title: High-dose dextromethorphan in amyotrophic lateral sclerosis: phase I safety and pharmacokinetic studies.
abstract: Much interest has focused on the role of glutamate-mediated excitotoxicity in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). We therefore conducted a phase I study of high-dose dextromethorphan (DM) in ALS. DM is a selective, noncompetitive antagonist of the N-methyl-D-aspartate subtype of the glutamate receptor. Thirteen patients were 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 common side effects were light-headedness, slurred speech, and fatigue. Detailed pharmacokinetic and neuropsychology studies were performed. This study demonstrates the feasibility of long-term administration of high-dose DM in ALS, as well as in other conditions associated with glutamate excitotoxicity.
authors.affiliation: Department of Neurology, Tufts University School of Medicine, Boston, MA.
authors.forename: D
authors.initials: D
authors.lastname: Hollander
authors.forename: J
authors.initials: J
authors.lastname: Pradas
authors.forename: R
authors.initials: R
authors.lastname: Kaplan
authors.forename: H L
authors.initials: HL
authors.lastname: McLeod
authors.forename: W E
authors.initials: WE
authors.lastname: Evans
authors.forename: T L
authors.initials: TL
authors.lastname: Munsat
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000704:Analysis of Variance; D003915:Dextromethorphan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D003915:Dextromethorphan