IN VIVO EVALUATION OF CANDIDATE DRUGS

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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.