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The mechanism of action of several antiepileptic drugs (AEDs) rests on their ability to modulate the activity of voltage-gated sodium currents that are responsible for fast action potential generation. Recent data indicate that lacosamide (a compound with analgesic and anticonvulsant effects in animal models) shares a similar mechanism. When compared with other AEDs, lacosamide has the unique ability to interact with sodium channel slow inactivation without affecting fast inactivation. This article reviews these findings and discusses their relevance within the context of neuronal activity seen during epileptiform discharges generated by limbic neuronal networks in the presence of chemical convulsants. These seizure-like events are characterized by sustained discharges of sodium-dependent action potentials supported by robust depolarizations, thus providing synchronization within neuronal networks. Generally, AEDs such as phenytoin, carbamazepine and lamotrigine block sodium channels when activated. In contrast, lacosamide facilitates slow inactivation of sodium channels both in terms of kinetics and voltage dependency. This effect may be relatively selective for repeatedly depolarized neurons, such as those participating in seizure activity in which the persistence of sodium currents is more pronounced and promotes neuronal excitation.
The clinical effectiveness of lacosamide has been demonstrated in randomized, double-blind, parallel-group, placebo-controlled, adjunctive-therapy trials in patients with refractory partial seizures. Further studies should determine whether the effects of lacosamide in animal models and in clinical settings are fully explained by its selective action on sodium current slow inactivation or whether other effects (e.g. interactions with the collapsinresponse mediator protein-2) play a contributory role.
KeywordsCarbamazepine Neuropathic Pain Sodium Channel Lamotrigine Lacosamide
This review was supported by grants from the Italian Ministry of Education, University & Research (FIRB2001 RBNE01NR34_011, PRIN 2003060538), the Canadian Institutes of Health Research (CIHR; Grant MT-8109), the Savoy Foundation and the Pierfranco and Luisa Mariani Foundation (R-06-50). Dr Giulia Curia was supported by a postdoctoral fellowship from Fragile X Research Foundation of Canada (FXRFC) in partnership with the CIHR.
Dr Emilio Perucca has received speaker’s or consultancy fees and/or research grants from Novartis, Bial, Pfizer, GlaxoSmithKline, UCB Pharma, Sanofi-aventis, Eisai, Johnson & Johnson and Valeant Pharmaceuticals. Dr Massimo Avoli has received grants from Pfizer and UCB Pharma. Drs Curia and Biagini have no conflicts of interest that are directly relevant to the current review.
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