Treatment Of Partial-onset Seizures Research Articles

Ezogabine for the Adjunctive Treatment of Partial Onset Seizures in Adults with Epilepsy

Partial seizures are frequently resistant to pharmacologic treatment. There are a plethora of medications currently approved for use in partial epilepsy. However, despite the large number of medications available, seizure control often remains elusive. A new medication with a unique mechanism of action has recently been approved for the adjunctive treatment of partial seizures in adults. Ezogabine (retigabine) exerts its actions at the level of voltage-gated potassium channels. In clinical trials it has demonstrated efficacy similar to that of other agents approved for resistant partial epilepsy. Adverse events tend to be central nervous system related. However, significant urinary retention has been noted in some persons exposed to the drug. A Risk Evaluation and Mitigation Strategy is being implemented to minimize urinary adverse events. Ezogabine represents an important addition to the partial epilepsy medication arsenal.

Lacosamide and Epilepsy

We will review all available studies on the use of lacosamide in the treatment of partial-onset seizures. The available evidence includes two open-label studies and three randomized controlled trials evaluating the safety and efficacy of oral lacosamide. One open-label study and one randomized controlled trial evaluating the safety and tolerability of intravenous lacosamide was also identified. Lacosamide was found to be efficacious with significant reduction in seizure frequency dosed 400-600 mg daily. Moreover, its adverse drug effects were mild and infrequently reported in the literature. Findings suggest that lacosamide is an effective agent for adjunctive treatment of refractory partial-onset seizures.

Abstract #8: Trial Methodology of a Randomized, Double-blind, Parallel-Group Study Evaluating the Clinical Effectiveness of Carisbamate, Topiramate, and Levetiracetam As Adjunctive Treatment of Partial Onset Seizures in Adults

Introduction International guidelines recommend assessing the overall long-term benefit of antiepileptic drugs (AEDs) using multidimensional measures. Effectiveness encompasses the effects of a product's efficacy, safety, and tolerability. Retention reflects effectiveness over time. This double-blind study (NCT00563459) was designed to compare the 6- and 12-month retention (as the primary parameter) of patients taking carisbamate (the investigational drug), topiramate, and levetiracetam when used as adjunctive treatment for partial onset seizures (POS). The retention hypotheses were that carisbamate would be at least as good as each comparator. Additionally, because cognitive and neuropsychiatric adverse events (AEs) have an impact on acceptance of therapy, the incidences of these AEs were assessed with the hypotheses that carisbamate would be superior to topiramate on cognitive AEs and superior to levetiracetam on neuropsychiatric AEs. The aforementioned hypotheses were analyzed using a fixed-sequence testing procedure. Methods Following a screening phase, ∼600 adult patients with POS and a history of inadequate response to treatment with e1AED had to be randomized in a 1:1:1 ratio to enter a 7-week titration period. Target daily doses of study medications were carisbamate 800 mg/day, topiramate 300 mg/day or levetiracetam 2000 mg/day, (dose adjustment could be done within the limits of 400–1200 mg/day; 200–400 mg/day; or 1000–3000 mg/day, respectively). After titration, patients entered the 17-week maintenance period. The 7-week titration and 17-week maintenance phases comprise the 6-month (24-week) core double-blind phase, with an option for an additional 6-month double-blind extension phase. The primary endpoint was the time from the first intake of study medication to any cause of discontinuation over the 6-month core double-blind phase. Cognitive AEs, neuropsychiatric AEs, reasons for discontinuation, seizure rates, cognitive changes relative to baseline assessed with a computerized cognitive test battery, and patient-reported mood states, behavioral, and cognitive changes relative to baseline using the Profiles of Mood Status questionnaire, Center for Epidemiologic Studies Depression Scale, and patient- and observer-reported Overall Mental Effects Questionnaire among the 3 treatment arms were assessed at 6- and 12-months post-randomization. This study design can provide unique information and meaningful data that might be valuable for clinical decision-making. Support Support was provided by Johnson & Johnson Pharmaceutical Research & Development , LLC.

Intravenous Levetiracetam In Children With Seizures: A Prospective Safety Study

In 2006, intravenous levetiracetam received US Food and Drug Administration (FDA) approval for adjunctive treatment of partial onset seizures in adults with epilepsy, 16 years or older. We have established the safety, tolerability, and dosage of intravenous levetiracetam in children. This prospective study included 30 children (6 months to <15 years of age). Patients were administered a single dose of intravenous levetiracetam (50 mg/kg, maximal dose 2500 mg) over 15 minutes. A blood level of levetiracetam was performed 10 minutes after the infusion. The treated children's average age was 6.3 years (range 0.5-14.8 years). The mean levetiracetam level was 83.3 microg/mL (range 47-128 microg/mL). There were no serious adverse reactions. Minor reactions included sleepiness, fatigue, and restlessness. An apparent decrease in seizure frequency across all seizure types was noted. The dose of 50 mg/kg was well tolerated by the patients and is a safe, appropriate loading dose.

Carisbamate as adjunctive treatment of partial onset seizures in adults in two randomized, placebo‐controlled trials

To assess the efficacy, safety, and tolerability of the investigational drug carisbamate as adjunctive treatment for partial-onset seizures (POS). Two identical, randomized, placebo-controlled, double-blind studies were conducted in adults with POS uncontrolled for >or=1 year. Therapy-refractory epilepsy patients (>or=16 years) remained on stable doses of prescribed antiepileptic drugs (<or=2) for an 8-week prospective baseline phase and were then randomized (1:1:1) to carisbamate 200 mg/day, carisbamate 400 mg/day, or placebo, for a 12-week double-blind phase. Primary efficacy end points were percent reduction in seizure frequency and responder rate (patients with >or=50% reduction in POS frequency) during the double-blind phase compared with the prospective baseline phase. Of the 565 patients randomized in study 1, 93% completed the study; of the 562 randomized in study 2, 94% completed the study. Patient characteristics were similar across both studies and treatment arms: mean age, 35 years (study 1, range 16-75 years) and 36 years (study 2, range 16-74 years); approximately 50% were men. Treatment with carisbamate 400 mg/day resulted in significant improvement (p < 0.01) in both efficacy measures compared with placebo in study 1 but not in study 2. Carisbamate 200 mg/day did not differ statistically from placebo in either study. Among the most common treatment-emergent adverse events (>or=5% in any group), those with an incidence exceeding placebo (>or=3%) were dizziness (400 mg/day group) and somnolence. Carisbamate 400 mg/day was effective in patients with refractory partial-onset seizures in one of these global studies. More than 200 mg/day of carisbamate is required for efficacy. Carisbamate was well-tolerated in both studies.

Safety and Efficacy Review: Lacosamide for the Treatment of Diabetic Neuropathic Pain

Objectives To provide background information on diabetic peripheral neuropathic pain (DPNP), current treatment options for DPNP, and information about lacosamide. To determine the safety and efficacy of lacosamide as a treatment option for DPNP. Methods A literature search was performed in order to describe DPNP, locate pertinent information about lacosamide, and determine the safety and efficacy of lacosamide for the treatment of DPNP in various trials. A search was also performed to review the effects of other medications on DPNP for the education of the reader as well as to make a comparison to lacosamide. Results DPNP is a common occurrence in patients with diabetes. Options for the treatment of DPNP include anti-depressants, anti-convulsants, opiates, and other alternative medications. One of the most recently studied drugs for DPNP is lacosamide, an anti-convulsant usually prescribed for the adjunct treatment of partial onset seizures. Three RCTs using lacosamide and an extension to one of the trials was found and reviewed. Rauck et al found that lacosamide titrated up to 400 mg divided twice daily to treat DPNP caused 60% of patients to have a significant decrease of 3.11 on the Likert Pain Scale as compared to 50.8% of patients in the placebo group having a decrease of 2.21 on the Likert Pain Scale from the beginning of treatment until conclusion of the trial. Shaibani et al performed an extension to the trial performed by Rauck et al and determined that the effects of lacosamide used for DPNP were maintained over a 2.5 year period. Wymer et al reproduced the results of the study done by Rauck et al by using 200 mg, 400 mg, and 600 mg of lacosamide divided twice daily and comparing them to placebo to see the difference in the Likert Pain Scale scores from the beginning of the trial to conclusion of the trial. The Likert Pain Scale differences were 1.8, 1.9, 2.5, and 2.0 for the placebo, 200 mg, 400 mg, and 600 mg dosage groups, respectively. In the 400 mg lacosamide daily group, 58% of subjects experienced a significant decrease in the Likert Pain Scale score. The 200 mg and 600 mg dosage groups showed no difference in the Likert Pain Scale scores. Ziegler et al studied the changes in pain scores from baseline to the last four weeks of maintenance therapy using lacosamide 400 mg and 600 mg versus placebo. No significant changes were seen in either group. The 400 mg and 600 mg groups lowered the pain scores -0.40 and -0.36 points below placebo, respectively. However, when broken into sections, the trial did show significant changes in pain scores. There were no significant differences in adverse effects across all trials using the 400 mg dose of lacosamide. No trials were found that compared lacosamide to any other drug for the treatment of DPNP. Conclusion Mixed results do show that lacosamide has the potential to effectively and safely lower pain scale scores in individuals with DPNP. However, due to a lack of consistent results and comparison studies with more established and accepted treatments, lacosamide cannot be recommended first line.

Acceptability and tolerability of levetiracetam oral solution for the treatment of partial-onset seizures: the SOLUCIÓN study

This cross-sectional, observational study evaluated the use of levetiracetam oral solution in usual clinical practice. Patients ≥ 16 years with partial-onset seizures (had received levetiracetam oral solution for ≥ 28 days) completed a study questionnaire assessing overall acceptability of levetiracetam oral solution, specific organoleptic characteristics (taste, taste intensity, aftertaste), ease of use and convenience. Tolerability was assessed by evaluating adverse events. Of 389 patients, 92.8% (361/389) were evaluable for acceptability, all (389) for tolerability; 65.3% (236/361) rated levetiracetam oral solution very acceptable or acceptable, 41.5% (150/361) pleasant or very pleasant, 54.3% (196/361) neither strong nor mild taste intensity and indicated the drug left an aftertaste (most stated aftertaste did not bother them), 75.3% very easy or easy to use and 61.8% very convenient or convenient to use. There was a positive relationship between overall acceptability of levetiracetam oral solution and favorable responses for organoleptic characteristics, ease of use, convenience and patients' evaluation of treatment compliance (P < 0.0001 for each). Of the 176/353 who previously received another antiepileptic drug and reported preference for a medication, 72.2% (127/176) preferred levetiracetam oral solution and 39/389 (10%) reported adverse events. Levetiracetam oral solution demonstrated a high degree of patient acceptability in adult patients with partial-onset seizures and was well tolerated.

Zonisamide as Adjunctive Therapy for Adults with Partial-Onset Epileptic Seizures: An Efficacy and Safety Review

Purpose To provide a review of randomized controlled trials (RCTs) on the efficacy and safety of zonisamide as an adjunctive treatment for partial-onset seizures in epilepsy patients ages 12 years and above. Methods Medline literature search for published double-blind RCTs involving zonisamide as adjunctive treatment for simple partial, complex partial, and secondarily generalized tonic-clonic seizures. Results Four RCTs comprising a total of 841 patients with medically-intractable simple partial, complex partial and secondarily generalized tonic-clonic seizures were published between the years 1993 and 2005. Zonisamide doses included 0, 100, 300, 400, 500 and 600 mg/day. Median change in frequency of all partial seizures compared to baseline was a 26.9%–51.3% decrease at zonisamide doses of 400–600 mg/day compared to a 4.7% increase to 18.1% decrease with placebo. Responder rates (&gt;50% reduction) for all partial seizures was 26.9%–52.5% for zonisamide at these doses versus 9.8%–22% reduction for placebo. A dose-response relationship was noted up to 500 mg/day. Seizure free rates during the double blind treatment phases were 5%–6.2% for full-dose zonisamide versus 2% for placebo in two of the RCTs. Side effects were mostly CNS in type: somnolence, fatigue, dizziness and ataxia. Mild weight loss and anorexia were reported. Symptomatic renal calculi and serious rashes were not reported, but a few cases of possible stones seen transiently on ultrasound occurred, in these 4 RCTs. Four deaths occurred: none were taking zonisamide, and two appeared to be related to suffocation during seizures. Suicidal ideation and behavior occurred equally in placebo- and ZNS-treated subjects. Post-approval information suggests the rare occurrences of metabolic acidosis, oligohydrosis and hyperthermia, more commonly in children. Conclusion Zonisamide at a daily dose up to 600 mg is effective and generally well tolerated as adjunctive therapy in adolescents and adults with refractory partial-onset seizures.

The Acrylamide (S)-2 As a Positive and Negative Modulator of Kv7 Channels Expressed in Xenopus laevis Oocytes

BackgroundActivation of voltage-gated potassium channels of the Kv7 (KCNQ) family reduces cellular excitability. These channels are therefore attractive targets for treatment of diseases characterized by hyperexcitability, such as epilepsy, migraine and neuropathic pain. Retigabine, which opens Kv7.2-5, is now in clinical trial phase III for the treatment of partial onset seizures. One of the main obstacles in developing Kv7 channel active drugs has been to identify compounds that can discriminate between the neuronal subtypes, a feature that could help diminish side effects and increase the potential of drugs for particular indications.Methodology/Principal FindingsIn the present study we have made a thorough investigation of the Bristol-Myers Squibb compound (S)-N-[1-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzo[1], [4]oxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide [(S)-2] on human Kv7.1-5 channels expressed in Xenopus laevis oocytes. We found that the compound was a weak inhibitor of Kv7.1. In contrast, (S)-2 efficiently opened Kv7.2-5 by producing hyperpolarizing shifts in the voltage-dependence of activation and enhancing the maximal current amplitude. Further, it reduced inactivation, accelerated activation kinetics and slowed deactivation kinetics. The mechanisms of action varied between the subtypes. The enhancing effects of (S)-2 were critically dependent on a tryptophan residue in S5 also known to be crucial for the effects of retigabine, (S)-1 and BMS-204352. However, while (S)-2 did not at all affect a mutant Kv7.4 with a leucine in this position (Kv7.4-W242L), a Kv7.2 with the same mutation (Kv7.2-W236L) was inhibited by the compound, showing that (S)-2 displays a subtype-selective interaction with in the Kv7 family.Conclusions/SignificanceThese results offer further insight into pharmacological activation of Kv7 channels, add to the understanding of small molecule interactions with the channels and may contribute to the design of subtype selective modulators.

Lacosamide for the treatment of partial-onset seizures

Lacosamide for the treatment of partial-onset seizures

Review of levetiracetam, with a focus on the extended release formulation, as adjuvant therapy in controlling partial-onset seizures

Levetiracetam is a second-generation antiepileptic drug (AED) with a unique chemical structure and mechanism of action. The extended release formulation of levetiracetam (Keppra XR(); UCB Pharma) was recently approved by the Food and Drug Administration for adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy. This approval is based on a double-blind, randomized, placebo-controlled, multicenter, multinational trial. Levetiracetam XR allows for once-daily dosing, which may increase compliance and, given the relatively constant plasma concentrations, may minimize concentration-related adverse effects. Levetiracetam's mode of action is not fully elucidated, but it has been found to target high-voltage, N-type calcium channels as well as the synaptic vesicle protein 2A (SV2A). Levetiracetam has nearly ideal pharmacokinetics. It is rapidly and almost completely absorbed after oral ingestion, is <10% protein-bound, demonstrates linear kinetics, is minimally metabolized through a pathway independent of the cytochrome P450 system, has no significant drug-drug interactions, and has a wide therapeutic index. The most common reported adverse events with levetiracetam XR were somnolence, irritability, dizziness, nausea, influenza, and nasopharyngitis. Levetiracetam XR provides an efficacious and well-tolerated treatment option for adjunctive therapy in the treatment of partial-onset seizures.

Clinical pharmacology of levetiracetam for the treatment of epilepsy

Levetiracetam is an antiepileptic drug that is mainly indicated for the adjunctive treatment of partial-onset seizures in adults and children and of myoclonic and primary generalized tonic–clonic seizures in patients with idiopathic generalized epilepsy. In Europe, levetiracetam is also indicated as monotherapy for partial-onset seizures in patients with newly diagnosed epilepsy. Synaptic vesicle protein 2A is the primary molecular target for its anticonvulsive effect but additional mechanisms may also contribute. Recent clinical and pharmacokinetic developments for levetiracetam are reviewed in specific populations, including the effects of age, pregnancy, birth and lactation, pediatric development, and ethnic origin. The population pharmacokinetics of levetiracetam and drug–drug interactions have been explored across large adult and pediatric populations. The exposure–response relationship has also been characterized in adults and children through nonlinear mixed-effects modeling. Finally, new formulations including intravenous infusion and extended-release once-daily tablets have been compared with immediate-release tablets and oral solution, and can be used interchangeably.

Truly "rational" polytherapy: maximizing efficacy and minimizing drug interactions, drug load, and adverse effects.

While several newer AEDs have study data that support monotherapy usage, most possess FDA indications for adjunctive treatment of partial onset seizures, leading to their initial (and often persistent) clinical use as adjunctive polytherapy for patients with refractory epilepsy. This review considers a practical approach to the appropriate role for polytherapy in epilepsy, presents the evidence for AED polytherapy, reviews the mythic but practically reasonable concept of “rational polytherapy,” and concludes with practical strategies for avoiding and employing polytherapy in clinical practice. The appropriate indications for AED polytherapy include transitional polytherapy during titration of a new adjunctive AED toward monotherapy or long-term maintenance AED polytherapy in medically refractory epilepsy.

Levetiractam in the treatment of two children with myoclonic status epilepticus

Levetiracetam (LEV) is approved as second line treatment for partial onset seizures in adults and children older than four years of age. Recently, an intravenous formulation was developed as an alternative to standard oral medication. We report the successful treatment of two children suffering from myoclonic status epilepticus with intravenous LEV. Intravenous application of LEV was safe and not associated with significant side effects. In conclusion, intravenous application of LEV appears to be a further option in treatment of children with myoclonic status epilepticus.

Brivaracetam: a rational drug discovery success story

Levetiracetam, the alpha-ethyl analogue of the nootropic piracetam, is a widely used antiepileptic drug (AED) that provides protection against partial seizures and is also effective in the treatment of primary generalized seizure syndromes including juvenile myoclonic epilepsy. Levetiracetam was discovered in 1992 through screening in audiogenic seizure susceptible mice and, 3 years later, was reported to exhibit saturable, stereospecific binding in brain to a approximately 90 kDa protein, later identified as the ubiquitous synaptic vesicle glycoprotein SV2A. A large-scale screening effort to optimize binding affinity identified the 4-n-propyl analogue, brivaracetam, as having greater potency and a broadened spectrum of activity in animal seizure models. Recent phase II clinical trials demonstrating that brivaracetam is efficacious and well tolerated in the treatment of partial onset seizures have validated the strategy of the discovery programme. Brivaracetam is among the first clinically effective AEDs to be discovered by optimization of pharmacodynamic activity at a molecular target.

Levetiracetam in Children: A Review

Levetiracetam is an antiepileptic drug approved for use by the US FDA as adjunctive therapy in partial-onset seizures in adults and children 4 years or older. It has also been approved as adjunctive treatment for adults and children 12 years and over with juvenile myoclonic epilepsy and for the treatment of primary generalized tonic–clonic seizures in adults and children over the age of 6 years with idiopathic generalized epilepsy. In Europe, in addition to these indications, it is also approved for use as monotherapy in the treatment of partial-onset seizures in patients from the age of 16 years with newly diagnosed epilepsy. It has a unique mechanism of action different to that of other antiepileptic drugs. The recent development of a parenteral intravenous formulation allows for its use when oral administration is not feasible. The most common serious side effects in children are behavioral. Its broad spectrum of action, lack of significant systemic side effects and the absence of interaction with other drugs makes it an attractive choice for use in children with epilepsy.

Levetiracetam [Keppra; UCB] has been approved by the European Commission for the treatment of partial onset seizures

Levetiracetam [Keppra; UCB] has been approved by the European Commission for the treatment of partial onset seizures

Determination of levetiracetam in human plasma/serum/saliva by liquid chromatography-electrospray tandem mass spectrometry

Background Levetiracetam (Keppra) is a novel antiepileptic drug recently approved by the U.S. Food and Drug Administration as an add-on therapy in the treatment of partial onset seizures in patients. We developed and describe a simple and rapid high performance liquid chromatography-electrospray tandem mass spectrometry (HPLC-ESI-MS/MS) assay for the determination of levetiracetam in human matrix (plasma, serum, or saliva). Methods An API-3000 or API-4000 triple–quadrupole mass spectrometer (Sciex, Concord, Canada) coupled with the IonSpray source and Shimadzu HPLC system (Shimadzu Scientific Instruments, Columbia, MD) was used employing ritonavir as internal standard (IS) for levetiracetam. One hundred microliters of serum (or plasma, saliva) was deproteinized by adding 150 μl of acetonitrile containing internal standard. After centrifugation, 100 μl of supernatant was diluted with 300 μl of water and 10 μl aliquot was injected onto a C-18 column. After a 2.5 min wash the valve was activated to initiate the isocratic elution program which eluted the levetiracetam and internal standard into the MS/MS system. Quantitation by MRM analysis was performed in the positive ion mode. Within-day and between-day imprecision were evaluated for levetiracetam using three levels of in-house controls. Reliability and accuracy of this method were assessed by comparison of targets with external QC material (ChromSystems), between laboratory comparisons and by recovery studies. Results Within-day coefficients of variation (CVs) were < 6.1% and between-day CVs were < 8.2%. The average spiked recoveries of levetiracetam added to the drug-free human plasma samples were 108% at low concentration level and 103% at high concentration level. Conclusions The method was found both specific and sensitive for the rapid and accurate measurement of levetiracetam in human matrices and correlated well with the Quest/Chantilly tandem mass spectrometric method ( r = 0.983).

Cerebral Blood Flow during Vagus Nerve Stimulation – a Transcranial Doppler Study

Background and Objectives: Vagus nerve stimulation (VNS) is an approved treatment of partial onset seizures and has recently shown antidepressant effects in patients with treatment-resistant depression. This study was conducted to investigate whether acute VNS has an influence on cerebral blood flow (CBF) in humans. Methods: This investigation was designed as an add-on study. In 10 patients with an implanted stimulator who participated in a multicenter clinical trial to evaluate the efficacy of VNS in depression, CBF was investigated by functional transcranial Doppler at baseline (before the stimulator was turned on for the first time) and during stimulation with three different stimulation intensities in a randomized order. Results: Immediately after every increase of the current, CBF velocity showed a nonsignificant increase. Otherwise, no change of CBF above standard deviation could be registered. Conclusion: Acute VNS does not have an influence on CBF velocity in depressive patients.

0160 Randomized, multicenter, dose-ranging trial of retigabine as adjunctive treatment for partial-onset seizures

0160 Randomized, multicenter, dose-ranging trial of retigabine as adjunctive treatment for partial-onset seizures