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Efficacy of Trimetrexate, a Potent Lipid-Soluble Antifolate, in the Treatment of Rodent Pneumocystis Carinii Pneumonia

Joseph A. Kovacs, Carmen J. Allegra^*, Susan Kennedy, Judith C. Swan, James Drake^*, Joseph E. Parrillo, Bruce Chabner^* AND Henry Masur

Critical Care Medicine Department, Clinical Center,
^* Clinical Pharmacology Branch, Division of Cancer Treatment,
Department of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

Trimetrexate is a lipid-soluble antifolate that has been shown in vitro to be a much more potent inhibitor of Pneumocystis carinii dihydrofolate reductase than the conventionally used inhibitor trimethoprim. To evaluate the in vivo efficacy of trimetrexate, steroid-treated rats which spontaneously develop P. carinii pneumonia were used. Rats treated with trimetrexate (25 mg/kg/d) plus sulfamethoxazole (250 mg/kg/d) orally responded at least as well as rats treated with trimethoprim (50 mg/kg/d) plus sulfamethoxazole. Trimetrexate alone administered orally was ineffective in treating P. carinii infection, but subcutaneous (sc) trimetrexate (7 mg/kg/d) significantly decreased the intensity of infection compared to controls. Trimetrexate is a potent antifolate that may provide an effective alternative to pentamidine and trimethoprim-sulfamethoxazole for treatment of P. carinii pneumonia in humans.

Accepted for publication April 17, 1988.