HIGH-DOSE DEXTROMETHORPHAN IN AMYOTROPHIC-LATERAL-SCLEROSIS - PHASE-ISAFETY AND PHARMACOKINETIC STUDIES

Much interest has focused on the role of glutamate-mediated excitotoxi city in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). W e therefore conducted a phase I study of high-dose dextromethorphan (D M) in ALS. DM is a selective, noncompetitive antagonist of the N-methy l-D-aspartate subtype of the glutamate receptor. Thirteen patients wer e given DM in an escalating dose fashion, to a target of 10 mg/kg/day or the maximum tolerable dose, and then maintained on this dose for up to 6 months. Total daily doses ranged from 4.8 to 10 mg/kg (median, 7 mg/kg). Side effects were dose limiting in most patients. The most co mmon side effects were light-headedness, slurred speech, and fatigue. Detailed pharmacokinetic and neuropsychology studies were performed. T his study demonstrates the feasibility of long-term administration of high-dose DM in ALS, as well as in other conditions associated with gl utamate excitotoxicity.