Acetaminophen not linked to glutathione plasma deficiency in HIV, McNeil maintains.

ACETAMINOPHEN NOT LINKED TO PLASMA GSH DEFICIENCY IN HIV, McNEIL SAYS, thus the oral analgesic can have no link, if taken as recommended, to any purported harm HIV-positive individuals may encounter as a result of taking acetaminophen. Specifically, Tylenol marketer McNeil Consumer Products argues in Sept. 11 comments to FDA, "there are no studies which show that acetaminophen reduces circulating plasma GSH levels."

The company's comments respond to a Feb. 14 citizen petition from Leonore Herzenberg, MD, Stanford University School of Medicine, and AIDS Treatment News Editor/Publisher John James asking FDA to investigate acetaminophen to determine whether the analgesic should be labeled with a use warning for HIV-infected people ("The Tan Sheet" March 24, p. 20).

The Herzenberg et al. letter cites a series of studies over a period of six years that show depleted levels of glutathione (GSH) are more pronounced in HIV-positive people as the disease progresses. Specifically, the letter from Herzenberg et al. says "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." Therefore, the authors state, "we respectfully request an investigation into this matter to determine if acetaminophen and other GSH-depleting drugs should be labeled with a utilization warning for HIV-infected people." Herzenberg et al. suggest that a "properly worded package insert warning should be adequate to prevent misuse by these individuals."

McNeil points out that "none of the HIV-infected individuals in the [Herzenberg] studies reported taking excessive amounts of products likely to alter GSH levels (e.g., alcohol, vitamin C, vitamin E) at screening and none was taking acetaminophen or N-acetylcysteine (NAC) when screening blood samples for GSH determination were obtained." There were no reports of any concomitant medications taken, if any, during the observational period of the studies, the company adds. "Thus, the principal study cited by the petitioners seems to contain no data relevant to their assertions concerning acetaminophen."

Moreover, J&J argues, "acetaminophen overdose is thought only to affect hepatic stores of GSH. Plasma levels have not been reported to have been affected." Therefore, the company maintains, "the mechanisms involved in acetaminophen overdose toxicity are completed unrelated to the mechanisms theorized by Herzenberg et al. for decreased survival rate in HIV-infected individuals with decreased systemic GSH levels."

The Herzenberg et al. studies "misstate that it is the direct effect of GSH depletion, caused, for example, by acetaminophen overdoses, that produces hepatic and renal failure," McNeil says. "In support of their statement, they cite only an article on intentional acetaminophen overdose. In actuality," McNeil says, "toxicity is a result of the formation of a reactive metabolite, the metabolism of which results in a transient depletion of GSH in the liver. However," J&J continues, "any injury that occurs is due to the reactive metabolite, not another secondary effect of GSH depletion, and is a local phenomenon in the liver, and is not related to GSH levels."

J&J also explains to FDA that no scientific data "exist that demonstrate that APAP [acetaminophen] use may affect long-term survival of HIV-infected patients. The implication that acetaminophen depletes total body GSH stores when taken as recommended on its packaging is unwarranted," the firm claims. Finally, McNeil says, "there is simply no compelling scientific data to support" the citizen petition's request for a label warning against misuse, and the current label for acetaminophen is "appropriate as written."