主催: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
会議名: WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
開催地: Kyoto
開催日: 2018/07/01 - 2018/07/06
Background: Opicapone is a high-affinity and long-acting third generation nitrocatechol COMT inhibitor for the adjunctive therapy in levodopa-treated Parkinson's disease (PD) patients.
Objectives: The aim of this study was to evaluate the effects of opicapone, as adjunctive therapy to levodopa, in reversing MPTP-induced Parkinson's-like syndrome in cynomolgus monkeys (Macaca Fascicularis).
Methods: Induction of a PD-like syndrome was performed by daily intravenous administrations of MPTP. Characterization of the animals included scoring with the Primate Parkinsonism Motor Rating Scale (PPMRS) and assessment of locomotor activity.
Results: MPTP produced a stable Parkinson's-like behavioural syndrome as evidenced by tremor, postural changes, rigidity, impaired movements and balance, (i.e., PPMRS scores between 10 and 15) and decreased locomotor activity (13% of their pre-MPTP values). Opicapone treatment per se, for 14 days, did not change either the PD-like symptoms or the decreased locomotor behaviour of the subjects. Ascending combinations of levodopa/benserazide dose-dependently decreased PPMRS reaching statistical significance for the levodopa/benserazide doses of 18/4.5 mg/kg and that effect was further enhanced in opicapone treated subjects. Similarly, levodopa/benserazide dose-dependently increased locomotor behaviour, reaching significance with levodopa/benserazide doses of 18/4.5 mg/kg. This increase was also potentiated in the presence of opicapone. Opicapone treated subjects as compared to those treated with vehicle, had significantly increased plasma levodopa levels (2-fold higher AUC) with no changes in Cmax while for 3-OMD, AUC and Cmax values were both significantly reduced 7-8 fold. Erythrocyte COMT activity was markedly reduced in opicapone treated subjects.
Conclusions: Opicapone inhibited erythrocyte COMT activity, increased plasma levodopa exposure and reduced plasma 3-OMD levels with a concomitant potentiation of the improvements in PD-like symptoms produced by levodopa/benserazide combinations.
