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PLoS One. 2014 Apr 16;9(4):e94034. doi: 10.1371/journal.pone.0094034. eCollection 2014.

Subchronic toxicological study of two artemisinin derivatives in dogs.

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1
Beijing Institute of Pharmacology and Toxicology, Beijing, China.

Abstract

The objective of our study was to profile and compare the systematic changes between orally administered artesunate and intramuscularly injected artemether at a low dose over a 3-month period (92 consecutive days) in dogs. Intramuscular administration of 6 mg kg-1 artemether induced a decreased red blood cell (RBC) count (anemia), concurrent extramedullary hematopoiesis in the spleen and inhibition of erythropoiesis in the bone marrow. We also observed a prolonged QT interval and neuropathic changes in the central nervous system, which demonstrated the cortex and motor neuron vulnerability, but no behavioral changes. Following treatment with artesunate, we observed a decreased heart rate, which was most likely due to cardiac conduction system damage, as well as a deceased RBC count, extramedullary hematopoiesis in the spleen and inhibition of erythropoiesis in the bone marrow. However, in contrast to treatment with artemether, neurotoxicity was not observed following treatment with artesunate. In addition, ultra-structural examination by transmission electron microscopy showed mitochondrial damage following treatment with artesunate. These findings demonstrated the spectrum of toxic changes that result upon treatment with artesunate and artemether and show that the prolonged administration of low doses of these derivatives result in diverse toxicity profiles.

PMID:
24739881
PMCID:
PMC3989207
DOI:
10.1371/journal.pone.0094034
[Indexed for MEDLINE]
Free PMC Article
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