Safinamide reduces dyskinesias and prolongs L-DOPA antiparkinsonian effect in parkinsonian monkeys

Introduction: Safinamide is a compound under investigation for use in the treatment of Parkinson's disease for combination with pharmacological therapy currently available. The objective of this study was to test the effects of safinamide in an animal model of L-DOPA-induced dyskinesias (LID), the MPTP lesioned dyskinetic macaque monkey, in comparison to and in combination with amantadine. Methods: LID and parkinsonian symptoms were measured in dyskinetic monkeys treated with L-DOPA with and without several dose levels of safinamide, amantadine, and the two in combination. Safinamide plasma levels were monitored during the experiments. Results: Safinamide pre-treatment (3, 10, 20 and 30 mg/kg) dose-dependently reduced LID scores, in two acute and one semi-chronic experiment. Intensity and duration of LID were reduced and inversely correlated with safinamide blood levels. All doses of safinamide tested prolonged the duration of the beneficial antiparkinsonian effect of L-DOPA. Amantadine (5 and 20 mg/kg) reduced LID, but reduced duration of antiparkinsonian response to L-DOPA. When added to amantadine (5 mg/kg), safinamide showed no (3 mg/kg) or modest (20 mg/kg) additional beneficial effects on LID while the combined treatment prevented the reduction of the duration of the L-DOPA antiparkinsonian effect observed with amantadine only. Conclusions: Safinamide and amantadine reduced LID in this primate model while only safinamide increased the duration of the antiparkinsonian response of L-DOPA, suggesting that safinamide may have effects on LID that are pharmacologically distinct from amantadine, which is in current clinical use for control of LID. (C) 2013 Elsevier Ltd. All rights reserved.