PROBLEMS WITH THE PRESENT INHIBITORS AND A RELEVANCE OF NEW AND IMPROVED COMT INHIBITORS IN PARKINSON'S DISEASE

Entacapone and tolcapone are reversible COMT inhibitors which have been approved for clinical use m patients with Parkinson disease (PD) Nebicapone is a third COMT inhibitor which has been studied in humans COMT inhibitors are used in combination with levodopa and a dopa decarboxylase (DDC) inhibitor Each of them has problems either in pharmacokinetics, pharmacodynamics, clinical efficacy or in safety All three inhibitors have short elimination half lives about 2-3 h Tolcapone is longer acting and more potent COMT inhibitor than entacapone, nebicapone lies in between However none of the present inhibitors cause a complete peripheral COMT inhibition Tolcapone and nebicapone have increased more levodopa AUC than entacapone which is reflected also m their clinical efficacy The most common adverse event with COMT inhibitors is dyskinesia which is usually managed by decreasing levodopa dose The greatest problem with tolcapone and probably also with nebicapone is their liver toxicity which is not seen with entacapone Tolcapone causes severe diarrhea more often than entacapone Though the present COMT inhibitors have improved significantly the treatment of advanced PD patients, they still have several problems and weaknesses leaving room for developing better COMT inhibitors