Heterosexual transmission of human immunodeficiency virus (HIV) accounts for 90% of all new
infections worldwide and significantly contributes to new
acquired immunodeficiency syndrome (
AIDS) cases in the USA. In a systematic effort to develop a microbicidal
contraceptive capable of preventing HIV transmission as well as providing
fertility control, we previously identified novel phenyl
phosphate derivatives of
3'-azido-3'-deoxythymidine (
zidovudine) that exhibit potent anti-HIV and spermicidal activities. This study reports the preclinical studies of our lead compound
WHI-07, 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl) methoxyalaninyl
phosphate, for use as a dual-function topical
microbicide. In vivo toxicity studies in non-human primates and rodents given
WHI-07 (20 mg kg(-1)) intravenously and intraperitonealy, respectively, had no detectable adverse effects on hematological and clinical chemistry profiles. The 13-week subchronic and reproductive toxicity potential of an intravaginal gel-microemulsion formulation of
WHI-07 was studied in mice to support its further development as a dual-function
microbicide. Groups of ten female B(6)C(3)F(1) mice were exposed intravaginally to a gel-microemulsion formulation containing 0, 0.5, 1.0 or 2.0%
WHI-07, 5 days a week, for 13 consecutive weeks. On a molar basis, these concentrations represent 1400-5700 times their in vitro spermicidal potency EC(50)) and 1.4 x 10(6)-5.7 x 10(6) times their in vitro anti-HIV activity(50)). After 13 weeks of intravaginal treatment, half of the treated mice were evaluated for toxicity and the other half were mated with untreated males to evaluate potential reproductive and developmental effects. The endpoints that were evaluated included survival,
body weight gain, hematological and clinical chemistries, absolute and relative organ weights and histopathology. The
WHI-07 applications did not cause
weight loss, morbidity, mortality or specific tissue lesions detectable by histopathology. Repeated intravaginal exposure of mice to
WHI-05 for 13 weeks had no adverse effects on subsequent reproductive performance (100% fertile), neonatal survival (>95%) or pup development. These findings collectively show that the experimental dual-function anti-HIV and
contraceptive agent
WHI-07 did not cause significant acute or subchronic toxicity.