TESTING OF EXPERIMENTAL 4 AMINOQUINOLINES IN MONKEY MODELS OF HUMAN MALARIA

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。疟疾仍然是世界上最具破坏性的疾病之一，每年造成100多万儿童死亡。50多年来，治疗疟疾的首选药物一直是氯喹（chloroquine， CQ），但由于氯喹耐药性在世界范围内日益普遍，这种药物的效用受到了影响。因此，研制安全有效的抗疟药物是全球卫生的一个优先事项。我们与热带医学系的同事一起开发了一系列4种氨基喹啉类药物，对恶性疟原虫引起的氯喹耐药疟疾具有活性。我们以前在人类疟疾的猴子模型中测试了一系列这些化合物，在恒河猴模型中测试了P. cynomolgi，这是人类间日疟疾的模型。我们以前测试的一种化合物（AQ13）被发现是一种有效的血液分裂剂，可在猴子身上对氯喹耐药分离物起作用，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AQ13联合使用的化合物的功效。利用我们的猴子模型，我们现在正在研究这类化合物是如何被肝脏中的P450酶代谢的。由于恒河猴的P450补体与人类相似，我们不仅能够评估功效，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 remains one of the world¿s most devastating diseases, killing over 1 million children a year. 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 will 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.