CEREBRAL MALARIA--BIOCHEMICAL PHARMACOLOGY

耐多药恶性疟原虫引起的脑型疟疾是一种 东南亚是严重的公共卫生问题。幸运的是，有两个新的 抗疟疾药物的类别，内氧化物和铁络合剂，有 能有效治疗脑型疟疾。这些药物在结构上是 与任何喹啉类抗疟药无关，也没有交叉- 抵抗。 铁和自由基在体内的作用方式中起着重要作用。 两种药物都有。过氧化内酯是有效的抗疟疾药物，因为 寄生体内的铁通过去除铁来催化它们转化为 一种寄生内生酶。此外，去铁胺的快速疗效 对昏迷的解救作用可能与其抑制脑脂有关 过氧化。因此，铁和氧化应激都发挥着重要作用，尽管 在两种药物的作用模式中扮演相反的角色。 该项目代表了拟议的3-ARM的生化组成部分 青蒿琥酯、去铁胺奎宁和奎宁的临床比较研究 用于治疗脑型疟疾。拟议的研究将会有所帮助。 阐明这两种药物的作用方式和毒性，并应 帮助选择和开发未来的治疗方案。 1)监测有关生化和寄生虫学参数 参加临床试验的患者。我们会寻找毒品- 接受青蒿琥酯治疗的患者血清中的烷化蛋白。我们 将确定这些药物如何影响血清氧化应激终点和 铁蛋白。我们还将寻找和表征抗药性 发生复发时的突变体。

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.