TOXICITY OF AIDS DRUGS ON HUMAN PLACENTA

艾滋病药物对人胎盘的毒性

• 批准号: 3144126
• 负责人: JOSEPH DANCIS
• 金额: $ 10.61万
• 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/3144126
• 关键词: antiAIDS agent; cell differentiation; cell growth regulation; communicable disease transmission; drug metabolism; embryo /fetus drug adverse effect; embryo /fetus toxicology; 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.

婴儿感染艾滋病毒通常发生在产前或产时。 的 预防或减少严重性的逻辑方法 治疗感染的母亲。 AZT和其他核苷是 目前正在考虑这种用途。 然而， AZT通常与骨髓抑制有关， 对快速增殖的组织有普遍的不良影响。 胎儿 暴露于最高浓度母体 在胎盘中给药。 干扰胎盘 可能会对胎儿产生严重的副作用。 我们最近 观察到AZT被胎盘广泛代谢， 局部毒性的可能性。 AZT的抗病毒作用， 毒性作用，归因于AZT的代谢物，特别是 三磷酸盐 一个安全的技术来调查这些问题之前， AZT和其它抗艾滋病药物的临床试验是非常需要的。 它 利用组织培养的人滋养层细胞， AZT的代谢及其对生长、分化和功能的影响 滋养层 这种方法将补充我们以前资助的研究 利用胎盘研究艾滋病药物的胎盘转移和代谢 灌注。 该提案的重点是潜在的风险， AZT和其他核苷及其代谢物的影响。 与目前的建议相反，目前的建议将集中在以下方面的影响： AZT，以及其他可能与治疗艾滋病有关的药物， 滋养层本身。 一种将增加一个新层面的额外办法 这条线或调查是一个两极分化的发展 应用双室滤室法体外建立合体滋养层屏障 装置. 这种模型在检验下列因素的影响方面有广泛的应用 AZT等药物，对滋养层功能、HIV病毒的传播 以及其他分子在胎盘中的转移。