Stampidine is a potential nonspermicidal broad-spectrum anti-human immunodeficiency virus microbicide.
OBJECTIVE
Stampidine (2,'3'-didehydro-3'-deoxythymidine-5'-(p-bromophenyl methoxy alaninyl phosphate) is a novel aryl phosphate derivative of stavudine/d4T with broad-spectrum anti-HIV activity in vitro and in vivo. This study investigated the potential utility of stampidine as a nonspermicidal microbicide.


METHODS
Prospective, controlled study.


METHODS
Center for Advanced Preclinical Sciences and Reproductive Biology Department.


METHODS
Seven sperm donors.


METHODS
Fifty-two sexually mature, female and twenty-four male New Zealand white rabbits.


METHODS
Human semen and genital tract epithelial cells were exposed to stampidine (up to 1 mM). Ovulated does in subgroups of 12 were artificially inseminated with rabbit semen pretreated with stampidine (1 mM) or vehicle. Does in subgroups of four and three, respectively, were exposed intravaginally to a gel or a thermoreversible ovule formulation with and without 0.5%, 1.0%, or 2.0% stampidine (9 to 36 mM) for 14 days.


METHODS
Effect of stampidine on human sperm motility, kinematics, penetration through cervical mucus, and epithelial cell viability. Reproductive parameters on gestation day 8. Vaginal tissues were histologically scored 24 hours after dosing.


RESULTS
Exposure of human sperm to stampidine even at a concentration 10(6)-times higher than its in vitro anti-HIV-1 activity (50% inhibitory concentration = 1 nM) had no adverse effect on sperm motility, kinematics, cervical mucus penetrability, or the viability of vaginal and endocervical epithelial cells. Reproductive indices of pregnancy rate, embryo implantation, and preimplantation losses were not affected by pretreatment of rabbit semen with stampidine. Gel formulations of 0.5% to 2.0% stampidine (9 to 36 mM) lacked mucosal toxicity.


CONCLUSIONS
The broad-spectrum anti-HIV agent stampidine had no adverse effect on sperm functions, was not cytotoxic, and did not induce mucosal toxicity. Stampidine has clinical potential as a prophylactic microbicide without contraceptive activity.
D'Cruz
Osmond J
OJ
Drug Discovery Program, Department of Virology, Parker Hughes Institute, 2657 Patton Road, St. Paul, MN 55113, USA. odcruz@ih.org
Uckun
Fatih M
FM
D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000737:chemistry; D001696:Biomechanical Phenomena; D002417:Cattle; D002582:Cervix Mucus / Q000502:physiology; D054306:Dideoxynucleotides; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D005260:Female; D005298:Fertility / Q000187:drug effects; D005782:Gels; D006678:HIV / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D009092:Mucous Membrane / Q000187:drug effects; D011247:Pregnancy; D011817:Rabbits; D013081:Sperm Motility / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects* / Q000502:physiology; D018119:Stavudine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry; D013938:Thymidine Monophosphate / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry; D014621:Vagina / Q000187:drug effects
D019380:Anti-HIV Agents; D054306:Dideoxynucleotides; D005782:Gels; C472384:stampidine; D013938:Thymidine Monophosphate; D018119:Stavudine