This translational research was built upon a series of discoveries made at the Johns Hopkins Medical Institutions. The late Dr. Ernest Bueding found that oltipraz, as an anti-schistosomal agent, caused a depletion in schistosomal glutatbione concentration and a simultaneous increase in host organ glutathione concentration. His colleagues, Drs. Thomas Kensler and Paul Talalay have studied oltipraz as a cancer chemopreventive agent based on its ability to increase host cell glutathione concentrations. Dr. Hans Prochaska, a former graduate student of Dr. Paul Talalay's made the pivotal discoveries for our project (again based on the ability of oltipraz to increase glutathione in cells and on the observation by others that HIV infected patients have depleted glutathione stores) by showing that oltipraz inhibits HIV replication in cells in vitro, that this inhibition occurs in both acutely infected cells and chronically infected cells, that this enzyme was irreversibly inhibited and that a specific metabolic product preferentially inhibits chronically infected cells while the parent drug preferentially inhibits acutely infected cells. These remarkable findings suggest that the parent drug is active as an irreversible inhibitor of the HIV reverse transcriptase while a metabolite is an irreversible inhibitor of some transcriptional event subsequent in the viral life cycle to integration of the proviral DNA. Our study illustrates the translation of these discoveries into an efficiently performed and rigorously conducted Phase I/II study that serves as a """"""""proof-of-principle"""""""" study to address the hypothesis that oltipraz has anti-HIV activity as defined by a >50% fall in p24 antiviral antigemia in humans at doses that are acceptable with respect to toxicity. Twenty-four HIV-infected subjects with a screening p24 antigenemia of >50 pg/ml were randomly assigned to three groups. One group of 6 received placebo and the other two groups of 9 received either 125 mg oltipraz q.d. or 500 mg. oltipraz once a week p.o. for 2 weeks as inpatients in our adult inpatient GCRC and for two additional weeks as ambulatory patients in our adult outpatient GCRC. The study was double-blinded and the blind was not broken until all case reports had been completed and all clinical decisions made. The clinical portion of the study was completed in November of 1996. The primary end-point data, i.e., p24 antigenemia, were completed in January of 1997 along with quantitative cultures and the plasma glutathionine-s- transferase levels. The plasma and red blood cell glutathionine levels and the drug and metabolite levels are still outstanding.
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