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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.

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., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

1. Evaluate the role of lidocaine infusion and it's opioid-sparing effect in the treatment of neuropathic pain in patients with malignancy. 2. Integrate suggested protocol of lidocaine-infusion taper and cross titration to mexiletine for patients with neuropathic pain in the setting of malignancy. Lidocaine infusion has been used for pain control for many years with beneficial effects. One study has shown that analgesic efficacy of lidocaine also predicts analgesic effects of mexiletine. While some institutions transition from continuous-infusion lidocaine to oral mexiletine, guidance is lacking on an effective conversion method in pain and palliative care settings. Lidocaine and mexiletine both have analgesic properties and have been predominantly studied for treatment of neuropathic pain. Specifically, lidocaine has been used for treatment of peripheral nerve injury, post-herpetic neuralgia, neuropathic cancer pain, diabetic neuropathy, fibromyalgia, and sickle cell pain. This is a retrospective case series of 10 cancer patients across four institutions with attention to dosing of both lidocaine and mexiletine. The cases were compiled over an 18-month period. The patients involved were adult hospitalized patients who were followed by the palliative care service and were receiving opioid therapy with concomitant intravenous lidocaine and subsequent oral mexiletine. The goal was to determine the average starting dose for oral mexiletine and determine the potential opioid-sparing effect of lidocaine. For cancer patients with suboptimal pain control on large doses of opioid, lidocaine infusion followed by oral mexiletine was well tolerated and effective. There was also an overall decrease in average MEDD. These cases propose a conversion recommendation from intravenous lidocaine to oral mexiletine for treatment of neuropathic pain in the setting of malignancy. Intravenous lidocaine is an effective option, and conversion to oral mexiletine appears to be safe and efficacious in patients who had a positive response to lidocaine. We propose a taper of lidocaine infusion over 2 days with a cross titration of mexiletine. Use an initial mexiletine dose of 150 mg every 12 hours, increased to a target dose of 200 mg every 8 hours if tolerated. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate possible treatment-related hemodynamic changes, we administered ranolazine or mexiletine to swine with heart failure (HF) and to controls.Background: Ranolazine and mexiletine potently inhibit depolarizing late Na+ current (INa,late) and Na+ entry into cardiomyocytes. Blocking Na+ entry may increase forward-mode Na/Ca exchange and reduce cellular Ca+2 load, further compromising systolic contraction during HF.Methods and Results: Anesthetized tachypaced HF swine received ranolazine (n = 9) or mexiletine (n = 7) as boluses, then as infusions; the same experiments were performed in 10 nonpaced controls. The swine with HF had characteristic elevated left ventricular end-diastolic pressure (LVEDP) and reduced maximal left ventricular pressure rise (+dP/dtmax) and left ventricular peak systolic pressure (LVSP). No significant change occurred after ranolazine dosing for any parameter: LVEDP, +dP/dtmax, LVSP, heart rate, maximal LV pressure fall rate (-dP/dtmax), or time constant for isovolumic relaxation. Similar results seen in additional swine with HF: 7 were given mexiletine, and 7 others were given ranolazine after a 27% rate decrement to maximize INa,late. Patch-clamped HF cardiomyocytes confirmed drug-induced INa,late blockade.Conclusions: Ranolazine or mexiletine blocking INa,late neither worsened nor improved hemodynamics during advanced HF. Although results must be clinically confirmed, they suggest inhibition of INa,late by ranolazine or mexiletine may not exacerbate HF in patients. [ABSTRACT FROM AUTHOR]

For applying a genotype‐based treatment in neonatal long QT syndrome (LQTS), early detection of the genotype becomes an important issue. We report a case of a neonate with LQTS type 3 that presented with 2:1 atrioventricular block and underwent a mexiletine infusion challenge test, and achieved shortening of the QTc and 1:1 atrioventricular conduction. The mexiletine infusion challenge test was helpful to make an early detection of the genotype of the LQTS and predicted the drug efficacy in a neonatal patient. [ABSTRACT FROM AUTHOR]

Mexiletine as the first choice drug in myotonia treatment is a chiral sodium channel blocker clinically used in its racemic form. The phenolic structure of this drug, prompted us to design its novel calix[4]arene-based cluster in a chalice-shaped structure. Therefore, the present study reports the synthesis and in-vitro anti-myotonic activity of the chalice-shaped cluster of mexiletine (namely calixmexitil) in comparison to its simple drug unit (mexitil) as the reference medication. The synthetic route included chemical modification of the calix[4] arene structure by grafting four 2-aminopropoxy moieties at the lower rim of the scaffold. Electrophysiological tests were performed for the determination of test compounds abilities to act as sodium channel blockers in inhibiting sodium currents (in use-dependent manner) in single skeletal muscle fibers. The experimental results showed an amplified (10-fold) potency in producing phasic block as an indication of the anti-myotonic activity and improved (3-fold) potency in producing use-dependent block for the cluster (calixmexitil) in relation to its monomer (mexiletine). The potency in producing phasic block and use-dependent block are two main factors to describe dose range, drug affinity, and side effects of an antimyotonic agent. Therefore, compared to mexiletine, calixmexitil with these improved factors can be considered as a "selective" anti-myotonic agent with low dose range. These improved pharmaceutical effects are maybe attributed to clustering effect and improved interaction of four impacted mexiletine units of the cluster with the sodium channels' structure in skeletal muscle fibers. [ABSTRACT FROM AUTHOR]

Background: Internationally, use of lidocaine infusions to treat cancer pain varies by center. Existing systematic reviews do not adequately inform use of lidocaine in cancer pain. Objective: To assess the effects of systemic sodium channel blockers on cancer pain in adults, review the dose protocols for administration, and assess toxicity. Design: Databases CENTRAL, MEDLINE, Embase, LILACS, CareSearch, and OpenGrey were searched from inception to 2016. Conference abstracts and reference lists were handsearched, and the lead investigators of included trials and Australian manufacturers were contacted. Included studies were randomized controlled trials evaluating one or more of lidocaine via intravenous or subcutaneous route, or mexiletine, flecainide, or tocainide via oral route; delivered at a site distant to the pain locus. The methodological quality of studies was assessed using the "risk of bias" domain-based evaluation by Jadad. Protocol is available on PROSPERO:CRD42016047092. Results: One positive (n = 50) and three negative (n = 10 each) crossover trials evaluated lidocaine versus placebo, and one trial (n = 16) compared lidocaine with dexmedetomidine. Meta-analysis of pooled data in 60 patients demonstrated a significant benefit of lidocaine infusion of 4–5 mg/kg over 30–80 minutes compared with placebo for >50% reduction in cancer pain. Secondary outcomes did not show a significant difference. Discussion: Based on the current available evidence, lidocaine infusion could be considered in refractory cancer pain where agents with level 1 evidence are ineffective. Further research is necessary to understand the protocol and population in which lidocaine may improve cancer pain and capitalize on the promising opportunities identified. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Sodium channel myotonia and paramyotonia congenita are caused by gain-of-function mutations in the skeletal muscle voltage-gated sodium channel hNav1.4. The first-line drug is the sodium channel blocker mexiletine; however, some patients show side effects or limited responses. We previously showed that two hNav1.4 mutations, p.G1306E and p.P1158L, reduce mexiletine potency in vitro, whereas another sodium channel blocker, flecainide, is less sensitive to mutation-induced gating defects. This observation was successfully translated to p.G1306E and p.P1158L carriers. Thus, the aim of this study was to perform a pharmacological characterization of myotonic Nav1.4 mutations clustered near the fast inactivation gate of the channel. We chose seven mutations (p.V1293I, p.N1297S, p.N1297K, p.F1298C, p.G1306E, p.I1310N, and p.T1313M) from the database of Italian and French networks for muscle channelopathies. Recombinant hNav1.4 mutants were expressed in HEK293T cells for functional and pharmacological characterization using the patch-clamp technique. All the studied mutations impair the kinetics and/or voltage dependence of fast inactivation, which is likely the main mechanism responsible for myotonia. The severity of myotonia is well-correlated to the enhancement of window currents generated by the intersection of the activation and fast inactivation voltage dependence. Five of the six mutants displaying a significant positive shift of fast inactivation voltage dependence reduced mexiletine inhibition in an experimental condition mimicking myotonia. In contrast, none of the mutations impairs flecainide block nor does p.T1313M impair propafenone block, indicating that class Ic antiarrhythmics may constitute a valuable alternative. Our study suggests that mutation-driven therapy would be beneficial to myotonic patients, greatly improving their quality of life. [ABSTRACT FROM AUTHOR]

Importance: In rare diseases it is difficult to achieve high-quality evidence of treatment efficacy because of small cohorts and clinical heterogeneity. With emerging treatments for rare diseases, innovative trial designs are needed.Objective: To investigate the effectiveness of mexiletine in nondystrophic myotonia using an aggregated N-of-1 trials design and compare results between this innovative design and a previously conducted RCT.Design, Setting, and Participants: A series of aggregated, double-blind, randomized, placebo-controlled N-of-1-trials, performed in a single academic referral center. Thirty Dutch adult patients with genetically confirmed nondystrophic myotonia (38 patients screened) were enrolled between February 2014 and June 2015. Follow-up was completed in September 2016.Interventions: Mexiletine (600 mg daily) vs placebo during multiple treatment periods of 4 weeks.Main Outcomes and Measures: Reduction in daily-reported muscle stiffness on a scale of 1 to 9, with higher scores indicating more impairment. A Bayesian hierarchical model aggregated individual N-of-1 trial data to determine the posterior probability of reaching a clinically meaningful effect of a greater than 0.75-point difference.Results: Among 30 enrolled patients (mean age, 43.4 [SD, 15.24] years; 22% men; 19 CLCN1 and 11 SCN4A genotype), 27 completed the study and 3 dropped out (1 because of a serious adverse event). In 24 of the 27 completers, a clinically meaningful treatment effect was found. In the Bayesian hierarchical model, mexiletine resulted in a 100% posterior probability of reaching a clinically meaningful reduction in self-reported muscle stiffness for the nondystrophic myotonia group overall and the CLCN1 genotype subgroup and 93% posterior probability for the SCN4A genotype subgroup. In the total nondystrophic myotonia group, the median muscle stiffness score was 6.08 (interquartile range, 4.71-6.80) at baseline and was 2.50 (95% credible interval [CrI], 1.77-3.24) during the mexiletine period and 5.56 (95% CrI, 4.73-6.39) during the placebo period; difference in symptom score reduction, 3.06 (95% CrI, 1.96-4.15; n = 27) favoring mexiletine. The most common adverse event was gastrointestinal discomfort (21 mexiletine [70%], 1 placebo [3%]). One serious adverse event occurred (1 mexiletine [3%]; allergic skin reaction). Using frequentist reanalysis, mexiletine compared with placebo resulted in a mean reduction in daily-reported muscle stiffness of 3.12 (95% CI, 2.46-3.78), consistent with the previous RCT treatment effect of 2.69 (95% CI, 2.12-3.26).Conclusions and Relevance: In a series of N-of-1 trials of mexiletine vs placebo in patients with nondystrophic myotonia, there was a reduction in mean daily-reported muscle stiffness that was consistent with the treatment effect in a previous randomized clinical trial. These findings support the efficacy of mexiletine for treatment of nondystrophic myotonia as well as the feasibility of N-of-1 trials for assessing interventions in some chronic rare diseases.Trial Registration: ClinicalTrials.gov Identifier: NCT02045667. [ABSTRACT FROM AUTHOR]

[Display omitted] • The platform can realize visual and quantitate monitoring of mexiletine in serum. • Ratiometric upconversion probe overcomes the fluorescence background interference. • Upconversion probe improves the resolution and accuracy of visual detection. • The dual-mode nanoprobe provides more situational applications. • Visual determining of antiarrhythmic drugs can warn the process of disease. Arrhythmia seriously threatens life and health, it requires long-term use of antiarrhythmic drugs such as mexiletine and needs to monitor the dosage of drugs in the body to ensure efficacy and avoid serious side effects. Here, we designed a sensing platform for real-time visual monitoring of drug efficacy using a ratiometric upconversion probe, which overcomes the fluorescence background interference in the serum, and improves the resolution and accuracy of visual detection. By combining lanthanide-doped upconversion nanoparticles (UCNPs) with readily available organic dyes, an efficient upconversion nanoprobe was constructed under the reaction mechanism of internal filtration effect (IFE) to realize the quantitative detection of mexiletine in serum. Due to the addition of mexiletine, the characteristic emission peak of the probe at 540 nm changes, while the fluorescence intensity at 655 nm is unchanged. Therefore, the visual detection of mexiletine in serum is realized according to the fluorescence intensity changes of I 540 /I 655. In addition, the designed sensing platform is combined with a smartphone to realize real-time visualization and quantitative monitoring of mexiletine, and the detection limits in fluorescence and colorimetric modes are as low as 55.6 nM and 469.75 nM respectively, consequently resulting in sensitive monitoring the effective dosage of drugs in the serum. The proposed detection platform provides a new sensing strategy for the visual determination of antiarrhythmic drugs and an instant device to warn the treatment process of the disease immediately. [ABSTRACT FROM AUTHOR]

Skeletal muscle sodium channelopathies are a group of neuromuscular disorders associated with mutations in the SCN4A gene. Because principal sodium channel isoforms expressed in the skeletal muscles and the heart are distinct one from the other, this condition usually spares cardiac functioning. Nonetheless, evidence on a possible link between skeletal muscle and cardiac sodium channelopathies has emerged in recent years. To date, eight patients bearing pathogenetic mutations in the SCN4A gene and manifesting cardiac electrophysiological alterations have been reported in literature. Among these patients, three presented a phenotype compatible with Brugada syndrome. We report the case of a 29-year-old patient affected by non-dystrophic myotonia associated with a p.G1306E mutation in the SCN4A gene, who presented symptoms of syncope and palpitation after the introduction of flecainide as an anti-myotonic agent. ECG and ajmaline challenge were consistent with the diagnosis of Brugada syndrome, leading to the implantation of a cardioverter defibrillator. No mutation in causative genes for Brugada syndrome was detected. Mexiletine treatment reduced myotonia without any cardiac adverse events. This case report highlights the clinical relevance of the recognition of cardiac electrophysiological alterations in skeletal muscle sodium channelopathies. The discovery of a possible pathogenetic linkage between skeletal muscle and cardiac sodium channelopathies may have significant implications in patients' management, also in light of the fact that class 1C anti-arrhythmics are potential triggers for life-threatening arrhythmias in patients with Brugada syndrome.

Mexiletine (Mex) has been recently appointed as an orphan-drug in myotonic-syndromes, being a potent use-dependent blocker of skeletal-muscle sodium channels (NaV1.4). Available evidences about a potential anti-oxidant effect of Mex and its tetramethyl-pyrroline-derivatives in vivo, suggest the possibility to further enlarge the therapeutic potential of Mex-like compounds in myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative stress. In line with this and based on our previous structure-activity-relationship studies, we synthesized new compounds with a tetramethyl-pyrroline-ring on the amino-group of both Mex (VM11) and of its potent use-dependent isopropyl-derivative (CI16). The compounds were tested for their ability to block native NaV1.4 and to exert cyto-protective effects against oxidative-stress injury in myoblasts. Voltage-clamp-recordings on adult myofibers were performed to assess the tonic and use-dependent block of peak sodium-currents (INa) by VM11 and CI16, as well as Mex, VM11 and CI16 were 3 and 6-fold more potent than Mex in producing a tonic-block of peak sodium-currents (INa), respectively. Interestingly, CI16 showed a 40-fold increase of potency with respect to Mex during high-frequency stimulation (10-Hz), resulting the strongest use-dependent Mex-like compound so far. The derivatives also behaved as inactivated channel blockers, however the voltage dependent block was modest. The experimental data fitted with the molecular-modeling simulation based on previously proposed interaction of main pharmacophores with NaV1.4 binding-site. CI16 and VM11 were then compared to Mex and its isopropyl derivative (Me5) for the ability to protect C2C12-cells from H2O2-cytotoxicity in the concentration range effective on Nav1.4. Mex and Me5 showed a moderate cyto-protective effect in the presence of H2O2, Importantly, CI16 and VM11 showed a remarkable cyto-protection at concentrations effective for use-dependent block of NaV1.4. This effect was comparable to that of selected anti-oxidant drugs proved to exert protective effect in preclinical models of progressive myopathies such as muscular dystrophies. Then, the tetramethyl-pyrroline compounds have increased therapeutic profile as sodium channel blockers and an interesting cyto-protective activity. The overall profile enlarges therapeutic potential from channelopathies to myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative-stress, i.e., muscular dystrophies.

BACKGROUND: The role of systemic use of local anesthetics in the treatment of neuropathic pain (NP) is still unclear. OBJECTIVE: To assess the efficacy and safety of systemic local anesthetics for NP. METHODS: To summarize and to discuss the rehabilitation perspective on the published Cochrane Systematic Review "Systemic administration of local anesthetic agents to relieve neuropathic pain" by Challapalli V et al. RESULTS: The review included 30 RCTs including patients with NP treated with iv lidocaine, oral mexiletine, lidocaine and mexiletine, or oral tocainide. Low-to-moderate quality of the evidence suggest that intravenous lidocaine or oral mexiletine may slightly reduce NP vs placebo, but the efficacy of these drugs is comparable to anticonvulsants or morphine. CONCLUSIONS: Systemic administration of local anesthetics is not supported by scientific evidence for pain relief as well as for functional improvement. [ABSTRACT FROM AUTHOR]

Long QT syndrome (LQTS) is a disorder of cardiac electrophysiology resulting in life-threatening arrhythmias; nowadays, only a few drugs are available for the management of LQTS. Focusing our attention on LQT2, one of the most common subtypes of LQTS caused by mutations in the human ether-à-go-go-related gene (hERG), in the present work, the stereoselectivity of the recently discovered mexiletine-derived urea 8 was investigated on the hERG potassium channel. According to preliminary in silico predictions, in vitro studies revealed a stereoselective behavior, with the meso form showing the greatest hERG opening activity. In addition, functional studies on guinea pig isolated left atria, aorta, and ileum demonstrated that 8 does not present any cardiac or intestinal liability in our ex vivo studies. Due to its overall profile, (R,S)-8 paves the way for the design and development of a new series of compounds potentially useful in the treatment of both congenital and drug-induced forms of LQTS., (© 2023 The Authors. Archiv der Pharmazie published by Wiley-VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

The aim of the study was to evaluate precisely the type of interactions between mexiletine (an antiarrhythmic drug) and four new generation antiepileptic drugs: lamotrigine, oxcarbazepine, topiramate and pregabalin in the maximal electroshock test in mice (MES). The isobolographic analysis was used to assess the nature of interactions between the tested drugs. Total brain concentrations of antiepileptics were also measured to detect possible pharmacokinetic interactions. The results obtained indicated that the mixture of mexiletine and pregabalin at the fixed ratios of 1:1 and 3:1 led to supra-additive interaction in terms of seizure suppression, while the proportion of 1:3 occurred additive. Synergism was also demonstrated for the combination of mexiletine and topiramate in all three proportions. Combinations of mexiletine with lamotrigine and mexiletine with oxcarbazepine were found to be additive. Adverse-effect profiles of mexiletine, antiepileptics and drug combinations were evaluated in the chimney test (motor coordination) and step-through passive-avoidance task (long-term memory). Mexiletine and drug combinations did not impair long-term memory. Moreover, all combinations of mexiletine with lamotrigine, oxcarbazepine and topiramate had no significant effect on motor coordination. However, the results from the chimney test indicated that pregabalin, administered alone at its ED50 dose from the MES-test, significantly impaired motor performance. Similar adverse effects were observed when mexiletine was co-administered with pregabalin at the fixed-dose ratio combinations of 1:1 and 1:3. However, reduction of pregabalin dose at the fixed ratio of 3:1 seems to prevent significant motor impairment. The results may indicate that mexiletine can be considered as an adjunctive drug in antiepileptic treatment, particularly in patients with concomitant cardiac arrhythmia. [ABSTRACT FROM AUTHOR]

The mechanisms underlying Ca2+/calmodulin-dependent protein kinase II (CaMKII)- induced arrhythmias in ischemia-reperfusion (I/R) are not fully understood. We tested the hypothesis that CaMKII increases late Na+ current (INa,L) via phosphorylation of Nav1.5 at Ser571 during I/R, thereby increasing arrhythmia susceptibility. To test our hypothesis, we studied isolated, Langendorff-perfused hearts from wild-type (WT) mice and mice expressing Nav channel variants Nav1.5-Ser571E (S571E) and Nav1.5-Ser571A (S571A). WT hearts showed a significant increase in the levels of phosphorylated CaMKII and Nav1.5 at Ser571 [p-Nav1.5(S571)] after 15 min of global ischemia (just before the onset of reperfusion). Optical mapping experiments revealed an increase in action potential duration (APD) and APD dispersion without changes in conduction velocity during I/R in WT and S571E compared with S571A hearts. At the same time, WT and S571E hearts showed an increase in spontaneous arrhythmia events (e.g., premature ventricular contractions) and an increase in the inducibility of reentrant arrhythmias during reperfusion. Pretreatment of WT hearts with the Na+ channel blocker mexiletine (10 µM) normalized APD dispersion and reduced arrhythmia susceptibility during I/R. We conclude that CaMKII-dependent phosphorylation of Nav1.5 is a crucial driver for increased INa,L, arrhythmia triggers, and substrate during I/R. Selective targeting of this CaMKII-dependent pathway may have therapeutic potential for reducing arrhythmias in the setting of I/R. [ABSTRACT FROM AUTHOR]

Summary: What is known and objective: Lidocaine infused at 1‐4 mg/min is an appropriate treatment modality for hemodynamically stable ventricular tachycardia (VT) with normal hepatic function. A case of acute lidocaine toxicity in the setting of left ventricular assist device (LVAD) is reported. Case summary: A 71‐year‐old with a HeartMate II LVAD on chronic mexiletine and normal liver function presented with ventricular tachycardia requiring systemic lidocaine and subsequently developed altered mental status with tremors. A lidocaine level obtained within 24 hours of infusion initiation was 7.9 mcg/mL. What is new and conclusion: This case highlights the potential for marked deviation from published pharmacokinetic parameters for a narrow therapeutic window agent with concurrent LVAD. [ABSTRACT FROM AUTHOR]

Aims Experimental studies and clinical reports suggest antiarrhythmic properties of mexiletine in different arrhythmias. We aimed at investigating mexiletine in experimental models of atrial fibrillation (AF) as well as in long-QT- (LQTS) and short-QT-syndrome (SQTS). Methods and results In 15 isolated rabbit hearts, erythromycin (300 µM) was infused for simulation of long-QT-2-syndrome. In further 13 hearts, veratridine was administered to simulate long-QT-3-syndrome. Both drugs induced a significant QT-prolongation (erythromycin: +87 ms, P  < 0.01; veratridine: +19 ms, P  < 0.05) and increased dispersion of repolarization (erythromycin: +55 ms, P  < 0.01; veratridine +31 ms, P  < 0.01). Additional infusion of mexiletine (25 µM) resulted in a significant reduction of dispersion (erythromycin: −43 ms, P  < 0.01; veratridine: −26 ms, P  < 0.05). Reproducible induction of torsade de pointes was observed in 13 of 15 erythromycin-treated hearts (192 episodes) and 6 of 13 veratridine-treated hearts (36 episodes). Additional infusion of mexiletine significantly reduced ventricular tachycardia (VT) incidence. With mexiletine, only 3 of 15 erythromycin-treated hearts (27 episodes) and 1 of 13 veratridine-treated hearts (2 episodes) presented polymorphic VT. In additional 9 hearts, the IK-ATP-channel-opener pinacidil was employed to simulate SQTS and significantly abbreviated ventricular repolarization (QT-interval: −18 ms, P  < 0.05) and enhanced induction of ventricular fibrillation (VF). Mexiletine reversed the effects of pinacidil, increase refractory period (+127 ms, P  < 0.01) and significantly suppressed induction of VF. In further 13 hearts AF was induced by combined treatment with acetylcholine/isoproterenol. Mexiletine also increased atrial refractory period (+80 ms, P  < 0.01) and thereby effectively suppressed atrial fibrillation. Conclusion Acute infusion of mexiletine significantly reduced the occurrence of polymorphic VT in the presence of pharmacologically simulated LQTS. Furthermore, mexiletine demonstrated potent antiarrhythmic properties in a model of SQTS and in AF. [ABSTRACT FROM AUTHOR]

Background: The central nervous system involvement, in terms of a maladaptive sensory-motor plasticity, is well known in patients with dystrophic myotonias (DMs). To date, there are no data suggesting a central nervous system involvement in non-dystrophic myotonias (NDMs). Objective: To investigate sensory-motor plasticity in patients with Myotonia Congenita (MC) and Paramyotonia Congenita (PMC) with or without mexiletine. Methods: Twelve patients with a clinical, genetic, and electromyographic evidence of MC, fifteen with PMC, and 25 healthy controls (HC) were included in the study. TMS on both primary motor cortices (M1) and a rapid paired associative stimulation (rPAS) paradigm were carried out to assess M1 excitability and sensory-motor plasticity. Results: patients showed a higher cortical excitability and a deterioration of the topographic specificity of rPAS aftereffects, as compared to HCs. There was no correlation among neurophysiological and clinical-demographic characteristics. Noteworthy, the patients who were under mexiletine showed a minor impairment of the topographic specificity of rPAS aftereffects as compared to those who did not take the drug. Conclusion: our findings could suggest the deterioration of cortical sensory-motor plasticity in patients with NDMs as a trait of the disease. [ABSTRACT FROM AUTHOR]

Skeletal muscle sodium channelopathies are a group of neuromuscular disorders associated with mutations in the SCN4A gene. Because principal sodium channel isoforms expressed in the skeletal muscles and the heart are distinct one from the other, this condition usually spares cardiac functioning. Nonetheless, evidence on a possible link between skeletal muscle and cardiac sodium channelopathies has emerged in recent years. To date, eight patients bearing pathogenetic mutations in the SCN4A gene and manifesting cardiac electrophysiological alterations have been reported in literature. Among these patients, three presented a phenotype compatible with Brugada syndrome. We report the case of a 29-year-old patient affected by non-dystrophic myotonia associated with a p.G1306E mutation in the SCN4A gene, who presented symptoms of syncope and palpitation after the introduction of flecainide as an anti-myotonic agent. ECG and ajmaline challenge were consistent with the diagnosis of Brugada syndrome, leading to the implantation of a cardioverter defibrillator. No mutation in causative genes for Brugada syndrome was detected. Mexiletine treatment reduced myotonia without any cardiac adverse events. This case report highlights the clinical relevance of the recognition of cardiac electrophysiological alterations in skeletal muscle sodium channelopathies. The discovery of a possible pathogenetic linkage between skeletal muscle and cardiac sodium channelopathies may have significant implications in patients' management, also in light of the fact that class 1C anti-arrhythmics are potential triggers for life-threatening arrhythmias in patients with Brugada syndrome. [ABSTRACT FROM AUTHOR]

Background: The SCN5A mutation, P1332L, is linked to a malignant form of congenital long QT syndrome, type 3 (LQT3), and affected patients are highly responsive to the Na+ channel blocking drug, mexiletine. In contrast, A647D is an atypical SCN5A mutation causing Brugada syndrome. An asymptomatic male with both P1332L and A647D presented with varying P wave/QRS aberrancy and mild QTc prolongation which did not shorten measurably with mexiletine. Objective: We characterized the biophysical properties of P1332L, A647D and wild-type (WT) Na+ channels as well as their combinations in order to understand our proband’s phenotype and to guide mexilitine therapy. Methods: Na+ channel biophysics and mexilitine-binding kinetics were assessed using heterologous expression studies in CHO-K1 cells and human ventricular myocyte modeling. Results: Compared to WT, P1332L channels displayed a hyperpolarizing shift in inactivation, slower inactivation and prominent late Na+ currents (INa). While A647D had no effect on the biophysical properties of INa, it reduced peak and late INa density when co-expressed with either WT or P1332L. Additionally, while P1332L channels had greater sensitivity to block by mexiletine compared to WT, this was reduced in the presence of A647D. Modelling studies revealed that mixing P1332L with A647D channels, action potential durations were shortened compared to P1332L, while peak INa was reduced compared to either A647D coexpressing with WT or WT alone. Conclusions: While A647D mitigates the lethal LQT3 phenotype seen with P1332L, it also reduces mexilitine sensitivity and decreases INa density. These results explain our proband’s mild repolarization abnormality and prominent conduction defect in the atria and ventricles, but also suggest that expression of P1332L with A647D yields a novel disease phenotype for which mexiletine pharmacotherapy is no longer suitable. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: In patients with ischemic heart disease and ventricular tachycardia (VT) refractory to high dose amiodarone, the two most common therapeutic options are adjunctive mexiletine therapy or catheter ablation. There are little existing data on the efficacy of these strategies. We examined the relative efficacy of adjunctive mexiletine and catheter ablation among patients enrolled in the VANISH trial. Methods: All subjects enrolled in the VANISH trial who had VT refractory to high dose (≥ 300 mg daily) amiodarone at baseline were included. Per protocol, subjects randomized to escalated drug therapy received adjunctive mexiletine. Results: Nineteen of the 259 patients were receiving high‐dose amiodarone at baseline and 11 were randomized to escalated therapy with mexiletine and 8 to ablation. The adjunctive mexiletine group had a higher rate of the primary composite outcome (death, VT storm, or appropriate shock) in comparison to catheter ablation (HR 6.87 [2.08–22.8]). Over 90% of the patients in the adjunctive mexiletine/group experienced a primary endpoint during a median 9.2 months’ follow‐up. There was no difference in the rate of adverse events between the two groups. Conclusions: Mexiletine has limited efficacy in the treatment of recurrent VT despite high‐dose amiodarone therapy, in patients with ischemic heart disease. Catheter ablation is a superior strategy in this population. [ABSTRACT FROM AUTHOR]

Ketamine, lidocaine, and mexiletine are potential nonopioid adjuvant medications for the use of refractory cancer-related pain, particularly when opioids are demonstrating limited objective benefit. This is a case report of a single patient admitted to a large academic medical center in the United States. The patient is a 43-year-old woman with a history of Crohn's disease complicated by rectal squamous cell carcinoma and complex, progressive, and intractable pelvic and rectal pain. Over the course of hospitalization, her pain demonstrated limited opioid responsiveness despite marked fluctuations of her oral morphine equivalent doses. She also demonstrates variable responsiveness to ketamine. Lidocaine continuous infusion ultimately proves beneficial, and she is discharged after conversion to oral mexiletine. An overview of the hospital system's protocols for ketamine and lidocaine continuous infusions for pain and considerations for transitioning to mexiletine from lidocaine infusion are included. [ABSTRACT FROM AUTHOR]

Mexiletine (Mex) has been recently appointed as an orphan-drug inmyotonic-syndromes, being a potent use-dependent blocker of skeletal-muscle sodium channels (NaV1.4). Available evidences about a potential anti-oxidant effect of Mex and its tetramethyl-pyrroline-derivatives in vivo, suggest the possibility to further enlarge the therapeutic potential of Mex-like compounds in myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative stress. In line with this and based on our previous structure-activity-relationship studies, we synthesized new compounds with a tetramethyl-pyrroline-ring on the amino-group of both Mex (VM11) and of its potent use-dependent isopropyl-derivative (CI16). The compounds were tested for their ability to block native NaV1.4 and to exert cyto-protective effects against oxidative-stress injury in myoblasts. Voltage-clamp-recordings on adult myofibers were performed to assess the tonic and use-dependent block of peak sodium-currents (INa) by VM11 and CI16, as well as Mex, VM11 and CI16 were 3 and 6-fold more potent than Mex in producing a tonic-block of peak sodium-currents (INa), respectively. Interestingly, CI16 showed a 40-fold increase of potency with respect to Mex during high-frequency stimulation (10-Hz), resulting the strongest use-dependent Mex-like compound so far. The derivatives also behaved as inactivated channel blockers, however the voltage dependent block was modest. The experimental data fitted with the molecular-modeling simulation based on previously proposed interaction of main pharmacophores with NaV1.4 binding-site. CI16 and VM11 were then compared to Mex and its isopropyl derivative (Me5) for the ability to protect C2C12-cells from H2O2-cytotoxicity in the concentration range effective on Nav1.4. Mex and Me5 showed a moderate cyto-protective effect in the presence of H2O2, Importantly, CI16 and VM11 showed a remarkable cyto-protection at concentrations effective for use-dependent block of NaV1.4. This effect was comparable to that of selected anti-oxidant drugs proved to exert protective effect in preclinical models of progressive myopathies such as muscular dystrophies. Then, the tetramethyl-pyrroline compounds have increased therapeutic profile as sodium channel blockers and an interesting cyto-protective activity. The overall profile enlarges therapeutic potential from channelopathies to myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative-stress, i.e., muscular dystrophies. [ABSTRACT FROM AUTHOR]

Background: Thromboelastography (TEG) in venous air embolism (VAE) has been poorly studied. We induced coagulation abnormalities by VAE in a rat model, assessed by TEG with and without mexiletine, a lidocaine analogue local anesthetic. Methods: Twenty-three Sprague Dawley rats instrumented under isoflurane anesthesia and allowed to recover five days prior to the experiments were randomized into three experimental groups: 1) VAE (n = 6); 2) VAE and mexiletine (n = 9); and 3) normal saline (NS) alone (control group, n = 8). Blood samples were collected at baseline, one hour (h) and 24 h in all groups and analyzed by TEG to record the R, K, angle α and MA parameters. Results: In Group 1, VAE decreased significantly R at 1 h (31%), K at 1 h (59%) and 24 h (34%); α increased significantly at 1 h (30%) and 24 h (22%). While R returned to baseline values within 24 h, K, MA and α did not. In group-2 (Mexiletine + VAE), K and R decreased at 1 h (48% and 29%, respectively) and at 24 h the changes were non-significant. Angle α increased at 1 h (28%) and remained increased for 24 h (25%). In group 3 (NS), only R was temporarily affected. MA increased significantly at 24 h only in the VAE alone group. Conclusion: As expected, VAE produced a consistent and significant hypercoagulable response diagnosed/confirmed by TEG. Mexiletine prevented the MA elevation seen with VAE and corrected R and K time at 24 h, whereas angle α remained unchanged. Mexiletine seemed to attenuate the hypercoagulability associated with VAE in this experiment. These results may have potential clinical applications and deserve further investigation. [ABSTRACT FROM AUTHOR]