-
Molecules (Basel, Switzerland) Aug 2022Mexiletine (MXL) is a class IB antiarrhythmic agent, acting as a non-selective voltage-gated sodium channel blocker, used in therapy as a racemic mixture ,-MXL...
Mexiletine (MXL) is a class IB antiarrhythmic agent, acting as a non-selective voltage-gated sodium channel blocker, used in therapy as a racemic mixture ,-MXL hydrochloride. The aim of the current study was the development of a new, fast, and efficient method for the chiral separation of MXL enantiomers using capillary electrophoresis (CE) and cyclodextrins (CDs) as chiral selectors (CSs). After an initial CS screening, using several neutral and charged CDs, at four pH levels, heptakis-2,3,6-tri-O-methyl-β-CD (TM-β-CD), a neutral derivatized CD, was chosen as the optimum CS for the enantioseparation. For method optimization, an initial screening fractional factorial design was applied to identify the most significant parameters, followed by a face-centered central composite design to establish the optimal separation conditions. The best results were obtained by applying the following optimized electrophoretic conditions: 60 mM phosphate buffer, pH 5.0, 50 mM TM-β-CD, temperature 20 °C, applied voltage 30 kV, hydrodynamic injection 50 mbar/s. MXL enantiomers were baseline separated with a resolution of 1.52 during a migration time of under 5 min; -MXL was the first migrating enantiomer. The method's analytical performance was verified in terms of precision, linearity, accuracy, and robustness (applying a Plackett-Burman design). The developed method was applied for the determination of MXL enantiomers in pharmaceuticals. A computer modeling of the MXL-CD complexes was applied to characterize host-guest chiral recognition.
Topics: Cyclodextrins; Electrophoresis, Capillary; Mexiletine; Research Design; Stereoisomerism
PubMed: 36080370
DOI: 10.3390/molecules27175603 -
Europace : European Pacing,... Nov 2022While mexiletine has been used for over 40 years for prevention of (recurrent) ventricular arrhythmias and for myotonia, patient access has recently been critically...
AIMS
While mexiletine has been used for over 40 years for prevention of (recurrent) ventricular arrhythmias and for myotonia, patient access has recently been critically endangered. Here we aim to demonstrate the effectiveness and safety of mexiletine in the treatment of patients with (recurrent) ventricular arrhythmias, emphasizing the absolute necessity of its accessibility.
METHODS AND RESULTS
Studies were included in this systematic review (PROSPERO, CRD42020213434) if the efficacy or safety of mexiletine in any dose was evaluated in patients at risk for (recurrent) ventricular arrhythmias with or without comparison with alternative treatments (e.g. placebo). A systematic search was performed in Ovid MEDLINE, Embase, and in the clinical trial registry databases ClinicalTrials.gov and ICTRP. Risk of bias were assessed and tailored to the different study designs. Large heterogeneity in study designs and outcome measures prompted a narrative synthesis approach. In total, 221 studies were included reporting on 8970 patients treated with mexiletine. Age ranged from 0 to 88 years. A decrease in ventricular arrhythmias of >50% was observed in 72% of the studies for pre-mature ventricular complexes, 64% for ventricular tachycardia, and 33% for ventricular fibrillation. Electrocardiographic effects of mexiletine were small; only in a subset of patients with primary arrhythmia syndromes, a relative (desired) QTc decrease was reproducibly observed. As for adverse events, gastrointestinal complaints were most frequently observed (33% of the patients).
CONCLUSIONS
In this systematic review, we present all the currently available knowledge of mexiletine in patients at risk for (recurrent) ventricular arrhythmias and show that mexiletine is both effective and safe.
Topics: Humans; Infant, Newborn; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Mexiletine; Arrhythmias, Cardiac; Ventricular Fibrillation; Electrocardiography; Heart Ventricles
PubMed: 36036670
DOI: 10.1093/europace/euac087 -
ACS Pharmacology & Translational Science Aug 2022Evaluation of arrhythmogenic drugs is required by regulatory agencies before any new compound can obtain market approval. Despite rigorous review, cardiac disorders...
Evaluation of arrhythmogenic drugs is required by regulatory agencies before any new compound can obtain market approval. Despite rigorous review, cardiac disorders remain the second most common cause for safety-related market withdrawal. On the other hand, false-positive preclinical findings prohibit potentially beneficial candidates from moving forward in the development pipeline. Complex models using cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CM) have been identified as a useful tool that allows for rapid and cost-efficient screening of proarrhythmic drug risk. Currently available hiPSC-CM models employ simple two-dimensional (2D) culture formats with limited structural and functional relevance to the human heart muscle. Here, we present the use of our 3D cardiac microphysiological system (MPS), composed of a hiPSC-derived heart micromuscle, as a platform for arrhythmia risk assessment. We employed two different hiPSC lines and tested seven drugs with known ion channel effects and known clinical risk: dofetilide and bepridil (high risk); amiodarone and terfenadine (intermediate risk); and nifedipine, mexiletine, and lidocaine (low risk). The cardiac MPS successfully predicted drug cardiotoxicity risks based on changes in action potential duration, beat waveform (i.e., shape), and occurrence of proarrhythmic events of healthy patient hiPSC lines in the absence of risk cofactors. We showcase examples where the cardiac MPS outperformed existing hiPSC-CM 2D models.
PubMed: 35983280
DOI: 10.1021/acsptsci.2c00088 -
Medicine Jul 2022This study aimed to characterize the genetic, pathological, and clinical alterations of 17 patients in China presenting with nondystrophic myotonia (NDM) and to analyze...
BACKGROUND
This study aimed to characterize the genetic, pathological, and clinical alterations of 17 patients in China presenting with nondystrophic myotonia (NDM) and to analyze the relationship between genotype and clinical phenotype.
METHODS
CLCN1 and SCN4A genes in patients with clinical features and muscle pathology indicative of NDM were sequenced. Furthermore, KCNE3 and CACNA1S genes were assessed in patients with wild-type CLCN1 and SCN4A.
RESULTS
Patients may have accompanying atypical myopathy as well as muscle hypertrophy, secondary dystonia, and joint contracture as determined by needle electromyography. All the study participants were administered mexiletine in combination with carbamazepine and showed significant improvements in myotonia symptoms in response to this therapy. CLCN1 gene mutation was detected in 8 cases diagnosed with myotonia congenital using gene screening. The detected mutations included 5 missense, 2 nonsense, 1 deletion, and 2 insertions. Further gene analysis showed 4 mutations in the SCN4A gene in patients diagnosed with paramyotonia congenita.
CONCLUSIONS
Myotonia congenita and paramyotonia congenita are the predominant forms of NDM in China. NDM may be best diagnosed using genetic analysis in associated with clinical features.
Topics: Chloride Channels; Humans; Mutation; Myotonia; Myotonic Disorders; NAV1.4 Voltage-Gated Sodium Channel
PubMed: 35866763
DOI: 10.1097/MD.0000000000029591 -
Frontiers in Physiology 2022The voltage-gated sodium channel Na1.5 plays an essential role in the generation and propagation of action potential in cardiomyocytes. Mutations in Na1.5 have been...
The voltage-gated sodium channel Na1.5 plays an essential role in the generation and propagation of action potential in cardiomyocytes. Mutations in Na1.5 have been associated with LQT syndrome, Brugada syndrome, and sudden arrhythmia death syndrome. Genetic studies showed that Na1.5 mutations vary across race-ethnic groups. Here we investigated an Asian-specific mutation Na1.5-P1090L associated with LQT syndrome. We found that Na1.5-P1090L mutation perturbed the sodium channel function. It altered the gating process of the channel and exhibited an enhanced window current. Treatment with mexiletine reversed the depolarization shift of the steady-state inactivation produced by P1090L. Mexiletine also modified the recovery from steady-state inactivation and the development of inactivation of P1090L. It rescued the dysfunctional inactivation of P1090L and reduced the P1090L channel's availability.
PubMed: 35864896
DOI: 10.3389/fphys.2022.904664 -
Cureus Jun 2022Bidirectional ventricular tachycardia (BVT) is a rare and unusual ventricular dysrhythmia that is characterized by a beat-to-beat alternation of the QRS axis. This can...
Bidirectional ventricular tachycardia (BVT) is a rare and unusual ventricular dysrhythmia that is characterized by a beat-to-beat alternation of the QRS axis. This can sometimes manifest as alternating left and right bundle branch blocks. To the best of our knowledge, there are two previous cases of BVT in the setting of type I myocardial infarction. Our case would be the third and showed a subtle change in the anterior-posterior axis that can be seen in lead V2. The coronary angiography of our patient demonstrated severe multivessel coronary artery disease with complete total occlusion of the proximal dominant right coronary artery, 100% in-stent restenosis of the ostial left circumflex, 40% stenosis of left main, and 90% stenosis of mid left anterior descending artery (LAD). The BVT resolved after two amiodarone boluses followed by a drip. We attempted to transition to oral mexiletine, however, the patient was unable to tolerate the medication due to intractable nausea and vomiting. The patient subsequently underwent high risk coronary artery bypass graft surgery with no further episodes of BVT following revascularization and was discharged after six weeks of hospitalization. Although rare, type I myocardial infarction is an important differential diagnosis of BVT.
PubMed: 35832750
DOI: 10.7759/cureus.25845 -
Biological & Pharmaceutical Bulletin 2022Evaluation of drug-induced cardiotoxicity is still challenging to avoid adverse effects, such as torsade de pointes (TdP), in non-clinical and clinical studies. Numerous...
Evaluation of drug-induced cardiotoxicity is still challenging to avoid adverse effects, such as torsade de pointes (TdP), in non-clinical and clinical studies. Numerous studies have suggested that human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a useful platform for detecting drug-induced TdP risks. Comprehensive in vitro Proarrhythmia Assay (CiPA) validation study suggested that hiPSC-CMs can assess clinical TdP risk more accurately than the human ether-a-go-go-related assay and QT interval prolongation. However, there were still some outliers, such as bepridil, mexiletine, and ranolazine, among the CiPA 28 compounds in the CiPA international multi-site study using hiPSC-CMs. In this study, we assessed the effects of the positive compound dofetilide, the negative compound aspirin, and several CiPA compounds (bepridil, mexiletine, and ranolazine) on the electromechanical window (E-M window), which were evaluated using multi-electrode array assay and motion analysis, in hiPSC-CMs. Similar to previous in vivo studies, dofetilide, which has a high TdP risk, decreased the E-M window in hiPSC-CMs, whereas aspirin, which has a low TdP risk, had little effect. Bepridil, classified in the high TdP-risk group in CiPA, decreased the E-M window in hiPSC-CMs, whereas ranolazine and mexiletine, which are classified in the low TdP-risk group in CiPA, slightly decreased or had little effect on the E-M window of hiPSC-CMs. Thus, the E-M window in hiPSC-CMs can be used to classify drugs into high and low TdP risk.
Topics: Aspirin; Bepridil; DNA-Binding Proteins; Humans; Induced Pluripotent Stem Cells; Mexiletine; Myocytes, Cardiac; Ranolazine; Risk Assessment
PubMed: 35786601
DOI: 10.1248/bpb.b22-00268 -
Clinical Pharmacology and Therapeutics Nov 2022Selective voltage-gated sodium channel blockers are of growing interest as treatment for pain. For drug development of such compounds, it would be critical to have a... (Randomized Controlled Trial)
Randomized Controlled Trial
Selective voltage-gated sodium channel blockers are of growing interest as treatment for pain. For drug development of such compounds, it would be critical to have a biomarker that can be used for proof-of-mechanism. We aimed to evaluate whether drug-induced changes in sodium conductance can be detected in the peripheral nerve excitability profile in 18 healthy subjects. In a randomized, double-blind, 3-way crossover study, effects of single oral doses of 333 mg mexiletine and 300 mg lacosamide were compared with placebo. On each study visit, motor and sensory nerve excitability measurements of the median nerve were performed (predose; and 3 and 6 hours postdose) using Qtrac. Treatment effects were calculated using an analysis of covariance (ANCOVA) with baseline as covariate. Mexiletine and lacosamide had significant effects on multiple motor and sensory nerve excitability variables. Depolarizing threshold electrotonus (TEd (40-60 ms)) decreased by mexiletine (estimated difference (ED) -1.37% (95% confidence interval (CI): -2.20, -0.547; P = 0.002) and lacosamide (ED -1.27%, 95% CI: -2.10, -0.443; P = 0.004) in motor nerves. Moreover, mexiletine and lacosamide decreased superexcitability (less negative) in motor nerves (ED 1.74%, 95% CI: 0.615, 2.87; P = 0.004, and ED 1.47%, 95% CI: 0.341, 2.60; P = 0.013, respectively). Strength-duration time constant decreased after lacosamide in motor- (ED -0.0342 ms, 95% CI: -0.0571, -0.0112; P = 0.005) and sensory nerves (ED -0.0778 ms, 95% CI: -0.116, -0.0399; P < 0.001). Mexiletine and lacosamide significantly decrease excitability of motor and sensory nerves, in line with their suggested mechanism of action. Results of this study indicate that nerve excitability threshold tracking can be an effective pharmacodynamic biomarker. The method could be a valuable tool in clinical drug development.
Topics: Humans; Lacosamide; Mexiletine; Cross-Over Studies; Voltage-Gated Sodium Channel Blockers; Healthy Volunteers; Double-Blind Method; Sodium
PubMed: 35762293
DOI: 10.1002/cpt.2694 -
Journal of Cardiovascular Development... Jun 2022Sudden infant death syndrome (SIDS), the most common cause of infant death in developed countries, is attributed to diverse trigger factors. Malignant cardiac...
Sudden infant death syndrome (SIDS), the most common cause of infant death in developed countries, is attributed to diverse trigger factors. Malignant cardiac dysrhythmias are potentially treatable etiologies, and congenital long QT syndrome (LQTS) is the most common cardiac ionic channelopathy confronted. β-Blockers or class Ib agents are the drugs of choice for the control of arrhythmias, and an implantable cardioverter defibrillator (ICD) should be considered for secondary prevention in survivors of lethal cardiac death. We report the case of a 4-day old neonate, later genetically confirmed as LQT type 3 (LQT3), who survived a pulseless torsades de pointes (TdP) attack and was successfully treated with propranolol, mexiletine, and ICD implantation.
PubMed: 35735813
DOI: 10.3390/jcdd9060184 -
Arquivos Brasileiros de Cardiologia May 2022
Topics: Anti-Arrhythmia Agents; Electrocardiography; Humans; Infant, Newborn; Long QT Syndrome; Mexiletine
PubMed: 35613201
DOI: 10.36660/abc.20210533