IN VIVO EVALUATION OF CANDIDATE DRUGS

本项目旨在通过研究以等于或超过预期临床有效剂量的延长阴道和腹腔给药的临床效应，在小鼠中确定拟议项目中开发的药物的毒性和药效学。药效学（此处定义为啮齿动物模型中供试药物的器官位置和组织蓄积速率）将与项目2.4中的研究者合作确定。将通过项目1中所述的组织样本的HPLC和毛细管电泳分析以及项目2中开发的体内试验证明组织定位和蓄积。此外，我们还将通过药物体外暴露于灵长类动物精子对精子活力、形态和体外抗精子能力测定的影响，评价候选药物对男性生育力的潜在影响。本项目的最终目的是确定阴道滴注候选药物对经阴道途径接种SIV的非人灵长类动物中SIV感染的疗效。拟议的研究将利用在其他项目中开发和体外测试的金属天然卟啉（MNP），并将提供体内模型毒性的初步证据。此外，它将提供MNP在灵长类动物模型中抗病毒感染的临床疗效的初步证据。

This project is directed to establishing the toxicity and pharmacodynamics, in the mouse, of drugs developed in the proposed program by studying the clinical effects of extended vaginal and intraperitoneal administration at doses equal to and in excess of those predicted to be clinically effective. Pharmacodynamics, here defined as organ location and rate of tissue accumulation of the test drug(s) in the rodent model will be determined in collaboration with investigators in projects 2.4. Tissue location and accumulation will be demonstrated by HPLC and capillary electrophoretic analyses of tissue samples as described in Project l, and by use of in vivo tests developed in Project 2. In addition we will evaluate the potential effects of candidate drugs on male fertility as determined by the effects of in vitro exposure of agents to primate sperm on sperm viability, morphology and in vitro measures of fertilizing capacity. A final aim of this project is to determine the efficacy of vaginal instillation of candidate drugs on SIV infection in non-human primates inoculated with SIV by the vaginal route. The proposed research will utilize metallonatural porphyrins (MNPs) developed and tested in vitro in the other projects and will provide initial evidence of toxicity in an in vivo model. Further, it will provide preliminary evidence of clinical efficacy of MNPs against viral infection in a primate model.