A Nonhuman Primate Model for Human Cerebral Malaria: Effects of Artesunate (Qinghaosu Derivative) on Rhesus Monkeys Experimentally Infected with Plasmodium coatneyi

Yoshimasa MaenoInstitute of Pathology, Case Western Reserve University, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Cleveland, Ohio, Thailand

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Arthur E. BrownInstitute of Pathology, Case Western Reserve University, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Cleveland, Ohio, Thailand

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C. Dahlem SmithInstitute of Pathology, Case Western Reserve University, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Cleveland, Ohio, Thailand

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Tatsuya TegoshiInstitute of Pathology, Case Western Reserve University, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Cleveland, Ohio, Thailand

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Tetsuhiko ToyoshimaInstitute of Pathology, Case Western Reserve University, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Cleveland, Ohio, Thailand

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Christian F. OckenhouseInstitute of Pathology, Case Western Reserve University, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Cleveland, Ohio, Thailand

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Kevin D. CorcoranInstitute of Pathology, Case Western Reserve University, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Cleveland, Ohio, Thailand

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Montip NgampochjanaInstitute of Pathology, Case Western Reserve University, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Cleveland, Ohio, Thailand

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Dennis E. KyleInstitute of Pathology, Case Western Reserve University, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Cleveland, Ohio, Thailand

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H. Kyle WebsterInstitute of Pathology, Case Western Reserve University, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Cleveland, Ohio, Thailand

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Masamichi AikawaInstitute of Pathology, Case Western Reserve University, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Department of Immunology, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Cleveland, Ohio, Thailand

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We studied the effects of artesunate on rhesus monkeys infected with Plasmodium 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 were 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. Parasitemias of these groups ranged from 13.3% to 19.5% before treatment. Twenty-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 sequestration 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 that artesunate not only reduced parasitemia, but also reduced the rate of parasitized red blood cell (PRBC) sequestration in cerebral microvessels. In an immunohistologic study, endothelial-leukocyte adhesion molecule-1 (ELAM-1) was not detected in group I after treatment with artesunate, 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 interferes with continued PRBC sequestration in the cerebral microvessels in cerebral malaria. By using this animal model, we may be able to evaluate strategies for management of severe malaria as well as for the development of antimalarials and vaccines to prevent and/or cure cerebral malaria.

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