Short-Term (13-week) toxicity study of 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl) methoxyalaninyl phosphate (WHI-07), a novel anti-HIV and contraceptive agent, in B6C3F1 mice.
The zidovudine derivative, WHI-07 (5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl) methoxyalaninyl phosphate), is a dual-function spermicidal agent with potent anti-HIV activity. In this study, groups of 20 female B6C3F1 mice were exposed intravaginally to a gel microemulsion containing 0, 0.5, 1.0, or 2.0% WHI-07, 5 days per week for 13 consecutive weeks. On a molar basis, these concentrations of WHI-07 are 1400- to 5700-times higher than its spermicidal EC(50) and 1.4 x 10(6) to 5.7 x 10(6) times higher than its in vitro anti-HIV IC(50). After 13 weeks of intravaginal treatment, mice were evaluated for toxicity. The endpoints that were used for evaluation included survival, body weight, hematologic and clinical chemistry profiles, absolute and relative organ weights, and histopathology. No effects related to WHI-07 treatments were observed on survival, mean body weight, and mean body-weight gain. Repeated intravaginal exposure of mice to WHI-07 for 13 weeks had no toxicologically significant effect on organ weights, and did not cause any adverse changes in hematology parameters or blood chemistry profiles. Extensive histopathologic examination of tissues showed no lesions of pathologic significance. Thus, intravaginal application of WHI-07, for up to 13 weeks, does not cause systemic toxicity.
D'Cruz
O J
OJ
Drug Discovery Program, Department of Reproductive Biology, Parker Hughes Institute, St. Paul, Minnesota 55113, USA. odcruz@ih.org
Uckun
F M
FM
D000282:Administration, Intravaginal; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000633:toxicity*; D001772:Blood Cell Count; D001835:Body Weight / Q000187:drug effects; D002624:Chemistry, Clinical; D054306:Dideoxynucleotides; D004305:Dose-Response Relationship, Drug; D004655:Emulsions; D005260:Female; D005782:Gels; D008136:Longevity / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000187:drug effects; D010316:Particle Size; D013089:Spermatocidal Agents / Q000008:administration & dosage / Q000633:toxicity*; D013938:Thymidine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity*; D018675:Toxicity Tests; D015215:Zidovudine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity*
C114570:5-bromo-6-methoxy-5, 6-dihydro-3'-azidothymidine-5'-(p-bromophenyl) methoxyalaninyl phosphate; D019380:Anti-HIV Agents; D054306:Dideoxynucleotides; D004655:Emulsions; D005782:Gels; D013089:Spermatocidal Agents; D013938:Thymidine Monophosphate; D015215:Zidovudine