The mode of action of chloroquine and related malarial schizontocides.
Use of fast-acting blood schizontocidal drugs such as chloroqune, amodiaquine, mepacrine or quinine, is essential for the treatment of acute malaria infections. The spread of resistance in Plasmodium falciparum to chloroquine, the most useful of these drugs, has been a serious problem since the 1960s, and the resistant strains show various degrees of cross-resistance to other drugs. Design of replacement drugs requires knowledge of their modes of action and mechanisms of resistance. At present, there are two theories to explain the mode of action of chloroquine (Box 1). In this debate, Coy Fitch advances the hypothesis that chloroquine acts by delaying the sequestration of Ferriprotoporphyrin IX (FP) into malaria pigment, thereby allowing FP to exert its intrinsic cellular toxicity. In contrast, David Warhurst proposes a new 'Permease theory' suggesting that chloroquine is imported into the parasite cytoplasm on a membrane carrier (the permease) under the influence of a proton gradient; the drug would then interfere with lysosomal digestion of haemoglobin, thus starving the parasite of amino acids for protein synthesis.