PLACENTA--ANTI-HIV THERAPY

胎盘素--抗艾滋病毒治疗

• 批准号: 3147323
• 负责人: Richard Kermit Miller
• 金额: $ 23.3万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3147323
• 关键词: 2'3' dideoxynucleoside; AIDS; AIDS therapy; combination chemotherapy; drug adverse effect; drug metabolism; embryo implantation; endometrium; high performance liquid chromatography; histology; human immunodeficiency virus; human tissue; perfusion; placenta; placental transfer; tissue /cell culture; trophoblast; zidovudine

Anti-HIV therapy [initially, dideoxyadenosine (DDI) , combination DDI and zidovudine (AZT), and possibly TAT inhibitors] will be investigated in the human placenta in vitro from 6-15 weeks of gestation and at term (38-40 weeks). These studies will address the issues of transplacental passage of these therapies, as well as their metabolism by the human placenta and the toxicity of these agents on the placenta itself. Multiple approaches will be undertaken to determine the kinetic and toxic responses: 1) Normal Human Placentas (HIV-Negative): Two technics will be used to study metabolism, transfer, cellular distribution, and toxicity: slice studies and dual lobular placental perfusion. Slice studies will compare placentas from early and term pregnancies for differences in tissue binding/incorporation, metabolism, cellular distribution, and toxic effects on the trophoblast. Dual perfusion studies will utilize term tissue to establish the bidirectional transfer of DDI from mother to fetus and from fetus to mother at therapeutic blood levels and potentially toxic blood levels. Since the perfusions can be performed for periods of 24 hrs, we will be able to evaluate whether DDI has any direct toxic effect on the placenta, especially since we have been able to demonstrate cell division occurring under these perfusion conditions. 2) Intercurrent Disease Placentae: Placentas from intrauterine growth retarded (IUGR) pregnancies will also be evaluated. It is recognized that IUGR does not necessarily have a common mechanism of origin, but such studies may approximate compromised pregnancies associated with HIV positive women. Similar studies as described above, for the perfusion studies, will be performed to study compromised placentas and their differential ability to alter the transfer/metabolism of DDI. 3) Implantation Model: This laboratory has recently developed a novel culture technic for trophoblast in three-dimension and functioning human endometrium from single cells. Such cultures provide the opportunity for studying how the trophoblast, the human endometrium, and the "implantation process" are affected by the drugs. Such studies would provide the opportunity to determine how anti-HIV drugs may adversely affect the developmental process via adversely affecting the placenta and/or endometrium. Future proposed studies would examine new anti-HIV therapy, e.g., TAT inhibitors and immunoglobulins, as these agents become clinically more relevant.

抗HIV疗法[最初是二乙基氧化核苷（DDI），组合DDI和 Zidovudine（AZT）以及可能的TAT抑制剂]将在 从6-15周的妊娠和期间，人体胎盘在体外体外 （38-40周）。 这些研究将解决移植的问题 这些疗法的通过以及人类的新陈代谢 胎盘和这些药物在胎盘本身上的毒性。 将采用多种方法来确定动力学和有毒 回答：1）正常的人胎盘（HIV阴性）：两种技术将 用于研究代谢，转移，细胞分布和 毒性：切片研究和双小叶胎盘灌注。 片 研究将比较早期和学期怀孕的胎盘 组织结合/融合，代谢，细胞的差异 分布和对滋养细胞的毒性作用。 双重灌注 研究将利用术语组织建立双向转移 DDI从母亲到胎儿，从胎儿到母亲在治疗性血液中 水平和潜在毒性血液水平。 因为灌注可以是 进行24小时的时间，我们将能够评估DDI是否 对胎盘有任何直接毒性作用，尤其是因为我们有 能够证明在这些灌注下发生的细胞分裂 状况。 2）胎盘间疾病胎盘：胎盘 还将评估宫内生长迟缓（IUGR）妊娠。 认识到IUGR不一定具有共同的机制 起源，但此类研究可能近似损害怀孕 与艾滋病毒阳性女性有关。 如上所述类似的研究 对于灌注研究，将进行研究 胎盘及其改变转移/代谢的差异能力 DDI。 3）植入模型：该实验室最近开发了 三维和功能的滋养细胞的新型文化技术 来自单细胞的人子宫内膜。 这样的文化提供了 研究滋养细胞，人子宫内膜和 “植入过程”受药物的影响。 这样的研究会 提供机会来确定抗HIV药物如何不利 通过不利影响胎盘影响发育过程 和/或子宫内膜。 未来提议的研究将检查新的抗HIV 随着这些药物的变化，例如TAT抑制剂和免疫球蛋白的治疗 临床上更相关。