Qinghaosu resistance in rodent malaria.

Resistance to qinghaosu (artemisinin) developed rapidly in a chloroquine-resistant line of Plasmodium yoelii (NS) passaged in mice, but was not produced in chloroquine-sensitive P. berghei. Development of resistance took place in an apparently stepwise fashion. After removal of drug selection pressure some resistance was lost which was regained rapidly within three passages when drug pressure was reapplied. The resistant QS line was cross-resistant to two reduced derivatives of artemisinin but not to propoxycarbonyl dihydroartemisinin or artesunate. No significant resistance was shown against primaquine, pyrimethamine, cycloguanil or pyrimethamine-sulphadoxine, but resistance to chloroquine was enhanced and marked resistance to quinine, mefloquine and amodiaquine was noted. It is suggested that the unusual cross-resistance pattern of the strain relates to changes in membrane characteristics.

The effect of combinations of qinghaosu (artemisinin) with standard antimalarial drugs in the suppressive treatment of malaria in mice.

Artemisinin is a novel antimalarial drug isolated in China from the wormwood plant Artemisia annua L. Studies with rodent malaria were carried out to detect antagonism and synergism with a variety of antimalarial drugs. Isobolograms of drug interaction were plotted at the ED90 level. With a normally susceptible strain of Plasmodium berghei, marked potentiative synergism was found with mefloquine, tetracycline and spiramycin. There was some synergism also with primaquine. Combinations of artemisinin with dapsone, sulfadiazine, sulfadoxine, pyrimethamine, pyrimethamine/sulfadoxine and cycloguanil showed antagonism. A high degree of potentiation was shown between artemisinin and primaquine with a primaquine-resistant strain, whilst the combination with mefloquine showed enhanced potentiation with a mefloquine-resistant strain. Combinations of artemisinin with mefloquine, primaquine, tetracycline or clindamycin showed marked potentiation with an artemisinin-resistant strain. The mechanisms underlying the drug interactions observed are discussed.

The effect of artemisinin combined with standard antimalarials against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum in vitro.

The activity of artemisinin (qinghaosu) in combination with some commonly-used antimalarial drugs was tested in vitro against a chloroquine-sensitive (NF54) and a chloroquine-resistant (K1) strain of Plasmodium falciparum. Both mefloquine and tetracycline showed marked potentiative synergism with artemisinin against both strains, whilst primaquine showed potentiation against K1. Combinations of artemisinin with pyrimethamine and with chloroquine were antagonistic. The results confirm observations on rodent malaria in vivo and indicate that the drug interactions seen were direct, through actions on the parasite, and not merely effects on drug distribution and metabolism in the mouse host.