WITHDRAWN. Neurological assessments after treatment with the antimalarial ß-arteether in neonatal and adult rats.

ABSTRACT

The World Health Organization currently recommends combinatorial treatment including artemisinins as first-line therapy against drug-resistant Plasmodium falciparum malaria. Although highly efficacious, artemisinin and its derivatives, including ß-arteether (ßAE), are associated with ototoxicity, tremors, and other autonomic and motor impairments in the clinic. Similar neurological symptoms, as well as brainstem lesions, have been observed in adult laboratory species (mice, rats, dogs, and non human primates) following acute treatment with ßAE; however, few long-term, nonclinical studies have been conducted. Furthermore, the majority of deaths attributed to malarial infection occur in children under age five, yet no laboratory studies have been initiated in neonatal or juvenile animals. In the current study, neonatal 7-day-old rats were administered intramuscular doses of 1-90mg/kg ßAE in sesame oil for up to eight treatment cycles (one cycle=7days treatment+7days without treatment). Neonates were tested for changes in sensorimotor function, and the same animals were tested as adults in the Functional Observational Battery, for motor activity, and in the 8-arm radial maze. Pups receiving a single cycle of 60 or 90mg/kg died within a week of treatment but had few behavioral changes and no brainstem pathology. In the long-term study, behavioral and motor changes and brainstem lesions were observed in a dose- and time-related manner. Rats given repeated cycles of 1 or 5mg/kg ßAE showed subtle motor abnormalities (e.g., slight loss of righting reflex) while repeated cycles of 10mg/kg ßAE treatment resulted in obvious motor and behavioral changes. Rats receiving 1mg/kg ßAE had no brainstem lesions whereas some rats treated with 5mg/kg ßAE and all rats treated with 10mg/kg ßAE had brainstem lesions. Brainstem lesions were observed after as few as five cycles and were characterized by gliosis, satellitosis and progressive necrosis in motor neurons of the trapezoid, vestibular, and olivary nuclei. This study shows that repeated treatment with clinically relevant doses of ßAE causes motor deficits associated with brainstem damage in rodents and suggests that repeated treatment with ßAE in children may elicit neurological damage.