Flunarizine blocks voltage-gated Na(+) and Ca(2+) currents in cultured rat cortical neurons: A possible locus of action in the prevention of migraine

Although flunarizine (FLN) has been widely used for migraine prophylaxis with clear success, the mechanisms of its actions in migraine prophylaxis are not completely understood. It has been hypothesized that migraine is a channelopathy, and abnormal activities of voltage-gated Na(+) and Ca(2+) channels might represent a potential mechanism of cortical hyperexcitability predisposing to migraine. The aim of the present study was to investigate the effects of FLN on Na(+) and Ca(2+) channels of cultured rat cortical neurons. Sodium currents (I(Na)) and calcium currents (I(Ca)) in cultured rat cortical neurons were monitored using whole-cell patch-clamp recordings. Both I(Na) and I(Ca) were blocked by FLN in a concentration-dependent manner with IC(50) values of 0.94μM and 1.77μM, respectively. The blockade of I(Na) was more powerful at more depolarizing holding potentials. The steady-state inactivation curve of I(Na) was shifted towards more hyperpolarizing potentials by FLN. FLN significantly delayed the recovery from fast inactivation of I(Na). Furthermore, the action of FLN in blocking I(Na) was enhanced at higher rates of channel activation. Blockades of these currents might help explain the mechanism underlying the preventive effect of FLN on migraine attacks.     

氟桂利嗪对青霉素致癎大鼠海马细胞单位放电特征的影响

目的：探讨青霉素癫癎模型大鼠海马神经元单位放电的特征。方法：36只Wistar雄性健康大鼠,随机分为正常对照组、癫癎模型组、癫癎预处理组,各12只。①正常对照组记录单位放电后处死;②癫癎模型组用青霉素钠按600万U／kg体重腹腔注射制作成癫癎模型,记录单位放电后处死;③癫癎预处理组制作模型前用盐酸氟桂利嗪按20mg／kg体重每隔12h灌胃共两次,第二次给药后2h制作成癫癎模型,然后作单位放电记录后处死。结果：①正常对照组大鼠共记录到24个单位海马神经元放电;②癫癎模型组共记录到78个单位海马神经元放电;③癫癎预处理组共记录到47个单位海马神经元放电。与正常对照组比较,癫癎模型组海马神经元单位放电频率增加,放电形式多为混合型,差异有极显著意义（P〈0．01）;与癫癎模型组比较,癫癎预处理组海马神经元单位放电频率降低,差异有统计学意义（P〈0．05）。结论：①癫癎大鼠是以暴发放电为主的混合型放电,抽搐时多表现为束簇状;②盐酸氟桂利嗪对癫癎大鼠放电有显著的抑制作用。     

通心络加西比灵治疗椎-基底动脉供血不足的临床观察

目的评价通心络加西比灵治疗椎-基底动脉供血不足的疗效,并与单用西比灵治疗作对照观察。方法A组给西比灵10mg／次,1日1次,口服;B组在A组基础上加用通心络3～4粒／次,口服,1日3次。一疗程15天,间歇5～7天,部分有效病人视病情可行第2疗程治疗。结果一疗程后评定,A、B两组痊愈分别为40例和73例;显效15例和20例;有效11例和5例;无效11例和4例。A、B两组的痊愈率分别为52．0％和71．6％（χ^2=7．94,P〈0．01）,显效痊愈率为71．4％和91．2％（χ^2=12．96,P〈0．01）,总有效率为85．7％和96．1％,（χ^2=4．69,P〈0．05）。有效病人随访2月未再复发率分别为63．6％和76．5％（χ^2=6．31,P〈0．05）。结论通心络合用西比灵治疗椎-基底动脉供血不足较单用西比灵治疗效果更加显著。     

SMAD2／3蛋白在沙鼠脑缺血再灌注及氟桂利嗪干预后脑内表达的研究

目的研究smad2／3在沙鼠脑缺血再灌注脑内表达及氟桂利嗪干预后对其表达的影响。方法35只沙鼠随机分假手术组、缺血再灌注组和氟桂利嗪治疗组3组,采用夹闭双侧颈总动脉制作沙鼠脑缺血再灌注模型,于缺血10min再灌注1d、3d、7d各时间点处死动物,用免疫组化方法检测各组沙鼠脑内smad2／3的表达情况。结果假手术组沙鼠脑内smad2／3弱阳性表达,而缺血再灌注1d、3d、7d后沙鼠脑内呈阳性或强阳性表达,两者比较差异有统计学意义（P〈0．01）;氟桂利嗪治疗组smad2／3的表达低于缺血再灌注组,2组比较差异有统计学意义（P〈0．05）。结论沙鼠脑内有smad2／3表达,脑缺血再灌注后,脑内smad2／3表达上调;氟桂利嗪干预后,其表达下调。     

多药耐药基因在小儿难治性癫痫外周血中的表达及氟桂利嗪对其表达的逆转作用

目的探讨难治性癫痫患儿外周血中多药耐药基因(MDR1)的表达及氟桂利嗪在其辅助治疗中的作用。方法采用RT PCR技术,检测MDR1在22例正常儿童和64例患儿辅助治疗前、后外周血中的表达情况,观察临床疗效和药物不良反应。结果难治性癫痫组未进行辅助治疗前MDR1 mRNA的表达水平明显高于正常对照组(P＜0.01)。辅助治疗后,氟桂利嗪组MDR1 mRNA的表达低于安慰剂组(P＜0.01),但高于正常对照组(P＜0.05);安慰剂组MDR1 mRNA的表达比正常对照组高1.14倍,与辅助治疗前相比,氟桂利嗪组MDR1 mRNA表达水平降低(P＜0.01),安慰剂组增高(P＜0.05)。氟桂利嗪组与安慰剂组治疗有效率分别为55.56％和3.57％。氟桂利嗪不良反应发生率为8.33％。结论检测外周血MDR1 mRNA的表达可以评估难治性癫痫患儿对抗癫痫药物的敏感程度;氟桂利嗪对MDR1 mRNA的表达有逆转作用,能减轻癫痫的发作,且小剂量氟桂利嗪副作用小,耐受性好。     

多塞平加氟桂利嗪治疗难治性肠易激综合征

目的　评价多塞平加氟桂利嗪治疗难治性肠易激综合征 (IBS)的疗效。方法　采用自身对照研究 ,4 6例非便秘型难治性IBS患者 ,予多塞平 12 .5mg ,bid或 2 5mg ,qn ,氟桂利嗪 5mg ,qn ,口服治疗 4周 ,通过比较患者治疗前后症状积分及减分率的变化评价疗效。结果　 5项主要相关症状积分均在治疗后显著性降低 (P <0 .0 0 1) ,总有效率为 76 .1%。结论　多塞平与氟桂利嗪联合治疗难治性IBS有良好疗效。     

通心络加氟桂利嗪治疗椎基底动脉供血不足102例临床分析

目的评价通心络加用氟桂利嗪(西比灵)(B组)治疗椎基底动脉供血不足102例的疗效,并与单用西比灵(A组)治疗77例作对照观察。方法A组给西比灵10mg口服,1次/d;B组在A组基础上加用通心络3-4粒,3次/d。一疗程15d,间歇5-7d,部分有效病人视病情可行第2疗程治疗。结果 一疗程后评定,A、B两组各痊愈40例和73例,显效15例和20例,有效11例和5例,无效11例和4例。A、B两组的痊愈率为52％和71％(r2=7.94,P<0.01),显效率分别为71.4％(55/77)和91.2％(93/102)(r2=12.96,P<0.01),总有效率85.7％(66/77)和96.1％(98/102),(r2=4.69,P<0.05),有效病人随访2月未复发率为63.6％(42/66)和76.5％(75/98)(r2=6.31,P<0.05)。结论通心络合用西比灵治疗椎基底动脉供血不足较单用西比灵治疗效果更加显著。因两药均易通过血脑屏障,针对脑血管的流体力学特点、血液成分及动力学状态对椎基底动脉供血不足发生、发展和转归的各种因素和环节有协同作用,以增加缺血区脑血流量和氧供,恢复脑细胞功能,促进其缺血症状的改善。     

Flunarizine in migraine prophylaxis: efficacy and tolerability of 5 mg and 10 mg dose levels

The use of flunarizine, a drug which has proven its efficacy in migraine, is often associated with important side effects. The aim of this paper has been to check their incidence at different dose levels (5 mg vs 10 mg). Our data confirm the occurrence of important side effects (in particular weight gain); on the other hand, they emphasize the dose-dependency of the side effects.     

Effects of extracellular calcium and of the calcium entry blockers flunarizine and nimodipine on contractile responses in human temporal arteries

Contraction induced by 124 mM potassium followed the depolarization of smooth-muscle cells and activation of potential-operated calcium channels in human temporal arteries. The contraction elicited consisted of two phases, one rapid and one slowly developing stable phase; both were affected by the two calcium entry blockers flunarizine and nimodipine but at significantly different concentrations. In calcium-free medium 124 mM potassium resulted in a weak contraction. Addition of calcium caused a concentration-dependent contraction that was attenuated by the calcium entry blockers at concentrations comparable to those inhibiting the second phase. The results suggested that in human temporal arteries flunarizine and nimodipine act as calcium entry blockers; there was good correlation with the therapeutic plasma concentration for nimodipine but not for flunarizine.     

阿魏酸钠联合氟桂利嗪治疗偏头痛疗效观察

目的观察中成药阿魏酸钠片联合西药氟桂利嗪胶囊治疗偏头痛的临床疗效。方法将81例符合国际头痛协会（IHS）制定的偏头痛诊断标准的患者，随机分成两组，接受阿魏酸钠片联合氟桂利嗪胶囊及单用氟桂利嗪胶囊的对比治疗，连用3个月，随访1年。结果两组总有效率有显著性差异（P〈0．05），控制复发率也有显著性差异（P〈0．05）。结论本疗法不仅疗效显著，而且对控制复发也有明显作用，疗法简单易行，副作用少，可作为偏头痛的常规用药。