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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 疟疾是人类的一个古老祸害，仍然是当今世界儿童的最大杀手之一。50多年来，氯喹（CQ）一直是疟疾的首选治疗药物，但由于世界范围内CQ耐药性的日益普遍，这种药物的效用受到了影响。因此，开发安全有效的抗疟药物是全球卫生的优先事项。与我们的同事在部门。TSPHTM，我们已经开发了一系列的4氨基喹啉，对由恶性疟原虫引起的氯喹抗性疟疾有活性。我们之前已经在人疟疾的猴模型中测试了一系列这些化合物，在恒河猴中测试了食蟹猴疟原虫，人间日疟的模型。我们之前测试的化合物之一（AQ 13）被发现是一种有效的血液杀线虫剂，可对抗猴子中的氯喹耐药分离株，已完成I期人体试验，目前正在马里进行II期试验。我们现在正在研究其他可能与AQ 13联合使用的化合物的疗效。使用我们的猴模型，我们现在正在研究这类化合物如何在肝脏中被P450酶代谢。由于恒河猴的P450补体与人类的相似，我们不仅能够评估疗效，而且能够观察药代动力学参数，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.