lacosamide and Seizures

This study was undertaken to estimate the cost-effectiveness of add-on cenobamate in the UK when used to treat drug-resistant focal seizures in adults who are not adequately controlled with at least two prior antiseizure medications, including at least one used adjunctively.. We estimated the cost per quality-adjusted life-year (QALY) for cenobamate compared to brivaracetam, eslicarbazepine, lacosamide, and perampanel in the UK National Health Service over a lifetime time horizon. We used a Markov cohort structure to determine response to treatment, using pooled data from three long-term studies of cenobamate. A network meta-analysis informed the likelihood of response to therapy with brivaracetam, eslicarbazepine, lacosamide, and perampanel relative to cenobamate. Once individuals discontinued treatment, they transitioned to subsequent treatment health states, including other antiseizure medicines, surgery, and vagus nerve stimulation. Costs included treatment, administration, routine monitoring, event management, and adverse events. Published evidence and expert opinion informed the likelihood of response to subsequent treatments, associated adverse events, and costs. Utility data were based on Short-Form six-dimension form utility. Discounting was applied at 3.5% per annum as per National Institute for Health and Care Excellence guidance. Uncertainty was explored through deterministic and probabilistic sensitivity analyses.. In the base case, cenobamate led to cost savings of £51 967 (compared to brivaracetam), £21 080 (compared to eslicarbazepine), £33 619 (compared to lacosamide), and £28 296 (compared to perampanel) and increased QALYs of 1.047 (compared to brivaracetam), 0.598 (compared to eslicarbazepine), 0.776 (compared to lacosamide), and 0.703 (compared to perampanel) per individual over a lifetime time horizon. Cenobamate also dominated the four drugs across most sensitivity analyses. Differences were due to reduced seizure frequency with cenobamate relative to comparators.. Cenobamate improved QALYs and was less costly than brivaracetam, eslicarbazepine, lacosamide, and perampanel. Therefore, cenobamate may be considered as a cost-effective adjunctive antiseizure medication for people with drug-resistant focal seizures.

Topics: Adult; Anticonvulsants; Cost-Benefit Analysis; Drug Resistant Epilepsy; Humans; Lacosamide; Seizures; State Medicine

Brivaracetam (BRV), cenobamate (CNB), eslicarbazepine acetate (ESL), lacosamide (LCM) and perampanel (PER) are antiseizure medications (ASMs) approved for adjunctive treatment of focal-onset seizures. So far, no randomised controlled trial directly compared the efficacy and safety of these drugs.. We estimated the comparative efficacy and safety of these ASMs for the treatment of focal-onset seizures in adults with epilepsy using a network meta-analysis (NMA).. We systematically searched (June week 4, 2021) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry ( http://www.clinicaltrials.gov ). There were no date limitations or language restrictions. Randomised, double-blinded, controlled, parallel-group, add-on studies that compared oral BRV, CNB, ESL, LCM, and PER versus any comparator over maintenance periods of at least 12 weeks and included adult patients with focal seizures uncontrolled by concomitant ASMs were identified. The efficacy outcomes were the proportions of patients with ≥ 50% and 100% reduction in baseline seizure frequency during the maintenance period. The tolerability outcomes were the proportions of participants who experienced at least one treatment-emergent adverse event (TEAE) and experienced at least one TEAE leading to discontinuation. Effect sizes were estimated by network meta-analyses within a frequentist framework. The hierarchy of competing interventions was established using the surface under the cumulative ranking curve (SUCRA).. Sixteen trials (BRV: n = 3, CNB: n = 1, ESL: n = 4, LCM: n = 4, PER: n = 4) were included, overall enrolling 4507 patients randomised to add-on active treatments (BRV = 803, CNB = 221, ESL =9 90, LCM = 1104, and PER = 1389) and 2246 to add-on placebo. Cenobamate was associated with a higher rate of ≥ 50% seizure frequency reduction than BRV [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.11-3.66], ESL (OR 1.93, 95% CI 1.07-3.48), LCM (OR 1.86, 95% CI 1.04-3.32), and PER (OR 2.07, 95% CI 1.16-3.70). There was a not statistically significant trend favouring CNB over ESL, LCM and PER for the seizure freedom outcome. Brivaracetam (OR 0.61, 95% CI 0.44-0.86) and LCM (OR 0.60, 95% CI 0.40-0.88) were associated with a lower proportion of participants experiencing TEAEs compared to ESL, and patients treated with PER were associated with a higher risk to experience at least one TEAE (OR 1.42, 95% CI 1.02-1.96) than BRV. According to SUCRA, CNB had the greatest likelihood of being the best option for the ≥ 50% and 100% seizure frequency reduction, and BRV and LCM had the highest probabilities of being the best-tolerated treatments.. Cenobamate ranked best for efficacy, and BRV and LCM were best tolerated over the other comparators. Although NMAs cannot replace direct comparisons, they may support physicians in clinical decision making.

Topics: Adult; Anticonvulsants; Carbamates; Chlorophenols; Dibenzazepines; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Lacosamide; Male; Middle Aged; Network Meta-Analysis; Nitriles; Pyridones; Pyrrolidinones; Randomized Controlled Trials as Topic; Seizures; Tetrazoles

A concise review of recent findings in brain tumor-related epilepsy (BTRE), with focus on the effect of antitumor treatment on seizure control and the management of antiepileptic drugs (AEDs).. Isocitrate dehydrogenase mutation and its active metabolite d -2-hydroxyglutarate seem important contributing factors to epileptogenesis in BTRE. A beneficial effect of antitumor treatment (i.e. surgery, radiotherapy, and chemotherapy) on seizure control has mainly been demonstrated in low-grade glioma. AED prophylaxis in seizure-naïve BTRE patients is not recommended, but AED treatment should be initiated after a first seizure has occurred. Comparative efficacy randomized controlled trials (RCTs) are currently lacking, but second-generation AED levetiracetam seems the preferred choice in BTRE. Levetiracetam lacks significant drug-drug interactions, has shown favorable efficacy compared to valproic acid in BTRE, generally causes no hematological or neurocognitive functioning adverse effects, but caution should be exercised with regard to psychiatric adverse effects. Potential add-on AEDs in case of uncontrolled seizures include lacosamide, perampanel, and valproic acid. Ultimately, in the end-of-life phase when oral intake of medication is hampered, benzodiazepines via nonoral administration routes are potential alternatives.. Management of seizures in BTRE is complex and with currently available evidence levetiracetam seems the preferred choice. Comparative efficacy RCTs in BTRE are warranted.

Topics: Anticonvulsants; Benzodiazepines; Brain Neoplasms; Epilepsy; Humans; Isocitrate Dehydrogenase; Lacosamide; Levetiracetam; Seizures; Valproic Acid

Status epilepticus is defined as the situation resulting from the failure of the mechanisms responsible for terminating an epileptic seizure. In 2015, an operational concept was adopted internationally in which two times are identified: a first time, at which treatment must begin (five minutes for convulsive status, 10-15 minutes for focal and non-convulsive status); and a second time, after which there is considered to be a high risk of subsequent sequelae (30 minutes in the case of the convulsive). It occurs in 3-42/100,000 children per year, who are refractory or super-refractory in 10-40% of cases.. This article will review the different therapeutic options for status, from early treatment at home to the different first-line (benzodiazepines), second-line (phenobarbital, valproic acid, phenytoin, levetiracetam and lacosamide) or third-line treatments, which include both pharmacological (anaesthetics, propofol, ketamine, lidocaine, topiramate, brivaracetam or perampanel) and non-pharmacological (ketogenic diet, immunomodulatory treatments or epilepsy surgery) therapies.. Early identification and treatment of a prolonged crisis are essential to prevent progression to status. Although with fewer sequelae than in adults, status epilepticus in children represents a cause of mortality of up to 3-5%, while 25% of them will develop subsequent epilepsy, as well as a considerable percentage of neurological sequelae.. Estado epiléptico pediátrico.. Introducción. El estado epiléptico se define como la situación resultante del fallo de los mecanismos responsables de finalizar una crisis epiléptica. En 2015, se adoptó internacionalmente un concepto operativo en el que se identifican dos tiempos: un primer momento, en el que hay que comenzar un tratamiento (cinco minutos para los estados convulsivos, 10-15 minutos para los estados focales y no convulsivos); y un segundo tiempo, a partir del cual se considera que hay un riesgo elevado de secuelas posteriores (30 minutos en los convulsivos). Ocurre en 3-42/100.000 niños al año, y son refractarios o superrefractarios en el 10-40% de las ocasiones. Desarrollo. En este artículo se revisarán las diferentes opciones terapéuticas del estado, desde el tratamiento precoz domiciliario hasta los diferentes tratamientos de primera línea (benzodiacepinas), segunda línea (fenobarbital, ácido valproico, fenitoína, levetiracetam y lacosamida) o tercera línea, que incluyen tanto terapias farmacológicas (anestésicos, propofol, cetamina, lidocaína, topiramato, brivaracetam o perampanel) como no farmacológicas (dieta cetógena, tratamientos inmunomoduladores o cirugía de epilepsia). Conclusiones. Son fundamentales la identificación y el tratamiento precoz de una crisis prolongada para evitar la evolución a estado. Aunque con menores secuelas que en los adultos, el estado epiléptico en niños representa una causa de mortalidad hasta del 3-5%, al mismo tiempo que un 25% de ellos desarrollará una epilepsia posterior, así como un porcentaje considerable de secuelas neurológicas.

Topics: Adult; Anesthetics; Anticonvulsants; Benzodiazepines; Child; Epilepsy; Humans; Ketamine; Lacosamide; Levetiracetam; Lidocaine; Phenobarbital; Phenytoin; Propofol; Seizures; Status Epilepticus; Topiramate; Valproic Acid

This is an updated version of the Cochrane review published in 2015. Around half of people with epilepsy will not achieve seizure freedom on their first antiepileptic drug; many will require add-on therapy. Around a third of people fail to achieve complete seizure freedom despite multiple antiepileptic drugs. Lacosamide has been licenced as an add-on therapy for drug-resistant focal epilepsy.. To evaluate the efficacy and tolerability of lacosamide as an add-on therapy for children and adults with drug-resistant focal epilepsy.. We searched the following databases (22 August 2019): the Cochrane Register of Studies (CRS Web), including the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid, 1946 to 20 August 2019), ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP), with no language restrictions. We contacted UCB Pharma (sponsors of lacosamide).. Randomised controlled trials of add-on lacosamide in people with drug-resistant focal epilepsy.. We used standard Cochrane methodology, assessing the following outcomes: 50% or greater reduction in seizure frequency; seizure freedom; treatment withdrawal; adverse events; quality of life; and cognitive changes. The primary analyses were intention-to-treat. We estimated summary risk ratios (RR) for each outcome presented with 99% confidence intervals (CI), except for 50% or greater seizure reduction, seizure freedom and treatment withdrawal which were presented with 95% CIs. We performed subgroup analyses according to lacosamide dose and sensitivity analyses according to population age, whereby data from children were excluded from the meta-analysis.. We included five trials (2199 participants). The risk of bias for all studies was low to unclear. All studies were placebo-controlled and assessed doses from 200 mg to 600 mg per day. One study evaluated lacosamide in children; all other studies were in adults. Trial duration ranged from 24 to 26 weeks. All studies used adequate methods of randomisation and were double-blind. Overall, the certainty of the evidence for the outcomes was judged as moderate to high, with the exception of seizure freedom which was low. The RR for a 50% or greater reduction in seizure frequency for all doses of lacosamide compared with placebo was 1.79 (95% CI 1.55 to 2.08; 5 studies; 2199 participants; high-certainty evidence). The RR for seizure freedom for all doses of lacosamide compared with placebo was 2.27 (95% CI 1.35 to 3.83; 5 studies; 2199 participants; low-certainty evidence). The RR for treatment withdrawal for all doses of lacosamide compared with placebo was 1.57 (95% CI 1.24 to 1.98; 5 studies; 2199 participants; moderate-certainty evidence). The estimated effect size for most outcomes did not change considerably following sensitivity analysis. For seizure freedom, however, the RR nearly doubled upon the exclusion of data from children (RR 4.04, 95% CI 1.52 to 10.73). Adverse events associated with lacosamide included: abnormal co-ordination (RR 6.12, 99% CI 1.35 to 27.77), blurred vision (RR 4.65, 99% CI 1.24 to 17.37), diplopia (RR 5.59, 99% CI 2.27 to 13.79), dizziness (RR 2.96, 99% CI 2.09 to 4.20), nausea (RR 2.35, 99% CI 1.37 to 4.02), somnolence (RR 2.04, 99% CI 1.22 to 3.41), vomiting (RR 2.94, 99% CI 1.54 to 5.64), and number of participants experiencing one or more adverse events (RR 1.12, 99% CI 1.01 to 1.24). Adverse events that were not significant were: vertigo (RR 3.71, 99% CI 0.86 to 15.95), rash (RR 0.58, 99% CI 0.17 to 1.89), nasopharyngitis (RR 1.41, 99% CI 0.87 to 2.28), headache (RR 1.34, 99% CI 0.90 to 1.98), fatigue (RR 2.11, 99% CI 0.92 to 4.85), nystagmus (RR 1.47, 99% CI 0.61 to 3.52), and upper respiratory tract infection (RR 0.70, 99% CI 0.43 to 1.15).. Lacosamide is effective and well-tolerated in the short term when used as add-on treatment for drug-resistant focal epilepsy. Lacosamide increases the number of people with 50% or greater reduction in seizure frequency and may increase seizure freedom, compared to placebo. Higher doses of lacosamide may be associated with higher rates of adverse events and treatment withdrawal. Additional evidence is required assessing the use of lacosamide in children and on longer-term efficacy and tolerability.

Topics: Adult; Anticonvulsants; Bias; Child; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsies, Partial; Humans; Lacosamide; Placebos; Randomized Controlled Trials as Topic; Seizures

To compare the evidence on efficacy, safety, tolerability, and impact on short term/long functional outcome of lacosamide (LCM) and phenytoin (PHT) in patients with status epilepticus.. We conducted a systematic literature search of relevant electronic databases using a suitable search strategy to identify studies directly comparing PHT and LCM, irrespective of dose and duration in patients with convulsive and/or nonconvulsive status epilepticus (SE). We used a standardized assessment form to extract information on the study design, data sources, methodologic framework, efficacy, and adverse events attributed to PHT and LCM from included studies and compared the efficacy and safety outcomes, using a fixed/random effect model.. Five studies were found to be eligible for inclusion out of 192 search items, enrolling a total of 115 and 166 participants (predominantly with SE) in LCM and PHT arm, respectively. Baseline characteristics were comparable between both arms. The proportion with seizure control was comparable between both arms (57.3% in LCM vs. 45.7% in PHT arm, p = 0.28) and even in the subgroup analysis separately for convulsive and non-convulsive SE. Proportion with treatment-emergent adverse events (TEAE) were comparable in both (17.6% vs. 12.2%, p = 0.20), but serious adverse events (SAE) were higher in PHT arm (5.1% vs. 0.8%, p = 0.049). The proportion with all-cause mortality and survival with moderate-severe disability were comparable between both arms (p = 0.23 and 0.37, respectively).. LCM has comparable efficacy with fewer SAEs as compared to PHT for achieving seizure control in patients with SE.

Topics: Anticonvulsants; Humans; Lacosamide; Phenytoin; Seizures; Status Epilepticus; Treatment Outcome

Lacosamide is an antiepileptic drug (AED) that has linear pharmacokinetics, predictable blood concentrations, and few drug interactions, setting it apart from other AEDs that require vigorous therapeutic drug monitoring (TDM) such as phenytoin and carbamazepine. However, there have been reports of altered lacosamide pharmacokinetics in some populations. The purpose of this review is to determine whether lacosamide pharmacokinetics are altered in certain patient populations, suggesting the need for TDM. A literature search of Medline, Scopus, Embase, and Cochrane trials was conducted on January 3, 2019 (and then updated on September 2, 2019) to search for articles relevant to the TDM or pharmacokinetics of lacosamide. A total of 56 relevant articles were found and included in this review. Dose of lacosamide is linearly correlated with plasma concentrations and efficacy. However, currently there is no well-established reference range. Overall, the recommended reference ranges varied from 2.2 to 20 mg/L. Lacosamide has very few clinically relevant drug-drug interactions; however, there seems to be a significant drug interaction between lacosamide and enzyme-inducer AEDs. Based on available literature, it appears that lacosamide pharmacokinetics may be altered in severe renal dysfunction, in patients on dialysis and with extremes of age. More evidence is currently needed on lacosamide pharmacokinetics in pregnancy and critical illness. While it is not practical to utilize TDM for all patients, TDM may be useful in patients taking enzyme-inducer AEDs, in patients with decreased renal function or on dialysis, and older adults.

Topics: Age Factors; Anticonvulsants; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Epilepsy; Humans; Kidney Diseases; Lacosamide; Renal Insufficiency; Seizures

Adjunctive lacosamide treatment might be promising to treat seizures. However, the results remained controversial. We conducted a systematic review and meta-analysis to compare the efficacy and safety of adjunctive lacosamide versus placebo in patients with seizures.. PubMed, EMbase, Web of science, EBSCO and Cochrane library databases were systematically searched. Randomized controlled trials (RCTs) assessing the effect of adjunctive lacosamide versus placebo on seizures were included. Two investigators independently searched articles, extracted data and assessed the quality of included studies. The primary outcomes were 50% responder rate and seizure freedom.. Four RCTs involving 1199 patients were included in the meta-analysis. Overall, compared with placebo treatment, adjunctive lacosamide treatment was associated with a significantly increased 50% responder rate (RR = 1.89; 95% CI = 1.51-2.36; P < 0.00001) and seizure freedom (RR = 4.97; 95% CI = 1.78-13.91; P = 0.002), but improved dizziness (RR = 3.97; 95% CI = 2.91-5.42; P < 0.00001), nausea (RR = 2.85; 95% CI = 1.75-4.66; P < 0.0001), vomiting (RR = 4.11; 95% CI = 2.23-7.57; P < 0.00001), diplopia (RR = 6.85; 95% CI = 3.36-13.94; P < 0.00001), treatment-emergent adverse events (RR = 2.29; 95% CI = 1.93-2.71; P < 0.00001) and serious adverse events (RR = 2.52; 95% CI = 1.33-4.78; P = 0.005).. Compared to placebo, adjunctive lacosamide resulted in a significantly improved 50% responder rate and seizure freedom, but with increased dizziness, nausea, vomiting, diplopia, treatment-emergent adverse events and serious adverse events.

Topics: Acetamides; Anticonvulsants; Humans; Lacosamide; Randomized Controlled Trials as Topic; Seizures

Nearly 10 years after its introduction into the market, the significance of lacosamide in genetic generalized epilepsies is still unclear. Its new mode of action may qualify lacosamide as a therapeutic agent in this entity, but only a limited number of cases have been published so far.. To describe the efficacy of lacosamide as treatment in a patient with the absence status epilepticus.. We report on a 28-year-old woman with genetic generalized epilepsy who suffered recurrent absence status epilepticus during video-EEG-monitoring. After treatment failure of first- and second-line medication, lacosamide was administered. The outcome in this patient was evaluated, and a systematic literature review was performed for the use of lacosamide in the absence status epilepticus.. After application of 400 mg lacosamide intravenously, the absence status epilepticus terminated within 30 minutes. No further seizures or epileptiform discharges reoccurred until the end of video-EEG-Monitoring 3 days later.. The role of lacosamide as a therapeutic option in patients with the absence status epilepticus is unclear. Only two cases have been reported so far with conflicting results. Further randomized controlled studies are required to validate the relevance of lacosamide as treatment for status epilepticus in genetic generalized and the absence epilepsy.

Topics: Acetamides; Adult; Anticonvulsants; Epilepsy, Absence; Female; Humans; Lacosamide; Seizures

Lacosamide (Vimpat

Topics: Animals; Anticonvulsants; Epilepsies, Partial; Humans; Lacosamide; Seizures

Four "third-generation" antiepileptic drugs (AEDs) were approved for adjunctive treatment of refractory focal onset seizures during the past 10 years. Long-term efficacy and safety of the drugs were demonstrated in large extension studies and in reports of subgroups of patients not studied in pivotal trials. Reviewing extension study and post-marketing outcome series for the four newer AEDs-lacosamide, perampanel, eslicarbazepine acetate and brivaracetam-can guide clinicians in treating and monitoring patients. AED extension studies evaluate treatment retention, drug tolerability, and drug safety during individualized treatment with flexible dosing and thus provide information not available in rigid pivotal trials. Patient retention in the studies ranged from 75 to 80% at 1 year and from 36 to 68% at 2-year treatment intervals. Safety findings were generally similar to those of pivotal trials, with no major safety risks identified and with several specific adverse drug effects, such as hyponatremia, reported. The third-generation AEDs, some through new mechanisms and others with improved tolerability compared to related AEDs, provide new options in efficacy and tolerability.

Topics: Acetamides; Anticonvulsants; Dibenzazepines; Drug-Related Side Effects and Adverse Reactions; Follow-Up Studies; Humans; Lacosamide; Longitudinal Studies; Medication Adherence; Nitriles; Product Surveillance, Postmarketing; Pyridones; Pyrrolidinones; Seizures

The aim of this review was to evaluate current literature for dosing recommendations for the use of antiepileptic medications in patients receiving renal replacement therapy (RRT).. With the assistance of an experienced medical librarian specialized in pharmacy and toxicology, we searched MEDLINE, EMBASE, CINAHL, Web of Science, WorldCat, and Scopus through May 2016.. Four hundred three articles were screened for inclusion, of which 130 were identified as potentially relevant. Micromedex® DRUGDEX as well as package inserts were used to obtain known pharmacokinetic properties and dosage adjustment recommendations in RRT if known.. Data regarding antiepileptic drug use in RRT are limited and mostly consist of case reports limiting our proposed dosing recommendations. Known pharmacokinetic parameters should guide dosing, and recommendations are provided where possible.. Additional studies are necessary before specific dosing recommendations can be made for most antiepileptic drugs in critically ill patients receiving RRT, specifically with newer agents.

Topics: Acetamides; Acute Kidney Injury; Amines; Anticonvulsants; Carbamates; Critical Illness; Cyclohexanecarboxylic Acids; Dibenzazepines; Dose-Response Relationship, Drug; Ethosuximide; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lacosamide; Lamotrigine; Levetiracetam; Phenobarbital; Phenylcarbamates; Phenylenediamines; Phenytoin; Piracetam; Propylene Glycols; Renal Dialysis; Renal Replacement Therapy; Seizures; Topiramate; Triazines; Valproic Acid; Zonisamide

To review the evidence for efficacy and safety of lacosamide in adult patients with refractory epilepsy and refractory status epilepticus (RSE).. A systematic literature search of MEDLINE, PubMed, EMBASE, IPA, Google and Google Scholar (through October 2014) was performed.. Fourteen studies assessing lacosamide in 3509 refractory epilepsy patients were included. In 3 RCTs, more patients had at least 50% reduction in seizure frequency with lacosamide compared to placebo with 38.3-41.1%, 38.1-41.2%, and 18.3-25.8%, in the 400 mg/day, 600 mg/day, and placebo groups, respectively. In non-comparative trials, 18-69% of patients achieved at least 50% reduction in seizure frequency, and 1.7-26.2% achieved seizure freedom. Non-responders were documented in two trials, with 26.2-34% having no response. Thirteen studies assessing lacosamide in 390 RSE patients were included. When assessing lacosamide's ability to terminate RSE, one comparative cohort study found no improvement in SE duration or seizure control with addition of lacosamide. Another study documented no difference compared to use of phenytoin. Eleven descriptive studies using lacosamide as add-on RSE therapy revealed seizure termination rates of 0-100% (median 64.7%). In all patients receiving lacosamide, dizziness (21.8%), vision disturbances (10.4%), drowsiness (7.4%), headache (7.0%), nausea (6.5%), and coordination problems (5.8%) were the most common adverse effects.. Based on evidence to date, adjunctive lacosamide is a treatment option to reduce seizure frequency in patients with refractory epilepsy and terminate seizures in patients with RSE. The safety information summary can be used to advise patients of potential adverse effects.

Topics: Acetamides; Anticonvulsants; Epilepsy; Humans; Lacosamide; Seizures

Around half of people with epilepsy will not achieve seizure freedom on their first antiepileptic drug; many will require add-on treatment with another drug. Sometimes multiple treatment combinations are tried to achieve maximum seizure control, although around a third of people do not achieve complete seizure control. Lacosamide is an antiepileptic drug that has been licensed as an add-on treatment for partial epilepsy.. To evaluate the efficacy and tolerability of lacosamide when used as an add-on treatment for patients with drug-resistant partial epilepsy.. We searched the Cochrane Epilepsy Group's Specialized Register (21 May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL , The Cochrane Library Issue 4, April 2015), MEDLINE (Ovid, 1946 to 21 May 2015), Scopus (1823 to 13 November 2014), ClinicalTrials.gov (21 May 2015) and the WHO International Clinical Trials Registry Platform (ICTRP, 21 May 2015). We imposed no language restrictions. We contacted UCB (sponsors of lacosamide) and experts in the field.. Randomised controlled trials of add-on lacosamide in people with drug-resistant partial epilepsy.. Two review authors independently assessed trials for inclusion and extracted the relevant data. We assessed the following outcomes: (1) 50% or greater reduction in seizure frequency; (2) seizure freedom; (3) treatment withdrawal for any reason; and (4) adverse events. Primary analyses were intention-to-treat. Summary risk ratios were estimated for each outcome.. We included three trials in our review (1311 participants), which were classified as having low risk of bias. All trials were placebo-controlled and assessed doses ranging from 200 mg to 600 mg per day. Trial duration ranged from 24 to 26 weeks. All trials used adequate methods of randomisation and were double-blind. Overall the quality of the evidence was rated as moderate to high. The overall risk ratio for a 50% or greater reduction in seizure frequency for all doses of lacosamide compared with placebo was 1.70 (95% confidence interval (CI) 1.38 to 2.10); for seizure freedom for all doses of lacosamide compared with placebo was 2.50 (95% CI 0.85 to 7.34); and for treatment withdrawal for all doses of lacosamide compared with placebo was 1.88 (95% CI 1.40 to 2.52). Adverse effects significantly associated with lacosamide were abnormal co-ordination (risk ratio (RR) 6.12, 99% CI 1.35 to 27.77), diplopia (RR 5.29, 99% CI 1.97 to 14.23), dizziness (RR 3.53, 99% CI 2.20 to 5.68), nausea (RR 2.37, 99% CI 1.23 to 4.58) and vomiting (RR 3.49, 99% CI 1.43 to 8.54). Adverse effects that were not statistically significant were headache (RR 1.34, 99% CI 0.83 to 2.18), fatigue (RR 2.11, 99% CI 0.92 to 4.85), nystagmus (RR 1.47, 99% CI 0.61 to 3.52) and somnolence (RR 1.44, 99% CI 0.67 to 3.09).. This review has shown lacosamide to be effective and fairly well tolerated in the short term when used as add-on treatment for drug-resistant partial epilepsy in adults. Higher doses of lacosamide may be more associated with adverse effects and withdrawal of the drug than lower doses. Additional evidence on children is needed, and longer-term efficacy is unknown.

Topics: Acetamides; Adult; Anticonvulsants; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsies, Partial; Humans; Lacosamide; Randomized Controlled Trials as Topic; Seizures

Many patients with critical illness have been noted to have nonconvulsive seizures (NCSs) and nonconvulsive status epilepticus (NCSE). How aggressively these seizures should be treated is unclear. Many investigators feel that the morbidity of NCSs and NCSE is different from that of generalized convulsive status epilepticus (GCSE), so treatment should be less urgent. Consequently, many nonsedating AEDs have been used to treat NCSs and NCSE in patients with critical illness. Randomized, controlled trials demonstrating the efficacy of AEDs in NCSs and NCSE are lacking. The Treatment of Recurrent Electrographic Nonconvulsive Seizures (TRENdS) study compared lacosamide to fosphenytoin in the treatment of NCSs. An update of the study is presented. This article is part of a Special Issue entitled "Status Epilepticus".

Topics: Acetamides; Anticonvulsants; Critical Illness; Humans; Lacosamide; Phenytoin; Recurrence; Seizures; Status Epilepticus

Occurrence of generalized tonic-clonic seizures (GTCS) is one of the most important risk factors of seizure-related complications and comorbidities in patients with epilepsy. Their prevention is therefore an important aspect of therapeutic management both in idiopathic generalized epilepsies and in focal epilepsies.. It has been shown that the efficacy of antiepileptic drugs (AEDs) varies across epilepsy syndromes, with some AEDs efficacious against focal seizures with secondary GTCS (sGTCS) but aggravating primary GTCS (pGTCS). In patients with pGTCS, evidence-based data support the preferential use of valproic acid, lamotrigine, levetiracetam and topiramate. In patients with sGTCS, all AEDs approved in the treatment of focal epilepsies might be used.. Both in pGTCS and sGTCS, additional data are required, specifically to inform about the relative efficacy of AEDs in relation to each other. Although valproic acid might be the most efficacious drug in idiopathic generalized epilepsies, it should be avoided in women of childbearing age due to its safety profile. In patients with sGTCS, AEDs for which the impact on this seizure type has been formally evaluated and which have demonstrated greater efficacy than placebo might preferentially be used, such as lacosamide, perampanel and topiramate.

Topics: Acetamides; Anticonvulsants; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Fructose; Humans; Lacosamide; Lamotrigine; Levetiracetam; Piracetam; Risk Factors; Seizures; Topiramate; Treatment Failure; Triazines; Valproic Acid

Secondary generalized tonic-clonic seizures (SGTCS) are among the most severe forms of seizures, and the main risk factor for sudden unexpected death in epilepsy (SUDEP). Whether some antiepileptic drugs (AEDs) might be more efficacious than others on SGTCS in patients with drug-resistant focal epilepsy thus represents an important clinical issue for which no data are currently available.. We performed a meta-analysis of randomized controlled trials of adjunctive AED in which information on efficacy outcomes (i.e., responder rate and/or frequency per 28 days relative to baseline) were available both for all seizure types and for SGTCS. The primary analysis evaluated the efficacy of AEDs on all types of seizure and on SGTCS by comparing the responder rates for AED and for placebo.. Responder rate was available both for all seizure types and for SGTCS in 13 of the 72 eligible trials, evaluating 7 AEDs. Only three AEDs--lacosamide, perampanel and topiramate--showed greater efficacy than placebo. However, confidence intervals of relative risks overlapped for all AEDs but pregabalin, which demonstrated significantly lower efficacy than lacosamide, perampanel, and topiramate. Moreover, there was a nonsignificant trend toward a lower relative risk of responder rate for SGTCS than for all seizure types, which appeared related to a greater response to placebo for this outcome.. Indirect comparison of AEDs using randomized placebo-controlled add-on trials does not support robust differences between AEDs to prevent SGTCS. Alternative designs for evaluation of therapeutic interventions in patients at risk for SGTCS-related complications are required.

Topics: Acetamides; Anticonvulsants; Chronic Disease; Death, Sudden; Early Medical Intervention; Epilepsies, Partial; Fructose; Humans; Lacosamide; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Recurrence; Risk Factors; Seizures; Topiramate; Treatment Outcome

Lacosamide (Vimpat(®)) is a functionalized amino acid available orally (as a syrup or tablet) and as an intravenous infusion. It is believed to exert its antiepileptic effect by selectively enhancing the slow inactivation of voltage-gated sodium channels. Lacosamide is approved in several countries worldwide as an adjunctive therapy for the treatment of partial-onset seizures; however, prescribing regulations differ between countries. This article reviews the use of lacosamide as indicated in adults and adolescents (aged 16-18 years) in the EU, where it is approved in this patient population as an adjunctive therapy to other AEDs in the treatment of partial-onset seizures, with or without secondary generalization. In three randomized, double-blind, placebo-controlled, multicentre studies in adults and adolescents (aged 16-18 years) with partial-onset seizures, adjunctive therapy with oral lacosamide (administered for an initial titration period followed by 12 weeks' maintenance therapy) generally reduced the frequency of seizures to a significantly greater extent than placebo, with antiepileptic efficacy sustained following longer-term treatment (up to 8 years) in this patient population. Oral and intravenous lacosamide were generally well tolerated in clinical studies, with the majority of adverse events being mild or moderate in severity. Very common adverse reactions following adjunctive therapy with oral lacosamide included diplopia, dizziness, headache and nausea; the tolerability profile of intravenous lacosamide appeared consistent with that of oral lacosamide, although intravenous administration was associated with local adverse events, such as injection site discomfort or pain, irritation and erythema. Thus, oral and intravenous lacosamide as an adjunctive therapy to other AEDs provides a useful option in the treatment of patients with partial-onset seizures.

Topics: Acetamides; Administration, Intravenous; Administration, Oral; Animals; Anticonvulsants; Clinical Trials as Topic; Disease Management; Drug Therapy, Combination; Epilepsies, Partial; Humans; Lacosamide; Seizures

Lacosamide is a third-generation antiepilepsy drug approved for adjunctive treatment of partial-onset seizures in adults. The pharmacology of lacosamide includes linear kinetics, complete bioavailability, and no major drug interactions. Lacosamide produces slow inactivation of neuronal sodium channels, which differentiates it from other sodium channel modulators, such as carbamazepine and phenytoin. The drug was effective with no major safety problems detected in three large placebo-controlled pivotal trials and has been released in Europe and the US at 200-400 mg/day, divided b.i.d.; an intravenous formulation is approved for temporary conversion from oral therapy. This article reviews the clinical development, pharmacology, and uses of lacosamide for treating partial-onset seizures in adults.

Topics: Acetamides; Adult; Anticonvulsants; Chemotherapy, Adjuvant; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Epilepsies, Partial; Humans; Lacosamide; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome

Lacosamide is an antiepileptic drug approved in the USA and Europe as adjunctive therapy for partial-onset seizures. Studies suggest that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels and possibly interacts with collapsin response mediator protein-2. The efficacy of lacosamide has been shown in animal models of epilepsy and Phase II/III clinical trials. Pharmacokinetic studies show that it is renally excreted, minimally bound to plasma proteins and has no known clinically relevant drug-drug interactions. Clinical trials show that lacosamide is well tolerated; the most common adverse events were dizziness, nausea and vomiting. In a Phase II/III pooled analysis, lacosamide 200 and 400 mg/day significantly reduced partial-onset seizure frequency and improved the 50% responder rate compared with placebo.

Topics: Acetamides; Animals; Anticonvulsants; Clinical Trials as Topic; Humans; Lacosamide; Seizures

Lacosamide is a functionalized amino acid, the antiepileptic effects of which appear to be due to a novel mode of action, namely the selective enhancement of slow inactivation of voltage-gated sodium channels. Lacosamide is available as oral or intravenous formulations. Bioequivalence between the oral tablet and the oral syrup of lacosamide has been established. The bioavailability of the oral lacosamide tablet was similar to that of a 30- or 60-minute intravenous infusion of lacosamide administered at the same dosage. Oral lacosamide when added concomitantly with between one and three antiepileptic drugs was effective in adult patients with uncontrolled partial-onset seizures with or without secondary generalization, according to pooled data (n = 1308) from three phase II/III studies that had a 12-week maintenance phase. The percentage of patients with a >or=50% reduction from baseline to the maintenance phase in seizure frequency was significantly greater with oral lacosamide 200 or 400 mg/day (34% and 40%) than with placebo (23%). The median percentage reduction in seizure frequency per 28 days from baseline to the maintenance phase was significantly greater with lacosamide 400 mg/day than with placebo in each of the three phase II/III studies. Lacosamide was generally well tolerated in adult patients with partial-onset seizures, with most treatment-emergent adverse events being of mild or moderate severity. Dizziness was the most common treatment-related adverse event. When used as short-term replacement for oral lacosamide, intravenous lacosamide was well tolerated when administered as a 15-, 30- or 60-minute infusion.

Topics: Acetamides; Anticonvulsants; Biological Availability; Drug Therapy, Combination; Epilepsies, Partial; Humans; Lacosamide; Seizures; Therapeutic Equivalency

To review the pharmacology, pharmacokinetics, efficacy, and safety of lacosamide, a new agent for use as adjunctive treatment in partial-onset seizures and a potential agent for treatment of neuropathic pain.. A MEDLINE search (1966-July 2009) was conducted using the key words lacosamide, harkoseride, SPM-927, ADD-234037, epilepsy, anticonvulsant, and neuropathic pain. Bibliographies of all articles retrieved were also reviewed.. All studies including humans and published in English with data describing lacosamide for the adjunctive treatment of partial-onset seizures and for treatment of neuropathic pain were reviewed.. Lacosamide is a functionalized amino acid molecule that selectively enhances the slow inactivation of voltage-gated sodium channels and interacts with the collapsin-response mediator protein-2. With its bioavailability of approximately 100%, minimal protein binding, and few drug-drug interactions, lacosamide has a favorable pharmacokinetic profile. Recent data suggest that lacosamide may have a role as adjunctive treatment of partial-onset seizures. Open-label studies showed a 14-47% reduction in seizure frequency, while placebo-controlled trials demonstrated a 26-40% reduction in seizure frequency. The 50% responder rates ranged from 32.7% to 41.2% with varying doses of lacosamide. Although lacosamide use is not approved by the Food and Drug Administration for treatment of neuropathic pain, studies demonstrated reductions of 2.01-3.60 in pain scale scores. The most common adverse effects, occurring in greater than 10% of subjects in the clinical trials, include arthralgia, ataxia, blurred vision, diplopia, dizziness, fatigue, headache, injection site pain (only in intravenous studies), nausea, tremor, upper respiratory tract infection, and vomiting.. Lacosamide is an effective agent for adjunctive treatment of refractory partial-onset seizures. Its exact role in the treatment of neuropathic pain needs to be determined.

Topics: Acetamides; Analgesics; Anticonvulsants; Chemotherapy, Adjuvant; Diabetic Neuropathies; Epilepsies, Partial; Humans; Lacosamide; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Seizures

The objective of this study is to evaluate the safety and tolerability of intravenous (IV) lacosamide infusion in patients aged ≥1 month to <17 years with epilepsy.. This Phase 2/3 open-label trial (EP0060; NCT02710890) enrolled patients in two age cohorts (cohort 1: ≥8 to <17 years; cohort 2: ≥1 month to <8 years). Eligible patients were receiving oral lacosamide as adjunctive treatment or monotherapy (in an open-label long-term trial or by prescription) or were not receiving lacosamide before enrolment. Patients initiated IV lacosamide (2-12 mg/kg/day or 100-600 mg/day; 15-60 minutes infusion) as a replacement for oral lacosamide or as adjunctive treatment. The primary outcomes were treatment-emergent adverse events (TEAEs) and discontinuations due to TEAEs.. In total, 103 patients were enrolled and completed the trial; 55 patients were included in cohort 1 (≥8 to <17 years), 48 in cohort 2 (≥1 month to <8 years). During the 4 weeks before screening, 74 (71.8%) patients had focal seizures, 12 (11.7%) had generalized seizures, and two (1.9%) had unclassified seizures. Most patients (74 [71.8%]) initiated lacosamide as adjunctive IV treatment. The mean overall duration of exposure to IV lacosamide was 1.18 days. Seventy-nine (76.7%) patients had one IV lacosamide infusion, 20 (19.4%) had two, one (1.0%) had three, and three (2.9%) had 10 infusions. Overall, five (4.9%) patients had a total of seven TEAEs. The only TEAEs reported in two or more patients were increased blood triglycerides (two [1.9%]). No serious or severe TEAEs were reported, and no patients discontinued due to TEAEs. No TEAEs were considered drug-related by the investigator. No consistent or clinically relevant treatment-related changes from baseline were observed for hematology, clinical chemistry parameters, vital signs, or 12-lead electrocardiograms.. IV lacosamide was generally well tolerated in pediatric patients (≥1 month to <17 years) with epilepsy, and no new safety concerns were identified.

Topics: Acetamides; Anticonvulsants; Child; Epilepsy; Humans; Lacosamide; Seizures

To evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of lacosamide (LCM) (up to 12 mg/kg/day or 600 mg/day) as adjunctive therapy in pediatric patients with epilepsy syndromes associated with generalized seizures.. Phase 2, multicenter, open-label exploratory trial (SP0966; NCT01969851; 2012-001446-18) of oral LCM for epilepsy syndromes associated with generalized seizures in pediatric patients ≥1 month to <18 years of age taking one to three concomitant antiseizure medications. The trial comprised a 6-week prospective baseline period, 6-week flexible titration period, and 12-week maintenance period.. Fifty-five patients (mean age: 9.2 years; 56.4% male) took at least one dose of LCM and had at least one post-baseline efficacy-related assessment. The median treatment duration was 127.0 days. There were no clinically significant mean or median changes or worsening from baseline to end of the titration period in the count of generalized spike-wave discharges per interpretable hour on 24-h ambulatory electroencephalogram recordings, or from baseline to the maintenance period in mean and median days with any generalized or focal to bilateral tonic-clonic seizures per 28 days. Treatment-emergent adverse events (TEAEs) were reported by 49 patients (89.1%), and three patients (5.5%) discontinued due to TEAEs. The median change and median percentage change in days with any generalized or focal to bilateral tonic-clonic seizures per 28 days from baseline to the maintenance period were both 0. Trends toward improvement (decrease) were observed in median change and median percentage change in days with each individual seizure type (absence, myoclonic, clonic, tonic, tonic-clonic, atonic, and focal to bilateral tonic-clonic) per 28 days.. Safety findings were consistent with the known safety profile of LCM and were as expected for the pediatric population. There was no worsening of generalized seizures with LCM. Limitations include the inability to correlate spike and wave data with clinical outcomes, and the lack of similar studies against which the results can be compared.

Topics: Anticonvulsants; Child; Double-Blind Method; Drug Therapy, Combination; Epilepsy, Generalized; Epileptic Syndromes; Female; Humans; Lacosamide; Male; Prospective Studies; Seizures; Treatment Outcome

Temporal lobe epilepsy (TLE) is often associated with drug-resistant seizures. We evaluated the efficacy and tolerability of lacosamide (LCM) versus controlled-release carbamazepine (CBZ-CR) monotherapy in adults with newly diagnosed TLE.. Exploratory post hoc analysis of patients with temporal focus of localization (indicated as the only localization focus) in a double-blind, noninferiority, phase 3 trial (SP0993; NCT01243177) in patients aged ≥ 16 years with newly diagnosed epilepsy randomized 1:1 to LCM or CBZ-CR monotherapy.. Of 886 treated patients in this trial, temporal lobe focus of localization (TLE) was reported as the single focus for 287 (32.4%) patients (LCM 134, CBZ-CR 153). A similar proportion of patients with TLE on LCM (82  [61.2%]) and CBZ-CR (99  [64.7%]) completed the trial. Kaplan-Meier estimates for 6- and 12-month seizure freedom at the last evaluated dose level (stratified by number of seizures in the 3 months before screening  [≤2 or >2 seizures]) were similar with LCM and CBZ-CR (6 months overall: 88.7% and 89.7%; 12 months overall: 78.3% and 81.7%). Treatment-emergent adverse events (TEAEs) were reported by fewer patients on LCM (73.9%) than CBZ-CR (81.0%). Drug-related TEAEs (assessed by the investigator) were reported in 41.8% of patients on LCM and 52.3% of patients on CBZ-CR; 11.2% of patients on LCM and 15.0% on CBZ-CR discontinued due to TEAEs.. Lacosamide was efficacious and generally well tolerated as monotherapy in patients with TLE with efficacy outcomes comparable with CBZ-CR, and fewer patients on LCM reported any TEAEs, drug-related TEAEs, or discontinued due to TEAEs.

Topics: Adult; Anticonvulsants; Benzodiazepines; Carbamazepine; Delayed-Action Preparations; Double-Blind Method; Epilepsy, Temporal Lobe; Humans; Lacosamide; Seizures; Treatment Outcome

Recently, a novel trial design has been proposed to overcome challenges with traditional placebo-controlled trials of antiepileptic drugs in infants and young children (≥1 month of age) (Auvin S, et al. Epilepsia Open 2019;4:537-43). The proposed time-to-event trial design involves seizure counting by caregivers and allows adjustment of the duration of the baseline period and duration of exposure to placebo or potentially ineffective treatment based on the patient's seizure burden and response. We performed post hoc analyses to mimic this trial design and evaluate its viability. As these analyses required trials with prolonged baseline and treatment periods and diary data, which is not a typical design of trials in infants and young children (1 month to <4 years of age), data from two trials in pediatric patients (4-16 years of age) were used.. We performed post hoc analyses of two randomized, double-blind, placebo-controlled trials of adjunctive levetiracetam (N159; NCT00615615) and lacosamide (SP0969; NCT01921205) in children and adolescents (4-16 years of age) with focal-onset seizures. In these analyses, patients were followed until they completed the 10-week maintenance period, discontinued during the maintenance period, or reached their "nth" seizure (n = number of seizures patient had during baseline). Efficacy was assessed by determining time to nth seizure.. In the analyses of both trials, patients on levetiracetam or lacosamide had a 34% lower risk of reaching their baseline seizure count during their 10-week maintenance period than patients on placebo. The previously published primary results of these trials also demonstrated efficacy of adjunctive levetiracetam and lacosamide.. Although these were post hoc analyses of trials in older children (4-16 years of age), our results provide supportive evidence for the utility of the novel time-to-event trial design for future trials in infants and young children (1 month to <4 years of age).

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Drug Therapy, Combination; Epilepsies, Partial; Epilepsy; Humans; Lacosamide; Levetiracetam; Seizures

This Phase III, long-term, open-label extension (OLE) trial (EP0009; NCT01832038) was conducted to evaluate the long-term safety, tolerability, and efficacy of adjunctive lacosamide (100-400 mg/day) in Chinese and Japanese people with epilepsy (PWE) (16-70 years) who had completed a double-blind, randomized, placebo-controlled trial of adjunctive lacosamide (EP0008; NCT01710657). PWE entered the OLE trial on 200 mg/day lacosamide and up to 3 concomitant antiseizure medications. Dose adjustments were permitted to optimize tolerability and seizure reduction. Safety variables were treatment-emergent adverse events (TEAEs) and discontinuations due to TEAEs. Efficacy variables were percent change in focal seizure frequency per 28 days from Baseline of the double-blind trial, ≥50 % and ≥75 % responder rates, seizure-freedom, and proportion of PWE on lacosamide monotherapy. Overall, 473 PWE (74.0 % Chinese and 26.0 % Japanese) were enrolled; 238 (50.3 %) PWE completed the trial and 235 (49.7 %) discontinued, most commonly due to lack of efficacy (81 [17.1 %]), adverse events (55 [11.6 %]), and consent withdrawn (49 [10.4 %]). During the trial, PWE received lacosamide for a median of 1016.0 days (∼3 years), with a total exposure of 1454.8 person-years; 321 (67.9 %) PWE received lacosamide for >24 months, and 246 (52.0 %) for >36 months. The median modal dose of lacosamide was 300 mg/day. Overall, 410/473 (86.7 %) PWE reported TEAEs, 244 (51.6 %) had a TEAE that was considered drug-related, and 49 (10.4 %) discontinued due to a TEAE. The most common TEAEs (≥20 % of PWE) were nasopharyngitis, dizziness, and upper respiratory tract infection. The median reduction in focal seizure frequency per 28 days from Baseline was 57.1 %, and the ≥50 % and ≥75 % responder rates were 57.1 % (269/471) and 29.7 % (140/471), respectively. Among PWE who completed 12, 24, and 36 months of treatment, the 12-, 24-, and 36-month seizure-freedom rates were 3.5 % (13/375), 3.4 % (11/321), and 2.0 % (5/247), respectively. Among PWE exposed to lacosamide for ≥6 months and ≥12 months, the proportions of PWE that maintained continuous monotherapy for ≥6 months and ≥12 months were 5.0 % (21/421) and 5.0 % (19/378), respectively. Overall, lacosamide was well-tolerated as long-term adjunctive therapy in Chinese and Japanese PWE and uncontrolled focal seizures, with improvements in seizure reduction maintained over 36 months of treatment.

Topics: Adult; Anticonvulsants; China; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Humans; Japan; Lacosamide; Seizures; Treatment Outcome

To evaluate efficacy and safety of lacosamide (up to 12 mg/kg/day or 400 mg/day) as adjunctive treatment for uncontrolled primary generalised tonic-clonic seizures (PGTCS) in patients (≥4 years) with idiopathic generalised epilepsy (IGE).. Phase 3, double-blind, randomised, placebo-controlled trial (SP0982; NCT02408523) in patients with IGE and PGTCS taking 1-3 concomitant antiepileptic drugs. Primary outcome was time to second PGTCS during 24-week treatment.. 242 patients were randomised and received ≥1 dose of trial medication (lacosamide/placebo: n=121/n=121). Patients (mean age: 27.7 years; 58.7% female) had a history of generalised-onset seizures (tonic-clonic 99.6%; myoclonic 38.8%; absence 37.2%). Median treatment duration with lacosamide/placebo was 143/65 days. Risk of developing a second PGTCS during 24-week treatment was significantly lower with lacosamide than placebo (Kaplan-Meier survival estimates 55.27%/33.37%; HR 0.540, 95% CI 0.377 to 0.774; p<0.001; n=118/n=121). Median time to second PGTCS could not be estimated for lacosamide (>50% of patients did not experience a second PGTCS) and was 77.0 days for placebo. Kaplan-Meier estimated freedom from PGTCS at end of the 24-week treatment period (day 166) for lacosamide/placebo was 31.3%/17.2% (difference 14.1%; p=0.011). More patients on lacosamide than placebo had ≥50% (68.1%/46.3%) or ≥75% (57.1%/36.4%) reduction from baseline in PGTCS frequency/28 days, or observed freedom from PGTCS during treatment (27.5%/13.2%) (n=119/n=121). 96/121 (79.3%) patients on lacosamide had treatment-emergent adverse events (placebo 79/121 (65.3%)), most commonly dizziness (23.1%), somnolence (16.5%), headache (14.0%). No patients died during the trial.. Lacosamide was efficacious and generally safe as adjunctive treatment for uncontrolled PGTCS in patients with IGE.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Dizziness; Double-Blind Method; Drug Therapy, Combination; Epilepsy, Generalized; Female; Headache; Humans; Kaplan-Meier Estimate; Lacosamide; Male; Middle Aged; Proportional Hazards Models; Seizures; Sleepiness; Treatment Outcome; Young Adult

To evaluate efficacy and tolerability of adjunctive lacosamide in children and adolescents with uncontrolled focal (partial-onset) seizures.. In this double-blind trial (SP0969; NCT01921205), patients (age ≥4-<17 years) with uncontrolled focal seizures were randomized (1:1) to adjunctive lacosamide/placebo. After a 6-week titration, patients who reached the target dose range for their weight (<30 kg: 8-12 mg/kg/d oral solution; ≥30-<50 kg: 6-8 mg/kg/d oral solution; ≥50 kg: 300-400 mg/d tablets) entered a 10-week maintenance period. The primary outcome was change in focal seizure frequency per 28 days from baseline to maintenance.. Three hundred forty-three patients were randomized; 306 (lacosamide 152 of 171 [88.9%]; placebo 154 of 172 [89.5%]) completed treatment (titration and maintenance). Adverse events (AEs) were the most common reasons for discontinuation during treatment (lacosamide 4.1%; placebo 5.8%). From baseline to maintenance, percent reduction in focal seizure frequency per 28 days for lacosamide (n = 170) vs placebo (n = 168) was 31.7% (. Adjunctive lacosamide was efficacious in reducing seizure frequency and generally well tolerated in patients (age ≥4-<17 years) with focal seizures.. NCT01921205.. This trial provides Class I evidence that for children and adolescents with uncontrolled focal seizures, adjunctive lacosamide reduces seizure frequency.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Lacosamide; Male; Prospective Studies; Seizures; Treatment Outcome

The purpose of this study was to compare the efficacy and safety of lacosamide (LCM) and sodium valproate (SVA) in lorazepam (LOR)-resistant SE.. Patients with LOR-resistant SE were randomized to intravenous LCM 400mg at the rate of 60mg/kg/min or SVA 30mg/kg at the rate of 100mg/min. The SE severity score (STESS), duration of SE and its etiology, and MRI findings were noted. Primary outcome was seizure cessation for 1h, and secondary outcomes were 24h seizure remission, in-hospital death, and severe adverse events (SAE).. Sixty-six patients were included, and their median age was 40 (range 18-90) years. Thirty-three patients each received LCM and SVA. Their demographic, clinical, STESS, etiology, and MRI findings were not significantly different. One-hour seizure remission was not significantly different between LCM and SVA groups (66.7% vs 69.7%; P=0.79). Twenty-four-hour seizure freedom was insignificantly higher in SVA (20, 66.6%) compared with LCM group (15, 45.5%). Death (10 vs 12) and composite side effects (4 vs 6) were also not significantly different in LCM and SVA groups. LCM was associated with hypotension and bradycardia (1 patient), and SVA with liver dysfunction (6).. In patients with LOR-resistant SE, both LCM and SVA have comparable efficacy and safety.

Topics: Acetamides; Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Lacosamide; Lorazepam; Male; Middle Aged; Pilot Projects; Seizures; Status Epilepticus; Treatment Outcome; Valproic Acid; Young Adult

Assess the safety of adjunctive lacosamide for the treatment of uncontrolled primary generalized tonic-clonic seizures in patients (16-65 years) with primary generalized (genetic) epilepsy (PGE).. An open-label pilot safety study (SP0961; NCT01118949), comprising 12 weeks' historical baseline, 4 weeks' prospective baseline, 3 weeks' titration (target: 400mg/day adjunctive lacosamide) and 6 weeks' maintenance. Patients who continued to the extension study (SP0962; NCT01118962) then received ≤59 weeks of flexible treatment (100-800mg/day lacosamide with flexible dosing of concomitant antiepileptic drugs). The primary outcomes for SP0961 were the mean change (±standard deviation) in absence seizure or myoclonic seizure days per 28days from prospective baseline to maintenance; for SP0962, the incidence of treatment-emergent adverse events (TEAEs) and withdrawals because of TEAEs.. Of the 49 patients who enrolled, 40 (82%) completed the pilot study and 9 discontinued (5 because of adverse events). Of the 39 patients who continued to the extension study, 10 discontinued (2 owing to TEAEs) and 29 (74%) completed the study. During the pilot study, patients reported a reduction in mean (±standard deviation) absence and myoclonic seizure days per 28days (-0.37±4.80, -2.19±5.80). Reductions were also observed during the extension study (-2.38±5.54, -2.78±6.43). Five patients in SP0961 and 2 patients in SP0962 experienced TEAEs of new or increased frequency of absence seizures or myoclonic seizures. The most common TEAEs during SP0961 were dizziness (39%) and nausea (27%), and during SP0962 were dizziness (26%) and upper respiratory tract infection (26%).. The safety profile of adjunctive lacosamide was similar to that previously published. Adjunctive lacosamide did not systematically worsen absence or myoclonic seizures, and appears to be well tolerated in patients with PGE.

Topics: Acetamides; Adolescent; Adult; Aged; Anticonvulsants; Epilepsy, Generalized; Female; Follow-Up Studies; Humans; Lacosamide; Male; Middle Aged; Pilot Projects; Seizures; Treatment Outcome; Young Adult

To quantify the relationship between exposure to lacosamide monotherapy and seizure probability, and to simulate the effect of changing the dose regimen.. Structural time-to-event models for dropouts (not because of a lack of efficacy) and seizures were developed using data from 883 adult patients newly diagnosed with epilepsy and experiencing focal or generalized tonic-clonic seizures, participating in a trial (SP0993; ClinicalTrials.gov identifier: NCT01243177) comparing the efficacy of lacosamide and carbamazepine controlled-release monotherapy. Lacosamide dropout and seizure models were used for simulating the effect of changing the initial target dose on seizure freedom.. Repeated time-to-seizure data were described by a Weibull distribution with parameters estimated separately for the first and subsequent seizures. Daily area under the plasma concentration-time curve was related linearly to the log-hazard. Disease severity, expressed as the number of seizures during the 3 months before the trial (baseline), was a strong predictor of seizure probability: patients with 7-50 seizures at baseline had a 2.6-fold (90% confidence interval 2.01-3.31) higher risk of seizures compared with the reference two to six seizures. Simulations suggested that a 400-mg/day, rather than a 200-mg/day initial target dose for patients with seven or more seizures at baseline could potentially result in an additional 8% of seizure-free patients for 6 months at the last evaluated dose level. Patients receiving lacosamide had a slightly lower dropout risk compared with those receiving carbamazepine.. Baseline disease severity was the most important predictor of seizure probability. Simulations suggest that an initial target dose >200 mg/day could potentially benefit patients with greater disease severity.

Topics: Acetamides; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Computer Simulation; Double-Blind Method; Epilepsy; Female; Humans; Lacosamide; Male; Middle Aged; Models, Biological; Patient Dropouts; Seizures; Severity of Illness Index; Time Factors; Young Adult

This non-interventional study was conducted to evaluate the efficacy and tolerability of intravenous lacosamide (LCM-iv) under routine conditions in daily clinical practice as a prospective registry.. Patients with any type of seizure or epilepsy syndrome were recruited in 16 neurological and neuropediatric centers in Germany if the treating physician decided to administer LCM-iv for any reason. Observation time per patient was 10 days with daily documentation of LCM-iv administration, type and frequency of seizures, currently used drugs and doses, and adverse events. Treatment efficacy, tolerability, and handling of LCM-iv were assessed using a five-step scale.. In 119 patients treating physicians classified epilepsies as focal in 66.1% and generalized in 17.4% (16.5% unclassifiable). Most common etiologies of seizures were tumors (36.1%) and cerebrovascular diseases (21.8%). Reasons for LCM-iv treatment included preparation for surgery (25.2%), convulsive (24.4%) and non-convulsive (18.5%) status epilepticus (SE), series of seizures (16.0%), gastrointestinal causes (5.9%), and acute seizures (4.2%). The median dose of LCM-iv was 300mg per day. In 45 of 64 patients (70.3%) with SE or series of seizures, epileptic activity ceased during observation time. Five patients showed abnormalities in ECG prior to the infusion and one patient afterwards, but during infusion no abnormalities were reported. Treating physicians rated efficacy and tolerability as very good or good in 77.6% and 93.1% of patients, respectively.. This large and independent multicenter registry on the use of LCM-iv in clinical practice demonstrates that LCM-iv is well-tolerated and highly efficacious when given in emergency situations, including patients experiencing SE. It is advisable to perform an electrocardiogram prior to LCM-iv administration.

Topics: Acetamides; Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Child; Child, Preschool; Epilepsy; Female; Germany; Humans; Infant; Lacosamide; Male; Middle Aged; Outcome Assessment, Health Care; Registries; Seizures; Status Epilepticus; Young Adult

The objective of this study was to examine cognitive and quality-of-life measures/quality of life outcomes with adjunctive lacosamide therapy in patients with treatment-resistant partial epilepsy.. This was a prospective, open-label, nonblinded, adjunctive therapy test-retest (within subjects) study of patients with treatment-resistant partial epilepsy in which outcome (cognitive functioning and mood/quality of life) was measured in the same subject before and after adjunctive lacosamide administration for 24weeks. The cognitive assessment included the following: Controlled Oral Word Association Test, Buschke Selective Reminding Test, Brief Visuospatial Memory Test-Revised, Stroop Color Word Test, Symbol Digit Modalities Test, Digit Span, Digit Cancellation, and Trails A and B. The quality-of-life measures/quality-of-life assessment included the following: Beck Depression Inventory-II, Profile of Mood States, and Quality of Life Inventory-89. Lacosamide was started at 100mg (50mg twice daily) and could be titrated as needed up to 400mg/day (200mg twice daily). Baseline concomitant AEDs were kept constant. Composite scores were calculated for a pre-post difference score for the cognitive and mood/quality-of-life measures separately and used in regression analyses to correct for the effects of age, education, seizure frequency, seizure severity, dose of lacosamide, and number of AEDs at baseline.. Thirty-four patients were enrolled (13 males, 21 females). Mean age was 38.8±2.43years. Mean seizure frequency decreased significantly from 2.0±2.55 seizures per week at baseline to 1.02±1.72 seizures per week at posttreatment (t=4.59, p<.0001) with a 50% responder rate seen in 18 patients (52.9%). No significant differences were found on the composite scores of the cognitive or the mood/quality-of-life measures after 6months of lacosamide.. Lacosamide appeared to have low risks of significant changes in cognition or mood/quality of life. In addition, the present study supports prior studies that have proven lacosamide as an effective adjunctive therapy for the treatment of resistant partial epilepsy.

Topics: Acetamides; Adult; Affect; Anticonvulsants; Cognition; Depression; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Lacosamide; Male; Neuropsychological Tests; Prospective Studies; Psychiatric Status Rating Scales; Quality of Life; Seizures; Treatment Outcome

To assess long-term use and safety of lacosamide (LCM) ≤800 mg/day monotherapy in patients with partial-onset seizures (POS) enrolled previously in a historical-controlled, conversion-to-monotherapy study (SP902; NCT00520741).. Patients completing or exiting SP902 with LCM as monotherapy or as adjunctive therapy were eligible to enter this 2-year open-label extension (OLE) trial (SP904; NCT00530855) at a starting dose ±100 mg/day of their final SP902 dose. Investigators could adjust the LCM dose to 100-800 mg/day and add up to two antiepileptic drugs to optimize tolerability and seizure reduction.. Three hundred twenty-two patients received LCM: 210 patients (65.2%) completed and 112 (34.8%) discontinued, most commonly owing to withdrawal of consent (9.3%). Two hundred fifty-eight patients (80.1%) had ≥1 year of and 216 (67.1%) had ≥2 years of LCM exposure, of whom 179/258 (69.4%) achieved LCM monotherapy lasting for any 12-month period, and 126/216 (58.3%) patients exposed for ≥24 months achieved LCM monotherapy for any 24-month period. Total exposure = 525.5 patient-years. The median modal dose was 500 mg/day. Two hundred ninety-two patients (90.7%) achieved LCM monotherapy at some point during the study. Sixty-five of 87 patients who exited and 193/235 who completed SP902 were exposed for ≥12 months, and 43.1% and 78.2%, respectively, achieved LCM monotherapy for ≥12 months. Median LCM monotherapy duration was 587.0 days (2-791 days); 91.0% of patients reported treatment-emergent adverse events, of which the most common were dizziness (27.3%), headache (17.1%), and nausea (14.3%). Compared with the SP902 study baseline, 74.2% of patients had a ≥50% seizure reduction and 5.6% were seizure-free at 24 months.. The majority of patients were receiving LCM monotherapy at 0, 12, and 24 months in this OLE. Lacosamide monotherapy (median dose of 500 mg/day) had a safety profile similar to that of adjunctive therapy studies. These results support the use of lacosamide as long-term monotherapy treatment for adults with POS.

Topics: Acetamides; Adolescent; Adult; Aged; Anticonvulsants; Cohort Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; International Cooperation; Lacosamide; Male; Middle Aged; Seizures; Treatment Outcome; Young Adult

To evaluate the efficacy and safety of adjunctive lacosamide treatment in Chinese and Japanese adults with uncontrolled focal (partial-onset) seizures (POS), with or without secondary generalization.. A 24-week, randomized, double-blind, placebo-controlled study (EP0008; NCT01710657) was conducted in patients (aged 16-70 years) with uncontrolled POS and taking 1-3 concomitant antiepileptic drugs from 72 sites across China and Japan. Following an 8-week Baseline period, randomized patients received lacosamide 200mg/day (100mg twice daily), 400mg/day (200mg twice daily), or placebo for 4-week Titration and 12-week Maintenance periods. The primary efficacy variable was the change in POS frequency per 28days from Baseline to Maintenance.. Overall, 692 patients were screened; 548 were randomized to placebo (n=184), lacosamide 200mg/day (n=183), or lacosamide 400mg/day (n=181); 485 (88.5%) completed the study. The median change (range) in POS frequency per 28days from Baseline to Maintenance was -3.33 (-754.3 to 165.2), -4.50 (-97.5 to 28.2), and -1.22 (-93.0 to 39.8) in the lacosamide 200mg/day, 400mg/day, and placebo groups, respectively. Significant percentage reductions in POS frequency over placebo per 28days from Baseline to Maintenance were observed for lacosamide 200mg/day (29.4% [95% CI 18.7-38.7%], p<0.001) and 400mg/day (39.6% [30.5-47.6%], p<0.001). Higher ≥50% and ≥75% responder and seizure freedom rates were observed in lacosamide-treated patients vs placebo. Treatment-emergent adverse events reported by ≥10% of all lacosamide-treated patients occurring at ≥2% difference compared with placebo were dizziness (25.9% vs 9.2%) and somnolence (10.2% vs 3.8%). Dose-proportional pharmacokinetics were consistent with earlier global pivotal trials.. Adjunctive lacosamide (200 and 400mg/day) was efficacious in reducing POS frequency in Chinese and Japanese patients with a safety and tolerability profile consistent with the three global pivotal studies.

Topics: Acetamides; Adolescent; Adult; Aged; Anticonvulsants; Asian People; China; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Japan; Lacosamide; Male; Middle Aged; Seizures; Treatment Outcome; Young Adult

To evaluate the efficacy and safety of lacosamide administered as either first add-on or later add-on antiepileptic drug (AED) therapy for patients with uncontrolled partial-onset seizures (POS).. In this open-label, multicentre trial, patients with POS initiated oral lacosamide (titrated to 400 mg/day) either as add-on to first AED monotherapy, or as later add-on to 1-3 concomitant AEDs after ≥ 2 previous AEDs. The primary efficacy variable was the proportion of patients achieving seizure freedom for the first 12 weeks of the 24-week Maintenance Phase.. 456 patients received ≥ 1 dose of lacosamide (96 as first add-on, 360 as later add-on). In the first add-on cohort, 27/72 (37.5%) patients completed 12 weeks treatment and remained seizure-free; 18/68 (26.5%) remained seizure-free after 24 weeks. 64/91 (70.3%) patients achieved ≥ 50% reduction in seizure frequency during maintenance treatment. This was accompanied by a mean 7.1 ± 16.00 point improvement from Baseline in the Quality of Life Inventory in Epilepsy (QOLIE-31-P) total score for 24-week completers, with improvement reported in all subscales. Most common treatment-emergent adverse events (TEAEs) were dizziness (31.3%) and headache (13.5%). In the later add-on cohort, 39/261 (14.9%) and 29/249 (11.6%) patients remained seizure-free after completing 12 and 24 weeks' treatment, respectively. 178/353 (50.4%) patients achieved ≥ 50% reduction in seizure frequency during maintenance treatment. Mean change in QOLIE-31-P total score was 4.8 ± 14.74 points among 24-week completers. Common TEAEs were dizziness (33.6%), somnolence (15.0%) and headache (11.4%).. Lacosamide initiated as first add-on treatment was efficacious and well tolerated in patients with uncontrolled POS.

Topics: Acetamides; Adolescent; Adult; Aged; Anticonvulsants; Cohort Studies; Drug Therapy, Combination; Female; Humans; Lacosamide; Male; Middle Aged; Prospective Studies; Quality of Life; Seizures; Treatment Outcome; Young Adult

The objective of this study was to describe a priori protocol-defined analyses to evaluate the safety and tolerability of adjunctive oral lacosamide (200-600 mg/day) in adults (ages 16-70 years) with partial-onset seizures (POS) using data pooled from three similarly designed randomized, double-blind, placebo-controlled trials (SP667, SP754 [NCT00136019], SP755 [NCT00220415]).. Patients with POS (≥2 years' duration, ≥2 previous antiepileptic drugs [AEDs]) uncontrolled by a stable dosing regimen of 1-3 concomitant AEDs were randomized to treatment with lacosamide at doses of 200 mg/day, 400 mg/day, or 600 mg/day, or placebo. Studies comprised a 4- to 6-week titration phase to target dose followed by a 12-week maintenance phase. Safety outcomes included treatment-emergent adverse events (TEAEs) of particular relevance to patients with POS, overall TEAEs, and discontinuations due to TEAEs. Post hoc analyses included evaluation of TEAEs potentially related to cognition and TEAEs leading to discontinuation analyzed by concomitant AEDs.. One thousand three hundred eight patients were randomized to and received treatment; 944 to lacosamide and 364 to placebo. Most patients (84.4%) were taking 2 or 3 concomitant AEDs. The most common drug-associated TEAEs (reported by ≥5% of patients in any lacosamide dose group and with an incidence at least twice that reported for placebo during the treatment phase) were dizziness (30.6% for lacosamide vs 8.2% for placebo), nausea (11.4% vs 4.4%), and diplopia (10.5% vs 1.9%). Common drug-associated TEAEs generally appeared to be dose-related, and the incidence of each was lower during the 12-week maintenance phase than during the titration phase. Most TEAEs were either mild or moderate in intensity; severe TEAEs were predominantly observed with lacosamide 600 mg/day. No individual serious TEAE occurred in ≥1% of all lacosamide-treated patients. Treatment-emergent adverse events led to discontinuation in 8.1%, 17.2%, and 28.6% of the lacosamide 200-, 400-, and 600-mg/day groups, respectively (vs 4.9% of placebo). Few TEAEs were related to rash, weight loss/gain, changes in clinical chemistry parameters, or psychiatric disturbances, or were seizure-related. The odds of reporting any potential cognition-related TEAE vs placebo increased with dose and were similar between lacosamide doses of 200 and 400mg/day and placebo (odds ratio 1.3, 95% confidence interval 0.7-2.4). Discontinuations due to TEAEs based on most commonly used AEDs taken in combination with lacosamide (all doses combined) were carbamazepine (15.3% [51/334] vs 3.9% [5/129] placebo), lamotrigine (19.2% [56/291] vs 4.3% [5/117]), and levetiracetam (10.1% [28/278] vs 3.9% [4/103]).. The safety and tolerability profile of adjunctive lacosamide in this detailed evaluation was similar to that observed in the individual double-blind trials. Adjunctive lacosamide was associated with TEAEs related to the nervous system and gastrointestinal tract, predominantly during titration.

Topics: Acetamides; Adolescent; Adult; Aged; Anticonvulsants; Body Weight; Cognition; Dose-Response Relationship, Drug; Double-Blind Method; Drug Eruptions; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Lacosamide; Male; Middle Aged; Seizures; Substance Withdrawal Syndrome; Young Adult

Long-term (up to 8 years of exposure) safety and efficacy of the antiepileptic drug lacosamide was evaluated in this open-label extension trial (SP615 [ClinicalTrials.gov identifier: NCT00552305]). Patients were enrolled following participation in a double-blind trial or one of two open-label trials of adjunctive lacosamide for partial-onset seizures. Dosage adjustments of lacosamide (100-800 mg/day) and/or concomitant antiepileptic drugs were allowed to optimize tolerability and seizure reduction. Of the 370 enrolled patients, 77%, 51%, and 39% had >1, >3, or >5 years of lacosamide exposure, respectively. Median lacosamide modal dose was 400mg/day. Common treatment-emergent adverse events (TEAEs) were dizziness (39.7%), headache (20.8%), nausea (17.3%), diplopia (17.0%), fatigue (16.5%), upper respiratory tract infection (16.5%), nasopharyngitis (16.2%), and contusion (15.4%). Dizziness (2.2%) was the only TEAE that led to discontinuation in >2% of patients. Ranges for median percent reductions in seizure frequency were 47-65%, and those for ≥ 50% responder rates were 49-63% for 1-, 3-, and 5-year completer cohorts. Exposure to lacosamide for up to 8 years was generally well tolerated, with a safety profile similar to previous double-blind trials, and efficacy was maintained.

Topics: Acetamides; Adult; Anticonvulsants; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Lacosamide; Male; Middle Aged; Seizures; Time Factors; Treatment Outcome

Status epilepticus (SE) and seizure clusters (SC) represent neurologic emergencies with a case fatality rate up to 34%, depending on cause and comorbidity. As SE becomes more refractory to treatment over time, appropriate medication is important. This study aimed to investigate efficacy and tolerability of intravenous (IV) lacosamide (LCM) in treatment of SC and SE. Data of patients with SE or SC who were treated with IV LCM between December 2009 and February 2011 in two Austrian centers were analyzed retrospectively. Clinical information was extracted from patients' charts. Forty-eight patients (26f/22m) aged median 62 years (range 17-95 years) were identified. Thirty-five percent of patients (17 of 48) had SC and 65% (31 of 48) had SE. SE was nonconvulsive in 10 (32%), convulsive in 11 (36%), and focal in 10 (32%) patients. SE was acute symptomatic in six (20%) and remote symptomatic in 11 (35%) patients. Fourteen (45%) had preexisting epilepsy. Median initial bolus dose was 200 mg (range 200-400 mg) in patients with SE and 200 mg in patients with SC. Maximum infusion rate was 60 mg/min. Cessation was observed in 42 patients (88%). Success rate in patients with SE receiving LCM as first or second drug was 100% (8 of 8), as third drug 81% (11 of 15), and as fourth or later drug 75% (6 of 8). There were no side effects observed except for pruritus and skin rash in two patients. These data support use of IV LCM as a potential alternative to standard antiepileptic drugs for acute treatment of seizure emergency situations, although randomized controlled studies are needed.

Topics: Acetamides; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Female; Humans; Infusions, Intravenous; Lacosamide; Male; Middle Aged; Seizures; Status Epilepticus; Treatment Outcome; Young Adult

Lacosamide is a new antiepileptic drug effective for adjunctive treatment of partial-onset seizures. We evaluated the safety and tolerability of an intravenous (i.v.) formulation of lacosamide (200-800 mg/day) infused over 10, 15, and 30 min as short-term replacement for oral lacosamide in patients with partial-onset seizures.. This multicenter, open-label, inpatient trial enrolled 160 patients from ongoing open-label, long-term trials who were taking stable doses of oral lacosamide and up to three concomitant antiepileptic drugs (AEDs). Serial cohorts of patients were converted from oral lacosamide treatment to the same intravenous doses infused over progressively shorter infusion durations: 30, 15, and 10 min for 2-5 days. A data monitoring committee (DMC) reviewed safety data for each cohort. The safety of intravenous lacosamide was assessed from adverse events (AEs), laboratory variables, electrocardiography findings, and physical/neurologic examinations.. A total of 160 patients received lacosamide 200-800 mg/day, i.v., for 2-5 days, of which 69% received 400-800 mg/day doses. The most common AEs (reported by or=400 mg/day). Injection-site events were rare and did not appear to be linked to infusion doses or rates. Lacosamide plasma concentrations were linearly related to dose across the cohorts.. This comprehensive evaluation supports the safety of an intravenous lacosamide infusion duration as short as 15 min for short-term (2-5 days) replacement for patients temporarily unable to take oral lacosamide.

Topics: Acetamides; Administration, Oral; Adult; Aged; Cohort Studies; Diplopia; Drug Administration Schedule; Epilepsies, Partial; Female; Humans; Infusions, Intravenous; Internationality; Lacosamide; Male; Middle Aged; Seizures; Young Adult

To evaluate the efficacy and safety of lacosamide (400 and 600 mg/day) as adjunctive treatment in patients with uncontrolled partial-onset seizures taking one to three concomitant antiepileptic drugs (AEDs).. This multicenter, double-blind, placebo-controlled trial randomized patients 1:2:1 to placebo, lacosamide 400 mg, or lacosamide 600 mg/day. After an 8-week baseline period, patients began treatment with placebo or lacosamide 100 mg/day, were force-titrated weekly (100 mg/day increments) to the target dose, and entered a 12-week maintenance period.. A total of 405 patients were randomized and received trial medication. Most (82.1%) were taking two to three concomitant AEDs. Median percent reductions in seizure frequency per 28 days from baseline to maintenance (intention-to-treat, ITT) were 37.3% for lacosamide 400 mg/day (p = 0.008) and 37.8% for lacosamide 600 mg/day (p = 0.006) compared to 20.8% for placebo, with responder rates of 38.3% and 41.2%, respectively, compared to placebo (18.3%, p < 0.001; ITT). Patients randomized to lacosamide showed large reductions in secondarily generalized tonic-clonic seizures, with median percent reductions in seizure frequency of 59.4% for lacosamide 400 mg/day and 93.0% for lacosamide 600 mg/day compared to 14.3% for placebo, and responder rates of 56.0% and 70.2% compared to placebo (33.3%). Dose-related adverse events included dizziness, nausea, and vomiting.. Adjunctive treatment with lacosamide 400 and 600 mg/day reduced seizure frequency for patients with uncontrolled partial-onset seizures. Lacosamide 400 mg/day provided a good balance of efficacy and tolerability; lacosamide 600 mg/day may provide additional benefit for some patients as suggested by secondary efficacy analyses, including response in patients with secondarily generalized tonic-clonic seizures.

Topics: Acetamides; Adolescent; Adult; Aged; Dizziness; Double-Blind Method; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Lacosamide; Male; Middle Aged; Seizures; Young Adult

Topics: Anticonvulsants; Epilepsy; Heart Arrest; Humans; Lacosamide; Seizures

Lacosamide (LCM) is a third-generation antiseizure medication (ASM), and its effect on sleep architecture was supported by a few studies in patients with drug-resistant epilepsy in which LCM was used as an add-on treatment. To gather knowledge on ASMs effects on sleep, this study aimed at evaluating the effects of LCM monotherapy on sleep in patients with focal epilepsy. Ten patients diagnosed with epilepsy (mean age 58.00 ± 14.77, 60.0% female, mean monthly seizure frequency 1.20 ± 2.48) starting LCM as monotherapy were included. Sleep architecture was assessed through polysomnography at baseline and at the 6-month follow-up visit. A significant decrease was observed in seizure frequency (p = 0.004), being all patients seizure-free at follow-up. At baseline, eight patients had poor sleep efficiency (< 85%). Sleep efficiency increased at follow-up, with only three patients having an index < 85% (p = 0.022). From baseline to follow-up, a significant decrease was observed in sleep latency (p = 0.022) and wakefulness after sleep onset (p = 0.047). Moreover, a significant decrease was observed in the percentage of stage 1 (Md = 6.70 vs Md = 3.85, p = 0.005) and stage 3 (Md = 27.70 vs Md = 22.35, p = 0.01) of Non-REM sleep. This study suggests that LCM monotherapy may positively impact sleep architecture in patients with epilepsy. The sleep efficiency improvement and the decrease of sleep latency and wakefulness after sleep onset observed at follow-up highlight better sleep stability and continuity in patients treated with LCM. Notably, all patients were seizure-free at follow-up, and seizure freedom may also concur to sleep structure improvement.

Topics: Acetamides; Anticonvulsants; Epilepsy; Female; Humans; Lacosamide; Male; Seizures; Sleep; Treatment Outcome

Patients in Japan often have difficulty in screening and selecting chronic-care and rehabilitation hospitals for transfer because of the high cost and unavailability of new antiseizure medications, such as perampanel and lacosamide. To investigate whether the requirement for perampanel and lacosamide interfered with patients' hospital transfer by comparing the number of days required for hospital transfer. Data were obtained from patients 1) who were diagnosed with intracerebral hemorrhage or cerebral infarction, 2) who were treated with antiseizure medications for epilepsy, and 3) who were transferred to another hospital. The main outcome measures were the length of hospital stay and days from the last seizure to hospital transfer.Ninety-four eligible patients were divided into those treated with perampanel or lacosamide (n = 18) and those treated with other agents (n = 76). The mean length of hospital stay and days from the last seizure to hospital transfer were 52.9 and 45.4 d in the perampanel and lacosamide group, and 32.7 and 28.6 d in the other medication group (p < 0.001). The mean antiseizure medication costs and total drug costs were U.S. $4.88 and $6.85 in the perampanel/lacosamide group and U.S. $1.94 and $4.41 in the other medication group (p < 0.001, p = 0.007), respectively. Considering antiseizure medication availability and cost in the transfer destination hospital is important when choosing medications for patients requiring hospital transfer from an acute-care hospital.

Topics: Hospitals; Humans; Japan; Lacosamide; Retrospective Studies; Seizures; Stroke

Lacosamide is a newer antiepileptic medication used in refractory neonatal seizures with limited safety and efficacy data. This case series spans 4 years and includes 38 neonates cared for in the neonatal, pediatric, and cardiovascular intensive care units, who received lacosamide for refractory seizures. Because lacosamide affects atrioventricular node function in adults, among other metrics, electrocardiogram (ECG) changes were monitored closely in these neonates. Within this cohort, 2 neonates were found to have atrial bigeminy on ECG and telemetry. Otherwise, lacosamide was generally well tolerated with sleepiness being the most common symptom noted. This case series reports data on the tolerability of lacosamide and emphasizes the importance of monitoring key cardiac intervals with ECG before and after the use of lacosamide in this population.

Topics: Acetamides; Adult; Anticonvulsants; Child; Epilepsy; Humans; Infant, Newborn; Lacosamide; Seizures; Treatment Outcome

To evaluate the efficacy and tolerability of adjunctive lacosamide (LCM) in patients with focal-onset seizures, with or without combined secondarily generalized seizures.. 106 patients aged ≥ 16 years were recruited consecutively in this single-center prospective observational study. All patients received LCM as an add-on treatment on the basis of clinical judgement. Seizure frequency, adverse events (AEs) and retention rates were obtained at 3 and 6 months after LCM introduction.. The overall response rates were 53.3 and 70.4% after 3 and 6 months, respectively, and the freedom of seizures at the same points was reached at 19 and 26.5%. The retention rates were 99.1% at the 3-month follow-up and 93.3% at the 6-month follow-up. The overall incidence of adverse events was 35.8%. The leading AEs were dizziness (16.98%) and sedation (6.6%).. Our study confirmed the efficacy and tolerability of adjunctive LCM in Chinese patients in real-life conditions. Based on our treatment experience, a universal maintenance dose of LCM would be needed in Chinese patients.

Topics: Anticonvulsants; Drug Therapy, Combination; Humans; Lacosamide; Prospective Studies; Seizures; Treatment Outcome

The effectiveness and tolerability of lacosamide (LCM) among Chinese children and adolescents with refractory epilepsy has not yet been established. Therefore, the objective of this study was to assess the effectiveness and tolerability of LCM among children and adolescents with refractory epilepsy in Xinjiang, Northwest China.. Effectiveness was assessed by measuring changes in seizure frequency at 3, 6 and 12 months compared with baseline. Patients that achieved ≥ 50% reduction in the frequency of all seizures per month, relative to baseline, were considered to be responders.. 105 children and adolescents with refractory epilepsy were enrolled in the study. The responder rates were 47.6%, 39.2%, and 31.9%, respectively at 3, 6, and 12 months. Seizure freedom rates were 32.4%, 28.9%, and 23.6% at 3, 6, and 12 months, respectively. The retention rates at 3, 6, and 12 months were 92.4%, 78.1%, and 69.5%, respectively. The maintenance dose of LCM within the responder group (8.2 ± 4.5 mg·kg. This real-world study of children and adolescents validated that LCM was both an effective and well-tolerated treatment option for the treatment of refractory epilepsy.

Topics: Acetamides; Adolescent; Anticonvulsants; Child; Drug Resistant Epilepsy; Drug Therapy, Combination; Humans; Lacosamide; Seizures; Treatment Outcome

To report the long-term efficacy of adjunctive lacosamide therapy in patients with juvenile myoclonic epilepsy whose generalized tonic-clonic seizures were significantly reduced by treatment.. A retrospective study was conducted in patients who visited the Department of Child Neurology, National Hospital Organization Nishiniigata Chuo Hospital and the Department of Pediatrics, National Hospital Organization Nagasaki Medical Center. Among patients who had been diagnosed with juvenile myoclonic epilepsy, those who received lacosamide as adjunctive therapy for refractory generalized tonic-clonic seizures for at least 2 years from January 2017 to December 2022, and who achieved seizure freedom or >50% seizure reduction in tonic-clonic seizures were included. The medical records and neurophysiological data of the patients were reviewed retrospectively.. Four patients met the inclusion criteria. The mean age at the onset of epilepsy was 11.3 years (range 10-12), and the mean age of starting lacosamide was 17.5 years (range 16-21). All patients received two or more antiseizure medications prior to lacosamide. Three of four patients had seizure freedom for more than 2 years, and the one remaining patient had >50% seizure reduction for more than one year. Only one patient had recurrent myoclonic seizures after starting lacosamide. The mean lacosamide dose at the last visit was 425 mg/day (range 300-600).. Adjunctive lacosamide therapy might be a treatment option for juvenile myoclonic epilepsy with generalized tonic-clonic seizures, which are not responsive to standard antiseizure medications.

Topics: Adolescent; Adult; Anticonvulsants; Child; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Humans; Lacosamide; Myoclonic Epilepsy, Juvenile; Retrospective Studies; Seizures; Treatment Outcome; Young Adult

The purpose of this study was to determine the efficacy of lacosamide (LCM) on interictal epileptiform discharges (IEDs) and evaluate the relationships between IEDs and seizure outcome in pediatric patients with focal epilepsy.. Patient inclusion criteria included (1) newly diagnosed focal epilepsy with unknown etiology; and (2) electroencephalogram recorded twice (before and after starting LCM) under the same conditions. The difference between the highest number of IEDs over five successive minutes (IEDs/5 min) and the location of IEDs was determined. Seizure outcome was evaluated one year after achieving the maintenance dose of LCM. Responders were identified as showing a ≥50% reduction in the pre-LCM seizure frequency.. Of 22 patients, 10 showed an increase in IEDs/5 min after starting LCM. The median IEDs/5 min before and after starting LCM was not significantly different, at 1.5 (interquartile range: 0, 31.75) and 10.5 (0, 80.5), respectively. No relationship was identified between the difference in IEDs/5 min and seizure outcome. Patients with multiple regional or diffuse IEDs had significantly poorer seizure outcome compared with patients without those IEDs (P = 0.036 and P = 0.039, respectively). Of 10 patients with single regional IEDs, a tendency of IEDs to disappear was observed between patients with frontal and non-frontal IEDs.. The effects of LCM on the number of IEDs may be unrelated to seizure outcome. LCM may be ineffective at improving seizure outcomes in patients with multiple regional or diffuse IEDs.

Topics: Child; Electroencephalography; Epilepsies, Partial; Humans; Lacosamide; Seizures

Status epilepticus in poststroke epilepsy is a challenging condition because of multiple vascular comorbidities and the advanced age of patients. Data on third-generation antiseizure medication (ASM) in this condition are limited. The aim of this study was to evaluate the efficacy of third-generation ASMs in the second- or third-line therapy of benzodiazepine-refractory status epilepticus in poststroke epilepsy following acute ischemic stroke.. Data on the effectiveness of third-generation ASMs in patients with status epilepticus in poststroke epilepsy were gathered from two German Stroke Registries and the Mainz Epilepsy Registry. We included only cases with epilepsy remote to the ischemic event. No patients with acute symptomatic seizures were included. The following third-generation ASMs were included: brivaracetam, lacosamide, eslicarbazepine, perampanel, topiramate, and zonisamide. The assessment of effectiveness was based on seizure freedom within 48 h since the start of therapy with the respective ASM. Seizure freedom was evaluated both clinically (clinical evaluation at least three times per day) and by daily electroencephalogram records.. Of the 138 patients aged 70.8 ± 8.1 years with benzodiazepine-refractory status epilepticus in ischemic poststroke epilepsy, 33 (23.9%) were treated with lacosamide, 24 (17.4%) with brivaracetam, 23 (16.7%) with eslicarbazepine, 21 (15.2%) with perampanel, 20 (14.5%) with topiramate, and 17 (12.3%) with zonisamide. Seizure freedom within 48 h was achieved in 66.7% of patients with lacosamide, 65.2% with eslicarbazepine, 38.1% with perampanel, 37.5% with brivaracetam, 35.0% with topiramate, and 35.3% with zonisamide (p < 0.05 for comparison of lacosamide or eslicarbazepine to other ASMs).. Based on these data, lacosamide and eslicarbazepine might be more favorable in the treatment of refractory status epilepticus in poststroke epilepsy, when administered as second- or third-line ASMs before anesthesia. Because of the fact that these ASMs share the same mechanism of action (slow inactivation of sodium channels), our findings could motivate further research on the role that this pharmaceutical mechanism of action has in the treatment of poststroke epilepsy.. This study was registered at ClinicalTrials.gov (NCT05267405).

Topics: Aged; Anticonvulsants; Benzodiazepines; Epilepsy; Humans; Ischemic Stroke; Lacosamide; Middle Aged; Retrospective Studies; Seizures; Status Epilepticus; Topiramate; Zonisamide

A 54-year-old South African man with a medical history of type 2 diabetes mellitus, seizure disorder, OSA, and latent TB presented to the ER with gradually progressive dyspnea over months. He also reported occasional dry cough and fatigue at presentation but denied fever, chills, chest pain, leg swelling, palpitations, or lightheadedness. He was treated with a course of levofloxacin for presumed community-acquired pneumonia as an outpatient without improvement and had tested negative for COVID-19. He denied occupational or environmental exposures or sick contacts, though he had traveled back to South Africa 1 year before presentation. He had complex partial seizures for the past 22 years, which had been well controlled on phenytoin (300 mg daily). His other home medications included dulaglutide, sertraline, and atorvastatin and had no recent changes. He quit smoking 30 years ago after smoking one pack per day for 10 years.

Topics: Biopsy; COVID-19; Diagnosis, Differential; Drug Substitution; Dyspnea; Humans; Lacosamide; Lung; Lung Diseases, Interstitial; Male; Middle Aged; Phenytoin; SARS-CoV-2; Seizures; Tomography, X-Ray Computed; Treatment Outcome; Voltage-Gated Sodium Channel Blockers

Childhood epilepsy with centrotemporal spikes (CECTS) is known as age-limited focal epilepsy syndrome in childhood. Lacosamide is a third-generation antiepileptic drug. This study aimed to evaluate the efficacy of lacosamide monotherapy for the treatment of CECTS.. We enrolled 18 patients (6 girls and 12 boys) who met the following criteria: 1) the age of onset of the seizures was between 3 and 13 years of age; 2) showing at least hemifacial and/or oropharyngeal seizures; 3) interictal discharges in central and/or middle temporal electrodes; 4) no intellectual disability; 5) treatment duration of lacosamide monotherapy over 6 months. We retrospectively collected and analyzed clinical data and treatment information. We evaluated the seizure occurrences during 0-3, 4-6, and 7-12 months from the treatment initiation and the last 6 months of the follow-up. We also evaluated the outcomes as seizure-free if the patients developed no seizures both over 6 months and 3 times of pretreatment mean seizure interval at the last follow-up.. Of the patients, 39%, 67% and 72% were seizure-free during 0-3, 4-6, and 7-12 months from treatment initiation, respectively. Finally, 83% of the patients achieved seizure freedom. Seizure freedom was achieved in 72% during the first 4 months of treatment. All patients continued lacosamide monotherapy during the study, although four patients showed transient fatigue or somnolence.. Lacosamide showed good efficacy for controlling seizures with fewer adverse effects, and therefore may be a good candidate as a first-line medication for the treatment of new-onset CECTS.

Topics: Anticonvulsants; Epilepsies, Partial; Female; Humans; Infant; Lacosamide; Male; Retrospective Studies; Seizures; Treatment Outcome

Lacosamide (LCM) is a new generation antiepileptic drug that affects the slow inactivation of voltage-gated sodium channels. We studied whether chronic LCM treatment prior to onset of absence seizures was able to prevent/reduce the development of absence seizures in GAERS rats, a well-validated animal model of absence epilepsy and epileptogenesis. Drug effects on the duration, mean duration, number and spectral characteristics of spike-wave discharges (SWDs) were measured both 1 and 2 months after treatment withdrawal and compared with the ethosuximide (ETX) that has anti-epileptogenic activity in GAERS. Furthermore, the acute effects of LCM on SWDs in adult GAERS were evaluated.. GAERS rats were administered either with LCM (10 mg/kg/day or 30 mg/kg/day, i.p) or ETX (25 mg/kg/day, i.p) or saline (%0.9 NaCl) until PN60 for 40 consecutive days starting from PN20. Animals were stereotaxically implanted with cortical screw electrodes under ketamine/xylazine anesthesia at PN53. Following recovery period, EEG were recorded at PN60 (last day of drug administration)- 61-62, PN90-91-92 and PN120-121-122 time periods for 3 consecutive days.. The chronic treatment with both LCM and ETX led to an ∼50% reduction in the development of spontaneous absence seizures in GAERS at PN90 and PN120 after the treatment withdrawal at PN60. The spectral analysis of EEG data revealed significant slowing of the peak frequency of SWDs in LCM treated animals at PN62.. These results confirm that chronic LCM treatment modifies the development of absence seizures in GAERS and suggest that LCM exerts beneficial effects on absence seizure epileptogenesis.

Topics: Animals; Electroencephalography; Epilepsy, Absence; Ethosuximide; Lacosamide; Rats; Rats, Wistar; Seizures; Sodium Channel Blockers

Lacosamide (LCM) is a third-generation anti-seizure medication (ASM) approved for focal onset epilepsy in patients aged ≥ 4.378 Previous studies have reported an efficacy of LCM as add-on treatment in brain tumor-related epilepsy (BTRE). To date, there are no studies in the literature focusing on lacosamide used in monotherapy to treat BTRE. In our retrospective study we investigated efficacy and tolerability of LCM in monotherapy in a multicenter national cohort of primary brain tumor patients.. We collected from 12 Italian Centers 132 patients with primary brain tumors who were treated with LCM in monotherapy. For each patient we evaluated seizure freedom at 3 and 6 months (primary endpoints), side effects and drop-out rate (secondary endpoints).. Overall, LCM led to seizure freedom in 64.4% of patients at 3 months and 55% at 6 months. Patients who used two or more ASMs before LCM had a worse seizure control than patients in monotherapy with LCM as first choice. In 14 patients, we observed seizure control despite tumor progression on magnetic resonance (MRI). Multivariate analysis showed that gross-total resection at diagnosis was significantly associated with higher seizure freedom rate at 6 months. Side effects were mainly mild (grade 1-2 according to CTCAE classification) and drop-out rate was low (1.5%). Main side effects were dizziness and somnolence.. This is the first study showing a good efficacy and tolerability of LCM when used in monotherapy in BTRE. Further prospective studies are needed to confirm these preliminary data, investigating also quality of life and neurocognitive functions.

Topics: Acetamides; Anticonvulsants; Brain Neoplasms; Drug-Related Side Effects and Adverse Reactions; Epilepsies, Partial; Epilepsy; Humans; Lacosamide; Quality of Life; Retrospective Studies; Seizures; Treatment Outcome

Umbelliferone (7-hydroxycoumarin; UMB) is a coumarin with many biological properties, including antiepileptic activity. This study evaluated the effect of UMB on the ability of classical and novel antiepileptic drugs (e.g., lacosamide (LCM), levetiracetam (LEV), phenobarbital (PB) and valproate (VPA)) to prevent seizures evoked by the 6-Hz corneal-stimulation-induced seizure model. The study also evaluated the influence of this coumarin on the neuroprotective properties of these drugs in two in vitro models of neurodegeneration, including trophic stress and excitotoxicity. The results indicate that UMB (100 mg/kg, i.p.) significantly enhanced the anticonvulsant action of PB (p < 0.01) and VPA (p < 0.05), but not that of LCM orLEV, in the 6-Hz test. Whether alone or in combination with other anticonvulsant drugs (at their ED50 values from the 6-Hz test), UMB (100 mg/kg) did not affect motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength; or passive avoidance tests, respectively. Pharmacokinetic characterization revealed that UMB had no impact on total brain concentrations of PB or VPA in mice. The in vitro study indicated that UMB has neuroprotective properties. Administration of UMB (1 µg/mL), together with antiepileptic drugs, mitigated their negative impact on neuronal viability. Under trophic stress (serum deprivation) conditions, UMB enhanced the neurotrophic abilities of all the drugs used. Moreover, this coumarin statistically enhanced the neuroprotective effects of PB (p < 0.05) and VPA (p < 0.001) in the excitotoxicity model of neurodegeneration. The obtained results clearly indicate a positive effect of UMB on the anticonvulsant and neuroprotective properties of the selected drugs.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electroshock; Lacosamide; Mice; Phenobarbital; Seizures; Umbelliferones

In newly diagnosed neurocysticercosis (NCC) with seizures, the choice of anti-seizure medication (ASM) seems to be arbitrary due to a lack of comparative studies. Although oxcarbazepine (OXC) is often considered efficacious for focal seizures in NCC, due to adverse effects, newer ASMs like levetiracetam (LCM) and lacosamide are also being explored.. This study was performed by case record review of children with newly diagnosed solitary viable parenchymal NCC aged 4-18years who received lacosamide and OXC at least for 12 weeks between August 2019 and April 2021, from a prospective registry of a tertiary care teaching hospital in north India. Seizure control, electroencephalographic abnormalities, resolution of inflammatory granulomas and adverse effects were compared between two arms at 12 and 24 weeks.. Total 31 (8.3 ± 4.7 years, 19 boys) and 72 (8.6 ± 4.2 years, 43 boys) completed at least 12 weeks follow-up in LCM and OXC groups, out of which 2 and 51 completed at least 24 weeks follow-up in LCM and OXC groups, respectively. The occurrence of breakthrough seizure was comparable in both arms at 12 and 24 weeks (1/31 and 2/22 in lacosamide group vs. 2/72 and 4/51 in OXC group, p = 0.66 and 0.59, respectively). Patients receiving OXC had more frequent treatment-emergent adverse events (p = 0.0001) and four patients required discontinuation due to severe adverse events (SAEs), while none in the lacosamide group had SAEs.. Lacosamide appears to be efficacious and safe for achieving seizure freedom in patients with solitary viable parenchymal neurocysticercosis.

Topics: Anticonvulsants; Child; Epilepsies, Partial; Female; Humans; Lacosamide; Levetiracetam; Male; Neurocysticercosis; Oxcarbazepine; Seizures; Treatment Outcome

Status epilepticus (SE) is a life-threatening medical emergency which is frequently encountered in the critical care setting and can be refractory to treatment. Refractory status epilepticus (RSE) is defined as SE that has failed to respond to adequately used first-line and second-line antiepileptic medications. Super refractory status epilepticus is defined as SE that persists for 24 hours or more after the use of an anaesthetic agent or recurs after its withdrawal.If SE persists beyond a period of 7 days it is referred to as prolonged, refractory status epilepticus (PRSE). There are limited data guiding treatment of RSE in the paediatric population.Lacosamide (LCM) is licensed as an adjunctive treatment for partial-onset seizures. Evidence for the efficacy of LCM in paediatric SE is scarce. This case report may suggest a synergistic effect of LCM on slow-activation sodium channels in conjunction with medications such as phenytoin that causes fast inactivation of sodium channels. The dual fast and slow inactivation of sodium channels may enhance the effectiveness in treatment of RSE. This is the first case report of PRSE in an infant, successfully treated with LCM. A brief review of literature is also a part of this report.

Topics: Anticonvulsants; Epilepsia Partialis Continua; Humans; Infant; Lacosamide; Seizures; Status Epilepticus

Most currently available antiepileptics are not fully effective in the prevention of seizures in absence epilepsy owing to the presence of blood-brain barrier (BBB). We aimed to test whether binding an antiepileptic drug, lacosamide (LCM), to glucose-coated gold nanoparticles (GNPs) enables efficient brain drug delivery to suppress the epileptic activity in WAG/Rij rats with absence epilepsy.. In these animals, intracranial-EEG recording, behavioral test, in vivo imaging of LCM and LCM-GNP conjugate distribution in the brain, inductively coupled plasma mass spectrometry analysis, immunofluorescence staining of glucose transporter (Glut)- 1, glial fibrillary acidic protein (GFAP), and p-glycoprotein (P-gp) and electron microscopy were performed.. Lacosamide-GNP conjugates decreased the amplitude and frequency of spike-wave-like discharges (SWDs) and alleviated the anxiety-like behavior as assessed by EEG and elevated plus-maze test, respectively (p < 0.01). The in vivo imaging system results showed higher levels of fluorescein dye tagged to LCM-GNP in the brain during the 5-day injection period (p < 0.01). Immunofluorescence staining displayed decreased P-gp, Glut-1, and GFAP expression by LCM-GNP conjugate treatment predominantly in the cerebral cortex suggesting a potential functionality of this brain region in the modulation of neuronal activity in our experimental setting (p < 0.01).. We suggest that the conjugation of LCM to GNPs may provide a novel approach for efficient brain drug delivery in light of the effectiveness of our strategy not only in suppressing the seizure activity but also in decreasing the need to use high dosages of the antiepileptics to reduce the frequently encountered side effects in drug-resistant epilepsy.

Topics: Animals; Anticonvulsants; Blood-Brain Barrier; Disease Models, Animal; Electroencephalography; Epilepsy, Absence; Gold; Lacosamide; Metal Nanoparticles; Rats; Seizures

Specific antiseizure medications (ASM) would improve the outcome in post-stroke epilepsy (PSE). The aim of this multicenter observational study was to compare different antiseizure monotherapies in PSE.. We collected the data from 207 patients with PSE who did not change their initial antiseizure monotherapy during the period of 12 months. Efficacy was assessed by a standardized three month seizure frequency and seizure freedom. Safety was estimated by the reported side effects.. The mean three month seizure frequency was 1.9 ± 3.1 on eslicarbazepine, 2.1 ± 3.2 on lacosamide, 3.4 ± 4.4 on levetiracetam, 4.3 ± 6.8 on lamotrigine, and 5.1 ± 7.3 on valproate (p < 0.05 for eslicarbazepine or lacosamide in comparison with levetiracetam, lamotrigine and valproate, respectively). The lowest seizure frequency and the highest seizure freedom was observed on ASMs acting via the slow inactivation of sodium channels in comparison to other mechanisms of action (0.7 ± 0.9 vs 2.2 ± 2.4, p < 0.01). Among side effects, the most frequently reported were vertigo (25%) and tiredness (15.9%). They were similar in all investigated groups of ASM. The independent factors increasing seizure frequency that were identified in multiple regression analyses were increased size of infarction, cortical involvement, hemorrhagic transformation, neurological deficits at admission and functional impairment. Administration of ASM with the mechanism of action via the slow inactivation of sodium channels was an independent factor decreasing the seizure frequency.. Our data show that antiseizure medications acting via the slow inactivation of sodium channels, such as lacosamide and eslicarbazepine, are well tolerated and might be associated with better seizure control in PSE.

Topics: Anticonvulsants; Epilepsies, Partial; Epilepsy; Humans; Lacosamide; Lamotrigine; Levetiracetam; Seizures; Sodium Channels; Stroke; Valproic Acid

Drug treatment for children with epilepsy should, ideally, be governed by evidence from adequate and well-controlled clinical studies. However, these studies are difficult to conduct, and so direct evidence supporting the informed use of specific drugs is often lacking. The Research Roundtable for Epilepsy (RRE) met in 2020 to align on an approach to therapy development for focal seizures in children age 1 month <2 years of age.. The RRE reviewed the regulatory landscape, epidemiology, seizure semiology, antiseizure medicine pharmacology, and safety issues applicable to this population.. After reviewing evidence, the conclusion was that pediatric efficacy trials would be impracticable to conduct but a waiver of the regulatory requirement to conduct any study would lead to an absence of information to guide dosing in a critical population. Review of available data and discussion of RRE attendees led to the conclusion that the requirements for extrapolation of efficacy from older children down to infants from age 1 month to <2 years old appeared to be met. After the RRE, the US Food and Drug Administration (FDA) approved brivaracetam for use in children with focal epilepsy above the age of 1 month in August 2021 and lacosamide in October 2021, both based on the principle of extrapolation from data in older children.. These recommendations should result in more rapid accessibility of antiseizure medications for infants.

Topics: Adolescent; Anticonvulsants; Child; Epilepsies, Partial; Epilepsy; Humans; Infant; Lacosamide; Seizures

Lacosamide is a novel antiepileptic drug. Although many antiepileptic drugs reportedly pose a risk to fetuses, patients with epilepsy are advised to continue their medications during pregnancy. There have been few reports on lacosamide use during pregnancy, and its effects on the fetus remain unclear. Here, we report a case of lacosamide use during pregnancy. The 33-year-old patient was treated with oral lacosamide (400 mg/d) for symptomatic partial epilepsy. She was concomitantly treated with folic acid (5 mg/d) beginning 4 days before her last menstrual cycle. She was also concomitantly treated with oral perampanel (2 mg/d) at 5-7 weeks' gestation for seizure control but discontinued perampanel after the pregnancy was discovered. She progressed through her pregnancy with only mild seizures. Fetal growth was normal and ultrasonography revealed no external malformations. The patient had an elective cesarean section at 37 weeks and 2 days owing to a previous post-cesarean pregnancy. Her baby boy weighed 3025 g; his Apgar score was 8 and 9, 1 and 5 min, respectively, and his umbilical artery blood pH was 7.348. He had no congenital anomalies and no neonatal drug withdrawal symptoms. This suggests that lacosamide may have a low risk of teratogenicity and fetal toxicity. Thus, this case is valuable for clinicians who are considering the administration of antiepileptic drugs during pregnancy. In the future, more reports on the use of lacosamide during pregnancy should be collected.

Topics: Adult; Anticonvulsants; Cesarean Section; Epilepsy; Female; Humans; Infant; Lacosamide; Male; Pregnancy; Seizures; Treatment Outcome

Many seizing neonates fail to respond to first-line anticonvulsant medications. Phenobarbital, an allosteric modulator of γ-aminobutyric acid type A (GABA. In vitro, we measured the effect of different lacosamide concentrations on seizure-like activity induced by the pro-convulsant drug 4-aminopyridine in neocortical brain slices (layer IV/V) from neonatal (postnatal day 8-11) and adult (1-1.6 months old) C57BL/6J mice. In vivo, we recorded the effect of different lacosamide concentrations on neonatal behavioral seizures induced by kainic acid. We studied neocortical apoptosis in vitro and in vivo, measuring terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling signal and cleaved-caspase 3.. Lacosamide reduced epileptiform activity in neocortical brain slices of neonates and adults in a concentration-dependent manner. In vivo, lacosamide reduced the duration and number of behavioral seizures. Lacosamide did not increase total or neuronal apoptosis in the neocortex in vitro or in vivo.. Lacosamide reduces neocortical seizure-like activity in neonatal mice in vitro and in vivo without an acute increase in apoptosis. Our results support the use of lacosamide to treat neonatal seizures, with the advantage of not increasing apoptosis acutely.

Topics: Animals; Apoptosis; gamma-Aminobutyric Acid; Lacosamide; Mice; Mice, Inbred C57BL; Seizures

Lacosamide is characterized by its novel dual mode of action on account of its structural components; its molecule contains a functional amino acid that selectively and slowly promotes the inactivation of voltage-gated sodium channels.. This study aims to assess the effectiveness and tolerability of Lacosamide with respect to its use in the treatment of focal epileptic patients.. This retrospective cohort study used data collected from the clinical notes or diaries of all epileptic patients who were treated in King Abdullah Medical City during the time period from 2014 to 2019. The multivariate Generalized Estimating Equation (GEE) repeated measure logistic regression analysis was used to assess the odds of having an improvised seizure rate.. Majority of the focal epileptic patients (57.9%) were diagnosed with temporal epilepsy, while 26.3% patients had frontal epileptic lesion/diagnoses. Majority of the patients (54.4%) had received a combination of old and new treatment. Out of the seven patients who reported side effects, 57.14% experienced dizziness and headache, tremors (n = 1), loss of balance (n = 1) and increased seizure with abnormal vision acuity and psychosis (n = 1). 84.2% patients experienced reduced median seizure frequency in 12-month period. However, on the basis of clinical characteristics, no significant difference was observed in the seizure control rate. No statistically significant differences were observed between male and female patients with respect to their average improvement rate across the four time points.. Lacosamide is an effective and well tolerable drug for patients with focal epilepsy.

Topics: Adult; Anticonvulsants; Cohort Studies; Epilepsies, Partial; Female; Humans; Lacosamide; Male; Middle Aged; Retrospective Studies; Saudi Arabia; Seizures; Treatment Outcome; Young Adult

Topics: Anticonvulsants; Humans; Lacosamide; Seizures

The antiepileptic drug lacosamide (LCM) is approved in the United States and the European Union as monotherapy as well as adjunctive therapy for the treatment of focal seizures in children ≥4 years of age and adults. Using real-world therapeutic drug monitoring data, we performed a pharmacometric analysis for 315 pediatric patients (>1 month to <18 years of age) who received lacosamide as both monotherapy and adjunctive therapy. Population pharmacokinetic modeling was performed using nonlinear mixed-effects modeling with a 1-compartment structural model with linear elimination, where clearance and volume of distribution were allometrically scaled for body weight, with no further need for age-associated maturation functions. A covariate analysis for age, sex, race, and coadministration of other antiepileptic drugs identified phenobarbital and felbamate to significantly increase lacosamide clearance (1.71- and 1.46-fold, respectively). Based on the developed population pharmacokinetic model, simulations were performed in virtual pediatric patients to explore age-associated dose requirements to match lacosamide exposure in patient groups of different age with the exposure achieved in children ≥4 year of age with the weight-based dosing recommendations provided by the US Food and Drug Administration. Based on this approach, our analysis suggested that children ≥3 years of age needed the same dose as recommended by the US Food and Drug Administration for children ≥4 years of age (12 mg/kg/d), while children 1 to 3 years of age may need 13 to 14 mg/kg/d and infants between 1 month and 1 year of age may need 15 to 18 mg/kg/d (based on their actual age) to match the exposure seen in children ≥4 years of age.

Topics: Adolescent; Age Factors; Anticonvulsants; Body Weight; Child; Child, Preschool; Drug Interactions; Drug Therapy, Combination; Electronic Health Records; Humans; Infant; Lacosamide; Metabolic Clearance Rate; Models, Biological; Racial Groups; Retrospective Studies; Seizures; Sex Factors

Status epilepticus (SE) is a neurological disorder characterized by a prolonged epileptic activity followed by subsequent epileptogenic processes. The aim of the present study was to evaluate the early effects of topiramate (TPM) and lacosamide (LCM) treatment on oxidative stress and inflammatory damage in a model of pilocarpine-induced SE.. Male Wistar rats were randomly divided into six groups and the two antiepileptic drugs (AEDs), TPM (40 and 80 mg/kg, i.p.) and LCM (10 and 30 mg/kg, i.p.), were injected three times repeatedly after pilocarpine administration. Rats were sacrificed 24 h post-SE and several parameters of oxidative stress and inflammatory response have been explored in the hippocampus.. The two drugs TPM and LCM, in both doses used, succeeded in attenuating the number of motor seizures compared to the SE-veh group 30 min after administration. Pilocarpine-induced SE decreased the superoxide dismutase (SOD) activity and reduced glutathione (GSH) levels while increasing the catalase (CAT) activity, malondialdehyde (MDA), and IL-1β levels compared to the control group. Groups with SE did not affect the TNF-α levels. The treatment with a higher dose of 30 mg/kg LCM restored to control level the SOD activity in the SE group. The two AEDs, in both doses applied, also normalized the CAT activity and MDA levels to control values. In conclusion, we suggest that the antioxidant effect of TPM and LCM might contribute to their anticonvulsant effect against pilocarpine-induced SE, whereas their weak anti-inflammatory effect in the hippocampus is a consequence of reduced SE severity.

Topics: Animals; Anticonvulsants; Biomarkers; Hippocampus; Inflammation; Interleukin-1beta; Lacosamide; Male; Motor Activity; Oxidative Stress; Pilocarpine; Rats, Wistar; Reactive Oxygen Species; Seizures; Status Epilepticus; Topiramate; Tumor Necrosis Factor-alpha

A 20-year-old man with drug-resistant generalized epilepsy (GE) was admitted for video electroencephalography (vEEG) monitoring under treatment with multiple antiepileptic drugs, including levetiracetam (3,000 mg/day), valproic acid (800 mg/day), and lacosamide (LCM) (100 mg/day). No seizures were noted after the withdrawal of levetiracetam. However, after the withdrawal of LCM, atypical absence seizures with a 2- to 2.5-Hz generalized spike and wave complex frequently appeared, followed by subsequent generalized-onset tonic-clonic seizures. After re-administration of LCM, the seizures and epileptic discharges clearly disappeared. Subsequent LCM titration was successful in achieving a seizure-free status. Our vEEG results suggest that LCM may be a worthwhile antiepileptic drug adjunct in refractory GE patients without a risk of worsening absence seizures.

Topics: Adult; Anticonvulsants; Electroencephalography; Epilepsy, Generalized; Humans; Lacosamide; Male; Seizures; Young Adult

Combination therapy with two or three antiseizure medications (ASMs) is sometimes a preferred method of treatment in epilepsy patients. (1) Background: To detect the most beneficial combination among three ASMs, a screen test evaluating in vivo interactions with respect to their anticonvulsant properties, was conducted on albino Swiss mice; (2) Methods: Classification of interactions among lacosamide (LCM) and selected second-generation ASMs (lamotrigine (LTG), pregabalin (PGB), oxcarbazepine (OXC), and topiramate (TPM)) was based on the isobolographic analysis in the mouse maximal electroshock-induced seizure (MES) model. Interactions among LCM and second-generation ASMs were visualized using a polygonogram; (3) Results: In the mouse MES model, synergy was observed for the combinations of LCM + TPM + PGB and LCM + OXC + PGB. Additivity was reported for the other combinations tested i.e., LCM + LTG + TPM, LCM + LTG + PGB, LCM + LTG + OXC, and LCM + OXC + TPM in this seizure model. No adverse effects associated with triple ASM combinations, containing LCM and second-generation ASMs were observed in mice; (4) Conclusions: The combination of LCM + TPM + PGB was the most beneficial combination among the tested in this study, offering synergistic suppression of tonic-clonic seizures in mice subjected to the MES model. Both the isobolographic analysis and polygonogram method can be recommended for experimental epileptology when classifying interactions among the ASMs.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Drug Interactions; Drug Synergism; Drug Therapy, Combination; Electroshock; Epilepsy; Lacosamide; Lamotrigine; Male; Mice; Oxcarbazepine; Pregabalin; Seizures; Topiramate

Optimal treatment with antiepileptic drugs (AEDs) is an important part of care for brain tumor patients with epileptic seizures. Lamotrigine and lacosamide are both examples of frequently used non-enzyme inducing AEDs with limited to no drug-drug interactions, reducing the risk of unfavorable side effects. This study aimed to compare the effectiveness of lamotrigine versus lacosamide.. In this multicenter study we retrospectively analyzed data of patients with diffuse grade 2-4 glioma with epileptic seizures. All patients received either lamotrigine or lacosamide during the course of their disease after treatment failure of first-line monotherapy with levetiracetam or valproic acid. Primary outcome was the cumulative incidence of treatment failure, from initiation of lamotrigine or lacosamide, with death as competing event, for which a competing risk model was used. Secondary outcomes were uncontrolled seizures after AED initiation and level of toxicity.. We included a total of 139 patients of whom 61 (44%) used lamotrigine and 78 (56%) used lacosamide. At 12 months, there was no statistically significant difference in the cumulative incidence of treatment failure for any reason between lamotrigine and lacosamide: 38% (95%CI 26-51%) versus 30% (95%CI 20-41%), respectively. The adjusted hazard ratio for treatment failure of lacosamide compared to lamotrigine was 0.84 (95%CI 0.46-1.56). The cumulative incidences of treatment failure due to uncontrolled seizures (18% versus 11%) and due to adverse events (17% versus 19%) did not differ significantly between lamotrigine and lacosamide.. Lamotrigine and lacosamide show similar effectiveness in diffuse glioma patients with epilepsy.

Topics: Anticonvulsants; Epilepsy; Glioma; Humans; Lacosamide; Lamotrigine; Retrospective Studies; Seizures; Treatment Outcome

We report the case of a previously healthy newborn who developed super-refractory status epilepticus after Group B streptococcal meningoencephalitis. After administration of first-, second- and third-line anticonvulsants without resolution of status epilepticus, we started intravenous lacosamide as adjunctive therapy to phenobarbital, phenytoin and continuous infusion of ketamine and midazolam. After administration of lacosamide, we observed a clear-cut improvement in the neurological clinical condition coupled with seizure control on continuous video-EEG monitoring, even after suspension of all other medications except for phenobarbital. No adverse effects ascribable to lacosamide were reported. The available data regarding the use of lacosamide for status epilepticus in adults and children are promising, although there is as yet only anecdotal evidence for neonatal status epilepticus. Its lack of potential interactions, good tolerability and the option of intravenous use lend to its appeal as treatment for status epilepticus. To the best of our knowledge, this is one of the first reported cases of effective lacosamide infusion in neonatal-onset super-refractory status epilepticus. This evidence should prompt further investigation on efficacy and safety of lacosamide to support its use in this population.

Topics: Anticonvulsants; Humans; Infant, Newborn; Lacosamide; Phenobarbital; Seizures; Status Epilepticus

The primary objective of this trial (SP1042; NCT02582866) was to assess long-term safety and tolerability of lacosamide monotherapy (200-600 mg/day) in adults with focal (partial-onset) seizures or generalized tonic-clonic seizures (without clear focal origin). This Phase III, long-term, open-label, multicenter, follow-up trial enrolled patients with epilepsy who were taking lacosamide in, and completed, the previous double-blind trial (SP0994; NCT01465997). Primary safety outcomes were treatment-emergent adverse events (TEAEs), discontinuations due to TEAEs, and serious TEAEs. One hundred and six patients were enrolled and received lacosamide: 84 (79.2%) completed the trial and 22 (20.8%) discontinued. The median duration of exposure was 854.0 days, with a median modal dose of 200 mg/day. Ninety-six (90.6%), 64 (60.4%), and 44 (41.5%) patients had ≥12, ≥24, and ≥36 months of lacosamide exposure, respectively. At least one TEAE was reported by 61 (57.5%) patients. The most common (≥4%) TEAEs were headache (10 [9.4%]), nasopharyngitis (eight [7.5%]), and back pain (five [4.7%]). One (0.9%) patient discontinued due to a TEAE (sudden unexpected death in epilepsy; not considered drug-related), 14 (13.2%) patients reported serious TEAEs, and seven (6.6%) patients reported TEAEs that were considered drug-related. Overall, long-term lacosamide monotherapy was generally well tolerated up to 600 mg/day, with no new safety signals identified.

Topics: Adult; Anticonvulsants; Epilepsy; Humans; Lacosamide; Seizures; Treatment Outcome

Still considered a new ASD, teratogenicity from lacosamide (LCM) exposure during pregnancy is unknown. LCM metabolism through several cytochrome P450 enzymes and minor glucuronidation metabolism in the liver may increase during pregnancy and theoretically lead to lower LCM levels during pregnancy and the risk of increased seizures. Our objective was to determine the impact of pregnancy on serum LCM levels in a series of women with epilepsy (WWE). We identified seven pregnancies with exposure to LCM with at least one level drawn during pregnancy. Patient ages ranged from 18 to 38 years (mean 26.4 years) and total daily doses of LCM ranged from 200 to 600 mg/day. Two patients had increased dose adjustments in response to breakthrough seizures. Dose normalized concentrations (DNC) showed an overall decrease over time through each trimester (p = 0.002) and significantly lower during trimester 2 and 3 (p = 0.001 and p = 0.004, respectively) compared to pre-pregnancy levels. There were no significant changes in seizure frequency and none of the neonates had teratogenic findings at time of birth. We are the first to report a case series on the changes in LCM levels during pregnancy with significant decreased LCM DNC levels during the second and third trimesters in comparison to pre-pregnancy values.

Topics: Adolescent; Adult; Anticonvulsants; Epilepsy; Female; Humans; Infant, Newborn; Lacosamide; Pregnancy; Seizures; Young Adult

Comorbid conditions in persons with epilepsy (PWE) are very common with depression being highly prevalent. Lacosamide (LCM) is used to treat patients with seizures, but the underlying pathways associating the seizures and comorbid depression are still unknown. Kynurenine pathway (KP) has a major role in seizures, inflammation as well as depression, considering which we evaluated the effect of LCM on kynurenine levels in murine model of neuroinflammation-mediated seizures. We then evaluated the effects on the depressive symptoms associated with seizures. Lipopolysaccharide (LPS) primed pilocarpine (PILO) is an established model for neuro-inflammation-mediated seizures. The anti-seizure and anti-depressive effects of 21 days of LCM administration were studied in this model. After 24 h of seizure termination, behavioral parameters viz. forced swimming test and sucrose preference test were performed to study its antidepressant effect. Biochemical estimations of levels of kynurenine, inflammatory cytokines, and oxidative markers were also evaluated. Lacosamide significantly reduced hippocampal kynurenine levels in LPS and LPS + PILO groups but did not show significant reduction in the PILO alone group. Levels of inflammatory cytokines and oxidative stress markers were also reduced significantly. Lacosamide has shown positive effects against neuroinflammation-mediated model of seizures comorbid with depression by reducing hippocampal kynurenine levels. No reduction in the PILO group is suggestive of the principal contribution of its anti-inflammatory and antioxidant activity in its anti-seizure potential in this model via KP.

Topics: Animals; Depression; Humans; Kynurenine; Lacosamide; Mice; Mice, Inbred C57BL; Seizures

In our recent studies, we identified compound N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) as a broad-spectrum hybrid anticonvulsant which showed potent protection across the most important animal acute seizure models such as the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (s.c. PTZ) test, and the 6-Hz (32 mA) test in mice. Therefore, AS-1 may be recognized as a candidate for new anticonvulsant effective in different types of human epilepsy with a favorable safety margin profile determined in the rotarod test in mice. In the aim of further pharmacological evaluation of AS-1, in the current study, we examined its activity in the 6-Hz (44 mA) test, which is known as the model of drug-resistant epilepsy. Furthermore, we determined also the antiseizure activity in the kindling model of epilepsy induced by repeated injection of pentylenetetrazole (PTZ) in mice. As a result, AS-1 revealed relatively potent protection in the 6-Hz (44 mA) test, as well as delayed the progression of kindling induced by repeated injection of PTZ in mice at doses of 15 mg/kg, 30 mg/kg, and 60 mg/kg. Importantly, the isobolographic analysis showed that a combination of AS-1 and valproic acid (VPA) at the fixed ratio of 1:1 displayed a supra-additive (synergistic) interaction against PTZ-induced seizures in mice. Thus, AS-1 may be potentially used in an add-on therapy with VPA. Moreover, incubation of zebrafish larvae with AS-1 substantially decreased the number, cumulative but not the mean duration of epileptiform-like events in electroencephalographic assay. Finally, the in vitro ADME-Tox studies revealed that AS-1 is characterized by a very good permeability in the parallel artificial membrane permeability assay test, excellent metabolic stability on human liver microsomes (HLMs), no significant influence on CYP3A4/CYP2D6 activity, and moderate inhibition of CYP2C9 in a concentration of 10 μM, as well as no hepatotoxic properties in HepG2 cells (concentration of 10 μM).

Topics: Animals; Anticonvulsants; Behavior, Animal; Dose-Response Relationship, Drug; Epilepsy; Ethosuximide; Lacosamide; Levetiracetam; Male; Mice; Pentylenetetrazole; Pyrrolidines; Seizures; Valproic Acid; Zebrafish

Epilepsy remains challenging to treat still no etiologic treatment has been identified, however, some antiepileptic drugs (AEDs) are able to modify the pathogenesis of the disease. Lacosamide (LCM) has been shown to possess complex anticonvulsant and neuroprotective actions, being an enhancer of the slow inactivation of voltage-gated sodium channels, and it has the potential to prevent epileptogenesis. Recent evidence has shown that LCM indirectly improves the function of GABAA receptors. Receptors at most GABAergic synapses involve the gamma-2 subunit, which contributes to both phasic and tonic inhibition, and its presence assures benzodiazepine sensitivity. Moreover, mutant gamma-2 subunits were associated with generalized epilepsy syndromes. In animal models, the expression of the gamma-2 subunit of the gamma-aminobutyric acid A receptor (GABAAg2) was shown to be increased in pentylenetetrazole (PTZ)-induced chemical kindling in Wistar rats.. This study hypothesized that LCM might affect the kindling process by influencing the expression of GABAA receptors in the hippocampus.. The gene and protein expression levels of the GABAAg2 were studied using RT-qPCR and immunofluorescent staining.. It was found that LCM treatment (10 mg/kg i.p. daily for 57 days) reduced the maximal intensity of the PTZ-induced seizures but did not prevent kindling. On the other hand, LCM treatment reverted the increase of mRNA expression of GABAAg2 in the hippocampus and prevented the decrease of GABAAg2 protein in the hippocampal CA1 region.. LCM could exhibit modulatory effects on the GABAergic system of the hippocampus that may be independent of the anticonvulsant action.

Topics: Animals; Anticonvulsants; Convulsants; Gene Expression Regulation; Hippocampus; Kindling, Neurologic; Lacosamide; Male; Microscopy, Confocal; Nerve Tissue Proteins; Pentylenetetrazole; Protein Subunits; Rats; Rats, Wistar; Receptors, GABA-A; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Seizures

Ring chromosome 20 syndrome is a rare chromosomal disorder characterized by refractory seizure, mental retardation, and behavioral problems. Although there are reports of the effective treatment of patients with antiepileptic drugs (AEDs), no study has reported the effects of lacosamide(LCM) in children with this syndrome. We report a 7-year-old boy with this syndrome whose refractory and behavioral abnormalities have been remarkably improved by treatment with LCM.. The patient was a 7-year-old boy with no medical or family history of epilepsy. He developed epilepsy with cessation of movement and derivation of the eyes followed by hyperkinetic seizures that made him squeak strangely and cling to his parents. The seizures lasted for less than a minute and were frequent (they occurred more than 30 times a day), particularly at night. Behavioral abnormalities such as hyperactivity also presented. Brain magnetic resonance imaging revealed no structural abnormalities, but an interictal electroencephalogram (EEG) indicated spikes and waves in the frontal lobe dominantly, and ictal single-photon emission computed tomography (SPECT) revealed a blood flow increase in the bilateral orbital frontal area in comparison to interictal SPECT. After chromosome examination, we diagnosed the patient with ring chromosome 20 syndrome (4/30 mosaic). Carbamazepine was ineffective, and seizures were exacerbated with levetiracetam (LEV). LCM was added to the treatment regimen with valproic acid (VPA) and lamotrigine (LTG); consequently, the seizures disappeared, and EEG results also improved. The patient's behavioral disorders, such as hyperactivity, were improved, and he was able to return to elementary school.. Although VPA and LTG are generally effective for the treatment of ring chromosome 20 syndrome, they do not completely suppress seizures. LCM can be considered an effective option for seizure control in patients with this syndrome.

Topics: Anticonvulsants; Carbamazepine; Child; Electroencephalography; Epilepsy; Humans; Lacosamide; Lamotrigine; Levetiracetam; Male; Ring Chromosomes; Seizures; Treatment Outcome; Valproic Acid

Benign convulsions with gastroenteritis are characterized by a cluster of seizures. Sodium channel blockers are efficacious. We prescribed lacosamide, a new channel blocker, for five patients. Patient age ranged from 17 to 33 months; all five experienced 1-4 generalized convulsions persisting for 30-120 s. One patient exhibited a transient splenial lesion on head magnetic resonance imaging. All received one dose (2 mg/kg) of lacosamide. The convulsions ceased, and no adverse drug effect was noted. A single dose of lacosamide was effective and well-tolerated in five patients with benign convulsions with gastroenteritis.

Topics: Child, Preschool; Female; Gastroenteritis; Humans; Infant; Lacosamide; Male; Seizures; Voltage-Gated Sodium Channel Blockers

Pharmacotherapy with two antiepileptic drugs in combination is usually prescribed to epilepsy patients with refractory seizures. The choice of antiepileptic drugs in combination should be based on synergistic cooperation of the drugs with respect to suppression of seizures. The selection of synergistic interactions between antiepileptic drugs is challenging issue for physicians, especially, if 25 antiepileptic drugs are currently available and approved to treat epilepsy patients. The aim of this study was to determine all possible interactions among 5 second-generation antiepileptic drugs (gabapentin (GBP), lacosamide (LCM), levetiracetam (LEV), pregabalin (PGB) and retigabine (RTG)) in the 6-Hz corneal stimulation-induced seizure model in adult male albino Swiss mice. The anticonvulsant effects of 10 various two-drug combinations of antiepileptic drugs were evaluated with type I isobolographic analysis associated with graphical presentation of polygonogram to visualize the types of interactions. Isobolographic analysis revealed that 7 two-drug combinations of LEV+RTG, LEV+LCM, GBP+RTG, PGB+LEV, GBP+LEV, PGB+RTG, PGB+LCM were synergistic in the 6-Hz corneal stimulation-induced seizure model in mice. The additive interaction was observed for the combinations of GBP+LCM, GBP+PGB, and RTG+LCM in this seizure model in mice. The most beneficial combination, offering the highest level of synergistic suppression of seizures in mice was that of LEV+RTG, whereas the most additive combination that protected the animals from seizures was that reporting additivity for RTG+LCM. The strength of interaction for two-drug combinations can be arranged from the synergistic to the additive, as follows: LEV+RTG > LEV+LCM > GBP+RTG > PGB+LEV > GBP+LEV > PGB+RTG > PGB+LCM > GBP+LCM > GBP+PGB > RTG+LCM.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Electroshock; Gabapentin; Lacosamide; Levetiracetam; Male; Mice; Muscle Strength; Seizures

Launching polytherapy with two or three antiseizure drugs (ASDs) in patients with epilepsy is still problematic. The choice of ASDs to combine them together is usually based on clinicians' experience and it requires knowledge about mechanisms of action of the studied ASDs and their drug-drug interactions, whose nature may be favorable, neutral or unfavorable. To characterize three-drug interaction among lacosamide (LCM), lamotrigine (LTG) and valproate (VPA), the type I isobolographic analysis was used. The antiseizure effects of three-drug combination were analyzed in a model of maximal electroshock-induced seizures (MES) in albino Swiss mice.. The seizure activity in mice was evoked by alternating current stimulation (25 mA, 500 V, 50 Hz, 0.2 s). Both, the type I isobolographic analysis and the test of parallelism of dose-response effects of the ASDs were used so as to properly classify interaction among three ASDs, administered in a fixed ratio combination of 1:1:1.. The three-drug mixture of LCM, LTG and VPA at the fixed ratio of 1:1:1 protected the experimental mice from MES-induced seizures; however, the reported interaction was sub-additive (antagonistic; p < 0.01) with isobolography.. The antagonistic pharmacodynamic interaction among LCM, LTG and VPA in the MES test in mice cannot be transferred to clinical settings and this unfavorable combination should not be recommended for patients with epilepsy.

Topics: Animals; Anticonvulsants; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Drug Therapy, Combination; Electroshock; Epilepsy; Lacosamide; Lamotrigine; Male; Mice; Seizures; Valproic Acid

The objective of this study was to evaluate all-cause and epilepsy-specific healthcare resource utilization and costs following lacosamide (LCM) initiation as adjunctive therapy for the treatment of epilepsy.. A noninterventional retrospective database analysis was conducted that examined patients diagnosed as having epilepsy who added LCM to existing antiepileptic drug (AED) therapy between 2009 and 2016 (the first LCM prescription was the index event). This study used a single-case design whereby patients served as their own controls. Patients were further required to have a minimum of 12 months of continuous eligibility before (preindex period) and after (postindex period) their index event. In the 12-month postindex period, the only allowed AED regimen change was the addition of LCM. Demographic and clinical characteristics were measured at index and during the preindex period, respectively. All-cause and epilepsy-specific healthcare resource utilization and costs were measured and compared in the pre- and postindex periods. Paired t- and McNemar's tests were conducted to assess the significant differences between pre- and postindex. Univariate analyses were used to analyze the impact of LCM on specific subpopulations.. The study sample comprised of 2171 patients: mean (standard deviation [SD]) age: 38.9 (19.3) years; 52.6% female. Just over half (56%) of these patients were on monotherapy before adding LCM. Prior to adding LCM, 28.8% of patients had an epilepsy-specific inpatient (IP) admission, and 35.7% of patients had an all-cause IP admission, compared with 18.2% and 26.1% of patients in the post-LCM period, respectively (both p < 0.0001). Likewise, 35.6% of patients had an epilepsy-specific emergency room (ER) visit, and 50.0% had an all-cause ER visit prior to adding LCM, compared with 23.8% and 42.1% in post-LCM, respectively (both p < 0.0001). After adding LCM, one-year mean [SD] epilepsy-specific IP admission costs decreased by 42.9% ($13,647 [$52,290] to $7788 [$32,321]), and all-cause IP admission costs decreased by 38.6% ($20,654 [$72,716] to $12,688 [$46,120]) (both p < 0.0001). One-year epilepsy-specific mean [SD] ER costs decreased by 35.2% ($691 [$1756] to $448 [$1909]; p < 0.0001), and all-cause ER cost decreased by 17.8% ($1217 [$3014] to $1000 [$2970]; p < 0.01).. Epilepsy-related IP hospitalizations and ER visits (indicators of seizures) were significantly reduced in patients with epilepsy 12 months after adding LCM as an adjunctive therapy to existing AED treatment in a real-world setting, leading to reduced healthcare resource utilization and epilepsy costs.

Topics: Adult; Anticonvulsants; Drug Therapy, Combination; Epilepsy; Female; Health Resources; Hospitalization; Humans; Lacosamide; Longitudinal Studies; Male; Middle Aged; Patient Acceptance of Health Care; Retrospective Studies; Seizures; United States; Young Adult

To assess the effectiveness and tolerability of lacosamide in paediatric clinical practice.. A search of our hospital's pharmacy database yielded all children <16 years old dispensed lacosamide for drug-resistant epilepsy between January 2011 and June 2016. Medical records were reviewed for clinical and drug details. Continued treatment for ≥12 months was considered an indicator of effectiveness and tolerability.. A total of 107 children (61 boys) satisfied inclusion criteria. Median age at lacosamide commencement was 9.9 years (interquartile range 6.7-13.7). Of those children, 57 (53%) children had focal epilepsy, with focal motor or impaired awareness seizures most commonly reported; 50 (47%) children had generalised epilepsy, most with tonic-clonic seizures, tonic seizures or epileptic spasms; 83 (78%) children had an intellectual disability, 24 (22%) had a physical disability and 22 (21%) had an autism spectrum disorder; 69 (65%) children continued lacosamide for ≥12 months. Reasons for discontinuation before 12 months in 38 (35%) children included ineffectiveness in 25 (66%), adverse events in 7 (18%) and worsening of seizures in 2 (5%). The most common adverse events were drowsiness, behavioural changes, unsteadiness, nausea and vomiting. Epilepsy type and comorbidities were not associated with continuation or reasons for discontinuation.. Most children continued treatment with lacosamide, suggesting effectiveness and tolerability. Lacosamide may prove to be a useful, 'broad-spectrum' antiepileptic medication in children for focal and generalised epilepsies and in association with comorbidities.

Topics: Anticonvulsants; Child; Databases, Factual; Drug Resistant Epilepsy; Female; Humans; Lacosamide; Male; Seizures; Treatment Outcome

Recently, we have reported that while agomelatine (Ago) is unable to prevent development of epilepsy it exerts a strong neuroprotective and anti-inflammatory response in the KA post-status epilepticus (SE) rat model. In the present study, we aimed to explore whether the brain-derived neurotrophic factor (BDNF) in the hippocampus is involved in the neuroprotective effect of Ago against the KA-induced SE and epileptiform activity four months later in rats. Lacosamide (LCM) was used as a positive control. The EEG-recorded seizure activity was also evaluated in two treatment protocols. In Experiment#1, Ago given repeatedly at a dose of 40 mg/kg during the course of SE was unable neither to modify EEG-recorded epileptiform activity nor the video- and EEG-recorded spontaneous seizures four months later compared to LCM (50 mg/kg). However, both Ago and LCM inhibited the expression of BDNF in the mossy fibers and also prevented neuronal loss in the dorsal hippocampal and the piriform cortex after SE. In Experiment#2, acute injection of Ago and LCM on epileptic rats, characterized by high seizure rates, did not prevent EEG-recorded paroxysmal events while only LCM decreased either absolute or relative powers of gamma (28-60 Hz) and high (HI) (60-120 Hz) frequency bands to baseline in the frontal and parietal cortex, respectively. Our results suggest that the protection against neuronal loss in specific limbic regions and overexpressed BDNF in the mossy fibers resulting from the repeated treatment with Ago and LCM, respectively, during SE is not a prerequisite for alleviation of epileptogenesis and development of epilepsy. In addition, a reduction of gamma and HI bands in the frontal and parietal cortex is not associated with EEG-recorded paroxysmal events after acute injection of LCM.

Topics: Acetamides; Animals; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Electroencephalography; Epilepsy, Temporal Lobe; Hippocampus; Kainic Acid; Lacosamide; Male; Neurons; Neuroprotective Agents; Rats; Rats, Wistar; Seizures; Signal Transduction; Status Epilepticus

Since lacosamide was approved as an adjuvant agent for the treatment of medically refractory focal epilepsy over ten years ago, it is becoming more widely used for the treatment of idiopathic (genetic) generalized epilepsies. Several studies have demonstrated efficacy in reducing primary generalized tonic-clonic seizures (GTCS), but efficacy is less well-characterized for myoclonic and absence seizures. A 29-year-old man with juvenile myoclonic epilepsy and medically refractory GTCS on a combination of levetiracetam and topiramate was started on lacosamide adjunctive therapy with the plan to replace topiramate. While his GTCS became controlled, he was witnessed to have confusional episodes, with waxing and waning responsiveness, lasting a few days, several times a month. After eight months of adjunctive lacosamide therapy, he was admitted to the epilepsy monitoring unit, where paroxysms of generalized spike-and-wave complexes, lasting for 30-90 minutes, were recorded, interrupted only by sleep. During these periods, he demonstrated psychomotor slowing and disorientation on examination. The absence status was successfully broken by lorazepam, and lacosamide was discontinued. The patient had no further confusional episodes at the most recent follow-up visit, four months after discharge.

Topics: Adult; Anticonvulsants; Drug Resistant Epilepsy; Drug Therapy, Combination; Humans; Lacosamide; Male; Myoclonic Epilepsy, Juvenile; Seizures; Status Epilepticus

Lacosamide is a third-generation antiepileptic drug. Its likely mechanism of action is via neuronal sodium channel blockade, via a unique manner compared with other antiepileptic drugs that block sodium channels. A paucity of information exists regarding lacosamide overdosage. Lacosamide overdosage is thought to cause QRS prolongation and seizures, due to its effect of sodium channel blockade. The potential efficacy of sodium bicarbonate to reverse the effects of lacosamide has not been well studied. Furthermore, prior reports of lacosamide toxicity have occurred in the setting of concomitant polypharmacy. Thus, the isolated toxic effects of the drug have not been well elucidated.. We report a case of a suspected, single-ingestion overdose on lacosamide. The patient developed signs of cardiotoxicity and seizure. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: After lacosamide overdosage, the emergency physician must be capable of acute management of subsequent lacosamide toxicity. Understanding the mechanisms of action causing toxicity due to this drug can help the clinician to anticipate the interventions that may be needed or useful to treat this potentially toxic ingestion.

Topics: Arrhythmias, Cardiac; Cardiotoxicity; Drug Overdose; Electrocardiography; Epilepsy; Female; Humans; Lacosamide; Middle Aged; Seizures; Sodium Bicarbonate

Topics: Animals; Anti-Arrhythmia Agents; Anticonvulsants; Disease Models, Animal; Dronedarone; Drug Synergism; Drug Therapy, Combination; Lacosamide; Lamotrigine; Male; Mice; Pregabalin; Seizures; Topiramate

Cannabidiol and cannabidiol-enriched products have recently attracted much attention as an add-on therapy for epilepsy, especially drug-resistant seizures. It should be, however, remembered that concomitant use of cannabidiol and antiepileptic drugs may pose a risk of interactions between them. For this reason, the aim of our study was to assess the effect of cannabidiol on the activity of selected new antiepileptic drugs in the electrically-induced seizure models in mice. We studied the effect of cannabidiol on the anticonvulsant action of topiramate, oxcarbazepine, lamotrigine, and pregabalin in the maximal electroshock-induced seizure test as well as on the activity of levetiracetam, tiagabine, lacosamide, and gabapentin in the 6 Hz seizure test in mice. We showed that cannabidiol increased the activity of topiramate, oxcarbazepine, pregabalin, tiagabine, and gabapentin. It did not affect the anticonvulsant effect of lamotrigine and lacosamide. Interestingly, cannabidiol attenuated the anticonvulsant activity of levetiracetam. Co-administration of antiepileptic drugs with cannabidiol did not cause adverse effects such as impairment of motor coordination, changes in neuromuscular strength or potentiation of the cannabidiol-induced hypolocomotion. Serum and brain levels of antiepileptic drugs and cannabidiol were determined by using HPLC in order to ascertain any pharmacokinetic contribution to the observed behavioral effects. Only interaction with levetiracetam was purely pharmacodynamic in nature because no changes in serum and brain concentration of either levetiracetam or cannabidiol were observed. Increased anticonvulsant activity of topiramate, oxcarbazepine, pregabalin, tiagabine, and gabapentin could be, at least in part, related to pharmacokinetic interactions with cannabidiol because there were changes in serum and/or brain concentrations of antiepileptic drugs and/or cannabidiol. Pharmacokinetic interactions cannot be also excluded between lacosamide and cannabidiol because cannabidiol increased brain concentration of lacosamide and lacosamide increased brain concentration of cannabidiol. Further pharmacokinetic studies are required to evaluate the type of interactions between cannabidiol and novel antiepileptic drugs.

Topics: Animals; Anticonvulsants; Brain; Cannabidiol; Chromatography, High Pressure Liquid; Disease Models, Animal; Drug Interactions; Drug Resistant Epilepsy; Electric Stimulation; Gabapentin; Lacosamide; Lamotrigine; Levetiracetam; Male; Mice; Oxcarbazepine; Pregabalin; Seizures; Tiagabine; Topiramate

Lacosamide is an antiepileptic drug (AED), which has proven to be effective to control seizures, including acute conditions such as status epilepticus. The aim of this study is to describe the clinical experience with lacosamide in neuro-oncological patients.. Multicenter retrospective study in patients with cancer-related seizures, who received lacosamide as an add-on therapy.. Forty-eight patients with benign and malignant tumors, including primary brain tumors, lymphomas, systemic cancer with central nervous system involvement, or paraneoplastic encephalitis, were included. Lacosamide was effective in the control of chronic seizures in patients with either benign or malignant tumors. The success rate was greater in malignant tumors, and drug-resistant epilepsies were more likely associated with benign tumors. Adverse events occurred in nearly 70% of patients, particularly in acute conditions and associated with the concomitant use of radio-/chemotherapy. Lacosamide-related adverse events were more likely somnolence and dizziness, which usually resolved after dose adjustment. After starting lacosamide, nearly half of the patients discontinued one of the baseline AEDs and decreased or discontinued dexamethasone. Fifteen patients with status epilepticus were treated with intravenous lacosamide, and 73% of them had their condition resolved without serious drug-related adverse events.. Lacosamide is an AED to consider in cases of cancer-related seizures. Lacosamide pharmacodynamics and pharmacokinetics allow the achievement of responder rates over 50% with no serious adverse effects, amelioration of side effects from other AEDs or radio-/chemotherapy, and no significant drug interactions. Furthermore, the intravenous formulation shows clear benefits in acute conditions such as status epilepticus.

Topics: Acetamides; Adult; Aged; Aged, 80 and over; Anticonvulsants; Brain Neoplasms; Female; Humans; Lacosamide; Male; Middle Aged; Retrospective Studies; Seizures; Treatment Outcome; Young Adult

To isobolographically determine the types of interactions that occur between retigabine and lacosamide (LCM; two third-generation antiepileptic drugs) with respect to their anticonvulsant activity and acute adverse effects (sedation) in the maximal electroshock-induced seizures (MES) and chimney test (motor performance) in adult male Swiss mice.. Type I isobolographic analysis for nonparallel dose-response effects for the combination of retigabine with LCM (at the fixed-ratio of 1:1) in both the MES and chimney test in mice was performed. Brain concentrations of retigabine and LCM were measured by high-pressure liquid chromatography (HPLC) to characterize any pharmacokinetic interactions occurring when combining these drugs.. Linear regression analysis revealed that retigabine had its dose-response effect line nonparallel to that of LCM in both the MES and chimney tests. The type I isobolographic analysis illustrated that retigabine combined with LCM (fixed-ratio of 1:1) exerted an additive interaction in the mouse MES model and sub-additivity (antagonism) in the chimney test. With HPLC, retigabine and LCM did not mutually change their total brain concentrations, thereby confirming the pharmacodynamic nature of the interaction.. LCM combined with retigabine possesses a beneficial preclinical profile (benefit index ranged from 2.07 to 2.50) and this 2-drug combination is worth recommending as treatment plan to patients with pharmacoresistant epilepsy.

Topics: Acetamides; Animals; Anticonvulsants; Brain; Carbamates; Dose-Response Relationship, Drug; Drug Combinations; Electroshock; Lacosamide; Male; Mice; Phenylenediamines; Psychomotor Performance; Seizures

To report the efficacy and tolerability of lacosamide as an add-on treatment in patients with gliomas and uncontrolled seizures despite conventional antiepileptic drugs (AEDs). We conducted an observational study on 71 patients to describe patterns of response to lacosamide and the association between clinico-pathological factors and seizure control. We observed at 3, 6 and 9 months a seizure reduction ≥ 50% in 74.6, 76 and 86.2% of patients and a seizure freedom in 42.2, 43 and 50%, respectively. The median number of seizures in the 3 months before treatment was 13, and decreased to 3 between baseline and 6 months, and to 0.5 between 6 and 9 months. The best seizure response was observed at 3 months (62%). Sixty per cent of patients displayed the maximum seizure control with doses of lacosamide of 100-250 mg/day, while 21% needed doses up to 400 mg/day. Seizure reduction ≥ 50% and seizure freedom were higher in patients who received lacosamide as first add-on compared to those who received a later adjunctive therapy. A reduction ≥ 50% of seizures was observed in a proportion of patients with progressive disease on MRI. Age > 45 years (OR 0.11, 95% CI 0.02-0.63, p = 0.013) was a significant predictor of seizure freedom at 9 months on multivariate analysis. The study suggests that lacosamide, when added to any baseline AEDs, is effective in obtaining a high seizure reduction and seizure freedom regardless of the tumor activity and response to antineoplastic therapies.

Topics: Adult; Anticonvulsants; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Female; Glioma; Humans; Lacosamide; Male; Middle Aged; Seizures; Treatment Outcome

Depression is the main psychiatric comorbidity in epilepsy with an estimated prevalence between 20% and 55% and one of the main determinants of quality of life. The aim of this study was to investigate the effect of lacosamide (LCM) on mood and anxiety symptoms in patients with focal onset seizures (FOS). The secondary objective was to evaluate if the potential modifications in variables were related to seizure control or to the intrinsic effect of LCM.. We performed a prospective multicenter study in 8 tertiary epilepsy centers in adults with FOS in which LCM was initiated as add-on therapy. Patients' mood and quality of life were evaluated through questionnaires and scales such as the Beck Depression Inventory-II (BDI-II), the State-Trait Anxiety Inventory (STAI-S/T), the Hospital Anxiety and Depression Scale (HADS), and the Quality of Life in Epilepsy-10 (QOLIE-10). Initiation of psychotropic medication was not allowed during the observation period. Patients with diagnosis of major depression or bipolar disorder were excluded. Evaluations were scheduled before LCM treatment, at 3 and 6months.. Forty-nine patients were included (51% female) with an average age of 39.5years (range 18-65). At the start of treatment with LCM, 65.3% of the patients were on treatment with one antiepileptic drug (AED). Based on BDI-II, 38.8% of patients had depressive symptoms and 46.9% according to HADS Depression (HADS-D), 63.3% of patients presented pathological levels of anxiety (STAI-S/T), and 44.9% according to HADS Anxiety (HADS-A). Quality of Life in Epilepsy-10 showed that 57.1% of patients had a relevant reduction in their quality of life. After LCM, the score on the BDI-II depression scale decreased significantly (p<0.001). Based on the STAI and HADS-anxiety scales, patients who had a pathological anxiety at baseline, significantly improved. The QOLIE-10 improved significantly over the observation period (p<0.001). At 6months, 28.3% of patients were seizure-free (67.4% were responders). The improvements on depression and anxiety scores were not statistically related to seizure control.. Lacosamide seems to have a positive effect on depressive and anxiety symptoms. Although the efficacy of LCM in seizure control was demonstrated, the antidepressant and anxiolytic effect on mood and anxiety seems to be an independent factor.

Topics: Adolescent; Adult; Affect; Aged; Anticonvulsants; Anxiety; Cognition; Depression; Drug Resistant Epilepsy; Epilepsy; Female; Humans; Lacosamide; Male; Middle Aged; Prospective Studies; Psychiatric Status Rating Scales; Quality of Life; Seizures; Surveys and Questionnaires; Treatment Outcome; Young Adult

Seizures in up to 30% of children with epilepsy become refractory to treatment, decreasing their quality of life. Studies suggest that lacosamide may be effective in pediatric patients with refractory epilepsy.. To assess the effectiveness and safety of lacosamide in a population of children with mostly focal refractory epilepsy.. Retrospective analysis of children aged <18years presenting to a single hospital in Spain. Data from baseline, and 3, 6, and 12months after lacosamide initiation were collected and analyzed. Response to lacosamide was categorized by seizure frequency (seizure freedom or ≥75%, ≥50%, and <50% reduction in seizures).. One hundred ninety-one pediatric patients (~55% male) with focal epilepsy treated with lacosamide were included. The mean age at lacosamide initiation was 9.4years, and the mean duration of epilepsy was 5.4years. Seizure-free rates at 3, 6, and 12months were 9.7%, 11.8%, and 16.0%. At 12months, 44.4% of the population had a ≥50% reduction in seizure frequency. When analyzing response according to the number of previous/concomitant AEDs, those patients who received ≤2 previous AEDs/fewer concomitant AEDs had significantly greater response rates than those who received greater numbers of previous/concomitant AEDs; however, no predictive factors for response were identified. The most common adverse events were seizure number increased (14.7%), diplopia (5.2%), dizziness (3.7%), ataxia (2.1%), and drowsiness (2.1%).. Lacosamide use in children with refractory focal epilepsy can result in a reduction in seizure rate that improves progressively over time with few adverse effects, making lacosamide a promising option in these patients.

Topics: Adolescent; Anticonvulsants; Ataxia; Child; Dizziness; Drug Resistant Epilepsy; Epilepsies, Partial; Female; Humans; Lacosamide; Male; Quality of Life; Retrospective Studies; Seizures; Spain; Treatment Outcome

The objective of this study was to analyze the effectiveness and long-term tolerability of adjuvant lacosamide (LCM) in a multicenter cohort. We aim to assess outcomes of LCM-containing antiepileptic drug (AED) combinations based upon 'mechanism of action' (MoA) and patient's clinical features.. Consecutive patients commenced on LCM, with focal epilepsy were identified from three Australian hospitals. The 12-month efficacy endpoints were greater than 50% reduction in seizure frequency (responders) and seizure freedom. Tolerability endpoints were cessation of LCM for any reason, cessation due to side-effects and censoring due to inefficacy. Outcomes were assessed according to concomitant AEDs according to their MoA and the clinical risk factor profile.. Three hundred ten patients were analyzed and followed for median 17.3months. Two hundred ninety-nine (97%) had drug-resistant epilepsy, and 155 (50%) had tried more than 7 AEDs at LCM commencement. Adjuvant LCM was associated with responder and seizure freedom rate of 29% and 9% respectively at 12months. Lower baseline seizure frequency, a prior 6-month period of seizure freedom at any time since epilepsy diagnosis and being on fewer concomitant AEDs were predictive of 12-month seizure freedom. Previous focal to bilateral tonic-clonic seizures (FBTCS), lower baseline seizure frequency, and concomitant AED reduction after LCM commencement were associated with improved LCM tolerability. No specific MoA AED combinations offered any efficacy or tolerability advantage.. Adjuvant LCM is associated with seizure freedom rates of 9% at 12months after commencement and is predicted by lower prior seizure frequency, a period of 6months or longer of seizure freedom since diagnosis and fewer concomitant AEDs. While the broad MoA of concomitant AEDs did not influence efficacy or tolerability outcomes, we have provided a framework that may be utilized in future studies to help identify optimal synergistic AED combinations.

Topics: Acetamides; Adolescent; Adult; Anticonvulsants; Australia; Cohort Studies; Drug Resistant Epilepsy; Epilepsies, Partial; Female; Humans; Lacosamide; Male; Retrospective Studies; Seizures; Treatment Outcome; Young Adult

To assess effectiveness and tolerability of first-line and conversion to lacosamide monotherapy for focal seizures.. Retrospective, non-interventional chart review of lacosamide monotherapy patients aged ≥16 years in Europe. Outcomes included retention rate at observational point (OP) 3 (12 ± 3 months), seizure freedom rates at OP2 (6 ± 3 months) and OP3 and adverse drug reactions (ADRs).. A total of 439 patients were included (98 first-line and 341 conversion to monotherapy; 128 aged ≥65 years [25 first-line and 103 conversion to monotherapy]). First-line and conversion to monotherapy retention rates were 60.2% (59/98; 95% confidence interval [CI] 49.8%-70.0%) and 62.5% (213/341; 57.1%-67.6%), respectively. Kaplan-Meier estimates of 12-month retention rates were 81.2% and 91.4% for first-line and conversion to monotherapy, respectively. First-line and conversion to monotherapy retention rates in patients aged ≥65 years were 60.0% (38.7%-78.9%) and 68.9% (59.1%-77.7%), respectively. At OP2, 66.3% of first-line and 63.0% of conversion to monotherapy patients were seizure free. At OP3, 60.2% of first-line and 52.5% of conversion to monotherapy patients were seizure free. In the ≥65 years subgroup, seizure freedom rates at OP2 were 72.0% and 68.0% for first-line and converted to monotherapy, respectively, and at OP3, 68.0% and 56.3%, respectively. Overall, 52 of 439 (11.8%) patients reported ADRs (16.4% in ≥65 years subgroup), most commonly dizziness (5.0%), headache (2.1%) and somnolence (1.6%).. Lacosamide was effective and well tolerated as first-line or conversion to monotherapy in a clinical setting in adult and elderly patients with focal seizures.

Topics: Acetamides; Adolescent; Adult; Aged; Anticonvulsants; Europe; Female; Humans; Lacosamide; Male; Middle Aged; Retrospective Studies; Seizures

Epilepsy is a serious neurological disease affecting about 1% of people worldwide (65 million). Seizures are controllable with antiepileptic drugs (AEDs) in about 70% of epilepsy patients, however, there remains about 30% of patients inadequately medicated with these AEDs, who need a satisfactory control of their seizure attacks. For these patients, one of the treatment options is administration of 2 or 3 AEDs in combination.. To determine the anticonvulsant effects of a combination of 3 selected AEDs (i.e., lacosamide - LCM, lamotrigine - LTG and phenobarbital - PB) at the fixed-ratio of 1:1:1 in a mouse maximal electroshock-induced (tonic-clonic) seizure model by using isobolographic analysis.. Seizure activity was evoked in adult male albino Swiss mice by a current (sinewave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Type I isobolographic analysis was used to detect interaction for the 3-drug combination.. With type I isobolographic analysis, the combination of LCM, LTG and PB (at the fixed-ratio of 1:1:1) exerted additive interaction in the mouse maximal electroshock-induced (tonic-clonic) seizure model.. The combination of LCM with LTG and PB produced additive interaction in the mouse tonicclonic seizure model, despite various molecular mechanisms of action of the tested AEDs.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Epilepsy; Lacosamide; Lamotrigine; Male; Mice; Phenobarbital; Seizures

Withdrawal of antiepileptic drugs (AEDs) is a standard procedure during presurgical epilepsy assessment. Rapid and, at times, even pre-hospital withdrawal of medication is performed in some centres to enhance the yield of recorded seizures during video-EEG monitoring. AED withdrawal, however, affects the propensity and speed of propagation of epileptic activity, may evoke more severe seizures, and may cause pitfalls in EEG interpretation. We report a case which had been recommended to undergo intracranial EEG recordings in order to clarify apparently discordant MRI findings and ictal EEG patterns when monitoring was performed following complete AED withdrawal. Re-evaluation to assess scalp EEG patterns at several drug levels during slow AED tapering showed a loss of localizing information with AED withdrawal due to contralateral and bitemporal spread of frontal epileptic activity. Our report demonstrates that in individual cases, rapid AED withdrawal during presurgical video-EEG monitoring can impair the validity of EEG recordings and lead to unnecessary risks and investigations during workup.

Topics: Acetamides; Anticonvulsants; Brain; Electroencephalography; Epilepsy; Humans; Lacosamide; Levetiracetam; Male; Piracetam; Preoperative Period; Seizures; Young Adult

Lacosamide (LCM) was recently introduced in the Middle East. The aim of this study was to evaluate the safety, tolerability, and efficacy of LCM in patients with focal onset seizures and determine if our results are comparable with those derived from Western countries.. This is a retrospective analysis from two medical centers on consecutive patients diagnosed as having focal onset seizures and treated with add-on LCM. The primary efficacy variables were the 50% responder and seizure-free rates, and the secondary outcome variables included the percentages of patients who achieved seizure remission during the last 6-month follow-up period and the percentages of discontinuation due to lack of efficacy or tolerability.. One hundred four patients with a mean age of 30.9 years and experiencing a mean of 9.4 seizures per month during baseline were included. The 50% responder rates were 69% and 70% at 6- and 24-month follow-ups, respectively. Patients concomitantly treated with a sodium channel blocker were less likely to achieve seizure remission during the last 6-month follow-up period while the early introduction of LCM resulted in a significantly higher likelihood of achieving such a remission. Eighty-eight percent of patients were still maintained on LCM at the last follow-up, and the most common adverse events consisted of dizziness and somnolence, double vision, and nausea/vomiting.. Our data show similar efficacy and tolerability to those reported from Western countries. Our results also substantiate the early introduction of LCM and support the dose reduction of baseline AED especially that of sodium channel blockers to minimize adverse events.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Dizziness; Dose-Response Relationship, Drug; Epilepsies, Partial; Female; Humans; Lacosamide; Male; Middle Aged; Middle East; Product Surveillance, Postmarketing; Retrospective Studies; Seizures; Treatment Outcome; Vomiting; Young Adult

The study aims to retrospectively compare the efficacy of lacosamide (LCS) and levetiracetam (LEV) in add-on treatment in patients with partial-onset epilepsy.. Patients who have been followed-up for at least one year due to diagnosis of partial epilepsy between September 2014 and December 2017 and who had no seizure control, despite using at least two antiepileptic monotherapies, and therefore undergone LEV or LCS add-on treatment were retrospectively reviewed. Of the patients, total number of seizures and seizure control rates 6 months before and 3 and 6 months after the add-on treatment were compared.. There was no statistically significant difference between the 30 patients in the LEV group (12 females, 18 males, mean age 29.7±6.6) and 28 patients in the LCS group (12 females, 16 males, mean age 28.2±6.4) in terms of age, gender and the duration of illness. When the LEV and LCS groups were evaluated separately, the mean number of seizures within 3 and 6 months after the add- on treatment were significantly lower than the mean number of seizures in the last 6 months before the add-on treatment (p<0.005 and p<0.005 respectively). There was no statistically significant difference between the two groups when compared with each other in terms of the rate of decrease in number of seizures and seizure control before and after the add-on treatment (p=0.445 and p=0.238, respectively).. LCS appears to be as effective as the currently well-established LEV in the treatment of partial onset seizures. No comparative study was found in the literature similar to this subject matter. There is a need for prospective studies for the comparison of the efficacies of these two drugs.. A vizsgálat célja a lacosamid (LCS) és a levetiracetam (LEV) kiegészítő kezelés hatékonyságának retrospektív összehasonlítása parciális kezdetű epilepsziában szenvedő betegek esetén.. Olyan betegek szerepeltek a vizsgálatban, akik parciális kezdetű epilepszia diagnózisát 2014 szeptembere és 2017 decembere között állapították meg, és utánkövetésük legalább egy évig zajlott, továbbá akiknél nem lehetett rohamkontrollt elérni legalább két epilepsziaellenes monoterápia alkalmazásával, ezért vagy LEV, vagy LCS kiegészítő kezelésben részesültek. Összehasonlítottuk a betegek hat hónappal a kiegészítő kezelés előtt mért összes rohamszámát és rohamkontrollarányaikat a kiegészítő kezelés után három, illetve hat hónappal mért értékekkel.. A LEV-csoportba 30 beteg (12 nő, 18 férfi, átlagéletkor 29,7±6,6 év), az LCS-csoportba 28 beteg került (12 nő, 16 férfi, átlagéletkor 28,2±6,4 év); a két csoport között nem volt statisztikailag szignifikáns különbség az életkor, a nem és a betegség fennállásának időtartama szempontjából. A LEV- és az LCS-csoport önálló értékelése esetén a kiegészítő kezelés után három és hat hónappal mért átlagos rohamszám szignifikánsan alacsonyabb volt, mint a kiegészítő kezelés előtt hat hónappal (p<0,005 és p<0,005). A két csoport eredményeit egymással összehasonlítva nem volt szignifikáns különbség a rohamszám csökkenésében és a rohamkontroll kiegészítő kezelés előtti, illetve utáni értékében (p=0,445 és p=0,238).. Az LCS ugyanolyan hatékonynak bizonyult a parciális kezdetű epilepszia kiegészítő kezelésében, mint a jelenleg leginkább használatos LEV. A szakirodalomban nem találtunk hasonló összehasonlító vizsgálatot. A jövőben prospektív vizsgálatokban kell összehasonlítani a két szer hatékonyságát.

Topics: Adult; Anticonvulsants; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsies, Partial; Female; Follow-Up Studies; Humans; Lacosamide; Levetiracetam; Male; Retrospective Studies; Seizures; Treatment Outcome

Post marketing analysis of anti-epileptic drug (AED) efficacy and tolerability is of great value to the clinician since it is more representative of clinical practice than clinical trial data. We analyzed our experience with lacosamide (LCM) in patients treated after marketing.. We identified all patients who were treated with LCM during the four year period after marketing, excluding patients who were in clinical trials. We recorded demographic data and analyzed efficacy and tolerability in patients who had at least one follow up visit or telephone call 3 months after the initiation of LCM.. A total of 165 patients met our inclusion criteria. The mean age was 41 years. The majority of the cohort had focal epilepsy (146 patients) (88.4%). The mean duration of treatment was 31.2 months. Eighty one patients (49.1%) were continuing LCM at last follow up. Adverse effects (AEs) and discontinuation were significantly more common when LCM was added to one or more Na-channel blocking agents (NCB) (p = 0.0003 and 0.17). The 50% responder rate was 26% at 3 months and increased to 49% at 36 months. Patients were more likely to continue the drug and less likely to have AEs with slower titration over >4 weeks (p = 0.02 for each). Four or more previously failed AEDs predicted poorer response rate compared to three or less AEDs (p = 0.001).. LCM use in clinical practice was associated with greater rate of seizure freedom than in clinical trials. Discontinuation and occurrence of AEs were significantly more likely with faster titration and adding LCM to NCB agents.

Topics: Adult; Aged; Anticonvulsants; Cohort Studies; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Lacosamide; Male; Middle Aged; Seizures; Treatment Outcome; Young Adult

Electronic health record (EHR) databases are a potential source for conducting research to generate real world evidence on patient outcomes. The objective of the study was to evaluate the feasibility of using EHR data to assess seizure outcomes in patients treated with lacosamide (LCM) monotherapy.. This was a retrospective cohort study conducted using the Optum clinical EHR database. The study sample comprised patients ≥17 years of age with epilepsy or seizures and treated with LCM monotherapy between 1 January 2009 and 31 December 2013. Structured and unstructured data from prescribed medication and abstracted physician note records were used to identify patients with epilepsy treated with LCM monotherapy and measure seizure frequency outcomes. The index date was the first date of LCM monotherapy, with a 6-month baseline period. Patients were observed for up to 12 months beginning on the index date (follow-up period). The EHR data were not sufficient to compute days supply and explicit duration of LCM and other antiepileptic drug (AED) therapies; therefore, LCM monotherapy was estimated from prescription dates of AEDs. Outcomes were change in seizures per month or change in seizure frequency category from baseline to follow-up. Descriptive statistics were used to describe baseline characteristics and study outcomes.. A total of 10,988 patients with at least one LCM prescription were identified during the study period, 470 of whom met all the selection criteria and were included in the study sample. Although many patients had abstracted physician note records that referred to their seizures, only 3.2% of the patients had seizure frequency information that could be used to quantify the number of seizures per month in both the baseline and follow-up periods; thus, this information could not be used to assess the effectiveness of LCM monotherapy on seizure outcomes.. Lacosamide monotherapy effectiveness was not estimated because the EHR prescription record data did not have sufficient information on days supply. Additionally, most patients' records did not contain adequate information to allow for evaluation of quantitative changes in seizure frequency based on the number of seizures per month. More studies are needed to validate these study findings.

Topics: Adolescent; Adult; Anticonvulsants; Cohort Studies; Electronic Health Records; Epilepsy; Female; Humans; Lacosamide; Male; Middle Aged; Retrospective Studies; Seizures; Time Factors; Treatment Outcome; Young Adult

A number of antiepileptic drugs (AEDs) are currently available for treating acute seizures. It is recommended to select the initial treatment option according to the type of epileptic syndrome and the patient's clinical characteristics, but little is known about the long-term retention rates of AEDs started in the emergency department.. We recruited patients admitted with seizures over a two-year period. All patients underwent early neurological assessment, EEG testing, and neuroimaging. The treatments received at baseline and at one year of follow-up were compared.. In total, 225 patients were included. Overall, monotherapy with levetiracetam was the regimen most often used in patients with new-onset seizures, whereas other AEDs were mainly used in patients previously treated with other drugs. Lacosamide use was most likely associated with the presence of lesion related seizures in elderly patients, and carboxamides with focal onset seizures of unknown cause. The mean retention rate of the total of AED treatments was nearly 70%. The main cause leading to discontinuation was the development of intolerable adverse events. Levetiracetam use decreased as lacosamide use increased in the overall group of patients.. Our study shows that there is a trend to use newer AEDs, particularly levetiracetam, as the first option in new-onset seizures in the emergency room. However, levetiracetam use significantly decreased over follow-up, mainly because of the development of adverse events. The use of other, better-tolerated AEDs, such lacosamide predominated in elderly patients and patients with lesion related seizures, or carboxamides in epilepsies of unknown etiology.

Topics: Acetamides; Acute Disease; Adolescent; Adult; Age Factors; Aged; Anticonvulsants; Confidence Intervals; Continuity of Patient Care; Electroencephalography; Female; Follow-Up Studies; Humans; Lacosamide; Male; Middle Aged; Patient Discharge; Retrospective Studies; Seizures; Treatment Outcome; Young Adult

Therapeutic doses of antiepileptic drugs (AEDs) may alter EEG background activity, which is considered an index of the functional state of the brain. Quantitative analysis (qEEG) of EEG background activity is a valid instrument to assess the effects of many centrally active drugs on the central nervous system, including AEDs. Lacosamide (LCM) is a new AED that could be a valid therapeutic choice in patients with brain tumor-related epilepsy (BTRE).. We used qEEG to analyze the possible effect of LCM as an add-on, on background EEG activity after 4 months in patients with BTRE.. We consecutively recruited sixteen patients with BTRE: Five dropped out for disease progression, five for scarce compliance, and six completed the study. For these reasons qEEG was performed at first visit and after 4 months only in six patients. For all frequency bands, LCM revealed no changes of mean relative power during rest with eyes closed, hyperpnoea (HP), and mental arithmetic task (MA); significant increment was found only in the theta mean relative power during opening and closing eyes (BR). After four months of therapy with LCM, one patient was seizure free, four had a seizure reduction ≥50%, and one showed a worsening in seizure frequency <50%.. Despite the limitation of a small series, these findings suggest that LCM seems to have only a mild interference on EEG background activity and confirm that LCM has a good efficacy on seizure control in patients with BTRE. This is the first study that evaluates the effect of LCM on background EEG activity, using qEEG in BTRE patients. Future research in this area could include prospective studies with qEEG for a longer follow-up period to assess the impact of AEDs on brain functions in this particular fragile patient population.

Topics: Adult; Anticonvulsants; Brain Neoplasms; Disease Progression; Electroencephalography; Epilepsy; Female; Glioma; Humans; Lacosamide; Male; Middle Aged; Psychological Tests; Research Design; Rest; Seizures

Perioperative seizure prophylaxis with antiepileptic drugs (AED) has been advocated in patients undergoing supratentorial craniotomy. The practice remains controversial. The reasoning presupposes that the possibility of an adverse drug reaction from the AED is lower than the probability of harm from a seizure. Even short periods of hypotension during the operation can lead to acute kidney and myocardial injury. We retrospectively evaluated cardiovascular effects and tolerability of levetiracetam (LEV) alone, LEV and lacosamid (LCM) as compared to phenytoin (PHT).. After IRB approval, the charts of individuals who underwent craniotomy from April 2007 to September 2011 were reviewed. Those receiving PHT were compared to those receiving LEV alone and LEV/LCM. The patient data included demographic, indication and procedure related data. The cumulative dose of norepinephrine (NET), atropine (ATR) and the change in systolic blood pressure during and after the administration of the AED were analyzed.. Five hundred thirty-eight patients were screened of which 122 were included for analysis. 40 patients with primary or secondary supratentorial brain tumors received LEV (19 female, 21 male; mean age 56 years), 41 patients received LEV/ LCM (16 female, 25 male; mean age 56 years) and 41 patients received PHT (15 female, 26 male; mean age 50 years). The commonest indications for craniotomy were glioblastoma (N.=14 vs. N.=12 vs. N.=15), meningiomas (N.=9 vs. N.=7 vs. N.=10), low-grade gliomas (N.=6 vs. N.=13 vs. N.=6) and brain metastases (N.=5 vs. N.=4 vs. N.=5). 1 LEV/LCM patient (2%) and 4 PHT patients (4.5%) had a seizure despite prophylaxis. Possible side effects were observed in 2 patients associated with PHT. During anesthesia there was a significant drop in systolic blood pressure in the PHT group after administration of the AED perioperatively when compared to LEV (P=0.001) and LEV/LCM (P≤0.0001) respectively. The mean cumulative doses of NET and ATR over the course of the operation did not differ significantly.. LEV alone and in combination with LCM for patients without and with symptomatic epilepsy as seizure prophylaxis provides a safe and feasible alternative to PHT. PHT was associated with an unfavorable drop in blood pressure during anesthesia and more adverse reactions.

Topics: Acetamides; Adult; Anticonvulsants; Blood Pressure; Craniotomy; Female; Humans; Hypotension; Lacosamide; Levetiracetam; Male; Middle Aged; Phenytoin; Piracetam; Pre-Exposure Prophylaxis; Retrospective Studies; Seizures; Supratentorial Neoplasms

The aim of this paper was to describe the synthesis of a library of 28 new 1,3-substituted pyrrolidine-2,5-dione as potential anticonvulsant agents. The anticonvulsant activity was evaluated using three acute models of seizures in mice (MES-maximal electroshock, scPTZ-subcutaneous pentylenetetrazole, and 6Hz-psychomotor seizure tests). The neurotoxicity was determined by rotarod test. The most promising compound was found to be N-[{morpholin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2,5-dione (15), as it was active in the MES (ED

Topics: Animals; Anticonvulsants; Mannich Bases; Mice; Pyrrolidines; Seizures

The knowledge of pharmacokinetic and pharmacodynamic properties of antiepileptic drugs is helpful in optimizing drug therapy for epilepsy. This study was designed to evaluate the pharmacokinetic and pharmacodynamic properties of lacosamide in experimentally induced hepatic and renal impairment in seizure animals. Hepatic or renal impairment was induced by injection of carbon tetrachloride or diclofenac sodium, respectively. After induction, the animals were administered a single dose of lacosamide. At different time points, maximal electroshock (MES) seizure recordings were made followed by isolation of plasma and brain samples for drug quantification and pharmacodynamic measurements. Our results showed a significant increase in the area under the curve of lacosamide in hepatic and renal impairment groups. Reduced clearance of lacosamide was observed in animals with renal impairment. Along with pharmacokinetic alterations, the changes in pharmacodynamic effects of lacosamide were also observed in all the groups. Lacosamide showed a significant protection against MES-induced seizures, oxidative stress, and neuroinflammatory cytokines. These findings revealed that experimentally induced hepatic or renal impairment could alter the pharmacokinetic as well as pharmacodynamic properties of lacosamide. Hence, these conditions may affect the safety and efficacy of lacosamide.

Topics: Acetamides; Administration, Oral; Animals; Anticonvulsants; Area Under Curve; Brain; Carbon Tetrachloride; Caspase 3; Caspase 9; Diclofenac; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Interleukins; Lacosamide; Liver Diseases; Male; Oxidative Stress; Rats, Wistar; Renal Insufficiency; Seizures; Tumor Necrosis Factor-alpha

Lacosamide (LCM) due to no known drug interaction and the absence of metabolic enzyme induction is a good candidate for an add-on medication, especially in combination with lamotrigine, levetiracetam (LEV), oxcarbazepine, topiramate, and valproic acid (VPA). Here we report for the first time, to our knowledge, that LCM can lower VPA and LEV serum levels. At present, there are no known explicable mechanisms of action of LCM, which lowers VPA and LEV. Here observed drug interaction of LCM is of clinical significance, which might be useful for other colleagues in the field.

Topics: Acetamides; Adolescent; Anticonvulsants; Brain Neoplasms; Drug Interactions; Epilepsies, Partial; Humans; Lacosamide; Levetiracetam; Neoplasms, Neuroepithelial; Piracetam; Seizures; Valproic Acid

The prevalence of seizures in the elderly will increase as populations age. Data is currently limited regarding treatment and especially tolerability of newer antiseizure medications (ASMs). In the current study we aimed to investigate the tolerability of lacosamide (LCS) and zonisamide (ZNS).. We performed a retrospective chart review of patients with seizures older than 60 treated with LCS or ZNS in the outpatient setting. We examined seizure variables, medical comorbidities, and concomitant medications. Primary outcomes were the retention rates at last follow up, and the discontinuation rate due to side effects.. Seventy-one (71) LCS and 39 ZNS patients were identified. Average age at LCS initiation was 71.0±7.0 years and 49% were medically refractory. Average duration of follow up was 23.1±21.2 months. At last follow up, the retention rate was 60% and seizure freedom rate 52%. Of the 19 discontinuations due to side effects, 7 (37%) were due to dizziness/gait instability. No predictors of discontinuation were identified. Average age at ZNS initiation was 69.7±6.9 years and 51% were medically refractory. Average duration of follow up was 46.3±38.3 months. At last follow up, the retention rate was 64% and seizure freedom rate was 67%. Of the 12 discontinuations due to side effects, 4 (33%) were due to cognitive or behavioral side effects. Predictors of discontinuation included a lower starting dose.. Lacosamide and zonisamide are viable options for the treatment of epilepsy in the elderly and have similar retention rates.

Topics: Acetamides; Aged; Anticonvulsants; Dizziness; Female; Gait; Humans; Isoxazoles; Lacosamide; Male; Postural Balance; Retrospective Studies; Seizures; Zonisamide

Psychiatric comorbidities are common in people with epilepsy. A retrospective study of characteristics associated with withdrawal due to psychiatric side effects was undertaken in patients with treated epilepsy participating in prospective audits with new antiepileptic drugs (AEDs). A total of 1058 treated patients with uncontrolled seizures (942 focal-onset seizures, 116 generalized genetic epilepsies [GGEs]) participated in eight prospective, observational audits from 1996 to 2014. These patients were prescribed adjunctive topiramate (n=170), levetiracetam (n=220), pregabalin (n=135), zonisamide (n=203), lacosamide (n=160), eslicarbazepine acetate (n=52), retigabine (n=64), or perampanel (n=54). Doses were titrated according to efficacy and tolerability to optimize zeizure outcomes and reduce side effects. Psychiatric comorbidities were recorded prior to and after the addition of each AED. At baseline, patients with focal-onset seizures (189 of 942; 20.1%) were statistically more likely to have psychiatric diagnoses compared to patients with GGEs (14 of 116, 12.1%; p=0.039). Following adjunctive AED treatment, neuropsychiatric adverse effects led to AED withdrawal in 1.9-16.7% of patients. Patients with a pre-treatment psychiatric history (22 of 209; 10.5%) were statistically more likely to discontinue their new AED due to psychiatric issues compared to patients with no previous psychiatric diagnosis (50 of 849; 5.9%; p=0.017). Patients receiving sodium channel blocking AEDs (4 of 212, 1.9%) were statistically less likely to develop intolerable psychiatric problems, compared to those on AEDs possessing other mechanisms of action (68 of 846, 8.0%; p=0.012). Depression was the commonest problem, leading to discontinuation of AEDs in 2.8% (n=30) patients. Aggression was statistically more common in men (11 of 527, 2.1%) compared to women (1 of 531, 0.2%; p=0.004). Patients with learning disability (12 of 122, 9.8%; p=0.0015) were statistically less likely to have psychiatric issues prior to adjunctive AED treatment compared to other patients (208 of 936, 22.2%), but there were no statistically significant differences once the new AEDs were added (8 of 122 patients with learning disability, 6.6%; 64 of 936 other patients, 6.8%). Awareness of these issues may assist clinicians in avoiding, identifying and treating psychiatric comorbidities in people with epilepsy.

Topics: Acetamides; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Dibenzazepines; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Fructose; Humans; Lacosamide; Levetiracetam; Male; Medical Audit; Mental Disorders; Middle Aged; Nitriles; Piracetam; Pregabalin; Prospective Studies; Pyridones; Retrospective Studies; Seizures; Sodium Channel Blockers; Topiramate; Young Adult

Epilepsy is a common neurologic disorder resulting in spontaneous, recurrent seizures. About 30-40% of patients are not responsive to pharmacologic therapies. This may be due to the differences between individual patients such as etiology, underlying pathophysiology, and seizure focus, and it highlights the importance of new drug discovery and testing in this field. Our goal was to determine the efficacy of lacosamide (LCM), a drug approved for the treatment of focal seizures, in a model of generalized epilepsy with cortical dysplasia (CD). We sought to compare LCM to levetiracetam (LEV), a drug that is currently used for the treatment of both partial and generalized epilepsy and to test its proficiency.. Pregnant rats were irradiated to produce pups with malformed cortices in a model of CD, which will be referred to as the "first hit." Adult animals, developed normally (NL) and irradiated (XRT), were surgically implanted with electroencephalography (EEG) electrodes. Baseline EEG was recorded on all rats prior to pretreatments with either LCM, LEV, or placebo (PBO). After 30 min, all rats were injected with a subconvulsive dose of pentylenetetrazole (PTZ), a γ-aminobutyric acid receptor A (GABA. LCM and LEV were both effective against seizures induced by PTZ. XRT rats had a higher seizure incidence with longer and more severe seizures than NL rats. Seizure duration was decreased with both LCM and LEV in all animals. In XRT rats, there was a significant reduction in acute seizure incidence and severity with both LCM and LEV after PTZ injection.. Our results suggest that LCM could be used as a potential treatment option for generalized epilepsy with CD as the underlying pathology.

Topics: Acetamides; Animals; Anticonvulsants; Electroencephalography; Female; GABA Antagonists; Lacosamide; Levetiracetam; Malformations of Cortical Development; Pentylenetetrazole; Piracetam; Pregnancy; Prenatal Exposure Delayed Effects; Radiation Exposure; Rats; Rats, Sprague-Dawley; Seizures

Posterior reversible encephalopathy syndrome (PRES) is a neuro-radiologic diagnosis that has become more widely recognized and reported over the past few decades. As such, there are a number of known risk factors that contribute to the development of this syndrome, including volatile blood pressures, renal failure, cytotoxic drugs, autoimmune disorders, pre-eclampsia, and eclampsia. This report documents the first reported case of PRES in a patient with severe alcoholic hepatitis with hepatic encephalopathy and delves into a molecular pathophysiology of the syndrome.

Topics: Acetamides; Adult; Anticonvulsants; Ascites; Brain; Electroencephalography; Female; Gastrointestinal Agents; Hepatic Encephalopathy; Hepatitis, Alcoholic; Humans; Lacosamide; Lactulose; Liver Function Tests; Magnetic Resonance Imaging; Patient Compliance; Posterior Leukoencephalopathy Syndrome; Pregnancy; Radiography; Rifamycins; Rifaximin; Seizures; Serum Albumin

The purpose of this study was to synthetize the focused library of 34 new piperazinamides of 3-methyl- and 3,3-dimethyl-(2,5-dioxopyrrolidin-1-yl)propanoic or butanoic acids as potential new hybrid anticonvulsants. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5-38 were prepared in a coupling reaction of the 3-methyl- or 3,3-dimethyl-2-(2,5-dioxopyrrolidin-1-yl)propanoic (1, 2) or butanoic acids (3, 4) with the appropriately substituted secondary amines in the presence of the N,N-carbonyldiimidazole reagent. The initial anticonvulsant screening was performed in mice (ip) using the 'classical' maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests as well as in the six-Hertz (6Hz) model of pharmacoresistant limbic seizures. The acute neurological toxicity was determined applying the chimney test. The broad spectra of activity across the preclinical seizure models in mice ip displayed compounds 7, 15, and 36. The most favorable anticonvulsant properties demonstrated 15 (ED50 MES=74.8mg/kg, ED50scPTZ=51.6mg/kg, ED50 6Hz=16.8mg/kg) which showed TD50=213.3mg/kg in the chimney test that yielded satisfying protective indexes (PI MES=2.85, PI scPTZ=4.13, PI 6Hz=12.70) at time point of 0.5h. As a result, compound 15 displayed comparable or better safety profile than clinically relevant AEDs: ethosuximide, lacosamide or valproic acid. In the in vitro assays compound 15 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and L-type calcium channels. Beyond the anticonvulsant properties, 6 compounds diminished the pain responses in the formalin model of tonic pain in mice.

Topics: Analgesics; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Injections, Intraperitoneal; Mice; Molecular Structure; Pain; Pain Measurement; Pentylenetetrazole; Piperazines; Pyrrolidinones; Seizures

The focused library of 21 new N-phenyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide, 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)propanamide, and 2-(2,5-dioxopyrrolidin-1-yl)butanamide derivatives as potential new hybrid anticonvulsant agents was synthesized. These hybrid molecules were obtained as close analogs of previously described N-benzyl derivatives and fuse the chemical fragments of clinically relevant antiepileptic drugs such as ethosuximide, levetiracetam, and lacosamide. The initial anticonvulsant screening was performed in mice (ip) using the 'classical' maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests, as well as in the six-Hertz (6Hz) model of pharmacoresistant limbic seizures. Applying the rotarod test, the acute neurological toxicity was determined. The broad spectra of activity across the preclinical seizure models in mice (ip) displayed compounds 4, 5, 11, and 19. The most favorable anticonvulsant properties demonstrated 4 (ED50 MES=96.9mg/kg, ED50scPTZ=75.4mg/kg, ED50 6Hz=44.3mg/kg) which showed TD50=335.8mg/kg in the rotarod test that yielded satisfying protective indexes (PI MES=3.5, PI scPTZ=4.4, PI 6Hz=7.6). Consequently, compound 4 revealed comparable or better safety profile than model antiepileptic drugs (AEDs): ethosuximide, lacosamide, and valproic acid. In the in vitro assays, compound 4 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and diltiazem site of L-type calcium channels.

Topics: Amides; Animals; Anticonvulsants; Calcium Channels; Drug Design; Humans; Injections, Intraperitoneal; Mice; Molecular Structure; Neurons; Pyrrolidines; Seizures

Topics: Acetamides; Adult; Anticonvulsants; Astrocytoma; Brain Neoplasms; Fatal Outcome; Humans; Injections, Subcutaneous; Lacosamide; Male; Palliative Care; Seizures

To review our clinical experience with intravenous (iv) lacosamide (LCM) in children less than 12 years old.. Use of LCM to treat children with epilepsy has been supported by multiple studies with limited information on iv use in children.. All children given iv LCM were identified from 2009 to 2015. Records were audited for demographics, seizure classification, etiology, EEG, imaging, indication. Baseline seizure frequency was based on parental reporting, continuous video EEG and direct observation.. 47 patients were identified with median age 6.5 years, 18 less than 3 years old, including 8 younger than 12 months. LCM was an adjunctive therapy of ≥2 antiepileptic drugs (AEDs). LCM was administered intravenously to treat epilepsia partialis continua (n = 3, dose range 5-10 mg/kg), status epilepticus (n = 11, median dose 7.2 mg/kg, range 4-11 mg/kg), and acute exacerbation of seizure frequency (n = 18, median dose 4.5 mg/kg, range 1-11 mg/kg). Parenteral form was substituted for oral form for 10 children treated with maintenance LCM unable to ingest/tolerate enteral medication and 5 who were given iv LCM to initiate maintenance treatment (median dose 4 mg/kg, range: 2-10 mg/kg). The infusion was effective for 24 out of 37 children (65%) naive to LCM. Sedation (one with ataxia) was noted in 5/36 children (14%), without any other identified adverse events.. This is the first published retrospective study of very young critically ill children receiving iv LCM. The acute tolerability at this dosing range represents a positive trend and need confirmation from larger studies.

Topics: Acetamides; Adolescent; Anticonvulsants; Child; Child, Preschool; Epilepsy; Female; Humans; Infant; Infusions, Intravenous; Lacosamide; Male; Retrospective Studies; Seizures; Treatment Outcome

Lacosamide is FDA-approved in patients 17 years or older with partial-onset epilepsy. We evaluated the efficacy and tolerability of lacosamide in children with refractory generalized epilepsy. We retrospectively reviewed records of 21 children with refractory generalized epilepsy treated with lacosamide in our institution from 2009-2013 divided into 2 subgroups- I, Lennox-Gastaut Syndrome, and II, other generalized epilepsies. Efficacy was defined as seizure freedom or ≥50% seizure reduction. Descriptive data analysis including seizure freedom was compared using c(2) analysis. There were eleven females and ten males with a mean age, of 11.9 years. Five patients became seizure free, nine had ≥50% seizure reduction, and seven had no response. Group I: seven had ≥50% improvement, one did not respond. Group II: five became seizure free, two had ≥50% improvement, five had no response. Lacosamide is effective and well tolerated in children with refractory generalized epilepsy particularly patients with Lennox-Gastaut Syndrome.

Topics: Acetamides; Adolescent; Anticonvulsants; Child; Child, Preschool; Drug Resistant Epilepsy; Epilepsy, Generalized; Female; Humans; Lacosamide; Male; Retrospective Studies; Seizures; Treatment Outcome; Young Adult

We evaluated the impact of planned dose reduction and mechanism of action of concomitant AEDs on tolerability in adults with partial-onset seizures undergoing lacosamide (LCM) titration.. Data were collected at baseline and 3-6 and 12-24 months post-LCM initiation. Subjects were categorized as having planned reduction of concomitant AEDs or not; AEDs were categorized as traditional sodium channel blockers (TSCB) or non-TSCB (NTSCB). Groups with/without planned reduction were compared on the presence and number of treatment-emergent adverse events (TEAEs) using chi-square tests or logistic regression and on time to LCM discontinuation with time-to-event methods controlling for standardized (STD) AED dose, a measure of concomitant AED load. Similar analyses were performed comparing subjects taking TSCB and NTSCB agents and used to identify relationships with ≥50% decreases in seizure frequency.. One hundred six adults (mean age 41.4 ± 13.4; 50% male) underwent LCM titration from June 2009-2011 with complete data. Reduction of concomitant AEDs was planned at the time of LCM initiation in 59 (55.7%) subjects. Fewer subjects with planned reduction had TEAEs (49.2% vs. 68.1%; p=0.05), and these subjects had a lower risk of TEAEs (OR 0.36; p=0.019) after adjusting for STD AED dose. The hazard ratio (95% CI) for LCM discontinuation was 0.46 (0.23, 0.94) in subjects with planned reduction of concomitant AEDs vs. others (p=0.033) and 3.29 (1.01, 10.70) in subjects taking TSCB vs. NTSCB agents (p=0.048). Among all cases, those who ever had TEAEs had significantly higher STD dose at both follow-up visits (p=0.033 and p=0.023, respectively). Seizure outcomes were not significantly different between groups at the last follow-up assessment.. Planned reduction of concomitant AEDs during LCM initiation and the use of NTSCB agents only are associated with a reduced risk of TEAEs and LCM discontinuation in adults with partial-onset seizures. This study extends prior observations by considering total AED load in the assessment of tolerability and supports the benefits of early reduction of concomitant AEDs during LCM initiation.

Topics: Acetamides; Adult; Aged; Anticonvulsants; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Lacosamide; Male; Middle Aged; Retrospective Studies; Seizures; Sodium Channel Blockers; Time; Treatment Outcome

This noninterventional, observational, postauthorization safety study (SP0942, NCT00771927) evaluated the incidence of predefined cardiovascular- (CV) and psychiatric-related treatment-emergent adverse events (TEAEs), in patients with epilepsy and uncontrolled partial-onset seizures, when initiating adjunctive therapy with lacosamide or another approved antiepileptic drug (AED) according to standard medical practice. Active recording of predefined TEAEs of interest took place at three-monthly recommended visits for up to 12months. Of 1004 patients who received at least one dose of adjunctive AEDs, 511 initially added lacosamide therapy, 493 added another AED, 69 were ≥65years of age, and 72 took concomitant antiarrhythmic drugs. Patients in the lacosamide cohort had a higher median frequency of partial-onset seizures (6.0 versus 3.5 per 28days) despite taking more concomitant AEDs (84.9% versus 66.9% took ≥2) at baseline. Patients who added lacosamide took a modal dose of 200mg/day over the treatment period (n=501), and 50.1% (256/511) completed 12months of treatment. Fifty-one point nine percent (256/493) of patients who added another AED completed the study, with the most commonly added AED being levetiracetam (28.4%). Four patients (0.8%) in each cohort, all <65years of age, reported predefined CV-related TEAEs. None were considered serious or led to discontinuation. One event each of sinus bradycardia (lacosamide), atrioventricular block first degree (lacosamide), and syncope (other AED) were judged to be treatment-related. Another patient in the other AED cohort reported bradycardia while taking concomitant antiarrhythmic drugs. Predefined psychiatric-related TEAEs were reported by 21 patients (4.1%) in the lacosamide cohort and 27 patients (5.5%) in the other AED cohort. Depression was the most common to be treatment-related (7/11 and 12/18 of patients reporting treatment-related psychiatric TEAEs, respectively). Serious psychiatric-related TEAEs were reported by four patients who added lacosamide (two cases of depression, two of suicide attempt) and one who added another AED (depression). Seven deaths occurred, all of which were considered unrelated/unlikely related to study medication. This thorough evaluation revealed a low incidence of predefined CV- and psychiatric-related TEAEs in patients taking adjunctive AED therapy according to standard medical practice. No specific safety concerns related to adjunctive lacosamide therapy were noted.

Topics: Acetamides; Adult; Aged; Anticonvulsants; Combined Modality Therapy; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Lacosamide; Levetiracetam; Longitudinal Studies; Male; Middle Aged; Piracetam; Seizures; Treatment Outcome

to evaluate the efficacy and safety of intravenous (IV) lacosamide (LCM) in the treatment of seizure clusters (SC) and status epilepticus (SE) in hospitalized adult patients.. we prospectively analyzed treatment response, seizure outcome, and adverse effects of IV LCM in 38 patients with seizure emergencies (15 with SC, 23 with SE) during a hospital stay. The loading dose of IV LCM was 200-400mg and the maintenance dose was 200-400mg daily. Response to IV LCM was evaluated within 20min, 4h and 24h of LCM infusion.. an acute anti-seizure effect after IV LCM was especially evident when it was first used - (SC) or second line (established SE) treatment. In particular, 87% of SC patients (13/15) and 80% of established SE (8/10) demonstrated response to LCM treatment, while no patients with super-refractory SE (0/8) responded to IV LCM according to our criteria. The loading of IV LCM was well tolerated, with mild adverse effects (2/38 temporary dizziness). In most patients, during and after administration of the loading dose of IV LCM a temporary (30min-1h) sedation was observed. No ECG and laboratory values-changes were documented in any of the patients.. LCM is an effective and well-tolerated treatment when used to treat SC in hospitalized adult patients. As add-on therapy, it may be useful to stop seizure activity in patients with focal SE not responding to first/second-line intravenous AEDs.

Topics: Acetamides; Administration, Intravenous; Adult; Aged; Aged, 80 and over; Anticonvulsants; Brain; Electroencephalography; Female; Hospitalization; Humans; Inpatients; Lacosamide; Male; Middle Aged; Prospective Studies; Seizures; Status Epilepticus; Treatment Outcome

The aim of this study was to determine the effects of xanthotoxin (8-methoxypsoralen) on the protective action of 5 various second- and third-generation antiepileptic drugs (i.e., lacosamide, lamotrigine, oxcarbazepine, pregabalin and topiramate) in the mouse maximal electroshock-induced seizure model. Seizure activity was evoked in adult male albino Swiss mice by a current (25mA, 500V, 0.2s stimulus duration) delivered via auricular electrodes. Drug-related adverse effects were determined in the chimney, grip-strength and passive avoidance tests. Total brain antiepileptic drug concentrations were measured to confirm pharmacodynamic nature of observed interactions with xanthotoxin. Results indicate that xanthotoxin (100mg/kg, i.p.) significantly enhanced the anticonvulsant action of lacosamide (P<0.01), oxcarbazepine (P<0.05), pregabalin (P<0.01), and topiramate (P<0.001), but not that of lamotrigine in the maximal electroshock-induced seizure test. Moreover, xanthotoxin (50mg/kg) still significantly potentiated the anticonvulsant action of lacosamide (P<0.05), pregabalin (P<0.05), and topiramate (P<0.001) in this seizure test. Xanthotoxin had no significant impact on total brain concentrations of the studied antiepileptic drugs in mice. Furthermore, combinations of xanthotoxin with oxcarbazepine or topiramate produced no adverse effects. However, xanthotoxin in combination with lacosamide, lamotrigine or pregabalin significantly reduced muscular strength in mice in the grip-strength test. In the chimney test, only the combinations of xanthotoxin with pregabalin significantly impaired motor coordination in mice. In conclusion, the combinations of xanthotoxin with oxcarbazepine and topiramate produce beneficial anticonvulsant pharmacodynamic interactions in the maximal electroshock-induced seizure test. A special caution is advised when combining xanthotoxin with pregabalin due to appearance of acute adverse effects.

Topics: Acetamides; Animals; Anticonvulsants; Carbamazepine; Drug Synergism; Electroshock; Fructose; Lacosamide; Lamotrigine; Male; Methoxsalen; Mice; Oxcarbazepine; Pregabalin; Seizures; Topiramate; Triazines

The choice of antiepileptic drug (AED) therapy in patients with brain tumor-related epilepsy (BTRE) is complicated, and there are a lack of robust clinical trial data to date.. The NEOPLASM (Neuroncologic Patients treated with LAcoSaMide) study was a 6-month, multicenter, retrospective, observational study in patients with BTRE treated with lacosamide. Patients were started on lacosamide because of a lack of efficacy or adverse events (AEs) with prior AEDs or suitability versus other AEDs, according to clinical practice. The primary efficacy variable was the seizure-free rate at 6months. Safety variables included the proportion of patients with an AE and the proportion with an AE that led to discontinuation.. Overall, 105 patients from 14 hospital centers were included in the analysis. Treatment with lacosamide for 6months resulted in a 30.8% seizure-free rate, and 66.3% of patients had a ≥50% seizure reduction (responders). In the subset of patients included because of a lack of efficacy with prior AEDs, seizure-free rates were 28.0%, and 66.7% of patients were responders. No statistically significant differences in efficacy were observed according to the mechanism of action or enzyme-inducing properties of concomitant AEDs. Adverse events were reported by 41.9% of patients at 6months, and 4.7% of them led to discontinuation. The most common AEs were somnolence/fatigue and dizziness. Notably, 57.1% of the patients who were switched to lacosamide because of AEs with their previous therapy did not report any AE at 6-month follow-up.. In this open-label, observational study, lacosamide appeared to be effective and well tolerated in a large population of patients with BTRE. Lacosamide may therefore be a promising option for the treatment of patients with BTRE.

Topics: Acetamides; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Brain Neoplasms; Epilepsy; Female; Follow-Up Studies; Humans; Lacosamide; Male; Middle Aged; Retrospective Studies; Seizures; Treatment Outcome; Young Adult

The purpose of this study was to synthesize the library of 33 new N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamides, 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)propanamides, and 2-(2,5-dioxopyrrolidin-1-yl)butanamides as potential new hybrid anticonvulsant agents. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. The coupling reaction of the 2-(2,5-dioxopyrrolidin-1-yl)propanoic acid, 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)propanoic acid, or 2-(2,5-dioxopyrrolidin-1-yl)butanoic acid with the appropriately substituted benzylamines in the presence of the coupling reagent, N,N-carbonyldiimidazole (CDI) generated the final compounds 4-36. Spectral data acquired via (1)H NMR, (13)C NMR, and LC-MS confirmed the chemical structures of the newly prepared compounds. The initial anticonvulsant screening was performed in mice intraperitoneally (ip), using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The rotarod test determined the acute neurological toxicity (NT). The results of preliminary pharmacological screening revealed that 25 compounds showed protection in half or more of the animals tested in the MES and/or scPTZ seizure models at the fixed dose of 100mg/kg. The broad spectra of activity across the preclinical seizure models displayed compounds 4, 7, 8, 13, 15-18, 24, and 26. The quantitative pharmacological studies in mice demonstrated the highest protection for compounds 4 (ED50 MES=67.65 mg/kg, ED50scPTZ=42.83 mg/kg); 8 (ED50 MES=54.90 mg/kg, ED50scPTZ=50.29 mg/kg); and 20 (ED50scPTZ=47.39 mg/kg). These compounds were distinctly more potent and provided better safety profiles in the rotarod test compared to valproic acid or ethosuximide, which were used as model AEDs. Compound 8 underwent only a slight metabolic change by the human liver microsomes (HLMs), and also did not affect the activity of human cytochrome P450 isoform, CYP3A4, in the in vitro assays.

Topics: Amides; Animals; Anticonvulsants; Benzylamines; Convulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Electroshock; Humans; Imidazoles; Male; Mice; Microsomes, Liver; Molecular Structure; Motor Activity; Pentylenetetrazole; Propionates; Pyrrolidines; Rotarod Performance Test; Seizures; Small Molecule Libraries; Structure-Activity Relationship

Six novel 3″-substituted (R)-N-(phenoxybenzyl) 2-N-acetamido-3-methoxypropionamides were prepared and then assessed using whole-cell, patch-clamp electrophysiology for their anticonvulsant activities in animal seizure models and for their sodium channel activities. We found compounds with various substituents at the terminal aromatic ring that had excellent anticonvulsant activity. Of these compounds, (R)-N-4'-((3″-chloro)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-5) and (R)-N-4'-((3″-trifluoromethoxy)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-9) exhibited high protective indices (PI=TD50/ED50) comparable with many antiseizure drugs when tested in the maximal electroshock seizure test to mice (intraperitoneally) and rats (intraperitoneally, orally). Most compounds potently transitioned sodium channels to the slow-inactivated state when evaluated in rat embryonic cortical neurons. Treating HEK293 recombinant cells that expressed hNaV1.1, rNaV1.3, hNaV1.5, or hNaV1.7 with (R)-9 recapitulated the high levels of sodium channel slow inactivation.

Topics: Acetamides; Administration, Oral; Amides; Amino Acids; Animals; Anticonvulsants; Cerebral Cortex; Electroshock; HEK293 Cells; Humans; Injections, Intraperitoneal; Male; Mice; Neurons; Patch-Clamp Techniques; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Seizures; Structure-Activity Relationship; Voltage-Gated Sodium Channel Blockers; Voltage-Gated Sodium Channels

The library of 27 new 1-(4-phenylpiperazin-1-yl)- or 1-(morpholin-4-yl)-(2,5-dioxopyrrolidin-1-yl)propanamides and (2,5-dioxopyrrolidin-1-yl)butanamides as potential new hybrid anticonvulsant agents was synthesized. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5, 10, 11, and 24 displayed the broad spectra of activity across the preclinical seizure models, namely, the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (scPTZ) test, and the six-hertz (6 Hz) model of pharmacoresistant limbic seizures. The highest protection was demonstrated by 11 (ED50 MES = 88.4 mg/kg, ED50 scPTZ = 59.9 mg/kg, ED50 6 Hz = 21.0 mg/kg). This molecule did not impair the motor coordination of animals in the chimney test even at high doses (TD50 > 1500 mg/kg), yielding superb protective indexes (PI MES > 16.97, PI PTZ > 25.04, PI 6 Hz > 71.43). As a result, 11 displayed distinctly better safety profile than clinically relevant AEDs ethosuximide, lacosamide, or valproic acid.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Electroshock; HEK293 Cells; Humans; Mice; Models, Molecular; Molecular Structure; Motor Activity; Piperazines; Seizures; Structure-Activity Relationship; Succinimides

Antiepileptic medications have been reported to cause disturbances in cardiac conduction. Lacosamide decreases seizure burden by modulating sodium channels. Although it has been demonstrated to have few side effects, there have been reports of clinically significant cardiac conduction disturbances. We report the case of a child with hypoplastic left-heart syndrome and well-controlled multifocal atrial tachycardia who developed haemodynamically significant atrial tachycardia after receiving two doses of lacosamide.

Topics: Acetamides; Anticonvulsants; Arrhythmias, Cardiac; Child, Preschool; Comorbidity; Humans; Hypoplastic Left Heart Syndrome; Isoxazoles; Lacosamide; Levetiracetam; Male; Piracetam; Seizures; Tachycardia, Sinus; Treatment Outcome; Zonisamide

The functionalized amino acid, lacosamide ((R)-2), and the α-aminoamide, safinamide ((S)-3), are neurological agents that have been extensively investigated and have displayed potent anticonvulsant activities in seizure models. Both compounds have been reported to modulate voltage-gated sodium channel activity. We have prepared a series of chimeric compounds, (R)-7-(R)-10, by merging key structural units in these two clinical agents, and then compared their activities with (R)-2 and (S)-3. Compounds were assessed for their ability to alter sodium channel kinetics for inactivation, frequency (use)-dependence, and steady-state activation and fast inactivation. We report that chimeric compounds (R)-7-(R)-10 in catecholamine A-differentiated (CAD) cells and embryonic rat cortical neurons robustly enhanced sodium channel inactivation at concentrations far lower than those required for (R)-2 and (S)-3, and that (R)-9 and (R)-10, unlike (R)-2 and (S)-3, produce sodium channel frequency (use)-dependence at low micromolar concentrations. We further show that (R)-7-(R)-10 displayed excellent anticonvulsant activities and pain-attenuating properties in the animal formalin model. Of these compounds, only (R)-7 reversed mechanical hypersensitivity in the tibial-nerve injury model for neuropathic pain in rats.

Topics: Acetamides; Alanine; Analgesics; Animals; Anticonvulsants; Benzylamines; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Female; Formaldehyde; Lacosamide; Male; Membrane Potentials; Mice; Neuralgia; Neurons; Patch-Clamp Techniques; Rats, Sprague-Dawley; Seizures; Tibial Nerve; Voltage-Gated Sodium Channel Blockers; Voltage-Gated Sodium Channels

Many patients with epilepsy are treated with antiepileptic drug (AED) polytherapy. Several factors influence the choice of early add-on therapy, and deciding on the most appropriate drug can be difficult. This study aimed to assess the efficacy and tolerability of lacosamide as early add-on therapy in patients with partial-onset seizures.. REALLY (REtrospective study of lAcosamide as earLy add-on aLong one Year) was a multicenter, retrospective, 1-year, real-life study. Patients included were aged older than 16 years, had partial-onset seizures, and were treated with lacosamide as add-on therapy after one or two prior AEDs. Data were collected retrospectively from clinical records. The primary study objective was to assess the efficacy of lacosamide over 12 months (seizure-free and responder rates), and the secondary objective was to assess the tolerability of lacosamide at 3, 6, and 12 months [adverse events (AEs) and discontinuation].. One hundred and ninety-nine patients were enrolled in the study; 89 patients (44.7 %) had tried one AED and 110 patients (55.3 %) had tried two AEDs before lacosamide. At 12 months, the proportion of patients who were seizure free was 44.9 %, and 76 % of patients were responders. The seizure-free rate at 12 months for patients who had previously received one or two AEDs was 58 and 34.3 %, and the responder rate at 12 months was 83.0 and 70.4 %, respectively. The AE rate was 21.5 % at 3 months, 27.1 % at 6 months, and 31.2 % at 12 months, with 7.0 % of patients discontinuing treatment because of an AE. The most common AE reported was dizziness (11.6 %). Cryptogenic epilepsy, a higher number of prior AEDs, and the use of a sodium channel blocker at onset were associated with a worse outcome. The number of concomitant AEDs decreased over 1 year (Z = 5.89; p < 0.001). Twenty-two patients were converted to lacosamide monotherapy with at least one evaluation ≥6 months from the beginning of monotherapy conversion.. Lacosamide was effective and well tolerated as early add-on treatment in patients who had received one or two previous AEDs.

Topics: Acetamides; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Drug Therapy, Combination; Female; Humans; Lacosamide; Male; Middle Aged; Retrospective Studies; Seizures; Young Adult

Two cases with partial onset epilepsy who developed status epilepticus (SE) on lacosamide (LCM) monotherapy are reported. LCM is an effective adjunctive antiepileptic drug (AED) for partial-onset epilepsy and as infusion in SE. It has also shown efficacy in monotherapy. The reported cases achieved control of seizures with adjunctive LCM treatment and were afterwards converted to monotherapy. Both patients subsequently developed SE while on LCM monotherapy. They were on monotherapy for at least 2 months after withdrawal of concomitant AEDs precluding the possibility of withdrawal-induced SE. Pharmacovigilance is indicated when LCM is administered in monotherapy in order to assess its proper therapeutic potential and its putative limitations especially in cases where it may prove ineffective. Moreover, vigilance is necessary whenever any concomitant antiepileptic is tapered regardless of the substances used. Higher doses may be needed when an AED is used in monotherapy.

Topics: Acetamides; Adult; Anticonvulsants; Dose-Response Relationship, Drug; Epilepsies, Partial; Humans; Lacosamide; Male; Middle Aged; Seizures; Status Epilepticus; Treatment Outcome

The influence of arachidonyl-2'-chloroethylamide (ACEA - a selective cannabinoid CB1 receptor agonist) on the anticonvulsant potency and acute adverse-effect potentials of clobazam, lacosamide, and pregabalin was determined in the maximal electroshock-induced seizure model and chimney test in mice. ACEA (2.5 mg/kg, i.p.) significantly enhanced the anticonvulsant potency of pregabalin in the mouse maximal electroshock-induced seizure model by decreasing the median effective dose (ED50 ) of pregabalin from 125.39 to 78.06 mg/kg (P < 0.05). In contrast, ACEA (2.5 mg/kg) had no significant impact on the anticonvulsant potency of clobazam and lacosamide in the mouse maximal electroshock-induced seizure model. On the other hand, ACEA (2.5 mg/kg) did not affect acute adverse effects of clobazam, lacosamide or pregabalin, and the median toxic doses (TD50 ) for the studied anti-epileptic drugs in combination with ACEA did not differ from the TD50 values as determined for the drugs administered alone in the chimney test. In conclusion, ACEA ameliorates the pharmacological profile of pregabalin, when considering both the anticonvulsant and the acute adverse effects of the drug in preclinical study on animals. The combination of pregabalin with ACEA can be of pivotal importance for patients with epilepsy as a potentially advantageous combination if the results from this study translate into clinical settings.

Topics: Acetamides; Animals; Anticonvulsants; Arachidonic Acids; Ataxia; Benzodiazepines; Brain; Clobazam; Dose-Response Relationship, Drug; Drug Synergism; Electroshock; Lacosamide; Lethal Dose 50; Male; Mice; Pregabalin; Psychomotor Performance; Receptor, Cannabinoid, CB1; Seizures

The 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.. We 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).. Sixty-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.. In 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.

Topics: Acetamides; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Epilepsies, Partial; Female; Follow-Up Studies; Humans; Lacosamide; Male; Middle Aged; Retrospective Studies; Seizures; Spain; Time Factors; Treatment Outcome; Young Adult

Nearly one third of patients presenting with mesial temporal lobe epilepsy (MTLE), the most prevalent lesion-related epileptic disorder in adulthood, do not respond to currently available antiepileptic medications. Thus, there is a need to identify and characterize new antiepileptic drugs. In this study, we used the pilocarpine model of MTLE to establish the effects of a third generation drug, lacosamide (LCM), on seizures, interictal spikes and high-frequency oscillations (HFOs, ripples: 80-200 Hz, fast ripples: 250-500 Hz).. Sprague-Dawley rats (250-300 g) were injected with pilocarpine to induce a status epilepticus (SE) that was pharmacologically terminated after 1h. Eight pilocarpine-treated rats were then injected with LCM (30 mg/kg, i.p.) 4h after SE and daily for 14 days. Eight pilocarpine-treated rats were used as controls and treated with saline. Three days after SE, all rats were implanted with bipolar electrodes in the hippocampal CA3 region, entorhinal cortex (EC), dentate gyrus (DG) and subiculum and EEG-video monitored from day 4 to day 14 after SE.. LCM-treated animals showed lower rates of seizures (0.21 (± 0.11) seizures/day) than controls (2.6 (±0.57), p<0.05), and a longer latent period (LCM: 11 (± 1) days, controls: 6.25 (± 1), p<0.05). Rates of interictal spikes in LCM-treated rats were significantly lower than in controls in CA3 and subiculum (p<0.05). Rates of ripples and fast ripples associated with interictal spikes in CA3 and subiculum as well as rates of fast ripples occurring outside of interictal spikes in CA3 were also significantly lower in LCM-treated animals. In controls, interictal spikes and associated HFOs correlated to seizure clustering, while this was not the case for isolated HFOs.. Our findings show that early treatment with LCM has powerful anti-ictogenic properties in the pilocarpine model of MTLE. These effects are accompanied by decreased rates of interictal spikes and associated HFOs. Isolated HFOs were also modulated by LCM, in a manner that appeared to be unrelated to its antiictogenic effects. These results thus suggest that distinct mechanisms may underlie interictal-associated and isolated HFOs in the pilocarpine model of MTLE.

Topics: Acetamides; Animals; Anticonvulsants; Disease Models, Animal; Electrocorticography; Electrodes, Implanted; Electroencephalography; Epilepsy, Temporal Lobe; Hippocampus; Lacosamide; Male; Pilocarpine; Rats, Sprague-Dawley; Seizures; Status Epilepticus; Treatment Outcome; Video Recording

A series of fluorinated analogs of the potent investigative anticonvulsant agent (4S,8aS)-4-phenylperhydropyrrolo[1,2-a]pyrazine-2,6-dione 1 was prepared and characterized by IR, 1H, 13C NMR and mass spectral data. The compounds have been evaluated in the in vivo rodent models of epilepsy. They displayed high activity in the 'classical' maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6Hz model of pharmacoresistant limbic seizures. The results showed that incorporating fluorine atoms into the phenyl ring of 1 can be beneficial for the anticonvulsant potency. The most promising meta-trifluoromethyl and meta-trifluoromethoxy derivatives (4S,8aS)-5h and (4S,8aS)-5l, respectively, displayed very broad spectra of activity across the preclinical seizure models.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Epilepsy; Halogenation; Hydrocarbons, Fluorinated; Male; Mice; Molecular Structure; Pentylenetetrazole; Pilocarpine; Pyrazines; Pyrroles; Rats; Rats, Sprague-Dawley; Seizures; Structure-Activity Relationship

Lacosamide is effective and well-tolerated antiepileptic drug (AED) in both children and adults.. This multicentric, prospective study investigates the efficacy and safety of lacosamide adjunctive therapy in children aged less than four years presenting with refractory focal seizures.. Lacosamide was added to the baseline therapy at a starting dose of 1-2 mg/kg/day and titrated to the final dose, ranging from 7 to 15.5 mg/kg/day. Efficacy was evaluated after a three-month period of therapy. When possible, we compared the initial efficacy and the retention after a minimum of 12 months of lacosamide, with regard to loss of efficacy (defined as the return to the baseline seizure frequency).. Twenty-four children were enrolled in the study. Mean age was 2.7 years. After a minimum three-month period of lacosamide add-on therapy, ten (42%) patients were responders (more than a 50% decrease in seizure frequency), of whom 4 (17%) became seizure free. Retention rate, after a minimum of 12 months of lacosamide, was evaluated in a group of 18 patients. In the latter group, eight patients (44%) were initial responders (three of whom seizure free). After 12 months of follow-up, four of them (22%) maintained the improvement, 2 (11%) of whom remained seizure free. A loss of efficacy was observed in 4 of the initial responders (50%). Adverse events were seen in 8 (33%) patients.. We conclude that lacosamide is an effective and a well-tolerated antiepileptic drug in an etiologically wide range of focal seizures. Therefore, lacosamide might represent a possible therapeutic option in infants and young children affected by uncontrolled focal epilepsy.

Topics: Acetamides; Anticonvulsants; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Epilepsies, Partial; Female; Follow-Up Studies; Humans; Infant; Lacosamide; Male; Prospective Studies; Seizures; Severity of Illness Index; Time Factors; Treatment Outcome

Topics: Acetamides; Anticonvulsants; Electroencephalography; Epilepsies, Partial; Humans; Lacosamide; Levetiracetam; Magnetic Resonance Imaging; Male; Middle Aged; Neurologic Examination; Piracetam; Seizures; Toothbrushing

Lacosamide (LCM), a new antiepileptic drug (AED) approved as adjunctive therapy for the treatment of patients with partial-onset seizures, has limited pharmacokinetic and drug interaction data. The main objectives of the present study were to investigate the effects of dose, age, gender, and hepatic enzyme-inducing AEDs on the pharmacokinetics of LCM as assessed by steady state serum LCM values.. An LCM AED therapeutic drug monitoring database was analyzed with regard to LCM serum concentrations and other relevant patient and AED drug information. One hundred twenty eight sera were identified. These were collected from 68 women and 61 men aged 19-66 years, who were prescribed a median LCM dose of 300 mg (range 50-600 mg).. Serum LCM concentrations were observed in the following main groupings: LCM monotherapy (n = 5), LCM with nonenzyme-inducing AEDs (n = 50), LCM with enzyme-inducing AEDs (n = 49), LCM with valproic acid (n = 20), and LCM with enzyme-inducing AEDs plus valproic acid (n = 4). Analysis of variance showed a correlation of dose with LCM concentrations (r = 0.53, P < 0.001), and women had statistically higher mean LCM concentration than did men, 37.2 ± 23.6 versus 26.8 ± 12.9 μmol/L (P = 0.001). Serum LCM concentrations were significantly lower (P = 0.002) in the enzyme-inducing AED group (carbamazepine and phenytoin) compared with the LCM monotherapy group and the nonenzyme-inducing group, 23.5 ± 11.0, 34.5 ± 7.7, and 32.7 ± 17.9 μmol/L, respectively.. Serum LCM concentrations increased dose dependently, were age independent, and were higher in women compared with men. Carbamazepine and phenytoin can significantly decrease serum LCM concentrations, probably via induction of LCM metabolism.

Topics: Acetamides; Adult; Aged; Anticonvulsants; Carbamazepine; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Enzyme Induction; Epilepsy; Female; Humans; Lacosamide; Male; Middle Aged; Phenytoin; Retrospective Studies; Seizures; Valproic Acid

In 2008, lacosamide (LCM) was licensed in Europe for the adjunctive treatment of focal-onset seizures. At that time a prospective audit was initiated at the Western Infirmary to assess outcomes with this antiepileptic drug (AED) in everyday clinical practice.. A total of 160 patients (74 M; 86 F, aged 14-74 years [median 42 years]) with uncontrolled focal-onset seizures (median monthly frequency 1; range 1-300) were started on LCM. After 12 weeks on stable AED doses (median 1 AED; range 1-4), LCM was added and the dose titrated as appropriate with a target range of 200-400 mg/day. Review took place every 6-8 weeks until 1 of 4 end-points was reached: seizure freedom for 6 months on a given LCM dose; ≥50% (responder) or <50% (marginal benefit) seizure reduction over 6 months compared with baseline on the highest tolerated LCM dose; withdrawal of LCM due to lack of efficacy, side effects, or both.. Of the 160 patients, 35 (21.9%) remained seizure-free for at least 6 months on a stable LCM dose, while 35 (21.9%) had a ≥50% reduction in seizure frequency and 54 (33.7%) reported a marginal benefit. Five patients became seizure-free on LCM monotherapy following withdrawal of their initial treatment. Outcomes were similar for patients taking LCM with traditional sodium blocking agents (n=56; 43 [76%] continued LCM) compared to those who also received AEDs with other mechanisms (n=84; 64 [76%] continued LCM). LCM was discontinued in 36 (22.5%) patients because of lack of efficacy (n=24, 15%) or side effects (n=12; 7.5%). Commonest side effects leading to withdrawal were nausea and vomiting, dizziness, sedation, headaches, tremor, and ataxia, particularly for patients also taking sodium valproate.. LCM is a well-tolerated and effective AED for focal-onset seizures with or without secondary generalisation, regardless of concomitant treatment. Commonest dose-related side effects were neurotoxic in nature.

Topics: Acetamides; Adolescent; Adult; Aged; Anticonvulsants; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Lacosamide; Male; Middle Aged; Seizures; Time Factors; Treatment Outcome; Young Adult

The influence of WIN 55,212-2 mesylate (WIN) on the anticonvulsant activity and acute neurotoxic potential of clobazam (CLB) and lacosamide (LCM) was studied in the maximal electroshock-induced seizure (MES) model and chimney test in mice.. indicate that WIN administered intraperitoneally, at doses of 2.5 and 5 mg/kg significantly enhanced the anticonvulsant action of CLB in the MES test by reducing its median effective dose (ED50) from 20.80 mg/kg to 12.05 mg/kg (P<0.05), and 8.22 mg/kg (P<0.001), respectively. In contrast, WIN (1.25 mg/kg) did not significantly potentiate the anticonvulsant activity of CLB against MES-induced seizures. Similarly, WIN at doses of 1.25, 2.5 and 5 mg/kg had no significant impact on the anticonvulsant action of LCM in the MES test. On the other hand, WIN (5 mg/kg) had no impact on the acute neurotoxic effects of CLB and LCM in the chimney test and the median toxic doses (TD50) for CLB and LCM were almost unchanged. Thus, WIN (5 mg/kg) elevated the protective index values for CLB (from 1.41 to 3.07) and LCM (from 3.60 to 4.91). In conclusion, WIN potentiates suppression of tonic-clonic seizures produced by CLB in the mouse MES model, without affecting acute neurotoxic adverse effects of CLB in the chimney test in mice, which is favorable from a preclinical point of view.

Topics: Acetamides; Animals; Anticonvulsants; Benzodiazepines; Benzoxazines; Clobazam; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Electroshock; Injections, Intraperitoneal; Lacosamide; Male; Mice; Morpholines; Motor Activity; Naphthalenes; Random Allocation; Seizures

Several antiepileptic drugs exert their activities by inhibiting Na(+) currents. Recent studies demonstrated that compounds containing a biaryl-linked motif (Ar-X-Ar') modulate Na(+) currents. We, and others, have reported that compounds with an embedded benzyloxyphenyl unit (ArOCH2Ar', OCH2=X) exhibit potent anticonvulsant activities. Here, we show that benzyloxybenzylammonium chlorides ((+)H3NCH2C6H4OCH2Ar' Cl(-)) displayed notable activities in animal seizure models. Electrophysiological studies of 4-(2'-trifluoromethoxybenzyloxy)benzylammonium chloride (9) using embryonic cortical neurons demonstrated that 9 promoted both fast and slow inactivation of Na(+) channels. These findings suggest that the potent anticonvulsant activities of the earlier compounds were due, in part, to the benzyloxyphenyl motif and provide support for the use of the biaryl-linked pharmacophore in future drug design efforts.

Topics: Animals; Anticonvulsants; Benzylammonium Compounds; Cerebral Cortex; Dose-Response Relationship, Drug; Mice; Molecular Structure; Neurons; Phenyl Ethers; Rats; Rats, Sprague-Dawley; Seizures; Structure-Activity Relationship

The object of this study was to determine the tolerability and activity of lacosamide in patients with brain tumors.. The authors reviewed the medical records at 5 US academic medical centers with tertiary brain tumor programs, seeking all patients in whom a primary brain tumor had been diagnosed and who were taking lacosamide.. The authors identified 70 patients with primary brain tumors and reviewed seizure frequency and toxicities. The majority of the patients had gliomas (96%). Fifty-five (78%) had partial seizures only, and 12 (17%) had generalized seizures. Most of the patients (74%) were started on lacosamide because of recurrent seizures. Forty-six patients (66%) reported a decrease in seizure frequency, and 21 patients (30%) reported stable seizures. Most of the patients (54 [77%]) placed on lacosamide did not report any toxicities.. This retrospective analysis demonstrated that lacosamide was both well tolerated and active as an add-on antiepileptic drug (AED) in patients with brain tumors. Lacosamide's novel mechanism of action will allow for concurrent use with other AEDs, as documented by its activity across many different types of AEDs used in this patient population. Larger prospective studies are warranted.

Topics: Acetamides; Adult; Anticonvulsants; Brain Neoplasms; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Glioblastoma; Humans; Lacosamide; Male; Middle Aged; Prevalence; Retrospective Studies; Secondary Prevention; Seizures; Treatment Outcome

Topics: Acetamides; Anticonvulsants; Brain Neoplasms; Female; Humans; Lacosamide; Male; Seizures

Lacosamide (LCM, Vimpat) is an anticonvulsant with a unique mode of action. This provides lacosamide with the potential to act additively or even synergistically with other antiepileptic drugs (AEDs). The objective of this study was to determine the presence of such interactions by isobolographic analysis.. The anticonvulsant effect of LCM in combination with other AEDs including carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), lamotrigine (LTG), topiramate (TPM), gabapentin (GBP), and levetiracetam (LEV) at fixed dose ratios of 1:3, 1:1, and 3:1, was evaluated in the 6-Hz-induced seizure model in mice. In addition, the impact of the combinations of LCM with the other AEDs on motor coordination was assessed in the rotarod test. Finally, AED concentrations were measured in blood and brain to evaluate potential pharmacokinetic drug interactions.. All studied AEDs produced dose-dependent anticonvulsant effects against 6-Hz-induced seizures. Combinations of LCM with CBZ, LTG, TPM, GBP, or LEV were synergistic. All other LCM/AED combinations displayed additive effects with a tendency toward synergism. Furthermore, no enhanced adverse effects were observed in the rotarod test by combining LCM with other AEDs. No pharmacokinetic interactions were seen on brain AED concentrations. Coadministration of LCM and TPM led to an increase in plasma levels of LCM, whereas the plasma concentration of PHT was increased by coadministration of LCM.. The synergistic anticonvulsant interaction of LCM with various AEDs, without exacerbation of adverse motor effects, highlights promising properties of LCM as add-on therapy for drug refractory epilepsy.

Topics: Acetamides; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Electric Stimulation; Lacosamide; Male; Mice; Mice, Inbred CBA; Motor Activity; Rotarod Performance Test; Seizures

Lamotrigine (LTG) is a popular modern antiepileptic drug (AED); however, its mechanism of action has yet to be fully understood, as it is known to modulate many members of several ion channel families. In heterologous systems, LTG inhibits Cav 2.3 (R-type) calcium currents, which contribute to kainic-acid (KA)-induced epilepsy in vivo. To gain insight into the role of R-type currents in LTG drug action in vivo, we compared the effects of LTG to two other AEDs in Cav 2.3-deficient mice and controls on KA-induced seizures.. Behavioral seizure rating and quantitative electrocorticography were performed after injection of 20 mg/kg (and 30 mg/kg) KA. One hour before KA injection, mice were pretreated with 30 mg/kg LTG, 50 mg/kg topiramate (TPM), or 30 mg/kg lacosamide (LSM).. Ablation of Cav 2.3 reduced total seizure scores by 28.6% (p = 0.0012), and pretreatment with LTG reduced seizure activity of control mice by 23.2% (p = 0.02). In Cav 2.3-deficient mice, LTG pretreatment increased seizure activity by 22.1% (p = 0.018) and increased the percentage of degenerated CA1 pyramidal neurons (p = 0.02). All three AEDs reduced seizure activity in control mice; however, only the non-calcium channel modulating AED, LSM, had an anticonvulsive effect in Cav 2.3-deficient mice. Furthermore, LTG altered electrocorticographic parameters differently in the two genotypes: decreasing relative power of ictal spikes in control mice but increasing relative power of high frequency fast ripple discharges during seizures in Cav 2.3-deficient mice.. These findings provided the first in vivo evidence for an essential role for Cav 2.3 in LTG pharmacology and shed light on a paradoxical effect of LTG in their absence. Furthermore, LTG appears to promote ictal activity in Cav 2.3-deficient mice by increasing high frequency components of seizures, resulting in increased neurotoxicity in the CA1. This paradoxical mechanism, possibly reflecting rebound hyperexcitation of pyramidal CA1 neurons after increased inhibition, may be key in understanding LTG-induced seizure aggravation observed in clinical practice.

Topics: Acetamides; Animals; Anticonvulsants; Calcium Channels, R-Type; Cation Transport Proteins; Disease Models, Animal; Electroencephalography; Fructose; Hippocampus; Lacosamide; Lamotrigine; Mice; Seizures; Topiramate; Triazines

Lacosamide (LCM) is a recently licensed antiepileptic drug available in the UK since 2008. It is thought to act through modulation of sodium channel slow inactivation. Its efficacy and tolerability have been shown in several regulatory randomised controlled trials, but assessments of its performance in large naturalistic settings are rare. We assessed a large cohort of consecutive people who started LCM at a single tertiary epilepsy centre, from June 2008 to June 2011. Forty-five percent of the 376 people included were still taking LCM at last follow-up, with estimated retention was 62% at one year, 45% at two years and 35% at three years. Eighteen percent reported a period of improvement in terms of significant seizure reduction or seizure freedom of at least six months duration whilst on LCM, of whom four people were seizure free for at least one year. Long-term efficacy in our centre appears similar to zonisamide and pregabalin when compared to historical controls. Adverse events were reported by 61%, CNS-related in the vast majority. Most clinical factors did not affect retention; withdrawal occurred more often because of inefficacy than because of adverse events. Retention rates for LCM, when compared to historical controls appear similar to lamotrigine, topiramate, pregabalin, zonisamide, higher than gabapentin, and lower than levetiracetam.

Topics: Acetamides; Adolescent; Adult; Age of Onset; Aged; Anticonvulsants; Cohort Studies; Drug Resistance; Drug Therapy, Combination; Epilepsy; Female; Humans; Kaplan-Meier Estimate; Lacosamide; Male; Middle Aged; Seizures; Survival Analysis; Treatment Failure; Young Adult

N-Benzyl 2-acetamido-2-substituted acetamides, where the 2-substituent is a (hetero)aromatic moiety, are potent anticonvulsants. We report the synthesis and whole animal pharmacological evaluation of 16 analogues where the terminal 2-acetyl group was removed to give the corresponding primary amino acid derivatives (PAADs). Conversion to the PAAD structure led to a substantial drop in seizure protection in animal tests, demonstrating the importance of the N-acetyl moiety for anticonvulsant activity. However, several of the PAADs displayed notable pain-attenuating activities in a mouse model.

Topics: Acetamides; Amino Acids; Animals; Anticonvulsants; Disease Models, Animal; Drug Evaluation, Preclinical; Male; Mice; Mice, Inbred Strains; Molecular Structure; Neuralgia; Seizures; Structure-Activity Relationship

To determine whether pharmacodynamic interactions between high doses of lacosamide (400-800 mg/day) and concomitant sodium channel antiepilepsy drugs (AEDs) can be minimized in patients with drug-resistant partial-onset seizures.. Patients were rapidly initiated with high-dose lacosamide (100 mg/week; increases to 400 to 800 mg/day), while simultaneously tapering concomitant sodium channel AEDs. Seizure frequency and side effects were evaluated at six time points: baseline, titration, 3, 6, 9 and 12 months.. Twenty-three patients had a baseline median of 4 seizures/month with persisting partial-onset seizures, despite previous treatment with an average of 6.8 AEDs. Mean decreases in monthly seizure frequency were as follows: 3 months 49.9% (P = 0.011), 6 months 55.4% (P = 0.010), 9 months 60.8% (P = 0.002) and 12 months 58.2% (P = 0.011). Most adverse events were mild CNS-related symptoms and occurred transiently only during titration - there was no significant relationship (χ(2) < 1.5, P > 0.1) between lacosamide dose and the presence of side effects at 3, 6, 9 or 12 months.. Drug-resistant patients rapidly titrated to high doses of lacosamide with simultaneous tapering of traditional sodium channel AEDs had marked reduction in CNS-related adverse events compared with patients treated in three previous pivotal trials that used fixed doses of concomitant AEDs.

Topics: Acetamides; Adult; Aged; Anticonvulsants; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Lacosamide; Male; Middle Aged; Prospective Studies; Seizures; Sodium Channel Blockers; Treatment Outcome

Seizures are common in critically ill patients and can impact morbidity and mortality. Traditional anti-epileptic drugs (AEDs) in this setting are not always effective and are associated with adverse events and drug interactions. Lacosamide (LCM) is a new AED which is available in parental form although few studies have evaluated the safety and efficacy of LCM in critically ill patients.. Critically ill patients at Emory University Hospital who received LCM from April 1, 2009 to February 1, 2010 were retrospectively reviewed. Primary outcome measure was incidence and time to seizure cessation. Adverse effects were also recorded.. LCM was administered in 24 patients including 13 episodes of refractory status epilepticus (RSE) occurring in 10 patients and for treatment of isolated seizures or following resolution of RSE in an additional 14 patients. Seizure cessation was achieved in 5/13 (38%) episodes of RSE (mean 11.2 h) while there was at least a 50% decrease in seizure frequency in 7/13 (54%). 11/14 patients (76%) who received LCM for treatment of isolated seizures or prevention of seizure recurrence remained seizure free. Three patients experienced a decline in systolic blood pressure (> 20 mmHg) while one patient experienced unexplained fever and one patient had elevation of liver function tests.. This preliminary data suggests that LCM may be a safe and effective alternative for treatment of seizures in critically ill patients. Further prospective, randomized controlled trials are needed to confirm these findings and further explore the incidence of adverse effects.

Topics: Acetamides; Adult; Aged; Aged, 80 and over; Anticonvulsants; Critical Illness; Female; Humans; Hypotension; Intensive Care Units; Lacosamide; Male; Middle Aged; Retrospective Studies; Seizures; Status Epilepticus; Treatment Outcome

In this study, the synthesis and anticonvulsant properties of sixteen 2/3-benzoylaminopropionanilide derivatives were described. Molecular design of the compounds has been based on the modification of lacosamide which is a functionalized amino acid with a novel anticonvulsant activity. The structural confirmation of the title compounds was achieved by spectral and analytical data. The anticonvulsant activity profile of synthesized compounds was determined by maximal electroshock (MES) and subcutaneous metrazole (scMet) seizure tests, whereas their neurotoxicity was examined using rotarod test. All these tests were performed in accordance with the procedures of the Antiepileptic Drug Development (ADD) program. The majority of the compounds were effective in the MES or scMet screening tests. None of the compounds showed neurotoxicity according to the rotarod test at studied doses. Most active compounds in the series were 3, 12 and 13, which bearing 2-methyl, 2-ethyl and 2-isopropyl substituent on the N-phenyl ring, respectively.

Topics: Acetamides; Anilides; Animals; Anticonvulsants; Benzoates; Convulsants; Electroshock; Injections, Subcutaneous; Lacosamide; Magnetic Resonance Spectroscopy; Male; Mice; Neurotoxicity Syndromes; Pentylenetetrazole; Postural Balance; Seizures; Spectrophotometry, Infrared; Structure-Activity Relationship

Pharmacological management remains the primary method to treat epilepsy and neuropathic pain. We have advanced a novel class of anticonvulsants termed functionalized amino acids (FAAs). In this study, we examine FAA derivatives from which the terminal acetyl moiety was removed and termed these compounds primary amino acid derivatives (PAADs). Twenty-seven PAADs were prepared; the central C(2) R-substituent was varied, including C(2) stereochemistry, and the compounds were tested in rodent models of seizures and neuropathic pain. C(2)-Hydrocarbon N-benzylamide PAADs were potent anticonvulsants and excellent anticonvulsant activity (mice, ip; rat, po) was observed for C(2) R-substituted PAADs in which the R group was ethyl, isopropyl, or tert-butyl, and the C(2) stereochemistry conformed to the d-amino acid configuration ((R)-stereoisomer). These values surpassed the activities of several clinical antiepileptic drugs. The C(2) (R)-ethyl and C(2) (R)-isopropyl PAADs also displayed excellent activities in the mouse (ip) formalin neuropathic pain model. Significantly, unlike the FAA structure-activity relationship, PAAD anticonvulsant activity increased upon substitution of a methylene unit for a heteroatom in the R-substituent that was one atom removed from the C(2) site, suggesting that these PAADs function by a different pathway than FAAs.

Topics: Amino Acids; Analgesics; Animals; Anticonvulsants; Convulsants; Electroshock; Formaldehyde; Male; Mice; Neuralgia; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Seizures; Stereoisomerism; Structure-Activity Relationship

Recently, we reported that select N'-benzyl 2-substituted 2-amino acetamides (primary amino acid derivatives (PAADs)) exhibited pronounced activities in established whole animal anticonvulsant (i.e., maximal electroshock seizure (MES)) and neuropathic pain (i.e., formalin) models. The anticonvulsant activities of C(2)-hydrocarbon N'-benzyl 2-amino acetamides (MES ED(50) = 13-21 mg/kg) exceeded those of phenobarbital (ED(50) = 22 mg/kg). Two additional studies defining the structure-activity relationship of PAADs are presented in this issue of the journal. In this study, we demonstrated that the anticonvulsant activities of (R)-N'-benzyl 2-amino-3-methylbutanamide and (R)-N'-benzyl 2-amino-3,3-dimethylbutanamide were sensitive to substituents at the 4'-N'-benzylamide site; electron-withdrawing groups retained activity, electron-donating groups led to a loss of activity, and incorporating either a 3-fluorobenzyloxy or 3-fluorophenoxymethyl group using a rationally designed multiple ligand approach improved activity. Additionally, we showed that substituents at the 4'-N'-benzylamide site of (R)-N'-benzyl 2-amino-3-methoxypropionamide also improved anticonvulsant activity, with the 3-fluorophenoxymethyl group providing the largest (∼4-fold) increase in activity (ED(50) = 8.9 mg/kg), a value that surpassed phenytoin (ED(50) = 9.5 mg/kg). Collectively, the pharmacological findings provided new information that C(2)-hydrocarbon PAADs represent a novel class of anticonvulsants.

Topics: Amino Acids; Analgesics; Animals; Anticonvulsants; Butyrates; Male; Mice; Neuralgia; Pain Measurement; Propionates; Rats; Rats, Sprague-Dawley; Seizures; Stereoisomerism; Structure-Activity Relationship

Primary amino acid derivatives (PAADs) (N'-benzyl 2-substituted 2-amino acetamides) are structurally related to functionalized amino acids (FAAs) (N'-benzyl 2-substituted 2-acetamido acetamides) but differ by the absence of the terminal N-acetyl group. Both classes exhibit potent anticonvulsant activities in the maximal electroshock seizure animal model, and the reported structure-activity relationships (SARs) of PAADs and FAAs differ in significant ways. Recently, we documented that PAAD efficacy was associated with a hydrocarbon moiety at the C(2)-carbon, while in the FAAs, a substituted heteroatom one atom removed from the C(2)-center was optimal. Previously in this issue, we showed that PAAD activity was dependent upon the electronic properties of the 4'-N'-benzylamide substituent, while FAA activity was insensitive to electronic changes at this site. In this study, we prepared analogues of (R)-N'-benzyl 2-amino-3-methylbutanamide to identify the structural components for maximal anticonvulsant activity. We demonstrated that the SAR of PAADs and FAAs diverged at the terminal amide site and that PAADs had considerably more structural latitude in the types of units that could be incorporated at this position, suggesting that these compounds function according to different mechanism(s).

Topics: Aminobutyrates; Animals; Anticonvulsants; Male; Mice; Rats; Rats, Sprague-Dawley; Seizures; Solubility; Stereoisomerism; Structure-Activity Relationship

A number of novel pyrrole[1,2-a]pyrazine derivatives were synthesized and evaluated in in vivo animal models of epilepsy. Among them, several compounds displayed promising seizure protection in the maximal electroshock seizure (MES), subcutaneous metrazol seizure (scMET), 6 Hz and pilocarpine-induced status prevention (PISP) tests, with ED(50) values comparable to the reference anticonvulsant drugs (AEDs). A critical influence of the stereochemistry and conformational preferences of the pyrrole[1,2-a]pyrazine core on in vivo pharmacological activity was observed. The mechanism of the anticonvulsant action of the agents synthesized is most probably not via inhibition of the voltage-dependent sodium (Na(+)) currents.

Topics: Animals; Anticonvulsants; Diketopiperazines; Electroshock; Epilepsy; Humans; Male; Mice; Models, Molecular; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Rats, Wistar; Seizures; Sodium Channel Blockers; Sodium Channels

We investigated the safety, tolerability, and effectiveness of lacosamide (LCM) in patients with acute recurrent seizures or with periodic epileptiform activity captured during continuous EEG monitoring. A total of 17 patients received LCM; 12 patients received LCM as a second or third antiepileptic drug (AED), one patient as a fourth AED, and one patient as a fifth AED. No additional AEDs were introduced after LCM in 15 patients. Twelve patients responded to LCM with improvement in the seizures or periodic epileptiform activity. Two patients required further AED management or burst suppression. No adverse effects, including symptomatic bradycardia and allergic reactions, were seen for intravenous infusion dosages up to 300 mg. Eleven patients were eventually discharged on LCM. LCM is an important new AED in the add-on treatment of acute recurrent seizures and periodic epileptiform activity in critically ill patients.

Topics: Acetamides; Adult; Aged; Aged, 80 and over; Anticonvulsants; Brain; Critical Illness; Electroencephalography; Female; Humans; Lacosamide; Male; Middle Aged; Seizures; Treatment Outcome

Subacute encephalopathy with seizures in chronic alcoholism (SESA) was first described in 1981 by Niedermeyer who reported alcoholic patients presenting with confusion, seizures and focal neurological deficits and is quite distinct from patients presenting with typical alcohol withdrawal seizures. EEG often reveals periodic discharges and spikes, but SESA presenting with non-convulsive status epilepticus has rarely been described. We report a case of SESA with non-convulsive status epilepticus in a patient who was initially suspected of having a typical alcohol withdrawal seizure. A 61 year old woman with a history of chronic alcoholism was admitted at an outside hospital for confusion thought to be secondary to an alcohol withdrawal seizure. She had right hemiparesis and later developed right facial twitching that did not respond to intravenous fosphenytoin and levetiracetam. She was transferred for further management. Upon arrival, lorazepam and fosphenytoin were given and right face clonic movements resolved. However, continuous EEG monitoring revealed ongoing non-convulsive status epilepticus (NCSE). Following treatment with IV valproate and lacosamide, there was resolution of NCSE. SESA is likely an under recognized clinical syndrome that is quite distinct from typical alcohol withdrawal seizures and requires a different diagnostic and management approach. NCSE is likely to account for the encephalopathy and focal neurological deficits seen in patients presenting with the clinical syndrome of SESA. Therefore, a high degree of suspicion is warranted and continuous EEG monitoring is recommended for alcoholic patients with encephalopathy and focal neurological deficits.

Topics: Acetamides; Alcohol Withdrawal Seizures; Alcoholism; Anticonvulsants; Brain Diseases; Confusion; Diffusion Magnetic Resonance Imaging; Electroencephalography; Female; Humans; Lacosamide; Lorazepam; Middle Aged; Neurologic Examination; Paresis; Patient Compliance; Phenytoin; Seizures; Status Epilepticus; Tomography, X-Ray Computed; Valproic Acid

This retrospective study reports the early experience with lacosamide (LCM) as adjunctive therapy in Spanish patients with refractory focal epilepsy. Sixty patients (mean age 38.3 years, 54% women, mean epilepsy duration 27.2 years, mean seizure rate 9.7/month, and 28% with mainly nocturnal seizures) taking ≥2 antiepileptic drugs (mean 2.2) were included. LCM maintenance doses were 200, 300, 400, and 500mg/day in 31, 16, 10, and 3 patients, respectively. Patients were followed up for 13-24 months. Twenty-eight patients (47%) reported a ≥50% reduction in seizure frequency. A ≥50% reduction in seizure frequency was reported by 65% and 40% of patients in the nocturnal seizure and diurnal seizure subgroups, respectively (p>0.05). Of the 28 responders, 2 achieved stable periods of seizure freedom of 6 and 11 months after starting LCM. Twenty patients (33%) reported drug-related adverse events (AEs); the most common was dizziness (16 patients). LCM was withdrawn in 8 patients (13%). There were no serious AEs. These results support the efficacy and safety of adjunctive LCM in patients with partial-onset seizures.

Topics: Acetamides; Adult; Aged; Anticonvulsants; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Lacosamide; Male; Middle Aged; Retrospective Studies; Seizures; Young Adult

The structure-activity relationship (SAR) for the N-benzyl group in the clinical antiepileptic agent (R)-lacosamide [(R)-N-benzyl 2-acetamido-3-methoxypropionamide, (R)-3] has been explored. Forty-three compounds were prepared and then evaluated at the National Institute of Neurological Disorders and Stroke Anticonvulsant Screening Program for seizure protection in the maximal electroshock (MES) and subcutaneous Metrazol models. Comparing activities for two series of substituted aryl regioisomers (2', 3', 4') showed that 4'-modified derivatives had the highest activity. Significantly, structural latitude existed at the 4'-site. The SAR indicated that nonbulky 4'-substituted (R)-3 derivatives exhibited superb activity, independent of their electronic properties. Activities in the MES test of several compounds were comparable with or exceeded that of (R)-3 and surpassed the activities observed for the traditional antiepileptic agents phenytoin, phenobarbital, and valproate.

Topics: Acetamides; Animals; Anticonvulsants; Convulsants; Disease Models, Animal; Electroshock; Hippocampus; Kindling, Neurologic; Male; Mice; Molecular Structure; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Seizures; Serine; Structure-Activity Relationship

Functional amino acids (FAAs) and alpha-aminoamides (AAAs) are two classes of antiepileptic drugs (AEDs) that exhibit pronounced anticonvulsant activities. We combined key structural pharmacophores present in FAAs and AAAs to generate a new series of compounds and document that select compounds exhibit activity superior to either the prototypical FAA (lacosamide) or the prototypical AAA (safinamide) in the maximal electroshock (MES) seizure model in rats. A representative compound, (R)-N-4'-((3''-fluoro)benzyloxy)benzyl 2-acetamido-3-methoxypropionamide ((R)-10), was tested in the MES (mice, ip), MES (rat, po), psychomotor 6 Hz (32 mA) (mice, ip), and hippocampal kindled (rat, ip) seizure tests providing excellent protection with ED(50) values of 13, 14, approximately 10 mg/kg, and 12 mg/kg, respectively. In the rat sciatic nerve ligation model (ip), (R)-10 (12 mg/kg) provided an 11.2-fold attenuation of mechanical allodynia. In the mouse biphasic formalin pain model (ip), (R)-10 (15 mg/kg) reduced pain responses in the acute and the chronic inflammatory phases.

Topics: Acetamides; Alanine; Amides; Amino Acids; Animals; Anticonvulsants; Benzylamines; Drug Evaluation, Preclinical; Lacosamide; Mice; Pain; Rats; Seizures; Structure-Activity Relationship; Treatment Outcome

Lacosamide ((R)-N-benzyl 2-acetamido-3-methoxypropionamide, (R)-1) is a low molecular weight anticonvulsant recently introduced in the United States and Europe for adjuvant treatment of partial-onset seizures in adults. In this study, we define the structure-activity relationship (SAR) for the compound's 3-oxy site. Placement of small nonpolar, nonbulky substituents at the 3-oxy site provided compounds with pronounced seizure protection in the maximal electroshock (MES) seizure test with activities similar to (R)-1. The anticonvulsant activity loss that accompanied introduction of larger moieties at the 3-oxy site in (R)-1 was offset, in part, by including unsaturated groups at this position. Our findings were similar to a recently reported SAR study of the 4'-benzylamide site in (R)-1 ( J. Med. Chem. 2010 , 53 , 1288 - 1305 ). Together, these results indicate that both the 3-oxy and 4'-benzylamide positions in (R)-1 can accommodate nonbulky, hydrophobic groups and still retain pronounced anticonvulsant activities in rodents in the MES seizure model.

Topics: Acetamides; Animals; Anticonvulsants; Electroshock; Hydrophobic and Hydrophilic Interactions; Lacosamide; Male; Mice; Rats; Rats, Sprague-Dawley; Seizures; Stereoisomerism; Structure-Activity Relationship

We have advanced a novel strategy to search for lacosamide ((R)-1) targets in the brain proteome where protein binding is expected to be modest. Our approach used lacosamide agents containing affinity bait (AB) and chemical reporter (CR) units. The affinity bait moiety is designed to irreversibly react with the target, and the CR group permits protein detection and capture. In this study, we report the preparation and evaluation of (R)-N-(4-azido)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-3) and show that this compound exhibits potent anticonvulsant activities in the MES seizure model in rodents. We compared the utility of (R)-3 with its isostere, (R)-N-(4-isothiocyanato)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-2), in proteomic studies designed to identify potential (R)-1 targets. We showed that despite the two-fold improved anticonvulsant activity of (R)-3 compared with (R)-2, (R)-2 was superior in revealing potential binding targets in the mouse brain soluble proteome. The difference in these agents utility has been attributed to the reactivity of the affinity baits (i.e., (R)-2: aryl isothiocyanate moiety; (R)-3: photoactivated aryl azide intermediates) in the irreversible protein modification step, and we conclude that this factor is a critical determinant of successful target detection where ligand (drug) binding is modest. The utility of (R)-2 and (R)-3 in in situ proteome studies is explored.

Topics: Acetamides; Animals; Anticonvulsants; Azides; Brain; Cells, Cultured; Isothiocyanates; Lacosamide; Ligands; Male; Mice; Mice, Inbred ICR; Proteome; Seizures; Serine; Stereoisomerism; Structure-Activity Relationship

(R)-Lacosamide ((R)-2, (R)-N-benzyl 2-acetamido-3-methoxypropionamide) has recently gained regulatory approval for the treatment of partial-onset seizures in adults. Whole animal pharmacological studies have documented that (R)-2 function is unique. A robust strategy is advanced for the discovery of interacting proteins associated with function and toxicity of (R)-2 through the use of (R)-2 analogues, 3, which contain "affinity bait (AB)" and "chemical reporter (CR)" functional groups. In 3, covalent modification of the interacting proteins proceeds at the AB moiety, and detection or isolation of the selectively captured protein occurs through the bioorthogonal CR group upon reaction with an appropriate probe. We report the synthesis, pharmacological evaluation, and interrogation of the mouse soluble brain proteome using 3 where the AB group is an isothiocyanate moiety. One compound, (R)-N-(4-isothiocyanato)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-9), exhibited excellent seizure protection in mice, and like (R)-2, anticonvulsant activity principally resided in the (R)-stereoisomer. Several proteins were preferentially labeled by (R)-9 compared with (S)-9, including collapsin response mediator protein 2.

Topics: Acetamides; Animals; Anticonvulsants; Brain; In Vitro Techniques; Intercellular Signaling Peptides and Proteins; Isothiocyanates; Lacosamide; Male; Mice; Mice, Inbred ICR; Nerve Tissue Proteins; Proteome; Seizures; Serine; Stereoisomerism; Structure-Activity Relationship

Lacosamide ((R)-2-acetamido-N-benzyl-3-methoxypropionamide; formerly harkoseride, SPM 927; Vimpat), has been recently approved by US and European regulatory authorities for use as add-on therapy for partial-onset seizures in adults. Because a number of anti-epileptic drugs are used to treat conditions beyond epilepsy, including anxiety, in the present study we investigated the anxiolytic potential of lacosamide in a conditioned emotional response (CER) model in rat, and the mouse marble burying assay. In each test lacosamide produced a significant effect consistent with anxiolysis, i.e. lacosamide increased suppression ratio in the CER test, and reduced the number of marbles buried in the marble burying assay. The doses necessary for an anxiolytic effect were higher than those necessary for efficacy in seizure tests conducted in the same species. For example in the mouse, the lacosamide oral ED(50) in the maximal electroshock seizure (MES) and 6 Hz tests was 5.3 and 9.6 mg/kg respectively, and the minimal effective dose in the marble burying assay was 30 mg/kg. In both seizure and anxiety tests, the (S)-enantiomer of lacosamide was inactive suggesting a similar mechanism of action, possibly use-dependent inhibition of sodium channel function (Errington et al., 2008). Efficacy in the CER model was equivalent to diazepam and pregabalin (Lyrica). In tests of side-effects, lacosamide had no effect on choice accuracy in the delayed match to position task of working memory, although at the 30 mg/kg dose, response rates and response latencies were significantly affected. In sum, the present results identify for the first time, an anxiolytic potential of lacosamide.

Topics: Acetamides; Animals; Anti-Anxiety Agents; Anticonvulsants; Anxiety; Dose-Response Relationship, Drug; Electroshock; Lacosamide; Male; Memory; Mice; Motor Activity; Rats; Rats, Sprague-Dawley; Seizures; Sodium Channels

Studies have shown that functionalized amino acids (FAA) exhibit outstanding activity in the maximal electroshock-induced seizure (MES) test in rodents. Affinity labels patterned in part after the potent antiepileptic (R)-N-benzyl-2-acetamido-3-methoxypropionamide ((R)-2) have been prepared as mechanistic probes to learn the pharmacological basis for FAA function. The chemical reactivity of the affinity labels with nucleophiles was assessed, and the labels were evaluated in in vitro radioligand assays and in the MES tests in rodents. The affinity labels did not bind to receptors known to effect seizure spread. Three affinity labels, (R,S)-N-benzyl-2-acetamido-6-isothiocyanatohexanamide ((R,S)-5), (R)-N-(4-isothiocyanatobenzyl)-2-acetamido-3-methoxypropionamide ((R)-6), and (R)-N-(3-isothiocyanatobenzyl)-2-acetamido-3-methoxypropionamide ((R)-7), possessed excellent in vivo anticonvulsant activity and exhibited maximal activity at later time periods than typically observed for FAA. The anticonvulsant activity of 6 and 7 resided primarily in the (R)-enantiomer and the activity of (R)-6 and (R)-7 in rats (po) exceeded that of phenytoin. The chemical properties, pharmacological profile, and marked stereospecificity associated with 6 and 7 anticonvulsant activity make these compounds useful pharmacological tools for the study of the mode of action of FAA.

Topics: Affinity Labels; Amino Acids; Animals; Anticonvulsants; Electroshock; Isothiocyanates; Mice; Radioligand Assay; Rats; Rats, Sprague-Dawley; Seizures; Stereoisomerism; Structure-Activity Relationship

We recently reported that the ED50 value for (R,S)-2,3-dimethoxypropionamide (1) in the maximal electroshock (MES)-induced seizure test in mice was 30 mg/kg (Choi, D.; Stables, J.P., Kohn, H. Bioorg. Med. Chem. 1996, 4, 2105). This value is comparable to that observed for phenobarbital (ED50 = 22 mg/kg). Compound 1 is structurally similar to a class of MES-selective anticonvulsant agents, termed functionalized amino acids (2), that were developed in our laboratory. The distinguishing feature of 2 is the differential activities observed for enantiomers. In this study, we asked whether comparable differences in activities were observed in the MES-induced seizure test for (R)- and (S)-1. We developed stereospecific syntheses for these enantiomers and showed that both compounds exhibit nearly equal anticonvulsant activity in mice (i.p.) (MES ED50 = 79-111 mg/kg). The surprisingly high ED50 values for (R)- and (S)-1 required our redetermining the ED50 value for (R,S)-1. We revised this value to 79 mg/kg. A limited structure-activity relationship study for 1 was conducted. Special attention was given to the C(2) methoxy unit in 1. We found that replacement of this moiety led to only modest differences in the MES activities upon ip administration to mice. Significantly, we observed an enhancement in the anticonvulsant activity for (R,S)-N-benzyl 2-hydroxy-3-methoxypropionamide ((R,S)-6) upon oral administration to rats ((R,S)-6: mice (i.p.) ED50 > 100, < 300 mg/kg; rat (oral) ED50 = 62 mg/kg). The activities of 3-methoxypropionamides, functionalized amino acids, and related compounds are discussed.

Topics: Acetamides; Amides; Animals; Anticonvulsants; Disease Models, Animal; Lacosamide; Mice; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Seizures