Toltzis P, Marx C M, Kleinman N, Levine E M, Schmidt E V
Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio.
J Infect Dis. 1991 Jun;163(6):1212-8. doi: 10.1093/infdis/163.6.1212.
A novel toxicity associated with zidovudine (AZT), the standard antiviral therapy for infection with human immunodeficiency virus, is described. When AZT was administered to mice to evaluate its safety during gestation, the animals failed to complete pregnancy successfully. Mice receiving AZT during gestation yielded fewer fetuses (P = .003) and greater numbers of resorptions (P = .003) per pregnant mouse compared with untreated animals. Drug effects on adult mice were assessed to determine if toxicity could account for the pregnancy failures. However, adult animals receiving AZT demonstrated no adverse effects with regard to growth, food consumption, activity, or ovarian histology. A direct toxic effect of AZT on the mouse embryo was tested by cultivating single-cell fertilized oocytes in vitro in the presence of increasing concentrations of drug. Exposure to AZT was highly correlated with failure to develop to the blastocyst stage (P less than .001). These data indicate that AZT has a direct toxic effect on the developing mouse embryo. Further analysis of the nature of this toxicity may be important in designing less toxic antiretroviral agents and in planning future uses of AZT.
本文描述了一种与齐多夫定（AZT）相关的新型毒性，AZT是治疗人类免疫缺陷病毒感染的标准抗病毒疗法。当给小鼠服用AZT以评估其在妊娠期的安全性时，这些动物未能成功完成妊娠。与未治疗的动物相比，在妊娠期接受AZT的小鼠每只怀孕小鼠的胎儿数量更少（P = 0.003），吸收胎数量更多（P = 0.003）。评估了药物对成年小鼠的影响，以确定毒性是否可解释妊娠失败。然而，接受AZT的成年动物在生长、食物消耗、活动或卵巢组织学方面未表现出不良反应。通过在体外培养单细胞受精卵母细胞并增加药物浓度，测试了AZT对小鼠胚胎的直接毒性作用。暴露于AZT与未能发育到囊胚阶段高度相关（P小于0.001）。这些数据表明AZT对发育中的小鼠胚胎有直接毒性作用。进一步分析这种毒性的性质对于设计毒性较小的抗逆转录病毒药物以及规划AZT的未来用途可能很重要。
