral nutrition in adult rats. Pediatr Res 19:514-518, 1985 6. Frst P: New developments in glutamine delivery. J Nutr 131: 2562S-2568S, 2001 7. Heird WC, Dell RB, Helms RA, et al: Amino acid mixture designed to maintain normal plasma amino acid patterns in infants and children requiring parenteral nutrition. Pediatrics 80:401-408, 1987 8. Heird WC, Hay W, Helms RA, et al: Pediatric parenteral amino acid mixture in low birth weight infants. Pediatrics 81:41-50, 1988 9. Christensen ML, Helms RA, Veal DF, et al: Clearance of N-acetyl-L-tyrosine in infants receiving a pediatrie amino acid solution. Clin Pharmacol 12:606-609, 1993 10. Van Goudoever JB, Sulkers EJ, Timmerman M, et al: Amino acid solutions for premature neonates during the first week of life: The role of N-acetyl-L-cysteine and Nacetyl-L-tyrosine. JPEN 18:404-408, 1994 11. Druml W, Hubl W, Roth E, et al: Utilization of tyrosine-containing dipeptides and Nacetyl-tyrosine in hepatic failure. Hepatology 21:923-928, 1985 12. Druml W, Roth E, Lenz K, et al: Phenylalanine and tyrosine metabolism in renal failure: Dipeptides as tyrosine source. Kidney Int 27:8282-8286, 1989 13. Druml W, Lochs H, Roth E, et al: Utilization of tyrosine dipeptides and acetyltyrosine in normal and uremic humans. Am J Physiol 260:E280-E285, 1991 14. Magnusson I, Ekman L, Wangdahl M, et al: N-acetyl-L-tyrosine and N-acetyl-Lcysteine as tyrosine and cysteine precursors during intravenous infusion in humans. Metabolism 38:957-961, 1989 15. Gazzaniga AB, Waxman K, Day AT, et al: Nitrogen balance in adult hospitalized patients with the use of a pediatrie amino acid model. Arch Surg 123:1275-1279, 1988 16. Ogwu V, Cohen G: A simple colorimetric method for the simultaneous determination of N-acetylcysteine and cysteine. Free Rad Biol Med 25:362-364, 1998 17. Robitaille L, Hoffer LJ: Measurement of branched chain amino acids in blood plasma by high-performance liquid chromatography. Can J Physiol Pharmacol 66:613-617, 1988 18. Mackenzie TA, Clark NG, Bistrian BR, et al: A simple method for estimating nitrogen balance in hospitalized patients: A review and supporting data for a previously proposed technique. J Am Coll Nutr 4:575-581, 1985

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19. Venta R: Year-long validation study and reference values for urinary amino acids using a reversed-phase HPLC method. Clin Chem 47:575-583, 2001 20. Rudman D, Kutner M, Ansley J, et al: Hypotyrosinemia, hypocystinemia, and failure to retain nitrogen during total parenteral nutrition of cirrhotic patients. Gastroenterology 81:1025-1035, 1981 21. Garibotto G, Tessari P, Verzola D, et al: The metabolic conversion of phenylalanine into tyrosine in the human kidney: Does it have nutritional implications in renal patients? J Renal Nutr 12:8-16, 2002 22. Rieck J, Halkin H, Almog S, et al: Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers. J Lab CHn Med 134:238-243, 1999 23. Liu W, Lopez JM, VanderJagt DJ, et al: Evaluation of aminoaciduria in severely traumatized patients. Clin Chim Acta 316:123128, 2002 24. Roberts SA, Ball RO, Moore AM, et al: The effect of graded intake of glycyl-Ltyrosine on phenylalanine and tyrosine metabolism in parenterally fed neonates with an estimation of tyrosine requirement. Pediatr Res 49:111-119, 2001 25. JPEN J Parenter Enteral Nutr. 2003 Nov-Dec;27(6):419-22. N-acetyl-L-tyrosine as a tyrosine source in adult parenteral nutrition. Hoffer LJ, Sher K, Saboohi F, Bernier P, MacNamara EM, Rinzler D. 26. Am J Psychiatry. 2003 Oct;160(10):1887-9. Reduction of brain dopamine concentration with dietary tyrosine plus phenylalanine depletion: an [11C]raclopride PET study. Montgomery AJ, McTavish SF, Cowen PJ, Grasby PM. 27. Nutr Neurosci. 2003 Aug;6(4):237-46. Effects of tyrosine, phentermine, caffeine Damphetamine, and placebo on cognitive and motor performance deficits during sleep deprivation. Magill RA, Waters WF, Bray GA, Volaufova J, Smith SR, Lieberman HR, McNevin N, Ryan DH. 28. Nutr Neurosci. 2003 Aug;6(4):221-35. A comparison of tyrosine against placebo, phentermine, caffeine, and D-amphetamine during sleep deprivation. Waters WF, Magill RA, Bray GA, Volaufova J, Smith SR, Lieberman HR, Rood J, Hurry M, Anderson T, Ryan DH. 29. Awad AG. Diet and drug interactions in the treatment of mental illness a review. Can J Psychiatry. 1984;29:609-613. 30. Camacho F, Mazuecos J. Treatment of vitiligo with oral and topical phenylalanine: 6 years of experience. Arch Dermatol. 1999;135:216-217

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31. Chakraborty DP, Roy S, Chakroborty AK. Vitiligo, psoralen, and meanogenesis: some observations and understanding. Pigment Cell Res. 1996;9(3):107-116. 32. Chiaroni P, Azorin JM, Bovier P, et al. A multivariate analysis of red blood cell membrane transports and plasma levels of L-tyrosine and L-tryptophan in depressed patients before treatment and after clinical improvement. Neuropsychobiology. 1990;23(1):1-7. 33. Deijen JB, Orlebeke JF. Effect of tyrosine on cognitive function and blood pressure under stress. Brain Res Bull. 1994;33(3):319-323. 34. Fernstrom JD. Can nutrient supplements modify brain function? Am J Clin Nutr. 2000;71(6 Suppl):1669S-1675S. 35. Fugh-Berman A, Cott JM. Dietary supplements and natural products as psychotherapeutic agents. Psychosom Med. 1999;61:712-728. 36. Gelenberg AJ, Wojcik JD, Falk WE, et al. Tyrosine for depression: a double-blind trial. J Affect Disord. 1990;19:125-132. 37. Growdon JH, Melamed E, Logue M, et al. Effects of oral L-tyrosine administration on CSF tyrosine and homovanillic acid levels in patients with Parkinson's disease. Life Sci. 1982;30:827-832, 38. Hull KM, Maher TJ. L-Tyrosine potentiates the anorexia induced by mixed-acting sympathomimetic drugs in hyperphagic rats. J Pharmacol Exp Ther. 1990;255(2):403409. 39. Hull KM, Tolland DE, Maher TJ. L-tyrosine potentiation of opioid-induced analgesia utilizing the hot-plate test. J Pharmacol Exp Ther. 1994;269(3):1190-1195. 40. Kelly GS. Nutritional and botanical interventions to assist with the adaptation to stress. Altern Med Rev. 1999;4940;249-265. 41. Kirschmann GJ and Kirschmann JD. Nutrition Almanac, 4th ed. New York, NY: McGraw-Hill;1966:304. 42. Koch R. Tyrosine supplementation for phenylketonuria treatment. Am J Clin Nutr. 1996;64(6):974-975. 43. Menkes DB, Coates DC, Fawcett JP. Acute tryptophan depletion aggravates premenstrual syndrome. J Affect Disord. 1994;3291):37-44. 44. Meyers S. Use of neurotransmitter precursors for treatment of depression. Altern Med Rev. 2000;5(1):64-71.

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45. Neri DF, Wiegmann D, Stanny RR, Shappell SA, McCardie A, McKay DL. The effects of tyrosine on cognitive performance during extended wakefulness. Aviat Space Environ Med. 1995;66(4):313-319. 46. Parry BL. The role of central serotonergic dysfunction in the aetiology of premenstrual dysphoric disorder: therapeutic implications. CNS Drugs. 2001;15(4):277285. 47. Pizzorno JE and Murray MT. Textbook of Natural Medicine, Vol 2. New York, NY: Churchill Livingstone; 1999:1049-1059. 48. Poustie VJ, Rutherford P. Tyrosine supplementation for phenylketonuria. Cochrane Database Syst Rev. 2000;(2):CD001507. 49. Riederer P. L-Dopa competes with tyrosine and tryptophan for human brain uptake. Nutr Metab. 1980;24(6):417-423. 50. Smith ML, Hanley WB, Clarke JT, et al. Randomised controlled trial of tyrosine supplementation on neuropsychological performance in phenylketonuria. Arch Dis Child. 1998;78(2):116-121. 51. van Spronsen FJ, van Rijn M, Bekhof J, Koch R, Smit PG. Phenylketonuria: tyrosine supplementation in phenylalanine-restricted diets. Am J Clin Nutr. 2001;73(2):153-157. 52. Wagenmakers AJ. Amino acid supplements to improve athletic performance. Curr Opin Clin Nutr Metab Care. 1999;2(6):539-544. 53. Yehuda S. Possible anti-Parkinson properties of N-(alpha-linolenoyl) tyrosine. A new molecule. Pharmacol Biochem Behav. 2002;72(1-2):7-11.

Linoleic Acid 56 Studies


1. Conjugated linoleic acid: A powerful anticarcinogen from animal fat sources. Ip C.; Scimeca J.A.; Thompson H.J. CANCER (USA) , 1994, 74/3 (1050-1054). 2. Conjugated linoleic acid and atherosclerosis in rabbits. Lee K.N.; Kritchevsky D.; Pariza M.W. Atherosclerosis (Ireland), 1994, 108/1 (19-25). 3. Conjugated linoleic acid (9,11- and 10,12-octadecadienoic acid) is produced in conventional but not germ-free rats fed linoleic acid. Chin S.F.; Storkson J.M.; Liu W.; Albright K.J.; Pariza M.W. J. NUTR. (USA) , 1994, 124/5 (694-701)

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4. Inhibitory effect of conjugated dienoic derivatives of linoleic acid and beta-carotene on the in vitro growth of human cancer cells. Shultz TD; Chew BP; Seaman WR; Luedecke LO. Cancer Lett (NETHERLANDS) Apr 15 1992, 63 (2) p125-33, 5. Conjugated linoleic acid suppresses mammary carcinogenesis and proliferative activity of the mammary gland in the rat. Ip C; Singh M; Thompson HJ; Scimeca JA. Cancer Res (UNITED STATES) Mar 1 1994, 54 (5) p1212-5. 6. Conjugated linoleic acid suppresses mammary carcinogenesis and proliferative activity of the mammary gland in the rat. CANCER RES. (USA) , 1994, 54/5 (1212-1215) 7. Effect of cheddar cheese consumption on plasma conjugated linoleic acid concentrations in men. NUTR. RES. (USA) , 1994, 14/3 (373-386) 8. Differential stimulatory and inhibitory responses of human MCF-7 breast cancer cells to linoleic acid and conjugated linoleic acid in culture. ANTICANCER RES. (Greece), 1992, 12/6 B (2143-2145). 9. Inhibitory effect of conjugated dienoic derivatives of linoleic acid and beta-carotene on the in vitro growth of human cancer cells. CANCER LETT. (Ireland), 1992, 63/2 (125133) 10. Inhibition of Listeria monocytogenes by fatty acids and monoglycerides. APPL. ENVIRON. MICROBIOL. (USA) , 1992, 58/2 (624-629) 11. Recognition of cervical neoplasia by the estimation of a free-radical reaction product (octadeca-9,11-dienoic acid) in exfoliated cells. CLIN. CHIM. ACTA (NETHERLANDS) , 1987, 163/2 (149-152). 12. Feeding conjugated linoleic acid to animals partially overcomes catabolic responses due to endotoxin injection. BIOCHEM. BIOPHYS. RES. COMMUN. (USA) , 1994, 198/3 (1107-1112). 13. Conjugated linoleic acid (9,11- and 10,12-octadecadienoic acid) is produced in conventional but not germ-free rats fed linoleic acid. J. NUTR. (USA) , 1994, 124/5 (694701). 14. Conjugated linoleic acid and atherosclerosis in rabbits. ATHEROSCLEROSIS (Ireland) , 1994, 108/1 (19-25). 15. Conjugated linoleic acid is a growth factor for rats as shown by enhanced weight gain and improved feed efficiency. J. NUTR. (USA) , 1994, 124/12 (2344-2349) 16. Cows' milk fat components as potential anticarcinogenic agents. Journal of Nutrition (USA) , 1997, 127/6 (1055-1060).

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17. Effects of dietary conjugated linoleic acid on lymphocyte function and growth of mammary tumors in mice. Anticancer Research (Greece) , 1997, 17/2 A (987-993). 18. Conjugated linoleic acid suppresses the growth of human breast adenocarcinoma cells in SCID mice. Anticancer Research (Greece) , 1997, 17/2 A (969-973).
19. Lymphatic recovery, tissue distribution, and metabolic effects of conjugated lioleic

acid in rats. Journal of Nutritional Biochemistry (USA) , 1997, 8/1 (38-43). 20. Proliferative responses of normal human mammary and MCF-7 breast cancer cells to linoleic acid, conjugated linoleic acid and eicosanoid synthesis inhibitors in culture. Anticancer Research (Greece) , 1997, 17/1 A (197-203) 21. Conjugated linoleic acid modulates hepatic lipid composition in mice. Lipids (USA) , 1997, 32/2 (199-204). 22. Dietary conjugated linoleic acid modulation of phorbol ester skin tumor promotion. Nutrition and Cancer (USA) , 1996, 26/2 (149-157). 23. The efficacy of conjugated linoleic acid in mammary cancer prevention is independent of the level or type of fat in the diet. Carcinogenesis (United Kingdom) , 1996, 17/5 (1045-1050). 24. Dietary modifiers of carcinogenesis. Environmental Health Perspectives (USA) , 1995, 103/SUPPL. 8 (177-184). 25. Effects of C18 fatty acid isomers on DNA synthesis in hepatoma and breast cancer cells. Anticancer Research (Greece) , 1995, 15/5 B (2017-2021). 26. Effect of timing and duration of dietary conjugated linoleic acid on mammary cancer prevention. Nutrition and Cancer (USA) , 1995, 24/3 (241-247). 27. The role of phenolics, conjugated linoleic acid, carnosine, and pyrroloquinoline quinone as nonessential dietary antioxidants. Nutrition Reviews (USA) , 1995, 53/3 (4958). 28. Dietary conjugated linoleic acid reduces plasma lipoproteins and early aortic atharosclerosis in hypercholasterolemic hamsters. Artery (USA) , 1997, 22/5 (266-277). 29. Cesano A, Visonneau S, Scimeca JA, et al. Opposite effects of linoleic acid and conjugated linoleic acid on human prostatic cancer in SCID mice. Anticancer Res 1998;18(3A):142934. 30. Thompson H, Zhu Z, Banni S, et al. Morphological and biochemical status of the mammary gland as influenced by conjugated linoleic acid: implication for a reduction in Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 308

mammary cancer risk. Cancer Res 1997;57:506772. 31. Ip C. Review of the effects of trans fatty acids, oleic acid, n-3 polyunsaturated fatty acids, and conjugated linoleic acid on mammary carcinogenesis in animals. Am J Clin Nutr 1997;66(suppl):1523S29S [review]. 32. Parodi PW. Cows' milk fat components as potential anticarcinogenic agents. J Nutr 1997;127:105560 [review]. 33. West DB, Delany JP, Camet PM, et al. Effects of conjugated linoleic acid on body fat and energy metabolism in the mouse. Am J Physiol 1998;275:R66772. 34. Park Y, Albright KJ, Liu W, et al. Effect of conjugated linoleic acid on body composition in mice. Lipids 1997;32:85358. 35. Sugano M, Tsujita A, Yamasaki M, et al. Conjugated linoleic acid modulates tissue levels of chemical mediators and immunoglobulins in rats. Lipids 1998;33:52127. 36. Nicolosi RJ, Rogers EJ, Kritchevsky D, et al. Dietary conjugated linoleic acid reduces plasma lipoproteins and early aortic atherosclerosis in hypercholesterolemic hamsters. Artery 1997;22:26677. 37. Lee KN, Kritchevsky D, Pariza MW, et al. Conjugated linoleic acid and atherosclerosis in rabbits. Atherosclerosis 1994;108:1925. 38. Houseknecht KL, Vanden Heuvel JP, Moya-Camarena SY, et al. Dietary conjugated linoleic acid normalizes impaired glucose tolerance in the Zucker diabetic fatty fa/fa rat. Biochem Biophys Res Commun 1998;244:67882. 39. Herbel BK, McGuire MK, McGuire MA, et al. Safflower oil consumption does not increase plasma conjugated linoleic acid concentrations in humans. Am J Clin Nutr 1998;67:33237. 40. Thom E. A pilot study with the aim of studying the efficacy and tolerability of Tonalin CLA on the body composition in humans. Medstat Research Ltd., Lillestrom, Norway, July 1997[unpublished]. 41. Banni S, Angioni E, Stefania M, et al. Conjugated linoleic acid and oxidative stress. J Am Oil Chem Soc. 1998; 75:261-267. 42. Belury MA. Conjugated linoleate: a polyunsaturated fatty acid with unique chemopreventive properties. Nutr Rev. 1995; 53:83-89.

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43. Cesano A, Visonneau S, Scimeca JA, et al. Opposite effects of linoleic acid and conjugated linoleic acid on human prostate cancer in SCID mice. Anticanc Res. 1998; 18:833-38. 44. de Deckere EA, van Amelsvoort JM, Mc Neill GP, Jones P. Effects of conjugated linoleic acid (CLA) isomers on lipid levels and peroxisome proliferation in the hamster. Br J Nutr. 1999; 82:309-17. 45. Gavino VC, Gavino G, Leblanc MJ, Tuchweber B. An isomeric mixture of conjugated linoleic acids but not pure cis-9, trans-11-octadecadienoic acid affects body weight gain and plasma lipids in hamsters. J Nutr. 2000; 130:27-29. 46. Houseknecht KL, Vanden Heuvel JP, Moya-Camarena SY, et al. Dietary conjugated linoleic acid normalizes impaired glucose tolerance in the Zucker diabetic fatty fa/fa rat. Biochem Biophys Res Commun. 1998; 244:678-682. 47. Lee KN, Pariza MW, Ntambi JM. Conjugated linoleic acid decreases hepatic stearoyl-CoA desaturase mRNA expression. Biochem Biophys Res Commun. 1998; 248:817-821. 48. McCarty MF. Downregulaton of macrophage activation by PPAR gamma suggests a role for conjugated linoleic acid in prevention of Alzheimer's disease. J Med Food. 1998; 1:217-226. 49. Moya-Camarena SY, Belury MA. Species differences in the metabolism and regulation of gene expression by conjugated linoleic acid. Nutr Rev. 1999; 57:336-340. 50. Ostrowski E, Muralitharan M, Cross RF. Dietary conjugated linoleic acids increase lean tissue and decrease fat deposition in growing pigs. J Nutr. 1999; 129:2037-2042. 51. Pariza MW, Park Y, Cook ME. Mechanisms of action of conjugated linoleic acid: evidence and speculation. Proc Soc Exp Biol Med. 2000; 223: 8-13. 52. Pariza MW, Parks Y, Cook ME. Conjugated linoleic acid and the control of cancer and obesity. Toxicol Sci. 1999; 51 (2 Suppl):107-110. 53. Pariza MW, Park Y, Kim S, et al. Mechanism of body fat reduction by conjugated linoleic acid. FASEB J. 1997; 11:A139. 54. Park Y, Albright KJ, Liu W, et al. Effect of conjugated linoleic acid on body composition in mice. Lipids. 1997; 32:853-858. 55. van den Berg JJ, Cook NE, Tribble DL. Reinvestigation of the antioxidant properties of conjugated linoleic acid. Lipids. 1995; 30:599-605.

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56. Yurawecz MP, Mossoba MM, Kramer JKG, Pariza MW, Nelson GJ, eds. Advances in Conjugated Linoleic Acid Research. Volume 1. Champaign, IL: AOCS Press; 1999.

Linolenic Acid 10 Studies


1. Botha JH, Robinson KM, Leary WP. The response of human carcinoma cell lines to gamma-linolenic acid with special reference to the effects of agents which influence prostaglandin and thromboxane syntheses. Prostaglandins Leukot Med. 1985; 19:63-77. 2. de Antueno R, Elliot M, Ells G, et al. In vivo and in vitro biotransformation of the lithium salt of gamma-linolenic acid by three human carcinomas. Br J Cancer. 1997; 75:1812-1818. 3. Fearon KC, Falconer JS, Ross JA, et al. An open-label phase I/II dose escalation study of the treatment of pancreatic cancer using lithium gammalinolenate. Anticancer Res. 1996; 16; 867-874. 4. Ferguson PJ. Synergistic cytotoxicity between gamma-linolenic acid and the flavonoid naringenin against a human oral squamous carcinoma cell line (Meeting abstract). Proc Annu Meet Am Assoc Cancer Res. 1997; 38:A2148. 5. Ilc K, Ferrero JM, Fischel JL, et al. Cytotoxic effects of two gamma linolenic salts (lithium gammalinolenate or meglumine gammalinolenate) alone or associated with a nitrosourea: an experimental study on human glioblastoma cell lines. Anticancer Drugs. 1999; 10:413-417. 6. Kairemo KJ, Jekunen AP, Korppi-Tommola ET, Pyrhonen SO. The effect of lithium gamma-linolenate therapy of pancreatic cancer on perfusion in liver and pancreatic tissues. Pancreas. 1998; 16:105-106. 7. Kinchington D, Randall S, Winther M, Horrobin D. Lithium gamma-linolenateinduced cytotoxicity against cells chronically infected with HIV-1. FEBS Lett. 1993; 330:219-221. 8. Ravichandran D, Cooper A, Johnson CD. Effect of lithium gamma-linoenate on the growth of experimental human pancreatic carcinoma. Br J Surg. 1998; 85:1201-1205. 9. Ravichandran D, Cooper A, Johnson CD. Growth inhibitory effect of lithium gammalinolenate on pancreatic cancer cell lines: the influence of albumin and iron. Eur J Cancer. 1998; 34:188-192.

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10. Seegers JC, Lotterling ML, Panzer A, et al. Comparative anti-mitotic effects of lithium gamma-linolenate, gamma-linolenic acid and arachidonic acid, on transformed and embryonic dells. Prostaglandins Leukot Essent Fatty Acids. 1998; 59:285-291.

Caprylic Acid - 9 Studies


1. Abate MA, Moore TL. Monooctanin use for gallstone dissolution. Drug Intell Clin Pharm. 1985; 19:708-713. 2. Kabara JJ. Fatty acids and derivatives as antimicrobial agents. In: Kabara JJ, ed. The Pharmacological Effect of Lipids I. Champaign, IL: American Oil Chemists' Society; 1978; 1-14. 3. Wyss O, Ludwig BJ, Joiner RR. The fungistatic and fungicidal action of fatty acids and related compounds. Arch Biochem. 1943;7,415. 4. Effect of Caprylic Acid on Performance and Mortality of Growing Rabbits.Skivanov V., M. Marounek: Effect of Caprylic Acid on Performance and Mortality of Growing Rabbits. Acta Vet. Brno 71, 2002: 435-439. 5. Enig MG. Lauric Oils as Antimicrobial Agents: Theory of Effect, Scientific Rationale, and Dietary Application as Adjunct Nutritional Support for HIV-Infected Individuals. in Watson R ed. Food and Nutrients in AIDS. CRC Press. Florida, pp81-97. 1999. 6. Isaacs CE, Kim KS and Thormar H. Inactivation of Enveloped Viruses in Human Bodily Fluids by Purified Lipids. Annal NY Acad Sci. 724: 457. 1994. 7. Sadeghi S et al. Dietary Lipids Modify the Cytokine Response to Bacterial Lipopolysaccharide in Mice. Immunology. 96(3): 404-10. 1999. 8. J Dairy Sci. 2005 Oct;88(10):3488-95. Antibacterial effect of caprylic acid and monocaprylin on major bacterial mastitis pathogens. Nair MK, Joy J, Vasudevan P, Hinckley L, Hoagland TA, Venkitanarayanan KS. Department of Animal Science, Unit 4040, University of Connecticut, Storrs 06269, USA. 9. Final report of the safety assessment for Caprylic/Capric Triglyceride.Anonymous J ENV PATH TOX Vol:4, 4 (1980) pp 105-20.

Glycerophosphorylcholine 11 Studies

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1. Pflgers Archiv European Journal of Physiology (Historical Archive). Publisher: Springer-Verlag GmbH. ISSN: 0031-6768 (Paper) 1432-2013 (Online) DOI: 10.1007/BF00583795. Issue: Volume 409, Numbers 4-5. Date:August 1987. Pages: 411 - 415 2. Transport Processes, Metabolism and Endocrinology; Kidney, Gastrointestinal Tract, and Exocrine Glands. Role and regulation of glycerophosphorylcholine in rat renal papilla. Gabriele Wirthensohn, Franz-X. Beck and Walter G. Guder. Biochim Biophys Acta. 1993 Jul 25;1150(1):25-34.Metabolism of the 'organic osmolyte' glycerophosphorylcholine in isolated rat inner medullary collecting duct cells. II. Regulation by extracellular osmolality. Bauernschmitt HG, Kinne RK. 3. Biochim Biophys Acta. 1985 Jan 9;833(1):111-8. 1-O-alkyl-2-acyl-sn-glycero-3phosphorylcholine is the precursor of platelet-activating factor in stimulated rabbit platelets. Evidence for an alkylacetyl-glycerophosphorylcholine cycle. Touqui L, Jacquemin C, Dumarey C, Vargaftig BB. 4. Biochim Biophys Acta. 1982 Mar 12;710(3):370-6. Phosphatidylcholine of blood lipoprotein is the precursor of glycerophosphorylcholine found in seminal plasma. Hammerstedt RH, Rowan WA. 5. Med Biol. 1985;63(2):81-7. Impaired glycerophosphorylcholine synthesis in murine muscular dystrophy. Infante JP.

6. FEBS Lett. 1985 Jul 8;186(2):205-10. Defective synthesis of glycerophosphorylcholine in murine muscular dystrophy; the primary molecular lesion? Infante JP.

7. Dev Neurosci. 1989;11(1):26-9. Regional and developmental estimations of glycerophosphorylcholine phosphodiesterase activities in rat brain. Kanfer JN, McCartney DG.

8. J Parasitol. 1995 Jun;81(3):335-40. Glycerophosphorylcholine, a component of both Ascaris suum muscle and Caenorhabditis elegans. Arevalo JI, Saz HJ, Nowak T, Larry JP.

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9. Kidney Cell Survival in High Tonicity - osmotic regulation of GPC: choline phosphodiesterase.Handler J.S.1; Kwon H.M. Comparative Biochemistry and Physiology -- Part A: Physiology, Volume 117, Number 3, July 1997, pp. 301306(6). Elsevier Science.

10. Glycerophosphorylcholine phosphocholine phosphodiesterase activity in cultured oligodendrocytes, astrocytes, and central nervous tissue of dysmyelinating rodent mutants. J. Yuan, D. G. McCartney, M. Monge, A. Espinosa de Los Monteros, B. Zalc, J. de Vellis, J. N. Kanfer. Journal of Neuroscience Research. Volume 31, Issue 1, 1992. Pages 68-74

Phosphatidylserine 13 Studies
1. Amaducc L, SMID Group. Phosphatidylserine in the treatment of Alzheimer's disease. Results of a multicenter study. Psychopharmacol Bull. 1988; 24:130-134. 2. Baer E, Maurukas J. Phosphatidyl serine. J Biol Chem. 1955; 212:25-38. 3. Blokland A, Honig W, Brouns F, Jolles J. Cognition-enhancing properties of subchronic phosphatidylserine (PS) treatment in middle-aged rats: comparison of bovine cortex PS with eggs PS and soybean PS. Nutr. 1999; 15: 778-783. 4. Casamenti F, Scali C, Pepeu G. Phosphatidylserine reverses the age-development decrease in cortical acetylcholine release: a microdialysis study. Eur J Pharmac. 1991; 194:11-16. 5. Crook T, Petrie W, Wells C, et al. Effects of phosphatidylserine in Alzheimer's disease. Psychopharmacol Bull. 1992; 28:61-66. 6. Crook TH, Tinklenberg J, Yesavage J, et al. Effects of phosphatidylserine in ageassociated memory impairment. Neurol. 1991; 41:644-649. 7. Folch J. Brain cephalin, a mixture of phosphatides. Separation from it of phosphatidyl serine, phosphatidyl ethanolamine, and a fraction containing an inositol phosphatide. J Biol Chem. 1942; 146:35-41. 8. Monteleleone P, Maj M, Reinat L, et al. Blunting by chronic phosphatidylserine administration of the stress-induced activation of the hypothalamo-pituitary-adrenal axis in healthy men. Eur J Pharmacol. 1992; 41:385-388.

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9. Nunzi MG, Milan F, Guidolin D, Toffano G. Dendritic spine loss in hippocampus of aged rats. Effect of brain phosphatidylserine. Neurobiol Aging. 1987; 8:501-510. 10. Pepeu G, Marconcini Pepeu I, Amaducc L. A review of phosphatidylserine pharmacological and clinical effects. Is phosphatidylserine a drug for the ageing brain? Pharmacol Res. 1996; 33:73-80. 11. Phosphatidylserine- a novel pharmacological approach to brain ageing. Clin Trials J. 1987; 24:1-130. 12. Villardita C, Grioli S, Salmeri G, et al. Multicentre clinical trial of brain phophatidylserine in elderly patients with intellectual deterioration. Clinic Trials J. 1987; 24:84-93. 13. Zanott A, Valzelli L, Toffano G. Chronic phosphatidylserine treatment improves spatial memory and passive avoidance in aged rats. Psychopharmacol. 1989; 99:316-321.

Pregenolone -23 Studies


1. Sahelian, Ray, M.D. Pregnenolone: Nature's Feel Good Hormone. (Garden City Park, New York: Avery Publishing Group, 1997), 57. 2. Roberts, E. (1995) "Pregnenolone-From Selye to Alzheimer and a Model of the Pregnenolone Sulfate Binding Binding Site on the GABAA Receptor," Biochemical Pharmacology 49:1 (1995): 1-16. 3. Regelson, William, M.D., and Carol Colman, The Super-Hormone Promise: Nature's Antidote to Aging. (New York: Pocket Books, 1996), 79. 4. Young, D. Gary, Pregnenolone: A Radical New Approach to Health, Longevity, and Emotional Well-Being. (Salem, Utah: Essential Science Publishing, 2000), 21. 5. Lee, John R., M.D. "Natural" vs. "Synthetic" Hormones, A Question of Semantics. (3 July 1998). 6. Flood, et al., "Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it." Proc Natl Acad Sci USA, (Mar 1, 1992): 1567-71. 7. Mathis, C, et al., "The neurosteroid pregnenolone sulfate blocks NMDA antagonistinduced deficits in a passive avoidance memory task." Psychopharmacology (Berl). (Oct. 1993): 201-6.

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8. Flood JF, et al., "Age related decrease of plasma testosterone in SAMPX mice: replacement improved age related impairment of learning and memory." Physiol Behav (Apr 1995): 669-73. 9. Rebel, P et al., "Biosynthesis and assay of neurosteroid in rats and mice: functional correlates." J Steroid Biochem Mol Biol, (June 1995), 355-60. 10. George, MS et al., "CSF neuroactive steroids in affective disorders: pregnenolone. progesterone, and DBI." Biol Psychiatry, (May 1994), 775-80. 11. Guth et al.. "Key role for pregnenolone in combination therapy that promotes recovery after spinal cord injury." Proc Natl Acad Sci USA (Dec 6, 1994), 12308-12. 12. Shiraki M1 et al., "The effect of estrogen and sex steroids and thyroid hormone preparation on bone mineral density in senile osteoporosis--a comparative study of the effect of 1 alphahydroxycholecalciferol on senile osteoporosis." Nippon Naibunpi Gakkai Zasshi (Feb 199 1)84-95. 13. Sahelian, Ray, MD, pregnenolone: A Practical Guide Melatonin/DHEA Research. 14. 1. Akwa Y, Young J, Kabbadj K, et al. Neurosteroids: biosynthesis, metabolism and function of pregnenolone and dehydroepiandrosterone in the brain. J Steroid Biochem Mol Biol. 1991;40(1-3):71-81. 15. Havlikova H, Hill M, Hampl R, Starka L. Sex- and age-related changes in epitestosterone in relation to pregnenolone sulfate and testosterone in normal subjects. J Clin Endocrinol Metab. 2002 May;87(5):2225-31. 16. Araghiniknam M, Chung S, Nelson-White T, Eskelson C, Watson RR. Antioxidant activity of dioscorea and dehydroepiandrosterone (DHEA) in older humans. Life Sci. 1996;59(11):L147-57. 17. Darnaudery M, Pallares M, Piazza PV, Le Moal M, Mayo W. The neurosteroid pregnenolone sulfate infused into the medial septum nucleus increases hippocampal acetylcholine and spatial memory in rats. Brain Res. 2002 Oct 4;951(2):237-42. 18. Mayo W, Lemaire V, Malaterre J, et al. Pregnenolone sulfate enhances neurogenesis and PSA-NCAM in young and aged hippocampus. Neurobiol Aging. 2005 Jan;26(1):10314. 19. Jaliffa CO, Howard S, Hoijman E, et al. Effect of neurosteroids on the retinal gabaergic system and electroretinographic activity in the golden hamster. J Neurochem. 2005 Jul 11. 20. Roberts E. Pregneolonefrom Selye to Alzheimer and a model of the pregnenolone sulfate binding site on the GABAA receptor. Biochem Pharmacol. 1995 Jan 6;49(1):1-16. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 316

21. McGavack TH, Chevalley J, Weissberg J. The use of delta 5-pregnenolone in various clinical disorders. J Clin Endocrinol Metab. 1951 Jun;11(6):559-77. 22. Dzugan SA, Arnold SR. Hypercholesterolemia treatment: a new hypothesis or just an accident? Med Hypotheses. 2002 Dec;59(6):751-6. 23.George MS, Guidotti A, Rubinow D, Pan B, Mikalauskas K, Post RM. CSF neuroactive steroids in affective disorders: pregnenolone, progesterone, and DBI. Biol Psychiatry. 1994 May 15;35(10):775-80.

Benfotiamine 32 Studies
1. Stracke H, Lindemann A, Federlin K. A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes. 1996;104(4):311-6. 2. Hammes HP, Du X, Edelstein D, et al. Benfotiamine blocks three major path- ways of hyperglycemic damage and pre- vents experimental diabetic retinopathy. Nat Med. 2003 Mar;9(3):294-9. Epub 2003 Feb 18. 3. Hammes HP, Du X, Edelstein D, et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experi- mental diabetic retinopathy. Nat Med. 2003 Mar;9(3):294-9. 4. 1. Bitsch R, Wolf M, Mller J. Bioavailability assessment of the lipophilic benfotiamine as compared to a water-soluble thiamin derivative. Ann Nutr Metab 1991;35(2):292-6. 5. Schreeb KH, Freudenthaler S, Vormfelde SV, et al. Comparative bioavailability of two vitamin B1 preparations: benfotiamine and thiamine mononitrate. Eur J Clin Pharmacol 1997; 52(4):319-20. 6. Loew D. Pharmacokinetics of thiamine derivatives especially of benfotiamine. Int J Clin Pharmacol Ther 1996;34(2):47-50. 7. Frank T, Bitsch R, Maiwald J, Stein G. High thiamine diphosphate concentrations in erythrocytes can be achieved in dialysis patients by oral administration of benfontiamine. Eur J Clin Pharmacol. 2000;56(3):251-7.

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8. Pike RL, Brown ML. Nutrition, An Integrated Approach, 3rd Ed. New York:MacMillan; 1986:467. 9. Hammes H-P, Du X, Edlestein D, et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic neuropathy. Nat Med 2003;9(3):294-99. 10. Monnier VM, Kohn RR, Cerami A. Accelerated age-related browning of human collagen in diabetes mellitus. Proc Natl Acad Sci 1984;81(2):583-7. 11. Brownlee M. The pathological implications of protein glycation. Clin Invest Med 1995;18(4):275-81. 12. Pomero F, Molinar Min A, La Selva M, et al. Benfotiamine is similar to thiamine in correcting endothelial cell defects induced by high glucose. Acta Diabetol 2001;38(3):135-8. 13. Stracke H, Hammes HP, Werkman D, et al. Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats. Exp Clin Endocrinol Diabetes 2001;109(6):300-6. 14. Babaei-Jadidi R, Karachalias N, Ahmed N, et al. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes 2003;52(8):2110-20. 15. Bergfeld R, MatsumaraT, Du X, Brownlee M. Benfotiamin prevents the consequences of hyperglycemia induced mitochondrial overproduction of reactive oxygen specifies and experimental diabetic neuropathy (Abstract) Diabetologia 2001; 44(Suppl1):A39. 16. 1996 Feb; 34(2): 47-50. Loew D. Pharmacokinetics of thiamine derivatives especially of Benfotiamine. Int J Clin Pharmacol Ther. 17. Stracke H, Lindemann A, Federlin K. A Benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes 1996; 104(4): 3116. 18. Lin J, Alt A, Liersch J, Bretzel RG, Brownlee MA, Hammes HP. Benfotiamine inhibits intracellular formation of advanced glycation endproducts in vivo. Diabetes. 2000 May; 49(Suppl1): A143 (P583).

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19. Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med. 2003 Mar; 9(3): 294-9. 20. Winkler G, Pal B, Nagybeganyi E, Ory I, Porochnavec M, Kempler P. Effectiveness of different Benfotiamine dosage regimens in the treatment of painful diabetic neuropathy. Arzneimittelforschung. 1999 Mar; 49(3): 220-4. 21. Koltai MZ. Prevention of cardiac autonomic neuropathy in dogs with Benfotiamine. In Gries FA, Federlin K. Benfotiamine in the Therapy of Polyneuropathy. New York: Georg Thieme Verlag, 1998; 45-9. 22. Ann N Y Acad Sci. 2005 Jun;1043:784-92. Inhibitors of advanced glycation end product formation and neurovascular dysfunction in experimental diabetes. Cameron NE, Gibson TM, Nangle MR, Cotter MA. School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK. n.e.cameron@abdn.ac.uk 23. High-dose thiamine therapy counters dyslipidemia and advanced glycation of plasma protein in streptozotocin-induced diabetic rats. Karachalias N, Babaei-Jadidi R, Kupich C, Ahmed N, Thornalley PJ.Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, UK. thorp@essex.ac.uk. 24. Curr Drug Targets. 2005 Jun;6(4):453-74. The role of AGEs and AGE inhibitors in diabetic cardiovascular disease. Thomas MC, Baynes JW, Thorpe SR, Cooper ME. 25. Clin Lab. 2005;51(5-6):257-73. Mutations in the transketolase-like gene TKTL1: clinical implications for neurodegenerative diseases, diabetes and cancer. Coy JF, Dressler D, Wilde J, Schubert P.R-Biopharm AG, Landwehrstrasse 54, 64293 Darmstadt, Germany. j.coy@r-biopharm.de 26. Int J Clin Pharmacol Ther. 2005 Feb;43(2):71-7. Erratum in: Int J Clin Pharmacol Ther. 2005 Jun;43(6):304. Benfotiamine in the treatment of diabetic polyneuropathy--a three-week randomized, controlled pilot study (BEDIP study). Haupt E, Ledermann H, Kopcke W. Saale-Klinik, Bad Kissingen, Lindenfels, Germany. BfA.Saaleklinik@tonline.de 27. Diabetologia. 2004 Dec;47(12):2235-46. Epub 2004 Dec 11. High-dose thiamine therapy counters dyslipidaemia in streptozotocin-induced diabetic rats.Babaei-Jadidi R, Karachalias N, Kupich C, Ahmed N, Thornalley PJ.Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex, CO4 3SQ, UK. 28. Diabetes Metab Res Rev. 2004 Jul-Aug;20(4):330-6. Thiamine and benfotiamine prevent increased apoptosis in endothelial cells and pericytes cultured in high glucose.

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Beltramo E, Berrone E, Buttiglieri S, Porta M. Department of Internal Medicine, University of Turin, Italy. elena.beltramo@unito.it 29. Diabetes. 2003 Aug;52(8):2110-20. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, Thornalley PJ. Department of Biological Sciences, University of Essex, Central Campus, Wivenhoe Park, Colchester, Essex, UK. 30. Nat Med. 2003 Mar;9(3):294-9. Epub 2003 Feb 18. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. Medical Clinic V, School of Clinical Medicine, Mannheim, Germany. 31. Eksp Klin Farmakol. 2002 Jul-Aug;65(4):37-41. [The immunometaboic effects of benfotiamine and riboxine on hemolytic anemia] [Article in Russian] Uteshev BS, Lazareva GA, Prokopenko LG.Pharmacology Department, State Medical University, ul. Ostrovityanova 1, Moscow, 117437 Russia. 32. MMW Fortschr Med. 2001 Apr 19;143(16):53. [Chronic alcohol abuse. Benfotiamine in alcohol damage is a must] [Article in German] Ayazpoor U.

SUPER ANTIOXIDANTS Vitamin A 41 STUDIES


1. Groff JL. Advanced Nutrition and Human Metabolism. 2nd ed. St Paul: West Publishing; 1995. 2. Ross AC. Vitamin A and retinoids. In: Shils M, ed. Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:305-327. 3. Semba RD. The role of vitamin A and related retinoids in immune function. Nutr Rev. 1998;56(1 Pt 2):S38-48.

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4. Semba RD. Impact of vitamin A on immunity and infection in developing countries. In: Bendich A, Decklebaum RJ, eds. Preventive Nutrition: The Comprehensive Guide for Health Professionals. 2nd ed. Totowa: Humana Press Inc; 2001:329-346. 5. McCullough, F. et al. The effect of vitamin A on epithelial integrity. Proceedings of the Nutrition Society. 1999; volume 58: pages 289-293. (PubMed) 6. Olson JA. Vitamin A. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington D.C.: ILSI Press; 1996:109-118. 7. Lynch SR. Interaction of iron with other nutrients. Nutr Rev. 1997;55(4):102-110. (PubMed) 8. Brody T. Nutritional Biochemistry. 2nd ed. San Diego: Academic Press; 1999. 9. Russell RM. The vitamin A spectrum: from deficiency to toxicity. Am J Clin Nutr. 2000;71(4):878-884. (PubMed) 10. Christian P, West KP, Jr. Interactions between zinc and vitamin A: an update. Am J Clin Nutr. 1998;68(2 Suppl):435S-441S. (PubMed) 11. Suharno D, West CE, Muhilal, Karyadi D, Hautvast JG. Supplementation with vitamin A and iron for nutritional anaemia in pregnant women in West Java, Indonesia. Lancet. 1993;342(8883):1325-1328. (PubMed) 12. Underwood BA, Arthur P. The contribution of vitamin A to public health. FASEB J. 1996;10(9):1040-1048. (PubMed) 13. Semba RD. Vitamin A and human immunodeficiency virus infection. Proc Nutr Soc. 1997;56(1B):459-469. 14. Field CJ, Johnson IR, Schley PD. Nutrients and their role in host resistance to infection. J Leukoc Biol. 2002;71(1):16-32. (PubMed) 15. West CE. Vitamin A and measles. Nutr Rev. 2000;58(2 Pt 2):S46-54. 16. Semba RD, Miotti PG, Chiphangwi JD, et al. Maternal vitamin A deficiency and mother-to-child transmission of HIV-1. Lancet. 1994;343(8913):1593-1597. (PubMed) 17. Thurnham DI, Northrop-Clewes CA. Optimal nutrition: vitamin A and the carotenoids. Proc Nutr Soc. 1999;58(2):449-457. (PubMed) 18. Food and Nutrition Board, Institute of Medicine. Vitamin A. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington D.C.: National Academy Press; 2001:65-126. (National Academy Press) Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 321

19. Comstock GW, Helzlsouer KJ. Preventive nutrition and lung cancer. In: Bendich A, Decklebaum RJ, eds. Preventive Nutrition: The Comprehensive Guide for Health Professionals. 2nd ed. Totowa: Humana Press Inc; 2001:97-129. 20. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334(18):1150-1155. (PubMed) 21. Prakash P, Krinsky NI, Russell RM. Retinoids, carotenoids, and human breast cancer cell cultures: a review of differential effects. Nutr Rev. 2000;58(6):170-176. (PubMed) 22. Bohlke K, Spiegelman D, Trichopoulou A, Katsouyanni K, Trichopoulos D. Vitamins A, C and E and the risk of breast cancer: results from a case-control study in Greece. Br J Cancer. 1999;79(1):23-29 (PubMed) 23. Franceschi S. Micronutrients and breast cancer. Eur J Cancer Prev. 1997;6(6):535539. (PubMed) 24. Longnecker MP, Newcomb PA, Mittendorf R, Greenberg ER, Willett WC. Intake of carrots, spinach, and supplements containing vitamin A in relation to risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 1997;6(11):887-892. (PubMed) 25. Michels KB, Holmberg L, Bergkvist L, Ljung H, Bruce A, Wolk A. Dietary antioxidant vitamins, retinol, and breast cancer incidence in a cohort of Swedish women. Int J Cancer. 2001;91(4):563-567. (PubMed) 26. Zhang S, Hunter DJ, Forman MR, et al. Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. J Natl Cancer Inst. 1999;91(6):547-556. (PubMed) 27. Ching S, Ingram D, Hahnel R, Beilby J, Rossi E. Serum levels of micronutrients, antioxidants and total antioxidant status predict risk of breast cancer in a case control study. J Nutr. 2002;132(2):303-306. (PubMed) 28. Dorgan JF, Sowell A, Swanson CA, et al. Relationships of serum carotenoids, retinol, alpha-tocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States). Cancer Causes Control. 1998;9(1):89-97. (PubMed) 29. Hulten K, Van Kappel AL, Winkvist A, et al. Carotenoids, alpha-tocopherols, and retinol in plasma and breast cancer risk in northern Sweden. Cancer Causes Control. 2001;12(6):529-537. (PubMed) 30. van Soest S, Westerveld A, de Jong PT, Bleeker-Wagemakers EM, Bergen AA. Retinitis pigmentosa: defined from a molecular point of view. Surv Ophthalmol. 1999;43(4):321-334. (PubMed)

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31. Berson EL, Rosner B, Sandberg MA, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol. 1993;111(6):761772. (PubMed) 32. Sibulesky L, Hayes KC, Pronczuk A, Weigel-DiFranco C, Rosner B, Berson EL. Safety of <7500 RE (<25000 IU) vitamin A daily in adults with retinitis pigmentosa. Am J Clin Nutr. 1999;69(4):656-663. (PubMed) 33. Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001. 34. March of Dimes. Accutane and Other Retinoids [Web page]. April, 2002. Available at: http://www.marchofdimes.com/professionals/681_1168.asp. Accessed December 12, 2003. 35. Michaelsson K, Lithell H, Vessby B, Melhus H. Serum retinol levels and the risk of fracture. N Engl J Med. 2003;348(4):287-294. (PubMed) 36. Promislow JH, Goodman-Gruen D, Slymen DJ, Barrett-Connor E. Retinol intake and bone mineral density in the elderly: the Rancho Bernardo Study. J Bone Miner Res. 2002;17(8):1349-1358. (PubMed) 37. Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women. JAMA. 2002;287(1):47-54. (PubMed) 38. Rohde CM, DeLuca H. Bone resorption activity of all-trans retinoic acid is independent of vitamin D in rats. J Nutr. 2003;133(3):777-783. (PubMed) 39. Johansson S, Melhus H. Vitamin A antagonizes calcium response to vitamin D in man. J Bone Miner Res. 2001;16(10):1899-1905. (PubMed) 40. Wang XD. Chronic alcohol intake interferes with retinoid metabolism and signaling. Nutr Rev. 1999;57(2):51-59. (PubMed) 41. Leo MA, Lieber CS. Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr. 1999;69(6):1071-1085. (PubMed)

Vitamin C 51 STUDIES
1. Carr AC, Frei B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr. 1999;69(6):1086-1107. (PubMed)

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2. Simon JA, Hudes ES. Serum ascorbic acid and gallbladder disease prevalence among US adults: the Third National Health and Nutrition Examination Survey (NHANES III). Arch Intern Med. 2000;160(7):931-936. (PubMed) 3.Sauberlich, HE. A history of scurvy and vitamin C. In Packer, L. and Fuchs, J. Eds. Vitamin C in health and disease. New York: Marcel Decker Inc. 1997: pages 1-24. 4. Stephen R, Utecht T. Scurvy identified in the emergency department: a case report. J Emerg Med. 2001;21(3):235-237. (PubMed) 5. Weinstein M, Babyn P, Zlotkin S. An orange a day keeps the doctor away: scurvy in the year 2000. Pediatrics. 2001;108(3):E55. (PubMed) 6. Food and Nutrition Board, Institute of Medicine. Vitamin C. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington D.C.: National Academy Press; 2000:95-185. (National Academy Press) 7. Losonczy KG, Harris TB, Havlik RJ. Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the Established Populations for Epidemiologic Studies of the Elderly. Am J Clin Nutr. 1996;64(2):190196. (PubMed) 8. Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med. 1996;334(18):1156-1162. (PubMed) 9. Enstrom JE, Kanim LE, Klein MA. Vitamin C intake and mortality among a sample of the United States population. Epidemiology. 1992;3(3):194-202. (PubMed) 10. Enstrom JE. Counterpoint--vitamin C and mortality. Nutr Today. 1993;28:28-32. 11. Osganian SK, Stampfer MJ, Rimm E, et al. Vitamin C and risk of coronary heart disease in women. J Am Coll Cardiol. 2003;42(2):246-252. (PubMed) 12. Khaw KT, Bingham S, Welch A, et al. Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study. European Prospective Investigation into Cancer and Nutrition. Lancet. 2001;357(9257):657-663. (PubMed) 13. Levine M, Wang Y, Padayatty SJ, Morrow J. A new recommended dietary allowance of vitamin C for healthy young women. Proc Natl Acad Sci U S A. 2001;98(17):98429846. (PubMed) 14. Frei B. To C or not to C, that is the question! J Am Coll Cardiol. 2003;42(2):253255.

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15. Yokoyama T, Date C, Kokubo Y, Yoshiike N, Matsumura Y, Tanaka H. Serum vitamin C concentration was inversely associated with subsequent 20-year incidence of stroke in a Japanese rural community. The Shibata study. Stroke. 2000;31(10):22872294. (PubMed) 16. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a review. J Am Diet Assoc. 1996;96(10):1027-1039. (PubMed) 17. Kromhout D. Essential micronutrients in relation to carcinogenesis. Am J Clin Nutr. 1987;45(5 Suppl):1361-1367. 18. Zhang S, Hunter DJ, Forman MR, et al. Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. J Natl Cancer Inst. 1999;91(6):547-556. (PubMed) 19. Michels KB, Holmberg L, Bergkvist L, Ljung H, Bruce A, Wolk A. Dietary antioxidant vitamins, retinol, and breast cancer incidence in a cohort of Swedish women. Int J Cancer. 2001;91(4):563-567. (PubMed) 20. Feiz HR, Mobarhan S. Does vitamin C intake slow the progression of gastric cancer in Helicobacter pylori-infected populations? Nutr Rev. 2002;60(1):34-36. (PubMed) 21. Jacques PF. The potential preventive effects of vitamins for cataract and age-related macular degeneration. Int J Vitam Nutr Res. 1999;69(3):198-205. (PubMed) 22. Jacques PF, Chylack LT, Jr., Hankinson SE, et al. Long-term nutrient intake and early age-related nuclear lens opacities. Arch Ophthalmol. 2001;119(7):1009-1019. (PubMed) 23. Simon JA, Hudes ES. Serum ascorbic acid and other correlates of self-reported cataract among older Americans. J Clin Epidemiol. 1999;52(12):1207-1211. (PubMed) 24. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001;119(10):1439-1452. (PubMed) 25. Cheng Y, Willett WC, Schwartz J, Sparrow D, Weiss S, Hu H. Relation of nutrition to bone lead and blood lead levels in middle-aged to elderly men. The Normative Aging Study. Am J Epidemiol. 1998;147(12):1162-1174. (PubMed) 26. Simon JA, Hudes ES. Relationship of ascorbic acid to blood lead levels. JAMA. 1999;281(24):2289-2293. (PubMed) 27. Dawson EB, Evans DR, Harris WA, Teter MC, McGanity WJ. The effect of ascorbic acid supplementation on the blood lead levels of smokers. J Am Coll Nutr. 1999;18(2):166-170. (PubMed)

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28. Gokce N, Keaney JF, Jr., Frei B, et al. Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation. 1999;99(25):3234-3240. (PubMed) 29. Duffy SJ, Gokce N, Holbrook M, et al. Treatment of hypertension with ascorbic acid. Lancet. 1999;354(9195):2048-2049. (PubMed) 30. Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A. 1976;73(10):3685-3689. 31. Creagan ET, Moertel CG, O'Fallon JR, et al. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. N Engl J Med. 1979;301(13):687-690. (PubMed) 32. Moertel CG, Fleming TR, Creagan ET, Rubin J, O'Connell MJ, Ames MM. Highdose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison. N Engl J Med. 1985;312(3):137-141. (PubMed) 33. Padayatty SJ, Sun H, Wang Y, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004;140(7):533-537. (PubMed) 34. Kaegi E, Task Force on Alternative Therapeuties of the Canadian Breast Cancer Research Initiative. Unconventional therapies for cancer: 5. Vitamins A, C, and E. CMAJ. 1998;158(11):1483-1488. (PubMed) 35. Lee DH, Folsom AR, Harnack L, Halliwell B, Jacobs DR, Jr. Does supplemental vitamin C increase cardiovascular disease risk in women with diabetes? Am J Clin Nutr. 2004;80(5):1194-1200. (PubMed) 36. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):2333. (PubMed) 37. Waters DD, Alderman EL, Hsia J, et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA. 2002;288(19):2432-2440. (PubMed) 38. Levy AP, Friedenberg P, Lotan R, et al. The effect of vitamin therapy on the progression of coronary artery atherosclerosis varies by haptoglobin type in postmenopausal women. Diabetes Care. 2004;27(4):925-930. (PubMed) 39. Hemila H. Vitamin C intake and susceptibility to the common cold. Br J Nutr. 1997;77(1):59-72. (PubMed)

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40. Johnston CS, Martin LJ, Cai X. Antihistamine effect of supplemental ascorbic acid and neutrophil chemotaxis. J Am Coll Nutr. 1992;11(2):172-176. (PubMed) 41. Gregory JF, 3rd. Ascorbic acid bioavailability in foods and supplements. Nutr Rev. 1993;51(10):301-303. 42. Johnston CS, Luo B. Comparison of the absorption and excretion of three commercially available sources of vitamin C. J Am Diet Assoc. 1994;94(7):779-781. 43. Austria R, Semenzato A, Bettero A. Stability of vitamin C derivatives in solution and topical formulations. J Pharm Biomed Anal. 1997;15(6):795-801. (PubMed) 44. DeRitter E. Physiologic availability of dehydro-L-ascorbic acid and palmitoyl-Lascorbic acid. Science. 1951;113:628-631. 45. Lee SH, Oe T, Blair IA. Vitamin C-induced decomposition of lipid hydroperoxides to endogenous genotoxins. Science. 2001;292(5524):2083-2086. (PubMed) 46. Podmore ID, Griffiths HR, Herbert KE, Mistry N, Mistry P, Lunec J. Vitamin C exhibits pro-oxidant properties. Nature. 1998;392(6676):559. 47. Carr A, Frei B. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J. 1999;13(9):1007-1024. (PubMed) 48. Basu TK. Vitamin C-aspirin interactions. Int J Vitam Nutr Res Suppl. 1982;23:8390. (PubMed) 49. Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001. 50. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345(22):1583-1592. (PubMed) 51. Collins R, Peto R, Armitage J. The MRC/BHF Heart Protection Study: preliminary results. Int J Clin Pract. 2002;56(1):53-56 (PubMed).

Vitamin E

- 78 Studies

1. Traber MG. Utilization of vitamin E. Biofactors. 1999;10(2-3):115-120. (PubMed)

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2. Traber MG. Vitamin E. In: Shils M, Olson JA, Shike M, Ross AC, eds. Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:347-362. 3. Food and Nutrition Board, Institute of Medicine. Vitamin E. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington D.C.: National Academy Press; 2000:186-283. (National Academy Press) 4. Traber MG. Does vitamin E decrease heart attack risk? summary and implications with respect to dietary recommendations. J Nutr. 2001;131(2):395S-397S. (PubMed) 5. Traber MG, Elsner A, Brigelius-Flohe R. Synthetic as compared with natural vitamin E is preferentially excreted as alpha-CEHC in human urine: studies using deuterated alpha-tocopheryl acetates. FEBS Lett. 1998;437(1-2):145-148. (PubMed) 6. Christen S, Woodall AA, Shigenaga MK, Southwell-Keely PT, Duncan MW, Ames BN. gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: physiological implications. Proc Natl Acad Sci U S A. 1997;94(7):3217-3222. (PubMed) 7. Li D, Saldeen T, Mehta JL. gamma-tocopherol decreases ox-LDL-mediated activation of nuclear factor-kappaB and apoptosis in human coronary artery endothelial cells. Biochem Biophys Res Commun. 1999;259(1):157-161. (PubMed) 8. Helzlsouer KJ, Huang HY, Alberg AJ, et al. Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst. 2000;92(24):2018-2023. (PubMed) 9. Jiang Q, Christen S, Shigenaga MK, Ames BN. gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr. 2001;74(6):714-722. (PubMed) 10. Sokol R. Vitamin E. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed: ILSI Press; 1996:130-136. 11. Ford ES, Sowell A. Serum alpha-tocopherol status in the United States population: findings from the Third National Health and Nutrition Examination Survey. Am J Epidemiol. 1999;150(3):290-300. (PubMed) 12. Knekt P, Reunanen A, Jarvinen R, Seppanen R, Heliovaara M, Aromaa A. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol. 1994;139(12):1180-1189. (PubMed) 13. Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med. 1996;334(18):1156-1162. (PubMed)

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14. Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med. 1993;328(20):1450-1456. (PubMed) 15. Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med. 1993;328(20):1444-1449. (PubMed) 16. Cherubini A, Zuliani G, Costantini F, et al. High vitamin E plasma levels and low low-density lipoprotein oxidation are associated with the absence of atherosclerosis in octogenarians. J Am Geriatr Soc. 2001;49(5):651-654. (PubMed) 17. Gale CR, Ashurst HE, Powers HJ, Martyn CN. Antioxidant vitamin status and carotid atherosclerosis in the elderly. Am J Clin Nutr. 2001;74(3):402-408. (PubMed) 18. McQuillan BM, Hung J, Beilby JP, Nidorf M, Thompson PL. Antioxidant vitamins and the risk of carotid atherosclerosis. The Perth Carotid Ultrasound Disease Assessment study (CUDAS). J Am Coll Cardiol. 2001;38(7):1788-1794. (PubMed) 19. Simon E, Gariepy J, Cogny A, Moatti N, Simon A, Paul JL. Erythrocyte, but not plasma, vitamin E concentration is associated with carotid intima-media thickening in asymptomatic men at risk for cardiovascular disease. Atherosclerosis. 2001;159(1):193200. (PubMed) 20. Jacques PF. The potential preventive effects of vitamins for cataract and age-related macular degeneration. Int J Vitam Nutr Res. 1999;69(3):198-205. (PubMed) 21. Gale CR, Hall NF, Phillips DI, Martyn CN. Plasma antioxidant vitamins and carotenoids and age-related cataract. Ophthalmology. 2001;108(11):1992-1998. (PubMed) 22. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001;119(10):1439-1452. (PubMed) 23. Teikari JM, Rautalahti M, Haukka J, et al. Incidence of cataract operations in Finnish male smokers unaffected by alpha tocopherol or beta carotene supplements. J Epidemiol Community Health. 1998;52(7):468-472. (PubMed) 24. Meydani SN, Meydani M, Blumberg JB, et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects. A randomized controlled trial. Jama. 1997;277(17):1380-1386. (PubMed) 25. Han SN, Meydani SN. Vitamin E and infectious diseases in the aged. Proc Nutr Soc. 1999;58(3):697-705. (PubMed)

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26. Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst. 1998;90(6):440-446. (PubMed) 27. Klein EA, Thompson IM, Lippman SM, et al. SELECT: the next prostate cancer prevention trial. Selenum and Vitamin E Cancer Prevention Trial. J Urol. 2001;166(4):1311-1315. (PubMed) 28. Azen SP, Qian D, Mack WJ, et al. Effect of supplementary antioxidant vitamin intake on carotid arterial wall intima-media thickness in a controlled clinical trial of cholesterol lowering. Circulation. 1996;94(10):2369-2372. (PubMed) 29. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996;347(9004):781-786. (PubMed) 30. Boaz M, Smetana S, Weinstein T, et al. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebocontrolled trial. Lancet. 2000;356(9237):1213-1218. (PubMed) 31. Rapola JM, Virtamo J, Ripatti S, et al. Randomised trial of alpha-tocopherol and betacarotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet. 1997;349(9067):1715-1720. (PubMed) 32. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342(3):154-160. (PubMed) 33. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet. 1999;354(9177):447-455. (PubMed) 34. Davi G, Ciabattoni G, Consoli A, et al. In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation. 1999;99(2):224-229. (PubMed) 35. Jain SK, McVie R, Jaramillo JJ, Palmer M, Smith T. Effect of modest vitamin E supplementation on blood glycated hemoglobin and triglyceride levels and red cell indices in type I diabetic patients. J Am Coll Nutr. 1996;15(5):458-461. (PubMed) 36. Paolisso G, D'Amore A, Galzerano D, et al. Daily vitamin E supplements improve metabolic control but not insulin secretion in elderly type II diabetic patients. Diabetes Care. 1993;16(11):1433-1437. (PubMed)

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37. Reaven PD, Herold DA, Barnett J, Edelman S. Effects of Vitamin E on susceptibility of low-density lipoprotein and low-density lipoprotein subfractions to oxidation and on protein glycation in NIDDM. Diabetes Care. 1995;18(6):807-816. (PubMed) 38. Meydani M. Antioxidants and cognitive function. Nutr Rev. 2001;59(8 Pt 2):S75-80; discussion S80-72. 39. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alphatocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med. 1997;336(17):1216-1222. (PubMed) 40. Masaki KH, Losonczy KG, Izmirlian G, et al. Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology. 2000;54(6):1265-1272. (PubMed) 41. Yu W, Sanders BG, Kline K. RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells involves Bax translocation to mitochondria. Cancer Res. 2003;63(10):2483-2491. (PubMed) 42. You H, Yu W, Munoz-Medellin D, Brown PH, Sanders BG, Kline K. Role of extracellular signal-regulated kinase pathway in RRR-alpha-tocopheryl succinate-induced differentiation of human MDA-MB-435 breast cancer cells. Mol Carcinog. 2002;33(4):228-236. (PubMed) 43. Neuzil J, Weber T, Schroder A, et al. Induction of cancer cell apoptosis by alphatocopheryl succinate: molecular pathways and structural requirements. FASEB J. 2001;15(2):403-415. (PubMed) 44. Brigelius-Flohe R, Kelly FJ, Salonen JT, Neuzil J, Zingg JM, Azzi A. The European perspective on vitamin E: current knowledge and future research. Am J Clin Nutr. 2002;76(4):703-716. (PubMed) 45. Weber T, Lu M, Andera L, et al. Vitamin E succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosisinducing ligand (Apo2 ligand) in vivo. Clin Cancer Res. 2002;8(3):863-869. (PubMed) 46. Malafa MP, Fokum FD, Mowlavi A, Abusief M, King M. Vitamin E inhibits melanoma growth in mice. Surgery. 2002;131(1):85-91. (PubMed) 47. Malafa MP, Neitzel LT. Vitamin E succinate promotes breast cancer tumor dormancy. J Surg Res. 2000;93(1):163-170. (PubMed) 48. Cheeseman KH, Holley AE, Kelly FJ, Wasil M, Hughes L, Burton G. Biokinetics in humans of RRR-alpha-tocopherol: the free phenol, acetate ester, and succinate ester forms of vitamin E. Free Radic Biol Med. 1995;19(5):591-598. (PubMed)

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49. Larry King leads $6 million advertising blitz for Ester-E. Phosphagenics Newsletter: Phosphagenics; October, 2004:6. http://www.phosphagenics.com/files/55VYK670JY/POH%20newsletter%20FINAL.pdf 50. Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001. 51. Berson EL, Rosner B, Sandberg MA, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol. 1993;111(6):761772. (PubMed) 52. Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Metaanalysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142(1):xx-xx. http://www.annals.org/cgi/content/full/0000605200501040-00110v1 53. Shekelle PG, Morton SC, Jungvig LK, et al. Effect of supplemental vitamin E for the prevention and treatment of cardiovascular disease. J Gen Intern Med. 2004;19(4):380389. (PubMed) 54. Eidelman RS, Hollar D, Hebert PR, Lamas GA, Hennekens CH. Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease. Arch Intern Med. 2004;164(14):1552-1556. (PubMed) 55. Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet. 2003;361(9374):2017-2023. (PubMed) 56. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345(22):1583-1592. (PubMed) 57. Collins R, Peto R, Armitage J. The MRC/BHF Heart Protection Study: preliminary results. Int J Clin Pract. 2002;56(1):53-56. (PubMed) 58. Taylor PR, Qiao YL, Abnet CC, Dawsey SM, Yang CS, Gunter EW, Wang W, Blot WJ, Dong ZW, Mark SD. Prospective study of serum vitamin E levels and esophageal and gastric cancers. J Natl Cancer Inst. 2003 Sep 17;95(18):1414-6. PMID: 13130117 59. Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology. 2003 Aug;38(2):413-9. PMID: 12883485

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60. Fariss MW, Zhang JG. Vitamin E therapy in Parkinson's disease. Toxicology. 2003 Jul 15;189(1-2):129-46. Review. PMID: 12821288

61. Ruffini I, Belcaro G, Cesarone MR, Geroulakos G, Di Renzo A, Milani M, Coen L, Ricci A, Brandolini R, Dugall M, Pomante P, Cornelli U, Acerbi G, Corsi M, Griffin M, Ippolito E, Bavera P. Evaluation of the local effects of vitamin E (E-Mousse) on free radicals in diabetic microangiopathy: a randomized, controlled trial. Angiology. 2003 Jul-Aug;54(4):415-21. PMID: 12934761 62. Jessup JV, Horne C, Yarandi H, Quindry J. The effects of endurance exercise and vitamin E on oxidative stress in the elderly. Biol Res Nurs. 2003 Jul;5(1):47-55. PMID: 12886670 63. Canbaz S, Duran E, Ege T, Sunar H, Cikirikcioglu M, Acipayam M. The effects of intracoronary administration of vitamin E on myocardial ischemia-reperfusion injury during coronary artery surgery. Thorac Cardiovasc Surg. 2003 Apr;51(2):57-61. PMID: 12730811 64. Manson JE, Bassuk SS, Stampfer MJ. Does vitamin E supplementation prevent cardiovascular events? J Womens Health (Larchmt). 2003 Mar;12(2):123-36. Review. PMID: 12741415 65. Chang CW, Chu G, Hinz BJ, Greve MD. Current use of dietary supplementation in patients with age-related macular degeneration. Can J Ophthalmol. 2003 Feb;38(1):27-32. PMID: 12608514 66. Letur-Konirsch H, Delanian S. Successful pregnancies after combined pentoxifylline-tocopherol treatment in women with premature ovarian failure who are resistant to hormone replacement therapy. Fertil Steril. 2003 Feb;79(2):439-41. PMID: 12568863 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 333

67. Olanow CW. Dietary vitamin E and Parkinson's disease: something to chew on. Lancet Neurol. 2003 Feb;2(2):74. PMID: 12849259 68. Martin A. Antioxidant vitamins E and C and risk of Alzheimer's disease. Nutr Rev. 2003 Feb;61(2):69-73. Review. PMID: 12674439 69. Mishima K, Tanaka T, Pu F, Egashira N, Iwasaki K, Hidaka R, Matsunaga K, Takata J, Karube Y, Fujiwara M. Vitamin E isoforms alpha-tocotrienol and gamma-tocopherol prevent cerebral infarction in mice. Neurosci Lett. 2003 Jan 30;337(1):56-60. PMID: 12524170 70. Rehim WM, Sharaf IA, Hishmat M, el-Toukhy MA, Rawash NA, Fouad HN. Antioxidant capacity in Fasciola hepatica patients before and after treatment with triclabendazole alone or in combination with ascorbic acid (vitamin C) and tocofersolan (vitamin E). Arzneimittelforschung. 2003;53(3):214-20. PMID: 12705178 71. Brockes C, Buchli C, Locher R, Koch J, Vetter W. Vitamin E prevents extensive lipid peroxidation in patients with hypertension. Br J Biomed Sci. 2003;60(1):5-8. PMID: 12680623 72. Lin Y, Huang R, Santanam N, Liu YG, Parthasarathy S, Huang RP. Profiling of human cytokines in healthy individuals with vitamin E supplementation by antibody array. Cancer Lett. 2002 Dec 10;187(1-2):17-24. PMID: 12359346 73. Scorolli L, Scalinci SZ, Limoli PG, Morara M, Vismara S, Scorolli L, Corazza D, Meduri R. [Photodynamic therapy for age related macular degeneration with and without antioxidants] Can J Ophthalmol. 2002 Dec;37(7):399-404. French. PMID: 12518724 74. Malafa MP, Fokum FD, Smith L, Louis A. Inhibition of angiogenesis and promotion of melanoma dormancy by vitamin E succinate.

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Ann Surg Oncol. 2002 Dec;9(10):1023-32. PMID: 12464597

75. Ghosh D, Das UB, Misro M. Protective role of alpha-tocopherol-succinate (provitamin-E) in cyclophosphamide induced testicular gametogenic and steroidogenic disorders: a correlative approach to oxidative stress. Free Radic Res. 2002 Nov;36(11):1209-18. PMID: 12592673 76. Liu L, Meydani M. Combined vitamin C and E supplementation retards early progression of arteriosclerosis in heart transplant patients. Nutr Rev. 2002 Nov;60(11):368-71. Review. PMID: 12462519 77. Boshtam M, Rafiei M, Sadeghi K, Sarraf-Zadegan N. Vitamin E can reduce blood pressure in mild hypertensives. Int J Vitam Nutr Res. 2002 Oct;72(5):309-14. PMID: 12463106 78. Jialal I, Devaraj S, Venugopal SK. Oxidative stress, inflammation, and diabetic vasculopathies: the role of alpha tocopherol therapy. Free Radic Res. 2002 Dec;36(12):1331-6. Review. PMID: 12607825

Vitamin B6 - 28 STUDIES
1. Leklem JE. Vitamin B-6. In: Machlin L, ed. Handbook of Vitamins. New York: Marcel Decker Inc; 1991:341-378. 2. Leklem JE. Vitamin B-6. In: Shils M, Olson JA, Shike M, Ross AC, eds. Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:413-422. 3. Hansen CM, Leklem JE, Miller LT. Vitamin B-6 status of women with a constant intake of vitamin B-6 changes with three levels of dietary protein. J Nutr. 1996;126(7):1891-1901. (PubMed) 4. Food and Nutrition Board, Institute of Medicine. Vitamin B6. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid,

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Biotin, and Choline. Washington D.C.: National Academy Press; 1998:150-195. (National Academy Press) 5. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA. 1995;274(13):1049-1057. (PubMed) 6. Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA. 1998;279(5):359-364. (PubMed) 7. Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1998;98(3):204-210. (PubMed) 8. Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ, Delport R, Potgieter HC. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr. 1994;124(10):1927-1933. (PubMed) 9. Meydani SN, Ribaya-Mercado JD, Russell RM, Sahyoun N, Morrow FD, Gershoff SN. Vitamin B-6 deficiency impairs interleukin 2 production and lymphocyte proliferation in elderly adults. Am J Clin Nutr. 1991;53(5):1275-1280. (PubMed) 10. Talbott MC, Miller LT, Kerkvliet NI. Pyridoxine supplementation: effect on lymphocyte responses in elderly persons. Am J Clin Nutr. 1987;46(4):659664. (PubMed) 11. Selhub J, Bagley LC, Miller J, Rosenberg IH. B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr. 2000;71(2):614S-620S. (PubMed) 12. Riggs KM, Spiro A, 3rd, Tucker K, Rush D. Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr. 1996;63(3):306-314. (PubMed) 13. Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Intake of vitamins B6 and C and the risk of kidney stones in women. J Am Soc Nephrol. 1999;10(4):840-845. (PubMed) 14. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of the intake of vitamins C and B6, and the risk of kidney stones in men. J Urol. 1996;155(6):18471851. (PubMed) 15. Bender DA. Non-nutritional uses of vitamin B6. Br J Nutr. 1999;81(1):7-20 (PubMed)

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16. Villegas-Salas E, Ponce de Leon R, Juarez-Perez MA, Grubb GS. Effect of vitamin B6 on the side effects of a low-dose combined oral contraceptive. Contraception. 1997;55(4):245-248. (PubMed) 17. Kleijnen J, Ter Riet G, Knipschild P. Vitamin B6 in the treatment of the premenstrual syndrome--a review. Br J Obstet Gynaecol. 1990;97(9):847-852. (PubMed) 18. Wyatt KM, Dimmock PW, Jones PW, Shaughn O'Brien PM. Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic review. Bmj. 1999;318(7195):1375-1381. (PubMed) 19. Vutyavanich T, Wongtra-ngan S, Ruangsri R. Pyridoxine for nausea and vomiting of pregnancy: a randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol. 1995;173(3 Pt 1):881-884. (PubMed) 20. Sahakian V, Rouse D, Sipes S, Rose N, Niebyl J. Vitamin B6 is effective therapy for nausea and vomiting of pregnancy: a randomized, double-blind placebo-controlled study. Obstet Gynecol. 1991;78(1):33-36. (PubMed) 21. Jewell D, Young G. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev. 2002(1):CD000145. (PubMed) 22. Ellis JM, Kishi T, Azuma J, Folkers K. Vitamin B6 deficiency in patients with a clinical syndrome including the carpal tunnel defect. Biochemical and clinical response to therapy with pyridoxine. Res Commun Chem Pathol Pharmacol. 1976;13(4):743-757. (PubMed) 23. Ellis J, Folkers K, Watanabe T, et al. Clinical results of a cross-over treatment with pyridoxine and placebo of the carpal tunnel syndrome. Am J Clin Nutr. 1979;32(10):2040-2046. (PubMed) 24. Keniston RC, Nathan PA, Leklem JE, Lockwood RS. Vitamin B6, vitamin C, and carpal tunnel syndrome. A cross-sectional study of 441 adults. J Occup Environ Med. 1997;39(10):949-959. (PubMed) 25. Spooner GR, Desai HB, Angel JF, Reeder BA, Donat JR. Using pyridoxine to treat carpal tunnel syndrome. Randomized control trial. Can Fam Physician. 1993;39:21222127. (PubMed) 26. Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001 27. Hansen CM, Shultz TD, Kwak HK, Memon HS, Leklem JE. Assessment of vitamin B-6 status in young women consuming a controlled diet containing four levels of vitamin B-6 provides an estimated average requirement and recommended dietary allowance. J Nutr. 2001;131(6):1777-1786. (PubMed) Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 337

28. Kretsch MJ, Sauberlich HE, Skala JH, Johnson HL. Vitamin B-6 requirement and status assessment: young women fed a depletion diet followed by a plant- or animalprotein diet with graded amounts of vitamin B-6. Am J Clin Nutr. 1995;61(5):1091-1101. (PubMed) 29. Ribaya-Mercado JD, Russell RM, Sahyoun N, Morrow FD, Gershoff SN. Vitamin B6 requirements of elderly men and women. J Nutr. 1991;121(7):1062-1074. (PubMed).

Magnesium - 86 Studies
1. Bucca C, Rolla G. Nebulised magnesium in asthma: the right solution for an old remedy? Lancet. 2003 Jun 21;361(9375):2095-6. PMID: 12826427 2. Jian W, Su L, Yiwu L. The effects of magnesium prime solution on magnesium levels and potassium loss in open heart surgery. Anesth Analg. 2003 Jun;96(6):1617-20, table of contents. PMID: 12760983 3. Zausinger S, Westermaier T, Plesnila N, Steiger HJ, Schmid-Elsaesser R. Neuroprotection in transient focal cerebral ischemia by combination drug therapy and mild hypothermia: comparison with customary therapeutic regimen. Stroke. 2003 Jun;34(6):1526-32. Epub 2003 May 01. PMID: 12730554 4. Geleijnse JM, Grobbee DE. Nutrition and healthhypertension. Ned Tijdschr Geneeskd. 2003 May 24;147(21):996-1000. PMID: 12811968 5. Suresh S, Lozono S, Hall SC. Large-dose intravenous methotrexate-induced cutaneous toxicity: can oral magnesium oxide reduce pain? Anesth Analg. 2003 May;96(5):1413-4, table of contents. PMID: 12707144 6. Sigman-Grant M, Warland R, Hsieh G. Selected lower-fat foods positively impact nutrient quality in diets of free-living Americans. J Am Diet Assoc. 2003 May;103(5):570-6. PMID: 12728214

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7.Haupt H, Scheibe F, Mazurek B. Therapeutic efficacy of magnesium in acoustic trauma in the guinea pig. ORL J Otorhinolaryngol Relat Spec. 2003 May-Jun;65(3):134-9. PMID: 12925813 8. Hoane MR, Knotts AA, Akstulewicz SL, Aquilano M, Means LW. The behavioral effects of magnesium therapy on recovery of function following bilateral anterior medial cortex lesions in the rat. Brain Res Bull. 2003 Apr 15;60(1-2):105-14. PMID: 12725898 9. Asai T, Nakatani T, Tamada S, Kuwabara N, Yamanaka S, Tashiro K, Nakao T, Komiya T, Okamura M, Kim S, Iwao H, Miura K. Activation of transcription factors AP-1 and NF-kappaB in chronic cyclosporine A nephrotoxicity: role in beneficial effects of magnesium supplementation. Transplantation. 2003 Apr 15;75(7):1040-4. PMID: 12698095 10. Sharkey JR, Giuliani C, Haines PS, Branch LG, Busby-Whitehead J, Zohoori N. Summary measure of dietary musculoskeletal nutrient (calcium, vitamin D, magnesium, and phosphorus) intakes is associated with lower-extremity physical performance in homebound elderly men and women. Am J Clin Nutr. 2003 Apr;77(4):847-56. PMID: 12663282 11. Seguro AC, de Araujo M, Seguro FS, Rienzo M, Magaldi AJ, Campos SB. Effects of hypokalemia and hypomagnesemia on zidovudine (AZT) and didanosine (ddI) nephrotoxicity in rats. Clin Nephrol. 2003 Apr;59(4):267-72. PMID: 12708566 12. Soliman HM, Mercan D, Lobo SS, Melot C, Vincent JL. Development of ionized hypomagnesemia is associated with higher mortality rates. Crit Care Med. 2003 Apr;31(4):1082-7. PMID: 12682476 13. Ilich JZ, Brownbill RA, Tamborini L. Bone and nutrition in elderly women: protein, energy, and calcium as main determinants of bone mineral density. Eur J Clin Nutr. 2003 Apr;57(4):554-65. PMID: 12700617 14. Cohen N, Almoznino-Sarafian D, Zaidenstein R, Alon I, Gorelik O, Shteinshnaider M, Chachashvily S, Averbukh Z, Golik A, Chen-Levy Z, Modai D. Serum magnesium aberrations in furosemide (frusemide) treated patients with congestive heart failure: pathophysiological correlates and prognostic Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 339

evaluation. Heart. 2003 Apr;89(4):411-6. PMID: 12639869 15. Lin PH, Aickin M, Champagne C, Craddick S, Sacks FM, McCarron P, MostWindhauser MM, Rukenbrod F, Haworth L; Dash-Sodium Collaborative Research Group. Food group sources of nutrients in the dietary patterns of the DASH-Sodium trial. J Am Diet Assoc. 2003 Apr;103(4):488-96. PMID: 12669013 16. Onagawa T, Ohkuchi A, Ohki R, Izumi A, Matsubara S, Sato I, Suzuki M, Minakami H. Woman with postpartum ventricular tachycardia and hypomagnesemia. J Obstet Gynaecol Res. 2003 Apr;29(2):92-5. PMID: 12755529 17. Singhi SC, Singh J, Prasad R. Hypo- and hypermagnesemia in an Indian Pediatric Intensive Care Unit. J Trop Pediatr. 2003 Apr;49(2):99-103. PMID: 12729292 18. van den Bergh WM, Albrecht KW, Berkelbach van der Sprenkel JW, Rinkel GJ. Acta Neurochir (Wien). 2003 Mar;145(3):195-9; discussion 199. Magnesium therapy after aneurysmal subarachnoid haemorrhage a dose-finding study for long term treatment. PMID: 12632115 19. Higgins JC. The 'crashing astimatic.' Am Fam Physician. 2003 Mar 1;67(5):997-1004. PMID: 12643359 20. Roy SR, Milgrom H. Managing outpatient asthma exacerbations. Curr Allergy Asthma Rep. 2003 Mar;3(2):179-89. PMID: 12562559 21. Cappell MS. Gastric and duodenal ulcers during pregnancy. Gastroenterol Clin North Am. 2003 Mar;32(1):263-308. PMID: 12635419 22. Igondjo-Tchen S, Pages N, Bac P, Godeau G, Durlach J. Marfan syndrome, magnesium status and medical prevention of cardiovascular complications by hemodynamic treatments and antisense gene therapy. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 340

Magnes Res. 2003 Mar;16(1):59-64. PMID: 12735484 23. Caron MF, Kluger J, Tsikouris JP, Ritvo A, Kalus JS, White CM. Pharmacotherapy. 2003 Mar;23(3):296-300. Effects of intravenous magnesium sulfate on the QT interval in patients receiving ibutilide. PMID: 12627926 24. Ferrari L, Meschi M, Musini S, Frattini A, Savazzi GM. Recenti Prog Med. 2003 Mar;94(3):136-41. Etiopathogenesis and clinical aspects of nephrolithiasis--at present. PMID: 12677782 25. Touyz RM. Role of magnesium in the pathogenesis of hypertension. Mol Aspects Med. 2003 Feb 6;24(1-3):107-36. PMID: 12537992 26. Levaux Ch, Bonhomme V, Dewandre PY, Brichant JF, Hans P. Effect of intra-operative magnesium sulphate on pain relief and patient comfort after major lumbar orthopaedic surgery. Anaesthesia. 2003 Feb;58(2):131-5. PMID: 12562408 27. Pamnani MB, Bryant HJ, Clough DL, Schooley JF. Increased dietary potassium and magnesium attenuate experimental volume dependent hypertension possibly through endogenous sodium-potassium pump inhibitor. Clin Exp Hypertens. 2003 Feb;25(2):103-15. PMID: 12611422 28. Czajkowski K, Wojcicka-Bentyn J, Grymowicz M, Smolarczyk R, MalinowskaPolubiec A, Romejko E. Calcium-phosphorus-magnesium homeostasis in pregnant women after renal transplantation. Int J Gynaecol Obstet. 2003 Feb;80(2):111-6. PMID: 12566182 29. Hata M, Miyao M, Mizuno Y. Osteoporosis as a lifestyle-related disease. Nippon Rinsho. 2003 Feb;61(2):305-13. PMID: 12638226 30. Zhang Y, Davies LR, Martin SM, Bawaney IM, Buettner GR, Kerber RE. Magnesium reduces free radical concentration and preserves left ventricular Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 341

function after direct current shocks. Resuscitation. 2003 Feb;56(2):199-206. PMID: 12589995 31. Belfort MA, Anthony J, Saade GR, Allen JC Jr; Nimodipine Study Group. A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. N Engl J Med. 2003 Jan 23;348(4):304-11. PMID: 12540643 32. Vink R, O'Connor CA, Nimmo AJ, Heath DL. Magnesium attenuates persistent functional deficits following diffuse traumatic brain injury in rats. Neurosci Lett. 2003 Jan 9;336(1):41-4. PMID: 12493598 33. Averbukh Z, Rosenberg R, Galperin E, Berman S, Cohn M, Cohen N, Modai D, Efrati S, Weissgarten J. Cell-associated magnesium and QT dispersion in hemodialysis patients. Am J Kidney Dis. 2003 Jan;41(1):196-202. PMID: 12500237 34. Meram I, Balat O, Tamer L, Ugur MG. Trace elements and vitamin levels in menopausal women receiving hormone replacement therapy. Clin Exp Obstet Gynecol. 2003;30(1):32-4. PMID: 12731741 35. Duley L, Gulmezoglu AM, Henderson-Smart DJ. Magnesium sulphate and other anticonvulsants for women with pre-eclampsia. Cochrane Database Syst Rev. 2003;(2):CD000025. PMID: 12804383 36. Nalos M, Asfar P, Ichai C, Radermacher P, Leverve XM, Froba G. Adenosine triphosphate-magnesium chloride: relevance for intensive care. Intensive Care Med. 2003 Jan;29(1):10-8. Epub 2002 Nov 02. PMID: 12528016 37. Margolin A, Kantak K, Copenhaver M, Avants SK. A preliminary, controlled investigation of magnesium L-aspartate hydrochloride for illicit cocaine and opiate use in methadone-maintained patients. J Addict Dis. 2003;22(2):49-61. PMID: 12703668 38. Egami I, Wakai K, Kunitomo H, Tamakoshi A, Ando M, Nakayama T, Ohno Y. Associations of lifestyle factors with bone mineral density among male Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 342

university students in Japan. J Epidemiol. 2003 Jan;13(1):48-55. PMID: 12587613 39. Cisse CT, Faye Dieme ME, Ngabo D, Mbaye M, Diagne PM, Moreau JC. Therapeutics indications and prognosis of eclampsia at Dakar University Teaching Hospital. J Gynecol Obstet Biol Reprod (Paris). 2003;32(3 Pt 1):239-45. PMID: 12773926 40. Darvish D. Magnesium may help patients with recessive hereditary inclusion body myopathy, a pathological review. Med Hypotheses. 2003 Jan;60(1):94-101. PMID: 12450772 41. Kato Y, Tamaki G, Tokumitsu M, Yamaguchi S, Yachiku S, Okuyama M. A case of urolithiasis associated with short bowel syndrome. Nippon Hinyokika Gakkai Zasshi. 2003 Jan;94(1):33-6. PMID: 12638204 42. Gulhas N, Durmus M, Demirbilek S, Togal T, Ozturk E, Ersoy MO. The use of magnesium to prevent laryngospasm after tonsillectomy and adenoidectomy: a preliminary study. Paediatr Anaesth. 2003 Jan;13(1):43-7. PMID: 12535038 43. Byrd RP Jr, Roy TM. Magnesium: its proven and potential clinical significance. South Med J. 2003 Jan;96(1):104. PMID: 12602735 44.: Kidd PM. Autism, an extreme challenge to integrative medicine. Part 2: medical management. Altern Med Rev. 2002 Dec;7(6):472-99. PMID: 12495373 45. Carlin Schooley M, Franz KB. Magnesium deficiency during pregnancy in rats increases systolic blood pressure and plasma nitrite. Am J Hypertens. 2002 Dec;15(12):1081-6. PMID: 12460704 46. Imazu M. Hypertension and insulin disorders. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 343

Curr Hypertens Rep. 2002 Dec;4(6):477-82. PMID: 12419178 47. Grzybek A, Klosiewicz-Latoszek L, Targosz U. Changes in the intake of vitamins and minerals by men and women with hyperlipidemia and overweight during dietetic treatment. Eur J Clin Nutr. 2002 Dec;56(12):1162-8. PMID: 12494300 48. Gryspeerdt S, Lefere P, Dewyspelaere J, Baekelandt M, van Holsbeeck B. Optimisation of colon cleansing prior to computed tomographic colonography. JBR-BTR. 2002 Dec;85(6):289-96. PMID: 12553658 49. Bhatia R, Prabhakar S, Grover VK. Tetanus. Neurol India. 2002 Dec;50(4):398-407. PMID: 12577086 50. Murck H. Magnesium and affective disorders. Nutr Neurosci. 2002 Dec;5(6):375-89. PMID: 12509067 51. Haas KM, Suzuki S, Yamaguchi N, Kato I, Ban K, Tanaka T, Fukuda S, Togari H. Nitric oxide further attenuates pulmonary hypertension in magnesium-treated piglets. Pediatr Int. 2002 Dec;44(6):670-4. PMID: 12421268 52. Minami T, Adachi T, Fukuda K. An effective use of magnesium sulfate for intraoperative management of laparoscopic adrenalectomy for pheochromocytoma in a pediatric patient. Anesth Analg. 2002 Nov;95(5):1243-4, table of contents. PMID: 12401602 53. Nakatani T, Asai T. Non-immunologic factor: immunosuppressive drug-induced nephrotoxicity. Hinyokika Kiyo. 2002 Nov;48(11):699-705. PMID: 12512145 54. Blackwell SC, Redman ME, Whitty JE, Refuerzo JS, Berry SM, Sorokin Y, Russell E, Cotton DB. The effect of intrapartum magnesium sulfate therapy on fetal cardiac Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 344

troponin I levels at delivery. J Matern Fetal Neonatal Med. 2002 Nov;12(5):327-31. PMID: 12607765 55. Unachak K, Louthrenoo O, Katanyuwong K. Primary hypomagnesemia in Thai infants: a case report with 7 years follow-up and review of literature. J Med Assoc Thai. 2002 Nov;85(11):1226-31. PMID: 12546321 56. Berger R, Garnier Y, Jensen A. Perinatal brain damage: underlying mechanisms and neuroprotective strategies. J Soc Gynecol Investig. 2002 Nov-Dec;9(6):319-28. PMID: 12445595 57. Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ. New migraine preventive options: an update with pathophysiological considerations. Rev Hosp Clin Fac Med Sao Paulo. 2002 Nov-Dec;57(6):293-8. Epub 2003 Feb 17. PMID: 12612763 58. Milionis HJ, Rizos E, Liamis G, Nikas S, Siamopoulos KC, Elisaf MS. Acid-base and electrolyte disturbances in patients with hypercalcemia. South Med J. 2002 Nov;95(11):1280-7. PMID: 12539994 59. Rao GN. Diet and kidney diseases in rats. Toxicol Pathol. 2002 Nov-Dec;30(6):651-6. PMID: 12512864 60. Anderson RA. A complementary approach to urolithiasis prevention. World J Urol. 2002 Nov;20(5):294-301. Epub 2002 Oct 17. PMID: 12522585 61. Paskitti M, Reid KH. Use of an adenosine triphosphate-based 'cocktail' early in reperfusion substantially improves brain protein synthesis after global ischemia in rats. Neurosci Lett. 2002 Oct 18;331(3):147-50. PMID: 12383918

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62. Gaby AR. Intravenous nutrient therapy: the "Myers' cocktail". Altern Med Rev. 2002 Oct;7(5):389-403. PMID: 12410623 63.Wilkes NJ, Mallett SV, Peachey T, Di Salvo C, Walesby R. Correction of ionized plasma magnesium during cardiopulmonary bypass reduces the risk of postoperative cardiac arrhythmia. Anesth Analg. 2002 Oct;95(4):828-34, table of contents. PMID: 12351253 64. Davis GK, Homer CS, Brown MA. Hypertension in pregnancy: do consensus statements make a difference? Aust N Z J Obstet Gynaecol. 2002 Oct;42(4):369-73. PMID: 12403283 65. Ichiba H, Tamai H, Negishi H, Ueda T, Kim TJ, Sumida Y, Takahashi Y, Fujinaga H, Minami H; Kansai Magnesium Study Group. Randomized controlled trial of magnesium sulfate infusion for severe birth asphyxia. Pediatr Int. 2002 Oct;44(5):505-9. PMID: 12225549 66. Asai T, Nakatani T, Yamanaka S, Tamada S, Kishimoto T, Tashiro K, Nakao T, Okamura M, Kim S, Iwao H, Miura K. Magnesium supplementation prevents experimental chronic cyclosporine a nephrotoxicity via renin-angiotensin system independent mechanism. Transplantation. 2002 Sep 27;74(6):784-91. PMID: 12364856 67. Plasma exchange in severe postpartum HELLP syndrome. Forster JG, Peltonen S, Kaaja R, Lampinen K, Pettila V. Acta Anaesthesiol Scand. 2002 Sep;46(8):955-8. PMID: 12190795 68. Kantas E, Cetin A, Kaya T, Cetin M. Effect of magnesium sulfate, isradipine, and ritodrine on contractions of myometrium: pregnant human and rat. Acta Obstet Gynecol Scand. 2002 Sep;81(9):825-30. PMID: 12225296 69. Memis D, Turan A, Karamanlioglu B, Sut N, Pamukcu Z. The use of magnesium sulfate to prevent pain on injection of propofol. Anesth Analg. 2002 Sep;95(3):606-8, table of contents. PMID: 12198045

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70. Buvanendran A, McCarthy RJ, Kroin JS, Leong W, Perry P, Tuman KJ. Intrathecal magnesium prolongs fentanyl analgesia: a prospective, randomized, controlled trial. Anesth Analg. 2002 Sep;95(3):661-6, table of contents. PMID: 12198056 71. Forlani S, De Paulis R, de Notaris S, Nardi P, Tomai F, Proietti I, Ghini AS, Chiariello L. Combination of sotalol and magnesium prevents atrial fibrillation after coronary artery bypass grafting. Ann Thorac Surg. 2002 Sep;74(3):720-5; discussion 725-6. PMID: 12238830 72. Tramer MR, Glynn CJ. Magnesium Bier's block for treatment of chronic limb pain: a randomised, double-blind, cross-over study. Pain. 2002 Sep;99(1-2):235-41. PMID: 12237201 73. Patrick L. Nonalcoholic fatty liver disease: relationship to insulin sensitivity and oxidative stress. Treatment approaches using vitamin E, magnesium, and betaine. Altern Med Rev. 2002 Aug;7(4):276-91. PMID: 12197781 74. Attygalle D, Rodrigo N. Magnesium as first line therapy in the management of tetanus: a prospective study of 40 patients. Anaesthesia. 2002 Aug;57(8):811-7. PMID: 12133096 75. Silverman RA, Osborn H, Runge J, Gallagher EJ, Chiang W, Feldman J, Gaeta T, Freeman K, Levin B, Mancherje N, Scharf S; Acute Asthma/Magnesium Study Group. IV magnesium sulfate in the treatment of acute severe asthma: a multicenter randomized controlled trial. Chest. 2002 Aug;122(2):489-97. PMID: 12171821 76. Li S, Lin S, Daggy BP, Mirchandani HL, Chien YW. Effect of formulation variables on the floating properties of gastric floating drug delivery system. Drug Dev Ind Pharm. 2002 Aug;28(7):783-93. PMID: 12236064

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77. van den Bergh WM, Zuur JK, Kamerling NA, van Asseldonk JT, Rinkel GJ, Tulleken CA, Nicolay K. Role of magnesium in the reduction of ischemic depolarization and lesion volume after experimental subarachnoid hemorrhage. J Neurosurg. 2002 Aug;97(2):416-22. PMID: 12186471 78. Garcia MC, Byrd RP Jr, Roy TM. Lethal iatrogenic hypermagnesemia. Tenn Med. 2002 Aug;95(8):334-6. PMID: 12174756 79. Patel S, Martinez-Ripoll M, Blundell TL, Albert A. J Mol Biol. 2002 Jul 26;320(5):1087-94. Structural enzymology of Li(+)-sensitive/Mg(2+)-dependent phosphatases. PMID: 12126627 80. Ulugol A, Aslantas A, Ipci Y, Tuncer A, Hakan Karadag C, Dokmeci I. Combined systemic administration of morphine and magnesium sulfate attenuates painrelated behavior in mononeuropathic rats. Brain Res. 2002 Jul 5;943(1):101-4. PMID: 12088843 81. Dagdelen S, Toraman F, Karabulut H, Alhan C. The value of P dispersion on predicting atrial fibrillation after coronary artery bypass surgery: effect of magnesium on P dispersion. Ann Noninvasive Electrocardiol. 2002 Jul;7(3):211-8. PMID: 12167181 82. Streetman DD, Bhatt-Mehta V, Johnson CE. Management of acute, severe asthma in children. Ann Pharmacother. 2002 Jul-Aug;36(7-8):1249-60. PMID: 12086560 83. Kaye P, O'Sullivan I. The role of magnesium in the emergency department. Emerg Med J. 2002 Jul;19(4):288-91. PMID: 12101132 84. Yamori Y, Liu L, Mu L, Zhao H, Pen Y, Hu Z, Kuga S, Negishi H, Ikeda K; Japan-China Cooperative Study Group: Chongqing Project. Diet-related factors, educational levels and blood pressure in a Chinese population sample: findings from the Japan-China Cooperative Research Project. Hypertens Res. 2002 Jul;25(4):559-64. PMID: 12358141 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 348

85. Aagaard NK, Andersen H, Vilstrup H, Clausen T, Jakobsen J, Dorup I. Muscle strength, Na,K-pumps, magnesium and potassium in patients with alcoholic liver cirrhosis -- relation to spironolactone. J Intern Med. 2002 Jul;252(1):56-63. PMID: 12074739 86. Malluche HH, Mawad H. Management of hyperphosphataemia of chronic kidney disease: lessons from the past and future directions. Nephrol Dial Transplant. 2002 Jul;17(7):1170-5. PMID: 12105237

Zinc 50 STUDIES

1: Nowak G, Szewczyk B, Wieronska JM, Branski P, Palucha A, Pilc A, Sadlik K, Piekoszewski W. Antidepressant-like effects of acute and chronic treatment with zinc in forced swim test and olfactory bulbectomy model in rats. Brain Res Bull. 2003 Jul 15;61(2):159-64. PMID: 12832002 2: Lambert JC, Zhou Z, Wang L, Song Z, McClain CJ, Kang YJ. Prevention of alterations in intestinal permeability is involved in zinc inhibition of acute ethanol-induced liver damage in mice. J Pharmacol Exp Ther. 2003 Jun;305(3):880-6. Epub 2003 Mar 06. PMID: 12626662 3: Roldan S, Winkel EG, Herrera D, Sanz M, Van Winkelhoff AJ. The effects of a new mouthrinse containing chlorhexidine, cetylpyridinium chloride and zinc lactate on the microflora of oral halitosis patients: a dual-centre, double-blind placebo-controlled study. J Clin Periodontol. 2003 May;30(5):427-34. PMID: 12716335 4: Winkel EG, Roldan S, Van Winkelhoff AJ, Herrera D, Sanz M. Clinical effects of a new mouthrinse containing chlorhexidine, cetylpyridinium chloride and zinc-lactate on oral halitosis. A dual-center, double-blind placebo-controlled study. J Clin Periodontol. 2003 Apr;30(4):300-6. PMID: 12694427 5: Orbak R, Cicek Y, Tezel A, Dogru Y. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 349

Effects of zinc treatment in patients with recurrent aphthous stomatitis. Dent Mater J. 2003 Mar;22(1):21-9. PMID: 12790293 6: Mossad SB. Effect of zincum gluconicum nasal gel on the duration and symptom severity of the common cold in otherwise healthy adults. QJM. 2003 Jan;96(1):35-43. PMID: 12509647 7: McElroy BH, Miller SP. Effectiveness of zinc gluconate glycine lozenges (Cold-Eeze) against the common cold in school-aged subjects: a retrospective chart review. Am J Ther. 2002 Nov-Dec;9(6):472-5. PMID: 12424502 8: Nowak G, Szewczyk B. Mechanisms contributing to antidepressant zinc actions. Pol J Pharmacol. 2002 Nov-Dec;54(6):587-92. Review. PMID: 12866713 9: Putt MS, Yu D, Kohut BE. Inhibition of calculus formation by dentifrice formulations containing essential oils and zinc. Am J Dent. 2002 Oct;15(5):335-8. PMID: 12537346 10: Rostan EF, DeBuys HV, Madey DL, Pinnell SR. Evidence supporting zinc as an important antioxidant for skin. Int J Dermatol. 2002 Sep;41(9):606-11. Review. PMID: 12358835 11: Bhandari N, Bahl R, Taneja S, Strand T, Molbak K, Ulvik RJ, Sommerfelt H, Bhan MK. Effect of routine zinc supplementation on pneumonia in children aged 6 months to 3 years: randomised controlled trial in an urban slum. BMJ. 2002 Jun 8;324(7350):1358. PMID: 12052800 12: Oken E, Duggan C. Update on micronutrients: iron and zinc. Curr Opin Pediatr. 2002 Jun;14(3):350-3. Review. PMID: 12011679 13: Cho YH, Lee SJ, Lee JY, Kim SW, Lee CB, Lee WY, Yoon MS. Antibacterial effect of intraprostatic zinc injection in a rat model of chronic Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 350

bacterial prostatitis. Int J Antimicrob Agents. 2002 Jun;19(6):576-82. PMID: 12135851 14: Bhandari N, Bahl R, Taneja S, Strand T, Molbak K, Ulvik RJ, Sommerfelt H, Bhan MK. Substantial reduction in severe diarrheal morbidity by daily zinc supplementation in young north Indian children. Pediatrics. 2002 Jun;109(6):e86. PMID: 12042580 15: Strand TA, Chandyo RK, Bahl R, Sharma PR, Adhikari RK, Bhandari N, Ulvik RJ, Molbak K, Bhan MK, Sommerfelt H. Effectiveness and efficacy of zinc for the treatment of acute diarrhea in young children. Pediatrics. 2002 May;109(5):898-903. PMID: 11986453 16: Lowe NM, Lowe NM, Fraser WD, Jackson MJ. Is there a potential therapeutic value of copper and zinc for osteoporosis? Proc Nutr Soc. 2002 May;61(2):181-5. Review. PMID: 12133199 17: Karyadi E, West CE, Schultink W, Nelwan RH, Gross R, Amin Z, Dolmans WM, Schlebusch H, van der Meer JW. A double-blind, placebo-controlled study of vitamin A and zinc supplementation in persons with tuberculosis in Indonesia: effects on clinical response and nutritional status. Am J Clin Nutr. 2002 Apr;75(4):720-7. PMID: 11916759 18: Afonne OJ, Orisakwe OE, Obi E, Dioka CE, Ndubuka GI. Nephrotoxic actions of low-dose mercury in mice: protection by zinc. Arch Environ Health. 2002 Mar-Apr;57(2):98-102. PMID: 12194165 19: Hwang IK, Go VL, Harris DM, Yip I, Song MK. Effects of arachidonic acid plus zinc on glucose disposal in genetically diabetic (ob/ob) mice. Diabetes Obes Metab. 2002 Mar;4(2):124-31. PMID: 11940110 20: Su JC, Birmingham CL. Zinc supplementation in the treatment of anorexia nervosa. Eat Weight Disord. 2002 Mar;7(1):20-2. Review. PMID: 11930982 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 351

21: Tsocheva-Gaitandjieva NT, Gabrashanska MP, Tepavitcharova S. Trace element levels in the liver of rats with acute and chronic fascioliasis and after treatment with zinc-copper hydroxochloride mixed crystals. J Helminthol. 2002 Mar;76(1):87-90. PMID: 12018202 22: Zemel BS, Kawchak DA, Fung EB, Ohene-Frempong K, Stallings VA. Effect of zinc supplementation on growth and body composition in children with sickle cell disease. Am J Clin Nutr. 2002 Feb;75(2):300-7. PMID: 11815322 23: Yoshida S, Tomita H. A case of Cronkhite-Canada syndrome whose major complaint, taste disturbance, was improved by zinc therapy. Acta Otolaryngol Suppl. 2002;(546):154-8. PMID: 12132614 24: Rahman MM, Wahed MA, Fuchs GJ, Baqui AH, Alvarez JO. Synergistic effect of zinc and vitamin A on the biochemical indexes of vitamin A nutrition in children. Am J Clin Nutr. 2002 Jan;75(1):92-8. PMID: 11756065 25: Prasad AS, Kucuk O. Zinc in cancer prevention. Cancer Metastasis Rev. 2002;21(3-4):291-5. Review. PMID: 12549767 26: Yoshida Y, Higashi T, Nouso K, Nakatsukasa H, Nakamura SI, Watanabe A, Tsuji T. Effects of zinc deficiency/zinc supplementation on ammonia metabolism in patients with decompensated liver cirrhosis. Acta Med Okayama. 2001 Dec;55(6):349-55. PMID: 11779097 27: Jampol LM, Ferris FL 3rd. Antioxidants and zinc to prevent progression of age-related macular degeneration. JAMA. 2001 Nov 21;286(19):2466-8. No abstract available. PMID: 11759670 28: Dijkhuizen MA, Wieringa FT, West CE, Martuti S, Muhilal. Effects of iron and zinc supplementation in Indonesian infants on micronutrient status and growth. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 352

J Nutr. 2001 Nov;131(11):2860-5. PMID: 11694609 29: Fong LY, Nguyen VT, Farber JL. Esophageal cancer prevention in zinc-deficient rats: rapid induction of apoptosis by replenishing zinc. J Natl Cancer Inst. 2001 Oct 17;93(20):1525-33. PMID: 11604475 30: Takagi H, Nagamine T, Abe T, Takayama H, Sato K, Otsuka T, Kakizaki S, Hashimoto Y, Matsumoto T, Kojima A, Takezawa J, Suzuki K, Sato S, Mori M. Zinc supplementation enhances the response to interferon therapy in patients with chronic hepatitis C. J Viral Hepat. 2001 Sep;8(5):367-71. PMID: 11555194 31: Christian P, Khatry SK, Yamini S, Stallings R, LeClerq SC, Shrestha SR, Pradhan EK, West KP Jr. Zinc supplementation might potentiate the effect of vitamin A in restoring night vision in pregnant Nepalese women. Am J Clin Nutr. 2001 Jun;73(6):1045-51. PMID: 11382658 32: Najda J, Stella-Holowiecka B, Machalski M. Low-dose zinc administration as an effective Wilson's disease treatment. Biol Trace Elem Res. 2001 Jun;80(3):281-4. PMID: 11508632 33: Iitaka M, Kakinuma S, Fujimaki S, Oosuga I, Fujita T, Yamanaka K, Wada S, Katayama S. Induction of apoptosis and necrosis by zinc in human thyroid cancer cell lines. J Endocrinol. 2001 May;169(2):417-24. PMID: 11312158 34: Yang HM, Chai JK, Guo ZR. [Effect of improved topical agents on healing time of deep second-degree burn wound] Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2001 May;15(3):162-4. Chinese. PMID: 11393958 35: Khatun UH, Malek MA, Black RE, Sarkar NR, Wahed MA, Fuchs G, Roy SK. A randomized controlled clinical trial of zinc, vitamin A or both in undernourished children with persistent diarrhea in Bangladesh. Acta Paediatr. 2001 Apr;90(4):376-80. PMID: 11332926

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36: Yoshikawa Y, Ueda E, Miyake H, Sakurai H, Kojima Y. Insulinomimetic bis(maltolato)zinc(II) complex: blood glucose normalizing effect in KK-A(y) mice with type 2 diabetes mellitus. Biochem Biophys Res Commun. 2001 Mar16;281(5):1190-3. PMID: 11243860 37: Hotz C, Brown KH. Identifying populations at risk of zinc deficiency: the use of supplementation trials. Nutr Rev. 2001 Mar;59(3 Pt 1):80-4. Review. PMID: 11330625 38: Ho E, Quan N, Tsai YH, Lai W, Bray TM. Dietary zinc supplementation inhibits NFkappaB activation and protects against chemically induced diabetes in CD1 mice. Exp Biol Med (Maywood). 2001 Feb;226(2):103-11. PMID: 11446433 39: Dreno B, Moyse D, Alirezai M, Amblard P, Auffret N, Beylot C, Bodokh I, Chivot M, Daniel F, Humbert P, Meynadier J, Poli F; Acne Research and Study Group. Multicenter randomized comparative double-blind controlled clinical trial of the safety and efficacy of zinc gluconate versus minocycline hydrochloride in the treatment of inflammatory acne vulgaris. Dermatology. 2001;203(2):135-40. PMID: 11586012 40: Bhutta ZA, Bird SM, Black RE, Brown KH, Gardner JM, Hidayat A, Khatun F, Martorell R, Ninh NX, Penny ME, Rosado JL, Roy SK, Ruel M, Sazawal S, Shankar A. Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries: pooled analysis of randomized controlled trials. Am J Clin Nutr. 2000 Dec;72(6):1516-22. PMID: 11101480 41: Saple DG, Ravichandran G, Desai A. Evaluation of safety and efficacy of ketoconazole 2% and zinc pyrithione 1% shampoo in patients with moderate to severe dandruff--a postmarketing study. J Indian Med Assoc. 2000 Dec;98(12):810-1. PMID: 11394481 42: Hirt M, Nobel S, Barron E. Zinc nasal gel for the treatment of common cold symptoms: a double-blind, placebo-controlled trial. Ear Nose Throat J. 2000 Oct;79(10):778-80, 782. PMID: 11055098

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43: Sayeg Porto MA, Oliveira HP, Cunha AJ, Miranda G, Guimaraes MM, Oliveira WA, dos Santos DM. Linear growth and zinc supplementation in children with short stature. J Pediatr Endocrinol Metab. 2000 Sep-Oct;13(8):1121-8. PMID: 11085191 44: Umeta M, West CE, Haidar J, Deurenberg P, Hautvast JG. Zinc supplementation and stunted infants in Ethiopia: a randomised controlled trial. Lancet. 2000 Jun 10;355(9220):2021-6. PMID: 10885352 45: Goel A, Chauhan DP, Dhawan DK. Protective effects of zinc in chlorpyrifos induced hepatotoxicity: a biochemical and trace elemental study. Biol Trace Elem Res. 2000 May;74(2):171-83. PMID: 11051590 46: Mocchegiani E, Muzzioli M. Therapeutic application of zinc in human immunodeficiency virus against opportunistic infections. J Nutr. 2000 May;130(5S Suppl):1424S-31S. Review. PMID: 10801955 47: Williams DR. Chemical speciation applied to bio-inorganic chemistry. J Inorg Biochem. 2000 Apr;79(1-4):275-83. Review. PMID: 10830878 48: Tahmaz L, Gokalp A, Kibar Y, Kocak I, Yalcin O, Ozercan Y. Effect of hypothyroidism on the testes in mature rats and treatment with levothyroxine and zinc. Andrologia. 2000 Mar;32(2):85-9. PMID: 10755190 49: Cacic M, Percl M, Jadresin O, Kolacek S. [The role of zinc in the initial treatment of Wilson's disease in children] Lijec Vjesn. 2000 Mar;122(3-4):77-81. Serbo-Croatian (Roman). PMID: 10932534 50: Penland JG. Behavioral data and methodology issues in studies of zinc nutrition in humans. J Nutr. 2000 Feb;130(2S Suppl):361S-364S. Review. PMID: 10721907

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Selenium 50 STUDIES
1: Santamaria A, Salvatierra-Sanchez R, Vazquez-Roman B, Santiago-Lopez D, Villeda-Hernandez J, Galvan-Arzate S, Jimenez-Capdeville ME, Ali SF. Protective effects of the antioxidant selenium on quinolinic acid-induced neurotoxicity in rats: in vitro and in vivo studies. J Neurochem. 2003 Jul;86(2):479-88. PMID: 12871589 2: Keskes-Ammar L, Feki-Chakroun N, Rebai T, Sahnoun Z, Ghozzi H, Hammami S, Zghal K, Fki H, Damak J, Bahloul A. Sperm oxidative stress and the effect of an oral vitamin E and selenium supplement on semen quality in infertile men. Arch Androl. 2003 Mar-Apr;49(2):83-94. PMID: 12623744 3: Di Leo MA, Ghirlanda G, Gentiloni Silveri N, Giardina B, Franconi F, Santini SA. Potential therapeutic effect of antioxidants in experimental diabetic retina: a comparison between chronic taurine and vitamin E plus selenium supplementations. Free Radic Res. 2003 Mar;37(3):323-30. PMID: 12688428 4: Xu J, Yang F, Chen L, Hu Y, Hu Q. Effect of selenium on increasing the antioxidant activity of tea leaves harvested during the early spring tea producing season. J Agric Food Chem. 2003 Feb 12;51(4):1081-4. PMID: 12568576 5: Kalinina EP, Zhuravskaia NS, Tsyvkina GI, Koziavina NV. [Correction of immune disorders with neoselenium in patients with chronic bronchitis] Klin Med (Mosk). 2003;81(3):43-6. Russian. PMID: 12698851 6: Chow CK, Hong CB. Dietary vitamin E and selenium and toxicity of nitrite and nitrate. Toxicology. 2002 Nov 15;180(2):195-207. Review. PMID: 12324194 7: El-Bayoumy K, Richie JP Jr, Boyiri T, Komninou D, Prokopczyk B, Trushin N, Kleinman W, Cox J, Pittman B, Colosimo S. Influence of selenium-enriched yeast supplementation on biomarkers of oxidative damage and hormone status in healthy adult males: a clinical pilot study. Cancer Epidemiol Biomarkers Prev. 2002 Nov;11(11):1459-65. PMID: 12433727 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 356

8: Burbano X, Miguez-Burbano MJ, McCollister K, Zhang G, Rodriguez A, Ruiz P, Lecusay R, Shor-Posner G. Impact of a selenium chemoprevention clinical trial on hospital admissions of HIV-infected participants. HIV Clin Trials. 2002 Nov-Dec;3(6):483-91. PMID: 12501132 9: Zuberbuehler CA, Messikommer RE, Wenk C. Choice feeding of selenium-deficient laying hens affects diet selection, selenium intake and body weight. J Nutr. 2002 Nov;132(11):3411-7. PMID: 12421860 10: Arai T, Magori E, Morimoto Y. Changes in activities of enzymes in erythrocytes from ddY mice supplemented with dietary selenium. Exp Anim. 2002 Oct;51(5):517-9. PMID: 12451715 11: Shor-Posner G, Lecusay R, Morales G, Campa A, Miguez-Burbano MJ. Neuroprotection in HIV-positive drug users: implications for antioxidant therapy. J Acquir Immune Defic Syndr. 2002 Oct 1;31 Suppl 2:S84-8. Review. PMID: 12394787 12: Dylewski ML, Mastro AM, Picciano MF. Maternal selenium nutrition and neonatal immune system development. Biol Neonate. 2002 Aug;82(2):122-7. PMID: 12169835 13: Holben DH, Smith AM, Ilich JZ, Landoll JD, Holcomb JP, Matkovic V. Selenium intakes, absorption, retention, and status in adolescent girls. J Am Diet Assoc. 2002 Aug;102(8):1082-7. PMID: 12171452 14: Hintze KJ, Lardy GP, Marchello MJ, Finley JW. Selenium accumulation in beef: effect of dietary selenium and geographical area of animal origin. J Agric Food Chem. 2002 Jul 3;50(14):3938-42. PMID: 12083862 15: Duffield-Lillico AJ, Reid ME, Turnbull BW, Combs GF Jr, Slate EH, Fischbach LA, Marshall JR, Clark LC. Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 357

Cancer Epidemiol Biomarkers Prev. 2002 Jul;11(7):630-9. PMID: 12101110 16: Popova NV. Perinatal selenium exposure decreases spontaneous liver tumorogenesis in CBA mice. Cancer Lett. 2002 May 8;179(1):39-42. PMID: 11880180 17: Murphy J, Hannon EM, Kiely M, Flynn A, Cashman KD. Selenium intakes in 18-64-y-old Irish adults. Eur J Clin Nutr. 2002 May;56(5):402-8. PMID: 12001010 18: Gierus M, Schwarz FJ, Kirchgessner M. Selenium supplementation and selenium status of dairy cows fed diets based on grass, grass silage or maize silage. J Anim Physiol Anim Nutr (Berl). 2002 Apr;86(3-4):74-82. PMID: 11972675 19: Gartner R, Gasnier BC, Dietrich JW, Krebs B, Angstwurm MW. Selenium supplementation in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations. J Clin Endocrinol Metab. 2002 Apr;87(4):1687-91. PMID: 11932302 20: Mehta U, Kang BP, Bansal G, Bansal MP. Studies of apoptosis and bcl-2 in experimental atherosclerosis in rabbit and influence of selenium supplementation. Gen Physiol Biophys. 2002 Mar;21(1):15-29. PMID: 12168721 21: Kurz B, Jost B, Schunke M. Dietary vitamins and selenium diminish the development of mechanically induced osteoarthritis and increase the expression of antioxidative enzymes in the knee joint of STR/1N mice. Osteoarthritis Cartilage. 2002 Feb;10(2):119-26. PMID: 11869071 22: Huang K, Yang S. Inhibitory effect of selenium on Cryptosporidium parvum infection in vitro and in vivo. Biol Trace Elem Res. 2002 Winter;90(1-3):261-72. PMID: 12666840

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23: Gazdik F, Horvathova M, Gazdikova K, Jahnova E. The influence of selenium supplementation on the immunity of corticoid-dependent asthmatics. Bratisl Lek Listy. 2002;103(1):17-21. PMID: 12061081 24: Gazdik F, Kadrabova J, Gazdikova K. Decreased consumption of corticosteroids after selenium supplementation in corticoid-dependent asthmatics. Bratisl Lek Listy. 2002;103(1):22-5. PMID: 12061082 25: Sepulveda RT, Zhang J, Watson RR. Selenium supplementation decreases coxsackievirus heart disease during murine AIDS. Cardiovasc Toxicol. 2002;2(1):53-61. PMID: 12189280 26: Miyazaki Y, Koyama H, Nojiri M, Suzuki S. Relationship of dietary intake of fish and non-fish selenium to serum lipids in Japanese rural coastal community. J Trace Elem Med Biol. 2002;16(2):83-90. PMID: 12195730 27: Muller AS, Pallauf J, Most E. Parameters of dietary selenium and vitamin E deficiency in growing rabbits. J Trace Elem Med Biol. 2002;16(1):47-55. PMID: 11878752 28: de Lorgeril M, Salen P, Accominotti M, Cadau M, Steghens JP, Boucher F, de Leiris J. Dietary and blood antioxidants in patients with chronic heart failure. Insights into the potential importance of selenium in heart failure. Eur J Heart Fail. 2001 Dec;3(6):661-9. PMID: 11738217 29: Sjunnesson H, Sturegard E, Willen R, Wadstrom T. High intake of selenium, beta-carotene, and vitamins A, C, and E reduces growth of Helicobacter pylori in the guinea pig. Comp Med. 2001 Oct;51(5):418-23. PMID: 11924801 30: Kang BP, Mehta U, Bansal MP. Selenium supplementation protects from high fat diet-induced atherogenesis in rats: role of mitogen stimulated lymphocytes and macrophage NO production.

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Indian J Exp Biol. 2001 Aug;39(8):793-7. PMID: 12018582 31: Vinceti M, Wei ET, Malagoli C, Bergomi M, Vivoli G. Adverse health effects of selenium in humans. Rev Environ Health. 2001 Jul-Sep;16(4):233-51. Review. PMID: 12041880 32: Zhang ZW, Shimbo S, Qu JB, Watanabe T, Nakatsuka H, Matsuda-Inoguchi N, Higashikawa K, Ikeda M. Dietary selenium intake of Chinese adult women in the 1990s. Biol Trace Elem Res. 2001 May;80(2):125-38. PMID: 11437178 33: Combs GF Jr. Selenium in global food systems. Br J Nutr. 2001 May;85(5):517-47. Review. PMID: 11348568 34: Finley JW, Ip C, Lisk DJ, Davis CD, Hintze KJ, Whanger PD. Cancer-protective properties of high-selenium broccoli. J Agric Food Chem. 2001 May;49(5):2679-83. PMID: 11368655 35: Federico A, Iodice P, Federico P, Del Rio A, Mellone MC, Catalano G, Federico P. Effects of selenium and zinc supplementation on nutritional status in patients with cancer of digestive tract. Eur J Clin Nutr. 2001 Apr;55(4):293-7. PMID: 11360134 36: Chanoine JP, Neve J, Wu S, Vanderpas J, Bourdoux P. Selenium decreases thyroglobulin concentrations but does not affect the increased thyroxine-to-triiodothyronine ratio in children with congenital hypothyroidism. J Clin Endocrinol Metab. 2001 Mar;86(3):1160-3. PMID: 11238502 37: Naziroglu M, Cay M. Protective role of intraperitoneally administered vitamin E and selenium on the antioxidative defense mechanisms in rats with diabetes induced by streptozotocin. Biol Trace Elem Res. 2001 Feb;79(2):149-59. PMID: 11330521

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38: Kiremidjian-Schumacher L, Roy M. Effect of selenium on the immunocompetence of patients with head and neck cancer and on adoptive immunotherapy of early and established lesions. Biofactors. 2001;14(1-4):161-8. Review. PMID: 11568453 39: Gartner R, Albrich W, Angstwurm MW. The effect of a selenium supplementation on the outcome of patients with severe systemic inflammation, burn and trauma. Biofactors. 2001;14(1-4):199-204. Review. PMID: 11568457 40: Abdollahi M, Rahmat-Jirdeh N, Soltaninejad K. Protection by selenium of lead-acetate-induced alterations on rat submandibular gland function. Hum Exp Toxicol. 2001 Jan;20(1):28-33. PMID: 11339622 41: Berger MM, Reymond MJ, Shenkin A, Rey F, Wardle C, Cayeux C, Schindler C, Chiolero RL. Influence of selenium supplements on the post-traumatic alterations of the thyroid axis: a placebo-controlled trial. Intensive Care Med. 2001 Jan;27(1):91-100. PMID: 11280679 42: Combs GF Jr. Impact of selenium and cancer-prevention findings on the nutrition-health paradigm. Nutr Cancer. 2001;40(1):6-11. Review. PMID: 11799925 43: Kim YS, Milner J. Molecular targets for selenium in cancer prevention. Nutr Cancer. 2001;40(1):50-4. Review. PMID: 11799923 44: Francescato HD, Costa RS, Rodrigues Camargo SM, Zanetti MA, Lavrador MA, Bianchi MD. Effect of oral selenium administration on cisplatin-induced nephrotoxicity in rats. Pharmacol Res. 2001 Jan;43(1):77-82. PMID: 11207069 45: Tutel'ian VA, Khotimchenko SA. [Selenium as an essential and deficient factor in the nutrition of Russian population] Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 361

Vestn Ross Akad Med Nauk. 2001;(6):31-4. Russian. PMID: 11517874 46: Shakhovskaia AK, Gmoshinskii IV, Vasil'ev AV, Loranskaia TI, Ovchinnikova IV, Orlova LA, Mazo VK. [Use of organic forms of selenium in nutrition of patients with gastrointestinal diseases] Vopr Pitan. 2001;70(3):22-4. Russian. PMID: 11517685 47: Helzlsouer KJ, Huang HY, Alberg AJ, Hoffman S, Burke A, Norkus EP, Morris JS, Comstock GW. Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst. 2000 Dec 20;92(24):2018-23. PMID: 11121464 48: Djujic IS, Jozanov-Stankov ON, Milovac M, Jankovic V, Djermanovic V. Bioavailability and possible benefits of wheat intake naturally enriched with selenium and its products. Biol Trace Elem Res. 2000 Dec;77(3):273-85. PMID: 11204469 49: Sieja K. Protective role of selenium against the toxicity of multi-drug chemotherapy in patients with ovarian cancer. Pharmazie. 2000 Dec;55(12):958-9. No abstract available. PMID: 11189880 50: McKenzie RC. Selenium, ultraviolet radiation and the skin. Clin Exp Dermatol. 2000 Nov;25(8):631-6. Review. PMID: 11167979

Copper 60 Studies

1. Linder MC, Hazegh-Azam M. Copper biochemistry and molecular biology. Am J Clin Nutr. 1996;63(5):797S-811S. (PubMed) 2. Turnlund JR. Copper. In: Shils M, Olson JA, Shike M, Ross AC, eds. Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:241-252.

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3. Uauy R, Olivares M, Gonzalez M. Essentiality of copper in humans. Am J Clin Nutr. 1998;67(5 Suppl):952S-959S. (PubMed) 4. Harris ED. Copper. In: O'Dell BL, Sunde RA, eds. Handbook of nutritionally essential minerals. New York: Marcel Dekker, Inc; 1997:231-273. 5. Food and Nutrition Board, Institute of Medicine. Copper. Dietary reference intakes for vitamin A, vitamin K, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, D.C.: National Academy Press; 2001:224-257. (National Academy Press) 6. Johnson MA, Fischer JG, Kays SE. Is copper an antioxidant nutrient? Crit Rev Food Sci Nutr. 1992;32(1):1-31. 7. Finley EB, Cerklewski FL. Influence of ascorbic acid supplementation on copper status in young adult men. Am J Clin Nutr. 1983;37(4):553-556. (PubMed) 8. Jacob RA, Skala JH, Omaye ST, Turnlund JR. Effect of varying ascorbic acid intakes on copper absorption and ceruloplasmin levels of young men. J Nutr. 1987;117(12):2109-2115. (PubMed) 9. Percival SS, Kauwell GP, Bowser E, Wagner M. Altered copper status in adult men with cystic fibrosis. J Am Coll Nutr. 1999;18(6):614-619. (PubMed) 10. Fox PL, Mazumder B, Ehrenwald E, Mukhopadhyay CK. Ceruloplasmin and cardiovascular disease. Free Radic Biol Med. 2000;28(12):1735-1744. (PubMed) 11. Jones AA, DiSilvestro RA, Coleman M, Wagner TL. Copper supplementation of adult men: effects on blood copper enzyme activities and indicators of cardiovascular disease risk. Metabolism. 1997;46(12):1380-1383. (PubMed) 12. Ford ES. Serum copper concentration and coronary heart disease among US adults. Am J Epidemiol. 2000;151(12):1182-1188. (PubMed) 13. Klevay LM. Cardiovascular disease from copper deficiency--a history. J Nutr. 2000;130(2S Suppl):489S-492S. (PubMed) 14. Kinsman GD, Howard AN, Stone DL, Mullins PA. Studies in copper status and atherosclerosis. Biochem Soc Trans. 1990;18(6):1186-1188. (PubMed) 15. Mielcarz G, Howard AN, Mielcarz B, et al. Leucocyte copper, a marker of copper body status is low in coronary artery disease. J Trace Elem Med Biol. 2001;15(1):31-35. (PubMed) 16. Wang XL, Adachi T, Sim AS, Wilcken DE. Plasma extracellular superoxide dismutase levels in an Australian population with coronary artery disease. Arterioscler Thromb Vasc Biol. 1998;18(12):1915-1921. (PubMed) 17. Klevay LM. Lack of a recommended dietary allowance for copper may be hazardous to your health. J Am Coll Nutr. 1998;17(4):322-326. (PubMed) 18. Milne DB, Nielsen FH. Effects of a diet low in copper on copper-status indicators in postmenopausal women. Am J Clin Nutr. 1996;63(3):358-364. (PubMed)

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19. Medeiros DM, Milton A, Brunett E, Stacy L. Copper supplementation effects on indicators of copper status and serum cholesterol in adult males. Biol Trace Elem Res. 1991;30(1):19-35. (PubMed) 20. Turley E, McKeown A, Bonham MP, et al. Copper supplementation in humans does not affect the susceptibility of low density lipoprotein to in vitro induced oxidation (FOODCUE project). Free Radic Biol Med. 2000;29(11):1129-1134. (PubMed) 21. Rock E, Mazur A, O'Connor J M, Bonham MP, Rayssiguier Y, Strain JJ. The effect of copper supplementation on red blood cell oxidizability and plasma antioxidants in middle-aged healthy volunteers. Free Radic Biol Med. 2000;28(3):324-329. (PubMed) 22. Percival SS. Copper and immunity. Am J Clin Nutr. 1998;67(5 Suppl):1064S-1068S. (PubMed) 23. Failla ML, Hopkins RG. Is low copper status immunosuppressive? Nutr Rev. 1998;56(1 Pt 2):S59-64.

24. Heresi G, Castillo-Duran C, Munoz C, Arevalo M, Schlesinger L. Phagocytosis and immunoglobulin levels in hypocupremic children. Nutr Res. 1985;5:1327-1334. 25. Kelley DS, Daudu PA, Taylor PC, Mackey BE, Turnlund JR. Effects of low-copper diets on human immune response. Am J Clin Nutr. 1995;62(2):412-416. (PubMed) 26. Conlan D, Korula R, Tallentire D. Serum copper levels in elderly patients with femoral-neck fractures. Age Ageing. 1990;19(3):212-214. (PubMed) 27. Eaton-Evans J, Mellwrath EM, Jackson WE, McCartney H, Strain JJ. Copper supplementation and the maintenance of bone mineral density in middle-aged women. J Trace Elem Exp Med. 1996;9:87-94. 28. Baker A, Harvey L, Majask-Newman G, Fairweather-Tait S, Flynn A, Cashman K. Effect of dietary copper intakes on biochemical markers of bone metabolism in healthy adult males. Eur J Clin Nutr. 1999;53(5):408-412. (PubMed) 29. Baker A, Turley E, Bonham MP, et al. No effect of copper supplementation on biochemical markers of bone metabolism in healthy adults. Br J Nutr. 1999;82(4):283-290. (PubMed) 30. Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001. 31. Bremner I. Manifestations of copper excess. Am J Clin Nutr. 1998;67(5 Suppl):1069S-1073S. (PubMed) 32. Fitzgerald DJ. Safety guidelines for copper in water. Am J Clin Nutr. 1998;67(5 Suppl):1098S-1102S. (PubMed) 33. Wood RJ, Suter PM, Russell RM. Mineral requirements of elderly people. Am J Clin Nutr. 1995;62(3):493-505. (PubMed)

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34. Br J Nutr. 2003 Jul;90(1):161-8. Adaptive responses in men fed low- and high-copper diets. Majsak-Newman G, Dainty JR, Lewis DJ, Langford NJ, Crews HM, Fairweather-Tait SJ. PMID: 12844388 35. Eur J Clin Nutr. 2003 May;57(5):706-12. Copper and zinc intake and serum levels in patients with juvenile rheumatoid arthritis. Silverio Amancio OM, Alves Chaud DM, Yanaguibashi G, Esteves Hilario MO. PMID: 12771972 36. J Dairy Sci. 2003 Apr;86(4):1240-9. Role of dietary copper in enhancing resistance to Escherichia coli mastitis. Scaletti RW, Trammell DS, Smith BA, Harmon RJ. PMID: 12741549 37. Contraception. 2003 Feb;67(2):161-3. Human spermatozoa motility analysis in a Ringer's solution containing cupric ions. Araya R, Gomez-Mora H, Vera R, Bastidas JM. PMID: 12586326 38. J Nutr. 2003 Feb;133(2):522-7. Low dietary copper increases fecal free radical production, fecal water alkaline phosphatase activity and cytotoxicity in healthy men. Davis CD. PMID: 12566494 39. J Nutr. 2002 Oct;132(10):3142-5. The timing of perinatal copper deficiency in mice influences offspring survival. Prohaska JR, Brokate B. PMID: 12368408 40. Am J Clin Nutr. 2002 Sep;76(3):687-8; author reply 688. Extra dietary copper inhibits LDL oxidation. Klevay LM. PMID: 12198019 41. Vet Rec. 2002 Jul 13;151(2):50-3. Effects of copper supplementation on the copper status of peripartum beef cows and their calves. Enjalbert F, Lebreton P, Salat O, Meschy F, Schelcher F. PMID: 12148603 42. Ceska Slov Farm. 2002 Jul;51(4):205-7. Anti-inflammatory activity of (o-cresotinate) copper and zinc aquacomplexes Sokolik J, Tumova I, Blahova M, Bernathova M, Svec P. PMID: 12183910 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 365

43. J Anim Sci. 2002 Jul;80(7):1999-2005. Effects of dietary copper on the expression of lipogenic genes and metabolic hormones in steers. Lee SH, Engle TE, Hossner KL. PMID: 12162670 44. J Nutr. 2002 May;132(5):1018-25. Dietary copper affects azoxymethane-induced intestinal tumor formation and protein kinase C isozyme protein and mRNA expression in colon of rats. Davis CD, Johnson WT. PMID: 11983831 45. Proc Nutr Soc. 2002 May;61(2):181-5. Is there a potential therapeutic value of copper and zinc for osteoporosis? Lowe NM, Lowe NM, Fraser WD, Jackson MJ. PMID: 12133199 46. Bull Exp Biol Med. 2002 Apr;133(4):334-5. Protective effect of copper-rutin complex in animals with experimental epilepsy. Tsaryuk VV, Potapovich AI, Kostyuk VA. PMID: 12124637 47. J Nutr. 2002 Feb;132(2):190-6. Skeletal unloading and dietary copper depletion are detrimental to bone quality of mature rats. Smith BJ, King JB, Lucas EA, Akhter MP, Arjmandi BH, Stoecker BJ. PMID: 11823577 48. Trop Anim Health Prod. 2002 Feb;34(1):75-80. A possible association between dietary intake of copper, zinc and phosphate and delayed puberty in heifers in Sudan. Ahmed MM, Fadlalla IM, Barri ME. PMID: 11887424 49. J Exp Biol. 2002 Jan;205(Pt 2):279-90. Copper metabolism in actively growing rainbow trout (Oncorhynchus mykiss): interactions between dietary and waterborne copper uptake. Kamunde C, Grosell M, Higgs D, Wood CM. PMID: 11821494 50. Nutrition. 2001 Sep;17(9):701-8. Low dietary zinc alters indices of copper function and status in postmenopausal women. Milne DB, Davis CD, Nielsen FH. PMID: 11527655

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51. J Nutr. 2001 Aug;131(8):2171-6. A longitudinal investigation of aggregate oral intake of copper. Pang Y, MacIntosh DL, Ryan PB. PMID: 11481413 52. J Anim Physiol Anim Nutr (Berl). 2001 Feb;85(1-2):29-37. The lowering effect of high copper intake on selenium retention in weanling rats depends on the selenium concentration of the diet. Yu S, Beynen AC. PMID: 11686770 53. Gig Sanit. 2001 Jan-Feb;(1):54-7. Providing athletes with trace elements during intensive exercise Nasolodin VV, Gladkikh IP, Meshcheriakov SI. PMID: 11236477 54. Biol Trace Elem Res. 2000 Dec;77(3):241-9. Effect of dietary copper on selenium toxicity in Fischer 344 rats. Tatum L, Shankar P, Boylan LM, Spallholz JE. PMID: 11204466 55. J Nutr. 2000 Nov;130(11):2838-43. Zinc and copper intakes and their major food sources for older adults in the 1994-96 continuing survey of food intakes by individuals (CSFII). Ma J, Betts NM. PMID: 11053529 56. Cancer Lett. 2000 Oct 16;159(1):57-62. Inadequate dietary copper increases tumorigenesis in the Min mouse. Davis CD, Newman S. PMID: 10974406 57. Inflamm Res. 2000 May;49(5):214-23. Nutritional supplementation with copper in the rat. I. Effects on adjuvant arthritis development and on some in vivo- and ex vivo-markers of blood neutrophils. Milanino R, Marrella M, Crivellente F, Benoni G, Cuzzolin L. PMID: 10893044 58. Nippon Ronen Igakkai Zasshi. 2000 Apr;37(4):304-8. Copper supplement with cocoa for copper deficiency in patients with long-term enteral nutrition Wakugami K, Suenaga H, Egashira A, Taira T, Tokashiki T, Yamazaki T, Maehara A, Uechi K. PMID: 10917028

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59. Proc Soc Exp Biol Med. 2000 Mar;223(3):282-7. Alterations in hypertrophic gene expression by dietary copper restriction in mouse heart. Kang YJ, Wu H, Saari JT. PMID: 10719841 60. Ann Nutr Metab. 2000;44(3):129-34. Plasma copper concentration as marker of copper intake from food. Konig JS, Elmadfa I. PMID: 11053900

Quercetin 20 STUDIES

1. Pharmacology. 2003 Oct;69(2):59-67. Protective Effect of Flavonoids against Agingand Lipopolysaccharide-Induced Cognitive Impairment in Mice. Patil CS, Singh VP, Satyanarayan PS, Jain NK, Singh A, Kulkarni SK. Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. 2. Clin Pharmacokinet. 2003;42(5):437-59. Clinical pharmacokinetics of antioxidants and their impact on systemic oxidative stress. Schwedhelm E, Maas R, Troost R, Boger RH. Institute of Experimental and Clinical Pharmacology, Clinical Pharmacology Unit, University Hospital of Hamburg-Eppendorf, Hamburg, Germany. schwedhelm@ukehamburg.de 3. Neurobiol Aging. 2002 Sep-Oct;23(5):891-97. Natural extracts as possible protective agents of brain aging. Bastianetto S, Quirion R. Department of Psychiatry and Pharmacology and Therapeutics, Douglas Hospital Research Centre, McGill University, 6875 LaSalle Boulevard, Verdun, Que, Canada H4H 1R3. 4. Mol Biol Cell. 2002 Jul;13(7):2502-17. Expression of caveolin-1 induces premature cellular senescence in primary cultures of murine fibroblasts. Volonte D, Zhang K, Lisanti MP, Galbiati F. Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. 5. Mech Ageing Dev. 2000 Dec 20;121(1-3):217-30. Antioxidants may contribute in the fight against ageing: an in vitro model. Hu HL, Forsey RJ, Blades TJ, Barratt ME, Parmar P, Powell JR. Molecular Physiology, Unilever Research Laboratory Colworth, Sharnbrook, Bedford MK44 1LQ, UK. 6. Eur J Clin Nutr. 2000 May;54(5):415-7. Quercetin intake and the incidence of cerebrovascular disease. Knekt P, Isotupa S, Rissanen H, Heliovaara M, Jarvinen R, Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 368

Hakkinen S, Aromaa A, Reunanen A. National Public Health Institute, Helsinki, Finland. paul.knekt@ktl.fi 7. Free Radic Biol Med. 1997;22(4):669-78. Quercetin protects cutaneous tissueassociated cell types including sensory neurons from oxidative stress induced by glutathione depletion: cooperative effects of ascorbic acid. Skaper SD, Fabris M, Ferrari V, Dalle Carbonare M, Leon A. Researchlife S.c.p.A., Castelfranco Veneto, Italy. 8. Exp Gerontol. 1982;17(3):213-7. Quercetin, flavonoids and the life-span of mice. Jones E, Hughes RE. 9. Biochem Pharmacol. 1992 Mar 17;43(6):1167-79. Effects of flavonoids on immune and inflammatory cell functions. Middleton E Jr, Kandaswami C. Department of Medicine, State University of New York, Buffalo 14203. 10. Lancet. 1993 Oct 23;342(8878):1007-11. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D. National Institute of Public Health and Environment Protection, Bilthoven, Netherlands. 11. Surgery. 2002 Feb;131(2):198-204. Quercetin inhibits human vascular smooth muscle cell proliferation and migration. Alcocer F, Whitley D, Salazar-Gonzalez JF, Jordan WD, Sellers MT, Eckhoff DE, Suzuki K, Macrae C, Bland KI. Department of Surgery, University of Alabama at Birmingham, 35294-0007, USA. 12. Res Commun Chem Pathol Pharmacol. 1992 Nov;78(2):211-8. Changes in the xanthine dehydrogenase/xanthine oxidase ratio in the rat kidney subjected to ischemiareperfusion stress: preventive effect of some flavonoids. Sanhueza J, Valdes J, Campos R, Garrido A, Valenzuela A. Unidad de Bioquimica Farmacologica y Lipidos, INTA, Universidad de Chile, Santiago. 13. Methods Find Exp Clin Pharmacol. 2001 May;23(4):175-81. Quercetin, a bioflavonoid, protects against oxidative stress-related renal dysfunction by cyclosporine in rats. Satyanarayana PS, Singh D, Chopra K. Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. 14. Free Radic Biol Med. 2002 Jul 1;33(1):63-70. Quercetin metabolism in the lens: role in inhibition of hydrogen peroxide induced cataract. Cornish KM, Williamson G, Sanderson J. School of Biological Sciences, University of East Anglia, Norwich, Norfolk, UK. 15. Zhongguo Yao Li Xue Bao. 1999 May;20(5):426-30. Quercetin decreased heart rate and cardiomyocyte Ca2+ oscillation frequency in rats and prevented cardiac hypertrophy in mice. Wang Y, Wang HY, Yuan ZK, Zhao XN, Wang JX, Zhang ZX. School of Medicine, State Key Laboratory of Coordination Chemistry, Nanjing University, China.

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16. Preferential requirement for protein tyrosine phosphatase activity in the 12-Otetradecanoylphorbol-13-acetate-induced differentiation of human colon cancer cells. Kuo ML, Huang TS, Lin JK. Institute of Toxicology, College of Medicine, National Taiwan University, Taipei. Biochem Pharmacol; 50(8):1217-22 1995 17. Effect of Quercitrin on acute and chronic experimental colitis in the rat De Medina F.S.; Galvez L.-H.; Romero J.A.; Zarzuelo A. F.S. De Medina, Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada Spain Journal of Pharmacology and Experimental Therapeutics (USA) , 1996, 278/2 (771-779) 18. Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices So FV, Guthrie N, Chambers AF, Moussa M, Carroll KK. Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada. Nutrition and Cancer (USA) , 1996, 26/2 (167 181) 19. Gitika B, Sai Ram M, Sharma SK, Ilavazhagan G, Banerjee PK. Quercetin protects C6 glial cells from oxidative stress induced by tertiarybutylhydroperoxide. Free Radic Res. 2006 Jan;40(1):95-102. PMID: 16298764 20. Yang JH, Hsia TC, Kuo HM, Lee Chao PD, Chou CC, Wei YH, Chung JG. Inhibition of Lung Cancer Cell Growth by Quercetin Glucuronides via G2/M Arrest and Induction of Apoptosis. Drug Metab Dispos. 2005 Nov 9; [Epub ahead of print] PMID: 16280456 [PubMed - as supplied by publisher]

Astaxanthin 20 STUDIES
1. Mol Cells. 2003 Aug 31;16(1):97-105. Astaxanthin inhibits nitric oxide production and inflammatory gene expression by suppressing I(kappa)B kinase-dependent NF-kappaB activation. Lee SJ, Bai SK, Lee KS, Namkoong S, Na HJ, Ha KS, Han JA, Yim SV, Chang K, Kwon YG, Lee SK, Kim YM. Vascular System Research Center and Department of Molecular and Cellular Biochemistry, Kangwon National University Biology, Chunchon 200-701, Korea. 2. Biochem Biophys Res Commun. 2003 Aug 1;307(3):704-12.

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Direct superoxide anion scavenging by a disodium disuccinate astaxanthin derivative: Relative efficacy of individual stereoisomers versus the statistical mixture of stereoisomers by electron paramagnetic resonance imaging. Cardounel AJ, Dumitrescu C, Zweier JL, Lockwood SF. Davis Heart and Lung Research Institute, 473 West 12th Avenue, Columbus, OH 432101252, USA. 3. Eur J Pharm Sci. 2003 Jul;19(4):299-304. Oral bioavailability of the antioxidant astaxanthin in humans is enhanced by incorporation of lipid based formulations. Mercke Odeberg J, Lignell A, Pettersson A, Hoglund P. Department of Clinical Pharmacology, Lund University Hospital, S-221 85 Lund, Sweden. johanna.odeberg@klinfarm.lu.se 4. J Med Food. 2003 Spring;6(1):51-6. Safety of an astaxanthin-rich Haematococcus pluvialis algal extract: a randomized clinical trial. Spiller GA, Dewell A. Health Research and Studies Center, Los Altos, CA 94023, USA. spiller@sphere.org 5. Invest Ophthalmol Vis Sci. 2003 Jun;44(6):2694-701. Effects of astaxanthin on lipopolysaccharide-induced inflammation in vitro and in vivo. Ohgami K, Shiratori K, Kotake S, Nishida T, Mizuki N, Yazawa K, Ohno S. Department of Ophthalmology and Visual Sciences, Hokkaido University Graduate School of Medicine, Sapporo, Japan. kohgami@med.hokudai.ac.jp 6. Trends Biotechnol. 2003 May;21(5):210-6. Haematococcus astaxanthin: applications for human health and nutrition. Guerin M, Huntley ME, Olaizola M. Mera Pharmaceuticals Inc., 73-4460 Queen Kaahumanu Hwy, Suite 110, Kailua-Kona, 96740, Hawaii, USA 7. Redox Rep. 2002;7(5):290-3. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 371

Astaxanthin protects beta-cells against glucose toxicity in diabetic db/db mice. Uchiyama K, Naito Y, Hasegawa G, Nakamura N, Takahashi J, Yoshikawa T. First Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. 8. J Pharm Sci. 2003 Apr;92(4):922-6. Improved aqueous solubility of crystalline astaxanthin (3,3'-dihydroxy-beta, betacarotene-4,4'-dione) by Captisol (sulfobutyl ether beta-cyclodextrin). Lockwood SF, O'Malley S, Mosher GL. Hawaii Biotech, Inc., 99-193 Aiea Heights Drive, Suite 200, Aiea, Hawaii 96701, USA. slockwood@hibiotech.com 9. Antioxid Redox Signal. 2003 Feb;5(1):139-44. Astaxanthin limits exercise-induced skeletal and cardiac muscle damage in mice. Aoi W, Naito Y, Sakuma K, Kuchide M, Tokuda H, Maoka T, Toyokuni S, Oka S, Yasuhara M, Yoshikawa T. Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, 602-0841. 10. Comp Biochem Physiol C Toxicol Pharmacol. 2002 Nov;133(3):443-51. Astaxanthin and canthaxanthin do not induce liver or kidney xenobiotic-metabolizing enzymes in rainbow trout (Oncorhynchus mykiss Walbaum). Page GI, Davies SJ. Fish Nutrition Unit, Department of Biological Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA, UK. pagegi@mapleleaf.ca 11. J Dermatol Sci. 2002 Oct;30(1):73-84. Modulatory effects of an algal extract containing astaxanthin on UVA-irradiated cells in culture. Lyons NM, O'Brien NM. Department of Food Science, Food Technology and Nutrition, University College Cork, Cork, Ireland. nob@ucc.ie 12. Life Sci. 2002 Apr 21;70(21):2509-20. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 372

Contribution of the antioxidative property of astaxanthin to its protective effect on the promotion of cancer metastasis in mice treated with restraint stress. Kurihara H, Koda H, Asami S, Kiso Y, Tanaka T. Institute for Health Care Science, Suntory Ltd., 1-1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka 618-8503, Japan. Hiroshi_Kurihara@suntory.co.jp 13. Arch Toxicol. 2002 Jan;75(11-12):665-75. Metabolism and CYP-inducer properties of astaxanthin in man and primary human hepatocytes. Kistler A, Liechti H, Pichard L, Wolz E, Oesterhelt G, Hayes A, Maurel P. Vitamins and Fine Chemicals, Human Nutrition and Health, F. Hoffmann-La Roche Ltd, Basel, Switzerland. kistlera@bluewin.ch 14. J Reprod Fertil Suppl. 2001;57:331-4. Effect of supplementation with the antioxidant astaxanthin on reproduction, pre-weaning growth performance of kits and daily milk intake in mink. Hansen KB, Tauson AH, Inborr J. Department of Animal Science and Animal Health, Royal Veterinary and Agricultural University, Gronnegardsvej 3, 1870 Frederiksberg C, Denmark. 15. Biochem Biophys Res Commun. 2001 Oct 19;288(1):225-32. Astaxanthin and peridinin inhibit oxidative damage in Fe(2+)-loaded liposomes: scavenging oxyradicals or changing membrane permeability? Barros MP, Pinto E, Colepicolo P, Pedersen M. Department of Botany, Stockholm University, SE-10691 Stockholm, Sweden. mpbarros@botan.su.se 16. J Atheroscler Thromb. 2000;7(4):216-22. Inhibition of low-density lipoprotein oxidation by astaxanthin. Iwamoto T, Hosoda K, Hirano R, Kurata H, Matsumoto A, Miki W, Kamiyama M, Itakura H, Yamamoto S, Kondo K. National Institute of Health and Nutrition, Tokyo, Japan. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 373

17. Methods Find Exp Clin Pharmacol. 2001 Mar;23(2):79-84. Effect of astaxanthin on the hepatotoxicity, lipid peroxidation and antioxidative enzymes in the liver of CCl4-treated rats. Kang JO, Kim SJ, Kim H. Department of Food and Nutrition, College of Human Ecology, Seoul National University, Korea. 18. Biochim Biophys Acta. 2001 Jun 6;1512(2):251-8. Efficient radical trapping at the surface and inside the phospholipid membrane is responsible for highly potent antiperoxidative activity of the carotenoid astaxanthin. Goto S, Kogure K, Abe K, Kimata Y, Kitahama K, Yamashita E, Terada H. Faculty of Pharmaceutical Sciences, University of Tokushima, Japan. Kogure@ph.tokushima-u.ac.jp 19. 0955-2863. 2000 Oct;11(10):482-490. Plasma appearance and distribution of astaxanthin E/Z and R/S isomers in plasma lipoproteins of men after single dose administration of astaxanthin(1). Osterlie M, Bjerkeng B, Liaaen-Jensen S. HIST, Department of Food Science, N-7004, Trondheim, Norway 20. Antimicrob Agents Chemother. 2000 Sep;44(9):2452-7. Astaxanthin-rich algal meal and vitamin C inhibit Helicobacter pylori infection in BALB/cA mice. Wang X, Willen R, Wadstrom T. Department of Infectious Diseases and Medical Microbiology, University of Lund, Sweden.

L-Carnosine - 28 Studies

1. Stadtman ER. Protein oxidation and aging. Science. 1992; 257(5074):1220-4. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 374

2. Preston JE, Hipkiss AR, Himsworth DT, et al. Toxic effects of beta-amyloid(25-35) on immortalised rat brain endothelial cell: protection by carnosine, homocarnosine and betaalanine. Neurosci Lett. 1998; 242(2):105-8. 3. Stadtman ER, Levine RL. Protein oxidation. Ann NY Acad Sci. 2000; 899:191-208. 4. Bierhaus A, Hofmann MA, Ziegler R, et al. AGEs and their interaction with AGEreceptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovascular Research. 1998; 37(3):586-600. 5. Munch G, Schinzel R, Loske C, et al. Alzheimer's disease-synergistic effects of glucose deficit, oxidative stress and advanced glycation endproducts. Journal of Neural Transmission. 1998; 105(4-5):439-61. 6. Hipkiss AR, Michaelis J, Syrris P. Non-enzymatic glycosylation of the dipeptide Lcarnosine, a potential anti-protein-cross-linking agent. FEBS Lett. 1995; 371(1):81-5. 7. Munch G, Mayer S, Michaelis J, et al. Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of beta-amyloid peptide. Biochim Biophys Acta. 1997; 1360(1):17-29. 8. Hipkiss AR, Chana H. Carnosine protects proteins against methylglyoxal-mediated modifications. Biochem Biophys Res Commun. 1998; 248(1):28-32. 9. Brownson C, Hipkiss AR. Carnosine reacts with a glycated protein. Free Radic Biol Med. 2000; 28(10):1564-70. 10. Hipkiss AR, Preston JE, Himswoth DT, et al. Protective effects of carnosine against malondialdehyde-induced toxicity towards cultured rat brain endothelial cells. Neurosci Lett. 1997; 238(3):135-8. 11. Boldyrev AA, Stvolinsky SL, Tyulina OV, et al. Biochemical and physiological evidence that carnosine is an endogenous neuroprotector against free radicals. Cell Mol Neurobiol. 1997; 17(2):259-71. 12. Hipkiss AR, Preston JE, Himsworth DT, et al. Pluripotent protective effects of carnosine, a naturally occurring dipeptide. Ann NY Acad Sci. 1998; 854:37-53. 13. McFarland GA, Holliday R. Retardation of the senescence of cultured human diploid fibroblasts by carnosine. Exp Cell Res. 1994; 212(2):167-75. 14. McFarland GA, Holliday R. Further evidence for the rejuvenating effects of the dipeptide L-carnosine on cultured human diploid fibroblasts. Exp Gerontol. 1999; 34(1):35-45.

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15. Yuneva MO, Bulygina ER, Gallant SC, et al. Effect of carnosine on age-induced changes in senescence-accelerated mice. J Anti-Aging Med. 1999; 2(4):337-42. 16. Horning MS, Blakemore LJ, Trombley PQ. Endogenous mechanisms of neuroprotection: role of zinc, copper, and carnosine. Brain Res. 2000; 852(1):56-61. 17. Huang X, Cuajungco MP, Atwood CS, et al. Cu(II) potentiation of alzheimer Ab neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem. 1999; 274(52):37111-6. 18. Atwood CS, Moir RD, Huang X, et al. Dramatic aggregation of Alzheimer Ab by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem. 1998; 273(21):12817-26. 19. Cherny RA, Legg JT, McLean CA, et al. Aqueous dissolution of Alzheimer's disease Ab amyloid deposits by biometal depletion. J Biol Chem. 1999; 274(33):23223-8. 20. Gulyaeva NV. Superoxide-scavenging activity of carnosine in the presence of copper and zinc ions. Biochemistry (Moscow). 1987; 52(7 Part 2):1051-4. 21. de la Torre JC. Cerebromicrovascular pathology in Alzheimer's disease compared to normal aging. Gerontology. 1997; 43(1-2):26-43. 22. Hipkiss AR, Preston JE, Himswoth DT, et al. Protective effects of carnosine against malondialdehyde-induced toxicity towards cultured rat brain endothelial cells. Neurosci Lett. 1997; 238(3):135-8. 23. Doble A. The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther. 1999; 81(3):163-221. 24. Boldyrev A, Song R, Lawrence D, et al. Carnosine protects against excitotoxic cell death independently of effects on reactive oxygen species. Neuroscience. 1999; 94(2):571-7. 25. Stvolinsky SL, Kukley ML, Dobrota D, et al. Carnosine: an endogenous neuroprotector in the ischemic brain. Cell Mol Neurobiol. 1999; 19(1):45-56. 26. Nagai K, Suda T, Kawasaki K, et al. Action of carnosine and beta-alanine on wound healing. Surgery. 1986;100(5):815-21. 27. Vizioli MR, Blumen G, Almeida OP, et al. Effects of carnosine on the development of rat sponge-induced granulation tissue. II. Histoautoradiographic observations on collagen biosynthesis. Cell Mol Biol. 1983; 29(1):1-9. 28. Ikeda D, Wada S, Yoneda C, et al. Carnosine stimulates vimentin expression in cultured rat fibroblasts. Cell Struct Funct. 1999; 24(2):79-87. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 376

Lycopene

50 Studies

1:Agarwal, S., and Rao A.V.; Tomato lycopene and low-density lipoprotein oxidation: a human dietary intervention study. Lipids, 33, 981-984 (1998). 2: Batieha, A.M,, Armenian, H.K., Norkus, E.P., Morris, J.,S., Spate, V.E., and Comstock, G.W. Serum micronutrients and subsequent risk of cervical cancer in a population-based nested case-control study. Cancer Epiderniol. Biomarkers Prev, 2: 335339 (1993.). 3: Belakbir, A., Ruiz, J.M., and Romero, L.; Yield and fruit quality of pepper (Capsicum annuum L.) in response to bioregulators. HortScience. 33(l): 85-87 (1998). 4: Ben-Shaul, Y. and Naftali, Y.; The development and ultrastructure of lycopene bodies in chromoplasts of Lycopersicum esculentum. Protoplasma 67: 333-344 (1969) 5: Bien, J.G., Brown, E.D., and Smith, J.C.; Determination of individual carotenoids in human plasma by high performance liquid chromatography. J. Liq. Chromatog. 8: 473484 (1985). 6: Bjelke, F.; Case-control study in Norway, Scand. J. Gastroenterol. 9: 42-49 (1974). 7: Block, G., Patterson, B., and Subar, A.; Fruit, vegetables, and cancer prevention: A review of the epidemi-ological evidence. Nutr. Cancer 18: 1-29 (1992). 8: Boskovic, M.A.; 1979. Fate of lycopene in dehydrated tomato products: Carotenoid isomerization in food systems. J. Food Sci. 44: 84-86 (1979). 9: Brady, W.E., Mares-Perlman, J.A., Bowen, R. and Stacewicz-Sapuntzakis, M.; Human serum carotenoid concentrations are related to physiologic and lifestyle factors. J. Nutr. 1 26(l): 129-137 (1996). 10: Britton, G.; "Carotenoids: Spectroscopy," 1B: pp, 57. Birkhauser Verlag, Boston, (1995). 11: Bushway, R.J.; Separation of carotenoids in fruits and vegetables by high performance liquid chromatography. J. Liq. Chromatog, 8: 1527-1547 (1985). 12: Cano, M, P., Ancos, B., Lobo, G., Monreal, M., and De-Ancos, B.; Effects of freezing and canning of papaya slices on their carotenoid composition. Z. Lebensmittel Unters. Forsch. 202(4): 279-284 (1996).

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13: Chandler, L.A. and Schwartz, S.J.; Isomerization and losses of trans-beta-carotene in sweet potatoes as affected by processing treatments. J. Agric Food Chem. 36:129-133 (1988). 14: Choo, YM., Yap, S.C., Ooi, C.X., Ma, A.X., Goh, S.H., and Ong, S.H.; Recovered oil from palm-pressed fiber: A good source of natural carotenoids, vitamin E, and sterols. JAOCS 73: 599-602 (1996). 15: Clinton, S.K., Emenhiser, C., Schwartz, S.J., Bostwick, D.G., Williams, A.W., Moore, B.J., and Erdman, J.W.; Cis-trans lycopene isomers, carotenoids, and retinol in the human prostate. Cancer Epidemiol. Biomarkers Prev. 5: 823-833 (1996). 16: Clinton, S.K.; Lycopene: Chemistry. biology, and implications for human health and disease. Nutr. Rev. 56(2): 35-51 (1998). 17: Colditz, G.A., Branch, L,G., and Lipnick, R.J.; Increased green and yellow vegetable intake and lowered cancer deaths in an elderly population. Am. Clin. Nutr. 41: 32-36 (1985). 18: Cole, E.R. and Kapur, N.S. ; The stability of lycopene. II. Oxidation during heating of tomato pulps. J. Sci. Food Agric. 8: 366-368 (1957). 19: Cole, E.R., and Kapur, N.S.; The stability of lycopene. I. Degradation by oxygen. J. Sci. Food Agric. 8: 360-365 (1957). 20: Cook-Mozaffari, P.J., Azordegan, F., and Day, N.E.; Oseophageal cancer studies in the Caspian Litoral of Iran: Results of a case-control study. Brit. J. Cancer 39: 292-309 (1979). 21: Countryman, C., Bankson, D., Collins, S., Man, B., and Lin, W.; Lycopene inhibits the growth of the HL-60 promyelocylic leukemia cell line. Clin. Chem. 37:1056 (1991). 22: Craft, N.E.; Carotenoid reversed-phase high-performance liquid chromatography methods: Reference compendium. Meth. Enzymol. 213: 185-205 (1992). 23: Crouzet, J., and Kanasawud, P.; . Formation of volatile compounds by thermal degradation of carotenoids. Meth. Enzymol. 213: 54-62 (1992). 24: Davies, B.H.; Carotenoids, In "Chemistry and Biochemistry of Plant Pigments," Vol. 2, 2nd ed., ed. T.W. Goodwin, pp. 38-165. Academic Press, New York (1976). 25: Di Mascio, P., Kaiser, S., and Sies, H.; Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch. Biochem. Biophys. 274: 532-538 (1989). 26: Diaz, M.N., Frei, B., Vita, J.A., and Keaney, J.F.; Antioxidants and atherosclerotic heart disease. New Eng. J. Med. 337: 408-416 (1997).. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 378

27: Duggar, B.M.; Lycopersicon: The red pigment of the tomato and the effects of conditions on its development. Washington Univ. Stud., 1: 22-45 (1913). 28: Duke, J.A. and Beckstrom-Stemberg, S.M.; Plants containing lycopene. Phytochemical database. USDA NCI Carotencid Food Composition Database. Agric. Res, Service, U.S. Dept. of Agriculture, Beltsville, Md. (1998). 29: Duke, J.A.; "Handbook of Phytochemical Constituents of GRAS Herbs and Other Economic Plants." CRC Press, Boca Raton, Fla.(1992). 30: Emenhiser, C., Sander, L.C., and Schwartz, S J.; Capabilitry of a polymeric C30 stationary phase to resolve cis-trans carotenoid isomers in reversed-phase liquid chromatography J. Chromatog A 707: 205 216 (1995). 31: Emenhiser, C., Simunovic, N, Sander, L. C., and Schwartz, S.J.; Separation of geometric isomers in biological extracts using a polymeric C 30 column in reversedphase liquid chromatography. J. Agric. Food Chem. 44: 3887-3893 (1996). 32: Epler, K,S., Sander, L.G, Ziegler, R.G., Wise, S.A., and Craft, N.E.; Evaluation of reversed-phase liquid chromatographic columns for recovery and selectivity ofselected carotenoids. J. Chromatog. 595: 89-101 (1992). 33: Ferruzzi, M.G., Sander, L.C., Rock, C.L., and Schwartz. S J.; Carotenoid determination in biological microsamples using liquid chromatography with a coulometric electrochemical array detector. Anal. Biochem. 256: 74-81 (1998). 34: Forman. M.R., et.al.; The correlation between two dietary assessments of carotenoid intake and plasma Garotenoid concentrations: Application of a carotenoid food composition database. Am. J. Clin, Nutr 58: 519-24 (1993). 35: Franceschi, S., Bidoli, E., La Vecchia, G., Talamini, R., D'Avanzo, B., and Negri, E.; Tomatoes and risk of digestive-tract cancers. Intl. J. Cancer 59(2): 181-184 ( 1994). 36: Gartner, C., Stahl, W, and Sies, H.; Lycopene is more bioavailable from tomato paste than from fresh tomatoes, Am. J. Clin. Nutr. 66: 116-122 (1997). 37: Gester, H.; The potential role of lycopene for human health. J. Am. Col. Nutr. 16(2): 109-126 (1997). 38: Giovannucci, E. L., Ascherio, A., Rimm, E. B., Stampfer, M.J., Colditz, G.A., and Willett, W.C.; Intake of carotenoids and retinol in relationship to risk of prostate cancer. J. NatI. Cancer Inst. 87: 1767-1776 (1995). 39: Godoy, H.T. and Rodriguez-Amaya, D.B.; Changes in individual carotenoids on processing and storage of mango (Mangifera indica) slices and puree. Intl. J. Food Sci. Technol. 22: 451-460 (1987).. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 379

40: Gross, J.; "Pigments in Vegetables: Chlorophylls and Carotenoids. pp. 148-249. Van Nostrand Reinhold, New York (1991). 41: Ha, T.K.K., Saffar, N., Talwar, D., Cooney, J., Simpson, K., O'-Reilly D., and Lean, M.E.J.; Abnormal antioxidant vitamin and carotenoid status in chronic renal failure. Q.J.M. 89: 765-769 (1996). 42: Harborne, J.B. and Baxter, H.; "Phytochemical Dictionary. A Handbook of Bioactive Compounds from Plants," Taylor & Frost, London (1983). 43: Henry, L,K., Catignani, G.L., and Schwartz, S.J.; Oxidative degradation kinetics of lycopene. lutein, 9-cis and all-trans beta-carotene. J. Am. Oil Chem. Soc, 75: 823-829 (1998). 44: Jarvinen, R,, Knekt, P., Seppanen, R., and Teppo, L.; Diet and breast cancer risk in a cohort of Finnish women. Cancer Lett. 114: 251-253 (1997). 45: Joyce, E.; Carotenoids of Brassica napus. J. Sci. Food Agric. 10: 342-348 ( 1959). 46: Joyce, E.; Some polyenes of Brassica rutabaga. Nature, 173: 311-312 (1954). 47: Kaplan, L.A., Lau, J.M., and Stein, E.A.; Carotenoid composition, concentrations, and relationships in various human organs. Clin. Physiol. Biochem, 8: 1-10 (1990). 48: Karrer, P, Helfenstein, A., Wehri, H., and Wettstein, A.; Pflanzenfarbstoffe. XXV. Leber die Konstitution des Lycopins und Carotins, Acta 14: 154-162 (1930). 49: Khachik, F, Beecher, G.R., and Smith, J.C. Jr.; Lutein, lycopene, and their oxidative metabolites in chemoprevention of cancer J. Cell Biochem, Suppl. 22: 236-246 (1995.) 50: Khachik, F., et.al.; Effect of food preparation on qualitative and quantitative distribution of major carotenoid constituents of tomatoes and several green vegetables, J. Agric. Food Chem, 40: 390-398 (1992).

Rosemary Leaf Powder - 20 STUDIES


1. Chemical composition, plant genetic differences, antimicrobial and antifungal activity investigation of the essential oil of Rosmarinus officinalis L. J Agric Food Chem. 2004 Jun 2;52(11):3530-5. 2. Effects of a novel gaseous antioxidative system containing a rosemary extract on the oxidation induced by nitrogen dioxide and ultraviolet radiation. Biosci Biotechnol Biochem. 2004 Apr;68(4):781-6.. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 380

3. Carnosic acid, a component of rosemary (Rosmarinus officinalis L.), promotes synthesis of nerve growth factor in T98G human glioblastoma cells. Biol Pharm Bull. 2003 Nov;26(11):1620-2. 4. Antioxidant activities of rosemary, sage, and sumac extracts and their combinations on stability of natural peanut oil. J Med Food. 2003 Fall;6(3):267-70. 5. Phenolic diterpenes, flavones, and rosmarinic acid distribution during the development of leaves, flowers, stems, and roots of Rosmarinus officinalis. Antioxidant activity. J Agric Food Chem. 2003 Jul 16;51(15):4247-53. 6. Quantitative determination of phenolic diterpenes in rosemary extracts. Aspects of accurate quantification. J Chromatogr A. 2003 May 2;995(1-2):119-25. 7. Aromas of rosemary and lavender essential oils differentially affect cognition and mood in healthy adults. Int J Neurosci. 2003 Jan;113(1):15-38. 8. Suppressive effects of rosmarinic acid on mesangioproliferative glomerulonephritis in rats. Nephron. 2002 Dec;92(4):898-904. 9. Carnosic acid inhibits proliferation and augments differentiation of human leukemic cells induced by 1,25-dihydroxyvitamin D3 and retinoic acid. Nutr Cancer. 2001;41(1-2):135-44. 10. Carnosol, an antioxidant in rosemary, suppresses inducible nitric oxide synthase through down-regulating nuclear factor-kappaB in mouse macrophages. Carcinogenesis. 2002 Jun;23(6):983-91. 11. Evaluation of the effectiveness of Rosmarinus officinalis (Lamiaceae) in the alleviation of carbon tetrachloride-induced acute hepatotoxicity in the rat. J Ethnopharmacol. 2002 Jul;81(2):145-54.

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12. Rosemary-stimulated reduction of DNA strand breaks and FPG-sensitive sites in mammalian cells treated with H2O2 or visible light-excited Methylene Blue. Cancer Lett. 2002 Mar 28;177(2):145-53. 13. Antioxidant properties of phenolic diterpenes from Rosmarinus officinalis. Acta Pharmacol Sin. 2001 Dec;22(12):1094-8. 14. Carnosol-induced apoptosis and downregulation of Bcl-2 in B-lineage leukemia cells. Cancer Lett. 2001 Sep 10;170(1):33-9. 15. Chemistry and antioxidative factors in rosemary and sage. Biofactors. 2000;13(1-4):161-6. 16. Inhibitory effects of rosmarinic acid on the proliferation of cultured murine mesangial cells. Nephrol Dial Transplant. 2000 Aug;15(8):1140-5. 17. Allied studies on the effect of Rosmarinus officinalis L. on experimental hepatotoxicity and mutagenesis. Int J Food Sci Nutr. 1999 Nov;50(6):413-27. 18. Pharmacology of rosemary (Rosmarinus officinalis Linn.) and its therapeutic potentials. Indian J Exp Biol. 1999 Feb;37(2):124-30. 19. Flavonoids in Rosmarinus officinalis leaves. Phytochemistry. 1994 Nov;37(5):1463-6. 20. Rosmarinic Acid Research Rosmarinic acid. Institut fur Pharmazeutische Biologie, Philipps-Universitat Marburg, Deutschhausstr. Marburg, Germany.

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382

Tocotrienols 40 STUDIES

1. J Gerontol A Biol Sci Med Sci 2000 Jun;55(6):B280-5 Effects of tocotrienols on life span and protein carbonylation in Caenorhabditis elegans. Adachi H, Ishii N. Life Science Research Center, Lion Corporation, Kanagawa, Japan. hadachi@lion.co.jp 2. N Engl J Med 1993 May 20;328(20):1450-6 Vitamin E consumption and the risk of coronary heart disease in men. Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115. 3. N Engl J Med 1993 May 20;328(20):1444-9 Vitamin E consumption and the risk of coronary disease in women. Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Channing Laboratory, Boston, MA 02115. 4. Lancet 1996 Mar 23;347(9004):781-6 Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS) Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Department of Medicine, Cambridge University. 5. JAMA 2001 Mar 7;285(9):1178-82 Effects of vitamin E on lipid peroxidation in healthy persons. Meagher EA, Barry OP, Lawson JA, Rokach J, FitzGerald GA. Center for Experimental Therapeutics, 811 Biomedical Research Bldg II/III, University of Pennsylvania, 421 Curie Blvd, Philadelphia, PA 19104-6160, USA. 6. JAMA 1995 Jun 21;273(23):1849-54 Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. Hodis HN, Mack WJ, LaBree L, Cashin-Hemphill L, Sevanian A, Johnson R, Azen SP. Atherosclerosis Research Unit, University of Southern California School of Medicine, Los Angeles 90033, USA. 7. Eur Heart J 2001 Jan;22(2):103-4 Clinical, public health, and research implications of the Heart Outcomes Prevention Evaluation (HOPE) Study. Yusuf S. 8. Am J Clin Nutr 1996 Mar;63(3):377-85 Inverse relation between the concentration of low-density-lipoprotein vitamin E and Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 383

severity of coronary artery disease. Regnstrom J, Nilsson J, Moldeus P, Strom K, Bavenholm P, Tornvall P, Hamsten A. Department of Medicine, the King Gustaf V Research Institute, Karolinska Hospital, Stockholm, Sweden. 9. N Engl J Med 1996 May 2;334(18):1156-62 Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM. Division of Epidemiology, University of Minnesota School of Public Health, Minneapolis 55454-1015, USA. 10. Am J Epidemiol 1994 Jun 15;139(12):1180-9 Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Knekt P, Reunanen A, Jarvinen R, Seppanen R, Heliovaara M, Aromaa A. Social Insurance Institution, Helsinki, Finland. 11. Sources And Consumption Of Antioxidants In The Diet Bieri J G J Am Oil Chem Soc 61 (12). 1984. 1917-1918. 1984 12. J Nutr 1985 Jun;115(6):807-13 Oral alpha-tocopherol supplements decrease plasma gamma-tocopherol levels in humans. Handelman GJ, Machlin LJ, Fitch K, Weiter JJ, Dratz EA. 13. J Intern Med 1996 Feb;239(2):111-7 Gamma, but not alpha, tocopherol levels in serum are reduced in coronary heart disease patients. Ohrvall M, Sundlof G, Vessby B. Department of Geriatrics, University of Uppsala, Sweden. 14. Proc Natl Acad Sci U S A 1997 Apr 1;94(7):3217-22 Gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: physiological implications. Christen S, Woodall AA, Shigenaga MK, Southwell-Keely PT, Duncan MW, Ames BN. Division of Biochemistry and Molecular Biology, University of California, Berkeley 94720, USA. 15. Proc Natl Acad Sci U S A 1993 Mar 1;90(5):1771-5 Gamma-tocopherol detoxification of nitrogen dioxide: superiority to alpha-tocopherol. Cooney RV, Franke AA, Harwood PJ, Hatch-Pigott V, Custer LJ, Mordan LJ. Cancer Research Center of Hawaii, University of Hawaii, Honolulu 96813. 16. J Gerontol A Biol Sci Med Sci 2000 Jun;55(6):B280-5 Effects of tocotrienols on life span and protein carbonylation in Caenorhabditis elegans. Adachi H, Ishii N. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 384

Life Science Research Center, Lion Corporation, Kanagawa, Japan. hadachi@lion.co.jp 17. Lipids 1995 Dec;30(12):1179-83 Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis. Tomeo AC, Geller M, Watkins TR, Gapor A, Bierenbaum ML. Kenneth L. Jordan Research Group, Montclair, New Jersey 07042, USA. 18. J Biol Chem 1993 May 25;268(15):11230-8 Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Parker RA, Pearce BC, Clark RW, Gordon DA, Wright JJ. Department of Metabolic Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543. 19. Am J Clin Nutr 1991 Apr;53(4 Suppl):1021S-1026S Lowering of serum cholesterol in hypercholesterolemic humans by tocotrienols (palmvitee). Qureshi AA, Qureshi N, Wright JJ, Shen Z, Kramer G, Gapor A, Chong YH, DeWitt G, Ong A, Peterson DM, et al. Advanced Medical Research, Madison, WI 53719. 20. Novel tocotrienols of rice bran modulate cardiovascular disease risk parameters of hypercholesterolomic humans Qureshi A.A.; Bradlow B.A.; Salser W.A.; Brace L.D. Dr. A.A. Qureshi, Advance Medical Research, 8251 Raymond Road, Madison, WI 53719 United States Journal of Nutritional Biochemistry ( J. NUTR. BIOCHEM. ) ( United States ) 1997 , 8/5 (290-298) 21. N Engl J Med 1990 Nov 8;323(19):1289-98 Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, Zhao XQ, Bisson BD, Fitzpatrick VF, Dodge HT. Department of Medicine, University of Washington School of Medicine, Seattle. 22. N Engl J Med 1983 Aug 18;309(7):385-9 Apolipoprotein A-I as a marker of angiographically assessed coronary-artery disease. Maciejko JJ, Holmes DR, Kottke BA, Zinsmeister AR, Dinh DM, Mao SJ. 23. Br Heart J 1988 Nov;60(5):397-403 High prevalence of hypertriglyceridaemia and apolipoprotein abnormalities in coronary artery disease. Barbir M, Wile D, Trayner I, Aber VR, Thompson GR. Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 385

24. Proc Natl Acad Sci U S A 2000 Oct 10;97(21):11494-9 Gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. Jiang Q, Elson-Schwab I, Courtemanche C, Ames BN. Division of Biochemistry and Molecular Biology, University of California, Berkeley, CA 94720, USA. 25. J Am Coll Cardiol 1999 Oct;34(4):1208-15 Differential effects of alpha- and gamma-tocopherol on low-density lipoprotein oxidation, superoxide activity, platelet aggregation and arterial thrombogenesis. Saldeen T, Li D, Mehta JL. Department of Forensic Medicine, University of Uppsala, Sweden. . 26. J Nutr Biochem 2001 Jun;12(6):318-329 Synergistic effect of tocotrienol-rich fraction (TRF(25)) of rice bran and lovastatin on lipid parameters in hypercholesterolemic humans. Qureshi AA, Sami SA, Salser WA, Khan FA. Advanced Medical Research, 8251 Raymond Road, 53719, Madison, WI, USA 27. Lipids 1993 Dec;28(12):1113-8 gamma-Tocotrienol as a hypocholesterolemic and antioxidant agent in rats fed atherogenic diets. Watkins T, Lenz P, Gapor A, Struck M, Tomeo A, Bierenbaum M. Kenneth L. Jordan Heart Fund, Montclair, New Jersey 07042. 28. J Nutr 2001 Jan;131(1):161S-163S Vitamin E: mechanisms of action as tumor cell growth inhibitors. Kline K, Yu W, Sanders BG. Division of Nutrition and. School of Biological Sciences, The University of Texas at Austin, Austin, TX 78712, USA. k.kline@mail.utexas.edu 29. J Nutr 1994 May;124(5):607-14 The chemoprevention of cancer by mevalonate-derived constituents of fruits and vegetables. Elson CE, Yu SG. Department of Nutritional Sciences, University of Wisconsin, Madison 53706-1571. 30. J Nutr 1999 Apr;129(4):804-13 Apoptosis and cell-cycle arrest in human and murine tumor cells are initiated by isoprenoids. Mo H, Elson CE. Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.

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31. J Nutr 1997 May;127(5):668-74 Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo. He L, Mo H, Hadisusilo S, Qureshi AA, Elson CE. Department of Nutritional Sciences, University of Wisconsin, Madison 53706, USA. 32. Nutr Cancer 1992;18(1):1-29 Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Block G, Patterson B, Subar A. Dept. of Social and Administrative Health Sciences, School of Public Health, University of California, Berkeley 94720. 33. Proc Soc Exp Biol Med 1999 Sep;221(4):294-311 Isoprenoid-mediated inhibition of mevalonate synthesis: potential application to cancer. Elson CE, Peffley DM, Hentosh P, Mo H. Department of Nutritional Sciences, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA. 34. J Nutr 1995 Jun;125(6 Suppl):1666S-1672S Suppression of mevalonate pathway activities by dietary isoprenoids: protective roles in cancer and cardiovascular disease. Elson CE. Department of Nutritional Sciences, University of Wisconsin-Madison 53706, USA. 35. Nutrition 1993 May-Jun;9(3):229-32 Long-term administration of tocotrienols and tumor-marker enzyme activities during hepatocarcinogenesis in rats. Rahmat A, Ngah WZ, Shamaan NA, Gapor A, Abdul Kadir K. Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur. 36. Comp Biochem Physiol C 1993 Sep;106(1):237-40 Glutathione S-transferase and gamma-glutamyl transpeptidase activities in cultured rat hepatocytes treated with tocotrienol and tocopherol. Ong FB, Wan Ngah WZ, Shamaan NA, Md Top AG, Marzuki A, Khalid AK. Jabatan Biokimia, Fakulti Perubatan, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala, Lumpur. 37. J Nutr 1997 May;127(5):668-74 Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo. He L, Mo H, Hadisusilo S, Qureshi AA, Elson CE. Department of Nutritional Sciences, University of Wisconsin, Madison 53706, USA. 38. Lipids 1995 Dec;30(12):1139-43 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 387

Effect of tocotrienols on the growth of a human breast cancer cell line in culture. Nesaretnam K, Guthrie N, Chambers AF, Carroll KK. Palm Oil Research Institute of Malaysia, Kuala Lumpur, Malaysia. 39. Lipids 1998 May;33(5):461-9 Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status. Nesaretnam K, Stephen R, Dils R, Darbre P. Division of Cell and Molecular Biology, School of Animal and Microbial Sciences, The University of Reading, Whiteknights, England. sarnesar@porim.gov.my 40. Int J Food Sci Nutr 2000;51 Suppl:S95-103 Tocotrienols inhibit growth of ZR-75-1 breast cancer cells. Nesaretnam K, Dorasamy S, Darbre PD. Palm Oil Research Institute of Malaysia, PO Box 10620, Kuala Lumpur 50720, Malaysia.

Raspberry Leaf Powder - 10 Studies


1. Han C, Ding H, Casto B, Stoner GD, D'Ambrosio SM. Inhibition of the growth of premalignant and malignant human oral cell lines by extracts and components of black raspberries. Nutr Cancer. 2005;51(2):207-17. PMID: 15860443 2. Huang C, Huang Y, Li J, Hu W, Aziz R, Tang MS, Sun N, Cassady J, Stoner GD. Inhibition of benzo(a)pyrene diol-epoxide-induced transactivation of activated protein 1 and nuclear factor kappaB by black raspberry extracts. Cancer Res. 2002 Dec 1;62(23):6857-63. PMID: 124608993. Xue H, Aziz RM, Sun N, Cassady JM, Kamendulis LM, Xu Y, Stoner GD, Klaunig JE 3. Xue H, Aziz RM, Sun N, Cassady JM, Kamendulis LM, Xu Y, Stoner GD, Klaunig JE. Inhibition of cellular transformation by berry extracts. Carcinogenesis. 2001 Feb;22(2):351-6. Erratum in: Carcinogenesis 2001 May;22(5):8313. PMID: 11181460 4. J Agric Food Chem. 2005 Jul 27;53(15):5922-31. Preclinical evaluation of rapeseed, raspberry, and pine bark phenolics for health related effects.

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388

Vuorela S, Kreander K, Karonen M, Nieminen R, Hamalainen M, Galkin A, Laitinen L, Salminen JP, Moilanen E, Pihlaja K, Vuorela H, Vuorela P, Heinonen M. 5. Viljanen K, Kylli P, Kivikari R, Heinonen M. Inhibition of protein and lipid oxidation in liposomes by berry phenolics. J Agric Food Chem. 2004 Dec 1;52(24):7419-24. PMID: 15563229 6. Vuorela S, Salminen H, Makela M, Kivikari R, Karonen M, Heinonen M. Effect of plant phenolics on protein and lipid oxidation in cooked pork meat patties. J Agric Food Chem. 2005 Nov 2;53(22):8492-7. PMID: 16248543 7. Puupponen-Pimia R, Nohynek L, Hartmann-Schmidlin S, Kahkonen M, Heinonen M, Maatta-Riihinen K, Oksman-Caldentey KM. Berry phenolics selectively inhibit the growth of intestinal pathogens. J Appl Microbiol. 2005;98(4):991-1000. PMID: 15752346 8. Puupponen-Pimia R, Nohynek L, Meier C, Kahkonen M, Heinonen M, Hopia A, Oksman-Caldentey KM. Antimicrobial properties of phenolic compounds from berries. J Appl Microbiol. 2001 Apr;90(4):494-507. PMID: 11309059 9. Puupponen-Pimia R, Nohynek L, Alakomi HL, Oksman-Caldentey KM. Bioactive berry compounds-novel tools against human pathogens. Appl Microbiol Biotechnol. 2005 Apr;67(1):8-18. Epub 2004 Dec 2. Review. PMID: 15578177 10. Viljanen K, Kylli P, Kivikari R, Heinonen M. Inhibition of protein and lipid oxidation in liposomes by berry phenolics. J Agric Food Chem. 2004 Dec 1;52(24):7419-24. PMID: 15563229

Citrus Bioflavonoids 11 STUDIES


1. Tirkey N, Pilkhwal S, Kuhad A, Chopra K. Hesperidin, a citrus bioflavonoid, decreases the oxidative stress produced by carbon tetrachloride in rat liver and kidney. BMC Pharmacol. 2005 Jan 31;5(1):2. PMID: 15683547 2. Garg A, Garg S, Zaneveld LJ, Singla AK. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 389

Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phytother Res. 2001 Dec;15(8):655-69. Review. PMID: 11746857 3. Emim JA, Oliveira AB, Lapa AJ. Pharmacological evaluation of the anti-inflammatory activity of a citrus bioflavonoid, hesperidin, and the isoflavonoids, duartin and claussequinone, in rats and mice. J Pharm Pharmacol. 1994 Feb;46(2):118-22. PMID: 8021799 4. WILLIAMS HL, HEDGECOCK LD. Citrus bioflavonoid, ascorbic acid and the B Vitamins in treatment of certain types of neurosensory deafness: preliminary report. Mayo Clin Proc. 1962 Aug 29;37:474-83. No abstract available. PMID: 14007172 5. MARTIN WC. Treatment of capillary fragility with soluble citrus bioflavonoid complex. Int Rec Med Gen Pract Clin. 1955 Feb;168(2):66-9. No abstract available. PMID: 14353570 6. Treatment of capillary fragility with soluble citrus bioflavonoid complex. Int Rec Med Gen Pract Clin. 1955 Feb;168(2):66-9. No abstract available. PMID: 14353570 7. Emim JA, Oliveira AB, Lapa AJ. Pharmacological evaluation of the anti-inflammatory activity of a citrus bioflavonoid, hesperidin, and the isoflavonoids, duartin and claussequinone, in rats and mice. J Pharm Pharmacol. 1994 Feb;46(2):118-22. PMID: 8021799 8. WILLIAMS HL, HEDGECOCK LD. Citrus bioflavonoid, ascorbic acid and the B Vitamins in treatment of certain types of neurosensory deafness: preliminary report. Mayo Clin Proc. 1962 Aug 29;37:474-83. No abstract available. PMID: 14007172 9. FABRICANT ND. Therapeutic failure of citrus bioflavonoids in the common cold and nasal allergy. Eye Ear Nose Throat Mon. 1956 Nov;35(11):717-9. No abstract available. PMID: 13365639 10. MACON WL Jr. Citrus bioflavonoids in the treatment of the common cold. Ind Med Surg. 1956 Nov;25(11):525-7. No abstract available. PMID: 13366468 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 390

11. MENKIN V. Anti-inflammatory activity of some water-soluble bioflavonoids. Am J Physiol. 1959 Jun;196(6):1205-10. No abstract available. PMID: 13661342

Rutin 16 STUDIES
1. Anon: Natural Medicines Comprehensive Database, 4th ed. Therapeutic Research Faculty, Stockton, CA; 2002. 2. Wijayanegara H, Mose JC, Achmad L et al: A clinical trial of hydroxyethylrutosides in the treatment of haemorrhoids of pregnancy. J Int Med Res 1992; 20(1):54-60. 3. De Jongste AB, Jonker JJ, Huisman MV et al: A double-blind three center clinical trial on the short-term efficacy of O-(B-hydroxyethyl)-rutosides in patients with postthrombotic syndrome. Thromb Haemost 1989; 62(3):826-829. 4. Bergqvist D, Hallbook T, Lindblad B et al: A double-blind trial of O-(Bhydroxyethyl)-rutoside in patients with chronic venous insufficiency. VASA 1981; 10(3):253-260. 5. Mann RJ: A double-blind trial of O.B-hydroxyethyl rutosides for stasis leg ulcers. Br J Clin Pract 1981; 35(2):79-81. 6. Partial reversal by rutin and quercetin of impaired cardiac function in streptozotocininduced diabetic rats. Can J Physiol Pharmacol. 2005 Apr;83(4):343-355. 7. Effect of rutin on total antioxidant status of rats exposed to cigarette smoke. Pharmacol Rep. 2005 Jan-Feb;57(1):84-9. 8. Modulation of aberrant crypt foci and apoptosis by dietary herbal supplements (quercetin, curcumin, silymarin, ginseng and rutin). Carcinogenesis. 2005 Apr 14; 9. Dietary rutin, but not its aglycone quercetin, ameliorates dextran sulfate sodiuminduced experimental colitis in mice: attenuation of pro-inflammatory gene expression. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 391

Biochem Pharmacol. 2005 Feb 1;69(3):395-406. 10. [Inhibitory effect of quercetin, rutin and puerarin on HDL oxidation induced by Cu2+] Sichuan Da Xue Xue Bao Yi Xue Ban. 2004 Nov;35(6):836-8. 11. [Effect of hesperidin and rutin on oxidative modification of high density lipoprotein in vitro] 12. Mechanisms involved in the antiplatelet activity of rutin, a glycoside of the flavonol quercetin, in human platelets. J Agric Food Chem. 2004 Jul 14;52(14):4414-8. 13. The modulating effects of quercetin and rutin on the mitomycin C induced DNA damage. Toxicol Lett. 2004 Jun 15;151(1):143-9. 14. Synergistic inhibition of low-density lipoprotein oxidation by rutin, gamma-terpinene, and ascorbic acid. Phytomedicine. 2004 Feb;11(2-3):105-13. 15. Bioavailability and efficiency of rutin as an antioxidant: a human supplementation study. Eur J Clin Nutr. 2000 Oct;54(10):774-82. 16. Protective effects of N-acetylcysteine and rutin on the lipid peroxidation of the lung epithelium during the adult respiratory distress syndrome. Shock. 2000 Jan;13(1):14-8.

Billberry - 17 Studies
FILED ACCORDING TO CONDITION OR FUNCTION Anti-angiogenic
1. Free Radic Res. 2002 Sep;36(9):1023-31. Anti-angiogenic property of edible berries. Roy S, Khanna S, Alessio HM, Vider J, Bagchi D, Bagchi M, Sen CK. Laboratory of Molecular Medicine, Department of Surgery, 512 Heart and Lung Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 392

Research Institute, Ohio State University Medical Center, 473 W. 12th Avenue, Columbus, OH 43210, USA.

Cancer
2. J Agric Food Chem. 2003 Jan 1;51(1):68-75. Induction of apoptosis in cancer cells by Bilberry (Vaccinium myrtillus) and the anthocyanins. Katsube N, Iwashita K, Tsushida T, Yamaki K, Kobori M. Fruit Processing Research Center, AOHATA Corporation, Takehara, Hiroshima 729-2392, Japan. 3. J Agric Food Chem. 2003 Sep 24;51(20):5867-5870. Resveratrol in Raw and Baked Blueberries and Bilberries. Lyons MM, Yu C, Toma RB, Cho SY, Reiboldt W, Lee J, Van Breemen RB. Food and Nutritional Science Division, California State University, Long Beach, Long Beach, California 90840; Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607; and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, Chicago, Illinois 60612. 4. Planta Med. 1996 Jun;62(3):212-6. In vitro anticancer activity of fruit extracts from Vaccinium species. Bomser J, Madhavi DL, Singletary K, Smith MA. Department of Food Science and Human Nutrition, University of Illinois, Urbana 61801, USA.

Capillary support
5. Pharmacol Res. 1995 Mar-Apr;31(3-4):183-7. (Animal Study) Effect of Vaccinium myrtillus anthocyanosides on ischaemia reperfusion injury in hamster cheek pouch microcirculation. Bertuglia S, Malandrino S, Colantuoni A. CNR Institute of Clinical Physiology, Pisa, Italy. 6. Arzneimittelforschung. 1976;26(5):832-5. (Animal Study) Studies on Vaccinium myrtillus anthocyanosides. II. Aspects of anthocyanins pharmacokinetics in the rat. Lietti A, Forni G. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 393

7. Arzneimittelforschung. 1976;26(5):829-32. Studies on Vaccinium myrtillus anthocyanosides. I. Vasoprotective and antiinflammatory activity. Lietti A, Cristoni A, Picci M.

Connective tissue
8. Klin Monatsbl Augenheilkd. 1996 Dec;209(6):368-72. [Effect of anthocyanins on human connective tissue metabolism in the human] [Article in German] Boniface R, Robert AM. Labor fur Bindegewebsbiochemie, Medizinische Fakultat, Universitat Paris, Val de Marne.

Dyslipidaemiae
9. Thromb Res. 1996 Dec 1;84(5):311-22. (Animal Study) Novel lipid-lowering properties of Vaccinium myrtillus L. leaves, a traditional antidiabetic treatment, in several models of rat dyslipidaemia: a comparison with ciprofibrate. Cignarella A, Nastasi M, Cavalli E, Puglisi L. Institute of Pharmacological Sciences, University of Milano, Italy.

Chronic Fatigue Syndrome


10. Altern Med Rev. 2001 Oct;6(5):450-9. Chronic fatigue syndrome: oxidative stress and dietary modifications. Logan AC, Wong C. CFS/FM Integrative Care Centre, Toronto, ON, Canada. alancloganND@excite.com

Cardiocascular and EYE


11. Curr Mol Med. 2003 Mar;3(2):149-59. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 394

Potential mechanisms of cancer chemoprevention by anthocyanins. Hou DX. Department of Biochemical Science and Technology, Faculty of Agriculture, Kagoshima University, Korimoto 1-21-24, Kagoshima 890-0065, Japan. hou@chem.agri.kagoshima-u.ac.jp

EYE
12. J Biol Chem. 2003 May 16;278(20):18207-13. Epub 2003 Mar 19. A2E-epoxides damage DNA in retinal pigment epithelial cells. Vitamin E and other antioxidants inhibit A2E-epoxide formation. Sparrow JR, Vollmer-Snarr HR, Zhou J, Jang YP, Jockusch S, Itagaki Y, Nakanishi K. Department of Ophthalmology and Chemistry, Columbia University, New York, New York 10028, USA. jrs88@columbia.edu 13. Altern Med Rev. 2001 Apr;6(2):141-66. Natural therapies for ocular disorders, part two: cataracts and glaucoma. Head KA. Thorne Research, Inc., P.O. Box 25, Dover, ID 83825,USA. kathi@thorne.com

Ulcer
14. Arzneimittelforschung. 1988 May;38(5):686-90. (Animal Study) Antiulcer activity of an anthocyanidin from Vaccinium myrtillus. Magistretti MJ, Conti M, Cristoni A. Research and Development Laboratories, Inverni della Beffa S.p.A., Milan, Italy.

Bilberry High in Quercetin


15. Eur J Clin Nutr. 2003 Jan;57(1):37-42. Consumption of black currants, lingonberries and bilberries increases serum quercetin concentrations. Erlund I, Marniemi J, Hakala P, Alfthan G, Meririnne E, Aro A. Biomarker Laboratory, National Public Health Institute, Helsinki, Finland. iris.erlund@ktl.fi 16. J Agric Food Chem. 2000 Jul;48(7):2960-5. Influence of domestic processing and storage on flavonol contents in berries. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 395

Hakkinen SH, Karenlampi SO, Mykkanen HM, Torronen AR. Department of Clinical Nutrition, Department of Physiology, University of Kuopio, PO box 1627, FIN-70211 Kuopio, Finland.

RNA
17. Mol Biotechnol. 2001 Oct;19(2):201-3. Isolation of high quality RNA from bilberry (Vaccinium myrtillus L.) fruit. Jaakola L, Pirttila AM, Halonen M, Hohtola A. Department of Biology, University of Oulu, P.O. Box 3000, FIN-90014 Oulu, Finland. Laura.Jaakola@oulu.fi

Red Wine Concentrate 14 STUDIES


1. Resveratrol reduces oxidation and proliferation of human retinal pigment epithelial cells via extracellular signal-regulated kinase inhibition. Chem Biol Interact. 2005 Jan 15;151(2):143-9. King RE, Kent KD, Bomser JA. Department of Food Science and Technology, Ohio State University, Columbus, OH

2. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res. 2004 Sep-Oct;24(5A):2783-840. Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y. Cytokine Research Laboratory, Department of Bioimmunotherapy, The University of Texas M. D.

3. Resveratrol-induced cellular apoptosis and cell cycle arrest in neuroblastoma cells and antitumor effects on neuroblastoma in mice. Surgery. 2004 Jul;136(1):57-66. 4. Anti-inflammatory Effects of Resveratrol in Lung Epithelial Cells: Molecular Mechanisms. Am J Physiol Lung Cell Mol Physiol. 2004 Jun 4

5. Identification of a p53-dependent pathway in the induction of apoptosis of human breast cancer cells by the natural product, resveratrol. Laux MT, Aregullin M, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 396

J Altern Complement Med. 2004 Apr;10(2):235-9.

6. Curcumin and resveratrol induce apoptosis and nuclear translocation and activation of p53 in human neuroblastoma. Anticancer Res. 2004 Mar-Apr;24(2B):987-98.

7. Resveratrol in raw and baked blueberries and bilberries. J Agric Food Chem. 2003 Sep 24;51(20):5867-70. Lyons MM, Yu C, Toma RB, Cho SY, Reiboldt W, Lee J, van Breemen RB. Food and Nutritional Science Division, California State University-Long Beach, CA 90840

8. Wine and tumors: study of resveratrol. Drugs Exp Clin Res. 2003;29(5-6):257-61. dependent antiproliferative and antiapoptotic action on DHL-4 cells. These results confirm resveratrol's potential therapeutic role on tumors. 9. Potent induction of cellular antioxidants and phase 2 enzymes by resveratrol in cardiomyocytes: protection against oxidative and electrophilic injury. Cao Z, Li Y. St. John's University College of Pharmacy and Allied Health Professions, Jamaica, NY Eur J Pharmacol. 2004 Apr 5;489(1-2):39-48. 10. Modulation of androgen receptor-dependent transcription by resveratrol and genistein in prostate cancer cells. Gao S, Liu GZ, Wang Z. The University of Texas M. D. Anderson Cancer Center, Houston, Texas . Prostate. 2004 May 1;59(2):214-25.

11. Resveratrol suppresses the angiogenesis and tumor growth of gliomas in rats. Clin Cancer Res. 2004 Mar 15;10(6):2190-202.

12. Neuroprotective effects of resveratrol against beta-amyloid-induced neurotoxicity in rat hippocampal neurons: involvement of protein kinase C. Br J Pharmacol. 2004 Mar;141(6):997-1005.

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397

13. Resveratrol in raw and baked blueberries and bilberries. J Agric Food Chem. 2003 Sep 24;51(20):5867-70. Lyons MM, Yu C, Toma RB, Cho SY, Reiboldt W, Lee J, van Breemen RB. Food and Nutritional Science Division, California State University-Long Beach, CA 90840 14. Resveratrol protects myocardial ischemia-reperfusion injury through both NOdependent and NO-independent mechanisms. Free Radic Biol Med. 2004 Mar 15;36(6):774-81.

Grape Skin Extract 48 STUDIES

1. Rosenkranz S, Knirel D, Dietrich H, Flesch M, Erdmann E, Bohm M. Inhibition of the PDGF receptor by red wine flavonoids provides a molecular explanation for the French paradox. FASEB J. 2002 Dec;16(14):1958-60. 2. Criqui MH, Ringel BL. Does diet or alcohol explain the French paradox? Lancet. 1994 Dec 24-31;344(8939-8940):1719-23. 3. Burr ML. Explaining the French paradox. JR Soc Health. 1995 Aug;115(4):217-9. 4. Lavayssiere R, Cabee A. MRI in France: the French paradox. J Magn Reson Imaging. 2001 Apr;13(4):528-33. 5. Mar MH, Zeisel SH. Betaine in wine: answer to the French paradox? Med Hypotheses. 1999 Nov;53(5):383-5. 6. De Beer D, Joubert E, Gelderblom W, Manley M. Antioxidant activity of South African red and white cultivar wines: free radical scavenging. J Agric Food Chem. 2003 Feb 12;51(4):902-9. 7. Cui J, Tosaki A, Cordis GA, et al. Cardioprotective abilities of white wine. Ann NY Acad Sci. 2002 May;957:308-16. 8. Bertelli AA, Migliori M, Panichi V, et al. Oxidative stress and inflammatory reaction modulation by white wine. Ann NY Acad Sci. 2002 May;957:295-301. 9. Ariga T. The antioxidative function, preventive action on disease and utilization of proanthocyanidins. Biofactors. 2004 21(1-4):197-201. 10. Bagchi D, Garg A, Krohn RL, et al. Protective effects of grape seed proanthocyanidins and selected antioxidants against TPA-induced hepatic and brain lipid

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398

peroxidation and DNA fragmentation, and peritoneal macrophage activation in mice. Gen Pharmacol. 1998 May;30(5):771-6. 11. Ye X, Krohn RL, Liu W, et al. The cytotoxic effects of a novel IH636 grape seed proanthocyanidin extract on cultured human cancer cells. Mol Cell Biochem. 1999 Jun;196(1-2):99-108. 12.. Deshane J, Chaves L, Sarkikonda KV, et al. Proteomics analysis of rat brain protein modulations by grape seed extract. J Agric Food Chem. 2004 Dec 29;52(26):7872-83. 13.. Rababah TM, Hettiarachchy NS, Horax R. Total phenolics and antioxidant activities of fenugreek, green tea, black tea, grape seed, ginger, rosemary, gotu kola and ginkgo extracts, vitamin E and tert-butylhydroquinone. J Agric Food Chem. 2004 Aug 11;52(16):5183-6. 14. Shi J, Yu J, Pohorly JE, Kakuda Y. Polyphenolics in grape seedsbiochemistry and functionality. J Med Food. 2003 Winter;6(4):291-9. 15. Hagerman A, Riedl K, Jones GA, et al. High molecular weight plant polyphenolics (tannins) as biological antioxidants. J Agric Food Chem. 1998 46:1887-92. 16. Natella F, Belelli F, Gentili V, Ursini F, Scaccini C. Grape seed proanthocyanidins prevent plasma postprandial oxidative stress in humans. J Agric Food Chem. 2002 Dec 18;50(26):7720-5. 17. Choi SM, Lee BM. An alternative mode of action of endocrine-disrupting chemicals and chemoprevention. J Toxicol Environ Health B Crit Rev. 2004 Nov-Dec;7(6):451-63. 18. Delmas D, Jannin B, Latruffe N. Resveratrol: Preventing properties against vascular alterations and aging. Mol Nutr Food Res. 2005 Apr 14. 19. Granieri M, Bellisarii FI, De Caterina R. Group B vitamins as new variables related to the cardiovascular risk. Ital Heart J Suppl. 2005 Jan;6(1):1-16. 20. Hannon-Fletcher MP, Armstrong NC, Scott JM, et al. Determining bioavailability of food folates in a controlled intervention study. Am J Clin Nutr. 2004 Oct;80(4):911-8. 21. Weiswasser JM, Nylen E, Arora S, Wakefield M, Sidawy AN. Syndrome X and diabetes: what is the mystery? Semin Vasc Surg. 2002 Dec;15(4):216-24. 22. Al-Awwadi NA, Araiz C, Bornet A, et al. Extracts enriched in different polyphenolic families normalize increased cardiac NADPH oxidase expression while having differential effects on insulin resistance, hypertension, and cardiac hypertrophy in highfructose-fed rats. J Agric Food Chem. 2005 Jan 12;53(1):151-7.

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23. Al Awwadi NA, Bornet A, Azay J, et al. Red wine polyphenols alone or in association with ethanol prevent hypertension, cardiac hypertrophy, and production of reactive oxygen species in the insulin-resistant fructose-fed rat. J Agric Food Chem. 2004 Sep 8;52(18):5593-7. 24. Kokavec A, Crowe SF. Effect on plasma insulin and plasma glucose of consuming white wine alone after a meal. Alcohol Clin Exp Res. 2003 Nov;27(11):1718-23. 25. Auger C, Teissedre PL, Grain P, et al. Dietary wine phenolics catechin, quercetin, and resveratrol efficiently protect hypercholesterolemic hamsters against aortic fatty streak accumulation. J Agric Food Chem. 2005 Mar 23;53(6):2015-21. 26. Sano T, Oda E, Yamashita T, et al. Anti-thrombotic effect of proanthocyanidin, a purified ingredient of grape seed. Thromb Res. 2005;115(1-2):115-21. 27. Fragopoulou E, Antonopoulou S, Nomikos T, Demopoulos CA. Structure elucidation of phenolic compounds from red/white wine with antiatherogenic properties. Biochim Biophys Acta. 2003 Jun 10;1632(1-3):90-9. 28. Yamakoshi J, Kataoka S, Koga T, Ariga T. Proanthocyanidin-rich extract from grape seeds attenuates the development of aortic atherosclerosis in cholesterol-fed rabbits. Atherosclerosis. 1999 Jan;142(1):139-49. 29. Vinson JA, Mandarano MA, Shuta DL, Bagchi M, Bagchi D. Beneficial effects of a novel IH636 grape seed proanthocyanidin extract and a niacin-bound chromium in a hamster atherosclerosis model. Mol Cell Biochem. 2002 Nov;240(1-2):99-103. 30. Das S, Cordis GA, Maulik N, Das DK. Pharmacological preconditioning with resveratrol: role of CREB-dependent Bcl-2 signaling via adenosine A3 receptor activation. Am J Physiol Heart Circ Physiol. 2005 Jan;288(1):H328-35. 31. Inoue H, Jiang XF, Katayama T, Osada S, Umesono K, Namura S. Brain protection by resveratrol and fenofibrate against stroke requires peroxisome proliferator-activated receptor alpha in mice. Neurosci Lett. 2003 Dec 11;352(3):203-6. 32. Weinberger Z, Richter ED. Cellular telephones and effects on the brain: the head as an antenna and brain tissue as a radio receiver. Med Hypotheses. 2002 Dec;59(6):703-5. 33. Martinez-Burdalo M, Martin A, Anguiano M, Villar R. Comparison of FDTDcalculated specific absorption rate in adults and children when using a mobile phone at 900 and 1800 MHz. Phys Med Biol. 2004 Jan 21;49(2):345-54. 34. Jang M, Pezzuto JM. Effects of resveratrol on 12-O-tetradecanoylphorbol-13-acetateinduced oxidative events and gene expression in mouse skin. Cancer Lett. 1998 Dec 11;134(1):81-9.

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35. Saito M, Hosoyama M, Ariga T, Kataoka S, Yamaji N. Antiulcer activity of grape seed extract and procyanidins. J Agric Food Chem. 1998 March19;46(4):1460-64. 36. Mittal A, Elmets CA, Katiyar SK. Dietary feeding of proanthocyanidins from grape seeds prevents photocarcinogenesis in SKH-1 hairless mice: relationship to decreased fat and lipid peroxidation. Carcinogenesis. 2003 Aug;24(8):1379-88. 37. 59. Ishikawa M, Maki K, Tofani I, Kimura K, Kimura M. Grape seed proanthocyanidins extract promotes bone formation in rats mandibular condyle. Eur J Oral Sci. 2005 Feb;113(1):47-52. 38. Mizutani K, Ikeda K, Kawai Y, Yamori Y. Resveratrol attenuates ovariectomyinduced hyypertension and bone loss in stroke-prone spontaneously hypertensive rats. J Nutr Sci Vitaminol (Tokyo). 2000 Apr;46(2):78-83. 39. Fan PH, Lou HX. Isolation and structure identification of grape seed polyphenols and its effects on oxidative damage to cellular DNA. Yao Xue Xue Bao. 2004 Nov;39(11):869-75. 40. Grape seed extract prevents H(2)O(2)-induced chromosomal damage in human lymphoblastoid cells. Biol Pharm Bull. 2004 Sep;27(9):1459-61. 41. Oral intake of proanthocyanidin-rich extract from grape seeds improves chloasma. Phytother Res. 2004 Nov;18(11):895-9. . 42. Supplementation with grape seed polyphenols results in increased urinary excretion of 3-hydroxyphenylpropionic Acid, an important metabolite of proanthocyanidins in humans. J Agric Food Chem. 2004 Aug 25;52(17):5545-9. 43. Neuroprotective effects of grape seed extract on neuronal injury by inhibiting DNA damage in the gerbil hippocampus after transient forebrain ischemia. Life Sci. 2004 Sep 3;75(16):1989-2001. 44. Grape seed extract affects proliferation and differentiation of human intestinal Caco-2 cells.J Agric Food Chem. 2004 Jun 2;52(11):3301-8. 45. The effect of grape-seed extract on 24 h energy intake in humans. Eur J Clin Nutr. 2004 Apr;58(4):667-73.

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46. Effect of a standardized grape seed extract on low-density lipoprotein susceptibility to oxidation in heavy smokers. Vigna GB. University of Ferrara, Ferrara, Italy. Metabolism. 2003 Oct;52(10):1250-7. 47. Polyphenolics in grape seeds-biochemistry and functionality. J Med Food. 2003 Winter;6(4):291-9. 48. Grape seed extract activates Th1 cells in vitro. Clin Diagn Lab Immunol 2002 Mar;9(2):470-6.

China Green Tea Leaf Powder - 100 Studies

1. J Agric Food Chem. 2003 Oct 22;51(22):6627-34. A Combination of Tea (Camellia senensis) Catechins Is Required for Optimal Inhibition of Induced CYP1A Expression by Green Tea Extract. Williams SN, Pickwell GV, Quattrochi LC. Department of Medicine, Section of Medical Toxicology, University of Colorado Health Sciences Center, Denver, Colorado 80262.

2. Biochem Biophys Res Commun. 2003 Oct 24;310(3):715-719. Suppression of Helicobacter pylori-induced gastritis by green tea extract in Mongolian gerbils. Matsubara S, Shibata H, Ishikawa F, Yokokura T, Takahashi M, Sugimura T, Wakabayashi K. Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 11, Tsukiji 5-chome, Chuo-ku, 104-0045, Tokyo, Japan 3. Cell Mol Life Sci. 2003 Aug;60(8):1760-3. Green tea epigallocatechin-3-gallate is an inhibitor of mammalian histidine decarboxylase. Rodriguez-Caso C, Rodriguez-Agudo D, Sanchez-Jimenez F, Medina MA. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 402

Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Malaga, Malaga, Spain. 4. Eur J Cancer Prev. 2003 Oct;12(5):391-5. Effects of green tea on carcinogen-induced hepatic CYP1As in C57BL/6 mice. Yang M, Yoshikawa M, Arashidani K, Kawamoto T. Department of Preventive Medicine/Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-Dong Chongno-Gu, 110-799 Seoul, Korea. 5. Eur J Cancer Prev. 2003 Oct;12(5):383-90. Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. Ahn WS, Yoo J, Huh SW, Kim CK, Lee JM, Namkoong SE, Bae SM, Lee IP. Department of Obstetrics and Gynaecology. 6. Phytomedicine. 2003;10(6-7):517-22. Hydroxyl radical and hypochlorous acid scavenging activity of small centaury (Centaurium erythraea) infusion. A comparative study with green tea (Camellia sinensis). Valentao P, Fernandes E, Carvalho F, Andrade PB, Seabra RM, Bastos ML. CEQUP/Servico de Farmacognosia, Faculdade de Farmacia, Universidade do Porto, Porto, Portugal. 7. Phytomedicine. 2003;10(6-7):494-8. Enhancement of neutral endopeptidase activity in SK-N-SH cells by green tea extract. Melzig MF, Janka M. Institut fur Pharmazie, Freie Universitat Berlin, Germany. melzig@zedat.fu-berlin.de 8. Br J Pharmacol. 2003 Oct;140(3):487-499. Epub 2003 Aug 26. Interactions of androgens, green tea catechins and the antiandrogen flutamide with the external glucose-binding site of the human erythrocyte glucose transporter GLUT1. Naftalin RJ, Afzal I, Cunningham P, Halai M, Ross C, Salleh N, Milligan SR. New Hunt's House, King's College London, Guys Campus, London SE1 1UL. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 403

9. Clin Cancer Res. 2003 Aug 15;9(9):3312-9. Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Chow HH, Cai Y, Hakim IA, Crowell JA, Shahi F, Brooks CA, Dorr RT, Hara Y, Alberts DS. Arizona Cancer Center, The University of Arizona, Tucson, Arizona 85724, USA. 10. Clin Exp Allergy. 2003 Sep;33(9):1252-5. Green tea-induced asthma: relationship between immunological reactivity, specific and non-specific bronchial responsiveness. Shirai T, Reshad K, Yoshitomi A, Chida K, Nakamura H, Taniguchi M. Department of Internal Medicine, Fujinomiya City General Hospital, Fujinomiya, Japan. fmyhsp@lilac.ocn.ne.jp 11. J Pharmacol Exp Ther. 2003 Oct;307(1):230-6. Epub 2003 Sep 03. Green tea polyphenol causes differential oxidative environments in tumor versus normal epithelial cells. Yamamoto T, Hsu S, Lewis J, Wataha J, Dickinson D, Singh B, Bollag WB, Lockwood P, Ueta E, Osaki T, Schuster G. Kochi Medical School, Japan. 12. Biol Pharm Bull. 2003 Sep;26(9):1235-8. Inhibitory effect of green tea polyphenols on membrane-type 1 matrix metalloproteinase, MT1-MMP. Oku N, Matsukawa M, Yamakawa S, Asai T, Yahara S, Hashimoto F, Akizawa T. Department of Medical Biochemistry and COE Program in the 21st Century, University of Shizuoka, School of Pharmaceutical Sciences. 13. Sichuan Da Xue Xue Bao Yi Xue Ban. 2003 Apr;34(2):303-5. [Protective effects of green tea on mice with the irradiating damage induced by gammaray][Article in Chinese] Wang Z, Zeng L, Xiao Y, Lu S, Gao X. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 404

Department of Nutrition and Food Hygiene, West China School of Public Health, Sichuan University, Chengdu 610041, China. 14. Int J Cancer. 2003 Oct 10;106(6):871-8. Green tea catechins inhibit VEGF-induced angiogenesis in vitro through suppression of VE-cadherin phosphorylation and inactivation of Akt molecule. Tang FY, Nguyen N, Meydani M. Vascular Biology Laboratory, JM USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.

15. J Urol. 2003 Sep;170(3):773-6. Inhibition of bladder tumor growth by the green tea derivative epigallocatechin-3-gallate. Kemberling JK, Hampton JA, Keck RW, Gomez MA, Selman SH. Department of Urology, Medical College of Ohio, 3065 Arlington Avenue, Dowling Hall 2170, Toledo, OH 43614-5807, USA. 16. J Neurochem. 2003 Sep;86(5):1189-200. Green tea polyphenols enhance sodium nitroprusside-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Zhang Y, Zhao B. Laboratory of Visual Information Processing, Institute of Biophysics, Academia Sinica, 15 Datun Road, Chaoyang District, Beijing 100101, China. 17. Brain Res Bull. 2003 Aug 30;61(4):399-406. Effects of delayed administration of (-)-epigallocatechin gallate, a green tea polyphenol on the changes in polyamine levels and neuronal damage after transient forebrain ischemia in gerbils. Lee SY, Kim CY, Lee JJ, Jung JG, Lee SR. Department of Pharmacology, Kyungpook National University, 700-422 Taegu, South Korea. 18. Recent Results Cancer Res. 2003;163:165-71; discussion 264-6. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 405

Chemoprevention of nonmelanoma skin cancer: experience with a polyphenol from green tea. Linden KG, Carpenter PM, McLaren CE, Barr RJ, Hite P, Sun JD, Li KT, Viner JL, Meyskens FL. Department of Dermatology, University of California, Irvine, 101 The City Drive, Orange, CA 92868, USA. 19. FASEB J. 2003 Oct;17(13):1913-5. Epub 2003 Aug 01. Dual mechanisms of green tea extract (EGCG)-induced cell survival in human epidermal keratinocytes. Chung JH, Han JH, Hwang EJ, Seo JY, Cho KH, Kim KH, Youn JI, Eun HC. Department of Dermatology, Seoul National University College of Medicine, and Laboratory of Cutaneous Aging Research, Clinical Research Institute, Seoul National University Hospital, Seoul, Korea. 20. Biochem Biophys Res Commun. 2003 Aug 15;308(1):64-7. Effect of green tea polyphenols on angiogenesis induced by an angiogenin-like protein. Maiti TK, Chatterjee J, Dasgupta S. Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, West Bengal, India. 21. Eur J Epidemiol. 2003;18(5):401-5. Relation of coffee, green tea, and caffeine intake to gallstone disease in middle-aged Japanese men. Ishizuk H, Eguchi H, Oda T, Ogawa S, Nakagawa K, Honjo S, Kono S. Department of Preventive Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan. 22. Nutr Cancer. 2003;45(2):226-35. Catechin content of 18 teas and a green tea extract supplement correlates with the antioxidant capacity. Henning SM, Fajardo-Lira C, Lee HW, Youssefian AA, Go VL, Heber D. UCLA Center for Human Nutrition, School of Medicine, Warren Hall 14-166, 900 Veteran Avenue, Los Angeles, CA 90095, USA. shenning@mednet.ucla.edu Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 406

23. Zhonghua Yu Fang Yi Xue Za Zhi. 2003 May;37(3):171-3. [Study on the protective effect of green tea on gastric, liver and esophageal cancers] [Article in Chinese] Mu LN, Zhou XF, Ding BG, Wang RH, Zhang ZF, Jiang QW, Yu SZ.School of Public Health, Fudan University, Shanghai 200032, China. 24. Drugs Aging. 2003;20(10):711-21. Potential therapeutic properties of green tea polyphenols in Parkinson's disease. Pan T, Jankovic J, Le W. Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA. 25. Curr Drug Targets Immune Endocr Metabol Disord. 2003 Sep;3(3):234-42. Skin photoprotection by green tea: antioxidant and immunomodulatory effects. Katiyar SK. Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. skatiyar@uab.edu 26. Chem Res Toxicol. 2003 Jul;16(7):865-72. Identification of potential aryl hydrocarbon receptor antagonists in green tea. Palermo CM, Hernando JI, Dertinger SD, Kende AS, Gasiewicz TA. Department of Environmental Medicine, University of Rochester, Rochester, New York 14642, USA. 27. Life Sci. 2003 Aug 8;73(12):1479-89. Action of green tea catechin on bone metabolic disorder in chronic cadmium-poisoned rats. Choi JH, Rhee IK, Park KY, Park KY, Kim JK, Rhee SJ. Department of Food Science and Nutrition, Catholic University of Daegu, 712-702, South Korea. 28. Ann N Y Acad Sci. 2003 May;993:351-61; discussion 387-93. Gene and protein expression profiles of anti- and pro-apoptotic actions of dopamine, Rapomorphine, green tea polyphenol (-)-epigallocatechine-3-gallate, and melatonin. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 407

Weinreb O, Mandel S, Youdim MB. Eve Topf, Haifa, Israel. 29. Life Sci. 2003 Aug 1;73(11):1383-92. Stimulatory effect of oral administration of green tea and caffeine on locomotor activity in SKH-1 mice. Michna L, Lu YP, Lou YR, Wagner GC, Conney AH. Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey and The University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ, USA. 30. Life Sci. 2003 Jul 25;73(10):1299-313. Green tea extract inhibits angiogenesis of human umbilical vein endothelial cells through reduction of expression of VEGF receptors. Kojima-Yuasa A, Hua JJ, Kennedy DO, Matsui-Yuasa I. Department of Food and Human Health Sciences, Graduate School of Human Life Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan. kojma@life.osaka-cu.ac.jp 31. Int J Cancer. 2003 Sep 10;106(4):574-9. Green tea and risk of breast cancer in Asian Americans. Wu AH, Yu MC, Tseng CC, Hankin J, Pike MC. Department of Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA. annawu@hsc.usc.edu 32. J Nutr. 2003 Jul;133(7 Suppl):2417S-2424S. Molecular targets for green tea in prostate cancer prevention. Adhami VM, Ahmad N, Mukhtar H. Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA. 33. FEBS Lett. 2003 Jul 10;546(2-3):265-70. Complex effects of different green tea catechins on human platelets.

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Lill G, Voit S, Schror K, Weber AA. Institut fur Pharmakologie und Klinische Pharmakologie, Universitatsklinikum Dusseldorf, Moorenstr 5, D-40225 Dusseldorf, Germany. 34. Arch Intern Med. 2003 Jun 23;163(12):1448-53. Cholesterol-lowering effect of a theaflavin-enriched green tea extract: a randomized controlled trial. Maron DJ, Lu GP, Cai NS, Wu ZG, Li YH, Chen H, Zhu JQ, Jin XJ, Wouters BC, Zhao J. Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. david.maron@vanderbilt.edu 35. Anticancer Res. 2003 Mar-Apr;23(2B):1533-9. Green tea polyphenol targets the mitochondria in tumor cells inducing caspase 3dependent apoptosis. Hsu S, Lewis J, Singh B, Schoenlein P, Osaki T, Athar M, Porter AG, Schuster G. Department of Oral Biology and Maxillofacial Pathology, School of Dentistry, AD1443. Medical College of Georgia, Augusta, GA 30912-1126, USA. shsu@mail.mcg.edu 36. Zhonghua Liu Xing Bing Xue Za Zhi. 2003 Mar;24(3):192-5. [A case-control study on drinking green tea and decreasing risk of cancers in the alimentary canal among cigarette smokers and alcohol drinkers] [Article in Chinese] Mu LN, Zhou XF, Ding BG, Wang RH, Zhang ZF, Chen CW, Wei GR, Zhou XM, Jiang QW, Yu SZ. School of Public Health, Fudan University, Shanghai 200032, China. 37. Arch Dermatol Res. 2003 Jul;295(3):112-6. Epub 2003 Jun 13. Comparative effects of polyphenols from green tea (EGCG) and soybean (genistein) on VEGF and IL-8 release from normal human keratinocytes stimulated with the proinflammatory cytokine TNFalpha. Trompezinski S, Denis A, Schmitt D, Viac J.

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INSERM U 346, Clinique Dermatologique, Hopital E. Herriot, 69437 Lyon, France. 38. Carcinogenesis. 2003 Jun;24(6):1105-9. Epub 2003 Apr 24. Prevention of dual promoting effects of pentachlorophenol, an environmental pollutant, on diethylnitrosamine-induced hepato- and cholangiocarcinogenesis in mice by green tea infusion. Umemura T, Kai S, Hasegawa R, Kanki K, Kitamura Y, Nishikawa A, Hirose M. Division of Pathology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. umemura@nihs.go.jp 39. DNA Cell Biol. 2003 Mar;22(3):217-24. A major constituent of green tea, EGCG, inhibits the growth of a human cervical cancer cell line, CaSki cells, through apoptosis, G(1) arrest, and regulation of gene expression. Ahn WS, Huh SW, Bae SM, Lee IP, Lee JM, Namkoong SE, Kim CK, Sin JI. Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea. 40. J Biochem (Tokyo). 2003 May;133(5):571-6. Inhibitory effects of green tea catechins on the activity of human matrix metalloproteinase 7 (matrilysin). Oneda H, Shiihara M, Inouye K. Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan. 41. Nutrition. 2003 Jun;19(6):536-40. Effect of green tea in the prevention and reversal of fasting-induced intestinal mucosal damage. Asfar S, Abdeen S, Dashti H, Khoursheed M, Al-Sayer H, Mathew T, Al-Bader A. Department of Surgery, Faculty of Medicine, Kuwait University, PO Box 24923, Safat 13110, Kuwait. sami@hsc.kuniv.edu.kw 42. Carcinogenesis. 2003 May;24(5):927-36.

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Treatment of green tea polyphenols in hydrophilic cream prevents UVB-induced oxidation of lipids and proteins, depletion of antioxidant enzymes and phosphorylation of MAPK proteins in SKH-1 hairless mouse skin. Vayalil PK, Elmets CA, Katiyar SK. Department of Dermatology, University of Alabama at Birmingham, 1670 University Blvd, Volker Hall 557, 35294, USA. 43. Exp Mol Med. 2003 Apr 30;35(2):136-9. Epigallocatechin gallate, a constituent of green tea, suppresses cytokine-induced pancreatic beta-cell damage. Han MK. Department of Microbiology, Chonbuk National University Medical School and Institute for Medical Sciences, Jeonju 560-756, Korea. 44. Oral Microbiol Immunol. 2003 Jun;18(3):192-5. Inhibitory effects of green tea catechins on protein tyrosine phosphatase in Prevotella intermedia. Okamoto M, Leung KP, Ansai T, Sugimoto A, Maeda N. Department of Oral Bacteriology, Tsurumi University School of Dental Medicine, Yokohama, Japan. 45. Phytother Res. 2003 May;17(5):566-7. Superoxide dismutase activity enhanced by green tea inhibits lipid accumulation in 3T3L1 cells. Mori M, Hasegawa N. Department of Food and Nutrition, Nagoya Bunri College, Nagoya, Japan. 46. Phytother Res. 2003 May;17(5):477-80. Powdered green tea has antilipogenic effect on Zucker rats fed a high-fat diet. Hasegawa N, Yamda N, Mori M. Department of Food and Nutrition, Nagoya Bunri College, Nagoya, Japan. hsgwn@nagoya-bunri.ac.jp Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 411

47. J Agric Food Chem. 2003 May 21;51(11):3379-81. Effect of selenium on the yield and quality of green tea leaves harvested in early spring. Hu Q, Xu J, Pang G. Laboratory of Food Processing and Quality Control, College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, People's Republic of China. 48. Antiviral Res. 2003 Apr;58(2):167-73. Inhibition of adenovirus infection and adenain by green tea catechins. Weber JM, Ruzindana-Umunyana A, Imbeault L, Sircar S. Departement de Microbiologie et d'Infectiologie, Faculte de Medecine, Universite de Sherbrooke, Que, Sherbrooke, Canada J1H 5N4. joseph.weber@usherbrooke.ca 49. Arch Pharm Res. 2003 Mar;26(3):214-23. Comparison of green tea extract and epigallocatechin gallate on blood pressure and contractile responses of vascular smooth muscle of rats. Lim DY, Lee ES, Park HG, Kim BC, Hong SP, Lee EB. Department of Pharmacology, College of Medicine, Chosun University, Gwangju 501759, Korea. dylim@chosun.ac.kr 50. Phytother Res. 2003 Apr;17(4):358-63. DNA degradation by water extract of green tea in the presence of copper ions: implications for anticancer properties. Malik A, Azam S, Hadi N, Hadi SM. Department of Biochemistry, Faculty of Life Science, AMU, Aligarh, India. 51. Thromb Haemost. 2003 May;89(5):866-74. Green tea epigallocatechin-3-gallate inhibits platelet signalling pathways triggered by both proteolytic and non-proteolytic agonists. Deana R, Turetta L, Donella-Deana A, Dona M, Maria Brunati A, De Michiel L, Garbisa S.

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Department of Biological Chemistry and Institute of the Neuroscience of the Italian National Research Council (CNR), University of Padova, Italy, E-mail: arianna.donella@unipd.it 52. J Immunol. 2003 Apr 15;170(8):4335-41. Neutrophil restraint by green tea: inhibition of inflammation, associated angiogenesis, and pulmonary fibrosis. Dona M, Dell'Aica I, Calabrese F, Benelli R, Morini M, Albini A, Garbisa S. Department of Experimental Biomedical Sciences, Medical School of Padova, Padova, Italy. 53. Curr Med Chem Anti-Canc Agents. 2002 Jul;2(4):441-63. Green tea catechins as novel antitumor and antiangiogenic compounds. Demeule M, Michaud-Levesque J, Annabi B, Gingras D, Boivin D, Jodoin J, Lamy S, Bertrand Y, Beliveau R. Laboratoire de Medecine Moleculaire, UQAM-Hocric;pital Sainte-Justine, Montreal, Canada. 54. Kidney Int. 2003 May;63(5):1785-90. Effect of green tea extract on cardiac hypertrophy following 5/6 nephrectomy in the rat. Priyadarshi S, Valentine B, Han C, Fedorova OV, Bagrov AY, Liu J, Periyasamy SM, Kennedy D, Malhotra D, Xie Z, Shapiro JI. The Department of Medicine, Medical College of Ohio, Toledo, Ohio 43614, USA. 55. Phytother Res. 2003 Mar;17(3):206-9. Protective effect of green tea polyphenol (-)-epigallocatechin gallate and other antioxidants on lipid peroxidation in gerbil brain homogenates. Lee SR, Im KJ, Suh SI, Jung JG. Department of Pharmacology, School of Medicine and Brain Research Institute, Keimyung University, Taegu, South Korea. srlee@dsmc.or.kr 56. FASEB J. 2003 May;17(8):952-4. Epub 2003 Mar 28.

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Neuroprotection and neurorescue against Abeta toxicity and PKC-dependent release of nonamyloidogenic soluble precursor protein by green tea polyphenol (-)epigallocatechin-3-gallate. Levites Y, Amit T, Mandel S, Youdim MB. Eve Topf and USA National Parkinson Foundation, Centers of Excellence for Neurodegenerative Diseases Research, Technion Faculty of Medicine, Haifa, Israel. 57. J Agric Food Chem. 2003 Apr 9;51(8):2421-5. Influence of green tea polyphenol in rats with arginine-induced renal failure. Yokozawa T, Cho EJ, Nakagawa T. Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. yokozawa@ms.toyama-mpu.ac.jp 58. J Pharmacol Exp Ther. 2003 Jul;306(1):29-34. Epub 2003 Mar 27. Green tea polyphenols induce differentiation and proliferation in epidermal keratinocytes. Hsu S, Bollag WB, Lewis J, Huang Q, Singh B, Sharawy M, Yamamoto T, Schuster G. Department of Oral Biology and Maxillofacial Pathology, School of Dentistry, AD1443. Medical College of Georgia, Augusta, GA 30912-1126, USA. shsu@mail.mcg.edu 59. Mutat Res. 2003 Feb-Mar;523-524:33-41. Anticlastogenic, antigenotoxic and apoptotic activity of epigallocatechin gallate: a green tea polyphenol. Roy M, Chakrabarty S, Sinha D, Bhattacharya RK, Siddiqi M. Department of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, 37 SP Mukherjee Road, Kolkata 700 026, India. 60. Cancer. 2003 Mar 15;97(6):1442-6. A phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma. Jatoi A, Ellison N, Burch PA, Sloan JA, Dakhil SR, Novotny P, Tan W, Fitch TR, Rowland KM, Young CY, Flynn PJ.

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Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. jatoi.aminah@mayo.edu 61. Int J Urol. 2003 Mar;10(3):160-6. Preventive effects of urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)nitrosamine in rat by green tea leaves. Sato D, Matsushima M. Second Department of Urology, Toho University of Medicine, Tokyo, Japan. sai2uro@oha.toho-u.ac.jp 62. J Biomed Sci. 2003 Mar-Apr;10(2):219-27. Green Tea Constituent (-)-Epigallocatechin-3-Gallate Inhibits Hep G2 Cell Proliferation and Induces Apoptosis through p53-Dependent and Fas-Mediated Pathways. Kuo PL, Lin CC. Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC. 63. Oncogene. 2003 Feb 20;22(7):1035-44. Inhibition of ultraviolet B-mediated activation of nuclear factor kappaB in normal human epidermal keratinocytes by green tea Constituent (-)-epigallocatechin-3-gallate. Afaq F, Adhami VM, Ahmad N, Mukhtar H. Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA. 64. FASEB J. 2003 Apr;17(6):702-4. Epub 2003 Feb 05. Green tea polyphenol epigallocatechin-3 gallate induces apoptosis of proliferating vascular smooth muscle cells via activation of p53. Hofmann CS, Sonenshein GE. Department of Biochemistry, Boston University School of Medicine, Massachusetts 02118, USA. 65. Yan Ke Xue Bao. 2000 Sep;16(3):194-8. Growth inhibition, induction of apoptosis by green tea constituent (-)-epigallocatechin-3gallate in cultured rabbit lens epithelial cells. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 415

Huang W, Li S, Zeng J, Liu Y, Wu M, Zhang M. Zhongshan Ophthalmic Center, Sun Yat-sen University of Medical Sciences, Guangzhou 510060, China. 66. Anticancer Res. 2002 Nov-Dec;22(6C):4115-20. Induction of p57 is required for cell survival when exposed to green tea polyphenols. Hsu S, Yu FS, Lewis J, Singh B, Borke J, Osaki T, Athar M, Schuster G. Department of Oral Biology and Maxillofacial Pathology, School of Dentistry, AD1443, Medical College of Georgia, Augusta, GA 30912-1126, USA. shsu@mail.mcg.edu 67. J Biochem Mol Biol. 2003 Jan 31;36(1):66-77. Signal transduction pathways: targets for green and black tea polyphenols. Park AM, Dong Z. The Hormel Institute, University of Minnesota, Austin, MN 55912, USA. 68. Clin Exp Pharmacol Physiol. 2003 Jan-Feb;30(1-2):88-95. Green tea catechins evoke a phasic contraction in rat aorta via H2O2-mediated multiplesignalling pathways. Shen JZ, Zheng XF, Wei EQ, Kwan CY. Department of Pharmacology, School of Medicine, Zhejiang University, Hubin Campus, Hangzhou, People's Republic of China. 69. Anticancer Res. 2002 Nov-Dec;22(6A):3373-8. Induction of apoptosis by the green tea flavonol (-)-epigallocatechin-3-gallate in human endothelial ECV 304 cells. Yoo HG, Shin BA, Park JC, Kim HS, Kim WJ, Chay KO, Ahn BW, Park RK, Ellis LM, Jung YD. Chonnam University Research Institute of Medical Sciences, Chonnam National University Medical School, Kwangju, Korea. 70. Cancer Detect Prev. 2002;26(6):411-8.

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Modification of lung cancer susceptibility by green tea extract as measured by the comet assay. Zhang H, Spitz MR, Tomlinson GE, Schabath MB, Minna JD, Wu X. Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center Box 189 1515 Holcombe Blvd, Houston, TX 77030, USA 71. Biol Pharm Bull. 2002 Dec;25(12):1513-8. Neuroprotective effects of the green tea components theanine and catechins. Kakuda T. Central Research Institute, Itoen, Ltd, Shuzuoka, Japan. 72. Life Sci. 2003 Jan 17;72(9):1073-83. Effects of green tea polyphenols on dopamine uptake and on MPP+ -induced dopamine neuron injury. Pan T, Fei J, Zhou X, Jankovic J, Le W. Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. 73. Asia Pac J Clin Nutr. 2002;11(4):292-7. Effect of green tea catechin on arachidonic acid cascade in chronic cadmium-poisoned rats. Choi JH, Chang HW, Rhee SJ. Department of Food Science and Nutrition, Catholic University of Daegu, Kyongsan-si, Korea. 74. Antivir Chem Chemother. 2002 Jul;13(4):223-9. Antiviral properties of prodelphinidin B-2 3'-O-gallate from green tea leaf. Cheng HY, Lin CC, Lin TC. Graduate Institute of Pharmaceutical Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China. 75. Atherosclerosis. 2003 Jan;166(1):23-30. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 417

Green tea catechins inhibit the cultured smooth muscle cell invasion through the basement barrier. Maeda K, Kuzuya M, Cheng XW, Asai T, Kanda S, Tamaya-Mori N, Sasaki T, Shibata T, Iguchi A. 76. J Periodontal Res. 2002 Dec;37(6):433-8. Improvement of periodontal status by green tea catechin using a local delivery system: a clinical pilot study. Hirasawa M, Takada K, Makimura M, Otake S. Department of Microbiology, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba Japan. masahira@mascat.nihon-u.ac.jp 77. Breast Cancer Res Treat. 2002 Dec;76(3):195-201. (-)-Epigallocatechin (EGC) of green tea induces apoptosis of human breast cancer cells but not of their normal counterparts. Vergote D, Cren-Olive C, Chopin V, Toillon RA, Rolando C, Hondermarck H, Le Bourhis X. Laboratoire de Biologic du Developpement (UPRES-EA 1033), Universite des Sciences et Technologies de Lille, Villeneuve d'Ascq, France. 78. Yakugaku Zasshi. 2002 Nov;122(11):995-9. [Glutamate transporter mediated increase of antitumor activity by theanine, an amino acid in green tea] [Article in Japanese] Sadzuka Y, Yamashita Y, Kishimoto S, Fukushima S, Takeuchi Y, Sonobe T. University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan. sadzuka@u-shizuokaken.ac.jp 79. Int J Cancer. 2002 Dec 10;102(5):439-44. The green tea polyphenol, epigallocatechin-3-gallate, protects against the oxidative cellular and genotoxic damage of UVA radiation. Tobi SE, Gilbert M, Paul N, McMillan TJ.

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Department of Biological Sciences, Institute of Environmental and Natural Sciences, Lancaster University, Lancaster, United Kingdom. 80. Int J Oncol. 2002 Dec;21(6):1307-15. Bioactivity of well-defined green tea extracts in multicellular tumor spheroids. Mueller-Klieser W, Schreiber-Klais S, Walenta S, Kreuter MH. Institute of Physiology and Pathophysiology, Johannes Gutenberg-University Mainz, 55099 Mainz, Germany. wolfgang.mueller-klieser@uni-mainz.de 81. Life Sci. 2002 Dec 6;72(3):257-68. Anti-proliferative and differentiation-inducing activities of the green tea catechin epigallocatechin-3-gallate (EGCG) on the human eosinophilic leukemia EoL-1 cell line. Lung HL, Ip WK, Wong CK, Mak NK, Chen ZY, Leung KN. Department of Biochemistry, The Chinese University of Hong Kong, Shatin, China. 82. Chem Phys Lipids. 2002 Dec;120(1-2):109-17. Antioxidant effects of green tea polyphenols on free radical initiated peroxidation of rat liver microsomes. Cai YJ, Ma LP, Hou LF, Zhou B, Yang L, Liu ZL. National Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu 730000, Lanzhou, People's Republic of China 83. Food Chem Toxicol. 2002 Dec;40(12):1745-50. Direct scavenging of nitric oxide and superoxide by green tea. Nakagawa T, Yokozawa T. Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Japan. 84. J Ethnopharmacol. 2002 Nov;83(1-2):109-16. Anti-diabetic activity of green tea polyphenols and their role in reducing oxidative stress in experimental diabetes. M C S, K S, Kuttan R. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 419

Amala Cancer Research Centre, Amala Nagar,Trichur 680 553, Kerala, India. 85. Zhonghua Yu Fang Yi Xue Za Zhi. 2002 Jul;36(4):243-6. [Green tea extracts protected against carbon tetrachloride-induced chronic liver damage and cirrhosis] [Article in Chinese] Xiao J, Lu R, Shen X, Wu M. Department of Hutyition and Food Hygiene, School of Health, Fudan University, Shanghai 200032, China. 86. Cancer Lett. 2002 Dec 15;188(1-2):163-70. Lack of inhibitory effects of green tea catechins in 1,2-dimetylhydrazine-induced rat intestinal carcinogenesis model: comparison of the different formulations, administration routes and doses. Hirose M, Yamaguchi T, Mizoguchi Y, Akagi K, Futakuchi M, Shirai T. Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, 158-8501, Tokyo, Japan. m-hirose@nihs.go.jp 87. Cancer Lett. 2002 Dec 15;188(1-2):9-13. Green tea: cancer preventive beverage and/or drug. Fujiki H, Suganuma M, Imai K, Nakachi K. Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, 770-8514, Tokushima, Japan. hfujiki@ph.bunri-u.ac.jp 88. Amino Acids. 2002;22(2):131-43. The specific anti-cancer activity of green tea (-)-epigallocatechin-3-gallate (EGCG). Wang YC, Bachrach U. Department of Molecular Biology, Hebrew University-Hadassah Medical School, Jerusalem, Israel. 89. Mol Med. 2002 Jul;8(7):382-92. Synthetic analogs of green tea polyphenols as proteasome inhibitors. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 420

Smith DM, Wang Z, Kazi A, Li LH, Chan TH, Dou QP. Drug Discovery Program, H Lee Moffitt Cancer Center & Research Institute, Departments of Interdisciplinary Oncology and Biochemistry & Molecular Biology, College of Medicine,University of South Florida, Tampa, FL 33612-9497, USA. 90. Neurotoxicology. 2002 Sep;23(3):289-300. Differential modulation of growth and glutathione metabolism in cultured rat astrocytes by 4-hydroxynonenal and green tea polyphenol, epigallocatechin-3-gallate. Ahmed I, John A, Vijayasarathy C, Robin MA, Raza H. Department of Anatomy, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates. 91. Drug Metab Dispos. 2002 Nov;30(11):1246-9. Contribution of presystemic hepatic extraction to the low oral bioavailability of green tea catechins in rats. Cai Y, Anavy ND, Chow HH. College of Pharmacy, University of Arizona, Tucson, Arizona 85724, USA. 92. Cancer Epidemiol Biomarkers Prev. 2002 Oct;11(10 Pt 1):1025-32. Pharmacokinetics of tea catechins after ingestion of green tea and (-)-epigallocatechin-3gallate by humans: formation of different metabolites and individual variability. Lee MJ, Maliakal P, Chen L, Meng X, Bondoc FY, Prabhu S, Lambert G, Mohr S, Yang CS. Laboratory for Cancer Research, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854-8020, USA. 93. Free Radic Biol Med. 2002 Oct 15;33(8):1097-105. Green tea polyphenol epigallocatechin-3-gallate inhibits the IL-1 beta-induced activity and expression of cyclooxygenase-2 and nitric oxide synthase-2 in human chondrocytes. Ahmed S, Rahman A, Hasnain A, Lalonde M, Goldberg VM, Haqqi TM. Department of Orthopedics, Case Western Reserve University, Cleveland, OH 441064946, USA.

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94. Ophthalmic Res. 2002 Jul-Aug;34(4):258-63. Green tea (Camellia sinensis) protects against selenite-induced oxidative stress in experimental cataractogenesis. Gupta SK, Halder N, Srivastava S, Trivedi D, Joshi S, Varma SD. Department of Pharmacology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India. skgup@hotmail.com 95. Inflammation. 2002 Oct;26(5):233-41. A green tea-derived polyphenol, epigallocatechin-3-gallate, inhibits IkappaB kinase activation and IL-8 gene expression in respiratory epithelium. Chen PC, Wheeler DS, Malhotra V, Odoms K, Denenberg AG, Wong HR. Division of Critical Care Medicine, Children's Hospital Medical Center and Children's Hospital Research Foundation, Cincinnati, OH 45244, USA. 96. Biochem Biophys Res Commun. 2002 Sep 20;297(2):412-8. Elevation of P-glycoprotein function by a catechin in green tea. Wang EJ, Barecki-Roach M, Johnson WW. Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Lafayette, NJ 07848, USA. 97. Asia Pac J Clin Nutr. 2002;11(3):232-6. Effects of green tea catechin on prostaglandin synthesis of renal glomerular and renal dysfunction in streptozotocin-induced diabetic rats. Rhee SJ, Kim MJ, Kwag OG. Department of Food Science and Nutrition, Catholic University of Daegu, Gyungsan-si, Gyungbuk, Korea. sjrhee@cataegu.ac.kr 98. Biol Pharm Bull. 2002 Sep;25(9):1238-40. Activity-guided fractionation of green tea extract with antiproliferative activity against human stomach cancer cells. Kinjo J, Nagao T, Tanaka T, Nonaka G, Okawa M, Nohara T, Okabe H.

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kinjojun@fukuoka-u.ac.jp 99. Am J Physiol Gastrointest Liver Physiol. 2002 Oct;283(4):G957-64. Prevention of hepatic ischemia-reperfusion injury by green tea extract. Zhong Z, Froh M, Connor HD, Li X, Conzelmann LO, Mason RP, Lemasters JJ, Thurman RG. Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, 27599, USA. 100. Mutat Res. 2002 Sep;512(1):37-65. Comparative antimutagenic and anticlastogenic effects of green tea and black tea: a review. Gupta S, Saha B, Giri AK. Division of Human Genetics and Genomics, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Calcutta 700 032, India.

Reduced L-Glutathione - 13 CITATIONS

1: Kaposzta Z, Clifton A, Molloy J, Martin JF, Markus HS. S-nitrosoglutathione reduces asymptomatic embolization after carotid angioplasty. Circulation. 2002 Dec 10;106(24):3057-62. PMID: 12473551 2: Fraternale A, Casabianca A, Orlandi C, Cerasi A, Chiarantini L, Brandi G, Magnani M. Macrophage protection by addition of glutathione (GSH)-loaded erythrocytes to AZT and DDI in a murine AIDS model. Antiviral Res. 2002 Dec;56(3):263-72. PMID: 12406509 3: Knight TR, Ho YS, Farhood A, Jaeschke H. Peroxynitrite is a critical mediator of acetaminophen hepatotoxicity in murine livers: protection by glutathione. J Pharmacol Exp Ther. 2002 Nov;303(2):468-75. PMID: 12388625

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4: Usberti M, Gerardi G, Micheli A, Tira P, Bufano G, Gaggia P, Movilli E, Cancarini GC, De Marinis S, D'Avolio G, Broccoli R, Manganoni A, Albertin A, Di Lorenzo D. Effects of a vitamin E-bonded membrane and of glutathione on anemia and erythropoietin requirements in hemodialysis patients. J Nephrol. 2002 Sep-Oct;15(5):558-64. PMID: 12455724 5: Cascinu S, Catalano V, Cordella L, Labianca R, Giordani P, Baldelli AM, Beretta GD, Ubiali E, Catalano G. Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2002 Aug 15;20(16):3478-83. PMID: 12177109 6: Arosio E, De Marchi S, Zannoni M, Prior M, Lechi A. Effect of glutathione infusion on leg arterial circulation, cutaneous microcirculation, and pain-free walking distance in patients with peripheral obstructive arterial disease: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc. 2002 Aug;77(8):754-9. PMID: 12173710 7: Ueno Y, Kizaki M, Nakagiri R, Kamiya T, Sumi H, Osawa T. Dietary glutathione protects rats from diabetic nephropathy and neuropathy. J Nutr. 2002 May;132(5):897-900. PMID: 11983810 8: Gao F, Yao CL, Gao E, Mo QZ, Yan WL, McLaughlin R, Lopez BL, Christopher TA, Ma XL. Enhancement of glutathione cardioprotection by ascorbic acid in myocardial reperfusion injury. J Pharmacol Exp Ther. 2002 May;301(2):543-50. PMID: 11961055 9: Inal ME, Akgun A, Kahraman A. Radioprotective effects of exogenous glutathione against whole-body gamma-ray irradiation: age- and gender-related changes in malondialdehyde levels, superoxide dismutase and catalase activities in rat liver. Methods Find Exp Clin Pharmacol. 2002 May;24(4):209-12. PMID: 12092007 10: Snyder AH, McPherson ME, Hunt JF, Johnson M, Stamler JS, Gaston B. Acute effects of aerosolized S-nitrosoglutathione in cystic fibrosis. Am J Respir Crit Care Med. 2002 Apr 1;165(7):922-6. PMID: 11934715

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11: Kaposzta Z, Martin JF, Markus HS. Switching off embolization from symptomatic carotid plaque using S-nitrosoglutathione. Circulation. 2002 Mar 26;105(12):1480-4. PMID: 11914258 12: Ortolani O, Conti A, De Gaudio AR, Moraldi E, Novelli GP. [Glutathione and N-acetylcysteine in the prevention of free-radical damage in the initial phase of septic shock] Recenti Prog Med. 2002 Feb;93(2):125-9. Italian. PMID: 11887346 13: Amer MA. Modulation of age-related biochemical changes and oxidative stress by vitamin C and glutathione supplementation in old rats. Ann Nutr Metab. 2002;46(5):165-8. PMID: 12378038

L-Cysteine 22 STUDIES
1. Neurosci Lett. 2003 Jul 31;346(1-2):97-100. L-cysteine sulphinate, endogenous sulphur-containing amino acid, inhibits rat brain kynurenic acid production via selective interference with kynurenine aminotransferase II. Kocki T, Luchowski P, Luchowska E, Wielosz M, Turski WA, Urbanska EM. Department of Pharmacology and Toxicology, Medical University, Jaczewskiego 8, 20090 Lublin, Poland. 2. Biochem Biophys Res Commun. 2003 May 23;305(1):94-100. L-cysteine administration prevents liver fibrosis by suppressing hepatic stellate cell proliferation and activation. Horie T, Sakaida I, Yokoya F, Nakajo M, Sonaka I, Okita K. Pharmaceuticals Research Laboratories, Ajinomoto Co, Inc, 1-1, Suzuki-cho, Kawasakiku, Kawasaki 210-8681, Japan. 3. Proc Nutr Soc. 2000 Nov;59(4):595-600. Glutathione and immune function. Droge W, Breitkreutz R. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 425

Department of Immunochemistry, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. W.Droege@dkfz-heidelberg.de 4. Toxicol Appl Pharmacol. 2000 Oct 1;168(1):72-8. gamma-Glutamyl transpeptidase and L-cysteine regulate methylmercury uptake by HepG2 cells, a human hepatoma cell line. Wang W, Clarkson TW, Ballatori N. Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, New York 14642, USA. 5. Amino Acids. 2000;18(4):319-27. Polyamines and thiols in the cytoprotective effect of L-cysteine and L-methionine on carbon tetrachloride-induced hepatotoxicity. Chen W, Kennedy DO, Kojima A, Matsui-Yuasa I. Department of Food and Nutrition, Faculty of Human Life Science, Osaka City University, Osaka, Japan. 6. Z Naturforsch [C]. 2000 Mar-Apr;55(3-4):271-7. Protective effect of L-cysteine and glutathione on rat brain Na+,K+-ATPase inhibition induced by free radicals. Tsakiris S, Angelogianni P, Schulpis KH, Behrakis P. Department of Experimental Physiology, University of Athens, Medical School, Greece. stsakir@cc.uoa.gr 7. Comp Biochem Physiol B Biochem Mol Biol. 1997 Feb;116(2):223-6. L-cysteine metabolism in guinea pig and rat tissues. Wrobel M, Ubuka T, Yao WB, Abe T. Department of Biochemistry, Okayama University Medical School, Japan. 8. Gross A, Hack V, Stahl-Hennig C, Droge W. AIDS Res Hum Retroviruses. 1996 Nov 20;12(17):1639-41. Elevated hepatic gamma-glutamylcysteine synthetase activity and abnormal sulfate levels in liver and muscle tissue may explain abnormal cysteine and glutathione levels in SIVinfected rhesus macaques. 9. Biochem Pharmacol. 1996 May 3;51(9):1111-6.

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Maintenance of hepatic glutathione homeostasis and prevention of acetaminopheninduced cataract in mice by L-cysteine prodrugs. Rathbun WB, Killen CE, Holleschau AM, Nagasawa HT. Department of Ophthalmology, University of Minnesota, Minneapolis, USA. 10. Jpn J Physiol. 1995;45(5):771-83. The central effect of L-cysteine on cardiovascular system of the conscious rat. Takemoto Y. Department of Physiology, Hiroshima University School of Medicine, Minami-ku, Japan. 11. FASEB J. 1994 Nov;8(14):1131-8. Functions of glutathione and glutathione disulfide in immunology and immunopathology. Droge W, Schulze-Osthoff K, Mihm S, Galter D, Schenk H, Eck HP, Roth S, Gmunder H. Department of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany. 12. Pharmacology. 1993;46(2):61-5. Cysteine and glutathione deficiency in AIDS patients: a rationale for the treatment with N-acetyL-cysteine. Droge W. Division of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, BRD. 13. Biochem Pharmacol. 1992 Jul 7;44(1):129-35. Acetaminophen-induced depletion of glutathione and cysteine in the aging mouse kidney. Richie JP Jr, Lang CA, Chen TS. American Health Foundation, Valhalla, NY 10595. 14. Biochem Pharmacol. 1992 Feb 4;43(3):483-8. Cysteine isopropylester protects against paracetamol-induced toxicity. Butterworth M, Upshall DG, Smith LL, Cohen GM. Toxicology Unit, School of Pharmacy, University of London, U.K. 15. Blood. 1992 Sep 1;80(5):1247-53. Antithrombotic properties of L-cysteine, N-(mercaptoacetyl)-D-Tyr-Arg-Gly-Aspsulfoxide (G4120) in a hamster platelet-rich femoral vein thrombosis model. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 427

Imura Y, Stassen JM, Bunting S, Stockmans F, Collen D. Center for Thrombosis and Vascular Research, University of Leuven, Belgium. 16. Jpn J Cancer Res. 1989 Feb;80(2):182-7. Enhanced antitumor effect of 5'-deoxy-5-fluorouridine by oral administration with Lcysteine. Iigo M, Nakajima Y, Araki E, Hoshi A. Chemotherapy Division, National Cancer Center Research Institute, Tokyo. 17. Am Rev Respir Dis. 1985 Nov;132(5):1049-54. Investigation of the protective effects of the antioxidants ascorbate, cysteine, and dapsone on the phagocyte-mediated oxidative inactivation of human alpha-1-protease inhibitor in vitro. Theron A, Anderson R. 18. J Biol Chem. 1984 May 10;259(9):5606-11. Free radical metabolites of L-cysteine oxidation. Harman LS, Mottley C, Mason RP. 19. Hum Genet. 1979;50(1):51-7. Chromosomal breakage in Crohn's disease: anticlastogenic effect of D-penicillamine and L-cysteine. Emerit I, Emerit J, Levy A, Keck M. 20. Biol Trace Elem Res. 2000 Jul;76(1):19-30. Study of the effect of the administration of Cd(II), cysteine, methionine, and Cd(II) together with cysteine or methionine on the conversion of xanthine dehydrogenase into xanthine oxidase. Esteves AC, Felcman J. Department of Chemistry, Pontificia Universidade Catolica do Rio de Janeiro, Rio de Janeiro, Brazil. 21. J Infect Dis. 2000 Sep;182 Suppl 1:S81-4. Regulation of cysteine-rich intestinal protein, a zinc finger protein, by mediators of the immune response. Cousins RJ, Lanningham-Foster L. Food Science and Human Nutrition Department, Center for Nutritional Sciences, University of Florida, Gainesville, FL 32611-0370, USA. 22. Am J Med. 1991 Sep 30;91(3C):140S-144S.

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Modulation of lymphocyte functions and immune responses by cysteine and cysteine derivatives. Droge W, Eck HP, Gmunder H, Mihm S. Division of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, F.R.G.

Coenzyme Q10 43 STUDIES


1: Muller T, Buttner T, Gholipour AF, Kuhn W. Coenzyme Q10 supplementation provides mild symptomatic benefit in patients with Parkinson's disease. Neurosci Lett. 2003 May 8;341(3):201-4. PMID: 12697283 [PubMed - indexed for MEDLINE] 2: Elshershari H, Ozer S, Ozkutlu S, Ozme S. Potential usefulness of coenzyme Q10 in the treatment of idiopathic dilated cardiomyopathy in children. Int J Cardiol. 2003 Mar;88(1):101-2. PMID: 12659993 [PubMed - indexed for MEDLINE] 3: Beal MF. Bioenergetic approaches for neuroprotection in Parkinson's disease. Ann Neurol. 2003;53 Suppl 3:S39-47; discussion S47-8. Review. PMID: 12666097 [PubMed - indexed for MEDLINE] 4: Lu WL, Zhang Q, Lee HS, Zhou TY, Sun HD, Zhang DW, Zheng L, Lee M, Wong SM. Total coenzyme Q10 concentrations in Asian men following multiple oral 50-mg doses administered as coenzyme Q10 sustained release tablets or regular tablets. Biol Pharm Bull. 2003 Jan;26(1):52-5. PMID: 12520172 [PubMed - indexed for MEDLINE] 5: Van Maldergem L, Trijbels F, DiMauro S, Sindelar PJ, Musumeci O, Janssen A, Delberghe X, Martin JJ, Gillerot Y. Coenzyme Q-responsive Leigh's encephalopathy in two sisters. Ann Neurol. 2002 Dec;52(6):750-4. PMID: 12447928 [PubMed - indexed for MEDLINE] 6: Ramadan LA, Abd-Allah AR, Aly HA, Saad-el-Din AA. Testicular toxicity effects of magnetic field exposure and prophylactic role of coenzyme Q10 and L-carnitine in mice.

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Pharmacol Res. 2002 Oct;46(4):363-70. PMID: 12361700 [PubMed - indexed for MEDLINE] 7: Turunen M, Wehlin L, Sjoberg M, Lundahl J, Dallner G, Brismar K, Sindelar PJ. beta2-Integrin and lipid modifications indicate a non-antioxidant mechanism for the antiatherogenic effect of dietary coenzyme Q10. Biochem Biophys Res Commun. 2002 Aug 16;296(2):255-60. PMID: 12163010 [PubMed - indexed for MEDLINE] 8: Sarter B. Coenzyme Q10 and cardiovascular disease: a review. J Cardiovasc Nurs. 2002 Jul;16(4):9-20. Review. PMID: 12597259 [PubMed - indexed for MEDLINE] 9: Koryagin AS, Krylova EV, Luk'yanova LD. Effect of ubiquinone-10 on the blood system in rats exposed to radiation. Bull Exp Biol Med. 2002 Jun;133(6):562-4. PMID: 12447465 [PubMed - indexed for MEDLINE] 10: Lamson DW, Plaza SM. Mitochondrial factors in the pathogenesis of diabetes: a hypothesis for treatment. Altern Med Rev. 2002 Apr;7(2):94-111. Review. PMID: 11991790 [PubMed - indexed for MEDLINE] 11: Beal MF. Coenzyme Q10 as a possible treatment for neurodegenerative diseases. Free Radic Res. 2002 Apr;36(4):455-60. Review. PMID: 12069110 [PubMed - indexed for MEDLINE] 12: Rozen TD, Oshinsky ML, Gebeline CA, Bradley KC, Young WB, Shechter AL, Silberstein SD. Open label trial of coenzyme Q10 as a migraine preventive. Cephalalgia. 2002 Mar;22(2):137-41. PMID: 11972582 [PubMed - indexed for MEDLINE] 13: Watts GF, Playford DA, Croft KD, Ward NC, Mori TA, Burke V. Coenzyme Q(10) improves endothelial dysfunction of the brachial artery in Type II diabetes mellitus. Diabetologia. 2002 Mar;45(3):420-6. PMID: 11914748 [PubMed - indexed for MEDLINE] 14: Lister RE. An open, pilot study to evaluate the potential benefits of coenzyme Q10 combined with Ginkgo biloba extract in fibromyalgia syndrome. J Int Med Res. 2002 Mar-Apr;30(2):195-9. PMID: 12025528 [PubMed - indexed for MEDLINE] Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 430

15: Huang CC, Kuo HC, Chu CC, Kao LY. Rapid visual recovery after coenzyme q10 treatment of leber hereditary optic neuropathy. J Neuroophthalmol. 2002 Mar;22(1):66. PMID: 11937918 [PubMed - indexed for MEDLINE] 16: Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG, Hersch SM, Beal MF. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease. J Neurosci. 2002 Mar 1;22(5):1592-9. PMID: 11880489 [PubMed - indexed for MEDLINE] 17: Brancato R, Fiore T, Papucci L, Schiavone N, Formigli L, Orlandini SZ, Gobbi PG, Carones F, Donnini M, Lapucci A, Capaccioli S. Concomitant effect of topical ubiquinone Q10 and vitamin E to prevent keratocyte apoptosis after excimer laser photoablation in rabbits. J Refract Surg. 2002 Mar-Apr;18(2):135-9. PMID: 11934201 [PubMed - indexed for MEDLINE] 18: Schilling G, Coonfield ML, Ross CA, Borchelt DR. Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in