CATECHOL-O-METHYLTRANSFERASE INHIBITION WITH TOLCAPONE REDUCES THE WEARING OFF PHENOMENON AND LEVODOPA REQUIREMENTS IN FLUCTUATING PARKINSONIAN-PATIENTS

Background-More than 50% of patients with Parkinson's disease develop motor response fluctuations (the ''wearing off'' phenomenon) after mor e than five years of levodopa therapy. Inhibition of catechol-O-methyl transferase by tolcapone has been shown to increase levodopa bioavaila bility and plasma elimination half life, thereby prolonging the effica cy of levodopa. Objectives-The primary objective was to evaluate the e fficacy of tolcapone in reducing ''wearing off'' in levodopa treated, fluctuating parkinsonian patients. Secondary objectives included asses sment of reduction in levodopa requirements, improvement in patients' clinical status, duration of improvements, and tolerability of tolcapo ne. Methods-In this multicentre, randomised, double blind, placebo con trolled trial, 58 patients received placebo, 60 received 100 mg tolcap one three times daily (tid), and 59 received 200 mg tolcapone tid, in addition to levodopa/benserazide. Results-After three months with 200 mg tolcapone tid, ''off'' time decreased by 26.2% of the baseline valu e, ''on'' time increased by 20.6% (P<0,01 v placebo), and the mean tot al daily levodopa dose decreased by 122 mg from the baseline dose of 6 76 mg (P<0.01). These responses were maintained up to nine months. Wit h 100 mg tolcapone tid, ''off'' time decreased by 31.5% (P<0.05), ''on '' time increased by 21.3% (P<0.01), and the mean total daily levodopa dose decreased by 109 mg from the baseline dose of 668 mg (P<0.05). W ith 200 mg tolcapone tid, unified Parkinson's disease rating scale mot or and total scores were significantly reduced, and quality of life (s ickness impact profile) scores were significantly improved. Both dosag es were well tolerated. Dyskinesia was the most often reported levodop a induced adverse event. Diarrhoea was the most often reported non-dop aminergic adverse event and the most frequent reason for withdrawal fr om the study: four patients in the 100 mg tolcapone tid group and six in the 200 mg tid group withdrew because of diarrhoea. Conclusion-Tolc apone prolongs ((on time in fluctuating parkinsonian patients while al lowing a reduction in daily levodopa dosage, thereby improving the eff icacy of long term levodopa therapy.