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 daily for 8d with intramuscular (IM) arteether (AE) at 20 mg/kg/d in a pharmacokinetic study. Neurologic 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 internal corrected for rate (QTc). Prominent neuropathic lesions were sharply limited to the pons and medulla. Neurologic 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/day for 28 d confirmed clinical neurologic abnormalities with high doses ( 25 mg/kg/day) after 6-14d. Neuropathological examination of rat brain sections at 5 levels from the rostal 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 1994
- Accession Number
- ADA283884
Entities
People
- Barry S. Levine
- J. M. Petras
- James O. Peggins
- Stephen J. Grate
- Thomas G. Brewer
Organizations
- Walter Reed Army Institute of Research