title: Evaluation of subchronic (13-week) and reproductive toxicity potential of intravaginal gel-microemulsion formulation of a dual-function phenyl phosphate derivative of bromo-methoxy zidovudine (compound whi-07) in B(6)C(3)F(1) mice.
abstract: 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.
authors.affiliation: Drug Discovery Program, Parker Hughes Institute, St. Paul, MN 55113, USA. odcruz@ih.org
authors.forename: O J
authors.initials: OJ
authors.lastname: D'Cruz
authors.forename: B
authors.initials: B
authors.lastname: Waurzyniak
authors.forename: S H
authors.initials: SH
authors.lastname: Yiv
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D002626:Chemistry, Pharmaceutical; D054306:Dideoxynucleotides; D004906:Erythrocyte Count / Q000187:drug effects; D005260:Female; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010755:Organophosphates / Q000737:chemistry; D012098:Reproduction / Q000187:drug effects*; D013089:Spermatocidal Agents / Q000633:toxicity*; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives* / Q000633:toxicity*; D018675:Toxicity Tests; D015431:Weight Loss / Q000187:drug effects; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000633:toxicity*
chemical_list: C114570:5-bromo-6-methoxy-5, 6-dihydro-3'-azidothymidine-5'-(p-bromophenyl) methoxyalaninyl phosphate; D019380:Anti-HIV Agents; D054306:Dideoxynucleotides; D010755:Organophosphates; D013089:Spermatocidal Agents; D013938:Thymidine Monophosphate; D015215:Zidovudine; C074782:phenylphosphate