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Scientific Reports May 2021Enhancement of the late Na current (I) increases arrhythmia propensity in the heart, while suppression of the current is antiarrhythmic. GS967 is an agent considered as...
Enhancement of the late Na current (I) increases arrhythmia propensity in the heart, while suppression of the current is antiarrhythmic. GS967 is an agent considered as a selective blocker of I. In the present study, effects of GS967 on I and action potential (AP) morphology were studied in canine ventricular myocytes by using conventional voltage clamp, action potential voltage clamp and sharp microelectrode techniques. The effects of GS967 (1 µM) were compared to those of the class I/B antiarrhythmic compound mexiletine (40 µM). Under conventional voltage clamp conditions, I was significantly suppressed by GS967 and mexiletine, causing 80.4 ± 2.2% and 59.1 ± 1.8% reduction of the densities of I measured at 50 ms of depolarization, and 79.0 ± 3.1% and 63.3 ± 2.7% reduction of the corresponding current integrals, respectively. Both drugs shifted the voltage dependence of the steady-state inactivation curve of I towards negative potentials. GS967 and mexiletine dissected inward I profiles under AP voltage clamp conditions having densities, measured at 50% of AP duration (APD), of -0.37 ± 0.07 and -0.28 ± 0.03 A/F, and current integrals of -56.7 ± 9.1 and -46.6 ± 5.5 mC/F, respectively. Drug effects on peak Na current (I) were assessed by recording the maximum velocity of AP upstroke (V) in multicellular preparations. The offset time constant was threefold faster for GS967 than mexiletine (110 ms versus 289 ms), while the onset of the rate-dependent block was slower in the case of GS967. Effects on beat-to-beat variability of APD was studied in isolated myocytes. Beat-to-beat variability was significantly decreased by both GS967 and mexiletine (reduction of 42.1 ± 6.5% and 24.6 ± 12.8%, respectively) while their shortening effect on APD was comparable. It is concluded that the electrophysiological effects of GS967 are similar to those of mexiletine, but with somewhat faster offset kinetics of V block. However, since GS967 depressed V and I at the same concentration, the current view that GS967 represents a new class of drugs that selectively block I has to be questioned and it is suggested that GS967 should be classified as a class I/B antiarrhythmic agent.
Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Dogs; Female; Heart; Heart Rate; Male; Mexiletine; Myocardium; Myocytes, Cardiac; Pyridines; Triazoles
PubMed: 33953276
DOI: 10.1038/s41598-021-88903-3 -
European Journal of Hospital Pharmacy :... Nov 2016Myotonia is found in a number of muscle diseases, including myotonic dystrophy and non-dystrophic myotonia. The resulting symptoms of myotonia can interfere with daily... (Review)
Review
INTRODUCTION
Myotonia is found in a number of muscle diseases, including myotonic dystrophy and non-dystrophic myotonia. The resulting symptoms of myotonia can interfere with daily activities such as walking or climbing the stairs. Due to the rarity of both these conditions, pharmacological treatment of myotonia is largely anecdotal and is led by specialist clinicians who tend to favour the use of mexiletine, a class 1b antiarrhythmic sodium antagonist.
OBJECTIVE
To identify and review randomised controlled trials in order to assess the efficacy and safety of use of mexiletine in myotonic dystrophy and non-dystrophic myotonia for two different patient cases.
SEARCH METHODS
The literature search was conducted using MEDLINE, EMBASE and The Cochrane Library (from January 1990 to December 2014). Specialist neurology centres were also contacted.
SELECTION CRITERIA
All randomised controlled trials between January 1990 and December 2014 which compared the use of mexiletine for the treatment of myotonia in patients who suffer from myotonic dystrophy and non-dystrophic were included in this review. Primary outcome: reduction of clinical myotonia.
RESULTS
Two randomised controlled trials were included for review. Both studies are underpowered; however, there is evidence to support the use of mexiletine for the improvement of clinical myotonia.
CONCLUSIONS
Larger randomised controlled trials are required, which look at the functional effect of myotonia as a primary outcome (ie, stair test) and the long-term use of mexiletine. This is needed to establish the ongoing efficacy and safety of the long-term use of mexiletine in the management of myotonia.
PubMed: 31156883
DOI: 10.1136/ejhpharm-2015-000839 -
Clinical Cardiology May 1990Mexiletine is a Class IB antiarrhythmic which has basic and clinical electrophysiologic properties similar to lidocaine. Like other Class I antiarrhythmic agents,... (Review)
Review
Mexiletine is a Class IB antiarrhythmic which has basic and clinical electrophysiologic properties similar to lidocaine. Like other Class I antiarrhythmic agents, mexiletine blocks the rapid inward sodium current responsible for phase 0 of the action potential. It has been noted in the clinical electrophysiology laboratory to have minimal effect on sinus node function and AV nodal and His-Purkinje system conduction. Pharmacokinetic studies have shown that oral absorption is rapid with bioavailability of 80-90%. Mexiletine is predominantly metabolized by the liver with elimination half-life of 9 to 12 hours. The antiarrhythmic effects of the primary drug's metabolites remain to be defined. Hemodynamic studies have shown mexiletine to have a lesser negative inotropic effect than procainamide or disopyramide. Although mexiletine as a single agent successfully suppresses 60 to 80% of spontaneous ventricular arrhythmias, it has lower efficacy in suppression of induced ventricular arrhythmias. Multiple studies have shown that as monotherapy mexiletine is effective in preventing the induction of ventricular tachycardia in approximately 20% of patients. When used in combination with a Class IA antiarrhythmic drug for suppression of induced ventricular arrhythmias, multiple investigators have reported greater efficacy. Neurological side effects (tremor, dizziness, memory loss) occur in approximately 10% of patients while gastrointestinal side effects (nausea, anorexia, gastric irritation) occur in up to 40% of patients. Proarrhythmia or other serious toxicity from the drug is uncommon.
Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Drug Therapy, Combination; Hemodynamics; Humans; Mexiletine
PubMed: 2189614
DOI: 10.1002/clc.4960130509 -
British Journal of Anaesthesia Jul 1979
Review
Topics: Adrenergic beta-Antagonists; Anesthetics; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Disopyramide; Dogs; Humans; Intraoperative Complications; Lidocaine; Mexiletine; Phenytoin; Procainamide; Succinylcholine
PubMed: 45077
DOI: 10.1093/bja/51.7.659 -
Journal of the American Heart... May 2017Although atrial fibrillation (AF) is the most common abnormal heart rhythm and its prevalence continues to rise, there is a marked paucity of effective and safe...
BACKGROUND
Although atrial fibrillation (AF) is the most common abnormal heart rhythm and its prevalence continues to rise, there is a marked paucity of effective and safe antiarrhythmic drugs for AF. This study was done to test whether combined use of dofetilide and mexiletine exhibits not only a synergistic effect on AF suppression but also a safer profile in drug-induced ventricular proarrhythmias.
METHODS AND RESULTS
The effects of dofetilide plus mexiletine on atrial effective refractory period (ERP), AF inducibility, QT, and QT-related ventricular arrhythmias were studied using the isolated arterially perfused rabbit atrial and ventricular wedge preparations. Dofetilide or mexiletine alone mildly to moderately prolonged atrial ERP, but their combined use produced a markedly rate-dependent increase in atrial ERP. Dofetilide (3 nmol/L) plus mexiletine (10 μmol/L) increased the ERP by 28.2% from 72.2±5.7 to 92.8±5.9 ms (n=9, <0.01) at a pacing rate of 0.5 Hz and by 94.5% from 91.7±5.2 to 178.3±12.0 ms (n=9, <0.01) at 3.3 Hz. Dofetilide plus mexiletine strongly suppressed AF inducibility. On the other hand, dofetilide at 10 nmol/L produced marked QT and T prolongation, steeper QT-BCL and T-BCL slopes, and induced early afterdepolarizations and torsade de pointes in the ventricular wedges. Mexiletine at 10 μmol/L reduced dofetilide-induced QT and T prolongation, QT-BCL and T-BCL slopes, and abolished early afterdepolarizations and torsade de pointes.
CONCLUSIONS
In rabbits, combined use of dofetilide and mexiletine not only synergistically increases atrial ERP and effectively suppresses AF inducibility, but also markedly reduces QT liability and torsade de pointes risk posed by dofetilide alone.
Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Drug Synergism; Drug Therapy, Combination; Female; Heart Atria; Heart Rate; Heart Ventricles; In Vitro Techniques; Long QT Syndrome; Male; Mexiletine; Phenethylamines; Rabbits; Refractory Period, Electrophysiological; Risk Assessment; Sulfonamides; Time Factors; Torsades de Pointes
PubMed: 28522677
DOI: 10.1161/JAHA.117.005482 -
Kardiologia Polska 2017Antiarrhythmic treatment of patients with recurrent ventricular tachyarrhythmia, in whom catheter ablation and amiodarone treatment were ineffective or contraindicated,...
BACKGROUND
Antiarrhythmic treatment of patients with recurrent ventricular tachyarrhythmia, in whom catheter ablation and amiodarone treatment were ineffective or contraindicated, is an unsolved clinical problem.
AIM
The study aims to evaluate the efficacy and tolerability of mexiletine in patients with recurrent ventricular tachyarrhythmias and/or electrical storm events, in whom standard treatment strategies failed to prevent ventricular tachyarrhythmia.
METHODS
We performed a retrospective cohort analysis of all patients treated with mexiletine for recurrent ventricular tachycardia and/or ventricular fibrillation in our institution between January 2011 and September 2015. The primary endpoints were total number of electrical storm events and ventricular tachycardia/ventricular fibrillation (VT/VF) episodes after the beginning of mexiletine therapy. Secondary endpoints were total number of implantable cardioverter-defibrillator (ICD) therapies and discontinuation of the therapy. Events were compared with a matched duration period before initiating mexiletine. Patients served as self-controls.
RESULTS
Seventeen patients were included in the study; 11 patients were males. Mean age was 64.2 ± 15.4 years. The median time of mexiletine treatment was eight months (interquartile range [IR]: 1-22 months). The mexiletine dose was 600 mg/day in 13 patients and 400 mg/day in four patients. In four patients the dose was modified during treatment in a range from 400 to 600 mg/day depending on clinical decision. Treatment with mexiletine significantly reduced the number of electrical storm events (14 episodes vs. two episodes; median and IR for 17 patients: 1 [0-1] vs. 0 [0-0], p = 0.0010), VT/VF episodes (285 vs. 74 episodes; median and IR for 17 patients: 7 [5-27] vs. 0 [0-5], p = 0.0115), and ICD interventions (317 interven-tions vs. nine interventions; median and IR for 17 patients: 10 [5-25] vs. 0 [0-2], p = 0.0006), in comparison with a matched period before initiation of treatment. In 14 out of 17 patients (82%) sufficient tolerability of mexiletine was observed. Only in three (18%) patients severe side effects of mexiletine treatment occurred requiring discontinuation of therapy.
CONCLUSIONS
Mexiletine was a sufficiently tolerated antiarrhythmic drug in short-term treatment of ventricular tachyarrhyth-mias in the studied population. Mexiletine may be effective in the treatment of recurring ventricular tachyarrhythmias or electrical storm events.
Topics: Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Combined Modality Therapy; Defibrillators, Implantable; Drug Tolerance; Humans; Male; Mexiletine; Middle Aged; Recurrence; Retrospective Studies; Treatment Outcome; Ventricular Fibrillation
PubMed: 29057449
DOI: 10.5603/KP.2017.0189 -
Neuromuscular Disorders : NMD Nov 2021The MYOMEX study was a multicentre, randomised, double-blind, placebo-controlled, cross-over study aimed to compare the effects of mexiletine vs. placebo in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
The MYOMEX study was a multicentre, randomised, double-blind, placebo-controlled, cross-over study aimed to compare the effects of mexiletine vs. placebo in patients with myotonia congenita (MC) and paramyotonia congenita (PC). The primary endpoint was the self-reported score of stiffness severity on a 100 mm visual analogic scale (VAS). Mexiletine treatment started at 200 mg/day and was up-titrated by 200 mg increment each three days to reach a maximum dose of 600 mg/day for total treatment duration of 18 days for each cross-over period. The modified intent-to-treat population included 25 patients (13 with MC and 12 with PC; mean age, 43.0 years; male, 68.0%). The median VAS score for mexiletine was 71.0 at baseline and decreased to 16.0 at the end of the treatment while the score did not change for placebo (81.0 at baseline vs. 78.0 at end of treatment). A mixed effects linear model analysis on ranked absolute changes showed a significant effect of treatment (p < 0.001). The overall score of the Individualized Neuromuscular Quality of Life questionnaire (INQoL) was significantly improved (p < 0.001). No clinically significant adverse events were reported. In conclusion, mexiletine improved stiffness and quality of life in patients with nondystrophic myotonia and was well tolerated.
Topics: Adult; Aged; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Mexiletine; Middle Aged; Myotonia; Myotonia Congenita; Myotonic Disorders; Quality of Life; Treatment Outcome
PubMed: 34702654
DOI: 10.1016/j.nmd.2021.06.010 -
Palliative Medicine Dec 2017Rectal tenesmus is a distressing symptom in patients with advanced cancer and challenging to treat. There is lack of consensus on the appropriate management of tenesmus... (Review)
Review
BACKGROUND
Rectal tenesmus is a distressing symptom in patients with advanced cancer and challenging to treat. There is lack of consensus on the appropriate management of tenesmus in this patient population.
AIM
To identify and examine the effectiveness of interventions to palliate rectal tenesmus caused by advanced cancer when surgery, radiotherapy or chemotherapy are no longer treatment options.
DESIGN
A systematic review of the literature following standard systematic review methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance.
DATA SOURCES
A comprehensive search of the electronic databases MEDLINE, EMBASE and the Cochrane Library was conducted from date of inception to April 2016. PubMed 'related articles' search, grey literature search and hand-searches of the bibliographies of relevant papers and textbooks were also performed. Non-cancer patients were excluded. Any studies involving surgery or radiotherapy to treat tenesmus were excluded. Studies involving interventions to treat pelvic pain syndromes without specific outcome measures on severity of tenesmus were excluded. The quality of the studies was assessed using a National Institute for Health and Clinical Excellence-recommended quality assessment tool.
RESULTS
From 861 studies, 9 met full criteria and were selected. All were case series investigating the use of pharmacological interventions (diltiazem, nifedipine, methadone, mexiletine hydrochloride, lidocaine and bupivacaine), anaesthetic interventions (lumbar sympathectomy, neurolytic superior hypogastric plexus block), and endoscopic laser interventions. The included studies showed substantial heterogeneity, and therefore, a meta-analysis was not feasible.
CONCLUSION
From this review, we identified a significant gap in research into the palliation of rectal tenesmus. A multimodal approach may be necessary due to the complexity of the pathophysiology of tenesmus. Future research should focus on randomised controlled trials of drug therapies whose potential effectiveness is suggested by case series.
Topics: Anesthesia; Anesthetics; Calcium Channel Blockers; Humans; Laser Therapy; Neoplasms; Palliative Care; Rectal Diseases
PubMed: 28590211
DOI: 10.1177/0269216317697897 -
Channels (Austin, Tex.) Dec 2021: Mutations in SCN5A that decrease Na current underlie arrhythmia syndromes such as the Brugada syndrome (BrS). in humans has two splice variants, one lacking a...
Expression defect of the rare variant/Brugada mutation R1512W depends upon the SCN5A splice variant background and can be rescued by mexiletine and the common polymorphism H558R.
: Mutations in SCN5A that decrease Na current underlie arrhythmia syndromes such as the Brugada syndrome (BrS). in humans has two splice variants, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077. We investigated the effect of splice variant background on loss-of-function and rescue for R1512W, a mutation reported to cause BrS. : We made the mutation in both variants and expressed them in HEK-293 cells for voltage-clamp study. After 24 hours of transfection, the current expression level of R1512W was reduced by ~50% in both Q1077del and Q1077 compared to the wild-type (WT) channel, respectively. The activation and inactivation midpoint were not different between WT and mutant channels in both splice variant backgrounds. However, slower time constants of recovery and enhanced intermediate inactivation were observed for R1512W/Q1077 compared with WT-Q1077, while the recovery and intermediate inactivation parameters of R1512W/Q1077del were similar to WT-Q1077del. Furthermore, both mexiletine and the common polymorphism H558R restored peak sodium current () amplitude of the mutant channel by increasing the cell surface expression of SCN5A. : These findings provide further evidence that the splice variant affects the molecular phenotype with implications for the clinical phenotype, and they provide insight into the expression defect mechanisms and potential treatment in BrS.
Topics: HEK293 Cells; Humans; Mexiletine; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Phenotype; Sodium
PubMed: 33535892
DOI: 10.1080/19336950.2021.1875645 -
Europace : European Pacing,... Jun 2023SCN5A mutations are associated with various cardiac phenotypes, including long QT syndrome type 3 (LQT3), Brugada syndrome (BrS), and cardiac conduction disease (CCD)....
AIMS
SCN5A mutations are associated with various cardiac phenotypes, including long QT syndrome type 3 (LQT3), Brugada syndrome (BrS), and cardiac conduction disease (CCD). Certain mutations, such as SCN5A-1795insD, lead to an overlap syndrome, with patients exhibiting both features of BrS/CCD [decreased sodium current (INa)] and LQT3 (increased late INa). The sodium channel blocker mexiletine may acutely decrease LQT3-associated late INa and chronically increase peak INa associated with SCN5A loss-of-function mutations. However, most studies have so far employed heterologous expression systems and high mexiletine concentrations. We here investigated the effects of a therapeutic dose of mexiletine on the mixed phenotype associated with the SCN5A-1795insD mutation in HEK293A cells and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
METHODS AND RESULTS
To assess only the chronic effects on trafficking, HEK293A cells transfected with wild-type (WT) SCN5A or SCN5A-1795insD were incubated for 48 h with 10 µm mexiletine followed by wash-out, which resulted in an increased peak INa for both SCN5A-WT and SCN5A-1795insD and an increased late INa for SCN5A-1795insD. Acute re-exposure of HEK293A cells to 10 µm mexiletine did not impact on peak INa but significantly decreased SCN5A-1795insD late INa. Chronic incubation of SCN5A-1795insD hiPSC-CMs with mexiletine followed by wash-out increased peak INa, action potential (AP) upstroke velocity, and AP duration. Acute re-exposure did not impact on peak INa or AP upstroke velocity, but significantly decreased AP duration.
CONCLUSION
These findings demonstrate for the first time the therapeutic benefit of mexiletine in a human cardiomyocyte model of SCN5A overlap syndrome.
Topics: Humans; Mexiletine; Cardiac Conduction System Disease; NAV1.5 Voltage-Gated Sodium Channel; Long QT Syndrome; Brugada Syndrome; Action Potentials; Myocytes, Cardiac
PubMed: 37369559
DOI: 10.1093/europace/euad154