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.

抗艾滋病毒治疗[最初，二脱氧腺苷(DDI)、联合DDI和 齐多夫定(AZT)，以及可能的TAT抑制剂]将在#年进行研究 妊娠6~15周及足月人胎盘的体外培养 (38-40周)。这些研究将解决经胎盘的问题 这些疗法的通过以及人类对它们的新陈代谢 胎盘以及这些药物对胎盘本身的毒性。 将采取多种方法来确定动力学和毒性 回应：1)正常人胎盘(HIV阴性)：两种技术将 用于研究新陈代谢、转移、细胞分布和 毒性：切片研究和双小叶胎盘灌注。切片 研究将比较早孕和足月妊娠的胎盘 组织结合/结合、新陈代谢、细胞 分布，以及对滋养细胞的毒性作用。双重灌流 研究将利用足月组织来建立双向移植 在治疗性血液中从母亲到胎儿和从胎儿到母亲的DDI 以及潜在的有毒血液水平。因为血液灌流可以 执行24小时，我们将能够评估DDI是否 对胎盘有任何直接的毒性作用，特别是在我们有 能够展示在这些灌流下发生的细胞分裂 条件。2)并发疾病胎盘：来自 宫内发育迟缓(IUGR)妊娠也将被评估。 人们认识到，IUGR不一定有共同的机制 起源，但这样的研究可能接近于不良妊娠 与艾滋病毒阳性妇女有关。如上所述的类似研究， 对于灌注研究，将对受损的研究进行 胎盘及其改变转移/代谢的分化能力 是DDI的。3)植入模型：这个实验室最近开发了一种 滋养层细胞立体功能培养新技术 人子宫内膜由单个细胞分化而来。这样的文化提供了 研究滋养层细胞、人类子宫内膜和 “植入过程”受到药物的影响。这样的研究将 提供机会来确定抗艾滋病毒药物如何产生不利影响 通过对胎盘的不利影响来影响发育过程 和/或子宫内膜。未来拟议的研究将检查新的抗艾滋病毒药物 治疗，如TAT抑制剂和免疫球蛋白，当这些药物成为 在临床上更相关。