Opicapone enhances the reversal of MPTP-induced Parkinson-like syndrome by levodopa in cynomolgus monkeys

Autores da FMUP
Participantes de fora da FMUP
- Bonifacio, Maria Joao
- Sousa, Filipa
Unidades de investigação
Abstract
Opicapone is a third generation nitrocatechol catechol-O-methyltransferase inhibitor that has received regional market approval for use as adjunctive therapy to levodopa in Parkinson's disease patients with motor fluctuations. This study evaluated the effects of opicapone as adjunct to levodopa in reversing a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinson's-like syndrome in cynomolgus monkeys in during opicapone preclinical development program. A Parkinson's-like syndrome was induced in cynomolgus monkeys by daily administrations of MPTP. Evaluation of the animals included scoring with the Primate Parkinsonism Motor Rating Scale (PPMRS) and assessment of locomotor activity. MPTP produced a stable Parkinson's-like behavioural syndrome as evidenced by tremor, postural changes, rigidity, impaired movements and balance, (PPMRS scores of 10-15) and decreased locomotor activity (13% of pre-MPTP values). Opicapone treatment alone, for 14 days, did not change Parkinson's-like symptoms nor decreased subject's locomotor behaviour. Ascending combinations of levodopa/benserazide dose-dependently decreased PPMRS and improved locomotor behaviour reaching statistical significance for levodopa/benserazide doses of 18/4.5 mg/kg and those effects were enhanced in opicapone treated subjects. Opicapone treated subjects as compared vehicle-treated, had markedly reduced erythrocyte catechol-O-methyltransferase activity, significantly increased plasma levodopa levels (1.8-fold higher AUC) with no statistically significant changes in C-max and significantly reduced 3-OMD AUC and C-max values (7.8- and 6.8-fold respectively). Opicapone potentiated the improvements in Parkinson's-like symptoms produced by levodopa/benserazide combinations with concomitant increase in plasma levodopa exposure, reduction of plasma 3-O-methyldopa levels and erythrocyte catechol-O-methyltransferase activity, results that were later demonstrated in 2 large Phase 3 studies in Parkinson's disease patients.
Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.
Dados da publicação
- ISSN/ISSNe:
- 0014-2999, 1879-0712
- Tipo:
- Article
- Páginas:
- 173742-173742
- Link para outro recurso:
- www.scopus.com
European Journal of Pharmacology Elsevier
Citações Recebidas na Web of Science: 4
Citações Recebidas na Scopus: 4
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Filiações
Keywords
- MPTP; Cynomolgus monkey; Opicapone; Parkinson's disease; Levodopa; Catechol-O-Methyltransferase
Proyectos asociados
Inervação simpática e mecanismos adrenérgicos locais na regulação funcional da córnea
Investigador Principal: Patrício Manuel Vieira Araújo Soares da Silva
Estudo Clínico Académico . 2019
Citar a publicação
Bonifacio MJ,Sousa F,Soares P. Opicapone enhances the reversal of MPTP-induced Parkinson-like syndrome by levodopa in cynomolgus monkeys. Eur. J. Pharmacol. 2021. 892. p. 173742-173742. IF:5,195. (2).