Pharmacokinetic and Pharmacodynamic Evaluation of Intramuscular Artesunate in Healthy Beagle Dogs

Kent Bennett Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland; Department of Pathology, Navy Medical Research Center, Silver Spring, Maryland

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Yuanzheng Si Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland; Department of Pathology, Navy Medical Research Center, Silver Spring, Maryland

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Thomas Steinbach Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland; Department of Pathology, Navy Medical Research Center, Silver Spring, Maryland

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Jing Zhang Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland; Department of Pathology, Navy Medical Research Center, Silver Spring, Maryland

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Qigui Li Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland; Department of Pathology, Navy Medical Research Center, Silver Spring, Maryland

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Pharmacokinetic and pharmacodynamic responses were evaluated after intramuscular (IM) injection of artesunate (AS). Twelve dogs were injected with IM AS at 2.5, 5, or 10 mg/kg into the left gluteal muscle. A second injection of only diluent was given in the right gluteal muscle. At 24 hours post-injection, plasma creatine kinase (CK) concentrations were elevated above normal. Muscle biopsies showed myocyte necrosis and acute inflammation, which was worse on the treated side. At 7 days after injection, CK concentrations were normal. Muscle biopsies showed mineralization, fibrosis, and chronic inflammation with less difference between sides. Compared with intravenous administration, IM AS resulted in a prolonged half-life for both AS and DHA. Intramuscular AS also had a lower mean dose-adjusted Cmax and a higher mean dose-adjusted area under the curve; but produced similar concentrations of dihydroartemisinin. These findings suggest that adverse reactions to IM artesunate are minor and temporary which justify further study of this route in treating severe malaria.

Author Notes

  • 1

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  • 2

    Hien TT, Davis TM, Chuong LV, Ilett KF, Sinh DXT, Phu NH, Agus C, Chiswell GM, White NJ, Farrar J, 2004. Comparative pharmacokinetics of intramuscular artesunate and artemether in patients with severe falciparum malaria. Antimicrob Agents Chemother 48 :4234–4239.

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  • 3

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    Dondorp A, Nosten F, Stepniewska K, Day N, White N, 2005. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 366 :717–725.

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    Batty KT, Thu LTA, Ilett KF, Tien NP, Powell SM, Hung NC, Mai TX, Chon VV, Thien HV, Binh TQ, Kim NV, Davis TM, 1998. A pharmacokinetic and pharmacodynamic study of arte-sunate for vivax malaria. Am J Trop Med Hyg 59 :823–827.

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    Griffith KS, Lewis LS, Mali S, Parise ME, 2007. Treatment of malaria in the United States: a systemic review. JAMA 297 :2264–2277.

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