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      New developments in the management of partial-onset epilepsy: role of brivaracetam

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          Abstract

          Currently, a number of novel anticonvulsant drugs, the so-called third generation, are in various stages of development. Several of them are already available or in ongoing clinical trials. These new compounds should take advantage of new insights into the basic pathophysiology of epileptogenesis, drug metabolism and drug interactions. Many of them still need to be further evaluated mainly in real-world observational trials and registries. Among newer anticonvulsant drugs for partial-onset seizures (POSs), rufinamide, lacosamide, eslicarbazepine and perampanel are those new treatment options for which more substantial clinical evidence is currently available, both in adults and, to some extent, in children. Among the newest anticonvulsant drugs, brivaracetam, a high-affinity synaptic vesicle protein 2A ligand, reported to be 10- to 30-fold more potent than levetiracetam, is highly effective in a broad range of experimental models of focal and generalized seizures. Unlike levetiracetam, brivaracetam does not inhibit high-voltage Ca 2+ channels and AMPA receptors and appears to inhibit neuronal voltage-gated sodium channels playing a role as a partial antagonist. Brivaracetam has a linear pharmacokinetic profile, is extensively metabolized and is excreted by urine (only 8%–11% unchanged). It does not seem to influence the pharmacokinetics of other antiepileptic drugs. It was approved in the European Union in January 2016 and in the US in February 2016 as an adjunctive therapy for the treatment of POS in patients older than 16 years of age. To date, its clinical efficacy as adjunctive antiepileptic treatment in adults with refractory POS at doses between 50 and 200 mg daily has been extensively assessed in two Phase IIb and four Phase III randomized controlled studies. Long-term extension studies show sustained efficacy of brivaracetam. Overall, the drug is generally well tolerated with only mild-to-moderate side effects. This is true also by intravenous route. Brivaracetam has not yet been evaluated as monotherapy or in comparison with other new anticonvulsant drugs.

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          Most cited references 68

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          A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology.

           Jerome Engel (2001)
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            Epidemiology, aetiology, and clinical management of epilepsy in Asia: a systematic review.

            Epilepsy is a significant, but often underappreciated, health problem in Asia. Here, we systematically review the literature on epidemiology, aetiology, and management of epilepsy in 23 Asian countries. Prevalence estimates are available for only 11 countries from door-to-door surveys and are generally low. Figures for annual incidence in China and India are similar to those in the USA and Europe but lower than those reported from Africa and Latin America. There is a peak in incidence and prevalence in childhood, but a second peak in elderly people, as seen in developed countries, has not been documented. The main causes are head injuries, cerebrovascular disease, CNS infections, and birth trauma. Availability of epilepsy care depends largely on economic factors. Imaging and neurophysiological facilities are available in most countries, but often only in urban centres. Costly drugs, a large treatment gap, limited epilepsy surgery, and negative public attitude to epilepsy are other notable features of management in Asia. An understanding of the psychosocial, cultural, economic, organisational, and political factors influencing epilepsy causation, management, and outcome should be of high priority for future investigations.
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              Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies.

              Three phase III studies (304 [ClinicalTrials.gov identifier: NCT00699972], 305 [NCT00699582], 306 [NCT00700310]) evaluated perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, as adjunctive therapy for refractory partial seizures. We report post hoc analyses of pooled study data by randomized dose. Patients with partial seizures despite receiving 1-3 antiepileptic drugs were randomized to once-daily placebo, perampanel 8 or 12 mg (studies 304, 305), or placebo, perampanel 2, 4, or 8 mg (study 306). Studies included a 6-week baseline period and double-blind treatment phase (6-week titration; 13-week maintenance). Primary end points were median change in partial seizure frequency (baseline vs. double-blind phase) and percentage of patients achieving ≥ 50% reduction in seizure frequency (baseline vs. maintenance). Here, these end points, together with secondary, exploratory, and safety end points, were assessed using pooled study data. The pooled intent-to-treat analysis set (randomized, treated patients with any seizure data) included 1,478 patients. Median changes in partial seizure frequency were greater with perampanel than placebo (perampanel 4 mg, -23.3%; 8 mg, -28.8%; 12 mg, -27.2%; placebo, -12.8%; p < 0.01, each dose vs. placebo), as were 50% responder rates (perampanel 4 mg, 28.5%; 8 mg, 35.3%; 12 mg, 35.0%; placebo, 19.3%; p < 0.05, each dose vs. placebo). In addition, median changes in complex partial plus secondary generalized seizure frequency were also greater with perampanel than placebo (perampanel 4 mg, -31.2%; 8 mg, -35.6%; 12 mg, -28.6%; placebo, -13.9%). Perampanel was generally well tolerated. The most frequent treatment-emergent adverse events (TEAEs) were dizziness, somnolence, and headache. Most TEAEs were mild/moderate; relatively few patients experienced severe TEAEs (placebo, 5.4%; perampanel, 8.9%) or serious TEAEs (placebo, 5.0%; perampanel, 5.5%). There were no deaths and no clinically important mean changes in laboratory values, electrocardiography (ECG) findings, or vital signs. Perampanel reduced partial seizure frequency and improved responder rates compared with placebo, with an acceptable tolerability profile. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.
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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
                2017
                06 March 2017
                : 11
                : 643-657
                Affiliations
                [1 ]Unit of Child and Adolescent Neuropsychiatry, Department of Medicine and Surgery, University of Salerno, Salerno
                [2 ]Department of Pediatrics, University of L’Aquila, L’Aquila, Italy
                Author notes
                Correspondence: Giangennaro Coppola, Unit of Child and Adolescent Neuropsychiatry, Department of Medicine and Surgery, S Giovanni di Dio and Ruggi d’Aragona Hospital, University of Salerno, Largo d’Ippocrate, Salerno 84100, Italy, Tel +39 089 672 578, Email gcoppola@ 123456unisa.it
                Article
                dddt-11-643
                10.2147/DDDT.S103468
                5345986
                28293101
                © 2017 Coppola et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. 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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