CEREBRAL MALARIA--BIOCHEMICAL PHARMACOLOGY

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Cerebral malaria due to multidrug-resistant Plasmodium falciparum is a serious public health problem is Southeast Asia. Fortunately, two new classes of antimalarial agents, endoperoxides and iron chelator, are effective in treating cerebral malaria. These drugs are structurally unrelated to any of the quinoline antimalarial and exhibit no cross- resistance. Iron and free radicals play important roles in the modes of action of both classes of drugs. Endoperoxides are effective antimalarial because intraparasitic iron catalyzes their conversion into by removing iron from an intraparasitic enzyme. Furthermore, the rapid effect of deferoxamine on resolution of coma may be due to its inhibition of cerebral lipid peroxidation. Thus, both iron and oxidant stress play important albeit opposite roles in the modes of action of both drugs. This project represent the biochemical component of the proposed 3-arm clinical study comparing artesunate, deferoxamine + quinine, and quinine in the treatment of cerebral malaria. The proposed studies will help elucidate the modes of action and toxicity of the two drugs, and should aid in the choice and development of future treatment protocols. 1) Monitor relevant biochemical and parasitological parameters in patients enrolled in the clinical trials. We will look for drug- alkylated proteins in the serum of patients receiving artesunate. We will determine how the drugs affect serum oxidant stress endpoints and iron proteins. We will also look for and characterized drug-resistant mutants when recrudescence occur.