First-generation Antiepileptic Drugs Research Articles

Possibility analysis of antiepileptic drugs import substitution in the Russian Federation

Relevance. Epilepsy is a common chronic disease of the nervous system that can be treated rationally, ensuring the possibility of remission in most patients. The availability of antiepileptic drugs (AEDs) for patients with epilepsy is an important characteristic for achieving a long and quality life. Domestic AED production in the Russian Federation guarantees accessible medicinal assistance.Objective. Assessment of the AED import substitution level in the Russian Federation.Methods. The assessment is based on an analysis of the State Register of Medicines (SRM), the list of vital and essential drugs (VED) for 2023, and the clinical recommendations of the Ministry of Health of the Russian Federation “Epilepsy and status epilepticus in adults and children”.Results. Currently, the SRM registers 27 international non-proprietary names of AEDs, 101 trade names, mainly in the form of oral dosage forms, and 1,355 nomenclature items. All AEDs are prescription drugs. Generally, 70.6% of AED manufacturers are domestic. In 2020, the share of manufacturers from the Russian Federation increased by 20%. However, only 14.2% of the substances are directly produced in the Russian Federation. A high 100% level of import substitution is available only for firstgeneration antiepileptic drugs, and for third-generation drugs it remains at 43%. Import substitution of antiepileptic drug substances stays significantly low — 75% — 47.5% — 14% for antiepileptic drugs of I — II — III generations, respectively.Conclusion. The level of import substitution of modern AEDs for generations II–III should be increased to improve the efficiency and safety of epilepsy therapy.

The implication of LPS/TLR4 and FXR receptors in hepatoprotective efficacy of indole-3-acetic acid and chenodeoxycholic acid

AimValproic acid (VPA) belongs to the first-generation antiepileptic drugs, yet its prolonged use can cause life-threatening liver damage. The importance of our study is to investigate the protective effect of indole-3-acetic acid (IAA), chenodeoxycholic acid (CDCA) and their combination on VPA-induced liver injury focusing on lipopolysaccharides (LPS)/toll-like receptor 4 (TLR4) pathway and farnesoid X receptor (FXR). MethodsThirty rats were randomly assigned into five groups, normal control group, VPA group received 500 mg/kg of VPA intraperitoneally. The remaining groups were orally treated with either 40 mg/kg of IAA, 90 mg/kg of CDCA, or a combination of both, along with VPA. All treatments were administered one hour after the administration of VPA for three weeks. Key findingsVPA group showed significant elevations in the liver weight/body weight ratio, serum aminotransferases, triglyceride, and total cholesterol levels. Hepatic glutathione (GSH) level and superoxide dismutase (SOD) activity were significantly decreased, while malondialdehyde (MDA) level, tumor necrosis factor-α (TNF-α), interleukin-1beta (IL-1β), lipopolysaccharide (LPS) and caspase 3 were significantly increased. Likewise, immunohistochemical analysis revealed that TLR4 expression was elevated, whereas FXR expression was downregulated in hepatocytes. IAA substantially ameliorated all previously altered parameters, whereas CDCA treatment showed a partial improvement compared to IAA. Surprisingly, combination therapy of IAA with CDCA showed an additive effect only in the hepatic expression of TLR4 and FXR proteins. SignificanceIAA could be a promising protective agent against VPA-induced liver injury.

Trimetazidine, an Anti-Ischemic Drug, Reduces the Antielectroshock Effects of Certain First-Generation Antiepileptic Drugs.

Trimetazidine (TMZ), an anti-ischemic drug for improving cellular metabolism, is mostly administered to patients with poorly controlled ischemic heart disease (IHD). Since IHD is considered the most frequent causative factor of cardiac arrhythmias, and these often coexist with seizure disorders, we decided to investigate the effect of TMZ in the electroconvulsive threshold test (ECT) and its influence on the action of four first-generation antiepileptic drugs in the maximal electroshock test (MES) in mice. The TMZ (up to 120 mg/kg) did not affect the ECT, but applied at doses of 20–120 mg/kg it decreased the antielectroshock action of phenobarbital. The TMZ (50–120 mg/kg) reduced the effect of phenytoin, and, when administered at a dose of 120 mg/kg, it diminished the action of carbamazepine. All of these revealed interactions seem to be pharmacodynamic, since the TMZ did not affect the brain levels of antiepileptic drugs. Furthermore, the combination of TMZ with valproate (but not with other antiepileptic drugs) significantly impaired motor coordination, evaluated using the chimney test. Long-term memory, assessed with a passive-avoidance task, was not affected by either the TMZ or its combinations with antiepileptic drugs. The obtained results suggest that TMZ may not be beneficial as an add-on therapy in patients with IHD and epilepsy.

Pharmacological Effects on Brain Morphology and Cognitive Functions in Idiopathic Generalized Epilepsy

Purpose: Sodium Valproate (VPA) is one of the first-generation Antiepileptic Drugs (AEDs) which mediates epileptic activities by releasing stimulators of Gamma-Aminobutyric Acid (GABA) and is greatly used to treat partial and generalized seizures. Lamotrigine )LTG( is commonly used as AEDs that are widely utilized in first-line monotherapy or in combination with other AEDs. Our specific goal was to compare these two AEDs with different molecular mechanisms on both cortical and subcortical brain structures, along with cognitive performance and dysfunctions.
 Materials and Methods: We conducted a retrospective study comparing LTG with sodium VPA, both administrated as monotherapy. Twenty patients with a confirmed generalized-epilepsy tonic-clonic seizure who had been treated at least 6 months with LTG (n=8) and Sodium VPA (n=12) were retrospectively recruited. We also included 12 age, gender, and education-matched Healthy Controls (HC). We evaluated cognitive performances. All participants underwent a Magnetic Resonance Imaging (MRI) scanner and T1-weighted MR images were acquired. Voxel-based morphometric alterations in the brain cortex, as well as subcortical structures, were inspected using Statistical Parametric Mapping (SPM) software.
 Results: The cognitive performance was revealed inferior in patients on Sodium VPA. Poor performance was associated with significant volume reduction in insula bilaterally, and subcortical structures of thalamus, cerebellum, and hippocampus compared to the HC. Comparing patients on LTG to HC revealed significant volume reduction in the anterior cingulate cortex in concordance with slight cognitive dysfunctions.
 Conclusion: These findings suggested that different molecular mechanisms of Antiepileptic Drugs (AEDs) may affect brain structures and cognition with different severity levels, presumably with more adverse effects induced by GABA mediations from sodium VPA.

Pharmacokinetic Drug-Drug Interactions among Antiepileptic Drugs, Including CBD, Drugs Used to Treat COVID-19 and Nutrients.

Anti-epileptic drugs (AEDs) are an important group of drugs of several generations, ranging from the oldest phenobarbital (1912) to the most recent cenobamate (2019). Cannabidiol (CBD) is increasingly used to treat epilepsy. The outbreak of the SARS-CoV-2 pandemic in 2019 created new challenges in the effective treatment of epilepsy in COVID-19 patients. The purpose of this review is to present data from the last few years on drug–drug interactions among of AEDs, as well as AEDs with other drugs, nutrients and food. Literature data was collected mainly in PubMed, as well as google base. The most important pharmacokinetic parameters of the chosen 29 AEDs, mechanism of action and clinical application, as well as their biotransformation, are presented. We pay a special attention to the new potential interactions of the applied first-generation AEDs (carbamazepine, oxcarbazepine, phenytoin, phenobarbital and primidone), on decreased concentration of some medications (atazanavir and remdesivir), or their compositions (darunavir/cobicistat and lopinavir/ritonavir) used in the treatment of COVID-19 patients. CBD interactions with AEDs are clearly defined. In addition, nutrients, as well as diet, cause changes in pharmacokinetics of some AEDs. The understanding of the pharmacokinetic interactions of the AEDs seems to be important in effective management of epilepsy.

Profiles of Indigenous Epileptic Patients in a Brazilian Village

Background: Epilepsy affects 50 million people worldwide, most of whom are low-income countries. Patients with epilepsy who live in socially isolated communities often require more medical attention. In Brazil, the estimated prevalence of epilepsy is approximately 2 million. Methods: This descriptive, cross-sectional study investigated the incidence of epilepsy among indigenous people residing in Jaguapiru Village, Dourados, Mato Grosso do Sul, Brazil. We reviewed the clinical histories of the participants and the results of electroencephalography (EEG), neuroimaging, and/or laboratory tests. Additionally, patients with nonepileptic paroxysmal events were identified. Findings: Of the 2,994 respondents, 49 had a confirmed diagnosis of epilepsy, and 22 had self-limited epileptic syndromes; these numbers exceeded the global prevalence but were similar to those reported in the Brazilian population. Focal epilepsy, predominantly of temporal lobe origin, was the most prevalent epileptic syndrome (71.4%). Febrile seizures occurred in only 0.4% of respondents -- much lower than that reported in the general population, which can be attributed to the cross-sectional study design. The aetiology of epilepsy was undetermined in 82.6% of cases, with the remaining cases attributed to head trauma, hypoxic-ischaemic encephalopathy, and brain malformations. A history of delayed neuropsychomotor development was significantly associated with epilepsy. Monotherapy with first-generation antiepileptic drugs was greatly effective in most epilepsy cases (87.7%). EEG helped to define focal epilepsies and diagnose seizures of nonepileptic origin; the latter mostly included cases of psychogenic crises and, less frequently, syncope. Interpretation: Identifying the epidemiological determinants of epilepsy in traditional communities is essential to establish public policies in countries such as Brazil. Funding: This study was conducted without external financial support. EEG was performed using the authors’ own equipment. Travel to the village for questionnaire application was funded by the authors as well. Imaging examinations (cranial computed tomography, magnetic resonance imaging) and laboratory tests, when performed, were provided by the National Health System. Declaration of Interest: The authors declare no financial conflicts of interest. Ethical Approval: This study was performed between November 2012 and November 2017 and was approved by the Research Ethics Committee Involving Human Beings of the Federal University of Grande Dourados and by the National Research Ethics Commission (CONEP; references 6810 and 64479, respectively), as well as the appropriate regulatory bodies and indigenous authorities. All of the participants or their legal representatives signed a free and informed consent form translated into the Guarani-Kaiwa language.

Therapeutic Drug Monitoring of Second- and Third-Generation Antiepileptic Drugs.

Therapeutic drug monitoring has traditionally been widely used for first-generation antiepileptic drugs (AEDs) such as carbamazepine and phenytoin. The last 2 decades have seen the introduction of second- and third-generation AEDs (eg, lamotrigine, levetiracetam, and topiramate) into clinical practice. To use data from the College of American Pathologists Therapeutic Drug Monitoring, Extended Proficiency Testing Survey to determine the performance of assays used for therapeutic drug monitoring of newer AEDs, including comparison of enzyme immunoassay and chromatographic techniques. Six years of proficiency testing surveys were reviewed (2013-2018). Steady growth was seen in participant volumes for newer AEDs. The analytical performance of automated enzyme immunoassays for lamotrigine, levetiracetam, and topiramate was similar to that of chromatographic methods, consistent with published literature using patient samples for comparisons. The majority of participating laboratories now use enzyme immunoassays to measure levetiracetam. Survey results reflect steadily growing interest in therapeutic drug monitoring of newer AEDs. The increasing availability of robust immunoassays for new AEDs should facilitate their clinical utility, especially for clinical laboratories that do not perform chromatographic assays for therapeutic drug monitoring.

Acute and chronic treatment with moclobemide, a reversible MAO-inhibitor, potentiates the antielectroshock activity of conventional antiepileptic drugs in mice

BackgroundDue to enhancing serotonergic and noradrenergic neurotransmission, moclobemide may influence seizure phenomena. In this study, we examined the effect of both acute and chronic treatment with moclobemide on seizures and the action of first-generation antiepileptic drugs: valproate, carbamazepine, phenobarbital and phenytoin. MethodsThe effect of moclobemide on seizures was assessed in the electroconvulsive threshold test, while its influence on antiepileptic drugs was estimated in the maximal electroshock test 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. ResultsGiven acutely, moclobemide at 62.5 and 75 mg/kg increased the electroconvulsive threshold. In contrast, chronic treatment with moclobemide up to 75 mg/kg did not influence this parameter. Acute moclobemide applied at subthreshold doses (up to 50 mg/kg) enhanced the antielectroshock effects of carbamazepine, valproate and phenobarbital. Chronic moclobemide (37.5‐75 mg/kg) increased the action of all four antiepileptic drugs. All revealed interactions, except these between moclobemide and phenobarbital, seem to have pharmacokinetic nature, because the antidepressant drug, either in acute or in chronic treatment, increased the brain concentrations of respective antiepileptic drugs. In terms of undesired neurotoxic effects, acute and chronic moclobemide, antiepileptic drugs, and their combinations did not produce significant motor or long-term memory impairment. ConclusionsAcute and chronic therapy with moclobemide can increase the effectiveness of some antiepileptic drugs against the maximal electroshock test. In mice, this effect was, at least partially, due to pharmacokinetic interactions. So far as the results of experimental studies can be transferred to clinical conditions, moclobemide seems safe for the application in patients with epilepsy and depression. Possibly, in the case of certain antiepileptic drugs combined with moclobemide, their doses should be adjusted downwards.

CHARACTERISTICS OF COGNITIVE STATUS OF EPILEPSY PATIENTS TREATED WITH MONOTHERAPY OF FIRST-GENERATION ANTIEPILEPTIC DRUGS

Epilepsy is one of the main health problems in neurology that can lead to cognitive decline. Generally, the epilepsy-associated cognitive decline is influenced by demographic, clinical, and treatment characteristics. This study aimed to determine the characteristics of cognitive status of epilepsy patients who received monotherapy using first-generation antiepileptic drugs (AEDs), namely phenytoin, carbamazepine, and valproic acid. It involved 93 epilepsy patients of Mutiara Sukma Mental Hospital (n=38) and Mataram General Hospital (n=55). Besides, 93 healthy patients were assigned as healthy control group (HC) subjects (n=93). Demographic characteristics collected from epilepsy and HC groups were age, gender, and years of education. Clinical characteristics taken from both groups were MoCA-Ina score. Clinical characteristics taken from epilepsy group were age at epilepsy onset, type of seizure (partial vs generalized), etiology (idiopathic vs structural), first-generation AED used, years of treatment, and cognitive status. The result of the study revealed that there were no significant different between the two groups in the means of age and years of education as well as the frequency of male gender (p>0.05). The mean of MoCA-Ina score of epilepsy group was significantly lower compared with HC group (p<0.05). The frequency of cognitive decline among epilepsy patients was 75.3%. The cognitive functions of epilepsy patients using monotherapy with carbamazepine, phenytoin, or valproic acid was significantly lower compared with healthy subjects. We conclude that there was high prevalence of epilepsy-associated cognitive impairment which was associated with male gender.

Dried Blood Microsampling-Based Therapeutic Drug Monitoring of Antiepileptic Drugs in Children With Nodding Syndrome and Epilepsy in Uganda and the Democratic Republic of the Congo.

Nodding syndrome is a highly debilitating, generalized seizure disorder, affecting children in subregions of sub-Saharan Africa. Despite numerous efforts to uncover the etiology, the exact cause of this syndrome still remains obscure. Therefore, to date, patients only receive symptomatic care, including the administration of first-generation antiepileptic drugs for seizure control. As data on the efficacy of drugs within this population are completely lacking, the aim of this study was to explore how therapeutic drug monitoring could help to understand the differential response to therapy. Considering the challenging environment in which sampling had to be performed (remote areas, devoid of electricity, running water, etc), dried blood matrices [ie, dried blood spots (DBSs)] and volumetric absorptive microsampling (VAMS) were considered fit-for-purpose. In addition, owing to the similarities between the syndrome and other forms of epilepsy, samples originating from patients suffering from (onchocerciasis-associated) epilepsy were included. In total, 68 patients with Nodding syndrome from Uganda, 58 Ugandan patients with epilepsy, and 137 patients with onchocerciasis-associated epilepsy from the Democratic Republic of the Congo were included. VAMS samples and DBS were analyzed using validated methods, involving manual extraction or fully automated extraction, respectively, before quantification using liquid chromatography coupled with tandem mass spectrometry. Analysis revealed that serum concentrations (calculated from DBS) within the respective reference ranges were attained in only 52.9% of the 68 Nodding syndrome patients treated with valproic acid, in 21.4% of the 56 Ugandan epilepsy patients treated with carbamazepine, and in 65.7% of the 137 onchocerciasis-associated epilepsy patients from the Democratic Republic of the Congo treated with phenobarbital. In all other instances, concentrations were subtherapeutic. Furthermore, on comparing DBS with VAMS concentrations, an inexplicable overestimation was observed in the latter. Finally, no obvious link could be observed between the obtained drug concentrations and the number of seizures experienced during the last month before sampling, elaborating the fact that the level of improvement in some patients cannot simply be linked to reaching therapeutic concentrations.

PCV46 STROKE AND THROMBOTIC EVENT ASSOCIATED WITH CONCOMITANT DIRECT ORAL ANTICOAGULANTS AND ANTIEPILEPTIC DRUGS IN THE FDA ADVERSE EVENT REPORTING SYSTEM

All direct oral anticoagulants (DOACs) are substrates of the efflux P-glycoprotein (P-gp) transporters. The hepatic enzyme cytochrome P450 also plays an important role in the metabolism of apixaban and rivaroxaban. Antiepileptic drugs (AEDs) may reduce absorption or and increase metabolism of DOACs and cause reduced antithrombotic efficacy of these drugs. Some case reports suggest that stroke and systemic embolism were caused with concomitant treatment AEDs-DOACs. However, there are no evidence whether concurrent use of metabolic inducers in patient taking DOACs was associated with increased risk of stroke and thrombotic events. We analyzed adverse event cases submitted to the Food and Drug Administration Adverse Event Reporting System from January 2010 to June 2019. We compared the proportion of cases reporting thromboembolic and ischemic adverse events with the concomitant use of DOACs and first-generation, metabolic inducing AEDs to the proportion of cases with DOACs and control AEDs. First generation AEDs were defined as phenytoin, phenobarbital, carbamazepine, and topiramate. Control AEDs were defined agents as lamotrigine and levetiracetam. During this observation, 214 thromboembolic and ischemic event cases reported in concomitant use of DOACs and AEDs. Compared with control AEDs, first generation AEDs were associated with increases in the odds of reporting outcomes [reporting odds ratio (ROR) 4.7, 95% confidence interval (CI) 3.3-6.6, p<0.0001]. In secondary analyses of dabigatran, rivaroxaban, and apixaban, inducing AEDs were similarly associated with increased reporting of outcome (ROR 2.2, 95%CI 1.3-4.0, ROR 7.3, 95%CI 4.3-12.7, and ROR 6.2, 95%CI 2.8-14.0). Edoxaban was not associated with the outcomes. We observed an increase in the odds of reporting anticoagulation treatment failure among patients treated with DOACs and concomitant first-generation AEDs compared to those treated with control AEDs.

Seizure-related injury and postictal aggression in refractory epilepsy patients

ObjectiveIn the general population, injury related to seizures often involves falls, head trauma, soft tissue injuries, burns and fractures. Additionally, postictal deleterious behavior changes can by experienced by patients. We seek to identify the risk for seizure-related injury (SRI) and postictal aggression (PIA) in patients with refractory epilepsy. MethodsSelf-reported SRI and PIA were gathered through a seizure questionnaire as part of the epilepsy center’s seizure safety protocol. Retrospective review of questionnaire, clinical course, and demographic data was completed. Statistical analysis of variables of interest was done using nonparametric methods. Results126 patient questionnaires were completed over a one-year duration. Most patients reported seizure related injury (56.3 %) and postictal aggression (52.4 %). Increased disease duration was associated with seizure related injury and its severity (Kwallis p = 0.025), with number of antiepileptic drugs (AEDs) as significant factors (p = 0.012). Postictal aggression was also associated with a longer duration of epilepsy (Ranksum p = 0.037, t-test p = 0.04) and higher seizure frequency (p = 0.017). Patients who reported seizure related injury and postictal aggression were on more AEDs (p = 0.0003, p = 0.01, respectively), with first-generation AEDs being most contributory. ConclusionThe majority of patients with seizures report seizure-related injuries and postictal aggression. Duration and AED regimen are significant risk factors and screening practices can potentially guide safety measures and recommendations.

Revisiting clinical practice in therapeutic drug monitoring of first-generation antiepileptic drugs

Due to the complex and diverse nature of epilepsy and antiepileptic drugs (AEDs), the implementation of therapeutic drug monitoring (TDM) can contribute significantly to the overall improvement of clinical outcome in epilepsy. Establishing and interpreting an individual serum drug concentration range by TDM is beneficial to prevent recurrence of epilepsy, as well as to avoid adverse drug effects. It enables optimization of dosage regimen, especially in case of drugs that follow non-linear pharmacokinetics, and in special populations such as pregnancy, pediatrics, geriatrics, critically ill, and liver and renal impairment. This review summarizes the ongoing clinical practice utilizing TDM of first-generation or conventional AEDs, such as valproic acid, phenytoin, carbamazepine, phenobarbital, primidone, ethosuximide, clonazepam, clobazam, piracetam, and sulthiame. Prospective and retrospective data describing the serum drug concentration–efficacy–toxicity relationship, pharmacokinetic parameters, activity of metabolites, overdose and treatment, and drugs that alter pharmacokinetics, have been described. The therapeutic decision should not be finalized based on serum drug concentration alone; other important factors to be considered are clinical laboratory data, patient history, signs and symptoms, pharmacogenetics, and electroencephalogram.

New Anticonvulsants: Interchangeability Issues and the Use of Generic Anticonvulsants in Clinical Practice

This article looks into interchangeability and therapeutic equivalence of innovator and generic anticonvulsants — the first-generation and new antiepileptic drugs (AEDs). The results of a number of clinical trials assessing therapeutic equivalence of generic AEDs support the opinion that these medicines could only be substituted provided an ultra-cautious approach is used, even if the case involves only one International Nonproprietary Name, including, but not limited to different dosage forms of one and the same product. The aim of the study was to analyse factors leading to incorrect assessment of therapeutic equivalence of new and generic anticonvulsant drugs, and to improve methodological approaches to conducting clinical trials of these products. The paper cites data from Russian and foreign sources which state that the substitution of AEDs in some patients in full remission may result in adverse reactions or relapse of seizures. The analysis of the experience of scientific, expert, and regulatory institutions made it possible to develop a course of actions to be used when substituting AEDs and conducting clinical trials that assess therapeutic equivalence of new and generic anticonvulsants. The proposed methodology will help minimise potential health risks brought about by various factors that result in incorrect assessment of AEDs therapeutic equivalence and interchangeability.

Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update.

Antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment. Since 1989, 18 new AEDs have been licensed for clinical use and there are now 27 licensed AEDs in total for the treatment of patients with epilepsy. Furthermore, several AEDs are also used for the management of other medical conditions, for example, pain and bipolar disorder. This has led to an increasingly widespread application of therapeutic drug monitoring (TDM) of AEDs, making AEDs among the most common medications for which TDM is performed. The aim of this review is to provide an overview of the indications for AED TDM, to provide key information for each individual AED in terms of the drug's prescribing indications, key pharmacokinetic characteristics, associated drug-drug pharmacokinetic interactions, and the value and the intricacies of TDM for each AED. The concept of the reference range is discussed as well as practical issues such as choice of sample types (total versus free concentrations in blood versus saliva) and sample collection and processing. The present review is based on published articles and searches in PubMed and Google Scholar, last searched in March 2018, in addition to references from relevant articles. In total, 171 relevant references were identified and used to prepare this review. TDM provides a pragmatic approach to epilepsy care, in that bespoke dose adjustments are undertaken based on drug concentrations so as to optimize clinical outcome. For the older first-generation AEDs (carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone, and valproic acid), much data have accumulated in this regard. However, this is occurring increasingly for the new AEDs (brivaracetam, eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, piracetam, pregabalin, rufinamide, stiripentol, sulthiame, tiagabine, topiramate, vigabatrin, and zonisamide).

Frequency of drug combinations between enzyme-inducing first-generation antiepileptic drugs and inducible drugs in patients with epilepsy

ObjectiveThe objective of the study was to systematically assess, through the analysis of administrative data, the frequency of combinations of first-generation enzyme-inducing (EI) antiepileptic drugs (AEDs) with drugs frequently prescribed in patients with epilepsy whose metabolism is induced by EIAEDs. MethodsFrom the population of Tuscany (a region in Italy of about 3,750,000 habitants), patients who had been treated with at least one first-generation EIAEDs (carbamazepine, phenytoin, phenobarbital, and primidone) and had received prescriptions of an inducible non-AED (NON-AED) included in a prespecified list of 103 inducible drugs were identified. ResultsAt the index date, 9221 patients with epilepsy were treated with at least one traditional EIAED, and there were 2538 drug combinations between EIAEDs and NON-AEDs, which may result in potentially serious clinical consequences, and 3317 combinations with NON-AEDs that have their metabolism consistently increased. ConclusionsPatients with epilepsy treated with traditional EIAEDs are at a very high risk of drug interactions.

Evaluation of long-term antiepileptic drug use in patients with temporal lobe epilepsy: Assessment of risk factors for drug resistance and polypharmacy

PurposeTo evaluate risk factors for drug resistance and polypharmacy in patients with temporal lobe epilepsy. MethodsPatients with temporal lobe epilepsy, treated for more than 5 years, completed questionnaires on antiepileptic drug use and effect. Logistic regression models were used for analysis of risk factors. ResultsOf 135 patients included in the study, 65% were classified as drug resistant and 41% identified as using polypharmacy. Poor effects associated with first-choice antiepileptic drug were reported by 59% of the patients, and 70% reported poor effects of second-line treatment. The most frequently used first-generation antiepileptic drugs had a similar mean effect to those of second-generation. Univariate regression analyses showed a significant association between drug resistance and mesial temporal sclerosis, seizure onset below 18 years, and lack of family history of epilepsy. However, multivariate regression analysis showed no association with any demographic or clinical features. Unsuccessful treatment with the first antiepileptic drug increased the risk of drug resistance by 18 times, and the risk of poor effect from the second antiepileptic drug by 9 times. Disease duration was associated with annual risk for drug resistance of 7% and for polypharmacy of 5%. ConclusionsA poor effect from initial pharmacotherapy is the only early risk factor for drug resistance found in this study. Long disease duration increases the risk of drug resistance and polypharmacy. Second-generation antiepileptic drugs provide no additional effect for poor responders to first-generation drugs.

Epilepsy in Asia: Disease burden, management barriers, and challenges.

This article reviews the burden of epilepsy in Asia, the challenges faced by people with epilepsy, and the management of epilepsy. Comparison is made with other parts of the world. For this narrative review, data were collected using specified search criteria. Articles investigating the epidemiology of epilepsy, diagnosis, comorbidities and associated mortality, stigmatization, and treatment were included. Epilepsy is a global health care issue affecting up to 70 million people worldwide. Nearly 80% of people with epilepsy live in low- and middle-income countries with limited resources. People with epilepsy are prone to physical and psychological comorbidities, including anxiety and depression, which can negatively impact their quality of life. Furthermore, people with epilepsy are at higher risk of premature death than people without epilepsy. Discrimination or stigmatization of people with epilepsy is common in Asia and can affect their education, work, and marriage opportunities. Access to epilepsy treatment varies throughout Asia. Although highly advanced treatment is available in some countries, up to 90% of people with epilepsy are not adequately treated or are not treated with conventional antiepileptic therapy in resource-limited countries. People in remote areas often do not receive any epilepsy care. First-generation antiepileptic drugs (AEDs) are available, but usually only in urban areas, and second-generation AEDs are not available in all countries. Newer AEDs tend to have more favorable safety profiles than first-generation AEDs and provide options to tailor therapy for individual patients, especially those with comorbidities. Active epilepsy surgery centers are present in some countries, although epilepsy surgery is often underutilized given the number of patients who could benefit. Further epidemiologic research is needed to provide accurate epilepsy data across the Asian region. Coordinated action is warranted to improve access to treatment and care.

Correction to: Volumetric absorptive microsampling as an alternative tool for therapeutic drug monitoring of first-generation anti-epileptic drugs.

We would like to call the reader's attention to the fact that unfortunately in fig. 2 of the original article the figure headings of both graphs are the same.

Volumetric absorptive microsampling as an alternative tool for therapeutic drug monitoring of first-generation anti-epileptic drugs.

Dosage adjustment of anti-epileptic drugs by therapeutic drug monitoring (TDM) is very useful, especially for the first-generation anti-epileptic drugs (AEDs). Microsampling-the collection of small volumes of blood-is increasingly considered a valuable alternative to conventional venous sampling for TDM. Volumetric absorptive microsampling (VAMS) allows accurate and precise collection of a fixed volume of blood, eliminating the volumetric blood hematocrit bias coupled to conventional dried blood spot collection. The aim of this study was to develop and validate an LC-MS/MS method for the determination and quantification of four anti-epileptic drugs (carbamazepine, valproic acid, phenobarbital, and phenytoin) and one active metabolite (carbamazepine-10,11-epoxide) in samples collected by VAMS. The method was fully validated based on international guidelines. Precision (%RSD) was below 10%, while, with a single exception, accuracy (%bias) met the acceptance criteria. Neither carry-over nor unacceptable interferences were observed, the method being able to distinguish between the isomers oxcarbazepine and carbamazepine-10,11-epoxide. All compounds were stable in VAMS samples for at least 1month when stored at room temperature, 4°C, and - 20°C and for at least 1week when stored at 60°C. Internal standard-corrected matrix effects were below 10%, with %RSDs below 4%. High (> 85%) recovery values were obtained and the effect of the hematocrit on the recovery was overall limited. Successful application on external quality control materials and on left-over patient samples demonstrated the validity and applicability of the developed procedure. Graphical abstract Graphical representation of the sampling, chemical structures, and the resulting chromatogram for volumetric absorptive microsampling (VAMS)-based therapeutic drug monitoring of first-generation anti-epileptic drugs by liquid chromatography with tandem mass spectrometric detection.