Glutathione-Depleting Drugs: Petition to the FDA

Recently Leonore A. Herzenberg (one of the authors of the NAC/glutathione study described above), and this writer, submitted a petition to the FDA, asking that it investigate whether acetaminophen and other glutathione-depleting drugs should carry a warning label telling users that there may be more risk for HIV-infected persons (especially for those with advanced disease) than for the general public. The petition process is a formal mechanism for citizens to request an FDA investigation of a matter which may affect public health.

Our petition is a three-page letter, which includes 9 references and several enclosures. The full text follows:

A series of studies over the last 6 years have demonstrated a pronounced glutathione (GSH) deficiency is frequent in HIV-infected adults and children and tends to become more pronounced as HIV disease progresses (see enclosed reportingand references). Recent studies document this progressive loss of GSH in peripheral blood lymphocytes of HIV-infected subjects at different stages of the disease, and demonstrate that GSH-deficient subjects with CD4 T cell counts below 200/ul of blood (i.e., with CDC-defined AIDS) are substantially more likely to die within 2 to 3 years than comparable subjects with GSH levels in normal range(Herzenberg et. al., manuscript enclosed).

We bring this GSH deficiency to your attention because certain commonly available drugs, notably acetaminophen, tend to deplete GSH and are potentially more toxic to GSH-deficient individuals Therefore, we are concerned that such drugs may be more dangerous for HIV infected individuals than previously thought. Specifically, the use of such drugs in the upper level of the safety range for uninfected individuals could be harmful to people with HIV infection, especially with AIDS.

For the above reasons, we respectfully request an investigation into this matter to determine whether acetaminophen and other GSH-depleting drugs should be labeled with a utilization warning for HIV-infected people. We recognize the value of these drugs and believe it would be overly drastic to remove them from circulation or prevent access for HIV-infected individuals. A properly worded package insert warning should be adequate to prevent misuse by these individuals.

We would appreciate action as promptly as possible on this petition. Acetaminophen is widely used within the HIV community often with physician's blessing and no caution with respect to over utilization. Many individuals consider it atotally safe drug that has only minimal consequences when overutilized. We hope that action by the agency will correct this impression and provide proper guidelines for utilization by HIV-infected people. Current evidence suggests that such action could be lifesaving.

(signed):

Leonore A. Herzenberg, Professor of Genetics, Stanford University School of Medicine

John S. James, Editor and Publisher, AIDS TREATMENT NEWS

PS. We have included several articles demonstrating GSH depletion in HIV-infected people and/or exploring the consequences of GSH depletion and repletion in model systems and HIV infected individuals. You will note that in a number of these studies, investigators use N-acetylcysteine (NAC) to replenish GSH. We and others (Herzenberg, et. al., Akerlundet. al., see enclosures) have recently completed trials demonstrating that NAC replenishes GSH in these individuals. In addition, our study includes monitoring data (not placebo controlled) indicating that GSH replenishment may be beneficial for HIV-infected individuals and hence strengthening the link between GSH depletion and poor prognosis in HIV disease. This petition, however, does not concern NAC administration. It is being submitted solely to request that the agency consider requiring the inclusion of appropriate warnings for HIV-infected people with respect to utilization of drugs that may deplete glutathione.

Enclosures:

1. Herzenberg, Leonore A., Stephen De Rosa, J. Gregson Dubs,Mario Roederer, Michael T. Anderson, Stephen W. Ela, Stanley C. Deresinski, and Leonard A. Herzenberg. 1997. Glutathione deficiency is associated with impaired survival in HIVdisease. PROC. NATL. ACAD. SCI. U.S.A., 94: 1967-1972;

2. Akerlund, B., C. Jarstrand, B. Lindeke, A. Sonnerborg, A.-C. Akerblad, O. Rasool. 1996. Effect of N-acetylcysteine(NAC) treatment on HIV-1 infection: a double-blind placebo-controlled trial. EUR J CLIN PHARMACOL ., 50:457-461;

3. Staal, Frank J.T., Stephen W. Ela, Mario Roederer, Michael T. Anderson, Leonore A. Herzenberg and Leonard A. Herzenberg.1992. Glutathione deficiency and HIV infection. THE LANCET,339:909-912;

4. Staal, Frank J.T., Mario Roederer, Dennis M. Israelski, Jeff Bubp, Larry A. Mole, Dennis McShane, Stanley C.Deresinski, William Ross, Howard Sussman, Paul A. Raju,Michael T. Anderson, Wayne A. Moore, Stephen W. Ela, Leonore A. Herzenberg and Leonard A. Herzenberg. 1991. Intracellular glutathione levels in T cell subsets decrease in HIV infected individuals. J AIDS RES. AND HUMAN RETROVIRUSES, 8:305-311;

5. Buhl, Roland, Kenneth J. Holroyd, Andrea Mastrangeli, Andre M. Cantin, H. Ari Jaffe, Faith B. Wells, Cesare Saltini, Ronald G. Crystal. 1989. Systemic glutathione deficiency in symptom-free HIV-seropositive individuals. THE LANCET (December 2, 1989) ii: 1294-1298.

6. Eck, Has-Peter, Helmut Gmunder, Martin Hartmann, Detlet Petzoldt, Volker Daniel and Wulf Droge. 1988. Low concentrations of acid-soluble thiol (cysteine) in the blood plasma of HIV-1-infected patients. BIOL. CHEM. 370:101-108;

7. Smith, C.V., T.N. Hansen, I.C. Hansen and W.T. Shearer.1990. Abstract: Glutathione concentrations in plasma and blood are markedly decreased in HIV-infected children. Sixth International Conference on AIDS -- San Francisco, Friday 22June 1990 II:368 (Abstract #2058);

8. Selected references relevant to GSH deficiency and HIV/AIDS [a list of 27 references];

9. Dubs, John Gregson, Malcolm Zaretsky, Stan Deresinski,Mario Roederer, Stephen De Rosa, Leonore A. Herzenberg, and Leonard A. Herzenberg. N-acetylcysteine restores glutathionein whole blood and in CD4 and CD8 T lymphocytes of HIV-infected persons in a placebo-controlled trial. Inpreparation (not enclosed).