New, antimalarial, tricyclic 1,2,4-trioxanes: evaluations in mice and monkeys

Am J Trop Med Hyg. 1994 Apr;50(4):522-6. doi: 10.4269/ajtmh.1994.50.522.

Abstract

We have concluded initial preclinical studies with synthetic trioxanes numbered 3-9 and have compared them with artemisinin (numbered 1) using CD-1 mice infected with Plasmodium berghei. Based on their antimalarial effectiveness in mice, two of these synthetic trioxanes were selected 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 lemurinus (Panamanian owl monkeys) infected with the Vietnam Smith/RE strain of P. falciparum and monitored for parasitemia. Trioxane numbered 8 at 12 mg/kg cleared parasitemia in two monkeys, but recrudescence occurred in one animal. Treatment of the recrudescent infection with 48 mg/kg was curative. Infections in two monkeys treated initially with 48 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 not curative; however, 48 mg/kg cured infections in all four monkeys treated. These preliminary observations show synthetic trioxanes numbered 8 and 9 to be as effective as arteether (numbered 2) against MDR in P. falciparum in the Aotus monkey.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antimalarials / chemical synthesis
  • Antimalarials / therapeutic use*
  • Aotus trivirgatus
  • Artemisinins*
  • Bridged-Ring Compounds / chemical synthesis
  • Bridged-Ring Compounds / therapeutic use*
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / therapeutic use*
  • Malaria / drug therapy*
  • Malaria, Falciparum / drug therapy*
  • Mice
  • Molecular Structure
  • Plasmodium berghei*
  • Sesquiterpenes / therapeutic use

Substances

  • Antimalarials
  • Artemisinins
  • Bridged-Ring Compounds
  • Heterocyclic Compounds
  • Sesquiterpenes
  • artemisinine
  • artemotil