IN VIVO EVALUATION OF CANDIDATE DRUGS

该项目旨在通过研究延长剂量的阴道和腹膜给药的临床效果，建立在拟议的计划中开发的药物在小鼠身上的毒性和药效学，剂量等于或超过预测的临床有效剂量。药效学，这里定义为测试药物(S)在啮齿动物模型中的器官位置和组织蓄积率，将与项目2.4中的研究人员合作确定。组织的定位和蓄积将通过高效液相色谱和毛细管电泳法对组织样本进行分析，如L项目所述，并使用项目2中开发的体内测试。此外，我们还将评估候选药物对男性生育能力的潜在影响，通过体外暴露于灵长类精子对精子活力、形态和体外受精能力的影响来确定候选药物的潜在影响。本项目的最终目的是确定通过阴道途径接种SIV的非人灵长类动物经阴道滴注候选药物对SIV感染的疗效。这项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(MNPs)，并将在体内模型中提供毒性的初步证据。此外，它将在灵长类动物模型中提供MNPs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.