Novel approaches to anticonvulsant drug discovery

Introduction: The history of epilepsy dates back to 2000 BC. Yet, it was not until 1912 that the activity of the first antiepileptic, phenobarbital was discovered by accident. After this discovery, the next antiepileptic drugs to be discovered (phenytoin and primidone) were based on the phenobarbital's structure. Then, in 1960, carbamazepine was developed empirically, while in 1962, valproate demonstrated anticonvulsant activity against experimental seizures. The next antiepileptic drugs synthesized were either modifications of the existing drugs (such as oxcarbazepine and pregabalin) or completely novel chemical structures (lacosamide, perampanel and retigabine).

Areas covered: The present paper briefly refers to the history of epilepsy and development of antiepileptic drugs. Further, the paper provides a discussion on the antiepileptogenic effects of antiepileptic drugs in terms of the constant percentage of epileptic patients with refractory seizures. The authors also review the likely factors involved in the false refractoriness (such as through the use of caffeine-containing beverages and smoking). Finally, the authors consider future directions in the search of novel antiepileptic drugs.

Expert opinion: In spite of the considerable number of newer antiepileptic drugs, the number of drug-resistant epileptic patients remains unchanged. This may be rather an indication of the suitability of the currently available discovery procedures for effective antiepileptic drugs in the whole population of epileptic patients. The authors, however, believe that it is likely that models of mimic chronic epilepsy will help bridge the gaps and aid in the discovery of novel antiepileptic drugs – ones that can effectively modify the course of the disease.     

Mechanisms of action of new antiepileptic drugs: rational design and serendipitous findings

After years without any major breakthroughs in the treatment of epilepsy disorders, a new wave of antiepileptic drugs have become available to clinicians. Felbamate, gabapentin, lamotrigine and vigabatrin are among the most promising of this new generation of drugs and, when used as add-on therapy, provide some improvement in a significant number of patients suffering from previously refractory epilepsy whilst exhibiting a lower risk of unwanted side-effects than traditional antiepileptic drugs. In this article,Neil Upton reviews the recent discoveries that suggest these four new agents exert their antiepileptic properties by acting through diverse and often novel mechanisms, some of which are by design, and some of which are by chance. Also highlighted are examples of the most innovative mechanistic approaches currently being adopted to produce the next generation of antiepileptic drugs.     

利伐沙班与抗癫痫药物相互作用的研究进展

心房颤动（房颤）导致的卒中是其严重并发症,非瓣膜性房颤导致脑梗死患者并发癫痫的风险比其他原因卒中患者更高,可能需要利伐沙班联合抗癫痫药物治疗。新型口服抗凝药物利伐沙班是口服直接Xa因子抑制剂,同时是CYP3A4和P-糖蛋白（P-gp）的底物,某些抗癫痫药物对CYP3A4和/或P-gp有诱导作用,与利伐沙班合用,可使利伐沙班血药浓度下降,血栓风险增加。对利伐沙班与丙戊酸钠、卡马西平、苯巴比妥、奥卡西平、左乙拉西坦以及其他抗癫痫药物合用的相互作用进行综述,并根据相关研究和病例报道给出推荐意见,为临床合理用药提供参考。     

Recent progress in anticonvulsant drug research: strategies for anticonvulsant drug development and applications of antiepileptic drugs for non-epileptic central nervous system disorders

Major advances in antiepileptic drug therapy have taken place since 1950s. In the first period, several antiepileptic drugs (AEDs) such as phenobarbital, diphenylhydantoin, ethosuximide, carbamazepine, benzodiazepines and valproic acid were introduced to epilepsy treatment. After 1990 many new generation drugs (lamotrigine, topiramate, gabapentine, pregabaline, felbamate, lacosamide, levetiracetam etc.) have been developed. These novel AEDs have offered some advantages such as fewer side effects, fewer drug-drug interactions, and better pharmacokinetic properties. But pharmacoresistance and therapeutic failure in 20-25% of the patients remain the main reasons to continue efforts to find safer and more efficacious drugs and ultimate a treatment for this devastating disease. Several AEDs especially novel compounds have been found to be effective also in the treatment of several other neurologic and psychiatric disorders. Chemical diversity of the newer antiepileptic drugs as well as those currently in clinical development is another point that encourages medicinal chemists to study this subject. This review summarizes recent studies on the development of potential anticonvulsant compounds in different chemical structures, their structure-activity relationships and also therapeutic usages of AEDs other than epilepsy.     

北京大学第一医院儿科门诊口服抗癫痫药应用分析

目的：了解我院儿科门诊口服抗癫痫药处方用药的基本情况和趋势,为临床合理用药提供参考。方法：查阅我院2013年1-4月的儿科门诊处方,每个星期随机抽取1日处方,对口服抗癫痫药的使用情况进行整理和分析。结果：916张含有口服抗癫痫药的处方纳入分析,抗癫痫药单一用药占68．67％（629／916）,联合用药占31．33％（287／916）。单一用药中使用率排序居前3位的口服抗癫痫药分别为：左乙拉西坦30．36％（191／629）、丙戊酸钠27．03％（170／629）、奥卡西平12．60％（78／629）。结论：从口服抗癫痫药使用的品种、联合用药方案及使用剂量来看,我院儿科门诊口服抗癫痫药使用情况基本合理,且以新型口服抗癫痫药为主,符合抗癫痫药的使用趋势。     

我院2005-2012年抗癫痫药应用分析

目的：评价我院抗癫痫药的应用情况与趋势。方法：采用世界卫生组织推荐的以限定日剂量（DDD）为指标的分析方法,对我院2005-2012年抗癫痫药的应用情况进行回顾性分析。结果：2005-2012年,托吡酯、卡马西平的销售金额逐渐下降,奥卡西平和左乙拉西坦的销售金额逐渐上升;用药频度（DDDs）排序列前2位的是卡马西平和苯巴比妥,奥卡西平的DDDs逐年上升,2012年已跃居至第1位;抗癫痫药的日均费用较稳定,但每种抗癫痫药的排序比值的变化各有不同。结论：我院目前临床上以传统抗癫痫药为主,但随着人们对新型抗癫痫药左乙拉西坦、奥卡西平等认识的加深,将来新型抗癫痫药的市场潜力巨大。     

颅脑手术后抗癫痫药物预防癫痫疗效分析

目的：分析抗癫痫药物在脑外科治疗中的使用情况,探讨抗癫痫药物在颅脑手术后癫痫的预防作用以及各种药物作用的强弱。方法：查阅2001～2007年医院神经外科住院患者的病例资料,利用spss软件分析术后使用抗癫痫药是否对术后癫痫的发生率产生影响,并比较4种常用抗癫痫药对术后癫痫的预防作用。结果：非癫痫患者有预防性用药的93例,术后无发作的89例,发作4例;未使用抗癫痫药物的38例,术后无发作的36例,发作2例。有预防性用药与无预防性用药的术后癫痫发生率分别为4．30％和5．26％（P〉0．05）,两组无统计学差异。苯妥英钠、苯巴比妥钠、丙戊酸钠、卡马西平4种抗癫痫药对非癫痫患者术后癫痫的预防作用无统计学差异。结论：对于非癫痫手术的患者,预防性使用抗癫痫药效果并不理想。外科中常用的四种抗癫痫药物在预防作用方面比较并无统计学差异。     

新型抗癫痫药之间及其与传统抗癫痫药的相互作用和机制*

分别综述了几种新型抗癫痫药（托吡酯、非氨酯、奥卡西平、拉莫三嗪、唑尼沙胺、左乙拉西坦、噻加宾、加巴喷丁及氨己烯酸）与传统抗癫痫药联合应用时以及这些新型抗癫痫药之间的相互作用及其发生机制，阐明细胞色素P450酶和葡萄糖苷酸转移酶在新型抗癫痫药的相互作用中的意义及重要性。为临床合理联合应用提供理论依据，提高抗癫痫治疗的可靠性、安全性和有效性。     

Neurotoxic/neuroprotective profile of carbamazepine, oxcarbazepine and two new putative antiepileptic drugs, BIA 2-093 and BIA 2-024

We investigated and compared the toxicity profile, as well as possible neuroprotective effects, of some antiepileptic drugs in cultured rat hippocampal neurons. We used two novel carbamazepine derivatives, (S)-(-)-10-acetoxy-10,11-dihydro-5H-dibenz[b, f]azepine-5-carboxamide (BIA 2-093) and 10, 11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepine-5-carboxamide (BIA 2-024), and compared their effects with the established compounds carbamazepine and oxcarbazepine. The assessment of neuronal injury was made by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl (MTT) assay, as well as by analysing morphology and nuclear chromatin condensation (propidium iodide staining), after hippocampal neurons were exposed to the drugs for 24 h. The putative antiepileptic drugs, BIA 2-093 or BIA 2-024 (at 300 microM), only slightly decreased MTT reduction, whereas carbamazepine or oxcarbazepine were much more toxic at lower concentrations. Treatment with the antiepileptic drugs caused nuclear chromatin condensation in some neurons, which is characteristic of apoptosis, and increased the activity of caspase-3-like enzymes, mainly in neurons treated with carbamazepine and oxcarbazepine. The toxic effect caused by carbamazepine was not mediated by N-methyl-D-aspartate (NMDA) or by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptors. Moreover, the antiepileptic drugs failed to protect hippocampal neurons from the toxicity caused by kainate, veratridine, or ischaemia-like conditions.     

Investigation of phenobarbital-carbamazepine-valproic acid interactions using population pharmacokinetic analysis for optimisation of antiepileptic drug therapy: an overview

Antiepileptic drugs are associated with a wide range of drug interactions. Although monotherapy with antiepileptic drugs is preferred, patients with multiple seizure types or refractory disease generally require various combinations of antiepileptic drugs. Pharmacokinetic interactions between antiepileptic drugs represent a major complication of epilepsy treatment with polytherapy. It is important to be aware of possible interactions, so as to anticipate clinical effects and to reduce the risk of both toxicity and seizures worsening when a drug is added to, or withdrawn from, the patient's antiepileptic drug regimen. This report is an overview of the drug-drug interactions between antiepileptic drugs (phenobarbital<-->carbamazepine, carbamazepine<-->valproic acid and phenobarbital<-->valproic acid) by population pharmacokinetic analysis.     

2012-2014年南京地区34家医院抗癫痫药物利用分析

目的: 评价南京地区医院抗癫痫药的应用现状及趋势。方法: 对南京地区34家医院2012-2014年抗癫痫药的品种、用量、销售金额、用药频度等进行回顾性统计、分析。结果: 南京地区抗癫痫药销售金额逐年增加。各年度新型抗癫痫药销售金额均占抗癫痫药总销售金额的六成左右,DDDs所占比例从2012年的35.43%增长至2014年的45.53%。金额排序中丙戊酸钠各年度一直占据36%左右,稳居第一;新型抗癫痫药加巴喷丁、左乙拉西坦、奥卡西平销售金额逐年大幅增加,苯妥英钠、托吡酯年销售金额略有起伏。DDDs排序中丙戊酸钠以绝对优势稳居第一;新型抗癫痫药除托吡酯外用药频度均呈逐年增加趋势,而传统AEDs除丙戊酸钠外均逐年降低。结论: 南京地区抗癫痫药丙戊酸钠、奥卡西平选用倾向大,传统抗癫痫药丙戊酸钠在抗癫痫药中仍占据重要地位,新型抗癫痫药如奥卡西平、左乙拉西坦、拉莫三嗪、加巴喷丁等不良反应、耐受性、对肝药酶的影响性等优于传统抗癫痫药,市场前景良好。     

Vagus nerve stimulation therapy

Until recently, antiepileptic drugs and traditional epilepsy surgery were the two primary treatment options available to patients with epilepsy. Drug therapy, however, does not always control seizures and can be associated with negative side effects. Additionally, only a minority of patients are candidates for epilepsy surgery. Vagus nerve stimulation (VNS) therapy, approved by the US FDA in 1997, is now a treatment option that is effective in reducing seizure frequency and severity as well as improving patient quality of life without the pharmacological side effects associated with traditional antiepileptic drugs. Provided here is an overview of VNS therapy and the VNS therapy system, including the history of vagal nerve stimulation, patient selection guidelines and new indications currently under investigation for this novel therapy.     

2017年下半年福州总医院抗癫痫药片剂分剂量使用的情况分析

目的 调查分析福州总医院住院患者分剂量使用抗癫痫片剂的使用情况和存在的问题,为保障患者用药安全提供参考。方法 随机抽取福州总医院2017年6~12月口服抗癫痫药物片剂的217名患者出院病历进行回顾性分析,统计分析不同抗癫痫药物分剂量使用情况及使用分剂量抗癫痫药物患者年龄、使用科室、不同癫痫药物分至不同剂量的情况。结果 分剂量使用抗癫痫片剂使用率为30.73%,分剂量使用率最高的药物为苯巴比妥,分剂量使用最高的科室为新生儿病区,丙戊酸钠缓释片分剂量的使用最多,均分至1/2片。结论 福州总医院抗癫痫药片剂分剂量的使用基本合理,药师应对片剂分剂量的准确性与合理性进行全程的药学监督,促进患者安全合理用药。     

Access to antiepileptic drug therapy in children in Camagüey Province,Cuba

Objective To describe access to antiepileptic drug therapy and estimate the prevalence of epilepsy in children in Camagüey Province, Cuba. Methods All the community pharmacies in the province were visited and information collected about the number of children receiving antiepileptic drugs in 2009. Availability and cost of each antiepileptic drug were determined. The prevalence of epilepsy was estimated by determining the number of children receiving antiepileptic drugs. Results There were 923 children who received a total of 977 antiepileptic drugs in Camagüey Province. The estimated prevalence of epilepsy was 5.18 per thousand children which is lower than previously reported rates in other low and lower‐middle income countries. Most of the children (871, 94%) received a single antiepileptic drug. Carbamazepine and valproate were the two most frequently prescribed antiepileptic drugs. Antiepileptic drugs were available from the local pharmacy on 76% of occasions. If the antiepileptic drug was not available from the local pharmacy, the parent had to travel to another pharmacy to obtain the medicine. Conclusions The estimated prevalence of epilepsy in children in Cuba is lower than that estimated in other lower‐middle income countries. Access to drug therapy in children with epilepsy can be achieved in lower‐middle income countries.     

我院432例抗癫痫药血药浓度监测数据分析

目的:分析抗癫痫药血药浓度监测结果,为临床合理用药提供参考。方法:建立抗癫痫药Access数据库,对我院2001年1月～2009年6月4种常用抗癫痫药的血药浓度监测结果进行统计、分析。结果:我院抗癫痫药血药浓度监测例数大体呈逐年上升趋势,共监测432例/次;血药浓度在治疗窗内所占比例为48.6%;卡马西平、苯巴比妥、苯妥英钠、丙戊酸钠血药浓度在治疗窗内的有效率分别为91.3%、77.8%、62.5%、88.2%;儿童(0～10岁)与老人(>60岁)进行血药浓度监测例数占总监测例数的22.2%;有43例采用抗癫痫药联合给药方案,占总例数的10%,其中偏离正常治疗浓度范围的有27例,占62.8%。结论:血药浓度监测结果是指导临床用药的重要依据之一,结合其他临床指标综合分析,可最大限度地促进抗癫痫药合理应用。     

Levetiracetam: the first SV2A ligand for the treatment of epilepsy

Levetiracetam is a multiple action drug that primarily acts through an interaction with the synaptic vesicle protein 2A. Levetiracetam is the first drug of its kind to be approved for the treatment of epilepsy and is now the most prescribed among the newer antiepileptic drugs. The discovery process identifying levetiracetam's antiepileptic potential was unique because it challenged several dogmas of antiepileptic drug discovery, and thereby encountered skepticism from the epilepsy community. This was contrasted by a very successful development programme leading to rapid regulatory approval by the FDA. The history of levetiracetam proves that a small core group of committed scientists and physicians, who dare to challenge the conventional scientific doctrine, can be successful in bringing to market a truly novel therapy for epilepsy patients.     

Choice of antiepileptic drugs for the elderly: possible drug interactions and adverse effects

INTRODUCTION: Antiepileptic drugs are prescribed to patients of all ages and are commonly prescribed to patients over the age of 65. When prescribing these drugs to patients of this age bracket, treatment should be based not only on the diagnosis and seizure type but also on the propensity of the drugs for adverse effects and their drug-drug interactions. AREAS COVERED: This article reviews antiepileptic drugs currently used for treating the elderly and highlights the adverse effects and potential drug-drug interactions for these treatments. The article was complied through literature searches of the Cochrane database of systematic reviews, MEDLINE and SCindeks. EXPERT OPINION: In elderly patients who have hepatic diseases, antiepileptic drugs that are not metabolized in the liver, such as levetiracetam, are preferred; in patients with moderate and severe renal failure, carbamazepine and valproic acid are the preferred antiepileptic drugs. Phenytoin, fosphenytoin, carbamazepine, oxcarbazepine and lamotrigine should not be prescribed in elderly patients with cardiac conduction abnormalities or a history of ventricular arrhythmia. While the majority of antiepileptic drugs interact with other drugs, hepatic enzymes and plasma proteins, a few newer antiepileptic drugs are free from such interactions (e.g., gabapentin, levetiracetam and tiagabine), which make them suitable candidates for elderly patients. However, in order to make further recommendations regarding the choice and dosing regimens of antiepileptic drugs in elderly patients, more extensive clinical research in this specific population is necessary.     

Antiepileptic-induced resistance to neuromuscular blockers: mechanisms and clinical significance

Prolonged administration of antiepileptic drugs is associated with several drug interactions. In the field of anaesthesia and critical care, patients exhibit both sensitivity and resistance to non-depolarising neuromuscular blockers (NDNMBs) after acute and long-term administration of antiepileptic drugs, respectively. Although antiepileptic therapy alone has only mild neuromuscular effects, acutely administered antiepileptic drugs can potentiate the neuromuscular effects of NDNMBs as a result of direct pre- and post-junctional effects. Resistance to NDNMBs during long-term antiepileptic therapy is due to multiple factors operating alone or in combination, including induction of hepatic drug metabolism, increased protein binding of the NDNMBs and/or upregulation of acetylcholine receptors.     

我院2001～2006年抗癫痫药血药浓度监测数据分析

目的:阐述治疗药物监测(TDM)对抗癫痫药合理应用的意义,关注临床科室对TDM的认识程度。方法:建立抗癫痫药Access数据库,对我院2001～2006年抗癫痫药TDM结果进行分析。结果:我院抗癫痫药监测例数逐年上升;由监测结果计算的抗癫痫药有效浓度、高血药浓度、低血药浓度比例显示血药浓度监测极有必要,但患者的个体用药信息缺乏限制了抗癫痫药个体化用药的发展。结论:TDM虽应用日益广泛,但仍需医师、药师共同努力,以最大限度地保证抗癫痫药的个体化应用。     

Pros and cons for the development of new antiepileptic drugs

There continues to be an escalation in the number of new antiepileptic drugs, with many recently marketed drugs and many more entering clinical trials. This growth begs the question as to whether we need additional antiepileptic drugs. We consider the answer to this question from the medical perspective and also from the viewpoint of the pharmaceutical industry, health providers and from a more global, international perspective. There is undoubtedly a medical need for new antiepileptic drugs, and despite growing competition, the antiepileptic drug market remains profitable. However, in health services with limited resources, it is important that this expense is not offset by failure to research more appropriate use of existing antiepileptic drugs that may have a greater impact on healthcare. This is especially true for developing countries where resources would be much better spent on prevention and closing the treatment gap (the difference between those who can be treated and those who are treated).