ps-15 and Pneumocystis-Infections

In a rat model of dual infection, we studied such dihydrofolate reductase (DHFR) inhibitors as PS-15 (25 mg/kg of body weight), epiroprim (100 mg/kg), and pyrimethamine (3 mg/kg) alone or in combination with various doses of dapsone (50, 25, or 5 mg/kg) for the prevention of pneumocystosis and toxoplasmosis. Rats latently infected with Pneumocystis carinii were immunosuppressed by corticosteroids for 7 weeks, and the drugs were administered from the initiation of the corticosteroid treatment. At week 5, the rats were inoculated intraperitoneally with the RH strain of Toxoplasma gondii. Infections were monitored by the counting of P. carinii cysts in lung homogenates and the titration of T. gondii in organs by quantitative culture and an indirect immunofluorescence assay. Fourteen of the 15 untreated rats died after T. gondii challenge, with P. carinii infection in the lungs and T. gondii infection in the lungs, liver, spleen, and brain. Of the three tested DHFR inhibitors, only PS-15 exhibited anti-P. carinii activity; none prevented toxoplasmosis in 100% of the rats. After the DHFR inhibitors were combined with dapsone (50 or 25 mg/kg), both pneumocystosis and toxoplasmosis were completely prevented. On the basis of these results, PS-15 and epiroprim combined with dapsone are candidates for use for the prevention of both pneumocystosis and toxoplasmosis.

Topics: Animals; Anti-Bacterial Agents; Antiprotozoal Agents; Dapsone; Drug Therapy, Combination; Folic Acid Antagonists; Immunosuppression Therapy; Pneumocystis Infections; Proguanil; Pyrimethamine; Rats; Rats, Wistar; Tetrahydrofolate Dehydrogenase; Toxoplasma; Toxoplasmosis, Animal; Trimethoprim

Several drugs have been shown to have anti-Pneumocystis carinii activity in clinical trials. Because of the large number of patients required, no more than 3 drugs can be compared for efficacy in human studies. However, the experimental animal model for P. carinii pneumonitis is remarkably similar to the human disease and was used to compare 10 drugs for the relative potency against this infection. All drugs were compared at doses known to prevent the pneumonitis in > 80% of animals and at one-tenth of this dose. Drugs effective at the lowest dose were further tested at one-hundredth the original doses, and drugs ineffective were retested at 10 and 100 times the original dose. Trimethoprim-sulfamethoxazole was the most effective drug, with azithromycin-sulfamethoxazole and clarithromycin-sulfamethoxazole next most effective. Intravenous pentamidine and clindamycin-primaquine were the least effective. Atovaquone, sulfadoxine-pyrimethamine, erythromycin-sulfisoxazole, PS-15, and dapsone-trimethoprim had intermediate activity.

Topics: Animals; Anti-Infective Agents; Atovaquone; Azithromycin; Clarithromycin; Clindamycin; Clinical Trials as Topic; Dapsone; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Humans; Naphthoquinones; Pentamidine; Pneumocystis Infections; Proguanil; Pyrimethamine; Rats; Sulfadoxine; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

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.

Topics: AIDS-Related Opportunistic Infections; Animals; Antimalarials; Dose-Response Relationship, Drug; Folic Acid Antagonists; Imides; Immunosuppressive Agents; Lung; Male; Phenyl Ethers; Pneumocystis Infections; Pneumonia, Pneumocystis; Proguanil; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Trimethoprim, Sulfamethoxazole Drug Combination