부산대학교 도서관

Rationale: L-Dopa induces dyskinesias during the treatment of Parkinson's disease and also in primates with nigrostriatal lesions produced by MPTP, but it is claimed that L-dopa does not provoke dyskinesia in humans or monkeys with an intact or mildly damaged nigrostriatal system. Objectives: This study assessed the behavioural and pharmacokinetic effects of chronic oral administration of L-dopa plus carbidopa alone, or with co-administration of the peripheral COMT inhibitor entacapone, to normal macaque monkeys. Repeated high dose L-dopa administration was shown to induce marked dyskinesias in monkeys with an intact nigrostriatal system, and the threshold for dyskinesia expression was increased by peripheral catechol-O-methyltransferase inhibition with entacapone. Methods: Six groups of normal macaque monkeys (n=8 per group; Macaca fascicularis) were treated with L-dopa (20, 40 or 80 mg/kg) plus carbidopa (5, 10 or 20 mg/kg) with or without the catechol-O-methyltransferase inhibitor entacapone (20, 40 or 80 mg/kg), or with entacapone alone (80 mg/kg), by oral administration once daily for 13 weeks. Results: Eleven of 16 animals receiving high dose L-dopa (80 mg/kg plus carbidopa 20 mg/kg PO with or without entacapone 80 mg/kg PO for 13 weeks) gradually developed reproducible and idiosyncratic combinations of chorea, athetosis and dystonia maximal at 60–100 min after L-dopa administration, which progressively intensified over the course of the study. The dyskinesias observed were similar in type and distribution to L-dopa-induced dyskinesia observed in patients with Parkinson's disease and in MPTP-treated primates. The occurrence of dyskinesia correlated with plasma concentrations of L-dopa, with animals displaying the most severe dyskinesias having significantly higher plasma concentrations of L-dopa one hour after dosing than animals with mild or moderate dyskinesia or no dyskinesia. Co-administration of entacapone with L-dopa plus carbidopa signi... [ABSTRACT FROM AUTHOR]