dextromethorphan and Huntington-Disease

Because of its interactions at N-methyl-D-aspartate and haloperidol specific sigma receptors, dextromethorphan may have symptomatic or protective effects in Huntington's Disease (HD). Escalating doses of dextromethorphan in 11 HD patients produced side effects of dysarthria, rash, and incoordination. At maximum doses, performance declined on a variety of measures of HD, including functional rating scales and quantitative exam scores, consistent with dose-related side effects. Windows of symptomatic benefit were not found. Serum levels of dextromethorphan and its metabolites, including the active compound dextrorphan, showed atypical relationships to dose and side effects, suggesting complex pharmacokinetics. Although not beneficial symptomatically, further trials of dextromethorphan as protective therapy in HD may be warranted.

Topics: Adult; Aged; Clinical Trials as Topic; Dextromethorphan; Drug Hypersensitivity; Female; Humans; Huntington Disease; Levorphanol; Male; Middle Aged

Pridopidine is an oral drug in clinical development for treatment of patients with Huntington's disease. This study examined the interactions of pridopidine with in vitro cytochrome P450 activity and characterized the effects of pridopidine on CYP2D6 activity in healthy volunteers using metoprolol as a probe substrate. The effect of food on pridopidine exposure was assessed.. The ability of pridopidine to inhibit and/or induce in vitro activity of drug metabolizing enzymes was examined in human liver microsomes and fresh hepatocytes. CYP2D6 inhibition potency and reversibility was assessed using dextromethorphan. For the clinical assessment, 22 healthy subjects were given metoprolol 100 mg alone and concomitantly with steady-state pridopidine 45 mg twice daily. Food effect on a single 90 mg dose of pridopidine was evaluated in a crossover manner. Safety assessments and pharmacokinetic sampling occurred throughout the study.. Pridopidine was found to be a metabolism dependent inhibitor of CYP2D6, the main enzyme catalysing its own metabolism. Flavin-containing monooxygenase heat inactivation of liver microsomes did not affect pridopidine metabolism-dependent inhibition of CYP2D6 and its inhibition of CYP2D6 was not reversible with addition of FeCN. As pridopidine is a metabolism-dependent inhibitor of CYP2D6, systemic levels of drugs metabolized by CYP2D6 may increase with chronic coadministration of pridopidine. Pridopidine can be administered without regard to food.

Topics: Area Under Curve; Cells, Cultured; Cross-Over Studies; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Dextromethorphan; Drug Interactions; Female; Ferricyanides; Food-Drug Interactions; Healthy Volunteers; Hepatocytes; Humans; Huntington Disease; Male; Metoprolol; Microsomes, Liver; Middle Aged; Piperidines