A NONHUMAN PRIMATE MODEL FOR HUMAN CEREBRAL MALARIA - EFFECTS OF ARTESUNATE (QINGHAOSU DERIVATIVE) ON RHESUS-MONKEYS EXPERIMENTALLY INFECTED WITH PLASMODIUM-COATNEYI

We studied the effects of artesunate on rhesus monkeys infected with P lasmodium coatneyi. Sixteen rhesus monkeys were divided in four groups . Group I consisted of three monkeys that were splenectomized and were treated with three doses (loading dose: 3.3 mg/kg, maintenance doses: 1.7 mg/kg) of artesunate, group II consisted of three monkeys that we re treated with three doses of artesunate (same as group I), group III consisted of two monkeys that were treated with one dose (3.3 mg/kg) of artesunate, and group IV consisted of five untreated monkeys. Paras itemias of these groups ranged from 13.3% to 19.5% before treatment. T wenty-four hours after administration, the parasitemia was reduced to 2.2% in group I and to < 0.1% in group II; parasitemia was lowered to 10.6% in group III only 3 hr after drug administration. The rate of se questration in the cerebral microvessels, which was 29.4% in untreated animals, was < 0.1% in groups I and II (24 hr after treatment), and 2 .0% in group III (3 hr after treatment). These data clearly indicate t hat artesunate not only reduced parasitemia, but also reduced the rate of parasitized red blood cell (PRBC) sequestration in cerebral microv essels. In an immunohistologic study, endothelial-leukocyte adhesion m olecule-1 (ELAM-1) was not detected in group I after treatment with ar tesunate, although the presence of CD36, thrombospondin, intercellular adhesion molecule-1, IgG, and C3 in the cerebral microvessels was not altered. This is the first in vivo study to show that artesunate inte rferes with continued PRBC sequestration in the cerebral microvessels in cerebral malaria. By using this animal model, we may be able to eva luate strategies for management of severe malaria as well as for the d evelopment of antimalarials and vaccines to prevent and/or cure cerebr al malaria.