TOXICITY OF AIDS DRUGS ON HUMAN PLACENTA

婴儿感染艾滋病毒通常发生在产前或产中。这个 预防或减轻疾病严重程度的合理途径 感染就是治疗被感染的母亲。AZT和其他核苷 目前正在考虑用于此类用途。然而，美国政府 AZT经常与骨髓抑制有关，增加了这种可能性 对快速增殖的组织有普遍的不良影响。胎儿 暴露在母体最高浓度下的组织 给胎盘注射药物。对胎盘的干扰 这种功能可能会对胎儿产生严重的次要影响。我们最近 观察到AZT被胎盘广泛代谢提高了 局部毒性的可能性。AZT的抗病毒作用及其临床意义 毒性作用，归因于AZT的代谢物，特别是 三磷酸盐。一种安全的技术来调查这些问题之前 使用AZT和其他抗艾滋病药物进行临床试验是非常可取的。它 建议将人滋养层细胞用于组织培养，以研究 AZT的代谢及其对生长、分化和功能的影响 滋养层细胞。这一方法将补充我们之前资助的研究 利用胎盘转移和代谢治疗艾滋病药物的研究进展 灌流。该提案的重点是 发育中胎儿对AZT等核苷及其代谢物的影响 与目前的提案形成鲜明对比的是，目前的提案将集中于 AZT，可能还有其他与艾滋病治疗有关的药物 滋养层本身。一种额外的方法，将添加新的维度 对这条线或探究的发展是一种两极分化 应用双腔滤池体外构建合体滋养层屏障 设备。这样的模型在检验的影响方面有广泛的应用 AZT等药物对滋养层功能、HIV病毒传播的影响 以及其他分子在胎盘上的转移。

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.