新型抗癫痫药物临床应用进展

新型抗癫痫药自1993年问世以来,目前包括拉莫三嗪、托吡酯、加巴喷丁、奥卡西平、左乙拉西坦、非氨酯、氨己烯酸、噻加宾、唑尼沙胺和普瑞巴林等。现在通过美国食品与药品管理局批准,并在我国注册应用的新型抗癫痫药物主要有：托吡酯、拉莫三嗪、奥卡西平、左乙拉西坦和加巴喷丁。近年来,关于这几种新型抗癫痫药物的研究较多,下面主要就其临床应用方面的新进展综述如下。     

青少年肌阵挛癫痫15例临床特点分析

目的:探讨青少年肌阵挛癫痫(JME)的临床特点。方法:总结15例JME患者的临床表现、脑电图特点及药物治疗预后。结果:15例均有肌阵挛发作(MS);合并失神发作(AS)3例;合并全面强直阵挛发作(GTCS)12例;三种发作类型均有2例;单独以肌阵挛为表现不伴有其他发作类型2例。脑电图特征是发作间期双侧导联的3～6 Hz棘慢波或多棘慢波,以前头部为主。应用丙戊酸钠、左乙拉西坦、拉莫三嗪治疗,发作完全控制10例,发作明显减少5例。结论:JME是一种较常见的特发性全面性癫痫综合征,详细询问病史结合规范的脑电图检查可尽早明确诊断。选择合适的抗癫痫药物治疗预后较好。     

新型抗癫痫药对儿童认知功能的影响

抗癫痫药(antiepileptic drug,AED)对认知功能的影响,特别是对于大脑正在发育阶段的婴幼儿的影响,倍受临床医生关注.传统的AED中,鲁米那和苯妥英钠引起的损害较卡马西平或丙戊酸钠更为严重.近十年来,出现了一些新型AED如拉莫三嗪、托吡酯、奥卡西平、噻加宾、加巴喷丁、氨己烯酸、左乙拉西坦等.对于新型AED,如高剂量或快速给药,在许多研究中均证实对认知有损害作用,其他的新型AED没有重大认知损害.另有许多研究得出新型AED可改善认知功能,这可从患者主诉和生活质量的提高中体现.     

奥卡西平联合拉莫三嗪治疗癫痫的效果及对认知功能的影响

目的研究奥卡西平联合拉莫三嗪治疗癫痫的效果及对认知功能的影响。方法选取于我院确诊的85例癫痫患者为研究对象,随机将其分为观察组(42例,奥卡西平联合拉莫三嗪治疗)和对照组(43例,左乙拉西坦联合托吡酯治疗)。比较两组患者的治疗效果。结果两组的治疗总有效率及不良反应总发生率比较,差异无统计学意义(P>0.05)。治疗后,两组的BDNF、IGF-1水平均明显升高,且观察组显著高于对照组(P<0.05)。治疗后,两组的认知功能各项目评分均显著升高,且观察组明显高于对照组(P<0.05)。结论上述两组药物治疗癫痫效果明显,但奥卡西平联合拉莫三嗪能够显著改善患者的认知功能。     

拉莫三嗪联合丙戊酸钠治疗小儿癫痫临床观察

目的探讨拉莫三嗪联合丙戊酸钠治疗小儿癫痫的效果及安全性。方法 116例癫痫患儿根据治疗方法分为联合组（拉莫三嗪联合丙戊酸钠治疗）58例,对照组（单用丙戊酸钠治疗）58例,比较2组总治疗效果、不同癫痫发作类型的治疗效果及不良反应。结果治疗12个月后,联合组无发作36例,显效10例,有效6例,无效6例,总有效率89.7%;对照组无发作30例,显效7例,有效5例,无效16例,总有效率72.4%,2组总有效率比较差异有统计学意义（P〈0.05）;联合组治疗单纯部分发作、复杂部分发作、继发性全身发作、全身强直阵挛发作及肌阵挛发作有效率均高于对照组（P〈0.05）;不良反应发生率联合组（12.1%）与对照组（10.3%）比较差异无统计学意义（P〉0.05）。结论拉莫三嗪联合丙戊酸钠治疗各种类型癫痫效果均较好,且不良反应轻。     

拉莫三嗪与其他抗癫痫药

拉莫三嗪 (利必通 )为苯基三嗪类新型抗癫痫药 ,属电压门控钠通道阻滞剂。临床主要用于治疗癫痫 ,也可用于Lennox -Gastaut综合征的癫痫发作。拉莫三嗪与其他抗癫痫药物合用 ,可能发生有临床意义的相互作用 ,应予注意。处方 1:拉莫三嗪与卡马西平拉莫三嗪 5 0mg× 6 0　 2 5mgqdpo(连服 2周后遵医嘱增加剂量 )卡马西平 0 .2g× 10 0　 0 .2gtidpo分析 :本方用于Lennox -Gastaut综合征的癫痫发作。用药后出现头晕、共济失调、复视等中枢神经系统反应 ,且未能很好的控制癫痫发作。两药合用 ,卡马西平诱导肝药酶使拉莫三嗪代谢加速 ,血药浓度…     

病毒性脑炎继发癫痫临床特征及抗癫痫药物干预效果研究

目的:探讨病毒性脑炎继发癫痫的临床特征及不同抗癫痫药的干预效果.方法:对115例病毒性脑炎继发癫痫患者的临床资料进行回顾性分析.结果:本组患者中以难治性癫痫居多(73.9％),其中难治性癫痫患者的年龄及癫痫病程均显著低于非难治性癫痫患者(P＜0.01);癫痫类型均以继发强直阵挛及复杂部分性、单纯部分性为主.抗癫痫治疗多为联合用药(90.4％),应用抗癫痫药物频率排前5位依次为左乙拉西坦、丙戊酸盐、卡马西平、氯硝西泮、苯巴比妥;有效率依次为左乙拉西坦87.5％、苯巴比妥75.0％、氯硝西泮73.3％、卡马西平71.4％、丙戊酸盐66.7％.结论:病毒性脑炎继发癫痫以难治性癫痫为主,多采取联合用药,其中新型抗癫痫药物左乙拉西坦疗效最佳,可单用也可联合,视患者实际情况确定.     

左乙拉西坦与奥卡西平治疗成人部分性发作癫痫的疗效比较

目的比较左乙拉西坦、奥卡西平治疗成人部分性发作癫痫的临床效果。方法选取本院收治的142例成人部分性发作癫痫患者作为研究对象,采用电脑随机分组法分成2组,每组71例。对照组采用左乙拉西坦治疗,观察组采用奥卡西平治疗,比较2组患者的疗效、治疗前后脑电图变化和不良反应发生率。结果观察组总有效率为81.69%,对照组为69.01%,差异无统计学意义(P 0.05);治疗后,观察组θ频段相对功率为(30.76±6.84)%,高于对照组的(22.03±6.72)%,差异有统计学意义(P 0.05);观察组癫痫样放电(IEA)减少大于50%者比率为60.56%,对照组为54.93%,差异无统计学意义(P 0.05);观察组不良反应发生率为9.86%,对照组为12.68%,差异无统计学意义(P 0.05)。结论左乙拉西坦、奥卡西平治疗成人部分性发作癫痫均疗效确切,安全性良好,可明显抑制IEA,其中奥卡西平对脑电图活动的影响更大。     

左乙拉西坦单药与添加治疗儿童癫痫疗效的临床分析

目的：对比左乙拉西坦单药与添加治疗儿童癫痫的临床疗效。方法：将在本院门诊就诊的70例儿童癫痫患者作为研究对象，分成两组，对照组给予左乙拉西坦单药治疗，研究组在其它抗癫痫药物的基础上给予左乙拉西坦添加治疗，比较两组的临床发作控制、脑电图改善情况进行评价。结果：经过治疗及1年的随访，对照组与研究组临床发作控制有效率分别为42.8%、71.4%，脑电图改善的总有效率分别为40.0%、65.7%，两组差异显著，P＜0.05。结论：左乙拉西坦添加治疗儿童癫痫疗效优于单药治疗，可以提高发作控制有效率及脑电图改善率，且副作用小、安全性高，值得临床使用。     

奥卡西平与左乙拉西坦治疗新诊癫痫的疗效

目的:观察奥卡西平与左乙拉西坦治疗新诊癫痫的疗效及对血脂、骨代谢的影响。方法:107例新诊的原发性癫痫患者随机分为奥卡西平组(52例)和左乙拉西坦组(55例),分别给予奥卡西平或左乙拉西坦单药治疗。治疗6月后观察2组疗效以及血脂指标、骨代谢指标变化情况。结果:2组疗效比较差异均无统计学意义(P0.05);治疗后,2组总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)均较治疗前升高(P0.05),高密度脂蛋白胆固醇(HDL-C)较治疗前无明显变化(P0.05),2组之间TC、TG、LDL-C、HDL-C水平比较差异无统计学意义(P0.05);治疗后,2组碱性磷酸酶(ALP)、骨特异性碱性磷酸酶(BAP)、磷(P)、钙(Ca)、甲状旁腺素(PTH)水平与治疗前比较差异无统计学意义(P0.05),2组之间比较差异无统计学意义(P0.05)。结论:奥卡西平与左乙拉西坦治疗癫痫疗效相当,应用半年即有导致血脂升高,但短期应用对骨代谢影响不明显。     

Interactions between angiotensin AT1 receptor antagonists and second‐generation antiepileptic drugs in the test of maximal electroshock

The anticonvulsant activity of angiotensin AT₁ receptor antagonists, losartan (2‐n‐butyl‐4‐chloro‐5‐hydroxymethyl‐1‐[(2′(1H‐tetrazol‐5‐yl)‐biphenil‐4‐yl)methyl]imidazole) and telmisartan (49‐[(1,49‐dimethyl‐29‐propyl[2,69‐bi‐1H‐benzimidazo]‐19‐yl)methyl]‐[1,19‐biphenyl]‐2‐carboxylic acid), has been reported recently. It is suggested that AT₁ receptor antagonists may affect the protective action of antiepileptic drugs. The aim of this study was to determine the influence of losartan and telmisartan on the anticonvulsant activity of some second‐generation antiepileptics (lamotrigine – LTG, oxcarbazepine – OXC, and topiramate – TPM). For this purpose, the maximal electroshock seizure (MES) test in mice was used. Additionally, the drug combinations were checked for adverse effects in the passive avoidance and chimney tests. In the MES test, losartan at the doses of 30 and 50 mg/kg, administered intraperitoneally (i.p.), potentiated the protective action of LTG (P < 0.01). This interaction was not accompanied by a significant change of LTG level either in plasma or in the brain. Telmisartan at the dose of 30 mg/kg i.p. enhanced the anticonvulsant action of TPM (P < 0.01). However, this interaction was pharmacokinetic in nature, as telmisartan significantly increased plasma and total brain concentrations of TPM (P < 0.001). The combinations of AT₁ receptor antagonists with antiepileptic drugs did not affect retention in the passive avoidance test or motor coordination in the chimney test. The potentiation of the anticonvulsant action of LTG by losartan probably on account of pharmacodynamic interactions, make this combination important for further experimental and clinical studies. The combination of telmisartan and TPM is less beneficial due to pharmacokinetic interactions.     

Topiramate monotherapy in the treatment of newly or recently diagnosed epilepsy

BACKGROUND: The efficacy of topiramate (TPM) as an adjunctive treatment for epilepsy has been established in placebo-controlled clinical trials. Clinical trials of antiepileptic monotherapy usually evaluate low and high doses of study drug or compare study drug with another active agent. OBJECTIVE: This article reviews available evidence for the use of TPM as monotherapy in patients with newly or recently diagnosed epilepsy. METHODS: A search of MEDLINE, EMBASE, BIOSIS, SCISEARCH, and the Cochrane Database of Systematic Reviews (all years) for reports of controlled trials of TPM monotherapy in patients with recently diagnosed (within the previous 3 years) epilepsy was conducted in January 2008 using the terms topiramate, epilepsy, newly diagnosed, recently diagnosed, and monotherapy. Identified trials were included in the review if they were published in peer-reviewed journals and enrolled > or = 20 patients. RESULTS: Three randomized, double-blind, controlled trials met the criteria for inclusion in the review. In a comparison of TPM 50 and 500 mg/d, the higher dose was associated with significantly greater freedom from seizures at 6 months compared with the lower dose (54% vs 39%, respectively; P = 0.02). The time to first seizure was significantly associated with mean plasma TPM concentrations (P = 0.015). In a comparison of TPM 50 and 400 mg/d, the time to first seizure was significantly longer with the higher dose compared with the lower dose (P<0.001, Kaplan-Meier analysis), and the probability of 12-month seizure freedom was significantly higher (76% vs 59%, respectively; P = 0.001). Again, the time to first seizure was significantly associated with mean plasma TPM concentrations (P = 0.029). In a comparative study of TPM 100 and 200 mg/d, carbamazepine 600 mg/d, and valproate 1250 mg/d, there was no significant difference in rates of 6-month seizure freedom with TPM 100 and 200 mg/d (49% and 44%, respectively), carbamazepine (44%), and valproate (44%). Adverse events in the 3 studies were similar between TPM dose groups, although the incidence generally increased with increasing doses, occurred early in treatment, and decreased with prolonged therapy. In a pooled analysis of the 3 trials, the most commonly occurring adverse events during dose titration were paresthesia (25%), fatigue (16%), dizziness (13%), somnolence (13%), and nausea (10%); the most frequent adverse events during maintenance therapy were headache (20%), decreased appetite (11%), and weight loss (11%). CONCLUSION: In the 3 studies reviewed, TPM monotherapy was effective and generally well tolerated in patients with newly diagnosed epilepsy.     

奥卡西平单药及添加治疗部分性癫(癎)的疗效和安全性前瞻研究

目的:评估奥卡西平单药与添加治疗部分性癫患者的疗效、耐受性和安全性。方法:前瞻性对在同济医院癫诊疗中心就诊的67名部分性癫患者应用奥卡西平后进行临床随访观察,分为单药治疗组和添加治疗组,用药的前3个月及后3个月进行对比观察。结果:2组患者治疗前后发作频率减少的平均百分率有显著性差异(P=0.002)。单药治疗组与添加治疗组相比,前者用药前3个月发作完全控制的百分率、用药后3个月发作频率减少50%的百分率和发作完全控制的百分率(P=0.02,0.017,0.019)均明显低于后者。单药治疗组或添加治疗组自身用药的3个月及后3个月发作减少50%的百分率、发作减少75%的百分率、发作完全控制百分率均无明显差异(P>0.05)。治疗引起的不良反应发生率为19.40%(13/67),主要出现于用药的前3月。结论:奥卡西平是治疗部分性癫的一线药物,可用于新诊断或其他药物无法耐受和疗效不佳患者的单药或添加治疗。     

Antiepileptic drugs on calcium currents recorded from cortical and PAG neurons: therapeutic implications for migraine

Cortex and periaqueductal grey (PAG) play a major role in the pathophysiology of migraine. Some antiepileptic drugs (AEDs) influence the activity of these structures by modulating high-voltage-activated (HVA) Ca(2+) channels and are effective in migraine prevention. The aim of the present study was to investigate the expression of total HVA Ca(2+) channels in cortical and PAG neurons and to study the differential action of AEDs on these channels. Isolated neurons were visually identified based on morphological criteria. HVA currents were recorded by whole-cell patch-clamp technique. The distribution ratio of L-, N-, P-, Q- and R-type HVA Ca(2+) channels was different between cortical and PAG neurons. In particular, we found that P- and Q-type HVA Ca(2+) channels were more expressed in PAG neurons than in cortical cells, whereas L- and R-type HVA Ca(2+) channels showed an opposite distribution. Interestingly, N-type HVA Ca(2+) channels were equally distributed in these two neuronal populations. A differential sensitivity to AEDs of HVA Ca(2+) channels located on cortical and PAG neurons was observed for topiramate (TPM), but not for lamotrigine (LTG) or levetiracetam (LEV). In fact, whereas both LTG and LEV were equally effective and potent in inhibiting HVA Ca(2+) currents in the two neuronal populations, TPM showed a much higher potency and efficacy in blocking these currents in PAG neurons than in cortical pyramidal cells. TPM, in fact, inhibited N-, P- and L-type channels in PAG neurons, whereas in cortical neurons this AED modulated only P- and L-type channels. Unlike the other AEDs investigated, valproic acid did not affect HVA Ca(2+) currents in cortical and PAG neurons. The negative modulation of specific subtypes of HVA Ca(2+) channels by various AEDs can restore normal electrical activity in target brain areas such as cortex and PAG, providing interesting therapeutic approaches in migraine prevention.     

Tolerability and effects on quality of life of twice-daily extended-release carbamazepine in adults with seizure disorders: an open-label, 12- to 36-month continuation study

BACKGROUND: An earlier 6-month, multicenter, open-label study in patients with complex partial seizures found that a switch from multiple daily doses of conventional carbamazepine (CBZ) to twice-daily CBZ extended-release capsules(CBZ-ERC) was well tolerated, with maintenance of seizure control over the study period and significant improvements in quality of life (P < 0.001). OBJECTIVE: The goal of the present study was to assess the tolerability and effects on quality of life of twice-daily CBZ-ERC over the longer term in patients with seizure disorders. METHODS: This was a multicenter, open-label assessment of the long-term(12-36 months) tolerability and quality-of-life effects of twice-daily CBZ-ERC given at a daily dose equivalent to the daily dose of CBZ taken before study en-try. The regimen could be adjusted as clinically indicated up to a daily dose of 1600 mg. Patients could receive up to 2 other antiepileptic drugs during the study. RESULTS: One hundred eighteen patients were enrolled. In patients completing>12 months of study therapy, a significant decrease in the highest mean 2-day frequency of generalized tonic-clonic seizures was observed over the first 12 months (P = 0.005). The significant improvements in quality of life achieved in the earlier study were maintained during the present study. Of 37 patients who were discontinued from the study, 9 met criteria mandating withdrawal from the study due to exacerbation of seizures. Three patients were discontinued from the study for adverse events judged to be unrelated to study drug. Low incidences of rash (3.4%) and weight gain (0.8%) were reported. CONCLUSIONS: In this population of adults with seizure disorders, CBZ-ERC twice daily was well tolerated during 12 to 36 months of open-label treatment,with no increase in seizure frequency or decrease in quality of life.     

Novel anticonvulsant drugs

Principles of complex mechanisms of action of anticonvulsants including latest reports concerning new antiepileptic drugs (AED) are considered. Different aspects of new anticonvulsant drugs (2nd generation) from preclinical and clinical testing, pharmacokinetics, and mono or combination therapy in children and adults are summarized. In the following condensed synopsis pharmacological and clinical characteristics of gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), pregabalin (PGB) and tiagabine (TGB) as well as topiramate (TPM) and zonisamide (ZNS) are discussed. In addition to the mechanisms of action, pharmacokinetics, interactions, indications and dosages as well as side effects are considered. Important data concerning the effect and tolerability of anticonvulsant drugs can be obtained from controlled studies. In comparison to drugs of the first generation (phenobarbital [PB], primidon [PRD], phenytoin [PHT], carbamazepine [CBZ] and valproic acid [VPA]) the potential for interactions and side effects due to enzyme induction or inhibition is reduced by most of the anticonvulsant drugs of the second generation. New anticonvulsant drugs increase the spectrum of treatment and represent further steps with regard to the optimization of an individual therapy of the epilepsies.     

Optimizing antiepileptic drug therapy in the elderly

OBJECTIVE: To review and evaluate the medical literature concerning antiepileptic drug (AED) therapy in elderly patients. DATA SOURCES: A MEDLINE search (1982-December 2004) was conducted. Bibliographies of the articles identified were also reviewed, and an Internet search engine was used to identify additional pertinent references. STUDY SELECTION AND DATA EXTRACTION: Clinical studies and reviews were evaluated, and relevant information was included. DATA SYNTHESIS: The elderly have the highest incidence of seizures among all age groups. Complex partial seizures are the most common, followed by primary generalized tonic-clonic seizures. An accurate diagnosis may prove difficult because of a low suspicion of epilepsy in the elderly and other diseases that may mimic seizures. Most AEDs are approved for treatment of elderly patients who have partial and tonic-clonic seizures. However, a number of age-related variables should be addressed when selecting an appropriate AED. Age-dependent differences in pharmacokinetics and pharmacodynamics of AEDs must be taken into account. Drug-drug interactions must be considered since elderly people often take multiple medications. The ultimate factor that often determines AED selection is tolerability. CONCLUSIONS: Numerous factors must be considered in treating elderly patients for seizures, but maximizing the ability of patients to tolerate drug therapy is often the basis for AED selection. Special consideration should be made along several lines, including elderly patients' cognitive functioning and their tendency to respond to lower AED concentrations.     

Clinical pharmacology and therapeutic use of the new antiepileptic drugs

Although older generation antiepileptic drugs (AEDs) such as carbamazepine, phenytoin and valproic acid continue to be widely used in the treatment of epilepsy, these drugs have important shortcomings such as a highly variable and nonlinear pharmacokinetics, a narrow therapeutic index, suboptimal response rates, and a propensity to cause significant adverse effects and drug interactions. In an attempt to overcome these problems, a new generation of AEDs has been introduced in the last decade. Compared with older agents, some of these drugs offer appreciable advantages in terms of less variable kinetics and, particularly in the case of gabapentin, levetiracetam and vigabatrin, a lower interaction potential. Lamotrigine, topiramate, zonisamide and felbamate protect against partial seizures and a variety of generalized seizure types, vigabatrin is effective against partial seizures (with or without secondary generalization) and infantile spasms, while the use of oxcarbazepine, tiagabine and gabapentin is mainly restricted to patients with partial epilepsy (and, in the case of oxcarbazepine, also primarily generalized tonic-clonic seizures). Levetiracetam, the latest AED to be introduced, has been found to be effective in partial seizures, but its potentially broader efficacy spectrum remains to be determined in clinical studies. Currently, the main use of new generation AEDs is in the adjunctive therapy of patients refractory to older agents. However, due to advantages in terms of tolerability and ease of use, some of these drugs are increasingly used for first-line management in certain subgroups of patients. Due to serious toxicity risks, felbamate and vigabatrin should be prescribed only in patients refractory to other drugs. In the case of vigabatrin, however, first line use may be justified in infants with spasms.     

特发性全面强直阵挛癫痫撤药与复发危险因素的前瞻性研究

目的观察抗癫痫药物（AEDs）有效控制的特发性全面强直阵挛发作癫痫患者在撤药后的复发情况,探讨影响复发的危险因素及缩短AEDs维持治疗时间的可能性。方法选择2005年10月至2008年10月间我院就诊的经AEDs有效控制特发性全面强直阵挛发作癫痫的患者,随机列入对照组（维持用药36个月逐渐减量至撤药）及研究组（维持用药24个月逐渐减量至撤药）,指导其撤除AEDs,随访24个月,记录复发情况。采用Kaplan-Meier模型及Log-rank检验比较两组的复发率,应用Cox比例风险模型分析影响复发的危险因素。结果对照组46例患者复发14例,累积复发率为30.4%;研究组40例患者复发13例,累积复发率为32.5%。两组复发率比较差异无统计学意义（log-rank统计值=2.29,P=0.34）。Cox多因素分析表明,年龄、病程、发作频率及合并用药数是影响复发的重要危险因素。结论特发性全面强直阵挛发作患者经有效控制后维持用药24个月撤除药物并未增加复发的风险。根据患者的年龄、病程、发作频率、合并用药积极审慎地调整维持用药时间是可行的。