唑尼沙胺添加治疗部分性癫癎的临床疗效及安全性：多中心随机双盲安慰剂对照研究

目的观察唑尼沙胺分散片添加治疗部分性发作或继发全面性发作、全面性强直一阵挛发作及失神发作的疗效及安全性。方法240例诊断明确的部分性发作患者,被随机分为唑尼沙胺组（120例）或对照组（120例）。回顾性基线期（12周）后,予初始剂量唑尼沙胺或安慰剂100mg／次,1次,d,3周内递增至100mg/次,3次/d;分别在治疗第0、2、4、8和16周时进行随访,评价治疗第5～16周时临床综合疗效的完全控制率和总有效率,以及药物安全性和不良反应。结果治疗第5～16周时,唑尼沙胺组患者癫痼完全控制率为34．04％（32／94）、总有效率74．47％（70／94）,对照组分别为13．08％（14／107）和42．99％（46／107）;两组临床综合疗效的完全控制率和总有效率比较,差异具有统计学意义（均P=0．000）。唑尼沙胺组患者常见药物不良反应包括食欲不振、嗜睡、疲劳、头晕、肝功能异常等,与对照组不良反应发生率比较差异有统计学意义（P=0．003）。结论唑尼沙胺作为添加药物治疗部分性发作或继发全面性发作、全面性强直一阵挛发作的疗效优于安慰剂,而且有较好的安全性和耐受性,是临床可以选择的新型抗癫癎药物之一。     

多中心、随机、双盲、安慰剂对照评价唑尼沙胺添加治疗癫(癎)部分性发作的疗效和安全性

目的 评价唑尼沙胺作为添加治疗癫(癎)部分性发作的疗效和安全性.方法 确诊为有癫(癎)部分性发作的217例癫(癎)患者,随机分配入唑尼沙胺治疗组(n=111)与安慰剂组(n=106)进行随机、双盲、安慰剂对照、多中心平行设计添加治疗.在3个月回顾性基线期后,给予患者初始剂量唑尼沙胺(100 mg/片)或安慰剂每次1片,每日1次口服,4周内递增至每次2片,每日2次.分别在治疗0、2、4、8、12和16周时进行随访.主要疗效指标为治疗结束后与基线期比较发作次数减少的中位百分比;次要疗效指标为发作次数减少大于50%的比例.同时观察研究药物的安全性与不良反应情况.结果 总发作次数减少率中位数在唑尼沙胺组为33.33%,安慰剂组为0;唑尼沙胺组总发作次数减少>50%者38例(34.23%),安慰剂组21例(19.81%),差异有统计学意义(χ3=5.7159,P=0.0168).唑尼沙胺组治疗后无发作13例(11.71%),有效25例(22.52%),临床有效率为34.23%;安慰剂组无发作5例(4.72%),有效16例(15.09%),临床有效率为19.81%,2组间比较差异有统计学意义(U=2.4701,P=0.0135).唑尼沙胺组与安慰剂组比较,其不良反应发生率差异无统计学意义,唑尼沙胺组较常见的不良反应有思睡、乏力、食欲下降、胃肠道不适、失眠和便秘.结论 唑尼沙胺作为部分性癫(癎)发作的添加药物有确定的疗效,安全耐受性较好,具有一定临床应用价值.     

苯巴比妥长期治疗癫(癎)患者的疗效观察

目的 探讨苯巴比妥长期治疗癫(癎)患者的疗效.方法 苯巴比妥(15岁以上,体质量超过30 kg患者每晚60 mg;15岁以下,体质量30 kg以下的患者每晚2 mg/kg)治疗136例全面性强直阵挛发作(GTCS)患者,其中50例联合其他抗癫(癎)药物(AEDs)治疗,随访5 a,观察疗效及药物不良反应.结果 136例...     

下期内容预告

本刊2011年第4期报道专题为抗癫癎药物的疗效与安全性,重点内容包括:新型抗癫癎药物在国内的应用;抗癫癎药性脑病;抗癫癎药物对心血管系统的影响;抗癫癎药物对内分泌及妇女妊娠的影响;抗癫癎药物对血液系统的影响;常用抗癫癎药物在临床应用中出现的皮肤不良反应;抗癫癎药物对患儿生长发育及认知功能的影响;唑尼沙胺添加治疗部分性癫癎有效性与安全性的多中心随机双盲安慰剂对照临床研究;不同底物对难治性癫癎细胞模型中整合素α₂表达的影响;低频重复经颅磁刺激治疗难治性癫癎大鼠模型的作用及对BDNF和NPY表达的影响;中药治疗癫癎的实验前研究     

随机、双盲、安慰剂对照、多中心研究唑尼沙胺添加用药治疗部分性癫(癎)发作的有效性和安全性

目的 评价唑尼沙胺(ZNS)作为添加用药治疗部分性癫(癎)发作的有效性和安全性.方法 采用多中心、随机、双盲、安慰剂对照、平行组、添加治疗设计.240例确诊为癫(癎)部分性发作的受试者按照1:1的比例随机分配到ZNS治疗组或安慰剂组.在前4周加鼋期内受试者自100 mg/d逐渐加量至300 mg/d,随后进入12周的稳定治疗期.在稳定期内可根据患者情况酌情减量,或加量至最大剂量400 mg/d.有效性评价的主要指标为稳定期部分性癫(癎)发作频率较基线值减少百分数的中位值,重要的次要评价指标为有效率,即部分性癫(癎)发作次数减少≥50%者的比例.同时对药物的安全性进行评价.结果 ZNS组受试者稳定期部分性癫(癎)发作频率较基线期减少百分数(48.4%)显著高于安慰剂组(26.6%),组间差异有统计学意义(F=4.904,P=0.028);ZNS组治疗部分性癫(癎)发作的有效率(48.6%)高于安慰剂组(34.9%),差异有统计学意义(X2=4.046,P=0.044),其中以复杂部分性癫(癎)的组间差异最为显著(分别为52.2%和33.3%,X2=5.607,P=0.018).ZNS组与安慰剂组不良事件发生率相当,与ZNS相关的不良事件多为头晕、头痛、嗜睡、食欲下降、恶心等.结论 ZNS能有效治疗部分性癫(癎),降低癫(癎)发作频率,对复杂部分性癫(癎)发作治疗效果尤为突出.ZNS耐受性良好,受试者用药安全性较高.     

多中心双盲、随机、安慰剂对照评价左乙拉西坦添加治疗难治性部分性癫(癎)发作的疗效及安全性

目的 评价左乙拉西坦(LEV)添加用药治疗难治性部分性癫(癎)发作的临床疗效及安全性.方法 随机、双盲、安慰剂对照、多中心平行设计添加治疗,确诊为有癫(癎)部分性发作的202例癫(癎)患者,平均年龄(32.8±12.7)岁,随机分配入LEV治疗组(n=102)与安慰剂组(n=100).在回顾8周基线期的癫(癎)发作频率后,进入逐量加药期.初始用药剂量为0.5 g,每日2次,2周后增加至1.0 g,每日2次服用,4周后加量至1.5 g,每日2次,随后维持该剂量治疗12周,最后逐渐减量并转入LEV开放治疗期.主要评价指标为16周治疗期内每周癫(癎)发作频率的比较、得出药物治疗发作频率减少50%有效率、安全性和药物不良反应.结果 在16周治疗期内,LEV组每周癫(癎)发作频率明显减少,较安慰剂组减少26.8%;每周发作频率较基线期下降数在LEV组与安慰剂组的组间差异为42.2%;部分性发作频率减少50%有效率为55.9%,与安慰剂组比的OR值为3.6;有11例治疗后完全无发作,两组相比均有显著统计学意义(P＜0.001).LEV组的主要不良事件为嗜睡、头晕、无力及血小板减少,但与安慰剂组比差异无统计学意义.结论 LEV添加用药治疗成人难治性部分性癫(癎)发作,可以显著减少癫(癎)发作频率,安全性良好.     

左乙拉西坦单药治疗各型癫癎的疗效和安全性临床观察

目的对50例单独应用左乙拉西坦（LEV）的癫癎患者进行临床观察和随访,以评估左乙拉西坦治疗各型癫癎的疗效和安全性。方法采用开放性自身对照方法对2009年6月~2010年3月本院及其门诊就诊的50例左乙拉西坦单药治疗的癫癎患者进行随访研究,收集治疗前后患者发作频率变化、发作情况、不良反应以及退出原因。其随访均在半年以上。结果 LEV单药治疗后癫癎发作完全控制率48%,有效率38%;其中部分性发作完全控制率40.9%,有效率45.5%;全面性发作完全控制率53.6%,有效率32.1%,对west综合症亦有效。不良反应包括情绪异常、易激惹12%（6/50）,头晕8%（4/50）,白细胞减少2%（1/50）;上述不良反应均为一过性,在2~5周内自然消失,未导致停药,未发现过敏以及肝、肾功能异常等严重不良反应。结论 LEV是一种安全有效的抗癫癎药物,对部分性和全面性发作均有效,且安全耐受性较好。     

抗癫(癎)药物应用指南Ⅱ:新型抗癫(癎)药物的药力和耐受性:难治性癫(癎)的治疗美国神经病学学会治疗学和技术评定分委会和质量标准分委会及美国癫(癎)协会报告

目的 对有关7种用以治疗儿童和成人部分性和全面性难治性癫(癎)的新型抗癫(癎)药物(AEDs):加巴喷丁(gabapentin,GBP)、拉莫三嗪(lamotrigine,LTG)、托吡酯(topiramate,TPM)、噻加宾(tiagabine,TGB)、奥卡西平(oxcarbazepine,OXC)、左乙拉西坦(1evetiracetam,LEV)和唑尼沙胺(zonisamide,ZNS)的药力(efficacy)、耐受性和安全性进行评估.方法 由23位成人神经病学家、小儿神经病学家、癫(癎)病学家和药理学家组成的专家组,依据从1987年到2002年9月Medline,Current Contents和Cochrane上发表的相关文献和2003年以前的指南提供的证据进行循证医学评估.结果 所有新型抗癫(癎)药物都适用于成人难治性部分性癫(癎)的添加治疗,加巴喷丁对混合性(癎)性发作有效,加巴喷丁、拉莫三嗪、托吡酯和奥卡西平对儿童难治性部分性癫(癎)有效.有限的证据还表明,拉莫三嗪和托吡酯对成人和儿童特发性全面性发作和Lennox-Gastaut综合征的添加治疗也有效.结论 抗癫(癎)药物的选择要考虑癫瘌发作和/或癫(癎)综合征的类型、患者的年龄、合用的药物、药物的耐受性、安全性和药力等因素.循证医学评估结果提供了难治性癫(癎)患者的抗癫(癎)药物应用指南,但尚需更为有力的证据用以鉴定其在癫(癎)型或综合征中疗效.     

抗癫癎药物应用指南Ⅱ:新型抗癫癎药物的药力和耐受性:难治性癫癎的治疗美国神经病学学会治疗学和技术评定分委会和质量标准分委会及美国癫癎协会报告

目的对有关7种用以治疗儿童和成人部分性和全面性难治性癫癎的新型抗癫癎药物(AEDs):加巴喷丁(gabapentin, GBP)、拉莫三嗪(lamotrigine,LTG)、托吡酯(topiramate,TPM)、噻加宾(tiagabine,TGB)、奥卡西平(oxcarbazepine,OXC)、左乙拉西坦(levetiracetam,LEV)和唑尼沙胺(zonisamide,ZNS)的药力(efficacy)、耐受性和安全性进行评估。方法由23位成人神经病学家、小儿神经病学家、癫癎病学家和药理学家组成的专家组,依据从1987年到2002年9月Medline,Current Contents和Cochrane上发表的相关文献和2003年以前的指南提供的证据进行循证医学评估。结果所有新型抗癫癎药物都适用于成人难治性部分性癫癎的添加治疗,加巴喷丁对混合性癎性发作有效,加巴喷丁、拉莫三嗪、托吡酯和奥卡西平对儿童难治性部分性癫癎有效。有限的证据还表明,拉莫三嗪和托吡酯对成人和儿童特发性全面性发作和Lennox-Gastaut综合征的添加治疗也有效。结论抗癫癎药物的选择要考虑癫癎发作和/或癫癎综合征的类型、患者的年龄...     

奥卡西平治疗癫癎的临床观察

目的观察奥卡西平(OXC)治疗癫疒间部分性发作/继发全面性强直-阵挛发作(PS/SGTCS)或特发性全面性强直-阵挛发作(GTCS)的疗效、耐受性和安全性。方法61例PS/SGTCS或GTCS患者,其中40例新诊断癫疒间和未经正规治疗的患者进入OXC单治组;而21例长期先后应用过多种抗癫疒间药治疗者进入OXC加治组。成人OXC起始量均为150 mg每晚1次,维持剂量(600~2 400)mg/d,分2次服用;儿童起始量(4~5)mg/kg每晚1次,维持剂量(30~40)mg/(kg.d)。进行自身对比开放性观察,同时分析单治组与加治组24周内的疗效、不良反应、耐受性和安全性。结果本组总有效率和显效率分别为62.3%和54.1%,控制率为49.2%,累积退出率为24.6%,3例(4.9%)失访,因不良反应和经济原因退出12例(19.7%),其中2例(3.3%)因皮疹退出。最常见的不良反应:乏力6例;头昏、头痛、嗜睡各5例;恶心、皮疹各2例。结论OXC治疗PS/SGTCS或GTCS的疗效明显,不良反应轻,耐受性好,安全性高。     

Dose-dependent safety and efficacy of zonisamide: a randomized, double-blind, placebo-controlled study in patients with refractory partial seizures

PURPOSE: To evaluate the safety and efficacy of zonisamide (ZNS) as adjunctive treatment in patients with refractory localization-related epilepsy. METHODS: This was a double-blind, placebo-controlled study of adjunctive ZNS in 351 patients with refractory partial seizures receiving a stable regimen of one to three antiepileptic drugs (AEDs). Patients were randomized to placebo or ZNS, 100 mg, 300 mg, or 500 mg/day (2:1:1:2) after a 12-week baseline. Dose titration was undertaken over a 6-week titration phase, which was followed by an 18-week fixed-dose assessment phase. Primary efficacy parameters were the differences between ZNS, 500 mg/day, and placebo in the change from baseline in frequency of complex partial (CP) seizures during the fixed-dose assessment phase and in the proportion of CP responders (> or =50% decrease from baseline in seizure frequency). Safety and tolerability also were assessed. RESULTS: Compared with placebo, the highest dose of ZNS (500 mg/day) resulted in a significantly greater decrease in CP seizure frequency from baseline (51.2% vs. 16.3%; p < 0.0001) and a significantly higher proportion of CP responders (52.3% vs. 21.3%; p < 0.001). Both ZNS, 500 mg/day, and 300 mg/day were statistically superior to placebo in reducing the frequency of "all seizures" and simple partial (SP) + CP seizures. For all seizures, a significant dose-response relation was observed (p < 0.0001).The most common adverse events were somnolence, headache, dizziness, and nausea during the titration phase and headache and pharyngitis during the fixed-dose assessment phase. CONCLUSIONS: ZNS provides dose-dependent, effective, and generally well-tolerated adjunctive therapy in patients with partial seizures.     

多中心、随机、双盲、安慰剂对照评价普瑞巴林添加治疗部分性癫癎发作的疗效和安全性

目的 评价普瑞巴林添加治疗部分性癫（癎）发作的疗效和安全性.方法采用随机、双盲、安慰剂对照、多中心平行设计添加治疗的方法,确诊为有部分性癫（癎）发作的225例癫（癎）患者,被随机分配入普瑞巴林治疗组（114例）与安慰剂组（111例）.在6周前瞻性基线期后,采用灵活剂量的普瑞巴林（150～600 mg·d-1）添加治疗成人部分性癫（癎）发作.主要疗效指标：部分性癫（癎）发作28 d-反应率.次要疗效指标：部分性癫（癎）发作28d-减少率、临床疗效评价、16周内癫（癎）无发作和发作减少率≥50％的病例比例、第13～16周癫（癎）无发作和发作减少率≥50％的病例比例以及临床疗效总评量表评分;并观察研究药物的安全性与不良反应情况.结果 普瑞巴林组部分性癫（癎）发作28 d-反应率（-40.24±37.88）％,显著高于安慰剂组（-22.84±37.61）％（F=15.063 9,P=0.000 l）.普瑞巴林组和安慰剂组的不良事件发生率分别为60.53％和47.75％,组间无显著差异;但普瑞巴林组的不良反应发生率较安慰剂组高（45.61％ vs 23.42％,P=0.000 7）,主要不良反应有头晕、嗜睡、视物模糊、乏力等.结论 普瑞巴林组的疗效显著优于安慰剂组.普瑞巴林作为部分性癫（痈）发作的添加药物有确定的疗效,安全耐受性较好,具有一定临床应用价值.     

Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial

OBJECTIVE: To evaluate the efficacy and safety of 500 mg bid and 1500 mg bid levetiracetam as adjunctive therapy for refractory partial seizures in a double-blind, randomized, placebo-controlled, parallel-group, multicenter trial. METHODS: The authors studied patients with uncontrolled partial seizures (minimum 12 per 12 weeks), regardless of whether they became secondarily generalized, for 38 weeks. A 12-week baseline was followed by random assignment to adjunctive therapy with placebo (n = 95), levetiracetam 1000 mg/day (n = 98), or levetiracetam 3000 mg/day (n = 101). Upward titration over 4 weeks was followed by 14 weeks of fixed dose treatment, and concluded with an 8-week medication withdrawal period or entering a follow-up study. RESULTS: Of 294 patients randomized, 268 completed the study. Partial seizure frequency during the entire evaluation period (primary efficacy variable) was lower with levetiracetam compared to placebo (p /=10%), mostly mild to moderate in severity, with incidences higher than placebo were asthenia, dizziness, flu syndrome, headache, infection, rhinitis, and somnolence. CONCLUSION: Adjunctive therapy with levetiracetam was effective and well tolerated in controlling partial seizures.     

Short-term efficacy and safety of zonisamide as adjunctive treatment for refractory partial seizures: a multicenter open-label single-arm trial in Korean patients

ObjectiveTo evaluate the efficacy and safety of adjunctive zonisamide (ZNS) therapy in Korean adults with uncontrolled partial epilepsy.MethodsStudy patients had an average of at least one seizure per 4-week (averaged over a 12-week historical baseline) despite the use of one to three antiepileptic drugs. The starting dose of ZNS was 100 mg/day, and was increased to 200 mg/day after 2 weeks. During the 12-week maintenance period, the dose of ZNS was adjusted to 200–400 mg/day based on the physicians’ discretion. The global evaluation scale (GES) and quality of life (QOLIE-31) were also evaluated.ResultsA total of 121 patients were enrolled, of which 88 patients completed the study. The median percent reduction in weekly seizure frequency over the treatment period was 59.0%. The ≥50% and ≥75% responder rates were 57.3% and 38.5%, respectively. Seizure freedom over the treatment period was observed in 25 patients, but seizure freedom throughout the 16-week treatment period was attained in only 16 patients. On investigator's GES, 84 patients were considered improved, with 33 patients showing marked improvement. In QOLIE-31 scale, seizure worry improved significantly but emotional well-being deteriorated. Treatment-emergent adverse events (AEs) were reported in 80 patients. The most common AEs were dizziness (28.1%), somnolence (24.0%), anorexia (18.2%), headache (14.0%), nausea (13.2%), and weight loss (10.7%). Twenty-two patients discontinued the trial due to drug-related AEs.ConclusionsOur results suggest that adjunctive ZNS therapy for the treatment of refractory partial epilepsy, though efficacious, is associated with significant tolerability problems.     

A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study Group

BACKGROUND AND OBJECTIVE: Topiramate is effective as adjunctive treatment of partial-onset seizures in adults. The efficacy and safety of topiramate as adjunctive therapy for the treatment of primary generalized tonic-clonic (PGTC) seizures were investigated in a randomized, double-blind, placebo-controlled study. METHODS: Eighty patients, 3 to 59 years old, who experienced three or more PGTC seizures during an 8-week baseline phase were randomly assigned to treatment with either topiramate (n = 39) or placebo (n = 41). Topiramate was titrated to target doses of approximately 6 mg/kg/day over 8 weeks and maintained for another 12 weeks. RESULTS: The median percentage reduction from baseline in PGTC seizure rate was 56.7% for topiramate patients and 9.0% for placebo patients (p = 0.019). The proportion of patients with 50% or higher reduction in PGTC seizure rate was 22/39 (56%) and 8/40 (20%) for the topiramate and placebo groups, respectively (p = 0.001). The median percentage reduction in the rate of all generalized seizures was 42.1% for topiramate patients and 0.9% for placebo patients (p = 0.003). The proportions of patients with 50% or higher reductions in generalized seizure rate were 18/39 (46%) and 7/41 (17%) for the topiramate and placebo groups, respectively (p = 0.003). The most common adverse events were somnolence, fatigue, weight loss, difficulty with memory, and nervousness. Treatment-limiting adverse events occurred in one patient in the topiramate group (anorexia and weight loss) and one in the placebo group (granulocytopenia and thrombocytopenia). CONCLUSION: Topiramate is well-tolerated and effective for the adjunctive treatment of PGTC seizures.     

Treatment of partial seizures with gabapentin: double-blind, placebo-controlled, parallel-group study

This double-blind study was conducted to evaluate the efficacy and safety of gabapentin 1200 mg/day and 1800 mg/day (t.i.d.) compared to placebo as an adjunctive therapy in patients with refractory epilepsy. Patients were included when they had partial seizures at least eight times during a 12-week baseline period despite treatment with one to two antiepileptic drugs. After baseline, eligible patients were randomized to gabapentin 1200 mg/day, 1800 mg/day, or placebo for 12-week treatment. The primary end-point, response ratio, was derived from seizure frequencies during treatment and baseline period based upon the seizure daily record by a patient. Of the 209 randomized patients, 86 received gabapentin 1200 mg/day, 41 received gabapentin 1800 mg/day, and 82 received placebo. A statistically significant difference was found between each of the two gabapentin groups and placebo for the primary efficacy end-point, response ratio (P < 0.005) with definite dose-response (P < 0.001). More gabapentin patients reported moderate to marked improvement in seizure frequency and intensity/duration of each seizure than placebo patients. Treatment-related adverse events were reported by approximately 65% of patients receiving gabapentin compared to approximately 46% of patients receiving placebo; somnolence and dizziness were the most common events. Gabapentin 1200 mg/day and 1800 mg/day significantly reduced the frequency of refractory seizures compared to placebo. Favorable tolerability of gabapentin was confirmed also in a Japanese population, consistent with previous global studies.     

Randomized, controlled clinical trial of zonisamide as adjunctive treatment for refractory partial seizures

PURPOSE: This study was designed to evaluate efficacy and safety of zonisamide (ZNS) as adjunctive treatment for patients with refractory partial seizures. METHODS: This randomized, double-blind, placebo-controlled study was conducted at four epilepsy treatment centers. It included a baseline phase (8 to 12 weeks) and a double-blind treatment phase (12 weeks). Initially, patients randomized to ZNS treatment were given a 7-mg/kg/d dosage. When investigators found that adverse effects could be reduced by gradually introducing ZNS, patients were allowed to begin treatment at lower doses (100 mg or approximately 1.5 mg/kg/d) titrated over several weeks to a maximum of 400 to 600 mg/d. Primary and secondary efficacy measures were the median percentage reduction from baseline in seizure frequency and the proportion of patients achieving a > or =50% reduction from baseline (responder rate). Patient and physician global assessments also served as indicators of efficacy. Safety was assessed primarily by treatment-emergent adverse events. RESULTS: ZNS-treated patients had a 28.9% reduction in seizure frequency, which differed significantly from the 4.7% increase in placebo-treated patients. The responder rate for ZNS-treated patients was 26.9%, compared with 16.2% for placebo-treated patients. At study's end, 66.2% of ZNS-treated patients and 12.3% of placebo-treated patients considered their condition improved; similarly, physicians assessed 63.6% of ZNS-treated patients and 10.8% of placebo-treated patients as improved. The most frequently reported adverse events with ZNS treatment included somnolence, irritability, dizziness, nausea, and fatigue. CONCLUSIONS: As adjunctive treatment, ZNS was generally well tolerated and significantly improved seizure control among patients with refractory partial seizures.