-
Pacing and Clinical Electrophysiology :... Nov 2023Mexiletine, a class Ib antiarrhythmic drug, exhibits its major antiarrhythmic effect via inhibition of the fast and late Na currents in myocardial tissues that are... (Review)
Review
Mexiletine, a class Ib antiarrhythmic drug, exhibits its major antiarrhythmic effect via inhibition of the fast and late Na currents in myocardial tissues that are dependent on the opening of Na channels for their excitation. Through a comprehensive examination of mexiletine's therapeutic benefits and potential risks, we aim to provide valuable insights that reinforce its role as a vital therapeutic option for patients with ventricular arrhythmias, long QT syndrome, and other heart rhythm disorders. This review will highlight the current understandings of the antiarrhythmic effects and rationales for recent off-label use and address the mortality and proarrhythmic effects of mexiletine utilizing published basic and clinical studies over the past five decades.
Topics: Humans; Anti-Arrhythmia Agents; Mexiletine; Arrhythmias, Cardiac; Long QT Syndrome; Myocardium
PubMed: 37846818
DOI: 10.1111/pace.14846 -
Pediatric Cardiology Dec 2023The autosomal recessive (AR) form of Long QT Syndrome (LQTS) is described both associated with deafness known as Jervell and Lange-Nielsen (JLN) syndrome, and without...
The autosomal recessive (AR) form of Long QT Syndrome (LQTS) is described both associated with deafness known as Jervell and Lange-Nielsen (JLN) syndrome, and without deafness (WD). The aim of the study is to report the characteristics of AR LQTS patients and the efficacy of the therapy. Data of all children with AR LQTS referred to the Bambino Gesù Children's Hospital IRCCS from September 2012 to September 2021were included. Three (30%) patients had compound heterozygosity and 7 (70%) had homozygous variants of the KCNQ1 gene, the latter showing deafness. Four patients (40%) presented aborted sudden cardiac death (aSCD): three with previous episodes of syncope (75%), the other without previous symptoms (16.6% of asymptomatic patients). An episode of aSCD occurred in 2/3 (66.7%) of WD and heterozygous patients, while in 2/7 (28%) JLN and homozygous patients and in 2/2 patients with QTC > 600 ms. All patients were treated with Nadolol. In 5 Mexiletine was added, shortening QTc and obtaining the disappearance of the T-wave alternance (TWA) in 3/3. Episodes of aSCD seem to be more frequent in LQTS patients with compound heterozygous variants and WD than in those with JLN and homozygous variants. Episodes of aSCD also appear more frequent in children with syncope or with QTc value > 600 ms, even on beta-blocker therapy, than in patients without syncope or with Qtc < 600 ms. However, our descriptive results should be confirmed by larger studies. Moreover, Mexiletine addition reduced QTc value and eliminated TWA.
Topics: Child; Humans; KCNQ1 Potassium Channel; Mexiletine; Long QT Syndrome; Jervell-Lange Nielsen Syndrome; Syncope; Heart Arrest; Deafness
PubMed: 37597120
DOI: 10.1007/s00246-023-03266-y -
Clinical Research in Cardiology :... Jun 2024Despite impressive developments in the field of ventricular arrhythmias, there is still a relevant number of patients with ventricular arrhythmias who require... (Review)
Review
Despite impressive developments in the field of ventricular arrhythmias, there is still a relevant number of patients with ventricular arrhythmias who require antiarrhythmic drug therapy and may, e.g., in otherwise drug and/or ablation refractory situations, benefit from agents known for decades, such as mexiletine. Through its capability of blocking fast sodium channels in cardiomyocytes, it has played a minor to moderate antiarrhythmic role throughout the recent decades. Nevertheless, certain patients with structural heart disease suffering from drug-refractory, i.e., mainly amiodarone refractory ventricular arrhythmias, as well as those with selected forms of congenital long QT syndrome (LQTS) may nowadays still benefit from mexiletine. Here, we outline mexiletine's cellular and clinical electrophysiological properties. In addition, the application of mexiletine may be accompanied by various potential side effects, e.g., nausea and tremor, and is limited by several drug-drug interactions. Thus, we shed light on the current therapeutic role of mexiletine for therapy of ventricular arrhythmias and discuss clinically relevant aspects of its indications based on current evidence.
Topics: Mexiletine; Humans; Anti-Arrhythmia Agents; Tachycardia, Ventricular; Treatment Outcome
PubMed: 38353682
DOI: 10.1007/s00392-024-02383-9 -
Archives of Cardiovascular Diseases 2024In France, mexiletine - a class I antiarrhythmic drug - can be prescribed for the symptomatic treatment of myotonia of the skeletal muscles in adult patients with... (Review)
Review
In France, mexiletine - a class I antiarrhythmic drug - can be prescribed for the symptomatic treatment of myotonia of the skeletal muscles in adult patients with myotonic dystrophy under a compassionate use programme. Mexiletine is used according to its summary of product characteristics, which describes its use for myotonia treatment in adult patients with non-dystrophic myotonia, a different neuromuscular condition without cardiac involvement. A cardiac assessment is required prior to initiation and throughout treatment due to potential proarrhythmic effects. The presence of conduction system disease, the most common cardiac manifestation of myotonic dystrophy, mandates repeated cardiac evaluations in patients with this condition, and becomes even more important when they are given mexiletine. A group of experts, including three neurologists and five cardiologists from French neuromuscular reference centres, were involved in a task force to develop a treatment algorithm to guide mexiletine use in myotonic dystrophy. The recommendations are based on data from a literature review of the safety of mexiletine-treated patients with myotonic dystrophy, the compassionate use protocol for mexiletine and the personal clinical experience of the experts. The main conclusion of the expert group is that, although existing safety data in mexiletine-treated patients with myotonic dystrophy are reassuring, cardiac assessments should be reinforced in such patients compared with mexiletine-treated patients with non-dystrophic myotonia. This expert opinion to guide mexiletine treatment in patients with myotonic dystrophy should help to reduce the risk of severe adverse events and facilitate interactions between specialists involved in the routine care of patients with myotonic dystrophy.
Topics: Adult; Humans; Algorithms; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Decision-Making; Compassionate Use Trials; Consensus; France; Mexiletine; Myotonic Dystrophy; Risk Assessment; Risk Factors; Treatment Outcome; Voltage-Gated Sodium Channel Blockers
PubMed: 38677940
DOI: 10.1016/j.acvd.2024.03.001 -
Neurological Sciences : Official... Feb 2024The rare nature of dystrophic and non-dystrophic myotonia has limited the available evidence on the efficacy of mexiletine as a potential treatment. To address this gap,...
BACKGROUND
The rare nature of dystrophic and non-dystrophic myotonia has limited the available evidence on the efficacy of mexiletine as a potential treatment. To address this gap, we conducted a systematic review and meta-analysis to evaluate the effectiveness and safety of mexiletine for both dystrophic and non-dystrophic myotonic patients.
METHODS
The search was conducted on various electronic databases up to March 2023, for randomized clinical trials (RCTs) comparing mexiletine versus placebo in myotonic patients. A risk of bias assessment was carried out, and relevant data was extracted manually into an online sheet. RevMan software (version 5.4) was employed for analysis.
RESULTS
A total of five studies, comprising 186 patients, were included in the meta-analysis. Our findings showed that mexiletine was significantly more effective than placebo in improving stiffness score (SMD = - 1.19, 95% CI [- 1.53, - 0.85]), as well as in reducing hand grip myotonia (MD = - 1.36 s, 95% CI [- 1.83, - 0.89]). Mexiletine also significantly improved SF-36 Physical and Mental Component Score in patients with non-dystrophic myotonia only. Regarding safety, mexiletine did not significantly alter ECG parameters but was associated with greater gastrointestinal symptoms (GIT) compared to placebo (RR 3.7, 95% CI [1.79, 7.64]). Other adverse events showed no significant differences.
CONCLUSION
The results support that mexiletine is effective and safe in myotonic patients; however, it is associated with a higher risk of GIT symptoms. Due to the scarcity of published RCTs and the prevalence of GIT symptoms, we recommend further well-designed RCTs testing various drug combinations to reduce GIT symptoms.
PubMed: 38403671
DOI: 10.1007/s10072-024-07412-z -
Frontiers in Pharmacology 2024Na1.4 is a voltage-gated sodium channel subtype that is predominantly expressed in skeletal muscle cells. It is essential for producing action potentials and stimulating... (Review)
Review
Na1.4 is a voltage-gated sodium channel subtype that is predominantly expressed in skeletal muscle cells. It is essential for producing action potentials and stimulating muscle contraction, and mutations in Na1.4 can cause various muscle disorders. The discovery of the cryo-EM structure of Na1.4 in complex with β1 has opened new possibilities for designing drugs and toxins that target Na1.4. In this review, we summarize the current understanding of channelopathies, the binding sites and functions of chemicals including medicine and toxins that interact with Na1.4. These substances could be considered novel candidate compounds or tools to develop more potent and selective drugs targeting Na1.4. Therefore, studying Na1.4 pharmacology is both theoretically and practically meaningful.
PubMed: 38725668
DOI: 10.3389/fphar.2024.1378315 -
Circulation Journal : Official Journal... Nov 2023Cardiac calmodulinopathy, characterized by a life-threatening arrhythmia and sudden death in the young, is extremely rare and caused by genes encoding calmodulin, namely...
BACKGROUND
Cardiac calmodulinopathy, characterized by a life-threatening arrhythmia and sudden death in the young, is extremely rare and caused by genes encoding calmodulin, namely calmodulin 1 (CALM1), CALM2, and CALM3.Methods and Results: We screened 195 symptomatic children (age 0-12 years) who were suspected of inherited arrhythmias for 48 candidate genes, using a next-generation sequencer. Ten probands were identified as carrying variants in any of CALM1-3 (5%; median age 5 years), who were initially diagnosed with long QT syndrome (LQTS; n=5), catecholaminergic polymorphic ventricular tachycardia (CPVT; n=3), and overlap syndrome (n=2). Two probands harbored a CALM1 variant and 8 probands harbored 6 CALM2 variants. There were 4 clinical phenotypes: (1) documented lethal arrhythmic events (LAEs): 4 carriers of N98S in CALM1 or CALM2; (2) suspected LAEs: CALM2 p.D96G and D132G carriers experienced syncope and transient cardiopulmonary arrest under emotional stimulation; (3) critical cardiac complication: CALM2 p.D96V and p.E141K carriers showed severe cardiac dysfunction with QTc prolongation; and (4) neurological and developmental disorders: 2 carriers of CALM2 p.E46K showed cardiac phenotypes of CPVT. Beta-blocker therapy was effective in all cases except cardiac dysfunction, especially in combination with flecainide (CPVT-like phenotype) and mexiletine (LQTS-like).
CONCLUSIONS
Calmodulinopathy patients presented severe cardiac features, and their onset of LAEs was earlier in life, requiring diagnosis and treatment at the earliest age possible.
Topics: Child; Child, Preschool; Humans; Infant; Infant, Newborn; Arrhythmias, Cardiac; Calmodulin; East Asian People; Long QT Syndrome; Phenotype; Tachycardia, Ventricular; Death, Sudden, Cardiac
PubMed: 37380439
DOI: 10.1253/circj.CJ-23-0195