ARTEETHER - RISKS OF 2-WEEK ADMINISTRATION IN MACACA-MULATTA

Male rhesus monkeys (Macaca mulatta) were administered daily doses of the antimalarial drug arteether. The 14-day treated group received eit her 24 mg/kg/day, 16 mg/kg/day, or 8 mg/kg/day. The seven-day treatmen t group received either 24 mg/kg/day or 8 mg/kg/day. All control cases in each group received the sesame oil vehicle alone. Neurologic signs were absent for animals in the seven and 14-day treatment groups exce pt for one monkey which showed diffuse piloerection on day 14, and ano ther monkey receiving 24 mg/kg/day for seven days showed mild lethargy after the fourth day. Mild, sporadic anorexia was noted in all animal s by day 14, and a single animal showed diffuse piloerection on day 14 . Surgical anesthesia preceded killing by exsanguination and was accom panied by perfusion fixation of the central nervous syste. Brain secti ons were cut and then stained for study by light microscopy. Evidence of neuronal pathology, both descriptive and numerical, was collected. The neuroanatomic and neuropathologic findings demonstrated that artee ther produced extensive brainstem injury when administered for 14 days . The magnitude of brainstem neurotoxicity was dose-dependent, where i njury was greatest ar the 24 mg/kg/day dose level, less at the 10 mg/k g/day dose level, and feast at the 8 mg/kg/day dose level. Arteether i nduced multiple systems injury to brainstem nuclei of 1) the reticular formation (cranial and caudal pontine nuclei, and medullary gigantoce llular and paragigantocellular nuclei); 2) the vestibular system (medi al, descending, superior, and lateral nuclei); and 3) the auditory sys tem (superior olivary nuclear complex and trapezoid nuclear complex). The vestibular nuclei and. the reticular formation were most severely injured, with the auditory system affected less. The cranial nerve nuc lei (somatic and splanchnic) appeared to escape damage, with the excep tion, of the abducens nerve nucleus. The same brainstem nuclear groups of seven-day treated monkeys appeared normal. The statistical data an concordant with the descriptive data in demonstrating: neurotoxic eff ects. In summary, no neurologic deficits were detected in any of the v ehicle control monkeys (14-day and seven-day cases). Monkeys in the 14 -day treatment group were free of clinical neurologic signs throughout the first week. At day 14, fine horizontal nystagmus was seen in one monkey, and another monkey exhibited diffuse piloerection. Monkeys in the seven-day treatment group were free of clinical neurologic signs e xcept for one case. This monkey was treated with 24/mg/kg/day of artee ther and exhibited lethargy after the fourth day. These indications of dysfunction arose too late to be practical indicators of neurotoxicit y.