EVALUATION OF DRUGS FOR ANTICRYPTOSPORIDIAL ACTIVITY

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Cryptosporidiosis is a well-recognized enteric disease in AIDS patients and other immunocompromised hosts, for which effective therapy is urgently needed. The long term goal is to identify treatment regimens for chronic cryptosporidiosis in AIDS patients. The specific aims of this proposed research are to determine the appropriate dose, treatment duration and therapeutic schedules that would enable individual drugs or drug combinations to either eradicate or control a cryptosporidial infection in immunosuppressed rats. Female Sprague-Dawley rats (225-250 gm) will be immunosuppressed with dexamethasone (0.25 mg/kg/day) for 10 days, infected with a standard dose of bovine-derived Cryptosporidium parvum oocysts, and then treated with drugs with specific modes of action against protozoans. Dependent on the specific aim the test animals will be sacrificed 11 to 79 days after oocyst inoculation, and the extent of infection determined histologically by analysis of hematoxylin and eosin stained sections of the small and large intestine. The severity of infection in a test drug-treatment group will be compared with that in immunosuppressed non-medicated control and drug-positive control groups. In addition to evaluating individual drugs for anticryptosporidial activity, drug combinations will be evaluated for synergistic anticryptosporidial activity in the immunosuppressed rat model. The principal aims are to identify drugs with anticryptosporidial activity and to characterize the conditions whereby these drugs can be an effective treatment for cryptosporidiosis and the eradication of the parasite.