抗癫痫类药物致药物超敏反应综合征的文献分析

目的探讨抗癫痫类药物致药物超敏反应综合征的临床特点、原因及常见致敏药物,为临床合理用药提供参考。方法检索从建库至2016年6月中国期刊全文数据库、万方数据库、中文科技期刊全文数据库(维普)和Pubmed数据库,查阅公开发表的抗癫痫药引起的超敏反应综合征案例报告,并进行统计和分析。结果综合文献报道纳入38例患者,其中中国人36例,日本人1例,法国人1例。致敏药物以苯巴比妥(36.84%)和卡马西平(39.47%)最常见。临床表现以发热、皮损为主。经治疗后35例好转,3例死亡。结论药物超敏反应综合征时有发生,临床应用时应密切关注患者的变化,以减少不良反应发生。     

New and investigational antiepileptic drugs

In the last fifteen years, new antiepileptic medications have been offered for the treatment of patients with epilepsy. Nevertheless, despite optimal medical treatment, up to 30% of patients still experience recurrent seizures and the challenge for new, more efficacious and better-tolerated drugs continues. New antiepileptic drugs include the evolution of pre-existing drugs and new compounds identified through the investigation of additional molecular targets, such as SV2A synaptic vesicle protein, voltage-gated potassium channels, ionotropic and metabotropic glutamate receptors, and gap junctions. This paper reviews the available information on various classes of molecules that are in the pipeline as well as on the innovative approaches to the treatment of epilepsy.     

The adverse effects of antiepileptic drugs in children

Efficacy of antiepileptic drugs (AEDs) are often equivalent, hence selection of an AED is often determined by the adverse effects (AEs). The development of neurocognitive AEs is almost inevitable with use of AEDs, especially in high-risk groups. Teratogenesis with major or minor malformations is of great concern during the first trimester of pregnancy, but an increasing body of information suggests that potential neurocognitive developmental delay may also occur with use of AEDs in the latter part of pregnancy. Decreased bone mineral density has been found in adults and children receiving both enzyme-inducing AEDs and valproate, an enzyme-inhibiting drug. AEDs may influence the lipid profile, body weight, reproductive, hormonal and other endocrine functions, and sleep architecture. There are age-specific AEs related to pharmacokinetic differences that have been highlighted in this review with emphasis on the pediatric population. A classification of AEs using different parameters is also included.     

Research advances in basic mechanisms of seizures and antiepileptic drug action

Epilepsy is a common neurological disease but the mechanism of seizure generation has been only partially unraveled. Furthermore, almost 30% of epileptic patients are resistant to pharmacological treatment. Therefore, elucidation of the basic mechanism of seizures and search for new antiepileptics in order to treat the drug-resistant form of epilepsy and to improve the efficacy of current therapies seem justified. The aim of this overview is a brief presentation of some new concepts and research directions in pathogenesis and pharmacotherapy of epilepsy. Development of ideas on the mechanisms of seizures and antiepileptic drugs reflects the progress in our understanding of the central nervous system physiology, particularly of neurotransmission. Hyperactivity of excitatory amino acid systems, insufficient GABA_A receptor-mediated neurotransmission, and disturbances in intrinsic properties of neuronal membranes are still regarded as the most important mechanisms of seizures. New data add to the complexity of GABA-glutamate interaction showing both excitatory and inhibitory role of GABA and glutamatergic neurons in the central nervous system. Moreover, besides synaptic NMDA and GABA_A receptors, also extrasynaptic receptors for the amino acid transmitters have been recently implicated in the pathomechanism of epilepsy. Changes in expression, polymorphisms, lost- or gain-function mutations as well as cellular energetic imbalance can contribute to the disturbed function of the ligand- and voltage-dependent sodium, potassium, chloride and calcium channels, resulting in epileptiform activity. Voltage-dependent sodium and calcium channel blockers, and GABA mimetics are the most clinically useful groups of antiepileptic drugs and the newest research in this field is focused on more selective and subtle regulations of their molecular targets. Of interest is an emerging role of extrasynaptic GABAA receptors, various kinds of potassium ion channels, hyperpolarization-activated cyclic nucleotide gated (HCN) channels, acid-sensing ion channels, and gap junctions in the regulation of neuronal excitability and seizures. Iono- and metabotropic glutamate receptors used to be viewed as an attractive target for new anticonvulsants, however, opinions are now less enthusiastic, since their competitive and non-competitive antagonists possess undesired side effects. Positive or negative allosteric modulators of glutamate receptors with fewer side-effects can be more promising. The introduction of new compounds acting through novel pharmacological mechanisms gives hope that the proportion of patients with uncontrolled epilepsy will substantially decrease. However, this may be possible if molecular background of the pharmacoresistance in epilepsy is deciphered.     

儿童抗癫痫药物超说明书用药调查分析

目的:了解抗癫痫药物在儿童患者中超说明书用药的情况,并分析原因,为儿童抗癫痫药物的合理使用提供参考.方法:分层随机抽取2012年9月-2013年8月的抗癫痫药物门诊处方,参照药品说明书的内容,判断使用抗癫痫药物的处方是否存在超说明书用药,统计分析超说明书用药的类型,计算超说明书用药发生率.结果:2 400张处方中,超说明书用药共955张,占所有处方的39.79%,主要是超适应证和超年龄用药.抗癫痫药物超说明书用药比例由高到低分别是:唑尼沙胺片(100%)、左乙拉西坦片(95.19%)、拉莫三嗪片(48.08%)、丙戊酸钠片(43.33%)等.结论:抗癫痫药在儿童癫痫患者中超说明书用药的发生率较高,尤其是唑尼沙胺和左乙拉西坦.其中大部分超适应证用药是有循证医学依据的,并非医师盲目用药.儿童用药的特殊性也是造成超说明书用药的重要原因.应尽可能规范超说明书用药行为,促进临床合理用药.     

Basic mechanisms of antiepileptic drugs and their pharmacokinetic/pharmacodynamic interactions: an update

This article aims to summarize the current views of AED action and the promising new targets for the pharmacotherapy of epilepsy. In the first section of this paper, a neurobiological basis of epilepsy treatment and brief pharmacological characteristics of classical and new AEDs will be presented. In the second part, the results of experimental studies that have combined AEDs with similar or different mechanisms of action will be discussed.     

Bone loss associated with use of antiepileptic drugs

Importance of the field: Epilepsy is a neurological disorder associated with several comorbidities, one of them being reduced bone health. As the bone loss most often is insidious and asymptomatic, they are usually not recognized, and thus untreated. The key message of this paper is to make clinicians aware of the problem.

Areas covered in this review: This article reviews data from basic and clinical studies of bone loss associated with usage of antiepileptic drugs (AEDs) within the last 4 decades.

What the reader will gain: The reader will learn that there is accumulating evidence of biochemical abnormalities indicating a disturbed bone metabolism, a decreased bone density and a 2 – 6 times increased risk of fractures among those with epilepsy compared to the general population. These findings most likely have many causes, both internal and external, but long-term use of AEDs seems to play an important role. Enzyme-inducing drugs, such as phenytoin, phenobarbital and carbamazepine, but also the enzyme inhibitor valproate, appear to have bone-depleting properties. Reduced bone density may be detected during the first 1 – 5 years of treatment. Although many theories have been launched, the exact mechanisms by which the the drugs affect bone architecture are not fully understood.

Take home message: We recommend clinicians to promote osteoprotective behavior among their epilepsy patients; that is, sunlight exposure and weight-bearing exercise as well as avoidance of risk factors such as bone-depleting drugs other than AEDs, smoking and heavy alcohol consumption. Enzyme inducing drugs should be avoided, if possible. Bone mineral density screening should be assessed on an individual basis, taking risk factors for bone loss into account. All patients taking AEDs on long-term basis ought to have adequate amounts of dietary calcium and vitamin D, and those who have developed bone loss should in addition be given specific antiosteoporotic treatment.     

A neurochemical study of the novel antiepileptic drug retigabine in mouse brain

The novel antiepileptic drug, retigabine, has been reported to have multiple mechanisms of action, including potentiation of gamma -aminobutyric acid (GABA) and glutamate synthesis. We have investigated its effects on several GABA- and glutamate-related neurochemical parameters in mouse brain. Mice were administered retigabine either as a single dose or daily for 5 days. At 4 h after dosing, brains were removed and analysed for GABA, glutamate, and glutamine concentrations and for the activities of GABA-transaminase and glutamic acid decarboxylase. Single doses of retigabine significantly lowered brain concentrations of glutamate and glutamine. Repeated treatment significantly reduced the activity of GABA-transaminase. The drug was essentially without effect on all other parameters investigated. These results suggest that retigabine blocks GABA metabolism rather than enhancing GABA synthesis. In addition, the drug may also lower brain concentrations of the excitatory neurotransmitter glutamate and its precursor, glutamine. These effects may contribute to the antiepileptic action of retigabine.     

Caffeine and the anticonvulsant potency of antiepileptic drugs: experimental and clinical data

Caffeine (1,3,7-trimethylxanthine) is the most commonly ingested stimulant in the world. The daily consumption of this methylxanthine in coffee, tea and soft drinks is approximately 200 mg per person, which yields a pharmacologically active blood concentration. Experimental data indicate that caffeine may either lower the convulsive threshold in experimental models of epilepsy or induce seizure activity in doses over 400 mg/kg in rodents. Interestingly, animal data have demonstrated that caffeine, at doses far below its convulsive potential, diminishes the protective effects of conventional antiepileptic drugs (AEDs--carbamazepine, phenobarbital, phenytoin, valproate) and the newer AED, topiramate against electroconvulsions in mice. However, in contrast to these AEDs, caffeine did not impair the anticonvulsant efficacy of other newer AEDs, lamotrigine, tiagabine, and oxcarbazepine in this experimental model of epileptic seizure. Although limited, the clinical data generally confirm the experimental findings, suggesting increased seizure frequency in epileptic patients who began ingesting caffeine in high quantities. Thus far, no analysis has been performed in epileptic patients to determine whether the hazardous effects of caffeine are dependent upon individual antiepileptic treatments. These data clearly indicate that methylxanthines should be avoided in epileptic patients.     

Influence of concurrent antiepileptic medication on the pharmacokinetics of lamotrigine as add-on therapy in epileptic children

1   Lamotrigine is a new antiepileptic drug, chemically unrelated to currently used antiepileptic medication. Its pharmacokinetics can be influenced by concomitant antiepileptic medication.
2   This study was performed to assess the pharmacokinetic profile of lamotrigine in three groups of children treated with different types of comedication: drugs known to induce, to inhibit or to have no clinically significant influence on drug metabolism, respectively.
3   Thirty-one children aged 6 months to 5 years were included and received a 2  mg  kg⁻¹ single oral dose. Lamotrigine plasma profiles were different between the three comedication groups. The half-lives (mean±s.d.) were: 7.7±1.8  h, 21.9±6.8  h, 44.7±10.2  h in the 'inducer', 'other' and 'inhibitor' groups respectively.
4   Patients were then dosed to steady state, with the dosage adjusted on the basis of the single dose pharmacokinetics to achieve a minimum plasma concentration between 1.5 and 3  mg  l⁻¹. The mean minimum plasma concentration for the three groups was 2.54±1.28  mg l⁻¹ at steady state.
5   Dosage of lamotrigine can be optimised with knowledge of the metabolic effects of antiepileptic comedication.     

Mechanisms of drug-induced delayed-type hypersensitivity reactions in the skin

Cutaneous drug reactions (CDRs) are the most commonly reported adverse drug reactions. These reactions can range from mildly discomforting to life threatening. CDRs can arise either from immunological or nonimmunological mechanisms, though the preponderance of evidence suggests an important role for immunological responses. Some cutaneous eruptions appear shortly after drug intake, while others are not manifested until 7 to 10 days after initiation of therapy and are consistent with delayed-type hypersensitivity. This review discusses critical steps in the initiation of delayed-type hypersensitivity reactions in the skin, which include protein haptenation, dendritic cell activation/migration and T-cell propagation. Recently, an alternative mechanism of drug presentation has been postulated that does not require bioactivation of the parent drug or antigen processing to elicit a drug-specific T-cell response. This review also discusses the role of various immune-mediators, such as cytokines, nitric oxide, and reactive oxygen species, in the development of delayed-type drug hypersensitivity reactions in skin. As keratinocytes have been shown to play a crucial role in the initiation and propagation of cutaneous immune responses, we also discuss the means by which these cells may initiate or modulate CDRs.     

不同类型抗癫痫药物对开颅手术患者术后早期高氨血症发病率的影响

目的：评价开颅手术患者应用左乙拉西坦、丙戊酸钠和卡马西平等3种不同抗癫痫药（AEDs）诱发高氨血症（AHA）的发生率、发作程度，并分析患者发生AHA的危险因素。方法：纳入2014年4月至2018年9月间在某院神经外科进行开颅手术的108患者，并将其随机分为左乙拉西坦组（n=36）、丙戊酸钠组（n=36）与卡马西平组（n=36）。3组患者术后分别口服左乙拉西坦片、丙戊酸钠片与卡马西平片进行癫痫预防治疗，在术前，手术当天，术后第1，3，7天检测并比较3组患者的血氨浓度、肝功能和凝血指标，评价3组患者术后AHA发生率、血氨浓度、血氨变化趋势及AEDs对患者肝功能和凝血功能的影响。根据术后患者是否发生AHA，将患者分为术后AHA组（n=70）与术后血氨正常组（n=38），比较2组患者的临床特征，评价患者发生AHA的危险因素。结果：左乙拉西坦组、丙戊酸组与卡马西平组分别有24（66.7%）例、29（80.6%）例及17（47.2%）例患者发生AHA，丙戊酸组患者AHA发生率显著高于卡马西平组（χ²=8.669，P=0.003）。丙戊酸钠组患者术后第3天和第7天血氨浓度及术后血氨的平均浓度均显著高于卡马西平组患者（P=0.023，<0.001，0.028）。术后第7天丙戊酸组患者ALT指标显著低于左乙拉西坦组与卡马西平组（均P<0.001）。影响患者术后发生AHA的危险因素包括：较低的年龄（t=2.061，P=0.042）与较高的术前血氨浓度（t=7.986，P<0.001）。AHA组患者术后总胆红素（t=3.788，P<0.001）、直接胆红素（t=3.329，P=0.001）和血清白蛋白（t=11.624，P<0.001）较术前显著降低，血浆凝血酶原时间显著延长（t=4.109，P<0.001）。而衡量急性肝炎的指标丙氨酸转氨酶没有显著变化（t=0.956，P=0.341）。结论：卡马西平对患者术后血氨浓度影响较小，是开颅手术患者的首选AEDs药物，而丙戊酸钠更适合肝脏氨基转移酶异常的患者。     

药物超敏反应安全评价体外替代方法的研究进展

超敏反应是药物的严重不良反应之一,严重时可危及患者生命。目前超敏反应(Ⅰ,Ⅳ型)临床前评价方法多为整体动物实验方法,基于动物福利和3R原则的考虑,以及体外替代方法的迅速发展,目前已建立了数种药物致敏性评价的体外替代方法,包括根据肥大细胞和嗜碱性粒细胞在Ⅰ型超敏反应中发挥的关键作用,用实验室易获得的肥大细胞和嗜碱性粒细胞系如RBL-2H3和KU812研究药物的Ⅰ型超敏反应,另外鉴于树突状细胞在Ⅳ型超敏反应中抗原呈递作用,用THP-1细胞构建的h-CLAT试验体系和LC-SA试验体系在皮肤致敏性的评价方面都显示出较好的发展前景。本文综合近年的国内外文献,对超敏反应的体外替代方法进行了综合论述和评估。     

Role of animal models in the study of drug-induced hypersensitivity reactions

Drug-induced hypersensitivity reactions (DHRs) are a major problem, in large part because of their unpredictable nature. If we understood the mechanisms of these reactions better, they might be predictable. Their unpredictable nature also makes mechanistic studies very difficult, especially prospective clinical studies. Animal models are vital to most biomedical research, and they are almost the only way to test basic hypotheses of DHRs, such as the involvement of reactive metabolites. However, useful animal models of DHRs are rare because DHRs are also unpredictable in animals. For example, sulfonamide-induced DHRs in large-breed dogs appear to be valid because they are very similar to the DHRs that occur in humans; however, the incidence is only approximately 0.25%, and large-breed dogs are difficult to use as an animal model. Two more practical models are penicillamine-induced autoimmunity in the Brown Norway rat and nevirapine-induced skin rash in rats. The toxicity in these models is clearly immune mediated. In other models, such as amodiaquine-induced agranulocytosis/hepatotoxicity and halothane-induced hepatotoxicity, the drug induces an immune response but there is no clinical toxicity. This finding suggests that regulatory mechanisms usually limit toxicity. Many of the basic characteristics of the penicillamine and nevirapine models, such as memory and tolerance, are quite different suggesting that the mechanisms are also significantly different. More animal models are needed to study the range of mechanisms involved in DHRs; without them, progress in understanding such reactions is likely to be slow.     

2013—2015年武汉大学人民医院神经内科抗癫痫药物的使用情况分析

目的 了解武汉大学人民医院抗癫痫药物的使用情况,为医护人员提供参考.方法 选取武汉大学人民医院2013年7月-2015年8月151份症状性癫痫病历进行回顾性分析,对患者的性别及年龄、病因、用药方案、抗癫痫药物的使用情况以及不良反应进行分类统计.结果 151例症状性癫痫患者中,男性多于女性;年龄多集中在51～64岁的患者;病因复杂,多集中在脑血管疾病、脑外伤、颅内感染3大原因;癫痫形式主要为全身性发作的强直阵挛性发作,抗癫痫治疗方案多采用单一用药的形式,而且丙戊酸钠和奥卡西平是临床上最常用的抗癫痫药物.结论 从药物流行病学角度考察了武汉大学人民医院神经内科抗癫痫药物的药物利用模式,对临床制定抗癫痫治疗方案具有积极的意义.     

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。