Mexiletine Research Articles

Isolation and characterization of a degradation product of mexiletine hydrochloride using FT-IR, LC-MS and NMR: method development and validation of stability indicating RP-HPLC method for quantification of characterized impurity

Mexiletine Hydrochloride is an antiarrhythmic drug used to treat acute and chronic ventricular arrhythmias. Significant degradation of unknown impurity was observed while evaluating the impurity profile of the Mexiletine Hydrochloride stability studies. The levels of the unknown impurity are more than the regulatory identification/qualification threshold level (0.08%). Mexiletine was forcefully subjected to various stress conditions, such as acidic, basic, oxidation, photolysis, and thermal. Among these stress conditions, we identified an unknown degradation impurity in the thermal stress (105°C for 15 days) of Mexiletine, the same as that of an unknown impurity observed in the stability studies. The present research reports the isolation of unknown impurity in thermal stress by preparative HPLC and the characterization of isolated unknown degradation impurity using LC-MS, FT-IR, and NMR techniques. The spectral data elucidated the structure of the degradation product, and it was identified as “(E)-2-(((1-(2,6-dimethylphenoxy)propan-2-yl)imino)methyl)-6-methylphenol”. A stability-indicating HPLC method was developed and validated to determine and quantify the degradation product in Mexiletine Hydrochloride. The levels of the unknown degradation product reduced to below the limit of detection (<0.007%) from 0.10% after applying its relative response factor “16.5” and complying with the regulatory threshold limits. It helps to extend the shelf life of Mexiletine.

Development and validation of stability indicating ultra‐high‐performance liquid chromatographic method for assay and impurities of mexiletine hydrochloride and mexiletine hydrochloride capsules

AbstractMexiletine (MEX) is an antiarrhythmic drug used to treat acute and chronic ventricular arrhythmias. A simple isocratic, rapid, specific, stability‐indicating, and sensitive reverse‐phase ultra‐high‐performance liquid chromatography (UHPLC) method was developed and successfully validated to quantify the assay and impurities of MEX hydrochloride. The new UHPLC method showed the optimum separation of MEX and its seven impurities in 20 min by using sodium acetate buffer (0.14 mM) with 0.3% of glacial acetic acid (pH 4.8) and methanol in the ratio of 40:60 (v/v) as mobile phase. The method used an Acquity HSS T3 (100 × 3.0 mm, 1.8 µm) chromatographic column at a 0.2 mL/min flow rate. The injection volume is 2 µL, and 254 nm is the detection wavelength. Note that, 25°C is the column oven temperature. The method is linear over the concentration range of the quantification limit (0.03%) to 150% (0.3%) of the specification level (0.2%) for the impurities and 50%–150% for the assay method. The quality control lab of bulk drugs and finished dosage form successfully applied the new UHPLC method for quantification of assay and impurities of MEX hydrochloride.

Expert Insights from a Delphi-driven Neurologists' Panel: Real-world Mexiletine use in Patients with Myotonic Disorders in Italy.

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. 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. 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. 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. 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.

Retracted: Curative Effect of Yangxin Dingji Capsule Combined With Mexiletine Hydrochloride on Postoperative Arrhythmia and Its Influences on the Vascular Endothelial Function in Coronary Bifurcation Lesions.

[This retracts the article DOI: 10.1155/2022/4078895.].

PO-04-159 PREVALENCE AND CHARACTERISTICS OF PATIENTS WITH LONG QT SYNDROME (LQTS) WHO APPEAR NON-RESPONSIVE TO CONVENTIONAL LQTS THERAPIES

Long QT syndrome (LQTS) is a potentially lethal cardiac channelopathy with a 1% to 5% annual risk of LQTS-triggered syncope/seizures or sudden cardiac arrest/death (SCA/SCD). Despite maximal LQTS-directed therapies, a subset of patients experience breakthrough cardiac events (BCEs). To describe the phenotype of “non-responders” defined as LQTS patients with recurrent BCEs despite maximal LQTS-directed therapy. Among the 1731 LQTS patients evaluated and treated at Mayo Clinic, a retrospective analysis was performed to identify those who experienced ≥1 BCE while on maximum treatment (combination of ≥2 device/denervation and/or pharmacologic therapies at maximally tolerated doses). Basic demographics, clinical characteristics, and frequency/type of BCEs defined as syncope/seizures, appropriate ICD shocks, SCA, or SCD were extracted from the electronic medical record. Overall, 32/1731 LQTS patients (2%) experienced ≥1 BCE with 13 (41%) occurring in the setting of medication nonadherence. Of the remaining 19 patients (1% of all LQTS patients; 37% female, mean age at last event of 11±8 years and mean QTc of 537±92ms), 7 (37%) had compound heterozygous (n=6) or homozygous (n=1) disease involving either KCNQ1 or KCNH2, including one Jervell and Lange-Nielsen syndrome patient, and 2 (11%) had high-risk minor LQTS genotypes (CALM2-mediated LQTS and CACNA1C-mediated Timothy syndrome). Notably, 5 (26%) had a complex cardiac sodium channelopathy with predominant features of LQT3 and multifocal ectopic Purkinje-related premature contractions. The remaining patients had treatment-refractory LQT2 (n=3; 16%) or LQT3 (n=2; 11%). At last follow-up, 2 patients (11%) died and 4 (2%) underwent cardiac transplant. For the remaining 13 patients, treatment was escalated after their last BCE. Twelve patients (92%) received an ICD and either atrial pacing (AP) + beta-blocker (BB) + mexiletine (MEX) [n=1, 8%], AP + left cardiac sympathetic denervation (LCSD) + ≥2 antiarrhythmic drugs (AADs) [n=4, 31%], bilateral denervation + BB [n=2, 15%], or LCSD + ≥1 AAD [n=5, 38%]. One patient (8%) was on LCSD + BB + MEX. Despite safe and effective treatment options, 1% of LQTS patients experience recurrent BCEs on maximal LQTS-directed therapy. Adherence to the outlined treatment program needs to be reinforced. In addition, compound heterozygous/homozygous KCNQ1-mediated disease and complex SCN5A-mediated channelopathies represent high-risk LQTS subsets in need of alternative management strategies.

SGK1 inhibition attenuated the action potential duration in patient- and genotype-specific re-engineered heart cells with congenital long QT syndrome

Long QT syndrome (LQTS) stems from pathogenic variants in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3) and is characterized by action potential duration (APD) prolongation. Inhibition of serum and glucocorticoid regulated kinase-1 (SGK1) is proposed as a novel therapeutic for LQTS. The study sought to test the efficacy of novel, selective SGK1 inhibitors in induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) models of LQTS. The mexiletine (MEX)-sensitive SCN5A-P1332L iPSC-CMs were tested initially compared with a CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 SCN5A-P1332L variant-corrected isogenic control (IC). The SGK1-I1 therapeutic efficacy, compared with MEX, was tested for APD at 90% repolarization (APD90) shortening in SCN5A-P1332L, SCN5A-R1623Q, KCNH2-G604S, and KCNQ1-V254M iPSC-CMs using FluoVolt. The APD90 was prolonged in SCN5A-P1332L iPSC-CMs compared with its IC (646 ± 7 ms vs 482 ± 23 ms; P < .0001). MEX shortened the APD90 to 560 ± 7 ms (52% attenuation, P < .0001). SGK1-I1 shortened the APD90 to 518 ± 5 ms (78% attenuation, P < .0001) but did not shorten the APD90 in the IC. SGK1-I1 shortened the APD90 of the SCN5A-R1623Q iPSC-CMs (753 ± 8 ms to 475 ± 19 ms compared with 558 ± 19 ms with MEX), the KCNH2-G604S iPSC-CMs (666 ± 10 ms to 574 ± 18 ms vs 538 ± 15 ms after MEX), and the KCNQ1-V254M iPSC-CMs (544 ± 10 ms to 475 ± 11ms; P = .0004). Therapeutically inhibiting SGK1 effectively shortens the APD in human iPSC-CM models of the 3 major LQTS genotypes. These preclinical data support development of SGK1 inhibitors as novel, first-in-class therapy for patients with congenital LQTS.

Vapor Sorption and Halogen-Bond-Induced Solid-Form Rearrangement of a Porous Pharmaceutical.

A porous, nonsolvated polymorph of the voltage-gated sodium channel blocker mexiletine hydrochloride absorbs iodine vapor to give a pharmaceutical cocrystal incorporating an I2Cl- anion that forms a halogen-π interaction with the mexiletine cations. The most thermodynamically stable form of the compound does not absorb iodine. This example shows that vapor sorption is a potentially useful and underused tool for bringing about changes in pharmaceutical solid form as part of a solid form screening protocol.

Molecular Modeling of Cardiac Sodium Channel with Mexiletine.

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 (VSDIII), whereas MEX stabilizes the activated state of VSDIII. 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 S6III, S6IV and P1IV. In both ensembles, the ligand NH3 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 VSDIII shifted helices S4-S5III, S5III, S6III and S6IV and tightened the TB site. In a model with activated VSDIII 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 S5III, P1III, S6III and S6IV. 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 VSDIII.

Abstract 10986: SGK1 Inhibition Attenuated the Action Potential Duration In-Patient and Genotype-Specific Re-Engineered Heart Cells With Congenital Long QT Syndrome

Background: Long QT syndrome (LQTS) often stems from pathogenic variants in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3) and is characterized cellularly by prolongation of the cardiac action potential duration (APD). We have shown that inhibition of serum and glucocorticoid regulated kinase-1 (SGK1) reduces I NaL and is proposed as a novel therapeutic strategy for LQT3. Objective: To test the efficacy of a potent and selective SGK1 inhibitor (SGK1-I) in human cardiomyocyte models of LQT1, LQT2, and LQT3. Methods: Induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) were generated from patients with either LQT1, LQT2, or LQT3. The mexiletine (MEX)-sensitive SCN5A-P1332L iPSC-CMs were tested initially. A CRISPR/Cas9 P1332L variant-corrected isogenic control (IC) was used as a control. The SGK1-I’s therapeutic efficacy was compared to MEX and to a commercially available SGK1 inhibitor (EMD638683). The novel SGK-I was then tested for APD shortening in SCN5A-R1623Q, KCNH2-G604S and KCNQ1-V254M iPSC-CMs. The APD90 values were recorded 4 hours after treatment using FluoVolt. Results: The APD90 was significantly prolonged in SCN5A-P1332L iPSC-CMs compared to its IC (646 ± 7 ms vs 482 ± 23 ms, p&lt;0.0001). MEX shortened the average APD90 to 560 ± 7 ms (52% attenuation). Interestingly, SGK1-I significantly shortened the APD to 518 ± 5 ms (78% attenuation) but did not further shorten the APD in the IC. SGK1-I also shortened the APD90 of the SCN5A-R1623Q iPSC-CMs from 753 ± 8 ms to 475 ± 19 ms compared to 558 ± 19 ms with MEX. The SGK1-I shortened the APD90 in KCNH2-G604S (666 ± 10ms to 574 ± 18ms for SGK1-I versus 538 ± 15 ms after MEX). EMD had limited APD shortening effects in SCN5A and KCNH2 iPSC-CMs. Interestingly, while neither MEX nor EMD reduced the APD90 in the KCNQ1-V254M iPSC-CMs, the novel SGK1-I reduced the APD90 from 544 ± 10 ms to 475 ± 11ms (p=0.0004). Conclusions: Therapeutically inhibiting SGK1 effectively shortens the cardiomyocyte APD in human heart cell models of the 3 major LQTS genotypes. The novel SGK1-I normalized the pathological APD prolongation almost fully (&gt; 70%) in the patient-derived SCN5A-P1332L iPSC-CM model. These pre-clinical data support further development of SGK1-I as a novel, first-in-class therapy for patients with congenital LQTS.

Designer Gelators for the Crystallization of a Salt Active Pharmaceutical Ingredient-Mexiletine Hydrochloride.

We report an approach to obtain drug-mimetic supramolecular gelators, which are capable of stabilizing metastable polymorphs of the pharmaceutical salt mexiletine hydrochloride, a highly polymorphic antiarrhythmic drug. Solution-phase screening led to the discovery of two new solvated solid forms of mexiletine, a type C 1,2,4-trichlorobenzene tetarto-solvate and a type D nitrobenzene solvate. Various metastable forms were crystallized within the gels under conditions which would not have been possible in solution. Despite typically crystallizing concomitantly with form 1, a pure sample of form 3 was crystallized within a gel of ethyl methyl ketone. Various type A channel solvates were crystallized from gels of toluene and ethyl acetate, in which the contents of the channels varied from those of solution-phase forms. Most strikingly, the high-temperature-stable form 2 was crystallized from a gel in 1,2-dibromoethane: the only known route to access this form at room temperature. These results exemplify the powerful stabilizing effect of drug-mimetic supramolecular gels, which can be exploited in pharmaceutical polymorph screens to access highly metastable or difficult-to-nucleate solid forms.

Chiral Discrimination of Mexiletine Enantiomers by Capillary Electrophoresis Using Cyclodextrins as Chiral Selectors and Experimental Design Method Optimization.

Mexiletine (MXL) is a class IB antiarrhythmic agent, acting as a non-selective voltage-gated sodium channel blocker, used in therapy as a racemic mixture R,S-MXL hydrochloride. The aim of the current study was the development of a new, fast, and efficient method for the chiral separation of MXL enantiomers using capillary electrophoresis (CE) and cyclodextrins (CDs) as chiral selectors (CSs). After an initial CS screening, using several neutral and charged CDs, at four pH levels, heptakis-2,3,6-tri-O-methyl-β-CD (TM-β-CD), a neutral derivatized CD, was chosen as the optimum CS for the enantioseparation. For method optimization, an initial screening fractional factorial design was applied to identify the most significant parameters, followed by a face-centered central composite design to establish the optimal separation conditions. The best results were obtained by applying the following optimized electrophoretic conditions: 60 mM phosphate buffer, pH 5.0, 50 mM TM-β-CD, temperature 20 °C, applied voltage 30 kV, hydrodynamic injection 50 mbar/s. MXL enantiomers were baseline separated with a resolution of 1.52 during a migration time of under 5 min; S-MXL was the first migrating enantiomer. The method’s analytical performance was verified in terms of precision, linearity, accuracy, and robustness (applying a Plackett–Burman design). The developed method was applied for the determination of MXL enantiomers in pharmaceuticals. A computer modeling of the MXL-CD complexes was applied to characterize host–guest chiral recognition.

Curative Effect of Yangxin Dingji Capsule Combined With Mexiletine Hydrochloride on Postoperative Arrhythmia and Its Influences on the Vascular Endothelial Function in Coronary Bifurcation Lesions.

Objective The aim of the study is to explore the curative effect of Yangxin Dingji capsule combined with mexiletine hydrochloride on postoperative ventricular arrhythmia (VA) and its influences on vascular endothelial function in coronary bifurcation lesions (CBL). Methods A total of 110 patients with CBL admitted to the hospital were enrolled as research subjects between January and December 2021. According to the random number table method, they were divided into a combination group and control group, with 55 cases in each group. The control group was treated with mexiletine hydrochloride, while the combination group was additionally treated with Yangxin Dingji capsules. All were continuously treated for 4 weeks. The clinical response rate between the two groups was compared. The frequencies of 24 h paroxysmal atrial fibrillation, premature atrial contraction, and premature ventricular contraction were compared by the Holter monitoring. The whole blood low-shear viscosity, whole blood high-shear viscosity, and fibrinogen (Fb) in both groups were measured by a full-automatic blood flow analyzer. The levels of plasma nitric oxide (NO), endothelin-1 (ET-1), and von Willebrand factor (vWF) were detected by the nitrate reductase method and enzyme-linked immunosorbent assay (ELISA). During treatment, the occurrence of adverse reactions (vomiting, loss of appetite, dry mouth, diarrhea, nausea) in both groups was statistically analyzed. Results After treatment, the total response rate of treatment in the combination group was significantly higher than that in the control group (P < 0.05). After treatment, frequencies of paroxysmal atrial fibrillation, premature atrial contraction, and premature ventricular contraction in the combination group were significantly lower than those in the control group (P < 0.05). Whole blood low-shear viscosity, whole blood high-shear viscosity, and the Fb level were significantly lower than those in the control group (P < 0.05). After treatment, the NO level in the combination group was significantly higher than that in the control group (P < 0.05), while levels of ET-1 and vWF were significantly lower than those in the control group (P < 0.05). During treatment, there was no significant difference in the total incidence of adverse reactions between the two groups (P > 0.05). Conclusion Yangxin Dingji capsule combined with mexiletine hydrochloride can significantly improve clinical effects in CBL patients, improve VA and vascular endothelial function, and reduce plasma viscosity without increasing the incidence of adverse reactions.

Derisking the Polymorph Landscape: The Complex Polymorphism of Mexiletine Hydrochloride

This work presents an updated solid-form discovery approach to the polymorphism of the antiarrhythmic drug mexiletine hydrochloride, in which experimental and computational techniques are combined to provide a rigorous characterization of the solid-form landscape of this compound. The resulting solid forms were characterized by powder and single-crystal X-ray diffraction, IR spectroscopy, differential scanning calorimetry, and 13C solid-state NMR. This approach reveals five solid-form types of mexiletine hydrochloride. Forms 1, 2, and 3 are mutually enantiotropically related anhydrous polymorphs, with Form 1 the room temperature stable form, Form 2 the high-temperature form, and Form 3 the thermodynamically stable polymorph between 148 and 167 °C. The final two forms termed Types A and B comprise two large families of isomorphous channel solvates, including a fourth nonsolvated form isostructural to the Type A solvates. We report 11 modifications of each solvate, in which a diverse range of solvents are included in the channels, without changing the fundamental structure of the drug framework. These experimental results go hand-in-hand with computational crystal structure prediction (using the AstraZeneca crystal structure prediction approach), which together suggest that it is unlikely further nonsolvated forms, at least with Z′ = 1, will be discovered under ambient conditions.

B-PO01-007 THE EFFICACY OF MEXILETINE TREATMENT IN PATIENT-SPECIFIC RE-ENGINEERED CARDIOMYOCYTE MODELS OF LONG QT SYNDROME TYPE 1, 2, AND 3

Long QT syndrome (LQTS) stems from pathogenic variants in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3) and is characterized by prolongation of the cardiac action potential duration (APD) at the cellular level. Mexiletine (MEX) is an effective therapy in some patients with LQT3 and may have therapeutic efficacy in LQT2 also. However, the efficacy of MEX to shorten APD in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) has not been tested. To test the efficacy of MEX in patient-specific re-engineered cardiomyocyte models of LQT1 (KCNQ1-V254M), LQT2 (KCNH2-G604S), and LQT3 (SCN5A-P1332L). iPSC-CMs were generated from a 29-year-old female (KCNQ1-V254M), a 16-year-old male (KCNH2-G604S), and an 8-year-old female (SCN5A-P1332L) with a history of syncope or sudden cardiac arrest. CRISPR-Cas9 G604S and P1332L variant-corrected isogenic controls were created to establish the curative level of APD shortening for LQT2 and LQT3 models. MEX’s therapeutic efficacy was tested for APD shortening in the 3 LQTS genotype-specific iPSC-CMs by recording the APD90 values 4 hours after treatment with 10 μM MEX using FluoVolt. The APD90 was prolonged significantly in KCNH2-G604S and SCN5A-P1332L iPSC-CMs compared to their isogenic controls (726 ± 8ms vs 425 ± 40ms in KCNH2-G604S, 654 ±8 ms vs 482 ± 23 ms in SCN5A-P1332L, p<0.0001). MEX shortened the APD90 on KCNH2-G604S iPSC-CMs from 726 ± 8ms to 605 ± 17 ms. MEX also shortened the average APD90 on SCN5A-P1332L to 570 ± 9 ms (49% attenuation relative to the isogenic control value). However, the APD90 in the KCNQ1-V254M iPSC-CMs was not significantly reduced. Clinically, MEX has shortened the P1332L-SCN5A positive patient’s QTc from 600 ms to 460 ms and the G604S-KCNH2 positive patient’s QTc from > 600 ms to 440 ms. The patient with KCNQ1-V254M has not been treated with MEX. This is the first ‘treatment-in-the-dish’ studies of patient-specific, re-engineered heart cells for all three major LQTS genotypes using MEX. Consistent with its clinical use in the patient herself, MEX normalized the pathological APD prolongation by nearly 50% in her LQT3 iPSC-CM model. Additionally, MEX effectively shortened the APD in the LQT2, but not in LQT1, cardiac cells.

Reduced current density, partially rescued by mexiletine, and depolarizing shift in activation of SCN5A W374G channels as a cause of severe form of Brugada syndrome.

Background SCN5A‐related Brugada syndrome (BrS) can be caused by multiple mechanisms including trafficking defects and altered channel gating properties. Most SCN5A mutations at pore region cause trafficking defects, and some of them can be rescued by mexiletine (MEX).ObjectiveWe recently encountered symptomatic siblings with BrS and sought to identify a responsible mutation and reveal its biophysical defects.MethodsTarget panel sequencing was performed. Wild‐type (WT) or identified mutant SCN5A was transfected into tsA201 cells. After incubation of transfected cells with or without 0.1 mM MEX for 24–36 hr, whole‐cell sodium currents (INa) were recorded using patch‐clamp techniques.ResultsThe proband was 29‐year‐old male who experienced cardiopulmonary arrest. Later, his 36‐year‐old sister, who had been suffering from recurrent episodes of syncope since 12 years, was diagnosed with BrS. An SCN5A W374G mutation, located at pore region of domain 1 (D1 pore), was identified in both. The peak density of W374G‐INa was markedly reduced (WT: 521 ± 38 pA/pF, W374G: 60 ± 10 pA/pF, p < .01), and steady‐state activation (SSA) was shifted to depolarizing potentials compared with WT‐INa (V1/2‐WT: −39.1 ± 0.8 mV, W374G: −30.9 ± 1.1 mV, p < .01). Incubation of W374G‐transfected cells with MEX (W374G‐MEX) increased INa density, but it was still reduced compared with WT‐INa (W374G‐MEX: 174 ± 19 pA/pF, p < .01 versus W374G, p < .01 versus WT). The SSA of W374G‐MEX‐INa was comparable to W374G‐INa (V1/2‐W374G‐MEX: −31.6 ± 0.7 mV, P = NS).ConclusionsReduced current density, possibly due to a trafficking defect, and depolarizing shift in activation of SCN5A W374G are underlying biophysical defects in this severe form of BrS. Trafficking defects of SCN5A mutations at D1 pore may be commonly rescued by MEX.

FSHD / OPMD / MYOTONIC DYSTROPHY: P.228 Need for therapy and effect of symptomatic treatment in myotonic disorders: the Myotonia observation survey of patient access to therapy (MyoPath)

Myotonic disorders are a family of conditions resulting from rare genetic mutations affecting skeletal muscle cells. They can be categorized as either dystrophic (DM) or non-dystrophic myotonia (NDM) and can have significant impact on patient quality of life (QoL), causing a range of symptoms including muscle stiffness. Mexiletine (MEX) is currently the only EU-approved antimyotonic therapy for adult patients with NDM. MyoPath aimed to obtain data on treatment access and impact on daily life for patients with myotonic disorders, as well as effectiveness of MEX therapy for these conditions.

Gating Properties of Mutant Sodium Channels and Responses to Sodium Current Inhibitors Predict Mexiletine-Sensitive Mutations of Long QT Syndrome 3.

BackgroundLong QT syndrome 3 (LQT3) is caused by SCN5A mutations. Late sodium current (late I Na) inhibitors are current-specific to treat patients with LQT3, but the mechanisms underlying mexiletine (MEX) -sensitive (N1325S and R1623Q) and -insensitive (M1652R) mutations remains to be elucidated.MethodsLQT3 patients with causative mutations were treated with oral MEX following i.v. lidocaine. Whole-cell patch-clamp techniques and molecular remodeling were used to determine the mechanisms underlying the sensitivity to MEX.ResultsIntravenous administration of lidocaine followed by MEX orally in LQT patients with N1325S and R1623Q sodium channel mutation shortened QTc interval, abolished arrhythmias, and completely normalized the ECG. In HEK293 cells, the steady-state inactivation curves of the M1652R channels were rightward shifted by 5.6 mV relative to the WT channel. In contrast, the R1623Q mutation caused a leftward shift of the steady-state inactivation curve by 15.2 mV compared with WT channel, and N1325S mutation did not affect steady-state inactivation (n = 5–13, P < 0.05). The extent of the window current was expanded in all three mutant channels compared with WT. All three mutations increased late I Na with the greatest amplitude in the M1652R channel (n = 9–15, P < 0.05). MEX caused a hyperpolarizing shift of the steady-state inactivation and delayed the recovery of all three mutant channels. Furthermore, it suppressed late I Na in N1325S and R1623Q to a greater extent compared to that of M1652R mutant channel. Mutations altered the sensitivity of Nav1.5 to MEX through allosteric mechanisms by changing the conformation of Nav1.5 to become more or less favorable for MEX binding. Late I Na inhibitors suppressed late I Na in N1325S and R1623Q to a greater extent than that in the M1652R mutation (n = 4–7, P < 0.05).ConclusionThe N1325S, R1623Q, and M1652R mutations are associated with a variable augmentation of late I Na, which was reversed by MEX. M1652R mutation changes the conformation of Nav1.5 that disrupt the inactivation of channel affecting MEX binding, corresponding to the poor response to MEX. The lidocaine test, molecular modeling, and drugs screening in cells expressing mutant channels are useful for predicting the effectiveness of late I Na inhibitors.

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)

IntroductionSpinal 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...

A systematic review of the effectiveness of palliative interventions to treat rectal tenesmus in cancer

Background: Rectal tenesmus is a distressing symptom in patients with advanced cancer and challenging to treat. There is lack of consensus on the appropriate management of tenesmus in this patient population. Aim: To identify and examine the effectiveness of interventions to palliate rectal tenesmus caused by advanced cancer when surgery, radiotherapy or chemotherapy are no longer treatment options. Design: A systematic review of the literature following standard systematic review methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. Data sources: A comprehensive search of the electronic databases MEDLINE, EMBASE and the Cochrane Library was conducted from date of inception to April 2016. PubMed ‘related articles’ search, grey literature search and hand-searches of the bibliographies of relevant papers and textbooks were also performed. Non-cancer patients were excluded. Any studies involving surgery or radiotherapy to treat tenesmus were excluded. Studies involving interventions to treat pelvic pain syndromes without specific outcome measures on severity of tenesmus were excluded. The quality of the studies was assessed using a National Institute for Health and Clinical Excellence–recommended quality assessment tool. Results: From 861 studies, 9 met full criteria and were selected. All were case series investigating the use of pharmacological interventions (diltiazem, nifedipine, methadone, mexiletine hydrochloride, lidocaine and bupivacaine), anaesthetic interventions (lumbar sympathectomy, neurolytic superior hypogastric plexus block), and endoscopic laser interventions. The included studies showed substantial heterogeneity, and therefore, a meta-analysis was not feasible. Conclusion: From this review, we identified a significant gap in research into the palliation of rectal tenesmus. A multimodal approach may be necessary due to the complexity of the pathophysiology of tenesmus. Future research should focus on randomised controlled trials of drug therapies whose potential effectiveness is suggested by case series.

Preparation and evaluation of monodispersed, submicron, non-porous silica particles functionalized with β-CD derivatives for chiral-pressurized capillary electrochromatography.

Submicron, non-porous, chiral silica stationary phase has been prepared by the immobilization of functionalized β-CD derivatives to isocyanate-modified silica via chemical reaction and applied to the pressurized capillary electrochromatography (pCEC) enantio-separation of various chiral compounds. The submicron, non-porous, cyclodextrin-based chiral stationary phases (sub_μm-CSP2) exhibited excellent chiral recognition of a wide range of analytes including clenbuterol hydrochloride, mexiletine hydrochloride, chlorpheniramine maleate, esmolol hydrochloride, and metoprolol tartrate. The synthesized submicron particles were regularly spherical and uniformly non-porous with an average diameter of around 800 nm and a mean pore size of less than 2 nm. The synthesized chiral stationary phase was packed into 10 cm × 100 μm id capillary columns. The sub_μm-CSP2 column used in the pCEC system showed better separation of the racemates and at a higher rate compared to those used in the capillary liquid chromatography mode (cLC) system. The sub_μm-CSP2 possessed high mechanical strength, high stereoselectivity, and long lifespan, demonstrating rapid enantio-separation and good resolution of samples. The column provided an efficiency of up to 170,000 plates/m for n-propylbenzene.