CAUSAL PROPHYLACTIC AND RADICAL CURATIVE ACTIVITY OF WR182393 (A GUANYLHYDRAZONE) AGAINST PLASMODIUM-CYNOMOLGI IN MACACA-MULATTA

Primaquine is the only currently available drug effective against pers istent tissue stages of relapsing malaria in humans. Causal prophylact ic and radical curative properties of WR182393 (a guanylhydrazone) wer e investigated as part of an effort to evaluate alternatives to primaq uine in the rhesus monkey (Macaca mulatta)/Plasmodium cynomolgi test m odel. The drug was suspended in dimethylsulfoxide for intramuscular (i m) injection. A pilot study indicated causal prophylactic activity in a regimen of 40 mg base/kg/day im for three days beginning the day bef ore intravenous challenge with 1 x 10(6) P. cynomolgi sporozoites. Reg imens of 31, 10, 3. 1, and 0 mg base/kg/day im for three days were the n tested in groups of two monkeys given a similar challenge. The two a nimals given 31 mg base/kg/day remained parasite-free. Average time to parasitemia for the lower dosage groups was 38, 18, and 8 days respec tively. Groups of two monkeys with sporozoite-induced P. cynomolgi inf ections were also treated for seven days with 31, 10, 3. 1, and 0 mg b ase/kg/day im in combination with 10 mg base/kg/day of chloroquine ora lly. Both monkeys given 31 mg base/kg/day did not relapse. The average time to relapse following treatment was 48, 29, and 8 days, respectiv ely, for the lower dosage groups. Compound WR182393 is the first non-8 -aminoquinoline class of drug to exhibit both causal prophylactic and radical curative properties against a relapsing primate, vivax-like ma laria.