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Opicapone improves the effects of L‐DOPA on the MPTP‐induced Parkinson's‐like syndrome in cynomolgus monkeys
Author(s) -
Bonifacio Maria Joao,
Medakkar Sonali,
Sousa Filipa,
Vivian Jeffrey A,
SoaresdaSilva Patricio
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.708.4
Subject(s) - benserazide , levodopa , mptp , parkinsonism , medicine , parkinson's disease , dyskinesia , anesthesia , pharmacology , disease
Background Opicapone is a high binding affinity and long‐acting third generation nitrocatechol COMT inhibitor under development for use as 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 a 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 C max while for 3‐OMD, AUC and C max values were both significantly reduced 7–8 fold. Erythrocyte COMT activity was markedly reduced in opicapone treated subjects. Conclusions Opicapone potentiated the improvements in PD‐like symptoms produced by levodopa/benserazide combinations with a concomitant increase in plasma levodopa exposure, reduction of plasma 3‐OMD levels and erythrocyte COMT activity.