DEVELOPMENTAL THERAPEUTICS FOR P CARINII PNEUMONITIS

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Pneumocystis carinii pneumonitis (PCP) is a major life-threatening infection associated with the acquired immune dificiency (AID) syndrome. Only two drugs are available for treatment, pentamidine and trimethoprim-sulfamethoxazole (TMP-SMZ). The manufacture of pentamidine has been discontinued and about 1/3 of patients will not respond to TMP-SMZ. The objective of this study is to develop new drugs for the treatment of PCP. The specific aims are to evaluate a variety of drugs in the corticosteroid treated rat model for PCP, using the expeirmental design of our previous studies in the development of TMP-SMZ for PCP. The animal model correlates precisely with the disease in humans and employs young Sprague-Dawley rats maintained on dexamethasone and tetracycline. Within 3 months of immunosuppression over 90% of animals develop extensive PCP. Drugs to be tested are selected because of known activity against other protozoal agents and include: allopurinol, suramin, nifurtimox, benzonidazole, melarsoprol, salicylhydroxamic acid and glycerol, a difluoromethylornithine, primaquine, quinacrine, emetine hydrochloride and ketoconazole. Initial experiments will screen drugs for efficacy by administering the test drug during the immunosuppression and determining the effect on the prevention of PCP in comparison to untreated controls. Promising drugs will then be tested for effects in the treatment of PCP once the pneumonitis is established, using 3 dose levels. When optimal doses of effective drugs are determined comparison will be made with the drugs in current use separately and in rational combinations. Efficacy will be determined from histological examination of lungs in comparison to untreated controls.