ASSESSMENT OF THE NEUROTOXICITY OF PARENTERAL ARTEMISININ DERIVATIVESIN MICE

In all experimental mammals tested (rats, dogs, primates), intramuscul ar injections of the oil-soluble antimalarial artemisinin derivatives artemether and arteether have produced an unusual pattern of selective damage to brain stein centers predominantly involved in auditory proc essing and vestibular reflexes. Artesunate, the most widely used of th ese compounds, is a water soluble hemisuccinate derivative given paren terally either by intravenous or intramuscular injection. The neurotox ic potential of parenteral artesunate and artemether was compared in a murine model. Adult Swiss albino mice were assigned randomly to 28-da y regimens of intramuscular artemether or artesunate in doses ranging from 30 to 100 mg/kg/day. At 30 mg/kg/day, no abnormalities were detec ted with either drug. At 50 mg/kg/day, abnormalities were observed in six of 12 artemether recipients and two of 12 artesunate recipients. T hese were reversible in all but one (artemether) mouse. At 100 mg/kg/d ay, eight of 36 artemether recipients, two of 36 artesunate recipients , and one of 18 control mice died. All but four surviving mice in the artemether group (86%) showed obvious and usually irreversible abnorma lities of balance and equilibrium, whereas only four artesunate recipi ents (11%) exhibited abnormalities, and these were reversible in each case (P < 0.001). At this dose the relative risk (95% confidence intel val) for death or disability was 5.3 (2.6-11.2) for artemether recipi ents. Intramuscular artemether is significantly more neurotoxic than i ntramuscular artesunate in this murine model.