Catechol-O-methyltransferase inhibitors in the management of Parkinson's disease

Parkinson's disease is the most common neurodegenerative disease in which the chemical pathology is known and effective symptomatic treatment, levodopa, is available. Therapy in the initial years after initiation with dopa decarboxylase inhibitors, carbidopa or benserazide, combined with levodopa results in favorable, stable responses. However, by 5 years after the initiation of treatment, over two thirds of patients experience motor fluctuations beginning initially with a "wearing-off" effect followed by more complex fluctuations including dyskinesias and "on-off" responses. A number of strategies have been developed in an attempt to deal with these complications including changing doses and frequencies, adding agonist medications, adding or substituting controlled-release levodopa, and surgical therapies. A more recent strategy has centered on increasing the availability of intracellular levodopa and synaptic dopamine by inhibiting the peripheral and central metabolism of levodopa to 3-O-methyldopa with the use of a catechol-O-methyltransferase inhibitor. To date, two of these inhibitors, tolcapone and entacapone, are available to treat the wearing-off phase of levodopa therapy.