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American Journal of Translational... 2021Intersubject variability in drug response, whether related to efficacy or toxicity, is well recognized clinically. Over the years, drug selection from our pharmacologic... (Review)
Review
Intersubject variability in drug response, whether related to efficacy or toxicity, is well recognized clinically. Over the years, drug selection from our pharmacologic armamentarium has moved from providers' preferred choices to more personalized treatments as clinicians' decisions are guided by data from clinical trials. Since the advent of more accessible and affordable pharmacogenomic (PGx) testing, the promise of precise pharmacotherapy has been made. Results have accumulated in the literature with numerous examples demonstrating the value of PGx to improve drug response or prevent drug toxicity. Unfortunately, limited availability of reimbursement policies has dampened the enthusiasm of providers and organizations. The clinical application of PGx knowledge remains difficult for most clinicians under real-world conditions in patients with numerous chronic conditions and polypharmacy. This may be due to phenoconversion, a condition where there is a discrepancy between the genotype-predicted phenotype and the observed phenotype. This condition complicates the interpretation of PGx results and may lead to inappropriate recommendations and clinical decision making. For this reason, regulatory agencies have limited the transfer of information from PGx laboratories directly to consumers, especially recommendations about the use of certain drugs. This mini-review presents cases (mexiletine, propafenone, clopidogrel, warfarin, codeine, procainamide) from historical observations where drug response was modified by phenoconversion. The cases illustrate, from decades ago, that we are still in great need of advanced clinical decision systems that cope with conditions associated with phenoconversion, especially in patients with polypharmacy.
PubMed: 35035679
DOI: No ID Found -
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 -
Archives of Cardiovascular Diseases 2024In France, mexiletine - a class I antiarrhythmic drug - can be prescribed for the symptomatic treatment of myotonia of the skeletal muscles in adult patients with... (Review)
Review
In France, mexiletine - a class I antiarrhythmic drug - can be prescribed for the symptomatic treatment of myotonia of the skeletal muscles in adult patients with myotonic dystrophy under a compassionate use programme. Mexiletine is used according to its summary of product characteristics, which describes its use for myotonia treatment in adult patients with non-dystrophic myotonia, a different neuromuscular condition without cardiac involvement. A cardiac assessment is required prior to initiation and throughout treatment due to potential proarrhythmic effects. The presence of conduction system disease, the most common cardiac manifestation of myotonic dystrophy, mandates repeated cardiac evaluations in patients with this condition, and becomes even more important when they are given mexiletine. A group of experts, including three neurologists and five cardiologists from French neuromuscular reference centres, were involved in a task force to develop a treatment algorithm to guide mexiletine use in myotonic dystrophy. The recommendations are based on data from a literature review of the safety of mexiletine-treated patients with myotonic dystrophy, the compassionate use protocol for mexiletine and the personal clinical experience of the experts. The main conclusion of the expert group is that, although existing safety data in mexiletine-treated patients with myotonic dystrophy are reassuring, cardiac assessments should be reinforced in such patients compared with mexiletine-treated patients with non-dystrophic myotonia. This expert opinion to guide mexiletine treatment in patients with myotonic dystrophy should help to reduce the risk of severe adverse events and facilitate interactions between specialists involved in the routine care of patients with myotonic dystrophy.
Topics: Adult; Humans; Algorithms; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Decision-Making; Compassionate Use Trials; Consensus; France; Mexiletine; Myotonic Dystrophy; Risk Assessment; Risk Factors; Treatment Outcome; Voltage-Gated Sodium Channel Blockers
PubMed: 38677940
DOI: 10.1016/j.acvd.2024.03.001 -
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 -
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 -
Neurology. Clinical Practice Oct 2021Myotonic dystrophy types 1 and 2 are progressive multisystem genetic disorders whose core clinical feature is myotonia. Mexiletine, an antagonist of voltage-gated sodium...
BACKGROUND AND OBJECTIVE
Myotonic dystrophy types 1 and 2 are progressive multisystem genetic disorders whose core clinical feature is myotonia. Mexiletine, an antagonist of voltage-gated sodium channels, is a recommended antimyotonic agent in the nondystrophic myotonias, but its use in myotonic dystrophy is limited because of lack of data regarding its long-term efficacy and safety profile.
METHODS
To address this issue, this study retrospectively evaluated patients with myotonic dystrophy receiving mexiletine over a mean time period of 32.9 months (range 0.1-216 months).
RESULTS
This study demonstrated that 96% of patients reported some improvement in myotonia symptoms with mexiletine treatment. No clinically relevant cardiac adverse events were associated with the long-term use of mexiletine.
CONCLUSIONS
These findings support that mexiletine is both safe and effective when used long-term in myotonic dystrophy.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence that mexiletine is a well-tolerated and effective treatment for myotonic dystrophy types 1 and 2.
PubMed: 34840883
DOI: 10.1212/CPJ.0000000000001073 -
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 -
Pharmacology Research & Perspectives Aug 2021Prolongation of the cardiac action potential (AP) and early after depolarizations (EADs) are electrical anomalies of cardiomyocytes that can lead to lethal arrhythmias...
Prolongation of the cardiac action potential (AP) and early after depolarizations (EADs) are electrical anomalies of cardiomyocytes that can lead to lethal arrhythmias and are potential liabilities for existing drugs and drug candidates in development. For example, long QT syndrome-3 (LQTS3) is caused by mutations in the Na 1.5 sodium channel that debilitate channel inactivation and cause arrhythmias. We tested the hypothesis that a useful drug (i.e., mexiletine) with potential liabilities (i.e., potassium channel inhibition and adverse reactions) could be re-engineered by dynamic medicinal chemistry to afford a new drug candidate with greater efficacy and less toxicity. Human cardiomyocytes were generated from LQTS3 patient-derived induced pluripotent stem cells (hIPSCs) and normal hIPSCs to determine beneficial (on-target) and detrimental effects (off-target) of mexiletine and synthetic analogs, respectively. The approach combined "drug discovery" and "hit to lead" refinement and showed that iterations of medicinal chemistry and physiological testing afforded optimized compound 22. Compared to mexiletine, compound 22 showed a 1.85-fold greater AUC and no detectable CNS toxicity at 100 mg/kg. In vitro hepatic metabolism studies showed that 22 was metabolized via cytochrome P-450, as previously shown, and by the flavin-containing monooxygenase (FMO). Deuterated-22 showed decreased metabolism and showed acceptable cardiovascular and physicochemical properties.
Topics: Animals; Behavior, Animal; Cells, Cultured; Female; Humans; Induced Pluripotent Stem Cells; Liver; Long QT Syndrome; Male; Mexiletine; Mice, Inbred BALB C; Myocytes, Cardiac; Rats, Sprague-Dawley; Seizures; Mice; Rats
PubMed: 34327875
DOI: 10.1002/prp2.828 -
Frontiers in Pharmacology 2023This study aimed to identify the different associations between antiarrhythmic drugs (AADs) and arrhythmias, and to determine whether pharmacokinetic drug interactions...
This study aimed to identify the different associations between antiarrhythmic drugs (AADs) and arrhythmias, and to determine whether pharmacokinetic drug interactions involving AADs increase the risk of AAD-related arrhythmias compared to using AADs alone. The disproportionality analysis of AAD-associated cardiac arrhythmias, including AAD monotherapies and concomitant use of pharmacokinetic interacting agents involving AADs, was conducted by using reporting odds ratio (ROR) and information component (IC) as detection of potential safety signals based on FAERS data from January 2016 to June 2022. We compared the clinical features of patients reported with AAD-associated arrhythmias between fatal and non-fatal groups, and further investigated the onset time (TTO) following different AAD regimens. A total of 11754 AAD-associated cardiac arrhythmias reports were identified, which was more likely to occur in the elderly (52.17%). Significant signals were detected between cardiac arrhythmia and all AAD monotherapies, with ROR ranging from 4.86 with mexiletine to 11.07 with flecainide. Regarding four specific arrhythmias in High Level Term (HLT) level, the AAD monotherapies with the highest ROR were flecainide in cardiac conduction disorders (ROR025 = 21.18), propafenone in rate and rhythm disorders (ROR025 = 10.36), dofetilide in supraventricular arrhythmias (ROR025 = 17.61), and ibutilide in ventricular arrhythmias (ROR025 = 4.91). Dofetilide/ibutilide, ibutilide, mexiletine/ibutilide and dronedarone presented no signal in the above four specific arrhythmias respectively. Compared with amiodarone monotherapy, sofosbuvir plus amiodarone detected the most significantly increased ROR in arrhythmias. The investigation showed the spectrum and risk of AAD-associated cardiac arrhythmias varied among different AAD therapies. The early identification and management of AAD-associated arrhythmias are of great importance in clinical practice.
PubMed: 37251345
DOI: 10.3389/fphar.2023.1170039 -
Frontiers in Neurology 2022Non-dystrophic myotonias (NDMs) are skeletal muscle ion channelopathies caused by or mutations. This study aimed to describe the clinical, myopathological, and genetic...
INTRODUCTION
Non-dystrophic myotonias (NDMs) are skeletal muscle ion channelopathies caused by or mutations. This study aimed to describe the clinical, myopathological, and genetic analysis of NDM in a large Chinese cohort.
METHODS
We reviewed the clinical manifestations, laboratory results, electrocardiogram, electromyography, muscle biopsy, genetic analysis, treatment, and follow-up of 20 patients (from 18 families) with NDM.
RESULTS
Cases included myotonia congenita (MC, 17/20) and paramyotonia congenita (PMC, 3/20). Muscle stiffness and hypertrophy, grip and percussion myotonia, and the warm-up phenomenon were frequently observed in MC and PMC patients. Facial stiffness, eye closure myotonia, and cold sensitivity were more common in PMC patients and could be accompanied by permanent weakness. Nine MC patients and two PMC patients had cardiac abnormalities, mainly manifested as cardiac arrhythmia, and the father of one patient died of sudden cardiac arrest. Myotonic runs in electromyography were found in all patients, and seven MC patients had mild myopathic changes. There was no difference in muscle pathology between MC and PMC patients, most of whom had abnormal muscle fiber type distribution or selective muscle fiber atrophy. Nineteen variants were found in 17 MC patients, among which c.795T>G (p.D265E) was a new variant, and two variants were found in three PMC patients. The patients were treated with mexiletine and/or carbamazepine, and the symptoms of myotonia were partially improved.
CONCLUSIONS
MC and PMC have considerable phenotypic overlap. Genetic investigation contributes to identifying the subtype of NDM. The muscle pathology of NDM lacks specific changes.
PubMed: 35350395
DOI: 10.3389/fneur.2022.830707