DEVELOPMENTAL THERAPEUTICS FOR P CARINII PNEUMONITIS

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The objective of the proposed research is the development of effective and safe drugs for the prevention and treatment of Pneumocystis carinii pneumonitis (PCP). Immunocompromised patients at high risk for PCP, especially those with AIDS, will benefit from such drugs. Currently available therapy is associated with a failure rate of about 25% and adverse effects occur in about 30% of cases. The research is intended to accomplish two aims: the establishment of a method for the in vitro cultivation of P. carinii and its adaptation to drug testing; and, to utilize the corticosteroid-treated rat model to screen new compounds and drug combinations for efficacy against PCP. The major thrust of the work is to cultivate P. carinii in sufficient quantity and purity to provide organisms for basic studies of structure and function. While consideration has been given to past and contemporary studies, the strategy proposed is to investigate through labor-intensive studies unique and often unconventional approaches to microbial cultivation. A wide range of cultural conditions with nutritional options, inhibitor deletions, growth stimulants, physical changes, electrolyte modification and host feeder cells will be investigated. A successful culture system will be utilized to study drug effects on P. carinii mitochondria, as well as overall cytopathogenicity and growth inhibition. The well-established corticosteroid-treated rat model will be used to evaluate new compounds (macrolides, quinolinemethanols, phenylphenols, dihydrofolate reductase and chitin synthesis inhibitors) and drug interactions for synergism. Drugs in or near clinical trials will be studied in rats for their relative efficacies to provide a guide for priorities in clinical trials.