Lacosamide

MedlinePlus

... with other medications to control certain types of seizures. Lacosamide is in a class of medications called ... mood. If you suddenly stop taking lacosamide, your seizures may happen more often. Your doctor will probably ...

Changes in hormone and lipid levels in male patients with focal seizures when switched from carbamazepine to lacosamide as adjunctive treatment to levetiracetam: A small phase IIIb, prospective, multicenter, open-label trial.

PubMed

Elger, Christian E; Rademacher, Michael; Brandt, Christian; Elmoufti, Sami; Dedeken, Peter; Eckhardt, Klaus; Tennigkeit, Frank; De Backer, Marc

2016-09-01

Treatment with enzyme-inducing antiepileptic drugs (AEDs) such as carbamazepine (CBZ) can lead to changes in reproductive, endocrine, and lipid parameters, resulting in clinical symptoms for some patients. Previous studies indicate that these changes can be reversed by switching to a nonenzyme-inducing AED. Lacosamide is a newer-generation AED, not known to induce or strongly inhibit cytochrome P450 (CYP450) enzymes. In this phase IIIb, prospective, multicenter, open-label, single-arm trial (NCT01375374), the serum concentrations of CYP-related reproductive hormones, thyroid hormones, and lipids were assessed in otherwise healthy male patients with focal seizures (N=11), before and after a switch from CBZ (600-1200mg/day at baseline) to lacosamide (target dose: 400mg/day by the end of titration) as adjunctive treatment to the nonenzyme-inducing AED levetiracetam (LEV, stable dosage of >1000mg/day throughout). Cross titration took place over 4weeks, followed by an 8-week maintenance period. Serum measurements were conducted at baseline and at the end of maintenance. The median serum sex-hormone-binding globulin (SHBG) concentration was towards the higher end of the normal range at baseline and decreased following the switch (61.7 to 47.5nmol/L, N=10, p=0.027 by Wilcoxon signed-rank test). Free androgen index (100×testosterone/SHBG) and free thyroxine serum concentration increased (25.4 to 36.4 and 13.0 to 14.9pmol/L, respectively, both N=10 and p=0.002). At baseline, the median progesterone serum concentration was below the normal range (0.7nmol/L), whereas median cholesterol and low-density lipoprotein concentrations were above the normal range (5.5 and 3.6mmol/L, respectively). By the end of maintenance, all measured parameters were within the normal range. The safety and tolerability profile of lacosamide was consistent with that observed in previous studies. Furthermore, antiseizure efficacy appeared to be maintained, suggesting that deinduction of CYP enzymes

Lacosamide Injection

MedlinePlus

Lacosamide injection is used in combination with other medications to control certain types of seizures in people who cannot take oral medications. Lacosamide injection is in a class of medications called ...

Why we prefer levetiracetam over phenytoin for treatment of status epilepticus.

PubMed

Zaccara, G; Giorgi, F S; Amantini, A; Giannasi, G; Campostrini, R; Giovannelli, F; Paganini, M; Nazerian, P

2018-06-01

Over last fifty years, intravenous (iv) phenytoin (PHT) loading dose has been the treatment of choice for patients with benzodiazepine-resistant convulsive status epilepticus and several guidelines recommended this treatment regimen with simultaneous iv diazepam. Clinical studies have never shown a better efficacy of PHT over other antiepileptic drugs. In addition, iv PHT loading dose is a complex and time-consuming procedure which may expose patients to several risks, such as local cutaneous reactions (purple glove syndrome), severe hypotension and cardiac arrhythmias up to ventricular fibrillation and death, and increased risk of severe allergic reactions. A further disadvantage of PHT is that it is a strong enzymatic inducer and it may make ineffective several drugs that need to be used simultaneously with antiepileptic treatment. In patients with a benzodiazepine-resistant status epilepticus, we suggest iv administration of levetiracetam as soon as possible. If levetiracetam would be ineffective, a further antiepileptic drug among those currently available for iv use (valproate, lacosamide, or phenytoin) can be added before starting third line treatment. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A fully validated method for the determination of lacosamide in human plasma using gas chromatography with mass spectrometry: application for therapeutic drug monitoring.

PubMed

Nikolaou, Panagiota; Papoutsis, Ioannis; Spiliopoulou, Chara; Voudris, Constantinos; Athanaselis, Sotiris

2015-01-01

A simple gas chromatographic method with mass spectrometry detection was developed and validated for the determination of lacosamide in human plasma. Lacosamide and the internal standard, levetiracetam-d6, were extracted from 200 μL plasma, by a solid-phase extraction through HF Bond Elut C18 columns, and derivatized using N-methyl-N-tert-butyldimethylsilyltrifluoroacetamide with 1% tert-butyldimethylsilylchloride in acetonitrile. The limit of quantification was found to be 0.20 μg/mL and the assay was linear up to 20.0 μg/mL with correlation coefficient ≥0.994. The intra- and interday precision values were <4.1% in terms of relative standard deviation (%) and the values of intra- and interday accuracy were found to be within -7.2 and 5.3% in terms of relative error (%). Absolute recovery of the method for lacosamide was determined at three concentration levels and ranged from 92.5 to 97.6%. The developed method uses small volumes of plasma and proved to be simple, rapid, and sensitive for the determination of lacosamide in plasma. This method can be used in routine every day analysis of plasma samples obtained from patients who follow respective antiepileptic treatment and for the investigation of clinical and forensic cases where lacosamide is involved. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Lacosamide: in partial-onset seizures.

PubMed

Cross, Sarah A; Curran, Monique P

2009-01-01

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.

Observational study of intravenous lacosamide in patients with convulsive versus non-convulsive status epilepticus.

PubMed

Moreno Morales, Eros Yamel; Fernandez Peleteiro, Manuel; Bondy Peña, Ernesto Carlo; Domínguez Lorenzo, Jose Maria; Pardellas Santiago, Elva; Fernández, Anxo

2015-07-01

Status epilepticus (SE) is an important emergency situation associated with high morbidity and mortality. The goal of pharmacological therapy-rapid seizure termination-is only achieved in just over half of patients with first-line anti-epileptic drug (AED) therapy and many patients require second and higher lines of AEDs to achieve seizure termination; therefore, there is a clear need for more effective treatment options. Lacosamide is a relatively new AED and the intravenous formulation has shown promise for treatment of SE. The aim of the current study was to compare electroencephalographic (EEG) response and seizure termination with intravenous lacosamide (±other AEDs) in patients with convulsive versus non-convulsive SE, in a Spanish intensive care setting. In this prospective, observational study, patients with convulsive or non-convulsive SE who received intravenous lacosamide 400 mg/day for 8 days were compared in terms of EEG response and seizure termination. Adverse events were not specifically assessed. Fifty-three patients (69.8 % male; mean age 55.2 years) were treated with lacosamide (mean dose 390.6 mg) as first- (20.8 %), second- (34 %), third (22.6 %) or fourth-line (22.6 %) treatment for convulsive (n = 23, 43.4 %) or non-convulsive (n = 30, 56.6 %) SE. The majority of patients (73.6 %) had a comorbid condition, predominantly hypertension (35.8 %), and most (79.2 %) received at least one concomitant AED, including midazolam (54.7 %), valproic acid (52.8 %), and levetiracetam (30.2 %). Patient characteristics and treatment received did not differ significantly between the convulsive and non-convulsive SE groups. EEG recordings following lacosamide treatment demonstrated the elimination of paroxysmal activity (disappearance and/or attenuation of epileptiform activity in >60 % of recording time) in 56.6 % of patients; 69.6 % of convulsive and 46.7 % of non-convulsive SE groups. Among all patients, 90.6 % showed some EEG improvement (disappearance of

A micromethod for the determination of the new antiepileptic drug levetiracetam (ucb LO59) in serum or plasma by high performance liquid chromatography.

PubMed

Ratnaraj, N; Doheny, H C; Patsalos, P N

1996-04-01

An isocratic high performance liquid chromatographic micromethod is described for the quantitation of levetiracetam (ucb L059) in plasma or serum of patients. The chromatography is performed on a 250 x 4 mm I.D. LiChrospher 60 RP-select B, 5-micron column, eluted with an acetonitrile/50 mM phosphate buffer (15:85 vol/vol, pH 5.6) mobile phase, and levetiracetam detected using ultraviolet absorbance at 220 nm. The limit of quantitation was 5 mumol/L and the within-batch and between-batch coefficients of variation were < 7%. No interference from commonly prescribed antiepileptic drugs (carbamazepine and its metabolite carbamazepine epoxide, ethosuximide, gabapentin, lamotrigine, phenobarbitone, phenytoin, primidone, valproic acid, and vigabatrin) was observed, and thus the method can be used to monitor levetiracetam in patients on polytherapy antiepileptic drug regimens.

Region-specific changes in gene expression in rat brain after chronic treatment with levetiracetam or phenytoin

PubMed Central

Hassel, Bjørnar; Taubøll, Erik; Shaw, Renee; Gjerstad, Leif; Dingledine, Ray

2014-01-01

Summary Purpose It is commonly assumed that antiepileptic drugs (AEDs) act similarly in the various parts of the brain as long as their molecular targets are present. A few experimental studies on metabolic effects of vigabatrin, levetiracetam, valproate, and lamotrigine have shown that these drugs may act differently in different brain regions. We examined effects of chronic treatment with levetiracetam or phenytoin on mRNA levels to detect regional drug effects in a broad, nonbiased manner. Methods mRNA levels were monitored in three brain regions with oligonucleotide-based microarrays. Results Levetiracetam (150 mg/kg for 90 days) changed the expression of 65 genes in pons/medulla oblongata, two in hippocampus, and one in frontal cortex. Phenytoin (75 mg/kg), in contrast, changed the expression of only three genes in pons/medulla oblongata, but 64 genes in hippocampus, and 327 genes in frontal cortex. Very little overlap between regions or drug treatments was observed with respect to effects on gene expression. Discussion We conclude that chronic treatment with levetiracetam or phenytoin causes region-specific and highly differential effects on gene expression in the brain. Regional effects on gene expression could reflect regional differences in molecular targets of AEDs, and they could influence the clinical profiles of AEDs. PMID:20345932

A long-term noninterventional safety study of adjunctive lacosamide therapy in patients with epilepsy and uncontrolled partial-onset seizures.

PubMed

Steinhoff, Bernhard J; Eckhardt, Klaus; Doty, Pamela; De Backer, Marc; Brunnert, Marcus; Schulze-Bonhage, Andreas

2016-05-01

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

A case of lacosamide-induced hepatotoxicity.

PubMed

Sunwoo, Jun-Sang; Byun, Jung-Ick; Lee, Sang Kun

2015-06-01

Lacosamide is a novel antiepileptic drug that acts mainly via the selective enhancement of slow inactivation of voltage-gated sodium channels. It has been reported that lacosamide is effective and generally tolerable as an adjuvant treatment in patients with partial seizures. There are few reports regarding liver damage caused by lacosamide. We describe a case of a patient with drug-resistant epilepsy who developed symptomatic hepatotoxicity after lacosamide administration. A 22-year-old female with a 2-year history of temporal lobe epilepsy was admitted to our hospital because of nausea, dizziness, and abnormal liver function tests. Lacosamide was added for further seizure control 9 days before the current presentation. Her liver enzymes were markedly increased: aspartate aminotransferase, 635 U/L; alanine aminotransferase, 697 U/L. Lacosamide was ceased immediately, whereas other medications (zonisamide, clobazam, and tianeptine) were not withdrawn. The level of liver enzymes improved significantly within a few days, and a diagnosis of lacosamide-induced hepatitis was made based on the obvious temporal relationship. This case report demonstrates that hepatotoxicity may develop in association with lacosamide therapy. Liver function tests should be prompted in patients with symptoms suggestive of adverse effects after the initiation of lacosamide. Further research is required to identify predisposing factors of lacosamideinduced hepatotoxicity.

Lacosamide monotherapy for partial onset seizures.

PubMed

Lattanzi, Simona; Cagnetti, Claudia; Foschi, Nicoletta; Provinciali, Leandro; Silvestrini, Mauro

2015-04-01

To evaluate the 1-year efficacy and safety of oral lacosamide as conversion monotherapy in adult patients with partial onset seizures with or without generalization. We prospectively followed-up consecutive patients converted to lacosamide monotherapy after 1-year seizure freedom on lacosamide add-on therapy and withdrawal of the concurrent antiepileptic drug (AED). Seizure occurrence, treatment compliance and drug toxicity were assessed every 3 months up to 1 year. The study outcomes were the retention rate of lacosamide as single AED and the seizure freedom under lacosamide monotherapy at 1 year from withdrawal of background AED. The safety variable was the prevalence of lacosamide related adverse events (AEs). Among the 58 included patients, at 1 year from withdrawal of background medication, 37 (63.8%) retained lacosamide as single AED and 32 (55.2%) were free from seizure occurrence under lacosamide monotherapy throughout the entire follow-up. The history of less than three lifetime AEDs turned out to be significant predictor of seizure freedom (adjusted OR = 6.38, 95% CI 1.85-21.98, p = 0.003). Twelve (20.8%) subjects reported mild to moderate AEs, with the commonest being drowsiness, dizziness, and headache. Conversion to lacosamide monotherapy could be effective and well tolerated in selected adults patients with partial onset seizures who had achieved seizure freedom during lacosamide add-on therapy. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Levetiracetam

MedlinePlus

... types of seizures in adults and children with epilepsy. Levetiracetam is in a class of medications called ... often than once every 2 weeks.Levetiracetam controls epilepsy but does not cure it. Continue to take ...

Safety of intravenous lacosamide in critically ill children.

PubMed

Welsh, Sarah S; Lin, Nan; Topjian, Alexis A; Abend, Nicholas S

2017-11-01

Acute seizures are common in critically ill children. These patients would benefit from intravenous anti-seizure medications with few adverse effects. We reviewed the usage and effects of intravenous lacosamide in critically ill children with seizures or status epilepticus. This retrospective series included consecutive patients who received at least one dose of intravenous lacosamide from April 2011 to February 2016 in the pediatric intensive care unit of a quaternary care children's hospital, including patients with new lacosamide initiation and continuation of outpatient oral lacosamide. Dosing and prescribing practices were reviewed. Adverse effects were defined by predefined criteria, and most were evaluated during the full admission. We identified 51 intensive care unit admissions (47 unique patients) with intravenous lacosamide administration. Lacosamide was utilized as a third or fourth-line anti-seizure medication for acute seizures or status epilepticus in the lacosamide-naïve cohort. One patient experienced bradycardia and one patient experienced a rash that were considered potentially related to lacosamide. No other adverse effects were identified, including no evidence of PR interval prolongation. Lacosamide was well tolerated in critically ill children. Further study is warranted to evaluate the effectiveness of earlier lacosamide use for pediatric status epilepticus and acute seizures. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Safety and tolerability of lacosamide monotherapy in the elderly: A subgroup analysis from lacosamide trials in diabetic neuropathic pain.

PubMed

Bainbridge, Jacquelyn; De Backer, Marc; Eckhardt, Klaus; Tennigkeit, Frank; Bongardt, Sabine; Sen, David; Werhahn, Konrad J; Shaibani, Aziz; Faught, Edward

2017-12-01

To assess the safety profile of lacosamide monotherapy in elderly (≥65 years) subjects with diabetic neuropathic pain (DNP). Of 1,863 DNP subjects in double-blind, randomized, placebo-controlled trials of lacosamide monotherapy (NCT00861445, NCT00235469, NCT00238524, NCT00135109, NCT00350103), 502 were elderly. Safety data from elderly subjects were compared with that of younger subjects (<65 years) within these DNP trials. It should be noted that lacosamide is approved for the treatment of focal (partial-onset) seizures; it is not approved/recommended for the treatment of DNP. Overall, cardiovascular diseases were prevalent in the DNP population, as was the use of cardiac, blood pressure, diabetes, and cholesterol-lowering medications among both young and elderly subjects. The most frequently reported adverse events (AEs) for lacosamide monotherapy (200, 400, and 600 mg/day combined) in elderly versus younger subjects were dizziness (16.2% vs. 13.2%), nausea (10.0% vs. 9.4%), and headache (8.0% vs. 8.7%). Incidences of cardiac disorder AEs were higher in elderly versus younger subjects receiving placebo (6.2% vs. 3.9%), lacosamide 200 (4.8% vs. 3.3%), lacosamide 400 (7.0% vs. 4.1%), and lacosamide 600 mg/day (7.7% vs. 4.0%). Discontinuation rates because of any AE in the elderly versus younger subjects were similar for placebo (8.8% vs. 7.0%) and lacosamide 200 mg/day (9.6% vs. 11.9%) and higher for lacosamide 400 (25.1% vs. 10.8%) and lacosamide 600 mg/day (52.7% vs. 28.3%). Lacosamide monotherapy was well tolerated in elderly subjects with DNP, with an overall AE profile consistent with that reported in epilepsy trials.

A case of refractary epilepsy and related pain due to dysmenorrhea solved with loading dose of lacosamide: clinical and neurophysiological correlates.

PubMed

Marchitto, Nicolino; Ceratti, Umberto; Dalmaso, Serenella; Raimondi, Gianfranco

2017-10-23

 In most cases, the etiology of epilepsy is unknown, although some individuals may develop epilepsy as a result of certain brain injuries, following a stroke, a brain tumor or because of drugs and alcohol. Even some rare genetic mutations may be related to the onset of the condition. Seizures are the result of excessive and abnormal activity of neurons in the cerebral cortex. In this case report we show a clinical case of refractory epilepsy due to pain related to uncontrolled dysmenorrhea. The patient, 43 yrs old, had a history of epilepsy of 20 years and ovarian cancer. She was treated with lamotrigine, clonazepam and levomepromazina maleato. At admission the patient shew seizures due to pain related to dysmenorrhea. In emergency we treated with verapamil hydrochloride 10 mg ev, subsequently verapamil hydrochloride 20 mg in 250 ml of saline solution as maintenance dose. Then we decided to administer a loading dose of 100 mg cpr of Lacosamide to stop the treatment with verapamil hydrochloride. With Lacosamide we solved the seizures in 24 hours.

Safety and tolerability of adjunctive lacosamide intravenous loading dose in lacosamide-naive patients with partial-onset seizures.

PubMed

Fountain, Nathan B; Krauss, Gregory; Isojarvi, Jouko; Dilley, Deanne; Doty, Pamela; Rudd, G David

2013-01-01

To examine the safety and tolerability of rapidly initiating adjunctive lacosamide via a single intravenous loading dose followed by twice-daily oral lacosamide in lacosamide-naive adults with partial-onset seizures. This open-label, multicenter trial, enrolled patients with epilepsy who were taking 1-2 antiepileptic drugs (AEDs) in one of four sequential cohorts containing 25 subjects each. An intravenous lacosamide loading dose (200, 300, or 400 mg) was administered over 15 min followed 12 h later by initiation of oral dosing consisting of one-half of the loading dose administered twice daily for 6.5 days. The first cohort was administered lacosamide 200 mg/day, followed by a cohort at 300 mg/day, and then a cohort at 400 mg/day. The results from each cohort were evaluated before enrolling the next highest dose level. The fourth cohort enrolled patients at the highest dose with clinically acceptable safety and tolerability results. Safety evaluations included treatment-emergent adverse events (TEAEs), patient withdrawals due to TEAEs, and changes in vital signs, 12-lead electrocardiography (ECG) studies, laboratory parameters, and clinical examinations. Postinfusion lacosamide plasma concentrations were also evaluated. A total of 100 patients were enrolled, 25 in each cohort. The loading dose for the repeat cohort was 300 mg; therefore, 25 patients were enrolled at 200 mg/day, 50 at 300 mg/day, and 25 at 400 mg/day. Most TEAEs occurred within the first 4 h following infusion; dose-related TEAEs (incidence ≥10%) during this timeframe included dizziness, somnolence, and nausea. Seven patients withdrew, all due to TEAEs: three (6%) from the combined 300 mg group and four (16%) from the 400 mg group; four of these patients discontinued within 4 h following infusion. The most common TEAEs leading to discontinuation (overall incidence >1%) were dizziness (6%), nausea (5%), and vomiting (3%). No clinically relevant pattern of changes from baseline ECG, clinical

Efficacy of lacosamide by focal seizure subtype.

PubMed

Sperling, Michael R; Rosenow, Felix; Faught, Edward; Hebert, David; Doty, Pamela; Isojärvi, Jouko

2014-10-01

The purpose of this post hoc exploratory analysis was to determine the effects of the antiepileptic drug, lacosamide, on focal (partial-onset) seizure subtypes. Patient data from the three lacosamide pivotal trials were grouped and pooled by focal seizure subtype at Baseline: simple partial seizures (SPS), complex partial seizures (CPS), and secondarily generalized partial seizures (SGPS). Both efficacy outcomes (median percent change from Baseline to Maintenance Phase in seizure frequency per 28 days and the proportion of patients experiencing at least a 50% reduction in seizures) were evaluated by lacosamide dose (200, 400, or 600 mg/day) compared to placebo for each seizure subtype. An additional analysis was performed to determine whether a shift from more severe focal seizure subtypes to less severe occurred upon treatment with lacosamide. In patients with CPS or SGPS at Baseline, lacosamide 400 mg/day (maximum recommended daily dose) and 600 mg/day reduced the frequency of CPS and SGPS compared to placebo. Likewise, a proportion of patients with CPS and SGPS at Baseline experienced at least a 50% reduction in the frequency of CPS and SGPS (≥50% responder rate) in the lacosamide 400 and 600 mg/day groups compared with placebo. For both outcomes, numerically greatest responses were observed in the lacosamide 600 mg/day group among patients with SGPS at Baseline. In patients with SPS at Baseline, no difference between placebo and lacosamide was observed for either efficacy outcome. An additional exploratory analysis suggests that in patients with SPS at Baseline, CPS and SGPS may have been shifted to less severe SPS upon treatment with lacosamide. The results of these exploratory analyses revealed reductions in CPS and SGPS frequency with adjunctive lacosamide. Reduction in CPS and SGPS may confound assessment of SPS since the CPS or SGPS may possibly change to SPS by effective treatment. Copyright © 2014 Elsevier B.V. All rights reserved.

[Fulminant liver failure in a patient on carbamazepine and levetiracetam treatment associated with status epilepticus].

PubMed

Skopp, Gisela; Schmitt, Horst Peter; Pedal, Ingo

2006-01-01

A 22-year-old female with a history of developmental delay and seizures successfully treated with carbamazepine and levetiracetam developed fulminant hepatic failure and subsequently died. She had been admitted to the hospital following secondary generalized seizures of 35 min duration. A circulatory shock as well as intoxication was taken into consideration during the clinical course. Autopsy failed to reveal a macroscopically discernible cause of death. Significant findings on microscopic examination included acute tubular necrosis in the kidneys, pre-existing marked accumulation of neutral lipid within the hepatocytes as well as hyperacute liver damage with evidence of almost complete hepatocyte necrosis. Carbamazepine and levetiracetam were simultaneously determined from blood and tissues such as liver, lungs, muscle and kidneys by LC-MS/MS following addition of lamotrigine as an internal standard and liquid-liquid extraction. Validation data are given for levetiracetam. Both carbamazepine and levetiracetam were present in blood at concentrations within or below the therapeutic range, respectively. Moreover, tissue concentrations suggested long-term administration of anticonvulsant drugs, which is in accordance with the medical history. After excessive drug concentrations could be ruled out, the metabolic consequences of a prolonged carbamazepine therapy to cause severe hepatic injury in the present case are discussed. A mechanism of injury to the hepatocytes may be membrane damage by either an increased production of free radicals and/or a decreased free radical scavenging capacity. Following ischemia with reperfusion and during hyperthermia, large amounts of free radicals are formed. Induction of the mixed oxidase activity during longterm administration of carbamazepine may also increase production of free radicals, leaving the hepatic cell more vulnerable to oxidative injury.

Clinical pharmacokinetic and pharmacodynamic profile of lacosamide.

PubMed

Cawello, Willi

2015-09-01

Lacosamide-a third-generation antiepileptic drug available in multiple formulations-was first approved in 2008 as adjunctive therapy for partial-onset seizures (POS) in adults. In 2014, lacosamide was approved as monotherapy for POS by the US Food and Drug Administration (FDA). A loading dose administration was approved in 2013 by the European Medicines Agency and in 2014 by the FDA. Unlike traditional sodium channel blockers affecting fast inactivation, lacosamide selectively enhances sodium channel slow inactivation. This mechanism of action results in stabilization of hyperexcitable neuronal membranes, inhibition of neuronal firing and reduction in long-term channel availability without affecting physiological function. Lacosamide is rapidly absorbed, with maximum plasma concentrations reached 0.5-4 h after intake. Oral bioavailability is high (100 %) for a dose up to 800 mg. Bioavailability is irrespective of food intake. Variability in pharmacokinetic parameters is low (coefficients of variation almost all <20 %). The pharmacokinetic profile of lacosamide is consistent in healthy subjects and across different patient populations studied. Lacosamide elimination from plasma occurs with a terminal half-life of approximately 13 h in young subjects and 14-16 h in elderly subjects; this difference does not impact the dose regimen. Lacosamide produces a pharmacodynamic effect that is closely correlated with its plasma concentration. The pharmacokinetic and pharmacodynamic relationship for reduction of seizure frequency can be described by a maximum effect (E max) model. Lacosamide does not induce or inhibit cytochrome P450 enzymes or known drug transporter systems, has low protein binding of less than 15 % and, because it has multiple elimination pathways, it has no clinically relevant interactions with commonly prescribed medications.

Teratogenic potential of antiepileptic drugs in the zebrafish model.

PubMed

Lee, Sung Hak; Kang, Jung Won; Lin, Tao; Lee, Jae Eun; Jin, Dong Il

2013-01-01

The zebrafish model is an attractive candidate for screening of developmental toxicity during early drug development. Antiepileptic drugs (AEDs) arouse concern for the risk of teratogenicity, but the data are limited. In this study, we evaluated the teratogenic potential of seven AEDs (carbamazepine (CBZ), ethosuximide (ETX), valproic acid (VPN), lamotrigine (LMT), lacosamide (LCM), levetiracetam (LVT), and topiramate (TPM)) in the zebrafish model. Zebrafish embryos were exposed to AEDs from initiation of gastrula (5.25 hours post-fertilization (hpf)) to termination of hatching (72 hpf) which mimic the mammalian teratogenic experimental design. The lethality and teratogenic index (TI) of AEDs were determined and the TI values of each drug were compared with the US FDA human pregnancy categories. Zebrafish model was useful screening model for teratogenic potential of antiepilepsy drugs and was in concordance with in vivo mammalian data and human clinical data.

Safety profile of levetiracetam.

PubMed

Arroyo, Santiago; Crawford, Pamela

2003-05-01

A good balance between safety and tolerability is necessary for an antiepileptic drug (AED) to be successful in the management of patients with epilepsy. Levetiracetam is one of the new generation of AEDs licensed as an add-on therapy for the treatment of patients with partial-onset seizures. Leveti-racetam's mechanisms of action are not fully understood. Controlled clinical trials, open-label studies, and postmarketing surveillance indicate that leveti-racetam has a favorable safety profile characterized by little effect on vital signs or clinical laboratory values, reported adverse events that are mild to moderate, and no known drug-drug interactions. The tolerability of levetiracetam may extend to both pediatric and elderly patients based on analyses of small numbers of patients. Tolerability is maintained over the long term. Levetirac-etam does not appear to have a different safety profile in learning-disabled patients. Levetiracetam appears to have a good balance between tolerability and efficacy in the treatment of a wide variety of patients with partial epilepsy.

Forced normalisation precipitated by lamotrigine.

PubMed

Clemens, Béla

2005-10-01

To report two patients with lamotrigine-induced forced normalization (FN). Evaluation of the patient files, EEG, and video-EEG records, with special reference to the parallel clinical and EEG changes before, during, and after FN. This is the first documented report of lamotrigine-induced FN. The two epileptic patients (one of them was a 10-year-old girl) were successfully treated with lamotrigine. Their seizures ceased and interictal epileptiform events disappeared from the EEG record. Simultaneously, the patients displayed de novo occurrence of psychopathologic manifestations and disturbed behaviour. Reduction of the daily dose of LTG led to disappearance of the psychopathological symptoms and reappearance of the spikes but not the seizures. Lamotrigine may precipitate FN in adults and children. Analysis of the cases showed that lamotrigine-induced FN is a dose-dependent phenomenon and can be treated by reduction of the daily dose of the drug.

Cardiovascular toxicity with levetiracetam overdose.

PubMed

Page, Colin B; Mostafa, Ahmed; Saiao, Ana; Grice, Jeffrey E; Roberts, Michael S; Isbister, Geoffrey K

2016-01-01

To describe the cardiovascular toxicity and pharmacokinetics of levetiracetam in overdose. A 43-year-old female presented 8 h post ingestion of 60-80 g of levetiracetam with mild central nervous system depression, bradycardia, hypotension and oliguria. Her cardiovascular toxicity transiently responded to atropine and intravenous fluids. A bedside echocardiogram demonstrated normal left and right ventricular contractility. Despite her cardiovascular toxicity and oliguria, she had normal serial venous lactates and renal function; and made a complete recovery over 48 h. Her levetiracetam concentration was 463 mcg/ml 8 h post ingestion (therapeutic range 10-40 mcg/ml) and her concentration-time data best fitted a one-compartment model with first-order input and an elimination half-life of 10.4 h. Levetiracetam in large ingestions appears to cause bradycardia and hypotension that is potentially responsive to atropine and intravenous fluids. Based on a normal echocardiogram, the mechanism for this effect may be levetiracetam acting at muscarinic receptors at high concentration. The pharmacokinetics of levetiracetam in overdose appeared to be similar to therapeutic levetiracetam dosing.

Comparative effectiveness of eight antiepileptic drugs in adults with focal refractory epilepsy: the influence of age, gender, and the sequence in which drugs were introduced onto the market.

PubMed

Mäkinen, Jussi; Peltola, Jukka; Raitanen, Jani; Alapirtti, Tiina; Rainesalo, Sirpa

2017-07-01

The first objective was to determine the long-term retention rate of eight antiepileptic drugs (AEDs) commonly used as adjunctive therapy in adults with focal refractory epilepsy. Second, we assessed the effects of age and gender on retention rates. Third, we examined if the retention rate could be influenced by the sequence in which the AEDs had entered the market. Patients with focal refractory epilepsy treated with any of the eight AEDs in Tampere University Hospital were identified retrospectively (N = 507). Retention rates were evaluated with the Kaplan-Meier method. Follow-up started at the first date of treatment and each individual was followed a maximum of 36 months. We calculated the following 3-year retention rates: lacosamide 77.1% (N = 137), lamotrigine 68.3% (N = 177), levetiracetam 66.7% (N = 319), clobazam 65.6% (N = 130), topiramate 61.6% (N = 178), zonisamide 60.4% (N = 103), pregabalin 54.6% (N = 127), and gabapentin 40.2% (N = 66). Lacosamide, levetiracetam, and clobazam were the most effective AEDs in the elderly. The retention rate for pregabalin was higher in males (65%) than females (51%) whereas females had higher retention rates for both topiramate (72 vs. 58%) and zonisamide (67 vs. 57%). The retention rate was influenced by the sequence in which these AEDs entered the market. We provide important information about practical aspects of these eight AEDs, revealing that there are differences in their effectiveness as adjunctive treatment for focal refractory epilepsy. Most importantly, the retention rate appears to be influenced by the sequence in which these AEDs were introduced onto the market.

Methotrexate Elimination When Coadministered With Levetiracetam.

PubMed

Reeves, David; DiDominick, Sarah; Finn, Suzanne; Kim, Hyeon Jin; Shake, Amanda

2016-12-01

Delayed elimination of methotrexate was previously reported in 2 patients receiving concomitant levetiracetam. To explore the potential interaction between methotrexate and levetiracetam in patients receiving high-dose methotrexate. This retrospective study reviewed the records of 81 adults receiving 280 cycles of methotrexate to determine the effects of levetiracetam on methotrexate elimination. Institutional review board approval was obtained. Levetiracetam was administered in 33 (12%) cycles of methotrexate. Patients receiving levetiracetam had significantly lower 24-hour methotrexate concentrations compared with those not receiving levetiracetam (2.91 vs 7.37 µmol/L, P = 0.005). Despite this difference, concentrations at 48 and 72 hours were similar between groups. Times to nontoxic methotrexate concentration (<0.1 µmol/L) were the same regardless of the presence of levetiracetam. The frequency of delayed elimination at 24, 48, and 72 hours was similar in both groups as was the frequency of delayed elimination at any time point. Cox regression demonstrated that levetiracetam was not a significant predictor of time to nontoxic methotrexate concentration (P = 0.796; HR = 1.058; 95% CI = 0.692-1.617), and logistic regression demonstrated that levetiracetam was not a significant predictor of delayed elimination at any time point. Levetiracetam use was similar between groups when comparing patients experiencing delayed elimination at any time point with those without delayed elimination (13% vs 10%, respectively, P = 0.527). This study does not support the previous reports of a significant interaction between levetiracetam and methotrexate. A clinically significant interaction is unlikely in those without additional risk factors for delayed elimination. © The Author(s) 2016.

Teratogenic Potential of Antiepileptic Drugs in the Zebrafish Model

PubMed Central

Lee, Sung Hak; Kang, Jung Won; Lin, Tao; Lee, Jae Eun; Jin, Dong Il

2013-01-01

The zebrafish model is an attractive candidate for screening of developmental toxicity during early drug development. Antiepileptic drugs (AEDs) arouse concern for the risk of teratogenicity, but the data are limited. In this study, we evaluated the teratogenic potential of seven AEDs (carbamazepine (CBZ), ethosuximide (ETX), valproic acid (VPN), lamotrigine (LMT), lacosamide (LCM), levetiracetam (LVT), and topiramate (TPM)) in the zebrafish model. Zebrafish embryos were exposed to AEDs from initiation of gastrula (5.25 hours post-fertilization (hpf)) to termination of hatching (72 hpf) which mimic the mammalian teratogenic experimental design. The lethality and teratogenic index (TI) of AEDs were determined and the TI values of each drug were compared with the US FDA human pregnancy categories. Zebrafish model was useful screening model for teratogenic potential of antiepilepsy drugs and was in concordance with in vivo mammalian data and human clinical data. PMID:24324971

Outcome of cancer-related seizures in patients treated with lacosamide.

PubMed

Toledo, M; Molins, A; Quintana, M; Santamarina, E; Martinez-Ricarte, F; Martínez-Saez, E; Salas-Puig, J

2018-01-01

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. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

DRESS syndrome: A case of cross-reactivity with lacosamide?

PubMed

Fong, Man Kei; Sheng, Bun

2017-06-01

A 42-year-old patient with epilepsy was admitted to the hospital for fever and generalized skin rash. He has known allergy to phenytoin. Valproate was started in 2012, but failed to control his seizure despite gradual increase in dosage. Phenobarbitone was added 16 days before admission and was stopped on admission. He was treated with beta-lactam antibiotics. The rash subsided gradually after the cessation of phenobarbitone. Lacosamide was subsequently added for seizure control. Unfortunately, he developed drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome soon after introduction of lacosamide that required the use of systemic steroid for acute hepatitis. A cross-reactivity with lacosamide was suspected in view of the rapid onset of DRESS syndrome after the initial rash resolution and soon after the introduction of lacosamide. We postulated that the rapid onset of DRESS syndrome may be related to the aromatic ring that is in common among phenytoin, phenobarbitone, and lacosamide.

Lamotrigine

MedlinePlus

Lamotrigine extended-release (long-acting) tablets are used with other medications to treat certain types of seizures in patients ... disintegrating tablets, and chewable tablets) other than the extended-release tablets are used alone or with other ...

[The efficacy of intravenous lacosamide in psychiatric hospital].

PubMed

Vakula, I N; Bojko, E O; Vorona, U A; Storozhuk, J A; Nikiforova, E U; Nikiforova, D I; Glazunova, T I

2016-01-01

To evaluate the efficacy and tolerability of intravenous lacosamide (vimpat) in inpatients with frequent partial-onset seizures and affective and cognitive disorders. Fifteen patients were enrolled including 14 patients diagnosed with «organic personality disorder associated with epilepsy» (cryptogenic or symptomatic epilepsy with frequent partial-onset and/or secondary-generalized seizures (serial seizures in some cases) and 1 patient with a preliminary diagnosis of «organic schizophrenia-like disorder», which was changed for «organic personality disorder associated with epilepsy» after examination. Patients were treated with 2--3 antiepileptic drugs (AEDs), but no one of them received earlier lacosamide. Lacosamide was used intravenously in drops in the dose of 200 or 400 mg daily during 5 days. In 4 patients with marked personality disorders, the frequency of seizures decreased by 75%, no seizures were noted after 2--3 days of treatment in 11 patients. A positive effect of lacosamide on the affective sphere and quality-of-life was observed in 11 (73.4%) patients with epilepsy. Mild and moderate adverse effects were found only in 2 patients. It has been concluded that lacosamide demonstrates the high efficacy in patients with frequent drug-resistant seizures.

Specific binding of lacosamide to collapsin response mediator protein 2 (CRMP2) and direct impairment of its canonical function: implications for the therapeutic potential of lacosamide.

PubMed

Wilson, Sarah M; Khanna, Rajesh

2015-04-01

The novel antiepileptic drug lacosamide (LCM; SPM927, Vimpat®) has been heralded as having a dual-mode of action through interactions with both the voltage-gated sodium channel and the neurite outgrowth-promoting collapsin response mediator protein 2 (CRMP2). Lacosamide's ability to dampen neuronal excitability through the voltage-gated sodium channel likely underlies its efficacy in attenuating the symptoms of epilepsy (i.e., seizures). While the role of CRMP2 in epilepsy has not been well studied, given the proposed involvement of circuit reorganization in epileptogenesis, the ability of lacosamide to alter CRMP2 function may prove disease modifying. Recently, however, the validity of lacosamide's interaction with CRMP2 has come under scrutiny. In this review, we address the contradictory reports concerning the binding of lacosamide to CRMP2 as well as the ability of lacosamide to directly impact CRMP2 function. Additionally, we address similarly the contradicting reports regarding the potential disease-modifying effect of lacosamide on the development and progression of epilepsy. As the vast majority of antiepileptic drugs influences only the symptoms of epilepsy, the ability to hinder disease progression would be a major breakthrough in efforts to cure or prevent this debilitating syndrome.

Development of lacosamide for the treatment of partial-onset seizures

PubMed Central

Doty, Pamela; Hebert, David; Mathy, Francois-Xavier; Byrnes, William; Zackheim, James; Simontacchi, Kelly

2013-01-01

Lacosamide is an antiepileptic drug (AED) available in multiple formulations that was first approved in 2008 as adjunctive therapy for partial-onset seizures (POS) in adults. Unlike traditional sodium channel blockers affecting fast inactivation, lacosamide selectively enhances sodium channel slow inactivation. This mechanism of action results in stabilization of hyperexcitable neuronal membranes, inhibition of neuronal firing, and reduction in long-term channel availability without affecting physiological function. Lacosamide has a well-characterized and favorable pharmacokinetic profile, including a fast absorption rate, minimal or no interaction with cytochrome P-450 izoenzymes, and a low potential for drug–drug interactions. Lacosamide clinical development included three placebo-controlled, double-blind, randomized trials conducted in more than 1300 patients, each demonstrating safety and efficacy of lacosamide compared to placebo as adjunctive therapy for adults with POS. The clinical use of lacosamide may broaden, pending results of trials evaluating its use as monotherapy for POS in adults, as treatment for epilepsy in pediatric subjects, and as adjunctive treatment for uncontrolled primary generalized tonic–clonic seizures in those with idiopathic generalized epilepsy. PMID:23859801

Lacosamide add-on therapy for partial epilepsy.

PubMed

Weston, Jennifer; Shukralla, Arif; McKay, Andrew J; Marson, Anthony G

2015-06-16

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

Lacosamide Pharmacokinetics in a Critically Ill Patient Receiving Continuous Venovenous Hemofiltration.

PubMed

Franquiz, Miguel J; Kalaria, Shamir N; Armahizer, Michael J; Gopalakrishnan, Mathangi; McCarthy, Paul J; Badjatia, Neeraj

2018-02-01

Lacosamide is a new-generation antiepileptic drug (AED) that is eliminated by both hepatic and renal mechanisms. Lacosamide elimination by continuous renal replacement therapy (CRRT) has never been studied. The objective of this case report was to describe lacosamide pharmacokinetics in the setting of CRRT. We describe a single patient admitted to the study center with status epilepticus and multiorgan failure. The patient required both continuous venovenous hemofiltration (CVVH) and several AEDs. He was receiving intravenous lacosamide 200 mg twice/day at steady state prior to sampling. Plasma lacosamide concentrations were derived using a validated high-performance liquid chromatography method. Parameters were calculated using Phoenix WinNonlin 7.1 software. The peak concentration at steady state was 7.7 mg/L, the trough concentration was 5.9 mg/L (goal 5-12 mg/L). The volume of distribution was 0.7 L/kg, the elimination half-life was 21 hours, and the sieving coefficient was 0.8 (± 0.06). Lacosamide was cleared by CVVH as demonstrated by the sieving coefficient, but plasma concentrations remained within goal range throughout the dosing interval. These results may suggest that lacosamide 200 mg twice/day is a useful dosing strategy for critically ill patients who require CVVH. © 2017 Pharmacotherapy Publications, Inc.

Relationship between plasma concentrations of lamotrigine and its early therapeutic effect of lamotrigine augmentation therapy in treatment-resistant depressive disorder.

PubMed

Kagawa, Shoko; Mihara, Kazuo; Nakamura, Akifumi; Nemoto, Kenji; Suzuki, Takeshi; Nagai, Goyo; Kondo, Tsuyoshi

2014-12-01

The relationship between plasma concentrations of lamotrigine and its therapeutic effects was prospectively studied on 34 (9 men and 25 women) inpatients with treatment-resistant depressive disorder during an 8-week treatment of lamotrigine augmentation using an open-study design. The subjects were depressed patients who had already shown insufficient response to at least 3 psychotropics, including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 12), bipolar I disorder (n = 7), and bipolar II disorder (n = 15). The final doses of lamotrigine were 100 mg/d for 18 subjects who were not taking valproate and 75 mg/d for 16 subjects taking valproate. Depressive symptoms were evaluated by the Montgomery Åsberg Depression Rating Scale (MADRS) before and after the 8-week treatment. Blood sampling was performed at week 8. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. There was a significant linear relationship between the plasma concentrations of lamotrigine and percentage improvements at week 8 (r = 0.418, P < 0.05). A stepwise multiple regression analysis showed that plasma lamotrigine concentrations alone had a significant effect on the percentage improvements at week 8 (standardized partial correlation coefficients = 0.454, P < 0.001). The receiver operating characteristics analysis indicated that a plasma lamotrigine concentration of 12.7 μmol/L or greater was significantly (P < 0.001) predictive of response (50% or more reduction in the MADRS score). The proportion of the responders was significantly higher in the groups with a lamotrigine concentration >12.7 μmol/L (11/15 versus 4/19, P < 0.01). The present study suggests that an early therapeutic response to lamotrigine is dependent on its plasma concentration and that a plasma lamotrigine concentration of 12.7 μmol/L may be a threshold for a good therapeutic response in treatment

Levetiracetam for Treatment of Neonatal Seizures

PubMed Central

Abend, Nicholas S.; Gutierrez-Colina, Ana M.; Monk, Heather M.; Dlugos, Dennis J.; Clancy, Robert R.

2011-01-01

Neonatal seizures are often refractory to treatment with initial antiseizure medications. Consequently, clinicians turn to alternatives such as levetiracetam, despite the lack of published data regarding its safety, tolerability, or efficacy in the neonatal population. We report a retrospectively identified cohort of 23 neonates with electroencephalographically confirmed seizures who received levetiracetam. Levetiracetam was considered effective if administration was associated with a greater than 50% seizure reduction within 24 hours. Levetiracetam was initiated at a mean conceptional age of 41 weeks. The mean initial dose was 16 ± 6 mg/kg and the mean maximum dose was 45 ± 19 mg/kg/day. No respiratory or cardiovascular adverse effects were reported or detected. Levetiracetam was associated with a greater than 50% seizure reduction in 35% (8 of 23), including seizure termination in 7. Further study is warranted to determine optimal levetiracetam dosing in neonates and to compare efficacy with other antiseizure medications. PMID:21233461

Lacosamide cardiac safety: a thorough QT/QTc trial in healthy volunteers.

PubMed

Kropeit, D; Johnson, M; Cawello, W; Rudd, G D; Horstmann, R

2015-11-01

To determine whether lacosamide prolongs the corrected QT interval (QTc). In this randomized, double-blind, positive- and placebo-controlled, parallel-design trial, healthy volunteers were randomized to lacosamide 400 mg/day (maximum-recommended daily dose, 6 days), lacosamide 800 mg/day (supratherapeutic dose, 6 days), placebo (6 days), or moxifloxacin 400 mg/day (3 days). Variables included maximum time-matched change from baseline in QT interval individually corrected for heart rate ([HR] QTcI), other ECG parameters, pharmacokinetics (PK), and safety/tolerability. The QTcI mean maximum difference from placebo was -4.3 ms and -6.3 ms for lacosamide 400 and 800 mg/day; upper limits of the 2-sided 90% confidence interval were below the 10 ms non-inferiority margin (-0.5 and -2.5 ms, respectively). Placebo-corrected QTcI for moxifloxacin was +10.4 ms (lower 90% confidence bound >0 [6.6 ms]), which established assay sensitivity for this trial. As lacosamide did not increase QTcI, the trial is considered a negative QTc trial. There was no dose-related or clinically relevant effect on QRS duration. HR increased from baseline by ~5 bpm with lacosamide 800 mg/day versus placebo. Placebo-subtracted mean increases in PR interval at tmax were 7.3 ms (400 mg/day) and 11.9 ms (800 mg/day). There were no findings of second-degree or higher atrioventricular block. Adverse events (AEs) were dose related and most commonly involved the nervous and gastrointestinal systems. Lacosamide (≤ 800 mg/day) did not prolong the QTc interval. Lacosamide caused a small, dose-related increase in mean PR interval that was not associated with AEs. Cardiac, overall safety, and PK profiles for lacosamide in healthy volunteers were consistent with those observed in patients with partial-onset seizures. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Lacosamide: A Review in Focal-Onset Seizures in Patients with Epilepsy.

PubMed

Hoy, Sheridan M

2018-05-01

Lacosamide (Vimpat ® ) is a functionalized amino acid (available orally and intravenously) approved in the EU and the USA for use as monotherapy and adjunctive therapy for the treatment of focal-onset seizures in adults, adolescents and children aged ≥ 4 years with epilepsy. In adults and adolescents (aged ≥ 16 years), oral lacosamide as adjunctive therapy to other antiepileptic drugs was generally effective in reducing seizure frequency during short-term (up to 18 weeks) treatment, with efficacy sustained over the longer-term (up to 8 years). Moreover, patients were effectively switched from adjunctive oral lacosamide to the same dosage of intravenous lacosamide. Oral lacosamide was an effective conversion to monotherapy agent in this patient population and as monotherapy demonstrated noninferiority to carbamazepine controlled release in terms of seizure freedom. Antiepileptic benefits were maintained during longer-term (≤ 2 years) monotherapy. The antiepileptic efficacy of lacosamide in children aged ≥ 4 years has been extrapolated from data from adults and adolescents, with a similar response expected provided paediatric dosage adaptations are used and safety is demonstrated. Indeed, preliminary data demonstrated the efficacy of short-term (16 weeks) adjunctive lacosamide in patients aged ≥ 4 to < 17 years. Oral lacosamide was generally well tolerated over the short- and longer-term when administered as adjunctive therapy, a conversion to monotherapy agent and monotherapy in adults and adolescents and when administered as adjunctive therapy in children aged ≥ 4 years. Thus, lacosamide is a useful option for the management of focal-onset seizures across a broad age range, starting as early as 4 years of age.

Comparison of Plasma, Saliva, and Hair Levetiracetam Concentrations.

PubMed

Karaś-Ruszczyk, Katarzyna; Kuczyńska, Julita; Sienkiewicz-Jarosz, Halina; Kurkowska-Jastrzębska, Iwona; Bienkowski, Przemyslaw; Restel, Magdalena; Samochowiec, Jerzy; Mierzejewski, Pawel

2017-06-01

Previous findings revealed high correlations between serum/plasma and saliva levetiracetam concentrations, indicating saliva as an alternative matrix for monitoring levetiracetam therapy. Levetiracetam concentration in the hair, which could reflect long-term drug exposure and patients' compliance, has not been systematically tested, as yet. The aim of this study was to determine the correlation between plasma, saliva, and hair levetiracetam concentrations in 47 patients with epilepsy. Plasma, saliva, and hair levetiracetam concentrations were measured by liquid chromatography-tandem mass spectrometry with positive ionization. Levetiracetam saliva and plasma concentrations were highly correlated (r = 0.93). Plasma concentrations were not influenced by sex, age, and other concomitant antiepileptic drugs. Levetiracetam hair concentrations correlated with plasma concentrations (r = 0.36) but not daily dose (mg/kg). Drug hair concentrations were not influenced by hair color or treatment (dyed). The results tend to indicate that saliva may be a reliable alternative to plasma for monitoring levetiracetam concentrations. Levetiracetam can also be detected in human hair.

[Therapeutic drug monitoring of levetiracetam].

PubMed

Dailly, Eric; Bouquié, Régis; Bentué-Ferrer, Danièle

2010-01-01

Levetiracetam is an anticonvulsant drug used to treat partial seizures, myoclonic seizures of juvenile myoclonic epilepsy and primary generalized tonic-clonic seizures. A review of the literature with an evidence-based medicine method highlighted parameters (age, renal failure, pregnancy, combination with other anticonvulsant drugs) which affect levetiracetam pharmacokinetics but no significant relationship between plasma concentration of levetiracetam and efficacy or toxicity. Concentrations usually observed in therapeutics is from 6 to 18 mg/L. However, the determination of an individual therapeutic concentration, associated with an effective and well tolerated therapy, could be recommended particularly before pregnancy. Consequently, therapeutic drug monitoring of levetiracetam which is not currently recommended could be possibly useful in specific clinical situations.

[Clinical experience with lacosamide in Galicia: the GALACO study].

PubMed

Rodriguez-Osorio, Xiana; Lopez-Gonzalez, Francisco J; Pato-Pato, Antonio; Cebrian-Perez, Ernesto; Marey-Lopez, José; Corredera-Garcia, Enrique; Rubio-Nazabal, Eduardo; Castro-Vilanova, M Dolores; Abella-Corral, Javier; Rodriguez-Regal, Ana; Amigo-Jorrin, M Campo; Pego-Reigosa, Robustiano

2015-12-16

Lacosamide is a sodium channel blocker antiepileptic drug authorized as an adjunctive therapy for focal seizures in adolescents and adults. To analyze the efficacy and safety of lacosamide in Galicia according to its use in daily clinical practice. Retrospective observational study in patients who started treatment with lacosamide between January 2014 and June 2013 in 10 hospitals in Galicia, Spain. Its efficacy and safety at 3, 6 and 12 months after starting lacosamide was assessed. We included 184 patients with a mean age of 44.2 ± 17.4 years old; 56.5% (n = 104) were male; 173 patients constituted the efficacy population. Mean duration of epilepsy was 18.8 ± 15.5 years. Seizure frequency was 2.5 ± 1.6 episodes/month. After 12 months, 68.2% of patients (n = 118) had >= 50% improvement (responders) and among them, 54 (45.8% of responder patients) were seizure free. Twenty-three percent (n = 43) suffered from adverse events after 12 months, being dizziness (10.3%) and instability (3.3%) the most frequently reported. After the 12 month visit, 87.5% of patients (n = 161) continued treatment with lacosamide. Lacosamide provides a very good efficacy and safety profile for patients with focal refractory epilepsy. High percentage of responders may be related to a less refractory population compared to other daily clinical practice studies. It constitutes an attractive therapeutic option for the treatment of focal epilepsies.

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

PubMed

Garcés, Mercedes; Villanueva, Vicente; Mauri, José Angel; Suller, Ana; García, Carolina; López González, Franscisco Javier; Rodríguez Osorio, Xiana; Fernández Pajarín, Gustavo; Piera, Anna; Guillamón, Edelmira; Santafé, Consuelo; Castillo, Ascensión; Giner, Pau; Torres, Nerea; Escalza, Inés; Del Villar, Ana; García de Casasola, Maria Carmen; Bonet, Macarena; Noé, Enrique; Olmedilla, Nuria

2014-07-01

Status epilepticus (SE) and acute repetitive seizures (ARSs) frequently result in emergency visits. Wide variations in response are seen with standard antiepileptic drugs (AEDs). Oral and intravenous (IV) formulations of lacosamide are approved as adjunctive therapy in the treatment of partial-onset seizures in adults and adolescents. The aim of the retrospective multicenter observational study (LACO-IV) was to analyze data from a large cohort of patients with SE or ARSs of varying severity and etiology, who received IV lacosamide in the emergency setting. Patient clinical data were entered into a database; lacosamide use and efficacy and tolerability variables were analyzed. In SE, IV lacosamide tended to be used mainly in nonconvulsive status epilepticus as second- or third-line treatment. The proportion of patients with no seizures when IV lacosamide was the last drug administered was 76.5% (70.9% SE and 83.7% ARSs). The rate of seizure cessation ≤ 24 h after IV lacosamide administration was 57.1% (49.1% SE and 67.4% ARSs). Of the factors analyzed, a shorter latency from seizure onset to IV lacosamide infusion influenced treatment response significantly. A nonsignificant tendency towards a higher response was seen with lacosamide dose >200mg versus ≤ 200 mg. Analysis of response according to mechanism of action showed no significant differences in response to IV lacosamide in patients receiving prior sodium channel blocker (SCB) or non-SCB AEDs in the overall or SE population; however, in ARSs, a tendency towards a higher response was observed in those receiving non-SCB AEDs. The frequency and nature of adverse events observed were in line with those reported in other studies (somnolence being the most frequent). In the absence of randomized prospective controlled studies of IV lacosamide, our observations suggest that IV lacosamide may be a potential alternative for treatment of SE/ARSs when seizures fail to improve with standard AEDs or when AEDs are

Epilepsy (generalised seizures).

PubMed

Cross, J Helen

2015-04-17

About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission. We conducted a systematic review and aimed to answer the following clinical question: What are the effects of additional treatments in people with drug-resistant epilepsy characterised by generalised seizures? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found four studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety on the addition of the following interventions: lacosamide, lamotrigine, levetiracetam, perampanel, and zonisamide versus the addition of placebo.

Development of lacosamide for the treatment of partial-onset seizures.

PubMed

Doty, Pamela; Hebert, David; Mathy, Francois-Xavier; Byrnes, William; Zackheim, James; Simontacchi, Kelly

2013-07-01

Lacosamide is an antiepileptic drug (AED) available in multiple formulations that was first approved in 2008 as adjunctive therapy for partial-onset seizures (POS) in adults. Unlike traditional sodium channel blockers affecting fast inactivation, lacosamide selectively enhances sodium channel slow inactivation. This mechanism of action results in stabilization of hyperexcitable neuronal membranes, inhibition of neuronal firing, and reduction in long-term channel availability without affecting physiological function. Lacosamide has a well-characterized and favorable pharmacokinetic profile, including a fast absorption rate, minimal or no interaction with cytochrome P-450 izoenzymes, and a low potential for drug-drug interactions. Lacosamide clinical development included three placebo-controlled, double-blind, randomized trials conducted in more than 1300 patients, each demonstrating safety and efficacy of lacosamide compared to placebo as adjunctive therapy for adults with POS. The clinical use of lacosamide may broaden, pending results of trials evaluating its use as monotherapy for POS in adults, as treatment for epilepsy in pediatric subjects, and as adjunctive treatment for uncontrolled primary generalized tonic-clonic seizures in those with idiopathic generalized epilepsy. © 2013 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals Inc. on behalf of The New York Academy of Sciences.

Levetiracetam-induced acute psychosis in a child

PubMed Central

Zaki, Syed Ahmed; Gupta, Saurabh

2014-01-01

Levetiracetam is well-tolerated and commonly used as a broad spectrum antiepileptic in both partial and generalized seizures. Few cases of levetiracetam-induced psychosis in children are reported in the literature. The present case of levetiracetam-induced acute psychosis highlights the adverse effect of this drug and also emphasizes the need for close monitoring of children on levetiracetam. PMID:24987186

Comparison of lacosamide concentrations in cerebrospinal fluid and serum in patients with epilepsy.

PubMed

May, Theodor W; Brandt, Christian; Helmer, Renate; Bien, Christian G; Cawello, Willi

2015-07-01

This study was carried out to estimate the exposure of the central nervous system (CNS) to the antiepileptic drug (AED) lacosamide, under steady state conditions, in patients with epilepsy who take oral lacosamide alongside up to three other AEDs. Twenty-seven serum and cerebral spinal fluid (CSF) samples were collected from 21 patients receiving lacosamide for the treatment of epilepsy (50-600 mg/day over two or three doses). This included 23 time-matched pairs of serum and CSF samples from 19 patients. The concentration of lacosamide in each sample was determined using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Linear regression was used to characterize the relationship between the CSF-to-serum ratio of lacosamide concentration and the time since dosing, the daily lacosamide dose, or the daily dose normalized by volume of distribution (Vd , approximated to total body water), and between the drug concentrations in each compartment (CSF vs. serum). Concentrations of lacosamide in CSF (mean ± standard deviation [SD] 7.37 ± 3.73 μg/ml, range 1.24-14.95, n = 27) and serum (mean ± SD 8.16 ± 3.82 μg/ml, range 2.29-15.45, n = 27) samples showed a good correlation over the dose range investigated. The mean CSF-to-serum ratio of lacosamide concentrations was 0.897 ± 0.193 (range 0.492-1.254, n = 23 time-matched pairs) and was independent of lacosamide dose. Drug concentrations in the CSF are often used to indicate those in the brain interstitial fluid. In patients with epilepsy who follow a stable oral AED dosing regimen, lacosamide concentration in CSF is approximately 85% of that found in serum, suggesting that serum may be a valuable indicator of lacosamide concentration in the CNS. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

Hallucination: A rare complication of levetiracetam theraphy.

PubMed

Erdogan, Seher; Bosnak, Mehmet

2017-01-01

Levetiracetam is a new antiepileptic drug. In addition to epilepsy, it is also used for treating anxiety disorders and dystonia as well as tardive dyskinesia associated with the use of levodopa and neuroleptic drugs. Phenytoin therapy in a 10-year-old boy with convulsions was discontinued following cardiac rhythm impairment. The patient was then started on levetiracetam. However, visual and auditory hallucinations were observed on the 1st day of levetiracetam therapy. Levetiracetam was discontinued and replaced with sodium valproate, and the hallucinations resolved. The purpose of this report was to remind physicians that hallucinations are one of the rare complications of levetiracetam.

Levetiracetam-induced neutropenia following traumatic brain injury.

PubMed

Bunnell, Kristen; Pucci, Francesco

2015-01-01

Levetiracetam is being increasingly utilized for post-traumatic brain injury seizure prophylaxis, in part because of its more favourable adverse effect profile compared to other anti-epileptics. This report highlights an unusual, clinically significant adverse drug reaction attributed to levetiracetam use in a patient with blunt traumatic brain injury. This study describes a case of isolated neutropenia associated with levetiracetam in a 52-year-old man with traumatic brain injury. The patient developed neutropenia on day 3 of therapy with levetiracetam, with an absolute neutrophil count nadir of 200. There were no other medications that may have been implicated in the development of this haematological toxicity. Neutropenia rapidly resolved upon cessation of levetiracetam therapy. Clinicians should be aware of potentially serious adverse reactions associated with levetiracetam in patients with neurological injury.

Current understanding of the mechanism of action of the antiepileptic drug lacosamide.

PubMed

Rogawski, Michael A; Tofighy, Azita; White, H Steve; Matagne, Alain; Wolff, Christian

2015-02-01

The antiepileptic drug lacosamide [(R)-2-acetamido-N-benzyl-3-methoxypropanamide], a chiral functionalized amino acid, was originally identified by virtue of activity in the mouse and rat maximal electroshock (MES) test. Attention was drawn to lacosamide because of its high oral potency and stereoselectivity. Lacosamide is also active in the 6 Hz seizure model but inactive against clonic seizures in rodents induced by subcutaneous pentylenetetrazol, bicuculline and picrotoxin. It is also ineffective in genetic models of absence epilepsy. At doses greater than those required to confer protection in the MES test, lacosamide inhibits behavioral and electrographic seizures in hippocampal kindled rats. It also effectively terminates seizures in the rat perforant path stimulation status epilepticus model when administered early after the onset of seizures. Lacosamide does not exhibit antiepileptogenic effects in kindling or post-status epilepticus models. The profile of lacosamide in animal seizure and epilepsy models is similar to that of sodium channel blocking antiepileptic drugs, such as phenytoin and carbamazepine. However, unlike these agents, lacosamide does not affect sustained repetitive firing (SRF) on a time scale of hundreds of milliseconds or affect fast inactivation of voltage-gated sodium channels; however, it terminates SRF on a time scale of seconds by an apparent effect on sodium channel slow inactivation. Lacosamide shifts the slow inactivation curve to more hyperpolarized potentials and enhances the maximal fraction of channels that are in the slow inactivated state. Currently, lacosamide is the only known antiepileptic drug in clinical practice that exerts its anticonvulsant activity predominantly by selectively enhancing slow sodium channel inactivation. Copyright © 2014 Elsevier B.V. All rights reserved.

Long-term lacosamide retention-Real-world experience at a tertiary epilepsy center in Ireland.

PubMed

McGinty, Ronan N; Costello, Daniel J

2017-03-01

To estimate the rate of long-term lacosamide retention among a real-world group of patients at a tertiary epilepsy center in Ireland. One-hundred adults first prescribed lacosamide for epilepsy between January 2010 and August 2014 at Cork University Hospital were randomly selected for a retrospective analysis of medical records covering two years of subsequent epilepsy clinic follow-up to ascertain whether lacosamide was continued or withdrawn. Of 100 patients, (51 males, mean age 40.8years, 94 with drug-resistant epilepsy, 76 with focal epilepsy, 25 with intellectual disabilities, 34 with mental health disorders, and 42 with medical comorbidities), lacosamide was prescribed as an adjunct in 85. Lacosamide retention at 12 and 24months was 76% and 71%, respectively. Twenty-five patients stopped lacosamide due to ineffective seizure control. Adverse-effects were responsible for lacosamide discontinuation in three patients and one patient stopped lacosamide pre-pregnancy. The relatively high retention rate at two years suggests that lacosamide is generally well tolerated among people with a range of different epilepsy subtypes, intellectual disabilities, medical comorbidities, and mental health disorders, and can aid seizure control in adult patients with a range of difficult-to-treat epilepsies. Copyright © 2016 Elsevier Inc. All rights reserved.

Hallucination: A rare complication of levetiracetam theraphy

PubMed Central

Erdogan, Seher; Bosnak, Mehmet

2017-01-01

Levetiracetam is a new antiepileptic drug. In addition to epilepsy, it is also used for treating anxiety disorders and dystonia as well as tardive dyskinesia associated with the use of levodopa and neuroleptic drugs. Phenytoin therapy in a 10-year-old boy with convulsions was discontinued following cardiac rhythm impairment. The patient was then started on levetiracetam. However, visual and auditory hallucinations were observed on the 1st day of levetiracetam therapy. Levetiracetam was discontinued and replaced with sodium valproate, and the hallucinations resolved. The purpose of this report was to remind physicians that hallucinations are one of the rare complications of levetiracetam. PMID:29270577

Lacosamide as adjunctive therapy in refractory epilepsy in adults: a systematic review.

PubMed

Paquette, Vanessa; Culley, Celia; Greanya, Erica D; Ensom, Mary H H

2015-02-01

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. Copyright © 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Lacosamide adjunctive therapy for partial-onset seizures: a meta-analysis

PubMed Central

Newman, Jennifer J.; Deshpande, Santosh; Jones, Philip M.

2013-01-01

Background. The relative efficacy and safety of lacosamide as adjunctive therapy compared to other antiepileptic drugs has not been well established. Objective. To determine if lacosamide provides improved efficacy and safety, reduced length of hospital stay and improved quality of life compared with other anti-epileptic therapies for adults with partial-onset seizures. Data Sources. A systematic review of the medical literature using Medline (1946–Week 4, 2012), EMBASE (1980–Week 3, 2012), Cochrane Central Register of Controlled Trials (Issue 1 of 12, January 2012). Additional studies were identified (through to February 7, 2012) by searching bibliographies, the FDA drug approval files, clinical trial registries and major national and international neurology meeting abstracts. No restrictions on publication status or language were applied. Study Selection. Randomized controlled trials of lacosamide in adults with partial-onset seizures were included. Data Extraction. Study selection, extraction and risk of bias assessment were performed independently by two authors. Authors of studies were contacted for missing data. Data Synthesis. All pooled analyses used the random effects model. Results. Three trials (1311 patients) met inclusion criteria. Lacosamide increased the 50% responder rate compared to placebo (RR 1.68 [95% CI 1.36 to 2.08]; I2 = 0%). Discontinuation due to adverse events was statistically significantly higher in the lacosamide arm (RR3.13 [95% CI 1.94 to 5.06]; I2 = 0%). Individual adverse events (ataxia, dizziness, fatigue, and nausea) were also significantly higher in the lacosamide group. Limitations. All dosage arms from the included studies were pooled to make a single pair-wise comparison to placebo. Selective reporting of outcomes was found in all of the included RCTs. Conclusions. Lacosamide as adjunctive therapy in patients with partial-onset seizures increases the 50% responder rate but with significantly more adverse events compared to

Lacosamide: A Review in Focal Seizures in Patients with Epilepsy.

PubMed

Scott, Lesley J

2015-12-01

Lacosamide (Vimpat(®)) is a functionalized amino acid available orally (as a solution or tablets) and as an intravenous infusion for use as monotherapy (only in the USA) or adjunctive therapy for the treatment of focal seizures in adult and adolescent (aged ≥17 years in the USA) patients with epilepsy. As adjunctive therapy to other antiepileptic drugs (AEDs), lacosamide provided effective seizure control and was generally well tolerated in adults and adolescents (aged ≥16 years) in randomized clinical trials and in the real-world setting. In clinical trials, adjunctive lacosamide provided significantly greater reductions in 28-day seizure rates than adjunctive placebo, with these benefits maintained after up to 8 years of therapy in open-label extension studies. Moreover, patients were effectively switched from oral to short-term intravenous adjunctive therapy at the same dosage, which may be particularly beneficial in situations where oral therapy is not suitable. Conversion to lacosamide monotherapy was superior to a historical-control cohort in patients with focal seizures converting from previous AED therapy. In the absence of head-to-head comparisons with other AEDs, the exact position of lacosamide relative to other AEDs remains to be fully determined. In the meantime, oral and intravenous lacosamide provides a useful option as monotherapy (only in the USA) or adjunctive therapy for the treatment of focal seizures in adult and adolescent (aged ≥17 years in the USA) patients with epilepsy.

Retention rates of new antiepileptic drugs in localization-related epilepsy: a single-center study.

PubMed

Peltola, J; Peltola, M; Auvinen, A; Raitanen, J; Fallah, M; Keränen, T

2009-01-01

We evaluated long-term retention rates of newer antiepileptic drugs (AED) in adults with localization-related epilepsy retrospectively. We estimated retention rates by Kaplan-Meier method in all 222 patients (age > or = 16) with localization-related epilepsy exposed to new AED at the Tampere University Hospital. There were 141 patients exposed to lamotrigine, 78 to levetiracetam, 97 to topiramate, 68 to gabapentin, and 69 to tiagabine. Three-year retention rate for lamotrigine was 73.5%, levetiracetam 65.4%, topiramate 64.2%, gabapentin 41.7%, and tiagabine 38.2%. The most common cause for withdrawal of these AED was lack of efficacy. Our study suggests that there are clinically significant differences among gabapentin, lamotrigine, levetiracetam, tiagabine, and topiramate as treatment for focal epilepsy in everyday practice. Gabapentin and tiagabine seem to be less useful than the other three AED. Furthermore, our study supports the value of retention rate studies in assessing outcome of the drugs in clinical practice.

An update in the initial management of paediatric status epilepticus.

PubMed

Lawton, Ben; Davis, Tessa; Goldstein, Henry; Tagg, Andrew

2018-06-01

Over the last 2 years, algorithms for the optimal management of status epilepticus have changed, as the medical community has recognized the need to terminate seizures in status in a timely manner. Recent research has evaluated the different choices of benzodiazepine and has given consideration to second-line treatment options. There has been a move to examine alternatives to phenytoin (such as levetiracetam and lacosamide) as second-line agents. Valproate should be used cautiously in view of the potential side effects. Three ongoing trials [Established Staus Epilepticus Treatment Trial (ESETT), Convulsive Status Epilepticus Paediatric Trial (ConSEPT), and emergency treatment with levetiracetam or phenytoin in status epilepticus in children (EcLiPSE)] are comparing the efficacy of levetiracetam and phenytoin. Benzodiazepines remain the first-line agent of choice, although there is ongoing discussion about the mode of administration and the best drug to choose. The results of ESETT, ConSEPT, and EcLiPSE will affect our future management of status, as we give consideration to levetiracetam as an alternative to phenytoin. Other medications such as lacosamide may emerge in future algorithms too.

Biopharmaceutic Risk Assessment of Brand and Generic Lamotrigine Tablets.

PubMed

Vaithianathan, Soundarya; Raman, Siddarth; Jiang, Wenlei; Ting, Tricia Y; Kane, Maureen A; Polli, James E

2015-07-06

The therapeutic equivalence of generic and brand name antiepileptic drugs has been questioned by neurologists and the epilepsy community. A potential contributor to such concerns is pharmaceutical quality. The objective was to assess the biopharmaceutic risk of brand name Lamictal 100 mg tablets and generic lamotrigine 100 mg tablets from several manufacturers. Lamotrigine was characterized in terms of the Biopharmaceutics Classification System (BCS), including aqueous solubility and Caco-2 permeability. A panel of pharmaceutical quality tests was also performed on three batches of Lamictal, three batches of Teva generic, and one batch of each of four other generics: appearance, identity, assay, impurity, uniformity of dosage units, disintegration, dissolution, friability, and loss on drying. These market surveillance results indicate that all brand name and generic lamotrigine 100 mg tablets passed all tests and showed acceptable pharmaceutical quality and low biopharmaceutic risk. Lamotrigine was classified as a BCS class IIb drug, exhibiting pH-dependent aqueous solubility and dissolution. At pH 1.2 and 4.5, lamotrigine exhibited high solubility, whereas lamotrigine exhibited low solubility at pH 6.8, including non-sink dissolution. Lamotrigine showed high Caco-2 permeability. The apparent permeability (Papp) of lamotrigine was (73.7 ± 8.7) × 10(-6) cm/s in the apical-to-basolateral (AP-BL) direction and (41.4 ± 1.6) × 10(-6) cm/s in the BL-AP direction, which were higher than metoprolol's AP-BL Papp of (21.2 ± 0.9) × 10(-6) cm/s and BL-AP Papp of (34.6 ± 4.6) × 10(-6) cm/s. Overall, lamotrigine's favorable biopharmaceutics from a drug substance perspective and favorable quality characteristics from a tablet formulation perspective suggest that multisource lamotrigine tablets exhibit a low biopharmaceutic risk.

Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study.

PubMed

Rastogi, Reena Gogia; Ng, Yu-Tze

2012-04-01

Lacosamide is a new antiepileptic drug that is currently approved by the US Food and Drug Administration (FDA) for adults 17 years or older for partial-onset seizures. The authors reviewed 21 pediatric patients (<17 years) with various seizure types who were started on oral lacosamide as part of a prospective add-on study as adjunctive therapy for refractory epilepsy. Five patients were excluded due to less than 3 months of meaningful follow-up. Maintenance dosages used ranged from 2.4 to 19.4 mg/kg/d. Eight of 16 (50%) patients had greater than 50% reduction in seizure frequency with adjunctive lacosamide therapy. Eight (50%) patients had generalized epilepsy including 4 with Lennox-Gastaut syndrome. Lacosamide was effective therapy for most seizure types but was particularly effective for partial-onset seizures. Lacosamide was effective in treating 5 of 8 (62.5%) localization-related epilepsies but only 2 of 8 (25%) generalized epilepsies, both Lennox-Gastaut syndrome patients with greater than 90% seizure reduction. None of these very refractory patients remained seizure free.

Efficacy and Safety of Lacosamide in Painful Diabetic Neuropathy

PubMed Central

Ziegler, Dan; Hidvégi, Tibor; Gurieva, Irina; Bongardt, Sabine; Freynhagen, Rainer; Sen, David; Sommerville, Kenneth

2010-01-01

OBJECTIVE To evaluate efficacy and safety of lacosamide compared with placebo in painful diabetic polyneuropathy. RESEARCH DESIGN AND METHODS Diabetic patients with at least moderate neuropathic pain were randomized to placebo or lacosamide 400 (in a slow or standard titration) or 600 mg/day over 6-week titration and 12-week maintenance periods. Primary efficacy criterion was intra-individual change in average daily Numeric Pain Rating Scale score from baseline to the last 4 weeks. RESULTS For the primary end point, pain reduction was numerically but not statistically greater with lacosamide compared with placebo (400 mg/day, P = 0.12; 600 mg/day, P = 0.18). Both doses were significantly more effective compared with placebo over the titration (P = 0.03, P = 0.006), maintenance (P = 0.01, P = 0.005), and entire treatment periods (P = 0.03, P = 0.02). Safety profiles between titration schemes were similar. CONCLUSIONS Lacosamide reduced neuropathic pain and was well tolerated in diabetic patients, but the primary efficacy criterion was not met, possibly due to an increased placebo response over the last 4 weeks. PMID:20067958

Cytisine inhibits the protective activity of various classical and novel antiepileptic drugs against 6 Hz-induced psychomotor seizures in mice.

PubMed

Tutka, Piotr; Kondrat-Wróbel, Maria W; Zaluska, Katarzyna; Żółkowska, Dorota; Florek-Łuszczki, Magdalena; Łuszczki, Jarogniew J

2017-01-01

Cytisine (CYT) is a partial agonist of brain α4β2 nicotinic acetylcholine receptors widely used in Central/Eastern Europe for smoking cessation. This study evaluated the effect of CYT on the ability of classical and novel antiepileptic drugs to prevent seizures evoked by the 6-Hz test, a model of psychomotor seizures in mice thought as a model of drug-resistant seizures. CYT administered intraperitoneally (i.p.) in a dose of 2 mg kg -1 significantly inhibited the anticonvulsant activity of lacosamide, levetiracetam, and pregabalin, increasing their median effective doses 50 (ED 50 ) values from 6.88 to 10.52 mg kg -1 (P < 0.05) for lacosamide, from 22.08 to 38.26 mg kg -1 (P < 0.05) for levetiracetam, and from 40.48 to 64.61 mg kg -1 (P < 0.01) for pregabalin, respectively. There were no significant changes in total brain concentrations of lacosamide, levetiracetam, and pregabalin following CYT i.p. administration. CYT administered in a dose of 2 mg kg -1 failed to change the protective action of clobazam, clonazepam, phenobarbital, tiagabine, and valproate in the 6-Hz test. Neither CYT (2 mg kg -1 ) alone nor its combination with the anticonvulsant drugs (at their ED 50 values from the 6-Hz test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; and grip strength and passive avoidance tests, respectively. CYT-evoked alterations in the protection provided by some antiepileptic drugs against seizures can be of serious concern for epileptic smokers, who might demonstrate therapeutic failure to lacosamide, levetiracetam, and pregabalin, resulting in possible breakthrough seizure attacks.

Distribution of lacosamide in the rat brain assessed by in vitro slice technique.

PubMed

Gáll, Zsolt; Vancea, Szende

2018-01-01

Lacosamide is a newer anticonvulsant and is the only one that enhances the slow inactivation of voltage gated sodium channels. It is also claimed to have disease-modifying potential, but its pharmacokinetic properties have been much less discussed in the literature. In rats, lacosamide shows restricted distribution to tissues, and the brain-to-plasma partition coefficient (K p ) is only 0.553. In this study, the brain disposition of lacosamide was evaluated in rat brains, and its neuropharmacokinetic parameters (i.e., protein binding and intracellular accumulation) were assessed using in vitro methods. Brain slice experiments and brain homogenate binding studies were performed for several drugs acting on the central nervous system, and drugs were assayed by using a liquid chromatography-mass spectrometry system. By applying a combined approach, it was found that (1) the unbound volume of distribution in the brain for lacosamide (V u,brain  = 1.37) was lower than that of other classical anticonvulsants; (2) the unbound fraction of lacosamide in the brain (0.899) was slightly lower than its unbound fraction in plasma (0.96); (3) the unbound intracellular-to-extracellular concentration ratio of lacosamide was 1.233, meaning that lacosamide was accumulated in the intracellular space because of its physicochemical properties and zwitterionic structure; and (4) the unbound brain-to-plasma concentration ratio of lacosamide was lower than the total brain-to-plasma concentration ratio (K p,uu,brain  = 0.42 vs. K p  = 0.553). In conclusion, the limited brain distribution of lacosamide is not related to its nonspecific protein-binding capacity; rather, an active transport mechanism across the blood-brain barrier may be involved, which reduces the anticonvulsant and/or antiepileptogenic actions of this drug.

Carbamazepine toxicity during combination therapy with levetiracetam: a pharmacodynamic interaction.

PubMed

Sisodiya, Sanjay M; Sander, Josemir W A S; Patsalos, Philip N

2002-02-01

Levetiracetam is a novel antiepileptic drug with an unknown mechanism of action. To-date levetiracetam is not known to be associated with any clinically significant pharmacokinetic interaction. Similarly, levetiracetam has not been associated with any pharmacodynamic interactions. We present four patients with severe refractory epilepsy in whom introduction of levetiracetam led to disabling symptoms compatible with carbamazepine toxicity requiring either carbamazepine dose reduction or levetiracetam withdrawal. As carbamazepine and carbamazepine-epoxide blood levels were not altered during levetiracetam co-medication, a pharmacodynamic interaction is suggested. Therefore, during levetiracetam co-medication with carbamazepine, patients should be monitored closely for symptoms of carbamazepine toxicity.

Budget impact analysis of adjunctive therapy with lacosamide for partial-onset epileptic seizures in Belgium.

PubMed

Simoens, Steven

2011-01-01

This study aims to compute the budget impact of lacosamide, a new adjunctive therapy for partial-onset seizures in epilepsy patients from 16 years of age who are uncontrolled and having previously used at least three anti-epileptic drugs from a Belgian healthcare payer perspective. The budget impact analysis compared the 'world with lacosamide' to the 'world without lacosamide' and calculated how a change in the mix of anti-epileptic drugs used to treat uncontrolled epilepsy would impact drug spending from 2008 to 2013. Data on the number of patients and on the market shares of anti-epileptic drugs were taken from Belgian sources and from the literature. Unit costs of anti-epileptic drugs originated from Belgian sources. The budget impact was calculated from two scenarios about the market uptake of lacosamide. The Belgian target population is expected to increase from 5333 patients in 2008 to 5522 patients in 2013. Assuming that the market share of lacosamide increases linearly over time and is taken evenly from all other anti-epileptic drugs (AEDs), the budget impact of adopting adjunctive therapy with lacosamide increases from €5249 (0.1% of reference drug budget) in 2008 to €242,700 (4.7% of reference drug budget) in 2013. Assuming that 10% of patients use standard AED therapy plus lacosamide, the budget impact of adopting adjunctive therapy with lacosamide is around €800,000-900,000 per year (or 16.7% of the reference drug budget). Adjunctive therapy with lacosamide would raise drug spending for this patient population by as much as 16.7% per year. However, this budget impact analysis did not consider the fact that lacosamide reduces costs of seizure management and withdrawal. The literature suggests that, if savings in other healthcare costs are taken into account, adjunctive therapy with lacosamide may be cost saving.

Correlation between the Efficacy of Lamotrigine and the Serum Lamotrigine Level during the Remission Phase of Acute Bipolar II Depression: A Naturalistic and Unblinded Prospective Pilot Study.

PubMed

Kikkawa, Akiyoshi; Kitamura, Yoshihisa; Aiba, Tetsuya; Hiraki, Koichi; Sendo, Toshiaki

2017-01-01

Lamotrigine has acute antidepressant effects in patients with bipolar disorder. However, there is little information regarding appropriate serum levels of lamotrigine and the time until remission after the start of lamotrigine therapy in patients with bipolar II depression. This was a naturalistic and unblinded prospective pilot study. Twelve patients' depressive symptoms were evaluated using the Montgomery-Åsberg Depression Rating Scale (MADRS) at the start of treatment and at the time of remission, and blood samples were obtained at the time of remission. Mahalanobis distance was used to analyze the relationship between the MADRS improvement rate and the serum lamotrigine level. Furthermore, we calculated the Spearman's rank correlation coefficient for the relationship between the MADRS improvement rate and the serum lamotrigine level, and produced box plots of the serum lamotrigine level at remission and the time until remission. The Mahalanobis distance for the patient that was co-administered lamotrigine and valproic acid differed significantly from those of the other patients (p<0.001). There was no linear relationship between the serum lamotrigine level and the MADRS improvement rate among the patients that did not receive valproic acid. The median time from the start of lamotrigine therapy until remission was 6 weeks. The serum lamotrigine level does not have an important impact on the acute therapeutic effects of lamotrigine on bipolar II depression. In addition, we consider that different treatment options should be considered for non-responders who do not exhibit any improvement after the administration of lamotrigine for approximately 6 weeks.

Assessment of the effects of lacosamide on sleep parameters in healthy subjects.

PubMed

Hudson, J Douglas; Guptill, Jeffrey T; Byrnes, William; Yates, Stephen L; Williams, Paulette; D'Cruz, O'Neill

2015-02-01

Seizures and antiepileptic drugs (AED) may disrupt sleep patterns in patients with epilepsy, thus evaluation of lacosamide effects on objective and subjective sleep measures is warranted. A multicenter, interventional, open-label study (NCT01530386) was conducted in healthy subjects without confounding effects of concomitant AED use, co-morbidities, or disease state to determine whether lacosamide impacts sleep parameters after 22 days of lacosamide exposure. After overnight polysomnography (PSG) to assess baseline parameters, lacosamide was initiated at 100mg/day (50mg twice daily) and increased by 100mg/day weekly to 300 mg/day (the mid-range maintenance dose for adjunctive therapy). The primary variable was change from baseline to post-treatment in wake after sleep onset (WASO). Secondary variables included additional objective sleep measures, subject-reported measures of sleep quality, daytime sleepiness, and tolerability. Change from baseline in WASO was analyzed using the Wilcoxon rank-sum test. A total of 27 subjects received ≥1 dose of lacosamide and 25 subjects completed the study. For WASO, median change from baseline was a 6-min reduction (95% confidence interval: -38, 77.5; p=0.1074) after lacosamide treatment; this was considered not clinically relevant. No clinically relevant changes were observed in any secondary variables. Thirteen subjects (48%) reported a treatment-emergent adverse event, none of which was severe or led to study discontinuation. Lacosamide 300 mg/day had no effect on objective or subjective sleep parameters in healthy subjects and was generally well tolerated. Copyright © 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Analgesic ineffectiveness of lacosamide after spinal nerve ligation and its sodium channel activity in injured neurons.

PubMed

Hagenacker, T; Schäfer, N; Büsselberg, D; Schäfers, M

2013-07-01

Lacosamide is a novel anti-epileptic drug that enhances the slow- and not fast-inactivating state of voltage-gated sodium channels. Lacosamide has demonstrated analgesic efficacy in several animal studies but preclinical studies on neuropathic pain models are rare, and recent clinical trials showed no superior analgesic effects. Here, we examine whether an acute or chronic administration of lacosamide (3-60 mg/kg, i.p.) attenuates pain behaviour induced by spinal nerve ligation (SNL). To validate the inhibitory efficacy of lacosamide on voltage-gated sodium channels, sodium currents in naïve and SNL-injured dorsal root ganglion (DRG) neurons were recorded using whole-cell patch clamping. Lacosamide only marginally attenuated thermal hyperalgesia, but not tactile allodynia when applied once 7 or 14 days after SNL and showed no analgesic effect when applied daily for 19 days. In naïve neurons, 100 μmol/L lacosamide inhibited sodium channel currents by 58% and enhanced the slow inactivation (87% for lacosamide vs. 47% for control). In contrast, lacosamide inhibited sodium currents in injured DRG neurons by only 15%, while the effects on slow inactivation were diminished. Isolated currents from the NaV 1.8 channel subtype were only marginally changed by lacosamide. The reduced effectiveness of lacosamide on voltage-gated sodium channel currents in injured DRG neurons may contribute to the reduced analgesic effect observed for the SNL model. © 2012 European Federation of International Association for the Study of Pain Chapters.

Intravenous Lacosamide in Pediatric Status Epilepticus: An Open-Label Efficacy and Safety Study.

PubMed

Poddar, Karan; Sharma, Rohan; Ng, Yu-Tze

2016-08-01

Lacosamide is an antiepilepsy drug approved by the Food and Drug Administration for patients aged 17 years and older for partial-onset seizures as monotherapy or adjunctive therapy. We reviewed the use of intravenous lacosamide in children aged less than 17 years with status epilepticus. Children who received at least one dose of intravenous lacosamide for status epilepticus at our tertiary care children's hospital from December 2011 to March 2014 were studied. Status epilepticus was defined as continuous seizure activity for longer than 20 minutes or two or more recurrent seizures without regaining baseline level of awareness. Efficacy was defined as seizure freedom or more than 50% reduction of seizures within 24 hours of administering lacosamide. Nine children with a mean age of 5.7 years (range: three months to 16 years) were included. The mean initial or loading dose was 8.7 mg/kg, with seven of nine patients receiving a dose of 10 mg/kg. The average total amount of intravenous lacosamide administered within the initial 24 hours was 13.8 mg/kg. Lacosamide was found to be efficacious in seven of nine (77.8%) patients. Four patients (44.4%) became seizure free. Two patients continued to have status epilepticus within 24 hours of lacosamide administration. Bradycardia was observed in one patient. In children with status epilepticus, intravenous lacosamide was efficacious in 78% of the patients and 44% become seizure free. In addition, no significant adverse reactions were observed. An appropriate safe, effective initial, or loading dose may be 10 mg/kg. Copyright © 2016 Elsevier Inc. All rights reserved.

Antiepileptic drugs and brain maturation: fetal exposure to lamotrigine generates cortical malformations in rats.

PubMed

Manent, Jean-Bernard; Jorquera, Isabel; Franco, Valentina; Ben-Ari, Yehezkel; Perucca, Emilio; Represa, Alfonso

2008-02-01

Intake of antiepileptic drugs (AEDs) during pregnancy can provoke severe and subtle fetal malformations associated with deleterious sequelae, reflecting the need for experimental investigations on the comparative teratogenic potential of these agents. We recently reported that prenatal exposure to vigabatrin and valproate, two AEDs which act through GABAergic mechanisms, induces hippocampal and cortical dysplasias in rodents. We have now investigated the effects of phenobarbital (PB, 30 mg/kg day) i.p.), a drug also endowed with GABAergic effects, and the new generation AEDs lamotrigine (LTG, 5-20mg/kg/day i.p.), topiramate (TPM, 10mg/kg/day i.p.), and levetiracetam (LEV, 50mg/kg/day i.p.) on brain development. Prenatal exposure to LTG induced hippocampal and cortical malformations in a dose-dependent manner, at maternal plasma concentrations within the clinically occurring range. These abnormalities were not observed after exposure to PB, TP and LEV. These observations raise concerns about potential clinical correlates and call for detailed comparative investigations on the consequences of AED use during pregnancy.

Lacosamide Inhibition of Nav1.7 Voltage-Gated Sodium Channels: Slow Binding to Fast-Inactivated States

PubMed Central

Jo, Sooyeon

2017-01-01

Lacosamide is an antiseizure agent that targets voltage-dependent sodium channels. Previous experiments have suggested that lacosamide is unusual in binding selectively to the slow-inactivated state of sodium channels, in contrast to drugs like carbamazepine and phenytoin, which bind tightly to fast-inactivated states. Using heterologously expressed human Nav1.7 sodium channels, we examined the state-dependent effects of lacosamide. Lacosamide induced a reversible shift in the voltage dependence of fast inactivation studied with 100-millisecond prepulses, suggesting binding to fast-inactivated states. Using steady holding potentials, lacosamide block was very weak at −120 mV (3% inhibition by 100 µM lacosamide) but greatly enhanced at −80 mV (43% inhibition by 100 µM lacosamide), where there is partial fast inactivation but little or no slow inactivation. During long depolarizations, lacosamide slowly (over seconds) put channels into states that recovered availability slowly (hundreds of milliseconds) at −120 mV. This resembles enhancement of slow inactivation, but the effect was much more pronounced at −40 mV, where fast inactivation is complete, but slow inactivation is not, than at 0 mV, where slow inactivation is maximal, more consistent with slow binding to fast-inactivated states than selective binding to slow-inactivated states. Furthermore, inhibition by lacosamide was greatly reduced by pretreatment with 300 µM lidocaine or 300 µM carbamazepine, suggesting that lacosamide, lidocaine, and carbamazepine all bind to the same site. The results suggest that lacosamide binds to fast-inactivated states in a manner similar to other antiseizure agents but with slower kinetics of binding and unbinding. PMID:28119481

Lacosamide Inhibition of Nav1.7 Voltage-Gated Sodium Channels: Slow Binding to Fast-Inactivated States.

PubMed

Jo, Sooyeon; Bean, Bruce P

2017-04-01

Lacosamide is an antiseizure agent that targets voltage-dependent sodium channels. Previous experiments have suggested that lacosamide is unusual in binding selectively to the slow-inactivated state of sodium channels, in contrast to drugs like carbamazepine and phenytoin, which bind tightly to fast-inactivated states. Using heterologously expressed human Nav1.7 sodium channels, we examined the state-dependent effects of lacosamide. Lacosamide induced a reversible shift in the voltage dependence of fast inactivation studied with 100-millisecond prepulses, suggesting binding to fast-inactivated states. Using steady holding potentials, lacosamide block was very weak at -120 mV (3% inhibition by 100 µ M lacosamide) but greatly enhanced at -80 mV (43% inhibition by 100 µ M lacosamide), where there is partial fast inactivation but little or no slow inactivation. During long depolarizations, lacosamide slowly (over seconds) put channels into states that recovered availability slowly (hundreds of milliseconds) at -120 mV. This resembles enhancement of slow inactivation, but the effect was much more pronounced at -40 mV, where fast inactivation is complete, but slow inactivation is not, than at 0 mV, where slow inactivation is maximal, more consistent with slow binding to fast-inactivated states than selective binding to slow-inactivated states. Furthermore, inhibition by lacosamide was greatly reduced by pretreatment with 300 µ M lidocaine or 300 µ M carbamazepine, suggesting that lacosamide, lidocaine, and carbamazepine all bind to the same site. The results suggest that lacosamide binds to fast-inactivated states in a manner similar to other antiseizure agents but with slower kinetics of binding and unbinding. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Specific binding of lacosamide to collapsin response mediator protein 2 (CRMP2) and direct impairment of its canonical function: implications for the therapeutic potential of lacosamide

PubMed Central

Wilson, Sarah M.; Khanna, Rajesh

2014-01-01

The novel anti-epileptic drug lacosamide (LCM; SPM927, Vimpat®) has been heralded as having a dual-mode of action through interactions with both the voltage-gated sodium channel and the neurite outgrowth-promoting collapsin response mediator protein 2 (CRMP2). Lacosamide’s ability to dampen neuronal excitability through the voltage-gated sodium channel likely underlies its efficacy in attenuating the symptoms of epilepsy (i.e. seizures). While the role of CRMP2 in epilepsy has not been well-studied, given the proposed involvement of circuit reorganization in epileptogenesis, the ability of lacosamide to alter CRMP2 function may prove disease-modifying. Recently, however, the validity of lacosamide’s interaction with CRMP2 has come under scrutiny. In this review, we address the contradictory reports concerning the binding of lacosamide to CRMP2, as well as, the ability of lacosamide to directly impact CRMP2 function. Additionally, we address similarly contradicting reports regarding the potential disease-modifying effect of lacosamide on the development and progression of epilepsy. As the vast majority of anti-epileptic drugs influence only the symptoms of epilepsy, the ability to hinder disease progression would be a major breakthrough in efforts to cure or prevent this debilitating syndrome. PMID:24944082

Block of human cardiac sodium channels by lacosamide: evidence for slow drug binding along the activation pathway.

PubMed

Wang, Ging Kuo; Wang, Sho-Ya

2014-05-01

Lacosamide is an anticonvulsant hypothesized to enhance slow inactivation of neuronal Na(+) channels for its therapeutic action. Cardiac Na(+) channels display less and incomplete slow inactivation, but their sensitivity toward lacosamide remains unknown. We therefore investigated the action of lacosamide in human cardiac Nav1.5 and Nav1.5-CW inactivation-deficient Na(+) channels. Lacosamide showed little effect on hNav1.5 Na(+) currents at 300 µM when cells were held at -140 mV. With 30-second conditioning pulses from -90 to -50 mV; however, hNav1.5 Na(+) channels became sensitive to lacosamide with IC50 (50% inhibitory concentration) around 70-80 µM. Higher IC50 values were found at -110 and -30 mV. The development of lacosamide block at -70 mV was slow in wild-type Na(+) channels (τ; 8.04 ± 0.39 seconds, n = 8). This time constant was significantly accelerated in hNav1.5-CW inactivation-deficient counterparts. The recovery from lacosamide block at -70 mV for 10 seconds was relatively rapid in wild-type Na(+) channels (τ; 639 ± 90 milliseconds, n = 8). This recovery was accelerated further in hNav1.5-CW counterparts. Unexpectedly, lacosamide elicited a time-dependent block of persistent hNav1.5-CW Na(+) currents with an IC50 of 242 ± 19 µM (n = 5). Furthermore, both hNav1.5-CW/F1760K mutant and batrachotoxin-activated hNav1.5 Na(+) channels became completely lacosamide resistant, indicating that the lacosamide receptor overlaps receptors for local anesthetics and batrachotoxin. Our results together suggest that lacosamide targets the intermediate preopen and open states of hNav1.5 Na(+) channels. Lacosamide may thus track closely the conformational changes at the hNav1.5-F1760 region along the activation pathway.

Severe apnea in an infant exposed to lamotrigine in breast milk.

PubMed

Nordmo, Elisabet; Aronsen, Lena; Wasland, Kristin; Småbrekke, Lars; Vorren, Solveig

2009-11-01

To report a case of severe apnea in an infant exposed to lamotrigine through breast-feeding. A 16-day-old infant developed several mild episodes of apnea that culminated in a severe cyanotic episode requiring resuscitation. A thorough examination at the hospital gave no evidence of underlying diseases that could explain the reaction. The mother had used lamotrigine in increasing doses throughout pregnancy, and at the time of the apneic episodes, she used 850 mg/day. The infant was fully breast-fed, and the neonatal lamotrigine serum concentration was 4.87 microg/mL at the time of admission. Breast-feeding was terminated, and the infant fully recovered. Although there are several reports on extensive passage of lamotrigine into breast milk, this is the first published report of a serious adverse reaction in a breast-fed infant. Lamotrigine clearance increases throughout pregnancy, and maternal dose increases are often necessary to maintain therapeutic effect. After delivery, clearance rapidly returns to preconception levels, enhancing the risk of adverse reactions in both mothers and breast-fed infants if the dose is not sufficiently reduced. In this case, the dose was slowly reduced after delivery, and the maternal lamotrigine serum concentration more than doubled in the week before the neonatal apneic episodes. A high lamotrigine concentration was detected in the breast milk, and the neonatal lamotrigine serum concentration was in the upper therapeutic range. The neonatal lamotrigine elimination half-life was approximately twice that seen in adults. The Naranjo probability scale indicated a probable relationship between apnea and exposure to lamotrigine through breast-feeding in this infant. Infants can be exposed to clinically relevant doses of lamotrigine through breast-feeding. Individual risk/benefit assessment is important, and close monitoring of both mother and child is advisable, especially during the first 3 weeks postpartum.

Lacosamide diminishes dryness-induced hyperexcitability of corneal cold sensitive nerve terminals.

PubMed

Kovács, Illés; Dienes, Lóránt; Perényi, Kristóf; Quirce, Susana; Luna, Carolina; Mizerska, Kamila; Acosta, M Carmen; Belmonte, Carlos; Gallar, Juana

2016-09-15

Lacosamide is an anti-epileptic drug that is also used for the treatment of painful diabetic neuropathy acting through voltage-gated sodium channels. The aim of this work was to evaluate the effects of acute application of lacosamide on the electrical activity of corneal cold nerve terminals in lacrimo-deficient guinea pigs. Four weeks after unilateral surgical removal of the main lachrimal gland in guinea pigs, corneas were excised and superfused in vitro at 34°C for extracellular electrophysiological recording of nerve terminal impulse activity of cold thermosensitive nerve terminals. The characteristics of the spontaneous and the stimulus-evoked (cooling ramps from 34°C to 15°C) activity before and in presence of lacosamide 100µM and lidocaine 100µM were compared. Cold nerve terminals (n=34) recorded from dry eye corneas showed significantly enhanced spontaneous activity (8.0±1.1 vs. 5.2±0.7imp/s; P<0.05) and cold response (21.2±1.7 vs. 16.8±1.3imp/s; P<0.05) as well as reduced cold threshold (1.5±0.1 vs. 2.8±0.2 Δ°C; P<0.05) to cooling ramps compared to terminals (n=58) from control animals. Both lacosamide and lidocaine decreased spontaneous activity and peak response to cooling ramps significantly (P<0.05). Temperature threshold was increased by the addition of lidocaine (P<0.05) but not lacosamide (P>0.05) to the irrigation fluid. In summary, the application of lacosamide results in a significant decrease of the augmented spontaneous activity and responsiveness to cold of corneal sensory nerves from tear-deficient animals. Based on these promising results we speculate that lacosamide might be used to reduce the hyperexcitability of corneal cold receptors caused by prolonged ocular surface dryness due to hyposecretory or evaporative dry eye disease. Copyright © 2016 Elsevier B.V. All rights reserved.

Levetiracetam-induced transaminitis in a young male with traumatic brain injury.

PubMed

Rachamallu, Vivekananda; Song, Michael M; Reed, Jace M; Aligeti, Manish

2017-11-01

Levetiracetam is a commonly prescribed antiepileptic drug for seizure prophylaxis in patients with traumatic brain injury (TBI). Levetiracetam metabolism has been reported to be non-dependent on hepatic cytochrome P450 (CYP450) isoenzyme system. Furthermore, levetiracetam and its metabolites are reported to be eliminated from systemic circulation via renal excretion. Therefore, due to its well-known renal clearance mechanism with no dosage adjustments recommended for hepatic impairment, levetiracetam is often chosen as the drug of choice in patients with suspected or ongoing hepatic dysfunction. Furthermore, monitoring of liver enzymes is often not considered to be critical in levetiracetam therapy. However, hepatotoxicity is still possible with levetiracetam. Here, we report on an 18-year-old male with TBI who developed transaminitis with levetiracetam therapy which resolved following the discontinuation of levetiracetam. A close monitoring of liver enzymes and early recognition of hepatotoxicity is still necessary and critical to preventing major sequelae stemming from levetiracetam-induced hepatotoxicity.

The effects of lacosamide on depression and anxiety in patients with epilepsy.

PubMed

Moseley, Brian D; Cole, Devlin; Iwuora, Ogonna; Strawn, Jeffrey R; Privitera, Michael

2015-02-01

Depression and anxiety are common in patients with epilepsy. Moreover, some antiepileptic drugs (AEDs) have mood stabilizing and anxiolytic effects, while others may worsen psychiatric symptoms. The effects of lacosamide, a third generation AED approved for the treatment of focal onset seizures, on depressive and anxiety symptoms are unknown. We evaluated changes in depression and anxiety following the initiation of lacosamide. We compared patients' scores on the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E, n = 91) and Generalized Anxiety Disorder 7-item (GAD-7, n = 20) scales prior to and following lacosamide treatment. Following the initiation of lacosamide, there were no significant changes in NDDI-E scores when all patients were analyzed aggregately (baseline: 12.14 ± 4.64 vs post-treatment: 11.91 ± 4.14, p = 0.51). Similarly, the mean GAD-7 scores at baseline (4.10 ± 4.52) and after treatment (4.75 ± 5.51) did not differ (p = 0.23). In the 25 patients with initial NDDI-E scores of >15, lacosamide was associated with a significant decrease in depressive symptoms (baseline: 17.60 ± 1.63 vs post-treatment: 14.64 ± 2.78, p < 0.001). NDDI-E and GAD-7 scores pre- and post-lacosamide initiation were not significantly affected by a history of mood disorders, concomitant psychiatric medications, or concomitant AEDs with mood-stabilizing effects. Copyright © 2014 Elsevier B.V. All rights reserved.

Lacosamide as an adjunctive therapy in pediatric patients with refractory focal epilepsy.

PubMed

Kim, Jon Soo; Kim, Hunmin; Lim, Byung Chan; Chae, Jong-Hee; Choi, Jieun; Kim, Ki Joong; Hwang, Yong Seung; Hwang, Hee

2014-06-01

To evaluate the efficacy and safety of lacosamide in pediatric patients with refractory focal epilepsy. We reviewed retrospectively the medical records of children younger than 18 years of age treated at Seoul National University Bundang Hospital, in whom oral lacosamide was used as an adjunctive treatment for refractory focal epilepsy. Clinical information regarding the patients' epilepsy and the outcome of lacosamide treatment was gathered and analyzed. Twenty-one patients (16 boys, 5 girls) were included, with a median age of 13.9 (range, 1.2-17.9) years. The mean number of concomitant antiepileptic drugs was 3.0 (range, 1-6) and the mean duration of follow-up was 10.1 (range, 6.1-13.0) months. The mean maintenance dose of lacosamide was 5.4 (range, 1.4-9.8) mg/kg/day. Fourteen patients (67%) were responders; four of these were seizure free at the last follow-up. Seven patients (33%) were nonresponders: two of these presented with <50% seizure reduction and five showed no change in seizure frequency. Two patients (10%) discontinued oral lacosamide because of adverse events (aggressive behavior and depression). Mild transient treatment-related adverse events were observed in eight of the 21 patients (38%). Lacosamide represents a useful drug that is effective for a wide range of pediatric refractory focal epilepsy and is well tolerated. Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Block of Human Cardiac Sodium Channels by Lacosamide: Evidence for Slow Drug Binding along the Activation Pathway

PubMed Central

Wang, Sho-Ya

2014-01-01

Lacosamide is an anticonvulsant hypothesized to enhance slow inactivation of neuronal Na+ channels for its therapeutic action. Cardiac Na+ channels display less and incomplete slow inactivation, but their sensitivity toward lacosamide remains unknown. We therefore investigated the action of lacosamide in human cardiac Nav1.5 and Nav1.5-CW inactivation-deficient Na+ channels. Lacosamide showed little effect on hNav1.5 Na+ currents at 300 µM when cells were held at −140 mV. With 30-second conditioning pulses from −90 to −50 mV; however, hNav1.5 Na+ channels became sensitive to lacosamide with IC50 (50% inhibitory concentration) around 70–80 µM. Higher IC50 values were found at −110 and −30 mV. The development of lacosamide block at −70 mV was slow in wild-type Na+ channels (τ; 8.04 ± 0.39 seconds, n = 8). This time constant was significantly accelerated in hNav1.5-CW inactivation-deficient counterparts. The recovery from lacosamide block at −70 mV for 10 seconds was relatively rapid in wild-type Na+ channels (τ; 639 ± 90 milliseconds, n = 8). This recovery was accelerated further in hNav1.5-CW counterparts. Unexpectedly, lacosamide elicited a time-dependent block of persistent hNav1.5-CW Na+ currents with an IC50 of 242 ± 19 µM (n = 5). Furthermore, both hNav1.5-CW/F1760K mutant and batrachotoxin-activated hNav1.5 Na+ channels became completely lacosamide resistant, indicating that the lacosamide receptor overlaps receptors for local anesthetics and batrachotoxin. Our results together suggest that lacosamide targets the intermediate preopen and open states of hNav1.5 Na+ channels. Lacosamide may thus track closely the conformational changes at the hNav1.5-F1760 region along the activation pathway. PMID:24563546

The retention of lacosamide in patients with epilepsy and intellectual disability in three specialised institutions.

PubMed

Brenner, J; Majoie, H J M; van Beek, S; Carpay, J A

2017-11-01

We describe the effectiveness of lacosamide as adjunctive therapy in patients with epilepsy and an intellectual disability. This information is relevant, as few data exist pertaining to this population with a high prevalence of (intractable) epilepsy. We performed a retrospective study in three specialised institutions. Inclusion criteria were (1) focal onset or symptomatic generalized (2) therapy-resistant epilepsy, (3) intellectual disability and (4) residence in a care-facility for people with intellectual disabilities (PWID). The primary outcome variables were the retention rates of lacosamide, estimated through Kaplan-Meier survival analysis. Secondary outcomes were reported seizure control, side effects and clinical factors influencing discontinuation. One hundred and thirty-two patients were included. The median retention time of lacosamide in our cohort was four years. The estimated one-, two- and three-year retention rates of lacosamide were 64%, 57% and 56% respectively. Severity of intellectual disability and seizure type did not influence whether lacosamide was continued. In 48.5% of patients, a reduction of seizure activity was reported. Side effects were at least part of the reason for discontinuing treatment in 26.5% of all patients. Common side effects were tiredness/somnolence (in 30.3%), aggression/agitation (24.2%), and instable gait (15.2%). Five deaths during follow-up were considered unlikely to be related to the use of lacosamide. One patient died unexpectedly within two months of treatment onset, probably this was a case of SUDEP. These retention rates of lacosamide in PWID are similar to rates of previously registered anti-epileptic drugs in PWID. Behavioural side effects were noted in a high proportion compared to the general literature on lacosamide. Other side effects were in line with this literature. Lacosamide seems effective and safe for PWID and refractory epilepsy. Copyright © 2017 British Epilepsy Association. Published by

Efficacy and safety of lacosamide in infants and young children with refractory focal epilepsy.

PubMed

Grosso, Salvatore; Parisi, Pasquale; Spalice, Alberto; Verrotti, Alberto; Balestri, Paolo

2014-01-01

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. Copyright © 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

The fetal safety of Levetiracetam: a systematic review.

PubMed

Chaudhry, Shahnaz Akhtar; Jong, Geert't; Koren, Gideon

2014-07-01

To systematically review the available published evidence on the fetal safety of Levetiracetam with focus on birth defects. Eight studies met the inclusion criteria; five pregnancy registries and one population based cohort study. A total of 27 major congenital malformations were reported among 1213 Levetiracetam monotherapy - exposed pregnant women, yielding an overall major malformation rate of 2.2% (27/1213) [95% confidence interval of 1.53-3.22]. In contrast, Levetiracetam polytherapy was associated with significantly higher malformation rate of 6.3% (34/541) [95% CI of 4.53-8.65] (P<0.001). Additionally 2 studies investigating child neurodevelopment in Levetiracetam - exposed children revealed that the measured achievements were well above those children exposed to valproic acid, and similar to unexposed controls. The current evidence suggests that the overall risk of major malformation after first trimester exposure to Levetiracetam is within the population baseline risk of 1-3%, with no apparent adverse effects on long term child development. Copyright © 2014 Elsevier Inc. All rights reserved.

Efficacy and tolerability of add-on Lacosamide treatment in adults with Lennox-Gastaut syndrome: An observational study.

PubMed

Andrade-Machado, René; Luque-Navarro-de Los Reyes, Jacob; Benjumea-Cuartas, Vanessa; Restrepo, Juan Felipe Alvarez; Jaramillo-Jiménez, Esteban; Andrade-Gutierrez, Greisys; Espinosa, Arlety Garcia

2015-12-01

To evaluate the efficacy, safety, and tolerability of lacosamide in adults with LGS in the clinical setting. The present report is a retrospective, open-label treatment study carried out from June 2013 to December 2014 at the National Institute of Colombia. Lacosamide was introduced as add-on therapy. All caregivers were instructed to initiate lacosamide at low doses (25-50 mg) and gradually increasing it every 2 weeks. The efficacy was evaluated based on the reduction in the rate of each countable type of seizure. We also evaluated the retention rate for lacosamide as the number of days with lacosamide during follow-up. The tolerability was evaluated base on account the adverse events. We found that lacosamide only improves the seizure rate in three out of 19 patients with LGS, in two of them by more than 50%. The highest seizure reduction rate was observed in the focal and tonic-clonic seizures. The most commonly reported adverse events were worsening of seizures, aggressiveness and irritability. Nine patients (47.4%) showed worsening of their behavior during the treatment with lacosamide. Lacosamide can exacerbate both, the tonic and astatic seizures, and the encephalopathy associated with this epileptic syndrome. However, it is interesting to consider the likelihood of suppression of generalized tonic-clonic and focal seizures. That is why; lacosamide could be an option after carefully balancing risks and benefits in each individual case. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

[Anticonvulsant hypersensitivity syndrome and lamotrigine-associated anticonvulsant hypersensitivity syndrome].

PubMed

Taillia, H; Alla, P; Fournier, B; Bounolleau, P; Ouologem, M; Ricard, D; Sallansonnet-Froment, M; de Greslan, T; Renard, J-L

2009-10-01

Anticonvulsant hypersensitivity syndrome (AHS) is defined by the association of high fever, cutaneous rash and multiorgan-system abnormalities (incidence, one in 1000 to one in 10,000 exposures). Fatal complications are described in 10%. This reaction usually develops 1 to 12 weeks after initiation of an aromatic anticonvulsant. Drug rash with eosinophilia and systemic symptoms (DRESS) can be discussed as differential diagnosis. Several hypotheses have been put forward to explain the pathogenesis of AHS. These include accumulation of toxic metabolites, antibody production and viral infection. The one based on toxic metabolites has found the greatest acceptance due to the fact that it can be proven by an in vitro test, the lymphocyte toxicity assay. In vivo, skin biopsies show characteristic findings of erythema multiform or typical leucocytoclastic angitis. The patch-test is positive in 80% of the cases. Lamotrigine-associated anticonvulsant hypersensitivity syndrome (LASH) is rare and was described in 1998. We report two new cases demonstrating the two particular configurations of apparition of LASH found in the 14 cases from the review of literature (Pubmed: anticonvulsant hypersensitivity syndrome - lamotrigine): high doses of lamotrigine (or lamotrigine in very young or old patients), and lamotrigine associated with another anti-epileptic (phenobarbital or sodium valproate). We discuss the links between DRESS after lamotrigine and LASH as illustrated in a new case.

Lacosamide: a review of its use as adjunctive therapy in the management of partial-onset seizures.

PubMed

Hoy, Sheridan M

2013-12-01

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.

Impact of impaired renal function on the pharmacokinetics of the antiepileptic drug lacosamide.

PubMed

Cawello, Willi; Fuhr, Uwe; Hering, Ursula; Maatouk, Haidar; Halabi, Atef

2013-10-01

The antiepileptic drug lacosamide is eliminated predominantly via the kidneys. Therefore, an evaluation of the impact of renal impairment on its pharmacokinetic profile is an important component of its safety assessment. The objective of this study was to evaluate the pharmacokinetic profile of lacosamide among individuals with renal impairment (mild, moderate, or severe) and among patients with end-stage renal disease (ESRD), including those on hemodialysis. This was an open-label, Phase I trial. The pharmacokinetics of a single oral 100-mg lacosamide dose were evaluated in five groups of participants: healthy controls, patients with mild, moderate, or severe renal impairment, and patients with ESRD (with and without hemodialysis). Forty participants completed the trial, eight in each group. In healthy volunteers, renal clearance accounted for approximately 30 % of total body clearance [geometric mean 0.5897 l/h (coefficient of variation 37.9 %) vs 2.13 l/h (20.8 %)]. With severe renal impairment, renal clearance was approximately 11 % of total body clearance [0.1428 l/h (31.8 %) vs 1.34 l/h (26.9 %)]. Terminal half-life and systemic exposure were increased with renal impairment, while total body clearance, renal clearance, and urinary excretion were decreased. Strong positive correlations between creatinine clearance, renal clearance, and urinary excretion were observed. Among patients with ESRD, approximately 50 % of lacosamide was cleared from systemic circulation by 4-h hemodialysis. In patients with essentially no renal clearance, nonrenal clearance was still present (1.1 l/h). Lacosamide was well tolerated by healthy volunteers and patients. In patients with mild-to-moderate renal impairment, lacosamide dose adjustment is not necessary, because total body clearance decreased by only approximately 20 %. Dose adjustment, however, is required for patients with severe renal impairment. Hemodialysis removes approximately 50 % of lacosamide from plasma; therefore

The effectiveness and safety of lacosamide in children with epilepsy in a clinical practice setting.

PubMed

Sanmartí-Vilaplana, Francesc; Díaz-Gómez, Asunción

2018-02-01

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. Copyright © 2017 Elsevier Inc. All rights reserved.

Pharmacokinetics of lacosamide and omeprazole coadministration in healthy volunteers: results from a phase I, randomized, crossover trial.

PubMed

Cawello, Willi; Mueller-Voessing, Christa; Fichtner, Andreas

2014-05-01

The antiepileptic drug lacosamide has a low potential for drug-drug interactions, but is a substrate and moderate inhibitor of the cytochrome P450 (CYP) enzyme CYP2C19. This phase I, randomized, open-label, two-way crossover trial evaluated the pharmacokinetic effects of lacosamide and omeprazole coadministration. Healthy, White, male volunteers (n = 36) who were not poor metabolizers of CYP2C19 were randomized to treatment A (single-dose 40 mg omeprazole on days 1 and 8 together with 6 days of multiple-dose lacosamide [200-600 mg/day] on days 3-8) and treatment B (single doses of 300 mg lacosamide on days 1 and 8 with 7 days of 40 mg/day omeprazole on days 3-9) in pseudorandom order, separated by a ≥ 7-day washout period. Area under the concentration-time curve (AUC) and peak concentration (C(max)) were the primary pharmacokinetic parameters measured for lacosamide or omeprazole administered alone (reference) or in combination (test). Bioequivalence was determined if the 90 % confidence interval (CI) of the ratio (test/reference) fell within the acceptance range of 0.8-1.25. The point estimates (90 % CI) of the ratio of omeprazole + lacosamide coadministered versus omeprazole alone for AUC (1.098 [0.996-1.209]) and C(max) (1.105 [0.979-1.247]) fell within the acceptance range for bioequivalence. The point estimates (90 % CI) of the ratio of lacosamide + omeprazole coadministration versus lacosamide alone also fell within the acceptance range for bioequivalence (AUC 1.133 [1.102-1.165]); C(max) 0.996 (0.947-1.047). Steady-state lacosamide did not influence omeprazole single-dose pharmacokinetics, and multiple-dose omeprazole did not influence lacosamide single-dose pharmacokinetics.

Comparative study of antiepileptic drug use during pregnancy over a period of 12 years in Spain. Efficacy of the newer antiepileptic drugs lamotrigine, levetiracetam, and oxcarbazepine.

PubMed

Martinez Ferri, M; Peña Mayor, P; Perez López-Fraile, I; Escartin Siquier, A; Martin Moro, M; Forcadas Berdusan, M

2018-03-01

The prescription pattern of antiepileptic drugs (AEDs) during pregnancy is changing but to what extent this is occurring in Spain remains unknown. The efficacy of newer drugs for controlling seizures is a key issue and may have changed over the years as doctors gained familiarity with these drugs during pregnancy. To assess these 2 topics, we report the results from the Spanish EURAP register gathered over a 12-year period. After signing informed consent forms, patients were included in the register and evaluated at onset of pregnancy, at the end of the second and third trimesters, after delivery, and one year after delivery. For the purposes of this study, we analysed AEDs, type of epilepsy, seizure frequency per trimester and throughout pregnancy, percentage of seizure-free pregnancies, and frequency of congenital malformations. We then compared data from 2 periods (June 2001-October 2007) and (January 2008-May 2015) RESULTS: We compared 304 monotherapies from the older period to 127 from the more recent one. There was a clear increase in the use of levetiracetam (LEV) with declining use of carbamazepine (CBZ), phenytoin, and phenobarbital; a slight decline in use of valproate (VPA), and a slight increase in the use of lamotrigine (LTG) and oxcarbazepine (OXC). Epilepsy types treated with CBZ and VPA remained unchanged, whereas fewer cases of generalised epilepsy were treated with LTG in the new period. This trend was not associated with significant changes in seizure frequency, but rather linked to better control over de novo seizures in the third trimester. LEV was similar to CBZ and VPA with regard to levels of seizure control, and more effective than LTG. Generalised epilepsy accounted for 64% of the cases treated with LEV. The prescription pattern of AEDs during pregnancy has changed in Spain, with diminishing use of CBZ, phenytoin, and phenobarbital. Changes also reflect the type of epilepsy, since there is less use of LTG for generalised epilepsy. LEV

Real world experience with lacosamide monotherapy- a single center 1-year follow-up study.

PubMed

Maloney, Eimer; McGinty, Ronan N; Costello, Daniel J

2018-05-01

Reporting of 'real-world' data on efficacy and tolerability of antiepileptic medications helps to inform physicians on how newer medications perform in the clinical setting, outside of the strict regimens of clinical trials. We report our experience of prescribing lacosamide monotherapy to a diverse range of patients at our epilepsy centre. We performed a single-centre, retrospective review of all patients who had been prescribed lacosamide monotherapy over the last 8 years. Efficacy is pragmatically reported based on reduction of seizure frequency and lacosamide retention rates. We identified 45 patients who were commenced on lacosamide monotherapy. Intent-to-treat analysis demonstrated a 51% (n = 23) 12 month retention rate. Forty percent (n = 18) achieved a greater than 50% reduction in seizure frequency and 35.5% (n = 16) became seizure free. We report real-world data showing a significant reduction in seizure frequency, a moderate rate of retention and an excellent side effect profile in our cohort of patients prescribed lacosamide monotherapy. Copyright © 2018 Elsevier B.V. All rights reserved.

Two case reports of oral ulcers with lamotrigine several weeks after oxcarbazepine withdrawal.

PubMed

O'Neill, Amy; de Leon, Jose

2007-05-01

To report two cases of mouth ulcers in lamotrigine patients after oxcarbazepine withdrawal. The first patient was a 35-year-old woman with bipolar disorder II (BD II) started on lamotrigine and tapered off oxcarbazepine while an inpatient. The second patient was a 36-year-old man with BD II. He was discharged on lamotrigine and oxcarbazepine with the recommendation of a slow withdrawal of oxcarbazepine. Many weeks after hospital discharge and after a stable lamotrigine dose had been established, both patients developed painful mouth ulcers that were diagnosed during outpatient visits. The first patient developed ulcers 39 days after oxcarbazepine was stopped and the ulcers resolved 4 days after lamotrigine discontinuation. The second patient was taking 1200 mg/day of oxcarbazepine and after leaving hospital decreased this to 600 mg/day. Twenty-two days after the oxcarbazepine decrease, he developed oral ulcers that resolved with oxcarbazepine and lamotrigine discontinuation. Lamotrigine is mainly metabolized by glucuronidation, specifically by the uridine 5'-diphosphate glucuronosyltransferases 1A4 (UGT1A4). Carbamazepine is a UGT1A4 inducer. These two cases suggest that oxcarbazepine may also induce lamotrigine metabolism. The discontinuation or dosage decrease of carbamazepine or oxcarbazepine may be associated with a slow increase of lamotrigine levels over several weeks and thus increase risk of lamotrigine toxicity that may manifest as oral ulcers. Hospital psychiatrists need to be aware that discontinuation of inducers may take several weeks to manifest as side effects.

Levetiracetam Clinical Pharmacokinetic Monitoring in Pediatric Patients with Epilepsy.

PubMed

Tan, Jason; Paquette, Vanessa; Levine, Marc; Ensom, Mary H H

2017-11-01

Levetiracetam is a broad-spectrum antiepileptic drug (AED) with a unique mechanism of action. Older AEDs can cause serious short- and long-term adverse drug reactions and complications, rendering them undesirable to use in pediatric patients. Characteristics that make levetiracetam a near-ideal AED include its broad spectrum of activity, good tolerability profile, and minimal drug-drug interactions. Clinical pharmacokinetic monitoring (CPM) is often recommended in pediatric patients for certain AEDs due to large interindividual pharmacokinetic differences and unpredictable drug disposition. Our objective was to determine whether monitoring levetiracetam concentrations is warranted for pediatric patients with epilepsy, using a previously published 9-step decision-making algorithm. A literature search of the MEDLINE (1946-August 2016), EMBASE (1974-August 2016), CENTRAL, and Google Scholar databases was performed to identify relevant English-language articles and answer the questions posed in the algorithm for levetiracetam CPM in pediatric epilepsies. Additional articles were identified from a manual bibliographic review of the relevant literature. We found that levetiracetam CPM met some criteria of the algorithm: levetiracetam is an appropriate adjunctive or monotherapy for pediatric patients with either focal or generalized seizures; it is readily measurable in plasma, with an appropriate degree of sensitivity, accuracy, and precision; it exhibits interindividual variation in pharmacokinetics; often, its pharmacologic effect cannot be easily measured; and the duration of therapy is expected to be long-term. However, important criteria not met include the following: there is no clear evidence for a concentration-response relationship for efficacy or toxicity; the proposed therapeutic range of 12-46 μg/mL is not well-defined and is generally considered as wide. Thus, clinical decision making is unlikely to be affected as a result of routine levetiracetam CPM. In

Lamotrigine add-on for drug-resistant partial epilepsy.

PubMed

Ramaratnam, S; Marson, A G; Baker, G A

2001-01-01

Epilepsy is a common neurological disorder, affecting almost 0.5 to 1% of the population. Nearly 30% of patients with epilepsy are refractory to currently available drugs. Lamotrigine is one of the newer antiepileptic drugs and is the topic of this review. To examine the effects of lamotrigine on seizures, side effects, cognition and quality of life, when used as an add-on treatment for patients with drug-resistant partial epilepsy. We searched the Cochrane Epilepsy Group trials register, the Cochrane Controlled Trials Register (Cochrane Library Issue 2, 2001), MEDLINE (January 1966 to April 2001) and reference lists of articles. We also contacted the manufacturers of lamotrigine (Glaxo-Wellcome). Randomized placebo controlled trials, of patients with drug-resistant partial epilepsy of any age, in which an adequate method of concealment of randomization was used. The studies may be double, single or unblinded. For crossover studies, the first treatment period was treated as a parallel trial. Two reviewers independently assessed the trials for inclusion and extracted data. Primary analyses were by intention to treat. Outcomes included 50% or greater reduction in seizure frequency, treatment withdrawal (any reason), side effects, effects on cognition, and quality of life. We found three parallel add-on studies and eight cross-over studies, which included 1243 patients (199 children and 1044 adults). The overall Peto's Odds Ratio (OR) and 95% confidence intervals (CIs) across all studies for 50% or greater reduction in seizure frequency was 2.71 (1.87, 3.91) indicating that lamotrigine is significantly more effective than placebo in reducing seizure frequency. The overall OR (95%CI) for treatment withdrawal (for any reason) is 1.12 (0.78, 1.61). The 99% CIs for ataxia, dizziness, nausea, and diplopia do not include unity, indicating that they are significantly associated with lamotrigine. The limited data available precludes any conclusions about effects on cognition

Lamotrigine add-on for drug-resistant partial epilepsy.

PubMed

Ramaratnam, S; Marson, A G; Baker, G A

2000-01-01

Epilepsy is a common neurological disorder, affecting almost 0.5 to 1% of the population. Nearly 30% of patients with epilepsy are refractory to currently available drugs. Lamotrigine is one of the newer antiepileptic drugs and is the topic of this review. To examine the effects of lamotrigine on seizures, side effects, cognition and quality of life, when used as an add-on treatment for patients with drug-resistant partial epilepsy. We searched the Cochrane Epilepsy Group trials register, the Cochrane Controlled Trials Register (Cochrane Library Issue 1, 2000), MEDLINE (January 1966 to December 1999) and reference lists of articles. We also contacted the manufacturers of lamotrigine (Glaxo-Wellcome). Randomized placebo controlled trials, of patients with drug-resistant partial epilepsy of any age, in which an adequate method of concealment of randomization was used. The studies may be double, single or unblinded. For crossover studies, the first treatment period was treated as a parallel trial. Two reviewers independently assessed the trials for inclusion and extracted data. Primary analyses were by intention to treat. Outcomes included 50% or greater reduction in seizure frequency, treatment withdrawal (any reason), side effects, effects on cognition, and quality of life. We found three parallel add-on studies and eight cross-over studies, which included 1243 patients (199 children and 1044 adults). The overall Peto's Odds Ratio (OR) and 95% confidence intervals (CIs) across all studies for 50% or greater reduction in seizure frequency was 2.71 (1.87, 3.91) indicating that lamotrigine is significantly more effective than placebo in reducing seizure frequency. The overall OR (95%CI) for treatment withdrawal (for any reason) is 1.12 (0.78, 1. 61). The 99% CIs for ataxia, dizziness, nausea, and diplopia do not include unity, indicating that they are significantly associated with lamotrigine. The limited data available preclude any conclusions about effects on

Evaluation of Brain Pharmacokinetic and Neuropharmacodynamic Attributes of an Antiepileptic Drug, Lacosamide, in Hepatic and Renal Impairment: Preclinical Evidence.

PubMed

Kumar, Baldeep; Modi, Manish; Saikia, Biman; Medhi, Bikash

2017-07-19

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.

NEOPLASM study: Real-life use of lacosamide in patients with brain tumor-related epilepsy.

PubMed

Villanueva, Vicente; Saiz-Diaz, Rosana; Toledo, Manuel; Piera, Ana; Mauri, Jose Angel; Rodriguez-Uranga, Juan Jesús; López-González, Francisco Javier; Gómez-Ibáñez, Asier; Garcés, Mercedes; González de la Aleja, Jesús; Rodríguez-Osorio, Xiana; Palao-Duarte, Susana; Castillo, Ascensión; Bonet, Macarena; Ruiz-Giménez, Jesús; Palau, Juan; Arcediano, Alberto; Toledo, Maria; Gago, Ana

2016-12-01

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Influence of xanthotoxin (8-methoxypsoralen) on the anticonvulsant activity of various novel antiepileptic drugs against maximal electroshock-induced seizures in mice.

PubMed

Zagaja, Mirosław; Andres-Mach, Marta; Patrzylas, Paweł; Pyrka, Daniel; Szpringer, Monika; Florek-Łuszczki, Magdalena; Żółkowska, Dorota; Skalicka-Woźniak, Krystyna; Łuszczki, Jarogniew J

2016-12-01

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. Copyright © 2016 Elsevier B.V. All rights

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Levetiracetam.

PubMed

Petruševska, Marija; Berglez, Sandra; Krisch, Igor; Legen, Igor; Megušar, Klara; Peternel, Luka; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Kopp, Sabine; Langguth, Peter; Mehta, Mehul; Polli, James E; Shah, Vinod P; Dressman, Jennifer

2015-09-01

Literature and experimental data relevant for the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levetiracetam are reviewed. Data on solubility and permeability suggest that levetiracetam belongs to class I of the biopharmaceutical classification system (BCS). Levetiracetam's therapeutic use, its wide therapeutic index, and its favorable pharmacokinetic properties make levetiracetam a valid candidate for the BCS-based biowaiver approach. Further, no BE studies with levetiracetam IR formulations in which the test formulation failed to show BE with the comparator have been reported in the open literature. On the basis of the overall evidence, it appears unlikely that a BCS-based biowaiver approach for levetiracetam IR solid oral dosage forms formulated with established excipients would expose patients to undue risks. Thus, the BCS-based biowaiver approach procedure is recommended for IR solid oral dosage form containing levetiracetam, provided the excipients in the formulation are also present in products that have been approved in countries belonging to or associated with the International Committee on Harmonization and are used in their usual quantities, and provided the dissolution profiles of the test and reference product comply with the current requirements for BCS-based biowaivers. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Anticonvulsant hypersensitivity syndrome to lamotrigine confirmed by lymphocyte stimulation in vitro.

PubMed

Karande, Sunil; Gogtay, Nithya J; Kanchan, Sandeep; Kshirsagar, Nilima A

2006-02-01

Anticonvulsant hypersensitivity syndrome (AHS) developing to lamotrigine, a non-aromatic anticonvulsant, has rarely been reported. We present a two-year-old boy with refractory epilepsy on valproic acid and lamotrigine therapy who developed fever and a maculopapular itchy rash. Blood investigations detected lymphocytosis and thrombocytopenia. With a presumptive diagnosis of AHS, lamotrigine was discontinued. The fever and rash resolved over the next three days and the child was discharged on valproic acid and clobazam. The diagnosis was confirmed by in vitro lymphocyte toxicity assay, which not only demonstrated increased cell death following exposure to lamotrigine, but also to the three first-line aromatic anticonvulsants: phenytoin, phenobarbital and carbamazepine. The potential of first-line aromatic anticonvulsants to cause AHS should be remembered in a patient who has developed AHS on exposure to lamotrigine. Timely recognition of this rare but potentially fatal drug reaction is important.

Lack of effect of lacosamide on the pharmacokinetic and pharmacodynamic profiles of warfarin.

PubMed

Stockis, Armel; van Lier, Jan Jaap; Cawello, Willi; Kumke, Thomas; Eckhardt, Klaus

2013-07-01

The aim of this study was to evaluate the effect of the antiepileptic drug lacosamide on the pharmacokinetics and pharmacodynamics of the anticoagulant warfarin. In this open-label, two-treatment crossover study, 16 healthy adult male volunteers were randomized to receive a single 25-mg dose of warfarin alone in one period and lacosamide 200 mg twice daily on days 1-9 with a single 25 mg dose of warfarin coadministered on day 3 in the other period. There was a 2-week washout between treatments. Pharmacokinetic end points were area under the plasma concentration-time curve (AUC(0,last) and AUC(0,∞) ) and maximum plasma concentration (Cmax ) for S- and R-warfarin. Pharmacodynamic end points were area under the international normalized ratio (INR)-time curve (AUCINR ), maximum INR (INRmax ), maximum prothrombin time (PTmax ) and area under the PT-time curve (AUCPT ). Following warfarin and lacosamide coadministration, Cmax and AUC of S- and R-warfarin, as well as peak value and AUC of PT and INR, were equivalent to those after warfarin alone. In particular, the AUC(0,∞) ratio (90% confidence interval) for coadministration of warfarin and lacosamide versus warfarin alone was 0.97 (0.94-1.00) for S-warfarin and 1.05 (1.02-1.09) for R-warfarin, and the AUCINR ratio was 1.04 (1.01-1.06). All participants completed the study. Coadministration of lacosamide 400 mg/day did not alter the pharmacokinetics of warfarin 25 mg or the anticoagulation level. These results suggest that there is no need for dose adjustment of warfarin when coadministered with lacosamide. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Efficacy and tolerability of lacosamide for secondary epileptic seizures in patients with brain tumor: A multicenter, observational retrospective study

PubMed Central

Sepúlveda-Sánchez, Juan Manuel; Conde-Moreno, Antonio; Barón, Manuel; Pardo, Javier; Reynés, Gaspar; Belenguer, Antonio

2017-01-01

The present observational, multicenter, retrospective study investigated the efficacy and tolerability of lacosamide in controlling secondary epileptic seizures in patients with brain tumors in Spain. Data from the medical records of patients ≥18 years of age with brain tumors, who had received at least one dose of lacosamide for seizure management between July 2013 and November 2013, were collected. The primary and secondary objectives of the present study were to assess the effectiveness and tolerability of lacosamide. Data from 39 patients (mean age, 54.1 years; 66.7% male) were collected, where the two main reasons for initiation of lacosamide treatment were the lack of efficacy of other antiepileptic drugs (in 76.9% of patients) and the presence of adverse events (12.8%) associated with other antiepileptic drugs. At the initiation of treatment, patients received a mean lacosamide dose of 138.5±68.3 mg/day. At 6 months, lacosamide had significantly reduced the mean number of seizures from 26.4 (standard deviation [SD], 50.4) seizures for the 6 months prior to lacosamide initiation to a mean of 9.4 (SD, 22.8) seizures during the 6 months subsequent to lacosamide initiation; P<0.001. Lacosamide was generally well tolerated; of the 25 patients who had complete safety data available at a 6-month follow-up, 3 patients (12%) reported an adverse event, including dizziness, asthenia, instability and irritability. The present retrospective analysis suggested that lacosamide is an effective and well-tolerated treatment in patients experiencing seizures due to brain tumors. Additional prospective studies with a larger patient population and randomized trial design are warranted. PMID:28599411

Efficacy and tolerability of lacosamide for secondary epileptic seizures in patients with brain tumor: A multicenter, observational retrospective study.

PubMed

Sepúlveda-Sánchez, Juan Manuel; Conde-Moreno, Antonio; Barón, Manuel; Pardo, Javier; Reynés, Gaspar; Belenguer, Antonio

2017-06-01

The present observational, multicenter, retrospective study investigated the efficacy and tolerability of lacosamide in controlling secondary epileptic seizures in patients with brain tumors in Spain. Data from the medical records of patients ≥18 years of age with brain tumors, who had received at least one dose of lacosamide for seizure management between July 2013 and November 2013, were collected. The primary and secondary objectives of the present study were to assess the effectiveness and tolerability of lacosamide. Data from 39 patients (mean age, 54.1 years; 66.7% male) were collected, where the two main reasons for initiation of lacosamide treatment were the lack of efficacy of other antiepileptic drugs (in 76.9% of patients) and the presence of adverse events (12.8%) associated with other antiepileptic drugs. At the initiation of treatment, patients received a mean lacosamide dose of 138.5±68.3 mg/day. At 6 months, lacosamide had significantly reduced the mean number of seizures from 26.4 (standard deviation [SD], 50.4) seizures for the 6 months prior to lacosamide initiation to a mean of 9.4 (SD, 22.8) seizures during the 6 months subsequent to lacosamide initiation; P<0.001. Lacosamide was generally well tolerated; of the 25 patients who had complete safety data available at a 6-month follow-up, 3 patients (12%) reported an adverse event, including dizziness, asthenia, instability and irritability. The present retrospective analysis suggested that lacosamide is an effective and well-tolerated treatment in patients experiencing seizures due to brain tumors. Additional prospective studies with a larger patient population and randomized trial design are warranted.

Increases of Catalase and Glutathione Peroxidase Expressions by Lacosamide Pretreatment Contributes to Neuroprotection Against Experimentally Induced Transient Cerebral Ischemia.

PubMed

Choi, Hyun Young; Park, Joon Ha; Chen, Bai Hui; Shin, Bich Na; Lee, Yun Lyul; Kim, In Hye; Cho, Jeong-Hwi; Lee, Tae-Kyeong; Lee, Jae-Chul; Won, Moo-Ho; Ahn, Ji Hyeon; Tae, Hyun-Jin; Yan, Bing Chun; Hwang, In Koo; Cho, Jun Hwi; Kim, Young-Myeong; Kim, Sung Koo

2016-09-01

Lacosamide is a new antiepileptic drug which is widely used to treat partial-onset seizures. In this study, we examined the neuroprotective effect of lacosamide against transient ischemic damage and expressions of antioxidant enzymes such as Zn-superoxide dismutase (SOD1), Mn-superoxide dismutase (SOD2), catalase (CAT) and glutathione peroxidase (GPX) in the hippocampal cornu ammonis 1 (CA1) region following 5 min of transient global cerebral ischemia in gerbils. We found that pre-treatment with 25 mg/kg lacosamide protected CA1 pyramidal neurons from transient global cerebral ischemic insult using hematoxylin-eosin staining and neuronal nuclear antigen immunohistochemistry. Transient ischemia dramatically changed expressions of SOD1, SOD2 and GPX, not CAT, in the CA1 pyramidal neurons. Lacosamide pre-treatment increased expressions of CAT and GPX, not SOD1 and 2, in the CA1 pyramidal neurons compared with controls, and their expressions induced by lacosamide pre-treatment were maintained after transient cerebral ischemia. In brief, pre-treatment with lacosamide protected hippocampal CA1 pyramidal neurons from ischemic damage induced by transient global cerebral ischemia, and the lacosamide-mediated neuroprotection may be closely related to increases of CAT and GPX expressions by lacosamide pre-treatment.

Levetiracetam as a possible contributor to acute kidney injury.

PubMed

Spengler, Danielle C; Montouris, Georgia D; Hohler, Anna D

2014-08-01

Levetiracetam is an antiepileptic medication that has been reported to be both well-tolerated and effective in treating generalized tonic-clonic, myoclonic, and partial-onset seizures. The adverse effects most commonly reported in tolerability trials include somnolence, fatigue/asthenia, headaches, dizziness, and nausea. However, there have been a few reports suggesting possible detrimental effects of levetiracetam on renal function. Here we describe the case of a previously healthy 23-year-old female patient who developed acute kidney injury 1 day after the initiation of levetiracetam therapy for new-onset seizures. Based on the time course of the patient's rise in serum creatinine and the exclusion of other causes, this case suggests that levetiracetam use contributed to the acute kidney injury. Levetiracetam is a widely used drug that has been reported to be generally tolerable and effective; however, it has the potential to negatively affect renal function. This potential consequence of therapy should be considered when deciding whether or not to prescribe this medication, and renal function should be monitored during treatment. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Efficacy and tolerability of levetiracetam for pediatric refractory epilepsy.

PubMed

Muramatsu, Kazuhiro; Sawaura, Noriko; Ogata, Tomomi; Makioka, Nishiki; Tomita, Keiko; Motojima, Toshino; Ida, Kuniko; Hazama, Kyoko; Arakawa, Hirokazu

2017-03-01

Levetiracetam has a high tolerability and is effective against various seizure types and epilepsy syndromes. However, no study has specifically evaluated the efficacy of levetiracetam in children with refractory epilepsy based on magnetic resonance imaging (MRI) findings and the presence of intellectual disability (ID). We retrospectively evaluated levetiracetam efficacy and safety in 49 pediatric patients who met the following inclusion criteria: (1) diagnosis of refractory epilepsy with first-line antiepileptic (AED) treatment ⩾2years, (2) younger than 20years old, and (3) received oral levetiracetam treatment for ⩾6months. We assessed the relationships of these outcomes with MRI findings and ID status. Eighteen (37%) patients achieved a ⩾50% reduction in seizure frequency, and the majority (78%) had no remarkable side effects. Twenty-two (45%) patients had previously been treated with more than seven antiepileptic drugs prior to levetiracetam. Among 18 patients who achieved a ⩾50% reduction in seizure frequency, 13 and 5 had negative and positive MRI findings, and 9 and 9 had and did not have ID, respectively. Our findings suggest that even for intractable pediatric cases with symptomatic etiology (i.e., MRI lesion and ID), levetiracetam has favorable efficacy for refractory epilepsy with tolerable adverse effects. Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Intravenous lacosamide for treatment of absence status epilepticus in genetic generalized epilepsy: A case report and review of literature.

PubMed

Reif, P S; Männer, A; Willems, L M; Kay, L; Zöllner, J P; Klein, K M; Rosenow, F; Strzelczyk, A

2018-04-06

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. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Rational polytherapy with lacosamide in clinical practice: results of a Spanish cohort analysis RELACOVA.

PubMed

Villanueva, Vicente; López-Gomáriz, Elena; López-Trigo, Javier; Palau, Juan; García, Manuel; Villarroya, Teresa; Bonet, Macarena; Santafé, Consuelo

2012-03-01

There has been little long-term success with polytherapy for patients with refractory partial-onset epilepsy. The rational combination of antiepileptic drugs based on their mechanism of action may help improve treatment efficacy and tolerability. Lacosamide, a novel sodium channel blocker (SCB), was investigated in 158 patients with partial-onset epilepsy in the prospective, multicenter, observational, RELACOVA cohort study conducted in Spain. After 12 months' treatment with lacosamide, 47% of patients were responders (≥50% reduction in seizure frequency) and 24% were seizure free. Lacosamide was well tolerated; dizziness was the most frequent adverse event. Efficacy was better (responder rate, 65% vs 38%; seizure free rate, 35% vs 17%) and there was a lower adverse event rate (33% vs 58%) in patients receiving non-SCBs (n=49) versus those receiving SCBs (n=104) as concomitant therapy at baseline. Further investigation of lacosamide combination therapy is warranted. Copyright © 2012 Elsevier Inc. All rights reserved.

Efficacy and Tolerability of Lacosamide in the Treatment of Children With Refractory Generalized Epilepsy.

PubMed

Miskin, Chandrabhaga; Khurana, Divya S; Valencia, Ignacio; Legido, Agustin; Hasbani, Daphne M; Carvalho, Karen S

2016-06-01

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. © The Author(s) 2016.

Levetiracetam in the Treatment of Epileptic Seizures After Liver Transplantation

PubMed Central

Lin, Chih-Hsiang; Chen, Chao-Long; Lin, Tsu-Kung; Chen, Nai-Ching; Tsai, Meng-Han; Chuang, Yao-Chung

2015-01-01

Abstract After liver transplantation, patients may develop seizures or epilepsy due to a variety of etiologies. The ideal antiepileptic drugs for these patients are those with fewer drug interactions and less hepatic toxicity. In this study, we present patients using levetiracetam to control seizures after liver transplantation. We retrospectively enrolled patients who received levetiracetam for seizure control after liver transplantation. We analyzed the etiology of liver failure that required liver transplantation, etiology of the seizures, outcomes of seizure control, and the condition of the patient after follow-up at the outpatient department. Hematological and biochemical data before and after the use of levetiracetam were also collected. Fifteen patients who received intravenous or oral levetiracetam monotherapy for seizure control after liver transplantation were enrolled into this study. All of the patients remained seizure-free during levetiracetam treatment. Two patients died during the follow-up, and the other 13 patients were alive at the end of the study period and all were seizure-free without neurological sequelae that interfered with their daily activities. No patients experienced liver failure or rejection of the donor liver due to ineffective immunosuppressant medications. The dosage of immunosuppressants did not change before and after levetiracetam treatment, and there were no changes in hematological and biochemical data before and after treatment. Levetiracetam may be a suitable antiepileptic drug for patients who undergo liver transplantation due to fewer drug interactions and a favorable safety profile. PMID:26402799

Levetiracetam in the Treatment of Epileptic Seizures After Liver Transplantation.

PubMed

Lin, Chih-Hsiang; Chen, Chao-Long; Lin, Tsu-Kung; Chen, Nai-Ching; Tsai, Meng-Han; Chuang, Yao-Chung

2015-09-01

After liver transplantation, patients may develop seizures or epilepsy due to a variety of etiologies. The ideal antiepileptic drugs for these patients are those with fewer drug interactions and less hepatic toxicity. In this study, we present patients using levetiracetam to control seizures after liver transplantation. We retrospectively enrolled patients who received levetiracetam for seizure control after liver transplantation. We analyzed the etiology of liver failure that required liver transplantation, etiology of the seizures, outcomes of seizure control, and the condition of the patient after follow-up at the outpatient department. Hematological and biochemical data before and after the use of levetiracetam were also collected. Fifteen patients who received intravenous or oral levetiracetam monotherapy for seizure control after liver transplantation were enrolled into this study. All of the patients remained seizure-free during levetiracetam treatment. Two patients died during the follow-up, and the other 13 patients were alive at the end of the study period and all were seizure-free without neurological sequelae that interfered with their daily activities. No patients experienced liver failure or rejection of the donor liver due to ineffective immunosuppressant medications. The dosage of immunosuppressants did not change before and after levetiracetam treatment, and there were no changes in hematological and biochemical data before and after treatment. Levetiracetam may be a suitable antiepileptic drug for patients who undergo liver transplantation due to fewer drug interactions and a favorable safety profile.

Lacosamide reduces HDAC levels in the brain and improves memory: Potential for treatment of Alzheimer's disease.

PubMed

Bang, Shraddha R; Ambavade, Shirishkumar D; Jagdale, Priti G; Adkar, Prafulla P; Waghmare, Arun B; Ambavade, Prashant D

2015-07-01

Lacosamide, a histone deacetylase (HDAC) inhibitor, has been approved for the treatment of epilepsy. Some HDAC inhibitors have been proven effective for the treatment of memory disorders. The present investigation was designed to evaluate the effect of lacosamide on memory and brain HDAC levels. The effect on memory was evaluated in animals with scopolamine-induced amnesia using the elevated plus maze, object recognition test, and radial arm maze. The levels of acetylcholinesterase and HDAC in the cerebral cortex were evaluated. Lacosamide at doses of 10 and 30mg/kg significantly reduced the transfer latency in the elevated plus maze. Lacosamide at a dose of 30mg/kg significantly increased the time spent with a familiar object in the object recognition test at the 24h interval and decreased the time spent in the baited arm. Moreover, at this dose, the number of errors in the radial arm maze at 3 and 24h intervals was minimized and a reduction in the level of HDAC1, but not acetylcholinesterase, was observed in the cerebral cortex. These effects of lacosamide are equivalent to those of piracetam at a dose of 300mg/kg. These results suggest that lacosamide at a 30mg/kg dose improves disrupted memory, possibly by inhibiting HDAC, and could be used to treat amnesic symptoms of Alzheimer's disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Levetiracetam interacts synergistically with nonsteroidal analgesics and caffeine to produce antihyperalgesia in rats.

PubMed

Tomić, Maja A; Micov, Ana M; Stepanović-Petrović, Radica M

2013-11-01

Levetiracetam is a novel anticonvulsant with antihyperalgesic efficacy in inflammatory pain. Nonsteroidal analgesics and caffeine, as analgesic adjuvant, are widely used against inflammatory pain. This study characterized the manner in which levetiracetam interacts with analgesics (ibuprofen, celecoxib, and paracetamol) and caffeine to suppress hyperalgesia in a model of localized inflammation. Rat paw inflammation was induced by intraplantar carrageenan (.1 mL, 1%). Hyperalgesia and antihyperalgesic effects of levetiracetam (orally), analgesics (orally), and caffeine (intraperitoneally) alone and 2-drug combinations of levetiracetam with analgesics or caffeine were examined by a modified paw pressure test. The type of interaction between components was determined by isobolographic analysis or by analysis of the log dose-response curves for drug combination and drugs alone. Levetiracetam (10-200 mg/kg), ibuprofen (12.5-100 mg/kg), celecoxib (3.75-30 mg/kg), paracetamol (50-200 mg/kg), caffeine (15-100 mg/kg), and 2-drug combinations of levetiracetam with analgesics/caffeine produced a significant, dose-dependent reduction of inflammatory hyperalgesia. Isobolographic analysis revealed that levetiracetam exerts a synergistic interaction with analgesics, with approximately 7-, 9-, and 11-fold reduction of doses of both drugs in combination of levetiracetam with paracetamol, celecoxib, and ibuprofen, respectively. Analysis of the log dose-response curves for levetiracetam (1-50 mg/kg) in the presence of caffeine (10 mg/kg) and levetiracetam applied alone also revealed a synergistic interaction. Levetiracetam's ED50 in the presence of caffeine was reduced approximately 11-fold. The presented data suggest that 2-drug combinations of levetiracetam and nonsteroidal analgesics or caffeine could be useful in treatment of inflammatory pain. The efficacy and the adverse effects of those mixtures should be explored further in clinical settings. Copyright © 2013

Early add-on lacosamide in a real-life setting: results of the REALLY study.

PubMed

Villanueva, Vicente; Garcés, Mercedes; López-Gomáriz, Elena; Serratosa, José María; González-Giráldez, Beatriz; Parra, Jaime; Rodríguez-Uranga, Juan; Toledo, Manuel; López González, Francisco Javier; Bermejo, Pedro; Giner, Pau; Castillo, Ascensión; Molins, Albert; Campos, Dulce; Mauri, José Ángel; Muñoz, Rosario; Bonet, Macarena; Serrano-Castro, Pedro; del Villar, Ana; Saiz-Díaz, Rosa Ana

2015-02-01

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

In vitro antineoplastic effects of brivaracetam and lacosamide on human glioma cells.

PubMed

Rizzo, Ambra; Donzelli, Sara; Girgenti, Vita; Sacconi, Andrea; Vasco, Chiara; Salmaggi, Andrea; Blandino, Giovanni; Maschio, Marta; Ciusani, Emilio

2017-06-06

Epilepsy is a frequent symptom in patients with glioma. Although treatment with antiepileptic drugs is generally effective in controlling seizures, drug-resistant patients are not uncommon. Multidrug resistance proteins (MRPs) and P-gp are over-represented in brain tissue of patients with drug-resistant epilepsy, suggesting their involvement in the clearance of antiepileptic medications. In addition to their anticonvulsant action, some drugs have been documented for cytotoxic effects. Aim of this study was to evaluate possible in vitro cytotoxic effects of two new-generation antiepileptic drugs on a human glioma cell line U87MG. Cytotoxicity of brivaracetam and lacosamide was tested on U87MG, SW1783 and T98G by MTS assay. Expression of chemoresistance molecules was evaluated using flow cytometry in U87MG and human umbilical vein endothelial cells (HUVECs). To investigate the putative anti-proliferative effect, apoptosis assay, microRNA expression profile and study of cell cycle were performed. Brivaracetam and lacosamide showed a dose-dependent cytotoxic and anti-migratory effects. Cytotoxicity was not related to apoptosis. The exposure of glioma cells to brivaracetam and lacosamide resulted in the modulation of several microRNAs; particularly, the effect of miR-195-5p modulation seemed to affect cell cycle, while miR-107 seemed to be implicated in the inhibition of cells migration. Moreover, brivaracetam and lacosamide treatment did not modulate the expression of chemoresistance-related molecules MRPs1-3-5, GSTπ, P-gp on U87MG and HUVECs. Based on antineoplastic effect of brivaracetam and lacosamide on glioma cells, we assume that patients with glioma could benefit by the treatment with these two molecules, in addition to standard therapeutic options.

Effects of WIN 55,212-2 (a synthetic cannabinoid CB1 and CB2 receptor agonist) on the anticonvulsant activity of various novel antiepileptic drugs against 6 Hz-induced psychomotor seizures in mice.

PubMed

Florek-Luszczki, Magdalena; Wlaz, Aleksandra; Zagaja, Mirosław; Andres-Mach, Marta; Kondrat-Wrobel, Maria W; Luszczki, Jarogniew J

2015-03-01

The purpose of this study was to determine the influence of WIN 55,212-2 mesylate (WIN-a non-selective cannabinoid CB1 and CB2 receptor agonist) on the anticonvulsant activity of various second- and third-generation antiepileptic drugs (i.e., gabapentin, lacosamide, levetiracetam, oxcarbazepine, pregabalin and tiagabine) in the mouse 6 Hz-induced psychomotor seizure model. Psychomotor seizures were evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3s stimulus duration) delivered via ocular electrodes. Additionally, total brain antiepileptic drug concentrations were measured. Results indicate that WIN (5 mg/kg, administered i.p.) significantly potentiated the anticonvulsant action of gabapentin (P < 0.05) and levetiracetam (P < 0.01), but not that of lacosamide, oxcarbazepine, pregabalin or tiagabine in the mouse psychomotor seizure model. Moreover, WIN (2.5 mg/kg) had no significant effect on the anticonvulsant activity of all tested antiepileptic drugs in the 6 Hz test in mice. Measurement of total brain antiepileptic drug concentrations revealed that WIN (5 mg/kg) had no impact on gabapentin or levetiracetam total brain concentrations, indicating the pharmacodynamic nature of interaction between these antiepileptic drugs in the mouse 6Hz model. In conclusion, WIN in combination with gabapentin and levetiracetam exerts beneficial anticonvulsant pharmacodynamic interactions in the mouse psychomotor seizure model. Copyright © 2015 Elsevier Inc. All rights reserved.

The Acute and Chronic Effects of the Novel Anticonvulsant Lacosamide in an Experimental Model of Status Epilepticus

PubMed Central

Wasterlain, Claude G.; Stöhr, Thomas; Matagne, Alain

2011-01-01

The effective management of status epilepticus (SE) continues to be a therapeutic challenge. The aim of this study was to investigate the efficacy of lacosamide treatment in an experimental model of self-sustaining SE. Rats were treated with lacosamide (3, 10, 30 or 50 mg/kg) either 10 minutes (early treatment) or 40 minutes (late treatment) after the initiation of perforant path stimulation. Early lacosamide treatment significantly and dose-dependently reduced acute SE seizure activity; late treatment showed only a non-significant trend towards reduced seizure activity. Early lacosamide treatment also dose-dependently reduced the number of spontaneous recurrent seizures following a 6-week waiting period, with 70% reduction at the highest dose tested (50 mg/kg); there was also a significant reduction in the number of spikes and the cumulative time spent in seizures. Late treatment with high-dose lacosamide (30–50 mg/kg) reduced the number of animals that developed spontaneous recurrent seizures (33% vs 100% in controls, P <0.05), but did not significantly reduce seizure severity or frequency in rats that developed spontaneous recurrent seizures.. The results presented here suggest that lacosamide deserves investigation for the clinical treatment of SE. Potential for disease modification in this rat model of self-sustaining SE will require further studies. PMID:21277168

Effect of morphine and lacosamide on levels of dopamine and 5-HIAA in brain regions of rats with induced hypoglycemia.

PubMed

Guzman, D Calderon; Garcia, E Hernandez; Mejia, G Barragan; Olguin, H Juarez; Gonzalez, J A Saldivar; Labra Ruiz, N A

2014-01-15

The study aimed to determine the effect of morphine and lacosamide on levels of dopamine and 5-HIAA in a hypoglycemic model. Female Wistar rats (n = 30), mean weight of 180 g were treated as follow: Group 1 (control) received 0.9% NaCl, Group II; morphine (10 mg kg(-1)), Group III; lacosamide (10 mg kg(-1)), Group IV; insulin (10 U.I. per rat), Group V; morphine (10 mg kg(-1))+insulin, Group VI; lacosamide (10 mg kg(-1))+ insulin. All administrations were made intraperitoneally every 24 h, for 5 days. Animals were sacrificed after the last dose to measure the levels of glucose in blood; dopamine and 5-HIAA in cortex, hemispheres and cerebellum/medulla oblongata regions. Levels of glucose decreased significantly in animals treated with morphine, lacosamide and all groups that received insulin alone or combined with respect to control group. Levels of Dopamine diminished significantly in cortex and increased significantly in hemispheres of animals that received morphine. In cortex, 5-HIAA increase significantly in the groups treated with morphine, morphine+insulin and lacosamide+insulin, however a significant decrease of the same substance was witnessed in cerebellum and medulla oblongata of animals that received morphine or lacosamide plus insulin. GSH increased significantly in cortex and cerebellum/medulla oblongata of animals treated with morphine and lacosamide alone or combined with insulin. Lipid peroxidation decreased significantly in cortex and cerebellum/medulla oblongata of groups that received lacosamide alone or combined with insulin. These results indicate that hypoglycemia induced changes in cellular regulation while morphine and lacosamide are accompanied by biochemical responses.

Lacosamide derivatives with anticonvulsant activity as carbonic anhydrase inhibitors. Molecular modeling, docking and QSAR analysis.

PubMed

Garro Martinez, Juan C; Vega-Hissi, Esteban G; Andrada, Matías F; Duchowicz, Pablo R; Torrens, Francisco; Estrada, Mario R

2014-01-01

Lacosamide is an anticonvulsant drug which presents carbonic anhydrase inhibition. In this paper, we analyzed the apparent relationship between both activities performing a molecular modeling, docking and QSAR studies on 18 lacosamide derivatives with known anticonvulsant activity. Docking results suggested the zinc-binding site of carbonic anhydrase is a possible target of lacosamide and lacosamide derivatives making favorable Van der Waals interactions with Asn67, Gln92, Phe131 and Thr200. The mathematical models revealed a poor relationship between the anticonvulsant activity and molecular descriptors obtained from DFT and docking calculations. However, a QSAR model was developed using Dragon software descriptors. The statistic parameters of the model are: correlation coefficient, R=0.957 and standard deviation, S=0.162. Our results provide new valuable information regarding the relationship between both activities and contribute important insights into the essential molecular requirements for the anticonvulsant activity.

Levetiracetam: the preclinical profile of a new class of antiepileptic drugs?

PubMed

Klitgaard, H

2001-01-01

Levetiracetam is a new antiepileptic drug (AED) devoid of anticonvulsant activity in the two classic screening models for AEDs, the maximal electroshock and pentylenetetrazol seizure tests in both mice and rats. This contrasts a potent seizure suppression in genetic and kindled mice and rats and against chemoconvulsants inducing partial seizures in rats. The highly selective action in "epileptic" animals distinguishes levetiracetam from classic and other new AEDs that have nearly equipotent effects in normal and "epileptic" animals. Levetiracetam induces minor behavioral alterations in normal and in kindled mice and rats. This results in an unusually high safety margin in animal models reflecting both partial and primary generalized epilepsy. Furthermore, experiments in the kindling model suggest that levetiracetam may possess antiepileptogenic properties due to a potent ability to prevent the development of kindling in mice and rats at doses devoid of adverse effects. Electrophysiologic recordings from different experimental models suggest that levetiracetam exerts a selective action against abnormal patterns of neuronal activity, which probably explains its selective protection in epileptic animals and its unique tolerability. This effect appears to derive from one or more novel mechanisms of action that do not involve a conventional interaction with traditional drug targets implicated in the modulation of inhibitory and excitatory neurotransmission. Instead, ligand-binding assays have disclosed a brain-specific binding site for levetiracetam. These studies reveal a unique preclinical profile of levetiracetam, distinct from that of all known AEDs, suggesting that levetiracetam could represent the first agent in a new class of AEDs.

Cognitive and behavioral effects of new antiepileptic drugs in pediatric epilepsy.

PubMed

Moavero, Romina; Santarone, Marta Elena; Galasso, Cinzia; Curatolo, Paolo

2017-06-01

In pediatric epilepsy, neurodevelopmental comorbidities could be sometimes even more disabling than seizures themselves, therefore it is crucial for the clinicians to understand how to benefit these children, and to choose the proper antiepileptic drug for the treatment of epilepsy associated to a specific neurodevelopmental disorder. Aim of this paper is to discuss the potential impact on cognition and behavior of new and newest AEDs and to guide the choice of the clinicians for a targeted use in epilepsy associated with specific neurodevelopmental disorders. Information in this review is mainly based on peer-reviewed medical publications from 2002 until October 2016 (PubMed). We choose to include in our review only the AEDs of second and third generation approved for pediatric population. Vigabatrin, lamotrigine, topiramate, levetiracetam, oxcarbazepine, zonisamide, rufinamide, lacosamide, eslicarbazepine, and perampanel have been included in this review. The most tolerated AEDs from a cognitive and behavioral point of view are lamotrigine and rufinamide, thus representing optimal drugs for children with cognitive and/or attention problems. Most of the new AEDs are initially licensed for adult patients. Data on children are usually very limited, both in terms of efficacy and safety, and the use standardized cognitive and behavioral outcome measures are very limited in pediatric clinical trials. Several factors including polytherapy, administration of AEDs with the same mechanism of action and the dose and titration of the drug, should be considered as important in the development of cognitive and behavioral side effects. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Novel antiepileptic drug lacosamide exerts neuroprotective effects by decreasing glial activation in the hippocampus of a gerbil model of ischemic stroke

PubMed Central

AHN, JI YUN; YAN, BING CHUN; PARK, JOON HA; AHN, JI HYEON; LEE, DAE HWAN; KIM, IN HYE; CHO, JEONG-HWI; CHEN, BAI HUI; LEE, JAE-CHUL; CHO, YOUNG SHIN; SHIN, MYOUNG CHUL; CHO, JUN HWI; HONG, SEONGKWEON; WON, MOO-HO; KIM, SUNG KOO

2015-01-01

Lacosamide, which is a novel antiepileptic drug, has been reported to exert various additional therapeutic effects. The present study investigated the neuroprotective effects of lacosamide against transient cerebral ischemia-induced neuronal cell damage in the hippocampal cornu ammonis (CA)-1 region of a gerbil model. Neuronal Nuclei immunohistochemistry demonstrated that pre- and post-surgical treatment (5 min ischemia) with 25 mg/kg lacosamide protected CA1 pyramidal neurons in the lacosamide-treated-ischemia-operated group from ischemic injury 5 days post-ischemia, as compared with gerbils in the vehicle-treated-ischemia-operated group. Furthermore, treatment with 25 mg/kg lacosamide markedly attenuated the activation of astrocytes and microglia in the ischemic CA1 region at 5 days post-ischemia. The results of the present study suggested that pre- and post-surgical treatment of the gerbils with lacosamide was able to protect against transient cerebral ischemic injury-induced CA1 pyramidal neuronal cell death in the hippocampus. In addition, the neuroprotective effects of lacosamide may be associated with decreased activation of glial cells in the ischemic CA1 region. PMID:26668588

Novel antiepileptic drug lacosamide exerts neuroprotective effects by decreasing glial activation in the hippocampus of a gerbil model of ischemic stroke.

PubMed

Ahn, Ji Yun; Yan, Bing Chun; Park, Joon Ha; Ahn, Ji Hyeon; Lee, Dae Hwan; Kim, In Hye; Cho, Jeong-Hwi; Chen, Bai Hui; Lee, Jae-Chul; Cho, Young Shin; Shin, Myoung Chul; Cho, Jun Hwi; Hong, Seongkweon; Won, Moo-Ho; Kim, Sung Koo

2015-12-01

Lacosamide, which is a novel antiepileptic drug, has been reported to exert various additional therapeutic effects. The present study investigated the neuroprotective effects of lacosamide against transient cerebral ischemia-induced neuronal cell damage in the hippocampal cornu ammonis (CA)-1 region of a gerbil model. Neuronal Nuclei immunohistochemistry demonstrated that pre- and post-surgical treatment (5 min ischemia) with 25 mg/kg lacosamide protected CA1 pyramidal neurons in the lacosamide-treated-ischemia-operated group from ischemic injury 5 days post-ischemia, as compared with gerbils in the vehicle-treated-ischemia-operated group. Furthermore, treatment with 25 mg/kg lacosamide markedly attenuated the activation of astrocytes and microglia in the ischemic CA1 region at 5 days post-ischemia. The results of the present study suggested that pre- and post-surgical treatment of the gerbils with lacosamide was able to protect against transient cerebral ischemic injury-induced CA1 pyramidal neuronal cell death in the hippocampus. In addition, the neuroprotective effects of lacosamide may be associated with decreased activation of glial cells in the ischemic CA1 region.

Generic substitution of lamotrigine among medicaid patients with diverse indications: a cohort-crossover study.

PubMed

Hartung, Daniel M; Middleton, Luke; Svoboda, Leanne; McGregor, Jessina C

2012-08-01

Controversy exists about the safety of substituting generic antiepileptic drugs (AEDs). Lamotrigine, the prototypical newer AED, is often used for psychiatric and neurological conditions other than epilepsy. The safety of generic substitution of lamotrigine in diverse populations of AED users is unclear. The objective of this study was to evaluate potential associations between generic substitution of lamotrigine and adverse consequences in a population of diverse users of this drug. This study was a retrospective cohort-crossover design using state Medicaid claims data from July 2006 through June 2009. Subjects were included in the cohort if they converted from brand to generic lamotrigine and had 2 years of lamotrigine use prior to conversion. The frequency of emergency department (ED) visits, hospitalizations and condition-specific ED visits or hospitalizations were recorded in the 60 days immediately following the conversion to generic lamotrigine, then compared with the incidence of the same events during a randomly selected time period indexed to one of the patient's past refills of branded lamotrigine. Multivariate conditional logistic regression was used to quantify the association between generic conversion and health services utilization while controlling for changes in lamotrigine dose and concurrent drug use. Of the 616 unique subjects included in this analysis, epilepsy was the most common diagnosis (41%), followed by bipolar disorder (32%), pain (30%) and migraine (18%). Conversion to generic lamotrigine was not associated with a statistically significant increase in the odds of an ED visit (adjusted odds ratio [AOR] = 1.35; 95% confidence interval [CI] 0.92, 1.97), hospitalization (AOR = 1.21; 95% CI 0.60, 2.50) or condition-specific encounter (AOR 1.75; 95 CI 0.87, 3.51). A statistically significant increase in ED visits, hospitalizations or condition-specific encounters was not observed following the switch from brand to generic lamotrigine

Demonstration of ameliorative effect of lacosamide: in a rat model of sepsis-induced critical illness polyneuropathy.

PubMed

Solmaz, Volkan; Aksoy, Dürdane; Yılmaz, Mustafa; Eser, Enes; Erbas, Oytun

2015-09-01

Critical illness neuropathy (CIN) is a condition that may occur in diseases with severe systemic response, particularly in sepsis. The aim of this study is to investigate the potential anti-inflammatory and lipid-peroxidation inhibiting activities of lacosamide by measuring tumour necrotizing factor-alpha (TNF-alpha), C-reactive protein (CRP), malondialdehyde (MDA) and white blood cells (WBC) using electroneuromyography (ENMG) in rats with sepsis-induced critical illness neuropathy (SICIN). Cecal ligation and puncture (CLP) procedure was performed on 39 rats to induce a sepsis model. The study groups were designed as follows: Group 1: normal (nonoperative); Group 2: (sham-operated); Group 3: CLP (untreated group); Group 4: CLP and lacosamide 20 mg/kg; Group 5: CLP and lacosamide 40 mg/kg. TNF-alpha, C reactive protein, MDA and WBC levels was measured and compound muscle action potential (CMAP) distal latans, amplitudes were measured by using ENMG in rats with SICIN. When untreated sepsis group was compared with both control and sham groups, CMAP amplitudes and latans were significantly lower (P < 000.1). When CLP, CLP+lacosamide 20 mg/kg and CLP+lacosamide 40 mg/kg groups were compared, plasma levels of TNF-alpha and MDA were significantly higher in the untreated CLP group (F = 12.74, P < 0.0001), (F = 19.43, P < 0.05). In the CLP+lacosamide 40 mg/kg group, CRP levels were significantly lower only compared to the CLP group (P < 0.001). We have showed that lacosamide may have beneficial effects on early SICIN by its potential anti-inflammatory and lipid peroxidation inhibiting activities; however, further comprehensive studies are required to clarify these effects.

Control of seizures in different stages of partial epilepsy: LACO-EXP, a Spanish retrospective study of lacosamide.

PubMed

Villanueva, Vicente; López, Francisco Javier; Serratosa, José María; González-Giraldez, Beatriz; Campos, Dulce; Molins, Albert; Rodriguez Uranga, Juan; Mauri, José Angel; Salas-Puig, Javier; Toledo, Manuel; Sánchez-Alvarez, Juan Carlos; Moreno, Antonio; Serrano-Castro, Pedro J; Saiz-Diaz, Rosa Ana; González de la Aleja, Jesús; de la Peña, Pilar; Asensio, Montserrat

2013-11-01

Lacosamide is approved as adjunctive therapy for focal epilepsies. The number of antiepileptic drugs (AEDs) tried is associated with prognosis. This multicenter, retrospective, observational study (LACO-EXP) in Spain in 500 adult patients with focal epilepsies examined the efficacy and tolerability of add-on lacosamide. Factors associated with better efficacy/tolerability were analyzed. After 12months, the responder rate (≥50% reduction in seizure frequency) was 57.1%, and the seizure-free rate was 14.9%. Efficacy was better when lacosamide was the first or second add-on AED, although there was a small chance to be seizure-free even for patients who had received ≤10 prior AEDs. The mechanism of action of concomitant AEDs is important in all the stages, but differences are smaller in the early stages. Lacosamide was generally well tolerated. A slower dosage-titration schedule was associated with a lower adverse event rate. Further investigation of the timing of initiation of lacosamide add-on therapy and ideal combinations of AEDs is required. © 2013.

LAM study: Effects of lacosamide on behaviour and quality of life in patients with epilepsy.

PubMed

Alfaro, A; Asensio, M; García-Escrivá, A; Medrano, V; Salom, J M; Tortosa, D; Palao, S; Lezcano, M; Berenguer, L; Navarro, M; Cerdán, M; Buendía, J F; Giner, J C

2016-12-16

Psychiatric comorbidities are common in epileptic patients, and evaluating the impact of antiepileptic drugs on patients' moods is therefore essential. The aim of this study is to assess the effects of lacosamide on behaviour and quality of life in people with epilepsy. We conducted a multicentre prospective observational study of poorly-controlled epileptic patients who received lacosamide as an adjuvant treatment. Patients were evaluated on 4 occasions during a 12-month period. The impact of lacosamide on patients' mood and quality of life was assessed with the Quality of Life in Epilepsy Inventory-10 (QOLIE-10), the Hospital Anxiety and Depression Scale (HADS), and the Barratt Impulsiveness Scale (BIS-11). As a secondary objective, we evaluated the effectiveness and safety of lacosamide. We included 55 patients with a mean age of 47.1±18.4 years. At baseline, 34.5% of the patients had psychiatric comorbidities; the mean number of crises in the previous month was 3.6±4.3. The QOLIE-10 and HADS scales revealed statistically significant improvements in patients with a poor baseline condition (anxiety, depression, and/or poor quality of life). The BIS-11 scale detected no impulsive behaviour during follow-up. After 12 months of treatment, 51.9% of the patients were seizure-free and 77.8% experienced a reduction of at least 50% in seizure frequency. Adverse effects were mild in most cases; lacosamide was discontinued in 10 patients (18.2%). Lacosamide is a safe and effective treatment option for patients with epilepsy and psychiatric comorbidities. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Lacosamide inhibits calcitonin gene-related peptide production and release at trigeminal level in the rat.

PubMed

Greco, M C; Capuano, A; Navarra, P; Tringali, G

2016-07-01

Several classes of drugs are effective in prevention and treatment of migraine, although they may differ among each other in their mode of action and in indications. One such class is represented by antiepileptics. Lacosamide is an approved antiepileptic drug that also shows antinociceptive activity in animal models, including analgesic efficacy in central and trigeminal pain. Calcitonin gene-related peptide (CGRP) is considered the main neuro-mediator of trigeminal signalling, playing an essential role in headache, migraine in particular. Here, we investigated the effects of lacosamide on CGRP signalling in both in vitro and ex vivo/vitro models in the rat. We assessed: (1) CGRP released from brainstem explants at baseline or after pharmacological challenges; and (2) CGRP levels in brain areas after in vivo treatments with test drugs. We found that: (1) lacosamide inhibits CGRP release from brainstem explants under basal conditions as well as after stimulation by 56 mM KCl, 10 μM veratridine or 1 μM capsaicin; and (2) the i.p. administration of nitroglycerine produces an increase in CGRP levels in the brainstem and trigeminal ganglia, which is inhibited by a pre-treatment with lacosamide. These findings provide preliminary evidence suggesting that lacosamide is able to control pain transmission under conditions affecting the trigeminal system, such as migraine. © 2015 European Pain Federation - EFIC®

Lacosamide in patients with gliomas and uncontrolled seizures: results from an observational study.

PubMed

Rudà, Roberta; Pellerino, Alessia; Franchino, Federica; Bertolotti, Cinzia; Bruno, Francesco; Mo, Francesca; Migliore, Enrica; Ciccone, Gianni; Soffietti, Riccardo

2018-01-01

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.

Drug-drug interaction between methotrexate and levetiracetam resulting in delayed methotrexate elimination.

PubMed

Bain, Emily; Birhiray, Ruemu E; Reeves, David J

2014-02-01

To report a case of delayed methotrexate (MTX) elimination while receiving concomitant levetiracetam. A 46-year-old man with relapsed osteosarcoma of the base of the skull receiving high-dose MTX tolerated his first cycle of MTX with elimination to nontoxic MTX levels (≤0.1 µmol/L) within 90 hours. After hospital discharge, the patient experienced seizures secondary to brain metastasis and started on levetiracetam, which was continued as maintenance therapy. The patient experienced delayed MTX elimination during cycles 2, 3, and 4 while receiving levetiracetam. On average, elimination to nontoxic MTX levels took 130 hours (106-144 hours). Before the fifth cycle of MTX, lorazepam was substituted for the levetiracetam. MTX was eliminated to nontoxic levels within 95 hours. During all cycles, the patient received standard supportive care and serum creatinine remained stable. No other drugs known to interact with MTX were administered. This possible drug interaction has only been reported once in the pediatric population. With a score of 6 on the Drug Interaction Probability Scale for evaluating causation of drug interactions, it is probable that the delayed MTX elimination was caused by an interaction with levetiracetam. Coadministration of levetiracetam and MTX may result in delayed elimination of MTX, increasing the likelihood of toxicity. Consideration should be given to temporarily switching from levetiracetam to another antiepileptic (ie, lorazepam) to prevent this interaction. This is particularly important in those experiencing delayed elimination with prior cycles of concomitant MTX and levetiracetam or those at greater risk for MTX toxicity.

Clinical stabilisation with lacosamide of mood disorder comorbid with PTSD and fronto-temporal epilepsy.

PubMed

Cuomo, Ilaria; Kotzalidis, Georgios D; De Filippis, Sergio

2017-08-23

Mood disorders are often complicated by comorbidity with epilepsy. Anxiety and personality disorders may worsen prognosis and treatment outcome. Lacosamide has been recently introduced as adjunctive treatment for partial epilepsy. Its mechanism consists of selective slow inactivation of voltage-gated sodium channels, thus promoting an extended stabilisation of cell membranes. Antiepileptic drugs have been largely used since the 1950s in psychiatry as mood stabilisers due to their membrane stabilising and anti-kindling effects. Like lithium, antiepileptic drugs are first choice treatment for Bipolar and Cyclothymic Disorders. We tested the efficacy of the most recent antiepileptic medication, lacosamide, in a patient with simultaneously occurring cyclothymic disorder, severe post-traumatic stress disorder, and fronto-temporal epilepsy. Lacosamide was titrated up to 200 mg/day, added on ongoing 750 mg/day lithium, 15 mg/day oral aripiprazole then switched to 400 mg/month long-acting aripiprazole, and 2 mg/day N-desmethyldiazepam. We observed EEG normalisation one month later, along with reduced anxiety and an additive effect to lithium-induced stabilisation of mood fluctuations since the second week of lacosamide addition. Further studies with this drug in the bipolar spectrum are warranted.

Pancytopenia associated with levetiracetam in an epileptic woman.

PubMed

García Carretero, Rafael; Romero Brugera, Marta; Olid-Velilla, Monica; Salamanca-Ramirez, Inmaculada

2016-12-07

Haematological toxicity due to antiepileptic drugs is uncommon, but the increased risk of aplastic anaemia has been reported. Few case reports have been published regarding pancytopenia associated with levetiracetam treatment, and its intrinsic pathogenesis is still unknown. We describe the case of a woman aged 77 years who presented with abdominal pain and loss of appetite. She had been taking valproic acid, due to a previous episode of epileptic seizures, and presented with drowsiness and dizziness. Valproate was discontinued and therapy with levetiracetam was initiated. 2 days later, we observed severe anaemia, leucopenia and thrombocytopenia, which were attributed to levetiracetam. Although she recovered soon after the treatment was discontinued, it took 2 weeks for cell counts to return to normal. 2016 BMJ Publishing Group Ltd.

The Effect of Levetiracetam on Closure of the Midline in Early Chicken Embryos.

PubMed

Ozgural, Onur; Armagan, Ercan; Bozkurt, Melih; Eroglu, Umit; Kahilogullari, Gokmen; Unlu, Agahan

2015-01-01

Genetic predisposition and some environmental factors play an important role in the development of neural tube defects. Levetiracetam is a new drug that has been approved in the treatment of partial seizures. We aimed in this study to determine the effect of levetiracetam on chick embryos. One hundred and sixty fertile non-pathogenic Super Nick eggs were incubated for 24 hours and were divided into four groups of 40 eggs each. Levetiracetam was administered via the sub-blastodermic route. The eggs were incubated for another 24 hours. All eggs were opened at the 48th hour, and the embryos were evaluated morphologically and histopathologically. The effects of levetiracetam on the embryo were correlated with the dose of levetiracetam. In the light of the results, it was determined that the use of increasing doses of levetiracetam led to defects of midline closure in early chicken embryos. Levetiracetam, a new antiepileptic drug that is effective especially on calcium ion concentration, leads to defects in midline closure in embryos in a dose-dependent manner. Further studies are needed to show the mechanism of embryonic damage and the mechanisms of its teratogenous effects associated with genetic and environmental factors.

Influence of adjunctive lacosamide in patients with seizures: a systematic review and meta-analysis.

PubMed

Liu, Hongju; Xu, Xiaoli

2018-07-01

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.

Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

PubMed

Kanner, Andres M; Ashman, Eric; Gloss, David; Harden, Cynthia; Bourgeois, Blaise; Bautista, Jocelyn F; Abou-Khalil, Bassel; Burakgazi-Dalkilic, Evren; Llanas Park, Esmeralda; Stern, John; Hirtz, Deborah; Nespeca, Mark; Gidal, Barry; Faught, Edward; French, Jacqueline

2018-06-13

To update the 2004 American Academy of Neurology (AAN) guideline for treating new-onset focal or generalized epilepsy with second- and third-generation antiepileptic drugs (AEDs). The 2004 AAN criteria were used to systematically review literature (January 2003-November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength. Several second-generation AEDs are effective for new-onset focal epilepsy. Data are lacking on efficacy in new-onset generalized tonic-clonic seizures, juvenile myoclonic epilepsy, or juvenile absence epilepsy, and on efficacy of third-generation AEDs in new-onset epilepsy. Lamotrigine (LTG) should (Level B) and levetiracetam (LEV) and zonisamide (ZNS) may (Level C) be considered in decreasing seizure frequency in adults with new-onset focal epilepsy. LTG should (Level B) and gabapentin (GBP) may (Level C) be considered in decreasing seizure frequency in patients ≥60 years of age with new-onset focal epilepsy. Unless there are compelling adverse effect-related concerns, ethosuximide or valproic acid should be considered before LTG to decrease seizure frequency in treating absence seizures in childhood absence epilepsy (level B). No high-quality studies suggest clobazam, eslicarbazepine, ezogabine, felbamate, GBP, lacosamide, LEV, LTG, oxcarbazepine, perampanel, pregabalin, rufinamide, tiagabine, topiramate, vigabatrin, or ZNS is effective in treating new-onset epilepsy because no high-quality studies exist in adults of various ages. A recent Food and Drug Administration (FDA) strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years old and perampanel as monotherapy received FDA approval. © 2018 American Academy of Neurology.

Levetiracetam Reverses Synaptic Deficits Produced by Overexpression of SV2A

PubMed Central

Yao, Jia; Bleckert, Adam; Hill, Jessica; Bajjalieh, Sandra M.

2011-01-01

Levetiracetam is an FDA-approved drug used to treat epilepsy and other disorders of the nervous system. Although it is known that levetiracetam binds the synaptic vesicle protein SV2A, how drug binding affects synaptic functioning remains unknown. Here we report that levetiracetam reverses the effects of excess SV2A in autaptic hippocampal neurons. Expression of an SV2A-EGFP fusion protein produced a ∼1.5-fold increase in synaptic levels of SV2, and resulted in reduced synaptic release probability. The overexpression phenotype parallels that seen in neurons from SV2 knockout mice, which experience severe seizures. Overexpression of SV2A also increased synaptic levels of the calcium-sensor protein synaptotagmin, an SV2-binding protein whose stability and trafficking are regulated by SV2. Treatment with levetiracetam rescued normal neurotransmission and restored normal levels of SV2 and synaptotagmin at the synapse. These results indicate that changes in SV2 expression in either direction impact neurotransmission, and suggest that levetiracetam may modulate SV2 protein interactions. PMID:22220214

Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury

PubMed Central

Jones, Kristen E.; Puccio, Ava M.; Harshman, Kathy J.; Falcione, Bonnie; Benedict, Neal; Jankowitz, Brian T.; Stippler, Martina; Fischer, Michael; Sauber-Schatz, Erin K.; Fabio, Anthony; Darby, Joseph M.; Okonkwo, David O.

2013-01-01

Object Current standard of care for patients with severe traumatic brain injury (TBI) is prophylactic treatment with phenytoin for 7 days to decrease the risk of early posttraumatic seizures. Phenytoin alters drug metabolism, induces fever, and requires therapeutic-level monitoring. Alternatively, levetiracetam (Keppra) does not require serum monitoring or have significant pharmacokinetic interactions. In the current study, the authors compare the EEG findings in patients receiving phenytoin with those receiving levetiracetam monotherapy for seizure prophylaxis following severe TBI. Methods Data were prospectively collected in 32 cases in which patients received levetiracetam for the first 7 days after severe TBI and compared with data from a historical cohort of 41 cases in which patients received phenytoin monotherapy. Patients underwent 1-hour electroencephalographic (EEG) monitoring if they displayed persistent coma, decreased mental status, or clinical signs of seizures. The EEG results were grouped into normal and abnormal findings, with abnormal EEG findings further categorized as seizure activity or seizure tendency. Results Fifteen of 32 patients in the levetiracetam group warranted EEG monitoring. In 7 of these 15 cases the results were normal and in 8 abnormal; 1 patient had seizure activity, whereas 7 had seizure tendency. Twelve of 41 patients in the phenytoin group received EEG monitoring, with all results being normal. Patients treated with levetiracetam and phenytoin had equivalent incidence of seizure activity (p = 0.556). Patients receiving levetiracetam had a higher incidence of abnormal EEG findings (p = 0.003). Conclusions Levetiracetam is as effective as phenytoin in preventing early posttraumatic seizures but is associated with an increased seizure tendency on EEG analysis. PMID:18828701

Prospective, open-label trial measuring satisfaction and convenience of two formulations of lamotrigine in subjects with mood disorders.

PubMed

Sajatovic, Martha; Thompson, Thomas R; Nanry, Kevin; Edwards, Suzanne; Manjunath, Ranjani

2013-01-01

Lamotrigine is an anticonvulsant drug indicated for the maintenance treatment of bipolar I disorder and for various types of epilepsy. An orally disintegrating tablet (ODT) of lamotrigine was developed to provide a formulation option that might increase patient convenience and satisfaction. Subjects with mood disorders who reported difficulty swallowing currently prescribed lamotrigine immediate-release medication (baseline) were enrolled and treated with lamotrigine ODT for three weeks (end of treatment). Subject satisfaction and convenience were measured using the Treatment Satisfaction Questionnaire for Medication (TSQM). Also measured were global psychopathology using the Clinical Global Impression severity index (CGI-S) and depressive symptoms using the Beck Depression Inventory (BDI-II). Lamotrigine ODT was found to be significantly more convenient to use than lamotrigine immediate-release (change in baseline TSQM convenience score: 23.3, n = 97, P < 0.001). The mean TSQM global satisfaction score was similar at baseline (76.3) and after treatment with lamotrigine ODT (76.0). There were no significant changes on CGI-S and BDI-II. Subjects reported that lamotrigine ODT was significantly more convenient than lamotrigine immediate-release, while both formulations were associated with good satisfaction. Lamotrigine ODT may be a treatment option for patients who have difficulty swallowing medication.

Does a normalizing electroencephalogram in benign childhood epilepsy with centrotemporal spikes abort attention deficit hyperactivity disorder?

PubMed

Schneebaum-Sender, Nira; Goldberg-Stern, Hadassa; Fattal-Valevski, Aviva; Kramer, Uri

2012-10-01

This retrospective study delineated the efficacy of antiepileptic drugs in preventing the need for methylphenidate in patients with benign childhood epilepsy with centrotemporal spikes and attention deficit hyperactivity disorder. Seventeen patients were identified. A reduction of electroencephalogram pathologic activity by more than 50% was achieved in some patients with the antiepileptic drugs levetiracetam, sulthiame, lamotrigine, clobazam, and valproic acid. Complete normalization was achieved in two patients with sulthiame. Improvement in attention along with the reduction of pathologic electroencephalogram activity was observed in four patients, two with sulthiame, and one each with lamotrigine and levetiracetam (which was ceased because of suicidal tendencies). However, this improvement in attention was either temporary or not significant enough to discontinue methylphenidate. Methylphenidate was eventually prescribed to all patients. Copyright © 2012 Elsevier Inc. All rights reserved.

Efficacy of lacosamide in children and adolescents with drug-resistant epilepsy and refractory status epilepticus: A systematic review.

PubMed

Ortiz de la Rosa, Johann Sebastián; Ladino, Lady Diana; Rodríguez, Paula Juliana; Rueda, María Camila; Polanía, Juan Pablo; Castañeda, Angie Catalina

2018-03-01

Lacosamide, is one of the newer antiepileptic drug approved for focal drug-resistant epilepsy as an add-on treatment in patients older than 16 years. However, there is growing evidence of its use, safety and efficacy in children. We aim to evaluate efficacy and tolerability of lacosamide in focal and generalized drug-resistant epilepsy and refractory status epilepticus in the pediatric population. We conducted a systematic review on MEDLINE, EMBASE, COCHRANE, Google Scholar and Scielo from January 2008 to January 2017. The primary outcome was the efficacy of lacosamide in children with drug-resistant epilepsy and refractory status epilepticus. Efficacy and adverse events attributed to lacosamide were extracted from each publication and systematically reported. We performed no meta-analyses due to limited available data. Of 175 abstracts identified by the search, 82 were reviewed as full-text. Twenty-six articles fulfilled eligibility criteria and described outcomes in 797 patients (57% male). The majority of studies were retrospective (69%) small series (84%). On average 51% of patients had 50% or greater seizure reduction. The mean seizure freedom rate was 24%. Adverse effects occurred in 18-59% of patients. The main events were dizziness, sedation, gastrointestinal upset, mood and behavioral changes. Half of the patients with Lennox Gastaut syndrome showed 50% or greater seizure reduction, 32% did not response to lacosamide and 17% suffered seizure aggravation. Current evidence shows lacosamide as a good option in pediatric patients with focal drug-resistant epilepsy and refractory status epilepticus as an add-on therapy given its efficacy on seizure control and safety profile. The use of lacosamide in Lennox-Gastaut syndrome shows conflicting data. Large randomized controlled studies in the pediatric population are necessary to substantiate these findings. Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Variation in dose and plasma level of lamotrigine in patients discharged from a mental health trust.

PubMed

Douglas-Hall, Petrina; Dzahini, Olubanke; Gaughran, Fiona; Bile, Ahmed; Taylor, David

2017-01-01

The objectives of this study were to investigate the dose of lamotrigine when prescribed with an enzyme inhibitor or enzyme inducer in patients discharged from a mental health trust and to determine the corresponding lamotrigine plasma concentrations and the factors that may affect these. All patients discharged on lamotrigine between October 2007 and September 2012 were identified using the pharmacy dispensing database. We recorded demographic details, lamotrigine dose and plasma levels and coprescribed medication. During the designated period, 187 patients were discharged on lamotrigine of whom 117 had their plasma levels recorded. The mean lamotrigine daily dose was 226.1 mg (range 12.5-800 mg) and the mean plasma level 5.9 mg/l (range 0.8-18.1 mg/l). Gender, ethnicity, diagnosis and smoking status had no significant effect on dose or plasma levels. Patients taking an enzyme-inducing drug ( n = 6) had significantly lower plasma levels [mean (SD) 3.40 (1.54) mg/l] than those not taking enzyme inducers [ n = 111; 6.03 (3.13) mg/l; p = 0.043]. Patients taking an enzyme-inhibiting drug ( n = 23) had significantly higher levels [7.47 (3.99) mg/l] than those not taking an inhibitor [ n = 94; 5.52 (2.75) mg/l; p = 0.035]. No significant difference was found between the doses of lamotrigine in patients taking an enzyme inhibitor and those not taking one ( p = 0.376). No significant difference was found between the doses of lamotrigine in patients taking an enzyme-inducing drug and those not taking any ( p = 0.574). Current dosing recommendations indicate that lamotrigine doses should be halved in individuals taking enzyme inhibitors and doubled in those on enzyme inducers. In our survey these recommendations were rarely followed with the consequence that patients received too high or too low a dose of lamotrigine, respectively.

Benefit of combination therapy in epilepsy: a review of the preclinical evidence with levetiracetam.

PubMed

Kaminski, Rafal M; Matagne, Alain; Patsalos, Philip N; Klitgaard, Henrik

2009-03-01

Levetiracetam (Keppra) is an antiepileptic drug (AED) characterized by a novel mechanism of action, unique profile of activity in seizure models, and broad-spectrum clinical efficacy. The present report critically reviews several preclinical studies focused on combination therapy with levetiracetam and other anticonvulsants in various seizure and epilepsy models. Administration of levetiracetam together with many different clinically used AEDs or other anticonvulsants generally enhances their protective activity and, among existing AEDs, this was particularly prevalent with valproate. The protective activity of other AEDs was also enhanced by levetiracetam, which seems to be a universal finding that is independent of seizure model or drug combination studied. However, particularly strong enhancement was observed when levetiracetam was combined with agents either enhancing GABAergic or reducing glutamatergic neurotransmission. Importantly, these combinations were not associated with exacerbation of side effects or pharmacokinetic interactions. Based on the available preclinical data, it appears that combination treatment with levetiracetam and other anticonvulsants provides additional therapeutic benefit that may be attributed to its novel and distinct mechanism of action. Moreover, combinations of levetiracetam with clinically used AEDs that enhance GABAergic inhibition may be considered for rational polytherapy, which is often necessary in drug-resistant patients.

Efficacy and tolerability of lacosamide as an adjunctive therapy in children with refractory partial epilepsy.

PubMed

Pasha, Ismail; Kamate, Mahesh; Didagi, Suresh K

2014-10-01

A unicentre, prospective study was performed to investigate the efficacy of lacosamide as adjunctive therapy in children with refractory partial epilepsy. The study was performed at a tertiary care hospital over a period of 30 months between November 2011 and May 2014. Seventy-nine children with refractory partial epilepsy (age 5-15 years) who had failed two or more antiepileptic drugs and in whom lacosamide was used as an add-on drug were enrolled. Lacosamide tablets were administered orally, at a dose of 25 mg for 1 week followed by 50 mg twice daily for the remaining period. Efficacy and tolerability evaluation was performed at every visit of titration, maintenance period (3 months), and two follow-up visits at monthly interval. Electrocardiogram and liver function tests were performed before enrollment and at the end of 3 months of lacosamide therapy. Patient's caregiver or investigator observed adverse events were recorded in a predesigned pro forma. A total of 79 patients with uncontrolled partial epilepsy screened from 531 epileptic children were enrolled, after they satisfied the inclusion and exclusion criteria. The mean age of children enrolled was 8.8 ± 3.1 years (range 5-15 years); 53 children (67.0%) were boys. Mean weight of the patients was 24.2 ± 9.8 kg. The mean age at the onset of seizures was 6.4 ± 3.5 years. The mean dose of lacosamide administered was 4.1 mg/kg. Three patients (3.8%) dropped out of the study, because of vomiting, aggressive behavior, and poor response, respectively. Of 76 patients (96.2%) entering the maintenance period, 35 patients (44.3%) were seizure free, 32 patients (40.6%) indicated ≥50% reduction in seizure frequency, 3 patients (3.8%) indicated 25-49% seizure reduction, and 9 patients (11.4%) either had no change in seizure frequency or experience increase in seizure frequency. Lacosamide is an effective add-on antiepileptic drug for children with refractory partial epilepsy and is well tolerated. Copyright © 2014

Pharmacodynamic and pharmacokinetic evaluation of coadministration of lacosamide and an oral contraceptive (levonorgestrel plus ethinylestradiol) in healthy female volunteers.

PubMed

Cawello, Willi; Rosenkranz, Bernd; Schmid, Bernhard; Wierich, Werner

2013-03-01

To determine whether the antiepileptic drug lacosamide affects the pharmacokinetics or pharmacodynamics of a combined oral contraceptive (OC; ethinylestradiol 0.03 mg plus levonorgestrel 0.15 mg). This was an open-label trial in healthy female volunteers. Eligible women entered cycle 1 of the trial on the first day of menstruation. Cycle 1 was a medication-free, run-in phase of approximately 28 days to confirm that normal ovulation occurred. Volunteers with confirmed ovulation entered the subsequent cycle and started taking OCs. After establishing ovulation suppression (defined as progesterone serum concentration <5.1 nm on day 21 of the menstrual cycle) in volunteers taking the OCs in cycle 2, lacosamide 400 mg/day was administered concomitantly in the subsequent cycle (cycle 3). The pharmacokinetic parameters of area under the concentration-time curve (AUC), maximum steady-state plasma drug concentration (Cmax ), and time to maximum concentration (tmax ) were measured for the OC components and lacosamide. A total of 37 volunteers completed cycle 1, and 32 completed cycle 2. In each of the 31 volunteers who completed the trial (through cycle 3), pharmacodynamic assessment showed progesterone serum concentration was <5.1 nm on day 21 of cycle 2, when the OC was administered alone, and on day 21 of cycle 3, when lacosamide was administered concomitantly. The AUC of ethinylestradiol alone versus together with lacosamide was 1,067 ± 404 versus 1,173 ± 330 pg h/ml. Corresponding values of Cmax were 116.9 ± 48.8 versus 135.7 ± 28.6 pg/ml. For levonorgestrel, the AUC alone was 74.2 ± 21.4 versus 80.9 ± 18.5 ng h/ml with lacosamide. Corresponding values of Cmax were 6.7 ± 1.9 versus 7.4 ± 1.5 ng/ml. The AUC and Cmax point estimates and almost all 90% confidence intervals (except for Cmax of ethinylestradiol) for ethinylestradiol and levonorgestrel (with and without lacosamide) were within the conventional bioequivalence range, and no

Effect of age and sex on lacosamide pharmacokinetics in healthy adult subjects and adults with focal epilepsy.

PubMed

Schaefer, Carina; Cawello, Willi; Waitzinger, Josef; Elshoff, Jan-Peer

2015-04-01

Age- and sex-related differences in body composition could affect the pharmacokinetic parameters of administered drugs. The purpose of this post hoc analysis was to investigate the influences of age and sex on the pharmacokinetics of lacosamide. This post hoc analysis used pharmacokinetic data taken at steady state from (i) two phase I studies of oral lacosamide in healthy adult subjects (n = 66), and (ii) a population pharmacokinetic analysis carried out using data from two phase III studies of adjunctive oral lacosamide in adults (n = 565) with focal epilepsy taking 1-3 concomitant anti-epileptic drugs. Phase I data were stratified by age and sex as 'younger female' (aged 18-40 years), 'younger male' (aged 18-45 years) or 'elderly male/female' (aged ≥65 years), then normalized by body weight (lean body weight or fat-free mass), height or volume of distribution, and analysed using non-compartmental analysis. Population pharmacokinetic data were stratified by sex and analysed using a one-compartment model. Minor numerical differences between lacosamide exposure [the area under the concentration-time curve at steady state over the dosage interval (AUCτ,ss)] and the maximum plasma concentration at steady state (C max,ss) in subjects of different ages or sexes were noted. The differences could be explained by a scaling factor between the drug applied and the plasma concentration. Following normalization by lean body weight or volume of distribution, an analysis of relative bioavailability resulted in 90 % confidence intervals of the ratios for AUCτ,ss and C max,ss for age (elderly to younger) or sex (male to female) falling within the range accepted for equivalence (80-125 %); without normalization, the 90 % confidence intervals were outside this range. Minor numerical differences in lacosamide plasma concentrations were noted in the comparison between male and female patients (aged 16-71 years) with focal epilepsy. Simulations using different body weights

Antinociceptive efficacy of lacosamide in the monosodium iodoacetate rat model for osteoarthritis pain

PubMed Central

Beyreuther, Bettina; Callizot, Noëlle; Stöhr, Thomas

2007-01-01

The etiology of osteoarthritis is multifactorial, with inflammatory, metabolic, and mechanical causes. Pain in osteoarthritis is initiated by mild intra-articular inflammation and degeneration of articular cartilage and subchondral bone. The principle of treatment with acetaminophen or non-steroidal anti-inflammatory drugs is to reduce pain and improve joint function. Recently, animal models for osteoarthritic pain behavior have been established. The most frequently used rat model for analyzing properties of drugs on the pathology of osteoarthritis is the injection of the metabolic inhibitor monosodium iodoacetate into the joint, which inhibits the activity of glyceraldehyde-3-phosphate dehydrogenase in chondrocytes. Here, we characterize the effect on pain behavior of lacosamide, a member of a family of functionalized amino acids that are analogues of endogenous amino acids and D-serine, in the monosodium iodoacetate rat model for osteoarthritis in comparison to diclofenac and morphine. Lacosamide (3, 10, and 30 mg/kg) was able to reduce secondary mechanical allodynia and hyperalgesia similarly to morphine (3 mg/kg). In contrast, diclofenac (30 mg/kg) was only effective in reducing secondary mechanical hyperalgesia. During the first week, pain is induced mainly by inflammation in the iodoacetate model, but afterwards inflammation plays only a minor role in pain. Lacosamide was able to inhibit pain at days 3, 7 and 14 after induction of arthritis. This shows that lacosamide is able to reduce pain behavior induced by multiple mechanisms in animals. PMID:17284318

Concerns regarding lamotrigine and breast-feeding.

PubMed

Liporace, Joyce; Kao, Amy; D'Abreu, Anelyssa

2004-02-01

Many women with epilepsy who are planning a pregnancy are treated with lamotrigine (LTG), resulting in greater fetal exposure to the drug. Current care guidelines suggest that mothers with epilepsy breast-feed their children. These recommendations are made without regard to how nursing newborns metabolize medication. Lamotrigine is extensively metabolized by glucuronidation, which is immature in neonates and may lead to accumulation of medication. This article reports LTG levels in full-term nursing newborns born to mothers with epilepsy on lamotrigine monotherapy. Serum LTG levels were obtained in nursing mothers and their neonates on Day 10 of life. Maternal LTG clearance during pregnancy and postpartum was determined and correlated with levels. Four mothers with partial epilepsy on LTG monotherapy were evaluated. Serum LTG levels in nursing newborns ranged from <1.0 to 2.0 microg/mL on Day 10 of life. Three babies had LTG levels >1.0 microg/mL. After excluding one child with an undetectable level, the LTG levels in newborns were on average 30% (range 20-43%) of the maternal drug level. No decline was noted in two children with repeat levels at 2 months. Serum concentrations of LTG in breast-fed children were higher than expected, in some cases reaching "therapeutic" ranges. These high levels may be explained by poor neonatal drug elimination due to inefficient glucuronidation. Our observation that not all newborns had a high LTG level suggests considerable genetic variability in metabolism. Our limited data suggest monitoring blood levels in nursing children and the need for individual counseling for women with epilepsy regarding breast-feeding.

Lamotrigine rechallenge after a skin rash. A combined study of open cases and a meta-analysis.

PubMed

Serrani Azcurra, Daniel J L

2013-01-01

To determine the safety of lamotrigine rechallenge after a first episode of skin rash in bipolar patients. An open cases prospective study was conducted with patients who, developed a skin rash when first treated with lamotrigine, were refractory to other treatments, and were offered lamotrigine rechallenge using a different dose titration. Additionally a review was performed on previous skin rash management strategies and lamotrigine rechallenge reports. Every 3 out of 10 lamotrigine rechallenge patients required drug interruption due to persistent rash. One of them was potentially serious and resolved by stopping the lamotrigine. The review of available literature identified several lamotrigine rechallenge studies with rates of positive results varying between 70% and 87% depending on the study. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis after rechallenge. The rate of rash was higher when rechallenge began between 4 weeks from initial rash (19% vs. 7%, P=.001) and decreased when first rash showed no potentially serious signs (0% vs.19%, P=.01). Rechallenge is a viable option after a benign lamotrigine-induced rash, and can even be rechallenged after rash with greater precautions when there exists one or two potentially serious signs. In cases of more serious rash there are no reliable data available on rechallenge safety and it may pose a significant risk. In those cases rechallenge should better be avoided between 4 weeks from first rash. Copyright © 2011 SEP y SEPB. Published by Elsevier Espana. All rights reserved.

Effects of lacosamide and carbamazepine on human motor cortex excitability: a double-blind, placebo-controlled transcranial magnetic stimulation study.

PubMed

Lang, Nicolas; Rothkegel, Holger; Peckolt, Hannes; Deuschl, Günther

2013-11-01

Lacosamide (LCM) and carbamazepine (CBZ) are antiepileptic drugs both acting on neuronal voltage-gated sodium channels. Patch-clamp studies demonstrated significant differences in how LCM and CBZ affect neuronal membrane excitability. Despite valuable information patch-clamp studies provide, they also comprise some constraints. For example, little is known about effects of LCM on intracortical synaptic excitability. In contrast, transcranial magnetic stimulation (TMS) can describe drug-induced changes at the system level of the human cerebral cortex. The present study was designed to explore dose-depended effects of LCM and effects of CBZ on motor cortex excitability with TMS in a randomized, double-blind, placebo-controlled crossover trial in healthy human subjects. Subjects received 600 mg CBZ, 200 mg LCM, 400 mg LCM or placebo preceding TMS measurements. Compared to placebo, TMS motor thresholds were significantly increased after carbamazepine and lacosamide, with a trend for a dose dependent effect of lacosamide. Both, carbamazepine and lacosamide did not affect TMS parameters of intracortical synaptic excitability. TMS measurements suggest that lacosamide and carbamazepine predominantly act on neuronal membrane excitability. Copyright © 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

The economic consequences of generic substitution for antiepileptic drugs in a public payer setting: the case of lamotrigine.

PubMed

Duh, Mei Sheng; Andermann, Frederick; Paradis, Pierre Emmanuel; Weiner, Jennifer; Manjunath, Ranjani; Crémieux, Pierre-Yves

2007-08-01

Generic substitution of antiepileptic drugs (AEDs) may increase pharmacy utilization, thus counterbalancing per-pill savings. The purpose of our study was to analyze the economic impact of government-mandated switching from branded to generic lamotrigine. Patients in a Canadian public pharmacy claims database using branded lamotrigine (Lamictal GlaxoSmithKline, UK) in 2002 converted to generic lamotrigine in 2003 and were observed from July 2002 to March 2006. Patients used branded lamotrigine for >or=90 days pre-generic entry and had >or=1 claim for generic lamotrigine post-generic entry. For the generic period, observed per-patient monthly drug costs were calculated as the sum of costs for lamotrigine, other AEDs, and non-AEDs. Expected per-patient drug costs were estimated assuming lamotrigine dose and other prescription drug utilization in the generic period were identical to those observed during the brand period. Differences between observed and expected costs were compared. Among 1,142 branded lamotrigine users, overall average monthly drug costs per person were expected to decrease by $30.55 due to lower pill costs. Instead, they fell by $11.98 from the brand to the generic periods (p < 0.001). Because of dosage changes, lamotrigine costs decreased by $29.92 instead of the anticipated $33.87 (p < 0.001). Increased pharmacy utilization caused other AED costs to rise by $6.29 versus the expected $0.36 (p < 0.001), while non-AED drug cost increased by $11.64 rather than by $2.95 (p < 0.001). We concluded that conversion to generic lamotrigine resulted in lower than expected cost savings. Further research is necessary to determine whether this is due to reduced effectiveness and/or tolerability. Payers may weigh smaller-than-expected cost reductions against a possible decrease in effectiveness to assess the relevance of mandatory generic switching of lamotrigine.

A system of equations to approximate the pharmacokinetic parameters of lacosamide at steady state from one plasma sample.

PubMed

Cawello, Willi; Schäfer, Carina

2014-08-01

Frequent plasma sampling to monitor pharmacokinetic (PK) profile of antiepileptic drugs (AEDs), is invasive, costly and time consuming. For drugs with a well-defined PK profile, such as AED lacosamide, equations can accurately approximate PK parameters from one steady-state plasma sample. Equations were derived to approximate steady-state peak and trough lacosamide plasma concentrations (Cpeak,ss and Ctrough,ss, respectively) and area under concentration-time curve during dosing interval (AUCτ,ss) from one plasma sample. Lacosamide (ka: ∼2 h(-1); ke: ∼0.05 h(-1), corresponding to half-life of 13 h) was calculated to reach Cpeak,ss after ∼1 h (tmax,ss). Equations were validated by comparing approximations to reference PK parameters obtained from single plasma samples drawn 3-12h following lacosamide administration, using data from double-blind, placebo-controlled, parallel-group PK study. Values of relative bias (accuracy) between -15% and +15%, and root mean square error (RMSE) values≤15% (precision) were considered acceptable for validation. Thirty-five healthy subjects (12 young males; 11 elderly males, 12 elderly females) received lacosamide 100mg/day for 4.5 days. Equation-derived PK values were compared to reference mean Cpeak,ss, Ctrough,ss and AUCτ,ss values. Equation-derived PK data had a precision of 6.2% and accuracy of -8.0%, 2.9%, and -0.11%, respectively. Equation-derived versus reference PK values for individual samples obtained 3-12h after lacosamide administration showed correlation (R2) range of 0.88-0.97 for AUCτ,ss. Correlation range for Cpeak,ss and Ctrough,ss was 0.65-0.87. Error analyses for individual sample comparisons were independent of time. Derived equations approximated lacosamide Cpeak,ss, Ctrough,ss and AUCτ,ss using one steady-state plasma sample within validation range. Approximated PK parameters were within accepted validation criteria when compared to reference PK values. Copyright © 2014 Elsevier B.V. All rights

Levetiracetam in Absence Epilepsy

ERIC Educational Resources Information Center

Verrotti, Alberto; Cerminara, Caterina; Domizio, Sergio; Mohn, Angelika; Franzoni, Emilio; Coppola, Giangennaro; Zamponi, Nelia; Parisi, Pasquale; Iannetti, Paola; Curatolo, Paolo

2008-01-01

The aim of the study was to assess the efficacy, tolerability, and safety of levetiracetam therapy in children and adolescents with absence epilepsy. Twenty-one participants (11 male, 10 female) with typical absence seizures were enrolled in this prospective study from seven centres in Italy. The mean age and age range at time of enrolment into…

Marked EEG worsening following Levetiracetam overdose: How a pharmacological issue can confound coma prognosis.

PubMed

Bouchier, Baptiste; Demarquay, Geneviève; Guérin, Claude; André-Obadia, Nathalie; Gobert, Florent

2017-01-01

Levetiracetam is an anti-epileptic drug commonly used in intensive care when seizure is suspected as a possible cause of coma. We propose to question the cofounding effect of Levetiracetam during the prognostication process in a case of anoxic coma. We report the story of a young woman presenting a comatose state following a hypoxic cardiac arrest. After a first EEG presenting an intermediate EEG pattern, a seizure suspicion led to prescribe Levetiracetam. The EEG showed then the appearance of burst suppression, which was compatible with a very severe pattern of post-anoxic coma. This aggravation was in fact related to an overdose of Levetiracetam (the only medication introduced recently) and was reversible after Levetiracetam cessation. The increased plasmatic dosages of Levetiracetam confirming this overdose could have been favoured by a moderate reduction of renal clearance, previously underestimated because of a low body-weight. This EEG dynamic was unexpected under Levetiracetam and could sign a functional instability after anoxia. Burst suppression is classically observed with high doses of anaesthetics, but is not expected after a minor anti-epileptic drug. This report proposes that Levetiracetam tolerance might not be straightforward after brain lesions and engages us to avoid confounding factors during the awakening prognostication, which is mainly based on the severity of the EEG. Hence, prognosis should not be decided on an isolated parameter, especially if the dynamic is atypical after a new prescription, even for well-known drugs. For any suspicion, the drug's dosage and replacement should be managed before any premature care's withdrawal. Copyright © 2016 Elsevier B.V. All rights reserved.

Seizures in Pediatric Patients With Liver Transplant and Efficacy of Levetiracetam.

PubMed

Kılıç, Betül; Güngör, Serdal; Arslan, Müjgan; Selimoğlu, Mukadder Ayşe; Yılmaz, Sezai

2017-07-01

The aim of this study was to evaluate the risk factors, clinical implications, and prognosis of new-onset seizures that occurred after pediatric liver transplantation, and to assess the efficacy of levetiracetam treatment. The clinical and laboratory data of liver transplanted 28 children who had seizures after liver transplantation and specifically of 18 children who received levetiracetam were analyzed retrospectively. Sixteen patients (88.9%) remained seizure-free and in 2 (11.1%), more than 50% reduction in seizures were detected with levetiracetam treatment. In conclusion, seizures are generally the most common complication by a spectrum of seizure types, and sometimes cause symptomatic epilepsy. The most common risk factors for seizures in transplant recipients is immunosuppressant toxicity. Currently, there isn't a specific treatment involving the transplant patient population. Levetiracetam may be preferable in pediatric patients as it's reliable for liver disease and has advantages in the treatment of postoperative seizures due to its intravenous usage.

Adjunctive levetiracetam treatment in pediatric Lennox-Gastaut syndrome.

PubMed

Kim, Hyo Jeong; Kim, Shin Hye; Kang, Hoon-Chul; Lee, Joon Soo; Chung, Hee Jung; Kim, Heung Dong

2014-10-01

Our aim was to investigate the efficacy and tolerability of levetiracetam as an add-on treatment in pediatric patients with Lennox-Gastaut syndrome. The study was an open-label, multicenter, observational clinical trial of levetiracetam as an add-on treatment in Lennox-Gastaut syndrome. Fifty-five patients aged 1.1-18.6 years (mean, 10.0 years) were enrolled. The study included a 4-8-week titration period and an 8-week maintenance period. The maintenance dose of levetiracetam was 20-80 mg/kg/day, according to its effectiveness and tolerability. The primary end point was reduction in seizure frequency, and related variables were also evaluated. Among 55 patents, 51 patients (92.7%) completed the study. Thirty-two patients (58.2%) experienced a more than 50% reduction in seizure frequency, and 15 patients (27.3%) became seizure free. A reduction in seizure frequency of more than 50% was observed in 21 of 36 patients (58.3%) with convulsive seizures, 7 of 12 patients (58.3%) with drop attacks, 2 of 4 patients (50.0%) with myoclonic seizures, and 2 of 3 patients (66.7%) with epileptic spasms. Overall, 34.5% of patients reported adverse events. None of the adverse events were life threatening, and the most common adverse event was hyperactivity (12.7%). This study suggests that levetiracetam is a safe and effective treatment in pediatric patients with Lennox-Gastaut syndrome. Copyright © 2014 Elsevier Inc. All rights reserved.

Benefit-risk assessment of levetiracetam in the treatment of partial seizures.

PubMed

Abou-Khalil, Bassel

2005-01-01

Levetiracetam is a novel antiepileptic drug that has been demonstrated as being effective in the management of partial seizures. It is rapidly and completely absorbed after oral administration and it is predominantly eliminated as unchanged drug in the urine. Its metabolism is independent of the cytochrome P450 enzyme system, nor does it induce cytochrome P450 enzymes. As a result of its pharmacokinetic features, levetiracetam has not been demonstrated to interact with other drugs in either direction. In double-blind, placebo-controlled trials, all the levetiracetam dosages tested were effective, including 1000 mg/day, 2000 mg/day and 3000 mg/day. The ineffective dose is not known. Efficacy seemed to be maintained in long-term studies, with no evidence of tolerance. In major double-blind, placebo-controlled trials discontinuation rates because of adverse events were 6.9-10.9% for levetiracetam-treated patients (all doses) compared with 5.3-8.6% for placebo-treated patients. The most common adverse events that differed between treatment groups and placebo control groups were somnolence, asthenia, dizziness and, in the US study, infection. Since levetiracetam was marketed, behavioural effects have been reported, namely irritability, agitation, anger and aggressive behaviour. These adverse effects are more likely in learning disabled individuals, those with prior psychiatric history and those with symptomatic generalised epilepsy. Overall, the risk has been estimated at 12-15%. Laboratory parameters overall seem to be not significantly affected by levetiracetam, although slight trends to lower white and red blood cell counts were detected in the studies. No organ toxicity has been described so far, with patient exposures exceeding 500,000. In summary, levetiracetam exhibits a very favourable safety profile in patients with partial onset seizures. Whereas somnolence, asthenia and dizziness were the most prominent adverse effects in clinical trials, behavioural adverse

Probable levetiracetam-related serum alkaline phosphatase elevation

PubMed Central

2012-01-01

Background Levetiracetam (LEV) is an antiepileptic drug with a favorable tolerability and safety profile with little or no effect on liver function. Case presentation Here, we reported an epileptic pediatric patient who developed a significant elevation in serum alkaline phosphatase level (ALP) during LEV monotherapy. Moreover, the serum ALP level was surprisingly decreased to normal after LEV discontinuation. The Naranjo Adverse Drug Reaction Probability Scale score was 6, indicating firstly LEV was a probable cause for the increased serum ALP. Conclusions Cautious usage and concerns of the LEV-associated potential ALP elevation should be considered when levetiracetam is prescribed to epilepsy patients, especially pediatric patients. PMID:22994584

Use of levetiracetam to treat tics in children and adolescents with Tourette syndrome.

PubMed

Awaad, Yasser; Michon, Anne Marie; Minarik, Sarah

2005-06-01

Some drugs currently used to treat tics in pediatric patients have drawbacks, including the risk of side effects. New therapeutic options with better safety profiles are needed. Levetiracetam is an antiepileptic drug with atypical mechanisms of action that might be beneficial for this indication. We evaluated the effects of levetiracetam on motor and vocal tics, behavior, and school performance in children and adolescents with tics and Tourette syndrome (TS). Sixty patients, < or =18 years of age, with tics and TS were enrolled in this prospective, open-label study. The initial starting dose of levetiracetam was 250 mg/day. The dosage was titrated over 3 weeks to 1,000 to 2,000 mg/day. Clinical outcomes were assessed with the Clinical Global Impression Scale, Yale Global Tic Severity Scale, and Revised Conners' Parent Rating Scale. Behavior and school performance were also recorded. All 60 patients showed improvements based on all of the scales used, and 43 patients improved with regard to behavior and school performance. Levetiracetam was generally well tolerated. Three patients discontinued treatment because of exaggeration of preexisting behavioral problems. Levetiracetam may be useful in treating tics in children and adolescents. Given its established safety profile, levetiracetam is a candidate for evaluation in a well-controlled trial. (c) 2005 Movement Disorder Society.

Occurrence and fate of amisulpride, sulpiride, and lamotrigine in municipal wastewater treatment plants with biological treatment and ozonation.

PubMed

Bollmann, Anna Franka; Seitz, Wolfram; Prasse, Carsten; Lucke, Thomas; Schulz, Wolfgang; Ternes, Thomas

2016-12-15

This study examines the transformation and removal of the atypical antipsychotics amisulpride and sulpiride and the anticonvulsant lamotrigine in municipal wastewater treatment plants (WWTPs). Amisulpride, sulpiride and lamotrigine were selected using a tailored non-target screening approach. In WWTPs, lamotrigine concentrations increased from 1.1 to 1.6μg/L while sulpiride and amisulpride exhibited similar concentrations, up to 1.1μg/L and 1.3μg/L, respectively. It was found that N2-glucuronide conjugates of lamotrigine were cleaved to form lamotrigine. Both lamotrigine and amisulpride were detected in groundwater with a concentration of 0.07μg/L. Sulpiride was identified but not quantified. This demonstrates that amisulpride, sulpiride and lamotrigine might be used as indicators for treated wastewater in raw waters used for drinking water production. Furthermore, it could be shown that all three pharmaceutical compounds are efficiently oxidized by ozonation, leading mainly to N-oxide oxidation products. No significant removal of the N-oxides of amisulpride, sulpiride and lamotrigine was observed in the bench-scale biodegradation experiments with activated sludge. This indicated their high biological persistence. Therefore, N-oxides might be appropriate as indicators for post-ozonation as a major technology for the advanced treatment of secondary effluent. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of arachidonyl-2'-chloroethylamide (ACEA) on the protective action of various antiepileptic drugs in the 6-Hz corneal stimulation model in mice.

PubMed

Luszczki, Jarogniew J; Patrzylas, Pawel; Zagaja, Miroslaw; Andres-Mach, Marta; Zaluska, Katarzyna; Kondrat-Wrobel, Maria W; Szpringer, Monika; Chmielewski, Jaroslaw; Florek-Luszczki, Magdalena

2017-01-01

Accumulating evidence indicates that cannabinoid CB1 receptor ligands play a pivotal role in seizures, not only in preclinical studies on animals, but also in clinical settings. This study was aimed at characterizing the influence of arachidonyl-2'-chloroethylamide (ACEA-a selective cannabinoid CB1 receptor agonist) co-administered with phenylmethylsulfonyl fluoride (PMSF) on the anticonvulsant potency of various antiepileptic drugs (clobazam, lacosamide, levetiracetam, phenobarbital, tiagabine and valproate) in the 6-Hz corneal stimulation model. Psychomotor seizures in male albino Swiss mice were evoked by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via corneal electrodes. Potential adverse effects produced by the antiepileptic drugs in combination with ACEA+PMSF were assessed using the chimney test (motor performance), passive avoidance task (remembering and acquisition of learning), and grip-strength test (muscular strength). Brain concentrations of antiepileptic drugs were measured by HPLC to exclude any pharmacokinetic contribution to the observed effect. ACEA (5 mg/kg, i.p.) + PMSF (30 mg/kg, i.p.) significantly potentiated the anticonvulsant potency of levetiracetam (P<0.05), but not that of clobazam, lacosamide, phenobarbital, tiagabine or valproate in the 6-Hz corneal stimulation model. Moreover, ACEA+PMSF did not significantly affect total brain concentrations of levetiracetam in mice. No behavioral side effects were observed in animals receiving combinations of the studied antiepileptic drugs with ACEA+PMSF. In conclusion, the combined administration of ACEA+PMSF with levetiracetam is associated with beneficial anticonvulsant pharmacodynamic interaction in the 6-Hz corneal stimulation model. The selective activation of cannabinoid CB1 receptor-mediated neurotransmission in the brain may enhance levetiracetam-related suppression of seizures in epilepsy patients, contributing to the efficacious treatment of epilepsy in future.

Effects of arachidonyl-2’-chloroethylamide (ACEA) on the protective action of various antiepileptic drugs in the 6-Hz corneal stimulation model in mice

PubMed Central

Patrzylas, Pawel; Zagaja, Miroslaw; Andres-Mach, Marta; Zaluska, Katarzyna; Kondrat-Wrobel, Maria W.; Szpringer, Monika; Chmielewski, Jaroslaw; Florek-Luszczki, Magdalena

2017-01-01

Accumulating evidence indicates that cannabinoid CB1 receptor ligands play a pivotal role in seizures, not only in preclinical studies on animals, but also in clinical settings. This study was aimed at characterizing the influence of arachidonyl-2′-chloroethylamide (ACEA–a selective cannabinoid CB1 receptor agonist) co-administered with phenylmethylsulfonyl fluoride (PMSF) on the anticonvulsant potency of various antiepileptic drugs (clobazam, lacosamide, levetiracetam, phenobarbital, tiagabine and valproate) in the 6-Hz corneal stimulation model. Psychomotor seizures in male albino Swiss mice were evoked by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via corneal electrodes. Potential adverse effects produced by the antiepileptic drugs in combination with ACEA+PMSF were assessed using the chimney test (motor performance), passive avoidance task (remembering and acquisition of learning), and grip-strength test (muscular strength). Brain concentrations of antiepileptic drugs were measured by HPLC to exclude any pharmacokinetic contribution to the observed effect. ACEA (5 mg/kg, i.p.) + PMSF (30 mg/kg, i.p.) significantly potentiated the anticonvulsant potency of levetiracetam (P<0.05), but not that of clobazam, lacosamide, phenobarbital, tiagabine or valproate in the 6-Hz corneal stimulation model. Moreover, ACEA+PMSF did not significantly affect total brain concentrations of levetiracetam in mice. No behavioral side effects were observed in animals receiving combinations of the studied antiepileptic drugs with ACEA+PMSF. In conclusion, the combined administration of ACEA+PMSF with levetiracetam is associated with beneficial anticonvulsant pharmacodynamic interaction in the 6-Hz corneal stimulation model. The selective activation of cannabinoid CB1 receptor-mediated neurotransmission in the brain may enhance levetiracetam-related suppression of seizures in epilepsy patients, contributing to the efficacious treatment of epilepsy in future. PMID

Lamotrigine Induced Whole Body Tics: A Case Report and Literature Review.

PubMed

Centorino, Michael B; Catalano, Glenn; Catalano, Maria C

2016-01-01

Lamotrigine is an anticonvulsant medication that also has utility in the treatment of bipolar disorder. It has been associated with many side effects, including rashes that can progress to Stevens-Johnson syndrome or toxic epidermal necrolysis. It has also been associated with the development of motor tics, most commonly in the head, neck, and shoulders. We will now present the case of a 45-year-old woman who developed tics that involved the entire left side of her body after her dose of lamotrigine was increased from 200 mg daily (2.0 mg/kg/day) to 225 mg daily (2.3 mg/kg/day). We will review the prior cases of lamotrigine induced tics, and compare them to the circumstances surrounding our patient. We will also discuss the neurobiology of tics and make suggestions to improve the tics, based on the reported cases.

Reversible postoperative blindness caused by bilateral status epilepticus amauroticus following thoracolumbar deformity correction: case report.

PubMed

Ibrahim, Tarik F; Sweis, Rochelle T; Nockels, Russ P

2017-07-01

Postoperative vision loss (POVL) is a devastating complication and has been reported after complex spine procedures. Anterior ischemic optic neuropathy and posterior optic neuropathy are the 2 most common causes of POVL. Bilateral occipital lobe seizures causing complete blindness are rare and have not been reported as a cause of POVL after spine surgery with the patient prone. The authors report the case of a 67-year-old man without a history of seizures who underwent a staged thoracolumbar deformity correction and developed POVL 6 hours after surgery. Imaging, laboratory, and ophthalmological examination results were nonrevealing. Routine electroencephalography study results were negative, but continuous electroencephalography captured bilateral occipital lobe seizures. The patient developed nonconvulsive status epilepticus despite initial treatment with benzodiazepines and loading doses of levetiracetam and lacosamide. He was therefore intubated for status epilepticus amauroticus and received a midazolam infusion. After electrographic seizure cessation for 48 hours, the patient was weaned off midazolam. The patient was maintained on levetiracetam and lacosamide without seizure recurrence and returned to his preoperative visual baseline status.

Efficacy and safety of levetiracetam for outpatient alcohol detoxification.

PubMed

Müller, C A; Schäfer, M; Schneider, S; Heimann, H M; Hinzpeter, A; Volkmar, K; Förg, A; Heinz, A; Hein, J

2010-07-01

Anticonvulsant drugs are increasingly being used for alcohol detoxification in in- and outpatient settings. The aim of this study was to examine the efficacy, medical safety and mid-term outcome of levetiracetam, a drug with no marked liver toxicity, for outpatient alcohol detoxification. This was an open-label observational study. After screening eligibility for outpatient alcohol detoxification, patients were seen daily for 5 days and received levetiracetam in a flexible dosage regime between 500 and 4 000 mg/d for a maximum of 7 days. Diazepam was used as a rescue medication. The severity of alcohol withdrawal was evaluated daily using the ALCOHOL WITHDRAWAL SYNDROME SCALE (AWSS). Mid-term treatment outcome was assessed at a 6-month follow-up. A total number of 131 consecutively admitted alcohol-dependent patients received an outpatient detoxification treatment, 122 (93.1%) completed the programme successfully. The mean initial dose of levetiracetam was 1 850 mg/d. Alcohol withdrawal syndrome as indicated by the AWSS score decreased clearly over 5 days. Overall, the medication was well tolerated. There was no treatment discontinuations due to side effects of levetiracetam. No serious medical complications, especially seizures or deliria, were observed during the detoxification. At the 6-month follow-up, 57 patients (43.5%) were still abstinent. Patients with previous detoxifications had a significant higher risk for relapse (HR=1.88; p=0.016; CI 95%: 1.12-3.14) than patients without previous treatments. The findings of this study provide some evidence that levetiracetam is an efficacious and safe treatment option for outpatient alcohol detoxification. Further randomised, controlled trials including mid- and long-term follow-ups are needed to confirm these findings. Copyright Georg Thieme Verlag KG Stuttgart New York.

The conduction block produced by oxcarbazepine in the isolated rat sciatic nerve: a comparison with lamotrigine.

PubMed

Guven, Mustafa; Kahraman, Ibrahim; Koc, Filiz; Bozdemir, Hacer; Sarica, Yakup; Gunay, Ismail

2011-01-01

Oxcarbazepine is an antiepileptic drug widely used for the treatment of neuropathic pain. In the present study, the effects of oxcarbazepine and lamotrigine on conduction properties in the rat sciatic nerves were examined. The experiments were conducted with in vitro sucrose-gap technique on the isolated wistar rat sciatic nerves. The compound action potentials were obtained by tonic (single) and phasic (10, 40, and 100 Hz) stimulation. Oxcarbazepine produced a significant concentration- and frequency-dependent reduction in the compound action potential amplitude. When the two drugs were applied at concentrations that produced equal levels of tonic (i.e., non-frequency-dependent) conduction block, oxcarbazepine produced the greatest phasic (i.e., frequency-dependent) conduction block, followed by lamotrigine. Oxcarbazepine and lamotrigine reduced the 4-aminopyridine-induced amplitude of delayed depolarization; however, oxcarbazepine had a significantly greater effect than lamotrigine. These results suggest that oxcarbazepine produces more potent frequency-dependent conduction block than lamotrigine, and suppresses the delayed depolarization which contributes to sensory signaling and may play a role in neuropathic pain. The findings provide insight into the mechanisms of action of oxcarbazepine and lamotrigine and may help in the development of novel therapies for neuropathic pain.

Effects of lamotrigine on hippocampal activation in corticosteroid-treated patients.

PubMed

Brown, E Sherwood; Zaidel, Liam; Allen, Greg; McColl, Roderick; Vazquez, Miguel; Ringe, Wendy K

2010-11-01

An extensive animal literature suggests that stress or excessive corticosteroid exposure is associated with changes in hippocampal function and memory. These findings are pertinent to psychiatric disorders with elevated cortisol, Cushing's disease and the millions of patients receiving prescription corticosteroids. In animals, agents that decrease glutamate release attenuate the effects of corticosteroids on the hippocampus. Minimal data are available on preventing or reversing the effects of corticosteroids on the human hippocampus. We previously reported improvement in memory in corticosteroid-treated patients given lamotrigine. In this report, we examined the impact of lamotrigine on task-related hippocampal activation in patients taking prescription corticosteroids. A total of 28 outpatients taking long-term oral prednisone for medical conditions, such as renal transplant rejection, were randomized to lamotrigine or placebo for 24 weeks. Hippocampal activation in response to a visual memory task was assessed with blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI). Consistent with a reduction in glutamate release, the right posterior hippocampus showed a significant decrease in task-related activation in the lamotrigine group as compared to the placebo group. The modest sample size and an assessment period of only 24 weeks are study limitations. Between-group differences in hippocampal activation were observed. The results suggest that an agent that modulates glutamate may modify the effects of long-term corticosteroid exposure on the human hippocampus. Copyright © 2010 Elsevier B.V. All rights reserved.

Continuous subcutaneous use of levetiracetam: a retrospective review of tolerability and clinical effects.

PubMed

Rémi, Constanze; Lorenzl, Stefan; Vyhnalek, Birgit; Rastorfer, Karin; Feddersen, Berend

2014-12-01

To evaluate the tolerability and clinical effects of subcutaneous (SC) levetiracetam for the treatment of epileptic seizures in a palliative care setting, we conducted a retrospective chart review of patients treated with subcutaneous levetiracetam in the Department of Palliative Medicine at the University Munich, between September 2006 and March 2013. The following parameters were extracted from the charts: reason for antiepileptic drug treatment, daily dose, concentration, infusion rate, co-administration of other drugs, and clinical effects. Furthermore, the charts were screened for signs of adverse drug reactions, e.g., irritation or pain at the infusion site. We identified 20 patients that were treated with levetiracetam SC in the inpatient (n = 7) and outpatient (n = 13) settings. Most patients (n = 17) tolerated the subcutaneous infusion well. Nineteen patients (95%) received levetiracetam in combination with other drugs. These were mainly metamizol (80%), midazolam (75%), and morphine (45%). The median dose of levetiracetam was 95.8 mg/h (SD 37 mg/h), median osmolarity of the infusion solution 2203 mOsmol/L (SD 717 mOsmol/L), and infusion rate 2 mL/h (SD 2.4 ml/h). In 16 patients (80%), seizures were controlled and status epilepticus were interrupted, respectively. We conclude that SC levetiracetam is an effective treatment and well tolerated in the palliative care setting.

Asymptomatic elevation of liver enzymes due to levetiracetam: a case report.

PubMed

Sethi, Nitin K; Sethi, Prahlad K; Torgovnick, Josh; Arsura, Edward; Cukierwar, Frances

2013-01-01

Levetiracetam is a commonly used broad-spectrum anticonvulsant efficacious in both partial and generalized seizures. It has an extremely favorable side effect profile with few drug-drug interactions, low potential for hematological and hepatic toxicity, and thus has rapidly become the preferred drug in patients with traumatic brain injuries who need seizure prophylaxis. We report, here, a patient who was started on levetiracetam for seizure prophylaxis after developing large bifrontal-parietal traumatic subdural hematomas (SDH) following a fall from a horse necessitating bifrontal craniotomies for evacuation. The patient developed an asymptomatic elevation of the liver enzymes. The liver enzymes trended back to normal after levetiracetam was stopped, and topiramate was initiated in its place.

Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Crossover Study Evaluating the Abuse Potential of the Antiepileptic Drug Lacosamide in Healthy Recreational Drug Users.

PubMed

Schoedel, Kerri A; Andreas, Jens-Otto; Doty, Pamela; Eckhardt, Klaus; Sellers, Edward M

2017-12-01

This phase 1, randomized, double-blind, placebo- and active comparator-controlled crossover study assessed the abuse potential of the antiepileptic drug, lacosamide. After a qualification phase, 38 healthy, recreational central nervous system-depressant users were randomized to treatment sequences comprising single oral therapeutic (200 mg) and supratherapeutic (800 mg) doses of lacosamide, alprazolam (1.5 and 3 mg), and placebo. Subjective effects were assessed for 24 hours following each dose using a range of scales, with a 5- to 9-day washout between treatments. Mean subjective effects for 200 mg lacosamide were statistically similar to placebo and significantly lower than with alprazolam for most end points. Lacosamide 800 mg elicited transient, statistically significant positive effects compared with placebo, but also persistent Bad Drug Effects including statistically greater maximum effect (Emax) scores for Nausea and Dysphoria compared with other treatments (P < 0.0002). Consistent with this, the 800 mg lacosamide dose showed a significantly lower "at this moment" Drug Liking visual analog scale (VAS) Emax compared with 3 mg alprazolam, but was not different from 1.5 mg alprazolam (73.1/100, 85.4/100, and 78.9/100, respectively, where 50 is neutral). Overall Drug Liking VAS and Take Drug Again VAS Emax for 800 mg lacosamide were not significantly different from placebo and were lower than those for both alprazolam doses (P < 0.0001). These results suggest that in recreational central nervous system-depressant users, lacosamide has detectable abuse-related subjective effects, but a relatively low potential for abuse compared with alprazolam. These findings contributed toward placement of lacosamide into Schedule V of the US Controlled Substances Act.

Effect of lacosamide on the steady-state pharmacokinetics of digoxin: results from a phase I, multiple-dose, double-blind, randomised, placebo-controlled, crossover trial.

PubMed

Cawello, Willi; Mueller-Voessing, Christa; Andreas, Jens-Otto

2014-05-01

Recent data suggest that P-glycoprotein may be involved in cellular transport of lacosamide. To investigate potential drug-drug interactions (DDIs) between lacosamide and digoxin, this phase I, multiple-dose, randomised, double-blind, placebo-controlled, crossover trial assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of digoxin administered in combination with lacosamide or placebo. Twenty healthy White male volunteers were randomised. After receiving digoxin 0.25 mg three times daily on day 1 (loading dose), participants received digoxin 0.25 mg once daily on days 2-22. Participants received either lacosamide (200 mg twice daily) or placebo on days 8-11 and vice versa on days 18-21, after a 6-day washout. The steady-state area under concentration-time curve over the dosing interval (AUC(24,ss)) and maximum steady-state plasma concentration (C(max,ss)) of digoxin were measured; ratios of these parameters for co-administration of digoxin + lacosamide versus digoxin alone were used to evaluate potential DDIs. Interaction was excluded if the 90 % confidence interval (CI) for the geometric mean ratio of AUC24,ss and C max,ss fell within the acceptance range for bioequivalence (0.8-1.25). The point estimates (90 % CI) of the geometric mean ratios for co-administration of digoxin with lacosamide versus digoxin alone for AUC(24,ss) [1.024 (0.979-1.071)] and C(max,ss) [1.049 (0.959-1.147)] were within the acceptance range for bioequivalence. Digoxin and lacosamide co-administration was generally well-tolerated. A small numerical increase in the mean PR interval following co-administered digoxin + lacosamide was observed versus digoxin alone and versus pre-treatment baseline values (178.5 vs. 170.4 or 166.8 ms, respectively). The RR interval increased in parallel. The change was not considered clinically relevant. Co-administration of steady-state digoxin (0.25 mg/day) with multiple-dose lacosamide (400 mg/day) versus digoxin alone revealed no

Intravenous levetiracetam terminates refractory status epilepticus in two patients with migrating partial seizures in infancy.

PubMed

Cilio, Maria Roberta; Bianchi, Roberto; Balestri, Martina; Onofri, Alfredo; Giovannini, Simona; Di Capua, Matteo; Vigevano, Federico

2009-09-01

To evaluate the efficacy and tolerability of intravenous (IV) levetiracetam in refractory status epilepticus of migrating partial seizures in infancy (MPSI). IV levetiracetam was infused in two infants, first as a loading dose of 60mg/kg in 30min, then at 30mg/kg twice a day. Both infants were continuously monitored with video-EEG before, during and after the drug trial. Blood count, liver enzymes, serum creatinine, ammonia and lactate blood levels were performed repeatedly before and after the IV levetiracetam administration. Follow-up was of 16 and 10 months. EEG monitoring allowed the diagnosis of MPSI, showing the typical seizures pattern in both patients. IV levetiracetam was effective in stopping status epilepticus in both infants. Levetiracetam also prevented the recurrence of status epilepticus during follow-up. No adverse reactions were observed during the infusion phase or during follow-up. MPSI is a newly recognized epileptic syndrome characterized by early onset of intractable partial seizures arisingly independently and sequentially from both hemispheres, migrating from one region of the brain to another and from one hemisphere to another. We report the efficacy of intravenous levetiracetam in resolving refractory status epilepticus in two infants with this new epilepsy syndrome.

Efficacy and safety of prophylactic levetiracetam in supratentorial brain tumour surgery: a systematic review and meta‐analysis

PubMed Central

Tsaousi, Georgia; Apostolidou, Eirini; Karakoulas, Konstantinos; Kouvelas, Dimitrios; Amaniti, Ekaterini

2016-01-01

Aims The aim of this study was to perform an up‐to‐date systematic review and meta‐analysis on the efficacy and safety of prophylactic administration of levetiracetam in brain tumour patients. Method A systematic review of studies published until April 2015 was conducted using Scopus/Elsevier, EMBASE and MEDLINE. The search was limited to articles reporting results from adult patients, suffering from brain tumour, undergoing supratentorial craniotomy for tumour resection or biopsy and administered levetiracetam in the perioperative period for seizure prophylaxis. Outcomes included the efficacy and safety of levetiracetam, as well as the tolerability of the specific regimen, defined by the discontinuation of the treatment due to side effects. Results The systematic review included 1148 patients from 12 studies comparing levetiracetam with no treatment, phenytoin and valproate, while only 243 patients from three studies, comparing levetiracetam vs phenytoin efficacy and safety, were included in the meta‐analysis. The combined results from the meta‐analysis showed that levetiracetam administration was followed by significantly fewer seizures than treatment with phenytoin (OR = 0.12 [0.03–0.42]: χ2 = 1.76: I2 = 0%). Analysis also showed significantly fewer side effects in patients receiving levetiracetam, compared to other groups (P < 0.05). The combined results showed fewer side effects in the levetiracetam group compared to the phenytoin group (OR = 0.65 [0.14–2.99]: χ2 = 8.79: I2 = 77%). Conclusions The efficacy of prophylaxis with levetiracetam seems to be superior to that with phenytoin and valproate administration. Moreover, levetiracetam use demonstrates fewer side effects in brain tumour patients. Nevertheless, high risk of bias and moderate methodological quality must be taken into account when considering these results. PMID:26945547

Pharmacokinetics, Safety, and Tolerability of Lamotrigine Chewable/Dispersible Tablet Following Repeat-Dose Administration in Healthy Chinese Volunteers.

PubMed

Li, Yan; Zhang, Fan; Xu, Yanmei; Hu, Joice; Li, Huafang

2018-03-26

In this open-label, single-center study, the pharmacokinetics, safety, and tolerability of lamotrigine chewable/dispersible tablets were assessed in healthy Chinese volunteers. Each volunteer (N = 16) received repeat doses of oral lamotrigine titrated from 25 mg to 50 mg to 100 mg over 42 days and was followed up for 10-17 days. Safety and tolerability were assessed throughout the study. Lamotrigine pharmacokinetic parameters were estimated using noncompartmental analysis. Overall, 15 (94%) volunteers completed the study. Lamotrigine serum concentrations peaked 2.5 hours postdose, with a mean terminal half-life of 36.8 hours. The apparent lamotrigine oral clearance was 1577.88 mL/h. The accumulation ratios (day 14 vs day 1) were 2.53 and 2.58 for area under the curve and peak concentration, respectively. Lamotrigine 25 to 100 mg once daily exhibited dose-proportional pharmacokinetics (based on area under the curve and peak concentration), following repeat dosing. Nine volunteers reported adverse events, 2 experienced oropharyngeal pain, each receiving 25 mg and 50 mg. One volunteer withdrew due to an increase in liver enzymes. No deaths, serious adverse effects, or skin rashes were reported during the study. No new safety concerns were observed. Overall, the pharmacokinetic profiles after repeat doses of lamotrigine chewable/dispersible tablets once daily in a Chinese population were similar to those observed in Western populations. © 2018, The American College of Clinical Pharmacology.

Treatment with lacosamide impedes generalized seizures in a rodent model of cortical dysplasia.

PubMed

Nemes, Ashley D; O'Dwyer, Rebecca; Najm, Imad M; Ying, Zhong; Gonzalez-Martinez, Jorge; Alexopoulos, Andreas V

2017-10-01

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 A ) antagonist used to provoke generalized seizures as a "second hit." 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. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Levetiracetam synergises with common analgesics in producing antinociception in a mouse model of painful diabetic neuropathy.

PubMed

Micov, Ana; Tomić, Maja; Pecikoza, Uroš; Ugrešić, Nenad; Stepanović-Petrović, Radica

2015-07-01

Painful diabetic neuropathy is difficult to treat. Single analgesics often have insufficient efficacy and poor tolerability. Combination therapy may therefore be of particular benefit, because it might provide optimal analgesia with fewer adverse effects. This study aimed to examine the type of interaction between levetiracetam, a novel anticonvulsant with analgesic properties, and commonly used analgesics (ibuprofen, aspirin and paracetamol) in a mouse model of painful diabetic neuropathy. Diabetes was induced in C57BL/6 mice with a single high dose of streptozotocin, applied intraperitoneally (150 mg/kg). Thermal (tail-flick test) and mechanical (electronic von Frey test) nociceptive thresholds were measured before and three weeks after diabetes induction. The antinociceptive effects of orally administered levetiracetam, analgesics, and their combinations were examined in diabetic mice that developed thermal/mechanical hypersensitivity. In combination experiments, the drugs were co-administered in fixed-dose fractions of single drug ED50 and the type of interaction was determined by isobolographic analysis. Levetiracetam (10-100 mg/kg), ibuprofen (2-50 mg/kg), aspirin (5-75 mg/kg), paracetamol (5-100 mg/kg), and levetiracetam-analgesic combinations produced significant, dose-dependent antinociceptive effects in diabetic mice in both tests. In the tail-flick test, isobolographic analysis revealed 15-, and 19-fold reduction of doses of both drugs in the combination of levetiracetam with aspirin/ibuprofen, and paracetamol, respectively. In the von Frey test, approximately 7- and 9-fold reduction of doses of both drugs was detected in levetiracetam-ibuprofen and levetiracetam-aspirin/levetiracetam-paracetamol combinations, respectively. These results show synergism between levetiracetam and ibuprofen/aspirin/paracetamol in a model of painful diabetic neuropathy and might provide a useful approach to the treatment of patients suffering from painful diabetic neuropathy

Neuroprotective properties of the novel antiepileptic lamotrigine in a gerbil model of global cerebral ischemia.

PubMed

Wiard, R P; Dickerson, M C; Beek, O; Norton, R; Cooper, B R

1995-03-01

Elevated glutamate levels are thought to be a primary cause of neuronal death after global cerebral ischemia. The purpose of this study was to investigate the potential neuroprotective effects of lamotrigine, a novel antiepileptic drug that inhibits the release of glutamate in vitro, with both behavioral and histological measures of global ischemia in gerbils. The common carotid arteries of gerbils were occluded for either 5, 10, or 15 minutes. Twenty-one days after reperfusion, gerbils were tested for impairments in a spatial memory task (Morris water maze). After water maze testing the animals were killed, and damage to hippocampal pyramidal cells was assessed. The effect of lamotrigine on the behavioral and histological outcome of either 5 or 15 minutes of global ischemia was evaluated. Bilateral occlusion of the common carotid arteries for 5 minutes resulted in severe degeneration of hippocampal CA1 and CA2 pyramidal cells. Lamotrigine significantly prevented loss of hippocampal CA1 neurons when administered acutely (100 mg/kg PO) immediately after reperfusion or when administered in two equal doses of 30 or 50 mg/kg 2 hours before and immediately after reperfusion. Gerbils subjected to 5 minutes of ischemic insult were not impaired in their ability to solve a spatial memory task 21 days after cerebral ischemia. However, gerbils subjected to 10 and 15 minutes of carotid artery occlusion showed significant impairment in their ability to solve a water maze task. Lamotrigine significantly protected against the cognitive deficits associated with 15 minutes of cerebral ischemia. Histologically, increased durations of cerebral ischemia resulted in a progressive loss of CA1, CA2, and CA3 pyramidal cells. Lamotrigine completely protected gerbils exposed to 15 minutes of cerebral ischemia against CA3 cell loss and greatly reduced damage to the CA1 and CA2 cell tracts of the hippocampus. Lamotrigine also reduced the mortality associated with 15 minutes of ischemia

Efficacy and tolerability of oral lacosamide as adjunctive therapy in pediatric patients with pharmacoresistant focal epilepsy.

PubMed

Gavatha, M; Ioannou, I; Papavasiliou, A S

2011-04-01

The results of adjunctive lacosamide treatment in 18 pediatric patients with pharmacoresistant focal epilepsy are reported. All had severe forms of focal epilepsy with or without secondary generalization and were concurrently receiving one to three other antiepileptic drugs. Lacosamide was administered orally, and final dose, after slow titration, ranged between 1.7 and 10 mg/kg. Mean treatment duration was 8 months (range=3 weeks-17 months). Treatment efficacy was assessed at two time points with a 1-year interval. The reported greater than 50% reduction in seizure frequency was 36% in the initial short-term and 20% in the following long-term assessment. Side effects, mostly somnolence and irritability, were reported by 39% of patients in both evaluations. Our data suggest that lacosamide treatment in pediatric patients is safe at doses up to 10 mg/kg/day without any major side effects, but studies in larger series are needed to validate and extend these findings. Copyright © 2011 Elsevier Inc. All rights reserved.

Levetiracetam efficacy on frontal lobe dysfunctions and anger rumination in patients with epilepsy.

PubMed

Gul, Amara; Mehreen, Saima

2018-06-12

This study compared the frontal lobe functioning and anger rumination between patients with epilepsy and healthy individuals. The second objective was to examine the efficacy of levetiracetam therapy on frontal lobe dysfunctions and anger rumination in patients with epilepsy. Participants (50 patients with epilepsy and 50 healthy individuals) completed the Frontal Assessment Battery (FAB) and Anger Rumination Scale (ARS). The patients had two testing sessions: pre- and post-levetiracetam therapies. The results showed that patients with epilepsy had frontal lobe dysfunctions in contrast with healthy individuals. Patients with epilepsy had higher anger rumination than healthy individuals. Compared with baseline performance, frontal lobe dysfunctions and anger rumination were significantly reduced after three months of levetiracetam therapy in patients with epilepsy. It is concluded that levetiracetam therapy may be beneficial in improving frontal lobe functioning and anger rumination thought pattern in patients with epilepsy. However, further studies are required to confirm this evidence. Copyright © 2018 Elsevier Inc. All rights reserved.

Levetiracetam Versus Phenytoin for Seizure Prophylaxis Following Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

PubMed

Yang, Yong; Zheng, Fangshuo; Xu, Xin; Wang, Xuefeng

2016-08-01

Seizure following traumatic brain injury (TBI) constitutes a common complication that requires effective prevention to improve the outcome of TBI. Phenytoin has been the only recommended antiepileptic drug (AED) for seizure prophylaxis; however, several shortcomings have affected its use. Intravenous levetiracetam has been available since 2006 and has been increasingly accepted as a seizure prophylaxis for brain injury, mainly due to its favorable pharmacokinetic features and minimal adverse events profile. However, the efficacy and safety of levetiracetam versus phenytoin for seizure prophylaxis following TBI are not well clarified. The aim of this study was to assess the efficacy and safety of levetiracetam versus phenytoin for seizure prophylaxis following TBI. We conducted a search of the MEDLINE, EMBASE, and Cochrane library databases to March 2016, and screened original research that included patients with TBI who received levetiracetam. We included randomized controlled trials (RCTs) or controlled observational cohort studies that compared levetiracetam and phenytoin, as well as uncontrolled case series regarding prophylactic levetiracetam following TBI. The outcomes included early or late seizure prophylaxis and safety. The estimates of seizure prophylaxis were pooled using a meta-analysis, and the estimates for the case series were pooled using descriptive statistics. A total of 1614 patients from 11 studies were included in this review, of whom 1285 patients from eight controlled studies (one RCT and seven cohort studies) were included in the meta-analysis. Levetiracetam was not superior to phenytoin with regard to early seizure prophylaxis (risk ratio [RR] 1.10, 95 % confidence interval [CI] 0.64-1.88); the estimate of early seizure incidence was 0.05 (95 % CI 0.02-0.08). Three studies that assessed late seizure did not indicate the superiority of levetiracetam to phenytoin. There were no differences in mortality during hospitalization or after 6�

The effects of lacosamide on cognition, quality-of-life measures, and quality of life in patients with refractory partial epilepsy.

PubMed

Lancman, Marcelo E; Fertig, Evan J; Trobliger, Robert W; Perrine, Kenneth; Myers, Lorna; Iyengar, Sloka S; Malik, Munazza

2016-08-01

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

Economic impact of generic substitution of lamotrigine: projected costs in the US using findings in a Canadian setting.

PubMed

LeLorier, Jacques; Duh, Mei Sheng; Paradis, Pierre Emmanuel; Latrémouille-Viau, Dominick; Lefebvre, Patrick; Manjunath, Ranjani; Sheehy, Odile

2008-04-01

Generic substitution may not always save health care costs for antiepileptic drugs (AED). (1) To examine the economic impacts of generic substitution of lamotrigine in Canada; and (2) to convert observed Canadian costs to a United States (US) setting. Health claims from Québec's health plan (RAMQ) between 08/2002 and 07/2006 were analyzed. Patients with > or = 1 epilepsy claim and treated with branded lamotrigine (Lamictal) before generic entry were selected. Health care costs ($/person-year) were compared during periods of branded and generic use of lamotrigine. Two cost-conversion methods were employed; one using purchasing power parities, US/Canada service use ratios, and exchange rate, and another employing Canadian health care utilization and US unit costs. 671 patients were observed during 1650.9 and 291.2 person-years of branded and generic use of lamotrigine, respectively. The generic-use period was associated with an increase in overall costs (2006 constant Canadian dollars) relative to brand use (C$7902 vs. C$6419/person-year; cost ratio (CR) = 1.22; p = 0.05), despite the lower cost of generic lamotrigine. Non-lamotrigine costs were 33% higher in the generic period (p = 0.013). Both conversion methods yielded increases in total projected health care costs excluding lamotrigine (2006 constant US dollars) during the generic period (Method 1: cost difference: US$1758/person-year, CR = 1.33, p = 0.01); Method 2: cost difference: US$2516, CR = 1.39, p = 0.004). Study limitations pertain to treatment differences, indicators used for conversion and possible claim inaccuracies. Use of generic lamotrigine in Canada was significantly associated with increased overall medical costs compared to brand use. Projected overall US health care costs would likely increase as well.

Interaction of an antiepileptic drug, lamotrigine with human serum albumin (HSA): Application of spectroscopic techniques and molecular modeling methods.

PubMed

Poureshghi, Fatemeh; Ghandforoushan, Parisa; Safarnejad, Azam; Soltani, Somaieh

2017-01-01

Lamotrigine (an epileptic drug) interaction with human serum albumin (HSA) was investigated by fluorescence, UV-Vis, FTIR, CD spectroscopic techniques, and molecular modeling methods. Binding constant (K b ) of 5.74×10 3 and number of binding site of 0.97 showed that there is a slight interaction between lamotrigine and HSA. Thermodynamic studies was constructed using the flourimetric titrations in three different temperatures and the resulted data used to calculate the parameters using Vant Hoff equation. Decreased Stern Volmer quenching constant by enhanced temperature revealed the static quenching mechanism. Negative standard enthalpy (ΔH) and standard entropy (ΔS) changes indicated that van der Waals interactions and hydrogen bonds were dominant forces which facilitate the binding of Lamotrigine to HSA, the results were confirmed by molecular docking studies which showed no hydrogen binding. The FRET studies showed that there is a possibility of energy transfer between Trp214 and lamotrigine. Also the binding of lamotrigine to HSA in the studied concentrations was not as much as many other drugs, but the secondary structure of the HSA was significantly changed following the interaction in a way that α-helix percentage was reduced from 67% to 57% after the addition of lamotrigine in the molar ratio of 4:1 to HSA. According to the docking studies, lamotrigine binds to IB site preferably. Copyright © 2016. Published by Elsevier B.V.

Efficacy and safety of adjunctive lacosamide for the treatment of partial-onset seizures in Chinese and Japanese adults: A randomized, double-blind, placebo-controlled study.

PubMed

Hong, Zhen; Inoue, Yushi; Liao, Weiping; Meng, Hongmei; Wang, Xuefeng; Wang, Wenmin; Zhou, Liemin; Zhang, Liming; Du, Xinlu; Tennigkeit, Frank

2016-11-01

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. Copyright

Treatment Effects of Onion (Allium cepa) and Ginger (Zingiber officinale) on Sexual Behavior of Rat after Inducing an Antiepileptic Drug (lamotrigine)

PubMed Central

Khaki, Arash; Farnam, Alireza; Badie, Arash Davatgar; Nikniaz, Hussein

2012-01-01

Objective: The aim of the present study was to evaluate the beneficial degree of sexual behavior in male rats after inducement of onion and ginger in lamotrigine receiving groups. Material and Methods: Wistar rats (n=70) (male=35, female=35) were allocated so that males were divided into seven groups: control (n=5) and test groups (n=35). Control group used normal Saline (3 cc for each rat). Lamotrigine group were given Lamotrigine (10 mg/kg). Onion group used onion fresh juice (3 cc for each rat/daily). Ginger group was fed on ginger powder (100 mg/kg/daily). Onion & Lamotrigine group used both onion juice (3 cc fresh onion juice for each rat/day) and Lamotrigine (10 mg/kg). Ginger & Lamotrigine group used both ginger powder (100 mg/kg/day) and Lamotrigine (10 mg/kg/day). Onion, ginger & Lamortigine group jointly used ginger powder (100 mg/kg/day) and onion juice (3 cc juice for each rat) and Lamotrigine (10 mg/kg/day). All groups were given treatments orally. For sexual behaviors, Estradiolbenzoate (50 microgram) and 6 hours before test (500 microgram) progesterone was injected to the female rats subcutaneously. Then rats were viewed for erection, ejaculation and cup. Results: There was maximum Serum total testosterone level in the onion group, there was maximum malondialdehyde (MDA) in the Lamotrigine group and there was maximum total antioxidant capacity in both the onion group and ginger group (p<0.05). Conclusion: Results revealed that administration of (100 mg/kg/day) of ginger powder, and freshly prepared onion juice (3 cc for each rat), significantly lowered the adverse effects of lamotrigine, and can have beneficial effects on sexual behavior in male rat. PMID:25207007

Antiepileptic drug combinations--have newer agents altered clinical outcomes?

PubMed

Stephen, Linda J; Forsyth, Murray; Kelly, Kevin; Brodie, Martin J

2012-02-01

In 2000, 332 (20.5%) of 1617 patients registered with the Western Infirmary Epilepsy Unit required antiepileptic drug (AED) polytherapy to remain seizure-free for at least 1 year. The analysis was repeated 10 years later. Of 2379 seizure-free patients, 20.4% (n=486 - 254 women, 232 men, aged 18-95 years [median age 49 years]) were receiving combination therapy. Two AEDs were taken by 395 (81.3%) patients in 2010, and by 287 (86.4%) in 2000. Sodium valproate with lamotrigine was the commonest of 64 successful pairings. As a combination, mean daily doses of both AEDs were lower (n=96; sodium valproate 1200 mg, lamotrigine 155 mg) than when sodium valproate was taken with carbamazepine or levetiracetam (n=42; 1621 mg; p<0.001), and lamotrigine was combined with topiramate or levetiracetam (n=33; 430 mg; p<0.001), suggesting possible synergism. In 2010, a higher percentage of patients (n=85) remained seizure-free on 3 AEDs (17.5% in 2010, 12.7% in 2000) in 57 separate regimens. Only 0.9% (n=3) of patients in 2000, and 1.2% (n=6) in 2010 responded to 4 AEDs. Levetiracetam (n=109; 10.2%) and topiramate (n=81; 7.6%) were the newer agents most commonly represented in successful combinations. These data tend to imply that drug substitution rather than addition has largely led to these marginally improved results. In the last decade, when used as adjunctive therapies, newer agents appear not to have impacted substantially on the likelihood of producing seizure freedom. An alternative approach to AED development may be required to change this disappointing scenario. Copyright © 2011 Elsevier B.V. All rights reserved.

Effects of carbamazepine and lamotrigine on functional magnetic resonance imaging cognitive networks.

PubMed

Xiao, Fenglai; Caciagli, Lorenzo; Wandschneider, Britta; Sander, Josemir W; Sidhu, Meneka; Winston, Gavin; Burdett, Jane; Trimmel, Karin; Hill, Andrea; Vollmar, Christian; Vos, Sjoerd B; Ourselin, Sebastien; Thompson, Pamela J; Zhou, Dong; Duncan, John S; Koepp, Matthias J

2018-06-13

To investigate the effects of sodium channel-blocking antiepileptic drugs (AEDs) on functional magnetic resonance imaging (fMRI) language network activations in patients with focal epilepsy. In a retrospective study, we identified patients who were treated at the time of language fMRI scanning with either carbamazepine (CBZ; n = 42) or lamotrigine (LTG; n = 42), but not another sodium channel-blocking AED. We propensity-matched 42 patients taking levetiracetam (LEV) as "patient-controls" and included further 42 age- and gender-matched healthy controls. After controlling for age, age at onset of epilepsy, gender, and antiepileptic comedications, we compared verbal fluency fMRI activations between groups and out-of-scanner psychometric measures of verbal fluency. Patients on CBZ performed less well on a verbal fluency tests than those taking LTG or LEV. Compared to either LEV-treated patients or controls, patients taking CBZ showed decreased activations in left inferior frontal gyrus and patients on LTG showed abnormal deactivations in frontal and parietal default mode areas. All patient groups showed fewer activations in the putamen bilaterally compared to controls. In a post hoc analysis, out-of-scanner fluency scores correlated positively with left putamen activation. Our study provides evidence of AED effects on the functional neuroanatomy of language, which might explain subtle language deficits in patients taking otherwise well-tolerated sodium channel-blocking agents. Patients on CBZ showed dysfunctional frontal activation and more pronounced impairment of performance than patients taking LTG, which was associated only with failure to deactivate task-negative networks. As previously shown for working memory, LEV treatment did not affect functional language networks. © 2018 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.

Safety and efficacy of adjunctive lacosamide among patients with partial-onset seizures in a long-term open-label extension trial of up to 8 years.

PubMed

Rosenfeld, William; Fountain, Nathan B; Kaubrys, Gintaras; Ben-Menachem, Elinor; McShea, Cindy; Isojarvi, Jouko; Doty, Pamela

2014-12-01

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. Copyright © 2014 Elsevier Inc. All rights reserved.

The effects of levetiracetam, sumatriptan, and caffeine in a rat model of trigeminal pain: interactions in 2-component combinations.

PubMed

Tomić, Maja A; Pecikoza, Uroš B; Micov, Ana M; Popović, Božidar V; Stepanović-Petrović, Radica M

2015-06-01

Levetiracetam is an antiepileptic drug with analgesic efficacy shown in pain models and small clinical trials. Sumatriptan is used in acute migraine treatment. Caffeine is widely consumed in some beverages/foods and is also an adjuvant in analgesic formulations. We examined the effects of systemic levetiracetam, sumatriptan, and caffeine and their interactions in 2-component combinations in the rat orofacial formalin test, a model of trigeminal pain. Rats received a subcutaneous injection of formalin solution into the perinasal area, and the total time spent in nociceptive behavior (face rubbing) was quantified. The antinociceptive effect of drugs/drug combinations was assessed 1 hour after per os administration. The type of interaction between levetiracetam/sumatriptan and caffeine was examined by comparing the effects of a fixed, effective dose of levetiracetam/sumatriptan alone with the effects of the same dose applied with increasing, subeffective doses of caffeine. The type of interaction between levetiracetam and sumatriptan was determined by isobolographic analysis. Levetiracetam (1-50 mg/kg) and sumatriptan (0.5-5 mg/kg) produced significant and dose-dependent antinociceptive effects in both phases of the orofacial formalin test (P ≤ 0.001). Caffeine (7.5-100 mg/kg) produced significant antinociception in the second phase of the test (P = 0.04). Caffeine (1-7.5 mg/kg) significantly reduced the antinociceptive effects of levetiracetam (25 mg/kg) (first phase P = 0.002, second phase P < 0.001) and sumatriptan (2.5 mg/kg) (first phase P = 0.014, second phase P = 0.027); dose-dependent inhibition was observed in the second phase. Levetiracetam and sumatriptan exerted an additive interaction in the second phase of the orofacial formalin test. Results indicate that levetiracetam may be useful for treatment of pain in the trigeminal region. Dietary caffeine might decrease the effects of levetiracetam and sumatriptan; this needs to be considered in clinical

Effects of Different Doses of Levetiracetam on Aquaporin 4 Expression in Rats with Brain Edema Following Fluid Percussion Injury

PubMed Central

Jin, Hongbo; Li, Wenling; Dong, Changzheng; Ma, Li; Wu, Jiang; Zhao, Wenqing

2016-01-01

Background This study was designed to investigate the effects of different doses of levetiracetam on aquaporin 4 (AQP4) expression in rats after fluid percussion injury. Material/Methods Sprague-Dawley rats were randomly divided into 4 groups: sham operation group, traumatic brain injury group, low-dose levetiracetam group, and high-dose levetiracetam group. Brain edema models were established by fluid percussion injury, and intervened by the administration of levetiracetam. Samples from the 4 groups were collected at 2, 6, 12, and 24 h, and at 3 and 7 days after injury. Histological observation was performed using hematoxylin-eosin staining and immunohistochemical staining. AQP4 and AQP4 mRNA expression was detected using Western blot assay and RT-PCR. Brain water content was measured by the dry-wet method. Results Compared with the traumatic brain injury group, brain water content, AQP4 expression, and AQP4 mRNA expression were lower in the levetiracetam groups at each time point and the differences were statistically significant (P<0.05). The intervention effects of high-dose levetiracetam were more apparent. Conclusions Levetiracetam can lessen brain edema from fluid percussion injury by down-regulating AQP4 and AQP4 mRNA expression. There is a dose-effect relationship in the preventive effect of levetiracetam within a certain extent. PMID:26927633

Results of phase 2 safety and feasibility study of treatment with levetiracetam for prevention of posttraumatic epilepsy.

PubMed

Klein, Pavel; Herr, Daniel; Pearl, Phillip L; Natale, JoAnne; Levine, Zachary; Nogay, Claude; Sandoval, Fabian; Trzcinski, Stacey; Atabaki, Shireen M; Tsuchida, Tammy; van den Anker, John; Soldin, Steven J; He, Jianping; McCarter, Robert

2012-10-01

To evaluate the safety and tolerability of treatment with levetiracetam and determine the trough levels of levetiracetam in patients with traumatic brain injury (TBI) who are at high risk for posttraumatic epilepsy (PTE). Open-label, nonrandomized phase 2 study with 2 arms comparing levetiracetam treatment vs observation. Two level 1 trauma centers. A total of 422 participants 6 years or older with TBI who have a 20% risk for PTE were screened. Of these participants, 205 (48.6%) were eligible. A total of 126 participants were enrolled: 86 adults and 40 children. A total of 66 participants were in the treatment group (46 adults and 20 children), and a total of 60 participants were in the observation group (40 adults and 20 children). Participants presenting within 8 hours after TBI received treatment, and those presenting more than 8 to 24 hours after TBI did not. Treatment with levetiracetam (55 mg/kg/d) for 30 days starting within 8 hours after injury. Number of adverse events, mood score, number of infections, trough level of levetiracetam, and PTE. Of the 66 participants treated with levetiracetam, 2 (3%) stopped treatment owing to toxicity (somnolence). The most common adverse events were fatigue, headache, and somnolence. Mood scores and number of infections did not differ between the treatment and observation groups. Mean trough levels of levetiracetam on days 2 to 30 ranged from 19.6 to 26.7 μg/mL. At 2 years, 13 of 86 adults (15.1%) and 1 of 40 children (2.5%) developed PTE. At 2 years, 5 of 46 treated adults (10.9%) and 8 of 40 untreated adults (20.0%) developed PTE (relative risk, 0.47; P=.18). Treatment with 55 mg/kg/d of levetiracetam (a dose with an antiepileptogenic effect on animals) for patients with TBI at risk for PTE is safe and well tolerated, with plasma levels similar to those in animal studies. The findings support further evaluation of levetiracetam treatment for the prevention of PTE. clinicaltrials.gov Identifier: NCT01463033.

Lamotrigine Augmentation Versus Placebo in Serotonin Reuptake Inhibitors-Resistant Obsessive-Compulsive Disorder: A Randomized Controlled Trial

PubMed Central

Khalkhali, Mohammadrasoul; Zarrabi, Homa; Kafie, Moosa; Heidarzadeh, Abtin

2016-01-01

Objective: Serotonin reuptake inhibitors are frequently used in first-line treatments for patients with obsessive-compulsive disorder. Nevertheless, many of these patients do not respond well to initial therapy. The hypothesis of glutamatergic dysfunction in specific brain regions has been proposed in the pathophysiology of obsessive-compulsive disorder. This study was designed to evaluate the possible efficacy of lamotrigine, a glutamatergic agent in Serotonin reuptake inhibitors-resistant patients with obsessive-compulsive disorder. Method: This study was a 12-week, double blind, randomized, placebo-controlled trial of adjunctive fixed-doses of lamotrigine (100 mg) to Serotonin reuptake inhibitors therapy in obsessive-compulsive disorder. Eligible subjects who had a total Y-BOCS of 21 or above were randomly assigned to receive adjunctive treatment with either lamotrigine (n = 26), or placebo (n = 27). Response to lamotrigine was defined as clinical improvement (>25% decrease in the total Y-BOCS score), which was administered at weeks 0, 8 and 12. Results: At the endpoint (week 12), significant differences were observed in obsession, compulsion, and total Y-BOCS scores comparing lamotrigine to placebo (P = 0.01, 0.005 and 0.007 respectively). The mean reduction in obsession, compulsion and total scores in lamotrigine group was about 4.15, 4.50 and 8.73, respectively. Similarly, the mean reductions in the placebo group were 2.52, 2.56 and 5.07. Effect sizes for efficacy measureswerecalculatedbyCohen’sd, and it was calculated as 0.54 for the total YBOCS. Conclusion: Our findings provide evidence that this augmentation is well tolerated and may be an effective strategy for patients with refractory obsessive-compulsive disorder. PMID:27437007

Lacosamide for uncontrolled primary generalized tonic-clonic seizures: An open-label pilot study with 59-week extension.

PubMed

Wechsler, Robert T; Yates, Stephen L; Messenheimer, John; Leroy, Robert; Beller, Cynthia; Doty, Pamela

2017-02-01

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. Copyright © 2016. Published by Elsevier B.V.

Depressive symptoms in epilepsy: prevalence, impact, aetiology, biological correlates and effect of treatment with antiepileptic drugs.

PubMed

Miller, J Mitchell; Kustra, Robert P; Vuong, Alain; Hammer, Anne E; Messenheimer, John A

2008-01-01

Occurring in up to 80% of patients with epilepsy, depression in epilepsy may manifest as (i) major depressive disorder, meeting Diagnostic and Statistical Manual, 4th edition (DSM-IV) diagnostic criteria; (ii) atypical depression or dysthymia; or (iii) a dysthymic-like disorder with intermittent symptoms that can be milder than those of major depression. Depressive symptoms impair patients' health-related quality of life and may affect the clinical course of epilepsy. Depressive symptoms in epilepsy have been attributed to several causes, including endocrine and/or metabolic effects of seizures; the psychological response to epilepsy and its associated mental, physical and social challenges; common pathogenic mechanisms between depression and epilepsy; and the adverse effects of certain antiepileptic drugs (AEDs), particularly GABAergic agents, such as vigabatrin, tiagabine, topiramate and phenobarbital. Whereas some AEDs impair mood, others appear to improve aspects of mood or are mood neutral. Demonstrable antidepressant efficacy of AEDs used to manage seizures could have a significant impact on the care of patients with epilepsy. The AED lamotrigine has been demonstrated to be effective in the treatment of depressive symptoms in patients with epilepsy. In randomized, double-blind, clinical trials in patients with epilepsy, depressive symptoms improved more with lamotrigine monotherapy than valproate monotherapy and more with lamotrigine adjunctive therapy than placebo. Results of open-label studies of lamotrigine monotherapy and adjunctive therapy are consistent with the results of double-blind clinical trials. Lamotrigine-associated improvement in depressive symptoms is independent of its anticonvulsant efficacy. In prospective assessments, gabapentin, levetiracetam and oxcarbazepine each exhibited potentially beneficial effects on depressive symptoms in patients with epilepsy. However, evidence for the efficacy of gabapentin, levetiracetam and oxcarbazepine in

Dramatic effect of levetiracetam in early-onset epileptic encephalopathy due to STXBP1 mutation.

PubMed

Dilena, Robertino; Striano, Pasquale; Traverso, Monica; Viri, Maurizio; Cristofori, Gloria; Tadini, Laura; Barbieri, Sergio; Romeo, Antonino; Zara, Federico

2016-01-01

Syntaxin Binding Protein 1 (STXBP1) mutations determine a central neurotransmission dysfunction through impairment of the synaptic vesicle release, thus causing a spectrum of phenotypes varying from syndromic and non-syndromic epilepsy to intellectual disability of variable degree. Among the antiepileptic drugs, levetiracetam has a unique mechanism of action binding SV2A, a glycoprotein of the synaptic vesicle release machinery. We report a 1-month-old boy manifesting an epileptic encephalopathy with clonic seizures refractory to phenobarbital, pyridoxine and phenytoin that presented a dramatic response to levetiracetam with full epilepsy control and EEG normalization. Genetic analysis identified a novel de novo heterozygous mutation (c.[922A>T]p.[Lys308(∗)]) in the STXBP1 gene that severely affects the protein. The observation of a dramatic efficacy of levetiracetam in a case of STXBP1 epileptic encephalopathy refractory to other antiepileptic drugs and considerations regarding the specific mechanism of action of levetiracetam modulating the same system affected by STXBP1 mutations support the hypothesis that this drug may be able to reverse specifically the disease epileptogenic abnormalities. Further clinical observations and laboratory studies are needed to confirm this hypothesis and eventually lead to consider levetiracetam as the first choice treatment of patients with suspected or confirmed STXBP1-related epilepsies. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Comorbidity of Stevens-Johnson syndrome and neutropenia associated with lamotrigine: a case report.

PubMed

Yasui-Furukori, Norio; Hashimoto, Kojiro; Tsuruga, Koji; Nakamura, Kazuhiko

2014-01-01

A 19-year-old woman with a medical history of depressive mood arrived and was treated with lamotrigine at 25 mg/day. On day 10, a high fever of 39.3 °C and a diffuse, erythematous, pruritic full-body rash involving the palms of her hands and the soles of her feet developed, and she was diagnosed with Stevens-Johnson syndrome (SJS). On day 17, white blood cell count (WBC) result was 1,240/μl with 54.1% neutrophils (670/μl), and the WBC decreased to 840/μl with 60.7% neutrophils (510/μl) on day 18. The trend toward improvement included skin symptoms after steroid pulse therapy using 1000 mg/day. Based on the clinical course, we concluded that the SJS and leukopenia and/or neutropenia are associated with lamotrigine. Monitoring of WBC should be kept in mind when administering lamotrigine. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Time-to-Seizure Modeling of Lacosamide Used in Monotherapy in Patients with Newly Diagnosed Epilepsy.

PubMed

Lindauer, Andreas; Laveille, Christian; Stockis, Armel

2017-11-01

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.

Add-on levetiracetam in children and adolescents with refractory epilepsy: results of an open-label multi-centre study.

PubMed

Callenbach, Petra M C; Arts, Willem Frans M; ten Houten, Robert; Augustijn, Paul; Gunning, W Boudewijn; Peeters, Els A J; Weber, Alma M; Stroink, Hans; Geerts, Yvette; Geerts, Ada T; Brouwer, Oebele F

2008-07-01

To study the efficacy and tolerability of add-on levetiracetam in children and adolescents with refractory epilepsy. In this prospective multi-centre, open-label, add-on study, 33 children aged 4-16 years (median 8.5 years) with epilepsy refractory to at least two antiepileptic drugs were treated with levetiracetam in addition to their present treatment regimen with a follow-up of 26 weeks. The starting dose of 10 mg/kg/day was increased with 2-week steps of 10 mg/kg/day, if necessary, up to a maximum dose of 60 mg/kg/day. Retention rate was 69.7% after 26 weeks on a median levetiracetam dosage of 22 mg/kg/day. Four children dropped-out because levetiracetam was ineffective, four because seizure frequency increased and/or seizures became more severe, and two because they developed aggressive behaviour. Compared to their baseline seizure frequency, 13 children (39.4%) had a >50% seizure reduction 12 weeks after initiation of levetiracetam, and 17 children (51.5%) at 26 weeks. At 26 weeks, nine children (27.3%) had been seizure-free for at least the last 4 weeks, terminal remission ranged from 0 to 187 days (mean 46 days). Levetiracetam was effective in both partial and primary generalized seizures, but had most effect in partial seizures. Most reported side effects were hyperactivity (48.5%), somnolence (36.4%), irritability (33.3%) and aggressive behaviour (27.3%). Severity of most side effects was mild. Five children had a serious adverse event, which all concerned hospital admissions that were not related to levetiracetam use. Levetiracetam proved to be an effective and well-tolerated add-on treatment in this group of children with refractory epilepsy.

Tolerability, pharmacokinetics, and bioequivalence of the tablet and syrup formulations of lacosamide in plasma, saliva, and urine: saliva as a surrogate of pharmacokinetics in the central compartment.

PubMed

Cawello, Willi; Bökens, Hilmar; Nickel, Brunhild; Andreas, Jens-Otto; Halabi, Atef

2013-01-01

To test for bioequivalence of 200 mg lacosamide oral tablet and syrup formulations. Additional objectives were to compare the pharmacokinetic profile of lacosamide in saliva and plasma, and to evaluate its tolerability. This open-label, randomized, two-way crossover trial was conducted in 16 healthy Caucasian male participants in Germany. The bioequivalence of 200 mg lacosamide tablet and syrup was evaluated using plasma to determine maximum measured concentration (C(max)) and area under the curve from zero to the last time point (AUC)(0-tz). Plasma and saliva samples for evaluation of pharmacokinetic parameters of lacosamide and the major metabolite O-desmethyl lacosamide (SPM 12809) were taken over 15 time points (0.5-72 h) and used to statistically compare bioavailability of the two. Urine samples were collected predose and over five time points (0-48 h) to evaluate the cumulative amount of unchanged drug and metabolite. Lacosamide median time to reach C(max) (t(max)) was 1 h for tablet and 0.5 h for syrup in plasma and saliva. Mean terminal half life (t(½)) for tablet and syrup was 12.5 and 12.4 h in plasma, and 13.1 and 13.3 h in saliva, respectively. Tablet and syrup mean plasma AUC(0-tz) was 84.5 and 83.3 μg/mL*h, respectively. Mean AUC(0-tz) in saliva was 93.2 μg/mL*h for tablet and syrup. Mean C(max) for tablet was 5.26 μg/mL in plasma and 5.63 μg/mL in saliva. Syrup mean C(max) was 5.14 and 8.32 μg/mL in plasma and saliva, respectively. Within 2 h of syrup administration, elevated lacosamide concentration in saliva compared to plasma was observed. The ratio of lacosamide syrup to tablet was 0.98 for C(max) and 0.99 for AUC(0-tz) in plasma, and 1.00 for AUC((0-tz)) in saliva; the 90% confidence intervals (CIs) for these parameters were within the range of 0.80-1.25, which meets accepted bioequivalence criteria. The syrup-to-tablet ratio for C(max) in saliva was 1.48, and the 90% CIs exceeded the accepted upper boundary for bioequivalence (1

Lack of efficacy of levetiracetam in oromandibular and cranial dystonia.

PubMed

Park, J E; Srivanitchapoom, P; Maurer, C W; Mathew, P; Sackett, J; Paine, R; Ramos, V L; Hallett, M

2017-08-01

To determine the efficacy of levetiracetam in oromandibular or cranial dystonia. We recruited seven subjects with oromandibular or cranial dystonia. Five completed the study, median age was 71 years (range 42-79 years), median disease duration was 12 years (range 2-30 years). Participants were randomized to receive levetiracetam or placebo and were then crossed over. They titrated up to a total daily dose of 4000 mg or the maximum tolerated dose over 3 weeks and maintained that dose for another 3 weeks. The primary endpoint was the percent change of the eyes, mouth, speech, and swallowing Burke-Fahn-Marsden (BFM) subscores from baseline to weeks 6 and 14. Additional endpoints included the BFM subscore at weeks 3 and 11, and the global dystonia severity (GDS) subscore at weeks 3, 6, 11, and 14, as well as all adverse side effects. The mean percent increase in the BFM subscore (placebo: 31.25%, levetiracetam: 12.16%) was not significantly different between the two arms according to the Friedman analysis. The Wilcoxon signed-rank test showed that these percent changes were not significant, indicating that there was no statistical clinical worsening in either arm. The mean percent change of the BFM subscore at weeks 3 and 11 and the mean percent change of the GDS subscore at weeks 3, 6, 11, and 14 were not significantly different between the two arms, and the Wilcoxon signed-rank test did not show statistical significance. Levetiracetam does not appear to be efficacious in patients with oromandibular or cranial dystonia. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Lamotrigine-induced tubulointerstitial nephritis and uveitis-atypical Cogan syndrome.

PubMed

Kolomeyer, Anton M; Kodati, Shyam

2015-12-01

To report a case of lamotrigine-induced tubulointerstitial nephritis and uveitis (TINU)-atypical Cogan syndrome. Case report. A 16-year-old boy with traumatic brain injury and seizures presented to the emergency department with facial swelling, rash, and back pain several days after increasing lamotrigine dose secondary to a breakthrough seizure. Creatinine, urine β2 microglobulin, and eosinophils were elevated. Antinuclear antibodies, antineutrophil cytoplasmic antibodies, angiotensin-converting enzyme, and complement were normal. Renal biopsy showed acute granulomatous tubulointerstitial nephritis. Lamotrigine was discontinued, intravenous steroids were initiated, and the patient was discharged on Ativan and prednisone. Subsequently, he was diagnosed with bilateral anterior uveitis (vision 20/30 bilaterally) and started on prednisolone and cyclopentolate. Two months later, he developed a branch retinal artery occlusion in the right eye (vision 20/70) and bilateral ocular hypertension for which timolol-brimonidine and dorzolamide were added. Neuroimaging and hypercoagulability workup was unremarkable. Vision and intraocular pressure improved, while uveitis remained recalcitrant. Several months later, the patient developed central serous retinopathy in the right eye (vision 20/30). Prednisone was stopped but restarted due to methotrexate intolerance. A month later, he reported dizziness and was diagnosed with severe bilateral sensorineural hearing loss. Brain magnetic resonance imaging showed foci of perivascular, subcortical, and cochlear enhancement. Transtympanic Decadron injections and infliximab infusions were initiated. At the final visit, vision remained at 20/30 with trace anterior chamber reaction bilaterally while on timolol-brimonidine, dorzolamide, and prednisolone. An idiosyncratic drug reaction should be considered in the differential diagnosis of TINU-atypical Cogan syndrome.

Results of Phase 2 Safety and Feasibility Study of Treatment With Levetiracetam for Prevention of Posttraumatic Epilepsy

PubMed Central

Klein, Pavel; Herr, Daniel; Pearl, Phillip L.; Natale, JoAnne; Levine, Zachary; Nogay, Claude; Sandoval, Fabian; Trzcinski, Stacey; Atabaki, Shireen M.; Tsuchida, Tammy; van den Anker, John; Soldin, Steven J.; He, Jianping; McCarter, Robert

2016-01-01

Objectives To evaluate the safety and tolerability of treatment with levetiracetam and determine the trough levels of levetiracetam in patients with traumatic brain injury (TBI) who are at high risk for posttraumatic epilepsy (PTE). Design Open-label, nonrandomized phase 2 study with 2 arms comparing levetiracetam treatment vs observation. Setting Two level 1 trauma centers. Patients A total of 422 participants 6 years or older with TBI who have a 20% risk for PTE were screened. Of these participants, 205 (48.6%) were eligible. A total of 126 participants were enrolled: 86 adults and 40 children. A total of 66 participants were in the treatment group (46 adults and 20 children), and a total of 60 participants were in the observation group (40 adults and 20 children). Participants presenting within 8 hours after TBI received treatment, and those presenting more than 8 to 24 hours after TBI did not. Intervention Treatment with levetiracetam (55 mg/kg/d) for 30 days starting within 8 hours after injury. Main Outcome Measures Number of adverse events, mood score, number of infections, trough level of levetiracetam, and PTE. Results Of the 66 participants treated with levetiracetam, 2 (3%) stopped treatment owing to toxicity (somnolence). The most common adverse events were fatigue, headache, and somnolence. Mood scores and number of infections did not differ between the treatment and observation groups. Mean trough levels of levetiracetam on days 2 to 30 ranged from 19.6 to 26.7 μg/mL. At 2 years, 13 of 86 adults (15.1%) and 1 of 40 children (2.5%) developed PTE. At 2 years, 5 of 46 treated adults (10.9%) and 8 of 40 untreated adults (20.0%) developed PTE (relative risk, 0.47; P=.18). Conclusion Treatment with 55 mg/kg/d of levetiracetam (a dose with an antiepileptogenic effect on animals) for patients with TBI at risk for PTE is safe and well tolerated, with plasma levels similar to those in animal studies. The findings support further evaluation of levetiracetam

[Rational combinations of antiepileptic drugs for refractory epilepsy].

PubMed

Yoshino, Aihide

2011-04-01

Although epilepsy surgery is most effective for patients with intractable epilepsy, a majority of them is not eligible for the surgery. Most of patients with refractory epilepsy are eventually treated with polypharmacy in hope of seizure control. Therefore, rational combinations of antiepileptic drugs are needed to control intractable seizures. Drug combinations should be rationally chosen based on the evidence of synergic efficacy and on avoidance of neurotoxicity. Several clinical studies suggest that the combination of valproate with lamotrigine has synergic antiepileptic effect. It has also been reported that the combination of carbamazepine with lamotrigine paradoxically decreases efficacy and increases toxicity. Animal studies using isobolography suggest that the combinations of topiramate with lamotrigine or levetiracetam are also promising on both seizure control and neurotoxicity. Clinical research is needed to examine these combinations.

A microdialysis study of the novel antiepileptic drug levetiracetam: extracellular pharmacokinetics and effect on taurine in rat brain

PubMed Central

Tong, X; Patsalos, P N

2001-01-01

Using a rat model which allows serial blood sampling and concurrent brain microdialysis sampling, we have investigated the temporal kinetic inter-relationship of levetiracetam in serum and brain extracellular fluid (frontal cortex and hippocampus) following systemic administration of levetiracetam, a new antiepileptic drug. Concurrent extracellular amino acid concentrations were also determined. After administration (40 or 80 mg kg−1), levetiracetam rapidly appeared in both serum (Tmax, 0.4 – 0.7 h) and extracellular fluid (Tmax, 2.0 – 2.5 h) and concentrations rose linearly and dose-dependently, suggesting that transport across the blood-brain barrier is rapid and not rate-limiting. The serum free fraction (free/total serum concentration ratio; mean±s.e.mean range 0.93 – 1.05) was independent of concentration and confirms that levetiracetam is not bound to blood proteins. The kinetic profiles for the hippocampus and frontal cortex were indistinguishable suggesting that levetiracetam distribution in the brain is not brain region specific. However, t1/2 values were significantly larger than those for serum (mean range, 3.0 – 3.3 h vs 2.1 – 2.3 h) and concentrations did not attain equilibrium with respect to serum. Levetiracetam (80 mg kg−1) was associated with a significant reduction in taurine in the hippocampus and frontal cortex. Other amino acids were unaffected by levetiracetam. Levetiracetam readily and rapidly enters the brain without regional specificity. Its prolonged efflux from and slow equilibration within the brain may explain, in part, its long duration of action. The concurrent changes in taurine may contribute to its mechanism of action. PMID:11454660

An 11-year review of levetiracetam ingestions in children less than 6 years of age.

PubMed

Lewis, J C; Albertson, T E; Walsh, M J

2014-11-01

Levetiracetam is a new anticonvulsant, which works to block high-voltage-activated Ca(++) channels in children, for partial-onset seizures. Reports of clinical experience with pediatric ingestions are minimal. The purpose of this study was to characterize the toxicity of accidental levetiracetam exposures in children less than 6 years of age. This was an 11-year retrospective observational case series of pediatric (< 6 years old) levetiracetam ingestions reported to a Poison Control System from 2002 to 2013. Case narratives were individually reviewed to collect desired information on exposure and clinical course. Inclusion criteria were levetiracetam as a single ingested medication, age less than 6 years, treatment in a health care facility, and followed to a known outcome. Eighty-two cases met inclusion criteria with 55% female patients and overall median age of 2.0 years (range: 1-60 months). The levetiracetam dose ingested was reported in 69 (84.1%) cases, with exact dose (median dose, 45.0 mg/kg; range, 10.5-1429 mg/kg) reported in 33 cases (40.2%). Of these, twenty-nine cases (88%) involved the oral solution formulation and 28 cases (85%) had unintentional therapeutic error as the cause of the exposure. No dose-response relationship was demonstrated; however, the odds of a levetiracetam-naive patient, (median dose, 26.9 mg/kg; N = 15) with an unintentional exposure, developing drowsiness or ataxia was 6 times that of a patient who was not naïve to levetiracetam (median dose, 70.1 mg/kg; N = 20) (Odds ratio [OR], 6.0; 95% confidence interval [CI], 1.03-35.91).Of the 82 cases, 17 (20.7%) developed untoward clinical effects of drowsiness and/or ataxia. Eighty patients (97.6%) were treated and discharged from the emergency department, and two patients (2.4%) were admitted. The two patients admitted included a two-month old who was accidentally given a dose 10 times that of her usual dose and a 3-year old who was lethargic on arrival to the hospital after

An Open-Label Study of Lamotrigine Adjunct or Monotherapy for the Treatment of Adolescents with Bipolar Depression

ERIC Educational Resources Information Center

Chang, Kiki; Saxena, Kirti; Howe, Meghan

2006-01-01

Objective: The treatment of pediatric bipolar depression has not been well studied. The authors wished to prospectively study the efficacy of lamotrigine as adjunctive or monotherapy in adolescents with bipolar disorder who were experiencing a depressive episode. Method: This was an 8-week open-label trial of lamotrigine with 20 adolescents ages…

Hyponatremia associated with repeated use of levetiracetam.

PubMed

Nasrallah, Khalil; Silver, Brian

2005-06-01

Levetiracetam (LEV) is increasingly used as adjunctive anticonvulsant therapy because of apparent low toxicity. Somnolence, asthenia, headache, dizziness, and nervousness are the most frequently reported side effects (1). We describe a patient, predisposed to the development of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), in whom hyponatremia developed after two challenges of LEV.

A single-blinded phenobarbital-controlled trial of levetiracetam as mono-therapy in dogs with newly diagnosed epilepsy.

PubMed

Fredsø, N; Sabers, A; Toft, N; Møller, A; Berendt, M

2016-02-01

Treatment of canine epilepsy is problematic. Few antiepileptic drugs have proven efficacy in dogs and undesirable adverse effects and pharmacoresistance are not uncommon. Consequently, the need for investigation of alternative treatment options is ongoing. The objective of this study was to investigate the efficacy and tolerability of levetiracetam as mono-therapy in dogs with idiopathic epilepsy. The study used a prospective single-blinded parallel group design. Twelve client-owned dogs were included and were randomised to treatment with levetiracetam (30 mg/kg/day or 60 mg/kg/day divided into three daily dosages) or phenobarbital (4 mg/kg/day divided twice daily). Control visits were at days 30, 60 and then every 3 months for up to 1 year. Two or more seizures within 3 months led to an increase in drug dosage (levetiracetam: 10 mg/kg/day, phenobarbital: 1 mg/kg/day). Five of six levetiracetam treated dogs and one of six phenobarbital treated dogs withdrew from the study within 2-5 months due to insufficient seizure control. In the levetiracetam treated dogs there was no significant difference in the monthly number of seizures before and after treatment, whereas in the phenobarbital treated dogs there were significantly (P = 0.013) fewer seizures after treatment. Five phenobarbital treated dogs were classified as true responders (≥50% reduction in seizures/month) whereas none of the levetiracetam treated dogs fulfilled this criterion. Adverse effects were reported in both groups but were more frequent in the phenobarbital group. In this study levetiracetam was well tolerated but was not effective at the given doses as mono-therapy in dogs with idiopathic epilepsy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Clinical management of elderly patients with epilepsy; the use of lacosamide in a single center setting.

PubMed

Rainesalo, Sirpa; Mäkinen, Jussi; Raitanen, Jani; Peltola, Jukka

2017-10-01

Lacosamide (LCM) is a third-generation antiepileptic drug (AED) for which there is limited experience in the treatment of elderly patients with epilepsy. This study was performed to evaluate the use of LCM in this particular patient group, focusing on its tolerability and effectiveness. This is a retrospective, single-center study, in patients over 60years old treated with LCM between 1/2010 and 5/2015. Altogether, 233 elderly patients receiving LCM were identified; of these, 67 fulfilled the inclusion criteria, i.e., LCM administered for at least 2weeks. Lacosamide was initiated for acute seizure disorders (prolonged complex partial seizures, recurrent seizures, or status epilepticus) in 54 patients (81%) and for chronic epilepsy in 13 patients in an outpatient setting. The mean follow-up period for LCM treatment was 14months. The mean daily dose of LCM at the end of follow-up was 368mg (range: 100-600) for those 57 patients that continued treatment. Ten patients (15%) stopped LCM treatment but none because of lack of efficacy and only three patients (4%) because of side effects. The most frequent side effects were dizziness, fatigue, and tremor. Lacosamide was well tolerated even at relatively high doses and in combination therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of hydroalcoholic extract of ginger on the liver of epileptic female rats treated with lamotrigine

PubMed Central

Poorrostami, Ameneh; Farokhi, Farah; Heidari, Reza

2014-01-01

Objective: Lamotrigine is an antiepileptic drug, widely used in the treatment of epilepsy; long-term use of this drug can cause hepatotoxicity. Zingiber officinale Roscoe (ginger) possesses antioxidant properties. In present research, the effect ofhydroalcoholic extract of ginger (HEG) on the liver of lamotrigine-treated epileptic rats was investigated Material and Methods: Forty-eight female Wistar rats were selected and allocated to 8 groups of 6 each. Group 1: Negative controls were treated with normal saline. Group 2: Positive controls were treated with lamotrigine (LTG) (10 mg/kg) daily by gavages for 4 consecutive weeks. Epilepsy was induced in treatment groups by i.p. injection of pentylenetetrazol (PTZ) (40 mg/kg). Group 3: Epileptic group received normal saline (10 ml/kg). Group 4: Epileptic group was treated with LTG (10 mg/kg). Groups 5 and 6: Epileptic groups received HEG (50 and 100 mg/kg). Groups 7 and 8: Epileptic groups received LTG and HEG (50 and 100 mg/kg). At the end of 28 days, blood samples were drawn and their livers were processed for light microscopy. Results: The mean values of TG, CHOL, AST, and ALT activity significantly rose (p<0.01) in groups 2, 3, and 4, while in rats treated with HEG (groups 5, 6, 7, and 8), the levels of liver enzymes significantly decreased (p<0.05) compared with epileptic group treated with lamotrigine (group 4). Histopathological changes of liver samples were comparable with respective control. Conclusion: These results suggest that hydroalcoholic extract of ginger improves liver function in lamotrigine-induced hepatotoxicity. PMID:25068142

A Pilot Chemical and Physical Stability Study of Extemporaneously Compounded Levetiracetam Intravenous Solution.

PubMed

Raphael, Chenzira D; Zhao, Fang; Hughes, Susan E; Juba, Katherine M

2015-01-01

Levetiracetam is a commonly used antiepileptic medication for tumor-related epilepsy. However, the 100 mL intravenous (IV) infusion volume can be burdensome to imminently dying hospice patients. A reduced infusion volume would improve patient tolerability. The purpose of this study was to evaluate the stability of 1000 mg/25 mL (40 mg/mL) levetiracetam IV solution in sodium chloride 0.9%. We prepared levetiracetam 40 mg/mL IV solution and added it to polyvinyl chloride (PVC) bags, polyolefin bags, and polypropylene syringes. Triplicate samples of each product were stored at refrigeration (2-8°C) and analyzed on days 0, 1, 4, 7, and 14. Samples were subjected to visual inspection, pH measurement, and stability-indicating high-performance liquid chromatography (HPLC) analysis. Over the 2-week storage period, there was no significant change in visual appearance or pH for any of the stability samples. The HPLC results confirmed that all stability samples retained 94.2-101.3% of initial drug concentration and no degradation products or leachable material from the packaging materials were observed. We conclude that levetiracetam 1000 mg/25 mL IV solution in sodium chloride 0.9% is physically and chemically stable for up to 14 days under refrigeration in polypropylene syringes, PVC bags, and polyolefin bags.

Quality of life, mood and seizure control in patients with brain tumor related epilepsy treated with lacosamide as add-on therapy: A prospective explorative study with a historical control group.

PubMed

Maschio, Marta; Zarabla, Alessia; Maialetti, Andrea; Fabi, Alessandra; Vidiri, Antonello; Villani, Veronica; Giannarelli, Diana

2017-08-01

Brain tumor-related epilepsy (BTRE) is often drug resistant and patients can be forced to take polytherapy that can adversely affect their quality of life (QoL). Lacosamide (LCM) is a new antiepileptic drug (AED) used as adjunctive therapy in patients with partial seizures with or without secondary generalization, with a favorable pharmacokinetic profile that seems to be effective and well tolerated. Therefore it represents a possible therapeutic choice for patients with BTRE. We propose a prospective study with a historical control group to evaluate the effect of LCM as add-on therapy on seizure control and quality of life in patients with BTRE. This study has been designed to test the superiority of Lacosamide over Levetiracetam as an add-on. We compared a prospective cohort of 25 patients treated with Lacosamide with a historical control group (n=19) treated with Levetiracetam as an add-on. We recruited 25 adult patients (M 18, F 7; mean age 41.9) affected by BTRE with uncontrolled partial-onset seizures treated with AED polytherapy. We added LCM as an add-on. Patients were evaluated at baseline, after 3months and at 6months. This population has been compared with a historical control group of 19 BTRE adult patients (M 13, F 6; median age 48.0, range: 28-70) with uncontrolled partial-onset seizures treated with LEV as add-on. The patients underwent QoL, mood and adverse events tests (Adverse Event Profile-AEP) and evaluation of seizure frequency. Twelve patients had high grade gliomas, and thirteen had low grade gliomas. During follow-up, thirteen patients underwent chemotherapy, three radiotherapy and five patients had disease progression. Nine patients had simple partial seizures, eight had complex partial seizures, and eight had secondary generalized seizures. Fifteen patients were in monotherapy and ten in polytherapy with AEDs. LCM was added up to reach the maximum dosage of 400mg/die (mean final dose 300mg/die). Four patients dropped out due to poor

Cognition in school-age children exposed to levetiracetam, topiramate, or sodium valproate.

PubMed

Bromley, Rebecca L; Calderbank, Rebecca; Cheyne, Christopher P; Rooney, Claire; Trayner, Penny; Clayton-Smith, Jill; García-Fiñana, Marta; Irwin, Beth; Morrow, James Irvine; Shallcross, Rebekah; Baker, Gus A

2016-11-01

To investigate the effects of prenatal exposure to monotherapy levetiracetam, topiramate, and valproate on child cognitive functioning. This was a cross-sectional observational study. Children exposed to monotherapy levetiracetam (n = 42), topiramate (n = 27), or valproate (n = 47) and a group of children born to women who had untreated epilepsy (n = 55) were enrolled retrospectively from the UK Epilepsy and Pregnancy Register. Assessor-blinded neuropsychological assessments were conducted between 5 and 9 years of age. Information was collected on demographic and health variables and adjusted for in multiple regression analyses. In the adjusted analyses, prenatal exposure to levetiracetam and topiramate were not found to be associated with reductions in child cognitive abilities, and adverse outcomes were not associated with increasing dose. Increasing dose of valproate, however, was associated with poorer full-scale IQ (-10.6, 95% confidence interval [CI] -16.3 to -5.0, p < 0.001), verbal abilities (-11.2, 95% CI -16.8 to -5.5, p < 0.001), nonverbal abilities (-11.1, 95% CI -17.3 to -4.9, p < 0.001), and expressive language ability (-2.3, 95% CI -3.4 to -1.6, p < 0.001). Comparisons across medications revealed poorer performance for children exposed to higher doses of valproate in comparison to children exposed to higher doses of levetiracetam or topiramate. Preconception counseling should include discussion of neurodevelopmental outcomes for specific treatments and their doses and women should be made aware of the limited nature of the evidence base for newer antiepileptic drugs. © 2016 American Academy of Neurology.

Levetiracetam for the treatment of hot flashes: a phase II study.

PubMed

Thompson, Susan; Bardia, Aditya; Tan, Angelina; Barton, Debra L; Kottschade, Lisa; Sloan, Jeff A; Christensen, Brad; Smith, DeAnne; Loprinzi, Charles L

2008-01-01

The objectives of this pilot trial were to assess the potential efficacy and safety of levetiracetam for the treatment of hot flashes, a major cause of morbidity among breast cancer survivors. Women, aged 18 years or more, with a history of breast cancer or those who wished to avoid estrogen because of a perceived increased risk of breast cancer, who were experiencing bothersome hot flashes (more than or equal to 14 times per week, for more than or equal to 1 month before study entry), were included. During the baseline week, general demographic characteristics, hot flash information, and quality of life data were obtained. At the beginning of week 2, patients were started on levetiracetam for a total of 4 weeks. Information about hot flashes, quality of life, and toxicity were collected during these 4 weeks and compared with the baseline week. After treatment with levetiracetam for 4 weeks (N = 19), mean hot flash scores (frequency times mean severity) were reduced by 57%, and mean hot flash frequencies were reduced by 53%, compared to the baseline week; both these reductions were greater than what would be expected with a placebo (20-25% reduction). There were significant improvements in abnormal sweating (p = 0.004), hot flash distress (p = 0.0002), and satisfaction of hot flash control (p = 0.0001), when comparing data from the fourth week of treatment to the baseline week. Twenty-nine percent of the subjects did not complete the study because of treatment-related adverse events, with the most frequently reported side effects being somnolence, fatigue, and dizziness, usually with mild to moderate intensity. The results of this pilot trial suggest that levetiracetam might be an effective therapy for the treatment of hot flashes. Further data are needed to test this hypothesis, evaluating the efficacy and toxicity of this agent.

Lacosamide in status epilepticus: Systematic review of current evidence.

PubMed

Strzelczyk, Adam; Zöllner, Johann Philipp; Willems, Laurent M; Jost, Julie; Paule, Esther; Schubert-Bast, Susanne; Rosenow, Felix; Bauer, Sebastian

2017-06-01

The intravenous formulation of lacosamide (LCM) and its good overall tolerability and safety favor the use in status epilepticus (SE). The aim of this systematic review was to identify and evaluate studies reporting on the use of LCM in SE. We performed a systematic literature search of electronic databases using a combined search strategy from 2008 until October 2016. Using a standardized assessment form, information on the study design, methodologic framework, data sources, efficacy, and adverse events attributed to LCM were extracted from each publication and systematically reported. In total, 522 SE episodes (51.7% female) in 486 adults and 36 children and adolescents were evaluated with an overall LCM efficacy of 57%. Efficacy was comparable between use in nonconvulsive (57%; 82/145) and generalized-convulsive (61%; 30/49; p = 0.68) SE, whereas overall success rate was better in focal motor SE (92%; 34/39, p = 0.013; p < 0.001). The efficacy with later positioning of LCM decreased from 100% to 20%. The main adverse events during treatment of SE are dizziness, abnormal vision, diplopia, and ataxia. Overall, lacosamide is well tolerated and has no clinically relevant drug-drug interactions. The available data regarding the use of LCM in SE are promising, with a success rate of 57%. The strength of LCM is the lack of interaction potential and the option for intravenous use in emergency situations requiring rapid uptitration. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry.

PubMed

Tomson, Torbjörn; Battino, Dina; Bonizzoni, Erminio; Craig, John; Lindhout, Dick; Perucca, Emilio; Sabers, Anne; Thomas, Sanjeev V; Vajda, Frank

2018-06-01

Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p<0·0001). After adjustment, multivariable

Efficacy, safety, and tolerability of lacosamide monotherapy versus controlled-release carbamazepine in patients with newly diagnosed epilepsy: a phase 3, randomised, double-blind, non-inferiority trial.

PubMed

Baulac, Michel; Rosenow, Felix; Toledo, Manuel; Terada, Kiyohito; Li, Ting; De Backer, Marc; Werhahn, Konrad J; Brock, Melissa

2017-01-01

Further options for monotherapy are needed to treat newly diagnosed epilepsy in adults. We assessed the efficacy, safety, and tolerability of lacosamide as a first-line monotherapy option for these patients. In this phase 3, randomised, double-blind, non-inferiority trial, patients from 185 epilepsy or general neurology centres in Europe, North America, and the Asia Pacific region, aged 16 years or older and with newly diagnosed epilepsy were randomly assigned in a 1:1 ratio, via a computer-generated code, to receive lacosamide monotherapy or controlled-release carbamazepine (carbamazepine-CR) twice daily. Patients, investigators, and trial personnel were masked to treatment allocation. From starting doses of 100 mg/day lacosamide or 200 mg/day carbamazepine-CR, uptitration to the first target level of 200 mg/day and 400 mg/day, respectively, took place over 2 weeks. After a 1-week stabilisation period, patients entered a 6-month assessment period. If a seizure occurred, the dose was titrated to the next target level (400 or 600 mg/day for lacosamide and 800 or 1200 mg/day for carbamazepine-CR) over 2 weeks with a 1-week stabilisation period, and the 6-month assessment period began again. Patients who completed 6 months of treatment and remained seizure-free entered a 6-month maintenance period on the same dose. The primary efficacy outcome was the proportion of patients remaining free from seizures for 6 consecutive months after stabilisation at the last assessed dose. The predefined non-inferiority criteria were -12% absolute and -20% relative difference between treatment groups. This trial is registered with ClinicalTrials.gov, number NCT01243177. The trial was done between April 27, 2011, and Aug 7, 2015. 888 patients were randomly assigned treatment. 444 patients taking lacosamide and 442 taking carbamazepine-CR were included in the full analysis set (took at least one dose of study treatment), and 408 and 397, respectively, were included in the per

Levetiracetam selectively potentiates the acute neurotoxic effects of topiramate and carbamazepine in the rotarod test in mice.

PubMed

Luszczki, Jarogniew J; Andres, Marta M; Czuczwar, Piotr; Cioczek-Czuczwar, Anna; Wojcik-Cwikla, Joanna; Ratnaraj, Neville; Patsalos, Philip N; Czuczwar, Stanislaw J

2005-12-01

The effect of levetiracetam (LEV) on the acute neurotoxic profiles of various antiepileptic drugs (carbamazepine [CBZ], phenytoin [PHT], phenobarbital [PB], valproate [VPA], lamotrigine [LTG], topiramate [TPM], oxcarbazepine [OXC], and felbamate [FBM]) was evaluated in the rotarod test, allowing the determination of median toxic doses (TD50 values) with respect to impairment of motor coordination in mice. The TD50 of LEV administered singly was 1601 mg/kg. Whilst LEV at 150 mg/kg, being its TID50 (a dose increasing the electroconvulsive threshold by 50%), was without effect with regards to motor coordination impairment associated with PHT, PB, VPA, LTG, OXC, and FBM, it significantly enhanced that associated with CBZ and TPM co-administration. Thus LEV (150 mg/kg) significantly decreased the TD50 of CBZ from 53.6 to 37.3 mg/kg (P<0.01) and that of TPM from 423 to 246 mg/kg (P<0.01). In addition LEV (75 mg/kg) significantly decreased the TD50 of TPM from 423 to 278 (P<0.01). That concurrent measurement of total brain LEV, CBZ, and TPM concentrations showed that concentrations were not significantly different when AEDs were administered singly compared to when they were administered in combination would suggest that there is no pharmacokinetic interaction between these AEDs. Thus, the observed potentialization of the acute neurotoxic effects of CBZ and TPM by LEV is the consequence of a pharmacodynamic interaction. These data support both experimental and clinical published data advocating that LEV may interact with some AEDs by pharmacodynamic mechanisms.

Lacosamide Isothiocyanate-based Agents: Novel Agents to Target and Identify Lacosamide Receptors

PubMed Central

Park, Ki Duk; Morieux, Pierre; Salomé, Christophe; Cotten, Steven W.; Reamtong, Onrapak; Eyers, Claire; Gaskell, Simon J.; Stables, James P.; Liu, Rihe; Kohn, Harold

2009-01-01

(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 analogs, 3, that 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. PMID:19795888

Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine

PubMed Central

Ku, Lawrence C.; Wu, Huali; Greenberg, Rachel G.; Hill, Kevin D.; Gonzalez, Daniel; Hornik, Christoph P.; Berezny, Alysha; Guptill, Jeffrey T.; Jiang, Wenlei; Zheng, Nan; Cohen-Wolkowiez, Michael; Melloni, Chiara

2016-01-01

Background Defining a drug's therapeutic index (TI) is important for patient safety and regulating the development of generic drugs. For many drugs, the TI is unknown. A systematic approach was developed to characterize the TI of a drug using therapeutic drug monitoring and electronic health record (EHR) data with pharmacokinetic (PK) modeling. This approach was first tested on phenytoin, which has a known TI, and then applied to lamotrigine, which lacks a defined TI. Methods Retrospective EHR data from patients in a tertiary hospital were used to develop phenytoin and lamotrigine population PK models and to identify adverse events (anemia, thrombocytopenia, and leukopenia) and efficacy outcomes (seizure-free). Phenytoin and lamotrigine concentrations were simulated for each day with an adverse event or seizure. Relationships between simulated concentrations and adverse events and efficacy outcomes were used to calculate the TI for phenytoin and lamotrigine. Results For phenytoin, 93 patients with 270 total and 174 free concentrations were identified. A de novo 1-compartment PK model with Michaelis-Menten kinetics described the data well. Simulated average total and free concentrations of 10-15 and 1.0-1.5 μg/mL were associated with both adverse events and efficacy in 50% of patients, resulting in a TI of 0.7–1.5. For lamotrigine, 45 patients with 53 concentrations were identified. A published 1-compartment model was adapted to characterize the PK data. No relationships between simulated lamotrigine concentrations and safety or efficacy endpoints were seen; therefore, the TI could not be calculated. Conclusions This approach correctly determined the TI of phenytoin but was unable to determine the TI of lamotrigine due to a limited sample size. The use of therapeutic drug monitoring and EHR data to aid in narrow TI drug classification is promising, but it requires an adequate sample size and accurate characterization of concentration–response relationships

Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine.

PubMed

Ku, Lawrence C; Wu, Huali; Greenberg, Rachel G; Hill, Kevin D; Gonzalez, Daniel; Hornik, Christoph P; Berezny, Alysha; Guptill, Jeffrey T; Jiang, Wenlei; Zheng, Nan; Cohen-Wolkowiez, Michael; Melloni, Chiara

2016-12-01

Defining a drug's therapeutic index (TI) is important for patient safety and regulating the development of generic drugs. For many drugs, the TI is unknown. A systematic approach was developed to characterize the TI of a drug using therapeutic drug monitoring and electronic health record (EHR) data with pharmacokinetic (PK) modeling. This approach was first tested on phenytoin, which has a known TI, and then applied to lamotrigine, which lacks a defined TI. Retrospective EHR data from patients in a tertiary hospital were used to develop phenytoin and lamotrigine population PK models and to identify adverse events (anemia, thrombocytopenia, and leukopenia) and efficacy outcomes (seizure-free). Phenytoin and lamotrigine concentrations were simulated for each day with an adverse event or seizure. Relationships between simulated concentrations and adverse events and efficacy outcomes were used to calculate the TI for phenytoin and lamotrigine. For phenytoin, 93 patients with 270 total and 174 free concentrations were identified. A de novo 1-compartment PK model with Michaelis-Menten kinetics described the data well. Simulated average total and free concentrations of 10-15 and 1.0-1.5 mcg/mL were associated with both adverse events and efficacy in 50% of patients, resulting in a TI of 0.7-1.5. For lamotrigine, 45 patients with 53 concentrations were identified. A published 1-compartment model was adapted to characterize the PK data. No relationships between simulated lamotrigine concentrations and safety or efficacy endpoints were seen; therefore, the TI could not be calculated. This approach correctly determined the TI of phenytoin but was unable to determine the TI of lamotrigine due to a limited sample size. The use of therapeutic drug monitoring and EHR data to aid in narrow TI drug classification is promising, but it requires an adequate sample size and accurate characterization of concentration-response relationships.

Randomized double-blind comparison of cognitive and EEG effects of lacosamide and carbamazepine.

PubMed

Meador, Kimford J; Loring, David W; Boyd, Alan; Echauz, Javier; LaRoche, Suzette; Velez-Ruiz, Naymee; Korb, Pearce; Byrnes, William; Dilley, Deanne; Borghs, Simon; De Backer, Marc; Story, Tyler; Dedeken, Peter; Webster, Elizabeth

2016-09-01

Differential effectiveness of antiepileptic drugs (AEDs) is more commonly determined by tolerability than efficacy. Cognitive effects of AEDs can adversely affect tolerability and quality of life. This study evaluated cognitive and EEG effects of lacosamide (LCM) compared with carbamazepine immediate-release (CBZ-IR). A randomized, double-blind, double-dummy, two-period crossover, fixed-dose study in healthy subjects compared neuropsychological and EEG effects of LCM (150mg, b.i.d.) and CBZ-IR (200mg, t.i.d.). Testing was conducted at screening, predrug baseline, the end of each treatment period (3-week titration; 3-week maintenance), and the end of each washout period (4weeks after treatment). A composite Z-score was derived for the primary outcome variable (computerized cognitive tests and traditional neuropsychological measures) and separately for the EEG measures. Other variables included individual computer, neuropsychological, and EEG scores and adverse events (AEs). Subjects included 60 healthy adults (57% female; mean age: 34.4years [SD: 10.5]); 44 completed both treatments; 41 were per protocol subjects. Carbamazepine immediate-release had worse scores compared with LCM for the primary composite neuropsychological outcome (mean difference=0.33 [SD: 1.36], p=0.011) and for the composite EEG score (mean difference=0.92 [SD: 1.77], p=0.003). Secondary analyses across the individual variables revealed that CBZ-IR was statistically worse than LCM on 36% (4/11) of the neuropsychological tests (computerized and noncomputerized) and 0% of the four EEG measures; none favored CBZ-IR. Drug-related AEs occurred more with CBZ-IR (49%) than LCM (22%). Lacosamide had fewer untoward neuropsychological and EEG effects and fewer AEs and AE-related discontinuations than CBZ-IR in healthy subjects. Lacosamide exhibits a favorable cognitive profile. Copyright © 2016 Elsevier Inc. All rights reserved.

The Clinical Effectiveness and Cost-Effectiveness of Lamotrigine in Borderline Personality Disorder: A Randomized Placebo-Controlled Trial.

PubMed

Crawford, Mike J; Sanatinia, Rahil; Barrett, Barbara; Cunningham, Gillian; Dale, Oliver; Ganguli, Poushali; Lawrence-Smith, Geoff; Leeson, Verity; Lemonsky, Fenella; Lykomitrou, Georgia; Montgomery, Alan A; Morriss, Richard; Munjiza, Jasna; Paton, Carol; Skorodzien, Iwona; Singh, Vineet; Tan, Wei; Tyrer, Peter; Reilly, Joseph G

2018-04-06

The authors examined whether lamotrigine is a clinically effective and cost-effective treatment for people with borderline personality disorder. This was a multicenter, double-blind, placebo-controlled randomized trial. Between July 2013 and November 2016, the authors recruited 276 people age 18 or over who met diagnostic criteria for borderline personality disorder. Individuals with coexisting bipolar affective disorder or psychosis, those already taking a mood stabilizer, and women at risk of pregnancy were excluded. A web-based randomization service was used to allocate participants randomly in a 1:1 ratio to receive either an inert placebo or up to 400 mg/day of lamotrigine. The primary outcome measure was score on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) at 52 weeks. Secondary outcome measures included depressive symptoms, deliberate self-harm, social functioning, health-related quality of life, resource use and costs, side effects of treatment, and adverse events. A total of 195 (70.6%) participants were followed up at 52 weeks, at which point 49 (36%) of those in the lamotrigine group and 58 (42%) of those in the placebo group were taking study medication. The mean ZAN-BPD score was 11.3 (SD=6.6) among those in the lamotrigine group and 11.5 (SD=7.7) among those in the placebo group (adjusted difference in means=0.1, 95% CI=-1.8, 2.0). There was no evidence of any differences in secondary outcomes. Costs of direct care were similar in the two groups. The results suggest that treating people with borderline personality disorder with lamotrigine is not a clinically effective or cost-effective use of resources.

Incidence of delayed seizures, delayed cerebral ischemia and poor outcome with the use of levetiracetam versus phenytoin after aneurysmal subarachnoid hemorrhage.

PubMed

Karamchandani, Rahul Ramesh; Fletcher, Jeffrey James; Pandey, Aditya Swarup; Rajajee, Venkatakrishna

2014-09-01

Current guidelines recommend against the use of phenytoin following aneurysmal subarachnoid hemorrhage (aSAH) but consider other anticonvulsants, such as levetiracetam, acceptable. Our objective was to evaluate the risk of poor functional outcomes, delayed cerebral ischemia (DCI) and delayed seizures in aSAH patients treated with levetiracetam versus phenytoin. Medical records of patients with aSAH admitted between 2005-2012 receiving anticonvulsant prophylaxis with phenytoin or levetiracetam for >72 hours were reviewed. The primary outcome measure was poor functional outcome, defined as modified Rankin Scale (mRS) score >3 at first recorded follow-up. Secondary outcomes measures included DCI and the incidence of delayed seizures. The association between the use of levetiracetam and phenytoin and the outcomes of interest was studied using logistic regression. Medical records of 564 aSAH patients were reviewed and 259 included in the analysis after application of inclusion/exclusion criteria. Phenytoin was used exclusively in 43 (17%), levetiracetam exclusively in 132 (51%) while 84 (32%) patients were switched from phenytoin to levetiracetam. Six (2%) patients had delayed seizures, 94 (36%) developed DCI and 63 (24%) had mRS score >3 at follow-up. On multivariate analysis, only modified Fisher grade and seizure before anticonvulsant administration were associated with DCI while age, Hunt-Hess grade and presence of intraparenchymal hematoma were associated with mRS score >3. Choice of anticonvulsant was not associated with any of the outcomes of interest. There was no difference in the rate of delayed seizures, DCI or poor functional outcome in patients receiving phenytoin versus levetiracetam after aSAH. The high rate of crossover from phenytoin suggests that levetiracetam may be better tolerated. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

The impact on health outcomes and healthcare utilisation of switching to generic medicines consequent to reference pricing: the case of lamotrigine in New Zealand.

PubMed

Lessing, Charon; Ashton, Toni; Davis, Peter

2014-10-01

Many countries have implemented generic reference pricing and substitution as methods of containing pharmaceutical expenditure. However, resistance to switching between medicines is apparent, especially in the case of anti-epileptic medicines. This study sought to exploit a nation-wide policy intervention on generic reference pricing in New Zealand to evaluate the health outcomes of patients switching from originator to generic lamotrigine, an anti-epileptic medicine. A retrospective study using the national health collections and prescription records was conducted comparing patients who switched from originator brand to generic lamotrigine with patients who remained on the originator brand. Primary outcome measures included switch behaviour, changes in utilisation of healthcare services at emergency departments, hospitalisations and use of specialist services, and mortality. Approximately one-quarter of all patients using the originator brand of lamotrigine switched to generic lamotrigine, half of whom made the switch within 60 days of the policy implementation. Multiple switches (three or more) between generic and brand products were evident for around 10% of switchers. Switch-back rates of 3% were apparent within 30 days post-switch. No difference in heath outcome measures was associated with switching from originator lamotrigine to a generic equivalent and hence no increased costs could be found for switchers. Switching from brand to generic lamotrigine is largely devoid of adverse health outcomes; however, creating an incentive to ensure a greater proportion of patients switch to generic lamotrigine is required to achieve maximal financial savings from a policy of generic reference pricing.

Levetiracetam mitigates doxorubicin-induced DNA and synaptic damage in neurons.

PubMed

Manchon, Jose Felix Moruno; Dabaghian, Yuri; Uzor, Ndidi-Ese; Kesler, Shelli R; Wefel, Jeffrey S; Tsvetkov, Andrey S

2016-05-11

Neurotoxicity may occur in cancer patients and survivors during or after chemotherapy. Cognitive deficits associated with neurotoxicity can be subtle or disabling and frequently include disturbances in memory, attention, executive function and processing speed. Searching for pathways altered by anti-cancer treatments in cultured primary neurons, we discovered that doxorubicin, a commonly used anti-neoplastic drug, significantly decreased neuronal survival. The drug promoted the formation of DNA double-strand breaks in primary neurons and reduced synaptic and neurite density. Pretreatment of neurons with levetiracetam, an FDA-approved anti-epileptic drug, enhanced survival of chemotherapy drug-treated neurons, reduced doxorubicin-induced formation of DNA double-strand breaks, and mitigated synaptic and neurite loss. Thus, levetiracetam might be part of a valuable new approach for mitigating synaptic damage and, perhaps, for treating cognitive disturbances in cancer patients and survivors.

Levetiracetam mitigates doxorubicin-induced DNA and synaptic damage in neurons

PubMed Central

Manchon, Jose Felix Moruno; Dabaghian, Yuri; Uzor, Ndidi-Ese; Kesler, Shelli R.; Wefel, Jeffrey S.; Tsvetkov, Andrey S.

2016-01-01

Neurotoxicity may occur in cancer patients and survivors during or after chemotherapy. Cognitive deficits associated with neurotoxicity can be subtle or disabling and frequently include disturbances in memory, attention, executive function and processing speed. Searching for pathways altered by anti-cancer treatments in cultured primary neurons, we discovered that doxorubicin, a commonly used anti-neoplastic drug, significantly decreased neuronal survival. The drug promoted the formation of DNA double-strand breaks in primary neurons and reduced synaptic and neurite density. Pretreatment of neurons with levetiracetam, an FDA-approved anti-epileptic drug, enhanced survival of chemotherapy drug-treated neurons, reduced doxorubicin-induced formation of DNA double-strand breaks, and mitigated synaptic and neurite loss. Thus, levetiracetam might be part of a valuable new approach for mitigating synaptic damage and, perhaps, for treating cognitive disturbances in cancer patients and survivors. PMID:27168474

Synergistic Interaction of Retigabine with Levetiracetam in the Mouse Maximal Electroshock-Induced Seizure Model: A Type II Isobolographic Analysis.

PubMed

Luszczki, Jarogniew J; Zagaja, Mirosław; Miziak, Barbara; Florek-Luszczki, Magdalena; Czuczwar, Stanislaw J

2015-01-01

To assess interactions between retigabine and levetiracetam in suppressing maximal electroshock-induced tonic seizures in Albino Swiss mice, type II isobolographic analysis was used. Total brain antiepileptic drug concentrations were measured with high pressure liquid chromatography. The combinations of retigabine with levetiracetam at the fixed-ratios of 1:5 and 1:10 were supra-additive (synergistic; p < 0.05) in terms of seizure suppression, while the combinations at the fixed-ratios of 1:1 and 1:2 were additive. No pharmacokinetic changes in total brain concentrations of levetiracetam and retigabine were documented, indicating the pharmacodynamic nature of interaction between these antiepileptic drugs in the mouse maximal electroshock-induced tonic seizure model. The combination of retigabine with levetiracetam at the fixed-ratios of 1:5 and 1:10 appears to be particularly beneficial combination exerting supra-additive interaction in suppressing maximal electroshock-induced tonic seizures. © 2015 S. Karger AG, Basel.

Fatigue during treatment with antiepileptic drugs: A levetiracetam-specific adverse event?

PubMed

Mula, Marco; von Oertzen, Tim J; Cock, Hannah R; Yogarajah, Mahinda; Lozsadi, Dora A; Agrawal, Niruj

2017-07-01

To examine the prevalence and clinical correlates of fatigue as an adverse event (AE) of antiepileptic drug (AED) treatment in patients with epilepsy. Data from 443 adult outpatients with epilepsy assessed with the Adverse Event Profile (AEP) and the Neurological Disorder Depression Inventory for Epilepsy (NDDIE) were analysed. Fatigue is reported by 36.6% of patients as always a problem during AED treatment. Fatigue is more likely to be reported by females (64.8% vs. 35.2%; Chi-Square=16.762; df=3; p=0.001) and during treatment with levetiracetam (42.3% vs. 33.2%; Chi-Square=11.462; df=3; p=0.009). The associations with the female gender and levetiracetam treatment were not mediated by depression, as identified with the NDDIE, and could not be simply explained by the large number of subjects on levetiracetam treatment, as analogous figures resulted from the analysis of a monotherapy subsample (41.7% vs. 30.3%; Chi-Square=11.547; df=3; p=0.009). One third of patients with epilepsy reports fatigue as a significant problem during AED treatment. Fatigue is more likely to be reported by females and seems to be specifically associated with LEV treatment. However, fatigue is not mediated by a negative effect of LEV on mood. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of lamotrigine, oxcarbazepine and topiramate on cognitive functions and oxidative stress in PTZ-kindled mice.

PubMed

Agarwal, Nidhi Bharal; Agarwal, Nitin Kumar; Mediratta, Pramod Kumari; Sharma, Krishna Kishore

2011-04-01

Cognitive impairment is frequently observed in epileptic patients. It has been seen that not only epilepsy but antiepileptic drugs also impair cognitive functions. The present study was undertaken to assess the effect of three anticonvulsants viz. lamotrigine (5mg/kg, p.o.), oxcarbazepine (15mg/kg, p.o.) and topiramate (10mg/kg, p.o.) on cognitive function and oxidative stress during pentylenetetrazole (PTZ)-kindling in mice. Kindling was induced by the administration of PTZ (25mg/kg, i.p.) on every alternate day till 5 weeks. Cognition was assessed after the development of kindling. Elevated plus maze (EPM) and passive avoidance response (PAR) tests were carried out after 24h and 48h of the last PTZ administration. After completion of behavioural tests malondialdehyde (MDA), glutathione levels, superoxide dismutase and catalase activity were measured as an indicator of oxidative stress. The results of the present study indicate that topiramate (10mg/kg) administration to kindled animals increased transfer latency and decreased step-down latency in EPM and PAR tests, respectively. However, lamotrigine and oxcarbazepine did not alter the two parameters. Topiramate administration to kindled as well as non-kindled animals has shown increase in MDA and decrease in glutathione levels. Lamotrigine and oxcarbazepine did not show significant alteration in oxidative stress parameters. To conclude, long term administration of topiramate impairs cognitive functions during experimental epilepsy while lamotrigine and oxcarbazepine are safer. Copyright © 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Initial post marketing experience with lacosamide in adult patients with epilepsy.

PubMed

Harden, Cynthia L; Cohn, Aaron; Lowe, Merredith; Serrano, Enrique

2012-02-01

The outcomes of adult epilepsy patients prescribed lacosamide for additional seizure control. Responders were defined as having at least a 50% decrease in seizure frequency Sixty-seven patients were evaluated. Forty-six out of 67 patients (69%) were responders. Twelve of 14 patients not taking sodium channel-acting AEDs were responders (86%) and 34/53 patients taking sodium channel-acting AEDs were responders (64%) (difference not significant). Copyright © 2011 Elsevier B.V. All rights reserved.

The effects of levetiracetam on neural tube development in the early stage of chick embryos.

PubMed

Guvenc, Yahya; Dalgic, Ali; Billur, Deniz; Karaoglu, Derya; Aydin, Sevim; Daglioglu, Ergun; Ozdol, Cagatay; Nacar, Osman Arikan; Yildirim, Ali Erdem; Belen, Deniz

2013-01-01

This study aimed to investigate the effects of a new generation antiepileptic agent, levetiracetam, on the neural tube development in a chick embryo model that corresponds to the first month of vertebral development in mammals. Forty-five Atabey® breed fertilized chicken eggs with no specific pathogens were randomly divided into 5 groups. All of the eggs were incubated at 37.8±2°C and 60±5 % relative humidity in an incubator. Group A was control group. The other eggs were applied physiological saline and drugs at a volume of 10 μL by the in ovo method at the 28th hour of the incubation period. Group B was given distilled water; Group C, physiological saline; Group D, Levetiracetam (L8668) at a dose equivalent to the treatment dose for humans (10 mg/ kg), and Group E, Levetiracetam (L8668) at a dose of 10 times the treatment dose. The embryos in all of the groups were removed from the shells at the 48th hour and morphologically and histologically evaluated. Of the 45 embryos incubated, neural tubes of 41 were closed and the embryos displayed normal development. Levetiracetam, at a dose equivalent to human treatment dose and 10 times the treatment dose, was shown not to cause neural tube defects in chick embryos.

MANAGEMENT OF A REEVE'S MUNTJAC ( MUNTIACUS REEVESI) WITH SEIZURES USING LEVETIRACETAM.

PubMed

Blatt, Emily R; Seeley, Kathryn E; Lovett, Mathew C; Junge, Randall E

2017-12-01

This report describes the diagnosis and management of idiopathic epilepsy in a 4-yr-old intact female Reeve's muntjac ( Muntiacus reevesi). The patient was initially witnessed to have isolated paroxysmal events consistent with epileptic seizures (altered consciousness, lateral recumbency, tonic/clonic movement of limbs) lasting less than 3 min with an immediate return to normal consciousness. The seizure frequency increased to >3 seizures within 24 hr and phenobarbital 3 mg/kg orally every 12 hr was started. Because of continued epileptic seizures and low serum phenobarbital levels, the dose was increased until significant elevations of aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were detected. Levetiracetam 40 mg/kg orally every 12 hr was initiated and the phenobarbital was weaned and discontinued. One breakthrough seizure has been witnessed in the 10 mo since starting levetiracetam.

A prospective study of cognitive fluency and originality in children exposed in utero to carbamazepine, lamotrigine, or valproate monotherapy.

PubMed

McVearry, Kelly M; Gaillard, William D; VanMeter, John; Meador, Kimford J

2009-12-01

To investigate the differential effects of fetal exposure to antiepileptic drugs (AEDs) on cognitive fluency and flexibility in a prospective sample of children. This substudy of the Neurodevelopmental Effects of Antiepileptic Drugs investigation enrolled pregnant women with epilepsy on AED monotherapy (carbamazepine, lamotrigine, and valproate). Blinded to drug exposure, 54 children were tested for ability to generate ideas in terms of quantity (fluency/flexibility) and quality (originality). Forty-two children met inclusion criteria (mean age=4.2 years, SD=0.5) for statistical analyses of drug exposure group differences. Fluency was lower in the valproate group (mean=76.3, SD=7.53) versus the lamotrigine (mean=93.76, SD=13.5, ANOVA P<0.0015) and carbamazepine (mean=95.5, SD=18.1, ANOVA P<0.003) groups. Originality was lower in the valproate group (mean=84.2, SD=3.23) versus the lamotrigine (mean=103.1, SD=14.8, ANOVA P<0.002) and carbamazepine (mean=99.4, SD=17.1, ANOVA P<0.01) groups. These results were not explained by factors other than AED exposure. Children prenatally exposed to valproate demonstrate impaired fluency and originality compared with children exposed to lamotrigine and carbamazepine.

Status epilepticus developing during lacosamide monotherapy

PubMed Central

Papacostas, Savvas S

2015-01-01

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. PMID:25628098

A noninterventional study evaluating the effectiveness and safety of lacosamide added to monotherapy in patients with epilepsy with partial-onset seizures in daily clinical practice: The VITOBA study.

PubMed

Runge, Uwe; Arnold, Stephan; Brandt, Christian; Reinhardt, Fritjof; Kühn, Frank; Isensee, Kathleen; Ramirez, Francisco; Dedeken, Peter; Lauterbach, Thomas; Noack-Rink, Matthias; Mayer, Thomas

2015-12-01

Evidence for the efficacy and safety of adjunctive lacosamide in the treatment of partial-onset seizures (POS) was gained during placebo-controlled clinical trials in patients with treatment-resistant seizures who were taking one to three concomitant antiepileptic drugs (AEDs). The VITOBA study (NCT01098162) evaluated the effectiveness and tolerability of adjunctive lacosamide added to one baseline AED in real-world clinical practice. We conducted a 6-month observational study at 112 sites across Germany. Adult patients (≥ 16 years) with POS received lacosamide adjunctive to only one baseline AED. Seizure frequency reduction at the end of the observation period was compared with a 3-month retrospective baseline period. Five hundred seventy-one patients received lacosamide at least once (Safety Set [SS]); 520 provided evaluable seizure records (Full Analysis Set [FAS]); and 499 took in-label dosages of lacosamide (up to 400 mg) and were evaluated for effectiveness (modified FAS). Median baseline seizure frequency was 2.0 per 28 days: 47.1% of patients (235/499, mFAS) took a concomitant sodium channel-blocking (SCB) AED; 38.1% (190/499) had only one lifetime AED; and 18.4% (92/499) were aged ≥ 65 years (mFAS). At the final visit, 72.5% (358/494) of patients showed a ≥ 50% reduction in seizure frequency from baseline, 63.8% (315/494) showed a ≥ 75% reduction, and 45.5% (225/494) were seizure-free. Seizure freedom rates were higher in patients aged ≥ 65 years (56.7%) compared with patients aged <65 years (43.1%), in patients with ≤ 5 years epilepsy duration (52.5%) versus >5 years duration (41.0%), and when added to first monotherapy (60.5%) rather than as a later therapy option. Treatment-emergent adverse events (TEAEs) were reported by 48.5% (277/571) of patients (SS), with a profile similar to that observed in pivotal trials; 466 of patients (81.6%, SS) continued lacosamide therapy after the trial. These results suggest that lacosamide use, added to one

Reversed-phase HPLC analysis of levetiracetam in tablets using monolithic and conventional C18 silica columns.

PubMed

Can, Nafiz O; Arli, Goksel

2010-01-01

Development and validation of an RP-HPLC method for determination of levetiracetam in pharmaceutical tablets is described. The separation and quantification of levetiracetam and caffeine (internal standard) were performed using a single analytical procedure with two different types of stationary phases, conventional Phenomenex Gemini C18 (100 x 4.6 mm, 5 microm) and Merck Chromolith Performance RP18e (100 x 4.6 mm, macropore size 2 mm, micropore size 13 nm) monolithic silica. Five-microliter aliquots of samples were injected into the system and eluted using water-acetonitrile (90 + 10, v/v) mobile phase pumped at the rate of 1 mL/min. The analyte peaks were detected at 200 nm using a diode array detector with adequate resolution. Validation studies were performed using the method recommended by the International Conference on Harmonization, the U.S. Pharmacopeia, and AOAC INTERNATIONAL, which includes accuracy, precision, range, limits, robustness, and system suitability parameters. Levetiracetam and caffeine were detected in about 7 min using the conventional column, whereas less than 5 min was required when the monolithic column was used. Calibration plots had r values close to unity in the range of 0.8-8.0 microg/mL. Assay of levetiracetam in a tablet formulation was demonstrated as an application to real samples.

Continuous subcutaneous levetiracetam in the management of seizures at the end of life: a case report.

PubMed

Wells, Geoffrey Howard; Mason, Louise D; Foreman, Emma; Chambers, John

2016-03-01

We report the case of a man who developed seizures on a background of recurrent metastatic squamous cell carcinoma with intracranial involvement. Initial seizure control with enteral levetiracetam was achieved, and when enteral and intravenous (i.v.) access was no longer available, a continuous subcutaneous infusion (CSCI) of levetiracetam successfully controlled his seizures without the need for sedating anticonvulsants. As a result, end-of-life care was able to be given with the patient retaining the ability to communicate with his family and healthcare staff. This report adds to the sparse but growing evidence base for the use of subcutaneous levetiracetam to manage seizures in palliative and end-of-life care. © The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Levetiracetam and topiramate poisoning: Two overdoses on those drugs with no lasting effects.

PubMed

Sarfaraz, Moaziz; Syeda, Rana Hasan

2017-05-30

Levetiracetam and topiramate are newer anticonvulsants, which is why international data on overdoses of these drugs are lacking. Only a few mild adverse reactions have been noted. These anticonvulsants have been the drug of choice for neurologists. Despite their wide usage, there is a dearth of literature on symptoms and signs of their toxicity. Presented here is the case of a 21-year-old female who overdosed twice on levetiracetam and topiramate. The woman was admitted and discharged after the first overdose. Ten days later, she took multiple tablets of both drugs and was seen again. Amazingly, the woman went home after the incident with no complications at all.

Pharmacokinetics of rectal levetiracetam as add-on treatment in dogs affected by cluster seizures or status epilepticus.

PubMed

Cagnotti, Giulia; Odore, Rosangela; Gardini, Giulia; Amedeo, Stefano; Bertone, Iride; Guerriero, Giulia; Lentini, Laura; Dappiano, Elena; D'Angelo, Antonio

2018-06-18

Levetiracetam can be used for seizure control alone or in combination with other antiepileptic medications. A previous study achieved the minimum targeted serum drug concentration after rectal administration of levetiracetam in healthy dogs. The purpose of the present study was to determine the pharmacokinetics of rectal LEV in dogs presented for cluster seizures or status epilepticus and potentially in treatment with other anti-epileptic drugs. Furthermore, preliminary information on response to this treatment as add-on to the standard treatment protocol is reported. Eight client-owned dogs were enrolled. Plasma levetiracetam concentrations (measured at 0, 30, 60, 90, 120, 180, 240, 360, 720, and 1440 min after drug administration) reached the minimum target concentration (5 μg/ml) at 30 min in all but one patient. At T1 (30 min) the mean concentration was 28.2 ± 15.5 μg/ml. Plasma concentrations remained above the targeted minimum concentration in all patients until 240 min and in 7/8 until 360 min. Six out of eight patients experienced no seizures in the 24-h period after hospitalization and were classified as "responders". Minimum plasma levetiracetam concentration can be reached after rectal administration of 40 mg/kg in dogs affected by cluster seizures and status epilepticus and concurrently receiving other antiepileptic drugs. These preliminary results may encourage the evaluation of rectal levetiracetam as an additional treatment option for cluster seizures and status epilepticus in a larger number of dogs.

Identification of a Lacosamide Binding Protein Using an Affinity Bait and Chemical Reporter Strategy: 14-3-3 ζ

PubMed Central

Park, Ki Duk; Kim, Dong Wook; Reamtong, Onrapak; Eyers, Claire; Gaskell, Simon J.; Liu, Rihe; Kohn, Harold

2011-01-01

We have advanced a useful strategy to elucidate binding partners of ligands (drugs) with modest binding affinity. Key to this strategy is attaching to the ligand an affinity bait (AB) and a chemical reporter (CR) group, where the AB irreversibly attaches the ligand to the receptor upon binding and the CR group is employed for receptor detection and isolation. We have tested this AB&CR strategy using lacosamide ((R)-1), a low-molecular-weight antiepileptic drug. We demonstrate that using a (R)-lacosamide AB&CR agent ((R)-2) 14-3-3 ζ in rodent brain soluble lysates is preferentially adducted, adduction is stereospecific with respect to the AB&CR agent, and adduction depends upon the presence of endogenous levels of the small molecule metabolite xanthine. Substitution of lacosamide AB agent ((R)- 5) for (R)-2 led to the identification of the 14-3-3 ζ adduction site (K120) by mass spectrometry. Competition experiments using increasing amounts of (R)-1 in the presence of (R)-2 demonstrated that (R)-1 binds at or near the (R)-2 modification site on 14-3-3 ζ. Structure-activity studies of xanthine derivatives provided information concerning the likely binding interaction between this metabolite and recombinant 14-3-3 ζ. Documentation of the 14-3-3 ζ-xanthine interaction was obtained with isothermal calorimetry using xanthine and the xanthine analogue 1,7-dimethylxanthine. PMID:21692503

Effect of caffeine on the anticonvulsant effects of oxcarbazepine, lamotrigine and tiagabine in a mouse model of generalized tonic-clonic seizures.

PubMed

Chrościńska-Krawczyk, Magdalena; Ratnaraj, Neville; Patsalos, Philip N; Czuczwar, Stanisław J

2009-01-01

Caffeine has been reported to be proconvulsant and to reduce the anticonvulsant efficacy of a variety of antiepileptic drugs (carbamazepine, phenobarbital, phenytoin, valproate and topiramate) in animal models of epilepsy and to increase seizure frequency in patients with epilepsy. Using the mouse maximal electroshock model, the present study was undertaken so as to ascertain whether caffeine affects the anticonvulsant efficacy of the new antiepileptic drugs lamotrigine, oxcarbazepine and tiagabine. The results indicate that neither acute nor chronic caffeine administration (up to 46.2 mg/kg) affected the ED(50) values of oxcarbazepine or lamotrigine against maximal electroshock. Similarly, caffeine did not modify the tiagabine electroconvulsive threshold. Furthermore, caffeine had no effect on oxcarbazepine, lamotrigine and tiagabine associated adverse effects such as impairment of motor coordination (measured by the chimney test) or long-term memory (measured by the passive avoidance task). Concurrent plasma concentration measurements revealed no significant effect on lamotrigine and oxcarbazepine concentrations. For tiagabine, however, chronic caffeine (4 mg/kg) administration was associated with an increase in tiagabine concentrations. In conclusion, caffeine did not impair the anticonvulsant effects of lamotrigine, oxcarbazepine, or tiagabine as assessed by electroconvulsions in mice. Also, caffeine was without effect upon the adverse potential of the studied antiepileptic drugs. Thus caffeine may not necessarily adversely affect the efficacy of all antiepileptic drugs and this is an important observation.

Efficacy and safety of lacosamide as an adjunctive therapy for refractory focal epilepsy in paediatric patients: a retrospective single-centre study.

PubMed

Toupin, Jean-François; Lortie, Anne; Major, Philippe; Diadori, Paola; Vanasse, Michel; Rossignol, Elsa; D'Anjou, Guy; Perreault, Sebastien; Larbrisseau, Albert; Carmant, Lionel; Birca, Ala

2015-12-01

Lacosamide is an antiepileptic drug approved for the treatment of focal epilepsy in adult patients. The aim of this observational study was to review our centre's experience with lacosamide and to characterize its effectiveness and tolerability as an adjunctive antiepileptic drug in a retrospective cohort of children with refractory focal epilepsy. We retrospectively reviewed the medical records of 22 patients who received lacosamide from November 2009 to April 2014 at the CHU Ste-Justine, University of Montreal. Treatment responders were defined as children with a ≥50% reduction in seizure frequency compared to baseline, and this was determined three months after the initiation of treatment and at the last follow-up visit. We included 14 boys and eight girls with a mean age of 12.9 years (SD: 5.2; range: 5.2-20.7 years) at the initiation of treatment. The average length of follow-up was 11.9 months. Patients had previously received an average of 7.5 antiepileptic drugs. The mean number of concomitant antiepileptic drugs was 2.3. The mean initial and maintenance doses were 2.9 and 8.4 mg/kg/d, respectively. Thirteen (59%) and ten (45%) patients were responders after three months of treatment and at the last follow-up visit, respectively. One became seizure-free. Adverse effects were reported in 11 patients and none were severe. Responders and non-responders were identical with respect to all studied parameters except gender, with the proportion of responders being greater in girls than in boys (75% vs 29%; p=0.035). Our study adds evidence that lacosamide appears to be a safe and effective adjunctive therapy for children with refractory focal epilepsy.

Properties of human brain sodium channel α-subunits expressed in HEK293 cells and their modulation by carbamazepine, phenytoin and lamotrigine

PubMed Central

Qiao, Xin; Sun, Guangchun; Clare, Jeffrey J; Werkman, Taco R; Wadman, Wytse J

2014-01-01

Background and purpose Voltage-activated Na+ channels contain one distinct α-subunit. In the brain NaV1.1, NaV1.2, NaV1.3 and NaV1.6 are the four most abundantly expressed α-subunits. The antiepileptic drugs (AEDs) carbamazepine, phenytoin and lamotrigine have voltage-gated Na+ channels as their primary therapeutic targets. This study provides a systematic comparison of the biophysical properties of these four α-subunits and characterizes their interaction with carbamazepine, phenytoin and lamotrigine. Experimental approach Na+ currents were recorded in voltage-clamp mode in HEK293 cells stably expressing one of the four α-subunits. Key results NaV1.2 and NaV1.3 subunits have a relatively slow recovery from inactivation, compared with the other subunits and NaV1.1 subunits generate the largest window current. Lamotrigine evokes a larger maximal shift of the steady-state inactivation relationship than carbamazepine or phenytoin. Carbamazepine shows the highest binding rate to the α-subunits. Lamotrigine binding to NaV1.1 subunits is faster than to the other α-subunits. Lamotrigine unbinding from the α-subunits is slower than that of carbamazepine and phenytoin. Conclusions and implications The four Na+ channel α-subunits show subtle differences in their biophysical properties, which, in combination with their (sub)cellular expression patterns in the brain, could contribute to differences in neuronal excitability. We also observed differences in the parameters that characterize AED binding to the Na+ channel subunits. Particularly, lamotrigine binding to the four α-subunits suggests a subunit-specific response. Such differences will have consequences for the clinical efficacy of AEDs. Knowledge of the biophysical and binding parameters could be employed to optimize therapeutic strategies and drug development. PMID:24283699

Lamotrigine and GABAA receptor modulators interact with menstrual cycle phase and oral contraceptives to regulate mood in women with bipolar disorder.

PubMed

Robakis, Thalia K; Holtzman, Jessie; Stemmle, Pascale G; Reynolds-May, Margaret F; Kenna, Heather A; Rasgon, Natalie L

2015-04-01

To examine the occurrence of menstrually-entrained mood cycling in women with treated bipolar disorder as compared to healthy controls, and to explore whether there is a specific effect of lamotrigine in dampening menstrually-entrained cyclicity of mood. Observational comparison study of daily self-ratings of mood, sleep, and insomnia obtained over a mean of four menstrual cycles in 42 women with bipolar disorder taking lamotrigine as part of their treatment, 30 women with bipolar disorder receiving mood stabilizing regimens without lamotrigine, and 13 healthy controls, all with physiological menstrual cycles. Additional exploratory analysis of interactions between psychopharmacological regimen and hormonal contraceptive use in the group of women with bipolar disorder, with the addition of 19 women with bipolar disorder who were using hormonal contraceptives. Women treated for bipolar disorder manifested lower average mood, longer average nightly sleep duration, and greater fluctuations in mood and sleep across menstrual cycle phases than healthy controls. Women with bipolar disorder who were taking lamotrigine had less fluctuation in mood both within and across menstrual cycle phases, and were more similar to the control group than to women with bipolar disorder who were not taking lamotrigine in this respect. In addition, medications with GABA-A receptor modulating effects were found to result in improved mood ratings when combined with hormonal contraceptives. Menstrually-entrained mood fluctuation is present in women treated for bipolar disorder to a greater degree than in healthy controls. Lamotrigine may be of use in mitigating this fluctuation. GABA-A receptor modulators in general may act synergistically with hormonal contraceptives to enhance mood in women with bipolar disorder; this hypothesis merits further study. Copyright © 2014 Elsevier B.V. All rights reserved.

Bioequivalence Between Generic and Branded Lamotrigine in People With Epilepsy: The EQUIGEN Randomized Clinical Trial.

PubMed

Berg, Michel; Welty, Timothy E; Gidal, Barry E; Diaz, Francisco J; Krebill, Ron; Szaflarski, Jerzy P; Dworetzky, Barbara A; Pollard, John R; Elder, Edmund J; Jiang, Wenlei; Jiang, Xiaohui; Switzer, Regina D; Privitera, Michael D

2017-08-01

Switching between generic antiepileptic drugs is a highly debated issue that affects both clinical care and overall health care costs. To evaluate the single-dose pharmacokinetic bioequivalence of 3 (1 branded and 2 generic drugs) on-market, immediate-release lamotrigine drug products. The Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy (EQUIGEN) single-dose study is a crossover, prospective, sequence-randomized, replicate pharmacokinetic study conducted at 5 US academic epilepsy centers. Fifty adults (≥18 years) with epilepsy who were taking concomitant antiepileptic drugs and not currently receiving lamotrigine were enrolled between July 18, 2013, and January 19, 2015. Every participant was randomly assigned to 1 of 3 equivalent sequences, each comprising 6 study periods, during which they had blood draws before and after medication administration. Forty-nine participants were included in intention-to-treat analyses. Participants received a single 25-mg dose of immediate-release lamotrigine at the start of each period, with the branded and the 2 most disparate generic products each studied twice. Lamotrigine was selected as the antiepileptic drug of interest because of its wide use, publications indicating problems with generic switches, and complaints to the US Food and Drug Administration regarding generic products. Both participants and study personnel were blinded to the specific generic products selected. The primary outcome was bioequivalence between products. Maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were compared, and average bioequivalence (ABE) was established if the 90% CIs of the ratios of the 2 products were within equivalence limits (80%-125%). Of the 50 randomized participants, 49 (98%) received all 3 lamotrigine products and completed at least 3 pharmacokinetic assessments and 46 (92%) completed all 6 pharmacokinetic assessments. Among the 49 participants, 28 (57

Levetiracetam reduces the frequency of interictal epileptiform discharges during NREM sleep in children with ADHD.

PubMed

Bakke, Kristin A; Larsson, Pål G; Eriksson, Ann-Sofie; Eeg-Olofsson, Orvar

2011-11-01

Symptoms of attention deficit hyperactivity disorder (ADHD) are more common in children with epilepsy than in the general paediatric population. Epileptiform discharges in EEG may be seen in children with ADHD also in those without seizure disorders. Sleep enhances these discharges which may be suppressed by levetiracetam. To assess the effect of levetiracetam on focal epileptiform discharges during sleep in children with ADHD. In this retrospective study a new semi-automatic quantitative method based on the calculation of spike index in 24-h ambulatory EEG recordings was applied. Thirty-five ADHD children, 17 with focal epilepsy, one with generalised epilepsy, and 17 with no seizure disorder were evaluated. Follow-up 24-h EEG recordings were performed after a median time of four months. Mean spike index was 50 prior to levetiracetam treatment and 21 during treatment. Seventeen children had no focal interictal epileptiform discharges in EEG at follow-up. Five children had a more than 50% reduction in spike index. Thus, a more than 50% reduction in spike index was found in 22/35 children (63%). Out of these an improved behaviour was noticed in 13 children (59%). This study shows that treatment with levetiracetam reduces interictal epileptiform discharges in children with ADHD. There is a complex relationship between epilepsy, ADHD and epileptiform activity, why it is a need for prospective studies in larger sample sizes, also to ascertain clinical benefits. Copyright © 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Human Metabolite Lamotrigine-N(2)-glucuronide Is the Principal Source of Lamotrigine-Derived Compounds in Wastewater Treatment Plants and Surface Water.

PubMed

Zonja, Bozo; Pérez, Sandra; Barceló, Damià

2016-01-05

Wastewater and surface water samples, extracted with four solid-phase extraction cartridges of different chemistries, were suspect-screened for the anticonvulsant lamotrigine (LMG), its metabolites, and related compounds. LMG, three human metabolites, and a LMG synthetic impurity (OXO-LMG) were detected. Preliminary results showed significantly higher concentrations of OXO-LMG in wastewater effluent, suggesting its formation in the wastewater treatment plants (WWTPs). However, biodegradation experiments with activated sludge demonstrated that LMG is resistant to degradation and that its human metabolite lamotrigine-N(2)-glucuronide (LMG-N2-G) is the actual source of OXO-LMG in WWTPs. In batch reactors, LMG-N2-G was transformed, following pseudo-first-order kinetics to OXO-LMG and LMG, but kinetic experiments suggested an incomplete mass balance. A fragment ion search applied to batch-reactor and environmental samples revealed another transformation product (TP), formed by LMG-N2-G oxidation, which was identified by high-resolution mass spectrometry. Accounting for all TPs detected, a total mass balance at two concentration levels in batch reactors was closed at 86% and 102%, respectively. In three WWTPs, the total mass balance of LMG-N2-G ranged from 71 to 102%. Finally, LMG-N2-G and its TPs were detected in surface water samples with median concentration ranges of 23-139 ng L(-1). The results of this study suggest that glucuronides of pharmaceuticals might also be sources of yet undiscovered, but environmentally relevant, transformation products.

Sensitive inexpensive spectrophotometric and spectrofluorimetric analysis of ezogabine, levetiracetam and topiramate in tablet formulations using Hantzsch condensation reaction

NASA Astrophysics Data System (ADS)

Ibrahim, F. A.; El-Yazbi, A. F.; Wagih, M. M.; Barary, M. A.

2017-09-01

Two highly sensitive, simple and selective spectrophotometric and spectrofluorimetric assays have been investigated for the analysis of ezogabine, levetiracetam and topiramate in their pure and in pharmaceutical dosage forms. The suggested methods depend on the condensation of the primary amino-groups in the three drugs with acetylacetone and formaldehyde according to Hantzsch reaction yielding highly fluorescent yellow colored dihydropyridine derivatives. The reaction products of ezogabine, levetiracetam and topiramate were measured spectrophotometrically at 418, 390 and 380 nm or spectrofluorimetrically at λem/ex of 495/425 nm, 490/415 nm and 488/410 nm, respectively. Various experimental conditions have been carefully studied to maximize the reaction yield. At the optimum reaction conditions, the calibration curves were rectilinear over the concentration ranges of 8-25, 60-180 and 80-200 μg/mL spectrophotometrically and 0.02-0.2, 0.2-1.2 and 0.2-1.5 μg/mL spectrofluorimetrically for ezogabine, levetiracetam and topiramate, respectively with good correlation coefficients. The suggested methods were applied successfully for the analysis of ezogabine, levetiracetam and topiramate in their commercial tablets with high percentage recoveries and negligible interference from various excipients in pharmaceutical dosage forms. The results were statistically analyzed and showed the absence of any significant difference between both developed and published methods. The procedures were validated and evaluated by the ICH guidelines revealing good reproducibility and accuracy. Therefore, the two proposed methods may be considered of high interest for practical and reliable analysis of ezogabine, levetiracetam and topiramate in pharmaceutical dosage forms.

Comparison Of Efficacy Of Phenytoin And Levetiracetam For Prevention Of Early Post Traumatic Seizures.

PubMed

Khan, Shahbaz Ali; Bhatti, Sajid Nazir; Khan, Aftab Alam; Khan Afridi, Ehtisham Ahmed; Muhammad, Gul; Gul, Nasim; Zadran, Khalid Khan; Alam, Sudhair; Aurangzeb, Ahsan

2016-01-01

The incidence of early post-traumatic seizures after civilian traumatic brain injury ranges 4-25%. The control of early post-traumatic seizure is mandatory because these acute insults may add secondary damage to the already damaged brain with poor outcome. Prophylactic use of anti-epileptic drugs have been found to be have variable efficacy against early post-traumatic seizures. The objective of this study was to compare the efficacy of Phenytion and Levetiracetam in prevention of early post-traumatic seizures in moderate to severe traumatic brain injury. This randomized controlled trial was conducted in department of Neurosurgery, Ayub Medical College, Abbottabad from March, 2012 to March 2013. The patients with moderate to severe head injury were randomly allocated in two groups. Patients in group A were given phenytoin and patients in group B were given Levetiracetam. Patients were followed for one week to detect efficacy of drug in terms of early post traumatic seizures. The 154 patients included in the study were equally divided into two groups. Out of 154 patients 115 (74.7%) were male while 29 (25.3%) were females. Age of patients ranges from 7-48 (24.15±9.56) years. Ninety one (59.1%) patients had moderate head injury while 63 (40.9%) patients had severe head injury. Phenytoin was effective in preventing early post traumatic seizures in 73 (94.8%) patients whereas Levetiracetam effectively controlled seizures in 70 (90.95%) cases (p-value of .348). There is no statistically significant difference in the efficacy of Phenytoin and Levetiracetam in prophylaxis of early posttraumatic seizures in cases of moderate to severe traumatic brain injury.

Should Levetiracetam or Phenytoin Be Used for Posttraumatic Seizure Prophylaxis? A Systematic Review of the Literature and Meta-analysis.

PubMed

Khan, Nickalus R; VanLandingham, Matthew A; Fierst, Tamara M; Hymel, Caroline; Hoes, Kathryn; Evans, Linton T; Mayer, Rory; Barker, Fred; Klimo, Paul

2016-12-01

Posttraumatic seizure (PTS) is a significant complication of traumatic brain injury (TBI). To perform a systematic review and meta-analysis to compare levetiracetam with phenytoin for seizure prophylaxis in patients diagnosed with severe TBI. An inclusive search of several electronic databases and bibliographies was conducted to identify scientific studies that compared the effect of levetiracetam and phenytoin on PTS. Independent reviewers obtained data and classified the quality of each article that met inclusion criteria. A random effects meta-analysis was then completed. During June and July 2015, a systematic literature search was performed that identified 6097 articles. Of these, 7 met inclusion criteria. A random-effects meta-analysis was performed. A total of 1186 patients were included. The rate of seizure was 35 of 654 (5.4%) in the levetiracetam cohort and 18 of 532 (3.4%) in the phenytoin cohort. Our meta-analysis revealed no change in the rate of early PTS with levetiracetam compared with phenytoin (relative risk, 1.02; 95% confidence interval, 0.53-1.95; P = .96). The lack of evidence on which antiepileptic drug to use in PTS is surprising given the number of patients prescribed an antiepileptic drug therapy for TBI. On the basis of currently available Level III evidence, patients treated with either levetiracetam or phenytoin have similar incidences of early seizures after TBI. ADE, adverse drug eventAED, antiepileptic drugCI, confidence intervalOR, odds ratioPTS, posttraumatic seizureTBI, traumatic brain injury.

[Lacosamide: a new generation in the treatment of epilepsy].

PubMed

Gil-Nagel, A; Marin, H

2011-02-01

Despite the large number of antiepileptic drugs (AED) available today, more than 30% of patients with epilepsy do not manage to achieve adequate control over their seizures. For patients, the administration of the latest AED can be a good alternative, prior to surgery or when there are contraindications against it. Third generation AED offer different mechanisms of action and tolerability profiles that are more favourable than those of the first and second generations. Lacosamide has recently been approved by the European Medicines Agency (EMEA) and its United States counterpart (FDA) as an adjuctive AED in partial onset seizures in adults over the age of 16, thus making it a novel option in the treatment of epilepsy.

Comparison of Motor Activity and Sleep in Patients with Complex Partial Seizures on Levetiracetam Treatment and a Group of Healthy Subjects

PubMed Central

Yilmaz, Hikmet

2007-01-01

Purpose: Levetiracetam-treated patients commonly report daytime drowsiness, fatique, asthenia and decreasing of motor activity. However the origin of these reported side effects are still debated, we aimed to clarify effect of levetiracetam on sleep. Therefore this prospective study was conducted to evaluate the effects of levetiracetam on motor activity, amount and continuity of sleep and napping. Methods: Various tests were performed on twenty two patients treated with levetiracetam (10 monotherapy, 12 add-on therapy) at least three days before the initiation of treatment, and consecutively for five to eight days at the third week of treatment. These tests included sleep logs, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Modified Maintenance of Wakefulness Test and actimetric measurements. In order to evaluate the sleep behavior of these patients the following sleep parameters were estimated: bedtime, wake-up time, sleep-onset time, sleep-offset time, sleep latency, total sleep time, wake time after sleep onset, fragmentation index, total activity score, nap episodes, total nap duration and sleep efficiency. Twenty members of staff from our hospital (Doctor, nurse, secretary, civil servant etc.) were evaluated as control subjects in the study. Results: After three-week treatment with levetiracetam (in particular with add-on therapy), Epworth Sleepiness Scale scores, napping episodes and total nap durations increased and sleep latencies decreased. While durations of Modified Maintenance of Wakefulness Test and total activity scores decreased. However the total sleep time and the sleep efficiency did not show any difference from the pre-treatment values. Conclusions: Our results suggest that levetiracetam leads to drowsiness by decreasing the daily motor activity and increasing the naps; however this agent does not have any major effects on total sleep time and sleep efficiency during night. Actimetric analyses give information about continuity of

Effects of phenobarbital and levetiracetam on PR and QTc intervals in patients with post-stroke seizure.

PubMed

Siniscalchi, Antonio; Scaglione, Francesco; Sanzaro, Enzo; Iemolo, Francesco; Albertini, Giorgio; Quirino, Gianluca; Manes, Maria Teresa; Gratteri, Santo; Mercuri, Nicola Biagio; De Sarro, Giovambattista; Gallelli, Luca

2014-12-01

Sudden unexplained/unexpected death (SUDEP) is related to high mortality in patients with epilepsy. The prolongation of QT interval, involved in cardiac arrhythmia-related SUDEP, may be precipitated by antiepileptic drugs (AEDs). In this study, we evaluated the effects of phenobarbital and levetiracetam on PR-QTc intervals in patients with post-stroke seizures. We performed an open-label, parallel group, prospective, multicenter study between June 2009 and December 2013 in patients older than 18 years of age with a clinical diagnosis of post-stroke seizure and treated with phenobarbital or levetiracetam. In order to exclude a role of cerebral post-stroke injury on modulation of PR and QTc intervals, patients with cerebral post-stroke injury and without seizures were also enrolled as controls. Interictal electrocardiography analysis revealed no significant difference in PR interval between patients treated with an AED (n = 49) and control patients (n = 50) (181.25 ± 12.05 vs. 182.4 ± 10.3 ms; p > 0.05). In contrast, a significantly longer QTc interval was recorded in patients treated with an AED compared with control patients (441.2 ± 56.6 vs. 396.8 ± 49.3 ms; p < 0.01). Patients treated with phenobarbital showed a significantly longer QTc interval than patients treated with levetiracetam (460.0 ± 57.2 vs. 421.5 ± 50.1 ms; p < 0.05). The study reported that in patients with late post-stroke seizures, phenobarbital prolonged QTc interval more so than levetiracetam.

Prevention of status epilepticus-induced brain edema and neuronal cell loss by repeated treatment with high-dose levetiracetam.

PubMed

Itoh, Kouichi; Inamine, Moriyoshi; Oshima, Wataru; Kotani, Masaharu; Chiba, Yoichi; Ueno, Masaki; Ishihara, Yasuhiro

2015-05-22

The management of status epilepticus (SE) is important to prevent mortality and the development of post-SE symptomatic epilepsy. Acquired epilepsy after an initial brain insult by SE can be experimentally reproduced in the murine model of SE induced by pilocarpine. In the present study, we evaluated the possibility of treatment with a high-dose of levetiracetam in this model. Repeated treatment with high-dose levetiracetam after termination of SE by diazepam significantly prevented the incidence of spontaneous recurrent seizures and mortality for at least 28 days. To determine the brain alterations after SE, magnetic resonance imaging was performed. Both T2-weighted imaging and diffusion-weighted imaging showed changes in the limbic regions. These changes in the limbic regions demonstrated the development of cytotoxic edema three hours after SE, followed by the development of vasogenic edema two days after SE. In the pilocarpine-SE model, the incidence of spontaneous recurrent seizures after SE was strongly associated with neuronal damage within a few hours to days after SE by the development of vasogenic edema via the breakdown of the blood-brain barrier in the limbic regions. High-dose levetiracetam significantly suppressed the parameters in the limbic areas. These data indicate that repeated treatment with high-dose levetiracetam for at least two days after SE termination by diazepam is important for controlling the neuronal damage by preventing brain edema. Therefore, these findings suggest that early treatment with high-dose levetiracetam after SE termination by diazepam may protect against adverse sequelae via the inhibition of neurotoxicity induced by brain edema events. Copyright © 2015 Elsevier B.V. All rights reserved.

Levetiracetam monotherapy for treatment of structural epilepsy in dogs: 19 cases (2010-2015).

PubMed

Kelly, Darren; Raimondi, Francesca; Shihab, Nadia

2017-10-14

To evaluate the efficacy and tolerability of levetiracetam monotherapy in dogs with structural epilepsy. Retrospective case series. Nineteen client-owned dogs with structural epilepsy. Seizure frequencies after initiation of treatment were used to evaluate the efficacy of levetiracetam monotherapy. Seizure control was considered good if no seizures occurred within three months of starting treatment or poor if seizures returned within one month of starting treatment. Tolerability was evaluated by considering the occurrence and severity of any reported side effects. Ten of the 19 dogs were considered to have a good response to treatment with 7 achieving complete seizure freedom. Nine dogs were considered to have poor response to treatment. There was a statistically significant reduction in the percentage of patients experiencing cluster seizures from 68.4% to 15.8% (p=0.002). Side effects were noted in 8 of the 19 dogs but were considered mild in all cases. Follow-up times ranged from 12 days to 426 days. When used in conjunction with other appropriate therapies, levetiracetam may be an efficacious option for monotherapy in dogs with structural epilepsy. Its tolerability makes it a suitable option for use in a wide variety of patients. © British Veterinary Association (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Pharmacological evidence for the involvement of the NMDA receptor and nitric oxide pathway in the antidepressant-like effect of lamotrigine in the mouse forced swimming test.

PubMed

Ostadhadi, Sattar; Ahangari, Mohammad; Nikoui, Vahid; Norouzi-Javidan, Abbas; Zolfaghari, Samira; Jazaeri, Farahnaz; Chamanara, Mohsen; Akbarian, Reyhaneh; Dehpour, Ahmad-Reza

2016-08-01

Lamotrigine is an anticonvulsant agent that shows clinical antidepressant properties. The aim of the present study was to investigate the involvement of N-methyl-d-aspartate (NMDA) receptors and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) synthesis in possible antidepressant-like effect of lamotrigine in forced swimming test (FST) in mice. Intraperitoneal administration of lamotrigine (10mg/kg) decreased the immobility time in the FST (P<0.01) without any effect on locomotor activity in the open-field test (OFT), while higher dose of lamotrigine (30mg/kg) reduced the immobility time in the FST (P<0.001) as well as the number of crossings in the OFT. Pretreatment of animals with NMDA (75mg/kg), l-arginine (750mg/kg, a substrate for nitric oxide synthase [NOS]) or sildenafil (5mg/kg, a phosphodiesterase [PDE] 5 inhibitor) reversed the antidepressant-like effect of lamotrigine (10mg/kg) in the FST. Injection of l-nitroarginine methyl ester (l-NAME, 10mg/kg, a non-specific NOS inhibitor), 7-nitroindazole (30mg/kg, a neuronal NOS inhibitor), methylene blue (20mg/kg, an inhibitor of both NOS and soluble guanylate cyclase [sGC]), or MK-801 (0.05mg/kg), ketamine (1mg/kg), and magnesium sulfate (10mg/kg) as NMDA receptor antagonists in combination with a sub-effective dose of lamotrigine (5mg/kg) diminished the immobility time of animals in the FST compared with either drug alone. None of the drugs produced significant effects on the locomotor activity in the OFT. Based on our findings, it is suggested that the antidepressant-like effect of lamotrigine might mediated through inhibition of either NMDA receptors or NO-cGMP synthesis. Copyright © 2016. Published by Elsevier Masson SAS.

Potential role for human P-glycoprotein in the transport of lacosamide.

PubMed

Zhang, Chunbo; Chanteux, Hugues; Zuo, Zhong; Kwan, Patrick; Baum, Larry

2013-07-01

Antiepileptic drugs (AEDs) do not effectively treat 30-40% of patients with epilepsy. Export of AEDs by P-glycoprotein (Pgp, ABCB1, or MDR1), which is overexpressed in the blood-brain barrier in drug-resistant patients, may be a mechanism for resistance to AEDs. For most recently approved AEDs, whether they are transported by Pgp is unknown. We investigated whether a new AED, lacosamide (LCM), is a substrate of human Pgp. LLC-PK1 and MDCKII cells transfected with the human MDR1 gene were used to determine the substrate status of LCM in concentration equilibrium transport assays (CETAs). An equal concentration of drug was initially loaded in both the apical and basal chambers, and the concentration in both chambers was measured up to 4 h. The experiments were repeated in the presence of the Pgp inhibitors verapamil and tariquidar. Caco-2 assays were used to determine the intrinsic permeability and efflux ratio of LCM as well as its potential to inhibit digoxin, a Pgp substrate. Lacosamide was transported by MDR1-transfected cells from basolateral to apical sides. The efflux of LCM could be completely blocked by verapamil or tariquidar. In Caco-2 assays, LCM showed high permeability without a significant efflux ratio; it did not inhibit digoxin, a Pgp substrate. Although LCM is a substrate of Pgp in CETA, Caco-2 data demonstrated that passive diffusion should play a major role in the overall disposition of LCM. The critical role of Pgp should be addressed in vivo. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Levetiracetam-induced interstitial nephritis in a patient with glioma.

PubMed

Mahta, Ali; Kim, Ryan Y; Kesari, Santosh

2012-01-01

A 45-year-old man with a new diagnosis of low grade glioma was started on an escalating dose of levetiracetam (Lev) for seizure management. He gradually developed intractable nausea/vomiting and a high creatinine concentration due to acute renal failure which was attributed to Lev-induced interstitial nephritis. The medication was changed and his renal function rapidly improved to his baseline. Copyright © 2011 Elsevier Ltd. All rights reserved.

Levetiracetam attenuates hippocampal expression of synaptic plasticity-related immediate early and late response genes in amygdala-kindled rats

PubMed Central

2010-01-01

Background The amygdala-kindled rat is a model for human temporal lobe epilepsy and activity-dependent synaptic plasticity. Hippocampal RNA isolated from amygdala-kindled rats at different kindling stages was analyzed to identify kindling-induced genes. Furthermore, effects of the anti-epileptic drug levetiracetam on kindling-induced gene expression were examined. Results Cyclooxygenase-2 (Cox-2), Protocadherin-8 (Pcdh8) and TGF-beta-inducible early response gene-1 (TIEG1) were identified and verified as differentially expressed transcripts in the hippocampus of kindled rats by in situ hybridization and quantitative RT-PCR. In addition, we identified a panel of 16 additional transcripts which included Arc, Egr3/Pilot, Homer1a, Ania-3, MMP9, Narp, c-fos, NGF, BDNF, NT-3, Synaptopodin, Pim1 kinase, TNF-α, RGS2, Egr2/krox-20 and β-A activin that were differentially expressed in the hippocampus of amygdala-kindled rats. The list consists of many synaptic plasticity-related immediate early genes (IEGs) as well as some late response genes encoding transcription factors, neurotrophic factors and proteins that are known to regulate synaptic remodelling. In the hippocampus, induction of IEG expression was dependent on the afterdischarge (AD) duration. Levetiracetam, 40 mg/kg, suppressed the development of kindling measured as severity of seizures and AD duration. In addition, single animal profiling also showed that levetiracetam attenuated the observed kindling-induced IEG expression; an effect that paralleled the anti-epileptic effect of the drug on AD duration. Conclusions The present study provides mRNA expression data that suggest that levetiracetam attenuates expression of genes known to regulate synaptic remodelling. In the kindled rat, levetiracetam does so by shortening the AD duration thereby reducing the seizure-induced changes in mRNA expression in the hippocampus. PMID:20105316

Role of high-dose levetiracetam as add-on therapy for intractable epilepsy: case report and brief review of the literature.

PubMed

Mateo-Carrasco, Hector; Serrano-Castro, Pedro Jesús; Molina-Cuadrado, Emilio; Goodwin, Mel; Nguyen, Timothy V; Kotecha, Primal N

2015-08-01

We discuss the case of a 5-year-old long-standing epileptic woman, who received oxcarbazepine 2.1 g/day, and levetiracetam 3 g/day (started in 2005 and up-titrated according to response). In October/2008, due to poor seizure control, patient consent was obtained and levetiracetam up-titrated to 6 g/day, remaining invariable for 72 months; zonisamide was added in July/2009 and up-titrated to 500 mg/day. This combination achieved seizure frequency reduction ≥50 %, however, the patient ultimately necessitated temporal lobectomy for complete remission. Occasional agitation and moderate depression were the main side effects. Three anti-epileptic drugs (including levetiracetam 6 g/day) achieved statistically-significant seizure frequency reduction ≥50 % compared with lower doses, but not seizure freedom. Low-dose risperidone was initiated due to transient dose-dependent agitation, although it did not lead to discontinuation. This report provides insightful information on the use of high-dose levetiracetam in focal refractory epilepsy. The concomitance of anti-epileptics may have contributed to both efficacy and toxicity. Therefore, the risk/benefit ratio must be individually weighed until larger studies are available.

Efficacy and safety of lacosamide as first add-on or later adjunctive treatment for uncontrolled partial-onset seizures: A multicentre open-label trial.

PubMed

Zadeh, Wendy Waldman; Escartin, Antonio; Byrnes, William; Tennigkeit, Frank; Borghs, Simon; Li, Ting; Dedeken, Peter; De Backer, Marc

2015-09-01

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. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Management of generalised convulsive status epilepticus (SE): A prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam--Pilot study.

PubMed

Mundlamuri, R C; Sinha, S; Subbakrishna, D K; Prathyusha, P V; Nagappa, M; Bindu, P S; Taly, A B; Umamaheswara Rao, G S; Satishchandra, P

2015-08-01

This study was conducted to compare the efficacy of phenytoin, valproate and levetiracetam in patients with GCSE. This randomised controlled prospective study was conducted on 150 patients to compare the efficacy of phenytoin (n = 50), valproate (n = 50) and levetiracetam (n = 50) along with lorazepam in patients with GCSE. All recruited patients received i.v. lorazepam (0.1mg/kg) followed by one of the 3 AEDs viz. phenytoin (20 mg/kg), valproate (30 mg/kg), and levetiracetam (25 mg/kg). Those who remained uncontrolled with 1st AED, received the other two AEDs sequentially. Clinical, imaging, EEG, etiological factors were analysed. Predictors of poor seizure control and outcome at discharge and at one month follow-up were assessed. In the phenytoin subgroup, the seizures could be controlled in 34 (68%) with lorazepam+phenytoin infusion. In the valproate subgroup (n = 50), seizures could be controlled in 34 (68%) with lorazepam+valproate infusion. In the levetiracetam subgroup (n = 50), seizures could be controlled in 39 (78%) with lorazepam+levetiracetam infusion. There was no statistically significant difference between the subgroups (p = 0.44). Overall, following lorazepam and 1st AED, 107/150 (71.3%) were controlled; with addition of 2nd AED, 130/150 (86.7%) and by adding 3rd AED, 138/150 (92%) were controlled. Fifteen out of 110 (13.6%) expired within 1 month of SE: phenytoin-6; valproate-4; and levetiracetam-5. Interestingly, 3 patients in the levetiracetam had post-ictal psychosis. Phenytoin, valproate, and levetiracetam are safe and equally efficacious following lorazepam in GCSE. The choice of AEDs could be individualised based on co-morbidities. SE could be controlled in 92% of patients with AEDs only and anaesthetics were not required in them. Copyright © 2015 Elsevier B.V. All rights reserved.

Modulatory effects of ketamine, risperidone and lamotrigine on resting brain perfusion in healthy human subjects.

PubMed

Shcherbinin, Sergey; Doyle, Orla; Zelaya, Fernando O; de Simoni, Sara; Mehta, Mitul A; Schwarz, Adam J

2015-11-01

Resting brain perfusion, measured using the MRI-based arterial spin labelling (ASL) technique, is sensitive to detect central effects of single, clinically effective, doses of pharmacological compounds. However, pharmacological interaction experiments, such as the modulation of one drug response in the presence of another, have not been widely investigated using a task-free ASL approach. We assessed the effects of three psychoactive compounds (ketamine, risperidone and lamotrigine), and their interaction, on resting brain perfusion in healthy human volunteers. A multivariate Gaussian process classification (GPC) and more conventional univariate analyses were applied. The four pre-infusion conditions for each subject comprised risperidone, lamotrigine and two placebo sessions. The two placebo conditions enabled us to evaluate the classification performance in a test-retest setting, in addition to its performance in distinguishing the active oral drugs from placebo (direct effect on brain perfusion). The post ketamine- or saline-infusion scans allowed the effect of ketamine, and its interaction with risperidone and lamotrigine, on brain perfusion to be characterised. The pseudo-continuous ASL measurements of perfusion were sensitive to the effects of ketamine infusion and risperidone. The GPC captured consistent changes in perfusion across the group and contextualised the univariate changes with a larger pattern of regions contributing to accurate discrimination of ketamine from placebo. The findings argue against perfusion changes confounding in the previously described evoked BOLD response to ketamine and emphasise the blockade of the NMDA receptor over neuronal glutamate release in determining the perfusion changes induced by ketamine.

Fate of carbamazepine, its metabolites, and lamotrigine in soils irrigated with reclaimed wastewater: Sorption, leaching and plant uptake.

PubMed

Paz, Anat; Tadmor, Galit; Malchi, Tomer; Blotevogel, Jens; Borch, Thomas; Polubesova, Tamara; Chefetz, Benny

2016-10-01

Irrigation with reclaimed wastewater may result in the ubiquitous presence of pharmaceutical compounds (PCs) and their metabolites in the agroecosystem. In this study, we focused on two highly persistent anticonvulsant drugs, lamotrigine and carbamazepine and two of its metabolites (EP-CBZ and DiOH-CBZ), aiming to elucidate their behavior in agricultural ecosystem using batch and lysimeter experiments. Sorption of the studied compounds by soils was found to be governed mainly by the soil organic matter level. Sorption affinity of compounds to soils followed the order lamotrigine > carbamazepine > EP-CBZ > DiOH-CBZ. Sorption was reversible, and no competition between sorbates in bi-solute systems was observed. The results of the lysimeter studies were in accordance with batch experiment findings, demonstrating accumulation of lamotrigine and carbamazepine in top soil layers enriched with organic matter. Detection of carbamazepine and one of its metabolites in rain-fed wheat previously irrigated with reclaimed wastewater, indicates reversibility of their sorption, resulting in their potential leaching and their availability for plant uptake. This study demonstrates the long-term implication of introduction of PCs to the agroecosystem. Copyright © 2016 Elsevier Ltd. All rights reserved.

Safety of Levetiracetam in Paediatrics: A Systematic Review

PubMed Central

Egunsola, Oluwaseun; Choonara, Imti; Sammons, Helen Mary

2016-01-01

Objective To identify adverse events (AEs) associated with Levetiracetam (LEV) in children. Methods Databases EMBASE (1974-February 2015) and Medline (1946-February 2015) were searched for articles in which paediatric patients (≤18 years) received LEV treatment for epilepsy. All studies with reports on safety were included. Studies involving adults, mixed age population (i.e. children and adults) in which the paediatric subpopulation was not sufficiently described, were excluded. A meta-analysis of the RCTs was carried out and association between the commonly reported AEs or treatment discontinuation and the type of regimen (polytherapy or monotherapy) was determined using Chi2 analysis. Results Sixty seven articles involving 3,174 paediatric patients were identified. A total of 1,913 AEs were reported across studies. The most common AEs were behavioural problems and somnolence, which accounted for 10.9% and 8.4% of all AEs in prospective studies. 21 prospective studies involving 1120 children stated the number of children experiencing AEs. 47% of these children experienced AEs. Significantly more children experienced AEs with polytherapy (64%) than monotherapy (22%) (p<0.001). Levetiracetam was discontinued in 4.5% of all children on polytherapy and 0.9% on monotherapy (p<0.001), the majority were due to behavioural problems. Conclusion Behavioural problems and somnolence were the most prevalent adverse events to LEV and the most common causes of treatment discontinuation. Children on polytherapy have a greater risk of adverse events than those receiving monotherapy. PMID:26930201

Efficacy, safety, and tolerability of lacosamide in patients with gain-of-function Nav1.7 mutation-related small fiber neuropathy: study protocol of a randomized controlled trial-the LENSS study.

PubMed

de Greef, Bianca T A; Merkies, Ingemar S J; Geerts, Margot; Faber, Catharina G; Hoeijmakers, Janneke G J

2016-06-30

Small fiber neuropathy generally leads to considerable pain and autonomic symptoms. Gain-of-function mutations in the SCN9A- gene, which codes for the Nav1.7 voltage-gated sodium channel, have been reported in small fiber neuropathy, suggesting an underlying genetic basis in a subset of patients. Currently available sodium channel blockers lack selectivity, leading to cardiac and central nervous system side effects. Lacosamide is an anticonvulsant, which blocks Nav1.3, Nav1.7, and Nav1.8, and stabilizes channels in the slow-inactivation state. Since multiple Nav1.7 mutations in small fiber neuropathy showed impaired slow-inactivation, lacosamide might be effective. The Lacosamide-Efficacy-'N'-Safety in Small fiber neuropathy (LENSS) study is a randomized, double-blind, placebo-controlled, crossover trial in patients with SCN9A-associated small fiber neuropathy, with the primary objective to evaluate the efficacy of lacosamide versus placebo. Eligible patients (the aim is to recruit 25) fulfilling the inclusion and exclusion criteria will be randomized to receive lacosamide (200 mg b.i.d.) or placebo during the first double-blinded treatment period (8 weeks), which is preceded by a titration period (3 weeks). The first treatment period will be followed by a tapering period (2 weeks). After a 2-week washout period, patients will crossover to the alternate arm for the second period consisting of an equal titration phase, treatment period, and tapering period. The primary efficacy endpoint will be the proportion of patients demonstrating a 1-point average pain score reduction compared to baseline using the Pain Intensity Numerical Rating Scale. We assume a response rate of approximately 60 % based on the criteria composed by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group for measurement of pain. Patients withdrawing from the study will be considered non- responders. Secondary outcomes will include changes in maximum

Effects of antiepileptic drugs on learning as assessed by a repeated acquisition of response sequences task in rats.

PubMed

Shannon, Harlan E; Love, Patrick L

2007-02-01

Patients with epilepsy can have impaired cognitive abilities. Antiepileptic drugs (AEDs) may contribute to the cognitive deficits observed in patients with epilepsy, and have been shown to induce cognitive impairments in healthy individuals. However, there are few systematic data on the effects of AEDs on specific cognitive domains. We have previously demonstrated that a number of AEDs can impair working memory and attention. The purpose of the present study was to evaluate the effects of AEDs on learning as measured by a repeated acquisition of response sequences task in nonepileptic rats. The GABA-related AEDs phenobarbital and chlordiazepoxide significantly disrupted performance by shifting the learning curve to the right and increasing errors, whereas tiagabine and valproate did not. The sodium channel blockers carbamazepine and phenytoin suppressed responding at higher doses, whereas lamotrigine shifted the learning curve to the right and increased errors, and topiramate was without significant effect. Levetiracetam also shifted the learning curve to the right and increased errors. The disruptions produced by triazolam, chlordiazepoxide, lamotrigine, and levetiracetam were qualitatively similar to the effects of the muscarinic cholinergic receptor antagonist scopolamine. The present results indicate that AEDs can impair learning, but there are differences among AEDs in the magnitude of the disruption in nonepileptic rats, with drugs that enhance GABA receptor function and some that block sodium channels producing the most consistent impairment of learning.

LIS1-associated classic lissencephaly: A retrospective, multicenter survey of the epileptogenic phenotype and response to antiepileptic drugs.

PubMed

Herbst, Saskia M; Proepper, Christiane R; Geis, Tobias; Borggraefe, Ingo; Hahn, Andreas; Debus, Otfried; Haeussler, Martin; von Gersdorff, Gero; Kurlemann, Gerhard; Ensslen, Matthias; Beaud, Nathalie; Budde, Joerg; Gilbert, Michael; Heiming, Ralf; Morgner, Rita; Philippi, Heike; Ross, Sophia; Strobl-Wildemann, Gertrud; Muelleder, Kerstin; Vosschulte, Paul; Morris-Rosendahl, Deborah J; Schuierer, Gerhard; Hehr, Ute

2016-04-01

Patients with LIS1-associated classic lissencephaly typically present with severe psychomotor retardation and drug-resistant epilepsy within the first year. To analyze the epileptogenic phenotype and response to antiepileptic therapy in LIS1-associated classic lissencephaly. Retrospective evaluation of 22 patients (8 months-24 years) with genetically and radiologically confirmed LIS1-associated classic lissencephaly in 16 study centers. All patients in our cohort developed drug-resistant epilepsy. In 82% onset of seizures was noted within the first six months of life, most frequently with infantile spasms. Later in infancy the epileptogentic phenotype became more variable and included different forms of focal seizures as well generalized as tonic-clonic seizures, with generalized tonic-clonic seizures being the predominant type. Lamotrigine and valproate were rated most successful with good or partial response rates in 88-100% of the patients. Both were evaluated significantly better than levetiracetam (p<0.05) and sulthiame (p<0.01) in the neuropediatric assessment and better than levetiracetam, sulthiame (p<0.05) and topiramate (p<0.01) in the family survey. Phenobarbital and vigabatrin achieved good or partial response in 62-83% of the patients. Our findings suggest that patients with LIS1-associated lissencephaly might benefit most from lamotrigine, valproate, vigabatrin or phenobarbital. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Adjunctive lacosamide for focal epilepsy: an open-label trial evaluating the impact of flexible titration and dosing on safety and seizure outcomes.

PubMed

Baulac, Michel; Coulbaut, Safia; Doty, Pamela; McShea, Cindy; De Backer, Marc; Bartolomei, Fabrice; Vlaicu, Mihaela

2017-06-01

To evaluate the safety and effectiveness of lacosamide in a real-life setting with the use of a flexible dose titration schedule and individualised maintenance doses up to the maximum approved dose of 400 mg/day. Adults with a diagnosis of focal seizures, with or without secondary generalization, were enrolled in this open-label Phase IV trial (NCT01235403). Lacosamide was initiated at 100 mg/day (50 mg bid) and uptitrated over a 12-week period to 200, 300 or 400 mg/day, based on safety and seizure control. Although dose increases were to be in increments of 100 mg/day, intermediate doses were permitted at each escalation step for one week for patients known to be particularly sensitive to starting new AEDs. After receiving a stable, effective dose for three weeks, patients entered the 12-week maintenance period. Primary outcomes were incidence of treatment-emergent adverse events (TEAEs) and withdrawal due to TEAEs. Seizure outcomes, all secondary, were median focal seizure frequency, ≥50% reduction in focal seizure frequency, and seizure freedom. One hundred patients with a mean age of 44 years were enrolled and 74 completed the trial. The incidence of TEAEs was 64.0% (n=100), with the most frequently reported (≥5% of patients) being dizziness, headache, and asthenia. Fourteen patients withdrew due to TEAEs, most frequently due to dizziness (six patients; 6.0%), vomiting (two patients; 2%), and tremor (two patients; 2%). Among patients with baseline and maintenance phase seizure data (n=75), median reduction in focal seizure frequency from baseline was 69.7% and the ≥50% responder rate was 69.3%. Among 74 patients who completed the maintenance phase, 21 (28.4%) were seizure-free. Flexible lacosamide dosing in this open-label trial was associated with a favourable tolerability and safety profile; the nature of the TEAEs was consistent with that observed in previous pivotal trials. Treatment with lacosamide was also associated with effective seizure

Simultaneous extraction and quantification of lamotrigine, phenobarbital, and phenytoin in human plasma and urine samples using solidified floating organic drop microextraction and high-performance liquid chromatography.

PubMed

Asadi, Mohammad; Dadfarnia, Shayessteh; Haji Shabani, Ali Mohammad; Abbasi, Bijan

2015-07-01

A novel and simple method based on solidified floating organic drop microextraction followed by high-performance liquid chromatography with ultraviolet detection has been developed for simultaneous preconcentration and determination of phenobarbital, lamotrigine, and phenytoin in human plasma and urine samples. Factors affecting microextraction efficiency such as the type and volume of the extraction solvent, sample pH, extraction time, stirring rate, extraction temperature, ionic strength, and sample volume were optimized. Under the optimum conditions (i.e. extraction solvent, 1-undecanol (40 μL); sample pH, 8.0; temperature, 25°C; stirring rate, 500 rpm; sample volume, 7 mL; potassium chloride concentration, 5% and extraction time, 50 min), the limits of detection for phenobarbital, lamotrigine, and phenytoin were 1.0, 0.1, and 0.3 μg/L, respectively. Also, the calibration curves for phenobarbital, lamotrigine, and phenytoin were linear in the concentration range of 2.0-300.0, 0.3-200.0, and 1.0-200.0 μg/L, respectively. The relative standard deviations for six replicate extractions and determinations of phenobarbital, lamotrigine, and phenytoin at 50 μg/L level were less than 4.6%. The method was successfully applied to determine phenobarbital, lamotrigine, and phenytoin in plasma and urine samples. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Two novel cocrystals of lamotrigine with isomeric bipyridines and in situ monitoring of the cocrystallization.

PubMed

Du, Shichao; Wang, Yan; Wu, Songgu; Yu, Bo; Shi, Peng; Bian, Lin; Zhang, Dejiang; Hou, Jie; Wang, Jingkang; Gong, Junbo

2017-12-15

Crystal engineering strategy was applied to develop new solid forms of lamotrigine. Two novel cocrystals of lamotrigine forming with 4,4'-bipyridine (2:1) and 2,2'-bipyridine cocrystal (1:1.5) were successfully obtained by neat grinding and liquid assisted grinding. The novel cocrystals were fully characterized and confirmed by X-ray diffraction, thermal and spectroscopic analysis. DXRxi Raman microscope was also used to identify the cocrystals. The factors such as solvent and the structure of coformers which influenced the cocrystal formation were discussed. Furthermore, the novel cocrystals were both obtained by slurry crystallization. Process analytical technologies including focused beam reflectance measurement and attenuated total reflectance Fourier Transform Infrared were applied to investigate the cocrystallization process and the mechanism. HPLC analysis showed that the dissolution rate and the solubility of the two novel cocrystals were both improved. Copyright © 2017 Elsevier B.V. All rights reserved.

Conversion to lacosamide monotherapy in the treatment of focal epilepsy: Results from a historical-controlled, multicenter, double-blind study

PubMed Central

Wechsler, Robert T; Li, George; French, Jacqueline; O'Brien, Terence J; D'Cruz, O'Neill; Williams, Paulette; Goodson, Robin; Brock, Melissa

2014-01-01

Objective To evaluate the efficacy and safety of conversion to lacosamide 400 mg/day monotherapy in adults with focal epilepsy. Methods This historical-controlled, double-blind study (NCT00520741) enrolled patients aged 16–70 years on stable doses of 1–2 antiepileptic drugs (AEDs) and experiencing 2–40 partial-onset seizures per 28 days during the 8-week prospective Baseline. Patients were randomized to lacosamide 400 or 300 mg/day (3:1 ratio), starting at 200 mg/day and titrated over 3 weeks to randomized dose. Patients then withdrew background AEDs over 6 weeks and entered a 10-week Monotherapy Phase. The primary assessment was the Kaplan-Meier–predicted percentage of patients on 400 mg/day in the full analysis set (FAS) meeting ≥1 predefined seizure-related exit criterion by day 112, compared with the historical-control threshold (65.3%). Results Four hundred twenty-five patients were enrolled and were eligible for safety analyses (400 mg/day, n = 319; 300 mg/day, n = 106). A total of 271 (63.8%) of 425 patients completed the Lacosamide Maintenance Phase (combined AED Withdrawal and Monotherapy Phases). Among 284 patients in the 400 mg/day group in the FAS, 82 (28.9%) met ≥1 exit criterion; the Kaplan-Meier–predicted exit percentage at day 112 for 400 mg/day (30.0%; 95% confidence interval [CI] 24.6–35.5%) was lower than the historical control. When exit events, withdrawal due to treatment-emergent adverse events (TEAEs), and withdrawal due to lack of efficacy were summed (n = 90), the predicted exit percentage (32.3%; 95% CI 26.8–37.8%) was also lower than the historical control. Most patients receiving 400 mg/day reported some improvement on the Clinical Global Impression of Change (75.4%) and Patient Global Impression of Change (74.3%). Overall, the most common (>10%) TEAEs were dizziness (24.0%), headache (14.4%), nausea (13.4%), convulsion (11.5%), somnolence (10.4%), and fatigue (10.1%); most (74.1%) were mild-to-moderate in intensity

Conversion to lacosamide monotherapy in the treatment of focal epilepsy: results from a historical-controlled, multicenter, double-blind study.

PubMed

Wechsler, Robert T; Li, George; French, Jacqueline; O'Brien, Terence J; D'Cruz, O'Neill; Williams, Paulette; Goodson, Robin; Brock, Melissa

2014-07-01

To evaluate the efficacy and safety of conversion to lacosamide 400 mg/day monotherapy in adults with focal epilepsy. This historical-controlled, double-blind study (NCT00520741) enrolled patients aged 16-70 years on stable doses of 1-2 antiepileptic drugs (AEDs) and experiencing 2-40 partial-onset seizures per 28 days during the 8-week prospective Baseline. Patients were randomized to lacosamide 400 or 300 mg/day (3:1 ratio), starting at 200 mg/day and titrated over 3 weeks to randomized dose. Patients then withdrew background AEDs over 6 weeks and entered a 10-week Monotherapy Phase. The primary assessment was the Kaplan-Meier-predicted percentage of patients on 400 mg/day in the full analysis set (FAS) meeting ≥ 1 predefined seizure-related exit criterion by day 112, compared with the historical-control threshold (65.3%). Four hundred twenty-five patients were enrolled and were eligible for safety analyses (400 mg/day, n = 319; 300 mg/day, n = 106). A total of 271 (63.8%) of 425 patients completed the Lacosamide Maintenance Phase (combined AED Withdrawal and Monotherapy Phases). Among 284 patients in the 400 mg/day group in the FAS, 82 (28.9%) met ≥ 1 exit criterion; the Kaplan-Meier-predicted exit percentage at day 112 for 400 mg/day (30.0%; 95% confidence interval [CI] 24.6-35.5%) was lower than the historical control. When exit events, withdrawal due to treatment-emergent adverse events (TEAEs), and withdrawal due to lack of efficacy were summed (n = 90), the predicted exit percentage (32.3%; 95% CI 26.8-37.8%) was also lower than the historical control. Most patients receiving 400 mg/day reported some improvement on the Clinical Global Impression of Change (75.4%) and Patient Global Impression of Change (74.3%). Overall, the most common (>10%) TEAEs were dizziness (24.0%), headache (14.4%), nausea (13.4%), convulsion (11.5%), somnolence (10.4%), and fatigue (10.1%); most (74.1%) were mild-to-moderate in intensity. Seventy-two patients (16

Enhanced efficacy of anticonvulsants when combined with levetiracetam in soman-exposed rats.

PubMed

Myhrer, Trond; Enger, Siri; Jonassen, Morten; Aas, Pål

2011-12-01

Results from studies based on microinfusions into seizure controlling brain sites (area tempestas, medial septum, perirhinal cortex, posterior piriform cortex) have shown that procyclidine, muscimol, caramiphen, and NBQX, but not ketamine, exert anticonvulsant effects against soman-induced seizures. The purpose of the present study was to examine whether levetiracetam (Keppra(®)) may enhance the anticonvulsant potency of the above drugs to become optimally effective when used systemically. Levetiracetam has a unique profile in preclinical models of epilepsy and has been shown to increase the potency of other antiepileptic drugs. The rats were pretreated with pyridostigmine (0.1mg/kg) to enhance survival and received anticonvulsants 20 min after onset of seizures evoked by soman (1.15 × LD(50)). The results showed that no single drug was able to terminate seizure activity. However, when levetiracetam (LEV; 50mg/kg) was combined with either procyclidine (PCD; 10mg/kg) or caramiphen (CMP; 10mg/kg) complete cessation of seizures was achieved, but the nicotinic antagonist mecamylamine was needed to induce full motor rest in some rats. In a subsequent experiment, rats were pretreated with HI-6 (125 mg/kg) to enhance survival and treatment started 40 min following seizure onset of a soman dose of 1.6 × LD(50). LEV (50mg/kg) combined with either PCD (20mg/kg) or CMP (20mg/kg) terminated seizure activity, but the survival rate was considerably higher for LEV+PCD than LEV+CMP. Both therapies could also save the lives of rats that were about to die 5-10 min after seizure onset. Thus, the combination of LEV and PCD or CMP may make up a model of a future autoinjector being effective regardless of the time of application. Copyright © 2011 Elsevier Inc. All rights reserved.

Development of New Method for Simultaneous Analysis of Piracetam and Levetiracetam in Pharmaceuticals and Biological Fluids: Application in Stability Studies

PubMed Central

Siddiqui, Farhan Ahmed; Sher, Nawab; Shafi, Nighat; Wafa Sial, Alisha; Ahmad, Mansoor; Mehjebeen

2014-01-01

RP-HPLC ultraviolet detection simultaneous quantification of piracetam and levetiracetam has been developed and validated. The chromatography was obtained on a Nucleosil C18 column of 25 cm × 0.46 cm, 10 μm, dimension. The mobile phase was a (70 : 30 v/v) mixture of 0.1 g/L of triethylamine and acetonitrile. Smooth flow of mobile phase at 1 mL/min was set and 205 nm wavelength was selected. Results were evaluated through statistical parameters which qualify the method reproducibility and selectivity for the quantification of piracetam, levetiracetam, and their impurities hence proving stability-indicating properties. The proposed method is significantly important, permitting the separation of the main constituent piracetam from levetiracetam. Linear behavior was observed between 20 ng/mL and 10000 ng/mL for both drugs. The proposed method was checked in bulk drugs, dosage formulations, physiological condition, and clinical investigations and excellent outcome was witnessed. PMID:25114921

Development of new method for simultaneous analysis of piracetam and levetiracetam in pharmaceuticals and biological fluids: application in stability studies.

PubMed

Siddiqui, Farhan Ahmed; Sher, Nawab; Shafi, Nighat; Wafa Sial, Alisha; Ahmad, Mansoor; Mehjebeen; Naseem, Huma

2014-01-01

RP-HPLC ultraviolet detection simultaneous quantification of piracetam and levetiracetam has been developed and validated. The chromatography was obtained on a Nucleosil C18 column of 25 cm×0.46 cm, 10 μm, dimension. The mobile phase was a (70:30 v/v) mixture of 0.1 g/L of triethylamine and acetonitrile. Smooth flow of mobile phase at 1 mL/min was set and 205 nm wavelength was selected. Results were evaluated through statistical parameters which qualify the method reproducibility and selectivity for the quantification of piracetam, levetiracetam, and their impurities hence proving stability-indicating properties. The proposed method is significantly important, permitting the separation of the main constituent piracetam from levetiracetam. Linear behavior was observed between 20 ng/mL and 10,000 ng/mL for both drugs. The proposed method was checked in bulk drugs, dosage formulations, physiological condition, and clinical investigations and excellent outcome was witnessed.

Use of levetiracetam in a population of patients aged 65 years and older: a subset analysis of the KEEPER trial.

PubMed

Ferrendelli, J A; French, J; Leppik, I; Morrell, M J; Herbeuval, A; Han, J; Magnus, L

2003-12-01

Levetiracetam (Keppra) was evaluated in a subset of patients aged >/=65 years (n=78) enrolled in a large (n=1030) open-label, phase IV trial (the KEEPER trial). A 4-week dose adjustment was followed by a 12-week evaluation period. An overall median reduction in partial seizures of 80.1% (n=65) was observed. Overall, 76.9% of patients were >/=50% responders, 56.9% were >/=75% responders, and 40.0% were 100% responders. Levetiracetam was well tolerated, with 42.3% of patients reporting one or more adverse events. A total of 15 patients (19.2%) experienced an adverse event that led to discontinuation. Somnolence (n=13,16.7%) and dizziness (n=7,9.0%) were the most commonly reported adverse events. Despite the limitations of the open-label study design, these data provide information regarding the use of levetiracetam as add-on therapy for the treatment of partial-onset seizures in patients >/=65 years of age, including those requiring concomitant medications.

Design, synthesis, and anticonvulsant activity of new hybrid compounds derived from 2-(2,5-dioxopyrrolidin-1-yl)propanamides and 2-(2,5-dioxopyrrolidin-1-yl)butanamides.

PubMed

Kamiński, Krzysztof; Zagaja, Mirosław; Łuszczki, Jarogniew J; Rapacz, Anna; Andres-Mach, Marta; Latacz, Gniewomir; Kieć-Kononowicz, Katarzyna

2015-07-09

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.

[Changes in quality of life and work function during phase prophylactic lamotrigine treatment in bipolar patients: 6 month, prospective, observational study].

PubMed

Gonda, Xenia; Kalman, Janos; Dome, Peter; Rihmer, Zoltan

2016-03-01

Bipolar disorder is a lifelong illness requiring lifelong pharmacotherapy. Therefore besides symptomatic remission, achievement of full work-related functioning and restoration of quality of life is a priority during successful treatment. The present prospective, observational, non-intervention study focused on investigating the effect of lamotrigine therapy on the quality of life and work-related function of bipolar patients in outpatient care. 969 bipolar or schizoaffective outpatients participated in the study who previously did not receive lamotrigine therapy. Our present phase-prophylactic study was a prospective, observational, non-intervention study with a six-month follow-up. Evaluations took place at baseline and at months 1, 2, 3 and 6. Patients were followed with a Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I). Changes in work-related function was evaluated using Social Adjustment Scale (SAS), while quality of life was assessed with the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) scale. SAS scoreds showed a consistent decrease in the overall sample and in all CGI-S initial groups reflecting the improvement of work-related function during the six months of the follow-up. Q-LES-Q values in the whole sample and in all initial CGI-S groups showed a steady increase indicating a continuous increase in quality of life during the study. Our results indicate that during long-term prophylactic lamotrigine therapy the work function and quality of life of bipolar patients shows a significant improvement, therefore lamotrigine provides a possibility for full functional remission and restoration of quality of life.

Dramatic response to levetiracetam in post-ischaemic Holmes’ tremor

PubMed Central

Striano, P; Elefante, Andrea; Coppola, Antonietta; Tortora, Fabio; Zara, Federico; Minetti, Carlo

2009-01-01

Holmes’ tremor refers to an unusual combination of rest, postural and kinetic tremor of extremities. Common causes of Holmes’ tremor include stroke, trauma, vascular malformations and multiple sclerosis, with lesions involving the thalamus, brain stem or cerebellum. Although some drugs (eg, levodopa and dopaminergic drugs, clonazepam and propranolol) have been occasionally reported to give some benefit, medical treatment of Holmes’ tremor is unsatisfactory, and many patients require thalamic surgery to achieve satisfactory control. We report a patient in whom post-ischaemic Holmes’ tremor dramatically responded to levetiracetam treatment. PMID:21686707

Dexamethasone alone and in combination with desipramine, phenytoin, valproic acid or levetiracetam interferes with 5-ALA-mediated PpIX production and cellular retention in glioblastoma cells.

PubMed

Lawrence, Johnathan E; Steele, Christopher J; Rovin, Richard A; Belton, Robert J; Winn, Robert J

2016-03-01

Extent of resection of glioblastoma (GBM) correlates with overall survival. Fluorescence-guided resection (FGR) using 5-aminolevulinic acid (5-ALA) can improve the extent of resection. Unfortunately not all patients given 5-ALA accumulate sufficient quantities of protoporphyrin IX (PpIX) for successful FGR. In this study, we investigated the effects of dexamethasone, desipramine, phenytoin, valproic acid, and levetiracetam on the production and accumulation of PpIX in U87MG cells. All of these drugs, except levetiracetam, reduce the total amount of PpIX produced by GBM cells (p < 0.05). When dexamethasone is mixed with another drug (desipramine, phenytoin, valproic acid or levetiracetam) the amount of PpIX produced is further decreased (p < 0.01). However, when cells are analyzed for PpIX cellular retention, dexamethasone accumulated significantly more PpIX than the vehicle control (p < 0.05). Cellular retention of PpIX was not different from controls in cells treated with dexamethasone plus desipramine, valproic acid or levetiracetam, but was significantly less for dexamethasone plus phenytoin (p < 0.01). These data suggest that medications given before and during surgery may interfere with PpIX accumulation in malignant cells. At this time, levetiracetam appears to be the best medication in its class (anticonvulsants) for patients undergoing 5-ALA-mediated FGR.

Levetiracetam reduces abnormal network activations in temporal lobe epilepsy.

PubMed

Wandschneider, Britta; Stretton, Jason; Sidhu, Meneka; Centeno, Maria; Kozák, Lajos R; Symms, Mark; Thompson, Pamela J; Duncan, John S; Koepp, Matthias J

2014-10-21

We used functional MRI (fMRI) and a left-lateralizing verbal and a right-lateralizing visual-spatial working memory (WM) paradigm to investigate the effects of levetiracetam (LEV) on cognitive network activations in patients with drug-resistant temporal lobe epilepsy (TLE). In a retrospective study, we compared task-related fMRI activations and deactivations in 53 patients with left and 54 patients with right TLE treated with (59) or without (48) LEV. In patients on LEV, activation patterns were correlated with the daily LEV dose. We isolated task- and syndrome-specific effects. Patients on LEV showed normalization of functional network deactivations in the right temporal lobe in right TLE during the right-lateralizing visual-spatial task and in the left temporal lobe in left TLE during the verbal task. In a post hoc analysis, a significant dose-dependent effect was demonstrated in right TLE during the visual-spatial WM task: the lower the LEV dose, the greater the abnormal right hippocampal activation. At a less stringent threshold (p < 0.05, uncorrected for multiple comparisons), a similar dose effect was observed in left TLE during the verbal task: both hippocampi were more abnormally activated in patients with lower doses, but more prominently on the left. Our findings suggest that LEV is associated with restoration of normal activation patterns. Longitudinal studies are necessary to establish whether the neural patterns translate to drug response. This study provides Class III evidence that in patients with drug-resistant TLE, levetiracetam has a dose-dependent facilitation of deactivation of mesial temporal structures. © 2014 American Academy of Neurology.

Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.

PubMed

Nevitt, Sarah J; Sudell, Maria; Weston, Jennifer; Tudur Smith, Catrin; Marson, Anthony G

2017-06-29

Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first-line treatment for partial onset seizures and sodium valproate for generalised onset seizures; however a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices. To compare the time to withdrawal of allocated treatment, remission and first seizure of 10 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures (simple partial, complex partial or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus). We searched the following databases: Cochrane Epilepsy's Specialised Register, CENTRAL, MEDLINE and SCOPUS, and two clinical trials registers. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. The date of the most recent search was 27 July 2016. We included randomised controlled trials of a monotherapy design in adults or children with partial onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types). This was an individual participant data (IPD) review and network meta-analysis. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary

Autoimmune Limbic Encephalitis and Syndrome of Inappropriate Antidiuretic Hormone Secretion Associated with Lamotrigine-induced Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) Syndrome.

PubMed

Ozisik, Lale; Tanriover, Mine Durusu; Saka, Esen

2016-01-01

Drug rash with eosinophilia and systemic symptoms (DRESS) is a severe drug hypersensitivity reaction characterized by rash, fever and multi-organ failure. Limbic encephalitis (LE) is a rare disorder characterized by cognitive dysfunction with memory disturbance, seizures and psychiatric symptoms. We herein present an unusual case of DRESS syndrome due to lamotrigine with reactivation of Epstein-Barr virus, which developed autoimmune LE and syndrome of inappropriate antidiuretic hormone secretion. Discontinuation of lamotrigine, administration of methylprednisolone and intravenous immunoglobulin led to improvement. The LE in this case might have been caused by an autoimmune inflammatory mechanism associated with DRESS syndrome.

Antiepileptic Drug Titration and Related Health Care Resource Use and Costs.

PubMed

Fishman, Jesse; Kalilani, Linda; Song, Yan; Swallow, Elyse; Wild, Imane

2018-02-27

Unexpected breakthrough seizures resulting from suboptimal antiepileptic drug (AED) dosing during the titration period, as well as adverse events resulting from rapid AED titration, may influence the titration schedule and significantly increase health care resource use (HRU) and health care costs. To assess the relationship between AEDs, HRU, and costs during AED titration and maintenance. Practicing neurologists were recruited from a nationwide panel to provide up to 3 patient records each for this retrospective medical chart review. Patients with epilepsy who were aged ≥ 18 years and had initiated an AED between January 1, 2014, and January 1, 2016, were followed for 6 months from AED initiation. Titration duration was the time from AED initiation to the beginning of treatment maintenance as determined by the physician. Outcomes were epilepsy-specific HRU (hospitalizations, emergency department visits, outpatient visits, physician referral, laboratory testing/diagnostic imaging, and phone calls) and related costs that occurred during the titration or maintenance treatment periods. Of 811 patients, 156, 128, 125, 120, 114, 107, and 61 initiated the following AEDs: levetiracetam, lamotrigine, lacosamide, valproate, topiramate, carbamazepine, and phenytoin, respectively. Most patients (619/803 [77.1%] with complete AED data) received monotherapy. Baseline characteristics were similar across AEDs (mean [SD] age, 36.6 [14.4] years; 59.0% male). Kaplan-Meier estimates of titration duration ranged from 3.3 weeks (phenytoin) to 8.1 weeks (lamotrigine). From titration to maintenance, the overall incidence of HRU per person-month decreased 54.5%-89.3% for each HRU measure except outpatient visits (24.6% decrease). Total epilepsy-related costs decreased from $80.48 to $42.77 per person-month, or 46.9% from titration to maintenance. AED titration periods had higher HRU rates and costs than AED maintenance, suggesting that use of AEDs with shorter titration requirements

Pharmacokinetics of Levetiracetam in Healthy Hispaniolan Amazon Parrots ( Amazona ventralis ) After Oral Administration of a Single Dose.

PubMed

Schnellbacher, Rodney; Beaufrère, Hugues; Vet, Dr Med; Arnold, Robert D; Tully, Thomas N; Mayer, Joerg; Divers, Stephen J

2014-09-01

Long-term anticonvulsive treatments have been poorly described in birds, and few pharmacokinetic studies have been performed, with mixed results. Levetiracetam, a new anticonvulsive drug, has shown good efficacy for monotherapy or adjunctive treatment of seizures in both human and veterinary medicine. To determine pharmacokinetics of levetiracetam in Hispaniolan Amazon parrots ( Amazona ventralis ), 20 healthy birds were randomly divided into 2 groups and administered either a 50 mg/kg (n = 10) or a 100 mg/kg (n = 10) oral dose of levetiracetam with no observable adverse effects. Blood samples were collected at baseline and at 12 time intervals (6 per group) for 16 hours. The concentration-time profiles resembled characteristic absorption, with maximum plasma concentrations of 61.0 μg/mL and 95.1 μg/mL at 60 minutes; terminal half-lives at 2.38 and 2.37 hours; volumes of distribution of 0.807 and 0.773 L/kg, with an area under the curve at 14 100 and 28 820 mg × min/L; and clearance rates of 3.65 and 3.60 mL/min per kg, respectively. Plasma concentrations were greater than 5.5 mg/L for up to 9.4 and 12 hours, suggesting an 8- and 12-hour oral dosing at 50 and 100 mg/kg, respectively, would be sufficient to maintain targeted values. Clinically, doses and frequencies may need escalation based on differences in species and individuals, and drug levels should be monitored.

Binding characteristics of levetiracetam to synaptic vesicle protein 2A (SV2A) in human brain and in CHO cells expressing the human recombinant protein.

PubMed

Gillard, Michel; Chatelain, Pierre; Fuks, Bruno

2006-04-24

A specific binding site for the antiepileptic drug levetiracetam (2S-(oxo-1-pyrrolidinyl)butanamide, Keppra) in rat brain, referred to as the levetiracetam binding site, was discovered several years ago. More recently, this binding site has been identified as the synaptic vesicle protein 2A (SV2A), a protein present in synaptic vesicles [Lynch, B., Lambeng, N., Nocka, K., Kensel-Hammes, P., Bajjalieh, S.M., Matagne, A., Fuks, B., 2004. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc. Natl. Acad. Sci. USA, 101, 9861-9866.]. In this study, we characterized the binding properties of levetiracetam in post-mortem human brain and compared them to human SV2A expressed in Chinese hamster ovary (CHO) cells. The results showed that the binding properties of levetiracetam and [3H]ucb 30889, an analogue that was previously characterized as a suitable ligand for levetiracetam binding site/SV2A in rat brain [Gillard, M., Fuks, B., Michel, P., Vertongen, P., Massingham, R. Chatelain, P., 2003. Binding characteristics of [3H]ucb 30889 to levetiracetam binding sites in rat brain. Eur. J. Pharmacol. 478, 1-9.], are almost identical in human brain samples (cerebral cortex, hippocampus and cerebellum) and in CHO cell membranes expressing the human SV2A protein. Moreover, the results are also similar to those previously obtained in rat brain. [3H]ucb 30889 binding in human brain and to SV2A was saturable and reversible. At 4 degrees C, its binding kinetics were best fitted assuming a two-phase model in all tissues. The half-times of association for the fast component ranged between 1 to 2 min and represent 30% to 36% of the sites whereas the half-times for the slow component ranged from 20 to 29 min. In dissociation experiments, the half-times were from 2 to 4 min for the fast component (33% to 49% of the sites) and 20 to 41 min for the slow component. Saturation binding curves led to Kd values for [3H]ucb 30889 of 53+/-7, 55+/-9, 70

Bioequivalence of generic lamotrigine 100-mg tablets in healthy Thai male volunteers: a randomized, single-dose, two-period, two-sequence crossover study.

PubMed

Srichaiya, Arunee; Longchoopol, Chaowanee; Oo-Puthinan, Sarawut; Sayasathid, Jarun; Sripalakit, Pattana; Viyoch, Jarupa

2008-10-01

Lamotrigine is an antiepileptic drug which has been used in the treatment of epilepsy and bipolar disorder. A search of the literature did not find previously published bioequivalence and pharmacokinetic evaluations of lamotrigine in healthy Thai male volunteers. The aim of this study was to compare the pharmacokinetic parameters between 2 brands of lamotrigine in healthy Thai male volunteers. A randomized, single-dose, 2-period, 2-sequence, crossover study design with a 2-week washout period was conducted in healthy Thai males. Subjects were randomized to receive either the test or reference formulation in the first period. All subjects were required to be nonsmokers and without a history of alcohol or drug abuse. Plasma samples were collected over a 120-hour period after 100-mg lamotrigine administration in each period. A validated high-performance liquid chromatography ultraviolet method was used to analyze lamotrigine concentration in plasma. Pharmacokinetic parameters were determined using a noncompartmental method. Bioequivalence between the test and reference products, as defined by the US Food and Drug Administration (FDA), is determined when the ratio for the 90% CIs of the difference in the means of the log-transformed AUC(0-t), AUC(0-infinity), and C(max) of the 2 products are within 0.80 and 1.25. Adverse events were determined by measuring vital signs after dosing. Subjects were also asked if they suffered from undesirable effects such as nausea, vomiting, dizziness, and headache. This bioequivalence study was performed in 24 healthy Thai males (mean [SD] age, 20.5 [1.3] years; range, 19-24 years; weight, 62.5 [7.4] kg; height, 172.8 [6.9] cm; body mass index, 20.9 [2.0] kg/m(2)). The mean (SD) C(max) and T(max) of the test formulation of lamotrigine were 1.7 (0.3) microg/mL and 1.2 (0.9) hours, respectively. The mean (SD) C(max) and T(max) of the reference formulation of lamotrigine were 1.7 (0.3) microg/mL and 1.4 (1.0) hours, respectively. The mean

Design of a novel bilayered gastric mucoadhesive system for localized and unidirectional release of lamotrigine

PubMed Central

Mohana Raghava Srivalli, K.; Lakshmi, P.K.; Balasubramaniam, J.

2012-01-01

Lamotrigine is a BCS class II drug with pH dependent solubility. The bilayered gastric mucoadhesive tablets of lamotrigine were designed such that the drug and controlled release polymers were incorporated in the upper layer and the lower layer had the mucoadhesive polymers. The major ingredients selected for the upper layer were the drug and control release polymer (either HPMC K15M or polyox) while the lower MA layer predominantly comprised of Carbopol 974P. A 23 full factorial design was constructed for this study and the tablets were optimized for parameters like tablet size, shape, ex vivo mucoadhesive properties and unidirectional drug release. Oval tablets with an average size of 14 mm diameter were set optimum. Maximum mucoadhesive bond strength of 79.3 ± 0.91 * 103 dyn/cm2 was achieved with carbopol when used in combination with a synergistic resin polymer. All the tested formulations presented a mucoadhesion time of greater than 12 h. The incorporation of methacrylic polymers in the lower layer ensured unidirectional drug release from the bilayered tablets. The unidirectional drug release was confirmed after comparing the dissolution results of paddle method with those of a modified basket method. Model independent similarity and dissimilarity factor methods were used for the comparison of dissolution results. Controlled drug release profiles with zero order kinetics were obtained with polyox and HPMC K15M which reported t90% at 6th and 12th hours, respectively. The “n” value with polyox was 0.992 and that with HPMC K15M was 0.946 indicating an approximate case II transport. These two formulations showed the potential for oral administration of lamotrigine as bilayered gastric mucoadhesive tablets by yielding highest similarity factor values, 96.06 and 92.47, respectively, between the paddle and modified basket method dissolution release profiles apart from reporting the best tablet physical properties and maximum mucoadhesive strength. PMID

Levetiracetam for the treatment of alcohol withdrawal syndrome: a multicenter, prospective, randomized, placebo-controlled trial.

PubMed

Richter, Christoph; Hinzpeter, Axel; Schmidt, Folkhard; Kienast, Thorsten; Preuss, Ulrich W; Plenge, Thomas; Heinz, Andreas; Schaefer, Martin

2010-12-01

Treatment of alcohol withdrawal syndrome (AWS) with benzodiazepines is limited by risk of abuse, intoxication, respiratory problems, and liver toxicity. Alternatives such as carbamazepine and valproate may also have safety problems, such as hepatotoxicity or central nervous adverse effects. We therefore investigated the safety and efficacy of levetiracetam (LV), a newer antiepileptic with a potentially favorable adverse-effect profile, for the treatment of AWS. One hundred six patients were enrolled in a prospective, randomized, double-blind, multicenter, placebo-controlled trial. Levetiracetam was administered in a fixed dose schedule over 6 days. Diazepam was added when symptom triggered as rescue medication. Severity of the AWS was measured with the AWS and Clinical Institute Withdrawal Assessment Scale. Although tolerability and safety data were similar in the LV group when compared with placebo, the total daily and weekly dose of diazepam as rescue medication and the severity of alcohol withdrawal symptoms did not differ significantly between groups. Our data so far do not support an additional effect of LV on the reduction of alcohol withdrawal symptoms.

Effects of WIN 55,212-2 mesylate on the anticonvulsant action of lamotrigine, oxcarbazepine, pregabalin and topiramate against maximal electroshock-induced seizures in mice.

PubMed

Luszczki, Jarogniew J; Wlaz, Aleksandra; Karwan, Slawomir; Florek-Luszczki, Magdalena; Czuczwar, Stanislaw J

2013-11-15

The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN - a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four second-generation antiepileptic drugs (lamotrigine, oxcarbazepine, pregabalin and topiramate) in the mouse maximal electroshock seizure model. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2s stimulus duration) delivered via auricular electrodes. Drug-related adverse effects were ascertained by use of the chimney test (evaluating motor performance), the step-through passive avoidance task (assessing long-term memory) and the grip-strength test (evaluating skeletal muscular strength). Total brain concentrations of antiepileptic drugs were measured by high-pressure liquid chromatography to ascertain any pharmacokinetic contribution to the observed antiseizure effect. Results indicate that WIN (5mg/kg, i.p.) significantly enhanced the anticonvulsant action of lamotrigine (P<0.05), pregabalin (P<0.001) and topiramate (P<0.05), but not that of oxcarbazepine in the maximal electroshock-induced tonic seizure test in mice. Furthermore, none of the investigated combinations of WIN with antiepileptic drugs were associated with any concurrent adverse effects with regards to motor performance, long-term memory or muscular strength. Pharmacokinetic characterization revealed that WIN had no impact on total brain concentrations of lamotrigine, oxcarbazepine, pregabalin and topiramate in mice. These preclinical data would suggest that WIN in combination with lamotrigine, pregabalin and topiramate is associated with beneficial anticonvulsant pharmacodynamic interactions in the maximal electroshock-induced tonic seizure test. © 2013 Published by Elsevier B.V.

Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.

PubMed

Nevitt, Sarah J; Sudell, Maria; Weston, Jennifer; Tudur Smith, Catrin; Marson, Anthony G

2017-12-15

Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first-line treatment for partial onset seizures and sodium valproate for generalised onset seizures; however a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices. To compare the time to withdrawal of allocated treatment, remission and first seizure of 10 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures (simple partial, complex partial or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus). We searched the following databases: Cochrane Epilepsy's Specialised Register, CENTRAL, MEDLINE and SCOPUS, and two clinical trials registers. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. The date of the most recent search was 27 July 2016. We included randomised controlled trials of a monotherapy design in adults or children with partial onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types). This was an individual participant data (IPD) review and network meta-analysis. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary

Clinical Usefulness of Aripiprazole and Lamotrigine in Schizoaffective Presentation of Tuberous Sclerosis.

PubMed

Lee, Seung-Yup; Min, Jung-Ah; Lee, In Goo; Kim, Jung Jin

2016-08-31

Tuberous sclerosis is not as rare as once thought and has high psychiatric comorbidities. However, bipolar or psychotic features associated with tuberous sclerosis have been rarely reported. This report first presents a tuberous sclerosis patient, resembling a schizoaffective disorder of bipolar type. A patient with known tuberous sclerosis displayed mood fluctuation and psychotic features. Her symptoms did not remit along with several psychiatric medications. After hospitalization, the patient responded well with lamotrigine and aripiprazole without exacerbation. As demonstrated in this case, tuberous sclerosis may also encompass bipolar affective or psychotic features. We would like to point out the necessity to consider bipolarity in evaluating and treating tuberous sclerosis.

Vigabatrin and lamotrigine in refractory epilepsy.

PubMed Central

Stolarek, I; Blacklaw, J; Forrest, G; Brodie, M J

1994-01-01

Epilepsy arises from an imbalance of inhibitory and excitatory influences in the brain. Vigabatrin (VIG) decreases the breakdown of the inhibitory neurotransmitter gamma-aminobutyric acid, whereas lamotrigine (LTG) reduces presynaptic excitatory amino acid release. 22 patients with refractory epilepsy, treated with an anticonvulsant regimen containing VIG, entered a balanced, double blind, placebo controlled, crossover trial of additional LTG. Treatment periods of 12 weeks (25 mg, 50 mg, 100 mg LTG twice daily for four weeks at each dose, and matched placebo) were followed by wash out intervals of four weeks. 14 of the 20 patients completing the study improved, resulting in a significant fall in seizure days and numbers. Analysis of seizure type confirmed a beneficial effect on partial and secondary generalised tonic-clonic seizures. At the highest LTG dose (200 mg daily) there was a median fall of 37% in seizure count with nine (45%) patients reporting > 50% reduction. Three of these patients were seizure free during this month of treatment. Side effects were minimal throughout the study. Concentrations of other antiepileptic drugs, including those of carbamazepine 10,11-epoxide, were not modified by LTG. This study suggests a substantial efficacy for a regimen containing VIG and LTG. Combinations of drugs with complementary modes of action may provide a rational pharmacological approach to the management of refractory epilepsy. PMID:8057114

Chronic treatment with the new anticonvulsant drug lacosamide impairs learning and memory processes in rats: A possible role of BDNF/TrkB ligand receptor system.

PubMed

Shishmanova-Doseva, Michaela; Peychev, Lyudmil; Koeva, Yvetta; Terzieva, Dora; Georgieva, Katerina; Peychev, Zhivko

2018-06-01

Cognitive impairment is considered a frequent side effect in the drug treatment of epilepsy. The objective of the present study was to investigate the effects of lacosamide (LCM) on learning and memory processes in rats, on the serum level of brain-derived neurotrophic factor (BDNF) and BDNF/TrkB ligand receptor system expression in the hippocampal formation. Male Wistar rats underwent long-term treatment with three different doses of lacosamide - 3 mg/kg (LCM 3), 10 mg/kg (LCM 10) and 30 mg/kg (LCM 30). All rats were subjected to one active and one passive avoidance tests. The BDNF/TrkB immunohistochemical expression in the hippocampus was measured and serum BDNF was determined. The LCM-treated rats made fewer avoidance responses than controls during acquisition training and in the memory retention test. The number of escapes in the LCM 10 and LCM 30 groups decreased throughout the test, while the rats in the LCM 3 group showed fewer escapes only in the memory test in the active avoidance task. In the step-down test, the latency time of the LCM-30 treated rats was reduced as compared with the controls during the learning session and the short- and long-term memory retention tests. Lacosamide induced a dose-dependent reduction of the hippocampal expression of BDNF and its receptor TrkB. We found no significant difference between BDNF serum levels in the test animals and controls. The results of the study suggest that LCM suppresses the learning and memory processes in rats, with the inhibition of hippocampal BDNF/TrkB ligand receptor system being one of the possible mechanisms causing this effect. Copyright © 2018 Elsevier Inc. All rights reserved.

A comparison of the efficacy of carbamazepine and the novel anti-epileptic drug levetiracetam in the tetanus toxin model of focal complex partial epilepsy

PubMed Central

Doheny, H C; Whittington, M A; Jefferys, J G R; Patsalos, P N

2002-01-01

The tetanus toxin seizure model, which is associated with spontaneous and intermittent generalized and non-generalized seizures, is considered to reflect human complex partial epilepsy. The purpose of the present study was to investigate and compare the anticonvulsant effects of carbamazepine with that of levetiracetam, a new anti-epileptic drug in this model. One μl of tetanus toxin solution (containing 12 mLD50 μl−1 of tetanus toxin) was placed stereotactically into the rat left hippocampus resulting in generalized and non-generalized seizures. Carbamazepine (4 mg kg−1 h−1) and levetiracetam (8 and 16 mg kg−1 h−1) were administered during a 7 day period via an osmotic minipump which was placed in the peritoneal cavity. Carbamazepine (4 mg kg−1 h−1) exhibited no significant anticonvulsant effect, compared to control, when the entire 7 day study period was evaluated but the reduction in generalized seizures was greater (35.5%) than that for non-generalized seizures (12.6%). However, during the first 2 days of carbamazepine administration a significant reduction in both generalized seizure frequency (90%) and duration (25%) was observed. Non-generalized seizures were unaffected. This time-dependent anticonvulsant effect exactly paralleled the central (CSF) and peripheral (serum) kinetics of carbamazepine in that steady-state concentrations declined over time, with the highest concentrations achieved during the first 2 days. Also there was a significant 27.3% reduction in duration of generalized seizures during the 7 day study period (P=0.0001). Levetiracetam administration (8 and 16 mg kg−1 h−1) was associated with a dose-dependent reduction in the frequency of both generalized (39 v 57%) and non-generalized (36 v 41%) seizures. However, seizure suppression was more substantial for generalized seizures. Also a significant dose-dependent reduction in overall generalized seizure duration was observed. These data provide

Levetiracetam is associated with decrease in subclinical epileptiform discharges and improved cognitive functions in pediatric patients with autism spectrum disorder.

PubMed

Wang, Minjian; Jiang, Li; Tang, Xiaoju

2017-01-01

Subclinical epileptiform discharges (SEDs) are common in pediatric patients with autism spectrum disorder (ASD), but the effect of antiepileptic drugs on SEDs in ASD remains inconclusive. This physician-blinded, prospective, randomized controlled trial investigated an association between the anticonvulsant drug levetiracetam and SEDs in children with ASD. A total of 70 children with ASD (4-6 years) and SEDs identified by electroencephalogram were randomly divided into two equal groups to receive either levetiracetam and educational training (treatment group) or educational training only (control). At baseline and after 6 months treatment, the following scales were used to assess each individual's behavioral and cognitive functions: the Chinese version of the Psychoeducational Profile - third edition (PEP-3), Childhood Autism Rating Scale (CARS), and Autism Behavior Checklist (ABC). A 24-hour electroencephalogram was recorded on admission (baseline) and at follow-up. The degree of satisfaction of each patient was also evaluated. Relative to baseline, at the 6-month follow-up, the PEP-3, CARS, and ABC scores were significantly improved in both the treatment and control groups. At the 6-month follow-up, the PEP-3 scores of the treatment group were significantly higher than those of the control, whereas the CARS and ABC scores were significantly lower, and the rate of electroencephalographic normalization was significantly higher in the treatment group. Levetiracetam appears to be effective for controlling SEDs in pediatric patients with ASD and was also associated with improved behavioral and cognitive functions.

Effect of levetiracetam on penicillin induced epileptic activity in rats.

PubMed

Arık, Aliye Erguvan; Bağırıcı, Faruk; Sefil, Fatih; Marangoz, Cafer

2014-01-01

The aim of this study was to investigate the effects of levetiracetam (LEV) on penicillin-induced epileptiform activity in rats. Penicillin was applied intracerebroventricularly (icv) at a dose of 500 IU to induce epileptiform activity. LEV was given intraperitoneally (ip) at doses of 20, 40, 80 mg/kg before penicillin injection. This agent reduced epileptiform activity by decreasing spike frequencies. The mean spike frequencies decreased significantly in all the LEV treated groups. There was no significant change in the spike amplitudes of the LEV groups compared with the control group. 40 mg/kg of LEV was determined as the most effective dose on reducing epileptiform activity. The results of this study suggest that LEV is an effective antiepileptic agent in penicillin-induced epilepsy.

Levetiracetam is associated with decrease in subclinical epileptiform discharges and improved cognitive functions in pediatric patients with autism spectrum disorder

PubMed Central

Wang, Minjian; Jiang, Li; Tang, Xiaoju

2017-01-01

Objective Subclinical epileptiform discharges (SEDs) are common in pediatric patients with autism spectrum disorder (ASD), but the effect of antiepileptic drugs on SEDs in ASD remains inconclusive. This physician-blinded, prospective, randomized controlled trial investigated an association between the anticonvulsant drug levetiracetam and SEDs in children with ASD. Methods A total of 70 children with ASD (4–6 years) and SEDs identified by electroencephalogram were randomly divided into two equal groups to receive either levetiracetam and educational training (treatment group) or educational training only (control). At baseline and after 6 months treatment, the following scales were used to assess each individual’s behavioral and cognitive functions: the Chinese version of the Psychoeducational Profile – third edition (PEP-3), Childhood Autism Rating Scale (CARS), and Autism Behavior Checklist (ABC). A 24-hour electroencephalogram was recorded on admission (baseline) and at follow-up. The degree of satisfaction of each patient was also evaluated. Results Relative to baseline, at the 6-month follow-up, the PEP-3, CARS, and ABC scores were significantly improved in both the treatment and control groups. At the 6-month follow-up, the PEP-3 scores of the treatment group were significantly higher than those of the control, whereas the CARS and ABC scores were significantly lower, and the rate of electroencephalographic normalization was significantly higher in the treatment group. Conclusion Levetiracetam appears to be effective for controlling SEDs in pediatric patients with ASD and was also associated with improved behavioral and cognitive functions. PMID:28919764

Long-term effect of antiepileptic drug switch on serum lipids and C-reactive protein.

PubMed

Mintzer, Scott; Miller, Rachael; Shah, Krunal; Chervoneva, Inna; Nei, Maromi; Skidmore, Christopher; Sperling, Michael R

2016-05-01

Prior studies have shown that switching patients from inducing antiepileptic drugs (AEDs) to lamotrigine, levetiracetam, or topiramate reduces serum lipids and C-reactive protein (CRP). These studies were all of short duration, and some drugs, such as zonisamide, have not been investigated. We recruited 41 patients taking phenytoin or carbamazepine who were being switched to zonisamide, lamotrigine, or levetiracetam. We measured serum lipids and CRP before the switch, >6weeks after, and >6months after. An untreated control group (n=14) underwent similar measurement. We combined these data with those of our previous investigation (n=34 patients and 16 controls) of a very similar design. There were no differences in outcome measures between the two inducing AEDs nor among the three noninducing AEDs. Total cholesterol (TC), atherogenic lipids, and CRP were higher under inducer treatment than in controls. All measures were elevated under inducer treatment relative to noninducer treatment, including TC (24mg/dL higher, 95% CI: 17.5-29.9, p<0.001) and CRP (72% higher, 95% CI: 41%-111%, p<0.001). The difference between drug treatments was clinically meaningful for atherogenic lipids (16%, 95% CI: 11%-20%, p<0.001) but small for high-density lipoprotein cholesterol (5%, 95% CI: 1%-9%, p<0.05). All measures were stable between 6weeks and 6months after drug switch. We demonstrate that switching from inducing to noninducing AEDs produces an enduring reduction in serum lipids and CRP. These results provide further evidence that inducing AEDs may be associated with elevated vascular disease risk. These are the first vascular risk marker data in patients taking zonisamide, which shows a profile similar to that of other noninducing AEDs. Copyright © 2016 Elsevier Inc. All rights reserved.

Clinical and electrographic features of sunflower syndrome.

PubMed

Baumer, Fiona M; Porter, Brenda E

2018-05-01

Sunflower Syndrome describes reflex seizures - typically eyelid myoclonia with or without absence seizures - triggered when patients wave their hands in front of the sun. While valproate has been recognized as the best treatment for photosensitive epilepsy, many clinicians now initially treat with newer medications; the efficacy of these medications in Sunflower Syndrome has not been investigated. We reviewed all cases of Sunflower Syndrome seen at our institution over 15 years to describe the clinical course, electroencephalogram (EEG), and treatment response in these patients. Search of the electronic medical record and EEG database, as well as survey of epilepsy providers at our institution, yielded 13 cases of Sunflower Syndrome between 2002 and 2017. We reviewed the records and EEG tracings. Patients were mostly young females, with an average age of onset of 5.5 years. Seven had intellectual, attentional or academic problems. Self-induced seizures were predominantly eyelid myoclonia ± absences and 6 subjects also had spontaneous seizures. EEG demonstrated a normal background with 3-4 Hz spike waves ± polyspike waves as well as a photoparoxysmal response. Based on both clinical and EEG response, valproate was the most effective treatment for reducing or eliminating seizures and improving the EEG; 9 patients tried valproate and 66% had significant improvement or resolution of seizures. None of the nine patients on levetiracetam or seven patients on lamotrigine monotherapy achieved seizure control, though three patients had improvement with polypharmacy. Valproate monotherapy continues to be the most effective treatment for Sunflower Syndrome and should be considered early. For patients who cannot tolerate valproate, higher doses of lamotrigine or polypharmacy should be considered. Levetiracetam monotherapy, even at high doses, is unlikely to be effective. Copyright © 2018 Elsevier B.V. All rights reserved.

Ischemic Stroke and Epilepsy in a Patient with Tourette´s Syndrome: Association with the Antiphospholipid Syndrome and Good Response to Levetiracetam

PubMed Central

Seijo-Martínez, M; Mosquera-Martínez, J.A; Romero-Yuste, S; Cruz-Martinez, J

2008-01-01

The role played by different humoral factors, including antiphospholipid antibodies, in the pathogenesis of Tourette syndrome (TS) is still presently unclear. We present a patient with chronic and severe TS who, at the age of 16 years, presented an ischemic stroke in the left posterior cerebral artery and/or postero-inferior temporal branch of the left medial cerebral artery. A complete study was negative with the exception of a positive lupus anticoagulant. The stroke was related with the primary antiphospholipid syndrome (APS). The stroke manifested visual abnormalities and thereafter by secondary generalized complex partial seizures. The epileptic syndrome was initially difficult to control but responded dramatically to levetiracetam. With this therapy, the manifestations of TS, especially the tics, improved. We conclude that some TS cases may present APS. In addition, levetiracetam may be useful in the management of TS. Further investigations should pursue both these facts. PMID:19018305

Three-Year Retention Rates of Levetiracetam, Topiramate, and Oxcarbazepine: A Retrospective Hospital-Based Study.

PubMed

Sunwoo, Jun-Sang; Park, Byeong-Su; Ahn, Seon Jae; Hwang, Sungeun; Park, Chan-Young; Jun, Jin-Sun; Kim, Dong Wook; Lee, Soon-Tae; Jung, Keun-Hwa; Park, Kyung-Il; Chu, Kon; Jung, Ki-Young; Lee, Sang Kun

We evaluated and compared the 3-year retention rates of levetiracetam (LEV), topiramate (TPM), and oxcarbazepine (OXC) in patients with epilepsy in routine clinical practice. We retrospectively reviewed medical records of patients with epilepsy who were newly prescribed LEV, TPM, or OXC from 2006 to 2010. The retention rates were estimated by the Kaplan-Meier analysis, and independent risk factors for drug discontinuation were analyzed by the Cox regression method. A total of 588 patients were included: LEV (n = 345), TPM (n = 190), and OXC (n = 53). Among them, 82% had focal epilepsy, whereas 14.8% had generalized epilepsy. The 3-year retention rates for LEV, TPM, and OXC, were 81.2%, 78.3%, and 54.7%, respectively. Levetiracetam and TPM had equivalent retention rates, whereas patients remained on OXC for a significantly shorter amount of time (P < 0.001). A lower retention rate for OXC was also evident in the subgroup analysis of focal epilepsy (P < 0.001). In generalized epilepsy, LEV and TPM revealed comparable retention rates (P = 0.255). The seizure-freedom rate did not differ among groups, whereas the rate of adverse effects leading to drug withdrawal of OXC (87.5%) was higher than that of LEV (34.4%, P < 0.001) and TPM (52.5%, P = 0.012). The current study suggested that LEV and TPM had comparable retention profiles in the long-term treatment for both focal and generalized epilepsy. Meanwhile, OXC therapy seemed to be relatively less useful because of its poor tolerability.

Intravenous levetiracetam vs phenytoin for status epilepticus and cluster seizures: A prospective, randomized study.

PubMed

Gujjar, Arunodaya R; Nandhagopal, Ramachandiran; Jacob, Poovathoor C; Al-Hashim, Abdulhakeem; Al-Amrani, Khalfan; Ganguly, Shyam S; Al-Asmi, Abdullah

2017-07-01

Status Epilepticus (SE) is a common medical emergency carrying a high morbidity and mortality. Levetiracetam (LEV) is a novel anticonvulsant effective against varied seizures. Few prospective studies have addressed its use in SE. We aimed to examine the efficacy of intravenous LEV in controlling SE and cluster attacks of seizures (CS), in comparison with IV phenytoin (DPH), using a prospective, randomized study design. Adult patients with SE or CS, following an initial dose of IV benzodiazepine to control ongoing seizure, were randomized to receive either medication. Rates of seizure control over 24h, adverse effects and outcomes were compared. A logistic regression model was used to identify outcome predictors. 52 patients with SE and 63 with CS received either LEV or DPH. In the SE group, LEV was effective in18/22(82%) and DPH in 22/30(73.3%) patients in controlling seizures. Among patients with CS, LEV was effective in 31/38(81.6%) and DPH in 20/25(80%). With the use of LEV, DPH or both, SE and CS were controlled among 92% and 96% of patients respectively. Adverse events included hypotension (in 2 on DPH) and transient agitation (2 on LEV). IV Levetiracetam controls status epilepticus or cluster seizures with an efficacy comparable to that of phenytoin. Use of these two agents consecutively may control >90% of all such conditions without resort to anaesthetic agents. Further studies should explore its efficacy in larger cohorts of epileptic emergencies. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Inhibition of sympathetic sprouting in CCD rats by lacosamide.

PubMed

Wang, Yuying; Huo, Fuquan

2018-05-14

Early hyperexcitability activity of injured nerve/neuron is critical for developing sympathetic nerve sprouting within dorsal root ganglia (DRG). Since lacosamide (LCM), an anticonvulsant, inhibits Na + channel. The present study tried to test the potential effect of LCM on inhibiting sympathetic sprouting in vivo. LCM (50 mg/kg) was daily injected intraperitoneally into rats subjected to chronic compression DRG (CCD), an animal model of neuropathic pain that exhibits sympathetic nerve sprouting, for the 1st 7 days after injury. Mechanical sensitivity was tested from day 3 to day 18 after injury, and then DRGs were removed off. Immunohistochemical staining for tyrosine hydroxylase (TH) was examined to observe sympathetic sprouting, and patch-clamp recording was performed to test the excitability and Na + current of DRG neurons. Early systemic LCM treatment significantly reduced TH immunoreactivity density in injured DRG, lowered the excitability level of injured DRG neurons, and increased paw withdrawal threshold (PWT). These effects on reducing sympathetic sprouting, inhibiting excitability and suppressing pain behavior were observed 10 days after the end of early LCM injection. In vitro 100 μM LCM instantly reduced the excitability of CCD neurons via inhibiting Na + current and reducing the amplitude of AP. All the findings suggest, for the first time, that early administration of LCM inhibited sympathetic sprouting and then alleviated neuropathic pain. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Emergency treatment with levetiracetam or phenytoin in status epilepticus in children-the EcLiPSE study: study protocol for a randomised controlled trial.

PubMed

Lyttle, Mark D; Gamble, Carrol; Messahel, Shrouk; Hickey, Helen; Iyer, Anand; Woolfall, Kerry; Humphreys, Amy; Bacon, Naomi E A; Roper, Louise; Babl, Franz E; Dalziel, Stuart R; Ryan, Mary; Appleton, Richard E

2017-06-19

Convulsive status epilepticus (CSE) is the most common life-threatening neurological emergency in childhood. These children are also at risk of significant morbidity, with acute and chronic impact on the family and the health and social care systems. The current recommended first-choice, second-line treatment in children aged 6 months and above is intravenous phenytoin (fosphenytoin in the USA), although there is a lack of evidence for its use and it is associated with significant side effects. Emerging evidence suggests that intravenous levetiracetam may be effective as a second-line agent for CSE, and fewer adverse effects have been described. This trial therefore aims to determine whether intravenous phenytoin or levetiracetam is more effective, and safer, in treating childhood CSE. This is a phase IV, multi-centre, parallel group, randomised controlled, open-label trial. Following treatment for CSE with first-line treatment, children with ongoing seizures are randomised to receive either phenytoin (20 mg/kg, maximum 2 g) or levetiracetam (40 mg/kg, maximum 2.5 g) intravenously. The primary outcome measure is the cessation of all visible signs of CSE as determined by the treating clinician. Secondary outcome measures include the need for further anti-seizure medications or rapid sequence induction for ongoing CSE, admission to critical care areas, and serious adverse reactions. Patients are recruited without prior consent, with deferred consent sought at an appropriate time for the family. The primary analysis will be by intention-to-treat. The primary outcome is a time to event outcome and a sample size of 140 participants in each group will have 80% power to detect an increase in CSE cessation rates from 60% to 75%. Our total sample size of 308 randomised and treated participants will allow for 10% loss to follow-up. This clinical trial will determine whether phenytoin or levetiracetam is more effective as an intravenous second-line agent for CSE, and

Vulnerability of an epileptic case to psychosis: sodium valproate with lamotrigine, forced normalization, postictal psychosis or all?

PubMed

Turan, A B; Seferoglu, M; Taskapilioglu, O; Bora, I

2012-10-01

Patients with epilepsy can be considered to be at high risk for developing psychotic disorders. Furthermore, there is association between seizure freedom or the disappearance of the interictal epileptiform events from the EEG record and the occurrence of psychotic symptoms. Also, several newer antiepileptic drugs have been reported to induce psychotic symptoms. We present a patient with epilepsy who developed psychotic symptoms under the treatment of valproic acid (VPA) and lamotrigine (LTG) combination. The mechanism underlying the association between LTG, seizure control and development of psychosis are discussed in the light of the literature.

Nonepileptic seizures under levetiracetam therapy: a case report of forced normalization process.

PubMed

Anzellotti, Francesca; Franciotti, Raffaella; Zhuzhuni, Holta; D'Amico, Aurelio; Thomas, Astrid; Onofrj, Marco

2014-01-01

Nonepileptic seizures (NES) apparently look like epileptic seizures, but are not associated with ictal electrical discharges in the brain. NES constitute one of the most important differential diagnoses of epilepsy. They have been recognized as a distinctive clinical phenomenon for centuries, and video/electroencephalogram monitoring has allowed clinicians to make near-certain diagnoses. NES are supposedly unrelated to organic brain lesions, and despite the preponderance of a psychiatric/psychological context, they may have an iatrogenic origin. We report a patient with NES precipitated by levetiracetam therapy; in this case, NES was observed during the disappearance of epileptiform discharges from the routine video/electroencephalogram. We discuss the possible mechanisms underlying NES with regard to alternative psychoses associated with the phenomenon of the forced normalization process.

Nonepileptic seizures under levetiracetam therapy: a case report of forced normalization process

PubMed Central

Anzellotti, Francesca; Franciotti, Raffaella; Zhuzhuni, Holta; D’Amico, Aurelio; Thomas, Astrid; Onofrj, Marco

2014-01-01

Nonepileptic seizures (NES) apparently look like epileptic seizures, but are not associated with ictal electrical discharges in the brain. NES constitute one of the most important differential diagnoses of epilepsy. They have been recognized as a distinctive clinical phenomenon for centuries, and video/electroencephalogram monitoring has allowed clinicians to make near-certain diagnoses. NES are supposedly unrelated to organic brain lesions, and despite the preponderance of a psychiatric/psychological context, they may have an iatrogenic origin. We report a patient with NES precipitated by levetiracetam therapy; in this case, NES was observed during the disappearance of epileptiform discharges from the routine video/electroencephalogram. We discuss the possible mechanisms underlying NES with regard to alternative psychoses associated with the phenomenon of the forced normalization process. PMID:24926197

Generic lamotrigine versus brand-name Lamictal bioequivalence in patients with epilepsy: A field test of the FDA bioequivalence standard.

PubMed

Ting, Tricia Y; Jiang, Wenlei; Lionberger, Robert; Wong, Jessica; Jones, Jace W; Kane, Maureen A; Krumholz, Allan; Temple, Robert; Polli, James E

2015-09-01

To test the current U.S. Food and Drug Administration (FDA) bioequivalence standard in a comparison of generic and brand-name drug pharmacokinetic (PK) performance in "generic-brittle" patients with epilepsy under clinical use conditions. This randomized, double-blind, multiple-dose, steady-state, fully replicated bioequivalence study compared generic lamotrigine to brand-name Lamictal in "generic-brittle" patients with epilepsy (n = 34) who were already taking lamotrigine. Patients were repeatedly switched between masked Lamictal and generic lamotrigine. Intensive PK blood sampling at the end of each 2-week treatment period yielded two 12-h PK profiles for brand-name and generic forms for each patient. Steady-state area under the curve (AUC), peak plasma concentration (Cmax ), and minimum plasma concentration (Cmin ) data were subjected to conventional average bioequivalence (ABE) analysis, reference-scaled ABE analysis, and within-subject variability (WSV) comparisons. In addition, generic-versus-brand comparisons in individual patients were performed. Secondary clinical outcomes included seizure frequency and adverse events. Generic demonstrated bioequivalence to brand. The 90% confidence intervals of the mean for steady-state AUC, Cmax , and Cmin for generic-versus-brand were 97.2-101.6%, 98.8-104.5%, and 93.4-101.0%, respectively. The WSV of generic and brand were also similar. Individual patient PK ratios for generic-versus-brand were similar but not identical, in part because brand-versus-brand profiles were not identical, even though subjects were rechallenged with the same product. Few subjects had seizure exacerbations or tolerability issues with product switching. One subject, however, reported 267 focal motor seizures, primarily on generic, although his brand and generic PK profiles were practically identical. Some neurologists question whether bioequivalence in healthy volunteers ensures therapeutic equivalence of brand and generic antiepileptic drugs

Influence of arachidonyl-2'-chloroethylamide, a selective cannabinoid CB1 receptor agonist, on the anticonvulsant and acute side-effect potentials of clobazam, lacosamide, and pregabalin in the maximal electroshock-induced seizure model and chimney test in mice.

PubMed

Florek-Luszczki, Magdalena; Zagaja, Miroslaw; Luszczki, Jarogniew J

2015-08-01

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. © 2015 Société Française de Pharmacologie et de Thérapeutique.

High-dose intravenous levetiracetam for acute seizure exacerbation in children with intractable epilepsy.

PubMed

Depositario-Cabacar, Dewi T; Peters, Jurriaan M; Pong, Amanda W; Roth, Julie; Rotenberg, Alexander; Riviello, James J; Takeoka, Masanori

2010-07-01

We review our experience with high-dose intravenous levetiracetam (IV-LEV) for acute seizure exacerbations in nine children with medically intractable epilepsy. All children had acute repetitive seizures-while on chronic antiepileptic drugs-that either led to hospitalization (eight) or occurred during hospitalization (one), and received doses of IV-LEV of 150 mg/kg/day or greater, with a mean dose of 228 +/- 48 mg/kg/day. Eight of nine children had resolution of the acute repetitive seizures. Seizure frequency was reduced to less than baseline in seven children (seizure-free in two, >/=80% reduction in four, and 50% reduction in one). Except for one child with increased seizures, IV-LEV was well tolerated in all children without complications.

Long-term exposure and safety of lacosamide monotherapy for the treatment of partial-onset (focal) seizures: Results from a multicenter, open-label trial.

PubMed

Vossler, David G; Wechsler, Robert T; Williams, Paulette; Byrnes, William; Therriault, Sheila

2016-10-01

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

Association between switching antiepileptic drug products and healthcare utilization: A systematic review.

PubMed

Kwan, Patrick; Palmini, André

2017-08-01

There is ongoing concern whether switching between different antiepileptic drug (AED) products may compromise patient care. We systematically reviewed changes in healthcare utilization following AED switch. We searched MEDLINE and EMBASE databases (1980-October 2016) for studies that assessed the effect of AED switching in patients with epilepsy on outpatient visits, emergency room visits, hospitalization and hospital stay duration. A total of 14 articles met the inclusion criteria. All were retrospective studies. Four provided findings for specific AEDs only (lamotrigine, topiramate, phenytoin and divalproex), 9 presented pooled findings from multiple AEDs, and 1 study provided both specific (lamotrigine, topiramate, oxcarbazepine, and levetiracetam) and pooled findings. Three studies found an association between a switch of topiramate and an increase in healthcare utilization. Another three studies found that a brand-to-generic lamotrigine switch was not associated with an increased risk of emergently treated events (ambulance use, ER visits or hospitalization). The outcomes of the pooled AED switch studies were inconsistent; 5 studies reported an increased healthcare utilization while 5 studies did not. Studies that have examined the association between an AED switch and a change in healthcare utilization report conflicting findings. Factors that may explain these inconsistent outcomes include inter-study differences in the type of analysis undertaken (pooled vs individual AED data), the covariates used for data adjustment, and the type of switch examined. Future medical claim database studies employing a prospective design are encouraged to address these and other factors in order to enhance inter-study comparability and extrapolation of findings. Copyright © 2017 Elsevier Inc. All rights reserved.

A systematic review on the role of anticonvulsants in the treatment of acute bipolar depression.

PubMed

Reinares, María; Rosa, Adriane R; Franco, Carolina; Goikolea, José Manuel; Fountoulakis, Kostas; Siamouli, Melina; Gonda, Xenia; Frangou, Sophia; Vieta, Eduard

2013-03-01

Despite the high morbidity and mortality associated with bipolar depression, the optimal treatment for this phase is still a matter of debate. The aim of the current review was to provide updated evidence about the efficacy and tolerability of anticonvulsants in the treatment of acute bipolar depression. A comprehensive review of randomized controlled trials (RCTs) evaluating the use of anticonvulsants for the treatment of acute bipolar depression up to June 2011 was conducted by means of the PubMed-Medline database. Eligibility criteria included active comparator-controlled or placebo-controlled randomized studies involving monotherapy or combination therapy. A total of 18 RCTs fulfilled the inclusion criteria. Studies supported the efficacy of divalproex as monotherapy in acute bipolar depression but small sample size was a common methodological limitation. Findings were inconclusive for lamotrigine and carbamazepine although overall lamotrigine may have a beneficial but modest effect. Negative results were found for levetiracetam and gabapentin but the evidence base on these agents is scant. All anticonvulsants were generally well tolerated. No double-blind RCTs were found for the use of other anticonvulsants such as oxcarbazepine, licarbazepine, zonisamide, retigabine, pregabalin, tiagabine, felbamate and vigabatrine in the acute treatment of bipolar depression. To sum up, taking into consideration the efficacy and tolerability profiles of anticonvulsants, current evidence supports the use of divalproex and lamotrigine in the treatment of acute bipolar depression. However, available data for most other anticonvulsants are inconclusive and further RCTs with larger sample sizes are needed before drawing firm conclusions.

Assessment of safety and efficacy of lamotrigine over the course of 1-year observation in Japanese patients with bipolar disorder: post-marketing surveillance study report

PubMed Central

Terao, Takeshi; Ishida, Atsuko; Kimura, Toshifumi; Yoshida, Mitsuhiro; Hara, Terufumi

2017-01-01

Background A post-marketing surveillance (PMS) study was conducted with a 1-year observation period to assess the safety and efficacy of lamotrigine in routine clinical practice in patients with bipolar disorder (BD). Patients and methods Central enrollment method was used to recruit patients diagnosed with BD who were being treated for the first time with lamotrigine to prevent the recurrence/relapse of BD mood episodes. Adverse drug reactions (ADRs) and recurrence/relapse were assessed. Improvement of mania and depression was also assessed using the Hamilton’s Rating Scale for Depression (HAM-D) and the Young Mania Rating Scale (YMRS) at treatment initiation, 4–6 months post treatment initiation, and 10–12 months post treatment initiation. Results A total of 237/989 patients (24.0%) reported ADRs, most commonly rash (9.1%), and the incidence of serious ADRs was 3.3% (33/989 patients). Skin disorders occurred in 130 patients (13.1%), mostly within 8 weeks post treatment. A total of 237/703 patients (33.7%) experienced recurrence/relapse of mood episodes. The 25th percentile of the time to recurrence/relapse of mood episodes was 105 days. Remission of depression symptoms (HAM-D ≤7) occurred in 147/697 patients (21.1%) at treatment initiation, rising to 361 patients (67.4%) at 10–12 months post treatment. Remission of manic symptoms (YMRS ≤13) occurred in 615/676 patients (91.0%) at treatment initiation, rising to 500 patients (97.3%) at 10–12 months post treatment. Conclusion The results of this PMS study suggest that lamotrigine is a well-tolerated and effective drug for preventing recurrence/relapse of BD in clinical practice. PMID:28652744

Efficacy of levetiracetam in primary hemifacial spasm.

PubMed

Kuroda, Takeshi; Saito, Yu; Fujita, Kazuhisa; Yano, Satoshi; Ishigaki, Seiichiro; Kato, Hirotaka; Murakami, Hidetomo; Ono, Kenjiro

2016-12-01

Hemifacial spasm (HFS) is a peripherally-induced movement disorder characterized by the involuntary, unilateral, intermittent, irregular, tonic or clonic contractions of muscles innervated by the ipsilateral facial nerve. Kindling-like hyperactivity of the facial nucleus induced by constant stimulation of compressing artery is considered as the predominant mechanism underlying the pathogenesis of HFS. As a treatment for HFS, microsurgical decompression and botulinum toxin injection have been shown to be highly successful. Anticonvulsant drugs relieve HFS in some patients; however, the use of such drugs is limited owing to their side effects, predominantly in elderly patients. We experienced two elderly HFS patients who exhibited a marked response to levetiracetam (LEV) without side effects. Although the exact underlying pharmacological mechanism remains unknown, we assume anti-kindling effect as one of the important pharmacological mechanism underlying the effect of LEV against HFS. Moreover, LEV is considered to be suitable for use in elderly patients because of its good tolerability. In addition, the lack of hepatic induction or inhibition makes it an easy and safe drug when used in addition to other anticonvulsants. Although the long-term benefit remains unknown, LEV may represent an alternative treatment for elderly HFS patients who are unable to undergo or decline surgical intervention and/or botulinum toxin injections or are intolerant to other anticonvulsants. Copyright © 2016 Elsevier Ltd. All rights reserved.

In vivo biocompatibility and in vitro characterization of poly-lactide-co-glycolide structures containing levetiracetam, for the treatment of epilepsy.

PubMed

Halliday, Amy J; Campbell, Toni E; Razal, Joselito M; McLean, Karen J; Nelson, Timothy S; Cook, Mark J; Wallace, Gordon G

2012-02-01

Epilepsy is a chronic neurological disorder characterized by recurrent seizures, and is highly resistant to medication with up to 40% of patients continuing to experience seizures whilst taking oral antiepileptic drugs. Recent research suggests that this may be due to abnormalities in the blood-brain barrier, which prevent the passage of therapeutic substances into the brain. We sought to develop a drug delivery material that could be implanted within the brain at the origin of the seizures to release antiepileptic drugs locally and avoid the blood brain barrier. We produced poly-lactide-co-glycolide drop-cast films and wet-spun fibers loaded with the novel antiepileptic drug Levetiracetam, and investigated their morphology, in vitro drug release characteristics, and brain biocompatibility in adult rats. The best performing structures released Levetiracetam constantly for at least 5 months in vitro, and were found to be highly brain biocompatible following month-long implantations in the motor cortex of adult rats. These results demonstrate the potential of polymer-based drug delivery devices in the treatment of epilepsy and warrant their investigation in animal models of focal epilepsy. Copyright © 2011 Wiley Periodicals, Inc.

Behavioral effects and somnolence due to levetiracetam versus oxcarbazepine - a retrospective comparison study of North Indian patients with refractory epilepsy.

PubMed

Shukla, Garima; Gupta, Anupama; Agarwal, Priya; Poornima, Shivani

2016-11-01

Levetiracetam (LEV) is often chosen early in the treatment of refractory epilepsy; however, its adverse effects have largely been studied as part of clinical trials. Oxcarbazepine and valproate (VPA) are the other commonly used AEDs and, hence, serve as good comparators. This study was conducted to evaluate behavioral abnormalities and somnolence among patients with epilepsy being treated with LEV and/or OXC compared with those receiving VPA. Data of consecutive patients attending our intractable epilepsy clinic over a 2 1/2-year period were reviewed, and patients with at least one seizure a month, who had been initiated on either or a combination of LEV, VPA, or OXC, were included for analysis. Data regarding behavioral adverse effects, daytime somnolence (EDS), and weight changes were collected apart from those regarding any major effect necessitating dose reduction or discontinuation of the AED. Among a total of 445 patients screened, 292 (93 F, median age: 21years [range: 8-54]; 237 focal and 55 generalized epilepsy) fulfilled inclusion criteria. Median epilepsy duration was 11years. Levetiracetam had been introduced in 114 patients, VPA in 134, and OXC in 151 during the study period. Twenty-three were on LEV+OXC, 27 on LEV+VPA, and 33 on VPA+OXC. Behavioral disturbances (irritability, obsessive manifestations, aggressiveness, and frank psychosis) were observed in 43 patients; 23 on introduction of LEV (20.2%); LEV was discontinued in 10 (9%). Daytime somnolence was reported by 28 patients, 15 on OXC (10%); 8 received oral modafinil for the same, while none discontinued this AED. Only one patient on LEV and 3 on VPA reported EDS. Menstrual disturbances were reported by 9, weight gain by 3, and severe hair loss by 2 females on VPA. Behavioral disturbances with levetiracetam are common among patients with refractory epilepsy while somnolence is common with oxcarbazepine. Antiepileptic drugs should be selected with this in perspective. Copyright © 2016 Elsevier

Perspectives on treatment options for mesial temporal lobe epilepsy with hippocampal sclerosis.

PubMed

Palleria, Caterina; Coppola, Antonietta; Citraro, Rita; Del Gaudio, Luigi; Striano, Salvatore; De Sarro, Giovambattista; Russo, Emilio

2015-01-01

Mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS) is a syndrome that is often refractory to drug treatment. The effects on specific syndromes are not currently available from the pre-marketing clinical development of new AEDs; this does not allow the prediction of whether new drugs will be more effective in the treatment of some patients. We have reviewed all the existing literature relevant to the understanding of a potential effectiveness in MTLE-HS patients for the latest AEDs, namely brivaracetam, eslicarbazepine, lacosamide, perampanel and retigabine also including the most relevant clinical data and a brief description of their pharmacological profile. Records were identified using predefined search criteria using electronic databases (e.g., PubMed, Cochrane Library Database of Systematic Reviews). Primary peer-reviewed articles published up to the 15 June 2015 were included. All the drugs considered have the potential to be effective in the treatment of MTLE-HS; in fact, they possess proven efficacy in animal models; currently considered valuable tools for predicting drug efficacy in TLE. Furthermore, for some of these (e.g., lacosamide and eslicarbazepine) data are already available from post-marketing studies while brivaracetam acting on SV2A like levetiracetam might have the same potential effectiveness with the possibility to be more efficacious considering its ability to inhibit voltage gated sodium channels; finally, perampanel and retigabine are very effective drugs in animal models of TLE.

Lamotrigine versus inert placebo in the treatment of borderline personality disorder: study protocol for a randomized controlled trial and economic evaluation.

PubMed

Crawford, Mike J; Sanatinia, Rahil; Barrett, Barbara; Byford, Sarah; Cunningham, Gillian; Gakhal, Kavi; Lawrence-Smith, Geof; Leeson, Verity; Lemonsky, Fenella; Lykomitrou, Georgia; Montgomery, Alan; Morriss, Richard; Paton, Carol; Tan, Wei; Tyrer, Peter; Reilly, Joseph G

2015-07-18

People with borderline personality disorder (BPD) experience rapid and distressing changes in mood, poor social functioning and have high rates of suicidal behaviour. Several small scale studies suggest that mood stabilizers may produce short-term reductions in symptoms of BPD, but have not been large enough to fully examine clinical and cost-effectiveness. A two parallel-arm, placebo controlled randomized trial of usual care plus either lamotrigine or an inert placebo for people aged over 18 who are using mental health services and meet diagnostic criteria for BPD. We will exclude people with comorbid bipolar affective disorder or psychosis, those already taking a mood stabilizer, those who speak insufficient English to complete the baseline assessment and women who are pregnant or contemplating becoming pregnant. Those meeting inclusion criteria and provide written informed consent will be randomized to up to 200mg of lamotrigine per day or an inert placebo (up to 400mg if taking combined oral contraceptives). Participants will be randomized via a remote web-based system using permuted stacked blocks stratified by study centre, severity of personality disorder, and level of bipolarity. Follow-up assessments will be conducted by masked researchers 12, 24 weeks, and 52 weeks after randomization. The primary outcome is the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD). The secondary outcomes are depressive symptoms, deliberate self-harm, social functioning, health-related quality of life, resource use and costs, side effects of treatment, adverse events and withdrawal of trial medication due to adverse effects. The main analyses will use intention to treat without imputation of missing data. The economic evaluation will take an NHS/Personal Social Services perspective. A cost-utility analysis will compare differences in total costs and differences in quality of life using QALYs derived from the EQ-5D. The evidence base for the use of

A multicentre randomised controlled trial of levetiracetam versus phenytoin for convulsive status epilepticus in children (protocol): Convulsive Status Epilepticus Paediatric Trial (ConSEPT) - a PREDICT study.

PubMed

Dalziel, Stuart R; Furyk, Jeremy; Bonisch, Megan; Oakley, Ed; Borland, Meredith; Neutze, Jocelyn; Donath, Susan; Sharpe, Cynthia; Harvey, Simon; Davidson, Andrew; Craig, Simon; Phillips, Natalie; George, Shane; Rao, Arjun; Cheng, Nicholas; Zhang, Michael; Sinn, Kam; Kochar, Amit; Brabyn, Christine; Babl, Franz E

2017-06-22

Convulsive status epilepticus (CSE) is the most common life-threatening childhood neurological emergency. Despite this, there is a lack of high quality evidence supporting medication use after first line benzodiazepines, with current treatment protocols based solely on non-experimental evidence and expert opinion. The current standard of care, phenytoin, is only 60% effective, and associated with considerable adverse effects. A newer anti-convulsant, levetiracetam, can be given faster, is potentially more efficacious, with a more tolerable side effect profile. The primary aim of the study presented in this protocol is to determine whether intravenous (IV) levetiracetam or IV phenytoin is the better second line treatment for the emergency management of CSE in children. 200 children aged between 3 months and 16 years presenting to 13 emergency departments in Australia and New Zealand with CSE, that has failed to stop with first line benzodiazepines, will be enrolled into this multicentre open randomised controlled trial. Participants will be randomised to 40 mg/kg IV levetiracetam infusion over 5 min or 20 mg/kg IV phenytoin infusion over 20 min. The primary outcome for the study is clinical cessation of seizure activity five minutes following the completion of the infusion of the study medication. Blinded confirmation of the primary outcome will occur with the primary outcome assessment being video recorded and assessed by a primary outcome assessment team blinded to treatment allocation. Secondary outcomes include: Clinical cessation of seizure activity at two hours; Time to clinical seizure cessation; Need for rapid sequence induction; Intensive care unit (ICU) admission; Serious adverse events; Length of Hospital/ICU stay; Health care costs; Seizure status/death at one-month post discharge. This paper presents the background, rationale, and design for a randomised controlled trial comparing levetiracetam to phenytoin in children presenting with CSE in whom

A Girl with Idiopathic Epilepsy Showing Forced Normalization after Levetiracetam Administration.

PubMed

Kawakami, Yasuhiko; Okazaki, Tetsuya; Takase, Masato; Fujino, Osamu; Itoh, Yasuhiko

2015-01-01

Forced normalization has been reported in association with almost all anti-epileptic drugs. We report on a 9-year-old girl with idiopathic epilepsy who showed forced normalization after administration of levetiracetam (LEV). She initially presented with generalized tonic-clonic seizures when she was 4 years old. Diffuse sharp and slow wave complexes (SWCs) were observed on electroencephalography (EEG). We prescribed sodium valproate (VPA) and benzodiazepines, but the seizures and EEG findings worsened gradually. Although subsequent administration of LEV stopped the seizures, the patient became subject to episodes of rage and violent behavior. Forced normalization was confirmed by the disappearance of SWCs on EEG. We reduced the dose of LEV and tried in various ways to resolve the situation, but finally we had to abandon LEV. To the best of our knowledge, this is the first report of a patient with idiopathic epilepsy but without disabilities in everyday life showing forced normalization associated with LEV administration.

Levetiracetam induced acute reversible psychosis in a patient with uncontrolled seizures

PubMed Central

Kumar, Nithin; Swaroop, H. S.; Chakraborty, Ananya; Chandran, Suhas

2014-01-01

Levetiracetam (LEV) is a relatively newer antiepileptic drug with novel mechanism of action. It was introduced to the market in the year 2000. Pre-marketing clinical trials of the drug reported good tolerability with a wide safety margin. On post-marketing updates, there are few reports of psychosis after treatment with the drug. Here, we report a case of 52-year-old epileptic man who developed acute, reversible psychosis within 3 days of initiation of treatment. The drug was prescribed at a dose of 500 mg per day. After 3 days of treatment, the patient developed visual hallucinations, mood swings, withdrawal and suspicious behavior. Delirium was ruled out as there was no fluctuation in his sensorium or focal neurological deficits. His lab investigations for electrolytes, renal function test, thyroid, liver function and other related tests levels were within normal limits. A diagnosis of LEV induced psychosis was reached based on clinical judgment and causality assessment. PMID:25298593

[Epileptic encephalopathy associated with forced normalization after administration of levetiracetam].

PubMed

Kikuchi, Takahiro; Kato, Mitsuhiro; Takahashi, Nobuya; Nakamura, Kazuyuki; Hayasaka, Kiyoshi

2013-09-01

Here we report a case of a 10-year-old female with unclassified epileptic encephalopathy who showed forced normalization after administration of levetiracetam (LEV). She initially presented with intractable tonic and myoclonic seizures that were observed about 10 times a day along with frequent multifocal sharp and slow wave complexes on electroencephalography (EEG). We were forced to decrease the topiramate dose because of the appearance of nystagmus, and her myoclonic seizures became worse. We added LEV (250 mg/day) and her tonic and myoclonic seizures disappeared one day after initiation of LEV administration. However, she showed hyporesponsiveness and akinesia. The disappearance of paroxysmal discharges on EEG confirmed the diagnosis of forced normalization. Despite continuous administration of LEV, tonic and myoclonic seizures relapsed within a month but her psychotic symptoms resolved simultaneously. To the best of our knowledge, this is the first reported case of forced normalization after LEV administration. It should be noted that LEV may cause forced normalization although it can be started at an adequate dosage.

Add-on lacosamide: a retrospective study on the relationship between serum concentration, dosage, and adverse events.

PubMed

Hillenbrand, Barbara; Wisniewski, Ilona; Jürges, Uta; Steinhoff, Bernhard J

2011-11-01

We performed a retrospective study in patients with poorly controlled epilepsy treated with add-on lacosamide (LCM) to investigate the relationship of LCM-related adverse events with LCM serum concentration and weight-dependent dosage. We collected serum concentrations, weight-related dosages, and occurrences of the seven most frequent adverse events according to the randomized double-blind, placebo-controlled trials. Seventy of 131 patients could be sufficiently evaluated. LCM serum concentrations and weight-related dosages in patients with and without typical adverse events did not differ significantly. Closer analysis of the data suggested that dizziness as the leading adverse event occurred significantly more often if LCM was combined with classic sodium channel blockers. There was a significant correlation between LCM serum concentrations and co-medication, so there is still evidence for dependent variables that might have a relevant impact in individual cases. However, our data do not allow definition of a safety range for LCM. Copyright © 2011 Elsevier Inc. All rights reserved.

Prescription trends and psychiatric symptoms following first receipt of one of seven common antiepileptic drugs in general practice.

PubMed

Josephson, Colin B; Engbers, Jordan D T; Jette, Nathalie; Patten, Scott B; Sajobi, Tolulope T; Marshall, Deborah; Lowerison, Mark; Wiebe, Samuel

2018-05-09

We sought to examine the risk of psychiatric symptoms associated with a first prescription for specific antiepileptic drugs (AEDs) used in monotherapy in a general cohort of patients with epilepsy. We used The Health Improvement Network database (comprising the years 2000-2012) to identify incident patients with epilepsy. The index date was that on which they met the case definition for epilepsy, and analyses only included patients who remained on monotherapy or received no AED therapy following diagnosis to avoid confounding by polytherapy. Psychiatric symptoms were defined using mental health clinical or treatment (medical or therapeutic) code. We analyzed the AED of interest as a time-varying covariate in multivariate Cox proportional hazard regression models controlling for confounding factors. We identified 9595 patients with incident epilepsy, 7400 of whom (77%) received a first-recorded AED prescription. Prescriptions for newer generation AEDs (lamotrigine and levetiracetam) steadily increased (constituting over 30% of all AED prescriptions by 2012) while valproate use significantly declined in females (~40% in 2002 to just over 20% by 2012). A total of 2190 patients were first exposed to carbamazepine (29.3%) and 222 to lamotrigine (3%), both of which were associated with a lower hazard of any coded psychiatric symptom or disorder in multivariate analyses (hazard ratio [HR]: 0.84, 95% confidence interval [95% CI]: 0.73-0.97; p = 0.02 and HR: 0.83, 95% CI: 0.70-0.99; p = 0.03, respectively, for carbamazepine and lamotrigine). Carbamazepine was also associated with a lower hazard for depression (HR: 0.81; 95% CI: 0.69-0.96; p = 0.013) and anxiety (HR: 0.77; 95% CI: 0.63-0.95; p = 0.013) in secondary analyses. This study provides evidence that carbamazepine and lamotrigine are associated with lower hazards for psychiatric symptoms following a diagnosis of epilepsy. These estimates can be used in clinical settings, and the precision should

[The use of lamotrigine in female patients].

PubMed

Schmitz, B; Bergmann, L

2007-08-01

Gender aspects are important when assessing the tolerability of antiepileptic drugs (AED). Due to its broad spectrum of action and to the lack of evidence for teratogenicity in monotherapy, lamotrigine (LTG) is an AED of first choice for women with epilepsy with child-bearing potential. In an observational study over 6 months including 832 women with epilepsy, we evaluated the efficacy and tolerability of LTG in monotherapy and add-on therapy, with a special focus on parameters of particular importance for women including changes in weight, skin, hair, and patterns of menstruation. Of the treated patients, 94% had seizure reduction of at least 50%. Adverse events occurred in 7.3%; 1% experienced serious adverse events, all of which were reversible. Ninety-six percent continued treatment throughout the observation period, and 83% reported improvement in quality of life by the end of the study. Cognition, functioning at work, and mood improved in 43-54% of patients. In most of them, weight remained stable. Those who were switched from valporate (VPA) or carbamazepine (CPZ) to LTG lost 3.2 kg and 3.1 kg (means), respectively. Many of the women described problems related to menstruation at the beginning of the study: variability in cycle length (31.2%), hypermenorrhea (17.3%), and pains (10%). Skin and hair problems were reported by 18.4% and 17.3%, respectively. There was improvement in all of these aspects at the end of the study, particularly for those women switched from VPA or CBZ to LTG. In summary, this observational study confirms the good tolerability of LTG with respect to issues particularly relevant to women. More complete elucidation of the correct LTG dosage, which varies widely according to the accompanying medication, will further improve treatment safety.

New antiepileptic drugs in pediatric epilepsy.

PubMed

Hwang, Hee; Kim, Ki Joong

2008-10-01

New antiepileptic drugs (AEDs), introduced since 1993, provide more diverse options in the treatment of epilepsy. Despite the equivalent efficacy and better tolerability of these drugs, more than 25% of patients remain refractory to treatment. Moreover, the issues for pediatric patients are different from those for adults, and have not been addressed in the development and application of the new AEDs. Recently published evidence-based treatment guidelines have helped physicians to choose the most reasonable AED, although they cannot fully endorse new AEDs because of the lack of well-designed, randomized controlled trials. We review the mechanisms of action, pharmacokinetic properties, adverse reactions, efficacy, and tolerability of eight new AEDs (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, vigabatrin, and zonisamide), focusing on currently available treatment guidelines and expert opinions regarding pediatric epilepsy.

The impact of age on lamotrigine and oxcarbazepine kinetics: a historical cohort study.

PubMed

Wegner, Ilse; Wilhelm, Abraham J; Sander, Josemir W; Lindhout, Dick

2013-10-01

Age as well as estrogen levels may have an impact on the pharmacokinetics of lamotrigine (LTG) and monohydroxycarbazepine (MHD), the active metabolite of oxcarbazepine (OXC). To assess the effects of age and menopause, we evaluated retrospectively a therapeutic drug-monitoring database. Samples from 507 women and 302 men taking LTG and 464 women and 319 men taking OXC were used to develop a population pharmacokinetic model. Data were analyzed using NONMEM software and were compared with a population pharmacokinetic model based on samples of 1705 women and 1771 men taking carbamazepine (CBZ). Age was a significant factor contributing to pharmacokinetic variability in individuals using LTG, OXC, and CBZ with increasing clearance as a function of bioavailability (Cl/F) over age 18, a maximum Cl/F at 33years (CBZ) and 36 years (LTG and OXC), and a gradual decrease of Cl/F towards older age. We found no effect of perimenopausal age range on LTG and MHD clearance. © 2013.

Levetiracetam protects against kainic acid-induced toxicity.

PubMed

Marini, Herbert; Costa, Cinzia; Passaniti, Maria; Esposito, Maria; Campo, Giuseppe M; Ientile, Riccardo; Adamo, Elena Bianca; Marini, Rolando; Calabresi, Paolo; Altavilla, Domenica; Minutoli, Letteria; Pisani, Francesco; Squadrito, Francesco

2004-01-23

We investigated the Levetiracetam (LVT) ability to protect the brain against kainic acid (KA) induced neurotoxicity. Brain injury was induced by intraperitoneal administration of KA (10 mg/kg). Sham brain injury rats were used as controls. Animals were randomized to receive either LVT (50 mg/kg) or its vehicle (1 ml/kg) 30 min. before KA administration. Animals were sacrificed 6 hours after KA injection to measure brain malonildialdehyde (MDA), glutathione levels (GSH) and the mRNA for interleukin-1beta (IL-1beta) in the cortex and in the diencephalon. Behavioral changes were also monitored. Intraperitoneal administration of LVT decreased significantly MDA in the cortex (KA + vehicle = 0.25 +/- 0.03 nmol/mg protein; KA + LVT = 0.13 +/- 0.01 nmol/mg protein; P < 0.005), and in the diencephalons (KA + vehicle = 1,01 +/- 0.2 nmol/mg protein; KA + LVT = 0,33 +/- 0,08 nmol/mg protein; P < 0.005), prevented the brain loss of GSH in both cortex (KA + vehicle = 5 +/- 1 micromol/g protein; KA + LVT = 15 +/- 2 micromol/g protein; P < 0.005) and diencephalons (KA + vehicle = 9 +/- 0.8 micromol/g protein; KA + LVT = 13 +/- 0.3 micromol/g protein; P < 0.05), reduced brain IL-1beta mRNA and markedly controlled seizures. Histological analysis showed a reduction of cell damage in LVT treated samples. The present data indicate that LVT displays neuro-protective effects against KA induced brain toxicity and suggest that these effects are mediated, at least in part, by inhibition of lipid peroxidation.

Beneficial Combination of Lacosamide with Retigabine in Experimental Animals: An Isobolographic Analysis.

PubMed

Luszczki, Jarogniew J; Zagaja, Mirosław; Miziak, Barbara; Kondrat-Wrobel, Maria W; Zaluska, Katarzyna; Wroblewska-Luczka, Paula; Adamczuk, Piotr; Czuczwar, Stanislaw J; Florek-Luszczki, Magdalena

2018-01-01

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. © 2017 S. Karger AG, Basel.

Additional Antiepileptic Mechanisms of Levetiracetam in Lithium-Pilocarpine Treated Rats

PubMed Central

Al-Shorbagy, Muhammad Y.; El Sayeh, Bahia M.; Abdallah, Dalaal M.

2013-01-01

Several studies have addressed the antiepileptic mechanisms of levetiracetam (LEV); however, its effect on catecholamines and the inflammatory mediators that play a role in epilepsy remain elusive. In the current work, lithium (Li) pretreated animals were administered LEV (500 mg/kg i.p) 30 min before the induction of convulsions by pilocarpine (PIL). Li-PIL-induced seizures were accompanied by increased levels of hippocampal prostaglandin (PG) E2, myeloperoxidase (MPO), tumor necrosis factor-α, and interleukin-10. Moreover, it markedly elevated hippocampal lipid peroxides and nitric oxide levels, while it inhibited the glutathione content. Li-PIL also reduced hippocampal noradrenaline, as well as dopamine contents. Pretreatment with LEV protected against Li-PIL-induced seizures, where it suppressed the severity and delayed the onset of seizures in Li-PIL treated rats. Moreover, LEV reduced PGE2 and MPO, yet it did not affect the level of both cytokines in the hippocampus. LEV also normalized hippocampal noradrenaline, dopamine, glutathione, lipid peroxides, and nitric oxide contents. In conclusion, alongside its antioxidant property, LEV anticonvulsive effect involves catecholamines restoration, as well as inhibition of PGE2, MPO, and nitric oxide. PMID:24098559

Antinociceptive and pronociceptive effect of levetiracetam in tonic pain model.

PubMed

Cortes-Altamirano, José Luis; Reyes-Long, Samuel; Olmos-Hernández, Adriana; Bonilla-Jaime, Herlinda; Carrillo-Mora, Paul; Bandala, Cindy; Alfaro-Rodriguez, Alfonso

2018-04-01

Levetiracetam (LEV) is a novel anticonvulsant with proven antinociceptive properties. However, the antinociceptive and pronociceptive effect of this drug has not yet been fully elucidated in a tonic pain model. Thirty-six male rats (Wistar) were randomized into six groups and underwent the formalin test as follows: rats in the control group were administered 50μL of 1% formalin in the paw; sham-group rats were administered 50μL of saline in the paw to mimick the application of formalin; the four experimental groups were administered LEV intragastrically (ig) (50, 100, 200 and 300mg/kg), and 40min later 50μL of 1% formalin was injected in the paw. LEV exhibited antinociceptive effect in the 300mg/kg LEV group (p<0.05) and a pronociceptive effect in the 100mg/kg LEV group (p<0.05) and in the 50mg/kg LEV group (p<0.001). The antinociceptive and pronociceptive effect of LEV in a tonic pain model is dose-dependent. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

Sulthiame but not levetiracetam exerts neurotoxic effect in the developing rat brain.

PubMed

Manthey, Daniela; Asimiadou, Stella; Stefovska, Vanya; Kaindl, Angela M; Fassbender, Jessica; Ikonomidou, Chrysanthy; Bittigau, Petra

2005-06-01

Antiepileptic drugs (AEDs) used to treat seizures in pregnant women, infants, and young children can cause cognitive impairment. One mechanism implicated in the development of neurocognitive deficits is a pathologic enhancement of physiologically occurring apoptotic neuronal death in the developing brain. We investigated whether the newer antiepileptic drug levetiracetam (LEV) and the older antiepileptic drug sulthiame (SUL) have neurotoxic properties in the developing rat brain. SUL significantly enhanced neuronal death in the brains of rat pups ages 0 to 7 days at doses of 100 mg/kg and above, whereas LEV did not show this neurotoxic effect. Dosages of both drugs used in the context of this study comply with an effective anticonvulsant dose range applied in rodent seizure models. Thus, LEV is an AED which lacks neurotoxicity in the developing rat brain and should be considered in the treatment of epilepsy in pregnant women, infants, and toddlers once general safety issues have been properly addressed.

Multifunctional Hybrid Compounds Derived from 2-(2,5-Dioxopyrrolidin-1-yl)-3-methoxypropanamides with Anticonvulsant and Antinociceptive Properties.

PubMed

Abram, Michał; Zagaja, Mirosław; Mogilski, Szczepan; Andres-Mach, Marta; Latacz, Gniewomir; Baś, Sebastian; Łuszczki, Jarogniew J; Kieć-Kononowicz, Katarzyna; Kamiński, Krzysztof

2017-10-26

The focused set of new pyrrolidine-2,5-diones as potential broad-spectrum hybrid anticonvulsants was described. These derivatives integrate on the common structural scaffold the chemical fragments of well-known antiepileptic drugs such as ethosuximide, levetiracetam, and lacosamide. Such hybrids demonstrated effectiveness in two of the most widely used animal seizure models, namely, the maximal electroshock (MES) test and the psychomotor 6 Hz (32 mA) seizure models. Compound 33 showed the highest anticonvulsant activity in these models (ED 50 MES = 79.5 mg/kg, ED 50 6 Hz = 22.4 mg/kg). Compound 33 was also found to be effective in pentylenetetrazole-induced seizure model (ED 50 PTZ = 123.2 mg/kg). In addition, 33 demonstrated effectiveness by decreasing pain responses in formalin-induced tonic pain, in capsaicin-induced neurogenic pain, and notably in oxaliplatin-induced neuropathic pain in mice. The pharmacological data of stereoisomers of compound 33 revealed greater anticonvulsant activity by R(+)-33 enantiomer in both MES and 6 Hz seizure models.

Role of levetiracetam in refractory seizures due to a rare progressive myoclonic epilepsy: Lafora body disease

PubMed Central

Hashmi, Mubashira; Saleem, Feroza; Mustafa, Muhammad Shahid; Sheerani, Mughis; Ehtesham, Zeeshan; Siddiqui, Khurram

2010-01-01

Lafora disease is one of the rare, most fatal progressive myoclonic epilepsies reported. We present a case of a teenager with intractable seizures and progressive mental decline, diagnosed as Lafora body disease on axillary skin biopsy. He was admitted with status epilepticus with refractory myoclonic and generalised tonic clonic seizures. Despite on maximum doses of multiple antiepileptic drugs and infusions of propofol and midazolam, his seizures were refractory to all forms of medical therapy tried. Levetiracetam (LEV), a pyrrolidine derivative, was introduced; he showed a prompt response and was weaned off successfully from infusions of anticonvulsants and mechanical ventilation within 48 h of introduction of LEV, followed by an almost seizure-free status. PMID:22791845

Design, synthesis and anticonvulsant activity of new hybrid compounds derived from N-phenyl-2-(2,5-dioxopyrrolidin-1-yl)-propanamides and -butanamides.

PubMed

Kamiński, Krzysztof; Rapacz, Anna; Filipek, Barbara; Obniska, Jolanta

2016-07-01

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. Copyright © 2016 Elsevier Ltd. All rights reserved.

Enalapril enhances the anticonvulsant activity of lamotrigine in the test of maximal electroshock.

PubMed

Łukawski, Krzysztof; Jakubus, Tomasz; Janowska, Agnieszka; Raszewski, Grzegorz; Czuczwar, Stanisław J

2013-01-01

The aim of this study was to find out whether angiotensin-converting enzyme (ACE) inhibitors, enalapril and cilazapril, affect the anticonvulsant action of some second-generation antiepileptics, lamotrigine (LTG), topiramate (TPM) and oxcarbazepine (OXC). The effects of ACE inhibitors on antiepileptic drugs were examined in the mouse model of maximal electroshock. Enalapril (30 mg/kg ip) potentiated the anticonvulsant action of LTG, decreasing its ED50 value from 5.3 to 3.6 mg/kg (p < 0.01). The anticonvulsant activity of TPM or OXC was not modified by enalapril. Cilazapril did not affect the protective activity of the studied antiepileptics. The interaction between enalapril and LTG could be pharmacodynamic in nature because enalapril did not change plasma and total brain concentrations of LTG. This study shows that there are no negative interactions between the studied antiepileptic drugs and enalapril or cilazapril. Enalapril even enhanced the anticonvulsant activity of LTG in the MES test in mice that is thought to be a predictive model of human generalized tonic-clonic seizures.

Therapeutic benefits of ACTH and levetiracetam in STXBP1 encephalopathy with a de novo mutation: A case report and literature review.

PubMed

Liu, Shunli; Wang, Liyuan; Cai, Xiao Tang; Zhou, Hui; Yu, Dan; Wang, Zhiling

2018-05-01

The case report aims to discuss the clinical symptoms and treatment of encephalopathy caused by a novel syntaxin- binding protein 1 (STXBP1) genetic mutation. The patient, a girl, was born at 38+4 weeks of gestation. She had frequent spasm attacks accompanied by obvious psychomotor development retardation since the neonatal period. Genetic screening identified a novel STXBP1 genetic mutation. Early-onset epileptic encephalopathy with STXBP1 mutation. We adjusted the antiepileptic strategy to oral levetiracetam and topiramate, and intravenous administration of adrenocorticotropic hormone(ACTH) for 2 weeks. Subsequently, prednisone was continued, and gradually reduced and withdrawn over 3 months. The treatment was effective with complete control of the epileptic seizures and improvements in the electroencephalogram readings. However, the effects on psychomotor ability were slow and limited. A literature review of STXBP1 mutation cases in which ACTH was administered showed that complete seizure control is observed in 60% of cases, 20% are partially affected, and the remaining 20% show no effect. ACTH and levetiracetam had good therapeutic effects in epilepsy control in this case of de novo STXBP1 mutation. ACTH is an effective drug for early-onset epileptic encephalopathy caused by STXBP1 mutation. However, controlling epilepsy using this therapy does not alter the psychomotor development retardation caused by the STXBP1 mutation.

Neurodevelopmental Effects of Antiepileptic Drugs.

PubMed

Kellogg, Marissa; Meador, Kimford J

2017-07-01

Increasing evidence suggests that exposure to certain antiepileptic drugs (AEDs) during critical periods of development may induce transient or long-lasting neurodevelopmental deficits across cognitive, motor and behavioral domains. The developing nervous system may endure prolonged chronic exposure to AEDs during pregnancy (in utero) or during childhood, which can lead to neurodevelopmental defects such as congenital neural tube defects, lower IQ, language deficits, autism and ADHD. To date, valproate is the most widely recognized AED to significantly negatively affect neurodevelopment, and demonstrates greater adverse effects than any other AEDs that have been assessed. Although some AEDs appear to have low risk (i.e., lamotrigine, levetiracetam), other AEDs have been implicated in a variety of studies detailed below, and many AEDs have not been adequately assessed. The purpose of this review article is to summarize our current understanding of the neurodevelopmental effects of AEDs.

The bone mineral content alterations in pediatric patients medicated with levetiracetam, valproic acid, and carbamazepine.

PubMed

Serin, Hepsen Mine; Koç, Zehra Pınar; Temelli, Berfin; Esen, İhsan

2015-10-01

The negative effect of antiepileptic drugs on bone health has been previously documented. However, which antiepileptic drug is safer in regard to bone health is still questionable. Our aims were to investigate the bone mineral density alterations in pediatric patients who receive antiepileptic medication for a minimum of two years and to compare the results of these drugs. Fifty-nine patients (32 males, 27 females; mean age: 8.6±4.6years) and a control group (13 males, 7 females; mean age: 7.6±3.3years) were included in the study. The patients were receiving necessarily the same antiepileptic drugs (AEDs) for at least two years, and none of the patients had mental retardation or cerebral palsy. The patients were divided into three groups: group 1 (patients receiving levetiracetam (LEV), n=20), group 2 (patients receiving carbamazepine (CBZ), n=11), and group 3 (patients receiving valproic acid (VPA), n=28). Plasma calcium (Ca), phosphorus (P), parathyroid hormone (PTH), alkaline phosphatase (ALP), vitamin D levels, and bone mineral density (BMD) values of femur and vertebras (L1-4) and z-scores (comparative results of BMD values of the patients with the age- and gender-matched controls in device database) of the groups were compared. The differences between P, PTH, ALP and age, Ca and BMD results, and vitamin D levels of the patients in all four groups was not statistically significant according to Kruskal-Wallis test (p>0.05). The z-score levels of all the patient and control groups were also not statistically significantly different compared with each other. In contrast to previous reports in pediatric patients, our study has documented that there is not a considerable bone loss in patients receiving long-term AED medication. Although levetiracetam has been proposed as bone-protecting medication, we did not observe any difference between AEDs regarding bone mineral density after two years of treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

Optimized and validated flow-injection spectrophotometric analysis of topiramate, piracetam and levetiracetam in pharmaceutical formulations.

PubMed

Hadad, Ghada M; Abdel-Salam, Randa A; Emara, Samy

2011-12-01

Application of a sensitive and rapid flow injection analysis (FIA) method for determination of topiramate, piracetam, and levetiracetam in pharmaceutical formulations has been investigated. The method is based on the reaction with ortho-phtalaldehyde and 2-mercaptoethanol in a basic buffer and measurement of absorbance at 295 nm under flow conditions. Variables affecting the determination such as sample injection volume, pH, ionic strength, reagent concentrations, flow rate of reagent and other FIA parameters were optimized to produce the most sensitive and reproducible results using a quarter-fraction factorial design, for five factors at two levels. Also, the method has been optimized and fully validated in terms of linearity and range, limit of detection and quantitation, precision, selectivity and accuracy. The method was successfully applied to the analysis of pharmaceutical preparations.

Levetiracetam-loaded biodegradable polymer implants in the tetanus toxin model of temporal lobe epilepsy in rats.

PubMed

Halliday, Amy J; Campbell, Toni E; Nelson, Timothy S; McLean, Karen J; Wallace, Gordon G; Cook, Mark J

2013-01-01

Approximately one-third of people with epilepsy receive insufficient benefit from currently available anticonvulsant medication, and some evidence suggests that this may be due to a lack of effective penetration into brain parenchyma. The current study investigated the ability of biodegradable polymer implants loaded with levetiracetam to ameliorate seizures following implantation above the motor cortex in the tetanus toxin model of temporal lobe epilepsy in rats. The implants led to significantly shorter seizures and a trend towards fewer seizures for up to 1 week. The results of this study indicate that drug-eluting polymer implants represent a promising evolving treatment option for intractable epilepsy. Future research is warranted to investigate issues of device longevity and implantation site. Copyright © 2012 Elsevier Ltd. All rights reserved.

Comparative evaluation of single and bilayered lamotrigine floating tablets

PubMed Central

Lakshmi, PK; Sridhar, M; Shruthi, B

2013-01-01

Aim: The purpose of this study was to prepare lamotrigine (LM) bilayered and single layered floating tablets and to compare their release profiles. Materials and Methods: LM floating tablets were prepared by direct compression method. Drug, hydroxy propyl methyl cellulose K4M, lactose monohydrate and polyvinylpyrrolidone K30 constitute controlled release layer components and floating layer components includes polymers and sodium bicarbonate. The prepared tablets were evaluated for physicochemical parameters such as hardness, friability, weight variation, thickness, floating lag time (FLT), floating time, in vitro buoyancy study, in vitro release studies. The drug-polymer interaction was studied by fourier transform infrared and differential scanning calorimetry. Results and Discussion: The FLT of all the formulations were within the prescribed limits (<3 min). When ethyl cellulose was used as floating layer component, tablets showed good buoyancy effect but eroded within 6-8 h. Hence it was replaced with hydroxypropyl cellulose -M hydrophilic polymer, which showed good FLT and floating duration for 16 h. Formulation LFC4 was found to be optimized with dissolution profile of zero order kinetics showing fickian diffusion. A comparative study of bilayered and single layered tablets of LM showed a highest similarity factor of 83.03, difference factor of 2.74 and t-test (P < 0.05) indicates that there is no significant difference between them. Conclusion: Though bilayered tablet possess many advantages, single layered tablet would be economical, cost-effective and reproducible for large scale production in the industry. However, the results of present study demonstrated that the in vitro development of bilayered gastro retentive floating tablets with controlled drug release profile for LM is feasible. PMID:24167788

Anticonvulsants for fibromyalgia.

PubMed

Üçeyler, Nurcan; Sommer, Claudia; Walitt, Brian; Häuser, Winfried

2013-10-16

Fibromyalgia (FM) is a clinically well-defined chronic condition of unknown aetiology characterised by chronic widespread pain that often co-exists with sleep problems and fatigue. People often report high disability levels and poor health-related quality of life (HRQoL). Drug therapy focuses on reducing key symptoms and disability, and improving HRQoL. Anticonvulsants (antiepileptic drugs) are drugs frequently used for the treatment of chronic pain syndromes. To assess the benefits and harms of anticonvulsants for treating FM symptoms. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 8, 2013), MEDLINE (1966 to August 2013), PsycINFO (1966 to August 2013), SCOPUS (1980 to August 2013) and the reference lists of reviewed articles for published studies and www.clinicaltrials.gov (to August 2013) for unpublished trials. We selected randomised controlled trials of any formulation of anticonvulsants used for the treatment of people with FM of any age. Two review authors independently extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion. We included eight studies: five with pregabalin and one study each with gabapentin, lacosamide and levetiracetam. A total of 2480 people were included into anticonvulsants groups and 1099 people in placebo groups. The median therapy phase of the studies was 13 weeks. The amount and quality of evidence were insufficient to draw definite conclusions on the efficacy and safety of gabapentin, lacosamide and levetiracetam in FM. The amount and quality of evidence was sufficient to draw definite conclusions on the efficacy and safety of pregabalin in FM. Therefore, we focused on our interpretation of the evidence for pregabalin due to our greater certainty about its effects and its greater relevance to clinical practice. All pregabalin studies had a low risk of bias. Reporting a 50% or greater reduction in pain was more frequent with

Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breast feeding: a systematic review and network meta-analysis

PubMed Central

Veroniki, Areti Angeliki; Rios, Patricia; Cogo, Elise; Straus, Sharon E; Finkelstein, Yaron; Kealey, Ryan; Reynen, Emily; Soobiah, Charlene; Thavorn, Kednapa; Hutton, Brian; Hemmelgarn, Brenda R; Yazdi, Fatemeh; D'Souza, Jennifer; MacDonald, Heather; Tricco, Andrea C

2017-01-01

Objectives Compare the safety of antiepileptic drugs (AEDs) on neurodevelopment of infants/children exposed in utero or during breast feeding. Design and setting Systematic review and Bayesian random-effects network meta-analysis (NMA). MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched until 27 April 2017. Screening, data abstraction and quality appraisal were completed in duplicate by independent reviewers. Participants 29 cohort studies including 5100 infants/children. Interventions Monotherapy and polytherapy AEDs including first-generation (carbamazepine, clobazam, clonazepam, ethosuximide, phenobarbital, phenytoin, primidone, valproate) and newer-generation (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, vigabatrin) AEDs. Epileptic women who did not receive AEDs during pregnancy or breast feeding served as the control group. Primary and secondary outcome measures Cognitive developmental delay and autism/dyspraxia were primary outcomes. Attention-deficit hyperactivity disorder, language delay, neonatal seizures, psychomotor developmental delay and social impairment were secondary outcomes. Results The NMA on cognitive developmental delay (11 cohort studies, 933 children, 18 treatments) suggested that among all AEDs only valproate was statistically significantly associated with more children experiencing cognitive developmental delay compared with control (OR=7.40, 95% credible interval (CrI) 3.00 to 18.46). The NMA on autism (5 cohort studies, 2551 children, 12 treatments) suggested that oxcarbazepine (OR 13.51, CrI 1.28 to 221.40), valproate (OR 17.29, 95% CrI 2.40 to 217.60), lamotrigine (OR 8.88, CrI 1.28 to 112.00) and lamotrigine+valproate (OR 132.70, CrI 7.41 to 3851.00) were associated with significantly greater odds of developing autism compared with control. The NMA on psychomotor developmental delay (11 cohort studies, 1145 children, 18 treatments) found that valproate (OR 4.16, CrI 2.04 to 8

Antiepileptic effects of levetiracetam in a rodent neonatal seizure model.

PubMed

Talos, Delia M; Chang, Meayoung; Kosaras, Bela; Fitzgerald, Erin; Murphy, Andrew; Folkerth, Rebecca Dunn; Jensen, Frances E

2013-01-01

Neonatal seizures can result in chronic epilepsy and long-term behavioral and cognitive deficits. Levetiracetam (LEV), an antiepileptic drug that binds to the synaptic vesicle protein 2A (SV2A), has been increasingly used off-label for the therapy of neonatal seizures. Preclinical data regarding the acute or long-term efficacy of LEV are lacking. We tested the anticonvulsant efficacy of LEV in a rat model of hypoxia-induced neonatal seizures. In addition, we evaluated the protective effects of postnatal day (P)10 LEV treatment on later-life kainic acid (KA)-induced seizure susceptibility and seizure-induced neuronal injury. Western blot and immunohistochemistry were used to assess the developmental regulation of SV2A in the rat and human brain. LEV pretreatment at P10 significantly decreased the cumulative duration of behavioral and electrographic seizures at both 25 and 50 mg/kg. At P40, KA-induced seizures and neuronal loss were significantly diminished in rats previously treated with LEV. LEV target SV2A is present in both neonatal rat and human brain and increases steadily to adulthood. LEV suppressed acute seizures induced by perinatal hypoxia and diminished later-life seizure susceptibility and seizure-induced neuronal injury, providing evidence for disease modification. These results support consideration of a clinical trial of LEV in neonatal seizures.

Levetiracetam exhibits protective properties on rat Schwann cells in vitro.

PubMed

Stettner, Mark; Dehmel, Thomas; Mausberg, Anne K; Köhne, Angelika; Rose, Christine R; Kieseier, Bernd C

2011-09-01

Oxidative stress and inflammation represent pathways causing substantial damage to the peripheral nervous system. Levetiracetam (LEV) is a commonly used antiepileptic drug targeting high-voltage activated N-type calcium channels. Recent evidence suggests that LEV may also act as a histone deacetylase inhibitor, suggesting that this drug exhibits both anti-inflammatory and anti-oxidative effects, and as such may represent an interesting candidate for treating inflammatory diseases affecting the peripheral nerve. Therefore, we analysed the influence of LEV ex vivo on purified Schwann cells from neonatal P3 rats as well as on dorsal root ganglia prepared from E15 rat embryos. LEV diminished a lipopolysaccharide (LPS)-induced increase of the pro-inflammatory signature molecules tumour necrosis factor alpha, matrix metalloproteinase 9 (MMP-9), and caspase 6. Furthermore, LEV decreased LPS-induced cell death and protected cells against oxidative stress in a glutamate-based oxidative stress model. MMP-2 activity, usually elevated during myelination and repair, was also found to be up-regulated following LEV, while LEV exhibited no negative effects on myelination. Intracellular sodium or calcium concentrations were unaltered by LEV. Thus, LEV may be a promising, well-tolerated drug that - besides its antiepileptic potential - mediates anti-inflammatory, anti-oxidative, and anti-apoptotic properties that may potentially be useful in treating diseases of the peripheral nerve. © 2011 Peripheral Nerve Society.

Prolonged neurophysiologic effects of levetiracetam after oral administration in humans.

PubMed

Epstein, Charles M; Girard-Siqueira, Lhys; Ehrenberg, Joshua Andrew

2008-07-01

To determine whether neurophysiological effects of levetiracetam (LEV) outlast its serum half-life of approximately 7 h. Demonstration of prolonged effects would help to explain the efficacy of LEV at conventional dosing intervals that are longer than the serum half-life. Following an oral dose of LEV 3 g in 12 normal volunteers, we compared transcranial magnetic stimulation (TMS) measures of motor threshold (MT) and recruitment with LEV serum levels and subjective ratings of toxicity over 48 h. Subjects used a two-dimensional visual-analog scale to estimate the time course of any side effects. LEV serum levels and subjective toxicity both peaked around 1 h after oral administration. MT elevation was delayed in comparison to peak serum levels and subjective toxicity. MT was maximally elevated at 6-9 h, and recruitment maximally reduced at 0.6-9 h. Changes in both measures had recovered by approximately 50% at 24 h. Despite the time difference between toxicity and TMS changes, toxicity estimates correlated with the maximum increase in MT. There is a substantial time lag between LEV serum levels and TMS measures of neuronal effects, and a similar temporal dissociation between subjective toxicity and maximum TMS change. The time course of neurophysiological effects, as measured by TMS, may help to explain the sustained clinical efficacy of LEV despite a short peripheral half-life.

An Update on Maternal Use of Antiepileptic Medications in Pregnancy and Neurodevelopment Outcomes

PubMed Central

Gerard, Elizabeth E.; Meador, Kimford J.

2015-01-01

Antiepileptic drugs (AEDs) are prescribed commonly to women of childbearing age. In utero exposure to some AEDs can have significant cognitive and behavioral consequences for the unborn child. Recently, prospective studies of women taking AEDs during pregnancy have added significantly to our understanding of cognitive and behavioral teratogenic risks posed by fetal AED exposure. Valproate is clearly associated with impaired cognitive development as well as an increased risk of disorders such as autism and autism spectrum disorder. Exposure to carbamazepine, lamotrigine, levetiracetam, or phenytoin monotherapy is associated with more favorable cognitive and behavioral outcomes than valproate, but more data are required to clarify if these AEDs have more subtle effects on cognition and behavior. There are insufficient data on the developmental effects of other AEDs in humans. Further, the underlying mechanisms of cognitive teratogenesis are poorly understood, including the genetic factors that affect susceptibility to AEDs. PMID:27617120

Update on neuropathic pain treatment for trigeminal neuralgia

PubMed Central

Al-Quliti, Khalid W.

2015-01-01

Trigeminal neuralgia is a syndrome of unilateral, paroxysmal, stabbing facial pain, originating from the trigeminal nerve. Careful history of typical symptoms is crucial for diagnosis. Most cases are caused by vascular compression of the trigeminal root adjacent to the pons leading to focal demyelination and ephaptic axonal transmission. Brain imaging is required to exclude secondary causes. Many medical and surgical treatments are available. Most patients respond well to pharmacotherapy; carbamazepine and oxcarbazepine are first line therapy, while lamotrigine and baclofen are considered second line treatments. Other drugs such as topiramate, levetiracetam, gabapentin, pregabalin, and botulinum toxin-A are alternative treatments. Surgical options are available if medications are no longer effective or tolerated. Microvascular decompression, gamma knife radiosurgery, and percutaneous rhizotomies are most promising surgical alternatives. This paper reviews the medical and surgical therapeutic options for the treatment of trigeminal neuralgia, based on available evidence and guidelines. PMID:25864062

Chimeric Agents Derived from the Functionalized Amino Acid, Lacosamide, and the α-Aminoamide, Safinamide: Evaluation of Their Inhibitory Actions on Voltage-Gated Sodium Channels, and Antiseizure and Antinociception Activities and Comparison with Lacosamide and Safinamide

PubMed Central

2015-01-01

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. PMID:25418676

Chimeric agents derived from the functionalized amino acid, lacosamide, and the α-aminoamide, safinamide: evaluation of their inhibitory actions on voltage-gated sodium channels, and antiseizure and antinociception activities and comparison with lacosamide and safinamide.

PubMed

Park, Ki Duk; Yang, Xiao-Fang; Dustrude, Erik T; Wang, Yuying; Ripsch, Matthew S; White, Fletcher A; Khanna, Rajesh; Kohn, Harold

2015-02-18

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.

Levetiracetam in adult patients with and without learning disability: focus on behavioral adverse effects.

PubMed

Brodtkorb, Eylert; Klees, Theresa M; Nakken, Karl O; Lossius, Rasmus; Johannessen, Svein I

2004-04-01

Optimal antiepileptic drug treatment in patients with learning disability (LD) represents a particular challenge. These patients are often unable to report toxicity, and side effects may manifest as behavioral problems. The aim of this open study was to compare efficacy and tolerability of levetiracetam (LEV) in patients with LD and those without LD. One hundred eighty-four consecutive adult patients who received LEV were followed for an average of 8.1 months. Fifty-six patients (30%) had LD. Thirty-nine percent of patients with refractory epilepsy (37% with and 40% without LD) had > 50% seizure reduction. Significantly more behavioral side effects (23% vs 10%) and a tendency toward less reported somatic central nervous side effects were found in the LD group. We conclude that LEV is equally effective and well tolerated in both patients with LD and patients without LD. However, behavioral problems are more frequent in patients with LD, whereas the tendency toward seizure increase is not enhanced.

Challenges in the treatment of convulsive status epilepticus.

PubMed

Zaccara, Gaetano; Giannasi, Gianfranco; Oggioni, Roberto; Rosati, Eleonora; Tramacere, Luciana; Palumbo, Pasquale

2017-04-01

Convulsive status epilepticus (CSE) is a medical emergency associated with high mortality and morbidity. The most recent definition of CSE is a convulsive seizure lasting more than 5min or consecutive seizures without recovery of consciousness. In adults, for the treatment of the early stages of CSE, diazepam, lorazepam or midazolam are the most common treatments, although the choice of agent seems less important than rapid treatment. Midazolam, when administered intramuscularly (best evidence), buccally, or nasally, is effective and safe in the pre-hospital setting. The antiepileptic drugs, phenytoin, valproate, levetiracetam and, more recently lacosamide, are used in CSE that persists after first-line treatments (established CSE). Phenytoin is more difficult to administer and is less well tolerated. Evidence of the efficacy of lacosamide is scarce. Anaesthetics are the drugs of choice for the treatment of refractory CSE (not responding to second-line drugs). Midazolam seems to be the best tolerated and is the most often used drug, followed by propofol and thiopental (pentobarbital in the USA). A few studies indicate that ketamine is effective with the possible advantage that it can be co-administered with other anaesthetics, such as midazolam or propofol. CSE becomes super-refractory after more than 24h of appropriate treatments and may last weeks. Several anaesthetics have been proposed but evidence is scarce. Autoimmune refractory CSE has been recently identified, and early treatment with immuno-modulatory agents (corticosteroids and IV immunoglobulins and also second-line agents such as cyclophosphamide and rituximab followed by chronic immunosuppressive treatment) is now recommended by many experts. Copyright © 2017. Published by Elsevier Ltd.

Pharmacotherapy of focal epilepsy in children: a systematic review of approved agents.

PubMed

Arya, Ravindra; Glauser, Tracy A

2013-04-01

Partial-onset seizures contribute the bulk of seizure burden in childhood epilepsy. The therapeutic decision making involves consideration of factors specific to drug, patient and socioeconomic situation. This paper systematically reviews the available efficacy/effectiveness evidence for various anti-epileptic drugs (AED) as monotherapy and adjunctive therapy for partial-onset seizures in children. Relevant randomized clinical trials (RCTs) were identified by a structured PubMed search, supplemented by an additional hand search of reference lists and authors' files. Eligible studies were reviewed and data extracted into tables. Included RCTs were classified based on accepted published criteria. Only efficacy and effectiveness outcome measures were evaluated since there is little scientifically rigorous comprehensive AED adverse effects data. Oxcarbazepine is the only AED with Class I evidence for efficacy/effectiveness as initial monotherapy for partial-onset seizures in children. Carbamazepine, clobazam, lamotrigine, phenobarbital, phenytoin, topiramate, valproate, vigabatrin and zonisamide have, at best, Class III efficacy/effectiveness evidence for monotherapy of partial-onset seizures in children. For adjunctive therapy, gabapentin, lamotrigine, levetiracetam, oxcarbazepine and topiramate have Class I efficacy/effectiveness evidence for treatment of pediatric partial-onset seizures. This efficacy/effectiveness analysis must not be used in isolation when selecting therapy. AED selection for a specific child needs to integrate a drug's efficacy/effectiveness data with its safety and tolerability profile, pharmacokinetic properties, available formulations, and patient specific characteristics. It is critical that physicians and patients incorporate all these relevant variables when choosing AED therapy.

Clinical experience with generic levetiracetam in people with epilepsy

PubMed Central

Chaluvadi, Siresha; Chiang, Sharon; Tran, Larry; Goldsmith, Corey E.; Friedman, David E.

2015-01-01

SUMMARY Purpose To describe the clinical outcomes of a compulsory switch from branded to generic levetiracetam (LEV) among people with epilepsy (PWE) in an outpatient setting. Methods We conducted a retrospective chart review of 760 unduplicated consecutive adult patients attending a tertiary care epilepsy clinic at Ben Taub General Hospital. On November 1, 2008 hospital policy required all patients receiving branded LEV to be automatically switched to generic LEV. We calculated the proportion of patients switching back to branded LEV and reasons for the switch back. Key Findings Of the 260 patients (34%) being prescribed LEV (generic and brand name) during the study period, 105 (42.9%) were switched back to brand name LEV by their treating physicians. Reasons for switch back included increase in seizure frequency (19.6% vs. 1.6%; p < 0.0001) and adverse effects (AEs) (3.3%). AEs included headache, fatigue, and aggression. Patient age was associated with switchback when controlling for gender, epilepsy classification, and treatment characteristics [relative risk (RR) 2.44; 95% confidence interval (CI) 2.09–2.84; p < 0.05)]. An increase in seizure frequency subsequent to generic substitution was associated with polytherapy compared to monotherapy (3.225; 1.512–6.880; p < 0.05). Significance A significant proportion of patients in our cohort on generic LEV required switch back to the branded drug. Careful monitoring is imperative because a compulsory switch from branded to generic LEV may lead to poor clinical outcomes, with risk of AEs and increased seizure frequency. PMID:21426334

Influence of administration vehicles and drug formulations on the pharmacokinetic profile of lamotrigine in rats.

PubMed

Castel-Branco, M M; Figueiredo, I V; Falcão, A C; Macedo, T R A; Caramona, M M

2002-10-01

Given that administration vehicles and drug formulations can affect drug bioavailability, their influence on the pharmacokinetic profile of lamotrigine (LTG), a new-generation anti-epileptic drug, was studied in rats. Three different formulations administered intraperitoneally at a dose of 10 mg/kg were used: (1) LTG suspended in a 0.25% methylcelulose solution, (2) LTG dissolved in a 50% propylene glycol solution, and (3) LTG isethionate dissolved in distilled water. Plasma and brain homogenate levels were determined in order to evaluate vehicle-dependent drug absorption. The results demonstrated rapid absorption of LTG when it was administered as an aqueous solution, in contrast to a slower and more erratic absorption after the injection of either the lipophilic solution or the suspension. A plasma peak was achieved 15 min post-dose with the aqueous solution, with a brain peak being achieved 15 min later, while with the other formulations both plasma and brain homogenate peaks were reached 2 h after LTG administration. This study suggests that LTG isethionate dissolved in distilled water is the most suitable formulation for successful LTG pharmacokinetic studies in rats.

Lamotrigine Uses in Psychiatric Practice-Beyond Bipolar Prophylaxis a Hope or Hype?

PubMed

Naguy, Ahmed; Al-Enezi, Najah

2017-04-19

Lamotrigine (LAM), an antiepileptic, with panoply of indications and uses in neurology, is FDA approved, in psychiatry, for bipolar prophylaxis. Apart from this indication, trend of its use in psychiatry is on the rise addressing a multitude of disorders. LAM remains one of only few psychotropic drugs with antiglutamate activity. This might render LAM a potential therapeutic option in treatment-resistant major psychiatric disorders. We reviewed LAM pharmacology and its diverse indications while examining the extant evidence. EMBASE, Ovid MEDLINE, PubMed, Scopus, Web of Science, and Cochrane Database of Systemic Reviews were searched for all relevant studies up to date of June 2016. Sound evidence supports use of LAM for acute bipolar depression and prophylaxis, treatment-resistant schizophrenia, treatment-resistant obsessive-compulsive disorder, posttraumatic stress disorder, depersonalization disorder, and affective dysregulation and behavioral dyscontrol domains of borderline personality disorder. Less compelling evidence is present for use in behavioral and psychological symptoms of dementia and neuropsychiatric sequelae of traumatic brain injury. No evidence supports use in autism spectrum disorder or acute unipolar depression. LAM is an important addition to the psychopharmacological armamentarium. Level of evidence supporting the use of LAM in off-label indications is highly variable, and hence, sound clinical judgment is necessary for its proper use and placement in real-life psychiatric practice and psychopharmacotherapy algorithms.

Newer antiepileptic drugs in the treatment of status epilepticus: impact on prognosis.

PubMed

Jaques, Léonore; Rossetti, Andrea O

2012-05-01

Newer antiepileptic drugs (AEDs) are increasingly prescribed and seem to have a comparable efficacy as the classical AEDs; however, their impact on status epilepticus (SE) prognosis has received little attention. In our prospective SE database (2006-2010), we assessed the use of older versus newer AEDs (levetiracetam, pregabalin, topiramate, lacosamide) over time and its relationship to outcome (return to clinical baseline conditions, new handicap, or death). Newer AEDs were used more often toward the end of the study period (42% of episodes versus 30%). After adjustment for SE etiology, SE severity score, and number of compounds needed to terminate SE, newer AEDs were independently related to a reduced likelihood of return to baseline (p<0.001) but not to increased mortality. These findings seem in line with recent findings on refractory epilepsy. Also, in view of the higher price of the newer AEDs, well-designed, prospective assessments analyzing the impact of newer AEDs on efficacy and tolerability in patients with SE appear mandatory. Copyright © 2012 Elsevier Inc. All rights reserved.

Lacosamide protects striatal and hippocampal neurons from in vitro ischemia without altering physiological synaptic plasticity.

PubMed

Mazzocchetti, Petra; Tantucci, Michela; Bastioli, Guendalina; Calabrese, Valeria; Di Filippo, Massimiliano; Tozzi, Alessandro; Calabresi, Paolo; Costa, Cinzia

2018-06-01

Lacosamide ([(R)-2-acetamido-N-benzyl-3-methoxypropanamide], LCM), is an antiepileptic that exerts anticonvulsant activity by selectively enhancing slow sodium channel inactivation. By inhibiting seizures and neuronal excitability it might therefore be a good candidate to stabilize neurons and protect them from energetic insults. Using electrophysiological analyses, we have investigated in mice the possible neuroprotective effect of LCM against in vitro ischemia obtained by oxygen and glucose deprivation (ODG), in striatal and hippocampal tissues, two brain structures particularly susceptible to ischemic injury and of pivotal importance for different form of learning and memory. We also explored in these regions the influence of LCM on firing discharge and on long-term synaptic plasticity. We found that in both areas LCM reduced the neuronal firing activity in a use-dependent manner without influencing the physiological synaptic transmission, confirming its anticonvulsant effects. Moreover, we found that this AED is able to protect, in a dose dependent manner, striatal and hippocampal neurons from energy metabolism failure produced by OGD. This neuroprotective effect does not imply impairment of long-term potentiation of striatal and hippocampal synapses and suggests that LCM might exert additional beneficial therapeutic effects beyond its use as antiepileptic. Copyright © 2018 Elsevier Ltd. All rights reserved.

Intravenous lacosamide in seizure emergencies: Observations from a hospitalized in-patient adult population.

PubMed

d'Orsi, Giuseppe; Pascarella, Maria Grazia; Martino, Tommaso; Carapelle, Elena; Pacillo, Francesca; Di Claudio, Maria Teresa; Mancini, Daniela; Trivisano, Marina; Avolio, Carlo; Specchio, Luigi M

2016-11-01

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. Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

The Effectiveness of Lamotrigine and Its Blood Levels for Pediatric Epilepsy.

PubMed

Iwasaki, Toshiyuki; Toki, Taira; Nonoda, Yutaka; Ishii, Masahiro

This study was conducted to evaluate the effectiveness of lamotrigine (LTG) over 2 years and the usefulness of measuring its blood levels during the follow-up of patients with epilepsy. We measured peak blood LTG levels of 32 patients with epilepsy (9.16 ± 3.34 years old; mean ± SD). The blood levels were measured at 6 months, 1 year, and 2 years after reaching the LTG maintenance dosage. The effectiveness of LTG was evaluated to determine the seizure reduction rate. The patients were classified as effective cases (mean of own seizure reduction rates >50%) and ineffective cases (≤50%). The results were that the dosage and blood level showed positive correlations in the case of combination use with sodium valproate (VPA) (r = 0.690), carbamazepine and/or phenobarbital (r = 0.940), and others (r = 0.548). In several groups, the blood levels and efficacies did not show any positive correlations. In the cases of combination use with VPA, the blood levels of effective cases and ineffective cases were significantly different (P = 0.001). The optimal range was 8-11.5 μg/mL based on the average and SD values in the effective cases. No patients had any side effects. In conclusion, no precise definition of the therapeutic range was possible because of the incomplete correlation between the blood level and seizure frequency. We recommend the optimal range of LTG as a therapeutic target without any side effects, and it was established that the range in the combination with VPA was 8-11.5 μg/mL.

Conformational Preference and Spectroscopical Characteristics of the Active Pharmaceutical Ingredient Levetiracetam.

PubMed

Luchian, Raluca; Vinţeler, Emil; Chiş, Cosmina; Vasilescu, Mihai; Leopold, Nicolae; Prates Ramalho, João P; Chiş, Vasile

2017-12-01

The analysis of the possible conformers and the conformational change between solid and liquid states of a particular drug molecule are mandatory not only for describing reliably its spectroscopical properties but also for understanding the interaction with the receptor and its mechanism of action. Therefore, here we investigated the free-energy conformational landscape of levetiracetam (LEV) in gas phase as well as in water and ethanol, aiming to describe the 3-dimensional structure and energetic stability of its conformers. Twenty-two unique conformers were identified, and their energetic stability was determined at density functional theory B3LYP/6-31+G(2d,2p) level of theory. The 6 most stable monomers in water, within a relative free-energy window of 0.71 kcal mol -1 and clearly separated in energy from the remaining subset of 16 conformers, as well as the 3 most stable dimers were then used to compute the Boltzmann populations-averaged UV-Vis and NMR spectra of LEV. The conformational landscape in solution is distinctly different from that corresponding to gas phase, particularly due to the relative orientations of the butanamide group. Aiming to clarify the stability of the possible dimers of LEV, we also investigated computationally the structure of a set of 11 nonhydrated and hydrated homochiral hydrogen-bonded LEV dimers. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Potential role of anticonvulsants in the treatment of obsessive-compulsive and related disorders.

PubMed

Wang, Hee Ryung; Woo, Young Sup; Bahk, Won-Myong

2014-10-01

We reviewed the extant literature to evaluate the current evidence regarding the efficacy and safety of anticonvulsants in the treatment of obsessive-compulsive and related disorders. Relevant literature was accessed using the Cochrane database, embase and PubMed on 29 October 2013. Prospective studies examining the efficacy of anticonvulsants in obsessive-compulsive and related disorders were included. Case reports, case series, and retrospective studies were excluded. A total of 10 studies were included in this review. The studies of obsessive-compulsive disorder, except for two negative studies, showed favorable efficacy results of anticonvulsants. In one study on body dysmorphic disorder, levetiracetam showed favorable efficacy. In two lamotrigine studies for pathologic skin-picking, the efficacy findings were inconsistent. In one trichotillomania study, topiramate had reduced hair-pulling symptoms. Despite limited evidence, our review suggests that anticonvulsants have a potential role in the treatment of obsessive-compulsive and related disorders. © 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.

Changes in brain activation during working memory and facial recognition tasks in patients with bipolar disorder with Lamotrigine monotherapy.

PubMed

Haldane, Morgan; Jogia, Jigar; Cobb, Annabel; Kozuch, Eliza; Kumari, Veena; Frangou, Sophia

2008-01-01

Verbal working memory and emotional self-regulation are impaired in Bipolar Disorder (BD). Our aim was to investigate the effect of Lamotrigine (LTG), which is effective in the clinical management of BD, on the neural circuits subserving working memory and emotional processing. Functional Magnetic Resonance Imaging data from 12 stable BD patients was used to detect LTG-induced changes as the differences in brain activity between drug-free and post-LTG monotherapy conditions during a verbal working memory (N-back sequential letter task) and an angry facial affect recognition task. For both tasks, LGT monotherapy compared to baseline was associated with increased activation mostly within the prefrontal cortex and cingulate gyrus, in regions normally engaged in verbal working memory and emotional processing. Therefore, LTG monotherapy in BD patients may enhance cortical function within neural circuits involved in memory and emotional self-regulation.

A survey of antiepileptic drug responses identifies drugs with potential efficacy for seizure control in Wolf-Hirschhorn syndrome.

PubMed

Ho, Karen S; Markham, Leah M; Twede, Hope; Lortz, Amanda; Olson, Lenora M; Sheng, Xiaoming; Weng, Cindy; Wassman, E Robert; Newcomb, Tara; Wassman, E Robert; Carey, John C; Battaglia, Agatino

2018-04-01

Seizures are present in over 90% of infants and children with Wolf-Hirschhorn syndrome (WHS). When present, they significantly affect quality of life. The goal of this study was to use caregiver reports to describe the comparative efficacies of commonly used antiepileptic medications in a large population of individuals with WHS. A web-based, confidential caregiver survey was developed to capture seizure semiology and a chronologic record of seizure treatments as well as responses to each treatment. Adverse events for each drug were also cataloged. We received 141 complete survey responses (47% response rate) describing the seizures of individuals ranging in age from 4months to 61years (90 females: 51 males). Using the Early Childhood Epilepsy Severity Scale (E-Chess), WHS-associated seizures are demonstrably severe regardless of deletion size. The best-performing antiepileptic drugs (AEDs) for controlling seizures in this cohort were broad spectrum drugs clobazam, levetiracetam, and lamotrigine; whereas, the three commonly used carboxamide class drugs: carbamazepine, phenytoin, and oxcarbazepine, were reported to have little effect on, or even exacerbate, seizures. The carboxamide class drugs, along with phenobarbital and topiramate, were also associated with the highest rate of intolerance due to cooccurrence of adverse events. Levetiracetam, clobazam, and clonazepam demonstrated higher tolerability and comparatively less severe adverse events (Wilcoxon rank sum comparison between performance of levetiracetam and carboxamide class drugs gives a p<0.0001 after multiple comparison adjustment). This is the largest survey to date assessing WHS seizures. This study design is susceptible to possible bias, as the data are largely drawn from caregiver report and investigators had limited access to medical records. Despite this, our data suggest that the genetic etiology of seizures, together with an accurate electroclinical delineation, are important components of drug

New hybrid molecules with anticonvulsant and antinociceptive activity derived from 3-methyl- or 3,3-dimethyl-1-[1-oxo-1-(4-phenylpiperazin-1-yl)propan-2-yl]pyrrolidine-2,5-diones.

PubMed

Kamiński, Krzysztof; Zagaja, Mirosław; Rapacz, Anna; Łuszczki, Jarogniew J; Andres-Mach, Marta; Abram, Michał; Obniska, Jolanta

2016-02-15

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. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breast feeding: a systematic review and network meta-analysis.

PubMed

Veroniki, Areti Angeliki; Rios, Patricia; Cogo, Elise; Straus, Sharon E; Finkelstein, Yaron; Kealey, Ryan; Reynen, Emily; Soobiah, Charlene; Thavorn, Kednapa; Hutton, Brian; Hemmelgarn, Brenda R; Yazdi, Fatemeh; D'Souza, Jennifer; MacDonald, Heather; Tricco, Andrea C

2017-07-20

Compare the safety of antiepileptic drugs (AEDs) on neurodevelopment of infants/children exposed in utero or during breast feeding. Systematic review and Bayesian random-effects network meta-analysis (NMA). MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched until 27 April 2017. Screening, data abstraction and quality appraisal were completed in duplicate by independent reviewers. 29 cohort studies including 5100 infants/children. Monotherapy and polytherapy AEDs including first-generation (carbamazepine, clobazam, clonazepam, ethosuximide, phenobarbital, phenytoin, primidone, valproate) and newer-generation (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, vigabatrin) AEDs. Epileptic women who did not receive AEDs during pregnancy or breast feeding served as the control group. Cognitive developmental delay and autism/dyspraxia were primary outcomes. Attention-deficit hyperactivity disorder, language delay, neonatal seizures, psychomotor developmental delay and social impairment were secondary outcomes. The NMA on cognitive developmental delay (11 cohort studies, 933 children, 18 treatments) suggested that among all AEDs only valproate was statistically significantly associated with more children experiencing cognitive developmental delay compared with control (OR=7.40, 95% credible interval (CrI) 3.00 to 18.46). The NMA on autism (5 cohort studies, 2551 children, 12 treatments) suggested that oxcarbazepine (OR 13.51, CrI 1.28 to 221.40), valproate (OR 17.29, 95% CrI 2.40 to 217.60), lamotrigine (OR 8.88, CrI 1.28 to 112.00) and lamotrigine+valproate (OR 132.70, CrI 7.41 to 3851.00) were associated with significantly greater odds of developing autism compared with control. The NMA on psychomotor developmental delay (11 cohort studies, 1145 children, 18 treatments) found that valproate (OR 4.16, CrI 2.04 to 8.75) and carbamazepine+phenobarbital+valproate (OR 19.12, CrI 1.49 to 337.50) were associated with

Studies on induction of lamotrigine metabolism in transgenic UGT1 mice

PubMed Central

Argikar, U. A.; Senekeo-Effenberger, K.; Larson, E. E.; Tukey, R. H.; Remmel, R. P.

2010-01-01

A transgenic ‘knock-in’ mouse model expressing a human UGT1 locus (Tg-UGT1) was recently developed and validated. Although these animals express mouse UGT1A proteins, UGT1A4 is a pseudo-gene in mice. Therefore, Tg-UGT1 mice serve as a ‘humanized’ UGT1A4 animal model.Lamotrigine (LTG) is primarily metabolized to its N-glucuronide (LTGG) by hUGT1A4. This investigation aimed at examining the impact of pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor (PPAR) activators on LTG glucuronidation in vivo and in vitro. Tg-UGT1 mice were administered the inducers phenobarbital (CAR), pregnenolone-16α-carbonitrile (PXR), WY-14643 (PPAR-α), ciglitazone (PPAR-γ), or L-165041 (PPAR-β), once daily for 3 or 4 days. Thereafter, LTG was administered orally and blood samples were collected over 24 h. LTG was measured in blood and formation of LTGG was measured in pooled microsomes made from the livers of treated animals.A three-fold increase in in vivo LTG clearance was seen after phenobarbital administration. In microsomes prepared from phenobarbital-treated Tg-UGT1 animals, 13-fold higher CLint (Vmax/Km) value was observed as compared with the untreated transgenic mice. A trend toward induction of catalytic activity in vitro and in vivo was also observed following pregnenolone-16α-carbonitrile and WY-14643 treatment. This study demonstrates the successful application of Tg-UGT1 mice as a novel tool to study the impact of induction and regulation on metabolism of UGT1A4 substrates. PMID:19845433

Behavioral effects of antiepileptic drugs in rats: Are the effects on mood and behavior detectable in open-field test?

PubMed

Zimcikova, Eva; Simko, Julius; Karesova, Iva; Kremlacek, Jan; Malakova, Jana

2017-11-01

Behavioral side effects of antiepileptic drugs (AEDs) are common including both positive and negative effects on mood, anxiety, depression, and psychosis. We aimed to evaluate behavioral patterns in rats after administration of lamotrigine, levetiracetam, phenytoin, topiramate, carbamazepine, gabapentin, pregabalin, and zonisamide. The open-field test was performed and locomotion, rearing, grooming, central latency and defecation were recorded over a 5min interval for each rat (8 rats in each group receiving AED and 16 controls). Kruskal-Wallis nonparametric test or ANOVA were used to assess differences among the groups. The experimental groups did not differ in latency to enter the center compartment, neither in the decline of locomotor activity in the 1st and the 5th minute of the observation, nor in number of rears. Significant differences among groups were observed in the total number of lines crossed, grooming, as well in the number of fecal pellets. Locomotor activity was significantly increased in lamotrigine, if compared with gabapentin and pregabalin (ANOVA; p <0.05). Rats exposed to topiramate displayed a significantly increased number of grooming (when compared to pregabalin: p<0.01). Defecation (the number of fecal pellets) significantly increased in the gabapentin and carbamazepine group. There are significant differences between AEDs in terms of their behavioral profile. It is of great importance to evaluate these effects in clinical practice to bring more clear insight into these positive or negative side effects of AEDs. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Bicarbonate refractory QRS prolongation and left bundle-branch block following escitalopram and lamotrigine overdose: A case report and literature review of toxic left bundle-branch block.

PubMed

Farkas, A N; Marcott, M; Yanta, J H; Pizon, A F

2018-05-02

Toxic prolongation of the QRS interval most often results from blockade of cardiac voltage-gated sodium channels and manifests on electrocardiogram with a right bundle-branch block-like morphology. Rarely, a left bundle-branch block (LBBB) morphology has been reported. We report a case of transient LBBB resultant from ingestion of lamotrigine and citalopram which was refractory to sodium bicarbonate therapy and eventually resolved spontaneously. Cases of toxic LBBB are less likely to respond to bicarbonate therapy, suggesting that this finding is due to a mechanism other than sodium channel blockade. © 2018 John Wiley & Sons Ltd.

Seizures and epileptiform activity in the early stages of Alzheimer disease.

PubMed

Vossel, Keith A; Beagle, Alexander J; Rabinovici, Gil D; Shu, Huidy; Lee, Suzee E; Naasan, Georges; Hegde, Manu; Cornes, Susannah B; Henry, Maya L; Nelson, Alexandra B; Seeley, William W; Geschwind, Michael D; Gorno-Tempini, Maria L; Shih, Tina; Kirsch, Heidi E; Garcia, Paul A; Miller, Bruce L; Mucke, Lennart

2013-09-01

most commonly prescribed antiepileptics, treatment outcomes appeared to be better for lamotrigine and levetiracetam than for phenytoin. Common clinical features of patients with aMCI- or AD-associated epilepsy at our center included early age at onset of cognitive decline, early incidence of seizures in the disease course, unilateral temporal epileptic foci detected by serial/extended EEG, transient cognitive dysfunction, and good seizure control and tolerability with lamotrigine and levetiracetam. Careful identification and treatment of epilepsy in such patients may improve their clinical course.

Evaluation of levetiracetam effects on pilocarpine-induced seizures: cholinergic muscarinic system involvement.

PubMed

Oliveira, A A; Nogueira, C R A; Nascimento, V S; Aguiar, L M V; Freitas, R M; Sousa, F C F; Viana, G S B; Fonteles, M M F

2005-09-16

Levetiracetam (LEV) is a new antiepileptic drug effective as adjunctive therapy for partial seizures. It displays a unique pharmacological profile against experimental models of seizures, including pilocarpine-induced seizures in rodents. Aiming to clarify if anticonvulsant activity of LEV occurs due to cholinergic alterations, adult male mice received LEV injections before cholinergic agonists' administration. Pretreatment with LEV (30-200 mg/kg, i.p.) increased the latencies of seizures, but decreased status epilepticus and death on the seizure model induced by pilocarpine, 400 mg/kg, s.c. (P400). LEV (LEV200, 200 mg/kg, i.p.) pretreatment also reduced the intensity of tremors induced by oxotremorine (0.5 mg/kg, i.p). [3H]-N-methylscopolamine-binding assays in mice hippocampus showed that LEV200 pretreatment reverts the downregulation on muscarinic acetylcholine receptors (mAChR), induced by P400 administration, bringing back these density values to control ones (0.9% NaCl, i.p.). However, subtype-specific-binding assays revealed that P400- and LEV-alone treatments result in M1 and M2 subtypes decrease, respectively. The agonist-like behavior of LEV on the inhibitory M2 mAChR subtype, observed in this work, could contribute to explain the reduction on oxotremorine-induced tremors and the delay on pilocarpine-induced seizures, by an increase in the attenuation of neuronal activity mediated by the M1 receptors.

Severe Hypernatremic Dehydration and Lower Limb Gangrene in an Infant Exposed to Lamotrigine, Aripiprazole, and Sertraline in Breast Milk.

PubMed

Morin, Caroline; Chevalier, Isabelle

Hypernatremic dehydration is well described in exclusively breastfed neonates, although life-threatening complications are rarely reported. The present article describes a case of severe hypernatremic dehydration in a previously healthy term neonate. Other published cases of severe complications of hypernatremic dehydration are discussed. The exclusively breastfed neonate described had severe hypernatremic dehydration because of inadequate milk intake, with disseminated intravascular coagulation and right lower limb gangrene that required amputation of all five toes and surgical debridement of the metatarsals. The usual etiology of hypernatremic dehydration in this age group is insufficient breast milk intake. Here, the infant's mother was treated for bipolar disorder with lamotrigine 250 mg orally once daily, aripiprazole 15 mg orally once daily, and sertraline 100 mg orally once daily. Awareness of these complications should prompt close follow-up of the infant with poor weight gain. The role of maternal medication as a risk factor for hypernatremic dehydration among exclusively breastfed infants needs to be further explored.

Therapeutic Drug Monitoring of Lacosamide in Norway: Focus on Pharmacokinetic Variability, Efficacy and Tolerability.

PubMed

Svendsen, Torleiv; Brodtkorb, Eylert; Baftiu, Arton; Burns, Margrete Larsen; Johannessen, Svein I; Johannessen Landmark, Cecilie

2017-07-01

Lacosamide (LCM) is a new antiepileptic drug (AED). Experience from therapeutic drug monitoring (TDM) in clinical practice is limited. The purpose of this study is to evaluate the pharmacokinetic variability of LCM in relation to efficacy and tolerability in patients with refractory epilepsy in a real-life setting. Variables included age, gender, daily doses and serum concentrations of LCM and other AEDs from the TDM-database at the National Center for Epilepsy in Norway. Clinical data regarding efficacy and tolerability were collected from medical records. The Norwegian Prescription Database (NorPD) was used to include population-based numbers of users. TDM-data from 344 patients were included. The median dose, serum concentration, and concentration/dose (C/D)-ratio of LCM was 350 (range 25-700) mg/day, 19.7 (range 8.1-56.2) µmol/L, and 0.06 (0.02-0.82) µmol/L/mg, respectively. Serum concentrations were reduced by 28% by concomitant use of enzyme inducers and increased by 30% in patients aged >65 years. Efficacy and tolerability were assessed in 227 patients: 29% had >50% seizure reduction (eight seizure free), 30% had no effect, and 44% reported adverse effects. In Norway, there were on average 500 patients per year using LCM in this period based on NorPD. The study demonstrated pharmacokinetic variability and use of TDM of LCM in Norway. Data were collected from multiple sources for improved pharmacovigilance. Serum concentrations were influenced by enzyme inducers and ageing, indicating the usefulness of TDM. Effect and tolerability were favorable within a suggested reference range of 10-40 µmol/L given drug-fasting conditions.

Mechanism of sodium channel block by local anesthetics, antiarrhythmics, and anticonvulsants

PubMed Central

Tikhonov, Denis B.

2017-01-01

Local anesthetics, antiarrhythmics, and anticonvulsants include both charged and electroneutral compounds that block voltage-gated sodium channels. Prior studies have revealed a common drug-binding region within the pore, but details about the binding sites and mechanism of block remain unclear. Here, we use the x-ray structure of a prokaryotic sodium channel, NavMs, to model a eukaryotic channel and dock representative ligands. These include lidocaine, QX-314, cocaine, quinidine, lamotrigine, carbamazepine (CMZ), phenytoin, lacosamide, sipatrigine, and bisphenol A. Preliminary calculations demonstrated that a sodium ion near the selectivity filter attracts electroneutral CMZ but repels cationic lidocaine. Therefore, we further docked electroneutral and cationic drugs with and without a sodium ion, respectively. In our models, all the drugs interact with a phenylalanine in helix IVS6. Electroneutral drugs trap a sodium ion in the proximity of the selectivity filter, and this same site attracts the charged group of cationic ligands. At this position, even small drugs can block the permeation pathway by an electrostatic or steric mechanism. Our study proposes a common pharmacophore for these diverse drugs. It includes a cationic moiety and an aromatic moiety, which are usually linked by four bonds. PMID:28258204

Mechanism of sodium channel block by local anesthetics, antiarrhythmics, and anticonvulsants.

PubMed

Tikhonov, Denis B; Zhorov, Boris S

2017-04-03

Local anesthetics, antiarrhythmics, and anticonvulsants include both charged and electroneutral compounds that block voltage-gated sodium channels. Prior studies have revealed a common drug-binding region within the pore, but details about the binding sites and mechanism of block remain unclear. Here, we use the x-ray structure of a prokaryotic sodium channel, NavMs, to model a eukaryotic channel and dock representative ligands. These include lidocaine, QX-314, cocaine, quinidine, lamotrigine, carbamazepine (CMZ), phenytoin, lacosamide, sipatrigine, and bisphenol A. Preliminary calculations demonstrated that a sodium ion near the selectivity filter attracts electroneutral CMZ but repels cationic lidocaine. Therefore, we further docked electroneutral and cationic drugs with and without a sodium ion, respectively. In our models, all the drugs interact with a phenylalanine in helix IVS6. Electroneutral drugs trap a sodium ion in the proximity of the selectivity filter, and this same site attracts the charged group of cationic ligands. At this position, even small drugs can block the permeation pathway by an electrostatic or steric mechanism. Our study proposes a common pharmacophore for these diverse drugs. It includes a cationic moiety and an aromatic moiety, which are usually linked by four bonds. © 2017 Tikhonov and Zhorov.

Levetiracetam attenuates rotenone-induced toxicity: A rat model of Parkinson's disease.

PubMed

Erbaş, Oytun; Yılmaz, Mustafa; Taşkıran, Dilek

2016-03-01

Levetiracetam (LEV), a second-generation anti-epileptic drug, is used for treatment of both focal and generalized epilepsy. Growing body of evidence suggests that LEV may have neuroprotective effects. The present study was undertaken to investigate the neuroprotective effects of LEV on rotenone-induced Parkinson's disease (PD) in rats. Twenty-four adult Sprague-Dawley rats were infused with rotenone (3 μg/μl in DMSO) or vehicle (1 μl DMSO) into the left substantia nigra pars compacta (SNc) under stereotaxic surgery. PD model was assessed by rotational test ten days after drug infusion. The valid PD rats were randomly distributed into two groups; Group 1 (n=8) and Group 2 (n=8) were administered saline (1 ml/kg/day, i.p.) and LEV (600 mg/kg/day, i.p.) through 21 days, respectively. The effects of LEV treatment were evaluated by behavioral (rotation score), biochemical (brain homovalinic acid level and oxidant/antioxidant status) and immunohistochemical (tyrosine hydroxylase) parameters. Apomorphine-induced rotations in PD rats were significantly suppressed by LEV treatment. While unilateral rotenone lesion induced a dramatic loss of dopaminergic neurons both in the striatum and SNc, LEV treatment significantly attenuated the degenerative changes in dopaminergic neurons. Furthermore, LEV significantly decreased lipid peroxide levels, a marker of lipid peroxidation, and induced glutathione levels, catalase and superoxide dismutase activity in PD rats compared with saline group. We conclude that LEV may have beneficial effects on dopaminergic neurons against rotenone-induced injury. The underlying mechanism may be associated with the attenuation of oxidative stress. Copyright © 2016 Elsevier B.V. All rights reserved.

Treatment of Established Status Epilepticus.

PubMed

Falco-Walter, Jessica J; Bleck, Thomas

2016-04-25

Status epilepticus is the most severe form of epilepsy, with a high mortality rate and high health care costs. Status epilepticus is divided into four stages: early, established, refractory, and super-refractory. While initial treatment with benzodiazepines has become standard of care for early status epilepticus, treatment after benzodiazepine failure (established status epilepticus (ESE)) is incompletely studied. Effective treatment of ESE is critical as morbidity and mortality increases dramatically the longer convulsive status epilepticus persists. Phenytoin/fosphenytoin, valproic acid, levetiracetam, phenobarbital, and lacosamide are the most frequently prescribed antiseizure medications for treatment of ESE. To date there are no class 1 data to support pharmacologic recommendations of one agent over another. We review each of these medications, their pharmacology, the scientific evidence in support and against each in the available literature, adverse effects and safety profiles, dosing recommendations, and limitations of the available evidence. We also discuss future directions including the established status epilepticus treatment trial (ESETT). Substantial further research is urgently needed to identify these patients (particularly those with non-convulsive status epilepticus), elucidate the most efficacious antiseizure treatment with head-to-head randomized prospective trials, and determine whether this differs for convulsive vs. non-convulsive ESE.

Review and update of the Hong Kong Epilepsy Guideline on status epilepticus.

PubMed

Fung, E Lw; Fung, B Bh

2017-02-01

Convulsive status epilepticus is the most extreme form of seizure. It is a medical and neurological emergency that requires prompt and appropriate treatment. Treatment of convulsive status epilepticus is usually divided into stages/steps. The International League Against Epilepsy has released a new definition of status epilepticus that may help to unify the definition in future studies. Over the last few years new information has become available regarding its management. The Rapid Anticonvulsant Medication Prior to Arrival Trial demonstrated non-inferiority of intramuscular midazolam in early status epilepticus compared with intravenous lorazepam. Valproate and levetiracetam have also emerged as possible alternatives to phenytoin in established status epilepticus. The potential role of lacosamide in this stage of status epilepticus remains to be defined. The ongoing Established Status Epilepticus Treatment Trial may help to determine the most effective treatment for benzodiazepine-resistant status epilepticus. Management of refractory status epilepticus and super-refractory status epilepticus remains mostly non-evidence-based. Increasing recognition of a possible autoimmune aetiology has led to the use of immune-modulation in super-refractory status epilepticus. Ketamine is also increasingly used in this challenging condition. There are also reports of potential use of a ketogenic diet and magnesium.

Pediatric status epilepticus: improved management with new drug therapies?

PubMed

Verrotti, Alberto; Ambrosi, Michela; Pavone, Piero; Striano, Pasquale

2017-06-01

Status Epilepticus (SE) is the most common neurological emergency of childhood. It requires prompt administration of appropriately selected anti-seizure medications. Areas covered: Following a distinction between estabilished and emergent drugs, we present pharmacological treatment options and their clinical utility in children, with a short mention on alternatives to drug treatment. We also propose an algorithm for the management of pediatric SE. For this review a Pubmed, Medline and Embase search was performed. Expert opinion: In early SE in children, in the prehospital setting, rectal diazepam or buccal midazolam are efficacious drugs; whereas in the hospital setting, intravenous lorazepam or diazepam are indicated. As regard estabilished stage of SE, in addition to the 'classic' compounds, such as phenytoin and phenobarbital, other drugs such as valproic acid, levetiracetam and lacosamide have been demonstrated efficacious. Treatment recommendations of refractory SE depend on retrospective case series and uncontrolled studies. We reported experiences about the use of midazolam, propofol, ketamine and lidocaine. They could be a valid option, but further prospective studies are necessary. Over the last few decades, important advances in basic mechanisms underlying refractory SE have been achieved, but few data are available regarding management of these stages.

The effect of topiramate and lamotrigine on rat bone mass, structure and metabolism.

PubMed

Simko, Julius; Fekete, Sona; Gradosova, Iveta; Malakova, Jana; Zivna, Helena; Valis, Martin; Palicka, Vladimir; Zivny, Pavel

2014-05-15

There is only limited data concerning the effect of the newer antiepileptic drugs on bone. The objective of this study was to determine the effect of topiramate (TPM) and lamotrigine (LTG) monotherapy on bone mineral density (BMD), mineral content (BMC), bone markers, body composition and bone mechanical strength in the orchidectomized (ORX) rat model. 24 orchidectomized Wistar rats were divided into control and test groups, 8 rats in each group. The control rats received standard laboratory diet (SLD) while rats in the test group were fed with SLD enriched with LTG or TPM for 12 weeks. Dual energy X-ray absorptiometry was used to measure bone mineral density. The concentrations of bone metabolism markers were assayed in bone homogenate. In addition, both femurs were measured and used for biomechanical testing. Compared to the control group, both test groups had significantly lower weight, fat mass, whole body and femur BMD, BMC and reduced mechanical strength of bone. All of these changes were more pronounced in rats exposed to LTG. In conclusion, both LTG and TPM significantly reduce BMD and body weight and impair mechanical strength of bone. A question arises as to the degree of dependence of the effect on the dose. Further studies are warranted to establish whether LTG and TPM may have a clinically significant effect on BMD exclusively in the model of gonadectomized rats, or whether the effect applies also in the model of gonadally intact animals, and in the respective human models. Copyright © 2014 Elsevier B.V. All rights reserved.

Epilepsy phenotypes in siblings with Norrie disease.

PubMed

Okumura, Akihisa; Arai, Eisuke; Kitamura, Yuri; Abe, Shinpei; Ikeno, Mitsuru; Fujimaki, Takuro; Yamamoto, Toshiyuki; Shimizu, Toshiaki

2015-11-01

Norrie disease is an X-linked recessive disorder that is characterized by congenital blindness. Although epileptic seizures are observed in some patients with Norrie disease, little is known about this phenomenon. Here, we report the manifestation of epilepsy in siblings with Norrie disease to increase our knowledge of epilepsy in this condition. Three brothers with congenital blindness were diagnosed with Norrie disease after genetic analyses indicated the deletion of exon 2 of the NDP gene. The eldest brother had suffered from epileptic seizures since the age of 11years, and his seizures were resistant to antiepileptic drugs. Although the second brother had no epileptic seizures, the youngest sibling had experiences epileptic seizures since the age of 8years. His seizures were controlled using lamotrigine and levetiracetam. An electroencephalography (EEG) revealed epileptiform discharges in the occipital areas in all three brothers. A study of these patients will increase our knowledge of epilepsy in patients with Norrie disease. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

[Impact of early benefit assessment on patients with epilepsy in Germany: Current healthcare provision and therapeutic needs].

PubMed

Strzelczyk, A; Hamer, H M

2016-04-01

Epilepsy is one of the most common chronic neurological diseases and represents a significant burden for patients, their families and society. In more than 75 % of patients anticonvulsant therapy consists of valproate, carbamazepine, lamotrigine or levetiracetam. There is a need for polytherapy in drug-refractory patients and they suffer from negative effects on quality of life and employment that is associated with high indirect costs. To allow a comprehensive treatment in this patient group, access to new anticonvulsants with novel modes of action is needed; however, all applications for new antiepileptic drugs failed to prove added benefits during the Pharmaceutical Market Restructuring Act (AMNOG) in Germany. One of the main reasons is the mandatory definition of a standard comparative therapy. It remains unclear whether there will be studies in the future which will fulfill the requirements of the current version of AMNOG. Observational studies after approval and marketing of new antiepileptic drugs could be better alternatives to prove added benefits for individual patients in the current German healthcare system.

[Neurological Disorders and Pregnancy].

PubMed

Berlit, P

2016-02-01

Neurological disorders caused by pregnancy and puerperium include the posterior reversible encephalopathy syndrome, the amniotic fluid embolism syndrome (AFES), the postpartum angiopathy due to reversible vasoconstriction syndrome, and the Sheehan syndrome. Hypertension and proteinuria are the hallmarks of preeclampsia, seizures define eclampsia. Hemolysis, elevated liver enzymes and low platelets constitute the HELLP syndrome. Vision disturbances including cortical blindness occur in the posterior reversible encephalopathy syndrome (PRES). The Sheehan syndrome presents with panhypopituitarism post partum due to apoplexia of the pituitary gland in severe peripartal blood loss leading to longstanding hypotension. Some neurological disorders occur during pregnancy and puerperium with an increased frequency. These include stroke, sinus thrombosis, the restless legs syndrome and peripheral nerve syndromes, especially the carpal tunnel syndrome. Chronic neurologic diseases need an interdisciplinary approach during pregnancy. Some anticonvulsants double the risk of birth defects. The highest risk exists for valproic acid, the lowest for lamotrigine and levetiracetam. For MS interval treatment, glatiramer acetate and interferones seem to be safe during pregnancy. All other drugs should be avoided. © Georg Thieme Verlag KG Stuttgart · New York.

Does in utero exposure of antiepileptic drugs lead to failure to reach full cognitive potential?

PubMed

McCorry, D; Bromley, R

2015-05-01

A clinical scenario of a young female on 800 mg of sodium valproate (VPA) who has recently failed lamotrigine (LTG) and levetiracetam (LEV) and who is currently planning a pregnancy is presented. Currently available data pertaining to the longer-term development of children exposed to antiepileptic drugs (AEDs) are reviewed along with considerations around the methodology and interpretation of such research. There is an accumulation of data highlighting significant risks associated with prenatal exposed to VPA, with the level of risk being mediated by dose. The majority of published evidence does not find a significant risk associated with carbamazepine (CBZ) exposure in utero for global cognitive abilities however the evidence for more specific cognitive skills are unclear. Limited data indicate that LTG may be a preferred treatment to VPA in terms of foetal outcome but further evidence is required. Too little data pertaining to LEV exposure is available and a lack of evidence regarding risk of this and other new AEDs should not be interpreted as evidence of safety. Copyright © 2015. Published by Elsevier Ltd.

Unfavorable effect of levetiracetam on cultured hippocampal neurons after hyperthermic injury.

PubMed

Sendrowski, Krzysztof; Sobaniec, Piotr; Poskrobko, Elżbieta; Rusak, Małgorzata; Sobaniec, Wojciech

2017-06-01

The aim of this study was to examine the viability of neurons and the putative neuroprotective effects of second-generation antiepileptic drug, levetiracetam (LEV), on cultured hippocampal neurons injured by hyperthermia. Primary cultures of rat's hippocampal neurons at 7day in vitro (DIV) were incubated in the presence or absence of LEV in varied concentrations under hyperthermic conditions. Cultures were heated in a temperature of 40°C for 24h or in a temperature of 41°C for 6h. Flow cytometry with Annexin V/PI staining as well as fluorescent microscopy assay were used for counting and establishing neurons as viable, necrotic or apoptotic. Additionally, the release of lactate dehydrogenase (LDH) to the culture medium, as a marker of cell death, was evaluated. Assessment was performed after 9DIV and 10 DIV. Incubation of hippocampal cultures in hyperthermic conditions resulted in statistically significant increase in the number of injured neurons when compared with non-heated control cultures. Intensity of neuronal destruction was dependent on temperature-value. When incubation temperature 40°C was used, over 80% of the population of neurons remained viable after 10 DIV. Under higher temperature 41°C, only less than 60% of neurons were viable after 10 DIV. Both apoptotic and necrotic pathways of neuronal death induced by hyperthermia were confirmed by Annexin V/PI staining. LEV showed no neuroprotective effects in the current model of hyperthermia in vitro. Moreover, drug, especially when used in higher concentrations, exerted unfavorable intensification of aponecrosis of cultured hippocampal neurons. Copyright © 2017. Published by Elsevier Urban & Partner Sp. z o.o.

Antiepileptic drug prescribing patterns in Iraq and Afghanistan war veterans with epilepsy.

PubMed

Rohde, Natalie N; Baca, Christine B; Van Cott, Anne C; Parko, Karen L; Amuan, Megan E; Pugh, Mary Jo

2015-05-01

We examined patterns of antiepileptic drug (AED) use in a cohort of Iraq/Afghanistan war veterans (IAVs) who were previously identified as having epilepsy. We hypothesized that clinicians would be more likely to prescribe newer AEDs and would select specific AEDs to treat seizures based on patient characteristics including gender and comorbidities. From the cohort of IAVs previously identified with epilepsy between fiscal years 2009 and 2010, we selected those who received AEDs from the Veterans Health Administration in FY2010. Regimens were classified as monotherapy or polytherapy, and specific AED use was examine overall and by gender. Multivariable logistic regression examined associations of age; gender; race/ethnicity; medical, psychiatric, and neurological comorbidities; and receipt of neurology specialty care associated with the six most commonly used AEDs. Among 256,284 IAVs, 2123 met inclusion criteria (mean age: 33years; 89% men). Seventy-two percent (n=1526) received monotherapy, most commonly valproate (N=425) and levetiracetam (n=347). Sixty-one percent of those on monotherapy received a newer AED (levetiracetam, topiramate, lamotrigine, zonisamide, oxcarbazepine). Although fewer women than men received valproate, nearly 90% (N=45) were of reproductive age (≤45years). Antiepileptic drug prescribing patterns were associated with posttraumatic stress disorder, bipolar disorder, cerebrovascular disease, dementia/cognitive impairment, headache, and receipt of neurological specialty care (all p<0.01). In this cohort of veterans with epilepsy, most received AED monotherapy and newer AEDs. Prescribing patterns were different for men and women. The patterns observed between AEDs and neurological/psychiatric comorbidities suggest that clinicians are practicing rational prescribing. Copyright © 2015. Published by Elsevier Inc.

[Comparisons of efficacy and safety of levetiracetam versus phenytoin for seizure prophylaxis in patients with brain injury: a meta analysis].

PubMed

Li, J N; Chen, Y M

2016-10-25

Objective: To systematically review the efficacy, side effects and case-fatality rate of levetiracetam (LEV) versus phenytoin (PHT) for seizure prophylaxis of brain injured patients. Methods: Randomized controlled trials of high quality about LEV versus PHT in seizure prophylaxis of brain injured patients from 2000 to 2016 were collected according to the key word PHT, LEV, brain injury in PubMed, Medline, Ovid, Springer, CNKI, Wanfang data and so on. Valid data were extracted to conduct meta-analysis by RevMan 5.3 software according to inclusion and exclusion criteria. Results: A total of 13 English articles were finally included with 2 529 patients in total.Meta-analysis showed that no significant differences were observed in LEV versus PHT at preventing the occurrence of seizures ( RR =0.88, 95% CI : 0.61-1.27). No superiority of either drug at preventing early seizures ( RR =0.74, 95% CI : 0.42-1.27). As to the occurrence of late seizures, the differences of the two drugs were not statistically significant ( RR =0.71, 95% CI : 0.43-1.20). Number of patients with side effect was not statistically significantly different between the two groups ( RR =0.73, 95% CI : 0.48-1.11). But significant difference was found between LEV and PHT in discontinuation because of side effect ( RR =0.11, 95% CI : 0.06-0.23); no significant differences were noted in the case-fatality rate of patients received pretreatment between the two drugs ( RR =1.57, 95% CI : 0.92-2.67). There were no significant differences between the two groups in the length of stay ( WMD =-1.03, 95% CI : -4.97-2.91). Conclusions: LEV and PHT demonstrate equal efficacy in seizure prevention after brain injury. The differences are insignificant in the side effect, the case-fatality rate and the length of stay between LEV and PH treatment, but adverse drug reactions requiring change in therapy occur more in PHT. Phenytoin remains the first choice for seizure prevention after brain injury based on the existing

The effect of levetiracetam on rat bone mass, structure and metabolism.

PubMed

Fekete, Sona; Simko, Julius; Gradosova, Iveta; Malakova, Jana; Zivna, Helena; Palicka, Vladimir; Zivny, Pavel

2013-11-01

To determine the effect of levetiracetam (LEV) Lon bone mineral density (BMD), mineral content (BMC), bone markers, body composition and bone mechanical strength in the orchidectomised (ORX) rat model. 16 orchidectomised Wistar rats were divided into control and test groups, 8 rats in each group. The control rats received standard laboratory diet (SLD) while rats in the test group were fed with SLD enriched with LEV for 12 weeks. BMD was measured by dual energy X-ray absorptiometry at the whole body, lumbar spine and femur. Bone marker concentrations were examined of osteoprotegerin (OPG) and insulin-like growth factor 1 (IGF-1) in serum, and amino-terminal propeptide of procollagen type I (PINP), carboxy-terminal cross-linking telopeptide of type I collagen (CTX-I), bone alkaline phosphatase (ALPL), and bone morphogenetic protein 2 (BMP-2) in bone homogenate. The femurs were used for biomechanical testing. Compared to the control group we found lower fat mass, lower BMD in the area of the left femur, lower BMC in both femurs, a reduced concentration of OPG, and an increased concentration of CTX-I of borderline statistical significance (p=0.0661). Biomechanical parameters did not differ between groups. Significant loss of BMD or BMC was seen at the left and right femur area in the LEV group. Administration of LEV in the ORX-rat model significantly decreased levels of OPG (marker of bone formation) in serum and increased levels of CTX-I (marker of bone resorption) in bone homogenate, but results in this study did not reveal any change in biomechanical bone strength. Administration of LEV in the ORX-rat model may reduce adipose tissue. Further studies in animals and humans will be needed to confirm these findings. Copyright © 2013 Elsevier B.V. All rights reserved.

[Antiepileptic drug-induced osteopathy. Subtypes, pathogenesis, prevention, early diagnosis and treatment].

PubMed

Bartl, R

2007-07-29

Published reports of studies on the long-term effects of anti-epileptic drugs (AED) on bone--its density, thickness, vitamin D metabolism and risk of fracture--have shown considerable methodological inadequacies (34). Despite these problems it has been clearly shown that patients with epilepsy who are on anti-epileptic drugs have a greater than normal risk of bone loss, abnormal mineralization and fractures. A patient on long-term treatment with AED has a two- to three-fold risk of sustaining a fracture. On average 50% of patients (ranging from 4-70% in different studies [18]) have an osteopathy (34). Type, dosage and duration of AED treatment determine the exact picture of the osteopathy--regardless of whether or not they are enzyme-inducing. Among the enzyme-inducing drugs, especially phenytoin, primidone, phenobarbital and carbamezapine have been investigated for their influence on vitamin D metabolism. Bone loss has also been noted even without evidence of vitamin D deficiency. Mixed forms of osteoporosis and osteomalacia occur particularly often and must be taken into account in any differentiated form of treatment. But the question remains unanswered whether current AEDs, such as lamotrigine, gabapentin or levetiracetam will cause little or no osteopathy. Comparable to the situation during long-term systemic administration of glucocorticoids, initial diagnosis, including the inexpensive dual-energy X-ray absorptiometry (DXA) and the serum concentration of 25-hydroxyvitamin D, must be obtained to determine whether initially there are any bone changes. In addition to a differentiated and clearly defined treatment of osteopathy in a patient with epilepsy, the aim must be to minimize the tendency towards seizures and their severity. The annual cost of adequate vitamin D substitution is about EUR 50, while biphosphonate treatment costs about EUR 500; the costs of vertebral or forearm fractures are about EUR 1000 and those of hip fracture about EUR 15,000. These

Comparative safety of anti-epileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomes.

PubMed

Veroniki, Areti Angeliki; Cogo, Elise; Rios, Patricia; Straus, Sharon E; Finkelstein, Yaron; Kealey, Ryan; Reynen, Emily; Soobiah, Charlene; Thavorn, Kednapa; Hutton, Brian; Hemmelgarn, Brenda R; Yazdi, Fatemeh; D'Souza, Jennifer; MacDonald, Heather; Tricco, Andrea C

2017-05-05

Pregnant women with epilepsy frequently experience seizures related to pregnancy complications and are often prescribed anti-epileptic drugs (AEDs) to manage their symptoms. However, less is known about the comparative safety of AED exposure in utero. We aimed to compare the risk of congenital malformations (CMs) and prenatal outcomes of AEDs in infants/children who were exposed to AEDs in utero through a systematic review and Bayesian random-effects network meta-analysis. MEDLINE, EMBASE, and Cochrane CENTRAL were searched from inception to December 15, 2015. Two reviewers independently screened titles/abstracts and full-text papers for experimental and observational studies comparing mono- or poly-therapy AEDs versus control (no AED exposure) or other AEDs, then abstracted data and appraised the risk of bias. The primary outcome was incidence of major CMs, overall and by specific type (cardiac malformations, hypospadias, cleft lip and/or palate, club foot, inguinal hernia, and undescended testes). After screening 5305 titles and abstracts, 642 potentially relevant full-text articles, and 17 studies from scanning reference lists, 96 studies were eligible (n = 58,461 patients). Across all major CMs, many AEDs were associated with higher risk compared to control. For major CMs, ethosuximide (OR, 3.04; 95% CrI, 1.23-7.07), valproate (OR, 2.93; 95% CrI, 2.36-3.69), topiramate (OR, 1.90; 95% CrI, 1.17-2.97), phenobarbital (OR, 1.83; 95% CrI, 1.35-2.47), phenytoin (OR, 1.67; 95% CrI, 1.30-2.17), carbamazepine (OR, 1.37; 95% CrI, 1.10-1.71), and 11 polytherapies were significantly more harmful than control, but lamotrigine (OR, 0.96; 95% CrI, 0.72-1.25) and levetiracetam (OR, 0.72; 95% CrI, 0.43-1.16) were not. The newer generation AEDs, lamotrigine and levetiracetam, were not associated with significant increased risks of CMs compared to control, and were significantly less likely to be associated with children experiencing cardiac malformations than control

Discovery of Lacosamide Affinity Bait Agents That Exhibit Potent Voltage-Gated Sodium Channel Blocking Properties

PubMed Central

2012-01-01

Lacosamide ((R)-1) is a recently marketed, first-in-class, antiepileptic drug. Patch-clamp electrophysiology studies are consistent with the notion that (R)-1 modulates voltage-gated Na+ channel function by increasing and stabilizing the slow inactivation state without affecting fast inactivation. The molecular pathway(s) that regulate slow inactivation are poorly understood. Affinity baits are chemical reactive units, which when appended to a ligand (drug) can lead to irreversible, covalent modification of the receptor thus permitting drug binding site identification including, possibly, the site of ligand function. We describe, herein, the synthesis of four (R)-1 affinity baits, (R)-N-(4″-isothiocyanatobiphenyl-4′-yl)methyl 2-acetamido-3-methoxypropionamide ((R)-8), (S)-N-(4″-isothiocyanatobiphenyl-4′-yl)methyl 2-acetamido-3-methoxypropionamide ((S)-8), (R)-N-(3″-isothiocyanatobiphenyl-4′-yl)methyl 2-acetamido-3-methoxypropionamide ((R)-9), and (R)-N-(3″-acrylamidobiphenyl-4′-yl)methyl 2-acetamido-3-methoxypropionamide ((R)-10). The affinity bait compounds were designed to interact with the receptor(s) responsible for (R)-1-mediated slow inactivation. We show that (R)-8 and (R)-9 are potent inhibitors of Na+ channel function and function by a pathway similar to that observed for (R)-1. We further demonstrate that (R)-8 function is stereospecific. The calculated IC50 values determined for Na+ channel slow inactivation for (R)-1, (R)-8, and (R)-9 were 85.1, 0.1, and 0.2 μM, respectively. Incubating (R)-9 with the neuronal-like CAD cells led to appreciable levels of Na+ channel slow inactivation after cellular wash, and the level of slow inactivation only modestly decreased with further incubation and washing. Collectively, these findings have identified a promising structural template to investigate the voltage-gated Na+ channel slow inactivation process. PMID:23509982

Lacosamide efficacy and tolerability in clinical practice - Post marketing analysis from a single dedicated epilepsy center.

PubMed

Baker, Mark D; Abou-Khalil, Bassel W; Arain, Amir; Tummala, Pavan; Azar, Nabil J; Haas, Kevin F; Sonmezturk, Hasan H

2018-06-13

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. Copyright © 2018 Elsevier B.V. All rights reserved.

A simple, rapid and stability indicating validated method for quantification of lamotrigine in human plasma and dry plasma spot using LC-ESI-MS/MS: Application in clinical study.

PubMed

Namdev, Kuldeep Kumar; Dwivedi, Jaya; Chilkoti, Deepak Chandra; Sharma, Swapnil

2018-01-01

Lamotrigine (LTZ) is a phenyltriazine derivative which belongs to anti-epileptic drugs (AEDs) class and prescribed as mono- or adjunctive-therapy in treatment of epilepsy. Therapeutic drug monitoring (TDM) of AEDs provides a valid clinical tool in optimization of overall therapy. However, TDM is challenging due to the high biological samples (plasma/blood) storage/shipment costs and the limited availability of laboratories providing TDM services. Sampling in the form of dry plasma spot (DPS) or dry blood spot (DBS) are suitable alternative to overcome these issues. We developed and validated a new method for quantification of LTZ in human plasma and DPS. The extraction of LTZ from plasma and DPS was performed using liquid-liquid extraction with diethyl ether and an extraction solution composed of diethyl ether- methyl tert-butyl ether- acetone (50:30:20, v/v/v), respectively. Lamotrigine- 13C3, d3 was used as internal standard (ISTD) and the chromatographic separation was achieved on Hypurity Advance C18 column (150×4.6mm, 5μm). Quantitative estimation of LTZ and ISTD was performed on a liquid chromatography tandem mass spectrometer coupled with electrospray ionization interface operated under positive mode of ionization. Calibration curves were linear (r 2 >0.99) over the concentration range of 10-3020ng/mL for both plasma and DPS. Statistical analysis provides insignificant difference between LTZ concentration extracted from plasma and DPS samples. The method is found suitable for application in clinical study and in therapeutic monitoring of LTZ. To the best of our knowledge this is the first report which describing a validated stability indicating assay for quantification of LTZ in dry plasma spot. Copyright © 2017 Elsevier B.V. All rights reserved.

Identification and characterization of stress degradants of lacosamide by LC-MS and ESI-Q-TOF-MS/MS: development and validation of a stability indicating RP-HPLC method.

PubMed

Ramisetti, Nageswara Rao; Kuntamukkala, Ramakrishna; Lakshetti, Sridhar; Sripadi, Prabhakar

2014-07-01

The current study dealt with the degradation behavior of lacosamide (LAC) under ICH prescribed stress conditions. LAC was found to be labile under acid and base hydrolytic stress conditions, while it was stable to neutral hydrolytic, oxidative, photolytic and thermal stress. In total, seven degradation products (DPs) were formed, which were separated on a C18 column using a stability-indicating method. LC-MS analyses indicated that one of the DPs had the same molecular mass as that of the drug. Structural characterization of DPs was carried out using ESI-Q-TOF-MS/MS technique. The degradation pathways and mechanisms of degradation of the drug were delineated by carrying out the degradation in different co-solvents viz. methanol, deuterated methanol, ethanol, 1-propanol and acetonitrile. The developed LC method was validated for the determination of related substances and assay of LAC as per ICH guidelines. This study demonstrates a comprehensive approach of LAC degradation studies during its development phase. Copyright © 2014. Published by Elsevier B.V.

Levetiracetam versus lorazepam in status epilepticus: a randomized, open labeled pilot study.

PubMed

Misra, U K; Kalita, J; Maurya, P K

2012-04-01

For the management of status epilepticus (SE), lorazepam (LOR) is recommended as the first and phenytoin or fosphenytoin as the second choice. Both these drugs have significant toxicity. Intravenous levetiracetam (LEV) has become available, but its efficacy and safety has not been reported in comparison to LOR. We report a randomized, open labeled pilot study comparing the efficacy and safety of LEV and LOR in SE. Consecutive patients with convulsive or subtle convulsive SE were randomized to LEV 20 mg/kg IV over 15 min or LOR 0.1 mg/kg over 2-4 min. Failure to control SE within 10 min of administration of one study drug was treated by the other study drug. The primary endpoint was clinical seizure cessation and secondary endpoints were 24 h freedom from seizure, hospital mortality, and adverse events. Our results are based on 79 patients. Both LEV and LOR were equally effective. In the first instance, the SE was controlled by LEV in 76.3% (29/38) and by LOR in 75.6% (31/41) of patients. In those resistant to the above regimen, LEV controlled SE in 70.0% (7/10) and LOR in 88.9% (8/9) patients. The 24-h freedom from seizure was also comparable: by LEV in 79.3% (23/29) and LOR in 67.7% (21/31). LOR was associated with significantly higher need of artificial ventilation and insignificantly higher frequency of hypotension. For the treatment of SE, LEV is an alternative to LOR and may be preferred in patients with respiratory compromise and hypotension.

Effectiveness of intravenous levetiracetam as an adjunctive treatment in pediatric refractory status epilepticus.

PubMed

Kim, Jon Soo; Lee, Jeong Ho; Ryu, Hye Won; Lim, Byung Chan; Hwang, Hee; Chae, Jong-Hee; Choi, Jieun; Kim, Ki Joong; Hwang, Yong Seung; Kim, Hunmin

2014-08-01

Intravenous levetiracetam (LEV) has been shown to be effective and safe in treating adults with refractory status epilepticus (SE). We sought to investigate the efficacy and safety of intravenous LEV for pediatric patients with refractory SE. We performed a retrospective medical-record review of pediatric patients who were treated with intravenous LEV for refractory SE. Clinical information regarding age, sex, seizure type, and underlying neurological status was collected. We evaluated other anticonvulsants that were used prior to administration of intravenous LEV and assessed loading dose, response to treatment, and any adverse events from intravenous LEV administration. Fourteen patients (8 boys and 6 girls) received intravenous LEV for the treatment of refractory SE. The mean age of the patients was 4.4 ± 5.5 years (range, 4 days to 14.6 years). Ten of the patients were neurologically healthy prior to the refractory SE, and the other 4 had been previously diagnosed with epilepsy. The mean loading dose of intravenous LEV was 26 ± 4.6 mg/kg (range, 20-30 mg/kg). Seizure termination occurred in 6 (43%) of the 14 patients. In particular, 4 (57%) of the 7 patients younger than 2 years showed seizure termination. No immediate adverse events occurred during or after infusions. The current study demonstrated that the adjunctive use of intravenous LEV was effective and well tolerated in pediatric patients with refractory SE, even in patients younger than 2 years. Intravenous LEV should be considered as an effective and safe treatment option for refractory SE in pediatric patients.

Short-term effect of levetiracetam monotherapy on haematological parameters in children with epilepsy: a prospective study.

PubMed

Dinopoulos, Argiris; Attilakos, Achilleas; Paschalidou, Maria; Tsirouda, Maria; Garoufi, Anastasia; Moustaki, Maria; Siafakas, Nikos; Papaevangelou, Vassiliki

2014-05-01

Studies evaluating the effect of levetiracetam (LEV) on haematological parameters in patients with epilepsy are very limited. Clinical trials have also reported an unexplained increased incidence of pharyngitis and rhinitis in LEV-treated patients. The objective of this study was to evaluate prospectively the changes in haematological parameters in children treated with LEV monotherapy. White blood cell, neutrophils, lymphocytes, monocytes, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration and platelets were measured in 22 children (13 females, mean age 6.70±4.23 years) with epilepsy, before and after 2 and 6 months of LEV monotherapy. Lymphocyte count was significantly decreased at 6 months (p=0.019) of treatment and this effect was not dose dependent. One child (4.5%) at 2 months and four children (18%) at 6 months of treatment had lymphocyte count below 10th percentile for age. There were no significant alterations in the other parameters evaluated during the study. LEV monotherapy may significantly decrease lymphocyte count at six months of treatment in children with epilepsy. Further prospective studies are needed to investigate the effect of LEV on haematological parameters and the possible association with the higher incidence of infections reported in children receiving LEV. Copyright © 2014 Elsevier B.V. All rights reserved.

An Investigation into the Polymorphism and Crystallization of Levetiracetam and the Stability of its Solid Form.

PubMed

Xu, Kailin; Xiong, Xinnuo; Guo, Liuqi; Wang, Lili; Li, Shanshan; Tang, Peixiao; Yan, Jin; Wu, Di; Li, Hui

2015-12-01

Levetiracetam (LEV) crystals were prepared using different solvents at different temperatures. The LEV crystals were systematically characterized by X-ray powder diffraction (XRPD) and morphological analysis. The results indicated that many kinds of crystal habits exist in a solid form of LEV. To investigate the effects of LEV concentration, crystallization temperature, and crystallization type on crystallization and solid phase transformation of LEV, multiple methods were performed for LEV aqueous solution to determine if a new solid form exists in solid-state LEV. However, XRPD data demonstrate that the LEV solid forms possess same spatial arrangements that are similar to the original solid form. This result indicates that the LEV concentration, crystallization temperature, and crystallization type in aqueous solution have no influence on the crystallization and solid phase transformation of LEV. Moreover, crystallization by sublimation, melt cooling, and quench cooling, as well as mechanical effect, did not result in the formation of new LEV solid state. During melt cooling, the transformation of solid form LEV is a direct process from melting amorphous phase to the original LEV crystal phase, and the conversion rate is very quick. In addition, stability investigation manifested that LEV solid state is very stable under various conditions. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

The effect of age and comedication on lamotrigine clearance, tolerability, and efficacy.

PubMed

Arif, Hiba; Svoronos, Alexandra; Resor, Stanley R; Buchsbaum, Richard; Hirsch, Lawrence J

2011-10-01

To compare pharmacokinetics, tolerability, and efficacy of lamotrigine (LTG) in older versus younger adults. We studied 686 adult outpatients seen at our center over 5 years. We compared apparent clearance (CL) of LTG in the youngest (16-36 years; n = 247) and oldest (55-92 years; n = 155) tertiles. We analyzed one-year retention for younger and older adults newly started on LTG, frequency of adverse effects causing intolerability, and rates of specific adverse effects. We also investigated 6-month seizure freedom. Median LTG CL of older adults taking LTG in monotherapy was approximately 22% lower compared to younger adults (28.8 vs. 36.5 ml/h/kg; p < 0.001). LTG CL in older adults was lower compared to younger adults in patients on polytherapy and on polytherapy without enzyme inducers or valproate. One-year retention for LTG was comparable in older (78.1%, 121/155) and younger (72.4%, 179/247) adults. Intolerability to LTG was higher in older (34.8%) versus younger adults (24.2%; p = 0.005). Imbalance, drowsiness, and dizziness were common intolerable side effects in both groups. Older patients had higher rates of intolerability due to imbalance (16% vs. 4%), drowsiness (13% vs. 7%), and tremor (5% vs. 2%) compared with younger patients. Rates of 6-month seizure freedom were comparable, and small numbers of each group benefited from very high levels of LTG (>15 μg/ml). LTG CL in monotherapy in older adults is approximately 20% lower than in younger adults. For a given serum LTG level, older adults are twice as likely to have significant adverse effects compared to younger adults. Older patients are more likely to experience imbalance, drowsiness, and tremor than younger patients. Younger adults tolerate LTG better than older adults, but one-year retention is comparable. Some patients may benefit from high serum levels of LTG. Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

Population pharmacokinetics modeling of oxcarbazepine to characterize drug interactions in Chinese children with epilepsy

PubMed Central

Wang, Yang; Zhang, Hua-nian; Niu, Chang-he; Gao, Ping; Chen, Yu-jun; Peng, Jing; Liu, Mao-chang; Xu, Hua

2014-01-01

Aim: To develop a population pharmacokinetics model of oxcarbazepine in Chinese pediatric patients with epilepsy, and to study the interactions between oxcarbazepine and other antiepileptic drugs (AEDs). Methods: A total of 688 patients with epilepsy aged 2 months to 18 years were divided into model (n=573) and valid (n=115) groups. Serum concentrations of the main active metabolite of oxcarbazepine, 10-hydroxycarbazepine (MHD), were determined 0.5–48 h after the last dosage. A population pharmacokinetics (PPK) model was constructed using NLME software. This model was internally evaluated using Bootstrapping and goodness-of-fit plots inspection. The data of the valid group were used to calculate the mean prediction error (MPE), mean absolute prediction error (MAE), mean squared prediction error (MSE) and the 95% confidence intervals (95% CI) to externally evaluate the model. Results: The population values of pharmacokinetic parameters estimated in the final model were as follows: Ka=0.83 h-1, Vd=0.67 L/kg, and CL=0.035 L·kg−1·h−1. The enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital) and newer generation AEDs (levetiracetam, lamotrigine, topiramate) increased the weight-normalized CL value of MHD by 17.4% and 10.5%, respectively, whereas the enzyme-inhibiting AED valproic acid decreased it by 3%. No significant association was found between the CL value of MHD and the other covariates. For the final model, the evaluation results (95% CI) were MPE=0.01 (−0.07–0.10) mg/L, MAE=0.46 (0.40–0.51) mg/L, MSE=0.39 (0.27–0.51) (mg/L)2. Conclusion: A PPK model of OXC in Chinese pediatric patients with epilepsy is established. The enzyme-inducing AEDs and some newer generation AEDs (lamotrigine, topiramate) could slightly increase the metabolism of MHD. PMID:25220641

Treatment of Established Status Epilepticus

PubMed Central

Falco-Walter, Jessica J.; Bleck, Thomas

2016-01-01

Status epilepticus is the most severe form of epilepsy, with a high mortality rate and high health care costs. Status epilepticus is divided into four stages: early, established, refractory, and super-refractory. While initial treatment with benzodiazepines has become standard of care for early status epilepticus, treatment after benzodiazepine failure (established status epilepticus (ESE)) is incompletely studied. Effective treatment of ESE is critical as morbidity and mortality increases dramatically the longer convulsive status epilepticus persists. Phenytoin/fosphenytoin, valproic acid, levetiracetam, phenobarbital, and lacosamide are the most frequently prescribed antiseizure medications for treatment of ESE. To date there are no class 1 data to support pharmacologic recommendations of one agent over another. We review each of these medications, their pharmacology, the scientific evidence in support and against each in the available literature, adverse effects and safety profiles, dosing recommendations, and limitations of the available evidence. We also discuss future directions including the established status epilepticus treatment trial (ESETT). Substantial further research is urgently needed to identify these patients (particularly those with non-convulsive status epilepticus), elucidate the most efficacious antiseizure treatment with head-to-head randomized prospective trials, and determine whether this differs for convulsive vs. non-convulsive ESE. PMID:27120626

A highly sensitive and selective sensor based on a graphene-coated carbon paste electrode modified with a computationally designed boron-embedded duplex molecularly imprinted hybrid membrane for the sensing of lamotrigine.

PubMed

Wang, Hongjuan; Qian, Duo; Xiao, Xilin; Gao, Shuqin; Cheng, Jianlin; He, Bo; Liao, Lifu; Deng, Jian

2017-08-15

An innovative electrochemical sensor, based on a carbon paste electrode (CPE) modified with graphene (GR) and a boron-embedded duplex molecularly imprinted hybrid membrane (B-DMIHM), was fabricated for the highly sensitive and selective determination of lamotrigine (LMT). Density functional theory (DFT) was employed to study the interactions between the template and monomers to screen appropriate functional monomers for rational design of the B-DMIHM. The distinct synergic effect of GR and B-DMIHM was evidenced by the positive shift of the reduction peak potential of LMT at B-DMIHM/GR modified CPE (B-DMIHM/GR/CPE) by about 300mV, and the 13-fold amplification of the peak current, compared to a bare carbon paste electrode (CPE). The electrochemical reduction mechanism of lamotrigine was investigated by different voltammetric techniques. It was illustrated that square wave voltammetry (SWV) was more sensitive than different pulse voltammetry (DPV) for the quantitative analysis of LMT. Thereafter, a highly sensitive electroanalytical method for LMT was established by SWV at B-DMIHM/GR/CPE with a good linear relationship from 5.0×10 -8 to 5.0×10 -5 and 5.0×10 -5 to 3.0×10 -4 molL -1 with a lower detection limit (1.52×10 -9 molL -1 ) based on the lower linear range(S/N=3). The practical application of the sensor was demonstrated by determining the concentration of LMT in pharmaceutical and biological samples with good precision (RSD 1.04-4.41%) and acceptable recoveries (92.40-107.0%). Copyright © 2017 Elsevier B.V. All rights reserved.

Three-dimensional isobolographic analysis of interactions between lamotrigine and clonazepam in maximal electroshock-induced seizures in mice.

PubMed

Luszczki, Jarogniew J; Czuczwar, Stanislaw J

2004-11-01

The anticonvulsant effects of lamotrigine (LTG) and clonazepam (CZP) and combinations thereof against maximal electroshock (MES)-induced seizures in mice were investigated using three-dimensional (3D) isobolographic analysis. With this method, the doses of fixed-ratio combinations of the drugs (1:3, 1:1 and 3:1) that elicited 16, 50 and 84% of the maximum anticonvulsant effect were determined. Additionally, to evaluate the characteristics of interactions observed with 3D isobolography, the brain concentrations of both drugs were verified pharmacokinetically. The 3D isobolographic analysis showed that LTG and CZP combined at the fixed ratios of 3:1 and 1:1 interacted synergistically in the MES test for all anticonvulsant effects between 16% and 84% of maximum. In contrast, the combination of LTG and CZP at the fixed ratio of 1:3 showed only pure additivity for all estimated effects in 3D isobolography. Moreover, none of the examined antiepileptic drugs altered the brain concentrations of the coadministered drug, so the observed interactions in the MES test are of a pharmacodynamic nature. The 3D isobolographic findings suggest that in epilepsy therapy, increased efficacy of seizure control (synergistic interaction) might be achieved by using LTG and CZP in combination. In this study, some important problems and assumptions related to statistical analysis of data in 3D isobolography are discussed.

Results of Phase II Pharmacokinetic Study of Levetiracetam for Prevention of Posttraumatic Epilepsy

PubMed Central

Klein, Pavel; Herr, Daniel; Pearl, Phillip L.; Natale, JoAnne; Levine, Zachary; Nogay, Claude; Sandoval, Fabian; Trzcinsky, Stacey; Atabaki, Shireen M.; Tsuchida, Tammy; van den Anker, John; Soldin, Steven J.; He, Jianping; McCarter, Robert

2015-01-01

Levetiracetam (LEV) has anti-epileptogenic effects in animals and is a candidate for prevention of epilepsy after traumatic brain injury. Pharmacokinetics of LEV in TBI patients are unknown. We report pharmacokinetics of TBI subjects ≥6 years with high PTE risk treated with LEV 55 mg/kg/day orally, nasogastrically or intravenously for 30 days starting ≤8 hours after injury in a phase 2 safety and pharmacokinetic study. 41 subjects (26 adults, 15 children) were randomized to PK studies on treatment days 3 and 30. 36/41 randomized subjects underwent PK study on treatment day 3, and 24/41 subjects on day 30. On day 3, mean Tmax was 2.2 hours, Cmax 60.2 μg/ml and AUC 403.7 h*/μg/ml. Tmax was longer in the elderly than in children and non-elderly adults (5.96 h vs. 1.5 h and 1.8 h, p=0.0001). AUC was non-significantly lower in children compared with adults and the elderly (317.4 h*/μg/ml vs. 461.4 and 450.2, p=0.08). Cmax trended higher in i.v.- versus tablet- or n.g.-treated subjects (78.4 μg/ml vs. 59 and 48.2, p=0.07). AUC for n.g. and i.v. administrations were 79% and 88% of oral administration. There were no significant PK differences between days 3 and 30. Treatment of TBI patients with high PTE risk with 55 mg/kg/day LEV, a dose with antiepileptogenic effect in animals, results in plasma LEV levels comparable to those in animal studies. PMID:22771222

Tics and other stereotyped movements as side effects of pharmacological treatment.

PubMed

Madruga-Garrido, Marcos; Mir, Pablo

2013-01-01

Tics and other stereotyped abnormal movements can be seen as adverse effects of some pharmacologic drugs. Among these drugs, antipsychotics may provoke tardive syndromes after a chronic exposure, primarily in the case of typical antipsychotics. These syndromes include tardive tics, tardive dyskinesia, or tardive akathisia, which present with tics or stereotyped movements as a clinical phenomenon. Psychostimulants (mainly methylphenidate) have traditionally been associated with the appearance of tics due to the increased dopamine activity caused by stimulants. Nevertheless, in recent years, several studies have concluded not only that methylphenidate does not exacerbate or reactivate tics but also that tics can improve with its use in patients with associated attention deficit and hyperactivity disorder and tic disorder. Antiepileptic drugs, although infrequently, can also induce tics, with carbamazepine and lamotrigine described as tic inducers. Other antiepileptics, including levetiracetam and topiramate, have been proposed as a potential treatment for tic disorders due to a positive effect on tics, especially in those with associated epileptic disorder. Clinical and therapeutic approaches to tics and stereotyped movements after exposure to antipsychotics, stimulants, and antiepileptic drugs will be reviewed in this chapter. © 2013 Elsevier Inc. All rights reserved.

Challenges in the pharmacological management of epilepsy and its causes in the elderly.

PubMed

Ferlazzo, Edoardo; Sueri, Chiara; Gasparini, Sara; Aguglia, Umberto

2016-04-01

Epilepsy represents the third most common neurological disorders in the elderly after cerebrovascular disorders and dementias. The incidence of new-onset epilepsy peaks in this age group. The most peculiar aetiologies of late-onset epilepsy are stroke, dementia, and brain tumours. However, aetiology remains unknown in about half of the patients. Diagnosis of epilepsy may be challenging due to the frequent absence of ocular witnesses and the high prevalence of seizure-mimics (i.e. transient ischemic attacks, syncope, transient global amnesia or vertigo) in the elderly. The diagnostic difficulties are even greater when patients have cognitive impairment or cardiac diseases. The management of late-onset epilepsy deserves special considerations. The elderly can reach seizure control with low antiepileptic drugs (AEDs) doses, and seizure-freedom is possible in the vast majority of patients. Pharmacological management should take into account pharmacokinetics and pharmacodynamics of AEDs and the frequent occurrence of comorbidities and polytherapy in this age group. Evidences from double-blind and open-label studies indicate lamotrigine, levetiracetam and controlled-release carbamazepine as first line treatment in late-onset epilepsy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Juvenile myoclonic epilepsy and narcolepsy: A series of three cases.

PubMed

Joshi, Puja Aggarwal; Poduri, Annapurna; Kothare, Sanjeev V

2015-10-01

This paper sets out to demonstrate the coexistence of juvenile myoclonic epilepsy (JME) and narcolepsy that raises the possibility of a shared genetic predisposition to both conditions. The electronic medical records (EMRs) were searched for narcolepsy and JME over 10years. We identified three young adult women diagnosed with JME in their teenage years, with myoclonic, generalized tonic-clonic, and absence seizure semiologies, along with psychiatric comorbidity, well managed on lamotrigine and/or levetiracetam. Our patients were also found to have disturbed sleep preceding the diagnosis of JME by many years, including excessive daytime sleepiness (EDS), fragmented nocturnal sleep, hypnagogic vivid hallucinations, and REM behavior disorder along with daytime cataplexy. They were ultimately diagnosed with coexisting narcolepsy, confirmed by sleep studies and multiple sleep latency testing, along with positive genetic testing for HLA-DQB1*0602 in all three patients. Stimulants, selective serotonin receptor inhibitors, and/or sodium oxybate were used to successfully treat their narcolepsy. The coexistence of JME and narcolepsy has not been well recognized and may be clinically relevant. In addition, it raises the possibility of a shared genetic predisposition to both conditions. Copyright © 2015 Elsevier Inc. All rights reserved.

In utero exposure to levetiracetam vs valproate: development and language at 3 years of age.

PubMed

Shallcross, R; Bromley, R L; Cheyne, C P; García-Fiñana, M; Irwin, B; Morrow, J; Baker, G A

2014-01-21

To compare the cognitive and language development of children born to women with epilepsy (WWE) exposed in utero to levetiracetam (LEV) or sodium valproate (VPA) and control children born to women without epilepsy not taking medication during pregnancy. The children, aged between 36 and 54 months, were recruited from the United Kingdom and assessed using the Griffiths Mental Development Scales and the Reynell Language Development Scale. Maternal demographic and epilepsy information was also collected for use in statistical regression. This is an observational study with researchers not involved in the clinical management of the mothers enrolled. After controlling for confounding variables, children exposed to LEV in utero (n = 53) did not differ from unexposed control children (n = 131) on any scale administered. Children exposed to VPA (n = 44) in utero scored, on average, 15.8 points below children exposed to LEV on measures of gross motor skills (95% confidence interval [CI] -24.5 to -7.1, p < 0.001), 6.4 points below on comprehension language abilities (95% CI -11.0 to -1.8, p = 0.005), and 9.5 points below on expressive language abilities (95% CI -14.7 to -4.4, p < 0.001). The current study indicates that children exposed to LEV in utero were superior in their language and motor development in comparison to children exposed to VPA. This information should be used collaboratively between health care professionals and WWE when deciding on women's preferred choice of antiepileptic drug.

Lamotrigine blocks repeated high-dose methamphetamine-induced behavioral sensitization to dizocilpine (MK-801), but not methamphetamine in rats.

PubMed

Nakato, Yasuya; Abekawa, Tomohiro; Inoue, Takeshi; Ito, Koki; Koyama, Tsukasa

2011-10-24

We recently proposed a new psychostimulant animal model of the progressive pathophysiological changes of schizophrenia. Studies using that model produced a treatment strategy for preventing progression. Lamotrigine (LTG) blocks repeated high-dosage methamphetamine (METH)-induced initiation and expression of prepulse inhibition deficit and development of apoptosis in the medial prefrontal cortex (mPFC). Moreover, it inhibits METH-induced increases in extracellular glutamate levels in the mPFC (Nakato et al., 2011, Neurosci. Lett.). Abnormal behavior induced by METH or NMDA receptor antagonists is regarded as an animal model of schizophrenia. This study examined the effects of LTG on the development of behavioral sensitization to METH and cross-sensitization to dizocilpine (MK-801) by repeated administration of high-dose METH (2.5mg/kg, 10 times s.c.). Rats were injected repeatedly with LTG (30mg/kg) after 120min METH administration (2.5mg/kg). Repeated co-administration of LTG blocked the development of behavioral cross-sensitization to MK-801 (0.15mg/kg), but it did not prevent behavioral sensitization to METH (0.2mg/kg). The LTG-induced prevention of increased glutamate by high-dose METH might be related to the former finding. Combined results of our previous studies and this study suggest that LTG is useful to treat schizophrenia, especially at a critical point in its progression. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Managing epilepsy in women of childbearing age.

PubMed

Crawford, Pamela M

2009-01-01

Epilepsy affects the menstrual cycle, aspects of contraception, fertility, pregnancy and bone health in women. It is common for seizure frequency to vary throughout the menstrual cycle. In ovulatory cycles, two peaks can be seen around the time of ovulation and in the few days before menstruation. In anovulatory cycles, there is an increase in seizures during the second half of the menstrual cycle. There is also an increase in polycystic ovaries and hyperandrogenism associated with valproate therapy. There are no contraindications to the use of non-hormonal methods of contraception in women with epilepsy. Non-enzyme-inducing antiepileptic drugs (AEDs) [valproate, benzodiazepines, ethosuximide, levetiracetam, tiagabine and zonisamide] do not show any interactions with the combined oral contraceptive (OC). There are interactions between the combined OC and hepatic microsomal-inducing AEDs (phenytoin, barbiturates, carbamazepine, topiramate [dosages>200 mg/day], oxcarbazepine) and lamotrigine. Pre-conception counselling should be available to all women with epilepsy who are considering pregnancy. Women with epilepsy should be informed about issues relating to the future pregnancy, including methods and consequences of prenatal screening, fertility, genetics of their seizure disorder, teratogenicity of AEDs, folic acid and vitamin K supplements, labour, breast feeding and care of a child. During pregnancy, the lowest effective dose of the most appropriate AED should be used, aiming for monotherapy where possible. Recent pregnancy databases have suggested that valproate is significantly more teratogenic than carbamazepine, and the combination of valproate and lamotrigine is particularly teratogenic. Most pregnancies in women with epilepsy are without complications, and the majority of infants are delivered healthy with no increased risk of obstetric complications in women. There is no medical reason why a woman with epilepsy cannot breastfeed her child. The AED

Evaluating the longer-term cognitive effects of adjunctive perampanel compared to lacosamide in a naturalistic outpatient setting.

PubMed

Meschede, Carolin; Witt, Juri-Alexander; Rademacher, Michael; von Wrede, Randi D; Elger, Christian E; Helmstaedter, Christoph

2018-04-22

This retrospective longitudinal study aims to compare the longer-term cognitive and behavioral side effects of adjunctive antiepileptic treatment with perampanel (PER) and lacosamide (LCM), two third generation antiepileptic drugs with suggested favorable cognitive profiles. The two drugs were monitored according to a previously established routine diagnostic protocol (Helmstaedter et al. E&B 2013;26:182-7) which facilitates the retrospective comparison of antiepileptic drug tolerability in a naturalistic outpatient setting. Records from 94 patients were evaluated who underwent neuropsychological assessment before and under adjunctive treatment with either PER (n = 57) or LCM (n = 37). Cognition was assessed using the EpiTrack screening for executive functions and a VLMT short form for verbal memory. Subjective assessments included a German QOLIE-10 adaptation (quality of life) and an extended Adverse Events Profile (AEP). The median follow-up interval was 36 weeks. Multivariate repeated measures statistics revealed a non-significant trend towards an interaction effect "time - treatment arm" on both executive function and memory. When analyzed separately executive functions and memory scores significantly improved under LCM (t = -2.76 p < 0.01 and t = -2.44 p < 0.05 respectively). Subjectively, PER was associated with improvements in 2/18 physiological domains and in the LCM group 1/9 cognitive domains deteriorated. Seizure freedom was achieved for five patients treated with LCM (14%) and 15 treated with PER (26%, χ 2  = 2.2, n.s.). In a naturalistic outpatient setting, chronic adjunctive treatment with PER and LCM did not negatively affect cognition and LCM may even improve cognition. Neither drug increased self-reported irritability or aggression. This suggests favorable longer-term tolerability. Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Activity of the anticonvulsant lacosamide in experimental and human epilepsy via selective effects on slow Na+ channel inactivation.

PubMed

Holtkamp, Dominik; Opitz, Thoralf; Niespodziany, Isabelle; Wolff, Christian; Beck, Heinz

2017-01-01

In human epilepsy, pharmacoresistance to antiepileptic drug therapy is a major problem affecting ~30% of patients with epilepsy. Many classical antiepileptic drugs target voltage-gated sodium channels, and their potent activity in inhibiting high-frequency firing has been attributed to their strong use-dependent blocking action. In chronic epilepsy, a loss of use-dependent block has emerged as a potential cellular mechanism of pharmacoresistance for anticonvulsants acting on voltage-gated sodium channels. The anticonvulsant drug lacosamide (LCM) also targets sodium channels, but has been shown to preferentially affect sodium channel slow inactivation processes, in contrast to most other anticonvulsants. We used whole-cell voltage clamp recordings in acutely isolated cells to investigate the effects of LCM on transient Na + currents. Furthermore, we used whole-cell current clamp recordings to assess effects on repetitive action potential firing in hippocampal slices. We show here that LCM exerts its effects primarily via shifting the slow inactivation voltage dependence to more hyperpolarized potentials in hippocampal dentate granule cells from control and epileptic rats, and from patients with epilepsy. It is important to note that this activity of LCM was maintained in chronic experimental and human epilepsy. Furthermore, we demonstrate that the efficacy of LCM in inhibiting high-frequency firing is undiminished in chronic experimental and human epilepsy. Taken together, these results show that LCM exhibits maintained efficacy in chronic epilepsy, in contrast to conventional use-dependent sodium channel blockers such as carbamazepine. They also establish that targeting slow inactivation may be a promising strategy for overcoming target mechanisms of pharmacoresistance. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Efficacy of levetiracetam versus fosphenytoin for the recurrence of seizures after status epilepticus.

PubMed

Nakamura, Kensuke; Inokuchi, Ryota; Daidoji, Hiroaki; Naraba, Hiromu; Sonoo, Tomohiro; Hashimoto, Hideki; Tokunaga, Kurato; Hiruma, Takahiro; Doi, Kent; Morimura, Naoto

2017-06-01

Benzodiazepines are used as first-line treatments for status epilepticus. Fosphenytoin (FPHT) is recommended for second-line therapy; however, intravenous injection of levetiracetam (LEV) may also be effective against status epilepticus. Herein, we compared the efficacy and safety of LEV as a second-line treatment for status epilepticus with FPHT in Japanese patients.Patients with status epilepticus were selected from the database of the Emergency and Critical Care Center of Hitachi General Hospital. The subjects were patients whose status epilepticus was successfully stopped by diazepam, and in whom FPHT or LEV was administered after diazepam. As LEV injections recently became clinically available in Japan, the choice of drug was determined by the treatment period. Thus, 21 patients who were intravenously injected with LEV as a second-line therapy and 42 matched patients (historical controls) who were treated with FPHT (1:2) were selected.The subjects had a mean age of 64.0 ± 2.2 years, and included 48 males and 15 females. The status epilepticus control rates of the FPHT and LEV groups did not differ significantly (81.0% [34/42] vs 85.1% [18/21], respectively; P  =  .69). As for serious adverse events, a reduction in blood pressure was observed in the FPHT group, but not in the LEV group. The oral anticonvulsant switching rates of the 2 groups were similar, but the same-drug switching rates of the FPHT and LEV groups were 8.1% and 77.8%, respectively.The efficacy of intravenous LEV injections after status epilepticus was equivalent to that of FPHT, and the incidence of adverse events was lower in the LEV group. LEV is effective and safe at preventing recurrent seizures after status epilepticus following benzodiazepine treatment.

Retrospective analysis of the efficacy and tolerability of levetiracetam in brain tumor patients.

PubMed

Newton, Herbert B; Goldlust, Samuel A; Pearl, Dennis

2006-05-01

Seizures are a common complication of primary (PBT) and metastatic (MBT) brain tumors, affecting approximately 50% of all patients during the course of their illness. Anti-convulsant therapy of these tumor-induced seizures is often inadequate with conventional anti-epileptic drugs (AEDs), due to a variety of factors, including activation of glutaminergic NMDA receptors, immune-mediated neuronal damage, and anatomic alterations of neuronal input pathways. Levetiracetam (LEV) is a new AED with a novel mechanism of action, which includes reducing the Ca++ current through neuron-specific, high voltage activated Ca++ channels (n-type). Because of this unique mechanism, it has been postulated that LEV may be effective in controlling tumor-induced seizures. A retrospective chart review was performed of all patients who had received LEV for seizure control. Forty-one patients were reviewed (22 female, 19 male), with a median age of 47.5 years (range 25-81). There were 34 patients with PBT and 7 with MBT. LEV was used as an add-on AED in 33 patients and as monotherapy in eight patients, with a median dose of 1500 mg/day (range 500-3500). The baseline median seizure frequency for the cohort was 1 per week. After the addition of LEV and follow-up for a minimum of 4 weeks, the median seizure frequency was reduced to 0 per week (59% of patients noted complete seizure control). Overall, the seizure frequency was reduced in 90% of patients (P<0.0001; Sign test). The most common toxicity was somnolence, noted in 37% of patients. LEV was very effective and well tolerated in brain tumor patients with seizures, and should be considered for add-on therapy to current AEDs, or as a substitute anti-convulsant for monotherapy.

Lamotrigine in binge-eating disorder associated with bipolar II depression and treatment-resistant type 2 diabetes mellitus: a case report.

PubMed

Yamamoto, Tetsuya; Kanahara, Nobuhisa; Hirai, Aizan; Watanabe, Hiroyuki; Iyo, Masaomi

2013-01-01

Lamotrigine (LMG) is an anticonvulsant currently registered for the treatment of bipolar disorder (BP) depression. We report the case of a 61-year-old woman with comorbid binge-eating disorder (BED), BP depression, and treatment-resistant type 2 diabetes mellitus (T2DM), in which LMG showed significant efficacy against BED and BP depression and resulted in a drastic decrease in plasma glucose levels. The patient had had untreated BP depression, BED, and T2DM for more than 30 years. We prescribed LMG at 25 mg/d for BP depression and titrated it up to 50 mg/d over 4 weeks, then maintained this dose for the next 16 weeks. At follow-up after the first 4-week period, she reported a significant decrease in compulsive eating impulses and depressive mood, and her positive reports were consistent in the following months. Hemoglobin A1c levels at National Glycohemoglobin Standardization Program decreased drastically from 9.6% to 7.1% over the 20 weeks after initiating treatment. This case suggests that LMG might be beneficial for BED with concomitant BP depression, and potentially for treatment-resistant T2DM, if this refractoriness is identified to result from comorbidity of BED and BP.

Determination of Levetiracetam in Human Plasma by Dispersive Liquid-Liquid Microextraction Followed by Gas Chromatography-Mass Spectrometry

PubMed Central

2016-01-01

Levetiracetam (LEV) is an antiepileptic drug that is clinically effective in generalized and partial epilepsy syndromes. The use of this drug has been increasing in clinical practice and intra- or -interindividual variability has been exhibited for special population. For this reason, bioanalytical methods are required for drug monitoring in biological matrices. So this work presents a dispersive liquid-liquid microextraction method followed by gas chromatography-mass spectrometry (DLLME-GC-MS) for LEV quantification in human plasma. However, due to the matrix complexity a previous purification step is required. Unlike other pretreatment techniques presented in the literature, for the first time, a procedure employing ultrafiltration tubes Amicon® (10 kDa porous size) without organic solvent consumption was developed. GC-MS analyses were carried out using a linear temperature program, capillary fused silica column, and helium as the carrier gas. DLLME optimized parameters were type and volume of extraction and dispersing solvents, salt addition, and vortex agitation time. Under chosen parameters (extraction solvent: chloroform, 130 μL; dispersing solvent: isopropyl alcohol, 400 μL; no salt addition and no vortex agitation time), the method was completely validated and all parameters were in agreement with the literature recommendations. LEV was quantified in patient's plasma sample using less than 550 μL of organic solvent. PMID:27830105

Influence of uridine diphosphate glucuronosyltransferase inducers and inhibitors on the plasma lamotrigine concentration in pediatric patients with refractory epilepsy.

PubMed

Yamamoto, Yoshiaki; Takahashi, Yukitoshi; Imai, Katsumi; Ikeda, Hiroko; Takahashi, Masaaki; Nakai, Masahiko; Inoue, Yushi; Kagawa, Yoshiyuki

2015-06-01

This study evaluated the influence of concomitant antiepileptic drugs (AEDs) on the plasma concentration of lamotrigine (LTG) in pediatric patients with epilepsy. We retrospectively reviewed 1653 plasma samples from 709 patients (aged 6 months to 16 years) and compared the concentration-to-dose ratio (CD ratio) of LTG among different AED regimens. The median CD ratio of patients receiving LTG monotherapy was 1.25 μg/mL/mg/kg. In patients receiving LTG plus VPA, the CD ratio was increased by about 140%. The CD ratio was elevated from a low VPA concentration (<40 μg/mL) and the increase was VPA concentration-dependent. In contrast, the median CD ratio of patients treated with LTG plus the inducers phenytoin, phenobarbital, and carbamazepine was 0.42, 0.63, and 0.66, respectively, and phenytoin significantly reduced the CD ratio in comparison with phenobarbital or carbamazepine (p < 0.001). Pediatric patients of all ages beyond infancy showed similar susceptibility to VPA or inducers, but infants had higher CD ratios compared with the other age groups. Among other AEDs, topiramate, ethosuximide, and rufinamide reduced the CD ratio. These findings should be useful for estimating interactions between LTG and concomitant AEDs. Copyright © 2015 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

A common reference-based indirect comparison meta-analysis of eslicarbazepine versus lacosamide as add on treatments for focal epilepsy.

PubMed

Brigo, Francesco; Trinka, Eugen; Bragazzi, Nicola Luigi; Nardone, Raffaele; Milan, Alberto; Grillo, Elisabetta

2016-11-01

Eslicarbazepine acetate (ESL) and lacosamide (LCM) have recently emerged as add-on treatments in patients with focal epilepsy experiencing seizures despite adequate monotherapy. Both drugs enhance slow inactivation of voltage-gated sodium channels. To date no randomized controlled trial (RCT) has directly compared ESL with LCM as add-on treatments for focal epilepsy. Our aim was to indirectly compare the efficacy of ESL and LCM used as add-on treatments in patients with focal epilepsy using common reference-based indirect comparison meta-analysis. We systematically searched RCTs in which ESL or LCM has been used as add-on treatment in patients with focal epilepsy and compared with placebo. Following outcomes were considered: ≥50% reduction in seizure frequency; seizure freedom; treatment withdrawal for any reason; ≥25% increase in seizure frequency. Random-effects Mantel-Haenszel meta-analyses were performed to obtain odds ratios (ORs) for the efficacy of ESL or LCM versus placebo. Adjusted indirect comparisons were then made between ESL and LCM using the obtained results, and comparing the minimum and the highest effective recommended daily dose of each drug. Eight studies were included. Indirect comparisons adjusted for dose-effect showed no difference between ESL and LCM for responder rate, seizure freedom, and withdrawal rates. We could not assess increase in seizure frequency due to lack of data. Indirect comparisons failed to find a significant difference in efficacy between add-on ESL and LCM in patients with focal epilepsy. Direct head-to-head clinical trials comparing ESL with LCM as add-on antiepileptic treatment are required to confirm these results. Copyright © 2016 Elsevier B.V. All rights reserved.

Lacosamide in the treatment of patients with epilepsy and intellectual disabilities: A long-term study of 136 patients.

PubMed

Böttcher, Stefan; Lutz, Martin T; Mayer, Thomas

2017-10-01

This study aimed to analyze the retention rate of lacosamide (LCM) in patients with epilepsy and intellectual disabilities (IDs), to identify factors influencing retention rate, and to investigate the LCM retention rate with and without concomitant sodium channel blocker (SCB). We hypothesized that the retention rate of LCM with concomitant SCB would be lower than without SCB. Using the Kaplan-Meier estimator, we conducted a monocentric, retrospective, observational, open-label study to evaluate LCM retention rates in patients with IDs and drug-resistant epilepsy. In addition, the impact of therapy-related variables on the long-term retention of LCM was evaluated. One hundred thirty-six subjects with IDs and drug-resistant epilepsy were included (age 2-66 years); most patients had focal epilepsy. Long-term retention rates were 62.0% at 1 year, 43.7% at 2 years, and 29.1% at 3 and 4 years. Reasons for LCM discontinuation included insufficient therapeutic benefits (69%), adverse events (11%), or a combination of both factors (8%). The LCM retention rate was influenced by the number of background antiepileptic drugs (AEDs). An additional and independent influence of concomitant therapy with SCB on retention rate could not be confirmed. One of the major challenges in medically caring for patients with epilepsy and IDs is the high rate of drug resistance. However, there is a lack of evidence-based information about the efficacy and tolerability of AEDs in this population. It has been shown that concomitant SCB use is a key factor in increasing the risk of LCM failure in children with epilepsy. This finding has not been replicated in our predominantly adult sample of patients with IDs. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Novel Hybrid Anticonvulsants Derived from Pyrrolidine-2,5-dione Scaffold with Broad Spectrum of Activity in the Preclinical Studies.

PubMed

Kaminski, Krzysztof

2017-01-01

The multifunctional ligands application is an emerging approach in drug delivery, mainly in the treatment of diseases with complex pathology, such as Alzheimer's, cancer, and epilepsy. Using this method many biomolecules with different properties are combined to form a single unit that can provide a complex broad spectrum activity. Thus, a new type of hybrid anticonvulsants based on the pyrrolidine-2,5-dione frame are detailed with the aim of acquiring more effective antiepileptic drugs (AED) that could suppress various human convulsions. These hybrid molecules attach to the chemical particles of clinically relevant AEDs such as ethosuximide, levetiracetam, and lacosamide. As a result of this hybridization process the compounds obtained were effective in three most important animal epilepsy models, namely the maximal electroshock seizure (MES) test, the subcutaneous pentylenetetrazole (scPTZ) test, and the six-Hertz (6 Hz) model in mice. These substances displayed wider spectrum of protection, more potent efficacy, and better safety profile than the aforementioned AEDs. Several compounds were also active in the formalin model of persistent pain in mice. The in vitro ligand binding studies have proved that the most conceivable molecular mechanism of anticonvulsant and antinociceptive action was the influence on the neuronal voltage-sensitive sodium and L-type calcium channels. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Comparison of Levetiracetam Dosing Regimens in End-Stage Renal Disease Patients Undergoing Intermittent Hemodialysis.

PubMed

Shiue, Harn J; Taylor, Maria; Sands, Kara A

2017-10-01

Levetiracetam (LEV) is primarily renally eliminated. In end-stage renal disease (ESRD) patients on hemodialysis (HD), pharmacokinetic studies recommend daily dosing with 50% supplemental doses after 4-hour HD sessions. However, poor medication adherence after HD could result in fluctuating plasma drug levels. To compare two LEV dosing regimens, daily versus twice-daily (BID), in ESRD patients undergoing HD. Consecutive ESRD patients (April 2013 to May 2014) receiving maintenance inpatient HD and prescribed LEV prior to admission to our academic tertiary hospital were prospectively analyzed. Demographics, initial lab values, adverse reactions, seizures, and LEV regimens were recorded. LEV levels were obtained pre-HD and post-HD along with levels after receiving post-HD doses. Recovery of plasma levels after HD was assessed by comparison of levels predialysis versus postdialysis and post-HD doses. We identified 22 patients who met inclusion criteria; 14 BID and 8 daily dosing. Mean predialysis, postdialysis, and post-HD dose plasma levels were higher in patients receiving LEV BID compared with daily (43.1 ± 6.3, 19.4 ± 5.2, 34.9 ± 4.3 vs 21.1 ± 3.9, 6.9 ± 1.5, 11.9 ± 1.7 µg/mL; P < 0.05). BID post-HD levels were 41.9 ± 4.6% of predialysis levels versus 36.9 ± 7.3% with daily dosing ( P = 0.275). Post-HD dose levels were 81.4±4.3% of predialysis on LEV BID versus 65.7 ± 8.8% on LEV daily ( P = 0.045). No seizures were reported during hospital admission in either group. Compared to LEV daily, BID dosing achieved significantly higher levels and a better recovery to predialysis levels. Although limited by small numbers, a similar relationship between postdialysis levels was not detected.

Non-health care facility anticonvulsant medication errors in the United States.

PubMed

DeDonato, Emily A; Spiller, Henry A; Casavant, Marcel J; Chounthirath, Thitphalak; Hodges, Nichole L; Smith, Gary A

2018-06-01

This study provides an epidemiological description of non-health care facility medication errors involving anticonvulsant drugs. A retrospective analysis of National Poison Data System data was conducted on non-health care facility medication errors involving anticonvulsant drugs reported to US Poison Control Centers from 2000 through 2012. During the study period, 108,446 non-health care facility medication errors involving anticonvulsant pharmaceuticals were reported to US Poison Control Centers, averaging 8342 exposures annually. The annual frequency and rate of errors increased significantly over the study period, by 96.6 and 76.7%, respectively. The rate of exposures resulting in health care facility use increased by 83.3% and the rate of exposures resulting in serious medical outcomes increased by 62.3%. In 2012, newer anticonvulsants, including felbamate, gabapentin, lamotrigine, levetiracetam, other anticonvulsants (excluding barbiturates), other types of gamma aminobutyric acid, oxcarbazepine, topiramate, and zonisamide, accounted for 67.1% of all exposures. The rate of non-health care facility anticonvulsant medication errors reported to Poison Control Centers increased during 2000-2012, resulting in more frequent health care facility use and serious medical outcomes. Newer anticonvulsants, although often considered safer and more easily tolerated, were responsible for much of this trend and should still be administered with caution.

The Use of Antiepileptic Drugs (AEDs) for the Treatment of Pediatric Aggression and Mood Disorders

PubMed Central

Munshi, Kaizad R.; Oken, Tanya; Guild, Danielle J.; Trivedi, Harsh K.; Wang, Betty C.; Ducharme, Peter; Gonzalez-Heydrich, Joseph

2010-01-01

Aggressive symptomatology presents across multiple psychiatric, developmental, neurological and behavioral disorders, complicating the diagnosis and treatment of the underlying pathology. Anti-Epileptic Drugs (AEDs) have become an appealing alternative in the treatment of aggression, mood lability and impulsivity in adult and pediatric populations, although few controlled trials have explored their efficacy in treating pediatric populations. This review of the literature synthesizes the available data on ten AEDs—valproate, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, topiramate, levetiracetam, zonisamide, gabapentin and tiagabine—in an attempt to assess evidence for the efficacy of AEDs in the treatment of aggression in pediatric populations. Our review revealed modest evidence that some of the AEDs produced improvement in pediatric aggression, but controlled trials in pediatric bipolar disorder have not been promising. Valproate is the best supported AED for aggression and should be considered as a first line of treatment. When monotherapy is insufficient, combining an AED with either lithium or an atypical anti-psychotic can result in better efficacy. Additionally, our review indicates that medications with predominately GABA-ergic mechanisms of action are not effective in treating aggression, and medications which decrease glutaminergic transmission tended to have more cognitive adverse effects. Agents with multiple mechanisms of action may be more effective. PMID:27713387

The Use of Antiepileptic Drugs (AEDs) for the Treatment of Pediatric Aggression and Mood Disorders.

PubMed

Munshi, Kaizad R; Oken, Tanya; Guild, Danielle J; Trivedi, Harsh K; Wang, Betty C; Ducharme, Peter; Gonzalez-Heydrich, Joseph

2010-09-10

Aggressive symptomatology presents across multiple psychiatric, developmental, neurological and behavioral disorders, complicating the diagnosis and treatment of the underlying pathology. Anti-Epileptic Drugs (AEDs) have become an appealing alternative in the treatment of aggression, mood lability and impulsivity in adult and pediatric populations, although few controlled trials have explored their efficacy in treating pediatric populations. This review of the literature synthesizes the available data on ten AEDs - valproate, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, topiramate, levetiracetam, zonisamide, gabapentin and tiagabine - in an attempt to assess evidence for the efficacy of AEDs in the treatment of aggression in pediatric populations. Our review revealed modest evidence that some of the AEDs produced improvement in pediatric aggression, but controlled trials in pediatric bipolar disorder have not been promising. Valproate is the best supported AED for aggression and should be considered as a first line of treatment. When monotherapy is insufficient, combining an AED with either lithium or an atypical anti-psychotic can result in better efficacy. Additionally, our review indicates that medications with predominately GABA-ergic mechanisms of action are not effective in treating aggression, and medications which decrease glutaminergic transmission tended to have more cognitive adverse effects. Agents with multiple mechanisms of action may be more effective.

Effects of antiepileptic drugs on attention as assessed by a five-choice serial reaction time task in rats.

PubMed

Shannon, Harlan E; Love, Patrick L

2005-12-01

Patients with epilepsy can have impaired cognitive abilities. Antiepileptic drugs (AEDs) may contribute to the cognitive deficits observed in patients with epilepsy, and have been shown to induce cognitive impairments in healthy individuals. However, there are few systematic data on the effects of AEDs on specific cognitive domains. We have previously evaluated a number of AEDs with respect to their effects on working memory. The purpose of the present study was to evaluate the effects of AEDs on attention as measured by five-choice serial reaction time behavior in nonepileptic rats. The GABA-related AEDs triazolam, phenobarbital, and chlordiazepoxide significantly disrupted performance by increasing errors of omission, whereas tiagabine, valproate, and gabapentin did not. The sodium channel blocker carbamazepine increased errors of omission at relatively high doses, whereas the sodium channel blockers phenytoin, topiramate, and lamotrigine were without significant effect. Levetiracetam had no effect on attention. The disruptions produced by triazolam, phenobarbital, chlordiazepoxide, and carbamazepine were similar in magnitude to the effects of the muscarinic cholinergic receptor antagonist scopolamine. The present results indicate that AEDs can disrupt attention, but there are differences among AEDs in the magnitude of the disruption in nonepileptic rats, with drugs that enhance GABA receptor function producing the most consistent disruption of attention.

Topiramate induced peripheral neuropathy: A case report and review of literature.

PubMed

Hamed, Sherifa Ahmed

2017-12-16

Drug-induced peripheral neuropathy had been rarely reported as an adverse effect of some antiepileptic drugs (AEDs) at high cumulative doses or even within the therapeutic drug doses or levels. We describe clinical and diagnostic features of a patient with peripheral neuropathy as an adverse effect of chronic topiramate (TPM) therapy. A 37-year-old woman was presented for the control of active epilepsy (2010). She was resistant to some AEDs as mono- or combined therapies (carbamazepine, sodium valproate, levetiracetam, oxcarbazepine and lamotrigine). She has the diagnosis of frontal lobe epilepsy with secondary generalization and has a brother, sister and son with active epilepsies. She became seizure free on TPM (2013-2017) but is complaining of persistent distal lower extremities paresthesia in a stocking distribution. Neurological examination revealed presence of diminished Achilles tendon reflexes, stocking hypesthesia and delayed distal latencies, reduced conduction velocities and amplitudes of action potentials of posterior tibial and sural nerves, indicating demyelinating and axonal peripheral neuropathy of the lower extremities. After exclusion of the possible causes of peripheral neuropathy, chronic TPM therapy is suggested as the most probable cause of patient's neuropathy. This is the first case report of topiramate induced peripheral neuropathy in the literature.

Eslicarbazepine and the enhancement of slow inactivation of voltage-gated sodium channels: a comparison with carbamazepine, oxcarbazepine and lacosamide.

PubMed

Hebeisen, Simon; Pires, Nuno; Loureiro, Ana I; Bonifácio, Maria João; Palma, Nuno; Whyment, Andrew; Spanswick, David; Soares-da-Silva, Patrício

2015-02-01

This study aimed at evaluating the effects of eslicarbazepine, carbamazepine (CBZ), oxcarbazepine (OXC) and lacosamide (LCM) on the fast and slow inactivated states of voltage-gated sodium channels (VGSC). The anti-epileptiform activity was evaluated in mouse isolated hippocampal slices. The anticonvulsant effects were evaluated in MES and the 6-Hz psychomotor tests. The whole-cell patch-clamp technique was used to investigate the effects of eslicarbazepine, CBZ, OXC and LCM on sodium channels endogenously expressed in N1E-115 mouse neuroblastoma cells. CBZ and eslicarbazepine exhibit similar concentration dependent suppression of epileptiform activity in hippocampal slices. In N1E-115 mouse neuroblastoma cells, at a concentration of 250 μM, the voltage dependence of the fast inactivation was not influenced by eslicarbazepine, whereas LCM, CBZ and OXC shifted the V0.5 value (mV) by -4.8, -12.0 and -16.6, respectively. Eslicarbazepine- and LCM-treated fast-inactivated channels recovered similarly to control conditions, whereas CBZ- and OXC-treated channels required longer pulses to recover. CBZ, eslicarbazepine and LCM shifted the voltage dependence of the slow inactivation (V0.5, mV) by -4.6, -31.2 and -53.3, respectively. For eslicarbazepine, LCM, CBZ and OXC, the affinity to the slow inactivated state was 5.9, 10.4, 1.7 and 1.8 times higher than to the channels in the resting state, respectively. In conclusion, eslicarbazepine did not share with CBZ and OXC the ability to alter fast inactivation of VGSC. Both eslicarbazepine and LCM reduce VGSC availability through enhancement of slow inactivation, but LCM demonstrated higher interaction with VGSC in the resting state and with fast inactivation gating. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effects of Oxcarbazepine and Levetiracetam on Calcium, Ionized Calcium, and 25-OH Vitamin-D3 Levels in Patients with Epilepsy.

PubMed

Aksoy, Duygu; Güveli, Betül Tekin; Ak, Pelin Doğan; Sarı, Hüseyin; Ataklı, Dilek; Arpacı, Baki

2016-02-29

The primary objective of the present study was to further elucidate the effects of oxcarbazepine (OXC) and levetiracetam (LEV) monotherapies on the bone health status of patients with epilepsy. This study included 48 patients who attended our epilepsy outpatient clinic, had a diagnosis of epilepsy, and were undergoing either OXC or LEV monotherapy and 42 healthy control subjects. The demographic and clinical features of the patients, including gender, age, onset of disease, daily drug dosage, and duration of disease, were noted. Additionally, the calcium, ionized calcium, and 25-OH vitamin-D3 levels of the participants were prospectively evaluated. The 25-OH vitamin-D3, calcium, and ionized calcium levels of the patients taking OXC were significantly lower than those of the control group. These levels did not significantly differ between the patients taking LEV and the control group, but there was a significant negative relationship between daily drug dose and ionized calcium levels in the LEV patients. In the present study, anti-epileptic drugs altered the calcium, ionized calcium, and 25-OH vitamin-D3 levels of epilepsy patients and resulted in bone loss, abnormal mineralization, and fractures. These findings suggest that the calcium, ionized calcium, and 25-OH vitamin-D3 levels of patients with epilepsy should be regularly assessed.

Levetiracetam Results in Increased and Decreased Alcohol Drinking with Different Access Procedures in C57BL/6J Mice

PubMed Central

Fish, Eric W.; Agoglia, Abigail E.; Krouse, Michael C.; Muller, R. Grant; Robinson, J. Elliott; Malanga, C.J.

2013-01-01

The antiepileptic, levetiracetam (LEV), has been investigated for the treatment of alcohol abuse. However, little is known about how LEV alters the behavioral effects of alcohol in laboratory animals. The acute effects of LEV on alcohol drinking by male C57BL/6J mice were investigated using two different drinking procedures, limited access (drinking-in-the-dark, or DID) and intermittent access (IA) drinking. In the first experiment (DID), mice had access to a single bottle containing alcohol or sucrose for four hours every-other day. In the second experiment (IA), mice had intermittent access to two bottles, one containing alcohol or sucrose and one containing water, for 24 h on Mon/Wed/Fri. In both experiments, mice were administered LEV (0.3 – 100 mg/kg i.p.) or vehicle 30 min before access to the drinking solutions. In the DID mice, LEV increased alcohol intake from 4.3 to 5.4 g/kg, while in the IA mice LEV decreased alcohol intake from 4.8 to 3.0 g/kg in the first 4 h of access and decreased 24 h alcohol intake from 20 g/kg to approximately 15 g/kg. These effects appear specific to alcohol, as LEV did not affect sucrose intake in either experiment. LEV appears to differentially affect drinking in animal models of moderate and heavier alcohol consumption. PMID:24322822

Intravenous Levetiracetam in the Rat Pilocarpine-Induced Status Epilepticus Model: Behavioral, Physiological and Histological Studies

PubMed Central

Zheng, Yi; Moussally, Jon; Cash, Sydney S.; Karnam, Havisha B.; Cole, Andrew J.

2010-01-01

Purpose Status epilepticus is a neurological emergency associated with neuronal injury, lasting behavioral disturbance, and a high rate of mortality. Intravenous levetiracetam (LEV), an antiepileptic drug approved to treat partial seizures, has recently been introduced. We sought to determine the effect of LEV administered intravenously in a chemoconvulsant model of status epilepticus. Methods We examined the effect of intravenous LEV in the rat lithium-pilocarpine model of status epilepticus. Ten or 30 minutes after the onset of behavioral status epilepticus, animals were treated with LEV (200–1200 mg/kg i.v.) administered in a single bolus. Behavioral responses were recorded. Selected animals had continuous EEG recording before, during and after the administration of LEV. Some animals were sacrificed 24 h after the experiment and processed for histochemical assessment of neuronal injury. Results When administered 30 minutes after the onset of behavioral epileptic seizures, transient attenuation of ictal behavior was observed in animals treated with 800 mg/kg or more of LEV. The duration of behavioral attenuation increased sharply as the dose rose to 1000 mg/kg or higher, from a mean of 4 minutes to 23.6 minutes. When administered 10 minutes after seizure onset, 400 mg/kg of LEV resulted in transient ictal behavioral attenuation, and higher doses caused relatively longer periods of attenuation. Pretreatment with LEV prior to pilocarpine also delayed the onset of seizures. EEG recordings, however, showed no significant attenuation of ictal discharge. By contrast, TUNEL staining demonstrated less neuronal injury in hippocampii and other limbic structures in animals that responded behaviorally to LEV. Conclusions Intravenous administration of LEV in a chemoconvulsant model of status epilepticus results in attenuation of behavioral manifestations of seizure discharge and in reduction of neuronal injury but does not significantly alter ictal discharge recorded by EEG

Intravenous levetiracetam in the rat pilocarpine-induced status epilepticus model: behavioral, physiological and histological studies.

PubMed

Zheng, Yi; Moussally, Jon; Cash, Sydney S; Karnam, Havisha B; Cole, Andrew J

2010-01-01

Status epilepticus is a neurological emergency associated with neuronal injury, lasting behavioral disturbance, and a high rate of mortality. Intravenous levetiracetam (LEV), an anti-epileptic drug approved to treat partial seizures, has recently been introduced. We sought to determine the effect of LEV administered intravenously in a chemoconvulsant model of status epilepticus. We examined the effect of intravenous LEV in the rat lithium-pilocarpine model of status epilepticus. Ten or 30 min after the onset of behavioral status epilepticus, animals were treated with LEV (200-1200 mg/kg i.v.) administered in a single bolus. Behavioral responses were recorded. Selected animals had continuous EEG recording before, during and after the administration of LEV. Some animals were sacrificed 24 h after the experiment and processed for histochemical assessment of neuronal injury. When administered 30 min after the onset of behavioral epileptic seizures, transient attenuation of ictal behavior was observed in animals treated with 800 mg/kg or more of LEV. The duration of behavioral attenuation increased sharply as the dose rose to 1000 mg/kg or higher, from a mean of 4-23.6 min. When administered 10 min after seizure onset, 400 mg/kg of LEV resulted in transient ictal behavioral attenuation, and higher doses caused relatively longer periods of attenuation. Pretreatment with LEV prior to pilocarpine also delayed the onset of seizures. EEG recordings, however, showed no significant attenuation of ictal discharge. By contrast, TUNEL staining demonstrated less neuronal injury in hippocampii and other limbic structures in animals that responded behaviorally to LEV. Intravenous administration of LEV in a chemoconvulsant model of status epilepticus results in attenuation of behavioral manifestations of seizure discharge and in reduction of neuronal injury but does not significantly alter ictal discharge recorded by EEG. Copyright 2009 Elsevier Ltd. All rights reserved.

Evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein.

PubMed

Wood, Martyn D; Gillard, Michel

2017-02-01

Brivaracetam (BRV) and levetiracetam (LEV) are effective antiepileptic drugs that bind selectively to the synaptic vesicle 2A (SV2A) protein. However, BRV differs from LEV in that it exhibits more potent and complete seizure suppression in animal models including in amygdala-kindled mice, where BRV afforded nearly complete seizure suppression. This raises the possibility that aside from potency differences, BRV and LEV may interact differently with the SV2A protein, which is not apparent in radioligand-binding competition studies. In this study, we used a recently identified SV2A allosteric modulator, UCB1244283, that appears to induce conformational changes in SV2A, to probe the binding properties of labeled BRV and LEV. Radioligand binding studies were carried out using [ 3 H]BRV and [ 3 H]LEV. Studies were performed in membranes from both recombinant cells expressing human SV2A protein and human brain tissue. The modulator increased the binding of both radioligands but by different mechanisms. For [ 3 H]BRV, the increase was driven mainly by an increase in affinity, whereas for [ 3 H]LEV, the increase was due to an increase in the number of apparent binding sites. Kinetic studies confirmed this differential effect. These studies suggest that LEV and BRV may act at different binding sites or interact with different conformational states of the SV2A protein. It is possible that some of the pharmacologic differences between BRV and LEV could be due to different interactions with the SV2A protein. © 2016 The Authors. Epilepsia published by Wiley Periodicals Inc. on behalf of International League Against Epilepsy.

Brand-to-generic levetiracetam switch in patients with epilepsy in a routine clinical setting.

PubMed

Markoula, Sofia; Chatzistefanidis, Dimitrios; Gatzonis, Stylianos; Siatouni, Anna; Siarava, Eleftheria; Verentzioti, Anastasia; Kyritsis, Athanassios P; Patsalos, Philip N

2017-05-01

The therapeutic equivalence of generic and brand antiepileptic drugs, based on studies performed on healthy volunteers, has been questioned. We compare, in a routine clinical setting, brand versus generic levetiracetam (LEV) bioequivalence in patients with epilepsy and also the clinical efficacy and tolerability of the substitution. A prospective, open-label, non-randomized, steady-state, multiple-dose, bioequivalence study was conducted in 12 patients with epilepsy (5 females), with a mean age of 38.4±16.2 years. Patients treated with the brand LEV (Keppra; UCB Pharma) were closely followed for a four-week period and subsequently switched to a generic LEV (Pharmaten) and followed for another four-week period. Blood samples were collected at the end of each 4-week period, during a dose interval for each formulation, for LEV concentration measurements by liquid chromatography mass spectrometry. Steady-state area under the curve (AUC) and peak plasma concentration (Cmax) data were subjected to conventional average bioequivalence analysis. Secondary clinical outcomes, including seizure frequency and adverse events, were recorded. Patients had epilepsy for a mean period of 14.1±10.6years and the mean daily LEV dose was 2583.3±763.7mg. The mean AUC±SD and Cmax±SD was 288.4±86.3(mg/L)h and 37.8±10.4mg/L respectively for brand LEV and 319.2±104.7(mg/L)h and 41.6±12.3mg/L respectively for the generic LEV. Statistic analysis showed no statistical significant difference in bioequivalence. Also, no change in seizures frequency and/or adverse events was recorded. In our clinical setting, generic LEV was determined to be bioequivalent to brand LEV. Furthermore, seizures frequency or/and adverse events were not affected upon switching from brand to generic LEV. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Guidelines for seizure management in palliative care: Proposal for an updated clinical practice model based on a systematic literature review.

PubMed

León Ruiz, M; Rodríguez Sarasa, M L; Sanjuán Rodríguez, L; Pérez Nieves, M T; Ibáñez Estéllez, F; Arce Arce, S; García-Albea Ristol, E; Benito-León, J

2017-02-27

Very little has been written on seizure management in palliative care (PC). Given this situation, and considering the forthcoming setting up of the Palliative Care Unit at our neurorehabilitation centre, the Clínica San Vicente, we decided to establish a series of guidelines on the use of antiepileptic drugs (AEDs) for handling seizures in PC. We conducted a literature search in PubMed to identify articles, recent manuals, and clinical practice guidelines on seizure management in PC published by the most relevant scientific societies. Clinical practice guidelines are essential to identify patients eligible for PC, manage seizures adequately, and avoid unnecessary distress to these patients and their families. Given the profile of these patients, we recommend choosing AEDs with a low interaction potential and which can be administered by the parenteral route, preferably intravenously. Diazepam and midazolam appear to be the most suitable AEDs during the acute phase whereas levetiracetam, valproic acid, and lacosamide are recommended for refractory cases and long-term treatment. These guidelines provide general recommendations that must be adapted to each particular clinical case. Nevertheless, we will require further well-designed randomised controlled clinical trials including large samples of patients eligible for PC to draft a consensus document recommending adequate, rational, and effective use of AEDs, based on a high level of evidence, in this highly complex area of medical care. Copyright © 2017 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.

Direct and indirect comparison meta-analysis of levetiracetam versus phenytoin or valproate for convulsive status epilepticus.

PubMed

Brigo, Francesco; Bragazzi, Nicola; Nardone, Raffaele; Trinka, Eugen

2016-11-01

The aim of this study was to conduct a meta-analysis of published studies to directly compare intravenous (IV) levetiracetam (LEV) with IV phenytoin (PHT) or IV valproate (VPA) as second-line treatment of status epilepticus (SE), to indirectly compare intravenous IV LEV with IV VPA using common reference-based indirect comparison meta-analysis, and to verify whether results of indirect comparisons are consistent with results of head-to-head randomized controlled trials (RCTs) directly comparing IV LEV with IV VPA. Random-effects Mantel-Haenszel meta-analyses to obtain odds ratios (ORs) for efficacy and safety of LEV versus VPA and LEV or VPA versus PHT were used. Adjusted indirect comparisons between LEV and VPA were used. Two RCTs comparing LEV with PHT (144 episodes of SE) and 3 RCTs comparing VPA with PHT (227 episodes of SE) were included. Direct comparisons showed no difference in clinical seizure cessation, neither between VPA and PHT (OR: 1.07; 95% CI: 0.57 to 2.03) nor between LEV and PHT (OR: 1.18; 95% CI: 0.50 to 2.79). Indirect comparisons showed no difference between LEV and VPA for clinical seizure cessation (OR: 1.16; 95% CI: 0.45 to 2.97). Results of indirect comparisons are consistent with results of a recent RCT directly comparing LEV with VPA. The absence of a statistically significant difference in direct and indirect comparisons is due to the lack of sufficient statistical power to detect a difference. Conducting a RCT that has not enough people to detect a clinically important difference or to estimate an effect with sufficient precision can be regarded a waste of time and resources and may raise several ethical concerns, especially in RCT on SE. Copyright © 2016 Elsevier Inc. All rights reserved.

Stability of Atenolol, Clonazepam, Dexamethasone, Diclofenac Sodium, Diltiazem, Enalapril Maleate, Ketoprofen, Lamotrigine, Penicillamine-D, and Thiamine in SyrSpend SF PH4 Oral Suspensions.

PubMed

Polonini, Hudson C; Loures, Sharlene; Lima, Luis Claudio; Ferreira, Anderson O; Brandão, Marcos Antônio F

2016-01-01

The objective of this study was to evaluate the stability of 10 commonly used active pharmaceutical ingredients compounded in oral suspensions using SyrSpend SF PH4 (atenolol 1.0 and 5.0 mg/mL, clonazepam 0.2 mg/mL, dexamethasone 1.0 mg/mL, diclofenac sodium 5.0 mg/mL, diltiazem 12.0 mg/mL, enalapril maleate 1.0 mg/mL, ketoprofen 20.0 mg/mL, lamotrigine 1.0 mg/mL, penicillamine-D 50.0 mg/mL, thiamine 100 mg/m) and stored both at controlled refrigerated (2°C to 8°C) and room temperature (20°C to 25°C). Stability was assessed by means of measuring percent recovery at varying time points throughout a 90-day period. The quantification of the active pharmaceutical ingredients was performed by a stability-indicating, high-performance liquid chromatographic method. The beyond-use date of the products was found to be at least 90 days for all suspensions (except atenolol 1 mg/mL, which was stable up to 60 days), both for controlled refrigerated temperature and room temperature. This confirms that SyrSpend SF PH4 is a stable suspending vehicle for compounding with a broad range of different active pharmaceutical ingredients.

Lacosamide modulates interictal spiking and high-frequency oscillations in a model of mesial temporal lobe epilepsy

PubMed Central

Behr, Charles; Lévesque, Maxime; Ragsdale, David; Avoli, Massimo

2016-01-01

Objective 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). Methods Sprague–Dawley rats (250–300 g) were injected with pilocarpine to induce a status epilepticus (SE) that was pharmacologically terminated after 1 h. Eight pilocarpine-treated rats were then injected with LCM (30 mg/kg, i.p.) 4 h 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. Results 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. Significance 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

Long-term efficacy and safety of lamotrigine monotherapy in Japanese and South Korean pediatric patients with newly diagnosed typical absence seizures: An open-label extension study.

PubMed

Yasumoto, Sawa; Ohtsuka, Yoko; Sato, Katsuaki; Kurata, Atsuyo; Numachi, Yotaro; Shimizu, Masahiro

2018-05-31

To investigate the efficacy and safety of long-term lamotrigine (LTG) monotherapy in Japanese and South Korean pediatric patients with newly diagnosed typical absence seizures. Six Japanese patients and one South Korean patient were enrolled in the extension phase of the study after completing the 12-week maintenance phase of an open-label clinical study of LTG monotherapy. During the extension phase, patients underwent efficacy and safety evaluation every 12 weeks. Of the seven patients, six patients completed the extension phase. The seizure-free rate confirmed by hyperventilation (HV)-electroencephalography ranged from 71.4% to 100.0% at each visit up to Week 168 of the extension phase. Similar effects were confirmed by HV-clinical signs and seizure diaries. Although no unexpected adverse events were observed, one Japanese patient was withdrawn from the extension phase due to mild drug-related rash developed 842 days after the start of LTG. Although the number of patients is limited, long-term LTG monotherapy appeared to be effective and generally well tolerated in Japanese and South Korean pediatric patients with typical absence seizures. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Isobolographic characterization of the anticonvulsant interaction profiles of levetiracetam in combination with clonazepam, ethosuximide, phenobarbital and valproate in the mouse pentylenetetrazole-induced seizure model.

PubMed

Dudra-Jastrzebska, Monika; Andres-Mach, Marta M; Ratnaraj, Neville; Patsalos, Philip N; Czuczwar, Stanislaw J; Luszczki, Jarogniew J

2009-11-01

This study was designed so as to characterize the interactions between levetiracetam (LEV) and the conventional antiepileptic drugs (AEDs) clonazepam (CZP), ethosuximide (ETS), phenobarbital (PB), and valproate (VPA) in suppressing pentylenetetrazole (PTZ)-induced clonic seizures in mice by use of type II isobolographic analysis. Adverse-effect profiles of the drugs in combination were determined and brain AED concentrations were measured. The combinations of VPA and ETS with LEV at the fixed-ratio of 1:2, CZP with LEV (1:20,000), and PB with LEV (1:20) were supra-additive (synergistic) in suppressing seizures. In contrast, VPA and ETS with LEV (1:1, 2:1, and 4:1), CZP with LEV (1:1000, 1:5000, and 1:10,000), and PB with LEV (1:1, 1:5, and 1:10) were additive. No adverse effects were observed. ETS significantly reduced brain LEV concentrations but no other pharmacokinetic changes were observed. The combinations of CZP with LEV (1:20,000); VPA and ETS with LEV (1:2); and PB with LEV (1:20) appear to be favorable combinations exerting supra-additive interactions in suppressing PTZ-induced seizures.

Eslicarbazepine acetate as a replacement for levetiracetam in people with epilepsy developing behavioral adverse events.

PubMed

Jalihal, Virupakshi; Shankar, Rohit; Henley, William; Parrett, Mary; Tittensor, Phil; McLean, Brendan N; Ahmed, Ammad; Sander, Josemir W

2018-03-01

Psychiatric and behavioral side effects (PBSEs) are a major cause of antiepileptic drug (AED) withdrawal. Levetiracetam (LEV) is a recognized first-line AED with good seizure outcomes but recognized with PBSEs. Eslicarbazepine (ESL) is considered to function similarly to an active metabolite of the commonly used carbamazepine (CBZ). Carbamazepine is used as psychotropic medication to assist in various psychiatric illnesses such as mood disorders, aggression, and anxiety. The aim was to evaluate the psychiatric profile of ESL in people who had LEV withdrawn due to PBSEs in routine clinical practice to see if ESL can be used as a possible alternative to LEV. A retrospective observational review was conducted in two UK epilepsy centers looking at all cases exposed to ESL since its licensing in 2010. The ESL group was all patients with treatment-resistant epilepsy who developed intolerable PBSEs to LEV, subsequently trialed on ESL. The ESL group was matched to a group who tolerated LEV without intolerable PBSEs. Psychiatric disorders were identified from case notes. The Hamilton Depression Scale (HAM-D) was used to outcome change in mood. Clinical diagnoses of a mental disorder were compared between groups using the Fisher's exact test. Group differences in HAM-D scores were assessed using the independent samples t-test (alpha=0.05). The total number of people with active epilepsy in the two centers was 2142 of whom 46 had been exposed to ESL. Twenty-six had previous exposure to LEV and had intolerable PBSEs who were matched to a person tolerating LEV. There was no statistical differences in the two groups for mental disorders including mood as measured by HAM-D (Chi-square test: p=0.28). The ESL was well tolerated and did not produce significant PBSEs in those who had PBSEs with LEV leading to withdrawal of the drug. Though numbers were small, the findings suggest that ESL could be a treatment option in those who develop PBSEs with LEV and possibly other AEDs

Imaging the cortical effect of lamotrigine in patients with idiopathic generalized epilepsy: a low-resolution electromagnetic tomography (LORETA) study.

PubMed

Clemens, Béla; Piros, Pálma; Bessenyei, Mónika; Tóth, Márton; Hollódy, Katalin; Kondákor, István

2008-10-01

Anatomical localization of the cortical effect of lamotrigine (LTG) in patients with idiopathic generalized epilepsy (IGE). 19 patients with untreated IGE were investigated. EEG was recorded in the untreated condition and 3 months later when LTG treatment abolished the seizures. 19-channel EEG was recorded, and a total of 2min artifact-free, waking EEG was processed to low-resolution electromagnetic tomography (LORETA) analysis. Activity (that is, current source density, A/m(2)) was computed in four frequency bands (delta, theta, alpha, and beta), for 2394 voxels that represented the cortical gray matter and the hippocampi. Group differences between the untreated and treated conditions were computed for the four bands and all voxels by multiple t-tests for interdependent datasets. The results were presented in terms of anatomical distribution and statistical significance. p<0.01 (uncorrected) changes (decrease of activity) emerged in the theta and the alpha bands. Theta activity decreased in a large cluster of voxels including parts of the temporal, parietal, occipital cortex bilaterally, and in the transverse temporal gyri, insula, hippocampus, and uncus on the right side. Alpha activity decreased in a relatively smaller cortical area involving the right temporo-parietal junction and surrounding parts of the cortex, and part of the insula on the right side. LTG decreased theta activity in several cortical areas where abnormally increased theta activity had been found in a prior study in another cohort of untreated IGE patients [Clemens, B., Bessenyei, M., Piros, P., Tóth, M., Seress, L., Kondákor, I., 2007b. Characteristic distribution of interictal brain electrical activity in idiopathic generalized epilepsy. Epilepsia 48, 941-949]. These LTG-related changes might be related to the decrease of seizure propensity in IGE.

Effect of chronic administration of phenobarbital, or bromide, on pharmacokinetics of levetiracetam in dogs with epilepsy.

PubMed

Muñana, K R; Nettifee-Osborne, J A; Papich, M G

2015-01-01

Levetiracetam (LEV) is a common add-on antiepileptic drug (AED) in dogs with refractory seizures. Concurrent phenobarbital administration alters the disposition of LEV in healthy dogs. To evaluate the pharmacokinetics of LEV in dogs with epilepsy when administered concurrently with conventional AEDs. Eighteen client-owned dogs on maintenance treatment with LEV and phenobarbital (PB group, n = 6), LEV and bromide (BR group, n = 6) or LEV, phenobarbital and bromide (PB-BR group, n = 6). Prospective pharmacokinetic study. Blood samples were collected at 0, 1, 2, 4, and 6 hours after LEV administration. Plasma LEV concentrations were determined by high-pressure liquid chromatography. To account for dose differences among dogs, LEV concentrations were normalized to the mean study dose (26.4 mg/kg). Pharmacokinetic analysis was performed on adjusted concentrations, using a noncompartmental method, and area-under-the-curve (AUC) calculated to the last measured time point. Compared to the PB and PB-BR groups, the BR group had significantly higher peak concentration (Cmax ) (73.4 ± 24.0 versus 37.5 ± 13.7 and 26.5 ± 8.96 μg/mL, respectively, P < .001) and AUC (329 ± 114 versus 140 ± 64.7 and 98.7 ± 42.2 h*μg/mL, respectively, P < .001), and significantly lower clearance (CL/F) (71.8 ± 22.1 versus 187 ± 81.9 and 269 ± 127 mL/h/kg, respectively, P = .028). Concurrent administration of PB alone or in combination with bromide increases LEV clearance in epileptic dogs compared to concurrent administration of bromide alone. Dosage increases might be indicated when utilizing LEV as add-on treatment with phenobarbital in dogs. Copyright © 2015 by the American College of Veterinary Internal Medicine.

Removal of triazine-based pollutants from water by carbon nanotubes: Impact of dissolved organic matter (DOM) and solution chemistry.

PubMed

Engel, Maya; Chefetz, Benny

2016-12-01

Adsorption of organic pollutants by carbon nanotubes (CNTs) in the environment or removal of pollutants during water purification require deep understanding of the impacts of the presence of dissolved organic matter (DOM). DOM is an integral part of environmental systems and plays a key role affecting the behavior of organic pollutants. In this study, the effects of solution chemistry (pH and ionic strength) and the presence of DOM on the removal of atrazine and lamotrigine by single-walled CNTs (SWCNTs) was investigated. The solubility of atrazine slightly decreased (∼5%) in the presence of DOM, whereas that of lamotrigine was significantly enhanced (by up to ∼70%). Simultaneous introduction of DOM and pollutant resulted in suppression of removal of both atrazine and lamotrigine, which was attributed to DOM-pollutant competition or blockage of adsorption sites by DOM. However the decrease in removal of lamotrigine was also a result of its complexation with DOM. Pre-introduction of DOM significantly reduced pollutant adsorption by the SWCNTs, whereas introduction of DOM after the pollutant resulted in the release of adsorbed atrazine and lamotrigine from the SWCNTs. These data imply that DOM exhibits higher affinity for the adsorption sites than the triazine-based pollutants. In the absence of DOM atrazine was a more effective competitor than lamotrigine for adsorption sites in SWCNTs. However, competition between pollutants in the presence of DOM revealed lamotrigine as the better competitor. Our findings help unravel the complex DOM-organic pollutant-CNT system and will aid in CNT-implementation in water-purification technologies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of levetiracetam in lipid peroxidation level, nitrite-nitrate formation and antioxidant enzymatic activity in mice brain after pilocarpine-induced seizures.

PubMed

Oliveira, A A; Almeida, J P C; Freitas, R M; Nascimento, V S; Aguiar, L M V; Júnior, H V N; Fonseca, F N; Viana, G S B; Sousa, F C F; Fonteles, M M F

2007-05-01

: Oxidative stress has been implicated in a large number of human degenerative diseases, including epilepsy. Levetiracetam (LEV) is a new antiepileptic agent with broad-spectrum effects on seizures and animal models of epilepsy. Recently, it was demonstrated that the mechanism of LEV differs from that of conventional antiepileptic drugs. Objectifying to investigate if LEV mechanism of action involves antioxidant properties, lipid peroxidation levels, nitrite-nitrate formation, catalase activity, and glutathione (GSH) content were measured in adult mice brain. The neurochemical analyses were carried out in hippocampus of animals pretreated with LEV (200 mg/kg, i.p.) 60 min before pilocarpine-induced seizures (400 mg/kg, s.c.). The administration of alone pilocarpine, 400 mg/kg, s.c. (P400) produced a significant increase of lipid peroxidation level in hippocampus. LEV pretreatment was able to counteract this increase, preserving the lipid peroxidation level in normal value. P400 administration also produced increase in the nitrite-nitrate formation and catalase activity in hippocampus, beyond a decrease in GSH levels. LEV administration before P400 prevented the P400-induced alteration in nitrite-nitrate levels and preserved normal values of catalase activity in hippocampus. Moreover, LEV administration prevented the P400-induced loss of GSH in this cerebral area. The present data suggest that the protective effects of LEV against pilocarpine-induced seizures can be mediated, at least in part, by reduction of lipid peroxidation and hippocampal oxidative stress.

The effect of lamotrigine and phenytoin on bone turnover and bone strength: A prospective study in Wistar rats.

PubMed

Simko, Julius; Karesova, Iva; Kremlacek, Jan; Fekete, Sona; Zimcikova, Eva; Malakova, Jana; Zivna, Helena; Valis, Martin; Palicka, Vladimir

2016-12-01

Some data suggest that exposure to lamotrigine (LTG) might be associated with impaired bone health in an orchidectomized rat model. The aim of this study was to determine if LTG poses any significant risk for bone in a gonadally intact animals and to compare the effect of LTG with that of phenytoin (PHT). Twenty-four rats were divided into control and test groups, (n=8 per group). Control rats received a standard laboratory diet (SDL), while rats in the test groups were fed a SLD enriched with LTG or PHT for 12 weeks. Dual energy X-ray absorptiometry was used to measure bone mineral density (BMD). The concentrations of bone turnover markers (BTM) were assayed in bone homogenates. The femurs were measured and biomechanically tested. Treatment with either LTG or PHT had no significant effect on BMD or on the biomechanical strength of the bones. In contrast to the effect of LTG, we did find significant changes in BTM in the PHT group: a highly significant decrease in the osteoprotegerin/receptor activator of nuclear factor kappa B ratio (p<0.01) and highly significant increases in bone alkaline phosphatase and amino-terminal propeptide of procollagen type I (p<0.001, p˂0.01, respectively). In the LTG group, the only significant change was a decrease in sclerostin (p˂0.05). The PHT level was 19.0 (15.6-19.5) μmol/l, which represents the lower end of the therapeutic range used in humans. The level of LTG was 60.7 (58.5-61.8) μmol/l. LTG has no effect on the BMD, BTM or mechanical strength in gonadally intact animals. Although a low dose of PHT was associated with enhanced BTM, it did not affect BMD or the biomechanical properties of the bones, similar to the results observed for LTG. Copyright © 2016 Elsevier B.V. All rights reserved.

Intravenous and oral levetiracetam in patients with a suspected primary brain tumor and symptomatic seizures undergoing neurosurgery: the HELLO trial.

PubMed

Bähr, Oliver; Hermisson, Mirjam; Rona, Sabine; Rieger, Johannes; Nussbaum, Susanne; Körtvelyessy, Peter; Franz, Kea; Tatagiba, Marcos; Seifert, Volker; Weller, Michael; Steinbach, Joachim P

2012-02-01

Levetiracetam (LEV) is a newer anticonvulsant with a favorable safety profile. There seem to be no relevant drug interactions, and an intravenous formulation is available. Therefore, LEV might be a suitable drug for the perioperative anticonvulsive therapy of patients with suspected brain tumors undergoing neurosurgery. In this prospective study (NCT00571155) patients with suspected primary brain tumors and tumor-related seizures were perioperatively treated with oral and intravenous LEV up to 4 weeks before and until 4 weeks after a planned neurosurgical procedure. Thirty patients with brain tumor-related seizures and intended neurosurgery were included. Three patients did not undergo the scheduled surgery after enrollment, and two patients were lost to follow-up. Therefore, 25 patients were fully evaluable. After initiation of therapy with LEV, 100% of the patients were seizure-free in the pre-surgery phase (3 days up to 4 weeks before surgery), 88% in the 48 h post-surgery phase and 84% in the early follow-up phase (48 h to 4 weeks post surgery). Treatment failure even after dose escalation to 3,000 mg/day occurred in three patients. No serious adverse events related to the treatment with LEV occurred. Our data show the feasibility and safety of oral and intravenous LEV in the perioperative treatment of tumor-related seizures. Although this was a single arm study, the efficacy of LEV appears promising. Considering the side effects and interactions of other anticonvulsants, LEV seems to be a favorable option in the perioperative treatment of brain tumor-related seizures.

Anti-inflammatory effects of the anticonvulsant drug levetiracetam on electrophysiological properties of astroglia are mediated via TGFβ1 regulation.

PubMed

Stienen, Martin N; Haghikia, Aiden; Dambach, Hannes; Thöne, Jan; Wiemann, Martin; Gold, Ralf; Chan, Andrew; Dermietzel, Rolf; Faustmann, Pedro M; Hinkerohe, Daniel; Prochnow, Nora

2011-01-01

The involvement of astrocytes as immune-competent players in inflammation and the pathogenesis of epilepsy and seizure-induced brain damage has recently been recognized. In clinical trials and practice, levetiracetam (LEV) has proven to be an effective antiepileptic drug (AED) in various forms of epileptic seizures, when applied as mono- or added therapy. Little is known about the mechanism(s) of action of LEV. Evidence so far suggests a mode of action different from that of classical AEDs. We have shown that LEV restored functional gap junction coupling and basic membrane properties in an astrocytic inflammatory model in vitro. Here, we used neonatal rat astrocytes co-cultured with high proportions (30%) of activated microglia or treated with the pro-inflammatory cytokine interleukin-1β to provoke inflammatory responses. Effects of LEV (50 µg·mL⁻¹) on electrophysiological properties of astrocytes (by whole cell patch clamp) and on secretion of TGFβ1 (by (ELISA)) were studied in these co-cultures. LEV restored impaired astrocyte membrane resting potentials via modification of inward and outward rectifier currents, and promoted TGFβ1 expression in inflammatory and control co-cultures. Furthermore, LEV and TGFβ1 exhibited similar facilitating effects on the generation of astrocyte voltage-gated currents in inflammatory co-cultures and the effects of LEV were prevented by antibody to TGFβ1. Our data suggest that LEV is likely to reduce the harmful spread of excitation elicited by seizure events within the astro-glial functional syncytium, with stabilizing consequences for neuronal-glial interactions. © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.

Prophylactic treatment with levetiracetam after status epilepticus: lack of effect on epileptogenesis, neuronal damage, and behavioral alterations in rats.

PubMed

Brandt, Claudia; Glien, Maike; Gastens, Alexandra M; Fedrowitz, Maren; Bethmann, Kerstin; Volk, Holger A; Potschka, Heidrun; Löscher, Wolfgang

2007-08-01

Levetiracetam (LEV) is a structurally novel antiepileptic drug (AED) which has demonstrated a broad spectrum of anticonvulsant activities both in experimental and clinical studies. Previous experiments in the kindling model suggested that LEV, in addition to its seizure-suppressing activity, may possess antiepileptogenic or disease-modifying activity. In the present study, we evaluated this possibility by using a rat model in which epilepsy with spontaneous recurrent seizures (SRS), behavioral alterations, and hippocampal damages develop after a status epilepticus (SE) induced by sustained electrical stimulation of the basal amygdala. Two experimental protocols were used. In the first protocol, LEV treatment was started 24h after onset of electrical amygdala stimulation without prior termination of the SE. In the second protocol, the SE was interrupted after 4h by diazepam, immediately followed by onset of treatment with LEV. Treatment with LEV was continued for 8 weeks (experiment #1) or 5 weeks (experiment #2) after SE, using continuous drug administration via osmotic minipumps. The occurrence of SRS was recorded during and after treatment. In addition, the rats were tested in a battery of behavioral tests, including the elevated-plus maze and the Morris water maze. Finally, the brains of the animals were analyzed for histological lesions in the hippocampal formation. With the experimental protocols chosen for these experiments, LEV did not exert antiepileptogenic or neuroprotective activity. Furthermore, the behavioral alterations, e.g., behavioral hyperexcitability and learning deficits, in epileptic rats were not affected by treatment with LEV after SE. These data do not support the idea that administration of LEV after SE prevents or reduces the long-term alterations developing after such brain insult in rats.

Reproductive toxicity after levetiracetam administration in male rats: Evidence for role of hormonal status and oxidative stress

PubMed Central

Kilic, Gozde; Kilic, Volkan; Ucarcan, Seyda; Atli, Ozlem

2017-01-01

Levetiracetam (LEV) is an antiepileptic drug commonly used in the treatment of epilepsy because of its excellent safety profile in all age groups. It is remarkable that there are no studies evaluating the toxic effects of this drug on the male reproductive system, as it is commonly used in male patients of reproductive age. From this point of view, our aim was to evaluate the possible toxic effects of LEV on the male reproductive system. Therefore, LEV was administered to male rats orally at 50, 150, and 300 mg/kg for 70 consecutive days. At the end of this period, alterations to body and organ weights were calculated, and sperm concentration, motility, and morphology were investigated by a computer-assisted sperm analysis system. Sperm DNA damage was determined by comet assay and histopathological examination of the testes was carried out. Serum testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were measured by ELISAs to determine the effects of hormonal status, while glutathione, superoxide dismutase, catalase, and malondialdehyde levels in the testes were measured by colorimetric assay kits to determine the role of oxidative status in potential toxicity. According to the results, sperm quality was decreased by LEV treatment in a dose-dependent manner. LEV induced significant DNA damage in the 150 and 300 mg/kg LEV-administered groups. Histopathology of the testes showed that LEV resulted in testicular injury in the 300 mg/kg LEV-administered group. Serum testosterone, FSH, and LH levels were significantly decreased in the 300 mg/kg LEV-administered group. Glutathione, superoxide dismutase, and catalase levels were significantly decreased in all experimental groups while malondialdehyde levels were significantly increased in 150 and 300 mg/kg LEV-administered groups. According to these results, it was determined that LEV administration decreased sperm quality and it was alleged that hormonal alteration and oxidative stress are

Reproductive toxicity after levetiracetam administration in male rats: Evidence for role of hormonal status and oxidative stress.

PubMed

Baysal, Merve; Ilgin, Sinem; Kilic, Gozde; Kilic, Volkan; Ucarcan, Seyda; Atli, Ozlem

2017-01-01

Levetiracetam (LEV) is an antiepileptic drug commonly used in the treatment of epilepsy because of its excellent safety profile in all age groups. It is remarkable that there are no studies evaluating the toxic effects of this drug on the male reproductive system, as it is commonly used in male patients of reproductive age. From this point of view, our aim was to evaluate the possible toxic effects of LEV on the male reproductive system. Therefore, LEV was administered to male rats orally at 50, 150, and 300 mg/kg for 70 consecutive days. At the end of this period, alterations to body and organ weights were calculated, and sperm concentration, motility, and morphology were investigated by a computer-assisted sperm analysis system. Sperm DNA damage was determined by comet assay and histopathological examination of the testes was carried out. Serum testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were measured by ELISAs to determine the effects of hormonal status, while glutathione, superoxide dismutase, catalase, and malondialdehyde levels in the testes were measured by colorimetric assay kits to determine the role of oxidative status in potential toxicity. According to the results, sperm quality was decreased by LEV treatment in a dose-dependent manner. LEV induced significant DNA damage in the 150 and 300 mg/kg LEV-administered groups. Histopathology of the testes showed that LEV resulted in testicular injury in the 300 mg/kg LEV-administered group. Serum testosterone, FSH, and LH levels were significantly decreased in the 300 mg/kg LEV-administered group. Glutathione, superoxide dismutase, and catalase levels were significantly decreased in all experimental groups while malondialdehyde levels were significantly increased in 150 and 300 mg/kg LEV-administered groups. According to these results, it was determined that LEV administration decreased sperm quality and it was alleged that hormonal alteration and oxidative stress are

Haematological toxicity of Valproic acid compared to Levetiracetam in patients with glioblastoma multiforme undergoing concomitant radio-chemotherapy: a retrospective cohort study.

PubMed

Tinchon, Alexander; Oberndorfer, Stefan; Marosi, Christine; Gleiss, Andreas; Geroldinger, Angelika; Sax, Cornelia; Sherif, Camillo; Moser, Walter; Grisold, Wolfgang

2015-01-01

Patients with glioblastoma multiforme (GBM) and symptomatic seizures are in need of a sufficient antiepileptic treatment. Haematological toxicity is a limiting side effect of both, first line radio-chemotherapy with temozolomide (TMZ) and co-medication with antiepileptic drugs. Valproic acid (VPA) and levetiracetam (LEV) are considered favourable agents in brain tumor patients with seizures, but are commonly reported to induce haematological side effects on their own. We hypothesized, that antiepileptic treatment with these agents has no increased impact on haematological side effects during radio-chemotherapy in the first line setting. We included 104 patients from two neuro-oncologic centres with GBM and standard radio-chemotherapy in a retrospective cohort study. Patients were divided according to their antiepileptic treatment with either VPA, LEV or without antiepileptic drug therapy (control group). Declines in haemoglobin levels and absolute blood cell counts for neutrophil granulocytes, lymphocytes and thrombocytes were analyzed twice during concomitant and once during adjuvant phase. A comparison between the examined groups was performed, using a linear mixed model. Neutrophil granulocytes, lymphocytes and thrombocytes significantly decreased over time in all three groups (all p < 0.012), but there was no significant difference between the compared groups. A significant decline in haemoglobin was observed in the LEV treated group (p = 0.044), but did not differ between the compared groups. As a novel finding, this study demonstrates that co-medication either with VPA or LEV in GBM patients undergoing first line radio-chemotherapy with TMZ has no additional impact on medium-term haematological toxicity.

Developmental effects of antiepileptic drugs and the need for improved regulations

PubMed Central

Loring, David W.

2016-01-01

Antiepileptic drugs (AEDs) are among the most common teratogenic drugs prescribed to women of childbearing age. AEDs can induce both anatomical (malformations) and behavioral (cognitive/behavioral deficits) teratogenicity. Only in the last decade have we begun to truly discriminate differential AED developmental effects. Fetal valproate exposure carries a special risk for both anatomical and behavioral teratogenic abnormalities, but the mechanisms and reasons for individual variability are unknown. Intermediate anatomical risks exist for phenobarbital and topiramate. Several AEDs (e.g., lamotrigine and levetiracetam) appear to possess low risks for both anatomical and behavioral teratogenesis. Despite advances in the past decade, our knowledge of the teratogenic risks for most AEDs and the underlying mechanisms remain inadequate. Further, the long-term effects of AEDs in neonates and older children remain uncertain. The pace of progress is slow given the lifelong consequences of diminished developmental outcomes, exposing children unnecessarily to potential adverse effects. It is imperative that new approaches be employed to determine risks more expediently. Our recommendations include a national reporting system for congenital malformations, federal funding of the North American AED Pregnancy Registry, routine meta-analyses of cohort studies to detect teratogenic signals, monitoring of AED prescription practices for women, routine preclinical testing of all new AEDs for neurodevelopmental effects, more specific Food and Drug Administration requirements to establish differential AED cognitive effects in children, and improved funding of basic and clinical research to fully delineate risks and underlying mechanisms for AED-induced anatomical and behavioral teratogenesis. PMID:26519545

Transient improvement after brief antiepileptic drug withdrawal in the epilepsy monitoring unit--possible relationship to AED tolerance.

PubMed

Azar, Nabil J; Lagrange, Andre H; Wang, Lily; Song, Yanna; Abou-Khalil, Bassel W

2010-05-01

A drug holiday seems to produce seizure interval prolongation (SIP) after reinstitution of antiepileptic drugs (AEDs). This effect was demonstrated mainly with carbamazepine. We evaluated SIP with newer AEDs and tested the relationship of SIP to history of AED tolerance. We prospectively studied patients with refractory epilepsy admitted to the Vanderbilt epilepsy monitoring unit (EMU) over a period of 12 months. We included only patients on levetiracetam, lamotrigine, or oxcarbazepine who had their AEDs withdrawn on admission and reinstituted without change upon discharge. We defined SIP as the interval from EMU discharge to first seizure minus the interval between the last two seizures before EMU admission. A total of 43 patients completed the study; 15 were on monotherapy. SIP was greater than zero in this patient group (p < 0.0001), with a mean prolongation of 19.4 +/- 28.0 days. The average SIP was higher (p = 0.01) in patients on monotherapy (29.7 +/- 23.8 days) than patients on polytherapy (13.9 +/- 29.0 days). SIP tended to be greater in patients with a prior history of AED tolerance (25.7 +/- 36.8 days) compared to patient with no prior history of AED tolerance (14.0 +/- 16.3 days). SIP does occur after brief AED withdrawal. This effect is greater in patients on monotherapy and tends to be larger in patients with a history of AED tolerance. The SIP effect may be related to the phenomenon of tolerance, clinically seen as resistance to AED therapeutic effect.

Association of HLA-A and HLA-B Alleles with Lamotrigine-Induced Cutaneous Adverse Drug Reactions in the Thai Population

PubMed Central

Koomdee, Napatrupron; Pratoomwun, Jirawat; Jantararoungtong, Thawinee; Theeramoke, Voralaksana; Tassaneeyakul, Wichittra; Klaewsongkram, Jettanong; Rerkpattanapipat, Ticha; Santon, Siwalee; Puangpetch, Apichaya; Intusoma, Utcharee; Tempark, Therdpong; Deesudchit, Tayard; Satapornpong, Patompong; Visudtibhan, Anannit; Sukasem, Chonlaphat

2017-01-01

Background: Lamotrigine (LTG) is commonly used for treatment of epilepsy and bipolar disorder. It is one of the common cause of cutaneous adverse drug reactions (CADR). Clinical symptoms of LTG-induced CADR range from maculopapular exanthema (MPE) to severe cutaneous adverse reactions (SCAR). This study aimed to determine the association of the LTG-induced CADR with human leukocyte antigen (HLA) alleles in Thai patients. Methods: Fifteen patients with LTG-induced CADR [10 MPE; 4 Stevens–Johnson syndrome; and 1 drug reaction with eosinophilia and systemic symptoms] and 50 LTG-tolerant controls were included in the study. HLA-A and HLA-B genotyping was performed using polymerase chain reaction-sequence-specific oligonucleotides probes. Results: The proportion of HLA-A∗02:07 and HLA-B∗15:02 allele carriers were significantly higher in the LTG-induced CADR group than in the tolerant controls [odds ratio (OR): 7.83; 95% confidence interval (CI): 1.60–38.25; P = 0.013, and OR: 4.89; 95% CI: 1.28–18.67; P = 0.014]. In addition, subjects with HLA-A∗33:03, HLA-B∗15:02, and HLA-B∗44:03 were significantly higher in the LTG-induced MPE group than in the tolerant controls (OR: 8.27; 95% CI: 1.83–37.41; P = 0.005, OR: 7.33; 95% CI: 1.63–33.02; P = 0.005; and OR: 10.29; 95% CI: 1.45–72.81; P = 0.029). In contrast to the LTG-induced MPE group, there were no significant differences between HLA alleles and LTG-induced SCAR group. Conclusion: HLA-A∗02:07 and HLA-B∗15:02 were associated with LTG-induced CADR in Thai patients. We also identified an association between HLA-A∗33:03, HLA-B∗15:02, and HLA-B∗44:03 and LTG-induced MPE in this population. These results suggest that these alleles could be useful screening markers for preventing CADR before LTG treatment in Thai patients, but further replication studies with larger sample sizes are needed. PMID:29238301

In Silico Docking and Electrophysiological Characterization of Lacosamide Binding Sites on Collapsin Response Mediator Protein-2 Identifies a Pocket Important in Modulating Sodium Channel Slow Inactivation*

PubMed Central

Wang, Yuying; Brittain, Joel M.; Jarecki, Brian W.; Park, Ki Duk; Wilson, Sarah M.; Wang, Bo; Hale, Rachel; Meroueh, Samy O.; Cummins, Theodore R.; Khanna, Rajesh

2010-01-01

The anti-epileptic drug (R)-lacosamide ((2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide (LCM)) modulates voltage-gated sodium channels (VGSCs) by preferentially interacting with slow inactivated sodium channels, but the observation that LCM binds to collapsin response mediator protein 2 (CRMP-2) suggests additional mechanisms of action for LCM. We postulated that CRMP-2 levels affects the actions of LCM on VGSCs. CRMP-2 labeling by LCM analogs was competitively displaced by excess LCM in rat brain lysates. Manipulation of CRMP-2 levels in the neuronal model system CAD cells affected slow inactivation of VGSCs without any effects on other voltage-dependent properties. In silico docking was performed to identify putative binding sites in CRMP-2 that may modulate the effects of LCM on VGSCs. These studies identified five cavities in CRMP-2 that can accommodate LCM. CRMP-2 alanine mutants of key residues within these cavities were functionally similar to wild-type CRMP-2 as assessed by similar levels of enhancement in dendritic complexity of cortical neurons. Next, we examined the effects of expression of wild-type and mutant CRMP-2 constructs on voltage-sensitive properties of VGSCs in CAD cells: 1) steady-state voltage-dependent activation and fast-inactivation properties were not affected by LCM, 2) CRMP-2 single alanine mutants reduced the LCM-mediated effects on the ability of endogenous Na+ channels to transition to a slow inactivated state, and 3) a quintuplicate CRMP-2 alanine mutant further decreased this slow inactivated fraction. Collectively, these results identify key CRMP-2 residues that can coordinate LCM binding thus making it more effective on its primary clinical target. PMID:20538611

Best practice guidelines for the management of women with epilepsy.

PubMed

Crawford, Pamela

2005-01-01

Being a woman with epilepsy is not the same as being a man with epilepsy. Epilepsy affects sexual development, menstrual cycle, aspects of contraception, fertility, and reproduction. MENSTRUAL CYCLE, EPILEPSY, AND FERTILITY: The diagnosis of epilepsy and the use of antiepileptic drugs (AEDs) present women of childbearing age with many problems; both the disease and its treatment can alter the menstrual cycle and fertility. CONTRACEPTION IN EPILEPSY: There are no contraindications to the use of nonhormonal methods of contraception in women with epilepsy (see Table 3). Nonenzyme-inducing AEDs (valproate sodium, benzodiazepines, ethosuximide, and levetiracetam) do not show any interactions with the combined oral contraceptive pill. There are interactions between the COCP and hepatic microsomal-inducing AEDs (phenytoin, barbiturates, carbamazepine, topiramate [doses above 200 mg/day], and oxcarbazepine) and also lamotrigine. SEXUALITY: The majority of women with epilepsy appear to have normal sex lives, although in some women with epilepsy, both the desire and arousal phases may be inhibited. PRECONCEPTION COUNSELING: Preconception counseling should be available to all women with epilepsy who are considering pregnancy. Women with epilepsy should be aware of a number of issues relating to future pregnancy, including methods and consequences of prenatal screening, genetics of their seizure disorder, teratogenicity of AEDs, folic acid and vitamin K supplements, labor, breast feeding, and childcare. PREGNANCY: The lowest effective dose of the most appropriate AED should be used, aiming for monotherapy where possible. Recent pregnancy databases have suggested that valproate is significantly more teratogenic than carbamazepine, and the combination of valproate sodium and lamotrigine is particularly teratogenic. Most pregnancies are uneventful in women with epilepsy, and most babies are delivered healthy with no increased risk of obstetric complications in women. BREAST

Influence of WIN 55,212-2 on the anticonvulsant and acute neurotoxic potential of clobazam and lacosamide in the maximal electroshock-induced seizure model and chimney test in mice.

PubMed

Florek-Luszczki, Magdalena; Zagaja, Miroslaw; Luszczki, Jarogniew J

2014-12-01

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. Copyright © 2014 Elsevier B.V. All rights reserved.

Recent antiseizure medications in the Intensive Care Unit.

PubMed

Orinx, Cindy; Legros, Benjamin; Gaspard, Nicolas

2017-08-01

Seizures and status epilepticus (SE), both clinical and subclinical, are frequent in critically ill patients. The list of available antiseizure medications (ASMs) is expanding and now includes older and widely used drugs as well as more recent medications with a better safety and pharmacokinetics profile. We review a selection of recent publications about the indications and administration of ASMs in critical care for the prophylaxis and treatment of seizures and SE, focusing on recent ASMs available as intravenous formulation and emphasizing pharmacokinetics and safety issues in relation to several aspects of critical illness. Levetiracetam, lacosamide and more recently brivaracetam, represent interesting alternatives to older ASMs, mostly due to a more favorable safety and pharmacokinetic profile. Low-quality studies suggest that this profile results in better tolerability in treated patients. Ketamine might represent a useful addition in our anesthetic armamentarium for refractory SE, due to its different mechanism of action and cardiovascular properties. Little evidence is available however to support the prophylactic use of ASMs in critically ill patients, except in specific settings (traumatic brain injury and subarachnoid hemorrhage). Head-to-head studies comparing recent and older ASMs in the treatment of acute seizures and SE are ongoing or awaiting publication. Administration of ASMs to critically ill patients needs to be adapted to organ dysfunction, and especially to renal dysfunction for recent drugs. Recent ASMs and could represent better treatment choices in critically ill patients than older ones but this needs to be confirmed in randomized controlled studies. In general, further studies are required to clarify the indications and optimal use of ASMs in the critical care setting.

Efficacy and tolerability of brivaracetam compared to lacosamide, eslicarbazepine acetate, and perampanel as adjunctive treatments in uncontrolled focal epilepsy: Results of an indirect comparison meta-analysis of RCTs.

PubMed

Brigo, Francesco; Bragazzi, Nicola Luigi; Nardone, Raffaele; Trinka, Eugen

2016-11-01

Brivaracetam (BRV), eslicarbazepine acetate (ESL), lacosamide (LCM), and perampanel (PER) have been recently marketed as adjunctive treatments for focal onset seizures. To date, no randomized controlled trial (RCT) has directly compared BRV with ESL, LCM, or PER. To compare BRV with the other add-on AEDs in patients with uncontrolled focal epilepsy, estimating their efficacy and tolerability through an adjusted, common-reference based indirect comparison meta-analysis. We systematically searched RCTs in which add-on treatment with ESL or LCM in patients with focal onset seizures have been compared with placebo. Efficacy and tolerability outcomes were considered. Random-effects Mantel-Haenszel meta-analyses were performed to obtain odds ratios (ORs) for the efficacy of BRV, LCM, ESL, or PER versus placebo. Adjusted indirect comparisons were then made between BRV and the other three AEDs using the obtained results, comparing the minimum and the highest effective recommended daily dose of each drug. Seventeen RCTs, with a total of 4971 patients were included. After adjusting for dose-effects, indirect comparisons showed no difference between BRV and LCM, ESL, or PER for responder rate and seizure freedom. Lower adverse events were observed with high dose BRV compared to high dose ESL or PER, but no difference was found in withdrawing because of adverse events. Indirect comparisons do not demonstrate a significant difference in efficacy between add-on BRV and LCM, ESL, or PER in focal epilepsy, and might suggest a better tolerability of BRV than ESL, and possibly also PER, at the highest effective recommended dose. Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Synthesis and anticonvulsant activities of N-benzyl (2R)-2-acetamido-3-oxysubstituted propionamide derivatives

PubMed Central

Morieux, Pierre; Stables, James P.; Kohn, Harold

2009-01-01

Lacosamide has been submitted for regulatory approval in the United States and Europe for the treatment of epilepsy. Previous synthetic methods did not permit the elaboration of the structure–activity relationship (SAR) for the 3-oxy site in lacosamide. We report an expedient five-step stereospecific synthesis for N-benzyl (2R)-2-acetamido-3-oxysubstituted propionamide analogs beginning with d-serine methyl ester. The procedure incorporated alkyl (e.g. methyl, primary, secondary, and tertiary) and aryl groups at this position. The SAR for the 3-oxy site showed maximal activity in animal seizure models for small 3-alkoxy substituents. PMID:18789868

The SKATE study: an open-label community-based study of levetiracetam as add-on therapy for adults with uncontrolled partial epilepsy.

PubMed

Steinhoff, Bernhard J; Somerville, Ernest R; Van Paesschen, Wim; Ryvlin, Philippe; Schelstraete, Isabelle

2007-08-01

The Safety of Keppra as Adjunctive Therapy in Epilepsy (SKATE) study aimed to evaluate the safety and efficacy of levetiracetam (Keppra, LEV) as add-on therapy for refractory partial seizures in clinical practice. This Phase IV, 16-week, open-label study recruited patients > or =16-year old with treatment-resistant partial seizures. LEV (1000 mg/day) was added to a stable concomitant antiepileptic drug regimen. LEV dosage was adjusted based on seizure control and tolerability to a maximum of 3000 mg/day. 1541 patients (intent-to-treat population) were recruited including 1346 (87.3%) who completed the study and 77.0% who declared further continuing on LEV after the trial. Overall, 50.5% of patients reported at least one adverse event that was considered related to LEV treatment. The most frequently reported drug-related adverse events were mild-to-moderate somnolence, fatigue, dizziness and headache. Serious adverse events considered related to LEV occurred in 1.0% of patients. 7.5% of patients reported adverse events as the most important reason for study drug discontinuation. The median reduction from baseline in the frequency of all seizures was 50.2%; 15.8% of patients were seizure free; 50.1% had seizure frequency reduction of > or =50%. At the end of the study, 60.4% of patients were considered by the investigator to show marked or moderate improvement. There was a significant improvement in health-related quality of life as assessed with the QOLIE-10-P (total score increasing from 55.6 to 61.6; p<0.001). This community-based study suggests that LEV is well tolerated and effective as add-on therapy for refractory partial seizures in adults. These data provide supportive evidence for the safety and efficacy of LEV demonstrated in the pivotal Phase III placebo-controlled studies.

A missed opportunity – consequences of unknown levetiracepam pharmacokinetics in a peritoneal dialysis patient

PubMed Central

2014-01-01

Background Levetiracetam is a frequently used drug in the therapy of partial onset, myoclonic and generalized tonic-clonic seizures. The main route of elimination is via the kidneys, which eliminate 66% of the unchanged drug as well as 24% as inactive metabolite that stems from enzymatic hydrolysis. Therefore dose adjustments are needed in patients with chronic kidney disease stage 5 D, i.e. patients undergoing dialysis treatment. In this patient population a dose reduction by 50% is recommended, so that patients receive 250–750 mg every 12 hours. However “dialysis” can be performed in using different modalities and treatment intensities. For most of the drugs pharmacokinetic data and dosing recommendations for patients undergoing peritoneal dialysis are not available. This is the first report on levetiracetam pharmacokinetics in a peritoneal dialysis patient. Case presentation A 73-y-old Caucasian male (height: 160 cm, weight 93 kg, BMI 36.3 kg/m2) was admitted with a Glasgow Coma Scale of 10. Due to diabetic and hypertensive nephropathy he was undergoing peritoneal dialysis for two years. Eight weeks prior he was put on levetiracetam 500 mg twice daily for suspected partial seizures with secondary generalization. According to the patient’s wife, levetiracetam lead to fatigue and somnolence leading to trauma with fracture of the metatarsal bone. Indeed, even 24 hours after discontinuation of levetiracetam blood level was still 29.8 mg/l (therapeutic range: 12 – 46 mg/l). Fatigue and stupor had disappeared five days after discontinuation of the levetiracepam. A single dose pharamockinetic after re-exposure showed an increased half life of 18.4 hours (normal half life 7 hours) and levetiracetam content in the peritoneal dialysate. Both half-life and dialysate content might help to guide dosing in this patient population. Conclusion If levetiracetam is used in peritoneal dialysis patients it should be regularly monitored to avoid supratherapeutic

Pharmacological Treatment of Pain in Cancer Patients: The Role of Adjuvant Analgesics, a Systematic Review.

PubMed

van den Beuken-van Everdingen, Marieke H J; de Graeff, Alexander; Jongen, Joost L M; Dijkstra, Denise; Mostovaya, Irina; Vissers, Kris C

2017-03-01

In patients with cancer, pain is one of the most feared and burdensome symptoms. Adjuvant analgesics are an important cornerstone on which treatment of pain in patients with cancer is based. To update our guidelines for the treatment of pain in patients with cancer, we performed a systematic review on the use of adjuvant analgesics in pain in cancer. A systematic search of the literature was performed searching for articles that studied the effect of (1) antidepressants, (2) anti-epileptics, (3) N-methyl-d-aspartate (NMDA) receptor antagonists, and (4) other adjuvant analgesics in patients with cancer pain and described their effects on pain intensity and/or side effects. Based on the keywords and after reading the full papers, we could include 12 papers on anticonvulsants, 10 papers on antidepressants, four on NMDA receptor antagonists, and 10 papers on other adjuvant analgesics. The methodological quality of the included papers was graded as low to very low. Overall, there was a low quality of evidence that gabapentin, pregabalin, amitriptyline, and venlafaxine were effective in reducing pain intensity in patients with cancer pain. There was insufficient evidence on the effectiveness of lamotrigine, levetiracetam, NMDA antagonists, cannabinoids, corticosteroids, and local anesthetics on reducing pain intensity in patients with cancer pain. The quality of currently available evidence on the effectiveness of adjuvant analgesics in the treatment of cancer pain is low. The treatment of pain associated with cancer should be tailored to the patient's personal preferences. © 2016 World Institute of Pain.

Evaluation of the pentylenetetrazole seizure threshold test in epileptic mice as surrogate model for drug testing against pharmacoresistant seizures.

PubMed

Töllner, Kathrin; Twele, Friederike; Löscher, Wolfgang

2016-04-01

Resistance to antiepileptic drugs (AEDs) is a major problem in epilepsy therapy, so that development of more effective AEDs is an unmet clinical need. Several rat and mouse models of epilepsy with spontaneous difficult-to-treat seizures exist, but because testing of antiseizure drug efficacy is extremely laborious in such models, they are only rarely used in the development of novel AEDs. Recently, the use of acute seizure tests in epileptic rats or mice has been proposed as a novel strategy for evaluating novel AEDs for increased antiseizure efficacy. In the present study, we compared the effects of five AEDs (valproate, phenobarbital, diazepam, lamotrigine, levetiracetam) on the pentylenetetrazole (PTZ) seizure threshold in mice that were made epileptic by pilocarpine. Experiments were started 6 weeks after a pilocarpine-induced status epilepticus. At this time, control seizure threshold was significantly lower in epileptic than in nonepileptic animals. Unexpectedly, only one AED (valproate) was less effective to increase seizure threshold in epileptic vs. nonepileptic mice, and this difference was restricted to doses of 200 and 300 mg/kg, whereas the difference disappeared at 400mg/kg. All other AEDs exerted similar seizure threshold increases in epileptic and nonepileptic mice. Thus, induction of acute seizures with PTZ in mice pretreated with pilocarpine does not provide an effective and valuable surrogate method to screen drugs for antiseizure efficacy in a model of difficult-to-treat chronic epilepsy as previously suggested from experiments with this approach in rats. Copyright © 2016 Elsevier Inc. All rights reserved.

From here to epilepsy: the risk of seizure in patients with Alzheimer's disease.

PubMed

Nicastro, Nicolas; Assal, Frédéric; Seeck, Margitta

2016-03-01

To describe the association between Alzheimer's disease and seizures by reviewing epidemiological data from available literature and to assess the putative pathophysiological links between neurodegeneration and altered cortical excitability. We also discuss specific antiepileptic treatment strategies in patients with Alzheimer's disease, as well as transient epileptic amnesia as a possible crossroads between degeneration and epilepsy. Regarding epidemiology, we searched publications in Pubmed, Medline, Scopus and Web of Science (until September 2015) using the keywords "incidence", "prevalence" and "frequency", as well as "Alzheimer's disease" and "seizures". In addition, therapeutic aspects for seizures in Alzheimer's disease were searched using the key words "antiepileptic drugs", "seizure treatment" and "Alzheimer". The prevalence and incidence rates of seizures were found to be increased 2 to 6-fold in patients with Alzheimer's disease compared to age-adjusted control patients. Treatment strategies have mainly been extrapolated from elderly patients without dementia, except for one single randomised trial, in which levetiracetam, lamotrigine and phenobarbital efficacy and tolerance were investigated in patients with Alzheimer's disease. Mouse models appear to show a major role of amyloid precursor protein and its cleavage products in the generation of cortical hyperexcitability. A link between Alzheimer's disease and epilepsy has long been described and recent cohort studies have more clearly delineated risk factors associated with the genesis of seizures, such as early onset and possibly severity of dementia. As genetic forms of Alzheimer's disease and experimental mouse models suggest, beta-amyloid may play a prominent role in the propagation of synchronised abnormal discharges, perhaps more via an excitatory mode than a direct neurodegenerative effect.

Modifications of Antiepileptic Drugs for Improved Tolerability and Efficacy

PubMed Central

Landmark, Cecilie Johannessen; Johannessen, Svein I.

2008-01-01

Introduction A large number of antiepileptic drugs (AEDs) are available today, but they may not be satisfactory regarding clinical efficacy, tolerance, toxicity or pharmacokinetic properties. The purpose of this review is to focus upon the rationale behind the chemical modifications of several recently marketed AEDs or drugs in development and to categorize them according to the main purposes for the improvements: better efficacy or tolerability accompanied by improved pharmacokinetic properties. Material and Method AEDs that have been chemically modified to new derivatives during the last years are reviewed based on recent publications and PubMed-searches. Results and Discussion Improvement in pharmacokinetic parameters may affect both tolerability and efficacy. Modifications to improve tolerability include various valproate analogues, divided into aliphatic amides, cyclic derivatives or amino acid conjugates. Furthermore, there are the carbamazepine analogues oxcarbazepine and eslicarbazepine, the felbamate analogues fluorofelbamate and carisbamate (RWJ 33369), and the lamotrigine analogue JZP-4. The levetiracetam analogues brivaracetam and seletracetam and the derivatives of gabapentin, pregabalin and XP13512, have improved selectivity compared to their parent compounds. Other new drugs have new mechanisms of action related to GABA and glutamate receptors; the glutamate antagonists like topiramate (talampanel and NS-1209), and GABAA receptor agonists, benzodiazepine or progesterone analogues (ELB-139 and ganaxolone). Conclusion Further challenges for development of new AEDs include investigations of target molecules affected by pathophysiological processes and detailed structure-activity relationships with focus on stereoselectivity. These potential drugs may become of importance in future drug therapy in epilepsy and other CNS disorders. PMID:19787095

New onset paediatric epilepsy in 1-5 years age group children--approach to management in a tertiary care centre with newer anti-epileptic levetiracetam.

PubMed

Barik, Kanai Lal; Paul, Uttam Kumar; Bhattacharyya, Anup Kumar; Adhikary, Amit; Agarwal, Gajanand; Rana, Kriti Sundar

2014-02-01

Epilepsy is a common paediatric neurologic disorder that is difficult to manage in a substantial portion of children, highlighting the continued need for more effective and better tolerated drugs. A multicentric study was conducted from August, 2011 to July, 2013 using levetiracetam (LEV) in newely diagnosed epilepsy in 122 young children of 1-5 years age group to find its role in practical scenario depending upon the knowledge from prior literature available. It has been demonstrated effective as adjunctive therapy as well as monotherapy for new-onset partial seizures and generalised tonic-clonic seizures (GTCS) but it acts better as adjunctive therapy than the monotherapy. When LEV was used as adjunctive therapy 15.4% children with partial seizure were seizure-free as compared to 11.12% in GTCS and when LEV was used as monotherapy 16.17% children with partial seizure were seizure-free as compared to 15.38% in GTCS. When LEV was used as add on therapy 16.67% children < 2 years were seizure-free as compared to 17.85% in > 2 years. When LEV was used as monotherapy 25.00% children < 2 years were seizure-free as compared to 18.18% > 2 years. So, it was found more efficacious in partial group of seizures than the GTCS variety. It also shows more efficacy in older age group (> 2 years) than the younger ones (< 2 years). Somnolence and behavioural changes were noted as ad- verse effects in a few cases. So, LEV is an important addition to the treatment of paediatric epilepsy.

Inverted-U response of lacosamide on pilocarpine-induced status epilepticus and oxidative stress in C57BL/6 mice is independent of hippocampal collapsin response mediator protein-2.

PubMed

Nirwan, Nikita; Siraj, Fouzia; Vohora, Divya

2018-06-18

Currently, lacosamide (LCM) is not approved for use in status epilepticus (SE) but several shreds of evidence are available to support its use. The present study was, therefore, undertaken to evaluate the effect of LCM on pilocarpine (PILO) induced SE and neurodegeneration in C57BL/6 mice and to ascertain the involvement of CRMP-2 in mediating above effect. Pilocarpine-induced SE model was developed to explore the effect of LCM 20, 40 and 80 mg/kg in mice. We assessed the seizure severity, seizure latency, spontaneous alternation behavior (SAB) and motor coordination by behavioral observation. Histopathological evaluation and measurement of the levels of CRMP-2, reduced glutathione (GSH) and malondialdehyde (MDA) were carried out in mice hippocampus. LCM exhibited a biphasic effect i.e., protection against SE at 20 mg/kg and 40 mg/kg dose whilst aggravated seizure-like behavior and mortality at 80 mg/kg. Further, it increased percentage alternation (i.e., restored spatial memory) in SAB and elevated motor impairment with increasing dose. Histologically, LCM 20 mg/kg and 40 mg/kg (but not 80 mg/kg) reduced neurodegeneration. LCM 20 mg/kg and 40 mg/kg reversed the elevated MDA and GSH levels while 80 mg/kg showed a tendency to increase oxidative stress. In contrast, LCM (at all doses) reversed the pilocarpine-induced elevation of collapsin response mediator protein-2 (CRMP-2). LCM protected against pilocarpine-induced SE, associated neurodegeneration and improved pilocarpine-associated impairment of spatial memory. The study reveals that CRMP-2 may not be mediating the inverted-U-response of LCM at least in pilocarpine model. Therefore, the anti-oxidant effect of LCM (and not its ability to modulate CRMP-2) was anticipated as the mechanism underlying neuroprotection. Copyright © 2018 Elsevier B.V. All rights reserved.

Neurological adverse events of new generation sodium blocker antiepileptic drugs. Meta-analysis of randomized, double-blinded studies with eslicarbazepine acetate, lacosamide and oxcarbazepine.

PubMed

Zaccara, Gaetano; Giovannelli, Fabio; Maratea, Dario; Fadda, Valeria; Verrotti, Alberto

2013-09-01

Analysis of overall tolerability and neurological adverse effects (AEs) of eslicarbazepine acetate (ESL), lacosamide (LCM) and oxcarbazepine (OXC) from double-blind, placebo-controlled trials. Indirect comparisons of patients withdrawing because of AEs, and the incidence of some vestibulocerebellar AEs between these three antiepileptic dugs (AEDs). We searched MEDLINE for all randomized, double-blind, placebo-controlled trials investigating therapeutic effects of fixed oral doses of ESL, LCM and OXC in patients with drug resistant epilepsy. Withdrawal rate due to AEs, percentages of patients with serious AEs, and the proportion of patients experiencing any neurological AE, nausea and vomiting were assessed for their association with the experimental drug. Analyses were performed between recommended daily doses of each AED according to the approved summary of product characteristics (SPC). Risk differences were used to evaluate the association of any AE [99% confidence intervals (CIs)] or study withdrawals because of AEs (95% CIs) with the experimental drug. Indirect comparisons between withdrawal rate and AEs dizziness, coordination abnormal/ataxia and diplopia were estimated according to network meta-analysis (Net-MA). Eight randomized, placebo-controlled, double-blind trials (4 with ESL, 3 with LCM, and 1 with OXC) were included in our analysis. At high doses (OXC 1200mg, ESL 1200mg and LCM 400mg) there was an increased risk of AE-related study withdrawals compared to placebo for all drugs. Several AEs were associated with the experimental drug. Both number and frequency of AEs were dose-related. At high recommended doses, patients treated with OXC withdrew from the experimental treatment significantly more frequently than patients treated with ESL and LCM. Furthermore, the AEs coordination abnormal/ataxia and diplopia were significantly more frequently observed in patients treated with OXC compared to patients treated with LCM and ESL. The overall tolerability

The Antiepileptic Drug Levetiracetam Suppresses Non-Convulsive Seizure Activity and Reduces Ischemic Brain Damage in Rats Subjected to Permanent Middle Cerebral Artery Occlusion

PubMed Central

Cuomo, Ornella; Rispoli, Vincenzo; Leo, Antonio; Politi, Giovanni Bosco; Vinciguerra, Antonio; di Renzo, Gianfranco; Cataldi, Mauro

2013-01-01

The antiepileptic drug Levetiracetam (Lev) has neuroprotective properties in experimental stroke, cerebral hemorrhage and neurotrauma. In these conditions, non-convulsive seizures (NCSs) propagate from the core of the focal lesion into perilesional tissue, enlarging the damaged area and promoting epileptogenesis. Here, we explore whether Lev neuroprotective effect is accompanied by changes in NCS generation or propagation. In particular, we performed continuous EEG recordings before and after the permanent occlusion of the middle cerebral artery (pMCAO) in rats that received Lev (100 mg/kg) or its vehicle immediately before surgery. Both in Lev-treated and in control rats, EEG activity was suppressed after pMCAO. In control but not in Lev-treated rats, EEG activity reappeared approximately 30-45 min after pMCAO. It initially consisted in single spikes and, then, evolved into spike-and-wave and polyspike-and-wave discharges. In Lev-treated rats, only rare spike events were observed and the EEG power was significantly smaller than in controls. Approximately 24 hours after pMCAO, EEG activity increased in Lev-treated rats because of the appearance of polyspike events whose power was, however, significantly smaller than in controls. In rats sacrificed 24 hours after pMCAO, the ischemic lesion was approximately 50% smaller in Lev-treated than in control rats. A similar neuroprotection was observed in rats sacrificed 72 hours after pMCAO. In conclusion, in rats subjected to pMCAO, a single Lev injection suppresses NCS occurrence for at least 24 hours. This electrophysiological effect could explain the long lasting reduction of ischemic brain damage caused by this drug. PMID:24236205

Antiepileptic drug therapy in patients with autoimmune epilepsy

PubMed Central

López Chiriboga, A. Sebastian; Britton, Jeffrey W.

2017-01-01

Objective: We aimed to report the pattern of usage and efficacy of antiepileptic drugs (AEDs) in patients with autoimmune epilepsy (AE). Methods: We retrospectively studied the Mayo Clinic's electronic medical record of patients with AE in which seizures were the main presenting feature. Clinical data, including demographics, seizure characteristics, type of AED and immunotherapy used, presence of neural antibody, and treatment outcomes, were reviewed. Results: The medical records of 252 adult patients diagnosed with autoimmune encephalitis and paraneoplastic disorders were reviewed. Seizure was the initial presentation in 50 patients (20%). Serum and/or CSF autoantibodies were detected in 41 (82%) patients, and 38 (76%) patients had neural autoantibodies. The majority (n = 43, 86%) received at least 1 form of immunotherapy in combination with AEDs, while the remainder received AEDs alone. Twenty-seven patients (54%) became seizure free: 18 (36%) with immunotherapy, 5 (10%) with AEDs alone, and 4 (8%) with AEDs after immunotherapy failure. Levetiracetam was the most commonly used (42/50); however, it was associated with 0% seizure-free response. AED seizure-free responses occurred with carbamazepine (n = 3) [3/16, 18.8%], lacosamide (n = 3) [3/18, 16.6%] with phenytoin (n = 1) [1/8, 12.5%], or oxcarbazepine (n = 2) [2/11, 18.1%]. Regardless of the type of therapy, voltage-gated potassium channel-complex antibody–positive patients were more likely to become seizure free compared with glutamic acid decarboxylase 65 antibody–positive cases (12/17 vs 2/10, p = 0.0183). Conclusions: In select patients, AEDs alone were effective in controlling seizures. AEDs with sodium channel blocking properties resulted in seizure freedom in a few cases. Prospective studies are needed to clarify AED selection and to elucidate their immunomodulatory properties in AE. PMID:28680914

Efficacy and tolerability of anti-epileptic drugs-an internet study.

PubMed

Wieshmann, U C; Baker, G

2017-05-01

To ascertain efficacy and tolerability of carbamazepine (CBZ), sodium valproate (VPA), lamotrigine (LTG) and levetiracetam (LEV) using the UKAED register (www.ukaed.info). Patients on CBZ (n=91), VPA (n=61), LTG (n=105), LEV (n=72) and healthy control subjects (CTR) on no medication (n=51) were extracted. All patients had anonymously provided information on seizure type and frequency and completed the Liverpool Adverse Event Profile (LAEP). The number of seizure-free patients in the last 4 weeks was overall CBZ/VPA/LTG/LEV=60%/79%/67%/67%, for generalized epilepsy was CBZ/VPA/LTG/LEV=67%/89%/65%/94%, and for localization-related epilepsy was CBZ/VPA/LTG/LEV=59%/71%/67%/57%. Mean LAEP scores were CBZ/VPA/LTG/LEV/CTR=42.21/39.66/39.86/43.01/29.69. The mean LAEP was significantly higher in patients reporting depression and in patients with active epilepsy than in patients without depression and remission. Central nervous system (CNS) adverse effects including memory problems, difficulty concentrating, depression, unsteadiness, restlessness, feelings of anger, shaky hands and dizziness were significantly more frequent in CBZ, VPA, LTG and LEV than in CTR. The feeling of anger was significantly more frequent in LEV, and depression was significantly more frequent in CBZ compared to the other drugs. In this Internet-based register of self-reported efficacy and tolerability, CBZ, VPA, LTG and LEV were similar. Self-reported CNS adverse effects were significantly more frequent than in controls. In addition, anger was associated with LEV and depression with CBZ. Confounding factors were depression and uncontrolled epilepsy. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Seizure-free outcome in randomized add-on trials of the new antiepileptic drugs.

PubMed

Gazzola, Deana M; Balcer, Laura J; French, Jacqueline A

2007-07-01

The goal of this study is to (1) provide clinically useful, previously unpublished comparative analyses of seizure-freedom rates for newer antiepileptic drugs (AEDs), and (2) recommend a standard for data presentation and analysis. Data were reviewed from placebo-controlled adjunctive trials in refractory patients of gabapentin (GPN), lamotrigine (LTG), topiramate (TOP), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), zonisamide (ZNS), and pregabalin (PGB). Seizure-freedom analyses in these publications, if included at all, consistently included both patients who completed the trial, and those who dropped out prior to completion (last observation carried forward, LOCF). This has the potential to increase reported seizure-free outcomes. Pharmaceutical companies were contacted for the provision of unpublished seizure-free data in the patients who completed the entire study. In most cases, LOCF analysis produced a higher rate of seizure freedom compared to complete analysis. A total of 0%-1.1% of the LOCF population was seizure-free in the GPN trials (complete data not available). For the remaining AEDs, seizure-freedom results in the LOCF versus complete populations were: 0.7% versus 0.8% (LTG trial); 12% versus 2.6% (OXC trial); 3.6%-6.4% versus 3.9%-7.1% (LEV trial); 3.7%-7.9% versus 1.3%-1.4% (PGB trial); and 6.0% versus 3.0% (ZNS trial, minus titration period). By employing LOCF, a clinically unrealistic picture of seizure-free rates may be reported. Access to complete data is informative, as it includes only those patients who were able to tolerate the drug at doses that produced seizure freedom. Ideally, data from both ITT and complete analyses should be made available.

Effect of the Anti-depressant Sertraline, the Novel Anti-seizure Drug Vinpocetine and Several Conventional Antiepileptic Drugs on the Epileptiform EEG Activity Induced by 4-Aminopyridine.

PubMed

Sitges, Maria; Aldana, Blanca Irene; Reed, Ronald Charles

2016-06-01

Seizures are accompanied by an exacerbated activation of cerebral ion channels. 4-aminopyridine (4-AP) is a pro-convulsive agent which mechanism of action involves activation of Na(+) and Ca(2+) channels, and several antiepileptic drugs control seizures by reducing these channels permeability. The antidepressant, sertraline, and the anti-seizure drug vinpocetine are effective inhibitors of cerebral presynaptic Na(+) channels. Here the effectiveness of these compounds to prevent the epileptiform EEG activity induced by 4-AP was compared with the effectiveness of seven conventional antiepileptic drugs. For this purpose, EEG recordings before and at three intervals within the next 30 min following 4-AP (2.5 mg/kg, i.p.) were taken in anesthetized animals; and the EEG-highest peak amplitude values (HPAV) calculated. In control animals, the marked increase in the EEG-HPAV observed near 20 min following 4-AP reached its maximum at 30 min. Results show that this epileptiform EEG activity induced by 4-AP is prevented by sertraline and vinpocetine at a dose of 2.5 mg/kg, and by carbamazepine, phenytoin, lamotrigine and oxcarbazepine at a higher dose (25 mg/kg). In contrast, topiramate (25 mg/kg), valproate (100 mg/kg) and levetiracetam (100 mg/kg) failed to prevent the epileptiform EEG activity induced by 4-AP. It is concluded that 4-AP is a useful tool to elicit the mechanism of action of anti-seizure drugs at clinical meaningful doses. The particular efficacy of sertraline and vinpocetine to prevent seizures induced by 4-AP is explained by their high effectiveness to reduce brain presynaptic Na(+) and Ca(2+) channels permeability.

Antidepressants and mood stabilizers effects on histone deacetylase expression in C57BL/6 mice: Brain region specific changes.

PubMed

Ookubo, Masanori; Kanai, Hirohiko; Aoki, Harusuke; Yamada, Naoto

2013-09-01

To determine whether treatment with various antidepressants or mood stabilizers leads to region-specific changes, we investigated the effects of their subchronic (14 days of intraperitoneal injection) administration on the tissue concentration of monoamines, dopamine, serotonin, and norepinephrine, and the protein expression of acetylated histone H3 (AcH3) and histone deacetylases (HDACs) in the mouse striatum (ST), nucleus accumbens (Acb), hippocampus (Hip), cingulate cortex (Cg), and amygdala (Amy). Subchronic administration with the antidepressants (S)-citalopram oxalate (ECM), duloxetine hydrochloride (DLX), and mirtazapine (MIR) commonly induced significant increases in dopamine and serotonin levels in the ST and Cg. By contrast, no common profiles for dopamine, serotonin, or norepinephrine were identified in the Acb, Hip, or Amy. Treatment with sodium valproate (VPA), lithium chloride (Li), lamotrigine (LTG), levetiracetam (LTM), olanzapine (OLZ), clozapine (CLZ), clomipramine (CLM), ECM, and DLX induced significant increases in AcH3 expression in the Acb, while treatment with CLM, ECM, DLX, MIR, carbamazepine (CBZ), LTG, LTM, OLZ, or CLZ induced significant increases in HDAC2 and HDAC3 in the ST. CLM, MIR, VPA, CBZ, LTG, LTM, OLZ, or CLZ induced significant increases in HDAC3 in the Cg, and ECM, DLX, MIR, VPA, CBZ, LTG, LTM, or OLZ resulted in significant increases in HDAC5 in the Amy. Collectively, the changes of monoamine content were restricted for mood stabilizer effects, but increased expression of HDAC2, HDAC3, or HDAC5 in the ST, Cg, or Amy was often found, supporting the possibility that antidepressant-like effects involve epigenetic modifications associated with changes in HDAC expression. Copyright © 2013 Elsevier Ltd. All rights reserved.

Simultaneous determination of ten antiepileptic drugs in human plasma by liquid chromatography and tandem mass spectrometry with positive/negative ion-switching electrospray ionization and its application in therapeutic drug monitoring.

PubMed

Yin, Lei; Wang, Tingting; Shi, Meiyun; Zhang, Ying; Zhao, Xiaojun; Yang, Yan; Gu, Jingkai

2016-03-01

A simple, rapid, and high-throughput liquid chromatography with tandem mass spectrometry method for the simultaneous quantitation of ten antiepileptic drugs in human plasma has been developed and validated. The method required only 10 μL of plasma. After simple protein precipitation using acetonitrile, the analytes and internal standard diphenhydramine were separated on a Zorbax SB-C18 column (50 × 4.6 mm, 2.7 μm) using acetonitrile/water as the mobile phase at a flow rate of 0.9 mL/min. The total run time was 6 min for each sample. The validation results of specificity, matrix effects, recovery, linearity, precision, and accuracy were satisfactory. The lower limit of quantification was 0.04 μg/mL for carbamazepine, 0.02 μg/mL for lamotrigine, 0.01 μg/mL for oxcarbazepine, 0.4 μg/mL for 10-hydroxycarbazepine, 0.1 μg/mL for carbamazepine-10,11-epoxide, 0.15 μg/mL for levetiracetam, 0.06 μg/mL for phenytoin, 0.3 μg/mL for valproic acid, 0.03 μg/mL for topiramate, and 0.15 μg/mL for phenobarbital. The intraday precision and interday precision were less than 7.6%, with the accuracy ranging between -8.1 and 7.9%. The method was successfully applied to therapeutic drug monitoring of 1237 patients with epilepsy after administration of standard antiepileptic drugs. The method has been proved to meet the high-throughput requirements in therapeutic drug monitoring. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Determination of a selection of anti-epileptic drugs and two active metabolites in whole blood by reversed phase UPLC-MS/MS and some examples of application of the method in forensic toxicology cases.

PubMed