Problems with the present inhibitors and a relevance of new and improved COMT inhibitors in Parkinson's disease

COMT inhibitors are used as adjuncts to levodopa, prolonging its half-life and thereby increasing its effectiveness and reducing levodopa-related motor complications in patients in moderate to advanced stages of Parkinson’s disease. Entacapone and tolcapone are reversible COMT inhibitors that have been approved for clinical use, whilst a third inhibitor, nebicapone, has been studied in humans. All three have short elimination half-lives, approximately 2-3 hours, and also have problems in pharmacodynamics, clinical efficacy or safety. Although tolcapone is a longer acting and more potent COMT inhibitor than entacapone, with nebicapone somewhere in between, none causes complete COMT inhibition. The most common adverse effect with COMT inhibitors is dyskinesia which is usually managed by reducing the levodopa dose. The greatest problem with tolcapone and nebicapone is liver toxicity which is not seen with entacapone, and tolcapone causes severe diarrhea more often than entacapone. The author concludes that whilst COMT inhibitors have significantly improved the treatment of advanced Parkinson’s disease, there are still considerable problems that require the development of better and safer examples.