Herbs, Hormones & Heavy

Metals
A study of CAM therapies in the
treatment of Chronic Lyme Disease
Dr Richard Horowitz
4232 Albany Post Road
Hyde Park, NY 12538
845-229-8977
Why Investigate CAM therapies for
Lyme dx and TBD’s?
• Ineffectiveness of AB’s in certain select
groups of pts
• High relapse rates among pts effectively
treated
• Side effects of antibiotics (yeast, GI,
LFT’s)
• Financial considerations: long term cost to
society for tx (Vanderhoof study$ 60-
70,000 per patient)
The History of Medicine
• 2000 BC Here, eat this root
• 1000 AD That root is heathen. Here,
say this prayer
• 1850 AD That prayer is superstition.
Here, drink this potion.
• 1940 AD That potion is snake oil.
Here, swallow this pill.
• 1985 AD That pill is ineffective.
Here, take this antibiotic.
• 2007 AD That antibiotic does not work anymore.
Here, eat this root.
What is CAM?
• New term “integrative” therapies used in
addition to standard medicine to improve the
quality of life of pts
• $47 billion/yr spent on various tx for diff.
illnesses, $5 billion/yr on herbal tx alone
1992: NIH launched OAM (Natl Ctr for
CAM)has funded 1500 clinical trials, w/ same
scientific rigor as conventional therapies
• 62% Americans use CAM therapies, including
herbs, vit’s, special diets, chiro, acupuncture,
massage, and relaxation therapies, ie Reiki,
meditation, guided imagery and yoga (Natl
Health Interview Survey conducted byl Natl
Center for Health Statistics
Efficacy & Safety of Herbal
Medicines
• Dietary Supplement Health and Education Act
1994 restricts regulation dietary suppl’s by
FDA (vit’s, min’s, herbs…)
• Clinical trials are therefore necessary to prove
that an herbal regimen is safe & efficacious
(German Commission E)
ex: PC-SPES: phase I & II studies’d PSA’s in
men with prostate Ca. NCI funded randomized
trial showed impurities (anticoagulant,
estrogens).
• Major University and Cancer centers are now
involved with CAM (Harvard, Sloan Kettering..)
Septra/Bactrim Septra/Bactrim
Quinolones Quinolones
Rifampin Rifampin
Macrolides / Ketolides Macrolides / Ketolides
Investigative Treatment Protocols for
Lyme Disease and Multiple Co-infections
Candida: Candida: Nystatin, Nystatin,
Diflucan, Acidophilus Diflucan, Acidophilus
?Leaky Gut ?Leaky Gut
?Food Allergies ?Food Allergies
?El syndrome, Heavy ?El syndrome, Heavy
metal toxicities metal toxicities
?Multiple chemical ?Multiple chemical
sensitivities sensitivities
Hormonal d/f Hormonal d/f
Therefore, drug regimens which are effective against multiple
organisms simultaneously and penetrate intracellularly and into
the CNS may be necessary to achieve significant clinical
improvement.
Immune Immune
dysregulation: dysregulation:
ANA+, HLA DR4 + ANA+, HLA DR4 +
Plaquenil Plaquenil
?Herbs / CAM tx ?Herbs / CAM tx
Tetracyclines Tetracyclines
Cleocin & Quinine Cleocin & Quinine
Mepron&Zithromax Mepron&Zithromax
Lariam Lariam
Artemesia Artemesia
Malarone Malarone
? Mycoplasma
? Chlamydia
Ehrlichia/Anapl.
Babesia
Viruses
Bartonella
Cell Wall: Cell Wall:
Penicillin / Penicillin /
Cephalosporins Cephalosporins
Cyst: Flagyl/Plaquenil Cyst: Flagyl/Plaquenil
?Neurotoxins ?Neurotoxins
?HBOT ?HBOT
?Heat Therapy ?Heat Therapy
?IV Glutathione ?IV Glutathione
Anti Anti- -Virals Virals
Borrelia burgdorferi
Chronic Lyme Disease: Differential
Diagnoses/Treatments
1. Lyme disease: cell wall, cystic, IC forms
2. Ehrlichiosis/ Anaplasmosis
3. Babesiosis/ piroplasmosis
4. Bartonellosis
5. Mycoplasma/ Chlamydial infections
6. Other TBD’s: RMSF, Typhus, Tularemia, Q-fever,
Brucellosis
7. Viruses: EBV,CMV, HHV-6 & 8, HIV, hepatitis, W. Nile
8. Immune dysfunction
9. Systemic Candidiasis/ Leaky Gut/ GI abnormalities
10. Multiple Chem Sensitivity/ Heavy Metal toxicity/ E.I. w/
mold?
Chronic Lyme Disease: Differential
Diagnoses/Treatments
11.Food allergies
12. Parasitic inf’s
13. Neurotoxins/ Brain fog
14. Sleep disorder w/ excessive daytime somnolence
15. Reactive hypoglycemia
16. Psychiatric hx/ hx drug use & addiction
17. Autonomic nervous system dys(f)
18. Endocrine & Metabolic disorders
19. Increased LFT’s
20. General deconditioning/ need for PT
All differential diagnoses needs to be considered in pts w/
persistent symptomatology!
Herbal/CAM therapies used for
Chronic Lyme Disease
• Buhner protocol (Samento, Andrographis,
Japanese knotwood..)
• Schart protocol (Diflucan/ Pen)
• Zhang protocol (TCMCoptis, HH, Circ P)
• Homeopathic protocols (Ledum, syphilitic
and malarial nosodes)
• Salt & Vit C protocol
• Rife machines
-None of these have been scientifically
validated by large controlled studies
Cowden Protocol: Background
• ILADS conference 2006: Dr Kinderlehrer
presented data on herbal therapies (Cumunda)
• ILADS preceptorship: Dr Tim Callaghan
introduced me to Dr Cowden, was using
Cumunda in his protocol
• Neutramedix contacted: sent free samples of
herbs for 30 pts to be enrolled in a 6 mo clinical
study. Subsequently over 170 pts enrolled in
one of 4 arms of study. Booklet created for our
pts to monitor compliance/ help w/ dosing
schedule.
Cowden protocol: Treatment Arms
of 6 month study
• Group 1: Full Cowden herbal protocol, no
antibiotics
• Group 2: Limited Cowden herbal protocol,
no antibiotics (Burbur, Parsley, Cumunda,
Quina, Samento)
• Group 3: Full Cowden herbal protocol, w/
antibiotics
• Group 4: Limited Cowden protocol, w/ ABs
Questions Addressed At Outset of
Study
• Is this herbal protocol safe? Efficacious?
• Effect on associated co-infections?
(Babesia, Bartonella…)
• Effect on removing heavy metal toxins?
(Algas/ Chlorella)
• Side effects?
• JH flares? If so, length, severity? Were
any of the detox herbs (Burbur, Parsley)
effective in flares?
• ? 6 months adequate to treat pts w/ CLD
Medical Issues Addressed by the
Cowden Protocol
• Bacterial infections (Lyme, co-inf’s)
Samento, Cumunda, Quina
• ToxinsMag++, Burbur, Parsley, Trace
minerals, Pinella
• Heavy MetalsAlgas, Chlorella
• Hormonal ImbalancesAdrenal support
• Mood/ Sleep disordersAmantilla, Avea
• PainCondura
Insure hydration
Optimize bowel health
(Probiotics, fiber, colon cleanses)
Detoxification
Principles
Antioxidant
Reserve
(alpha lipoic acid, diet)
Optimize
mitochondrial function
(NT factor, CoQ 10, NADH)
Minimize toxic
Exposure
(air & H2O purifiers, clean diet)
Assist &
Balance biotransformation
(NAC, Gly, B vit’s)
Why are Addressing Toxins, Heavy
Metals, and Hormones Important?
• Bb Tox 1, Quinolinic Acid, cytokines: ? role in
neurocognitive deficits
• Studies by Dr Shoemaker: VCS, use of
Actos/Questran
• Studies on Glutathione in Lyme disease
(Horowitz, LDA conference 2004)
• Studies on Heavy Metal Toxicity among Lyme
pts (Horowitz, 16
th
Intl Sci Conf on Lyme
disease, 2003)
• Issues of GH secretion, sex hormones
(testosterone), Abn DHEA/Cortisol levels, occult
thyroid disease ( ? Wilson’s syndrome)
Upregulation of Phase II Metabolic Pathways of the Liver
Glutathione
Conjugation
•Glutathione
•NAC
•Ellagic Acid
•Watercress
•Silymarin
Sulfation
•Sodium Sulfate
•MSM
•Cysteine
•Alpha Lipoic Acid
Glucuronidation
•Preventium
•Artichoke Leaf
Acetylation
•Pantothenic Acid
•Magnesium
•Vitamin B6
Methylation
•Folate
•Vitamin B12
•Vitamin B6
Amino Acid
Conjugation
•Glycine
Prostaglandins
Leukotrienes
Petroleum Distilates
Estrogen
Testosterone
Thyroxine
Cortisol
Adrenaline
Melatonin
DHEA
Bile Acids PABA
Estrogen
Fat Soluble Vitamins
Steroid Hormones
Pesticides (DDT)
Histamine
Estrogen
Mercury
Lead
Cadmium
Dopamine
Epinephrine
Modulators of Phase I Metabolic Pathways of the Liver
Cytochrome P450
Ellagic Acid Green Tea Catechins Watercress glucosinolates Silymarin
Magnitude of Exposure to
Toxins
1. Pesticides: EPA office of Prevention,
Pesticides, & Toxic substances
• 1999 > 4 billion lbs. of pesticides produced
2. EPA: 1982 National Adipose Tissue
Survey
• 100% of Americans: benzene, xylene,
toluene, styrene, dioxin, PCBs
– These are some of the most potent cancer
causing chemicals known to mankind
Magnitude of Exposure to
Toxins
3. CDC: 2003 study, 2500 subjects,
$6.5M
• 116 different pollutants (13 heavy metals,
14 combustion byproducts, 10 pesticides)
4. Environmental Working Group: Washington,
D.C.
• 167 different chemicals found
• 201 first time mothers: PBDE found in
breast milk
Magnitude of Exposure to Toxins
Magnitude of Exposure to Toxins
It’s in the AIR
• Industrial smokestacks dioxins, PCBs
• Carpets > 200 different chemicals outgas
• Pressed wood: formaldehyde
• DDT from clouds 2º spraying in Africa
– WHO: Not one animal, plant, or human can be
found without traces of DDT or its byproducts
• EPA: Study 350 NJ residents
– PCE 90%
– TCE 29%
– Benzene 90%
It’s in the Water
• Cover article of “USA Today” > 10 years ago:
Average city H
2
O > 500 chemicals
– Local spring water is more expensive than gas!
– One of the chemicals is TCE, which was found in
H
2
O in Woburn, MA where rates of leukemia
was seen in children
– BU school of medicine: TCE found in MA, OH, MN
municipal drinking water
– Many municipal water supplies had TCE levels 30-
80x EPA max allowable levels
– TCE learning disabilities, tingling & numbness,
cancer
It’s in the Food
• DDT & Dioxin: Air Soil uptake in plants
• Pesticides: Apples sprayed 14x per season
• Mercury: Fish
• Cadmium: Shellfish, milk, potatoes, leafy
green vegs
• Aluminum: Cookware, cans
• Arsenic: Pressure treated wood
– As toxicity in children Aplastic anemia, cancer
• Plastic wrap: Phtalates damage hormone
receptors
Environmental Toxins
• So these toxins are EVERYWHERE
• They SLOWLY ACCUMULATE (fat
soluble)
• They can MIMIC EVERY DISEASE
PROCESS
Toxicity Associated Symptoms &
Conditions
• Headaches
• Mineral imbalances (zn & ca)
• Kidney dysfunction
• Fertility problems
• Abnormal pregnancy outcome
• Immune system depression
• Multiple chemical sensitivities
• Fibromyalgia
• Recurrent yeast infections
• Tinnitus
• Contact dermatitis
• Learning disorders
• Cancer
• Panic attacks
• Memory loss
• Parkinson’s disease
• Broad mood swings
• Fatigue
• Chronic fatigue syndrome
• Muscle weakness
• Unusual response to meds or
supplements
• Increasing sensitivity to
exogenous exposures: odors,
medications, etc.
• Worsening of symptoms after
anesthesia or pregnancy
Toxic Metals
1. Ubiquitous in the environment
2. Accumulates slowly, and toxicity is
unexpected unless there is acute poisoning
3. They can cause any symptom such as
fatigue, muscle and joint pains, headaches,
paresthesias, memory loss, confusion,
psychiatric abnormalities
• Same symptoms seen in chronic Lyme
Disease patients
4. Escapes recognition since regular testing is
not generally performed
OVERLAPPING SX OF HEAVY METALS AND TBD’S
SYMPTOMS HEAVY METALS LD/CO-INFX
Fatigue
FMS sx
Joint pain
Paresthesias
Cognitive d/f
Ataxia /
Incoordination

Abd sx
Urinary sx
Visual sx
Auditory sx
Psych sx
Popular News
05/29/03 - 4:15 pm Video Available
Testing Our Air For Mercury
A new National Wildlife Federation report shows the rain falling from Texas skies
contains levels of mercury that far exceed what the Environmental Protection
Agency considers safe for people and wildlife.
More than 98 percent of the rain samples exceeded the EPA's standard.
Mercury is a neuro-toxin that contaminates fish and poses a health risk to people
and wildlife that eat them.
For the full report, check out the National Wildlife Federation's Web site.
By the Numbers - New York
•The highest mercury level measured in New York rain (29.9 ng/L) was 8.5 times the EPA human health
standard for mercury in lakes
•84% of the rain samples in New York exceeded the EPA human health standard for mercury in lakes
•The average rain sample collected in New York was nearly two times the EPA’s human health standard
for mercury in lakes
MERCURY
Sources Biochemistry Clinical Symptoms
- Mining and
Chemical
Industries
- Fish/Shellfish
- Dental work and
medical
treatment
(thimerasol)
-SH binding
-Oxidative stress
-Penetrates nerves and
binds to cysteines on
Ach receptors resulting
in neurologic
dysfunction.
-retrograde axonal
transport
-Denervation of nerve
fibers similar to the
pathology of
MS, and Hg can leak into
the BBB and reduce
nerve conduction
velocity and VEP
-CFS, FMS, joint pain
-metallic taste,
changes in vision &
hearing
-tremors, ataxia
-cognitive
dysfunction,
depression,
irritability
-renal and GI
disturbances
-weight loss
-increased
susceptibility to
infections
-peripheral
neuropathy
-autoimmunity
LEAD
Sources Biochemistry Clinical Symptoms
-Drinking water
-Dinnerware with
lead glazing
-Paint products
-Soil around older
homes painted
with lead based
paints are still
contaminated
with lead
-SH binding
-Alters calcium-mediated
cellular processes
-Reduces nerve
conduction velocity in
peripheral nerves
-Interferes in the heme
biosynthetic pathway
leading to anemia
-Fatigue
-Encephalopathy
with impaired
concentration, short-
term memory
deficits, insomnia,
anxiety, depression,
irritability, decreased
IQ
-Elevated BP,
chronic renal failure,
anemia
- Abd colic,
peripheral nerve
dysfunction,
reproductive
dysfunction
Arsenic and Old Lace
ARSENIC
Sources Biochemistry Clinical Symptoms
Inorganic / Toxic
-Wood
-Pesticides
-Cigarette smoke
Organic / Non-
toxic
-Seafood
*Consumption of
seafood before a
DMSA urine
challenge may
result in urinary
As; clinically
misleading
-Tightly binds
dihydrolipoic acid,
inhibits pyruvate
Acetyl CoA, 1
st
step in
Krebs cycle
-Competes with PO
4
for
binding to ATP lower
energy ADP
-Binds SH groups of
tissue proteins
-Multiple cardiac,
vascular, and
neurologic sx (i.e.
peripheral
neuropathy and
paresthesias)
-Aplastic anemia
-Cancer
CADMIUM
Sources Biochemistry Clinical Symptoms
-Cigarette smoke
-Industrial
pollution:
Zn & Pb smelting,
electroplating,
rechargeable
batteries, paint
Pigments
-Food: major
sources
are green leafy
vegs, potatoes,
liver, milk,
shellfish.
-Competes with Zn at
cellular binding sites
loss of enzyme activity
-Target organs is 1
kidneys and liver, also
lungs 2
-Renal dysfunction
w/ proteinuria /
aminoaciduria (loss
of amino acids
chronic fatigue,
toxic brain
syndrome
-Emphysema
-HTN/vascular dz
-Osteopenia
-Prostate Cancer
ALUMINUM
Sources Biochemistry
Clinical
Symptoms
-Cookware
-Antiperspir’s
-Antacids
-Aluminum
cans
-Hemodialysis
-Potent neurotoxin
-Associated with
increased
neurofibrillary
tangles and brain
degeneration
-Known to
accumulated in
neurons in pts with
ALS and
Parkinson’s
-Encephalopathy
-Abnl speech
-Myoclonic jerks
WHAT IS DMSA?
• DMSA (meso-2,3-dimercaptosuccinic
acid) is an FDA approved chelating
agent that mobilizes heavy metals.
– Chen, S. et al, Persistent effect of in utero meso-2,3-
dimercaptosuccinic acid (DMSA) on immune function
and lead-induced immunotoxicity. Toxicology. 132(1),
67-69, 1999.
– Miller, A.L. Dimercaptosuccinic acid (DMSA), a non-
toxic, water-soluble treatment for heavy metal toxicity.
Altern Med Rev. 3(3), 199-207, 1998.
DMSA
• Heavy metals accumulate x years leaves
the blood no longer measurable there
start compartmentalizing.
• DMSA diffuses into and effectively competes
with tissue binding sites releases metals
from sequestered sites in tissues.
• Rationale for provocation test w/ chelating
agent
– Toxic metals accumulate in non-exchange pools in
specific tissues.
– DMSA disturbs the body stores of toxic metals &
binds to them, so a certain quantity will redistribute
into the blood as a stable complex eliminated in
the urine
LABORATORY MEASUREMENTS OF
THE HEAVY METALS
• 2 separate laboratories were used to ensure reliability
and concordance of results:
1. Metametrix
• Strict quality assurance and proficiency test
programs including NYS DOH, Centre de
Toxicologie de Quebec.
• CLIA certified
• NYS licensed
2. Doctor’s Data
• QA / proficiency test programs including NYS
DOH, Centre de Toxicologie de Quebec.
• CLIA certified
• CAP certified
LABORATORY MEASUREMENTS OF
THE HEAVY METALS
• Inductively coupled plasma / mass spectrometry (ICP-
MS)
– Elements are identified according to mass and
quantified based upon a comparison of the intensity
of each mass to known standards and controls
• Quality Control
– Blanks & Duplicates
– Certified controls & Calibration standards
– Double blind studies
– Participation in external performance evaluation
programs (CLIA, CAP, NYSDOH, etc)
Patient 1: Normal blood Hg
Patient 1: Urine heavy metals post provocation w/
DMSA: Hg, Pb, As, Cd
RESULTS
• 43 Patients tested by Metametrix: 41% showed
evidence of elevated levels of heavy metals
– As (3%), Cd (9%), Hg (29%), Al (47%), Bo
(18%), & Pb (21%).
• 50 Patients test by Doctor’s Data: 58% showed
evidence of elevated levels of heavy metals.
– As (8%), Cd (0%), Hg (52%), Al (2%), Bo (not
tested), & Pb (8%)
• Combined results from both labs: 56% showed
evidence of elevated levels of heavy metals
(2003). This was w/ 24 hr provoked urine chal.
• 2007: > 2000 pts tested thru DD> 95% test +
for at least one heavy metal in elevated range w/
6 hr urine DMSA challenge
Importance of Detoxifying Heavy
Metals
• 15-20 % of CLD pts improve sx of fatigue,
myalgias, arthralgias, and neuro-cognitive sx
with detoxification of heavy metals
• Heavy metals impact immune (f), ie Hg, and may
interfere w/ long term tx results
• oxidative stress w/ heavy metalsdamage
cell membranes (?mitochondria)
• ? Responsible for AI overlap in certain CLD pts
• Heavy metal burden may lead to mineral
deficiencies (Mag++, Zn), ? Effect on immune
(f), oxidative stress, and inflammatory cytokines
Effect of Mineral Deficiencies on
Biochemical (f)
• Mag++ Nec in appx 300 detox enzymes in the body.
Deficiency results in muscle spasm, tremors, anxiety,
Raynauds phen, arrhythmias,
• Cu+SOD (free radicals), polyphenol oxidase (detox
chem’s), tyrosinase & dopa oxidase (neurotransmitters),
Cytochrome C oxidase (energy)
• Zn++ Nec in > 90 enzymes (alcohol dehydrogenase,
Phase I rxn, converts alcoholsaldehydes. If low,
biochem bottleneck, with shift to chloral hydrate and
toxic brain symptoms)
-Older pts gen have signif lower level of plasma Zn,
levels of inflammatory cytokines and IL 10, and plasma
oxidative stress. Compared to the placebo gp, Zn
supplemented gp had incidence of infections, TNF-,
& plasma oxidative stress markers (NIH funded study)
Am J Clin Nutr 2007; 85: 837-844
Detoxification/Chelation/Nutritional
Supplementation
• Detoxification: Skin (saunas), Colon (probiotics,
fiber, cleanses), Kidneys (fluids), liver ( vit’s, min’s,
herbs to phase I & II detox pathways)
• Chelation : 6 hr urine DMSA challenge, then using
oral (DMSA, DEPEN..), rectal (EDTA), transdermal
(DMPS, GSH), or IV (DMPS, EDTA) to remove
heavy metals, replacing minerals
• Nutritional Supplementation : Focus on using NAC,
Glycine, DIM, Sulforaphane glucosinalate, Med
Caps DPO, lipoic acid, MTV w/ min’s (Mag++,
Zn+..)
Hormonal Problems Among Lyme
Patients
• Hypothalamic-pituitary axis may be affected
check FSH, LH, GH and IGF1, TSH & ACTH
levels
• Impt to test full TFT’s (new range TSH 0.5-2.5; 1
or less may be necessary for significant clinical
improvement) with thyroid AB’s, DHEA/Cortisol
levels, sex hormones.
• “Normal” ranges may not be applicable
• ? Xenoestrogens/toxins blocking receptor
sitescertain pts need to have hormone levels
at the higher range of “normal” to have clinical
improvement
Hormonal Problems Among Lyme
Patients : Adrenal Fatigue
• Adrenal fatigue: A spectrum disorder in between
Addison’s and Cushing’s disease
• Etiology: Any form of chronic stress (physical,
emotional, psychological, environmental,
infectious, in combination)
• Symptoms: fatigue, non-regenerative sleep, salt
craving, hypoglycemia, libido,
low BP/ postural hypotension,
depression/irritability, memory/focus, time to
recover from illness, injury, or trauma
• Associated Diseases: CFS, Fibromyalgia,
alcoholism, RA, Chronic allergies/asthma
Laboratory Testing for Adrenal
Fatigue
• Problems w/ blood testing: population
used to standardize the tests may have
included many people w/ some level of
adrenal fatigue, & lab tests are defined &
standardized based on statistical norms,
not physiologically optimal norms
• 24 hr urinary cortisol testif levels are in
the bottom 1/3 of “Normal” range, suspect
adrenal (f)
• Blood tests: do not measure tissue levels
• ACTH Challenge: + if cortisol levels < 2x
DHEA/Cortisol Salivary testing
• Aeron labs: California
• Metametrix laboratory: Georgia
• Genova diagnostics (Great Smokies)
• Diagnostek labs
4 x per day saliva test : 8am, noon, 4pm,
10 pm
• Measures tissue levels hormones
Case Presentation #1
• 48 yo W/F, PMH signif for Lyme dx (EM rash),
depression, & allergic rhinitis.
• Sx started 2001 w/ fatigue, migratory myalgias
& arthralgias, paresthesias, nt sweats, chills &
flushing, HA’s, insomnia & cognitive difficulties
• PE unremarkable except for sl cervical LN’s
• Labs: signif for Lyme W Blot IgM +, low “N” B12
level at 362, ESR, B pertussis IgG +. All other
labs WNL (AI markers, ANA 1:80 negative,
hormonal eval w/ free T3 1x, then to normal
• Clinical course: rotated through multiple courses
of AB’s x appx 1 yr w/out significant benefit
Case Presentation #1
• Patient was started on Licorice extract,
Adrenal essence ( Vit B6, pantothenic
acid, PABA, Cordyceps, Ginsenosides,&
Rhodiola) which are herbs/vit’s designed
to support the stress response & adrenal
hormone production, Adrenal complex
(adrenal glandular extract), and low dose
Cortef which was slowly to 5 mg PO BID
• Clinical course: 1
st
time pt reported signif
energy, jt pain & sleep, 40% 60%
Normal (f)
Case Presentation # 2
• 10 yo W/M PMH signif for Lyme dx w/ + Lyme
IFA, IgG W Blot +, Lyme Dot Blot +.
• Sx started in 2
nd
& 3
rd
grade w/ reading prob’s,
diff retaining info, temper tantrums. Sx
progressed to fatigue, myalgias, arthralgias,
neck stiffness, HA’s, chills/ hot-cold feelings,
paresthesias extremities, palpit’s, insomnia, &
cognitive diff’s
• PE unremarkable. Further testing revealed +
Bartonella PCR
• Clinical course: rotated thru diff AB’s. Signif
improvement w/ high dose Amox, Prob, Biaxin &
Mepron. Energy was not consistent however.
Had problem w/ stamina, and fatigue post-
prandially
Case Presentation # 2
• Pt plateaud after being on AB’s (98 % N),
AB’s DC’d, given Diflucan to clear out for
yeast, & was instructed to follow
hypoglycemic diet. 2 mo’s later, all sx
returned w/ fatigue, aches & pains,
memory/concentration. AB’s restarted, all
sx again improved
• Ordered heavy metal testing to address
resistant/relapsing sx
Case Presentation # 2
• Pt started on IV Rocephin 2g/d w/ Actigall,
Zithro, pulse Tindamax for ongoing resistant
cognitive problems. Sent for neuropsych eval. IV
glutathione 1 g 3x/wk started w/ oral chelation w/
low dose DMSA (100 mg Chemet TID on
weekends, slowly to 300 mg TID before meals)
• Pt w/ good clinical improvement, energy,
cognitive improvement, jt pain. Concentration
signif better days on IV glutathione. Finished 4
mo IV therapy, then plateaud again w/ sx
• Patient sent off DHEA/Cortisol saliva testing to
evaluate for adrenal fatigue causing resistant sx
Case Presentation # 2
• Pt added licorice extract, vit/herbal supplement
w/ B vit’s, PABA, Cordyceps, & Rhodiola, and
Cortef was started low dose (2.5 mg am, to 5
mg am, 5mg BID, eventually to 10mg am/ 5mg
pm based on clinical response)
• Strong + clinical improvement w/ energy.
Cortef was gradually and DC’d over sev mo’s,
all sx again, Cortef was again restarted,
stabilized at 5 mg/ am. S
• School grades signif improved, dyslexia. Also
started on cognitive remediation (Dr Shea)
• Rotated onto EDTA suppositories for Pb
• 4/07 : 2 mo sx free. Started on limited Cowden
protocol. 6/07 still sx free. Able to participate in
sports (wrestling), finished school w/out problem
Medical Issues Addressed by the
Cowden Protocol
• Bacterial infections (Lyme, co-inf’s)
Samento, Cumunda, Quina
• ToxinsMag++, Burbur, Parsley, Trace
minerals, Pinella
• Heavy MetalsAlgas, Chlorella
• Hormonal ImbalancesAdrenal support
• Mood/ Sleep disordersAmantilla, Avea
• PainCondura
Cowden protocol results
Full Cowden protocol/ No Antibiotics
• Overall response to treatment : There was a
1.32 mean improvement on overall symptoms (mild-mod
improvement), with the median at 2 (moderate
improvement) N=50 pts
(Scoring -3 signif worse, +3 =signif better)
• Patients also reported a 20% mean improvement in
overall sx, 30-40% median improvement using a scoring
scale of 0-100% after 6 months of treatment
• 30% (15/50) had no help, or were sl. worse
• 70% (35/50) had moderate improvement
• Side effects/ JH rxns: 30/50 (60%) had JH rxns, and only
30% improved with the use of Burbur & or Parsley
Cowden protocol results
Limited Cowden protocol, No AB’s
• Overall response to treatment : 23 patients/ average 3-4
months on herbal protocol
• Mean improvement in sx: 1.17 (slight improvement)
• Median improvement in sx: 2 (moderate improvement)
• 16/23 (70%) had moderate improvement
• 7/23 (30%) had no improvement or worsening of
symptoms
• 11/23 experienced Jarish-Herxheimer flares (48%) and
there were no consistent results found w/ the use of
Burbur &/or Parsley
• Comparable results of limited & Full protocol early on,
need to have similar sample size (50) at 6 months to
draw definitive conclusions
Cowden protocol results
Full Cowden protocol w/ Antibiotics
• Overall response to treatment : The mean
response to treatment was .78 (slightly better),
and the median response to treatment was 1 (sl.
better), but only 7/50 pts responded on the
questionnaire, and did not finish 6 months of
combined therapy.
• Can not draw any significant conclusions at this
point in time regarding the use of the herbal
therapy in combination w/ antibiotics
Cowden protocol results
Limited Cowden protocol w/ AB’s
• Overall response to treatment : N=24, average
2-3 months of treatment
• Patients reported a mean response to treatment
of .83 and median response of 1 (mild
improvement)
• Patients also reported a mean improvement of
5.75%, and median improvement of 9.5% (scale
of 0-100%) after 2-3 months of therapy
• Can not draw any significant conclusions at this
point in time due to patients not completing 6
months of the protocol, and N=24
Conclusions
• Full herbal protocol without AB’s showed a moderate
improvement in sx in 70% pts
• Side effects included: JH reactions in up to 60 % pts at
some pt during the study. Several pts reported nausea,
loose stools, rash. The Cumunda &/or Quina and
Samento dosage had to be ’d or temporarily stopped for
JH rxns and slowly increased back to the normal dosage
• Banderol was substituted for sev pts w/ ongoing JH rnxs
• Efficacy of Burbur & Parsley for JH rnxs was variable
• No abN lab results were reported (CBC, CMP w/ LFT’s)
• No effect of herbs on Babesiosis. Mepron & macrolide,
Malarone, Lariam +/or Artemesia was nec to effect
clinical improvements in this gp of pts
Conclusions
• Heavy metal testing was performed on several
patients after using Algas and Chlorella for 6
months. Results are pending, ? Efficacy
• Amantilla (Valerian) was helpful in a subset of
patients w/ overlapping anxiety disorders, and
was helpful w/ sleep at higher dosages (30
drops HS)
• Avea and Condura were not regularly used, so
no conclusions can be reached regarding their
efficacy w/ depression & pain
Patient #1 Pre/Post DMSA Urine Challenge
after 6 mo Cowden Protocol
Patient #1 Pre/Post DMSA Urine Challenge
after 6 mo Cowden Protocol
Patient #2 Pre/Post DMSA Urine Challenge
after 6 mo Cowden Protocol
Patient #2 Pre/Post DMSA Urine Challenge
after 6 mo Cowden Protocol
Patient #3 Pre/Post DMSA Urine Challenge
after 6 mo Cowden Protocol
Patient #3 Pre/Post DMSA Urine Challenge
after 6 mo Cowden Protocol
Conclusions
• Chronic Lyme disease is a symptom complex of
multiple co-inf’s. Differential diagnoses discussed
earlier in the talk (20) should be considered in all
pts failing therapy
• Antibiotic tx at HVHAC includes addressing cell
wall, cystic, and IC forms simultaneously (occ w/
double IC regimen if Bartonella +, M. fermentans
PCR +) where AB’s are combined to address
Lyme & co-inf’s concurrently
• Lyme pts freq test + for heavy metal toxin
exposure. Appx 15-20% improve clinically w/ oral
chelation (DMSA, D-PEN, lipoic acid, Vit C)
• Lyme pts freq test + for adrenal dysfunction. Appx
1/3 improve w/ adrenal supplements and/or Cortef
(hydrocortisone)
Conclusions
• IV GSH has been shown to be effective in a
subset of resistant Lyme patients, implying a
need to include a detoxification regime in the
treatment plan. Detox protocols would include
Mag++, NAC, GLY, lipoic acid, DIM,
sulforaphane glucosinalate, diet w prot, crucif
veg’s
• IV GSH also addresses heavy metal burden, but
it is unclear which chem’s/toxins are being
removed w/ treatment. Since GSH may have an
effect within min’s in select pts to improve CNS
(f), is there an effect on removing inflamm
cytokines & Quinolinic acid?
Cytokine Inhibition for Treatment of
Alzheimer’s Disease
• Open label trial of TNF- inhibitor (etanercept)
for the tx of AD. 25-50 mg etanercept given by
extrathecal injection into a cervical spine
interspinous space weekly x 6mo.
• Results: Signif improvement in sev cognitive &
functional assessment (MMSE, ADAS-Cog,
Severe Impairment Battery). Improvements
began at 1 mo, were sustained for 6 mo duration
of the trial
Tobrinick E, et al. TNF- modulation for treatment
of Alzheimer’s Disease: A 6 mo pilot study. Med
GenMed. 2006;8(2)
Role of Inflammatory Mediators in
Neurotoxicity
• Inflamm processes are involved in the neurotoxicity of
AD. Microglia are activated by B amyloid & proinflamm
cytokines. Activated microglia in turn release proinflamm
cytokines (IL-1-, IL-6, TNF-) that may lead to neuronal
death and dys(f) by a variety of mechanisms, including:
1) Enhancement of glutamate-induced excitotoxicity
2) Inhibition of long term potentiation, which limits (f)
plasticity after neuronal injury
3) Inhibition of hippocampal neurogenesis
Recent studies have reported TNF- levels in the CSF
of AD pts, and a single nucleotide polymorphism in the
TNF- gene is associated w/ earlier onset AD
Lyme dx pts are known to have levels of IL-1, 6, & TNF-
. ? Role of these proinflamm cytokines w/ CNS LD
& ? Role of Actos to modulate levels of TNF-
Role of Inflammatory Mediators
and NO/ONOO Cycle in Illness
• A Common Etiologic Mechanism for CFS,
MCS, FM, PTSD and ?CLD : Dr Martin
Pall, Professor of Biochemistry and Basic
Medical Sciences, Wash State Univ.
• Above illnesses share many sx in common
• Illnesses can be initiated by a variety of
factors (viral, bacterial, physical or emot
trauma, exposure to VOS’s , pesticides…)
• These diverse stressors can all NO, and
several can NMDA receptor activity &
NO & its oxidant product peroxynitrite
Role of Inflammatory Mediators
and NO/ONOO Cycle in Illness
• NO peroxynitrite oxidative stress
stimulates NF-B production of
iNOS (nitric oxide synthetase) NO in a
vicious cycle
• NF-B IL-1, IL-6, IL-8, TNF-, IFN
which may contribute to symptoms and
signs of these varied illnesses
• Therapy should focus on down-regulation
of NO/ONOO cycle biochemistry
(Antioxidants, CoQ10, B vit’s, -lipoic acid,
Mag++, Zn++, omega 3 FA’s, glutathione
precursors, tetracyclines…)
Role of Endogenous Exotoxins
• Quinolinic Acid (Quin) is a neurotoxic metabolite
of the L-tryptophan-kynurenine pathway that
activates the NMDA receptor class of excitatory
AA receptors to produce excitotoxic lesions.
Lyme dx pts have been shown to have levels
of Quinolinic acid. ? Role in CNS dx ?Role for IV
GSH & antioxidant therapies
1) -Oxidative stress as a mechanism for quinolinic acid-induced
hippocampal damage: protection by melatonin and deprenyl
W.M.H. Behan, et al. British Jnl Pharm (1999) 128, 1754-1760
2) -Enhanced neuronal damage by co-administration of quinolinic acid
and free radicals, and protection by adenosine A2A receptor
antagonists W.M.H Behan et al. British Jnl Pharm (2002) 35, 1435-1442
3) -Neuroprotective effects of the mGlu5R antagonist MPEP towards
quinolinic acid-induced striatal toxicity: involvement of pre- and
post-synaptic mechanisms and lack of direct NMDA blocking
activity. Popoli et al. Jnl of Neurochemistry 2004, 89, 1479-1489
4) -Quinolinic Acid Is Extruded from the Brain by a Probenecid-
Sensitive Carrier System: A Quantitative Analysis. Morrison et al, Jnl of
Neurochemistry 1999, 72, 2135-2144
Conclusions
• Cowden herbal protocol w/ hormonal support & heavy
metal detoxification may effect an improvement in a
significant # of CLD pts
• Once pts have achieved a significant level of
improvement with AB’s, it may be reasonable in certain
subsets of pts to rotate them solely onto an herbal
protocol w/ proper diet, exercise, & stress reduction
programs in place
• Herbs (Samento, Cumunda, Quina, Burbur, Parsley)
may also be added to any AB regimen, instead of
doses of prior AB’s or adding a new AB. This should be
considered in pts w/ GI intolerance to higher doses of
AB’s or who have failed prior combination therapies
• Babesiosis is not effectively treated w/ this protocol
• Down regulation of NO/ONOO cycle & inflamm
cytokines should be investigated as a potential
mechanism to help CLD pts +/- neurological sx
Intravenous Glutathione: A Novel Approach for Treating Resistant Symptoms in Chronic
Lyme Disease
Background:
Chronic Lyme Disease must be seen in the light of multiple tick borne diseases, including HME,
HGE, Babesiosis, Mycoplasma infections, and Bartonella henselae. The mechanisms
responsible for ongoing symptoms have been hypothesized to be secondary to persistent
Borrelial infection, occult and/or resistant co-infections, autoimmune mechanisms, and/or other
neurotoxins.
Among known toxins, heavy metals such as mercury and lead have been found in Lyme
disease patients with a small percentage of patients (10-15%) reporting improvement in
resistant symptoms (fatigue, joint aches, cognitive dysfunction) with removal of the
corresponding heavy metals (Horowitz, Abstract 16th International Lyme Conference, June
2003).
A novel approach to remove toxins from the body involves Glutathione (GSH) (Perlmutter,
2000). GSH is an endogenous peptide made in the liver, which plays an important role in
various metabolic functions including its role as an antioxidant and in Phase II liver detoxification
of various chemicals. A trial of GSH was therefore undertaken to determine its role in patients
with Lyme Disease with chronic resistant symptoms. Patients signed a consent form prior to
treatment discussing risks, benefits, and alternatives. Glutathione has shown to be a safe
treatment in other clinical trials (Usberti M. et. al. Effects of a vitamin E-bonded membrane and
of glutathione on anemia and erythropoietin requirements in hemodialysis patients. Journal of
Nephrology. 15(5):558-64, 2002 Sep-Oct.; Cascinu S Neuroprotective effect of reduced
glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized,
double-blind, placebo-controlled trial. Journal of Clinical Oncology. 20(16):3478-83, 2002 Aug
15.)
Method:
118 patients with Lyme Disease were given IV GSH over a 5-10 minute period. 80
patients were given 1000mg of GSH and 38 patients were given 2000mg of GSH. The
GSH was stored in a refrigerator and protected from direct light until patient
administration. Patients’ symptoms scores before and after treatment with GSH (0-
100% self reported scale) were recorded after a 30-minute interval.
Results:
Among 80 patients given 1000mg GSH, 36% (29/80) had no clinical improvement (0%
improvement on self-reported scale), 40% (32/80) had a mild clinical improvement (1 to
10% improvement), 6% (5/80) had moderate clinical improvement (11 to 20%
improvement), and 18% (14/80) had marked clinical improvement (21 to 60%
improvement in clinical symptom scores). Mean improvement in symptoms after 30
minutes of 1000mg of GSH administration was 9%.
Among 37 patients given 2000mg of GSH, 27% (10/37) had no clinical improvement,
46% (17/37) had mild clinical improvement, 16% (6/37) had moderate clinical
improvement, and 11% (4/37) had marked clinical improvement. Mean improvement in
symptoms after 30 minutes of 2000mg of IV GSH was 9.5%.
Improvements from a single dose of IV GSH lasted from several hours to 2-3 days
before patients experienced a relapse in symptoms. There were no significant adverse
effects from GSH except for transient nausea & rare pressure like feelings and
paresthesias. One patient had a vagal event with needle insertion (before GSH
administration) and 2 patients experienced a flare up of Lyme symptoms after injection,
which subsequently resolved.
Intravenous Glutathione: A Novel Approach for Treating Resistant Symptoms in
Chronic Lyme Disease
Results: (cont’d)
There were also 8 chronic Lyme Disease patients who underwent
a 1-2 month GSH trial, with doses ranging from 400mg IV 3x/wk to
2000mg per day. These patients generally comprised a group of
difficult to treat “non-responders”. There were no adverse side
effects from longer-term use of GSH. Among that group, 1 patient
out of 8 had no clinical response, and the other 7 patients had
sustained positive clinical improvements ranging from 10% to
35%, with a mean improvement of 20%. These patients reported
consistent improvements in cognitive functioning, energy,
headaches, muscle strength, muscle pain, and joint pain.R
Discussion:
Patients who experienced the most significant benefit from Glutathione were often
patients who had failed multiple antibiotic regimens in the past and were considered
treatment resistant. Several patients who had significant neurologic dysfunction with
dysarthria, incoordination, and muscle weakness experienced a rapid and dramatic
improvement in symptoms with a single dose of IV GSH.
Metabolic functions of GSH include DNA synthesis and repair, protein synthesis,
prostaglandin synthesis, amino acid transport, enzyme activation, prevention of oxidative
cell damage, enhancement of immune system function, and metabolism of toxins and
carcinogens (Annals of Pharmacotherapy: Glutathione in Health & Disease:
pharmacotherapeutic issues:1995 Dec., Vol. 29, 1263-1273). Since patients reported
improvement in fatigue, joint pain, muscle pain, mood swings, headaches, balance,
dizziness, speech problems, and cognitive difficulties within 30 minutes of
administration, GSH may be acting to metabolize toxins in the short term, and may have
an effect on prostaglandins, interleukins, oxidative stress & immune modulation in the
long term. Alternatively, the rapid initial improvement in symptoms may be a placebo
response due to the novelty of trying a new treatment approach; however, the sustained
response among patients given longer term treatments suggests that something other or
in addition to a placebo response is in effect.
Although this clinical report suggests that IV GSH may be useful to patients with
symptoms that persist after antibiotic treatment, only a placebo-controlled trial can
determine efficacy. The optimal dose, duration of therapy, and exact mechanism of IV
GSH remains to be elucidated.
Dr. Richard I. Horowitz
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