L -Dopa induces dyskinesia in normal monkeys: behavioural and pharmacokinetic observations
| Autor: | I B Linden, R. K. B. Pearce, M Heikkila, Peter Jenner |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Male
Dyskinesia Drug-Induced medicine.medical_specialty Levodopa Dopamine Agents Pharmacology COMT inhibitor chemistry.chemical_compound Oral administration Internal medicine otorhinolaryngologic diseases medicine Animals Entacapone Movement Disorders Catechol-O-methyl transferase Behavior Animal Dose-Response Relationship Drug business.industry MPTP nervous system diseases Macaca fascicularis Endocrinology Dyskinesia chemistry Carbidopa Female medicine.symptom business medicine.drug |
| Zdroj: | Psychopharmacology. 156:402-409 |
| ISSN: | 1432-2072 0033-3158 |
| DOI: | 10.1007/s002130100733 |
| Popis: | 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 significantly lowered peak plasma concentrations of L-dopa and this was reflected by a decrease in the severity of dyskinesias, with only one animal receiving entacapone and high dose L-dopa plus carbidopa showing severe dyskinesia, while four receiving high dose L-dopa plus carbidopa alone did so. Conclusions: These results show for the first time that chronic oral L-dopa administration can provoke dyskinesias in primates independently of nigrostriatal damage, and that this effect is dose related. |
| Databáze: | OpenAIRE |
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