DEVELOPMENT THERAPEUTICS FOR P CARINII PNEUMONITIS

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Pneumocystis carinii pneumonitis (PCP) is fatal in the immunocompromised host. It occurs in 75% of AIDS patients and with the most effective treatment the fatality rate is 25%. Furthermore, adverse reactions occur in over 40% of patients to drugs in current use. The objective of the proposed study is to identify effective and safe drugs for PCP. The corticosteroid-treated rat model will be used for in vivo studies to determine the therapeutic and prophylactic efficacies of a series of hydroxynephthoquinone compounds, one of which we have already found to have anti-P. carinii activity in preliminary studies. The relative efficacies of menoctone, parvaquone, lawsone, danthron, alkannin, lapinone, lapachone and buparvaquone will be determined by experiments in which each compound is administered to a group of P. carinii immunosuppressed rats for 6 to 8 weeks, after which the extent of pulmonary infection will be compared to untreated controls. Therapeutic effects will be determined by administration of the drugs at varying dose levels to animals with well established PCP. Histology of pulmonary parenchyma will determine the extent of PCP. Potential synergistic combinations of hydroxynaphthoquinones will be tested with a pyridine, clopidol and the quinolone, decoquinate. All drugs will be compared to the 3-hydroxy-1, 4-naphthoquinone (St. Jude #1) we have found to have anti-P. carinii activity. P. carinii "cidal" and "static" effects will be determined. The inhibition of P. carinii by a hydroxynaphthoquinone compound suggests the site of action to be on mitochondrial respiration, as occurs with other protozoa. We propose to isolate P. carinii mitochondria from intracystic sporozoites. P. carinii cysts will be separated from host cells and other microbes by centrifugation methods to isolate mitochondria. Rat hepatocyte mitochondria will serve as controls and 02 uptake will be measured by the method Frye and Williams. Drugs will be applied and the inhibition expressed as an EC 50 (concentration required to cause 50% inhibition of respiration). Correlations will be made between in vitro and in vivo activity of each drug. Thus, an in vitro system to screen drugs for anti-P carinii activity might be developed.