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Movement Disorders Parkinson’s Disease Emerging Role of Safinamide in Parkinson’s Disease Therapy Jaime Kulisevsky 1,2,3 1. Movement Disorders Unit, Neurology Department, Sant Pau Hospital, Autonomous University of Barcelona, Barcelona, Spain; 2. Estudis de Ciències de la Salut, Universitat Oberta de Catalunya (UOC), Barcelona, Spain; 3. CIBERNED, Instituto de Salud Carlos III, Madrid, Spain Abstract Parkinson’s disease is associated with motor complications, especially dyskinesias, which limit dopaminergic replacement therapy. Safinamide is a water-soluble, orally active a-aminoamide derivative that modulates dopaminergic and glutamatergic neurotransmission with a unique dual mechanism of action. It improves motor symptoms, motor complications, quality of life and ‘on’ and ‘off’ time even in combination with other Parkinson’s disease (PD) medications, such as dopamine agonists and levodopa (LD). Safinamide reduces ‘off’ time and extends ‘on’ time without troublesome dyskinesia. Furthermore, safinamide maintains its effects after long-term treatment and has a favourable pharmacokinetic and side-effect profile. It therefore has the potential to become an important drug in PD management. This review will summarise data from animals, healthy human subjects and patients with PD on the long-term efficacy and safety of safinamide. Keywords Add-on therapy, dyskinesia, dopaminergic, monoamine oxidase b, non-dopaminergic, Parkinson’s disease, safinamide Disclosure: Jaime Kulisevsky has received honoraria for lecturing or participating in advisory boards of Abbvie, Lundbeck, Teva, UCB and Zambon, and research support from Instituto de Salud Carlos III, Spain. Acknowledgements: Editorial assistance was provided by Catherine Amey at Touch Medical Media, London. Received: 1 August 2014 Accepted: 22 August 2014 Citation: European Neurological Review, 2014;9(2):108–112 Correspondence: Jaime Kulisevsky, Sant Pau Hospital, Sant Antoni M Claret 167, 08025 Barcelona, Spain. E: jkulisevsky@santpau.cat Support: The publication of this article was supported by Zambon SpA. The views and opinions expressed are those of the author and do not necessarily reflect those of Zambon SpA. Parkinson’s disease (PD) is a neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta – non-dopaminergic neurotransmission is also involved. In the basal ganglia circuitry there are many non-dopaminergic neurotransmitters and neuromodulators involved in the control of motor symptoms and implicated in the development of motor complications following long-term levodopa (LD) therapy. 1–4 Indeed, PD is no longer seen purely as a disease of the dopaminergic system. 5 In particular, overactive glutamate transmission plays a role in the progression of PD. 6–8 Targeting non-dopaminergic systems is thus a complementary approach to improve and control such motor complications, removing the need for further increases in LD, which may otherwise worsen motor fluctuations. 4 Safinamide (see Figure 1) is an oral, once-a-day adjunctive therapy developed for any stage of PD. Safinamide is a unique molecule with novel mechanisms of action (dopaminergic and non-dopaminergic) that include monoamine oxidase-B (MAOB) inhibition, sodium channel blockade and calcium channel modulation, thus inhibiting the excessive glutamate release. The sodium channel inhibition is concentration- and state-dependent, and does not influence physiological activity, avoiding depressant effects on the central nervous system (CNS). Safinamide does not affect L-type calcium channels (no effects in blood pressure and heart rate). 9–12 Safinamide is more selective for MAO-B versus MAO-A than selegiline and rasagiline: 1,000-fold in humans, compared with 127-fold for selegiline and 103-fold for rasagiline. 10,13–15 This higher selectivity is related to the absence of diet restrictions pertaining to the clinical use of the drug. Moreover, the MAO-B inhibition is totally 108 reversible, allowing better clinical manageability and limiting possible drug–drug interactions. 10,14,15 In animal models, safinamide has been shown to reduce LD-induced dyskinesias. 10,16 It may also have neuroprotective effects. 8 Safinamide inhibits a-1 receptors in the endoplasmic reticulum. 17 These receptors are believed to be multifunctional regulatory proteins with a role in CNS development, plasticity and neurodegeneration. Safinamide has been shown to completely prevent forebrain dopamine depletion and neuronal cell death in the gerbil substantia nigra when administered prior to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 18 In animal epilepsy models, safinamide was shown to counteract neuronal death that had been induced by excitotoxin. 19 Possible mechanisms of action for safinamide’s potential neuroprotective properties are MAO-B inhibition 20 and reduction in glutamate release. 10,11 The efficacy and safety of safinamide has been evaluated in clinical studies as add-on therapy to dopamine agonists (DAs) in early-stage PD 21–23 and as add-on to LD (with possibly other anti-Parkinson’s drugs) in mid- to late-stage PD. 24–26 Evidence from Healthy Volunteers Four clinical trials in male, healthy volunteers, which included a food interaction trial, covering doses from 25  μg/kg to 10  mg/kg were carried out to investigate the pharmacokinetics, pharmacodynamics and tolerability of safinamide, administered in single or repeated doses to steady state. 27 The trials showed that near complete inhibition of MAO-B is achieved with a safinamide dose of 0.3  mg/kg and that enteral absorption of the drug is linear and proportional to the doses © Touc h ME d ic al ME d ia 2014