Clinical efficacy and safety of the newer antiepileptic drugs as adjunctive treatment in adults with refractory partial-onset epilepsy: A meta-analysis of randomized placebo-controlled trials

School of Biomedical Sciences and Pharmacy, University of Newcastle, Australia.
Epilepsy research (Impact Factor: 2.02). 07/2012; 103(1). DOI: 10.1016/j.eplepsyres.2012.06.005
Source: PubMed


To evaluate the clinical efficacy and safety of the newer antiepileptic drugs (AEDs), namely, Eslicarbazepine (ESL), Retigabine/Ezogabine (RTG), Carisbamate (CAR), Lacosamide (LAC), Brivaracetam (BRI) or Perampanel (PER) as adjunctive therapy for adults with partial-onset seizures (POS).

A systematic review of Randomized placebo-controlled Trials (RCTs) of newer AEDs was conducted. Electronic databases and identified bibliographies were searched to retrieve RCTs. The primary outcomes were responder rates and withdrawal rates, adverse effects. Pooled effects of odds ratio (OR), risk ratio (RR) and risk differences (RD) were derived from meta-analysis implemented in Revmen 5.1.

In total, 15 RCTs were included. All the studies contained a baseline and treatment phase. The pooled OR of all newer AEDs vs placebo was 2.16 (95% CI: 1.82, 2.57) for responder rates, 1.54 (1.12, 2.10) for withdrawal rates, 1.67 (1.34, 2.08) for adverse effects. The indirect comparisons between individual newer AED and all other newer AEDs suggested the similar results in responder rates (ORs, BRI 1.79 [-1.50, 5.08], RTG 1.41 [0.49, 2.33]).

The pooled ORs suggested newer AEDs might be more effective than placebo while with higher incidence of adverse effects. The indirect comparisons suggested BRI, followed by RTG, might be more effective than all other newer AEDs, which could be confirmed by future clinical studies.

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    • "Despite the availability of several AEDs, up to 30% of patients remain resistant to treatment [4] [5]. Adjunctive therapy is warranted for such patients, but there are limited clinical data on AED combinations for treatment optimization [6]. Results from randomized controlled trials (RCTs), using strict inclusion/exclusion criteria and titration to one of three fixed doses, indicated that EZG/RTG was superior to placebo as an adjunctive therapy in patients with partial-onset seizures [7] [8] [9]. "
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    ABSTRACT: To assess efficacy/tolerability of ezogabine (EZG)/retigabine (RTG) in combination with specified monotherapy antiepileptic drug (AED) treatments in adults with uncontrolled partial-onset seizures using a flexible dosing regimen. NCT01227902 was an open-label, uncontrolled study of flexibly dosed EZG/RTG. Adults with partial-onset seizures must have been taking either carbamazepine/oxcarbazepine (CBZ/OXC), lamotrigine (LTG), levetiracetam (LEV), or valproic acid (VPA). The study comprised a screening/baseline phase, a 4-week titration phase (initiation on 150mg/day [50mg three times daily (TID)] with weekly increases of 150mg/day [50mg TID] over 4 weeks to 600mg/day), and a flexible dose evaluation (FDE) phase (optional weekly dose changes of 50-150mg/day, to an optimal daily dosage [300-1200mg/day]). The primary efficacy endpoint was percentage of patients experiencing a ≥50% reduction from baseline in partial seizure frequency (responder rate) during the treatment phase (titration and FDE phases). Safety and tolerability were also assessed. Patients (N=203) were enrolled and received ≥1 dose of EZG/RTG. The dose of EZG/RTG prescribed most frequently during the treatment phase was 600mg/day for all AED groups. Responder rates during the treatment phase were: 40.0% (CBZ/OXC), 32.0% (LTG), 50.0% (LEV), and 56.9% (VPA). Treatment-emergent adverse events occurred in 82% (CBZ/OXC), 76% (LTG), 73% (LEV), and 67% (VPA) of patients; most were of mild-to-moderate intensity. EZG/RTG was effective as adjunctive therapy to CBZ/OXC, LTG, LEV, and VPA, using a flexible dosing regimen, in adults with partial-onset seizures; safety and tolerability were consistent with that previously observed. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
    Seizure 08/2015; 30. DOI:10.1016/j.seizure.2015.06.002 · 1.82 Impact Factor
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    • "Avalanche length is given by the number of active frames, while avalanche size is given by the total number of active electrodes. The avalanche shown here has a length of 5 and a size of 9. patients with partial-onset seizures with or without secondary generalized seizures (see reviews and analysis by Gao et al., 2013; Rheims and Ryvlin, 2013; Steinhoff et al., 2013; Zaccara et al., 2013). "
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    ABSTRACT: Perampanel (Fycompa®) is and AMPA receptor antagonist used as an adjunctive treatment of partial-onset seizures. We asked whether perampanel has AMPA receptor antagonist activity in both cerebral cortex and hippocampus, associated with antiepileptic efficacy, and also in cerebellum, associated with motor side-effects, in rodent and human brain. We also asked if epileptic and non-epileptic human cortex is similarly responsive to AMPA receptor antagonism by perampanel. In rodent models, perampanel decreased epileptic-like activity in multiple seizure models. However, doses of perampanel that had anticonvulsant effects were within the same range as those engendering motor side effects. Perampanel inhibited native rat and human AMPA receptors from the hippocampus as well as the cerebellum that were reconstituted into Xenopus oocytes. In addition, with the same technique, perampanel inhibited AMPA receptors from hippocampal tissue that was removed from a patient undergoing surgical resection for refractory epilepsy. Perampanel inhibited AMPA receptor-mediated ion currents from all the tissues investigated with similar potency (IC50 values ranging from 2.6 to 7.0 μM). Cortical slices from the left temporal lobe derived from the same patient were studied in a 60-microelectrode array. Large field potentials were evoked on at least 45 channels of the array and 10 μM perampanel decreased their amplitude and firing rate. Perampanel also produced a 33% reduction in the branching parameter demonstrating effects of perampanel at the network level. These data suggest that perampanel blocks AMPA receptors globally across the brain to account for both its antiepileptic and side-effect profile in rodents and epileptic patients.
    Journal of Pharmacology and Experimental Therapeutics 07/2014; 351(1). DOI:10.1124/jpet.114.212779 · 3.97 Impact Factor
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    • "Combinatorial therapy of AEDs is not the first option as it may potentiate the occurrence of adverse side effects due to neurotoxicity and/or hepato-toxicity [10] [12] [13] [14] [15]. However, it is important to note that side effects have not only been reported for AED combinatorial therapy but also for monotherapy [10] [11] [13] [16]. Hence, the current aim of antiepileptic drug discovery is to identify novel active compounds that can provide a safer option with higher efficacy to control pharmaco-resistant seizures compared to currently available AEDs. "
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    PLoS ONE 12/2013; 8(12):e81634. DOI:10.1371/journal.pone.0081634 · 3.23 Impact Factor
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