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Am. J. Trop. Med. Hyg., 79(1), 2008, pp. 36-41
Copyright © 2008 by The American Society of Tropical Medicine and Hygiene

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Pharmacokinetic and Pharmacodynamic Evaluation of Intramuscular Artesunate in Healthy Beagle Dogs

Kent Bennett*, Yuanzheng Si, Thomas Steinbach, Jing Zhang, AND 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

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.

Received April 29, 2007. Accepted for publication April 20, 2008.

Acknowledgments: The authors thank Peter Weina, Adam Haeberle, Colin Ohrt, members of the Clinical Pharmacology Department at the Walter Reed Army Institute of Research, and four anonymous reviewers for valuable comments on the manuscript.

Financial support: This study was supported by the US Army Research and Materiel Command.

Disclaimer: The opinions or assertions contained herein are the private views of the authors and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense.

* Address correspondence to Kent Bennett, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500. E-mail: Kent.Bennett{at}us.army.mil

Authors’ addresses: Kent Bennett, Yuanzheng Si, Jing Zhang, and Qigui Li, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500, E- mails : Kent.Bennett{at}us.army.mil, Yuanzheng.Si{at}amedd.army.mil, Jing.Zhang{at}amedd.army.mil, and Qigui.Li{at}amedd.army.mil. Thomas Steinbach, Division of Pathology, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500, E-mail: Thomas.Steinbach{at}med.navy.mil.






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Copyright © 2008 by the American Society of Tropical Medicine and Hygiene.