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Current Medicinal Chemistry 2021Mexiletine is an antiarrhythmic drug belonging to IB class, acting as sodium channel blocker. Besides its well-known activity on arrhythmias, its usefulness in the... (Review)
Review
Mexiletine is an antiarrhythmic drug belonging to IB class, acting as sodium channel blocker. Besides its well-known activity on arrhythmias, its usefulness in the treatment of myotonia, myotonic dystrophy and amyotrophic lateral sclerosis is now widely recognized. Nevertheless, it has been retired from the market in several countries because of its undesired effects. Thus, several papers were reported in the last years about analogues and homologues of mexiletine being endowed with a wider therapeutic ratio and a more selectivity of action. Some of them showed sodium channel blocking activity higher than the parent compound. It is noteworthy that mexiletine is used in therapy as a racemate even though a difference in the activities of the two enantiomers was widely demonstrated, with (-)-(R)-enantiomer being more active: this finding led several research groups to study mexiletine and its analogues and homologues in their optically active forms. This review summarizes the different synthetic routes used to obtain these compounds. They could represent an interesting starting point to new mexiletine-like compounds without common side effects related to the use of mexiletine.
Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Humans; Mexiletine; Sodium Channel Blockers; Voltage-Gated Sodium Channel Blockers
PubMed: 32364065
DOI: 10.2174/0929867327666200504080530 -
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 -
Journal of Clinical Neuromuscular... Sep 2016The Guillain-Barré syndrome (GBS) is one of the few neuropathies well known to the general public, in part because of its association with swine flu vaccinations in...
The Guillain-Barré syndrome (GBS) is one of the few neuropathies well known to the general public, in part because of its association with swine flu vaccinations in 1976. GBS has again reached the general public with its possible association with Zika virus. The virus, borne by infected Aedes aegypti mosquitos, is being linked to birth defects when pregnant women are bitten and infected. There are early reports also linking GBS to Zika infection, which could expose a wider range of infected people to the neuropathy. This summer infected Aedes mosquitos will likely reach southern portions of the United States, and travelers to countries where Aedes is endemic will increase. It is important to appreciate that the neurologic consequences of Zika virus are being actively investigated, and firm associations and consequences are yet to be established. Small fiber neuropathies are common and can be due to a number of underlying diseases, and a recent review also indicates that many are idiopathic. One cause is Sjögren syndrome, and a case series reviews clinical features. The diagnosis and underlying features of primary lateral sclerosis are a clinical challenge. Similarities between primary lateral sclerosis and hereditary spastic paraparesis (HSP) have long been noted. With a wide spectrum of gene mutations associated with HSP, clinical distinction between the 2 disorders is problematic. A review covers the wide spectrum of HSP. With no cure, the progression of amyotrophic lateral sclerosis (ALS) to respiratory failure is predictable. This could easily result in marked depression among patients, and 2 studies have explored the frequency and severity of depression. The cause of ALS remains unknown, and when no hereditary factor is apparent, environmental questions arise as possible contributing factor(s). The most notable association is with military service, although specific occupational or environmental linkages are not well sorted out. Two recent reports address these issues. There is good news for ALS patients with muscle cramps with the results of a multicenter randomized and placebo-controlled trial showing that mexiletine is effective in reducing this common symptom. The treatment of myasthenia gravis with various agents, the use of patient-reported outcome measures in myasthenia gravis, and the occurrence of myocarditis in this disease are reviewed. Necrotizing autoimmune neuropathies, the co-occurrence of inclusion body myositis and a form of T-cell leukemia are discussed as are valosin-containing protein (VCP)-opathy and bone health in patients with dystrophinopathy.
PubMed: 27552392
DOI: 10.1097/CND.0000000000000139 -
La Revue de Medecine Interne Mar 2017Erythromelalgia is a rare intermittent vascular acrosyndrome characterized by the combination of recurrent burning pain, warmth and redness of the extremities. It is... (Review)
Review
Erythromelalgia is a rare intermittent vascular acrosyndrome characterized by the combination of recurrent burning pain, warmth and redness of the extremities. It is considered in its primary form as an autosomal dominant neuropathy related to mutations of SCN9A, the encoding gene of a voltage-gated sodium channel subtype Nav1.7. Secondary erythromelalgia is associated with myeloproliferative disorders, drugs (bromocriptine, calcium channel blockers), or clinical conditions such as rheumatic diseases or viral infection. Primary familial erythromelalgia include genetics and sporadic forms associated with small fibers neuropathy. Aspirin is a useful treatment of erythromelagia associated with myeloproliferative disorders. Treatment of primary erythromelalgia is difficult, individualized, with sodium channel blockers such as lidocaine, carbamazepine and mexiletine.
Topics: Calcium Channel Blockers; Diagnostic Techniques and Procedures; Erythromelalgia; Humans; Sodium Channel Blockers
PubMed: 27639908
DOI: 10.1016/j.revmed.2016.08.012 -
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 -
Oncotarget Feb 2017
Topics: Amines; Animals; Anti-Arrhythmia Agents; Chloride Channels; Humans; Ligands; Mexiletine; Mice; Muscle, Skeletal; Muscular Diseases; Mutation; Precision Medicine; Rats; Sarcolemma; Sodium Channel Blockers; Syndrome
PubMed: 28199958
DOI: 10.18632/oncotarget.15263 -
Value in Health : the Journal of the... Jul 2021Mexiletine is a long-known drug used for the treatment of arrhythmias and repurposed in the 1980s for patients with nondystrophic myotonia (NDM). Recently, the price of...
OBJECTIVES
Mexiletine is a long-known drug used for the treatment of arrhythmias and repurposed in the 1980s for patients with nondystrophic myotonia (NDM). Recently, the price of mexiletine in Europe increased significantly after registration as an orphan drug for NDM. This led to international discussions on affordability and willingness to reimburse mexiletine in the absence of background information that would justify such a price. Our objective was to calculate a cost-based price for mexiletine for adult patients with NDM based on detailed information on development costs.
METHODS
We calculated a fair price based on a cost-based pricing model for commercial mexiletine to treat adults with NDM using a recent European drug-pricing model as a framework to include actual costs incurred. Three scenarios were applied: 1 with minimum estimated costs, 1 with maximum estimated costs, and 1 with costs as if mexiletine was innovative.
RESULTS
The calculated fair price of mexiletine per patient per year (PPPY) is €452 for the minimum scenario and €1996 for the maximum scenario. By using hypothetical R&D costs used for innovative drugs, the price would be €6685 PPPY. In Europe, the list price of mexiletine ranges from €30 707-60 730 PPPY, based on 600 mg daily.
CONCLUSIONS
The current list price for mexiletine in Europe is manifold higher than any scenario of the cost-based models. Accounting for the reduced costs for clinical development in a repurposing scenario, the cost-based pricing model provides a fair commercial price range, which can be used as benchmark for pricing negotiations and/or reimbursement decisions.
Topics: Anti-Arrhythmia Agents; Commerce; Drug Repositioning; Europe; Humans; Mexiletine; Myotonia; Orphan Drug Production
PubMed: 34243835
DOI: 10.1016/j.jval.2021.02.004 -
Neurologic Clinics Aug 2020Muscle cramps, defined as a painful contraction of a muscle or muscle group, are a common symptom most people have experienced throughout their lifespan. In some cases... (Review)
Review
Muscle cramps, defined as a painful contraction of a muscle or muscle group, are a common symptom most people have experienced throughout their lifespan. In some cases cramps can be frequent, severe, and disabling, thus requiring medical assessment and intervention. Physiologic states such as pregnancy and exercise are associated with excessive muscle cramps, as are numerous medical and neurologic conditions, medications such as diuretics and statins, and peripheral nerve hyperexcitability syndromes. Treatment options for muscle cramps are limited, although recent studies have shown that mexiletine could be a safe and efficient alternative for patients with amyotrophic lateral sclerosis.
Topics: Adult; Disease Management; Female; Humans; Male; Mexiletine; Middle Aged; Muscle Cramp; Pregnancy; Voltage-Gated Sodium Channel Blockers; Young Adult
PubMed: 32703476
DOI: 10.1016/j.ncl.2020.03.011 -
Muscle & Nerve Jul 2022The muscle relaxant methocarbamol and the antimyotonic drug mexiletine are widely used for the treatment of muscle spasms, myotonia, and pain syndromes. To determine...
INTRODUCTION/AIMS
The muscle relaxant methocarbamol and the antimyotonic drug mexiletine are widely used for the treatment of muscle spasms, myotonia, and pain syndromes. To determine whether these drugs affect muscle spindle function, we studied their effect on the resting discharge and on stretch-induced action potential frequencies of proprioceptive afferent neurons.
METHODS
Single unit action potential frequencies of proprioceptive afferents from muscle spindles in the murine extensor digitorum longus muscle of adult C57BL/6J mice were recorded under resting conditions and during ramp-and-hold stretches. Maximal tetanic force of the same muscle after direct stimulation was determined. High-resolution confocal microscopy analysis was performed to determine the distribution of Na 1.4 channels, a potential target for both drugs.
RESULTS
Methocarbamol and mexiletine inhibited the muscle spindle resting discharge in a dose-dependent manner with IC values around 300 μM and 6 μM, respectively. With increasing concentrations of both drugs, the response to stretch was also affected, with the static sensitivity first followed by the dynamic sensitivity. At high concentrations, both drugs completely blocked muscle spindle afferent output. Both drugs also reversibly reduced the specific force of the extensor digitorum longus muscle after tetanic stimulation. Finally, we present evidence for the presence and specific localization of the voltage-gated sodium channel Na 1.4 in intrafusal fibers.
DISCUSSION
In this study we demonstrate that both muscle relaxants affect muscle spindle function, suggesting impaired proprioception as a potential side effect of both drugs. Moreover, our results provide additional evidence of a peripheral activity of methocarbamol and mexiletine.
Topics: Animals; Methocarbamol; Mexiletine; Mice; Mice, Inbred C57BL; Muscle Spindles; Muscle, Skeletal; Neurons, Afferent
PubMed: 35373353
DOI: 10.1002/mus.27546 -
BMJ Open Sep 2018Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive neuromuscular disease. Cold exposure often leads to worsening of motor symptoms including paresis....
Study protocol for the MEXiletine hydrochloride administration trial: a placebo-controlled, randomised, double-blind, multicentre, crossover study of its efficacy and safety in spinal and bulbar muscular atrophy (MEXPRESS).
INTRODUCTION
Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive neuromuscular disease. Cold exposure often leads to worsening of motor symptoms including paresis. Although mexiletine hydrochloride administration has been shown to be effective for the treatment of several muscular diseases, its effectiveness in SBMA has not been validated to date. The trial will test it as a symptomatic drug for cold paresis. This study is the first trial to evaluate the efficacy and safety of mexiletine hydrochloride administration in patients with SBMA.
METHODS AND ANALYSIS
A placebo-controlled, randomised, double-blind, multicentre, crossover clinical trial will be conducted to assess the safety and efficacy of mexiletine hydrochloride in patients with SBMA. The eligible patients will be assigned randomly in a 1:1 ratio to two groups in a double-blind manner. Participants will take mexiletine hydrochloride (300 mg/day) or a placebo orally three times a day for 4 weeks (period 1). After a 1-week washout period, participants will take the other drug for 4 weeks (period 2). The primary endpoint is the difference in distal latencies between room temperature and cold exposure conditions.
ETHICS AND DISSEMINATION
This study will be conducted in compliance with the Helsinki Declaration and the Ethical Guidelines for Medical and Health Research Involving Human Subjects by the Japanese government and has been approved by the ethics committee of Nagoya University Graduate School of Medicine, as a central institutional review board, and by each facility. The results will be disseminated in peer-reviewed journals and at scientific conferences.
TRIAL REGISTRATION NUMBER
UMIN000026150; Pre-results.
Topics: Adult; Aged; Aged, 80 and over; Humans; Male; Middle Aged; Activities of Daily Living; Bulbo-Spinal Atrophy, X-Linked; Cold Temperature; Cross-Over Studies; Double-Blind Method; Drug Monitoring; Japan; Mexiletine; Neurologic Examination; Paresis; Treatment Outcome; Voltage-Gated Sodium Channel Blockers; Multicenter Studies as Topic; Randomized Controlled Trials as Topic
PubMed: 30206090
DOI: 10.1136/bmjopen-2018-023041