TESTING OF EXPERIMENTAL 4 AMINOQUINOLINES IN MONKEY MODELS OF HUMAN MALARIA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 疟疾，一种古老的人类祸害，今天仍然是世界上儿童的最大杀手之一。50多年来，治疗疟疾的首选药物一直是氯喹(CQ)，但由于全世界对CQ的耐药性日益普遍，这种药物的效用受到了影响。因此，开发安全有效的抗疟疾药物是全球卫生优先事项。与我们部门的同事一起。热带医学研究所，TSPHTM，我们开发了一系列4种氨基喹啉类药物，对恶性疟原虫引起的氯喹耐药性疟疾具有活性。我们之前曾在人类疟疾的猴子模型猕猴体内测试过一系列这些化合物，食蟹猴是人类间日疟的模型。我们之前测试的其中一种化合物(AQ13)被发现是一种有效的血液分裂剂，可以对抗猴子对氯喹耐药菌株，已经完成了第一阶段的人体试验，目前正在马里进行第二阶段的试验。我们现在正在研究其他化合物的疗效，这些化合物可能会与AQ13结合使用。利用我们的猴子模型，我们现在正在观察这类化合物是如何由肝脏中的P450酶代谢的。由于恒河猴的P450补体与人类相似，我们不仅能够评估疗效，而且能够查看药代动力学参数，包括吸收、生物利用度、AUC、排泄率和其他可能预测这些化合物用于治疗人类疟疾的能力的因素。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Malaria, an ancient scourge of mankind, is still one of the biggest killers of children in the world today. The treatment of choice for malaria for over 50 years has been chloroquine (CQ) but the utility of this drug has been compromised by the increasing prevalence of CQ resistance worldwide. Consequently, the development of safe and effective antimalarials is a global health priority. Together with our colleagues at the Dept. of Tropical Medicine, TSPHTM, we have developed a series of 4 aminoquinolines active against chloroquine-resistant malaria caused by Plasmodium falciparum. We have previously tested a series of these compounds in a monkey model of human malaria, P. cynomolgi in the rhesus macaque, a model of human vivax malaria. One of the compounds we tested previously (AQ13) was found to be an efficacious blood schizonticide against a chloroquine resistant isolate in the monkeys, has completed Phase I human trials, and is currently being tested in Phase II trials in Mali. We are now looking at the efficacy of other compounds which can potentially be used in combination with AQ13.Using our monkey models we are now looking at how this class of compounds is metabolized by P450 enzymes in the liver. Because the P450 complement of the rhesus macaque is similar to that of humans, we are not only able to assess efficacy but have the ability to look at pharmacokinetic parameters, including absorption, bioavailability, AUC, rate of excretion, and other factors which may be predictive of the ability of these compounds to be used for treatment of human malaria.