CEREBRAL MALARIA--BIOCHEMICAL PHARMACOLOGY

由多药耐药恶性疟原虫引起的脑型疟疾是一种 严重的公共卫生问题是东南亚。 幸运的是，两个新的 抗疟剂，内过氧化物和铁螯合剂的类别， 对脑型疟疾有效。 这些药物在结构上 与任何喹啉类抗疟药无关，并且没有交叉- 阻力 铁和自由基在铁的作用方式中起着重要的作用。 这两种毒品。 内过氧化物是有效的抗疟药， 内寄生铁催化它们转化为通过去除铁从 一种寄生体内酶 此外，去铁胺的快速效果 可能与其抑制脑脂质代谢有关 过氧化作用 因此，铁和氧化应激都起重要作用， 在两种药物的作用模式中起相反的作用。 该项目代表了拟议的3臂生物化学组件 青蒿琥酯、去铁胺+奎宁和奎宁的临床比较研究 脑型疟疾的治疗。 拟议的研究将有助于 阐明两种药物的作用机制和毒性，并应 帮助选择和发展未来的治疗方案。 1)监测相关生化和寄生虫学参数， 参加临床试验的患者。 我们要找毒品- 在接受青蒿琥酯的患者血清中的烷基化蛋白。 我们 将确定药物如何影响血清氧化应激终点， 铁蛋白 我们还将寻找和鉴定耐药的 突变时复发。

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.