D'Cruz O J, Waurzyniak B, Yiv S H, Uckun F M
Department of Reproductive Biology, Drug Discovery Program, Parker Hughes Institute, St. Paul, Minnesota, USA.
Contraception. 2000 Jan;61(1):69-76. doi: 10.1016/s0010-7824(99)00118-3.
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 United States. 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) which exhibit potent anti-HIV and spermicidal activities. This study reports the preliminary preclinical study of our lead compound WHI-05, 5-bromo-6-methoxy-5, 6-dihydro-3'-azidothymidine-5'-(p-methoxyphenyl) methoxyalaninyl phosphate, for use as a dual-function topical microbicide. Acute toxicity studies have shown that WHI-05 has no detectable adverse effects on laboratory animals. The 13-week subchronic and reproductive toxicity potential of intravaginal gel-microemulsion formulation of WHI-05 were studied in mice to support its further development as a virucidal spermicide. Groups of 10 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-05, 5 days/week for 13 consecutive weeks. On a molar basis, these concentrations represent 300 to 1200 times their in vitro spermicidal potency, and 1.5x10(4) to 6.1x 10(4) times their in vitro anti-HIV activity. After 13 weeks of intravaginal treatment, one half of treated mice were evaluated for toxicity, and the other half were mated with untreated males to evaluate potential reproductive and developmental effects. Repetitive intravaginal application of WHI-05 to yield a local concentration 6.1x10(4) times higher than its in vitro HIV IC(50) value and 1200 times higher than its spermicidal EC(50)96%), or pup development. These findings collectively show that the experimental dual-function anti-HIV and contraceptive agent, WHI-05, did not cause significant acute or subchronic and reproductive toxicity under the test conditions.
人类免疫缺陷病毒（HIV）的异性传播占全球所有新感染病例的90%，在美国新获得性免疫缺陷综合征（AIDS）病例中也占显著比例。为了系统地研发一种既能预防HIV传播又能控制生育的杀微生物避孕药，我们之前鉴定出了3'-叠氮基-3'-脱氧胸苷（齐多夫定）的新型苯基磷酸酯衍生物，这些衍生物具有强大的抗HIV和杀精活性。本研究报告了我们的先导化合物WHI-05（5-溴-6-甲氧基-5,6-二氢-3'-叠氮胸苷-5'-(对甲氧基苯基)甲氧基丙氨酰磷酸酯）作为双功能局部杀微生物剂的初步临床前研究。急性毒性研究表明，WHI-05对实验动物没有可检测到的不良影响。在小鼠中研究了WHI-05阴道凝胶微乳制剂的13周亚慢性和生殖毒性潜力，以支持其作为杀病毒杀精剂的进一步开发。将10只雌性B(6)C(3)F(1)小鼠分为几组，每周5天，连续13周经阴道给予含0%、0.5%、1.0%或2.0% WHI-05的凝胶微乳制剂。按摩尔计算，这些浓度分别是其体外杀精效力的300至1200倍，以及其体外抗HIV活性的1.5×10(4)至6.1×10(4)倍。经阴道治疗13周后，对一半经治疗的小鼠进行毒性评估，另一半与未治疗的雄性小鼠交配，以评估潜在的生殖和发育影响。重复经阴道应用WHI-05，使局部浓度比其体外HIV半数抑制浓度（IC(50)）值高6.1×10(4)倍，比其杀精半数有效浓度（EC(50)）高1200倍，未发现对母体健康、生育力（产仔数）或幼仔发育有显著影响。这些研究结果共同表明，在测试条件下，实验性双功能抗HIV和避孕剂WHI-05不会引起显著的急性、亚慢性和生殖毒性。
