101 LUWS Va!iey Rgd, Suite 210 San Rafael, California 64903 Tel: (413>$?

$62%; Fp% (&X5) ;Q&95~908 e-mail: ppsi@c&corn .I ,_’ 6 .J
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fctwmrr=ists@xnnirg seAugust 12,2uO3 Frederick S. Mayer ’ Dpcuments Management Branch Food and,Dr&g Administration (FDA) Department &f HealthfH@nan Services 5600 Fishers’ Lane, Room 4-62 Rockville, MD 20857
R.Ph., M.P.H. President 101 Lucas Valley Road, Suite 210 San Rafa@, California 94903 E-Mail: ppsi@aoi.com

in2

Tel: (415) 479-8628 Fax: (41.5) 479-8608 Website: ppsinc.org

Re: Citizen’ Petition (Addition) to Filings of Msr@ t6, fSg8 Regard.ing s: Labeling All Herbals, OT& and Prescriptions Drugs for Adverse Drugs Effects and Drug Interactions Citizen’ s Petition Docket No. 98P-0169~CPI

Pharmacistd Planning Service,. Inc. (PPSI), a 501 C (3) nonprofit public health, consumer and pharmacy education organizations submits additions to its Citizen’ Petition filed March 16,1996, regarding the need for labeling s the drug interactions and adverse drug events which are occurring when Herbal meditines prescription drugs are mixed with herbal supplements can also alter test results by direct interference with certain : immunoass’ ays. Drug hkrbal interactions can result in unexpected concentrations of therapeutic drugs. We have not heard from the FDA regarding our Citizen’ Petition for over s one year. We submit the following review article “Review of Abnormal Lab Test Results and Toxic.Effects Due to the Use of Herbal Medicines’ by : Amitaba D&gupta, Ph.D. from the American Journal of Clinical Pathology, AJCP, 120 (I): 127-137,i2003, with over sixty references

educed in Congress to overturg the r our Citizen’ Petition. s

Review of Abnormal Laboratory Test Resultsand Toxic &ffee@Due to Use of Herbal Medicines s Amitava Dasgupta, PhD Am J Clin Path01120(1): 127-137,2003.6 2003 American Society of Clinical Pathologists,Inc. Posted07/29/2003

,

Abstract and Introduction
Abstract Herbal medicinesare usedwidely in the United States,and accordingto a recent survey, the majority of people who use herbal medicinesdo not inform their physiciansabout their use.Herbal medicinescan causeabnormaltest resultsand confusion in proper diagnosis.Herbal medicinescan alter test resultsby direct interferencewith certain!timunoassays.Drugherb interactionscan result in unexpectedconcentrations therapeuticdrugs. For example,low concenirationsof several of drugs (eg, cyclosporine,theophylline, digoxin) can”beobservedin patientswho initiated self-medicatioriwith St John’ WOK s Herbal medicinescan alter physiology, and thesechangescan be reflected in abnormaltest results.For example,kava-kava can causedrug-inducedhepatitis, leadingto unexpectedhigh concentrations liver enzymes.Use of toxic herbal products of such as ma huang (an ephedra-containing herbal product), Chan Su, and comfrey may causedeath.Otha toxic effects of herbal medicinesinclude cardiovasculartoxic effects,hematologictoxic effects,neurotoxic effects, ntphrotoxic effects, carcinogeniceffects,and allergic reactions. Introduction Herbal medicines,including Chineseherbal products,are readily availablein the United Statesfrom health food stores without prescriptions.Ayurvedic medicinesare usedwidely in India, and somepreparationsare availablein the United States.Ginseng,St John’ wart, ma huang; kava, ginkgo biloba, Dan Shen,feverfew, garlic, ginger, saw palmetto,comfrey, s pokeweed,hawthorn, dong quai, and cat’ claw are usedby the generalpopulation in the United States.Intendedusesof s commonherbal medicinesare given in Table 1. Gulla et alI’ publisheda survey of 369 patient-escortpairs and reportedthat -_-1“ . ” ‘ 174 patients(47.2%) usedherbs.The most common herbal product usedwas ginseng(20%) followed by echinacea (19%), ginkgo biloba (15%), and St Johns wart (14%).111 Severalherbal productsinterfere with immunoassays usedfor monitoring the concentrationsof therapeuticdrugs. Herbal medicinesalso can causetoxic effects, leadingto abnormaltest results.Therefore,the common belief that anything natural is safe is not correct. This review summarizesabnormaltest resultsassociated with the use of herbal medicines,as well as interactionsbetweenWesternmedicinesand herbal,products. This review also summarizesthe toxic effects of commonly usedherbal products.

Regulatory Issues Affecting H,erbal Medicines
The US Food and Drug administration(FDA) mandatesthat only medicineshave to be proven to be safe before being releasedinto the market. Herbal productsdo not fall under the categoryof drugs as long as they..arecnot arketed the m‘ for prevention’ any diseases, as such, FDA approval is not needed.Herbal products are clas$ised as “dietary supplements” of and, and are marketedpursuantto the Dietary SupplementHealth and Education,actof 1994.However, herbal productsare regulateddifferently in other countries.In the UniteclI&igdom~ any product notgranted a’ licenseas a medical product by the MedicinesControl Agency is treatedas a food, and no health claim or medical advice can be given on the label, Similarly, herbal productsare sold as dietary supplementsin the Netherlands.In Germany,herbal monographsare preparedby an interdisciplinarycommittee(German CommissionE), using historic information; chemical,pharmacologic,clinical, and toxicologic studies;casereports; epidemiologic data; and unpublishedmanufacturers’ If an herb has$n approved data. monograph,it can be marketed. ,

Monday, August 11,2003 America Online: PPSI

i * Efffect of Herbal Medicines on Clinical Laboratory Tksting


j

Abnormal laboratory test/resultsdue to the use of herbal medicinescan be classified in 3 categories:

Abnormal test results due to direct interferenceof a componentof the herbal medicine with the assay Unexpectedconcentrationof a therapeuticdrug due to drug-herb interactions Abnormal test results due to toxic effects of the herbal product Interference of ChineseiMedicines With Digoxin Xmmunoassays, The Chinesemedicine C&n Su is preparedfrom the dried white secretionaf the auricular glands and the skin glands of Chinesetoads (Bufo mei&ostictus Schneider or Bufo bufo gargarzinas Gantor). Chan Su also is a major componentof the traditional Chinesemedicines Lu-Shen-Wan and kyushin.12s31 Thesemedicines are used as remediesfor tonsillitis, sore

throat,furuncle,andpal@tations. Chan Su also is usedfor stimulationof myocardialcontractionand pain @lief.[4]The
cardiatonic effect of Ghan Su is due to its,major bufadienolides,such as bufalin, cinobufagin, and resibufogenin.151 Bufalin is known to block vasodilatation and increasesvasoconstrictionand vascularresistanceand, thus, blood pressureby inhibiting Na+,K-l--ATPase.161 high dosages,Chan Su causescardiac arrhythmia, breathlessness, At seizure, and coma. The death of a Chinesewoman after ingestion of Chineseherbal tea containing Chan Su has been reported.171 Structural similarity between bufadienolides and digoxin accountsfor the toxic effects and serum digoxin-like immunoreactivity of Chan Su. Fushimi and AminoI’ reporteda serum concentrationof 0.4 ng/mL (0.5 1 nmol/L) in a healthy volunteer after ingestion of kyushin tablets containing Chan Su as the major component.PanesarI reported an apparent digoxin concentrationof jO.88ng/mL (1.1:nmol/L) in healthy volunteerswho ingestedLu-Shen-Wan pills. The author used the fluorescencepolarization immunoassay(FPIA) of digoxin for the study. An apparentdigoxin concentrationof 4.9 ng/mL (6.3 nmol/L) was reporteidin 1 woman who died of ingestion of Chineseherbal tea containing Chan Su.171 jl\lthough Chan Su falsely elevatesthe serurndigoxin concentrationwhen the FPIA is used,negative interference of Chan Su in serum digoxin measurement been reported with the microparticle enzyme immunoassay(MEIA, Abbott Laboratories; Chicago, IL). has However, interfering componentsin Chan Su are bound very strongly to serum proteins, while digoxin is only 25% protein bound. Therefore,monitoring the free digoxin concentrationeliminatesthis interference.Another way to eliminate this interferenceis to use the /chemiluminesceht assay(Bayer Diagnostics,Tarrytown, NY).I’ OI Dan Shen is a Chinesemedicine preparedfrom the root of the Chinesemedicinal plant Salvia miltiorrhiza! This herb has been in use in China for many centuriesfor treating various cardiovasculardiseases,including,angina pectoris, and it now is available in the United States.More than20 diterpeneqt.&ones known as “tanshinones” have been isolatea from Dan Shen. These compoundshave structural simila&y with digoxin. FeedingDan Shento mice causeddigoxin-like immunoreactivity in serumwhen measuredby the FPIA. The presenceof Dan Shen falsely elevatedserum digoxin concentrationsas measured by the FPIA and falsely lowered the digoxin concentrationswhen measuredby the MEIA. However, no interferencewas observedwhen the chemiluminescentassaywas used.11’ Interferenceof Dan Shen in the FPIA and MESA can be ,t21 eliminated by measuring/ digoxin becausethe digoxin-like immunoreactivecomponentsof Dan Shen have much higher free serum protein binding than digoxin. The EMIT 2000 digoxin assayand a recently FDA-approved turbidimetric digoxin immunoassay(Bayer Diagnostics) also are free from interferencefrom Dan Shen. Interestingly, the same Chinesemedicine preparedby different ma!nufacturers showed significantly different digoxin-like immunoreactivity, presumablybecause Chinesemedicinesare not preparedby following rtgorous standardizationprocessesas used in the preparationof Western medicines.I13l I McP.aeI*41 reported a casein which ingestion of Siberian ginsengwas associatedwith elevated digoxin cobcentrationsin a 74-year-oldman, In this jpatient,the serum digoxin concentrationshad been maintained between 0.9 and 2.2 ng/mL (1.2-2.8 nmol/L) for a period of 10 years, After ingestion of Siberian ginseng,his serum digoxin concentration @eased to 5.2 ng/mL (6.7 nmol/L), although the patient did not experienceany signs of digoxin toxicity. The patient stoppedtaking Siberian ginseng,and the serum digoxin concentrationreturned to a normal value.It41 Our study indicatesthat Siberian ginseng producesonly modest interferencein the digoxin FPIA and MEIA. Asian ginseng It51 also showedmodestpositive (FPIA) and modest negative (MEIA) interference. Interferencesof herbal products in therapeuticdrug monito:mgof digoxin are given in Table 2. Abnormal Drug Concehtrations Due to Use of Herbal Medicines Severalherbal medicines lower the seizure threshold maintainedby phenobarbital,offsetting the beneficial anticonvulsant activity. Evening primrose oil is used as a remedy for premenstrualsyndrome,diabetic neuropathy, and attentiondeficit/hyperactivity disorder. Evening primrose oil contains gamolenic acid that lowers the seizure threshold maintained by

severalanticonvulsants.l\“I Borage oil (starflower) also contains j&C&g& acid. Shankhapushpi,an ayurvedic medicine for epilepsy, has adversely affected the effectivenessof phenytoin. Dandekai et all”1 observed 2 patients experienceloss of seizurecontrol after self-medication with&hankhapushpi. The serum ph~enytoin concentration dropped from 9.6 pg/mL (38.0 nmol/L) to 5.1 ug/mL (20.2 umol/L) after ingestion of this herbal product (1 teaspoon3 times a day).l7’ Warfarin. Warfarin is an anticoagulant with a narrow therapeutic range. The drug has potentially serious consequences if bleeding comphcationsdevelop or if a subtherapeuticlevel occurs, thus failing to protect the patient from mromboembolic events.Severalherbs interact with warfarln. The herbs that may increasethe risk of bleeding (potentiate’ effects of warfarin) include angeiicaroot, armca flower, ansine,bogbean,borage seedoil, capsicum, feverfew, garlic, ginger, ginkgo, horse chestnut,licorice root, and willow bark. The herbs with documentedinteraction with warfarin include Dan Shen,ginseng, Siberian ginseng, Devil’ claw, and dong quai, among othersI’ s * A 47-year-old man with a mechanical heart valve took warfarin for 5 years and had an averageinternational normalized ratio (INR) of 4. Within 2 weeks of using ginseng, his INR dropped to 1.5, but 2 weeks after discontinuing ginseng use, it returned to 3.3. Fortunately, no adverseeffects occurred during the 2 weeks with a subtherapeutic1~R.1191 subtherapeuticINR due A to the intake of soy protein in the form of soy milk also has been reported in a 70-yea&old man. INR values returned to normal 2 weeks after discontinuation of soy milk .lzol Conversely Dan Shen causedinappropriately increasedanticoagulation 21*221 Apart from inhibition of platelet aggrekation, Dan Shen (INR values ranging from 5.5-8.4) in patients taking warfarin.1 also promotestibrinolysis due to antithrombin III-like activities. Dan Shen increasesthe concentration of warfarin owing to a decreasein clearance.1221 Dong quai is a Chinesemedicine used for treatment of menstrual cramps, irregular menses,and menopausalsymptoms. A 46-year-old woman withstabilized atria1fibrillation who was taking warfarin experienceda greater than 2:fold rise in prothrombin time (23 5 seconds;baseline,,16.2 seconds)and INR (4:05, baseline value, 1.89) after taking hong quai for 4 weeks. A month later, her INR was 4.9 and the prothrombin time was 27.0 seconds.At that time, the patient admitted taking dong quai. The patient was advised to discontinue dong quai, and her INR was 2.48 and the prothrombin t{me was 18.5 seconds4 weeks after wi’ thdrawal of the herb.I23lDong quai contains coumarins, which are natural vitamin K antagonists.1241 Boldo-fenugreek also increasesINR and bleeding time in patientstaking warfarin,1251 Licorice. Licorice may offset the ability of spironolactonesto reduce blood pressure.Licorice is used as an antias a remedy for gastric and peptic ulcers. Carbenoxolone, one of the components of licorice, can inflammatory herb and elevateblood pressureand causehypokalemia. However, discontinuation of licorice results in the return!of blood pressureto normal.1261

aiso

Significantly Lower Concentrations ofbrugs Due to Concurrent Use of St John’ Wort s St John’ wort is preparedfrom Hypericup, a perennial aromatic shrub with bright yellow flowers that bloom EtomJune to s September.The flowers are believed to be most abundantand brightest around June 24, the day traditionally believed to be the birthday of John the Faptist. Therefore, the name St John’ wort becamepopular for this herbal product. Many chemicals s have been isolated from St John’ wort, including hypericin, pseudohypericin,quercetin, isoquercitrin, rut@, amentoflavone, s hyperforin, other flavondids, and xanthones. Interestingly melatonin, a human pineal gland hormone, is ‘ found in St also Johns w~rt.I~~IThe mechanism of action of St John’ wort is not well established.l’ s *I Severalreports describeunexpectedlow concentrationsof certain therapeutic drugs dueto concurrent use of St John’ wort. s Johne et a112’ reported that 10 days’ of St John’ wort resulted in a decreaseof trough serum digoxhi concentrationsby I use s confirmed the lower digoxin concentrations injhealthy volunteers 33% and peak digoxin concentration by 26%. Durr et a11301 who concurrently took St John’ wort. The authors also demonstratedthat St John’ wort activates cytochrome P-450 mixeds s function oxidase liver er&ymes (CYP3A4) responsiblefor metabolism of digoxin.and many other drugs.13eI Barone et a11311 reported.2 casesin which renal transplant recipients started self-medication with St John’ wart. Both patients experienced s subtherapeuticconcentraffonsof cyclospbrine, and in 1 patient, acute graft rejection developed owing to the low cyclosporine concentration.In both patients, termination of the use of St John’ wort returned the cyclosporine concentrationsto s therapeutic levels.13’St John’ wort also reduced the area under the curve of the HIV-l protease inhibitor indinavir by a I s mean of 57% and decreasedthe extrapolated trough by 8 1%. A reduction in indinavir concentration of this magnitude could lead to treatment failure.i321,,A report describesan interaction between St John’ wort and theophylline. After she began case s taking St John’ wort, a patient who had been taking 300 mg of theophylline twice~daily required a dosageiincrease 800 mg s to twice daily to maintain aserum theophylline concentration of 9.2 @mL (51 ymol/L). Seven days after,discontinuation of St John’ wort, her theophylhne concentration increasedto 19.6 pg/mL (109 umol/L).1331 s

B

Fugh-Berman[341 l&er Fugh-Berman and Ernst[351 and have wtitt@ &$iews on interactions between herbi and-drugs.The most common interactions between her& and drugs are summarizedin.Table 3. 1 Unexpected Presence bf a Drug in a Patient Who Never Used That Drug: Herbal Medicines Adulteiated With Western Medicines ; The adulteration of Chi$eseherbal products with Western drugs is a seriousproblem. Of 2,069 samplesytraditional Chinese medicines obtained fro? 8 hospitals in Taiwan, 23.7% contained pharmaceuticals,most commonly caffe?e, acetaminophen, indomethacin,hydroch’ iorothiazide,and prednisolone.t3’ Nonsteroidal anti-inflammatory drugs and betlzpdiazepineshave jl been found in, many CM&se medicines sold outside Asia. Theseherbs include i$&acle-Xerb, tung shuehi and Cuifong To,ukuwan.[371 Heavy x&eta1 contaminati& also was found in herbal products. Ko[~~]reported that 24 of?54 Asian patented medicines obtained fro? herbal stores iri California containedlead, 36 products contained arsenic, and’ products contained 3! ! mercury. I Nelson et a1[3ql reported a caseof aplastic anemia associatedwith the use of herbal medication in a 12-year-old boy. The authors demonstratedtde presenceof phienylbuta,zone the herbal pr&paration,,butthat medication was qot listed as an in ingredient in the packaie insert. The boy had a hemoglobin concentrationof 8 g/dL (80 g/L), a neutrophil count of 2OO/mL, and a platelet count of $OOO/mL.These hematologic abnormalities are *elated to phenylbutazonetoxicjt$.[391Lau et a1f401 reported a casein tihicp a 33-year-old patient had a serum phenytoin concentration of 48.5 pg/mL (192 @no&). The patient had a history of a seizure disorder that was managedwith 400 mg sodium valproate 3 times a day, 200.m& of carbamazepine twice a day, and 150 rni of phenobarbit& every evening. No phenytoin was given. The patient consum&d:aproprietary Chinesemedicine before admission to the hospital. The manufacturer’ information leaflets statedthatths capsulescontained s pure Chinesemedicines and were effective for controlling epiieps$.[401 Goudie and Kaye14’reported a c$se of severe l hypoglycemia in a patient (fasting glucose level, 37.8 mg/dL E2.1mmol/L]) due to use of a Chinese medi@e, ZhenQi, for diabetes.Analysis of this herbal medicine showed the presenceof glyburide, a sulfonylurea. A sulfonylqea overdosecan lead to profound hypoglycemia.[4’ ] Abnormal Laboratod, Test Results Due to Toxic Effects of Herbal Medicines Kava-Kava and Abnotimal Liver Funbtion Test Results. Kava is an herbal sedative with a purported a@mxiety or calming effect. Kava is hrepared from a South Pacific plant (Piper m&thy&cum). The main bioactive bofnpoundsinclude yangonin, desmethoxyy’ angonin, -methoxyyangonin, kavain, and dihydroxykavin.These component’Arepresent in the 11 s lipid-soluble kava extra&tor kava resin.[421 1 Kava can have additive ieffectswith central nervous system depressants. patient who was taking alprazklam (Xanax), A cimetidine, and terazosih became letharjjc and disoriented after ingesting kava.r43] .Kava lactones can &&bit cytochrome P450 activities and have a potential for itieraction with drugs that are metabolized by the liver. [441 Hea+ consumption of kava has been associated wid increasedcon&ntrations of w..OLE-Obj...= -hydroxysteroid dehydrogenas& (converts cortisol to cortisone). Therefore: concentrationsof cortisol may increase.Renin activity and aldosteroneconcentrkions in serum usually decrease. Lead Poisoning Due toiHerbs: Abnormal Laboratory Test Results. Unexpected lead poisoning may occur owing to the use of herbal medicines‘ contaminatedwith Iead.C3*l Anderson et a@1 reported a case of lead poisoning ih a 23-year-old man with a 5-day historyof devere,diffuse abdominal pain, vomiting, @d diarrhea followed by con&pation. $he laboratory investigation showed elevatedbilirubin and alanine transaminaseconcentrations,but the alkaIine phosphitase activity was normal. The urinary porphyrin screenwas positive, indicating the possibility of acute porphyria. Furthyr +vestigation showed elevatedconcentrationsof zinc protoporphyrin (145 pmol& referencerange, ~70 pmol/L) and lead (77 pg/dL [3.7 pmol/L]). The patient was taking & herb purchasedin India. After discontinbation bf the herbal medicine; his blOo$ concentrationsof Wu lead and zinc protoporphyrin were reduaed significantly. r651 et all@1reported 2 casesof lead poiso&g due to the Chinese herbal medicine Cordyckps. One patient:had a blood lead concentratiqn of 130 pg/dL (6.3 pmol/L), and &other patient had a lead concentrationof 461 pg/dL (2.2 pmtjl/L). The lead content in the Chinesemedicine was found to bk qs high as 20,000 ppm.[@I

Herbal Medicinqand

Surgery

reportdd their recomm&dation for discontinuation of herbal products before surgery. T$e American Society Ang-Lee et aI[671 of Anesthesiologistssugbestedthat patients should discontinue their herbal medicines at least 2 weeks .bt$oresurgery. Ang Lee et a1167l recommend&d garlic and ginseng should be discontinuedat least 7 days before surgery becauseboth herbs that have been reported to ag’ gravatebleeding. Ginkgo biloba should be discontinued 3 days before surgery:b&ause it inhibits

,

Monday, August 11,2003 America Online: PPSI

platelet aggregation,causing bleeding. Kava should be discontinued,at.least hours before surgery becausekava can 24 increasethe sedativeeffect of anesthetics.Ma hr.&g (epheclra)should be &continued 24 hours before surgery becausema huang increasesthe blood pressureand the heart rate. St John’ wort should be discontinued 5 days beforeisurgery. s

Misidentification

/ Labeling of herbal products may not accurately reflect the content,:andadverseevents or interactions attributed to specific herbs may be related to misidentification. of the plant.f6’ For example, a caseof neonatal androgenization~withSiberian l ginsengwas due to an unrelated speciesof Chinese silk vine.[691 More than 48 casesof nephrotoxicity attributed to fang-ji in a weight-loss preparation were due to gunng-fang-ji.[70]

.and Adult&ation

of Herbal 1i)roducts

Tsxk Effects of fierbnl Mek&ines
Many commonly used herbal medicines are toxic. The toxic effects of common herbal products are given i&r TabIe.4. Toxic effects of herbal medicinesrange from allergic reaction to cardiovascular,hepatic, renal, neurologic, and dermatologic toxic effects. Although ginseng is considered safe, the toxicity of ginseng has been reported in the literature. : Ginseng In 1979, the term ginseng abusesyndrome was coined as a result of a study of 133 people who took ginseng for 1 month. Most subjectsexperiencedcentral nervous system stimulation. The effect of ginseng on mood seemstotbe dose-dependent. At a dose of lessthan 15igfd, subjects experienceddepersonalizationand confusion, At a dose of more ihan 15 g/d, some subjectsexperienceddepression.Fourteen patients experiencedginseng abusesyndrome, which is characterizedby symptoms of hypertension,nervousness,, sleeplessness, eruption, and morning diarrhea.[“l An episode of Stevensskin Johnsonsyndromewas reported in a 27-year-old man following ingestion of ginseng.at a dose of 2 pills for 3 days. The patient recoveredafter 30 days.172] Vaginal bleeding has been reported in casesrelated to ginseng use. Interestingly, 1 patient had undergonea hysterectomy 14 years earlier.[73lThere is a casereport describing symptoms including msomnia, headache, irritability, and visual ha!lucinations when phenelzine was taken concurrently with ginseng.[74] Ginkgo Bioba ’ Ginkgo biloba is prepared from dried leaves of the ginkgo tree by organic extraction (acetone/water).It isused mainly to sharpenmental focus and to improve diabetesmellitus-related circulatory disorders.-It also is used as a remedy for impotence and vertigo. The most common adverseeffects of ginkgo are gastric disturbances,headache,and dizziness.Miwa et a1[7s] reported a caseof a 36-year-old woman who had a generalizedseiiure 4 hours after the ingestion of 70toj80 gingko nuts. One commonly reported ladverseeffect of ginkgo biloba is bleeding. Spontaneousintracerebral hemorrhage occurred in a 72year-old woman who took 50 mg of ginkgo 3 times a day for 6 months.l76lFessendenet alc7’reported a caseof l postoperativebleeding after laparoscopiocholecystectomy.One report describeda 70-year-old man with bleeding from the iris into the anterior chamber of the eye 1 week after beginning a self-prescribedregimen of a concentrate3ginkgo biloba extract in a dosageof 40 /mg twice a day;[78]His only medication was 325 mg of aspirin daily. After the spontaneousbleeding episode,he continued taking the aspirin but stopped,takingthe ginkgo product. During a 3-month follow-up period, he had no mrther bleeding episode.[7*] Echinacea The Australian Adverse Drug Reaction Advisory Committee received 1 I reports of adversereactions associatedwith echinaceabetweenJuly 1996 and September 1997. There were 3 reports of hepatitis; 3 reports of asthma;;1 report each of rash, myalgia, and nausea;1 report of urticaria; and 1 report of anaphylaxis.There are other published reports of echinacea use associatedwith contact dermatitis and anaphylaxis.17’ l Garlic Garlic is promoted for lowering cholesterol and blood pressurelevels. Garlic contains various sulfur-containing compounds, which are derived from allicin. Chopped garlic-and-oil mixes left at room temperature can result in fatal botulism food poisoning according to the FDA. Clostrfdium bottilinum bacteria are dispersedthroughout the environment but are not dangerousin the presenceof oxygen. The sporesproduce a deadly’ toxin in anaerobic, low-acid conditions. The garlic-and-oil mixture producesthat environment.[*O] Ma Huang (Ephedra-Containing Herbal Diet Pills) 1 Ma huang (ephedra)is commonly found in herbal weight-loss products that o&en are referred to as herbal fen-phen, an alternative to fenfluramine, a prescription drug that was withdrawn from the market owing to its toxic effects. Herbal fenphen products sometimescontain St John’ wart and are sold as “herbal Prozac.!’ s “Herbal ecstasy”another ephedrine-

Monday, August 11,2003 America Online: PPSI

1

containing product, chn induce a euphoric state. The FDA has strongly advised consumersnot to useiephedrine-containing . @oductsmarketed asialtemativesto street drug& Th& German &n?&l+&ti E’ contraindicated use of kphedra by patients with high blood pressure,glaucoma, or thyrotoxicosis. (-) Ephedrine 1sthe predominant alkaloid of ephedra$lants. Other phenylalanine-derivedalkaloids found are (+) pseudoephedrine, norephedrine, (+> norpseudoephed$ne,(-I-)N(-) methylephedrine,and!phenylpropanolamine.Haher and Benowitz[*‘ evaluated 140 reports of ephedrahelatedtoxic effects l that were submitted to the FDA between June 1997 and March 3 1, 1999. The authors concluded that ‘ 8% of caseswere 3 definitely related to ephedraand another 3 1% were possibly related. Of the reports, 47%involved cardiovascularproblems and 18% involved problems with the central nervous system.Hypertension was the single most frequent adversereaction, followed by palpitations, tachycardia, stroke, and seizure.Ten eventsresulted in death, and 13 event” c&sed permanent disability. The authors concluded that use of a dietary supplementthat contains ephedramay pose a sertoushealth risk.[*]l

Conclusion

:

Contrary to popular belief that natural is safe, herbal medicines can causesignificant toxic effects and eken death. St John’ s wort demonstratedsigmficant and potentially dangerousdrug interactions with several Western medicines. Several Chinese medicines such as Cha.nSu, Dan She& and ginseng can interfere with digoxin immunoassayresults. Abnormal laboratory test results can be encounteredin otherwise healthy patients who aretaking herbal products. For example, elevated liver enzyme concentrationscan‘ bbserved in people taking kava-kava. These abnormal laboratory tests in many ,c+es are a reflection of be / the toxicity of herbs. / /

Tsbles

j

Table 1. Intend&d Uses of Common Herbal Medicines
Herbal Medicine Intended Use Ginseng Tonic capable of invigorat&users physically, mentaily, and sexually; also used for dealing ‘ pith stress;used in China for more than 5,000 y : Siberian ginseng Sim,ilarto ,ginseng : : St John’ wart Treatment of mood disorders,particularly depression s Ginkgo biloba Mainly to sharpenmental focus in otherwise healthy adults and also in people with de4entia; improvement of blood flow in the brain and peripheral circulation; treatment of diabetesmellitus-related circulatory disorders, impotence, and vertigo / Kava Relief of anxiety and stress;sedative Valerian Treatment of insomnia Echinacea Immune stimulant that helps increaseresistanceto colds, influenza, and other infectionsiwound healing Saw palmetto Treatment of benign prostatic hypertrophy Relief from migraine headacheand arthritis Feverfew Garlic bo lower cholesterol levels and blood pressure;prevention of heart attack and strbke j Ginger Prevention of motion sickness,morning sickness,and nausea 3 Treatment of urinary tract infection; decreasekidney stone formation Cranberry Aloe To heal wounds, burns, skin ulcers; also used as a laxative / /I Senna Laxative To alleviate problems associatedwith menstruation and menopause : Don; quai Cat’ claw Immuno$timulant with antiviral activity; also used by people with AIDS; prevention of colds and influenza; s treatment of chronic fatigue syndrome I Hawthorn For heart failure, hypertension, and angina pectoris antineoplastic;eating uncijoked berry or root may causeserious poisoning Pokeweed 1 Antiviral and ‘

Table 2. Interference of Herba) Products in Therapeutic Drug Monitor&g
Chan Su High

of Digoxin*

Herbal Product Level of Interference Comments Chan Sd has active componentssuch as bufalin, which cross-reactwith digoxin assays,; only Bayer assayhas j no interference; monitoring free digoxm also eliminates interference Falsely elevated (APIA) or falsely:low (MEIA) digoxin level; no interference with EMIT, Moderate Dan Shen ’ Bayer, Randox, Roche, or / i Beckman assays;monitoring free digoxin eliminates interference Additive effect with digoxin;,also interferes with digoxin assay’ Uzara rodt (diuretic) Falsely elevated(FPIA) or falsely low (MEXA) digoxin level; no interference with EMIT, Moderate Siberian ginseng

Monday, August 11,2003 America Online: PPSI

j_ Bayer, Randox,Roche; or . beckman assays;monitoring f&&ligoxin #& n@ eliminate interference _. Falsely el&ated (FPIA) or falsely ldw @i&A) digoxin lev‘ no interferencewith EMIT, el; Asian ginseng Moderate / Bayer, Randox, Rothe, or I $eckman assays;monitoring free digoxin doesnot eliminate interfirence

FPIA, fluorescence polarikation immunoassay;MEIA, microparticle enzymeimmunoassay. * Bayer Diagnostics,Tar&own, NY; Roclie Diagnostics,Indianapolis,IN; Beckman Coulter, Fullerton, CA. I

Table 3. CommoniDrug-Herb’ hteractioud
Comments Herbal Product Interacting Drug Ginsengmay decrease effectivenessof warfarin / GinsengWarfaiin insomnia, and irritability ; i Phenelzine Toxic symptoms;eg,headache, Lethargy, incoherence,nausea St John’ wort Pafoxetinehydrochloride s Digoxin Decrhased AUC; peak and trough conce&ration, digoxin; may reduceeffectivenessof digoxin of Cyclosporine Lower cyclospor$e conc&tration due to increasedclearancemay causetranspImi rejection Theophylline Lower concentration, thus decreases efficacy of theophylline ) the Lower concentrationmay causetreatmentfailure in patientswith HIV : Indinavir Ginkgo biloba Aspirin Bleeding; ginkgo can inhibit PAF Warfarin Hemorrhage Thiazide Hyhertension alcohol Kava Alprazolam Additive effects with CNS depressants, Increasedeffectivenessof warfarin;‘ bleeding ; Garlic Warfsirin Increasedeffectivenessof warfarin, bleeding : Ginger Warfarin Increasedeffectivenessof warfarin; bleeding Feverfew Wkfarin Dong qu$i containscoumarin; dong quai increasesINR for w-&far& ca&$s bleeding Warfaiin Dong quai Increasedeffectivenessofwarfarin owing to r‘ educedelimination ofwarfarin Dan Shen Warfarin Warfarin Catisesdecline in INR Soy tiilk Comfrey Phenobarbial Increasedmetabolismof comfrey producing a lethal meiabolite from pyrroli$idine; severe hepatotoxic effects Phenobarbital May lower seizurethreshold,requiring dosageincrease Borage oil Evening primrose oil Phenobarbital May lower s&ure threshold,requiring dosageincre&e Spironolactone May offset the effect of SpironoIactone : Licorice Shankhapushpi PheQytoin Lower phenytoin level and loss of seizurecontrol I AUC, areaunder the cur& CNS, central nervoussystem;INR, internationalnormalizedratio; PAF, platelet-activatingfactor. /

Table-4. Potentialiy Toxic Hdrbs
Herd Toxic Effector System Affected Intended Use (Shotild Anyone Use?) Comfrby Hepatotoxic Repairing of bone and muscle; prevention of kidney stones ’ , EphedraCardiovascularHerbal weight loss / Chan Su CardiovascularTonic for heart Borageoil Hepatotoxic; hepatocail-cinogenic Sourceof essentialfatty acids; rheumatoidarthritis; hjpertension i j CalamusCarcirjogenic Psychoactive,n$ promoted in the United States Chaparral Hepatotokic; nephrotoxici:carcinogenic.Generalcleansingtonic; blood thinner; arthritis irepedy; weight loss product Pseudoald&teronism(sodium and water Treatmentof peptic ulcer; flavoring agentreten&, hypertension, Licorice heart failure)

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systemcWe@s associated dietary supplerflents with containing 24 _ * Hailer CA, Beno$tz NL. Adverse?nd cent@ fi@vousephedra alkalaids.iNEngl J Med. 2000;343:1833-1838. I 1 Reprint Address Dr Dasgupta: Dept of Pa&logy and LaboratoryMedicine,University of Texas-Houston Medical School,,6431 Fannin,MSB 2.292,Houston,TX 77036.

Review of Abnormal Laboratory Test Results and Toxic Effec& Due to Use of Herbal Medicines Amitava Dasiupta, PhD Am J Clin Path01120(1):127-137,2003. Oi2003 American Society of Clinical Pathologists, Inc. Posted 07/29/2003

Abstract and Introduction

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Abstract Herbal medicines are used widely in the United States,and,according to a recent survey, the majority of people who use herbal medicines do not inform their physmians about their use. Herbal medicines can causeabnormal kestresults and confusion in proper diagnosis. Herbal medibines can alter test results by direct interference with certain immunoassays.Drugherb interactions can result in unexpected concentrations of therapeutic drugs. For example, low conbentrationsof several drugs (eg, cyclosporine, theophylline, digoxin) can be observed in patients who initiated self-medication with St John’ wart. s Herbal medicines can alter physiology, and these changescan be reflected in abnormal test results. F&example, kava-kava can causedrug-induced hepatitis, leading to unexpected high concentrations of liver enzymes. Use of toxic herbal products such as ma huang (an ephedra-containing herbal product], Chan Su, and comfrey may cause death. Oth,ertoxic effects of herbal medicines include cardiovascular toxic effects, hematologic toxic effects, neurotoxic effects, ne@rotoxic effects, carcinogenic effects, and allergic reactions. Introduction Herbal medicines, including Chinese herbalrproducts, are readily available in the United States fi-om h&lth food stores without prescriptions. Ayurvedid medicinesjare used widely in India, and some preparations are available in the United States.Ginseng, St John’ wort, ma huang, kava, ginkgo biloba, Dan Shen,.feverfew, garlic, ginger, skw palmetto, comfrey, s pokeweed, hawthorn, dong quai, and cat’ claw are used by the general popuIation in the United States.Intended uses of s common herbal medicines are given in T&l&l. Gulla et alU1published a survey of 369 patient-escort pairs and reported tha 174 patients (47.2%) used herbs. The most Common herbal product used was ginseng (20%) followed by echinacea(19%), * ginkgo biloba (15%), and St John’ wort (14%).I’ s l Several herbal products interfere with immunoassaysused for monitoring the concentrations of therapeutic drugs. Herbal medicines also can causetoxic effects, leading to abnormal test results. Therefore, the common belief that anything natural is safe is not correct. This review summarizes abnormal test results associatedwith the use of herbal medicines, as well as interactions between Western medicines and herbal”products.This review also summarizes the toxic effects of commonly , used herbal products.

Regulatory Issues Affecting H&bal Medicines
The?JS Food and ‘ Drug administrationyFDA) mandatesthat only medicines have to be proven to be safe before being releasedinto the market. Herbal products do not fall under the category of drugs &slong as they se?@ :marketedfor the prevention of any diseases,and, as such, FDA approval is no; needed.Herbal products are classi&d as “dietary supplements” and are marketed pursuant to the Dietary SupplementX’ ealth and Education tict of 1.994.However, herbal products are regulated differently in other countries. In’ United”Kingdom; any Product not granted a license as a medical product by the the Medicines Control Agency is treated as a food, and no health claim or medical advice can &given on the label. Similarly, herbal products are sold as dietary supplements in the Netherlands. In Germany, herbal monographs are/preparedby an interdisciplinary committee (German Commission E), using historicjnformation; chemical, pharmacologic, clinical, and toxicologic studies; casereports; epidemiologic data; and unpublished manufacturers’ data. If an herb ihas an approved *. 1 monograph, it can be marketed.

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