FRANÇAIS HIV AND NUTRITION PREVIOUS PAGE NEXT PAGE SUBSCRIBE Chester Myers' Nutrition Series Information relating to HIV & Nutrition: HIV & Use of Tylenol - About Acetaminophen (Tylenol) toxicity
The information in these pages is about acetaminophen toxicity and its relevance to HIV disease.
Glutathione, an important tripeptide antioxidant(1) in all cells of the human body is particularly important for the lungs (mucosal lining(2)), liver (detoxification(3)) and eyes (especially regarding cataract formation)(4). It may be logical to ask whether it helps to provide protection against CMV retinitis. In HIV disease there is general oxidative stress(5), and levels of glutathione, along with other thiols, tend to decline in the absence of supplementation with N-acetyl-cysteine &/or glutamine(6). Related factors are varied, but relevant to HIV disease is that low magnesium, which is common with HIV and a source of oxidative stress, compromises glutathione status(7), and this, in turn, compromises immunity(8). Low selenium levels are also frequent with HIV disease. This is another stress for those with HIV which also impacts on glutathione via glutathione peroxidase expression. One of the many likely results is defects in the arachidonate cascade, especially involving certain leukotrienes(9), some of the compounds, along with prostaglandins and thromboxanes, produced from certain dietary fats, which control important body functions. More information is available on these in other monographs by the author in this same series (list at end of this monograph).
Glutathione is destroyed by oxdidative mechanisms. One common oxidant known to destroy glutathione is acetaminophen (see following). Because the liver is often the most sensitive to acetaminophen's toxicity(10), this chemical is used as a 'standard' to cause liver damage in animal model studies where some other compound is being studied as retrieval therapy.(11)
There are many reports about acetaminophen toxicity and morbidity associated with its use.(12) Although alcohol use is most often associated with acetaminophen toxicity, in one study an association was noted between acetaminophen toxicity and both fasting, and to a lesser extent, use of alcohol.(13) Toxicity reports have been associated even with hospital use of this drug(14). It is reported to be "the most commonly reported drug overdose in the United States".(15) Thousands of referrals to emergency departments have been noted to result from use of acetaminophen for children.(16) Fewer deaths have been observed to result from acetaminophen overdose "in Hong Kong than in other Western societies".(17) In Philadelphia, 560 patients, who were admitted to hospital between 1987 and 1993 for acetaminophen-induced liver toxicity, were studied, and survival was noted to have improved from <50% to 78% with time in spite of increasing incidence - nonetheless, it was concluded that "severe acetaminophen-induced hepatotoxicity remains a serious condition".(18) Of greatest concern should be use of acetaminophen during disease because of the likelihood of exacerbation of already existing glutathione deficiency(19). Glutathione declines with HIV disease, and it would seem any additional move to cause greater decline would be unwise.
There are many references that could be cited. Only a few are given herein. A few more are highlighted as following.
A. One 1993 newspaper report noted statements from the New York gastroenterologist Dr. Donald Kotler. He noted that he had decided against use of Tylenol as a control for his aspirin study (the aspirin study was later terminated because of stomach problems from the high dose of aspirin). A second newspaper clipping (1997) provides further caution about Tylenol:
from page A13 of The Toronto Star, Sunday, February 23, 1997
"Common drug may help those with HIV"
"SAN FRANCISCO (Reuter) - Researchers say a drug used to treat painkiller overdoses may prolong the lives of people infected with the virus that causes AIDS.
"The drug, called N-acetylcysteine (NAC), is normally used to treat overdoses of the common painkiller acetaminophen (found in remedies such as Tylenol).
"A daily NAC tablet may suffice to maintain adequate levels of a critical molecule in HIV patients, the researchers said yesterday. Those with ample levels of glutathione, a molecule normally found throughout the body, are likely to live longer than patients with low levels, said Leonora and Leonard Herzenberg, genetics professors at Stanford University School of Medicine.
"The more glutathione patients have in their CD4 T cells - the primary cells targeted by the HIV virus - the longer they are likely to survive, they found.
"What we show for the first time in this work is that people with HIV who have lower glutathione levels have a much lower probability of surviving over the course of three years than do people with normal glutathione levels," Leonard Herzenberg said yesterday at the annual meeting of the American Association of Immunologists in San Francisco.
"Leonard Herzenherg said it was "logical to suggest that NAC will help HIV patients live longer. But we don't know this for sure." He said there should be a clinical trial to see whether NAC increased HIV patients' long-term survival.
"His wife Leonora told a news conference the researchers would not recommend that people with HIV take NAC until "there is good, solid, double-blind controlled evidence."
"But she said NAC is non-toxic and does not harm people - "so we don't feel uncomfortable in saying: here's a dietary supplement that you could take that would possibly improve things and is not likely to hurt you."
"The research also raised the possibility that drugs such as acetaminophen are hazardous to people with HIV or with other conditions that suppress immune function, she said.
"Leonore Herzenberg and John James, publisher of the newsletter AIDS Treatment News, are asking the U.S. Food and Drug Administration to consider requiring drug companies to label glutathione-depleting drugs such as acetaminophen with a warning stating the potential hazard to people with HIV.
"Of the study's 204 patients, 99 had CD4 counts below 200 cells per microlitre of blood - the threshold clinicians view as an imminent threat to survival.
"Most who had such low levels of CD4 cells and also had low levels of glutathione died within three years.
"In contrast, of the 28 people who started the study with low CD4 counts but maintained normal glutathione levels, 23 survived. In other words, about 80 per cent of these people survived, even though their CD4 cell counts indicated their survival was unlikely," Leonard Herzenberg said.
(This information was scanned directly from The Toronto Star by Chester Myers. Bold and italics were added here for emphasis.)
B. Pages 267-283 of Kaplowitz et al, Chap. 16, "Glutathione, Alcohol, and Hepatotoxicity", in Nutrition and the Origins of Disease, ed. Ch. H. Halsted & R. B. Rucker, Academic Press, 1989. This reference notes safety of acetaminophen at levels up to 8g/dy "in normal individuals", and liver death from an acute dose of >10g. Lower levels are noted to be toxic in presence of chronic alcohol exposure due to activation of the P-450 cytochrome system by ethanol. This is of increased significance with increasing use of protease inhibitors which are also metabolized in the P450 cytochrome system. Since glutathione is the compound destroyed, and since glutathione (as well as other thiols) is low in HIV disease, then we need to be careful of use of acetaminophen-containing medications unless only occasionally used, and then hopefully with NAC. Use of NAC is likely okay for maintenance of glutathione, but will likely reverse deficiency with difficulty. The oxidation of glutathione by acetaminophen is pretty straightforward chemistry. It is no surprise that this oxidation is ominously increased in HIV disease.(20)
C. Eck et al, "Metabolic disorder as early consequence of simian immunodeficiency virus infection in rhesus macaques", The Lancet 338:1991:346-347. The first paragraph of this indicates studies of glutathione deficiency in humans with HIV. Ominously, in the macaque model, the authors note that thiol deficiency started within a few days of HIV infection! Little wonder that one research group suggested AIDS to be "the consequence of a virus-induced cysteine deficiency".(21) (This is also the source of the unreliability in HIV infection of the homocysteine testing for B12).
D. Abstract regarding an in vitro study, related to low plasma cysteine, cystine and intracellular glutathione (S Mihm and others, "Modulation of transcription factor NF kappa B activity by intracellular glutathione levels and by variations of the extracellular cysteine supply", FASEB J 9:1995:246-252).
E. Abstract (noted in reference 7) re role of low magnesium in RBC glutathione. We must remember that Mg is a common deficiency in HIV disease. Measurement of serum magnesium is probably the best test (although only 0.3% of the body's magnesium is in the blood serum, and there is another 0.5% in the red blood cells). Again, I argue against exacerbation of the glutathione problem with administered known toxic materials such as acetaminophen. The liver is an important organ. It must deal with many extra toxicities from the many drugs used in HIV disease! Indeed, it is difficult to understand why acetaminophen is allowed as an over-the-counter drug even in the absence of disease! N-acetylcysteine, on the other hand, has been noted to enhance cellular cytotoxicity,(22) and to give dramatic improvement in health when combined with certain antivirals.(23)
F. Regarding exercise (rat model - CK Sen and others, "Exercise-induced oxidative stress: Glutathione supplementation and deficiency", J Appl Physiol 77:1994:2177-2187). If there is negligence regarding micronutrient supplementation in HIV disease, then there should be caution against strenuous exercise.
G. Abstract re glutathione deficiency and protein energy malnutrition (PEM - data from humans). Does acetaminophen use make wasting more likely? Other research indicates this to be highly likely.(6)
H. Abstract re glutathione deficiency and morbidity. (W Droge and others, "Functions of glutathione and glutathione disulfide immunology and immunopathology", FASEB J 8:1994:1131-1138.)
I. Both aspirin and indomethacin, contrary to results with acetaminophen, have been noted to be possibly beneficial in HIV disease (abstract PuB 7016, International AIDS Conference, Amsterdam; AS Bourinbaiar, S Leehuang, "The non-steroidal anti-inflammatory drug, indomethacin, as an inhibitor of HIV replication", FEBS Letters 360:1995:85-88). These two compounds are both antiinflammatories that inhibit the enzyme cyclo-oxygenase. We need to keep in mind that acetaminophen is a potent oxidant - not so for aspirin, which is an antioxidant. Blocking of inflammatory response is a logical approach, especially if the anti-inflammatory compound is also an antioxidant.
J. A monograph by the author regarding cysteine is available with references (this is a companion to another monograph HIV and Cysteine revisited, also by Chester Myers). Also, for more on this subject by the author, see "Staying up-to-date with nutrition information for PLWHIVAIDS", Canadian AIDS News 6:1993:9, and the accompanying text box "New information on wasting".
Considering that glutathione is one of the body's natural defences against HIV, it would seem that encouraging any decrease in its level would be dangerous to consider.(24) We need to be careful of playing Russian Roulette with our lives.
Re use of N-acetyl cysteine (NAC) in HIV/AIDS
"Oral N-acetylcysteine transiently increases the concentrations of cysteine and glutathione in mononuclear cells of patients with HIV infection. A sustained increase in intracellular cysteine may be necessary to normalize intracellular glutathione. This may be accomplished by repeat administration of [NAC]" (de Quay et al, 1992, University of Bern, Switzerland) - 30 mg NAC/kg body weight, results monitored 2-4 hrs later
"The apparent 'over-protection' of patients' [peripheral blood lymphocytes] by NAC treatment could be reason enough to apply early therapy with this molecule." (René et al, 1992, Institut Pasteur, France & Stanford University, USA) - study with HIV+ patients, using "600 to 1200 mg of NAC per day"
"Preliminary findings indicate that in patients who self-administer the GSH prodrug N-acetylcysteine (NAC), GSH levels can be restored to normal." (Staal et al, 1992, Stanford University)
".. we have proposed already in 1988 to consider N-acetyl-cysteine (NAC) or other cysteine derivatives such as thiazolidine compounds for the treatment of [HIV-infected persons].." (Droge et al, 1993, German Cancer Research Centre)
"Many reports [1988 onwards] indicate that HIV infected individuals including asymptomatic patients, were found to express decreased plasma cysteine and intracellular [glutathione] levels. .. N-acetyl-Cysteine administration to HIV seropositive patients seems to prevent early cell death and to induce an 'overprotection' status in patients' PBLs" (Olivier et al, 1993, France) - 600-1800 mg/day used
in combination with AZT & ddC in a 1 yr study, higher CD4+ counts and fewer AIDS events with AZT+ddC+NAC, than with either AZT or AZT+ddC (Feregrino-Goyos et al, 1994, General Hospital of Mexico) - 1500 mg NAC/day
"After the onset of the NAC treatment this expected decline [of CD4 cells] was inhibited while it continued in the placebo group." (Jarstrand et al, 1994, Huddinge University Hospital, Sweden) - "They were given 800 mg of NAC/day .."
"When we treat patients for less than six months with NAC, we don't see much change. However, when the NAC treatment is longer than six months, NAC will restore apoptosis back to normal levels. This is a preliminary result ... I am convinced that oxidative stress is indeed involved in the progression from HIV infection to the AIDS stage." (Montagnier, 1995, Pasteur Institute, France)
"The decrease in mean [body cell mass]/body fat ratios was prevented by N-acetyl-cysteine, .." (Kinscherf et al, 1996, University of Heidelberg and the German Cancer Research Centre) - non-HIV study with 400 mg NAC per day
To get started with supplementation, a good multivitamin containing minerals could be considered. A minimum of 25 mg of vitamin B6, 50 mcg each of selenium and chromium, and no more than 10,000 i.u. of vitamin A could be a rule of thumb in choosing this multivitamin with minerals. In addition, another 50-75 mg of zinc, 400-800 i.u. of vitamin E from a natural source, vitamin B12 by a non-stomach route, and 800-1500 mg of N-acetyl cysteine (NAC) may be useful.
References
1. D GerardMonnier, J Chaudiere, "Metabolism and antioxidant function of glutathione", Pathologie Biologie 44:1996:75-85.
2. MA Baz and others, "Glutathione depletion in epithelial lining fluid of lung allograft patients", Am J Respir Crit Care Med 153:1996:742-746; PM Suter and others, "N-Acetyl-cysteine Enhances Recovery from Acute Lung Injury in Man - A Randomized, Double-Blind, Placebo-Controlled Clinical Study", Chest 105:1994:190-194.
3. TM Bray & CG Taylor, "Tissue Glutathione, Nutrition, and Oxidative Stress", Can J Physiol Pharmacol 71:1993:746-751; M Chiba, KS Pang, "Glutathione depletion kinetics with acetaminophen - A simulation study", Drug Metab Dispos 23:1995:622-630.
4. WB Rathburn and others, "Prevention of acetaminophen- and naphthalene-induced cataract and glutathione loss by CySSME", Investig Ophthalmol Vis Sci 37:1996:923-929; SD Varma and others, "Prevention of Cataracts by Nutritional and Metabolic Antioxidants", Crit Rev Food Sci Nutr 35:1995:111-129; PG Wells and others, "In vivo murine studies on the biochemical mechanism of acetaminophen cataractogenicity", Can J Physiol Pharmacol 73:1995:1123-1129.
5. HP Broquist, "Buthionine Sulfoximine, an Experimental Tool to Induce Glutathione Deficiency: Elucidation of Gluthathione and Ascorbate in Their Role as Antioxidants", Nutr Rev 50:110-111; R Buhl, "Imbalance between oxidants and antioxidants in the lungs of HIV-seropositive individuals", Chem-Biol Interactions 91:1994:147-158; B de Quay and others, "Glutathione depletion in HIV-infected patients: role of cysteine deficiency and effect of oral N-acetylcysteine", AIDS 6:1992:815-819; B Helbling and others, "Decreased release of glutathione into the systemic circulation of patients with HIV infection", Eur J Clin Invest 26:1996:38-44; C Jarstrand & B Åkerlund, "Oxygen radical release by neutrophils of HIV-infected patients", Chem-Biol Interactions 91:1994:141-146; O Lopez and others, "Increased plasma thiobarbituric acid-reactive substances (TBARS) before opportunistic infection symptoms in HIV infected individuals", Clinica Chimica Acta 247:1996:181-187; A Meyer and others, "Intravenous N-acetylcysteine and lung glutathione of patients with pulmonary fibrosis and normals", Am J Respir Crit Care Med 152:1995:1055-1060; PA Raju and others, "Glutathione Precursor and Antioxidant Activities of N-Acetylcysteine and Oxothiazolidine Carboxylate Compared in in Vitro Studies of HIV Replication", AIDS Res and Human Retroviruses 10:1994:961-967; C Sappey and others, "Stimulation of Glutathione Peroxidase Activity Decreases HIV Type 1 Activation after Oxidative Stress", ibid 10:1994:1451-1461.
6. B Akerlund and others, "Effect of N-acetylcysteine (NAC) treatment on HIV-1 infection: A double blind placebo controlled trial", Eur J Clin Pharmacol 50:1996:457-461; P Aukrust and others, "Increased levels of oxidized glutathione in CD4(+) lymphocytes associated with disturbed intracellular redox balance in human immunodeficiency virus type 1 infection", Blood 86:1995:258-267; R Denno and others, "Glutamine-enriched total parenteral nutrition enhances plasma glutathione in the resting state", J Surg Res 61:1996:35-38; R Kinscherf and others, "Low plasma glutamine in combination with high glutamate levels indicate risk for loss of body cell mass in healthy individuals: the effect of N-acetyl-cysteine", J Mol Med 74:1996:393-400; MK Robinson and others, "Glutathione deficiency and HIV infections", letter to editor, The Lancet 339:1992:1403-1604; JK Shabert, "Glutamine deficiency as a cause of human immunodeficiency virus wasting", Med Hypoth 46:1996:252-256; CY Yim and others, "Use of Nacetyl cysteine to increase intracellular glutathione during the induction of antitumor responses by IL-2", J Immunol 152:1994:5796-5805.
7. IT Mak and others, "Loss of red blood cell glutathione during Mg deficiency: Prevention by vitamin E, D-propranolol, and Chloroquine", Am J Physiol - Cell Physiol 36:1994:C1366-C1370.
8. ME Blazka and others, "Role of proinflammatory cytokines in acetaminophen hepatotoxicity", Toxicol Appl Pharmacol 133:1995:43-52; RD Goldin and others, "Acetaminophen and macrophage activation", Internat Hepatol Commun 4:1995:16-18; SS Tukel, "Effects of acetaminophen on methemoglobin, superoxide dismutase and Na+-K+ ATPase activities of human erythrocytes", Biochem Mol Biol Internat 35:1995:719-724; V Witkosarsat and others, "Immunomodulatory Role of Phagocyte-derived Chloramines Involving Lymphocyte Glutathione", Mediators of Inflammation 2:1993:235-241; CY Yim and others, "Use of N-Acetyl cysteine to increase intracellular glutathione during the induction of antitumor reponses by IL-2", J Immunol 152:1994:5796-5805.
9. E Mayatepek and others, "Deficient Synthesis of Cysteinyl Leukotrienes in Glutathione Synthetase Deficiency", Internat J Tissue Reactions - Exp Clin Aspects 15:1993:245-252.
10. PJ Donnelly and others, "Inhibition of Mitochondrial Respiration in Vivo is an early event in acetaminophen-induced Hepatotoxicity", Arch Toxicol 68:1994:110-118.
11. SA Baranowitz, PFA Maderson, "Acetaminophen toxicity is substantially reduced by beta-carotene in mice", Internat J Vitamin Nutr Res 65:1995:175-180; E Cho and others, "Metabolic changes of acetaminophen after intravenous administration to rats pretreated with a hepatoprotective agent, YH-439", Res Commun Mol Pathol Pharmacol 91:1996:3-16; E Rafeiro and others, "Effects of N-acetylcysteine and dithiothreitol on glutathione and protein thiol replenishment during acetaminophen-induced toxicity in isolated mouse hepatocytes", Toxicol 93:1994:209-224; I Sakaida and others, "Protection against acetaminophen-induced liver injury in vivo by an iron chelator, deferoxamine", Scand J Gastroent 30:1995:61-67; EJ Wang and others, "Protective effects of garlic and related organosulfur compounds on acetaminophen-induced hepatotoxicity in mice", Toxicol Appl Pharmacol 136:1996:146-154.
12. S Chandra and others, "Stimulated hepatic tissue repair underlies heteroprotection by thioacetamide against acetaminophen-induced lethality", Hepatology 21:1995:477-486; SHL Thomas, "Paracetamol (Acetaminophen) Poisoning", Pharmacol Therapeutics 60:1993:91-120.
13. DC Whitcomb, GD Block, "Association of acetaminophen hepatotoxicity with fasting and ethanol use", JAMA 23:1994:1845-1850.
14. BS Dean and others, "Outpatient N-acetylcysteine treatment for acetaminophen poisoning: An ethical dilemma or a new financial mandate?", Veter Human Tocicol 38:1996:L222-224.
15. P Blakely, BR McDonald, "Acute renal failure due to acetaminophen ingestion: A case report and review of the literature", J Am Soc Nephrol 6:1995:48-53.
16. GR Bond and others, "Acetaminophen ingestion in childhood - Cost and relative risk of alternative referral strategies", J Toxicol - Clin Toxicol 32:1994:513-525.
17. TYK Chan, "The epidemiology of acetaminophen (paracetamol) poisoning in Hong Kong", Veter Human Toxicol 38:1996:443-444.
18. AJ Makin and others, "A 7-year experience of severe acetaminophen-induced hepato-toxicity (1987-1993)", Gastroenterol 109:1995:1907-1916.
19. AC White and others, "Glutathione Deficiency in Human Disease", J Nutr Biochem 5:1994:218-226.
20. A Esteban, M PerezMateo, V Boix, M Gonzalez, M Portilla, A Mora, "Abnormalities in the metabolism of acetaminophen in patients infected with the human immunodeficiency virus (HIV)", Meth Findings Exp Clin Pharmacol 19:1997:129-132.
21. H Droge and others, "Effects of Nacetylcysteine (NAC) on the T cell System. In VIVO results of a Placebo-Controlled Double-Blind Trial", Conference on Oxidative Stress in HIV/AIDS - A Potential for Therapies, NIH, Bethesda, 1993.
22. RL Roberts and others, "Nacetylcysteine Enhances Antibody-Dependent Cellular Cytotoxicity in Neutrophils and Mononuclear Cells from Healthy Adults and Human Immunodeficiency Virus-Infected Patients", J Infect Dis 172:1995:1492-1502.
23. M Feregrino-Goyos and others, "AZT Monotherapy compared to AZT + DDC combined antiviric therapy and AZT + DDC + NAC (100 patients each group)", Internat AIDS Conf, Yokahama, 1994.
24. AT Palamara and others, "Glutathione inhibits HIV replication by acting at late stages of the virus life cycle", AIDS Res Human Retroviruses 12:1996:1537-1541.
In this series:
HIV & Diet revisited
HIV & Dietary Supplements revisited
HIV & Nutrients revisited
HIV & Cysteine revisited
HIV & Copper and Zinc revisited
HIV & Vitamin B12
HIV & Carnitine
HIV & The Gut
HIV & Liquid Food Supplements
HIV & Use of Tylenol - About Acetaminophen toxicity
References for HIV & Nutrition
HIV and Nutrition: Rationale for NAC
Author, Chester Myers, holds both honours B.Sc. and M.Sc. (1969) degrees in physical chemistry from Dalhousie University, and a Ph.D. (1975) from the University of Toronto (biophysical chemistry) where he investigated the mechanism of action of one of the digestive enzymes. In addition to publishing in the scientific literature and having authored several patents, he has written extensively on topics regarding health and HIV. The latter include articles in The Positive Side, Canadian AIDS News, and monographs available from the AIDS Committee of Toronto (ACT), the Community AIDS Treatment Information Exchange (CATIE), and various other organizations.
Disclaimer:
The material in this publication is for information purposes only. It does not endorse any particular treatment program nor strategy; neither is it intended as medical advice nor as a replacement for medical advice.
©This document is copyrighted by Chester Myers. All materials may be reprinted and/or distributed without prior permission. However, reprints may not be edited. |
