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Am. J. Trop. Med. Hyg., 51(3), 1994, pp. 251-259
Copyright © 1994 by The American Society of Tropical Medicine and Hygiene

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Fatal Neurotoxicity of Arteether and Artemether

Thomas G. Brewer, Stephen J. Grate, James O. Peggins, Peter J. Weina, J. M. Petras, Barry S. Levine, Melvin H. Heiffer AND Brian G. Schuster
Divisions of Experimental Therapeutics, Pathology, and Neuropsychiatry, Walter Reed Army Institute of Research, Washington, District of Columbia; Toxicology Research Laboratory, Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois

Artemisinin (qinghaosu) and several derivatives have been developed and are in use as antimalarial drugs but scant information is available regarding animal or human toxicity. Following a eight-day, multiple-dose, 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 progressive syndrome of clinical neurologic defects with progressive cardiorespiratory collapse and death in five of six animals. Neurologic findings included gait disturbances, loss of spinal and pain response reflexes, and prominent loss of brain stem and eye reflexes. Animals had prolongation of QT interval corrected for rate (QTc) on electrocardiograms (ECGs) with bizarre ST-T segment changes. Prominent neuropathic lesions were noted to be primarily limited to the pons and medulla. Similar 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, and 20 mg/kg/day. Injury, graded by a pathologist blinded to the dose group, showed a dose-related, region-specific injury in all animals that was most pronounced in the pons. Further studies in Sprague-Dawley rats using IM administration of AE and artemether (AM) at a dose of 12.5–50 mg/kg/day for 28 days confirmed the onset of a clinical neurologic syndrome with dose-related changes in body weight, activity, and seizure-like activity, stereotypic movement disorders, and ECG changes. Neuropathologic examination of rat brain sections at five levels from the rostral cerebrum to the caudal medulla showed a dose-related, region-specific pattern of injury characterized by a loss of Nissl substance and hyalinized neuron cell bodies; these changes are congruent with those noted in dogs. No significant differences were noted in the extent, type, or distribution of lesions in brains of rats treated with equivalent doses of AE or AM. We conclude that 1) a dose-related neurologic syndrome associated with movement disturbances, spasticity, and depressed sensorium in dogs and rats occurred after daily IM injections of two artemisinin antimalarial drugs, AE and AM; 2) a prolonged QTc interval was noted as a preterminal clinical finding in dogs and rats treated with high-dose AE; 3) central nervous system neuropathic changes were noted to occur in a dose-related and anatomic-specific manner in both dogs and rats treated with daily IM 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.




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Copyright © 1994 by the American Society of Tropical Medicine and Hygiene.