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Frontiers in Neurology 2020The aim of our study was to evaluate the long-term efficacy and safety of mexiletine in 112 patients affected by genetically confirmed non-dystrophic myotonias. The...
The aim of our study was to evaluate the long-term efficacy and safety of mexiletine in 112 patients affected by genetically confirmed non-dystrophic myotonias. The study was performed at the Neurophysiologic Division of Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome and the Children's Hospital Bambino Gesù, Rome. The treatment was accepted by 59 patients according to clinical severity, individual needs, and concerns about a chronic medication. Forty-three patients were affected by recessive congenita myotonia, 11 by sodium channel myotonia, and five by dominant congenital myotonia. They underwent clinical examination before and after starting therapy, and Electromyography (EMG). A number of recessive myotonia patients underwent a protocol of repetitive nerve stimulations, for detecting and quantifying the transitory weakness, and a modified version of the Timed Up and Go test, to document and quantify the gait impairment. Treatment duration ranged from 1 month to 20 years and the daily dosages in adults ranged between 200 and 600 mg. No patient developed cardiac arrhythmias causing drug discontinuation. Mexiletine was suspended in 13 cases (22%); in three patients, affected by Sodium Channel myotonia, because flecainide showed better efficacy; in one patient because of a gastric cancer antecedent treatment; in four patients because of untreatable dyspepsia; and five patients considered the treatment not necessary. In our experience, mexiletine is very useful and not expensive. We did not observe any hazarding cardiac arrhythmias. Dyspepsia was the most frequent dose-limiting side effect.
PubMed: 32655465
DOI: 10.3389/fneur.2020.00300 -
Channels (Austin, Tex.) Dec 2021: Mutations in SCN5A that decrease Na current underlie arrhythmia syndromes such as the Brugada syndrome (BrS). in humans has two splice variants, one lacking a...
Expression defect of the rare variant/Brugada mutation R1512W depends upon the SCN5A splice variant background and can be rescued by mexiletine and the common polymorphism H558R.
: Mutations in SCN5A that decrease Na current underlie arrhythmia syndromes such as the Brugada syndrome (BrS). in humans has two splice variants, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077. We investigated the effect of splice variant background on loss-of-function and rescue for R1512W, a mutation reported to cause BrS. : We made the mutation in both variants and expressed them in HEK-293 cells for voltage-clamp study. After 24 hours of transfection, the current expression level of R1512W was reduced by ~50% in both Q1077del and Q1077 compared to the wild-type (WT) channel, respectively. The activation and inactivation midpoint were not different between WT and mutant channels in both splice variant backgrounds. However, slower time constants of recovery and enhanced intermediate inactivation were observed for R1512W/Q1077 compared with WT-Q1077, while the recovery and intermediate inactivation parameters of R1512W/Q1077del were similar to WT-Q1077del. Furthermore, both mexiletine and the common polymorphism H558R restored peak sodium current () amplitude of the mutant channel by increasing the cell surface expression of SCN5A. : These findings provide further evidence that the splice variant affects the molecular phenotype with implications for the clinical phenotype, and they provide insight into the expression defect mechanisms and potential treatment in BrS.
Topics: HEK293 Cells; Humans; Mexiletine; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Phenotype; Sodium
PubMed: 33535892
DOI: 10.1080/19336950.2021.1875645 -
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 -
Muscle & Nerve Mar 2021To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double-blind randomized controlled trial.
METHODS
Twenty ALS subjects were randomized to placebo and mexiletine 300 or 600 mg daily for 4 wk and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT).
RESULTS
RMT was unchanged with 4 wk of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (P = .039). Reductions of motor evoked potential (MEP) amplitude (P = .013) and accommodation half-time (P = .002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 wk on mexiletine.
CONCLUSIONS
The relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half-time supports the reduction of cortical and axonal hyperexcitability with mexiletine.
Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Axons; Cortical Excitability; Double-Blind Method; Electrodiagnosis; Electromyography; Evoked Potentials, Motor; Female; Humans; Male; Median Nerve; Mexiletine; Middle Aged; Neural Conduction; Preliminary Data; Transcranial Magnetic Stimulation; Voltage-Gated Sodium Channel Blockers
PubMed: 33340120
DOI: 10.1002/mus.27146 -
Membranes Dec 2022A sodium channel blocker mexiletine (MEX) is used to treat chronic pain, myotonia and some arrhythmias. Mutations in the pore domain (PD) of voltage-gated sodium...
A sodium channel blocker mexiletine (MEX) is used to treat chronic pain, myotonia and some arrhythmias. Mutations in the pore domain (PD) of voltage-gated sodium channels differently affect tonic block (TB) and use-dependent block (UDB) by MEX. Previous studies identified several MEX-sensing residues in the hNav1.5 channel and demonstrated that the channel block by MEX increases with activation of the voltage-sensing domain III (VSD), whereas MEX stabilizes the activated state of VSD. Structural rationales for these observations are unclear. Here, Monte Carlo (MC) energy minimizations were used to dock MEX and its more potent analog, Thio-Me2, into the hNav1.5 cryo-EM structure with activated VSDs and presumably inactivated PD. Computations yielded two ensembles of ligand binding poses in close contacts with known MEX-sensing residues in helices S6, S6 and P1. In both ensembles, the ligand NH group approached the cation-attractive site between backbone carbonyls at the outer-pore bottom, while the aromatic ring protruded ether into the inner pore (putative UDB pose) or into the III/IV fenestration (putative TB pose). In silico deactivation of VSD shifted helices S4-S5, S5, S6 and S6 and tightened the TB site. In a model with activated VSD and three resting VSDs, MC-minimized energy profile of MEX pulled from the TB site towards lipids shows a deep local minimum due to interactions with 11 residues in S5, P1, S6 and S6. The minimum may correspond to an interim binding site for MEX in the hydrophobic path to the TB site along the lipid-exposed sides of repeats III and IV where 15 polar and aromatic residues would attract cationic blockers. The study explains numerous experimental data and suggests the mechanism of allosteric modification of the MEX binding site by VSD.
PubMed: 36557159
DOI: 10.3390/membranes12121252 -
Muscle & Nerve Oct 2022Peripheral neuropathies commonly affect quality of life of patients due to pain, sleep disturbances, and fatigue, although trials have not adequately explored these... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION/AIMS
Peripheral neuropathies commonly affect quality of life of patients due to pain, sleep disturbances, and fatigue, although trials have not adequately explored these domains of care. The aim of this study was to assess the impact of nortriptyline, duloxetine, pregabalin, and mexiletine on pain, sleep, and fatigue in patients diagnosed with cryptogenic sensory polyneuropathy (CSPN).
METHODS
We implemented a Bayesian adaptive design to perform a 12-wk multisite, randomized, prospective, open-label comparative effectiveness study in 402 CSPN patients. Participants received either nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). At prespecified analysis timepoints, secondary outcomes, Patient Reported Outcomes Measurement Information System (PROMIS) surveys including Short Form (SF)-12, pain interference, fatigue, and sleep disturbance, were collected.
RESULTS
Mexiletine had the highest quit rate (58%) due to gastrointestinal side effects, while nortriptyline (38%) and duloxetine (38%) had the lowest quit rates. If tolerated for the full 12 wk of the study, mexiletine had the highest probability (>90%) of positive outcomes for improvements in pain interference and fatigue. There was no significant difference among the medications for sleep disturbance or SF-12 scores. Adverse events and lack of efficacy were the two most common reasons for cessation of therapy.
DISCUSSION
Physicians caring for patients with CSPN should consider mexiletine to address pain and fatigue, although nortriptyline and duloxetine are better medications to trial first since they are better tolerated. Future research should compare other commonly used medications for CSPN to determine evidence-based treatment strategies.
Topics: Activities of Daily Living; Bayes Theorem; Diabetic Neuropathies; Double-Blind Method; Duloxetine Hydrochloride; Fatigue; Humans; Mexiletine; Nortriptyline; Pain; Pregabalin; Prospective Studies; Quality of Life; Sleep; Treatment Outcome
PubMed: 35585718
DOI: 10.1002/mus.27637 -
Oncotarget Aug 2018Due to conflicting evidence regarding first-line therapies for chronic post-surgical pain (CPSP), here we comparatively evaluated the efficacy and safety of first-line...
BACKGROUND
Due to conflicting evidence regarding first-line therapies for chronic post-surgical pain (CPSP), here we comparatively evaluated the efficacy and safety of first-line therapies for the prevention of CPSP.
MATERIALS AND METHODS
MEDLINE, EMBASE, and Cochrane CENTRAL databases were searched for randomized, controlled trials (RCTs) of systemic drugs measuring pain three months or more post-surgery. Pairwise meta-analyses (a frequentist technique directly comparing each intervention against placebo) and network meta-analyses (a Bayesian technique simultaneously comparing several interventions via an evidence network) compared the mean differences for primary efficacy (reduction in all pain), secondary efficacy (reduction in moderate or severe pain), and primary safety (drop-out rate from treatment-related adverse effects). Ranking probabilities from the network meta-analysis were transformed using surface under the cumulative ranking analysis (SUCRA). Sensitivity analyses evaluated the impact of age, gender, surgery type, and outlier studies.
RESULTS
Twenty-four RCTs were included. Mexiletine and ketamine ranked highest in primary efficacy, while ketamine and nefopam ranked highest in secondary efficacy. Simultaneous SUCRA-based rankings of the interventions according to both efficacy and safety revealed that nefopam and mexiletine ranked highest in preventing CPSP. Through the sensitivity analyses, gabapentin and ketamine remained the most-highly-ranked in terms of efficacy, while nefopam and ketamine remained the most-highly-ranked in terms of safety.
CONCLUSIONS
Nefopam and mexiletine may be considered as first-line therapies for the prevention of CPSP. On account of the paucity of evidence available on nefopam and mexiletine, gabapentin and ketamine may also be considered. Venlafaxine is not recommended for the prevention of CPSP.
PubMed: 30174798
DOI: 10.18632/oncotarget.22611 -
Drug Discovery Today Jul 2021Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular genetic disease with an estimated prevalence of approximately at least half a million individuals based... (Review)
Review
Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular genetic disease with an estimated prevalence of approximately at least half a million individuals based on its vast ethnic variation. Building upon a well-known physiopathology and several proof-of-concept therapeutic approaches, herein we compile a comprehensive overview of the most recent drug development programs under preclinical and clinical evaluation. Specifically, close to two dozen drug developments, eight of which are already in clinical trials, explore a diversity of new chemical entities, drug repurposing, oligonucleotide, and gene therapy-based approaches. Of these, repurposing of tideglusib, mexiletine, or metformin appear to be therapies with the most potential to receive marketing authorization for DM1.
Topics: Animals; Drug Development; Humans; Myotonic Dystrophy
PubMed: 33798646
DOI: 10.1016/j.drudis.2021.03.024 -
JMIR Cardio Jan 2023Drug-induced prolongation of the corrected QT interval (QTc) increases the risk for Torsades de Pointes (TdP) and sudden cardiac death. Medication effects on the QTc...
BACKGROUND
Drug-induced prolongation of the corrected QT interval (QTc) increases the risk for Torsades de Pointes (TdP) and sudden cardiac death. Medication effects on the QTc have been studied in controlled settings but may not be well evaluated in real-world settings where medication effects may be modulated by patient demographics and comorbidities as well as the usage of other concomitant medications.
OBJECTIVE
We demonstrate a new, high-throughput method leveraging electronic health records (EHRs) and the Surescripts pharmacy database to monitor real-world QTc-prolonging medication and potential interacting effects from demographics and comorbidities.
METHODS
We included all outpatient electrocardiograms (ECGs) from September 2008 to December 2019 at a large academic medical system, which were in sinus rhythm with a heart rate of 40-100 beats per minute, QRS duration of <120 milliseconds, and QTc of 300-700 milliseconds, determined using the Bazett formula. We used prescription information from the Surescripts pharmacy database and EHR medication lists to classify whether a patient was on a medication during an ECG. Negative control ECGs were obtained from patients not currently on the medication but who had been or would be on that medication within 1 year. We calculated the difference in mean QTc between ECGs of patients who are on and those who are off a medication and made comparisons to known medication TdP risks per the CredibleMeds.org database. Using linear regression analysis, we studied the interaction of patient-level demographics or comorbidities on medication-related QTc prolongation.
RESULTS
We analyzed the effects of 272 medications on 310,335 ECGs from 159,397 individuals. Medications associated with the greatest QTc prolongation were dofetilide (mean QTc difference 21.52, 95% CI 10.58-32.70 milliseconds), mexiletine (mean QTc difference 18.56, 95% CI 7.70-29.27 milliseconds), amiodarone (mean QTc difference 14.96, 95% CI 13.52-16.33 milliseconds), rifaximin (mean QTc difference 14.50, 95% CI 12.12-17.13 milliseconds), and sotalol (mean QTc difference 10.73, 95% CI 7.09-14.37 milliseconds). Several top QT prolonging medications such as rifaximin, lactulose, cinacalcet, and lenalidomide were not previously known but have plausible mechanistic explanations. Significant interactions were observed between demographics or comorbidities and QTc prolongation with many medications, such as coronary disease and amiodarone.
CONCLUSIONS
We demonstrate a new, high-throughput technique for monitoring real-world effects of QTc-prolonging medications from readily accessible clinical data. Using this approach, we confirmed known medications for QTc prolongation and identified potential new associations and demographic or comorbidity interactions that could supplement findings in curated databases. Our single-center results would benefit from additional verification in future multisite studies that incorporate larger numbers of patients and ECGs along with more precise medication adherence and comorbidity data.
PubMed: 36662566
DOI: 10.2196/41055 -
International Journal of Molecular... Jan 2023The voltage-gated sodium channels represent an important target for drug discovery since a large number of physiological processes are regulated by these channels. In... (Review)
Review
The voltage-gated sodium channels represent an important target for drug discovery since a large number of physiological processes are regulated by these channels. In several excitability disorders, including epilepsy, cardiac arrhythmias, chronic pain, and non-dystrophic myotonia, blockers of voltage-gated sodium channels are clinically used. Myotonia is a skeletal muscle condition characterized by the over-excitability of the sarcolemma, resulting in delayed relaxation after contraction and muscle stiffness. The therapeutic management of this disorder relies on mexiletine and other sodium channel blockers, which are not selective for the Na1.4 skeletal muscle sodium channel isoform. Hence, the importance of deepening the knowledge of molecular requirements for developing more potent and use-dependent drugs acting on Na1.4. Here, we review the available treatment options for non-dystrophic myotonia and the structure-activity relationship studies performed in our laboratory with a focus on new compounds with potential antimyotonic activity.
Topics: Humans; Mexiletine; Muscle, Skeletal; Myotonia; NAV1.4 Voltage-Gated Sodium Channel; Syndrome; Voltage-Gated Sodium Channel Blockers
PubMed: 36614292
DOI: 10.3390/ijms24010857