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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Developmental toxicology studies of WHI-07, a novel nucleoside analogue-based dual-function microbicide, administered intravaginally to rabbits.

The zidovudine derivative, 5-bromo-6-methoxy-5,6-dihydro-3-azidothymidine-5'-(p-bromophenyl) methoxy alaninyl phosphate (WHI-07), is a dual-function spermicidal and anti-HIV agent with contraceptive and microbicidal activity. In previous subchronic and reproductive toxicity studies and a two-year carcinogenicity study, daily intravaginal application of 0.5 to 2.0% WHI-07 via a gel-microemulsion, was shown to cause no local, systemic and reproductive toxicity or increased carcinogenicity in mice. To evaluate the developmental toxicity potential of WHI-07 in a nonrodent model, subgroups of 20 superovulated NZW rabbits were artificially inseminated and exposed intravaginally to a gel-microemulsion containing 0, 0.5, 1.0, or 2.0% WHI-07 during major organogenesis [gestation days 6-18]. The dose of WHI-07 was equivalent to 1.4x10(6) to 5.7x10(6) times its anti-HIV IC50 and 1400 to 5700 times its spermicidal EC50. Throughout the duration of the experiment (GD 0-29), clinical observations, food consumption, and body weights were recorded. Reproductive and fetal parameters were evaluated following uterotomies on GD 29. Measurements included numbers of corpora lutea, pregnancy, number and distribution of implantations, resorptions, live and dead fetuses, fetal weight, sex ratio, and gross external and skeletal malformations and variations. Maternal food consumption and body weight gain were unaffected by WHI-07 treatment. Hematologic and clinical chemistry determinations on GD 19 and 29 revealed no treatment-related maternal effects. Prior studies of repeated intravaginal administration of WHI-07 gel-microemulsion revealed lack of local toxicity to rabbit vaginal mucosa. In the current study, no drug-related gross lesions were apparent at necropsy. Reproductive indices, ie, pregnancy rate, gravid uterine weights, litter size, number of corpora lutea, implantation sites, pre- and postimplantation losses, viable fetuses, resorptions, fetal body weights, and fetal sex ratio, were not affected by intravaginal exposure to WHI-07. External, and skeletal examinations of fetuses for malformations and variations did not reveal any evidence of teratogenicity in any WHI-07-treated groups. Intravaginal administration of WHI-07 at concentrations as high as 2% did not produce teratogenicity or other developmental toxicity in rabbit conceptus. These findings indicated that WHI-07 shows unique clinical potential to become the active ingredient of a new female-controlled topical microbicidal vaginal contraceptive for women who are at high risk of acquiring HIV/AIDS.[1]


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