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The Journal of Pharmacology and... Mar 2023The cardiac sodium channel Na1.5 is a key contributor to the cardiac action potential, and dysregulations in Na1.5 can lead to cardiac arrhythmias. Na1.5 is a target of...
The cardiac sodium channel Na1.5 is a key contributor to the cardiac action potential, and dysregulations in Na1.5 can lead to cardiac arrhythmias. Na1.5 is a target of numerous antiarrhythmic drugs (AADs). Previous studies identified the protein 14-3-3 as a regulator of Na1.5 biophysical coupling. Inhibition of 14-3-3 can remove the Na1.5 functional coupling and has been shown to inhibit the dominant-negative effect of Brugada syndrome mutations. However, it is unknown whether the coupling regulation is involved with AADs' modulation of Na1.5. Indeed, AADs could reveal important structural and functional information about Na1.5 coupling. Here, we investigated the modulation of Na1.5 by four classic AADs, quinidine, lidocaine, mexiletine, and flecainide, in the presence of 14-3-3 inhibition. The experiments were carried out by high-throughput patch-clamp experiments in an HEK293 Na1.5 stable cell line. We found that 14-3-3 inhibition can enhance acute block by quinidine, whereas the block by other drugs was not affected. We also saw changes in the use- and dose-dependency of quinidine, lidocaine, and mexiletine when inhibiting 14-3-3. Inhibiting 14-3-3 also shifted the channel activation toward hyperpolarized voltages in the presence of the four drugs studied and slowed the recovery of inactivation in the presence of quinidine. Our results demonstrated that the protein 14-3-3 and Na1.5 coupling could impact the effects of AADs. Therefore, 14-3-3 and Na1.5 coupling are new mechanisms to consider in the development of drugs targeting Na1.5. SIGNIFICANCE STATEMENT: The cardiac sodium channel Na1.5 is a target of commonly used antiarrhythmic drugs, and Na1.5 function is regulated by the protein 14-3-3. The present study demonstrated that the regulation of Na1.5 by 14-3-3 influences Na1.5's response to antiarrhythmic drugs. This study provides detailed information about how 14-3-3 differentially regulated Na1.5 functions under the influence of different drug subtypes. These findings will guide future molecular studies investigating Na1.5 and antiarrhythmic drugs outcomes.
Topics: Humans; Anti-Arrhythmia Agents; Mexiletine; 14-3-3 Proteins; Quinidine; HEK293 Cells; Lidocaine; Sodium Channels
PubMed: 36460339
DOI: 10.1124/jpet.122.001407 -
Zhonghua Xin Xue Guan Bing Za Zhi Nov 2022To determine the electrophysiological effects and related mechanisms of late sodium current inhibitors on hearts with short QT intervals. The electrophysiological...
[Impact of late sodium current inhibition on cardiac electrophysiology parameters and ventricular arrhythmias in isolated Langendorff perfused rabbit hearts with short QT interval].
To determine the electrophysiological effects and related mechanisms of late sodium current inhibitors on hearts with short QT intervals. The electrophysiological study was performed on isolated Langendorff perfused rabbit hearts. A total of 80 New Zealand White rabbits were used and 34 hearts without drug treatment were defined as control group A, these hearts were then treated with I opener pinacidil, defined as pinacidil group A. Then, 27 hearts from pinacidil group A were selected to receive combined perfusion with sodium channel inhibitors or quinidine, a traditional drug used to treat short QT syndrome, including ranolazine combined group (=9), mexiletine combined group (=9), and quinidine combined group (=9). Nineteen out of the remaining 46 New Zealand rabbits were selected as control group B (no drug treatments, =19), and then treated with pinacidil, defined as pinacidil group B (=19). The remaining 27 rabbits were treated with sodium inhibitors or quinidine alone, including ranolazine alone group (=9), mexiletine alone group (=9), and quinidine alone group (=9). Electrocardiogram (ECG) physiological parameters of control group A and pinacidil group A were collected. In control group B and pinacidil group B, programmed electrical stimulation was used to induce ventricular arrhythmias and ECG was collected. ECG physiological parameters and ventricular arrhythmia status of various groups were analyzed. The concentrations of pinacidil, ranolazine, mexiletine and quinidine used in this study were 30, 10, 30 and 1 μmol/L, respectively. Compared with control group A, the QT interval, 90% of the repolarization in epicardial and endocardial monophasic action potential duration (MAPD-Epi, MAPD-Endo) was shortened, the transmural dispersion of repolarization (TDR) was increased, and the effective refractor period (ERP) and post-repolarization refractoriness (PRR) were reduced in pinacidil group A (all <0.05). Compared with the pinacidil group A, MAPD-Epi, MAPD-Endo, QT interval changes were reversed in quinidine combined group and mexiletine combined group (all <0.05), but not in ranolazine combined group. All these three drugs reversed the pinacidil-induced increases of TDR and the decreases of ERP and PRR. The induced ventricular arrhythmia rate was 0 in control group B, and increased to 10/19 (χ=13.6, <0.05) in pinacidil group B during programmed electrical stimulation. Compared with the pinacidil group B, incidences of ventricular arrhythmia decreased to 11% (1/9), 11% (1/9) and 0 (0/9) (χ=4.5, 4.5, 7.4, <0.05) respectively in ranolazine group, mexiletine group and quinidine group. Inhibition of late sodium current does not increase but even decreases the risk of malignant arrhythmia in hearts with a shortened QT interval. The antiarrhythmic mechanism might be associated with the reversal of the increase of TDR and the decrease of refractoriness (including both ERP and PRR) of hearts with shortened QT interval.
Topics: Rabbits; Animals; Quinidine; Mexiletine; Pinacidil; Sodium; Ranolazine; Electrophysiologic Techniques, Cardiac; Arrhythmias, Cardiac
PubMed: 36418277
DOI: 10.3760/cma.j.cn112148-20220705-00518 -
Frontiers in Cardiovascular Medicine 2022Brugada syndrome (BrS) is associated with ventricular tachyarrhythmias. However, the presence of electrical strom (ES) and its management still debated.
BACKGROUND
Brugada syndrome (BrS) is associated with ventricular tachyarrhythmias. However, the presence of electrical strom (ES) and its management still debated.
OBJECTIVES
We present the outcome and management of 44 BrS patients suffering from ES.
METHODS
A systematic literature review and pooled analysis Through database review including PubMed, Web of Science, Cochrane Libary and Cinahl studies were analyzed. Evidence from 7 reports of 808 BrS patients was identified.
RESULTS
The mean age of patients suffering from ES was 34 ± 9.5 months (94.7% males, 65.8% spontaneous BrS type I). Using electrophysiological study ventricular tachycardia/ventricular fibrillation were inducible in 12/23 (52.2%). Recurrence of ES was documented in 6.1%. Death from ES was 8.2% after a follow-up of 83.5 ± 53.4. In up to 27 ES resolved without treatment. External shock was required in 35.6%, internal ICD shock in 13.3%, Overdrive pacing, left cardiac sympathetic block and atropin in 2.2%. Short-term antiarrhythmic management was as the following: Isopreterenol or Isopreterenol in combination with quinidine 35.5%, orciprenaline in 2.2%, quinidine 2.2%, disopyramide 2.2% or denopamide 2.2%. However, lidocaine, magensium sulfate, mexiletine and propanolol failed to control ES.
CONCLUSION
Although ES is rare in BrS, this entity challenges physicians. Despite its high mortality rate, spontaneous termination is possible. Short-term management using Isoproterenol and/or quinidine might be safe. Prospective studies on management of ES are warranted.
PubMed: 36386327
DOI: 10.3389/fcvm.2022.981715 -
Toxicology Letters Jan 2023Tetrodotoxin (TTX) potently inhibits TTX-sensitive voltage-gated sodium (Na) channels in nerve and muscle cells, potentially resulting in depressed neurotransmission,...
Tetrodotoxin (TTX) potently inhibits TTX-sensitive voltage-gated sodium (Na) channels in nerve and muscle cells, potentially resulting in depressed neurotransmission, paralysis and death from respiratory failure. Since a wide range of pharmaceutical drugs is known to also act on Na channels, the use of medicines could predispose individuals to a higher susceptibility towards TTX toxicity. We therefore first assessed the inhibitory effect of selected medicines that act on TTX-sensitive (Riluzole, Chloroquine, Fluoxetine, Valproic acid, Lamotrigine, Lidocaine) and TTX-resistant (Carbamazepine, Mexiletine, Flecainide) Na channels on spontaneous neuronal activity of rat primary cortical cultures grown on microelectrode arrays (MEA). After establishing concentration-effect curves, binary mixtures of the medicines with TTX at calculated NOEC, IC and IC values were used to determine if pharmacodynamic interactions occur between TTX and these drugs on spontaneous neuronal activity. At IC and IC values, all medicines significantly increased the inhibitory effect of TTX on spontaneous neuronal activity of rat cortical cells in vitro. Subsequent experiments using human iPSC-derived neuronal co-cultures grown on MEAs confirmed the ability of selected medicines (Carbamazepine, Flecainide, Riluzole, Lidocaine) to inhibit spontaneous neuronal activity. Despite the need for additional experiments using human iPSC-derived neuronal co-cultures, our combined data already highlight the importance of identifying and including vulnerable risk groups in the risk assessment of TTX.
Topics: Animals; Humans; Rats; Carbamazepine; Flecainide; Lidocaine; Riluzole; Tetrodotoxin; Voltage-Gated Sodium Channels
PubMed: 36375636
DOI: 10.1016/j.toxlet.2022.11.005 -
Crystal Growth & Design Nov 2022We report an approach to obtain drug-mimetic supramolecular gelators, which are capable of stabilizing metastable polymorphs of the pharmaceutical salt mexiletine...
We report an approach to obtain drug-mimetic supramolecular gelators, which are capable of stabilizing metastable polymorphs of the pharmaceutical salt mexiletine hydrochloride, a highly polymorphic antiarrhythmic drug. Solution-phase screening led to the discovery of two new solvated solid forms of mexiletine, a type C 1,2,4-trichlorobenzene tetarto-solvate and a type D nitrobenzene solvate. Various metastable forms were crystallized within the gels under conditions which would not have been possible in solution. Despite typically crystallizing concomitantly with form 1, a pure sample of form 3 was crystallized within a gel of ethyl methyl ketone. Various type A channel solvates were crystallized from gels of toluene and ethyl acetate, in which the contents of the channels varied from those of solution-phase forms. Most strikingly, the high-temperature-stable form 2 was crystallized from a gel in 1,2-dibromoethane: the only known route to access this form at room temperature. These results exemplify the powerful stabilizing effect of drug-mimetic supramolecular gels, which can be exploited in pharmaceutical polymorph screens to access highly metastable or difficult-to-nucleate solid forms.
PubMed: 36345390
DOI: 10.1021/acs.cgd.2c00925 -
Minerva Cardiology and Angiology Dec 2023To evaluate the clinical outcomes of oral mexiletine (oMXT) to treat ventricular tachyarrhythmias (VTAs) in the era of implantable cardioverter-defibrillator (ICD)...
INTRODUCTION
To evaluate the clinical outcomes of oral mexiletine (oMXT) to treat ventricular tachyarrhythmias (VTAs) in the era of implantable cardioverter-defibrillator (ICD) technology.
EVIDENCE ACQUISITION
A systematic search was conducted using PubMed, Embase and Cochrane databases following the PRISMA guidelines to collect literature data reporting oMXT efficacy and safety outcomes in treating VTAs in ICD recipients.
EVIDENCE SYNTHESIS
Final analysis included four studies accounting for a total of 91 patients with recurrent VTAs treated with oMXT. Amiodarone therapy was initially attempted in most patients (91.2%), while catheter ablation was performed in one-third of patients. VTA recurrences were observed in 55/91 patients (60.4%) during oMXT treatment compared to 91/91 (100%) before treatment (P<0.001). Appropriate therapies occurred in 55/88 ICD patients (62.5%) during oMXT treatment compared to 80/88 (90.9%) before treatment (P<0.001). After oMXT introduction, there was a significant reduction of the individual burden of VTA episodes and appropriate ICD therapies per patient, showing Hedges'g values of -1.103 (P=0.002) and -1.474 (P=0.008), respectively. Safety analysis showed a sample-weighted overall side-effect rate of 30%, while 21% of patients required drug reduction or discontinuation. Aggregated meta-regression analysis of the included studies and remote literature revealed a linear correlation between oMXT dosage and the overall side effects rate (r = 0.48; P=0.014).
CONCLUSIONS
Oral mexiletine provides an adjunctive treatment to manage VTAs and reduces appropriate therapies in ICD patients with moderate efficacy and acceptable safety profiles. These observations await confirmation through randomised clinical trials.
Topics: Humans; Mexiletine; Defibrillators, Implantable; Anti-Arrhythmia Agents; Treatment Outcome; Tachycardia, Ventricular
PubMed: 36305779
DOI: 10.23736/S2724-5683.22.06176-2 -
Bioengineering (Basel, Switzerland) Oct 2022The SCN5A mutations have been long associated with long QT variant 3 (LQT3). Recent experimental and computation studies have reported that mexiletine effectively treats...
The SCN5A mutations have been long associated with long QT variant 3 (LQT3). Recent experimental and computation studies have reported that mexiletine effectively treats LQT3 patients associated with the A1656D mutation. However, they have primarily focused on cellular level evaluations and have only looked at the effects of mexiletine on action potential duration (APD) or QT interval reduction. We further investigated mexiletine's effects on cardiac cells through simulations of single-cell (behavior of alternant occurrence) and 3D (with and without mexiletine). We discovered that mexiletine could shorten the cell's APD and change the alternant's occurrence to a shorter basic cycle length (BCL) between 350 and 420 ms. The alternant also appeared at a normal heart rate under the A1656D mutation. Furthermore, the 3D ventricle simulations revealed that mexiletine could reduce the likelihood of a greater spiral wave breakup in the A1656D mutant condition by minimizing the appearance of rotors. In conclusion, we found that mexiletine could provide extra safety features during therapy for LQT3 patients because it can change the alternant occurrence from a normal to a faster heart rate, and it reduces the chance of a spiral wave breakup. Therefore, these findings emphasize the promising efficacy of mexiletine in treating LQT3 patients under the A1656D mutation.
PubMed: 36290499
DOI: 10.3390/bioengineering9100531 -
Clinical and Translational Science Dec 2022Measuring muscle velocity recovery cycles (MVRCs) is a method to obtain information on muscle cell excitability, independent of neuromuscular transmission. The goal was... (Randomized Controlled Trial)
Randomized Controlled Trial
Measuring muscle velocity recovery cycles (MVRCs) is a method to obtain information on muscle cell excitability, independent of neuromuscular transmission. The goal was to validate MVRC as a pharmacodynamic (PD) biomarker for drugs targeting muscle excitability. As proof-of-concept, sensitivity of MVRC to detect effects of mexiletine, a voltage-gated sodium channel (Na ) blocker, was assessed. In a randomized, double-blind, two-way crossover study, effects of a single pharmacologically active oral dose of 333 mg mexiletine was compared to placebo in 15 healthy male subjects. MVRC was performed predose, and 3- and 5-h postdose using QTrac. Effects of mexiletine versus placebo were calculated using a mixed effects model with baseline as covariate. Mexiletine had significant effects on MVRC when compared to placebo. Early supernormality after five conditioning stimuli was decreased by mexiletine (estimated difference -2.78% [95% confidence interval: -4.16, -1.40]; p value = 0.0003). Moreover, mexiletine decreased the difference in late supernormality after five versus one conditioning stimuli (5XLSN; ED -1.46% [-2.26, -0.65]; p = 0.001). These results indicate that mexiletine decreases the percentage increase in velocity of the muscle fiber action potential after five conditioning stimuli, at long and short interstimulus intervals, which corresponds to a decrease in muscle membrane excitability. This is in line with the pharmacological activity of mexiletine, which leads to use-dependent Na 1.4 blockade affecting muscle membrane potentials. This study shows that effects of mexiletine can be detected using MVRC in healthy subjects, thereby indicating that MVRC can be used as a tool to demonstrate PD effects of drugs targeting muscle excitability in early phase drug development.
Topics: Male; Humans; Mexiletine; Cross-Over Studies; Double-Blind Method; Muscles; Biomarkers
PubMed: 36281627
DOI: 10.1111/cts.13418 -
Journal of Pharmacological and... 2022Cardiac contractility evaluation using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has recently attracted much attention as a clinical...
Cardiac contractility evaluation using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has recently attracted much attention as a clinical cardiotoxicity predictive model. Most studies on this were conducted under spontaneous beating conditions and involved video-based analyses. Cardiac contractility is known to be influenced by beating rates; accordingly, beating rate control is recommended to accurately analyze the effects of drugs on cardiac contractility. Therefore, we investigated the relationship between contraction parameters and beating rates of cardiac cell sheet tissues by directly measuring the contraction force and compared the effects of ion channel drugs (mexiletine, ranolazine, and dofetilide) on contraction parameters under spontaneous beating conditions with those under pacing (1 Hz) conditions. To characterize the contraction/relaxation kinetics, we introduced a novel analysis tool, called a "C-V loop," a plot of contraction force versus force-changing rate ("velocity"). When we increased the beating rate, the contraction force, force-changing rate, and relaxation time markedly decreased. The occurrence frequencies of beating arrest and irregular beats at high concentration ranges of mexiletine and ranolazine were more suppressed in paced samples than in spontaneously beating ones. We also found that relaxation time increased by treatment with dofetilide and contraction amplitude decreased in a concentration-dependent manner by mexiletine treatment only in the samples under pacing. These drug responses were consistent with the previous reports using human samples. These results indicated that beating rate control is necessary to stably evaluate the effects of drugs on contractility and that tests under 1-Hz pacing are more relevant to clinical settings.
Topics: Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Ranolazine; Mexiletine; Cells, Cultured
PubMed: 36273536
DOI: 10.1016/j.vascn.2022.107228 -
Annals of Clinical and Translational... Nov 2022Patients with spinal and bulbar muscular atrophy (SBMA) often experience muscular weakness under cold exposure. (Randomized Controlled Trial)
Randomized Controlled Trial Observational Study
OBJECTIVE
Patients with spinal and bulbar muscular atrophy (SBMA) often experience muscular weakness under cold exposure.
METHODS
In our previously conducted observational study, we assessed nerve conduction and grip strength to examine the effect of cold exposure on motor function, based on which we conducted a randomized controlled trial to evaluate the efficacy and safety of mexiletine hydrochloride in SBMA (MEXPRESS).
RESULTS
In the observational study, 51 consecutive patients with SBMA and 18 healthy controls (HCs) were enrolled. Of the patients with SBMA, 88.0% experienced cold paresis. Patients with SBMA exhibited greater prolongation of ulnar nerve distal latency under cold (SBMA, 5.6 ± 1.1 msec; HC, 4.3 ± 0.6 msec; p <0.001); the change in the distal latencies between room temperature and cold exposure conditions correlated with the change in grip power. In the MEXPRESS trial, 20 participants took mexiletine or lactose, three times a day for 4 weeks with a crossover design. There was no difference in distal latencies at room temperature and under cold exposure between mexiletine and placebo groups as the primary endpoint. However, tongue pressure and 10-sec grip and release test under cold exposure were improved in the mexiletine group. There were no serious adverse events throughout the study period.
INTERPRETATION
Cold paresis is common and associated with prolongation of distal latency in SBMA. The results of the phase II clinical trial revealed that mexiletine showed short-term safety, but it did not restore cold exposure-induced prolongation of distal latency.
Topics: Humans; Mexiletine; Bulbo-Spinal Atrophy, X-Linked; Pressure; Tongue; Muscle Weakness; Paresis
PubMed: 36208052
DOI: 10.1002/acn3.51667