title: Catechol-O-methyltransferase inhibitor tolcapone prolongs levodopa/carbidopa action in parkinsonian patients.
abstract: The wearing-off phenomenon frequently complicates levodopa therapy of Parkinson's disease (PD). These response fluctuations appear when intrasynaptic dopamine concentrations begin to reflect the swings in levodopa availability that attend standard dosing regimens. Drugs that prolong the biologic half-life of levodopa and dopamine should thus prove beneficial. We administered levodopa/carbidopa in combination with single oral doses of tolcapone (Ro 40-7592), an inhibitor of catechol-O-methyltransferase, under controlled conditions to 10 PD patients with the wearing-off phenomenon. Tolcapone prolonged the antiparkinson response to levodopa/carbidopa by about 67% at several doses ranging from 50 to 400 mg (p < 0.05). There was no significant change in the peak levodopa effect on parkinsonian signs or in the severity of dyskinesias. No dose-limiting adverse effects occurred. Multiple daily dosing with tolcapone would thus be expected to safely reduce the wearing-off phenomenon associated with levodopa/carbidopa therapy.
authors.affiliation: Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
authors.forename: J W
authors.initials: JW
authors.lastname: Roberts
authors.forename: G
authors.initials: G
authors.lastname: Cora-Locatelli
authors.forename: D
authors.initials: D
authors.lastname: Bravi
authors.forename: M A
authors.initials: MA
authors.lastname: Amantea
authors.forename: M M
authors.initials: MM
authors.lastname: Mouradian
authors.forename: T N
authors.initials: TN
authors.lastname: Chase
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001577:Benzophenones / Q000009:adverse effects / Q000627:therapeutic use*; D002230:Carbidopa / Q000627:therapeutic use*; D065098:Catechol O-Methyltransferase Inhibitors; D004357:Drug Synergism; D006801:Humans; D007980:Levodopa / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D009596:Nitrophenols; D010302:Parkinson Disease, Secondary / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010919:Placebos; D000077867:Tolcapone
chemical_list: D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D009596:Nitrophenols; D010919:Placebos; D007980:Levodopa; D000077867:Tolcapone; D002230:Carbidopa