Abstract
The current pandemic of sexually transmitted HIV / AIDS has created an urgent need for a new type of microbicide, one that is both a spermicide and a virucide. WHI-07 is a novel 5-bromo 6-methoxy aryl phosphoramidate derivative of 3-azido-3-deoxythymidine (zidovudine, ZDV / AZT) with potent anti-HIV and spermicidal activities. WHI-07 was rationally designed to bypass the thymidine kinase dependency of ZDV activation in genital tract secretions. WHI-07 was formulated via a nontoxic gel-microemulsion for intravaginal use as a potential candidate anti-HIV spermicide. The in vivo efficacy as well as safety studies of WHI-07 included: (i) vaginal as well as rectal microbicide efficacy studies in the feline immunodeficiency virus (FIV) / domestic cat model for AIDS; (ii) in vivo retention of anti-HIV activity in the nonhuman primate; (iii) vaginal contraceptive efficacy studies in rabbits; (iv) single- and/ or multiple-dose toxicity studies in mice, rabbits, cats as well as monkeys; (v) mucosal, reproductive, and developmental toxicity studies in mice and rabbits; (vi) cytotoxicity, mutagenicity, and genotoxicy tests using human and yeast cells; and (vii) long-term carcinogenicity studies in mice. WHI-07 which exhibited nanomolar in vitro anti-HIV IC50 and low micromolar spermicidal EC50 values was significantly less active against genital epithelial cells and did not induce primary DNA damage in human and yeast cells. WHI-07 retained full activity in TK-deficient cells, the main carriers of HIV in semen. Both vaginal as well as rectal instillation of WHI-07 gel-microemulsion, either alone or in combination with a vanadocene dithiocarbamate, effectively protected domestic cats from a subsequent vaginal or rectal exposure to feline T cells chronically infected with a mucosally transmissible FIV strain. WHI-07 gel-microemulsion was a potent vaginal contraceptive in the rabbit model. Both short-term (up to 90 days) and long-term (2-yr) repetitive intravaginal administrations of WHI-07 at concentrations as high as 5.7 ´ 106 times its in vitro anti-HIV IC50 and 5700-times its spermicidal EC50 were not associated with mucosal, systemic, reproductive or developmental toxicity in mice and rabbits and did not produce increased carcinogenicity in mice. WHI-07 has clinical potential as a safe prophylactic contraceptive anti-HIV microbicide for sexually active women.
Keywords: contraceptive, microbicide, toxicity, zidovudine
15