First-line Antiepileptic Drug Research Articles

Zonisamide: one of the first-line antiepileptic drugs in focal epilepsy

Zonisamide: one of the first-line antiepileptic drugs in focal epilepsy

Brain Tumours and Prophylactic Antiepileptic Drug Prescribing Patterns by Neurosurgeons Practising in Australasia

Prescribing patterns amongst practising Australasian neurosurgeons regarding the use of prophylactic antiepileptic drugs (AEDs) in patients with newly diagnosed intrinsic brain tumours are not well established. This study aimed to determine the rate of prophylactic AED prescribing in this clinical context and to determine if there were some particular factors that influenced prescribers in their decision. A survey was conducted, and of the 91 respondents, 23 (25.3%) prescribed prophylactic AEDs. No neurosurgeons practising in New Zealand prescribed, whereas within Australian states/territories, prescribing was most common in Western Australia (3/4, 75.0%) and Queensland (8/18, 44.4%) and less common in the Australian Capital Territory (0/2, 0.0%) and South Australia (1/7, 14.3%). The most commonly prescribed first-line AED was phenytoin (n = 15, 68.2%) followed by levetiracetam (n = 5, 22.7%). The duration of prescription varied from 1 week to 6 months, with 6 weeks chosen by most prescribers (n = 7, 35%). Important factors that influence the decision to prescribe include tumour location and a history of previous seizure/s, whereas the presence of oedema or haemorrhage and patients’ age do not seem to be major influences amongst prescribers.

Complications during the management of pediatric refractory status epilepticus with benzodiazepine and pentobarbital infusions.

Sir, Patten et al. in their interesting study compared complications in the management of refractory status epilepticus (RSE) treated with benzodiazepine and pentobarbital infusions. The authors addressed that children with RSE, who required pentobarbital therapy had a longer hospital stay and were more likely develop hypotension, require inotropic support, need intubation, mechanical ventilation, peripheral nutrition, and blood products. Furthermore, they were more likely to develop hypertension and movement disorder after or during weaning.[1] I presume that these results ought to be cautiously taken owing to the presence of the following three limitations. (1) The data were taken from a single center. (2) The study period was relatively short (3 years). (3) The size of the studied cohort was small (n = 28). Conducting a large scale multicenter study over an extended period could better evaluate that the issue. Despite the aforementioned three limitations, the observation in Patten et al's. study[1] on more complications associated with pentobarbital infusion compared to benzodiazepine infusion renders pentobarbital less recommended first-line in treating patients with RSE. This observation supports the recently published Indian consensus guidelines on the management of childhood convulsive status epilepticus[2] and recommendations of the Italian League Against Epilepsy,[3] which stress that the initial management of RSE should consist of a parenteral benzodiazepine (lorazepam, diazepam, or midazolam) by any route feasible and when first-line anti-epileptic drugs fail, sodium phenytoin, and phenobarbital should be used. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

New avenue in the treatment of temporal lobe epilepsy by classical anti-epileptics: A hypothetical establishment of executioner Caspase 3 inactivation by molecular modeling.

Patients with temporal lobe epilepsy (TLE) are prescribed first-line antiepileptic drugs and surgery to the management of this disorder. Unfortunately, the surgical treatment has been shown to be beneficial for the selected patients but fails to provide a seizure-free outcome in 20–30% of TLE patients. In our present study, we investigate the possibilities of marketed antiepileptic drugs in a different manner to improve the present situation in TLE. Molecular docking simulation study and various open source computational tools were used to perform the study. AutoDock 4.2 MGL tools, Pymol visualize tools, Patch dock server, and Swarm Dock servers (protein-protein docking) were used to perform the molecular modeling. FTsite and computed atlas of surface topography of protein open source server were used to understand the pocket and ligand binding information respectively. Toxtree application was used to determine the toxicity profile of the drug by Cramers rule. The obtained molecular docking models (Caspase 3, Procaspase 8, and Fas-associated death domain [FADD]) with selected compounds (Clonazepam, Clobazepam, and Retigabine) showed promising trio blocking event of FADD, Caspase 3, and Procaspase 8 (−6.66 kcal, −8.1 kcal, 6.46 kcal) by Clonazepam respectively. Protein-protein interaction study (Swarm Dock, Patch Dock server) indicated promising results that helped to establish our hypothesis. Toxtree showed a quantitative structure toxicity relationship report that helps to clarify the toxicity of the selected compounds. Clonazepam showed a trio inhibition property that may lead to develop a new era of the new generation benzodiazepine prototype drugs in the future. Filtered compounds will further process for higher in vitro, in vivo models for better understanding of the mechanism.

Degeneration and regeneration of GABAergic interneurons in the dentate gyrus of adult mice in experimental models of epilepsy.

Mounting evidence showed that GABAergic interneurons play an important role in the generation of seizures by regulating excitatory/inhibitory balance in the hippocampus; however, there is a continuous debate regarding the alteration in the number of hippocampal GABAergic interneurons during epileptogenesis. Here, we investigated the degeneration and regeneration of GABAergic interneurons in the dentate gyrus during epileptogenesis using glutamic acid decarboxylase-green fluorescence protein (GAD67-GFP) knock-in mice. Pentylenetetrazol (PTZ)-induced chronic kindling model and lithium-pilocarpine-induced status epilepticus (SE) model were used in this study. We found a progressive loss of GABAergic interneurons in the dentate gyrus during post-SE epileptogenesis rather than PTZ kindling. Both types of epileptogenic insults significantly promoted the proliferation of neural progenitor cells in the dentate gyrus; however, compared to 80% neuronal differentiation ratio in the control group, there was a remarkable decrease in PTZ kindling and pilocarpine models, that is 58% and 29%, respectively. Double/triple immunofluorescence labeling revealed no newborn neurons colabeled with GFP in both intact and epileptic dentate gyrus. In addition, valproate (a first-line antiepileptic drug) treatment prevented the loss of GABAergic interneurons but still failed to induce the regeneration of GAD67-positive interneurons in the dentate gyrus during post-SE epileptogenesis. These results indicate that degeneration of GABAergic interneurons may depend on the type of epileptogenic insult and that no newborn GABAergic interneurons occur in the adult dentate gyrus during epileptogenesis.

What are the best ways to deliver benzodiazepines in children/patients with prolonged convulsive seizures?

Aetiology is the main determinant of morbidity and mortality in convulsive status epilepticus (CSE) but longer seizure durations may also increase risk of worse outcome. Thirty minutes of seizure activity is usually the time period used in longstanding definitions of CSE but it is not acceptable to wait for 30 minutes before treatment. Whilst intravenous therapy is best, pre-hospital treatment by a non-intravenous route is most practical in treating children. Benzodiazepines are the main class of first-line emergency antiepileptic drugs. This review will examine the available data on benzodiazepines according to: stability in the conditions of the emergency room services, drug absorption via non-intravenous route, clinical efficacy and safety, and ease of delivery and social acceptability.

Carbamazepine-induced cutaneous reactions: A simple assay to identify patients carrying the HLA-A*31:01 allele

Aims. Treatment with the first-line antiepileptic drug, carbamazepine (CBZ), is associated with adverse cutaneous reactions in up to 10% of patients. One predisposition to these side-effects has been linked to the HLA-A*31:01 allele. HLA-typing is costly and time-consuming. A single nucleotide polymorphism (SNP, rs1061235A > T) has been suggested as a marker for the HLA-A*31:01 allele. We sought to develop and validate a simple, fast and inexpensive assay for rs1061235 to apply in the Norwegian population. Methods. We designed a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay for the SNP and tested it on a set of 16 samples with known HLA-A alleles. Results. The assay identified all HLA-A*31:01 alleles present, but also marked for HLA-A*33:03. In a second set of 204 samples from Norwegian epilepsy patients with unknown HLA alleles, nine samples heterozygous for the rs1061235 were found. Subsequent HLA-typing showed that one sample was HLA-A*33:01, whereas the other eight were identified as HLA-A*31:01. The remaining 195 samples were correctly identified as neither carrying the rs1061235 SNP nor HLA-A*31:01. The sensitivity and specificity of the rs1061235 SNP test was 100% and 99.5%, respectively. Misinterpretation of the rare HLA-A*33 variants as HLA-A*31:01 has minor consequence, as it only would result in choosing an alternative drug to CBZ. Conclusion. We have designed and validated a simple, fast and inexpensive test for the rs1061235A> T SNP as a marker for HLA-A*31:01 in the Norwegian population for potential use in a personalized treatment approach to patients planned to receive CBZ.

Research Highlights: highlights from the latest articles focusing on a new gene set for better drug response prediction of epilepsy patients.

PharmacogenomicsVol. 15, No. 5 News & ViewsResearch Highlights: Highlights from the latest articles focusing on a new gene set for better drug response prediction of epilepsy patientsRuchi Baghel , Ajay Jajodia , Sandeep Grover & Ritushree KukretiRuchi BaghelGenomics & Molecular Medicine Unit, Institute of Genomics & Integrative Biology (IGIB), Council of Scientific & Industrial Research (CSIR), Mall Road, Delhi 110 007, IndiaSearch for more papers by this author , Ajay JajodiaGenomics & Molecular Medicine Unit, Institute of Genomics & Integrative Biology (IGIB), Council of Scientific & Industrial Research (CSIR), Mall Road, Delhi 110 007, IndiaSearch for more papers by this author , Sandeep GroverGenomics & Molecular Medicine Unit, Institute of Genomics & Integrative Biology (IGIB), Council of Scientific & Industrial Research (CSIR), Mall Road, Delhi 110 007, IndiaSearch for more papers by this author & Ritushree Kukreti* Author for correspondence: E-mail Address: ritus@igib.res.inGenomics & Molecular Medicine Unit, Institute of Genomics & Integrative Biology (IGIB), Council of Scientific & Industrial Research (CSIR), Mall Road, Delhi 110 007, IndiaSearch for more papers by this authorPublished Online:5 May 2014https://doi.org/10.2217/pgs.14.11AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail View articleFiguresReferencesRelatedDetailsCited ByDysfunction of the SNARE complex in neurological and psychiatric disordersPharmacological Research, Vol. 165Integration of epigenomics and metabolomics: From biomarkers discovery to personalized medicineEvaluating the Role of Genetic Variants on first-line antiepileptic drug response in North India: Significance of SCN1A and GABRA1 Gene Variants in Phenytoin Monotherapy and its Serum Drug Levels1 June 2016 | CNS Neuroscience & Therapeutics, Vol. 22, No. 9Synergistic association of STX 1A and VAMP 2 with cryptogenic epilepsy in North Indian population14 June 2016 | Brain and Behavior, Vol. 6, No. 7 Vol. 15, No. 5 Follow us on social media for the latest updates Metrics Downloaded 92 times History Published online 5 May 2014 Published in print April 2014 Information© Future Medicine LtdPDF download

The efficacy of intravenous sodium valproate and phenytoin as the first-line treatment in status epilepticus: a comparison study

BackgroundStatus epilepticus (SE) is a serious neurological condition and requires prompt treatment. Sodium valproate has been used to treat SE successfully but its role as the first-line antiepileptic drug (AED) is still controversial. This study evaluated the efficacy of intravenous sodium valproate to determine if it is non-inferior to intravenous phenytoin in SE treatment.MethodsPatients diagnosed as SE during 2003–2010 who were of an age of more than 15 years and received either intravenous sodium valproate or intravenous phenytoin as the first-line treatment were enrolled. Clinical characteristics and outcomes of SE were recorded and analyzed. The differences of outcomes between sodium valproate and phenytoin group were determined by descriptive statistics.ResultsDuring the study period, there were 37 and 17 SE patients who received intravenous phenytoin and intravenous sodium valproate as the first-line treatment, respectively. All patients received diazepam 10 mg intravenously as a rescue medication before starting the antiepileptic agents if uncontrolled except one patient in the sodium valproate group. There were no significant differences between the phenytoin and sodium valproate groups in all outcome variables including numbers of patients with clinically-controlled seizures, non-dependent patients, time to seizure control, and duration of hospitalization, and death. No serious cardiovasculars event such as hypotension occurred in either group.ConclusionIntravenous sodium valproate is non-inferior to intravenous phenytoin as the first-line treatment in SE with no significant cardiovascular compromises.

Antiepileptics Topiramate and Levetiracetam Alleviate Behavioral Deficits and Reduce Neuropathology in APPswe/PS1dE9 Transgenic Mice

The close relationship between epileptic seizure and Alzheimer's disease (AD) has been demonstrated in the past decade. Valproic acid, a traditional first-line antiepileptic drug, exerted protective effects in transgenic models of AD. It remains uncertain whether new antiepileptic drugs could reverse neuropathology and behavioral deficits in AD transgenic mice. APPswe/PS1dE9 transgenic mice were used in this study, which over express the Swedish mutation of amyloid precursor protein together with presenilin 1 deleted in exon 9. 7-month-old APPswe/PS1dE9 transgenic mice were treated daily with 20mg/kg topiramate (TPM) and 50mg/kg levetiracetam (LEV) for 30days by intraperitoneal injection to explore the effects of TPM and LEV on the neuropathology and behavioral deficits. The results indicated that TPM and LEV alleviated behavioral deficits and reduced amyloid plaques in APPswe/PS1dE9 transgenic mice. TPM and LEV increased Aβ clearance and up-regulated Aβ transport and autophagic degradation. TPM and LEV inhibited Aβ generation and suppressed γ-secretase activity. TPM and LEV inhibited GSK-3β activation and increased the activation of AMPK/Akt activation. Further, TPM and LEV inhibited histone deacetylase activity in vivo. Therefore, TPM and LEV might have the potential to treat AD effectively in patient care.

Clinical experience with intravenous valproate as first-line treatment of status epilepticus and seizure clusters in selected populations

Objective: The aim of this study was to evaluate the efficacy and safety of intravenous valproate (i.v. VPA) as first-line treatment of status epilepticus (SE) and seizure clusters in selected patient populations. Methods: We enrolled 23 patients (11 females and 12 males; mean age: 61 years) with SE who received i.v. VPA as first-line therapy (25 mg/kg in 100 mL saline infused over 15 min). ECG tracing was monitored before, during, and after infusion. Liver function and serum ammonia tests were conducted after 24 and 72 h of treatment. We evaluate the response of SE to i.v. therapy and short-term outcome. Results: In 15 out of 23 patients (65%), i.v. VPA was effective. In our population, we retrospectively identified three different subgroups: patients with cardiorespiratory comorbidities discouraging the use of traditional SE first-line drugs, patients with specific epileptic subsyndromes (such as idiopathic generalized epilepsy), and patients affected by psycho-organic syndromes. No significant adverse effects were detected. Discussion: Our study shows the clinical relevance of i.v. VPA as first-line therapy of SE in patients with medical conditions contraindicating the use of traditional first-line antiepileptic drugs for SE, and in those presenting with specific forms of SE.

Assessment and comparison of health-related quality-of-life (HRQOL) in patients with epilepsy in India

Seizure frequency, medical and psychiatric morbidities, number and nature of antiepileptic drugs, and medication side effects have been correlated with decreased HRQOL scores in patients with epilepsy. Quality of Life in Epilepsy-31 patient inventory was translated and validated in two regional languages and administered to 80 patients with epilepsy who were on first-line antiepileptic drugs and classified as responders and nonresponders. The outcomes were measured based on 7 domains, such as seizure worry, overall QOL, emotional well-being, and energy/fatigue and based on the overall score of the scale. For both translations, Cronbach's alpha (coefficient) was greater than 0.70 [except for the seizure worry scale (0.69) in the Hindi questionnaire]. There was statistical difference (p<0.0001) of HRQOL scores between responders and nonresponders of epilepsy. The HRQOL score was lower in nonresponders. The most affected domain was emotional well-being in both groups, and the least affected domains were energy/fatigue in responders and medication effect in nonresponders.

A Computerized Standard Protocol Order Entry for Pediatric Inpatient Acute Seizure Emergencies Reduces Time to Treatment

Time to treatment of seizures is critical to efficacy. We performed a quality initiative and evaluated time to treatment of inpatient seizure emergencies with first- and second-line medicines before and after implementation of a computerized, standard treatment protocol. Data from 125 patients revealed that 179 seizure episodes required first-line antiepileptic drugs, and the mean time to treatment was 7.72 minutes. In 87 episodes, patients (49%) received the drugs within 5 minutes. Forty-six episodes required second-line drugs. In 17 (37%), patients received them within 30 minutes (mean 49.48 minutes). After implementation of the protocol, the mean time to treatment with first-line drugs was 3.74 minutes, a reduction of >50% (P < .0001). The mean time to treatment with second-line drugs was 25.05 minutes, a reduction of ∼50% (P < .0001). This effective model for reducing the time to treatment of seizure emergencies may be useful to similar institutions.

Interaction of Carbamazepine with Herbs, Dietary Supplements, and Food: A Systematic Review

Background. Carbamazepine (CBZ) is a first-line antiepileptic drug which may be prone to drug interactions. Systematic review of herb- and food-drug interactions on CBZ is warranted to provide guidance for medical professionals when prescribing CBZ. Method. A systematic review was conducted on six English databases and four Chinese databases. Results. 196 out of 3179 articles fulfilled inclusion criteria, of which 74 articles were reviewed and 33 herbal products/dietary supplement/food interacting with CBZ were identified. No fatal or severe interactions were documented. The majority of the interactions were pharmacokinetic-based (80%). Traditional Chinese medicine accounted for most of the interactions (n = 17), followed by food (n = 10), dietary supplements (n = 3), and other herbs/botanicals (n = 3). Coadministration of 11 and 12 of the studied herbal products/dietary supplement/food significantly decreased or increased the plasma concentrations of CBZ. Regarding pharmacodynamic interaction, Xiao-yao-san, melatonin, and alcohol increased the side effects of CBZ while caffeine lowered the antiepileptic efficacy of CBZ. Conclusion. This review provides a comprehensive summary of the documented interactions between CBZ and herbal products/food/dietary supplements which assists healthcare professionals to identify potential herb-drug and food-drug interactions, thereby preventing potential adverse events and improving patients' therapeutic outcomes when prescribing CBZ.

Zonisamide Should be Considered a First-Line Antiepileptic Drug for Patients with Newly Diagnosed Partial Epilepsy

Zonisamide Should be Considered a First-Line Antiepileptic Drug for Patients with Newly Diagnosed Partial Epilepsy

Ideal characteristics of an antiepileptic drug: how do these impact treatment decisions for individual patients?

Effective management of epilepsy requires a holistic approach that takes into account the needs of the individual patient. Antiepileptic drug (AED) treatment must therefore look beyond efficacy to ensure that the patient's overall health status and quality of life (QoL) are optimized. Because the primary objective of AED treatment is to control seizures over the long term, the ideal AED should, first and foremost, demonstrate sustained efficacy and favourable tolerability. In addition, it should have a broad spectrum of activity; its pharmacokinetic profile should be stable and predictable and allow the option of once-daily dosing; and it should not interact with other medications and concomitant AEDs. Because the efficacy of first-line AEDs is broadly comparable, choice of treatment should be based on the individual patient's specific clinical characteristics. In particular, the primary and secondary prevention of comorbid conditions should be taken into consideration, because this can reduce the risk of mortality and improve health outcomes and QoL. Treatment selection must also take into account the patient's particular lifestyle and priorities, to maximize the likelihood of long-term treatment adherence. Advances in genetic testing may help inform choice of treatment - not only by elucidating a patient's underlying aetiology, but also by helping to avoid unnecessary side effects. Although certain patient populations (e.g. women of childbearing potential, adolescents, the elderly) require particular consideration when choosing the most appropriate treatment, every patient's unique clinical characteristics and personal circumstances must be taken into account to ensure treatment success and optimize their QoL.

Epilepsy surgery trends in the United States, 1990–2008

# {#article-title-2} Englot et al.1 concluded that after the failure of 2 antiepileptic drug (AED) trials, patients “should be referred … for surgical evaluation.” The authors considered their recommendation consistent with the guidelines of the American Academy of Neurology (AAN).1 However, what the AAN recommended was the referral of patients “who have failed appropriate trials of first-line AEDs.” …

Genetic association analysis of transporters identifies ABCC2 loci for seizure control in women with epilepsy on first-line antiepileptic drugs

The ATP-binding cassette (ABC) superfamily of transporters is known to efflux antiepileptic drugs (AEDs) primarily in the brain, gastrointestinal tract, liver, and kidneys. In addition, they are also known to be involved in estrogen disposition and may modulate seizure susceptibility and drug response. The objective of the present study was to investigate the role of genetic variants from ABC transporters in seizure control in epilepsy patients treated with monotherapy of first-line AEDs for 12 months. On the basis of gene coverage and functional significance, a total of 98 single nucleotide polymorphisms from ABCB1, ABCC1, and ABCC2 were genotyped in 400 patients from North India. Of these, 216 patients were eligible for therapeutic assessment. Genetic variants were compared between the 'no-seizures' and the 'recurrent-seizures' groups. Bonferroni corrections for multiple comparisons and adjustment for covariates were performed before assessment of associations. Functionally relevant promoter polymorphisms from ABCC2: c.-1549G>A and c.-1019A>G either considered alone or in haplotype and diplotype combinations were observed for a significant association with seizure control in women (odds ratio>3.5, P<10, power>95%). Further, low protein-expressing CGT and TGT (c.-24C>T, c.1249G>A, c.3972C>T) haplotypes were always observed to be present in combination with the AG (c.-1549G>A, c.-1019A>G) haplotype that was over-represented in women with 'no seizures'. The distribution of the associated variants supports the involvement of ABCC2 in controlling seizures in women possibly by lowering of its expression. The biological basis of this finding could be an altered interaction of ABCC2 with AEDs and estrogens. These results necessitate replication in a larger pool of patients.

Concise guide to the currently available drug options in epilepsy

AbstractOur Drug review of epilepsy provides an overview of the wide range of first‐line, second‐line and alternative antiepileptic drugs available, followed by a review of the prescription data and sources of further information.

Effects of SCN1A and GABA Receptor Genetic Polymorphisms on Carbamazepine Tolerability and Efficacy in Chinese Patients with Partial Seizures: 2‐Year Longitudinal Clinical Follow‐Up

To investigate the tolerability and efficacy of carbamazepine treatment in patients with partial-onset seizures and the association with polymorphisms in the sodium channel α-subunit type 1 (SCN1A), and gamma-aminobutyric acid (GABA) receptor genes among the Chinese Han population. 448 patients were genotyped for single nucleotide polymorphisms selected of the SCN1A and GABA-receptor genes. Monotherapy with carbamazepine (CBZ) was administered to the patients. The effectiveness of CBZ treatment was evaluated with regard to efficacy by the decrease in seizures and tolerability by retention rates. SCN1A rs3812718 A/G with CBZ tolerability (P= 0.038) throughout 24 months of clinical follow-up and the GABRA1 rs2290732 A/G were significantly associated with CBZ tolerability (P= 0.001). The maintenance dose and serum level of CBZ in AA genotype carriers of rs3812718 A/G were significantly higher than those of GG genotype carriers between 3 and 12 months of follow-up. The proportion of AA genotype carriers of rs2298771 A/G with seizure free was significantly higher than that of AG+GG genotype carriers from 3 months to 15 months of follow-up (P < 0.05). rs3812718 A/G and rs2290732 A/G polymorphisms affected the tolerability of CBZ. rs2298771 A/G was associated with efficacy of CBZ treatment.