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Pharmacokinetic and Pharmacodynamic Evaluation of Intramuscular Artesunate in Healthy Beagle Dogs

Pharmacokinetic and Pharmacodynamic Evaluation of Intramuscular Artesunate in Healthy Beagle Dogs,Kent Bennett,Yuanzheng Si,Thomas Steinbach,Jing Zhan

Pharmacokinetic and Pharmacodynamic Evaluation of Intramuscular Artesunate in Healthy Beagle Dogs  
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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.
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