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Am. J. Trop. Med. Hyg., 50(2), 1994, pp. 181-186
Copyright © 1994 by The American Society of Tropical Medicine and Hygiene

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Evaluation of WR250417 (A Proguanil Analog) for Causal Prophylactic Activity in the Plasmodium cynomolgi-Macaca mulatta Model

Michael D. Edstein, Kevin D. Corcoran, G. Dennis Shanks, Montip Ngampochjana, Pranee Hansukjariya, Jetsumon Sattabongkot, H. Kyle Webster AND Karl H. Rieckmann
U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; Army Malaria Research Unit, Liverpool Military Area, New South Wales, Australia

The Plasmodium cynomolgi-Macaca mulatta model has been used to test the antimalarial activity of new drugs for both radical cure and causal 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 106 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.




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M. D. Edstein, B. M. Kotecka, A. L. Ager, K. S. Smith, C. A. DiTusa, D. S. Diaz, D. E. Kyle, G. A. Schiehser, D. P. Jacobus, K. H. Rieckmann, et al.
Antimalarial pharmacodynamics and pharmacokinetics of a third-generation antifolate JPC2056 in cynomolgus monkeys using an in vivo in vitro model
J. Antimicrob. Chemother., October 1, 2007; 60(4): 811 - 818.
[Abstract] [Full Text] [PDF]


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Copyright © 1994 by the American Society of Tropical Medicine and Hygiene.