title: A 13-week subchronic intravaginal toxicity study of the novel broad-spectrum anti-HIV and spermicidal agent, N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (PHI-346) in mice.
abstract: The nonnucleoside inhibitor (NNI) of HIV-1 reverse transcriptase, PHI-346 (N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea), is a dual-function spermicidal agent with potent anti-HIV activity against drug-sensitive as well as drug-resistant HIV-1 strains with genotypic and phenotypic NNI resistance. PHI-346 was formulated via a lipophilic gel-microemulsion for intravaginal use as a potential dual-function microbicide. To evaluate the toxicity potential of short-term intravaginal exposure to PHI-346, groups of 15 female B6C3F1 and CD-1 mice were exposed intravaginally to a gel-microemulsion containing 0, 0.5, 1.0, or 2.0% PHI-346, 5 days per week for 13 consecutive weeks. On a molar basis, these concentrations of PHI-346 are 350 to 1,400-times higher than its spermicidal EC50 and nearly 5 x 10(6) to 2 x 10(7) times higher than its in vitro anti-HIV IC50. After 13 weeks of intravaginal treatment, B6C3F1 mice were evaluated for survival, body weight gain, absolute and relative organ weights. Blood was analyzed for hematology and clinical chemistry profiles. Microscopic examination was performed on hematoxylin and eosin-stained tissue sections from each study animal. Placebo control and PHI-346 dosed female CD-1 mice were mated with untreated males in order to evaluate if PHI-346 has any deleterious effects on the reproductive performance. There were no treatment-related mortalities. Mean body weight gain during the dosing period was not reduced by PHI-346 treatment. The hemogram or blood chemistry profiles revealed lack of systemic toxicity following daily intravaginal instillation of PHI-346 for 13 weeks. No clinically significant changes in absolute and relative organ weights were noted in PHI-346 dose groups. Extensive histopathological examination of tissues revealed no treatment-related abnormalities in any of the three PHI-346 dose groups. Repeated intravaginal exposure of CD-1 mice to increasing concentrations of PHI-346 for 13 weeks had no adverse effect on their subsequent reproductive capability, perinatal outcome, growth, and development of offspring. Collectively, these findings demonstrate that repetitive intravaginal administration of PHI-346 at concentrations as high as 1,400-times its spermicidal EC50 and 2 x 10(7) times its in vitro anti-HIV IC50 was not associated with local or systemic toxicity and did not adversely affect the reproductive performance in mice. PHI-346 may be useful as an active ingredient of a safe vaginal microbicide for prevention of the sexual transmission of multidrug-resistant HIV-1.
authors.affiliation: Drug Discovery Program, Parker Hughes Institute, St. Paul, Minnesota 55113, USA. odcruz@ih.org
authors.forename: Osmond J
authors.initials: OJ
authors.lastname: D'Cruz
authors.forename: Barbara
authors.initials: B
authors.lastname: Waurzyniak
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000282:Administration, Intravaginal; D000631:Aminopyridines / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D019963:Clinical Chemistry Tests; D004305:Dose-Response Relationship, Drug; D005260:Female; D005298:Fertility / Q000187:drug effects; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006403:Hematologic Tests; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity; D013089:Spermatocidal Agents / Q000008:administration & dosage / Q000633:toxicity*; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity*; D018675:Toxicity Tests
chemical_list: D000631:Aminopyridines; D019380:Anti-HIV Agents; C122094:N-(2-(1-cyclohexenyl)ethyl)-N'-(2-(5-bromopyridyl))thiourea; D018894:Reverse Transcriptase Inhibitors; D013089:Spermatocidal Agents; D054303:HIV Reverse Transcriptase; D013890:Thiourea