Levodopa: past, present, and future.

Levodopa has been the mainstay of treatment for Parkinson's disease (PD) for more than 40 years. During this time, researchers have strived to optimize levodopa formulations to minimize side effects, enhance central nervous system (CNS) bioavailability, and achieve stable therapeutic plasma levels. Current strategies include concomitant treatment with inhibitors of dopa decarboxylase (DDC) and catechol-O-methyltransferase (COMT) to prolong the peripheral levodopa half-life and increase CNS bioavailability. Levodopa combined with DDC inhibition is the current standard method of delivering levodopa for symptomatic treatment of PD. Recent research suggests that continuous dopaminergic stimulation that more closely approximates physiological stimulation may delay or prevent the development of motor fluctuations ('wearing off') and dyskinesias. Strategies currently being used to achieve more continuous dopaminergic stimulation include the combination of an oral levodopa/DDC inhibitor with a COMT inhibitor and the enteral infusion of a levodopa gel formulation. Attempts are underway to develop oral and transdermal very long-acting levodopa preparations.