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) 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.
Posner
G H
GH
Department of Chemistry, Johns Hopkins University, Baltimore, Maryland.
Oh
C H
CH
Webster
H K
HK
Ager
A L
AL
Rossan
R N
RN
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000627:therapeutic use*; D001029:Aotus trivirgatus; D037621:Artemisinins; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000627:therapeutic use*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000627:therapeutic use*; D008288:Malaria / Q000188:drug therapy*; D016778:Malaria, Falciparum / Q000188:drug therapy*; D051379:Mice; D015394:Molecular Structure; D010962:Plasmodium berghei; D012717:Sesquiterpenes / Q000627:therapeutic use
D000962:Antimalarials; D037621:Artemisinins; D001952:Bridged-Ring Compounds; D006571:Heterocyclic Compounds; D012717:Sesquiterpenes; C031327:artemisinin; C055141:artemotil