-
Expert Opinion on Pharmacotherapy 2023Mexiletine is a class IB sodium-channel blocker. Unlike class IA or IC antiarrhythmic drugs, mexiletine rather shortens than prolongs action potential duration;...
INTRODUCTION
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.
AREAS COVERED
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.
EXPERT OPINION
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.
Topics: Humans; Mexiletine; Anti-Arrhythmia Agents; Sodium Channel Blockers; Tachycardia, Ventricular; Arrhythmias, Cardiac
PubMed: 37306465
DOI: 10.1080/14656566.2023.2223964 -
Cureus Sep 2020Mirogabalin is a novel ligand for the α2δ subunit of voltage-gated calcium channels and is used to treat neuropathic pain in a similar manner to pregabalin. Although...
Mirogabalin is a novel ligand for the α2δ subunit of voltage-gated calcium channels and is used to treat neuropathic pain in a similar manner to pregabalin. Although the frequency of pregabalin-induced neutropenia has been reported as 0.3%-1%, mirogabalin-induced neutropenia has not previously been reported in the literature. Herein, we report what we believe is the first case of neutropenia induced by mirogabalin. A 77-year-old woman with squamous cell carcinoma of the lung had been taking mirogabalin at 10 mg/day for six weeks prior to admission to our hospital. She had received two courses of chemotherapy with carboplatin and nanoparticle albumin-bound (nab)-paclitaxel for lung cancer until four months before admission, followed by two courses of nivolumab until one month before admission. The patient was hospitalized for urinary tract infection (UTI), which improved with oral amoxicillin/clavulanic acid at 500/125 mg three times daily for five days (until the fifth hospital day). After that, she underwent rehabilitation to improve muscle strength. During rehabilitation, neutropenia (1,278/µL) was noted, acetaminophen and mexiletine were ceased, and filgrastim was started on hospital day 17. The neutrophil count was 755/µL on hospital day 18. Mirogabalin was discontinued on hospital day 19. The neutrophil count fell to 320/µL and 118/µL on hospital day 20 and day 21, respectively, and recovered to 1,064/µL on hospital day 24. Acetaminophen and mexiletine were resumed on hospital day 31 and neutropenia has not recurred since.
PubMed: 33029462
DOI: 10.7759/cureus.10182 -
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 -
Europace : European Pacing,... Aug 2018Experimental studies and clinical reports suggest antiarrhythmic properties of mexiletine in different arrhythmias. We aimed at investigating mexiletine in experimental... (Comparative Study)
Comparative Study
AIMS
Experimental studies and clinical reports suggest antiarrhythmic properties of mexiletine in different arrhythmias. We aimed at investigating mexiletine in experimental models of atrial fibrillation (AF) as well as in long-QT- (LQTS) and short-QT-syndrome (SQTS).
METHODS AND RESULTS
In 15 isolated rabbit hearts, erythromycin (300 µM) was infused for simulation of long-QT-2-syndrome. In further 13 hearts, veratridine was administered to simulate long-QT-3-syndrome. Both drugs induced a significant QT-prolongation (erythromycin: +87 ms, P < 0.01; veratridine: +19 ms, P < 0.05) and increased dispersion of repolarization (erythromycin: +55 ms, P < 0.01; veratridine +31 ms, P < 0.01). Additional infusion of mexiletine (25 µM) resulted in a significant reduction of dispersion (erythromycin: -43 ms, P < 0.01; veratridine: -26 ms, P < 0.05). Reproducible induction of torsade de pointes was observed in 13 of 15 erythromycin-treated hearts (192 episodes) and 6 of 13 veratridine-treated hearts (36 episodes). Additional infusion of mexiletine significantly reduced ventricular tachycardia (VT) incidence. With mexiletine, only 3 of 15 erythromycin-treated hearts (27 episodes) and 1 of 13 veratridine-treated hearts (2 episodes) presented polymorphic VT. In additional 9 hearts, the IK-ATP-channel-opener pinacidil was employed to simulate SQTS and significantly abbreviated ventricular repolarization (QT-interval: -18 ms, P < 0.05) and enhanced induction of ventricular fibrillation (VF). Mexiletine reversed the effects of pinacidil, increase refractory period (+127 ms, P < 0.01) and significantly suppressed induction of VF. In further 13 hearts AF was induced by combined treatment with acetylcholine/isoproterenol. Mexiletine also increased atrial refractory period (+80 ms, P < 0.01) and thereby effectively suppressed atrial fibrillation.
CONCLUSION
Acute infusion of mexiletine significantly reduced the occurrence of polymorphic VT in the presence of pharmacologically simulated LQTS. Furthermore, mexiletine demonstrated potent antiarrhythmic properties in a model of SQTS and in AF.
Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Disease Models, Animal; Heart Conduction System; Heart Rate; Isolated Heart Preparation; Long QT Syndrome; Mexiletine; Rabbits; Tachycardia, Ventricular; Time Factors
PubMed: 29016765
DOI: 10.1093/europace/eux221 -
Journal of Medicinal Chemistry May 2021Ventricular cardiac arrhythmia (VA) arises in acquired or congenital heart disease. Long QT syndrome type-3 (LQT3) is a congenital form of VA caused by cardiac sodium...
Ventricular cardiac arrhythmia (VA) arises in acquired or congenital heart disease. Long QT syndrome type-3 (LQT3) is a congenital form of VA caused by cardiac sodium channel (I) SCN5A mutations that prolongs cardiac action potential (AP) and enhances I current. Mexiletine inhibits I and shortens the QT interval in LQT3 patients. Above therapeutic doses, mexiletine prolongs the cardiac AP. We explored structure-activity relationships (SAR) for AP shortening and prolongation using dynamic medicinal chemistry and AP kinetics in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using patient-derived LQT3 and healthy hiPSC-CMs, we resolved distinct SAR for AP shortening and prolongation effects in mexiletine analogues and synthesized new analogues with enhanced potency and selectivity for I. This resulted in compounds with decreased AP prolongation effects, increased metabolic stability, increased I selectivity, and decreased avidity for the potassium channel. This study highlights using hiPSC-CMs to guide medicinal chemistry and "drug development in a dish".
Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Behavior, Animal; Cardiac Conduction System Disease; Cells, Cultured; Drug Design; Drug Stability; Half-Life; Humans; Induced Pluripotent Stem Cells; Long QT Syndrome; Male; Mexiletine; Mice; Mice, Inbred BALB C; Myocytes, Cardiac; NAV1.5 Voltage-Gated Sodium Channel; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship
PubMed: 33942619
DOI: 10.1021/acs.jmedchem.0c01545 -
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 -
CNS Drugs Sep 2014Pain is one of the most troublesome sequelae of stroke. Some of this post-stroke pain is caused by the brain lesion itself; this is called central post-stroke pain... (Review)
Review
Pain is one of the most troublesome sequelae of stroke. Some of this post-stroke pain is caused by the brain lesion itself; this is called central post-stroke pain (CPSP). Although the prevalence of CPSP is low (1-8 %), persistent, often treatment-resistant, painful sensations are a major problem for stroke patients. The pathogenesis of CPSP remains unknown, but suggested underlying causes include hyperexcitation in the damaged sensory pathways, damage to the central inhibitory pathways, or a combination of the two. For pharmacological treatment, amitriptyline, an adrenergic antidepressant, is currently the first-line drug for CPSP. However, its effect is frequently incomplete and a high dose is commonly not tolerated in stroke patients. Lamotrigine, an antiepileptic, was also found to be effective in a controlled trial and can be used as an alternative or additive therapy. GABAergic drugs with potential calcium channel-blocking effects, such as gabapentin or pregabalin, have recently emerged as a potentially useful therapy. These drugs are effective in various neuropathic pain syndromes, but their effect on CPSP remains to be proven. Pregabalin may improve pain-related anxiety and sleep disturbances. Fluvoxamine and mexiletine may be used adjunctively in some patients. Non-pharmacological treatments such as motor cortex stimulation or deep brain stimulation are used in some centers, but are not proven to be effective. Further well designed clinical trials as well as basic research should be performed to improve our understanding of the pathophysiology of CPSP and to develop better treatment strategies.
Topics: Animals; Humans; Pain; Pain Management; Stroke
PubMed: 25112542
DOI: 10.1007/s40263-014-0194-y -
Journal of Cardiovascular... Nov 2021β-Blockers are first-line therapy in patients with long QT syndrome (LQTS). However, β-blockers had genotype dependent efficacy (LQT1>LQT2>LQT3). Sodium channel... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
β-Blockers are first-line therapy in patients with long QT syndrome (LQTS). However, β-blockers had genotype dependent efficacy (LQT1>LQT2>LQT3). Sodium channel blockers have been recommended as add-on therapy for LQT3 patients. However, the pooled effect of sodium channel blockers in all LQTS patients remains unknown.
METHODS
We conducted a systematic electronic search of PubMed, Embase, and the Cochrane Library. Fixed effects model was used to assess the effect of sodium channel blockers on QTc, cardiac events (CEs), and the proportion of QTc ≥ 500 ms and QTc ≤ 460 ms in LQTS patients.
RESULTS
Pooled analysis of 14 studies with 213 LQTS (9 LQT1 + 63 LQT2 + 135 LQT3 + 6 others) patients showed that sodium channel blockers significantly shortened QTc by nearly 50 ms (mean difference [MD], -49.43; 95% confidence interval [CI], -57.80 to -41.05, p < .001), reduced the incidence of CEs (risk ratio [RR], 0.23; 95% CI, 0.11-0.47; p < .001) and the proportion of QTc ≥ 500 ms (RR, 0.33; 95% CI, 0.24-0.47; p < .001), and increased the proportion of QTc ≤ 460 ms (RR, 10.33; 95% CI, 4.62-23.09; p < .001). Sodium channel blockers significantly shortened QTc both in LQT3 and LQT2 patients, while the QTc shortening effect in LQT3 was superior to that in LQT2 (57.39 vs. 36.61 ms). Mexiletine, flecainide, and ranolazine all significantly shortened QTc, and the QTc shortening effect by mexiletine was the best (60.70 vs. 49.08 vs. 50.10 ms).
CONCLUSIONS
Sodium channel blockers can be useful both in LQT3 and LQT2 patients. Mexiletine, flecainide and ranolazine significantly shortened QTc in LQTS patients, and the QTc shortening effect by mexiletine was the best.
Topics: Adrenergic beta-Antagonists; Electrocardiography; Flecainide; Humans; Long QT Syndrome; Mexiletine; Ranolazine; Sodium Channel Blockers
PubMed: 34427958
DOI: 10.1111/jce.15223 -
The Cochrane Database of Systematic... Oct 2019Lidocaine, mexiletine, tocainide, and flecainide are local anesthetics which give an analgesic effect when administered orally or parenterally. Early reports described... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Lidocaine, mexiletine, tocainide, and flecainide are local anesthetics which give an analgesic effect when administered orally or parenterally. Early reports described the use of intravenous lidocaine or procaine to relieve cancer and postoperative pain. Interest reappeared decades later when patient series and clinical trials reported that parenteral lidocaine and its oral analogs tocainide, mexiletine, and flecainide relieved neuropathic pain in some patients. With the recent publication of clinical trials with high quality standards, we have reviewed the use of systemic lidocaine and its oral analogs in neuropathic pain to update our knowledge, to measure their benefit and harm, and to better define their role in therapy.
OBJECTIVES
To evaluate pain relief and adverse effect rates between systemic local anesthetic-type drugs and other control interventions.
SEARCH METHODS
We searched MEDLINE (1966 through 15 May 2004), EMBASE (January 1980 to December 2002), Cancer Lit (through 15 December 2002), Cochrane Central Register of Controlled Trials (2nd Quarter, 2004), System for Information on Grey Literature in Europe (SIGLE), and LILACS, from January 1966 through March 2001. We also hand searched conference proceedings, textbooks, original articles and reviews.
SELECTION CRITERIA
We included trials with random allocation, that were double blinded, with a parallel or crossover design. The control intervention was a placebo or an analgesic drug for neuropathic pain from any cause.
DATA COLLECTION AND ANALYSIS
We collected efficacy and safety data from all published and unpublished trials. We calculated combined effect sizes using continuous and binary data for pain relief and adverse effects as primary and secondary outcome measurements, respectively.
MAIN RESULTS
Thirty-two controlled clinical trials met the selection criteria; two were duplicate articles. The treatment drugs were intravenous lidocaine (16 trials), mexiletine (12 trials), lidocaine plus mexiletine sequentially (one trial), and tocainide (one trial). Twenty-one trials were crossover studies, and nine were parallel. Lidocaine and mexiletine were superior to placebo [weighted mean difference (WMD) = -11; 95% CI: -15 to -7; P < 0.00001], and limited data showed no difference in efficacy (WMD = -0.6; 95% CI: -7 to 6), or adverse effects versus carbamazepine, amantadine, gabapentin or morphine. In these trials, systemic local anesthetics were safe, with no deaths or life-threatening toxicities. Sensitivity analysis identified data distribution in three trials as a probable source of heterogeneity. There was no publication bias.
AUTHORS' CONCLUSIONS
Lidocaine and oral analogs were safe drugs in controlled clinical trials for neuropathic pain, were better than placebo, and were as effective as other analgesics. Future trials should enroll specific diseases and test novel lidocaine analogs with better toxicity profiles. More emphasis is necessary on outcomes measuring patient satisfaction to assess if statistically significant pain relief is clinically meaningful.
Topics: Administration, Cutaneous; Anesthesia, Local; Anesthetics, Local; Humans; Neuralgia; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 31684682
DOI: 10.1002/14651858.CD003345.pub2 -
Clinical and Translational Science Aug 2022Lamotrigine, approved for use as an antiseizure medication as well as the treatment of bipolar disorder, inhibits sodium channels in the brain to reduce repetitive...
Lamotrigine, approved for use as an antiseizure medication as well as the treatment of bipolar disorder, inhibits sodium channels in the brain to reduce repetitive neuronal firing and pathological release of glutamate. The shared homology of sodium channels and lack of selectivity associated with channel blocking agents can cause slowing of cardiac conduction and increased proarrhythmic potential. The Vaughan-Williams classification system differentiates sodium channel blockers using biophysical properties of binding. As such, Class Ib inhibitors, including mexiletine, do not slow cardiac conduction as measured by the electrocardiogram, at therapeutically relevant exposure. Our goal was to characterize the biophysical properties of Na 1.5 block and to support the observed clinical safety of lamotrigine. We used HEK-293 cells stably expressing the hNa 1.5 channel and voltage clamp electrophysiology to quantify the potency (half-maximal inhibitory concentration) against peak and late channel current, on-/off-rate binding kinetics, voltage-dependence, and tonic block of the cardiac sodium channel by lamotrigine; and compared to clinically relevant Class Ia (quinidine), Ib (mexiletine), and Ic (flecainide) inhibitors. Lamotrigine blocked peak and late Na 1.5 current at therapeutically relevant exposure, with rapid kinetics and biophysical properties similar to the class Ib inhibitor mexiletine. However, no clinically meaningful prolongation in QRS or PR interval was observed in healthy subjects in a new analysis of a previously reported thorough QT clinical trial (SCA104648). In conclusion, the weak Na 1.5 block and rapid kinetics do not translate into clinically relevant conduction slowing at therapeutic exposure and support the clinical safety of lamotrigine in patients suffering from epilepsy and bipolar disorder.
Topics: Anticonvulsants; Flecainide; HEK293 Cells; Humans; Lamotrigine; Mexiletine; Sodium Channel Blockers; Sodium Channels
PubMed: 35579204
DOI: 10.1111/cts.13311