Neurotoxicity in animals due to arteether and artemether

Abstract

Several artemisinin (qinghaosu) derivatives have been developed and are in use as antimalarial drugs but scant animal or human toxicity data are available. We noted a progressive syndrome of clinical neurological defects with cardio-respiratory collapse and death in 5/6 dogs dosed daily for 8 d with intramuscular arteether (AE) at 20 mg/kg/d in a pharmacokinetic study. Neurological findings included gait disturbances, loss of spinal reflexes, pain response reflexes and prominent loss of brain-stem and eye reflexes. Electrocardiography showed prolongation of the QT interval corrected for rate (QTc). Prominent neuropathic lesions were sharply limited to the pons and medulla. Neurological injury, graded by a pathologist ‘blinded’ to dose group, showed a dose-related region-specific injury which was most pronounced in the pons and medulla in all animals. Rats treated with AE and artemether (AM) at 12·5 to 50 mg/kg/d for 28 d confirmed clinical neurological abnormalities with high doses (>25 mg/kg/d) after 6–14 d. Neuropathological examination of rat brain sections at 5 levels from the rostral cerebrum to the caudal medulla showed a dose-related pattern of injury characterized by hyalinized neuron cell bodies and loss of Nissl substance; changes congruent with those noted in dogs. No significant difference was noted in the extent, type, or distribution of lesions in the brains of rats treated with equivalent doses of AE or AM. We conclude that (i) a neurological syndrome with central nervous system neuropathological changes occurred in a dose-related, and anatomically specific manner in both dogs and rats given moderately high daily doses of AE or AM; (ii) prolonged QTc interval was a preterminal clinical finding in dogs and rats treated with high dose AE; (iii) the mechanism and aetiology of these lesions was not determined in this study but a long-lived toxic drug metabolite is suggested.