NEW, ANTIMALARIAL, TRICYCLIC 1,2,4-TRIOXANES - EVALUATIONS IN MICE AND MONKEYS

We have concluded initial preclinical studies with synthetic trioxanes numbered 3-9 and have compared them with artemisinin (numbered 1) usi ng CD-1 mice infected with Plasmodium berghei. Based on their antimala rial effectiveness in mice, two of these synthetic trioxanes were sele cted for evaluation in Aotus monkeys infected with multidrug-resistant (MDR) P. falciparum. Trioxane numbered 8 (12 and 48 mg/kg), trioxane numbered 9 (12 and 48 mg/kg) and arteether (numbered 2, 48 mg/kg) were administered intramuscularly in three 12-hr doses to A. lemurinus lem urinus (Panamanian owl monkeys) infected with the Vietnam Smith/RE str ain of P. falciparum and monitored for parasitemia. Trioxane numbered 8 at 12 mg/kg cleared parasitemia in two monkeys, but recrudescence oc curred in one animal. Treatment of the recrudescent infection with 48 mg/kg was curative. Infections in two monkeys treated initially with 4 8 mg/kg were cured (six-month follow-up). Trioxane numbered 9 produced a similar outcome: 12 mg/kg suppressed parasitemia in two monkeys but was nut curative; however, 48 mg/kg cured infections in all four monk eys treated. These preliminary observations show synthetic trioxanes n umbered 8 and 9 to be as effective as arteether (numbered 2) against M DR in P. falciparum in the Aotus monkey.