mexiletine

美西律
  • 文章类型: Journal Article
    美西律是IB类钠通道阻滞剂。与IA或IC类抗心律失常药物不同,美西律缩短而不是延长动作电位持续时间;因此,它与致心律失常作用的相关性较小。
    最近,新的欧洲室性心律失常患者管理和心源性猝死预防指南已经出版,包括重新评估一些已建立的旧的抗心律失常药物。
    美西律提供一线,最新指南强调的LQT3患者的基因型特异性治疗策略.除了这个建议,目前的研究报告表明,在治疗难治性室性心律失常和电风暴中,美西律辅助治疗可能为有或没有导管消融等介入治疗的患者提供稳定的可能性。
    UNASSIGNED: Mexiletine is a class IB sodium-channel blocker. Unlike class IA or IC antiarrhythmic drugs, mexiletine rather shortens than prolongs action potential duration; therefore, it is less associated with proarrhythmic effects.
    UNASSIGNED: Recently, new European Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death were published, including a reappraisal of some established older antiarrhythmic drugs.
    UNASSIGNED: Mexiletine offers a first-line, genotype-specific treatment strategy for LQT3 patients as emphasized by the most recent guidelines. Besides this recommendation, current study reports suggest that in therapy-refractory ventricular tachyarrhythmias and electrical storms adjunctive mexiletine treatment may offer the possibility of stabilizing patients with or without concomitant interventional therapy such as catheter ablation.
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  • 文章类型: Case Reports
    背景:SCN5A编码的Nav1.5钠通道中的致病变异导致3型长QT综合征(LQT3)。这里,我们介绍了1例重度LQT3患儿,该患儿对多种药物治疗以及双侧星状神经节切除术均难以治疗.病人的新变种,p.F1760C-SCN5A,涉及Nav1.5局部麻醉结合域的关键残基。
    目的:使用TSA-201和患者特异性诱导的多能干细胞衍生的心肌细胞(iPSC-CMs)对p.F1760C-SCN5A变体进行功能表征。
    方法:使用全细胞膜片钳评估p.F1760C-SCN5A与利多卡因(Lido)相关的钠电流,氟卡尼(Flec),TSA-201细胞中的苯妥英(PHT)。产生p.F1760C-SCN5A和CRISPR-Cas9变体校正的等基因对照(IC)iPSC-CM。使用荧光电压染料测量有/没有美西律或PHT的动作电位持续时间(APD)。
    结果:与野生型(WT)细胞(-86.3±0.9mV;p<0.0001)相比,在F1760C细胞(-72.2±0.7mV)中,失活的V1/2显著右移,导致窗口电流显著增加。F1760C将钠延迟电流从WT中的峰的0.18±0.04%增加2倍至F1760C中的峰的0.49±0.07%(p=0.0005)。F1760CiPSC-CM(601±4ms)与ICiPSC-CM(423±15ms;p<0.0001)相比,基线APD至90%复极化(APD90)显著增加。同时,用10μM美西律治疗4小时未能缩短APD90,用5μMPHT治疗可显着降低F1760CiPSC-CM的APD90(453±6ms;p<0.0001)。
    结论:苯妥英拯救了一种新型p.F1760C-SCN5A变体的电生理表型和APD。抗癫痫药,苯妥英,可能是治疗LQT3的有效替代疗法,特别是对于破坏利多卡因/美西律结合位点的变体。
    Pathogenic variants in the SCN5A-encoded Nav1.5 sodium channel cause type 3 long QT syndrome (LQT3). We present the case of an infant with severe LQT3 who was refractory to multiple pharmacologic therapies as well as bilateral stellate ganglionectomy. The patient\'s novel variant, p.F1760C-SCN5A, involves a critical residue of the Nav1.5\'s local anesthetic binding domain.
    The purpose of this study was to characterize functionally the p.F1760C-SCN5A variant using TSA-201 and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
    Whole-cell patch clamp was used to assess p.F1760C-SCN5A associated sodium currents with/without lidocaine (Lido), flecainide, and phenytoin (PHT) in TSA-201 cells. p.F1760C-SCN5A and CRISPR-Cas9 variant-corrected isogenic control (IC) iPSC-CMs were generated. FluoVolt voltage dye was used to measure the action potential duration (APD) with/without mexiletine or PHT.
    V1/2 of inactivation was right-shifted significantly in F1760C cells (-72.2 ± 0.7 mV) compared to wild-type (WT) cells (-86.3 ± 0.9 mV; P <.0001) resulting in a marked increase in window current. F1760C increased sodium late current 2-fold from 0.18% ± 0.04% of peak in WT to 0.49% ± 0.07% of peak in F1760C (P = .0005). Baseline APD to 90% repolarization (APD90) was increased markedly in F1760C iPSC-CMs (601 ± 4 ms) compared to IC iPSC-CMs (423 ± 15 ms; P <.0001). However, 4-hour treatment with 10 μM mexiletine failed to shorten APD90, and treatment with 5μM PHT significantly decreased APD90 of F1760C iPSC-CMs (453 ± 6 ms; P <.0001).
    PHT rescued electrophysiological phenotype and APD of a novel p.F1760C-SCN5A variant. The antiepileptic drug PHT may be an effective alternative therapeutic for the treatment of LQT3, especially for variants that disrupt the Lido/mexiletine binding site.
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  • 文章类型: Journal Article
    非营养不良性肌张力障碍是由SCN4A基因中的功能获得突变或CLCN1基因中的功能丧失突变引起的罕见的肌肉兴奋过度障碍。临床上,它们的特点是肌强直,定义为自愿收缩后延迟的肌肉松弛,导致肌肉僵硬的症状,疼痛,疲劳,和弱点。诊断基于病史和检查结果,肌电图上存在肌电强直,和遗传确认。在没有遗传确认的情况下,详细的电生理测试支持诊断,排除其他相关疾病,并分析不确定意义的变体(如果存在)。钠通道阻滞剂对症治疗,比如美西律,通常是管理的第一步,以及教育患者潜在的麻醉并发症。
    The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications.
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