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首页> 外文期刊>Journal of applied toxicology >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.
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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.

机译：溴甲氧基齐多夫定（化合物whi-07）的双功能磷酸苯酯衍生物的阴道内凝胶微乳剂在B（6）C（3）F（1）中的亚慢性（13周）和生殖毒性潜力的评估老鼠。

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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. Copyright 2000 John Wiley & Sons, Ltd.
机译：人类免疫缺陷病毒（HIV）的异性传播占全球所有新感染的90％，并在美国导致新获得性免疫缺陷综合症（AIDS）病例。在开发能够预防HIV传播并提供生育控制的杀微生物避孕药的系统研究中，我们先前确定了3'-叠氮基3'-脱氧胸苷（zidovudine）的新型磷酸苯酯衍生物，它们具有强大的抗HIV和杀精子活性。 。这项研究报告了我们的铅化合物WHI-07（5-溴-6-甲氧基-5,6-二氢-3'-叠氮胸苷-5'-（对溴苯基）甲氧基丙氨酰磷酸酯）的临床前研究，功能外用杀菌剂。分别在静脉内和腹膜内给予WHI-07（20 mg kg（-1））的非人类灵长类动物和啮齿动物的体内毒性研究对血液学和临床化学特性没有可检测到的不利影响。在小鼠中研究了WHI-07阴道内凝胶微乳剂的13周亚慢性和生殖毒性潜力，以支持其作为双功能杀微生物剂的进一步发展。将十只雌性B（6）C（3）F（1）小鼠的组每周5天连续5周阴道内暴露于含有0、0.5、1.0或2.0％WHI-07的凝胶微乳剂中，连续13周。以摩尔计，这些浓度代表其体外杀精子效力EC（50）的1400-5700倍和其体外抗HIV活性（50）的1.4 x 10（6）-5.7 x 10（6）倍。阴道内治疗13周后，评估了一半的小鼠的毒性，另一半与未经治疗的雄性交配，以评估其潜在的生殖和发育影响。评估的终点包括生存率，体重增加，血液和临床化学，绝对和相对器官重量以及组织病理学。 WHI-07的应用并未导致体重减轻，发病率，死亡率或组织病理学可检测到的特定组织损伤。小鼠重复阴道内暴露于WHI-05，持续13周对随后的生殖性能（100％可育），新生儿存活率（> 95％）或幼仔发育没有不利影响。这些发现共同表明，实验性双功能抗HIV和避孕药WHI-07不会引起明显的急性或亚慢性毒性。版权所有2000 John Wiley＆Sons，Ltd.

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