[The therapy of wearing-off]

Wearing-off, predictable end of dose deterioration, is one of the major problems of long-term levodopa treatment for Parkinson's disease. The mechanisms of wearing-off are (1) loss of striatal dopamine storage, (2) change in the peripheral pharmacokinetics of levodopa and (3) modification of dopamine receptors. The main therapeutic strategy for wearing-off is continuous stimulation of dopamine system. For this purpose, we increase frequency of levodopa doses and use long half-life dopamine agonist(continuous stimulation of dopamine receptors), COMT inhibitor and MAOB inhibitor (prolongation of the half-life of levodopa and dopamine), and zonisamide (long-term increase of dopamine synthesis).