FATAL NEUROTOXICITY OF ARTEETHER AND ARTEMETHER

Artemisinin (qinghaosu) and several derivatives have been developed an d are in use as antimalarial drugs but scant information is available regarding animal or human toxicity. Following a eight-day, multiple-do se, pharmacokinetic study of arteether (AE) (10 mg/kg/day [n = 6] and 20 mg/kg/day [n = 6]) in dogs, all high-dose animals displayed a progr essive syndrome of clinical neurologic defects with progressive cardio respiratory collapse and death in five of six animals. Neurologic find ings included gait disturbances, loss of spinal and pain response refl exes, and prominent loss of brain stem and eye reflexes. Animals had p rolongation of QT interval corrected for rate (QTc) on electrocardiogr ams (ECGs) with bizarre ST-T segment changes. Prominent neuropathic le sions were noted to be primarily limited to the pens and medulla. Simi lar lesions with dose-related severity were noted in eight other dogs studied in a second study with intramuscular (IM) administration of AE in sesame oil during a 28-day, dose-ranging study using 5, 10, 15, an d 20 mg/kg/day. Injury, graded by a pathologist blinded to the dose gr oup, showed a dose-related, region-specific injury in all animals that was most pronounced in the pens. Further studies in Sprague-Dawley ra ts using LM administration of AE and artemether (AM) at st dose of 12. 5-50 mg/kg/day for 28 days confirmed the onset of a clinical neurologi c syndrome with dose-related changes in body weight, activity, and sei zure-Like activity, stereotypic movement disorders, and ECG changes. N europathologic examination of rat brain sections at five levels from t he rostral cerebrum to the caudal medulla showed a dose-related, regio n-specific pattern of injury characterized by a loss of Nissl substanc e and hyalinized neuron cell bodies; these changes are congruent with those noted in dogs. No significant differences were noted in the exte nt, type, or distribution of lesions in brains of rats treated with eq uivalent doses of AE or AM. We conclude that 1) a dose-related neurolo gic syndrome associated with movement disturbances, spasticity, and de pressed sensorium in dogs and rats occurred after daily LM injections of two artemisinin antimalarial drugs, AE and AM; 2) a prolonged QTc i nterval was noted as a preterminal clinical finding in dogs and rats t reated with high-dose AE; 3) central nervous system neuropathic change s were noted to occur in a dose-related and anatomic-specific manner i n both dogs and rats treated with daily LM injections of AE or AM; and 4) the mechanism and etiology for this lesion are not known from this study, but the findings suggest a long lived toxic drug metabolite.