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      Clinical utility of eslicarbazepine: current evidence

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          Abstract

          Eslicarbazepine acetate (ESL) is a new antiepileptic drug whose mechanism of action is blockade of the voltage-gated sodium channel (VGSC). However, in respect to carbamazepine and oxcarbazepine, the active ESL metabolite (eslicarbazepine) affects slow inactivation of VGSC and has a similar affinity for the inactivated state and a lower affinity for the resting state of the channel. This new antiepileptic drug has been recently approved in Europe (trade name Zebinix) and in the United States (trade name Stedesa) for adjunctive treatment in adult subjects with partial-onset seizures, with or without secondary generalization. Following oral administration, ESL is rapidly and extensively metabolized by hepatic esterases to eslicarbazepine. This active metabolite has a linear pharmacokinetic profile, a low binding to plasma proteins (<40%), and a half-life of 20–24 hours and is mainly excreted by kidneys in an unchanged form or as glucuronide conjugates. ESL is administered once a day and has a low potential for drug–drug interactions. Efficacy and safety of this drug in patients with focal seizures have been assessed in four randomized clinical trials, and responder rates (percentage of patients with a ≥50% improvement of their seizures) ranged between 17% and 43%. Adverse events were usually mild to moderate, and the most common were dizziness, somnolence, diplopia, abnormal coordination, blurred vision, vertigo, headache, fatigue, nausea, and vomiting. ESL may be considered an interesting alternative to current antiepileptic drugs for the treatment of drug-resistant focal epilepsies. Additionally, it is under investigation in children with focal epilepsies, in patients with newly diagnosed focal epilepsies, and also in other neurological and psychiatric disorders.

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          Most cited references 62

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          Genomics and drug response.

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            The epidemiology of epilepsy revisited.

            Epidemiology is the study of the dynamics of a medical condition in a population. There are many shortcomings in the understanding of the epidemiology of epilepsy mostly caused by methodological problems. These include diagnostic accuracy, case ascertainment, and selection bias. In this article recent progress in this area is discussed and suggestions for future research are made. It is generally accepted that in developed countries the incidence is around 50/100 000/year. In resource-poor countries, the incidence is likely to be higher. Prevalence of active epilepsy is in the range of 5-10/1000 in most locations, although it might be higher in some isolates. Age-specific incidence rates have changed, with a decrease in younger age groups and an increase in persons above 60 years. The overall prognosis for seizure control is good and over 70% will enter remission. Epilepsy carries an increased risk of premature death particularly in patients with chronic epilepsy. Sudden unexpected death has been increasingly recognized as a major culprit for this increased mortality. There is geographic variation in the incidence of epileptic syndromes likely to be associated with genetic and environmental factors, although as yet causality has not been fully established. The complete range of aetiologies in the general population is not known. Few predictors of outcome are recognized and it is difficult to prognosticate in any individual case. Knowledge is patchy about the epidemiology of sudden unexpected death in epilepsy. Future epidemiological research needs to address these issues if we are to progress.
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              The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels.

              We hypothesized that lacosamide modulates voltage-gated sodium channels (VGSCs) at clinical concentrations (32-100 muM). Lacosamide reduced spiking evoked in cultured rat cortical neurons by 30-s depolarizing ramps but not by 1-s ramps. Carbamazepine and phenytoin reduced spike-firing induced by both ramps. Lacosamide inhibited sustained repetitive firing during a 10-s burst but not within the first second. Tetrodotoxin-sensitive VGSC currents in N1E-115 cells were reduced by 100 muM lacosamide, carbamazepine, lamotrigine, and phenytoin from V(h) of -60 mV. Hyperpolarization (500 ms) to -100 mV removed the block by carbamazepine, lamotrigine, and phenytoin but not by lacosamide. The voltage-dependence of activation was not changed by lacosamide. The inactive S-stereoisomer did not inhibit VGSCs. Steady-state fast inactivation curves were shifted in the hyperpolarizing direction by carbamazepine, lamotrigine, and phenytoin but not at all by lacosamide. Lacosamide did not retard recovery from fast inactivation in contrast to carbamazepine. Carbamazepine, lamotrigine, and phenytoin but not lacosamide all produced frequency-dependent facilitation of block of a 3-s, 10-Hz pulse train. Lacosamide shifted the slow inactivation voltage curve in the hyperpolarizing direction and significantly promoted the entry of channels into the slow inactivated state (carbamazepine weakly impaired entry into the slow inactivated state) without altering the rate of recovery. Lacosamide is the only analgesic/anticonvulsant drug that reduces VGSC availability by selective enhancement of slow inactivation but without apparent interaction with fast inactivation gating. The implications of this unique profile are being explored in phase III clinical trials for epilepsy and neuropathic pain.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                10 February 2015
                : 9
                : 781-789
                Affiliations
                [1 ]Department of Medicine, Unit of Neurology, Florence Health Authority, Florence, Italy
                [2 ]Department of Neuroscience, Psychology, Pharmacology and Child Health (NEUROFARBA), University of Florence, Florence, Italy
                [3 ]Department of Pediatrics, University of Perugia, Perugia, Italy
                Author notes
                Correspondence: Gaetano Zaccara, Unit of Neurology, San Giovanni di Dio Hospital, Via Di Torregalli n 3, 50143 Florence, Italy, Email gaetano.zaccara@ 123456asf.toscana.it
                Article
                dddt-9-781
                10.2147/DDDT.S57409
                4330027
                © 2015 Zaccara et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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