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07 Gallagher Glutathione
07 Gallagher Glutathione
American Academy of Anti Aging Medicine
Manalapan, Florida
Martin Gallagher, MD, DC, MS, ABOIM
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• Know the functions of Glutathione
• Understand the importance of Glutathione in
Detoxification
• Become familiar with the routes of
administration of Glutathione
Objectives • Understand the IV dosing for various medical
conditions
• Learn established protocols for safe
administration of Glutathione
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• Glutathione is primarily synthesized in the
liver
• It is involved in DNA synthesis and repair,
protein and prostaglandin synthesis,
Glutathione amino acid transport, metabolism of
toxins and carcinogens, immune system
Synthesis function, prevention of oxidative cell
damage, and enzyme activation
• Cellular glutathione levels increase during
exercise
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Glutathione: What is it?
Same concentration
Tri‐Peptide: Found in high
within the cell as
Cysteine, glycine, concentrations in
Potassium, Glucose
glutamic acid almost every cell
and Cholesterol
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Glutathione
• Primary cellular defense against free radicals.
• Functions both as an antioxidant (in the form of glutathione
peroxidase) and as a detoxifying agent for many xenobiotics.
• Most effective way of increasing levels is IV
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Neuroprotective effects: Glutathione is
synthesized by neurons and glial cells.
In laboratory research, it has been
Glutathione suggested that glutathione protects
synthesis in Brain against toxins by acting as an antioxidant.
Glutathione is also known to modify
protein sulfhydryl groups associated with
toxins, perhaps increasing the excretion of
these compounds from the cell
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GLUTATHIONE
Protection from:
• Oxidative Stress
• Mercury & Toxic metals
• Alcohol
• Persistent Organic Pollutants (POP)
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GLUTATHIONE
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Glutathione (po) and Disease
• Orally, glutathione is used for treating cataracts, glaucoma,
preventing aging, treating or preventing alcoholism, asthma,
cancer, heart disease (atherosclerosis and
hypercholesterolemia), hepatitis, liver disease, diseases that
cause immunosuppression (including AIDS and chronic fatigue
syndrome), memory loss, Alzheimer's disease, osteoarthritis,
Parkinson's disease, and detoxifying metal and drugs.
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• Glutathione exists in both reduced
(GSH) and oxidized (GSSH) states
• It is one of the major endogenous
antioxidants produced by the cells
GLUTATHIONE • Neutralization of free radicals and
reactive oxygen compounds
• Maintains exogenous antioxidants
such as vitamins C and E in their
reduced (active) forms
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Inhaled and IM Glutathione
Inhaled glutathione (INHG) is
Intramuscular Glutathione (IM)
used for treating lung diseases,
is used for preventing toxicity of
including idiopathic pulmonary
chemotherapy and for treating
fibrosis, cystic fibrosis, COPD,
male infertility.
asthma, and lung disease in
individuals with HIV disease.
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IV Glutathione is used for preventing anemia in
patients undergoing hemodialysis, preventing
renal dysfunction after coronary bypass surgery,
IV treating Parkinson's disease, improving blood
Glutathione and flow and decreasing clotting in individuals with
atherosclerosis, treating diabetes, and
Disease preventing toxicity of chemotherapy.
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Sulphur
compounds may
react with patients
Excellent Safety
with
Profile
hypersensitivity or
Glutathione reactive airway
disease (RAD)
Safety & Routes
of ASTHMA: Inhaled
Administration (nebulized)
glutathione can
Routes include:
cause
PO, IV, Inhaled
bronchospasm in
individuals with
asthma
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Chemotherapy toxicity: As a chemotherapy
adjunct, 1.5 to 3 grams/m² administered over a
15‐20 minutes immediately prior to chemotherapy
Glutathione
IV, IM with Chemo Also, glutathione 1.5 grams/m2 administered
over 15 minutes prior to cisplatin plus glutathione
600 mg intramuscularly on days 2 to 5, has been
used
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Glutathione, Drugs and Alcohol
ASTHMA: Inhaled
Acetaminophen and
(nebulized) glutathione
ETOH may decrease
can cause
the therapeutic effects
bronchospasm in
of Glutathione
individuals with asthma
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• Glutathione deficiency is associated
with aging, age‐related macular
Glutathione degeneration (AMD), diabetes, lung
and gastrointestinal disease, pre‐
Deficiency disorders eclampsia, Parkinson's disease and
other neurodegenerative disorders,
and poor prognosis in AIDS).
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• Anti‐cancer effects: Preliminary
evidence suggests that glutathione
intake from fruits and vegetables might
be associated with a reduced risk of
pharyngeal cancer
Glutathione Antioxidant effects: The clinical effects
Effects of glutathione are thought to be related
to its antioxidant effects.
• In laboratory research, reduced
glutathione has been shown to reduce
the production of reactive oxygen
species
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• There is evidence that reduced levels
of glutathione are associated with
Parkinson's disease.
• However, there is debate as to whether
reduced glutathione levels result from
Glutathione increased oxidative stress, which is
associated with Parkinson's disease
and PD pathogenesis, or whether glutathione
depletion itself actually contributes to
Parkinson's disease pathogenesis?
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• There is some preliminary evidence
that glutathione depletion may
potentiate inflammation associated
with Parkinson's disease by increasing
inflammatory cytokine production and
activity
Glutathione • Research in animal models suggests
and PD that glutathione supplementation is
unlikely to be effective, as glutathione
cannot penetrate neurons.
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Anti‐viral effects: Glutathione may inhibit
the activity of enzymes that help the flu virus
colonize cells lining the mouth and throat.
Glutathione,
Flu‐infected mice fed glutathione‐enriched
Flu, Cirrhosis drinking water have lower tissue virus levels
than untreated mice.
Hepatic effects: In individuals with cirrhosis,
oral glutathione has no effect on liver
function tests
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• Currently, researchers are investigating
whether administering glutathione
precursors, such as glutamine and
IV NAC, might increase glutathione levels
Glutathione • Following intravenous glutathione in
metabolism human research, reduced glutathione
levels increased after ten minutes;
however, they were reduced to normal
after 20 minutes.
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GSH decreases with age (1% per yr)
Age matched normals have decreased
GSH
GLUTATHIONE
Major protector of MtDNA
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GLUTATHIONE
• Regulation of the nitric oxide cycle is
critical for life
• Glutathione enhances the function
of citrulline as part of the nitric oxide cycle
• It is used in metabolic and biochemical
reactions such as DNA synthesis and repair,
protein synthesis, prostaglandin synthesis,
amino acid transport, and enzyme
activation
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“Failure to detoxify” is common thread
FM/CFS/MCS/EMFS
Auto‐Immune diseases including Lyme
Chronic Inflammation
Glutathione
Clinical Indications
Liver, gut (SIBO), kidney disease
Toxic Metal Syndrome
Neurogenic inflammation: “brain fog”, MS, Dementia, PD,
neuropathies, “chemo brain"
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50% less glutathione (GSH) in the substantia nigra of Parkinson’s patients
GSH 600 mg IV bid x 30 days
42 % decline in disability & continued effect 2‐4 months after stopped
IV Protects both telomeres and mtDNA
Glutathione Perry TL, et al. Idiopathic Parkinson's disease: A disorder due to nigra
glutathione deficiency. Neuroscience Letter
protects 1986;67:269‐74
Neurons Sechi G, et al. Reduced intravenous glutathione in the treatment of early
Parkinson's disease. Prog
Neuropsychopharmacol Biol Psychiatry 1996;20:1159‐70
Johnson WM, et al. Dysregulation of glutathione homeostasis in
neurodegenerative diseases. Nutrients. 2012 Oct
9;4(10):1399‐440. doi: 10.3390/nu4101399.
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Intravenous Glutathione and
Claudication
“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”
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IV Glutathione
vs. IV Saline Placebo
Conclusion: In patients with peripheral
artery disease, glutathione prolongs PFWD and
shows an improvement of macro‐circulatory and
micro‐circulatory parameters.
ENRICO AROSIO, MD; SERGIO DE MARCHI, MD;
MASSIMO
ZANNONI, MD; MANLIO PRIOR, MD;
AND ALESSANDRO LECHI, MD
Mayo Clin Proc, August 2002, Vol 77
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Studies using intravenous glutathione have
found it to be useful for reducing the side
effects
and increasing the efficacy of
chemotherapy
Glutathione
drugs (particularly cisplatin in women with
and ovarian cancer)
Chemotherapy
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, randomised
trial. Ann Oncol 1997;8:569–73.
Cascinu S, Cordella L, Del Ferro E, et al. Neuroprotective effect of reduced glutathione on
cisplatin‐based chemotherapy in advanced gastric cancer: a randomized double‐blind placebocontrolled
trial. J Clin Oncol 1995;13:26–32.
De Maria D, Falchi AM, Venturino P. Adjuvant radiotherapy of the pelvis with or without reduced
glutathione: a randomized trial in patients operated on for endometrial cancer. Tumori
1992;78:374–6.
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Neurodegenerative disorders
(Alzheimer’s, Parkinson’s, and
Huntington’s diseases, amyo‐ trophic
lateral sclerosis, Friedreich’s ataxia)
GSH
Depletion Pulmonary disease (COPD, asthma,
and acute respiratory distress
syndrome)
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Immune diseases (HIV, autoimmune disease)
Cystic fibrosis
Aging process itself
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Glutathione Toxicology
Toxicology
• There is insufficient reliable information
available about the toxicology of
glutathione.
Interactions with Drugs
• None known.
Interactions with Herbs &
Supplements
• None known.
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Decrease the need by decreasing toxic load
Decrease POP’s by not consuming conventionally
grown foods (ear organic)
How to
Increase your Limit Alcohol consumption
GSH levels?
Take other antioxidant vitamins to decrease
oxidative stress
Take ALA orally or IV which helps to recycle GSH,
although not involved in its production
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Cysteine availability is the rate‐limiting step in the
de novo production of glutathione.
Glutathione
& NAC
Cysteine does not make it through the digestive
track, supplemental cysteine in the form of whey or
N‐acetylcysteine (NAC) is effective at raising levels.
While there is substantial variation, 1000 mg/d of
NAC will substantially increase glutathione in
virtually all patients.
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• Direct administration: Most effective
• Used effectively in a wide range of
diseases:
GSH • Parkinson’s, peripheral obstructive
arterial disease, cystic fibrosis,
Route of emphysema, COPD, preterm infants
autism, contrast‐induced nephropathy,
Administration chronic otitis media, lead exposure,
nail biting, nonalcoholic fatty liver
disease, exercise‐induced fatigue—the
list is long and surprisingly diverse.
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• Obvious strategy is to directly
administer glutathione.
• This can be done orally, topically,
intravenously, intra‐ nasally, or in
nebulized form.
GSH Routes • Glutathione administered
intravenously, inhaled, and ingested
• IV & Intranasal administration
increases systemic levels.
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GSH Routes of Administration
• NAC (p.o.): 1‐2g daily
• Nebulized: 200‐1000mg
• Glut Push: 200‐2000mg
• IV: 1‐4g
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IV Glutathione Rx
• Dose: 600 to 800 mg IV diluted in 20ml SW infused over 15‐20 min, 2‐
3x/wk
• Push: 1‐2 grams IV post “Myer’s Cocktail” is a common dose once
established on glut
• Precautions: Rapid infusion can provoke respiratory distress, coughing,
rhinorrhea, and vertigo.
• Common clinical outcome: increased energy, improved memory
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Glutathione Push
• Safe
• Dosage: 500‐2500 mg
• Mix in 5‐10 ml of sterile
water
• Push over 3‐5
minutes
• Repeat 2‐3 times per week
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GLUTATHIONE Protocol
• Can be a Push or IV depending on dose
• Standard Dose 1000 mg = 5cc
2000 mg = 10cc
• Push: Mix any dose up to 2000 mg with 10cc syringe of NS
• Drip: Any dose 2500 mg or higher in 50cc NS bag.
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IV Glutathione Rx
• Dose: 600 to 800 mg IV diluted in 20ml SW infused over 15‐20 min, 2‐
3x/wk
• Push: 1‐2 grams IV post “Myer’s Cocktail” is a common dose once
established on glut
• Precautions: Rapid infusion can provoke respiratory distress,
coughing, rhinorrhea, and vertigo.
• Common clinical outcome: increased energy, improved memory
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CONTACT INFORMATION
Martin P. Gallagher, MD, DC, MS, ABOIM
Board Certified Family Medicine
Chiropractor
Physician Acupuncturist
Medical Director
Medical Wellness Associates
6402 State Route 30
Jeannette, Pa. 15644
724-523-5505
gpmmwa@gmail.com
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QUESTIONS
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Pearce RK, Owen A, Daniel S, et al. Alterations in the distribution of glutathione in the substantia nigra in
Parkinson's disease. J Neural Transm 1997;104:661‐77. Merad‐Boudia M, Nicole A, Santiard‐Baron D, et al.
Mitochondrial impairment as an early event in the process of apoptosis induced by glutathione depletion in
neuronal cells: relevance to Parkinson's disease. Biochem Pharmacol 1998;56:645‐55.
Sechi G, Deledda MG, Bua G, et al. Reduced intravenous glutathione in the treatment of early Parkinson's
disease. Prog Neuropsychopharmacol Biol Psychiatry 1996;20:1159‐70.
De Mattia G, Bravi MC, Laurenti O, et al. Influence of reduced glutathione infusion on glucose metabolism in
patients with non‐insulin‐dependent diabetes mellitus. Metabolism 1998;47:993‐7.
Ciuchi E, Odetti P, Prando R. The effect of acute glutathione treatment on sorbitol level in erythrocytes from
diabetic patients. Diabetes Metab 1997;23:58‐60.
Glutathione Usberti M, Lima G, Arisi M, et al. Effect of exogenous reduced glutathione on the survival of red blood cells in
hemodialyzed patients. J Nephrol 1997;10:261‐5.
Amano J, Suzuki A, Sunamori M. Salutary effect of reduced glutathione on renal function in coronary artery
References bypass operation. J Am Coll Surg 1994;179:714‐20
Cook GC, Sherlock S. Results of a controlled clinical trial of glutathione in cases of hepatic cirrhosis. Gut
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Witschi A, Reddy S, Stofer B, et al. The systemic availability of oral glutathione. Eur J Clin Pharmacol
1992;43:667‐9. Hagen TM,
Wierzbicka GT, Bowman BB, et al. Fate of dietary glutathione: disposition in the gastrointestinal tract. Am J
Physiol 1990;259(4 Pt 1):G530‐5. 5364
• Aw TY, Wierzbicka G, Jones DP. Oral glutathione increases tissue glutathione in vivo. Chem Biol Interact
1991;80:89‐97.
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• Bishop C, Hudson VM, Hilton SC, Wilde C. A pilot study of the effect of inhaled buffered reduced
glutathione on the clinical status of patients with cystic fibrosis. Chest. 2005;127(1):308‐317.
• Stav D, Raz M. Effect of N‐acetylcysteine on air trapping in COPD: a random‐ ized placebo‐controlled
study. Chest. 2009;136(2):381‐386.
• Pizzorno J. The path ahead: clinical experience in decreasing mercury load. Integrative Med Clin J.
2011;10(4):10‐13.
• Pizzorno J. The path ahead: what should we tell our patients about alcohol? Integrative Med Clin J.
2012;11(6):8‐11.
• Pizzorno J. The path ahead: persistent organic pollutants (POPs)—a serious clinical concern. Integrative
Glutathione •
Med Clin J. 2013;12(2):8‐11.
Biswas SK, Rahman I. Environmental toxicity, redox signaling and lung inflam‐ mation: the role of
References •
glutathione. Mol Aspects Med. 2009;30(1‐2):60‐76.
Hall MN, Niedzwiecki M, Liu X, et al. Chronic arsenic exposure and blood glu‐ tathione and glutathione
disulfide concentrations in bangladeshi adults. Environ Health Perspect. 2013;121(9):1068‐1074.
• Teixeira FK, Menezes‐Benavente L, Galvão VC, Margis‐Pinheiro M. Multigene families encode the major
enzymes of antioxidant metabolism in Eucalyptus grandis L. Genet Mol Biol. 2005;28(3):529‐538.
• Marí M, Morales A, Colell A, García‐Ruiz C, Fernández‐Checa JC. Mitochondrial glutathione, a key
survival antioxidant. Antioxid Redox Signal. 2009;11(11):2685‐2700. doi: 10.1089/ARS.2009.2695.
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• Li N, Jia X, Chen CY, et al. Almond consumption reduces oxidative DNA dam‐ age and
lipid peroxidation in male smokers. J Nutr. 2007;137(12):2717‐2722.
• Sharma H, Datta P, Singh A, et al. Gene expression profiling in practitioners of
• Sudarshan Kriya. J Psychosom Res. 2008;64(2):213‐218.
• Hauser RA, Lyons KE, McClain T, Carter S, Perlmutter D. Randomized, double‐
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•
•
Arosio E, De Marchi S, Zannoni M, Prior M, Lechi A. Effect of glutathione infu‐
sion on leg arterial circulation, cutaneous microcirculation, and pain‐free walk‐ ing
Glutathione
•
distance in patients with peripheral obstructive arterial disease: a randomized, double‐
blind, placebo‐controlled trial. Mayo Clin Proc. 2002;77(8):754‐759.
Bishop C, Hudson VM, Hilton SC, Wilde C. A pilot study of the effect of inhaled buffered
References
reduced glutathione on the clinical status of patients with cystic fibrosis. Chest.
2005;127(1):308‐317.
• Stav D, Raz M. Effect of N‐acetylcysteine on air trapping in COPD: a random‐ ized
placebo‐controlled study. Chest. 2009;136(2):381‐38
47
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• Allen J, Bradley RD (September 2011). "Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human
volunteers". Journal of Alternative and Complementary Medicine. 17 (9): 827–33. doi:10.1089/acm.2010.0716. PMC 3162377 .
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• 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;87:438‐43.
• 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;48:985‐9.
• Borok Z, Buhl R, Grimes GJ, et al. Effect of glutathione aerosol
on oxidant‐antioxidant imbalance in idiopathic pulmonary
fibrosis. Lancet 1991;338:215‐6.
Glutathione • Marrades RM, Roca J, Barbera JA, et al. Nebulized glutathione
induces bronchoconstriction in patients with mild asthma. Am
References J Respir Crit Care Med 1997;156(2 Pt 1):425‐30.
• 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,
randomised trial. Ann Oncol 1997;8:569‐73.
• Cascinu S, Cordella L, Del Ferro E, et al. Neuroprotective effect
of reduced glutathione on cisplatin‐based chemotherapy in
advanced gastric cancer: a randomized, double‐blind, placebo‐
controlled trial. J Clin Oncol 1995;13:26‐32
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