PHASE I AND II STUDIES OF INVESTIGATIONAL AMINOQUINOLINES

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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. The worldwide incidence and mortality of malaria are overwhelming, with more than 300 million cases and 1-2 million deaths each year. Despite the overwhelming nature of this problem, antimalarial therapy is in serious difficulty. Chloroquine (CQ), which has been the single most important malarial for more than forty years, is now compromised by the steadily increasing prevalence of CQ resistance in Southeast Asia, South America and Africa. Alternative drugs such as mefloquine and halofantrine are themselves compromised by increasing resistance in Southeast Asia, especially Thailand. Quinine and quinidine are compromised by both their toxicity, and the emergence of partial resistance. In addition, CQ is the only antimalarial known to be safe for use in pregnant women. For all these reasons, AQs similar to CQ which were active against resistant parasites, would be a major asset in the treatment of malaria. If those compounds were similar enough to CQ, they might be similarly nontoxic, and could therefore be a major improvement over alternatives such as tetracycline (which cannot be given to children less than eight years of age or to pregnant women) and artemisinin (which produced cerebellar toxicity in dogs and may dissolve fetuses in pregnant mice and rats). This study is based on an investigational aminoquinoline (AQ-13) which is active against chloroquine (CQ)-susceptible, CQ resistant, mefloquine-resistant and multiply resistant P. falciparum in vitro; against a CQ-susceptible parasite similar to P. vivax in vivo in rhesus monekys (P. Cynomolgi); and against CQ-resistant P. falciparum in vivo in squirrel monkeys. The specific aims of this project are to: 1) define the safety and pharmacokinetics of an investigational aminoquinoline (AQ-13) among adult volunteers in New Orleans; 2) define the efficacy and pharmacokinetics of AQ-13 for asymptomatic CQ-susceptible P. falciparum infections in Maliam adults; and 3) define the efficacy and pharmacokinetics of AQ-13 for symptomatic chloroquine resistant P. falciparum infections in Malian adults.