Interventions to achieve tonic exposure to levodopa: Delaying or preventing the onset of motor complications

Variations in levodopa delivery and subsequent dopamine exposure may lead t o motor fluctuations and dyskinesias in patients with Parkinson's disease, as the therapeutic window for levodopa narrows with disease progression. Lo ngterm exposure to the oscillations in levodopa-derived dopamine also is su ggested to cause postsynaptic changes within the dopaminergic system, leadi ng to further reductions in the drug's efficacy. The need to extend the act ions of levodopa led to the development of the catechol-O-methyl transferas e (COMT) inhibitors, which are the newest agents introduced to manage the s ymptoms of Parkinson's disease. Entacapone and tolcapone are two potent, se lective, and reversible COMT inhibitors that effectively augment levodopa's pharmacokinetics by increasing area under the plasma concentration versus time curve and plasma elimination half-life without significantly affecting peak levodopa concentrations. This enhanced pharmacokinetic effect results in marked improvements in patients' clinical response. In patients experie ncing end-of-dose wearing-off, the addition of either entacapone or tolcapo ne led to improvements in "on" time, "off" time, and the Unified Parkinson' s Disease Rating Scale scoring system, even though many patients already we re receiving optimum dosages of various other antiparkinsonian drugs. Tn pa tients with stable responses to long-term levodopa, addition of tolcapone s ignificantly reduced the onset of motor fluctuations. These data, combined with the potential for delaying the onset of motor fluctuations, suggest th at COMT inhibition may enhance levodopa's short- and long-term efficacy.