细胞色素P450氧化酶基因多态性与抗癫(癎)药物关系研究进展

细胞色素P450(CYP)氧化酶是许多抗癫药物(AEDs)的代谢酶,许多研究证实CYP基因存在遗传多态性并存在种族差异,其多态性可影响抗癫药物的血药浓度。本文综述了相关的研究进展。     

抗癫(癎)药物致死性副作用

正如任何药物都有个别的极端副作用一样,抗癫(癎)药物(Antiepileptic Drugs,AEDs)的致死性副作用也是极为少见,甚至罕见的不良反应,了解这种少见的不良反应发生的规律、特征及发生机制,合理地避开其诱发因素,远比忽略它的存在更有利于临床用药的安全性.     

妊娠期癫(癎)发作和抗癫(癎)药物对胎儿脑神经元突触素的影响

目的探索妊娠期癫发作和抗癫药对胎儿脑神经元突触素p38(synaptophysin)的影响,以加深对妊娠期癫发作危害胎儿脑发育的认识。方法6月龄引产胎儿分为3组:1组为妊母正常组(6例),2组为妊母应用抗癫药物控制发作组(6例),3组为妊母未应用抗癫药物控制发作组(6例)。运用免疫组化法检测突触素p38在各组胎儿脑部颞叶海马旁回的变化。结果1组免疫组化切片阳性表达产物光密度值(OD)为0.17±0.05,2组为0.16±0.08,3组为0.11±0.07,1、2组阳性表达产物无显著差异(P>0.05),而1、2组分别与3组比较,均有差异(P<0.05),p38在妊母未应用抗癫药物控制发作组胎儿海马旁回中的表达较妊母正常组及妊母应用抗癫药物控制发作组明显减少。结论研究结果表明妊期癫发作对胎儿脑发育的危害比抗癫药物对胎儿的毒性更大。     

癫(癎)术后抗癫(癎)药物的治疗模式

目的 探讨癫(癎)术后抗癫(癎)药物的应用方法及影响因素.方法 2002-2005年在我院接受了手术治疗的170例癫(癎)患者,根据不同手术时段分为3组,A组:2002年至2003年10月的病例;B组:2003年11月至2004年10月药师与临床医生一起对癫(癎)手术患者进行用药教育的病例;C组:2004年11月至2005年10月接受全程化药学服务的病例.对随访1年后各组之间的疗效、用药安全性、抗癫(癎)药应用依从性等指标进行了比较,初步探讨术后应用抗癫(癎)药的规律.结果 B组和C组在疗效(71%、81%)、用药安全性、抗癫(癎)药用药依从性等指标上均优于A组(46%),差异均有统计学意义(X2=7.08、15.50,P<0.05).结论 神经内外科医生、药师合作的个体化癫(癎)术后全程化服务是一种较新的、有效的癫(癎)术后管理模式.     

17例弈棋相关性癫(癎)发作临床特点分析

目的:分析与弈棋相关的癫(癎)发作患者的临床特征.方法:选取2012年1月～2015年12月上海交通大学医学院附属新华医院神经内科癫(癎)数据库中与弈棋相关的癫(癎)发作患者17例进行随访,收集患者的人口学资料、起病年龄、癫(癎)发作类型、发作频率、影像学资料以及脑电图资料等,并对患者数据进行统计学分析.结果:17例患者均表现为与弈棋相关的癫(癎)发作,其中12例为棋奕性癫(癎),2例单次发作,3例为继发性癫(癎)弈棋相关性发作.2例棋奕性癫(癎)患者的动态脑电图提示(痫)样放电,2例继发性癫(癎)弈棋相关性发作患者的动态脑电图亦发现异常放电.行为学干预有助于预防再次发作,而抗癫(癎)药物(AED)并无特异疗效.结论:出现弈棋相关性癫(癎)发作的患者首先需明确病因.继发性癫(癎)弈棋相关性发作可考虑AED治疗;反射性癫(癎)行为学干预有助于预防再次发作,AED治疗非首选.     

影响新诊断癫(癎)患者初次药物治疗效果的因素

目的 探讨影响新诊断癫(癎)患者初次药物治疗效果的因素.方法 对155例年龄4～68岁新诊断的癫(癎)患者给予单药治疗,至少观察1年,以稳定期初次发作时间和早期治疗失败时间为终点事件,其中治疗失败的原因包括发作控制不佳和/或不能耐受药物不良反应.采用Cox回归分析判断癫(癎)患者临床特点及实验室检查结果对药物治疗效果的影响.结果 多因素Cox回归分析显示:癫(癎)家族史(HR=2.39,P<0.05)、EEG癫(癎)波(HR=2.05,P<0.005)、治疗前发作次数(HR=1.76,P<0.05)是影响稳定期初次发作时间的因素;女性患者(HR=4.25,P<0.001)、部分性发作(HR=2.54,P<0.05)、EEG癫(癎)波(HR=3.11,P<0.005)是影响早期治疗失败时间的因素.结论 EEG癫(癎)波、癫(癎)家族史、治疗前发作次数、发作类型(部分性发作)、女性患者是影响新诊断癫(癎)患者初次药物治疗效果的因素.     

癫(癎)性精神障碍患者临床用药调查

目的:了解癫性精神障碍患者临床药物使用情况。方法:对89例癫性精神障碍患者使用抗癫药和抗精神病药情况进行分析。结果:在癫性精神障碍治疗中,抗癫药以卡马西平使用频度最高达65.2%,抗癫药不良反应发生率为15.7%,抗精神病药不良反应以锥体外系反应居首位。结论:在癫性精神障碍治疗中,应合理使用抗癫药与抗精神病药。     

奥卡西平治疗癫(癎)的临床研究

目的观察奥卡西平(OXC)治疗癫癎的疗效、耐受性和安全性。方法294例患者,120例加用OXC治疗,174例单用OXC治疗。通过逐步加量的方法达到目标剂量。结果本组总有效率为86.05%,完全控制为39.8%;其中单药治疗组控制率45.98%,总有效率为89.08%,添加治疗组控制率为30.83%,总有效率为81.67%。单药治疗组不良反应总发生率为15.52%,添加组不良反应发生率为26.67%,2组比较,添加治疗组出现的反应相对多于单药治疗组。结论奥卡西平治疗癫癎有效、安全、稳定。     

抗癫(癎)药物对认知功能的影响

癫(癎)是脑部神经元异常放电高度同步化活动所引起的,由不同症状和体征组成的短暂性临床现象.其特点是脑部持续存在的导致癫(癎)反复发作的易感性,以及由于这种疾病引起的神经生物、认知、心理和社会功能障碍等方面的后果.     

抗癫癎药物致癎作用的临床观察

目的研究抗癫癎药物(AEDs)的致癎作用及对其的预防和治疗.方法总结32例AEDs致癫癎发作加重患者的临床资料.结果32例中以服用卡马西平最多(19.12%)、次之为巴比妥类药物(15%)、苯妥英钠(14.5%)、合并用药(14.29%)、苯二氮( )类(8.69%)、丙戊酸钠(2.78%).32例经停药并合理选择其他抗癫癎药物及减少药物剂量治疗,27例有效,5例无效.结论AEDs能致癫癎发作加重,应合理选择抗癫癎药物.     

抗癫药物对妊娠癫癎患者子代的致畸风险

目的:旨在评估抗癫癎药物(AEDs)对妊娠癫癎患者子代出现先天畸形的风险。方法:对妊娠癫癎患者采用登记和随访研究,分析其孕期AEDs用药情况、癫癎发作、妊娠结局及子代出现畸形的风险。结果:入选105例妊娠癫癎患者。服用AEDs患者79/105例(75.2%),未服用AEDs患者26/105例(24.8%)。单药治疗60/79例(75.9%),其中1/60例(1.7%)流产;患者子代中2/60例(3.3%)先天性畸形(1例服用卡马西平,出现先天性心脏动脉导管未闭;1例服用拉莫三嗪,出现无胚心)。联合用药19/79例(24.1%),子代无先天畸形出现。未服用AEDs患者中有2/26例(7.7%)流产,其余患者子代未出现先天畸形。结论:妊娠癫癎孕妇多数于孕期仍服用AEDs,且以单药治疗居多;使用AEDs(分别为卡马西平和拉莫三嗪)患者子代出现2例先天性畸形;丙戊酸钠易致畸但仍在妊娠癫癎中经常使用,本研究中服用丙戊酸钠孕妇未出现子代先天性畸形。     

ABCB1基因C3435T多态性与癫痫耐药关系的Meta分析

目的 运用Meta分析的方法综合评价ATP结合盒B亚家族成员1转运蛋白基因(ABCB1)C3435T多态性与癫痫耐药的相关性. 方法 制定原始文献的纳入和排除标准及检索策略,检索中外文数据库,收集有关ABCB1 C3435T多态性与抗癫痫药物(AEDs)治疗反应相关性的研究报告,采用等位基因型(C vs T)以及共显性模型(CC vs TT,CT vs TT)、显性模型(CC+CT vs TT)和隐性模型(CC vs CT+TT)等基因遗传模型进行对比与定量综合分析,同时按人种所属地域(亚裔人与白种人)进行亚组分析. 结果 共23篇文献纳入Meta分析,包括3704例癫痫耐药患者和4160例治疗有效患者,入选文献无发表偏倚.统计分析显示:C3435T位点多态性与癫痫耐药无统计学关联;等位基因C与T相比,随机效应模型:OR=1.05,95％ CI:0.94～1.18,P=0.390.各基因型对比以及进行亚组分析后也未发现统计学关联. 结论 ABCB1 C3435T多态性与癫痫耐药无关联.     

ABCG1基因多态性与中国汉族人群缺血性脑卒中的相关性研究

目的探讨ATP结合盒G亚组成员1(ABCG1)的基因多态性与缺血性脑卒中的相关性。方法采用病例-对照方法,在中国北方汉族人群中收集389例缺血性脑卒中患者(病例组)与380名正常体检者(对照组)进行对照研究。按改良的TOAST分型将病例组分为动脉粥样硬化血栓形成型亚组(207例)和小动脉闭塞型亚组(182例),采用聚合酶链式反应-连接酶检测方法测定ABCG1基因rs225374位点的多态性。结果在动脉粥样硬化血栓形成型亚组,rs225374位点GG基因型和G等位基因分布频率显著高于对照组(25.6%vs 17.9%,P=0.030;49.8%vs 43.4%,P=0.037);小动脉闭塞型亚组与对照组比较,rs225374位点的基因型和等位基因分布频率差异无显著性。结论 ABCG1基因rs225374位点的多态性与中国北方汉族人群动脉粥样硬化血栓形成性缺血性脑卒中的发病具有一定相关性。     

Treatment and Discontinuation of Antiepileptic Drugs in Childhood Epilepsy

Abstract: The process of discontinuing anticonvulsant therapy was studied clinicoelectroencephalographically on 285 children with epilepsy. The subjects were divided into two groups electroencephalographically: First, 190 cases of the formally discontinued group which had antiepiletic drugs withdrawn after the cessation of clinical seizures and suppressing epileptic discharges for over two years and, second, 95 cases which were informally discontinued. The relapse rate after discontinuation was significantly lower in the former group, 2.1%, than the latter group, 21.1%. Concerning the seizure-free period, among the cases free from clinical seizures for over three years at the time of withdrawal, the relapse rate was significantly lower than the rest of the cases. Moreover, the spike-free period proved to be a more reliable indicator for stopping medication than the seizure-free period. From these findings, the withdrawal of antiepileptic drugs should be started after suppression of epileptic discharges for over two years in childhood epilepsy.     

Initiation of Treatment and Selection of Antiepileptic Drugs in Childhood Epilepsy

Summary:  Purpose: A retrospective study was carried out on 53 cases with childhood epilepsy to evaluate the validity of the initial selection of antiepileptic drug (AED).
Methods: We investigated the AEDs selected at the beginning of the treatment from the medical records of 53 untreated cases. A follow-up study was undertaken to evaluate the effects of the AEDs. In the second study, we investigated the AEDs of 10 cases with atypical benign partial epilepsy (ABPE), to clarify whether the initial AEDs selected for rolandic epilepsy were related to the appearance of ABPE.
Results: The AEDs used at the initial stage consisted of carbamazepine (CBZ), valproic acid (VPA), phenobarbital (PB), and vitamin B₆. The main AEDs were CBZ and VPA for localization-related epilepsy, and VPA for generalized epilepsy. The initial selection of AEDs in 41 (85.4%) of 48 cases treated with AEDs were considered to be correct from the results of follow-up. We could not specify any AEDs that related to the appearance of ABPE.
Conclusions: The selection of AED in this series was considered to be most appropriate. We proposed a criterion to determine whether to begin the AED treatment immediately at the initial seizure.     

多药耐药相关蛋白1基因多态性及蛋白表达与癫痫患者耐药机制关系的研究

目的探讨多药耐药相关蛋白1 (MRP1)基因G128C (rs41395947)、C218T (rs41494447)、G2168A(rs4148356)、G3173A(rs41410450)多态性及MRP1蛋白水平与癫痫耐药的关系,进一步探究MRP1基因多态性更易导致癫痫患者对哪种抗癫痫药物(AED)耐药。方法对2017年11月至2018年6月就诊于包头医学院第一附属医院门诊、病房和包头中心医院癫痫门诊,且诊断符合2014年国际抗癫痫联盟关于癫痫的诊断标准,均经视频脑电图及头颅MRI证实的31例耐药性癫痫患者和67例药物敏感性癫痫患者进行调查问卷。采用DNA测序的方法分别检测MRP1基因,从而分析其多态性分布情况,采用酶联免疫吸附(ELISA)测定的方法分别检测两组人群中MRP1蛋白的浓度,采用化学发光法检测癫痫患者卡马西平、丙戊酸钠的血药浓度。结果经DNA测序发现,AED耐药组和AED敏感组癫痫患者MRP1基因中第128位和第3173位未出现基因突变,第218位、2168位中存在单核苷酸多态性。MRP1的C218 T(rs41494447)突变5例,其中AED耐药组4例,ADE敏感组1例,C218T(rs41494447)多态性在AED耐药组与AED敏感组中的分布差异无统计学意义(P 0. 05)。MRP1的G2168A(rs4148356)突变9例,其中AED耐药组6例,ADE敏感组3例,G2168 A (rs4148356)多态性在AED耐药组与AED敏感组中的分布差异有统计学意义(P 0. 05); MRP1的2168位GA基因型在AED耐药组67%高于AED敏感组33%。MRP1蛋白水平测定结果:AED耐药组高于AED敏感组,差异有统计学意义(P 0. 05)。MRP1的2168位GA基因型患者的卡马西平、丙戊酸钠血药浓度低于GG基因型患者,差异有统计学意义(P 0. 05)。比较MRP1的C218T(rs41494447)、G2168A(rs4148356)不同基因型的MRP1浓度,差异无统计学意义(P 0. 05)。结论MRP1的G2168A (rs4148356)多态性可能是癫痫患者发生AEDs耐药的风险位点。MRP1基因的G128 C (rs41395947)、C218 T (rs41494447)、G3173 A (rs41410450)三个位点可能不是癫痫患者发生AEDs耐药的风险位点。MRP1蛋白高表达可能是引起癫痫患者耐药的一个因素。癫痫患者中存在MRP1的G2168A单核苷酸多态性者更易对卡马西平、丙戊酸钠耐药。耐药性癫痫患者MRP1基因218位点及2168位点突变可能不是引起MRP1蛋白高表达的原因。     

白细胞介素-1B多态性与神经胶质瘤的关联

目的 探讨白细胞介素-1B(IL-1B)多态性与神经胶质瘤的相关性.方法 采用聚合酶链反应-限制性片段长度多态性检测152例神经胶质瘤患者和201例正常对照组IL-1B-511C/T和-31T/C多态性.结果 IL-1 B-511 C/T位点:与CC基因型相比,TT基因型显著增加了神经胶质瘤的发病风险(x2 =5.61,P=0.021).与C等位基因相比,T等位基因显著增加了神经胶质瘤的发病风险(x2 =5.71,P=0.019).未发现IL-1B-31T/C多态性频率分布在对照组和神经胶质瘤组之间存在明显差异.IL-1B-511C/T和-31T/C两位点单倍型分析显示,-511C/-31T单倍型显著降低了神经胶质瘤的发病风险(x2=4.89,P=0.03),-511T/-31C单倍型显著增加了神经胶质瘤的发病风险(x2=18.55,P＜0.001).结论 IL-1B可能是中国人群神经胶质瘤发病的易感基因.     

Association between ABCB1 polymorphisms and response to first-generation antiepileptic drugs in a Tunisian epileptic population

Purpose: We aimed in this study to investigate the association between the ATP-Binding Cassette sub-family B, member1 (ABCB1) polymorphisms: C1236T (rs1128503), G2677T (rs2032582) and C3435T (rs1045642), and the resistance to antiepileptic drugs (AEDs).

Materials and methods: The Polymerase Chain Reaction–Restriction Fragment Length Polymorphism genotyping of ABCB1 polymorphisms was conducted on 153 Tunisian epileptic patients treated with AEDs.

Results: Two genetic polymorphisms of the ABCB1 gene seemed to influence the response to AEDs. In fact, the G2677T T and the C3435T T alleles appeared to increase the risk of developing AEDs resistance (ORs* = 3.13; 95%CI = [1.16–8.98]; p = 0.024 and ORs* = 3.10; 95%CI = [1.15–8.37]; p = 0.025), respectively. However, the C1236T T allele did not seemed to influence the response to AEDs (ORs* = 1.14; 95%CI = [0.53–3.88]; p = 0.471). Haplotypic analysis indicated high-degree linkage disequilibrium of ABCB1 polymorphisms. Our results showed a synergic effect, in fact patients with the CTT and TTT haplotypes were more likely to be drug resistant than patients with the CGC haplotype, these associations remained significant even after adjustment for confounding parameters (ORs* = 2.68; 95%CI = [1.11–8.25]; p = 0.033 and ORs* = 3.76; 95%CI = [1.69–21.05]; p = 0.006, respectively).

Conclusion: The G2677T T and C3435T T alleles as well as the TT, CTT and TTT haplotypes seemed to be significantly associated with drug-resistance epilepsy in our population. Genetic predisposition, involved in this resistance, may contribute to the establishment of a personal optimized therapy for newly diagnosed epileptic patients.     

Association study of CACNA1C polymorphisms with large artery atherosclerotic stroke in Chinese Han population

Aims Ischemic stroke (IS) is one of the most common diseases of neurology and the main cause of death and disability in Chinese population. CACNA1C was considered to be involved in the process of atherosclerosis, but there was little information about the association between genotypic polymorphisms of CACNA1C and ischemic stroke. Our study was designed to elucidate the relationship between four single-nucleotide polymorphisms (SNPs) variants in CACNA1C gene and the risk of large-artery atherosclerotic (LAA) stroke patients.

Methods A total of 384 subjects were enrolled in this study, including 192 LAA stroke cases and 192 healthy controls. And four SNPs variants in CNCNA1C gene were genotyped using in-house developed multiplex tagged-amplicon deep sequencing (TAm-Seq). Statistical analysis were conducted using χ2 test and binary logistic regression analysis.

Results We found one variant was significantly associated with LAA stroke in the allele models (rs10848683, p = 0.036, OR = 1.371, 95%CI: 1.021–1.841). And rs10848683 was also found to associate with LAA stroke under recessive model (p = 0.027, OR = 0.618, 95% CI: 0.403–0.947) after adjustment for gender and age. We also found that significant difference existed between haplotypes (rs229961-rs215976-rs216008-rs10848683) and LAA stroke (C-T-C-C, p = 0.017, OR = 2.265, 95%CI: 1.136–4.518; G-C-C-C, p = 0.046, OR = 1.891, 95% CI: 1.003–3.565; C-T-C-T, p = 0.001, OR = 0.256, 95%CI: 0.101–0.645).

Conclusion The results suggested that there was a potential association between CNCNA1C gene and the risk factor of LAA stroke in Chinese Han population.     

Multidrug resistance in patients undergoing resective epilepsy surgery is not associated with C3435T polymorphism in the ABCB1 (MDR1) gene

PURPOSE: The C3435T polymorphism in the gene coding for P-glycoprotein (ABCB1) has been correlated with drug resistance in patients with epilepsy. However, replication studies have revealed conflicting results and the reason for this is not clear. We investigated the frequency of C3435T polymorphism in epileptic Turkish patients who underwent resective epilepsy surgery and compared our results with healthy controls. METHODS: DNA samples were obtained from 100 healthy controls and 89 consecutive adult patients who underwent resective brain surgery due to refractory seizures at our epilepsy center. Genotypes for the C3435T polymorphism were determined by PCR and restriction analysis. RESULTS: Comparison of drug-resistant patients and healthy controls revealed no significant difference in allele frequency (C vs. T; chi(2)=0.015, p=0.90) and genotype frequency (chi(2)=2.05, p=0.36). The findings in the pure hippocampal sclerosis (HS) group (n=73) were not significantly different from control subjects, either (allele frequency: chi(2)=0.29, p=0.59; genotype frequency: chi(2)=2.14, p=0.34). CONCLUSIONS: Our findings failed to prove an association between C3435T polymorphism and drug resistance in a sample of Turkish patients with refractory epilepsy who underwent resective brain surgery.