Artemisinin derivatives: toxic for laboratory animals, safe for humans?

A discrepancy seems to prevail with regard to the toxicity and safety of the artemisinin family of antimalarials. While these compounds have been found to be virtually void of any serious side effects in humans, their neurotoxicity in animal models has raised concerns about their use. In this paper, we present selected examples of both pre-clinical and clinical studies dealing with adverse effects of artemisinin drugs. We suggest that the prolonged presence of artemisinins upon slow release from oil-based intramuscular formulations is the main cause of the observed toxicity in laboratory animals. In contrast, oral intake of these compounds, which is by far the most common formulation used for treatment of malaria patients, results in rapid clearance of these drugs and is thus unlikely to cause any toxicity in human subjects. Another plausible factor may be the relatively high doses of artemisinin compounds used in animal studies. In conclusion, the observation of the toxicity of artemisinin compounds in animals, but not in humans, is most likely due to different pharmacokinetic profiles after different routes of administrations.