CEREBRAL MALARIA--BIOCHEMICAL PHARMACOLOGY

由多重耐药性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，有两个新 抗疟药、内过氧化物和铁螯合剂的类别是 对治疗脑型疟疾有效。 这些药物在结构上 与任何喹啉抗疟药无关，并且没有交叉作用 阻力。 铁和自由基在其作用方式中发挥重要作用 两类药物。 内过氧化物是有效的抗疟药，因为 内寄生铁通过去除铁来催化其转化为 一种体内寄生酶。 此外，去铁胺的快速作用 昏迷的缓解可能与其抑制脑脂质有关 过氧化。 因此，铁和氧化应激都很重要，尽管 两种药物的作用方式相反。 该项目代表了拟议的 3 臂的生化成分 比较青蒿琥酯、去铁胺奎宁和奎宁的临床研究 在治疗脑型疟疾方面。 拟议的研究将有助于 阐明两种药物的作用方式和毒性，并应 帮助选择和制定未来的治疗方案。 1) 监测相关生化和寄生虫学参数 患者参加了临床试验。 我们将寻找毒品—— 接受青蒿琥酯治疗的患者血清中的烷基化蛋白质。 我们 将确定药物如何影响血清氧化应激终点以及 铁蛋白。 我们还将寻找并鉴定耐药性 当复发发生时突变体。

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.