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Current Topics in Toxicology   Volumes    Volume 3 
Fatal neurotoxicity of the artemisinin derivatives is related to drug pharmacokinetic profiles in animal species
Qigui Li, Wilbur K. Milhous, Peter J. Weina
Pages: 1 - 16
Number of pages: 16
Current Topics in Toxicology
Volume 3 

Copyright © 2006 Research Trends. All rights reserved


Artemisinin has been identified as the active antimalarial principle of qinghaosu, a plant used for centuries to treat malaria in China. Artemisinin, and its developed analogues dihydroartemisinin (DHA), artemether (AM), arteether (AE), artesunate (AS), and artelinate (AL), are highly effective against the erythro-cytic stages of P. falciparum in vivo and in vitro. In the past decade, in vivo toxicity studies have showed a dose-dependent neurotoxic effect associated with movement disturbances, spasticity, brain tissue damages, and even death in animal species administered intra-muscularly with oil-soluble artemisinin derivatives, AM and AE. In contrast, few neurotoxic effects were induced by water-soluble artemisinins, AS and AL, which in early studies never induced any CNS side-effects in animal species after intravenous injection. To date, however, neuro-toxicity has not been convincingly demonstrated in humans treated with any of the artemisinins. Pharmacokinetic profiles demonstrate that fatal neurotoxicity was caused by the oil-soluble artemisinins (sesame oil vehicle) because the drug depot in the intramuscular injection sites resulted in a long drug exposure time due to the slow and prolonged absorption in the muscle and accumulation in the blood. The mild and light toxicities induced by the water-soluble agents in contrast were found to be a result of their very short half-lives and lack of accumulation. In conclusion, drug exposure time has been demonstrated to play a more important role in producing neuro-toxicity than drug exposure level, production of the more active metabolite (DHA), or having the drug located in the CNS system. Therefore, appropriate dose regiments with the correct formulations are necessary in avoiding neurotoxicity in humans and in animal species.

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