The chemotherapy of rodent malaria. LIV. Combinations of ‘Fenozan B07’ (Fenozan-50F), a difluorinated 3,3′-spirocyclopentane 1,2,4-trioxane, with other drugs against drug-sensitive and drug-resistant parasites

Abstract

Fenozan B07, a 1,2,4-trioxane endoperoxide with potent blood schizontocidal activity against drug-sensitive and drug-resistant rodent malaria parasites, exerted a modest potentiating action when administered with chloroquine (CQ) to mice infected with parasites of the CQ-resistant P. yoelii ssp. NS, but not when given to mice infected with the CQ-sensitive P. berghei N strain. The reason why this potentiation may be of particular value in the treatment of severe falciparum malaria is discussed. Mefloquine and halofantrine displayed a similar level of potentiation with Fenozan B07 against the CQ-resistant parasites. However, antagonism was shown by combinations of Fenozan B07 with pyronaridine or the 8-aminoquinoline WR 238 605 when used against CQ-resistant parasites. Mefloquine with Fenozan B07 is also antagonistic against a highly mefloquine-resistant line of P. yoelii ssp. NS. The reasons behind such antagonism are not known. The importance is stressed of using carefully selected drug combinations of novel antimalarials, rather than single drugs, in order to impede the selection of drug-resistant parasites, but only after adequate, preclinical, toxicity testing.