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02610_2 STAMPIDINE IS A POTENTIAL NONCONTRACEPTIVE BROAD-SPECTRUM ANTI-HIV MICROBICIDE DCruz Osmond J. Stampidine [2,3-didehydro-2,3-dideoxythymidine 5-[p-bromophenyl methoxyalaninyl phosphate], a novel aryl phosphate derivative of stavudine (STV/d4T) is a potent broad-spectrum anti-HIV agent with potential as a new class of noncontraceptive microbicide. Stampidine was 100-fold more potent than STV/d4T against clinical HIV-1 isolates of non-B envelope subtypes (A, C, F and G). Stampidine inhibited the in vitro replication of 20 genotypically and phenotypically nucleoside analog reverse transcriptase inhibitor (NRTI)-resistant and 6 non-nucleoside-resistant HIV-1 isolates at nanomolar concentrations. Stampidine exhibited potent in vivo anti-HIV activity in Hu-PBL-SCID mice against a NRTI-resistant clinical HIV-1 isolate and dose-dependent antiretroviral effect in chronically feline immunodeficiency virus-infected cats. Stampidine was non toxic even at cumulative dose levels as high as 8.4 g/kg and exhibited favorable pharmacokinetics in mice, rats, dogs, and cats. We investigated the potential utility of stampidine as a noncontraceptive microbicide for prevention of sexual transmission of HIV via semen. Exposure of human semen to stampidine, even at a concentration 106-times higher than its in vitro anti-HIV-1 activity had no effect on sperm functions or the viability of genital tract epithelial cells. In the rabbit model, reproductive indices were not affected by pretreatment of rabbit semen with stampidine prior to artificial insemination and gel formulations of stampidine did not induce mucosal toxicity. These attributes are particularly useful for the clinical development of stampidine (i) as a noncontraceptive anti-HIV microbicide and; (ii) as a prophylactic antiviral agent to curb the transmission of HIV via semen. Dr. Osmond J. DCruz |
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