A newly synthesized
biguanide inhibitor of
dihydrofolate reductase in Plasmodium species was evaluated for its anti-Pneumocystis carinii activity. The compound N-3-(2,4,5-trichlorophenoxypropyloxy)-N'-(1-methylethyl)imidoca rbonimidic
diamide hydrochloride, designated
PS-15, was administered prophylactically and therapeutically to immunosuppressed rats latently infected with P. carinii. Doses of 5 and 25 mg of
PS-15 per kg of
body weight per day given orally during 7 weeks of
dexamethasone immunosuppression prevented P. carinii
infection in all (100%) 19 rats given the
drug, while 6 of 9 (67%) untreated control rats developed P. carinii
pneumonitis. A single weekly dose of 50 mg of
PS-15 per kg also prevented the
infection in all 10 rats. P. carinii
pneumonitis was established after 4 weeks of immunosuppression and was then treated orally for 3 weeks with 25, 5, and 1 mg of
PS-15 per kg/day. Complete resolution of the
infection occurred in all (100%) 10 rats given 25 mg of
PS-15, 6 of 9 (67%) 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 the 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.