TOXICITY OF AIDS DRUGS ON HUMAN PLACENTA

艾滋病药物对人胎盘的毒性

• 批准号: 3144127
• 负责人: JOSEPH DANCIS
• 金额: $ 10.65万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-11-01 至 1992-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3144127
• 关键词: antiAIDS agent; cell differentiation; cell growth regulation; communicable disease transmission; drug metabolism; embryo /fetus drug adverse effect; embryo /fetus toxicology; female; high performance liquid chromatography; human pregnant subject; human tissue; placenta; placental transfer; tissue /cell culture; trophoblast; zidovudine

HIV infection of infants generally occurs ante-or intra-partum. The logical approach to the prevention or the reduction in the severity of infection is to treat the infected mother. AZT and other nucleosides are currently under consideration for such use. However, the administration of AZT is often associated with bone marrow depression raising the possibility of a general adverse effect on rapidly proliferating tissue. The fetal tissue that is exposed to the highest concentration of maternally administered medication in the placenta. Interference with placental function could have serious secondary effects in the fetus. Our recent observation that AZT is extensively metabolized by the placenta raises the possibility of local toxicity. The antiviral effect of AZT, as well as its toxic effects, is attributed to metabolites of AZT, particularly the triphosphate. A safe technique for investigating these questions before clinical trials with AZT and other anti-AIDS drugs is highly desirable. It is proposed to employ human trophoblast in tissue culture to study the metabolism of AZT and its effect on growth, differentiation and function of the trophoblast. This approach will complement our previously funded study of the placental transfer and metabolism of drugs for AIDS using placental perfusion. That proposal focuses on the potential exposure of the developing fetus to AZT and other nucleosides and their metabolites in contrasts to the present proposal which will concentrate on the effects of AZT, and possibly other drugs related to the treatment of AIDS on the trophoblast itself. An additional approach which would add a new dimension to this line or inquiry is the development of a polarized syncytiotrophoblast barrier in vitro by using bicameral filter chamber devices. Such a model have a wide application in examining the effects of AZT and other drugs, on trophoblast function, the transmission of HIV virus and the transfer of other molecules across the placenta.

婴儿的HIV感染通常发生在伴有静脉内或伴形。 这 预防或降低严重程度的逻辑方法 感染是为了治疗受感染的母亲。 AZT和其他核苷是 目前正在考虑此类使用。 但是，管理 AZT通常与骨髓抑郁症有关，从而增加了可能性 对快速增殖组织的一般不利影响。 胎儿 暴露于最高浓度母体的组织 在胎盘中服用药物。 干扰胎盘 功能可能对胎儿产生严重的继发作用。 我们最近 观察到AZT被胎盘广泛代谢 局部毒性的可能性。 AZT及其的抗病毒作用 有毒作用归因于AZT的代谢产物，特别是 三磷酸盐。 在调查这些问题之前的安全技术 非常需要使用AZT和其他抗AID药物进行临床试验。 它 建议在组织培养中利用人类滋养细胞研究 AZT的代谢及其对生长，分化和功能的影响 滋养细胞。 这种方法将补充我们先前资助的研究 使用胎盘的辅助药物的胎盘转移和代谢 灌注。 该提案的重点是潜在的暴露 在AZT和其他核苷及其代谢物中发展为胎儿 与本提案形成对比，该提议将集中于 AZT，以及可能与治疗艾滋病治疗的其他药物 滋养细胞本身。 另一种方法将增加新的维度 对此行或查询是两极分化的发展 通过使用双色滤波器室内的合成胞育肉芽细胞屏障体外 设备。 这样的模型在检查的影响方面具有广泛的应用 AZT和其他药物，关于滋养细胞功能，HIV病毒的传播 以及其他分子在胎盘中的转移。