ROLE OF ARTEETHER IN THE TREATMENT OF MALARIA AND PLANS FOR FURTHER DEVELOPMENT

Arteether has potent antimalarial activity in vitro against drug resistant Plasmodium falciparum. Preclinical studies of arteether injection have been completed, and phase I safety, tolerance and pharmacokinetic studies are in progress in The Netherlands. No intolerance has yet been observed. Production has been established in a pilot scale in The Netherlands by A.C.F. Beheer BV. Toxicity studies have been conducted in rats and dogs: 3 mg/kg/d for 28 d had no effect. At higher dosages, toxic effects on heart, brain, bone marrow, kidney and liver were observed. Cardiotoxicity is characterized in the dog by a dose-related prolongation of the QTc interval and inversion of the T-wave in some animals. Arrhythmias have not been observed. Electrocardiographic changes returned to baseline values after cessation of daily drug administration. Neuronal toxicity was observed in dogs given daily doses of 6.75 or 15 mg/kg/d intramuscularly for 28 d. Signs of lethargy, incoordination, and abnormal responses appeared in the fourth week. Electroencephalograms exhibited no abnormality. Neuronal degeneration and subsequent myelin degeneration, particularly affecting the cerebellum and other portions of the mid- and hind-brain, were observed. Clinical signs of neurotoxicity did not resolve completely within 30 d after cessation of dosing, and histopathological damage in the brain was still evident. Behavioural and histological evidence of neurotoxicity was also observed in rats. The neurotoxic effects of arteether and artemether in rats and dogs were similar.