ps-15 and Disease-Models--Animal

Sixteen Saimiri sciureus monkeys were administered PS-15-atovaquone, PS-15-sulfamethoxazole, PS-15-dapsone, PS-15 alone, and atovaquone alone. The in vitro antimalarial activity of serum against Plasmodium falciparum obtained from these monkeys at 3, 6, and 12 hr after the administration of drug(s) were measured by bioassay and analyzed by Duncan's and Newman-Keul's tests. PS-15-atovaquone was found to be the most effective antimalarial combination, followed by PS-15-sulfamethoxazole, PS-15-dapsone, PS-15 alone, and atovaquone alone. These dual PS-15 combinations are effective combinations and, in-particular, PS-15-atovaquone is worthy of further evaluation.

Topics: Animals; Antimalarials; Atovaquone; Biological Assay; Dapsone; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Humans; Malaria, Falciparum; Naphthoquinones; Proguanil; Regression Analysis; Saimiri; Sulfamethoxazole

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

The Plasmodium cynomolgi-Macaca mulatta model has been used to test the antimalarial activity of new drugs for both radical cure and casual prophylaxis. The proguanil analog WR250417 (also known as PS-15) was evaluated for causal prophylactic activity in rhesus monkeys infected with P. cynomolgi bastianelli. Four monkeys were orally dosed with 40 mg/kg/day of WR250417 over three days (-1, 0, and +1). Sporozoite-induced infection of P. cynomolgi was initiated on day 0 with 1 x 10(6) sporozoites to each monkey. Compound WR250417 extended the prepatent period from an average of 8.5 days for controls (n = 2) to a mean of 18.3 days (range 18-19 days, n = 4) for drug-treated monkeys. Analysis of plasma drug concentrations by high-performance liquid chromatography showed that the monkeys converted the WR250417 to its putative principal active metabolite WR99210 (a dihydrotriazine). These findings demonstrate that WR250417 and its principal metabolite do not prevent primary infection by P. cynomolgi.

Topics: Administration, Oral; Animals; Antimalarials; Chromatography, High Pressure Liquid; Disease Models, Animal; Female; Half-Life; Macaca mulatta; Malaria; Male; Plasmodium cynomolgi; Proguanil; Triazines