Sex differences in variables associated with excessive daytime sleepiness in patients with epilepsy.

OBJECTIVE: Excessive daytime sleepiness (EDS) is common in patients with epilepsy (PWE). The Epworth Sleepiness Scale (ESS) is a self-reported measure of sleepiness in widespread use. The purpose of this study was to identify contributors to the ESS score in PWE and to identify variables associated with a high score indicative of EDS. METHODS: A cross-sectional study was performed on 115 PWE presenting to the epilepsy clinic. Self-reported questionnaires were administered and demographic and clinical information was gathered from the electronic medical record. Regression analyses were performed. RESULTS: A high ESS score was found in nearly 20% of the cohort. Obstructive sleep apnea (OSA) risk, standardized anti-seizure drug (ASD) dose, and female sex were associated with an increased likelihood of a high ESS score. Assessment of the ESS without the use of a cutpoint showed that standardized ASD dose and OSA risk were associated with the ESS in men, but standardized ASD dose was not associated with the ESS in women. Higher use of valproic acid and oxcarbazepine in men and higher use of lamotrigine in women may be contributing factors. SIGNIFICANCE: Sex is likely to be a key factor in determining contributors to EDS in PWE.

(+)-Borneol enantiomer ameliorates epileptic seizure via decreasing the excitability of glutamatergic transmission.

Epilepsy is one common brain disorder, which is not well controlled by current pharmacotherapy. In this study we characterized the therapeutic potential of borneol, a plant-derived bicyclic monoterpene compound, in the treatment of epilepsy and elucidated the underlying mechanisms. The anti-seizure potency and properties of borneol were assessed in both acute and chronic mouse epilepsy models. Administration of (+)-borneol (10, 30, 100 mg/kg, i.p.) dose-dependently attenuated acute epileptic seizure in maximal-electroshock seizure (MES) and pentylenetetrazol (PTZ)-induced seizure models without obvious side-effect on motor function. Meanwhile, (+)-borneol administration retarded kindling-induced epileptogenesis and relieved fully kindled seizures. Importantly, (+)-borneol administration also showed therapeutic potential in kainic acid-induced chronic spontaneous seizure model, which was considered as a drug-resistant model. We compared the anti-seizure efficacy of 3 borneol enantiomers in the acute seizure models, and found (+)-borneol being the most satisfying one with long-term anti-seizure effect. In electrophysiological study conducted in mouse brain slices containing the subiculum region, we revealed that borneol enantiomers displayed different anti-seizure mechanisms, (+)-borneol (10 µM) markedly suppressed the high frequency burst firing of subicular neurons and decreased glutamatergic synaptic transmission. In vivo calcium fiber photometry analysis further verified that administration of (+)-borneol (100 mg/kg) inhibited the enhanced glutamatergic synaptic transmission in epilepsy mice. We conclude that (+)-borneol displays broad-spectrum anti-seizure potential in different experimental models via decreasing the glutamatergic synaptic transmission without obvious side-effect, suggesting (+)-borneol as a promising anti-seizure compound for pharmacotherapy in epilepsy.

Open-label study to investigate the safety and efficacy of adjunctive perampanel in pediatric patients (4 to <12 years) with inadequately controlled focal seizures or generalized tonic-clonic seizures.

OBJECTIVE: Study 311 (NCT02849626) was a global, multicenter, open-label, single-arm study that assessed safety, tolerability, pharmacokinetics, and pharmacokinetics/pharmacodynamics of once-daily adjunctive perampanel oral suspension in pediatric patients (aged 4 to <12 years) with focal seizures (FS) (with/without focal to bilateral tonic-clonic seizures [FBTCS]) or generalized tonic-clonic seizures (GTCS). METHODS: In the 311 Core Study, a 4-week Pre-treatment Period (Screening/Baseline) preceded a 23-week Treatment Period (11-week Titration; 12-week Maintenance) and 4-week Follow-up. Endpoints included safety/tolerability (primary endpoint), median percent change in seizure frequency per 28 days from Baseline (Treatment Period), and 50% responder and seizure-freedom rates (Maintenance Period). Patients were stratified by age (4 to <7; 7 to <12 years) and concomitant enzyme-inducing anti-seizure drug (EIASD) use. RESULTS: One hundred eighty patients were enrolled (FS, n = 149; FBTCS, n = 54; GTCS, n = 31). The Core Study was completed by 146 patients (81%); the most common primary reason for discontinuation was adverse event (AE) (n = 14 [8%]). Mean (standard deviation) daily perampanel dose was 7.0 (2.6) mg/day and median (interquartile range) duration of exposure was 22.9 (2.0) weeks. The overall incidence of treatment-emergent AEs (TEAEs; 89%) was similar between patients with FS (with/without FBTCS) and GTCS. The most common TEAEs were somnolence (26%) and nasopharyngitis (19%). There were no clinically important changes observed for cognitive function, laboratory, or electrocardiogram (ECG) parameters or vital signs. Median percent reductions in seizure frequency per 28 days from Baseline were as follows: 40% (FS), 59% (FBTCS), and 69% (GTCS). Corresponding 50% responder and seizure-freedom rates were as follows: FS, 47% and 12%; FBTCS, 65% and 19%; and GTCS, 64% and 55%, respectively. Improvements in response/seizure frequency from Baseline were seen regardless of age or concomitant EIASD use. SIGNIFICANCE: Results from the 311 Core Study suggest that daily oral doses of adjunctive perampanel are generally safe, well tolerated, and efficacious in children age 4 to <12 years with FS (with/without FBTCS) or GTCS.

Antiepileptic Drugs in Pediatrics.

Epilepsy affects approximately 1% of the population. First-line treatment for epilepsy is the administration of anti-seizure medication, also referred to as antiepileptic drugs (AEDs), although this nomenclature is erroneous as these medications typically do not impact underlying epileptogenic processes; the goal of these medications is to control symptoms. Over 30% of patients are classified as having "medically refractory" epilepsy, i.e., lack of adequate seizure control despite trials of two or three AEDs (Kwan and Brodie, N Engl J Med 342:314-9, 2000). Epilepsy is associated with worse quality of life in children, adolescents, and their families (Cianchetti et al., Seizure 24:93-101, 2015). Patients with epilepsy have a two to three times greater risk of death than the general population, by various causes including sudden unexplained death in epilepsy patients (SUDEP) (Abdel-Mannan et al., Epilepsy Behav 90:99-106, 2019). It is these factors, among others, that have motivated the continued development of AEDs. This chapter will review the history and evolution of AED development, features of specific AEDs with a focus on the newest generation, and examples of AEDs in development.

Extracellular Vesicles as Diagnostics and Therapeutics for Structural Epilepsies.

Extracellular vesicles (EVs) are small vesicles involved in intercellular communication. Data is emerging that EVs and their cargo have potential as diagnostic biomarkers and treatments for brain diseases, including traumatic brain injury and epilepsy. Here, we summarize the current knowledge regarding changes in EV numbers and cargo in status epilepticus (SE) and traumatic brain injury (TBI), which are clinically significant etiologies for acquired epileptogenesis in animals and humans. We also review encouraging data, which suggests that EVs secreted by stem cells may serve as recovery-enhancing treatments for SE and TBI. Using Gene Set Enrichment Analysis, we show that brain EV-related transcripts are positively enriched in rodent models of epileptogenesis and epilepsy, and altered in response to anti-seizure drugs. These data suggest that EVs show promise as biomarkers, treatments and drug targets for epilepsy. In parallel to gathering conceptual knowledge, analytics platforms for the isolation and analysis of EV contents need to be further developed.

The Therapeutic Role of Perampanel in Treating Pediatric Patients With Dravet Syndrome: A Scoping Review.

Sodium channelopathies are genetic disorders caused by mutations in genes, including sodium voltage-gated channel alpha subunit 1 (SCN1A), that lead to several epilepsy syndromes. Traditional treatments with sodium channel blockers often have limited effectiveness and side effects. Dravet syndrome (DS), a severe epilepsy starting in infancy, presents significant treatment challenges. Perampanel (PER), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, has shown promise for DS, reducing seizure frequency and improving quality of life (QoL). The limited availability of randomized controlled trials on PER among DS is challenging, but broader studies on refractory epilepsies offer insights. Real-world studies support PER's efficacy, underscoring its potential for managing refractory seizures in DS. Studies showed long-term effectiveness in reducing seizure frequency and enhancing QoL. While PER has minimal impact on cognitive development, it significantly improves seizure control. Numerous studies confirm the use of PER as an effective adjunctive treatment for DS; however, it is crucial to observe the safety profile, especially for pediatric sodium channelopathy patients. Common side effects include dizziness, drowsiness, and irritability, necessitating careful management. Long-term safety is generally favorable, but monitoring for behavioral and mood changes is essential. Additionally, the response to PER in DS varies widely, complicating its use. The limited clinical data and the need for careful dosage monitoring, especially in children, present significant challenges. Side effects, potential drug interactions, and high costs further complicate treatment. Despite increasing attention to its cost-effectiveness, accessibility remains limited in some regions, posing significant barriers for many families. In this paper, we review the role of PER in treating pediatric patients with DS, emphasizing clinical evidence and practical considerations.

Efficacy and tolerability of perampanel in pediatric patients with Dravet syndrome.

Background: In 1978, Charlotte Dravet first described a form of epilepsy termed Dravet syndrome (DS). It is a form of genetic epilepsy with early-onset, intractable epilepsy episodes, and neurodevelopmental delay. In children, DS can lead to refractory seizures that are resistant to standard therapy. Recently, perampanel (PER) was approved as an antiepileptic drug for patients as young as 4 years old. Methods: The medical records were retrospectively reviewed and patients with DS who used PER were included in this study. The diagnosis was established using whole-exome sequencing, and the collected data included the patients' demographic characteristics, seizure pattern, PER dosage, laboratory and imaging findings. Results: This study included 18 pediatric patients with a clinical diagnosis of DS. The mean age of PER initiation was 7.67±3.865. Most patients had two types of seizures (61.1%) followed by three types (22.2%), with generalized tonic-clonic being the most frequently reported type of seizure. The mean efficacy of PER was 29.17%±29.368%, and only one patient had an efficacy of 100%. Moreover, patients aged 8 years and younger presented with higher efficacy than those who were older (49.17%±34.120% vs. 19.17%±21.829%, P=0.03). Conclusions: This study presented supporting evidence of the promising therapeutic effect of PER among patients with DS. PER can be considered one of the treatment options for this group of patients. However, several patients presented with unfavorable side effects that led to medication cessation. Future multicenter studies are required to explore further treatment options for patients with DS.

Anti-epileptogenic effects of synaptic vesicle protein 2A modulation in a mouse model of Alzheimer's disease.

OBJECTIVE: To assess the effects of synaptic vesicle protein 2A (SV2A) modulators brivaracetam and levetiracetam on amygdala kindling epileptogenesis in Tg2576 mice, a model of Alzheimer's disease which exhibits sensitivity to seizures. METHODS: First, aged Tg2576 mice (13-25 months; n = 17) were treated subcutaneously with either brivaracetam (10 mg/kg/day), levetiracetam (150 mg/kg/day) or vehicle via osmotic pumps for 28 days prior to, and during electrical amygdala kindling epileptogenesis. Next, we treated young (4-6 months; n = 24) Tg2576 mice with brivaracetam (10 mg/kg/day) or vehicle for 28 days and allowed one week's 'washout' before commencing kindling. Progression of seizure severity and duration were compared between treatment groups and wildtype mice (WT). RESULTS: In older Tg2576 mice, treatment with brivaracetam (p < 0.001) and levetiracetam (p < 0.05) before and during kindling significantly delayed the progression of seizure severity, compared to vehicle. Animals treated with brivaracetam required significantly more stimulations to reach the first class V (convulsive) seizure and had a lower mortality rate (p < 0.05) compared to those treated with vehicle. Young Tg2576 mice also exhibited increased susceptibility to kindling epileptogenesis compared to WT. Treatment with brivaracetam in younger animals only prior to kindling also delayed kindling acquisition compared to vehicle treatment, increasing the number of stimulations required to experience class V seizures (p < 0.05). SIGNIFICANCE: Brivaracetam treatment displayed marked anti-epileptogenic effects in both aged and young Tg2576 mice, including when treatment is ceased prior to initiating kindling. Targeting SV2A might represent a strategy for prevention of epilepsy in patients with Alzheimer's disease.

Clinical experience on the use of perampanel in epilepsy among child neurologists in the Philippines.

BACKGROUND: Perampanel is the latest anti-seizure medication introduced in the Philippines in 2015. This was initially approved as an adjunctive treatment for focal seizures and those with secondary generalization among individuals 12 years old and above. By March 2020, it has been approved also for generalized seizures and in children 4 years and above. The general objective of this research is to describe the clinical experience of Filipino child neurologists on the use of perampanel in children. METHODS: This is a cross-sectional descriptive study that surveyed child neurologists with review of medical records of children who have received perampanel as either an adjunctive therapy or monotherapy for epilepsy. RESULTS: There were 65 patients included in the study aged 1 to 18 years with a mean age of 10.0 ± 5.2 years and a median of 10 years. Follow-up duration were between 2 weeks to more than a year. Perampanel was started in 98.5% as an add-on treatment between 5 months and 18 years of age. The responder rate is 69.2% (45/65), seizure-free rate is 29.2% (19/65), seizure-aggravation rate is 9.2% (6/65), and perampanel retention rate is 83.1% (54/65). Treatment emergent adverse events were noted in 53.8% of the children with somnolence (20.0%), gait problems (12.3%), weight gain (10.8%) and dizziness (9.2%) as the most common events experienced. Dizziness was experienced significantly more among children 12 to 18 years of age. CONCLUSION: Perampanel is seen to be effective and relatively safe to use among Filipino children.

Abnormal Behavior Episodes Associated With Zonisamide in Three Dogs: A Case Report.

Psychiatric adverse effect associated with anti-seizure drugs has been well-recognized in human medicine. This case report describes three dogs with presumptive idiopathic epilepsy presented for abnormal behavior episodes. Abnormal behavior episodes included sudden rage and aggression to the family members, insomnia, restlessness, and/or constant attention-seeking behavior. MRI study and cerebrospinal fluid analysis in two dogs were unremarkable. The abnormal behavior episodes deteriorated along with gradual dose increment of zonisamide and these episodes almost completely disappeared within 5 days after discontinuation of zonisamide. The exact same episodes relapsed within days after re-administration of zonisamide and disappeared again shortly after discontinuation of zonisamide. Dose adjustments of other anti-seizure medications in case 2 did not result in significant changes in these behavior episodes. Although psychiatric adverse effects including aggressive behavior associated with zonisamide are widely recognized in humans, this is the first report in dogs in the clinical setting.

Efficacy and pharmacokinetics evaluation of 4-(2-chloro-4-fluorobenzyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H)-one (GM-90432) as an anti-seizure agent.

Epilepsy is a common chronic neurological disease characterized by recurrent epileptic seizures. A seizure is an uncontrolled electrical activity in the brain that can cause different levels of behavior, emotion, and consciousness. One-third of patients fail to receive sufficient seizure control, even though more than fifty FDA-approved anti-seizure drugs (ASDs) are available. In this study, we attempted small molecule screening to identify potential therapeutic agents for the treatment of seizures using seizure-induced animal models. Through behavioral phenotype-based screening, 4-(2-chloro-4-fluorobenzyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H)-one (GM-90432) was identified as a prototype. GM-90432 treatment effectively decreased seizure-like behaviors in zebrafish and mice with chemically induced seizures. These results were consistent with decreased neuronal activity through immunohistochemistry for pERK in zebrafish larvae. Additionally, electroencephalogram (EEG) analysis revealed that GM-90432 decreases seizure-specific EEG events in adult zebrafish. Moreover, we revealed the preferential binding of GM-90432 to voltage-gated Na+ channels using a whole-cell patch clamp technique. Through pharmacokinetic analysis, GM-90432 effectively penetrated the blood-brain barrier and was distributed into the brain. Taken together, we suggest that GM-90432 has the potential to be developed into a new ASD candidate.

Efficacy and tolerability of perampanel as a first add-on therapy with different anti-seizure drugs.

PURPOSE: To investigate the efficacy and tolerability of perampanel (PER) when administered as a first add-on therapy to patients with focal epilepsy or idiopathic generalized epilepsy (IGE) taking one other antiseizure drug (ASD). METHODS: This multicentre, retrospective, one-year observational study collected data from patients (≥12 years) who initiated treatment with PER as first add-on therapy. Patients had to be experiencing inadequate seizure control on ASD monotherapy and tried ≤3 ASD monotherapies before initiating PER. Multivariate logistic regression analyses were performed, adjusted for the number and type of previous seizures, duration and aetiology of epilepsy. RESULTS: Of the 149 patients included in the study (mean age 41 years; 54.4 % male), 118 (79.2 %) were still receiving PER as first add-on treatment after 12 months. Mean PER dose was 6.2 mg/day. At 12 months, 45.6 % were seizure-free and 84.6 % responders. A significant difference in seizure freedom rate was found between patients with IGE and patients with focal epilepsy, but not in responders. Reduced seizure control was observed when PER was administered with strong enzyme-inducing ASDs; conversely, increased seizure control was seen when the same dose of PER was combined with enzyme-inhibiting ASDs. The most frequent adverse events were dizziness (15.4 %), irritability (14.1 %) and drowsiness (14.1 %); no differences in tolerance were observed among different combinations. CONCLUSION: PER demonstrated a good efficacy and safety profile when used as a first add-on therapy in patients who did not respond to monotherapy. PER dose adjustments may optimize seizure control when combined with strong enzyme-inducing or enzyme-inhibiting ASDs.

Impact of Early Initiation of Eslicarbazepine Acetate on Economic Outcomes Among Patients with Focal Seizure: Results from Retrospective Database Analyses.

INTRODUCTION: This study assessed the association between early initiation of eslicarbazepine acetate (ESL) as first-line therapy (1L cohort) or as first adjunctive regimen to either levetiracetam (LEV) or lamotrigine (LTG) (add-on cohort), and healthcare resource utilization (HCRU) and charges among adults with treated focal seizures (FS). METHODS: This retrospective, longitudinal cohort analysis used Symphony Health's Integrated Dataverse (IDV®) claims data to identify patients aged ≥ 18 years with a diagnosis of FS who had a new prescription for ESL between April 2015 and June 2018. Baseline was the 90-day period immediately prior to the date of the first-dispensed claim for ESL (index date) with a follow-up of 1-4 consecutive 90-day periods. Linear regression models were estimated to assess changes in HCRU and charge outcomes. RESULTS: There were 274 and 153 patients who received ESL in the 1L cohort and add-on cohort, respectively. The 1L cohort experienced significant reductions from baseline during follow-up in all-cause inpatient (IP; P < 0.0001), emergency room (ER; P < 0.0001), and outpatient (OP; P < 0.0001) visits; FS-related IP (P = 0.006) and OP (P < 0.0001) visits; total, medical, all-cause ER and OP, and FS-related medical charges (P < 0.05); and significant increases in total prescription and anti-seizure drug (ASD)-related prescription (P < 0.001) charges. The add-on cohort experienced significant reductions in all-cause IP (P = 0.009) and all-cause and FS-related OP visits (P < 0.0001 for both) and significant increases in total prescription and ASD-related prescription (P < 0.001) charges during the follow-up period. In both cohorts, the increases in prescription charges were smaller than the reduction in total medical charges. CONCLUSION: Early initiation of ESL as 1L or add-on therapy was associated with statistically significant reductions in all-cause IP and all-cause and FS-related OP visits during follow-up compared to baseline. The 1L cohort also had statistically significant reductions in all-cause ER visits, FS-related IP visits, and total, medical, all-cause ER and OP, and FS-related medical charges. Knowledge of healthcare resource utilization (HCRU) and costs of care in patients taking anti-seizure drugs (ASDs) is required to inform prescribing and formulary decision-making. Levetiracetam (LEV) and lamotrigine (LTG) are the most widely used first-line (1L) ASDs in the USA. Eslicarbazepine acetate (ESL), a third-generation ASD with sodium channel-modulating activity, is typically used in later lines of therapy. Sodium channel-blocking anti-seizure drugs may represent an effective treatment option for patients with epilepsy in the 1L setting. This study assessed the association between early initiation of ESL as 1L therapy (1L cohort) or as first adjunctive therapy to either LEV or LTG (add-on cohort), and HCRU and charges among adults with treated focal seizures (FS). The results showed that following ESL initiation the 1L cohort experienced significant reductions in all-cause inpatient (IP), emergency room (ER), and outpatient (OP) visits; FS-related IP and OP visits; and total, medical, all-cause ER and OP, and FS-related medical charges, and significant increases in total prescription and ASD-related prescription charges. The add-on cohort showed significant reductions in all-cause IP and all-cause and FS-related OP visits and significant increases in total prescription and ASD-related prescription charges. In both cohorts, the increases in prescription charges were smaller than the reduction in total medical charges. These data imply that use of ESL as 1L therapy in adult patients with FS could help conserve scarce healthcare resources and reduce the burden on healthcare budgets. These findings may inform selection of ASD therapy in this patient population.

Potential protein-binding displacement interactions with perampanel: An in vitro analysis.

Plasma protein binding and effects on volume of distribution and pharmacologically active, circulating-drug concentrations are complex issues. Protein-binding displacement often underlies drug-drug interactions. Perampanel is a once-daily oral anti-seizure drug for focal seizures and primary generalized tonic-clonic seizures. Perampanel is also indicated for monotherapy use for focal seizures in the United States. Perampanel is extensively but slowly metabolized via CYP3A4. Its elimination t½ is about 100 h, and it displays substantial plasma protein binding (>95%). Here, we examine perampanel's potential to displace highly bound anti-seizure drugs and the ability of warfarin, a standard highly protein-bound drug, to displace perampanel. Protein binding of perampanel, phenytoin, valproate, and warfarin was assessed using equilibrium dialysis. Plasma samples containing each compound were dialyzed against phosphate buffered saline. For phenytoin, valproate, and warfarin, plasma samples were also dialyzed in the presence of perampanel. After 24 h equilibrium dialysis, amounts of test compounds were analyzed to calculate plasma protein binding. At clinically relevant concentrations, perampanel did not displace other highly bound drugs or vice versa. Protein-binding displacement may confound therapeutic drug monitoring of extensively protein-bound medications. Without empirical data, clinicians might be concerned that addition of perampanel could alter unbound concentrations of other medications, resulting in adverse effects. Our data indicate perampanel has low potential for drug interactions resulting from protein-binding displacement.

Perampanel as monotherapy and adjunctive therapy for focal onset seizures, focal to bilateral tonic-clonic seizures and as adjunctive therapy of generalized onset tonic-clonic seizures.

Introduction: Perampanel is an antiepileptic drug approved in the USA and Europe as monotherapy and adjunctive therapy for focal onset seizures and as adjunctive therapy for generalized tonic-clonic seizures. Areas covered: This an overview of animal data, pharmacokinetics, and clinical data published on Perampanel indexed in PubMed. Expert opinion: Pharmacological studies suggest that perampanel acts via noncompetitive antagonism of the ionotropic AMPA receptor of glutamate. The efficacy of perampanel has been shown in animal models of epilepsy and Phase II/III clinical trials. Efficacy and safety have been evaluated in the phase III trials of adjunctive treatment of focal epilepsy with median focal onset seizure reduction rates of 23% for 4 mg/d, 26-31% for 8 mg/day, and 18-35% for 12 mg/day. Fifty percent responder rates were 29% for 4 mg/day, 33-38% for 8 mg/day, and 34-36% for 12 mg/day. A pivotal Phase III trial in generalized onset tonic-clonic seizures showed a median seizure reduction by 76.5% (8 mg) versus 38.4% placebo and 50% seizure responder rate of 64.2% versus 30.9% placebo. Perampanel showed good safety and tolerability profile across 2-12 mg doses. Perampanel as a broad-spectrum antiepileptic drug has a potential to be an alternative treatment of multiple types of epileptic seizures.

Forced normalization after turning off vagus nerve stimulation in Lennox-Gastaut syndrome.

Forced normalization is the development of psychiatric symptoms in a patient experiencing remission of seizures. We present a case of Lennox Gastaut syndrome in which forced normalization developed after vagus nerve stimulation was stopped. The patient had drug resistant epilepsy and failed anti-seizure drugs, vagus nerve stimulation, and a partial callosotomy. The patient had multiple types of seizures including drop attacks, absences, and tonic-clonic seizures. He tried vagus nerve stimulation for two years without success. Forced normalization developed after the vagus nerve stimulator was turned off. This is the first case to our knowledge to describe forced normalization after turning off the vagus nerve stimulator.

High-performance counter-current chromatography isolation and initial neuroactivity characterization of furanocoumarin derivatives from Peucedanum alsaticum L (Apiaceae).

BACKGROUND: Medicinal plants are a proven source of drug-like small molecules with activity towards targets relevant for diseases of the central nervous system (CNS). Plant species of the Apiaceae family have to date yielded a number of neuroactive metabolites, such as coumarin derivatives with acetylcholinesterase inhibitory activity or anti-seizure activity. PURPOSE: To accelerate the discovery of neuroactive phytochemicals with potential as CNS drug leads, we sought to rapidly isolate furanocoumarins, primary constituents of the dichloromethane (DCM) extract of the fruits of Peucedanum alsaticum L. (Apiaceae), using high-performance counter-current chromatography (HPCCC) and to evaluate their neuroactivity using both in vitro and in vivo microscale bioassays based on cholinesterase ELISAs and zebrafish epilepsy models. RESEARCH METHODS AND PROCEDURE: In this study the DCM extract was subjected to HPCCC for the efficient separation (60 min) and isolation of furanocoumarins. Isolated compounds were identified with TOF-ESI-MS and NMR techniques and examined as inhibitors of AChE and BChE using ELISA microtiter assays. Anti-seizure properties of the extract and of the isolated compounds were evaluated using a zebrafish epilepsy model based on the GABAA antagonist pentylenetetrazol (PTZ), which induces increased locomotor activity and seizure-like behavior. RESULTS: The solvent system, composed of n-heptane, ethyl acetate, methanol and water (3:1:3:1, v/v/v/v), enabled the isolation of 2.63 mg lucidafuranocoumarin A (purity 98%) and 8.82 mg bergamottin (purity 96%) from 1.6 g crude DCM extract. The crude extract, at a concentration of 100 µg/ml, exhibited a weak inhibitory activity against acetylcholinesterase (AChE) (9.63 ±â€¯1.59%) and a moderate inhibitory activity against butyrylcholinestrase (BChE) (49.41 ±â€¯2.19%). Lucidafuranocoumarin A (100 µg/ml) was inactive against AChE but showed moderate inhibition towards BChE (40.66 ±â€¯1.25%). The DCM extract of P. alsaticum fruits (0.62-1.75 µg/ml) and bergamottin (2-10 µm) exhibited weak anti-seizure activity, while lucidafuranocoumarin A (10-16 µm) was found to significantly inhibit PTZ-induced seizures. The percentage of seizure inhibition for the isolated compounds, at their most bioactive concentration, was 26% for bergamottin and 69% for lucidafuranocoumarin A. CONCLUSION: Our findings underscore the utility of HPCCC for the rapid isolation of rare coumarin derivatives, and the potential of microscale in vivo bioassays based on zebrafish disease models for the rapid assessment of neuroactivity of these drug-like natural products.

Prediction of Response to Treatment in Children with Epilepsy.

OBJECTIVE: This study was conducted to predict the response to treatment in patients treated with anti-epilepsy drugs. MATERIAL AND METHODS: This analytical questionnaire-based study was conducted in 2014 among 128 patients with epilepsy admitted to Mofid Children's Hospital, Tehran, Iran. The inclusion criteria were children 2 months to 12 yr of age with epilepsy and patients who experienced fever and seizure attacks at least once were excluded from the study. Patients were followed up for 6 months and the response to their treatment was recorded. The good response to treatment was defined as the absence of seizure with two drugs during follow up. RESULTS: Seventy-two patients (56.3%) were boys. The age of the first seizure was under 2 yr old in 90 patients (70.3%). History of febrile convulsion, family history of epilepsy and history of asphyxia was found in 16 (12.5%), 41 (32%), and 27 (21.1%) patients, respectively. Seizure etiology was idiopathic in 90 patients (70.3%), and the number of seizures was 1-2 in 36 patients (28.1%). Overall, 57 patients (44.5%) had cerebral lesion according to CT scan or MRI, and EEG was abnormal in 101 patients (78.9%). In 6-month follow-up, 40 patients (31.3%) responded well to the treatment and 88 patients (68.8%) responded poorly to the treatment. History of asphyxia (OR = 6.82), neonatal jaundice (OR = 2.81) and abnormal EEG (OR = 0.19) were effective factors in response to treatment. CONCLUSION: Abnormal EEG is an effective factor in treatment response in the children studied.

Brief history of anti-seizure drug development.

The mainstay of therapy for epilepsy is anti-seizure drugs (ASDs, also referred to as anticonvulsants and anti-epileptic medications). Through much of the past century, only a handful for ASDs were available for clinical use. However, with the creation of the U.S. National Institutes of Health/National Institute of Neurological Disorders and Stroke (NINDS)-sponsored Anticonvulsant Screening Program (ASP), coupled with the emergence of high-throughput screening platforms and methodologies, and advances in our understanding of the fundamental neurobiology of epilepsy, ASD development has greatly accelerated over the past 25 years. More than 18 new ASDs have been approved for clinical use since the inception of the ASP. Despite this remarkable success and the emergence of drugs possessing more favorable pharmacokinetic profiles that act on novel molecular targets, there has been increasing recognition that the paradigms for drug discovery have not yielded significant improvements in therapeutic efficacy, and that disease modification (i.e., anti-epileptogenesis), among other challenges, must be addressed. Thus, with the renewed framework and mission of improving the lives of people with epilepsy, the name of the ASP was changed to the Epilepsy Therapy Screening Program (ETSP). This review briefly summarizes the history of ASD development and outlines some of the challenges and opportunities for the next generation of drug therapies for the epilepsy field.

Evaluation of perampanel as monotherapy for focal seizures: Experience from open-label extension studies.

Perampanel, a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, is approved for adjunctive treatment of focal seizures, with or without secondarily generalized seizures, and for primary generalized tonic-clonic seizures in patients with epilepsy aged ≥ 12 years. Perampanel was recently approved for monotherapy use for focal seizures in the U.S.A. Anti-seizure drug monotherapy may be preferable to polytherapy, which is generally associated with increased toxicity, non-compliance, and cost. Here, we report cases where patients had converted to perampanel monotherapy during open-label extension (OLEx) portions of 9 Phase II and III studies. Of 2245 patients who enrolled in the OLEx studies, we identified 7 patients with drug-resistant focal seizures who discontinued all non-perampanel anti-seizure drugs and were maintained on perampanel monotherapy for ≥ 91 days until the end of data cut-off. Patients received perampanel monotherapy for up to 1099 days (157 weeks), most at a modal dose of 12 mg. Seizure data were available for 6 patients, of whom 5 had a ≥ 90% reduction in overall seizure frequency between baseline and their last 13-week period of monotherapy (3 were seizure-free). Perampanel monotherapy was generally well tolerated and the safety profile during perampanel monotherapy was consistent with clinical and post-marketing experience in the adjunctive setting. This analysis included a small proportion of patients with highly drug-resistant focal seizures who converted to monotherapy during OLEx studies. While these limited data are encouraging in suggesting that perampanel might be useful as a monotherapy, further studies are required to explore outcomes in a less drug-resistant population, where a larger proportion of patients might benefit from monotherapy.