The chemotherapy of rodent malaria. LVI. Studies on the development of resistance to natural and synthetic endoperoxides.

Chloroquine-sensitive Plasmodium berghei N and chloroquine-resistant P. yoelii ssp. NS were exposed to selection pressure, in the '2% relapse technique', from artemisinin, artesunate, a bicyclic, synthetic endoperoxide Ro 41-3823 (an analogue of arteflene) or Fenozan B07, a synthetic 1,2,4-trioxane endoperoxide. Whereas resistance against artemisinin did develop to a moderate level in both parasites, only a low level of resistance or none developed to the other compounds, and resistant parasites readily lost resistance once drug-selection pressure was withdrawn. The relevance of these observations and the experience of other investigators are discussed in relation to the possible risk that resistance may be developed in nature once endoperoxides are deployed widely against multidrug-resistant P. falciparum.