Maximizing the benefit : risk ratio of levodopa therapy in Parkinson's disease

For over 30 years, levodopa has been the gold standard for managing the sym ptoms of Parkinson's disease. Treatment with levodopa has resulted in a mar ked decrease in disease-associated mortality and morbidity. However, one of its drawbacks is that many patients experience a shorter duration of respo nse and increased motor fluctuations with disease progression and longterm levodopa therapy. These increased motor fluctuations, including dyskinesias , may be the consequence of oxidative stress or inability to store and regu late intrasynaptic dopamine concentrations with disease progression. Clinic al investigations have demonstrated that continuous dopaminergic stimulatio n may widen the therapeutic window for levodopa and improve motor fluctuati ons. Strategies for providing continuous dopaminergic replacement include a dministration of levodopa by continuous infusion, controlled-release levodo pa, long-acting dopamine agonists, and inhibitors of levodopa metabolism. T he catechol-O-methyltransferase inhibitors that block a compensatory metabo lic pathway for levodopa and prolong its duration may improve the consisten cy of the dopaminergic response.