Re: H2O toxicity 2 July 2003
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Christopher S Tyler,

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Re: Re: H2O toxicity

As I stated in my 'diatribe', I invite Peter Flegg to go ahead and partake of this innocuous 'water', that is, go on these drugs for a year and then report back to the forum. Could he please provide evidence that treating people deemed infected with HIV with a failed chemotherapy agent, AZT, is warranted considering;

1) AZT doesn't triphosphorylate in vivo to nearly sufficient levels in order to have an antiretrovial effect;

2) The well known toxicities of AZT including anemia (bone marrow destruction), mitochondrial dysfunction, and genetic mutations.

Considering the pressure for governments of countries like South Africa to provide AZT and the like to its people, I believe a discussion of the dangers of such 'medications' is warranted on this forum.

To quote from "A Critical Analysis of the Pharmacology of AZT and its Use in AIDS", the Perth Group writes:

Although AZT is not efficiently triphosphorylated it is very efficiently mono-phosphorylated. The mono-phosphorylation of AZT could act as an inhibitor of phosphorylation of cellular constituents, including cellular nucleotides. Indeed, in 1986 Furman and his associates showed that, in vitro, exposure of cells to 50mM of AZT for 72 h led to a decrease of approximately 95% in dTTP and dCTP and a decrease of approximately 63% in dGTP. This decrease in the triphosphorylated nucleotides in its turn will lead to decreased cellular DNA synthesis. In the presence of such a profound, global reduction in the concentrations of the naturally occuring nucleotides, one would predict untoward effects on many tissues, especially those with the most rapid cellular turnover including the gut and the bone marrow. Indeed, 'a characteristic feature of zidovudine therapy is an elevated MCV [mean corpuscular red cell volume]' (54), and 'The antiviral agent zidovudine (AZT), used for treating the human immunodeficiency virus (HIV), often causes severe megaloblastic anemia' (55), anaemia 'caused by impaired DNA synthesis' (55).

Current Medical Research and Opinion Vol. 15: Supplement, 1999

Please find below a truncated list of quotes from the medical literature regarding problems with AZT. This list is by no means exhaustive.

Chris Tyler

<b>Bone Marrow Suppression/Anemia:</B>

“nearly one half of patients treated with AZT for [HIV]-associated disease develop transfusion-dependent anaemia due to bone marrow depression” Dainiak N et al. 3’-Azido-3’-deoxythymidine (AZT) inhibits proliferation in vitro of human haematopoietic progenitor cells. British Journal of Haematology. 1988;69:299-304. ----------------------------

“more than half of all AIDS patients may not benefit from the drug because it is more toxic for them than their AIDS infection. The most serious side effect of AZT is to suppress the bone marrow, leaving patients highly vulnerable to bacterial infections” Kolata G. Imminent marketing of AZT raises problems; marrow suppression hampers AZT use in AIDS victims. Science. 1987 Mar 20;235:1462-3. ------------------------------

“We found that 78.2% of the patients with mild or severe anaemia at baseline had received zidovudine [AZT]” Mocroft A et al. Anaemia is an independent predictive marker for clinical prognosis of HIV-infected patients from across Europe. AIDS. 1999;13:943-50. -------------------------

“While effective drug therapy is continued in zidovudine[AZT]-treated HIV-infected patients…PROCRIT Reduces Transfusion Requirements and Helps Lift the Burden of Anemia.” Advertisement for PROCRIT. 1997.

<b>Mitochondrial Dysfunction</b>

“typical mitochondrial myopathy has been reported to be expressed among many patients with AIDS treated with long-term azidothymidine (AZT) therapy" and "for AIDS patients, it is urgently necessary to develop a remedy substituting this toxic substance, AZT” Hayakawa M et al. Massive conversion of guanosine to 8-hydroxy- guanosine in mouse liver mitochondrial DNA by administration of azidothymidine. Biochem Biophys Res Commun. 1991;176:87-93. ----------------------

“A severe proximal myopathy, predominantly affecting the legs, seems to be a significant complication of long-term zidovudine therapy, even at reduced doses; it affected 18% of our patients who had received treatment for more than 200 days. Other drugs could not be implicated. The pathogenesis is obscure; the myopathy resolves on cessation of zidovudine, but not on dose-reduction, though there is then a risk of rebound encephalitis.” Helbert M et al. Zidovudine-associated myopathy. Lancet. 1988 Sep 17;2:689-90. -----------------------

“Long term therapy with [AZT] can induce a toxic myopathy associated with mitochondrial changes” Chariot P, Gherardi R. Partial cytochrome c oxidase deficiency and cytoplasmic bodies in patients with zidovudine myopathy. Neuro Muscul Disorders. 1991;1:357-363. ----------------------

<b>Increased Risk of Sickness and Death</b>

“Extended follow-up of patients in one [AZT] trial, the Concorde study, has shown a significantly increased risk of death among the patients treated early...where is the evidence that for a patient with a CD4 count of 450 cells per cubic millimeter and a low plasma viral level, it would not be better to wait before initiating therapy?...In 1990...a patient with a CD4 count of 450 cells per cubic millimeter would have been advised to start monotherapy with zidovudine. We now tell such a patient that, in fact, follow-up data for up to 4.5 years since that time have shown no survival benefit” Phillips AN, Smith GD et al. Viral load and combination therapy for Human Immunodeficiency Virus. N Engl J Med. 1997 Mar 27;336(13) -------------------------

“The mortality rate was significantly higher among [a group of 1372] patients who had received antiretroviral therapy [principally AZT] before enrollment in the clinic” Chaisson RE, Keruly JC, Moore RD. Sex, race, drug use and progression of human immunodeficiency virus disease. N Engl J Med. 1995;333(12):751-6. -------------------

“Only 38% of the HLP [Healthy long-term positives] had ever used zidovudine [AZT] or other nucleoside analogues, compared with 94% of the progressors.” Buchbinder S et al. Long-term HIV-1 infection without immunologic progression. AIDS. 1994;8:1123. --------------------------

“after starting antiretroviral treatment...the estimated probability of developing lymphoma 36 months, [was] 46.4% (CI, 19.6% to 75.5%)...a direct role of therapy itself cannot be totally discounted...Zidovudine can act as a mutagen” Pluda JM et al. Development of non-Hodgkin lymphoma in a cohort of patients with severe human immunodeficiency virus (HIV) infection on long-term antiretroviral therapy. Ann Intern Med. 1990 Aug 15;113(4):276-82.

----------------- “The Concorde trial showed no difference in the survival rates for symptom-free HIV-positive individuals between those given immediate and those given deferred zidovudine, and Chaisson et al found previous use of zidovudine to be a negative indicator, with an increase in the risk ratio for death or disease progression of 1.7” Scott WF. The Delta Trial. Lancet. 1996;348(9036):1238.

<b>General problems</b>

“Perinatal treatment with 3'-azido-3'-deoxythymidine (AZT) has been found to reduce the rate of maternal-infant transmission of HIV; however, AZT is clastogenic at therapeutic doses in adult patients and induces cancers in the offspring of mice treated in utero. The purpose of the present study was to investigate the mutagenicity of AZT at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus of the human lymphoblastoid cell line, TK6, following in vitro exposures. ..There was a significant increase over background in hprt Mfs [mutation frequencies] in TK6 cells exposed to 300mM AZT for 3 days (1.8-fold increase). In cells exposed for 6 days, there was a decrease in...cell survival. ..These preliminary results indicate that AZT treatment is mutagenic and produces large deletions in human cells.”

Sussman HE et al. Mutagenicity of AZT in the human lymphoblastoid cell line, TK6. 2nd National AIDS Malignancy Conference. 1998 Apr;94. ----------------------

Competing interests:   None declared