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

Data de publicação: Data Ahead of Print:

Autores da FMUP

  • Patrício Manuel Vieira Araújo Soares Da Silva

    Autor

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

European Journal of Pharmacology  Elsevier

Tipo:
Article
Páginas:
173742-173742
Link para outro recurso:
www.scopus.com

Citações Recebidas na Web of Science: 4

Citações Recebidas na Scopus: 4

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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

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