tolcapone and Parkinson-Disease--Secondary

Parkinson disease progression is associated with the development of levodopa short-duration responses and dyskinesias, as well as gait freezing. Levodopa dose adjustment and adjunctive treatment with dopamine agonists form the major therapeutic strategies. Catechol O-methyltransferase inhibitors are also appropriate considerations, whereas other drugs, including selegiline, amantadine, anticholinergic agents, and propranolol, have a more minor role.

Topics: Amantadine; Antiparkinson Agents; Benzophenones; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Cholinergic Antagonists; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Combinations; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease, Secondary; Propranolol; Randomized Controlled Trials as Topic; Selegiline; Tolcapone

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.

Topics: Adolescent; Adult; Aged; Benzophenones; Carbidopa; Catechol O-Methyltransferase Inhibitors; Drug Synergism; Humans; Levodopa; Middle Aged; Nitrophenols; Parkinson Disease, Secondary; Placebos; Tolcapone