Second-generation Antiepileptic Drugs Research Articles

The Frequency and Structure of Adverse Drug Reactions in the Pharmacotherapy of Epilepsy

The problem of the safety of antiepileptic therapy due to the duration of treatment and the need for regular intake of antiepileptic drugs (AEDs) is extremely significant. Adverse reactions (ADRs) may outweigh any positive effect of therapy associated with seizure reduction. The purpose of the study: to analyze the frequency and structure of ADRs of AEDs. Materials and Methods: The work was carried out within the framework of comprehensive research on the topic No. 210-16 "Epidemiological, genetic and neurophysiological aspects of diseases of the nervous system (central, peripheral and vegetative) and preventive medicine" (registration number 0120.0807480). Results: The frequency of ADRs against the background of third-generation AEDs was not inferior to that against the background of receiving second-generation AEDs, while the structure of ADRs was different: third-generation AEDs had a higher incidence of ADRs from the central nervous system, including a worsening of the course of epilepsy. The ratio of the chances of valproic acid accumulation with the achievement of toxic concentration in the blood and the development of un-desirable side effects in poor metabolizers (carriers of the polymorphism of CYP2C9*2 or CYP2C9*3) the gene encoding the cytochrome P450 isoenzyme 2C9 of the liver is 5.94 and 4.27, respectively. Conclusion: A personalized approach to ensuring the safety of valproic acid preparations based on taking into account the carriage of polymorphisms of the CYP2C9 gene allows to reduce the incidence of ADRs in patients receiving valproic acid preparations from 59.28% to 10.78%. The introduction of a personalized approach to the administration of valproates to patients suffering from epilepsy in the Krasnoyarsk Territory did not lead to an increase in direct costs.

Radiolabeling of Zonisamide for a Diagnostic Perspective.

Epilepsy is one of the oldest and the most common chronic neurological diseases. Antiepileptic drugs (AEDs) are the backbone of epilepsy treatment. However, epileptogenesis has not been fully elucidated. One of the critical reasons for this is the lack of reliable biomarkers. Neuroimaging suggests a non-invasive examination and investigation tool that can detect critical pathophysiological changes involved in epileptogenesis and monitor disease progression. In the current study, the radiolabeling potential of Zonisamide (ZNS) (the secondgeneration AED) with Technetium-99m (99mTc) is examined to neuroimage the epileptogenic processes by contributing to the development of potential radiotracers. ZNS was labeled with 99mTc and the radiochemical yield of [99mTc]Tc-ZNS was determined with TLRC (Thin Layer Liquid Radio Chromatography and HPLRC (High Performance Liquid Radio Chromatography) radiochromatographic methods. In vitro behavior of [99mTc]Tc-ZNS was determined with time-dependent uptake of [99mTc]Tc-ZNS on the SHSY5Y human neuroblastoma cells. The radiochemical yield of [99mTc]Tc-ZNS was determined as 98.03 ± 1.24% (n = 6) according to radiochromatographic studies results. [99mTc]Tc-ZNS demonstrated 5.38 and 6.18 times higher uptake values than the control group on the human neuroblastoma SH-SY5Y cell line at 120 and 240 minutes, respectively. This study showed that the current radiolabeled antiepileptic drug has a diagnostic potential to be used in imaging neurological processes.

Impact of levetiracetam on cognitive impairment, neuroinflammation, oxidative stress, and neuronal apoptosis caused by lipopolysaccharides in rats

IntroductionNeuroinflammation is associated with the elevation of toxic proinflammatory mediators that promote neurodegeneration and subsequently affect cognition. Causes of inflammation in the neuronal cells are believed to initiate various neurodegenerative disorders, mainly Alzheimer’s disease. Levetiracetam is a second-generation antiepileptic drug. There is evidence supporting the memory-enhancing effect of levetiracetam from numerous experimental and clinical studies. Therefore, this research focused on finding its protective effects against lipopolysaccharides prompted cognitive impairment and exploring possible mechanisms underlining their neuroprotection. MethodologyTwo doses (100 or 200 mg/kg) of levetiracetam were administrated orally for 30 days. Additionally, four doses (250 µg/kg) of lipopolysaccharide were injected peripherally to induce neurotoxicity. Behavioral tests were carried out using various maze models. At the end of the tests, brain tissues were collected for biochemical evaluations. Cholinergic, neuroinflammatory, apoptosis, and oxidative-related parameters were analyzed in the brain homogenate to explore the possible mechanisms of action of levetiracetam. ResultsIn lipopolysaccharide-induced rats, levetiracetam indicated a reduction (p < 0.01) in transfer latency using the elevated plus-maze. An improvement (p < 0.01) in novel and familiar objects exploration time using novel object recognition test. A rise (p < 0.05) in novel arm entries and extended time spent in the novel arm using the Y-maze test. In extension, the levels of acetylcholine (p < 0.001), anti-inflammatory factors (transforming growth factor-β1; p < 0.01 and interleukin-10; p < 0.05), and an antioxidant (catalase; p < 0.01) were elevated in lipopolysaccharide-induced rats after the administration of levetiracetam. In contrast, inflammatory factors (cyclooxygenase-2; p < 0.05, nuclear factor kappa B; p < 0.05, tumor necrosis factor-α; p < 0.01, and interleukin-6 (p < 0.01), apoptosis inducers (BCL2-associated X protein; p < 0.05 and Caspase-3 (p < 0.001), and oxidative stress (malondialdehyde; p < 0.05) were considerably reduced with levetiracetam in lipopolysaccharide-induced rats. ConclusionThe collective results suggested that levetiracetam may be able to treat neuroinflammatory-related memory loss by enhancing cholinergic activity while reducing neuroinflammation, cellular apoptosis, and oxidative stress.

Investigating Neuroprotective Potential of Berberine, Levetiracetam and their Combination in the Management of Alzheimer's Disease Utilizing Drug Repurposing Strategy.

The aim of the present work was to evaluate the neuroprotective potential of berberine, levetiracetam and their combination in lead acetate-induced neurotoxicity by applying a drug repositioning approach. Alzheimer's disease (AD) is a neurodegenerative disease characterized by impairment of memory, disturbances in reasoning, planning, language and perception. Currently, there are only four drugs approved by US-FDA for AD; therefore, there is an extensive need for new drug development. The drug repositioning approach refers to the development of new uses for existing or abandoned pharmaceuticals. Several studies support the neuroprotective abilities of anti-oxidants resulting in neuronal protection against neurotoxins, suppression of oxidative stress and promotion of memory, learning and cognitive functions. Many natural polyphenols are being investigated as a potential therapeutic option for AD. Levetiracetam (LEV), a second-generation antiepileptic drug, is a new molecule that is clearly differentiated from conventional antiepileptic drugs by its pharmacologic properties. LEV also has been previously demonstrated to protect against oxidative stress-induced neurotoxicity in several models of seizures. Berberine (BBR) is an anti-inflammatory and anti-oxidant phytoconstituent. To study the therapeutic effect of berberine, levetiracetam and their physical mixture in lead acetate-induced neurotoxicity in Swiss albino mice for probable application in the management of Alzheimer's disease. Neurotoxicity was induced in Swiss albino mice by lead acetate. Behavioural parameters, such as transfer latency time and percentage alternation, were studied using Morris water maze (MWM), Elevated plus-maze test (EPM) and Y-maze for the assessment of improvement in learning and memory. Concentrations of acetylcholinesterase, MDA and GSH in the brain were also estimated. Brain samples were subjected to histopathological studies. Results revealed that the combination of BBR and LEV exhibited a significant neuroprotective effect by decreasing escape latency time and increasing time spent in the target quadrant in MWM. The combination also decreases transfer latency time in EPM and acetylcholinesterase levels in the brain as compared to standard donepezil. Reduced neuronal damage was also confirmed by the histopathological report. Leveteracitam, berberin and their combination resulted in the significant conservation of various behavioural, biochemical, enzymatic and anti-oxidant parameters that were evaluated. The neuroprotective effect of plain leveteracitam and berberin was significantly better than their combination. The anticipated synergism or additive effect was not observed with the combination of leveteracitam and berberin in lead acetate-induced neurotoxicity.

Cubosome-based thermosensitive in situ gelling system for intranasal administration of lamotrigine with enhanced antiepileptic efficacy

Lamotrigine (LTG) is a second-generation antiepileptic drug that belongs to Biopharmaceutics Classification System (BCS) class II. LTG has a low probability of crossing the BBB if administered orally. This study was designed to fabricate LTG cubosomal dispersion that is further loaded in a thermosensitive in situ gel to increase nasal residence time and enhance drug absorption across the nasal mucosal membrane. LTG-loaded cubosomes exhibited an entrapment efficiency ranging from 24.83% to 60.13%, a particle size ranging from 116.2 to 197.6 nm, and a zeta potential ≤ −25.5 mV. The selected LTG-loaded cubosomal formulation was loaded in a thermosensitive in situ gel (cubogel) employing different concentrations of poloxamer 407. In vitro release study revealed sustained drug release from cubosomal and cubogel compared with free drug suspension. In vivo studies revealed enhanced antiepileptic efficacy of LTG cubogel and LTG cubosomes compared with free drug in rats with pilocarpine-induced epilepsy by stimulating the release of gamma-aminobutyric acid (GABA), total antioxidant capacity (TAC), and serotonin and by inhibiting the release of Ca2+, dopamine, acetylcholine (Ach), C-reactive protein (CRP), and glial fibrillary acidic protein (GFAP). LTG cubogel exhibited superior activity over LTG cubosomes. These findings reveal that the developed cubosomal thermosensitive in situ gel can enhance the antiepileptic efficacy of LTG via the intranasal route.

A retrospective comparative fractal and radiomorphometric analysis of the effect of 3 generations of anti-epileptic drugs on the mandible

The present study investigated the possible impacts of anti-epileptic drugs (AEDs) on trabecular and cortical bone in the mandible. Fractal dimension (FD) and the radiomorphometric parameters of mandibular cortical width (MCW), panoramic mandibular index (PMI), and mandibular cortical index (MCI) were assessed on 497 dental panoramic radiographs (DPRs) of patients in the case group and controls. AEDs were compared according to 3 generations, duration of use, and patient age and sex. FD of the angle and body of the mandible and MCW were significantly lower in the case group than in the control group (P < .001). FD values in the ramus and angle were lower in first-generation and third-generation AEDs than in second-generation drugs (P ≤ .011). FD in the mandibular body was lower in first-generation and second-generation AED users than in third-generation drugs (P=.017). Drug use for at least 1 year resulted in significantly lower values for all FDs and MCW values and more class 3 MCI assessments than short-duration use, but PMI was higher with more than 1 year of AED use (P ≤ .020). Age and sex had no significant effects. AEDs caused significant changes in bone compared with controls in some FD values, MCW, and MCI. The effect of drug generation is pronounced in trabecular bone. Anti-epileptic drug use for more than 1 year had a greater effect than short-term use.

Is Levetiracetam Monotherapy Effective And Safe In Children With Epilepsy

Introduction: Levetiracetam a second-generation antiepileptic drug with a broad spectrum and a wide safety margin, is used in both focal and generalized seizure treatment. In this study, we decided determine efficacy, side effects and safety of levetiracetam monotherapy in children with epilepsy. Methods: The medical records of consecutive 102 patients who were treated with levetiracetam monotherapy were evaluated retrospectively. Results: Total of 102 patients on levetiracetam monotherapy, 50 (49%) girls and 52 (51%) boys, were evaluated. Median age of the patients is 121.5 (62.25-178.5) months. Majority of the patients (95.1%) had generalized epilepsy. Twenty-seven (26.5%) patients had concomitant neurological problems. Dosing of levetiracetam was 20-80 mg/kg/day. Twenty eight (27.5%) patients had adverse reactions. The most common side effects were nervousness (10.8%) and enuresis nocturna (3.9%). Nervousness (4.9%), enuresis nocturna (1%) and headache (1%) were the reason for discontinuation. Twenty four (51.1%) of abnormal pre-treatment EEG had recovered and 74 (72.5%) of patients were seizure free after levetiracetam treatment. There was a statistically significant difference between levetiracetam treatment pre- and post-EEG abnormality (p=0.001). All over 10 (9.8%) patients were discontinued the treatment due to adverse effects (n:7, 6.9%) and inefficacy (n:3, 3%) at the 12 month of the treatment. The retention rate was 90.2%. Conclusion: This study suggests that levetiracetam monotherapy had high percentage of seizure reduction, low rates of serious adverse events and inefficacy, significant difference on pre-treatment EEG recovery in children.

The Plasma Concentration Profiles and Pharmacokinetics of Levetiracetam among Thai Adult Patients Undergoing Intermittent Hemodialysis

Background: Levetiracetam is a second-generation antiepileptic drug that is primarily eliminated in urine via glomerular filtration and requires dose adjustment in patients with renal insufficiency. However, there are still a lack of evidence on pharmacokinetics including dialysis clearance of levetiracetam among patients undergoing intermittent hemodialysis. Objective: To assess the plasma concentrations and pharmacokinetic parameters of levetiracetam in patients undergoing intermittent hemodialysis. Materials and Methods: A pharmacokinetic study was conducted on six Thai adult patients receiving intermittent hemodialysis. The patients received levetiracetam 1,000 to 1,500 mg administered by intravenous injection once daily. Blood samples were obtained prior to hemodialysis, during the hemodialysis session, and post-hemodialysis to investigate levetiracetam pharmacokinetic parameters in each phase of treatments. Results: Five of six patients had residual urine volume of more than 50 mL/day. The Pharmacokinetic parameters derived from the present study were as followed, the median dialysis clearance was 9.07 L/hour (IQR 7.13, 12.17), the median elimination rate constant (Ke) was 0.30 hour⁻¹ (IQR 0.24, 0.56), and the median elimination halflife (t½) during hemodialysis session was 2.34 hours (IQR 1.25, 2.91). The present study found the median percentage of levetiracetam plasma concentration reduction after four hours of hemodialysis was 76.89% (IQR 69.02, 85.43). Overall, plasma concentration of levetiracetam was decreased during intermittent hemodialysis sessions. Conclusion: The findings of the present study support the use of LEV dosing of 1,000 to 1,500 mg/day and a supplemental dose after each hemodialysis session should be considered. Levetiracetam dose reduction in patients undergoing intermittent hemodialysis will lead to subtherapeutic plasma concentrations. Levetiracetam plasma concentration should be monitored in patients receiving intermittent hemodialysis. Keywords: Levetiracetam; Hemodialysis; Pharmacokinetics; Antiepileptic drug

Drug Utilization and Evaluation of Antiepileptic Drugs in a Tertiary Care Hospital

Abstract: Aim: Drug utilization and evaluation (DUE) study of antiepileptic drugs in a tertiary care hospital. Methods: A total of 110 case records of patients were included in a prospective observational study which was conducted for duration of 6 months. The prescription pattern was analyzed based on age, gender, route of administration, indication, duration of therapy, type of seizures, generation of Anti-Epileptic Drugs (AEDs), and rationality. Results: AEDs were prescribed more for patients between the ages of 51-60 years. The majority of patients receiving AEDs were males and AEDs were mostly used in the neurology department followed by neurosurgery and general medicine. Levetiracetam was prescribed most commonly as monotherapy. Lorazepam and midazolam were the most common add-on drugs. Gabapentin was mostly prescribed for severe neuropathic pain. The oral route was the common route of administration of AEDs. AEDs were highly prescribed for prophylaxis of seizures. Second-generation AEDs were highly used compared to other drugs. Conclusion: Second-generation AEDs were used as monotherapy and were found to be effective in reducing seizures and economically affordable for patients. As monotherapy, levetiracetam was the drug of choice followed by lorazepam. Keywords: Drug Utilization Evaluation (DUE), Epilepsy, Antiepileptic drugs, Levetiracetam, Phenytoin, Seizures.

Felbamate add-on therapy for drug-resistant focal epilepsy.

This is an updated version of the Cochrane Review first published in 2011, and most recently updated in 2019. Epilepsy is a chronic and disabling neurological disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available antiepileptic drugs and require treatment with multiple antiepileptic drugs in combination. Felbamate is a second-generation antiepileptic drug that can be used as add-on therapy to standard antiepileptic drugs. To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with drug-resistant focal-onset epilepsy. For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 13 July 2021) on 15 July 2021. There were no language or time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. We searched for randomised placebo-controlled add-on studies of people of any age with drug-resistant focal seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel-group or cross-over design. Two review authors independently selected studies for inclusion and extracted information. In the case of disagreements, a third review author arbitrated. Review authors assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. We included four randomised controlled trials, representing a total of 236 participants, in the review. Two trials had parallel-group design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. We judged all four studies to be at an unclear risk of bias overall. Bias arose from the incomplete reporting of methodological details, the incomplete and selective reporting of outcome data, and from participants having unstable drug regimens during experimental treatment in one trial. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the extracted data. Only one study reported the outcome of 50% or greater reduction in seizure frequency, whilst three studies reported percentage reduction in seizure frequency compared to placebo. One study claimed an average seizure reduction of 35.8% with add-on felbamate whilst another study claimed a more modest reduction of 4.2%. Both studies reported that seizure frequency increased with add-on placebo and that there was a significant difference in seizure reduction between felbamate and placebo (P = 0.0005 and P = 0.018, respectively). The third study reported a 14% reduction in seizure frequency with add-on felbamate but stated that the difference between treatments was not significant. There were conflicting results regarding treatment withdrawal. One study reported a higher treatment withdrawal for placebo-randomised participants, whereas the other three studies reported higher treatment withdrawal rates for felbamate-randomised participants. Notably, the treatment withdrawal rates for felbamate treatment groups across all four studies remained reasonably low (less than 10%), suggesting that felbamate may be well tolerated. Felbamate-randomised participants most commonly withdrew from treatment due to adverse effects. The adverse effects consistently reported by all four studies were headache, dizziness and nausea. All three adverse effects were reported by 23% to 40% of felbamate-treated participants versus 3% to 15% of placebo-treated participants. We assessed the evidence for all outcomes using GRADE and rated the evidence as very low certainty, meaning that we have little confidence in the findings reported. We mainly downgraded evidence for imprecision due to the narrative synthesis conducted and the low number of events. We stress that the true effect of felbamate could likely be significantly different from that reported in this current review update. In view of the methodological deficiencies, the limited number of included studies and the differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with drug-resistant focal-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.

Management of epilepsy in brain tumor patients.

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

Особенности применения ламотриджина в современном лечении эпилепсии

Более 70 млн человек во всем мире страдают от эпилепсии — обременительного неврологического заболевания, которое может влиять на продолжительность жизни и приводить к инвалидности. Ламотриджин — это современный противоэпилептический препарат второго поколения. По сравнению с препаратами первого поколения (фенобарбитал, фенитоин, примидон, карбамазепин, вальпроат) он отличается меньшим количеством побочных эффектов и лучшей переносимостью. Основной механизм действия ламотриджина связан с блокированием натриевых каналов. К тому же известно его влияние на кальциевые каналы, ГАМКергические, серотонинергические эффекты. Комплексный механизм действия обусловливает широкий спектр показаний при эпилепсии, то есть возможно купирование как генерализованных, так и фокальных приступов. Ламотриджин отличается линейной фармакокинетикой. Он быстро и хорошо всасывается при приеме внутрь: общая биодоступность при пероральном приеме составляет 98 %, максимальная концентрация в плазме крови достигается через 1–3 ч после приема. На сегодня ламотриджин имеет убедительно доказанную эффективность как противоэпилептический препарат (как в монотерапии, так и в составе комбинированной терапии) при первично-генерализованных тонико-клонических, простых и сложных парциальных, вторично-генерализованных припадках, абсансах и атипичных абсансах, миоклонических приступах, а также при синдроме Леннокса — Гасто у пациентов в возрасте 2 лет и старше. Не менее важно и то, что ламотриджин также эффективен при ассоциированных с эпилепсией психических нарушениях: эпилептической депрессии, эпилептической дисфории, эпилептических психозах, психомоторных и соматовегетативных эквивалентах приступов. Итак, ламотриджин является одним из новейших противоэпилептических препаратов, который эффективно применяется при лечении эпилепсии у детей и взрослых.

Vigabatrin - new data on indications and safety in paediatric epilepsy.

Vigabatrin (VGB), a second-generation antiepileptic drug, is effective for the treatment of infantile spasms and focal seizures, primarily in tuberous sclerosis complex (TSC) patients. However, reports of adverse events of VGB, including VGB-associated visual field loss and brain abnormalities in neuroimaging, have raised concerns about the broader use of VGB and thus significantly limited its application. The goal of this review was to summarise the recent therapeutic guidelines, the use of VGB in focal seizures and new VGB applications as a disease-modifying treatment in TSC patients. Moreover, we discuss the current opinions on potential VGB-associated toxicity and the safety of VGB.

Treating Status Epilepticus: Phenytoin Versus Levetiracetam.

For decades, phenytoin has been the drug of choice for the treatment of epilepsy but also the second-line treatment for status epilepticus (SE). However, newer antiepileptic drugs (AEDs) have emerged as safer alternatives for the suppression of seizures. Consequently, phenytoin has recently fallen under scrutiny in the research world, prompting many studies to compare its efficacy to these other drugs, most notably levetiracetam. Levetiracetam is a second-generation AED, which is gaining wide clinical use as the second-line agent in treating SE patients. This review focuses on several clinical studies that have directly compared the effectiveness of phenytoin and levetiracetam in suppressing SE seizure activity. Additionally, this review highlights several advantages of using levetiracetam over phenytoin in this clinical context.

Interactions among Lacosamide and Second-Generation Antiepileptic Drugs in the Tonic-Clonic Seizure Model in Mice.

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

Sotalol does not interfere with the antielectroshock action of selected second-generation antiepileptic drugs in mice

BackgroundDue to blocking β-receptors, and potassium KCNH2 channels, sotalol may influence seizure phenomena. In the previous study, we have shown that sotalol potentiated the antielectroshock action of phenytoin and valproate in mice.Materials and methodsAs a continuation of previous experiments, we examined the effect of sotalol on the action of four chosen second-generation antiepileptic drugs (oxcarbazepine, lamotrigine, pregabalin, and topiramate) against the maximal electroshock in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay, while those of sotalol by liquid chromatography–mass spectrometry.ResultsSotalol at doses of up to 100 mg/kg did not affect the electroconvulsive threshold. Applied at doses of 80–100 mg/kg, sotalol did not affect the antielectroshock action of oxcarbazepine, lamotrigine, pregabalin, or topiramate. Sotalol alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory. Finally, sotalol significantly decreased the brain concentrations of lamotrigine and increased those of oxcarbazepine and topiramate. Pharmacokinetic interactions, however, did not influence the final antielectroshock effects of above-mentioned drug combinations. On the other hand, the brain concentrations of sotalol were not changed by second-generation antiepileptics used in this study.ConclusionSotalol did not reduce the antielectroshock action of four second-generation antiepileptic drugs examined in this study. Therefore, this antidepressant drug should not interfere with antiseizure effects of lamotrigine, oxcarbazepine, pregabalin, and topiramate in patients with epilepsy. To draw final conclusions, our preclinical data should still be confirmed in other experimental models and clinical conditions.

Levetiracetam monotherapy in children with epilepsy: Experience from a tertiary pediatric neurology center

ObjectivesLevetiracetam (LEV) is a second-generation antiepileptic drug with high efficacy and tolerability in children and adults with epilepsy. We aimed to retrospectively assess the long-term efficacy, tolerability, and safety of LEV monotherapy in children with epilepsy. MethodsAll patients who received LEV monotherapy at the Ankara University Children Hospital between January 2010 and June 2020 were evaluated. This retrospective pediatric cohort study determined the efficacy and safety of LEV monotherapy in 281 outpatients with epilepsy. ResultsThere were 281 patients, 50.5% female, aged 5 months to 18 years with a mean age of 9 years. Of these, 48% of patients had idiopathic epilepsy, 40.6% had symptomatic epilepsy, and 11,4% had cryptogenic/genetic epilepsy. Primary generalized seizures occurred in 61.6% of patients, focal seizures in 19.6%, both generalized and focal seizures in 15,3%, focal to bilateral tonic-clonic seizures in 2.5%, and undefined type of seizure in 1.1%. A total of 22.8% patients had an accompanying extra neurological disease, mostly cardiological and hematological. The range of final daily dose was 10–71 mg/kg/day, with mean 29.5 mg/kg/day. Duration of therapy ranged from 7 days to 96 months, with median 12 months (IQR: 6–22). For the all cohort, a 6th month retention rate was 81%, a 12th month retention rate was 71.4%, and a 24th month retention rate was 61.8%. Eighty five percent of the patients had a seizure reduction of at least 50% and 55.9% of patients remained seizure-free for median 12 months treatment duration with LEV monotherapy. Improvement of electroencephalography (EEG) findings was found in 42% of patients on control EEGs. A total of 67 adverse events were documented in 45 (16%) patients. The most common adverse events were behavioral problems such as aggression (n:18) and irritability (n:17). The discontinuation rate due to adverse events was 2.5%, and due to inefficacy was 5.3%. ConclusionThe present study suggests that the high retention rates, high percentage of seizure reduction, the low discontinuation rate due to adverse events and inefficacy, and the relatively benign and transient profile of adverse events make LEV preferable as monotherapy in the pediatric population.

Amiodarone Enhances Anticonvulsive Effect of Oxcarbazepine and Pregabalin in the Mouse Maximal Electroshock Model.

Accumulating experimental studies show that antiarrhythmic and antiepileptic drugs share some molecular mechanisms of action and can interact with each other. In this study, the influence of amiodarone (a class III antiarrhythmic drug) on the antiseizure action of four second-generation antiepileptic drugs was evaluated in the maximal electroshock model in mice. Amiodarone, although ineffective in the electroconvulsive threshold test, significantly potentiated the antielectroshock activity of oxcarbazepine and pregabalin. Amiodarone, given alone or in combination with oxcarbazepine, lamotrigine, or topiramate, significantly disturbed long-term memory in the passive-avoidance task in mice. Brain concentrations of antiepileptic drugs were not affected by amiodarone. However, the brain concentration of amiodarone was significantly elevated by oxcarbazepine, topiramate, and pregabalin. Additionally, oxcarbazepine and pregabalin elevated the brain concentration of desethylamiodarone, the main metabolite of amiodarone. In conclusion, potentially beneficial action of amiodarone in epilepsy patients seems to be limited by neurotoxic effects of amiodarone. Although results of this study should still be confirmed in chronic protocols of treatment, special precautions are recommended in clinical conditions. Coadministration of amiodarone, even at low therapeutic doses, with antiepileptic drugs should be carefully monitored to exclude undesired effects related to accumulation of the antiarrhythmic drug and its main metabolite, desethylamiodarone.

Correlation of elevated lamotrigine and levetiracetam serum/plasma levels with toxicity: A long-term retrospective review at an academic medical center.

Lamotrigine and levetiracetam are widely used second-generation anti-epileptic drugs. Existing literature indicates that overdose of either drug is typically benign, but neurologic and cardiac toxicity can occur in some cases. In this retrospective study, we analyzed a large dataset of serum/plasma drug levels for lamotrigine and levetiracetam. The data covered 1,930 unique patients (5,046 levels) for lamotrigine and 2,451 patients (4,359 levels) for levetiracetam. We performed detailed chart review on all patients with one or more lamotrigine levels greater than 14.0 mg/L (293 unique patients) and all patients with one or more levetiracetam levels of 80 mg/L or higher (106 unique patients). No deaths directly attributable to lamotrigine or levetiracetam toxicity were reported. For cases with lamotrigine levels greater than 14.0 mg/L, the majority of patients were asymptomatic (55.3 %, n = 162). The most common presenting symptoms were ataxia (14.3 %, n = 42), seizures (14.0 %, n = 41), dizziness (11.9 %, n = 35), and altered mental status (11.6 %, n = 34). There were 12 overdoses (11 intentional) involving lamotrigine, all of which presented with either altered mental status (n = 8) or seizures (n = 4). The highest estimated dose reportedly ingested was 20 g. Cardiac toxicity was observed in two cases involving intentional overdose of lamotrigine. For patients with levetiracetam serum/plasma levels of 80 mg/L or higher, 48 patients (45.3 %) were asymptomatic. Symptomatic patients most commonly presented with seizures (31.1 %, n = 33) and altered mental status (15.1 %, n = 16), and none showed cardiac symptoms. There were only two cases involving intentional levetiracetam overdose, one of which presented with altered mental status after ingestion of 45 g and the other asymptomatic after ingestion of 6 g. Overall, our data is consistent with previous investigations that lamotrigine and levetiracetam toxicity most typically presents with neurologic symptoms and rarely cardiac arrhythmias. Approximately half of the patients with elevated lamotrigine or levetiracetam drug levels are asymptomatic.

Protective effects of 1,2-benzisoxazole-3-methanesulfonamide (zonisamide)- loaded polymeric micelles against neurotoxicity in spinal cord: In vitro

The incidence and prevalence of spinal cord injury (SCI) as a high disabling injury have enc ouraged the researchers to find some therapeutic strategies. The spinal cord is highly sensitive to oxidative stress and maintaining homeostasis is essential for redox status in neurons. Therefore, in this study. On the other hand, the application of drugs can induce some unwanted effects on the viability of neurons. Therefore, in this study, 1,2-benzisoxazole-3-methanesulfonamide (zonisamide) as a second-generation antiepileptic drug was formulated by micelles and characterized by TEM and DLS techniques. Afterward the protective effects of 1,2-benzisoxazole-3-methanesulfonamide-loaded micelles against stimulated oxidative stress and cytotoxicity were assessed by MTT, ROS, staining and enzyme activity assays. It was shown that the fabricated 1,2-benzisoxazole-3-methanesulfonamide-loaded micelles with a size of about 60–90 nm have a good colloidal stability and show a sustained drug release at physiological pH. Furthermore, it was determined that the neuroprotective effects of 1,2-benzisoxazole-3-methanesulfonamide-loaded micelles against cytotoxicity, ROS production, morphological changes, caspase-3 activation triggered by H2O2 was more pronounced than non-formulated drug. In conclusion, this study may provide useful information regarding the advancement of therapeutic approach for treatment of SCI.