Treatment Of Partial-onset Seizures Research Articles

Brivaracetam: A Review in Partial-Onset (Focal) Seizures in Patients with Epilepsy.

Brivaracetam (Briviact(®); BRIVLERA™) is a high affinity synaptic vesicle protein 2A (SV2A) ligand available orally (as a tablet or solution) or intravenously (as a bolus or infusion) in various countries worldwide, including the USA, Canada and those of the EU. It is approved as adjunctive therapy for the treatment of partial-onset seizures (POS) in adults (aged ≥18years) [USA, EU and Canada] and adolescents (aged 16 to <18years) [USA and EU] with epilepsy. In multinational, phase III studies in adults and adolescents (aged ≥16years), oral brivaracetam as adjunctive therapy to other antiepileptic drugs (AEDs) was generally associated with significant median percent reductions over placebo in seizure frequency and significant improvements in the proportion of patients achieving a ≥50% reduction in seizure frequency compared with placebo. These benefits appeared to be sustained during up to 96months' therapy in follow-up studies. Whether administered orally or intravenously, adjunctive brivaracetam was generally well tolerated in clinical studies, with the majority of treatment-emergent adverse events (TEAEs) being mild or moderate in intensity. In the absence of head-to-head studies, definitive conclusions on the comparative efficacy and tolerability of brivaracetam versus newer AEDs are not yet possible. In the meantime, brivaracetam extends the options currently available for the treatment of POS in patients aged ≥16years with epilepsy.

Survey of Physicians' Understanding of Specific Risks Associated with Retigabine.

BackgroundFollowing reports of discoloration, including retinal pigmentation, in addition to known significant risks of urinary retention, central nervous system effects, and QTc prolongation, the retigabine indication was restricted to adjunctive treatment of partial onset seizures where other appropriate drug combinations have proved inadequate or have not been tolerated.ObjectiveTo ascertain the effectiveness of educational initiatives as reflected in physicians’ understanding of retigabine-associated risks, management, and patient selection.MethodologyAn online, cross-sectional survey, designated a post-authorization safety study (24/9/2014–30/1/2015), recruited retigabine prescribers (RP) and retigabine non-prescribers (RNP) in seven countries, who had been sent a retigabine Dear Health Care Professional letter (June 2013). Questions tested understanding of the significant risks associated with retigabine.Results414/467 participants completed all questions (RP, n = 141; RNP, n = 273) and were included in the analysis. 74.2 % of these participants (RP, 77.3 %; RNP, 72.5 %) correctly identified the label indication. 81.9 % of participants (RP, 86.5 %; RNP, 79.5 %) recognized that specific retigabine-associated risks included pigment changes of ocular tissues, including the retina. 81.6 % of participants (RP, 87.2 %; RNP, 78.8 %) recognized that a comprehensive ophthalmologic examination is required. 99.8 % of participants (RP, 100.0 %; RNP, 99.6 %) acknowledged the requirement for action in case of retinal pigmentation or vision changes. RP and RNP results were similar to the overall participants’ analysis, with a trend toward stronger understanding among RP.ConclusionMost participants recognized the appropriate population for retigabine treatment and the requirement to monitor for adverse events including retinal pigmentation and vision changes. Understanding was satisfactory among RNP but stronger among RP.

Eslicarbazepine Acetate Monotherapy: A Review in Partial-Onset Seizures.

Eslicarbazepine acetate (Aptiom(®)) is a once-daily, orally administered antiepileptic drug (AED) approved previously in the EU, USA and several other countries for use as adjunctive therapy for the treatment of partial-onset seizures. Based on the findings of two randomized, dose-blinded, conversion-to-monotherapy phase III trials in patients with uncontrolled partial epilepsy, the US license for eslicarbazepine acetate has recently been expanded to include use as monotherapy for partial-onset seizures. The pivotal trials demonstrated that seizure control following conversion from other AEDs was superior for eslicarbazepine acetate monotherapy (1200 or 1600mg once daily) compared with a pseudo-placebo historical control. Other efficacy outcomes appeared to support the benefit of treatment, with up to 10% of patients remaining seizure free and up to 46% of patients experiencing a ≥50% reduction from baseline in standardized seizure frequency during the monotherapy periods of the trials. Eslicarbazepine acetate monotherapy was generally well tolerated, with most treatment-emergent adverse events being mild to moderate in severity. Its tolerability profile was generally consistent with the established profile of the drug based on its use as adjunctive therapy. Thus, once-daily eslicarbazepine acetate, either as monotherapy or adjunctive therapy, represents a useful option for the treatment of patients with partial-onset seizures. The recent licensing of the drug in the USA as monotherapy expands the range of treatment options for patients with partial-onset seizures and increases the opportunity to tailor therapy to the individual patient.

Carbamazepine versus phenytoin monotherapy for epilepsy: an individual participant data review.

Carbamazepine versus phenytoin monotherapy for epilepsy: an individual participant data review.

Levetiracetam: Pharmacological properties, safety and efficacy in the pediatric population with epilepsy

Age-specific distribution of epilepsy is bimodal, with the highest incidence being in childhood. Seizures can affect life as early as day one. There is a paramount variation of epilepsy in childhood and adolesence with regards to its etiology and prognosis. Antiepileptic drugs, being the mainstay of treatment, necessitates that their use in this vulnerable age group must be made after a thorough look into the available evidence. The data on levetiracetam (LEV), a second-generation antiepileptic, spans from randomized controlled trials to case reports in various pediatric epilepsy and epileptic syndromes. This review is a compilation and critical analysis of the data on the differences in the pharmacokinetic properties of LEV in children versus adults, drug-interactions, efficacy of LEV in various contexts, namely, as add-on, as monotherapy, in partial and generalized seizures, in specific epilepsy syndromes such as benign epilepsy with centrotemporal spikes, epileptic syndromes with contin- uous spike and wave during sleep, Lennox-Gastaut syndrome, Jeavons syndrome and epilepsy associated with tuberous sclerosis. LEV is an effective option for the treatment of partial-onset seizures as both an add-on in refractory epilepsy and monotherapy in newly diagnosed focal epilepsies. There are preliminary but promising data available on various epileptic syndromes and epi- leptic encephalopathies that can nudge researchers towards further work in these areas in order to generate evidences that is more substantial. The safety and tolerability profile of LEV is favorable, though, behavioral and neuropsychiatric adverse events are reportedly higher in children versus adults. The neuropsychiatric adverse events are often observed against the background of previously existing behavioral issues and neurocognitive impairments.

Carbamazepine versus phenobarbitone monotherapy for epilepsy: an individual participant data review.

Carbamazepine versus phenobarbitone monotherapy for epilepsy: an individual participant data review.

Safety and Effectiveness of Lacosamide as Adjunctive Treatment for Partial-onset Seizures (POS) in Hispanic/Latino Patients from Mexico: Post-hoc Analysis of an Open-label Trial (P4.265) and Safety and Effectiveness of Lacosamide as a First Add-on (FAO) or Later Add-on (LAO) Treatment of Partial-onset Seizures (POS) in Adults: an Open-label Trial (P4.262)

In the 2015 AAN Annual Meeting abstracts “Safety and Effectiveness of Lacosamide as Adjunctive Treatment for Partial-onset Seizures (POS) in Hispanic/Latino …

EFFICACY AND TOLERABILITY OF LEVETIRACETAM (KEPPRA®) IN THE TREATMENT OF EPILEPSY: REVIEW OF LITERATURE

In spite of substantial progress in epileptology, complete seizure control cannot be achieved in a considerable proportion of patients (about 30 %); in this regard, the synthesis of new antiepileptic drugs (AEDs) and rational combinations of available AEDs in view of their mechanisms of action remains relevant. Of particular interest are drugs with different mechanisms of action in relation to other AEDs (these drugs include levetiracetam, lacosamide, perampanel, etc.). The authors provide a literature review dealing with one of the new drugs – levetiracetam (Keppra) that has a different mechanism of action, as compared with other AEDs. Levetiracetam has been approved for use as initial monotherapy for partial-onset epilepsy with or without secondary generalization in patients who are at least 16 years of age, as adjunctive treatment of partial-onset seizures with and without secondary generalization in babies who are at least 1 month old (oral solution) or in children who are at least 6 years old (tablets), and in patients who are at least 12 years of age as adjunctive treatment of myoclonic seizures in juvenile myoclonic epilepsy and as therapy for generalized tonic-clonic seizures in idiopathic generalized epilepsy. The review details the mechanism of action of levetiracetam, its pharmacokinetics, and data on its efficacy and tolerability in the treatment of epilepsy. The findings have led to the conclusion that levetiracetam is a well-studied and promising drug used in the monoand polytherapy of different forms of epilepsy.

Efficacy and safety of USL255 (Qudexy™ XR; extended-release topiramate) for adjunctive treatment of partial-onset seizures: The PREVAIL study

Efficacy and safety of USL255 (Qudexy™ XR; extended-release topiramate) for adjunctive treatment of partial-onset seizures: The PREVAIL study

Long-term efficacy and safety of lacosamide monotherapy in the treatment of partial-onset seizures: A multicenter evaluation

PurposeThe goal of this study is to report the efficacy and tolerability of lacosamide (LCM) monotherapy, as first-line and conversion regimens, in the treatment of patients with partial-onset seizures. MethodsWe retrospectively reviewed the charts of patients with focal epilepsy on LCM monotherapy from six centers in Spain. Efficacy and tolerability were evaluated in the overall group and in subgroups of patients who were naive to antiepileptic drug (AED) therapy (Group 1) and those who had previously been treated with AEDs (Group 2). ResultsSixty-six patients were identified including 18 patients in Group 1 and 48 patients in Group 2. Patients were followed up for 0.5–54 months in monotherapy (mean 15.5 months). Forty-two (63.6%) patients remained seizure-free during all the follow-up. At 6 and 12 months, seizure-free rates were 77.6% and 72.3%, respectively. The drug was withdrawn in 10 (15%) patients (3 side effects, 6 lack of efficacy, 1 other reason). Fifteen (22.7%) patients reported mild to moderate side effects with the use of LCM. No differences were found between Groups 1 and 2 regarding efficacy outcomes or tolerability issues. ConclusionsIn our series more than two-thirds of the patients remained seizure-free on LCM monotherapy. Side effects were generally mild and led to discontinuation in only 3/66 (4.5%) patients. Our experience suggests that LCM monotherapy, either as first-line or after conversion, may be a valuable option for patients with focal epilepsy.

Safety and Effectiveness of Lacosamide as a First Add-on (FAO) or Later Add-on (LAO) Treatment of Partial-onset Seizures (POS) in Adults: an Open-label Trial (P4.262)

Safety and Effectiveness of Lacosamide as a First Add-on (FAO) or Later Add-on (LAO) Treatment of Partial-onset Seizures (POS) in Adults: an Open-label Trial (P4.262)

Population pharmacokinetic analysis for 10-monohydroxy derivative of oxcarbazepine in pediatric epileptic patients shows no difference between Japanese and other ethnicities

Oxcarbazepine is an anti-epileptic drug, which is almost completely metabolized by cytosolic enzymes in the liver to the active 10-monohyroxy metabolite (MHD) following oral administration. The pharmacokinetic (PK) profiles of MHD were evaluated in pediatric epileptic patients and a possible ethnic difference in PK of MHD between Japanese and non-Japanese pediatric patients was assessed. A non-linear mixed effect modeling approach was used to determine the PK of MHD. A one-compartment population model with first-order absorption appropriately described the PK of MHD. No clinically relevant differences were found for using body surface area or weight to explain between-patient variability, therefore the final model included the effects of body weight on apparent clearance (CL/F) and apparent volume of distribution (V/F) of MHD, and in addition, the effect of 3 concomitant anti-epileptic drugs (carbamazepine, phenobarbital and phenytoin) on CL/F of MHD. Inclusion of ethnicity as a covariate in the final model, concluded no ethnic difference with respect to CL/F of MHD between Japanese and non-Japanese patients. Hence, oxcarbazepine can be generally applied using the same dosage and administration for the treatment of partial onset seizures in pediatric patients, regardless of ethnicity.

Factors influencing response to intravenous lacosamide in emergency situations: LACO-IV study

Status epilepticus (SE) and acute repetitive seizures (ARSs) frequently result in emergency visits. Wide variations in response are seen with standard antiepileptic drugs (AEDs). Oral and intravenous (IV) formulations of lacosamide are approved as adjunctive therapy in the treatment of partial-onset seizures in adults and adolescents. The aim of the retrospective multicenter observational study (LACO-IV) was to analyze data from a large cohort of patients with SE or ARSs of varying severity and etiology, who received IV lacosamide in the emergency setting. Patient clinical data were entered into a database; lacosamide use and efficacy and tolerability variables were analyzed. In SE, IV lacosamide tended to be used mainly in nonconvulsive status epilepticus as second- or third-line treatment. The proportion of patients with no seizures when IV lacosamide was the last drug administered was 76.5% (70.9% SE and 83.7% ARSs). The rate of seizure cessation ≤24h after IV lacosamide administration was 57.1% (49.1% SE and 67.4% ARSs). Of the factors analyzed, a shorter latency from seizure onset to IV lacosamide infusion influenced treatment response significantly. A nonsignificant tendency towards a higher response was seen with lacosamide dose >200mg versus ≤200mg. Analysis of response according to mechanism of action showed no significant differences in response to IV lacosamide in patients receiving prior sodium channel blocker (SCB) or non-SCB AEDs in the overall or SE population; however, in ARSs, a tendency towards a higher response was observed in those receiving non-SCB AEDs. The frequency and nature of adverse events observed were in line with those reported in other studies (somnolence being the most frequent). In the absence of randomized prospective controlled studies of IV lacosamide, our observations suggest that IV lacosamide may be a potential alternative for treatment of SE/ARSs when seizures fail to improve with standard AEDs or when AEDs are contraindicated or not recommended.

Update On the Use of Lacosamide in the Treatment of Partial-Onset Seizures

ABSTRAT: Lacosamide has a novel mechanism of action, namely selective enhancement of slow inactivation of voltage-gated sodium channels. Trial data and clinical experience indicate that it is effective in the treatment of partial-onset seizures, and that it is well tolerated. Pivotal early clinical trials demonstrated median percent reductions in seizure frequency ranging from 26 to 35.3% in the 200 mg/day, from 36.4 to 39% in the 400 mg/day, and from 37.8 to 40% in the 600 mg/day treatment groups. Dose-related adverse events were similar in the early clinical trials, and were mainly CNS complaints including dizziness, nausea, vomiting, fatigue, ataxia, abnormal vision, diplopia and nystagmus. Because of the dose-dependent adverse events and lack of additional efficacy at the 600 mg/day daily dose, lacosamide has been approved as an adjunctive treatment at recommended daily doses of 200–400 mg/day.

The discovery and development of perampanel for the treatment of epilepsy

Introduction: Perampanel is a novel AMPA receptor antagonist, approved in over 35 countries as an adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged 12 years and older (18 years and older in Canada). These countries include the members of the European Union, the USA, Canada and Switzerland. The AMPA receptor antagonist, perampanel, is the first approved antiepileptic drug to inhibit excitation of postsynaptic membranes through the selective inhibition of glutamate receptors.Areas covered: This drug discovery case history focuses on the discovery and profiling of perampanel. It analyzes the pharmacological, behavioral and molecular mechanisms of perampanel and how they contribute to the therapeutic benefits of the drug. The article is based on the data reported in published preclinical and clinical studies, product labels and poster presentations.Expert opinion: Preclinical studies of perampanel have identified its broad-spectrum antiseizure effects in acute seizure models, with a narrow therapeutic index in the rotarod test similar to other AMPA receptor antagonists. This narrow therapeutic index is a potential problem for AMPA receptor antagonists. However, the discovery that perampanel has a very long half-life in humans, with gradual accumulation in plasma, could contribute to the development of tolerance. This, coupled with the identification of an optimal dosing strategy for individual patients, may help to maximize the utility of perampanel in the treatment of epilepsy.

EPA-0298 – Pregabalin abuse among opiate addicted patients

Introduction Pregabalin is a novel GABA-analogue approved for the treatment of partial onset seizures, neuropathic pain, and general anxiety disorder. Pregabalin has been classified as a Schedule V drug with a low risk of inflicting abuse or addiction. However, some publications have indicated that pregabalin may have a potential for abuse among patients with past or current opiate addiction. Aims We hypothesized that pregabalin might be abused my patients who were undergoing an opiate replacement therapy and never had an indication for taking pregabalin on medical grounds. Methods Urine specimens from 124 patients with opiate dependency syndrome and from 111 patients with other addiction disorders (alcohol, benzodiazepines, cannabis, amphetamines) were screened for pregabalin by means of a mass spectrometer analysis. Results We found 12.1% of all urine specimens from patients with opiate addiction to be positive for pregabalin. None of the patients concerned had a medical indication for using pregabalin. In the control group, 2.7% of the patients were tested positively for pregabalin, due to their taking it regularly for chronic pain or general anxiety. Conclusions Our data suggest that pregabalin is liable to be abused among patients with opiate dependency syndrome. Thus, vigilance and caution are called for when patients with a past or current opiate dependency are exposed to treatment with pregabalin.

Retigabine – a new antiepileptic drug with a different mechanism of action

Retigabine belongs to a new generation of antiepileptic drugs. Its mechanism of action is different from that previously known. Retigabine opens potassium channels of subfamily Kv 7, especially Kv 7.2 and Kv 7.3. The drug enhances GABA-ergic transmission. It is well absorbed from the digestive system and undergoes metabolism via glucuronidation and acetylation. There is no interaction between retigabine and other antiepileptic drugs except lamotrigine. The drug has been registered as treatment of partial onset seizures with or without secondary generalization in adults. The efficacy of retigabine is being tested in other types of seizures and disorders characterized by neuronal hyperexcitability. Neuroprotective activity of retigabine is also being researched.

Pregabalin abuse among opiate addicted patients

Pregabalin is a novel GABA-analogue approved for the treatment of partial onset seizures, neuropathic pain, and general anxiety disorder. Pregabalin has been classified as a Schedule V drug with a low risk of inflicting abuse or addiction. However, some publications have indicated that pregabalin may have a potential for abuse among patients with past or current opiate addiction. Thus, we hypothesized that pregabalin might be abused by patients who were undergoing an opiate replacement therapy and never had an indication for taking pregabalin on medical grounds. Urine specimens from 124 patients with opiate dependency syndrome and from 111 patients with other addiction disorders (alcohol, benzodiazepines, cannabis, amphetamines) were screened for pregabalin by means of a mass spectrometer analysis. We found 12.1 % of all urine specimens from patients with opiate addiction to be positive for pregabalin. None of the patients concerned had a medical indication for using pregabalin. In the control group, 2.7 % of the patients were tested positively for pregabalin, due to their taking it regularly for chronic pain or general anxiety. Our data suggest that pregabalin is liable to be abused among individuals with opiate dependency syndrome Thus, vigilance and caution are called for when patients with a past or current opiate dependency are exposed to treatment with pregabalin.

PP201—An Open-Label, Randomized, Single-Centre, Four-Way Crossover Study to Evaluate the Pharmacokinetics of Single, Oral Doses of Retigabine/Ezogabine in Healthy Adult Taiwanese Subjects

Retigabine (RTG)/ezogabine, N-[2-amino-4(4-fluorobenzylamino)-phenyl] carbamic acid ethyl ester, is a novel antiepileptic compound. In 2011, RTG was approved by the FDA and European Commission as adjunctive treatment for partial onset seizures in adults aged ≥18 years. The global pivotal studies did not include Asian countries. The purpose of this study was to characterize the pharmacokinetics (PK) of single 50, 100, 200, and 400-mg doses of RTG and N-acetyl metabolites of RTG (NAMR) in healthy Taiwanese subjects.

Ezogabine (KCNQ2/3 channel opener) prevents delayed activation of meningeal nociceptors if given before but not after the occurrence of cortical spreading depression

We proposed recently that induction of delayed activation of trigeminovascular neurons by cortical spreading depression (CSD) can explain the delayed onset of headache after the migraine aura ("aura"). This prompted us to search for ways to block the neuronal activation by CSD — a preclinical correlate of an attempt to find a drug that can block the initiation of headache when administered shortly after onset of aura (i.e., preemptively). Because migraine headache and epileptic seizures are comorbid chronic neurological disorders characterized by hyperexcitable brain networks, we began the search for such goal with an M-type potassium channel opener. We opted to use ezogabine, recently approved by the FDA as adjunctive treatment of partial onset seizures in adults, because it is a selective KCNQ2/3 channel opener. When CSD was induced before ezogabine injection (8.25mg/kg, i.p.), 40% (6/15) of the units doubled their firing rate about 45min later for about 95min. Similarly, when CSD was induced before vehicle was injected (4% DMSO, 0.5% methylcellulose), 50% (3/6) of the units doubled their firing rate about 30min later for about 120min. When CSD was triggered 1h after ezogabine injection, it activated only 8% of the units. By itself, ezogabine injection resulted in a 30% attenuation of ongoing firing in all 10 control units. Thus, activation of KCNQ2/3 channels during the aura is unlikely to preempt the onset of headache but may reduce the incidence of migraine if given during prodromes that precede the headache by hours. Given the mechanistic similarities between migraine aura and epileptic seizures, it may be worthwhile to determine whether preemptive administration of ezogabine can prevent oncoming seizures in patients whose warning signs precede their seizures by more than an hour.