TESTING OF EXPERIMENTAL 4 AMINOQUINOLINES IN MONKEY MODELS OF HUMAN MALARIA

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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.