The chemotherapy of rodent malaria. LVIII. Drug combinations to impede the selection of drug resistance, Part. 2: The new generation--artemisinin or artesunate with long-acting blood schizontocides.

Abstract

The search for combinations of antimalarial drugs that will impede the selection of drug resistance, especially in Plasmodium falciparum, is currently focused on the use of a member of the artemisinin family, with a short half-life, in association with a relatively long-acting blood schizontocide. Experiments with such 'third-generation' combinations, in mice infected either with chloroquine-sensitive P. berghei or P. chabaudi, or chloroquine-resistant P. yoelii ssp. NS, have produced interesting results. The data collected, using the '2% relapse technique' (2%RT), indicate that a combination of artemisinin with mefloquine can impede to a significant degree, although by no means completely, the selection of resistance to both compounds in P. berghei and in P. yoelii ssp. NS. Similarly, a combination of artesunate with pyronaridine impedes the selection of resistance to these compounds in P. berghei. Parallels are drawn between observations with such combinations in man and in the rodent models which, it is argued, once again demonstrate their value in predicting the protective value of using different types of antimalarials together. Evidence is presented that resistance to single compounds may emerge more rapidly when a high dose is employed in the 2%RT than a lower dose. It is noted also that the rate at which resistance to pyronaridine is selected by a given dose varies with the species of rodent Plasmodium, and the relevance of this to the malarial parasites of human is discussed.