Studies of the neurotoxicity of oral artemisinin derivatives in mice

Intramuscular injections of high doses of the oil-soluble antimalarial arte misinin derivatives artemether and arteether produce an unusual pattern of selective damage to brain stem centers in experimental mammals, predominant ly those involved in auditory processing and vestibular reflexes. We have s hown recently in adult Swiss albino mice that parenteral artesunate, a wate r-soluble derivative, is significantly less neurotoxic than intramuscular a rtemether in this murine model. Using the same model, in which the drugs we re administered daily for 28 days, the neurotoxic potential of the oral dru gs was assessed and compared with the parenteral routes of administration. The dose causing neurotoxicity or death in 50% of animals (ED50), was appro ximately 300 mg/kg/day of oral artemether and artesunate compared to 50 mg/ kg/day of intramuscular artemether. Doses of intramuscular artemether > 100 mg/kg/day were uniformly lethal. When oral artemether was given in peanut oil there was an increase in neurotoxicity and mortality compared with the aqueous suspension (P = 0.002), and when the food pellets were coated with artemether in oil, giving relatively constant oral intake, neurotoxicity wa s further increased; ED50 = 150 mg/kg/day (P = 0.017). These data indicate that once-daily oral administration of artesunate or artemether is relative ly safe, presumably because the central nervous system is exposed transient ly, whereas constant exposure either from depot intramuscular injection of oil-based drug, or constant oral intake carries relatively greater neurotox ic potential.