title: Evaluation of WR250417 (a proguanil analog) for causal prophylactic activity in the Plasmodium cynomolgi-Macaca mulatta model.
abstract: The Plasmodium cynomolgi-Macaca mulatta model has been used to test the antimalarial activity of new drugs for both radical cure and casual prophylaxis. The proguanil analog WR250417 (also known as PS-15) was evaluated for causal prophylactic activity in rhesus monkeys infected with P. cynomolgi bastianelli. Four monkeys were orally dosed with 40 mg/kg/day of WR250417 over three days (-1, 0, and +1). Sporozoite-induced infection of P. cynomolgi was initiated on day 0 with 1 x 10(6) sporozoites to each monkey. Compound WR250417 extended the prepatent period from an average of 8.5 days for controls (n = 2) to a mean of 18.3 days (range 18-19 days, n = 4) for drug-treated monkeys. Analysis of plasma drug concentrations by high-performance liquid chromatography showed that the monkeys converted the WR250417 to its putative principal active metabolite WR99210 (a dihydrotriazine). These findings demonstrate that WR250417 and its principal metabolite do not prevent primary infection by P. cynomolgi.
authors.affiliation: U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: M D
authors.initials: MD
authors.lastname: Edstein
authors.forename: K D
authors.initials: KD
authors.lastname: Corcoran
authors.forename: G D
authors.initials: GD
authors.lastname: Shanks
authors.forename: M
authors.initials: M
authors.lastname: Ngampochjana
authors.forename: P
authors.initials: P
authors.lastname: Hansukjariya
authors.forename: J
authors.initials: J
authors.lastname: Sattabongkot
authors.forename: H K
authors.initials: HK
authors.lastname: Webster
authors.forename: K H
authors.initials: KH
authors.lastname: Rieckmann
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D005260:Female; D006207:Half-Life; D008253:Macaca mulatta; D008288:Malaria / Q000097:blood / Q000517:prevention & control*; D008297:Male; D016789:Plasmodium cynomolgi; D002727:Proguanil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014227:Triazines / Q000097:blood
chemical_list: D000962:Antimalarials; D014227:Triazines; C082651:PS 15; C006201:BRL 6231; D002727:Proguanil