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: 2.19). 07/2012; DOI: 10.1016/j.eplepsyres.2012.06.005
Source: PubMed

ABSTRACT OBJECTIVE: 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). METHODS: 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. RESULTS: 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]). CONCLUSIONS: 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.

  • [Show abstract] [Hide abstract]
    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 · 3.86 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Placebo response can be defined as any therapeutic change on placebo, while the nocebo response is any ill effect during placebo exposure. Several meta-analytic approaches have investigated the extent of placebo response in randomized, placebo-controlled, clinical trials of focal epilepsies. Placebo response rates (proportion of patients with ≥50% improvement of seizures versus baseline) ranging from 9.9% up to 15.2% have been reported. Interestingly, a sham response of 15.8% has been noted in trials of transcranial magnetic stimulation. Recently, nocebo response rates of 60.3% and 3.9% were noted, which were defined as the proportion of patients with adverse events (AEs) and those withdrawing because of intolerable AEs, respectively. Factors which were found to influence placebo response were as follows: the year of publication (with more recent studies showing higher rates of placebo response), some clinical characteristics of recruited patients (lower placebo response rates with a history of 7 or more prior lifetime AEDs, a high baseline seizure frequency, prior epilepsy surgery, and higher age at diagnosis), trial design and statistical analysis, and whether studies have been conducted in children or adults. Furthermore, placebo and nocebo rates were correlated with respective seizure outcome and adverse events of the experimental AED. Several mechanisms of placebo and nocebo responses are discussed. Specifically, the role of positive or negative expectations of patients and of investigators may influence the placebo and the nocebo response. Finally, recommendations are given on how to address placebo and nocebo responses in clinical practice. Copyright © 2015 Elsevier Inc. All rights reserved.
    Epilepsy & Behavior 02/2015; DOI:10.1016/j.yebeh.2014.12.004 · 2.06 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective Brivaracetam (BRV) is a new antiepileptic drug candidate rationally designed for high affinity and selectivity for the synaptic vesicle protein 2A. This study explored anti-ictogenic and antiepileptogenic effects of BRV in rats at different stages of development.Methods Using a rapid kindling model in P14, P21, P28, and P60 rats, we studied two doses of BRV: 10 and 100 mg/kg injected intraperitoneally 30 min before afterdischarge assessment. We also assessed blood and brain concentrations of BRV 30 min after the injection.ResultsBRV 100 mg/kg significantly increased the afterdischarge threshold (ADT) at all ages, whereas BRV at 10 mg/kg increased ADT in P60, P28, and P21 rats. BRV also shortens the afterdischarge duration (ADD), achieving statistical significance with 10 and 100 mg/kg at P60 and with 100 mg/kg at P21. At P60, BRV increases the number of stimulations required to achieve a stage 4–5 seizure in a dose-dependent manner. At P28 and P21, BRV increased the number of stimulations required to develop a stage 4–5 seizure in a dose-dependent manner with almost complete elimination of stage 4–5 seizures. In contrast, at P14, BRV had no effect on the number of stage 4–5 seizures. An age-related decrease in blood and brain concentrations of BRV was observed 30 min after injection of BRV 10 mg/kg, whereas with 100 mg/kg there were no significant age-correlated differences in brain and serum BRV concentrations.SignificanceBRV exerted dose-dependent anti-ictogenic effects from P60 to P14 independent of brain maturation. BRV also exhibited antiepileptogenic effects at P60, whereas this effect need to be further evaluated at P28 and P21. We did not observe any effect on epileptogenesis at P14 at either dose.
    Epilepsia 03/2015; DOI:10.1111/epi.12973 · 4.58 Impact Factor