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Many antiseizure medications cause apoptotic cell death in developing brains. The newer antiseizure medication lacosamide is increasingly used in neonates and infants. Neurotoxicity of lacosamide and its combination with levetiracetam was studied in neonatal mice. Animals received single or repeat injections of saline, phenobarbital (75mg/kg), lacosamide (20-40mg/kg), levetiracetam (100mg/kg), lacosamide (40mg/kg) + levetiracetam (100mg/kg) and euthanized at 6 to 30 hours. Cells undergoing apoptosis were increased in the brains of phenobarbital-treated animals. Densities of apoptotic profiles following lacosamide and levetiracetam treatment did not differ from saline-treated controls. Findings suggest that lacosamide, levetiracetam and their combination do not cause apoptosis in developing mouse brains. ANN NEUROL 2024;96:812-818., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Carbamazepine (CBZ) use has been limited by multiple adverse reactions. Lacosamide (LCM) is a functional amino acid anti-seizure medication (ASM), approved for focal seizure patients more than 4 years old. It is non-inferior in terms of efficacy to controlled release CBZ and was proven to have better tolerability. This study examines the effect of abruptly changing CBZ to LCM in epilepsy patients with elevated gamma-glutamyl transpeptidase (GGT). Consenting adult patients aged 18 years old and above, with controlled focal seizure disorder for more than 2 years, who were consistently taking CBZ and who had elevated GGT were included in this study. Out of 1526 patients screened, only 12 satisfied the inclusion criteria. After abruptly changing CBZ to LCM, the GGT level significantly dropped from a median of 141.5 to 63.5 IU/L (z = 3.06, p = 0.0005). Moreover, there was significantly lower proportion of patients with abnormal GGT levels after the switch in medications was done (100% vs. 66.7%, McNemar χ 2  = 8, p = 0.008). Moderate to high levels of GGT in patients with focal epilepsy can be decreased by changing CBZ to LCM. Moreover, abruptly changing CBZ to LCM without cross-titration may be safe and effective in preventing seizure incidence within a 1-month period. PLAIN LANGUAGE SUMMARY: Although carbamazepine (CBZ) is the standard drug for focal seizures, its numerous side effects, especially in the liver, limits its use in a lot of patients with epilepsy. Gamma-glutamyl transferase (GGT), which is elevated in liver disease of whatever cause including intake of CBZ, is associated with increased mortality. In this study, we found that abruptly changing CBZ to Lacosamide (LCM) can significantly decrease the GGT level in 1 month without apparent increase in seizure recurrence and side effects. Therefore, we conclude that high levels of GGT may be decreased by abruptly changing CBZ to LCM., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Lacosamide (LCM) is a third-generation antiseizure medication (ASM) currently approved for the treatment of focal seizures in children aged greater than one month. There are limited data on its efficacy in the neonatal age group. We describe our experience with LCM as an adjunct ASM for the treatment of neonatal seizures., Methods: A retrospective chart review over a five-year period (2018 to 2022) was conducted at Le Bonheur Children's Hospital to identify neonates with electroencephalography (EEG)-proven seizures who were treated with LCM. Data were collected on electroclinical seizure characteristics, underlying etiology, ASMs, treatment response, and any adverse effects., Results: A total of 15 neonates with EEG-confirmed seizures who were treated with LCM were included. Ten neonates achieved seizure cessation after LCM was added to their ASM regimen consisting of phenobarbital, levetiracetam, or both. No new treatment-related adverse effects were noted., Conclusions: LCM is effective as an adjunct treatment for neonatal seizures. Randomized controlled studies are needed to establish its effectiveness and adequate dosing regimen in this population., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: To evaluate the efficacy, safety, and tolerability of adjunctive lacosamide therapy against focal seizures in young children (1 month - 4 years)., Methods: This non-randomized, open-label, and self-controlled real-world study included 105 children (1 month-4 years) with focal seizures treated with adjunctive lacosamide therapy at Children's Hospital of Chongqing Medical University., Results: (1) The 50% response rates at 3, 6, 9, and 12 months of follow-up were 58.1%, 61.0%, 57.1%, and 56.2%, while the seizure-free rates were 27.6%, 34.3%, 32.4%, and 37.1%, respectively. The 50% response rate of the first addition of lacosamide for focal seizures was much higher than the second and later added treatment at 3 months (p = 0.038). After 1 year of follow-up, these children showed an improvement in neurodevelopmental levels (p < 0.05). (2) Lacosamide retention rate was 72.7% (64/88) after 1 year of follow-up. Lack of efficacy and serious adverse events were independent risk factors for the lacosamide retention rate. (3) During adjunctive lacosamide therapy, 13 (12.4%) patients reported adverse events and five (4.7%) patients withdrew due to adverse events, including vomiting drowsiness, ataxia (0.94%), neck itching with eczema (0.94%), irritability (1.88%), and gastrointestinal discomfort (0.94%)., Conclusion: Adjunctive lacosamide therapy was effective, safe, and well-tolerated in young Chinese children with focal seizures in this study., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Lacosamide was the first approved third-generation antiepileptic drug. However, real-world data regarding its adverse cardiac reactions in large samples still need to be completed. We evaluated the cardiac safety profile of lacosamide using the Food and Drug Administration Adverse Event Reporting System (FAERS). We performed disproportionality analysis computing reporting odds ratio (ROR) as a quantitative metric to assess the signal of lacosamide-related cardiac adverse events (AEs) from 2013 Q1 to 2022 Q4. The signal was considered significant when the lower limit of the 95% confidence interval (CI) of the ROR exceeded 1, and ≥ 5 AEs were reported. Serious and nonserious cases were compared by statistical analysis, and signals were further prioritized using a rating scale. A total of 812 cardiac AEs associated with lacosamide were identified, and 92 signals were detected, of which 17 AEs were significantly associated signals. The median time-to-onset (TTO) for moderate priority signals was 10 days, whereas for weak priority signals, it was 54 days. Notably, all cardiac AEs exhibited an early failing pattern, indicating the risk gradually decreasing. Based on the comprehensive analysis of the FAERS database and prioritization of cardiac AE signals, our research enhances the awareness among healthcare professionals regarding cardiac AEs associated with lacosamide., (© 2024. The Author(s).)

Lacosamide is a relatively new antiepileptic drug that exerts its anticonvulsant effect by selectively inactivating sodium channels. Since its launch, it has been used widely for the treatment of intractable epilepsy, but there are scant data on the toxic or lethal blood concentrations. Here, we report a case of drug poisoning following simultaneous high-dose self-administration of lacosamide and mirtazapine. We developed and validated an approach that uses liquid chromatography coupled with electrospray ionization-tandem mass spectrometry to determine the concentrations of lacosamide and mirtazapine in cadaveric blood, urine and liver. Calibration curves showed good linearity (r 2  > 0.995), and our method enabled repeatable and accurate quantification, with intra- and inter-assay coefficients of variation not exceeding 10.9 % and 12.8 %, respectively, for each target drug. We used the method to measure the drug concentrations in the blood of a dead victim and found a lacosamide concentration of 91.9 μg/mL and a mirtazapine concentration of 12.0 μg/mL. The blood mirtazapine concentration was in the lethal range, and that of lacosamide was about 10 times the therapeutic range. The synergistically central nervous system depressive and cardiotoxic effects of these drugs may have contributed to the cause of death. We concluded that the cause of death in this case was lacosamide and mirtazapine poisoning., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: There is growing evidence supporting the safety and effectiveness of lacosamide in older children. However, minimal data are available for neonates. We aimed to determine the incidence of adverse events associated with lacosamide use and explore the electroencephalographic seizure response to lacosamide in neonates., Methods: A retrospective cohort study was conducted using data from seven pediatric hospitals from January 2009 to February 2020. For safety outcomes, neonates were followed for ≤30 days from index date. Electroencephalographic response of lacosamide was evaluated based on electroencephalographic reports for ≤3 days., Results: Among 47 neonates, 98% received the first lacosamide dose in the intensive care units. During the median follow-up of 12 days, 19% of neonates died, and the crude incidence rate per 1000 patient-days (95% confidence interval) of the adverse events by diagnostic categories ranged from 2.8 (0.3, 10.2) for blood or lymphatic system disorders and nervous system disorders to 10.5 (4.2, 21.6) for cardiac disorders. Electroencephalographic seizures were observed in 31 of 34 patients with available electroencephalographic data on the index date. There was seizure improvement in 29% of neonates on day 1 and also in 29% of neonates on day 2. On day 3, there was no change in 50% of neonates and unknown change in 50% of neonates., Conclusions: The results are reassuring regarding the safety of lacosamide in neonates. Although some neonates had fewer seizures after lacosamide administration, the lack of a comparator arm and reliance on qualitative statements in electroencephalographic reports limit the preliminary efficacy results., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.R. and S.E. are employees of UCB Pharma. M.K. is an employee of Barrington James Ltd on behalf of UCB Pharma and a PhD student at London School of Hygiene & Tropical Medicine. N.F. is a former employee of UCB Pharma and current employee of Ferring SAS. RAS was an employee of University of Michigan at the time of study., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Migraine affects 11-15% of people worldwide, and the calcitonin gene-related peptide (CGRP) is released during the migraine attack, producing pulsating pain of migraine. Also, lacosamide reacts with collapsin-response mediator protein 2, preventing its phosphorylation and leading to the inhibition of CGRP release in the trigeminal system., Objective: The primary outcome was the difference in the serum level of CGRP-LI after three months of treatment with either lacosamide and ibuprofen or ibuprofen alone in episodic migraine patients. The secondary outcomes were assessing safety and efficacy of lacosamide in episodic migraine patients., Methods: We conducted an open-label randomized controlled trial on episodic migraine patients aged 10-55 years diagnosed according to (ICHD-3) in Kafr El-Sheikh University Hospital, Egypt. We assessed serum levels of CGRP-LI before and three months after treatment in our two groups, the lacosamide, and the control groups. We also assessed the side effects of treatment in each group, the percentage of patients who achieved ≥ 50% reduction in the migraine monthly days (MMD) frequency and the percentage of patients who achieved pain freedom within 2 h in ≥ 4 of 5 attacks in each group., Results: 200 episodic migraine patients completed the study. There was a statistically significantly higher reduction in the serum CGRP-LI level in the lacosamide group compared with the control group. In addition, lacosamide was well tolerated by patients. Also, the lacosamide group had statistically significant higher percentage of patients who achieved ≥ 50% reduction in the migraine monthly days (MMD) frequency and pain freedom within two hours in ≥ 4 of 5 attacks with P-values 0.002, 0.02 respectively., Conclusion: The daily use of lacosamide 50 mg Bid for three months in episodic migraine patients was associated with a significant reduction in serum CGRP-LI, better clinical outcomes regarding frequency and duration of migraine attacks, and was well tolerated by patients. These results were derived from an open-label pilot study that needed to be thoroughly investigated by a large-scale, randomized, double-blinded, placebo-controlled study., Trial Registration:  We registered our trial on ClinicalTrials.gov, named after "The Lacosamide's Effect on Calcitonin Gene-related Peptide in Migraine Patients," and with a clinical trial number (NCT05632133)-August 8, 2023., (© 2024. The Author(s).)

Lacosamide, a voltage-gated sodium channel inhibitor, is an anti-seizure medication (ASM) from the age of 4. We report on the case of a woman treated with lacosamide for pharmacoresistant epilepsy who breastfed her infant for more than 6 months after birth. The infant's blood concentrations of lacosamide were 2.4 mg/L on Day 1 and less than 1 mg/L on Day 10 (reference values are 1-10 mg/L). No adverse drug reactions (ADRs) were reported for the infant. Eight cases of breastfeeding by mothers receiving lacosamide are described in the literature. These data confirm that a significant amount of lacosamide seems to pass into breast milk, with a relative infant dose (RID) above 20% in two cases but a low RID (1.8%) in another case. Nevertheless, blood tests, performed in two breastfed infants, revealed low concentrations of lacosamide. No ADRs were reported in eight of the breastfed infants; however, one infant, whose mother was also treated with levetiracetam, presented poor feeding and sleepiness at Day 15 of life. Given the well-known benefits of breastfeeding for both mothers and their infants, as well as the above reassuring data, breastfeeding of healthy full-term infants could be possible for mothers on lacosamide monotherapy. Nonetheless, relatives should be warned that data concerning the safety of lacosamide during breastfeeding are scarce and that long-term neurodevelopment outcomes in breastfed children are unknown. Clinical monitoring of breastfed infants for drowsiness, adequate weight gain, or cutaneous rash is recommended. Additionally, the infants' serum levels should be measured in case of an unexplained adverse reaction., (© 2023 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Objectives: Assess the bioequivalence of lacosamide extended-release (XR) capsules and immediate-release (IR) tablets and answer real-world clinical questions regarding the use of lacosamide XR., Methods: An open-label, randomized, two-treatment, two-sequence, oral comparative bioavailability study was conducted to assess the bioequivalence of two lacosamide formulations. Participants were randomized 1:1 to receive lacosamide XR capsules (400 mg once-daily) or IR tablets (200 mg twice-daily) in 1 of 2 sequences over 7-day periods. Primary outcome was the area under the lacosamide concentration-time curve over 24 h at steady-state (AUC 0-τ,ss ). Secondary outcomes were maximum (C max,ss ) and minimum concentrations at steady-state (C min,ss ). Bioequivalence was established when 90% confidence intervals (CIs) for geometric least square means ratios (GLSMs) were between 80% and 125%. Adverse events (AEs) and other safety outcomes were also assessed. Pharmacokinetic simulations, including adherent and partially adherent dosing scenarios with XR and IR formulations, modeled the clinical use of lacosamide XR., Results: Thirty-five healthy adult males were enrolled in the bioequivalence study. After 7 days of study drug, mean AUC 0-τ,ss , C max,ss , and C min,ss values were similar between XR and IR formulations; all 90% CIs for GLSMs were between 80% and 125%. AEs were mild and no serious AEs or other clinically significant safety findings were observed. Pharmacokinetic simulations suggested that partial adherence affected formulations similarly; and the best strategy for switching formulations was to take the morning lacosamide IR dose followed by the evening lacosamide XR dose, as this resulted in the most consistent lacosamide plasma concentrations., Conclusions: Once-daily lacosamide XR capsules were bioequivalent to twice-daily lacosamide IR tablets. Pharmacokinetic simulations indicated lacosamide XR and IR formulations were similarly affected by partial adherence, though once-daily dosing with lacosamide XR may offer clinical advantages, and formulations can be easily switched. These results support the use of lacosamide XR capsules as a once-daily alternative to lacosamide IR tablets., Competing Interests: Declaration of Competing Interests J. Wheless has received support, served on the speaker’s bureau, and/or served as a paid consultant for Biomarin, Envision, Epiwatch, Jazz, LivaNova, Marinus, Neurelis, Neuro Event Labs, Praxis, the Herbert Shainberg Foundation, SK Life Science, Stoke, TSC Alliance, UCB, and Xenon. B. Gidal has served on the speaker’s bureau and/or served as a paid consultant for Azurity, Catalyst, Jazz, and SK Life Science. L. Gong, S. Lyu, X. Zheng, R. Li, W. Chang, and M. Tan are employees of Aucta Pharmaceuticals, Inc., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Lacosamide (LCM) has shown promising efficacy and safety outcomes in clinical trials. However, the evidence is limited among pediatric patients especially under four years in real-world. The study investigated the treatment outcomes and safety of LCM in patients under four years based on the data of the epilepsy registry of Children in China., Methods: A prospective cohort study was conducted among patients under 4 years who newly received LCM as monotherapy or adjunctive therapy. The treatment outcomes were measured by retention rate of LCM, 50 % response rates and seizure-free rates during follow-up. The retention rate of LCM was assessed using the Kaplan-Meier survival model. Adverse events were reported as a percentage of all participants., Results: Of 109 participants (mean follow-up: 18.6 months), 59 received LCM as monotherapy and 50 as adjunctive therapy. Sixty patients had focal epilepsy, 44 had generalized epilepsy and 5 had combined generalized and focal epilepsy. 70 % of patients in the monotherapy group and 41 % in the adjunctive therapy group remained on LCM treatment without additional treatments for at least one year. In patients with monotherapy, 50 % response rate and seizure-free rate were 75 % and 56 % at 12 months, respectively. In adjunctive therapy group, these rates were 51 % and 36 %, respectively. Lower baseline seizure frequency in both treatment groups (monotherapy: p < 0.001; adjunctive therapy: p = 0.02) and younger age groups within the monotherapy group (P = 0.04) correlated with a higher LCM retention rate. Adverse events were reported by 15 patients (13.8 %), with somnolence being the most common (7 of 15 patients)., Conclusion: With a comprehensive information and high-quality of data, the study demonstrates the effective treatment outcome and safety of LCM. The study adds reliable evidence to exiting real-word evidence of LCM in the specific age group of patients with epilepsy to fill the evidence gap., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2024. Published by Elsevier Ltd.)

Purpose: To draw clinical attention to rashes caused by lacosamide., Methods: This retrospective analysis included patients admitted to the Department of Pediatrics, Second Affiliated Hospital of Xi'an Jiaotong University between January 2021 and September 2023. We focused on patients who developed rashes after lacosamide treatment and analyzed all patients who exhibited rashes after lacosamide treatment to analyze the risk factors., Results: In total, 190 patients received lacosamide, of whom four developed allergies (2.1 %). Three patients had severe rashes, and two patients had high fever. All of these adverse events improved after the withdrawal of lacosamide. Of the 13 patients reported to date, including the four patients in this study, eight used various antiseizure medicines, including seven patients who used four or more antiseizure medicines. Four patients underwent testing for HLA-B*1502, and two patients were positive. Patients developed rashes within 1-10 days after treatment initiation, and the duration of the rash ranged 2-37 days., Conclusions: Lacosamide-induced rash was detected in 2.1 % of patients in our cohort. Rashes are potentially serious, and prompt evaluation is required. Rashes are more likely to occur when multiple antiseizure medicines are used simultaneously, typically within 10 days of treatment initiation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim of the Study: To evaluate the safety of lacosamide (LCM) monotherapy during pregnancy and breastfeeding., Material and Methods: Patients taking LCM monotherapy treated at the university epilepsy clinic were prospectively followed up during pregnancy, delivery, and breastfeeding. Data on seizure frequency, LCM dosage, pregnancy course, delivery and breastfeeding, birth outcome, congenital malformation, and development of newborns was collected., Results: Four pregnancies in three patients with refractory focal epilepsy treated with LCM monotherapy were reported. One of these pregnancies ended in a miscarriage during the seventh week of gestation. The average daily LCM dose at the time of conception was 300 mg. Treatment with LCM was continued throughout pregnancy and breastfeeding. The dose of LCM was increased in two pregnancies: in one case following a seizure relapse, and in the other case as a preventive measure to avoid an increase in seizure frequency. Seizure frequency remained stable during pregnancy in two cases. All deliveries were carried out via caesarean section, with an average gestational age at birth of 37.6 weeks. The Apgar score was 10 in all newborns, and no congenital malformations were detected. At the age of 12 months, normal developmental milestones were reached. Infants were breastfed without any complications., Conclusions and Clinical Implications: This case series adds to a growing body of evidence suggesting the relative safety of LCM monotherapy throughout pregnancy and breastfeeding.

A simple, specific, accurate and stability-indicating reversed-phase high-performance liquid chromatographic method was developed for the determination of lacosamide, using C18 column and a mobile phase composed of phosphate buffer (pH 4.0):acetonitrile (40:60 v/v). The retention time of lacosamide was found to be 2.7 min. Linearity was established for lacosamide in the range of 10-50 μg/mL. The percentage recovery of lacosamide was found to be in the range of 97.37-99.20%. The drug was subjected to acid, alkali, oxidation, dry heat and photolytic degradation. The degradation studies indicated condition was well resolved from the pure drug with significant differences in their retention time values. This method can be successfully employed for quantitative analysis of lacosamide in bulk drug and formulation., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Many pharmacokinetic studies of lacosamide (LCM) have been reported, but no large-scale clinical study has been conducted on genetic polymorphisms that affect the metabolism of LCM. Therefore, we designed a pharmacogenetic study of LCM to explore the effect of genetic polymorphisms on serum LCM concentration. We evaluated the pharmacodynamic characteristics of LCM, including clinical efficacy and toxicity., Methods: Adult patients with epilepsy who received LCM at Seoul National University Hospital were enrolled. Blood samples were obtained from 115 patients taking LCM for more than 1 month with unchanged doses and were used to analyze the serum LCM concentration, the concentration/dose (C/D) ratio and the single nucleotide polymorphisms (SNPs) of the cytochrome P450 (CYP)2C9 and CYP2C19 genes. In addition, clinical information-including efficacy, toxicity, and concomitant drugs-was collected., Results: The serum LCM concentration showed a linear correlation with the daily dose (r = .66, p < .001). In genetic analysis, 43 patients (38.7%) were extensive metabolizers (EMs), 51 (45.9%) were intermediate metabolizers (IMs), and 17 (15.3%) were poor metabolizers (PMs). In the group comparison, mean serum concentrations and the C/D ratio showed significant differences between the three groups (p = .01 and p < .001, respectively). The C/D ratios of IM (27.78) and PM (35.6) were 13% and 39% higher than those of EM (25.58), respectively. In the pharmacodynamic subgroup analysis, patients in the ineffective LCM group had significantly lower serum concentrations (6.39 ± 3.25 vs. 8.44 ± 3.68 μg/ml, p = .024), whereas patients with adverse events had higher serum concentrations than those without adverse events (11.03 ± 4.32 vs. 7.4 ± 3.1 μg/ml, p < .001). Based on this, we suggest a reference range for LCM in the Korean population (6-9 μg/ml)., Significance: Genetic polymorphisms of the CYP2C19 gene affect the serum LCM concentration. Because efficacy and toxicity are apparently related to serum LCM levels, the genetic phenotype of CYP2C19 should be considered when prescribing LCM for patients with epilepsy., (© 2022 International League Against Epilepsy.)

Purpose: Understanding the effects of antiepileptic drugs on glial cells and glia-mediated inflammation is a new approach to future treatment of epilepsy. Little is known about direct effects of the antiepileptic drug lacosamide (LCM) on glial cells. Therefore, we aimed to study the LCM effects on glial viability, microglial activation, expression of gap-junctional (GJ) protein Cx43 as well as intercellular communication in an in vitro astrocyte-microglia co-culture model of inflammation., Methods: Primary rat astrocytes co-cultures containing 5% (M5, "physiological" conditions) or 30% (M30, "pathological inflammatory" conditions) of microglia were treated with different concentrations of LCM [5, 15, 30, and 90 μg/ml] for 24 h. Glial cell viability was measured by MTT assay. Immunocytochemistry was performed to analyze the microglial activation state. Western blot analysis was used to quantify the astroglial Cx43 expression. The GJ cell communication was studied via Scrape Loading., Results: A concentration-dependent incubation with LCM did not affect the glial cell viability both under physiological and pathological conditions. LCM induced a significant concentration-dependent decrease of activated microglia with parallel increase of ramified microglia under pathological inflammatory conditions. This correlated with an increase in astroglial Cx43 expression. Nevertheless, the functional coupling via GJs was significantly reduced after incubation with LCM., Conclusion: LCM has not shown effects on the glial cell viability. The reduced GJ coupling by LCM could be related to its anti-epileptic activity. The anti-inflammatory glial features of LCM with inhibition of microglial activation under inflammatory conditions support beneficial role in epilepsy associated with neuroinflammation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: 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., Methods: 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., Results: 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., Conclusion: Lamotrigine and lacosamide show similar effectiveness in diffuse glioma patients with epilepsy., (© 2021. The Author(s).)

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., (© 2021, The American College of Clinical Pharmacology.)

Epilepsy is one of the most common brain disorders, affecting more than 50 million people worldwide. Although its treatment is currently symptomatic, the last generation of anti-seizure drugs is characterized by better pharmacokinetic profiles, efficacy, tolerability and safety. Lacosamide is a third-generation anti-seizure drug that stands out due to its good efficacy and safety profile. It is used with effectiveness in the treatment of partial-onset seizures with or without secondary generalization, primary generalized tonic-clonic seizures and off-label in status epilepticus. Despite scarcely performed until today, therapeutic drug monitoring of lacosamide is proving to be advantageous by allowing the control of inter and intra-individual variability and promoting a successful personalized therapy, particularly in special populations. Herein, the pharmacology, pharmacokinetics, and clinical data of lacosamide were reviewed, giving special emphasis to the latest molecular investigations underlying its mechanism of action and therapeutic applications in pathologies besides epilepsy. In addition, the pharmacokinetic characteristics of lacosamide were updated, as well as current literature concerning the high pharmacokinetic variability observed in special patient populations and that must be considered during treatment individualization., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Lacosamide (LCM) is the antiepileptic drug approved by the U.S. Food and Drug Administration in 2008 that facilitates slow activation of the voltage-gated sodium channels. Neutropenia and cardiac events including sinus node dysfunction (SND) and atrioventricular block have been previously reported as adverse effects of LCM. To date, there have been no reports of severe agranulocytosis resulting in death associated with LCM. Additionally, there have been no reports of concomitant SND and agranulocytosis after LCM administration. Herein we report the first case of LCM-induced severe SND followed by agranulocytosis., Case Presentation: The patient with focal epilepsy was initiated on LCM 100 mg/day and the dose was increased to 200 mg/day on the 9 th hospital day. Severe SND developed on the 10 th hospital day and LCM was discontinued. Thereafter agranulocytosis appeared on the 11 th hospital day, and the patient died from septic shock on the 15 th hospital day., Conclusions: This case illustrates the need for careful follow-up of the electrocardiogram and the complete blood cell counts when initiating LCM. Moreover, it should be noticed that various side effects may occur simultaneously in the early period of LCM use, even for a short time and at low dosages.

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.

Clinically, temporal lobe epilepsy (TLE) is the most prevalent type of partial epilepsy and often accompanied by various comorbidities. The present study aimed to evaluate the effects of chronic treatment with the antiepileptic drug (AED) lacosamide (LCM) on spontaneous motor seizures (SMS), behavioral comorbidities, oxidative stress, neuroinflammation, and neuronal damage in a model of TLE. Vehicle/LCM treatment (30 mg/kg, p.o.) was administered 3 h after the pilocarpine-induced status epilepticus (SE) and continued for up to 12 weeks in Wistar rats. Our study showed that LCM attenuated the number of SMS and corrected comorbid to epilepsy impaired motor activity, anxiety, memory, and alleviated depressive-like responses measured in the elevated plus maze, object recognition test, radial arm maze test, and sucrose preference test, respectively. This AED suppressed oxidative stress through increased superoxide dismutase activity and glutathione levels, and alleviated catalase activity and lipid peroxidation in the hippocampus. Lacosamide treatment after SE mitigated the increased levels of IL-1β and TNF-α in the hippocampus and exerted strong neuroprotection both in the dorsal and ventral hippocampus, basolateral amygdala, and partially in the piriform cortex. Our results suggest that the antioxidant, anti-inflammatory, and neuroprotective activity of LCM is an important prerequisite for its anticonvulsant and beneficial effects on SE-induced behavioral comorbidities.

This study evaluated the effect of lacosamide (LCM) on biochemical and mitochondrial parameters after PTZ kindling in mice. Male mice were treated on alternative days for a period of 11 days with LCM (20, 30, or 40 mg/kg), saline, or diazepam (2 mg/kg), before PTZ administration (50 mg/kg). The hippocampi were collected to evaluate free radicals, the activities of superoxide dismutase (SOD), catalase (CAT), and the mitochondrial complexes I-III, II, and II-III, as well as Bcl-2 and cyclo-oxygenase-2 (COX-2) expressions. Hippocampi, blood, and bone marrow were collected for genotoxic and mutagenic evaluations. LCM 40 mg/kg increased latency and decreased percentage of seizures, only on the 3rd day of observation. The dose of 30 mg/kg only showed positive effects on the percentage of seizures on the 2nd day of observation. LCM decreased free radicals and SOD activity and the dose of 40 mg/kg were able to increase CAT activity. LCM 30 and 40 mg/kg improved the enzymatic mitochondrial activity of the complex I-III and LCM 30 mg/kg improved the activity of the complex II. In the comet assay, the damage induced by PTZ administration was reduced by LCM 20 and 30 mg/kg. The dose of 20 mg/kg increased COX-2 expression while the highest dose used, 40 mg/kg, was able to reduce this expression when compared to the group treated with LCM 20 mg/kg. Although LCM did not produce the antiepileptogenic effect in vivo, it showed the neuroprotective effect against oxidative stress, bioenergetic dysfunction, and DNA damage induced by the repeated PTZ administration., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

This study has developed and validated a novel UPLC method to quantify lacosamide (LCM), oxcarbazepine (OXC), and lamotrigine (LTG) in children with epilepsy in Xinjiang, China. Phenytoin sodium was used as the internal standard. The mobile phase contained ammonium dihydrogen phosphate solution (10 mmol/L, pH = 4.0) and methanol (55:45, v/v). The flow rate, injection volume, column temperature, and detection wavelength were 0.2 mL/min, 2 μL, 30°C, and 240 nm, respectively. The method was linear within 0.5-40, 2.5-80, and 2.5-40 μg/mL for LCM, 10-hydroxycarbazepine (MHD), and LTG, respectively (r 2  ≥ 0.998). The intra- and inter-day precision as measured by the relative standard deviation values was between 1.36 and 4.50, 0.54 and 1.91, and 0.58 and 1.56%. Recovery ranged from 96.58 to 106.22%. All serum samples could be maintained for up to 3 h at ambient temperature, 24 h at 4°C, 30 days at -30°C, and after successive freeze-thaw cycles (24 h per cycle) in the absence of significant degradation., (© 2020 John Wiley & Sons, Ltd.)

Background: 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., Objective: This study aims to assess the effectiveness and tolerability of Lacosamide with respect to its use in the treatment of focal epileptic patients., Methods: 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., Results: 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., Conclusion: Lacosamide is an effective and well tolerable drug for patients with focal epilepsy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Epilepsy and antiepileptic drugs can affect negatively the cognitive abilities of patients., Aim: The present study aimed to evaluate the effect of topiramate (TPM) and lacosamide (LCM) on the emotional and cognitive re-sponses in naive animals and in animals with pilocarpine-induced status epilepticus., Materials and Methods: Male Wistar rats were randomly divided into 6 groups and status epilepticus was evoked in half of them by a single i.p. administration of pilocarpine (Pilo) (320 mg/kg): Pilo-veh, Pilo-TPM (80 mg/kg) and Pilo-LCM (30 mg/kg). Matched naive rats were treated with the same doses as follows: C-veh, C-TPM, and C-LCM. In a step-down passive avoidance test, the learning session was held for one day, the early retention test was conducted on day 2, and the long-term memory test - on day 7. Motor activity and anxiety were evaluated in an open field test., Results: The Pilo-TPM and Pilo-LCM groups increased the time spent on the platform compared to Pilo-veh animals while the C-LCM animals decreased the time compared to C-veh animals during short- and long-term memory retention tests. TPM and LCM exerted an anxiolytic effect in naive rats. The two antiepileptic drugs were unable to alleviate the hyperactivity, but they alleviated the impulsivity associated with decreased anxiety level in epileptic rats., Conclusions: Our findings suggest that LCM and TPM have a beneficial effect on cognition both in naive and epileptic rats. While the two antiepileptic drugs can produce an anxiolytic effect in naive rats, they alleviate the impulsivity after pilocarpine treatment., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Cognitive and psychiatric problems are common in people with epilepsy. They can have multiple causes, including structural brain lesions, the active epilepsy, and the effect of anti-epileptic therapy. Since patients' treatment compliance and quality of life are affected by cognitive and emotional status, it is crucial for clinicians to understand how anti-seizure medications (ASMs) affect cognition and mood, and to choose the proper ASM., Objective: To conduct a literature review of the impact on cognition and mood status of lacosamide (LCM) in people with epilepsy., Methods: Wesearched PubMed, the Cochrane Database of Systematic Reviews and reference lists of articles for all types of articles with no limitations on publication date., Results: A total of 251 records were obtained, including 247 articles in PubMed and 4 articles from reference lists. We included 2 meta-analyses, one randomized controlled trials and 14 observational studies after the screening process. Most studies agree LCM has low risk of treatment-emergent adverse events (TEAEs) on cognition. Comparisons with other ASMs, LCM may be preferable to carbamazepine, topiramate and perampanel, and not inferior to lamotrigine. In spite of low incident rate, depression is the most common psychiatric change of LCM. There are no consistent positive or negative psychiatric effects of LCM., Conclusion: Lacosamide has limited impact on cognitive and mood status in this review. Several factors including mechanism of co-administration of ASMs and personal history of psychiatric disorder should be considered as important in the development of cognitive and psychiatric side effects. However, the heterogeneity between studies make the quality of evidence weaker and further trials are needed., Competing Interests: Conflict of interest The authors have no conflict of interest to report., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Jeavons syndrome is a childhood genetic generalized epilepsy characterized by eyelid myoclonia with or without absences, eyelid closure-induced epileptiform discharges and/or seizures and photoparoxysmal response. This syndrome accounts for up to 12.9% of generalized epilepsies, however, it is frequently under-reported. The utility of lacosamide in genetic generalized epilepsy and Jeavons syndrome is unclear. We present a case of a 15-year-old female with medically refractory Jeavons syndrome with seizure resolution in response to lacosamide monotherapy at standard daily doses. She had failed treatment with adequate trials of ethosuximide, valproic acid, lamotrigine, topiramate and the ketogenic diet, either as monotherapy or in combination. The frequency of seizures was confirmed in the epilepsy monitoring unit. She was treated with a loading dose of 200 mg of intravenous lacosamide and started at a maintenance dose of 100 mg, twice daily. The EEG showed a dramatic response with resolution of seizures and dramatic improvement in interictal discharges. She remained seizure-free for 11 months on lacosamide monotherapy after which seizures recurred in the setting of medication non-compliance. This highlights the potential role of lacosamide as an option in this syndrome if other drugs are ineffective or not tolerated.

Mood disorders such as depression and anxiety have a high prevalence in adult patients with epilepsy, and their evaluation is crucial in choosing the most appropriate antiepileptic drug (AED) with regard to side effects, which can account for long-term discontinuation, poor compliance, and ultimately, failure of seizure control. While more evidence is provided for older AEDs on their effect on mood changes, newer AEDs such as lacosamide have not yet been extensively studied. We performed a systematic review of the literature available on the impact of lacosamide on mood in adult patients with epilepsy. A literature search on MEDLINE, COCHRANE, Scielo, and Clinicaltrials.gov databases was performed, and articles where mood scales where specifically reported as primary or secondary outcome measures were included. Articles differed greatly in terms of inclusion criteria, concomitant AEDs, seizure reduction control, and outcome measures. If lacosamide is used as add-on, two studies point towards a beneficial effect on depressive and anxiety symptoms, two studies claim no effects on mood, and one reports a positive effect only in patients with major depressive symptoms at baseline. Additional evidence from either retrospective or comparative drug studies indicates no effects of lacosamide on mood. Even though presently, a negative effect on mood seems unlikely, whether lacosamide could exert a beneficial impact on mood remains controversial. Multicenter, randomized, controlled, double-blind studies are needed to assess the impact on lacosamide on mood disorders, given the low evidence level (Class III and IV) of currently available studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Temporal lobe epilepsy (TLE) is the most common form of epilepsy with focal seizures, and currently available drugs may fail to provide a thorough treatment of the patients. The present study demonstrates the utility of glucose-coated gold nanoparticles (GNPs) as selective carriers of an antiepileptic drug, lacosamide (LCM), in developing a strategy to cross the blood-brain barrier to overcome drug resistance. Intravenous administration of LCM-loaded GNPs to epileptic animals yielded significantly higher nanoparticle levels in the hippocampus compared to the nanoparticle administration to intact animals. The amplitude and frequency of EEG-waves in both ictal and interictal stages decreased significantly after LCM-GNP administration to animals with TLE, while a decrease in the number of seizures was also observed though statistically insignificant. In these animals, malondialdehyde was unaffected, and glutathione levels were lower in the hippocampus compared to sham. Ultrastructurally, LCM-GNPs were observed in the brain parenchyma after intravenous injection to animals with TLE. We conclude that glucose-coated GNPs can be efficient in transferring effective doses of LCM into the brain enabling elimination of the need to administer high doses of the drug, and hence, may represent a new approach in the treatment of drug-resistant TLE., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Lacosamide, an antiepileptic drug prescribed for children with refractory focal epilepsy, is generally well tolerated, with dose-dependent adverse effects. We describe 4 children who developed a movement disorder in conjunction with the initiation and/or uptitration of lacosamide. Three patients developed dyskinesias involving the face or upper extremity whereas the fourth had substantial worsening of chronic facial tics. The patients all had histories suggestive of opercular dysfunction: 3 had seizure semiologies including hypersalivation, facial and upper extremity clonus while the fourth underwent resection of polymicrogyria involving the opercula. Onset, severity, and resolution of dyskinesias correlated with lacosamide dosing. These cases suggest that pediatric patients with dysfunction of the opercular cortex are at increased risk for developing drug-induced dyskinesias on high-dose lacosamide therapy. Practitioners should be aware of this potential side effect and consider weaning lacosamide or video electroencephalography (EEG) for differential diagnosis, particularly in pediatric patients with underlying opercular dysfunction.

Objectives: This study was performed to evaluate the efficacy and tolerability of lacosamide (LCM) for paroxysmal kinesigenic dyskinesia (PKD) in children., Methods: We retrospectively reviewed the medical charts of pediatric PKD patients (aged <16 years) treated with LCM. Data regarding demographic characteristics, proline-rich transmembrane protein 2 (PRRT2) gene variant, clinical features of PKD, dose of LCM, efficacy, and adverse events were recorded., Results: Four eligible patients (3 males, 1 female) were identified, with an age of onset ranging from 8.3 to 14.7 years. PRRT2 variant was evaluated in three children and a c.649dupC variant was identified in one child with a positive family history. Attacks were bilateral in three children and left-sided in one. Two children had a family history of PKD and one child had a family history of benign infantile epilepsy. Treatment with carbamazepine failed in two children due to drowsiness and auditory disturbance. The initial dose of LCM was 50 mg/day in three children and 100 mg/day in one. All patients were attack-free within a few days. The maintenance dose was mostly similar to the initial dose. No adverse events related to LCM were reported during follow-up., Conclusions: LCM is an effective and well-tolerated treatment for PKD in children, and low-dose treatment may be viable., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Purpose: The aim of this study was to evaluate the tolerability and efficacy of lacosamide (LCM) in Lebanese children with focal-onset seizures and to determine if specific variables are predictive of better effectiveness., Methods: This is a retrospective analysis from three medical centers on consecutive children diagnosed with focal onset seizures and initiated on LCM. The seizure frequencies following the introduction of LCM were recorded and compared to the baseline monthly frequency at 3, 6, 12, 18, and 24 months. The primary efficacy variables were the 50% responder and seizure-free rates. The secondary outcome variables included the terminal 6-month seizure remission and percentages of discontinuation due to lack of efficacy or tolerability., Results: 58 patients with a mean age of 10 years experiencing a mean of 36.2 seizures per month during baseline were included. The seizure-free rates were 32.8%, 29.7%, and 12.5% at 6, 12 and 24 months follow up, respectively. Patients concomitantly treated with a sodium channel blocker were less likely to achieve a terminal 6-month seizure remission while the early introduction of LCM resulted in a significantly higher likelihood of attaining such a remission. 74.1% of patients were still maintained on LCM at the last follow-up. The most common adverse events consisted of dizziness, somnolence, nausea, vomiting, and rarely double vision., Conclusions: LCM is efficacious and overall well tolerated in children with focal-onset seizures and exhibits higher efficacy with early introduction and when added to a non-sodium channel blocker., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

We report the outcome of a pilot, open-label study that tested the potential of lacosamide (200 mg/bi.d) as an effective and safe symptomatic treatment against acute painful oxaliplatin-induced peripheral neurotoxicity (OXAIPN). Lacosamide was introduced in 18 colorectal cancer patients with evidence of clinically significant acute, painful OXAIPN after infusion of the third course (T1) of oxaliplatin-based chemotherapy (FOLFOX4) and was maintained until completion of all 12 courses (T4). The OXA-Neuropathy Questionnaire (OXA-NQ) was used to record the severity of acute OXAIPN; the PI-NRS estimated the severity of neuropathic pain, while the chronic OXAIPN was graded with TNSc. The EuroQOL (EQ-5D) instrument was also applied. The Patient Global Impression of Change (PGIC) scale measured the lacosamide-attributed perception of change. LCM-responders were considered those with ≥50% reduction in PI-NRS and OXA-NQ scores at T4, compared to T1. Patients experienced on T1 a median number of acute OXAIPN symptoms of 4 and had a median neuropathic pain severity score of 6, which was strongly related to lower quality of life, according to EQ-VAS (P < .001). At T4, 12 patients (66.7%) were classified as responders. A significant clinical improvement was documented in the severity of acute OXAIPN and neuropathic pain in relation to lacosamide (P < .001) at T4 compared to T1, which was associated with improved EQ-VAS scores (P < .001). Twelve patients scored PGIC ≥5 (lacosamide-attributed) at T4. There were no incidences of early drop-outs for safety reasons. Lacosamide appears to be an effective and well-tolerated symptomatic treatment against acute, painful OXAIPN., (© 2020 Peripheral Nerve Society.)

Objectives: To assess tolerability and efficacy of lacosamide in adults with cerebrovascular epilepsy etiology (CVEE)., Materials and Methods: Exploratory post hoc analyses of a double-blind, initial monotherapy trial of lacosamide vs carbamazepine-controlled release (carbamazepine-CR) (SP0993; NCT01243177); a double-blind conversion to lacosamide monotherapy trial (SP0902; NCT00520741); and an observational study of adjunctive lacosamide added to one antiepileptic drug (SP0973 VITOBA; NCT01098162). Patients with CVEE were identified based on epilepsy etiology recorded at baseline., Results: In the initial monotherapy trial, 61 patients had CVEE (lacosamide: 27; carbamazepine-CR: 34). 20 (74.1%) patients on lacosamide (27 [79.4%] on carbamazepine-CR) reported treatment-emergent adverse events (TEAEs), most commonly (≥10%) headache, dizziness, and fatigue (carbamazepine-CR: headache, dizziness). A numerically higher proportion of patients on lacosamide than carbamazepine-CR completed 6 months (22 [81.5%]; 20 [58.8%]) and 12 months (18 [66.7%]; 17 [50.0%]) treatment without seizure at last evaluated dose. In the conversion to monotherapy trial, 26/30 (86.7%) patients with CVEE reported TEAEs, most commonly (≥4 patients) dizziness, convulsion, fatigue, headache, somnolence, and cognitive disorder. During lacosamide monotherapy, 17 (56.7%) patients were 50% responders and six (20.0%) were seizure-free. In the observational study, 36/83 (43.4%) patients with CVEE reported TEAEs, most commonly (≥5%) fatigue and dizziness. Effectiveness was assessed for 75 patients. During the last 3 months, 60 (80%) were 50% responders and 42 (56.0%) were seizure-free., Conclusions: These exploratory post hoc analyses suggested lacosamide was generally well tolerated and effective in patients with CVEE, with data from the initial monotherapy trial suggesting numerically better efficacy than carbamazepine-CR., (© 2020 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Objective: Lacosamide (LCM) is an antiepileptic drug (AED) with insufficient clinical experience in patients with intellectual disability (ID). They often have more severe epilepsy with comorbidities. The objective was to evaluate the efficacy and tolerability of lacosamide (LCM) in patients with refractory epilepsy with and without ID in a real-life setting, taking drug monitoring (TDM) data into account therapeutic., Methods: Retrospectively, we identified 344 patients using LCM from the TDM service covering the majority of the country, at the National Center for Epilepsy in Norway (2013-2018). Clinical and TDM data were available for 132 patients., Results: Forty-four of the 132 patients (33%) had ID. The retention rate was significantly higher in the ID vs the non-ID group after 1 year (84% vs 68%, P < .05). By combining clinical and TDM data, we demonstrated that 37/38 responding patients had serum concentrations above the lower limit of the reference range (>10 µmol/L), and 16/17 with lower concentrations were non-responders. Mean serum concentration/dose ratios were similar in both groups, 0.06 and 0.07 µmol/L/mg. There were no significant differences regarding efficacy and tolerability. The risk of LCM withdrawal was significantly higher when LCM was added to sodium channel blockers, even if the latter was discontinued., Significance: Lacosamide was generally well tolerated in patients with drug-resistant epilepsy, where one third had ID, and in these patients the retention rate was higher. The combination of clinical and TDM data could possibly facilitate LCM therapy in these vulnerable patients., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Small fibre neuropathy is a common pain disorder, which in many cases fails to respond to treatment with existing medications. Gain-of-function mutations of voltage-gated sodium channel Nav1.7 underlie dorsal root ganglion neuronal hyperexcitability and pain in a subset of patients with small fibre neuropathy. Recent clinical studies have demonstrated that lacosamide, which blocks sodium channels in a use-dependent manner, attenuates pain in some patients with Nav1.7 mutations; however, only a subgroup of these patients responded to the drug. Here, we used voltage-clamp recordings to evaluate the effects of lacosamide on five Nav1.7 variants from patients who were responsive or non-responsive to treatment. We show that, at the clinically achievable concentration of 30 μM, lacosamide acts as a potent sodium channel inhibitor of Nav1.7 variants carried by responsive patients, via a hyperpolarizing shift of voltage-dependence of both fast and slow inactivation and enhancement of use-dependent inhibition. By contrast, the effects of lacosamide on slow inactivation and use-dependence in Nav1.7 variants from non-responsive patients were less robust. Importantly, we found that lacosamide selectively enhances fast inactivation only in variants from responders. Taken together, these findings begin to unravel biophysical underpinnings that contribute to responsiveness to lacosamide in patients with small fibre neuropathy carrying select Nav1.7 variants., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Lacosamide (LCM) is a new generation antiepileptic drug. It has only been available in Asia in recent years. A retrospective study at two hospitals in Hong Kong was performed to investigate the post-marketing efficacy and tolerability of the drug. A total of 81 subjects were recruited, among which 88% had drug-resistant epilepsy. The most common type of epilepsy was focal with unknown etiology. All patients used LCM as adjunctive therapy. The 50% responder rate was 42% at 12 weeks after achievement of maximal dose of LCM. No specific factor correlated with responsiveness including concomitant enzyme-inducing or sodium channel blocking anticonvulsants. Withdrawal rate within first 12 weeks after drug initiation was 14% while that at any time upon follow-up was 23%. Two cases of uncommon adverse reaction of myoclonus were also reported. The mechanism was postulated to be the sodium channel inhibiting action of LCM. Our study has shown LCM to have comparable efficacy and tolerability in post-marketing experience when compared with the landmark randomized controlled trials., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Lacosamide (LCM) is a well-tolerated and increasingly used second-generation AED, and side effects such as atrial fibrillation are rare and poorly characterized. Supported by a literature review, we share our experience of the management of the first reported case of cardioembolic cerebral infarcts in the context of de novo atrial fibrillation, which appeared following a 200-mg intravenous infusion of LCM for the treatment of non-convulsive status epilepticus. Case report and literature review using search items including "atrial fibrillation OR atrial flutter AND LCM" in the thesaurus of Medline. We found three cases of atrial fibrillation/atrial flutter secondary to LCM, one following a 200-mg intravenous infusion. In one patient, previous risk factors for atrial fibrillation were reported and another was started on warfarin; all required suspension of LCM for cessation of atrial fibrillation. Previous risk factors for atrial fibrillation in our patient were older age, male gender, obesity, hypertension, valvular disease, first-degree atrioventricular block and left anterior fascicle block. Atrial fibrillation appeared at the end of the infusion and ceased after a loading dose of amiodarone and suspension of LCM. Apixaban was initiated indefinitely five days later, and MRI showed four acute silent infarctions. The appearance of atrial fibrillation has severe therapeutic and clinical implications and the use of LCM might be reconsidered within a context of increased predisposition to developing atrial fibrillation. If atrial fibrillation appears, the drug should be discontinued and anticoagulation should be considered according to embolic risk. Further investigation is needed in order to better categorize the risk profile of lacosamide regarding atrial fibrillation.

Introduction : Lacosamide has been used in epilepsy patients in the United States, Europe and Asia since it was approved by the FDA in 2008. Many patients have benefited from this drug as a new generation of sodium channel blocker. With the worldwide use of this drug, its adverse effects have gradually emerged, especially some rare adverse events. Areas covered : The present review aims to summarize the adverse effects of lacosamide reported in the literature in recent years to promote the safe clinical application of the drug. Expert opinion : In more than 10 years of experience in drug usage, adverse reactions of lacosamide have also been gradually discovered. The review showed that lacosamide is safe and effective in antiepileptic treatment, and its common side effects are dizziness, headache, drowsiness, diplopia, and cardiovascular abnormalities. Skin rashes, hematotoxicity and heart damage, psychological symptoms and suicide risk have also been reported and emphasized.

Lacosamide is a functionalized amino acid with antiepileptic function. Therapeutic drug monitoring (TDM) in patients for lacosamide is critical as it allows clinicians to control epileptic seizures. A single liquid-liquid extraction step was applied for the extraction of lacosamide from whole blood samples which were thereafter analyzed by GC-MS. Optimum extraction conditions were selected on the basis of experiments with various solvents at different pHs, indicating ethyl acetate at pH 12 as the most efficient parameters for the extraction of lacosamide. Method exhibited linearity from 2 to 100 μg/mL with R 2  = 0.998. Accuracy and precision were evaluated at three concentrations and found to be within acceptable limits. LOD and LOQ were determined at 0.1 and 0.5 μg/mL, respectively. Lacosamide was found to be stable at storage conditions. The developed method was applied successfully in clinical samples and postmortem blood sample from an overdose case., (© 2019 American Academy of Forensic Sciences.)

Background: 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., Objective: This study hypothesized that LCM might affect the kindling process by influencing the expression of GABAA receptors in the hippocampus., Methods: The gene and protein expression levels of the GABAAg2 were studied using RT-qPCR and immunofluorescent staining., Results: 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., Conclusion: LCM could exhibit modulatory effects on the GABAergic system of the hippocampus that may be independent of the anticonvulsant action., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Neuropathic pain is a common pain condition that has a major negative impact on health-related quality of life. However, despite decades of research, it remains difficult to treat neuropathic pain. Lacosamide is a sodium-channel blocker that is efficacious in animal models of neuropathic pain. In humans, its effect in neuropathic pain is inconclusive, based on inconsistent results and very large placebo responses. Previous trials have not used patient stratification or looked for predictors for response., Methods: This study will be conducted as a multicenter, randomized, double-blind, placebo-controlled, parallel, phase 2, proof-of-concept, phenotype-stratified study. The study will enroll 108 patients with peripheral neuropathic pain who will be randomized to a 12-week treatment with lacosamide or placebo up to 400 mg/day in a 2:1 ratio. The primary objective is to compare the change in the mean value of the patients' daily ratings of average pain intensity from baseline to the last week of treatment in patients with and without the irritable nociceptor phenotype in the per-protocol population. A supportive objective is to compare the effect of lacosamide with that of placebo in the two phenotypes. Secondary and tertiary outcomes include the Patient Global Impression of Change, pain relief, presence of 30% and 50% pain reduction, sleep disturbance, depression, and anxiety., Discussion: We will examine the concept of individualized therapy based on phenotyping, and expect that this study will provide important information on the usefulness of lacosamide in the treatment of peripheral neuropathic pain., Trial Registration: ClinicalTrials.gov, NCT03777956 . Registered on 18 December 2018.

Objective: 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., Methods: 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., Results: 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)., Conclusions: 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., (Copyright © 2019 UCB Pharma. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of the study was to evaluate the harmful effects of sepsis on the urogynecological tissues and the ability of Lacosamide (LCM) on Lipopolysaccharide (LPS)-induced cytokine production, oxidative stress and apoptotic pathways, in the experimental rat sepsis model., Methods: Twenty-four female Wistar albino rats (12 months old) were divided into 3 groups as follows: control group (Group I) (0.1 ml/oral and i.p. saline, single dose), sepsis group (Group II) (5 mg/kg LPS, i.p. single dose) and sepsis + LCM group (Group III) (5 mg/kg LPS, i.p. single dose and 40 mg/kg LCM). Six hours after the last LPS administration, the animals were sacrificed. Subsequently, the analyses of urogenital tissues total oxidant/antioxidant status, histopathological and immunohistochemical analyses were performed., Results: Total oxidant capacity (TOC) and oxidative stress index (OSI) values in the urogenital tissues were increased in the urogenital tissues in Group II [Total antioxidant capacity (TAC) was decreased] compared to group I (p < 0.05). LCM improved these values (p < 0.05). The immunohistochemical markers (Tumor Necrosis Factor-alpha (TNF-α), interleukin-1 beta (IL-1β), heat shock protein 70 (HSP-70), C-reactive protein (CRP), Malondialdehyde (MDA) were significantly increased in Group II (p < 0.001). With the administration of LCM (Group III), the expressions of above-mentioned markers were markedly decreased (p < 0.001). Marked hyperemia and slight hemorrhages with neutrophil leukocyte infiltrations were seen histopathologically in Group II. LCM treatment ameliorated the pathological findings., Conclusion: These findings demonstrated that sepsis caused oxidative stress, apoptosis and inflammation in the urogenital tissues. We revealed that LCM ameliorated the damage caused by sepsis in urogenital tissue.

Background: Lacosamide (Vimpat®) is an anticonvulsant used to treat partial-onset seizures. Little is known about the characteristics and outcomes of patients exposed to lacosamide., Objective: To characterize lacosamide exposures reported to US poison centers with regard to patient demographics, clinical effects, and outcomes., Methods: This retrospective observational study queried the National Poison Data System (NPDS) for single substance lacosamide exposures from January 2008 to December 2016. Variables of interest included age, gender, medical outcome, management site, level of healthcare facility, reason for exposure, and clinical effects., Results: Lacosamide exposures were identified in 1124 patients, ranging from ages 2 months to 99 years. Six hundred and twenty-two patients (55.3%) were female. Nine hundred and seventy-six patients (86.8%) had minimal or no toxic effects. Life-threatening exposures numbered 30 cases (2.7%). There was one death. Five hundred and forty-eight patients (48.8%) did not require healthcare management while 537 (47.7%) were either referred to or already at a hospital. Among those treated at a healthcare facility, 269 (50.1%) did not require admission. Thirty-three patients (6.1%) were admitted to a psychiatric facility, 68 (12.7%) to a non-critical care unit, and 93 (17.3%) to a critical care unit. Six hundred and thirty-two exposures (56.2%) were due to therapeutic error. Suicide attempts numbered 168 (14.9%). Neurologic, gastrointestinal, and cardiovascular symptoms were commonly encountered., Conclusion: Lacosamide exposures infrequently cause death or disability; however, a considerable proportion of the study population required intensive care. Exposed patients with symptoms require healthcare evaluation.

Background: Excessive consumption of ethanol is known to activate the mTORC1 pathway and to enhance the Collapsin Response Mediator Protein-2 (CRMP-2) levels in the limbic region of brain. The latter helps in forming microtubule assembly that is linked to drug taking or addiction-like behavior in rodents. Therefore, in this study, we investigated the effect of lacosamide, an antiepileptic drug and a known CRMP-2 inhibitor, which binds to CRMP-2 and inhibits the formation of microtubule assembly, on ethanol-induced conditioned place preference (CPP) in mice., Methods: The behavior of mice following ethanol addiction and withdrawal was assessed by performing different behavioral paradigms. Mice underwent ethanol-induced CPP training with alternate dose of ethanol (2 g/kg, po) and saline (10 ml/kg, po). The effect of lacosamide on the expression of ethanol-induced CPP and on ethanol withdrawal associated anxiety and depression-like behavior was evaluated. The effect of drug on locomotor activity was also assessed and hippocampal CRMP-2 levels were measured., Results: Ethanol-induced CPP was associated with enhanced CRMP-2 levels in the hippocampus. Lacosamide significantly reduced the expression of ethanol-induced CPP and alleviated the levels of hippocampal CRMP-2 but aggravated withdrawal-associated anxiety and depression in mice., Conclusion: The present study demonstrated the beneficial effect of lacosamide in attenuation of expression of ethanol induced conditioned place preference via reduction of hippocampal CRMP-2 level. These findings suggest that lacosamide may be investigated further for ethanol addiction but not for managing withdrawal., (Copyright © 2019 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

Sepsis-induced central nervous system damage is called sepsis-associated encephalopathy (SAE). In addition to neuroinflammation, oxidative stress and apoptosis act in the development of SAE. In the current study, we evaluated the protective effects of lacosamide (LCM) on neuroinflammation induced by lipopolysaccharide (LPS). Twenty-four Wistar albino rats were divided into 3 groups as controls, LPS group (5 mg/kg i.p.), and LPS plus LCM group (5 mg/kg i.p and 40 mg/kg i.p, respectively). In the rat brain, LPS-induced tissue damage was revealed histopathologically as hyperemia and microhemorrhages. LCM pretreatment ameliorated these histopathological changes. LPS decreased brain TAS levels and significantly increased MDA, CRP, HSP, IL-1β, and TNF-α expressions in the cortex, hippocampus, and cerebellum. Western analysis revealed increased brain tissue levels of TNF-α, NF-Kβ, and caspase-3 following LPS. Prophylactic LCM treatment reversed these parameters including oxidative stress, inflammation, and apoptosis in the cortex, hippocampus, and cerebellum.