-
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 -
World Journal of Clinical Cases Jan 2024Paramyotonia congenita (PMC) stands as a rare sodium channelopaty of skeletal muscle, initially identified by Eulenburg. The identification of PMC often relies on...
BACKGROUND
Paramyotonia congenita (PMC) stands as a rare sodium channelopaty of skeletal muscle, initially identified by Eulenburg. The identification of PMC often relies on electromyography (EMG), a diagnostic technique. The child's needle EMG unveiled trains of myotonic discharges with notably giant amplitudes, alongside irregular wave trains of myotonic discharges. This distinctive observation had not surfaced in earlier studies.
CASE SUMMARY
We report the case of a 3-year-old female child with PMC, who exhibited laryngeal stridor, muffled speech, myotonia from birth. Cold, exposure to cool water, crying, and physical activity exacerbated the myotonia, which was relieved in warmth, yet never normalized. Percussion myotonia was observable in bilateral biceps. Myotonia symptoms remained unchanged after potassium-rich food consumption like bananas. Hyperkalemic periodic paralysis was excluded. Cranial magnetic resonance imaging yielded normal results. Blood potassium remained within normal range, while creatine kinase showed slight elevation. Exome-wide genetic testing pinpointed a heterozygous mutation on chromosome SCN4A: c.3917G>A (p.G1306E). After a six-month mexiletine regimen, symptoms alleviated.
CONCLUSION
In this case revealed the two types of myotonic discharges, and had not been documented in other studies. We underscore two distinctive features: Giant-amplitude potentials and irregular waves.
PubMed: 38322461
DOI: 10.12998/wjcc.v12.i3.587 -
Journal of Neuromuscular Diseases 2024Myotonic disorders, such as non-dystrophic myotonias (NDMs) and myotonic dystrophies (DMs) are characterized by a delay in muscle relaxation after a contraction...
BACKGROUND
Myotonic disorders, such as non-dystrophic myotonias (NDMs) and myotonic dystrophies (DMs) are characterized by a delay in muscle relaxation after a contraction stimulus. There is general consensus that protocols to treat myotonia need to be implemented.
OBJECTIVE
Mexiletine is the only pharmacological agent approved for the symptomatic treatment of myotonia in adult patients with NDM and is considered to be the first-line treatment for DMs; however, its production in Italy was halted in 2022 making its availability to patients problematic.
METHODS
A panel of 8 Italian neurologists took part in a two-round Delphi panel between June and October 2022, analyzing the current use of mexiletine in Italian clinical practice.
RESULTS
The panelists assist 1126 patients (69% DM type1, 18% NDM and 13% DM type2). Adult NDM patients receive, on average, 400-600 mg of mexiletine hydrochloride (HCl) while adult DM patients receive 100-600 mg, per day in the long-term. The severity of symptoms is considered the main reason to start mexiletine treatment for both NDM and DM patients. Mexiletine is reckoned to have a clinical impact for both NDM and DM patients, but currently drug access is problematic.
CONCLUSIONS
Mexiletine treatment is recognized to have a role in the reduction of the symptomatic burden for NDM and DM patients. Patient management could be improved by facilitating access to therapy and developing new drug formulations.
Topics: Adult; Humans; Mexiletine; Myotonia; Neurologists; Myotonic Dystrophy; Italy
PubMed: 38306059
DOI: 10.3233/JND-230115 -
Emergency Medicine International 2024[This retracts the article DOI: 10.1155/2022/4078895.].
Retracted: Curative Effect of Yangxin Dingji Capsule Combined With Mexiletine Hydrochloride on Postoperative Arrhythmia and Its Influences on the Vascular Endothelial Function in Coronary Bifurcation Lesions.
[This retracts the article DOI: 10.1155/2022/4078895.].
PubMed: 38299003
DOI: 10.1155/2024/9756981 -
Journal of Molecular Modeling Jan 2024In this study, the molecular structure of the mexiletine molecule was investigated. Since the Mexiletine molecule is a drug active ingredient, its molecular structure...
CONTEXT
In this study, the molecular structure of the mexiletine molecule was investigated. Since the Mexiletine molecule is a drug active ingredient, its molecular structure and spectroscopic properties are important. The effects of intramolecular hydrogen bonding on Nuclear Magnetic Resonance Parameters (NMR), Electron Paramagnetic Resonance (EPR) parameters and molecular docking studies were examined in the mexiletine molecule. The effects of intramolecular hydrogen bonding on EPR parameters and molecular docking studies are the most important steps for this study.
METHOD
Conformational space scanning required for molecular structure calculations was carried out with the Molecular Mechanic Force Field method. DFT method with 6-311 + + G(d,p) basis set level was used to obtain the most stable structure among the conformations. NMR parameters (H and C chemical shift values) were also performed using the same basis set as the DFT method. The radicals created to calculate the Electron Paramagnetic Resonance parameters were modeled using the DFT/B3LYP/6-311 + + G(d,p) method basis set level. Molecular Docking studies were carried out with the Autodock vina program.
PubMed: 38228865
DOI: 10.1007/s00894-024-05838-y -
Perioperative Medicine (London, England) Jan 2024
PubMed: 38212790
DOI: 10.1186/s13741-024-00361-3 -
Neurology Jan 2024
PubMed: 38165356
DOI: 10.1212/WNL.0000000000207915 -
Heart Rhythm Mar 2024Brugada syndrome (BrS) is an inherited cardiac arrhythmogenic disease that predisposes patients to sudden cardiac death. It is associated with mutations in SCN5A, which...
BACKGROUND
Brugada syndrome (BrS) is an inherited cardiac arrhythmogenic disease that predisposes patients to sudden cardiac death. It is associated with mutations in SCN5A, which encodes the cardiac sodium channel alpha subunit (Na1.5). BrS-related mutations have incomplete penetrance and variable expressivity within families.
OBJECTIVE
The purpose of this study was to determine the role of patient-specific genetic background on the cellular and clinical phenotype among carriers of Na1.5_p.V1525M.
METHODS
We studied sodium currents from patient-specific human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and heterologously transfected human embryonic kidney (HEK) tsA201 cells using the whole-cell patch-clamp technique. We determined gene and protein expression by quantitative polymerase chain reaction, RNA sequencing, and western blot and performed a genetic panel for arrhythmogenic diseases.
RESULTS
Our results showed a large reduction in I density in hiPSC-CM derived from 2 V1525M single nucleotide variant (SNV) carriers compared with hiPSC-CM derived from a noncarrier, suggesting a dominant-negative effect of the Na1.5_p.V1525M channel. I was not affected in hiPSC-CMs derived from a V1525M SNV carrier who also carries the Na1.5_p.H558R polymorphism. Heterozygous expression of V1525M in HEK-293T cells produced a loss of I function, not observed when this variant was expressed together with H558R. In addition, the antiarrhythmic drug mexiletine rescued I function in hiPSC-CM. SCN5A expression was increased in the V1525M carrier who also expresses Na1.5_p.H558R.
CONCLUSION
Our results in patient-specific hiPSC-CM point to a dominant-negative effect of Na1.5_p.V1525M, which can be reverted by the presence of Na1.5_p.H558R. Overall, our data points to a role of patient-specific genetic background as a determinant for incomplete penetrance in BrS.
Topics: Humans; Brugada Syndrome; Sodium; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Myocytes, Cardiac; NAV1.5 Voltage-Gated Sodium Channel
PubMed: 38008367
DOI: 10.1016/j.hrthm.2023.11.019 -
Contemporary Clinical Trials... Dec 2023Response adaptive randomization is popular in adaptive trial designs, but the literature detailing its execution is lacking. These designs are desirable for...
BACKGROUND
Response adaptive randomization is popular in adaptive trial designs, but the literature detailing its execution is lacking. These designs are desirable for patients/stakeholders, particularly in comparative effectiveness research, due to the potential benefits including improving participant buy-in by providing more participants with better treatment during the trial. Frequentist approaches have often been used, but adaptive designs naturally fit the Bayesian methodology; it was developed to deal with data as they come in by updating prior information.
METHODS
PAIN-CONTRoLS was a comparative-effectiveness trial utilizing Bayesian response adaptive randomization to four drugs, nortriptyline, duloxetine, pregabalin, or mexiline, for cryptogenic sensory polyneuropathy (CSPN) patients. The aim was to determine which treatment was most tolerable and effective in reducing pain. Quit and efficacy rates were combined into a utility function to develop a single outcome, which with treatment sample size, drove the adaptive randomization. Prespecified interim analyses allowed the study to stop for early success or update the randomization probabilities to the better-performing treatments.
RESULTS
Seven adaptations to the randomization occurred before the trial ended due to reaching the maximum sample size, with more participants receiving nortriptyline and duloxetine. At the end of the follow-up, nortriptyline and duloxetine had lower probabilities of participants that had stopped taking the study medication and higher probabilities were efficacious. Mexiletine had the highest quit rate, but had an efficacy rate higher than pregabalin.
CONCLUSIONS
Response adaptive randomization has become a popular trial tool, especially for those utilizing Bayesian methods for analyses. By illustrating the execution of a Bayesian adaptive design, using the PAIN-CONTRoLS trial data, this paper continues the work to provide literature for conducting Bayesian response adaptive randomized trials.
PubMed: 37965484
DOI: 10.1016/j.conctc.2023.101220 -
Herzschrittmachertherapie &... Dec 2023Electrical storm due to recurrent ventricular tachycardias (VTs) is a life-threatening arrhythmic emergency. The authors present a case report of a 69-year-old male...
Electrical storm due to recurrent ventricular tachycardias (VTs) is a life-threatening arrhythmic emergency. The authors present a case report of a 69-year-old male patient with VT storm of non-ischemic etiology. Despite optimal medical treatment escalated by amiodarone antiarrhythmic drug therapy, the patient experienced multiple implantable cardioverter defibrillator (ICD) shocks. An electrophysiological study revealed an epicardial substrate; however, considering the patient's extreme obesity and active anticoagulant effect, catheter ablation was deemed to be unfeasible. Subsequently, mexiletine was added to the patient's drug regimen, resulting in successful control of arrhythmias during the following 6 months. Although the most recent European guidelines for the management of patients with ventricular arrhythmias mention mexiletine only for the treatment of LQT3 patients, its use for treatment-refractory VT storm seems to also be an important indication area.
Topics: Male; Humans; Aged; Mexiletine; Treatment Outcome; Anti-Arrhythmia Agents; Tachycardia, Ventricular; Defibrillators, Implantable; Catheter Ablation
PubMed: 37917362
DOI: 10.1007/s00399-023-00976-x