Resistance to chloroquine (CQ), the drug of choice for malaria prophylaxis for 50 years, is one of the major health problems facing the developing world and travelers to malaria-endemic areas. We have recently found that modification of the isopentyl diaminoalkane side chain of chloroquine obviates chloroquine resistance in vitro. This strategy has yielded a series of CQ analogs with IC50s similar to CQ against CQ-susceptible Plasmodium falciparum and against CQ-resistant, mefloquine-resistant and multiply-resistant P. falciparum in vitro. We first tested these compounds for toxicity in mice and monkeys and tested their efficacy against P. cynomolgi in rhesus monkeys and against a CQ-resistant strain of P. falciparum in Saimiri monkeys. In mice no untoward toxicities were observed with doses of 5 mg/kg SC x 4 days. In rhesus monkeys no detectable adverse effects were observed with 7 mg/kg IM for 5 days nor 5 mg/kg per os for 7 days. The compounds were given per os to rhesus monkeys infected with P. cynomolgi (a simian model of human P. vivax) and to Saimiri monkeys infected with CQ-resistant P. falciparum. Serum samples for drug levels were taken at intervals throughout the treatment regimen. We found that a 5 mg/kg/day for 7 days dose of these compounds was sufficient to cure the rhesus monkeys and a similar dose was effective for the Saimiri monkeys. We are currently analyzing serum drug levels and determining the metabolic products of these compounds. One of these compounds (AQ13) is being produced in sufficient quantities for human trials, slated to begin in the summer of 1997.
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