ANTI-PNEUMOCYSTIS-CARINII ACTIVITY OF PS-15, A NEW BIGUANIDE FOLATE ANTAGONIST

A newly synthesized biguanide inhibitor of dihydrofolate reductase in Plasmodium species was evaluated for its anti-Pneumocystis carinii act ivity. The compound noxypropyloxy)-N'-(1-methylethyl)imidocarbonimidic diamide hydrochloride, designated PS-15, was administered prophylacti cally and therapeutically to immunosuppressed rats latently infected w ith P. carinii. Doses of 5 and 25 mg of PS-15 per kg of body weight pe r day given orally during 7 weeks of dexamethasone immunosuppression p revented P. carinii infection in all (100%) 19 rats given the drug, wh ile 6 of 9 (67%) untreated control rats developed P. carinii pneumonit is. A single weekly dose of 50 mg of PS-15 per kg also prevented the i nfection in all 10 rats. P. carinii pneumonitis was established after 4 weeks of immunosuppression and was then treated orally for 3 weeks w ith 25, 5, and 1 mg of PS-15 per kg/day. Complete resolution of the in fection occurred in all (100%) 10 rats given 25 mg of PS-15, 6 of 9 (6 7%) rats given 5 mg of PS-15, and 6 of 8 (75%) rats given 1.0 mg of PS -15 per kg per day and in all (100%) 9 rats treated with trimethoprim- sulfamethoxazole. PS-15 was well tolerated at all doses. Because drug studies in the P. carinii rat model have been highly predictable of th e effects of drugs on the disease in humans, these experiments suggest that PS-15 may have promise as a drug for the treatment of P. carinii pneumonitis in humans.