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PloS One 2015Mexiletine and lidocaine are widely used class IB anti-arrhythmic drugs that are considered to act by blocking voltage-gated open sodium currents for treatment of... (Comparative Study)
Comparative Study
Mexiletine and lidocaine are widely used class IB anti-arrhythmic drugs that are considered to act by blocking voltage-gated open sodium currents for treatment of ventricular arrhythmias and relief of pain. To gain mechanistic insights into action of anti-arrhythmics, we characterized biophysical properties of Nav1.5 and Nav1.7 channels stably expressed in HEK293 cells and compared their use-dependent block in response to mexiletine and lidocaine using whole-cell patch clamp recordings. While the voltage-dependent activation of Nav1.5 or Nav1.7 was not affected by mexiletine and lidocaine, the steady-state fast and slow inactivation of Nav1.5 and Nav1.7 were significantly shifted to hyperpolarized direction by either mexiletine or lidocaine in dose-dependent manner. Both mexiletine and lidocaine enhanced the slow component of closed-state inactivation, with mexiletine exerting stronger inhibition on either Nav1.5 or Nav1.7. The recovery from inactivation of Nav1.5 or Nav1.7 was significantly prolonged by mexiletine compared to lidocaine. Furthermore, mexiletine displayed a pronounced and prominent use-dependent inhibition of Nav1.5 than lidocaine, but not Nav1.7 channels. Taken together, our findings demonstrate differential responses to blockade by mexiletine and lidocaine that preferentially affect the gating of Nav1.5, as compared to Nav1.7; and mexiletine exhibits stronger use-dependent block of Nav1.5. The differential gating properties of Nav1.5 and Nav1.7 in response to mexiletine and lidocaine may help explain the drug effectiveness and advance in new designs of safe and specific sodium channel blockers for treatment of cardiac arrhythmia or pain.
Topics: Anti-Arrhythmia Agents; HEK293 Cells; Humans; Lidocaine; Membrane Potentials; Mexiletine; NAV1.5 Voltage-Gated Sodium Channel; NAV1.7 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Sodium Channel Blockers
PubMed: 26068619
DOI: 10.1371/journal.pone.0128653 -
The Journal of Pharmacology and... Mar 2023The cardiac sodium channel Na1.5 is a key contributor to the cardiac action potential, and dysregulations in Na1.5 can lead to cardiac arrhythmias. Na1.5 is a target of...
The cardiac sodium channel Na1.5 is a key contributor to the cardiac action potential, and dysregulations in Na1.5 can lead to cardiac arrhythmias. Na1.5 is a target of numerous antiarrhythmic drugs (AADs). Previous studies identified the protein 14-3-3 as a regulator of Na1.5 biophysical coupling. Inhibition of 14-3-3 can remove the Na1.5 functional coupling and has been shown to inhibit the dominant-negative effect of Brugada syndrome mutations. However, it is unknown whether the coupling regulation is involved with AADs' modulation of Na1.5. Indeed, AADs could reveal important structural and functional information about Na1.5 coupling. Here, we investigated the modulation of Na1.5 by four classic AADs, quinidine, lidocaine, mexiletine, and flecainide, in the presence of 14-3-3 inhibition. The experiments were carried out by high-throughput patch-clamp experiments in an HEK293 Na1.5 stable cell line. We found that 14-3-3 inhibition can enhance acute block by quinidine, whereas the block by other drugs was not affected. We also saw changes in the use- and dose-dependency of quinidine, lidocaine, and mexiletine when inhibiting 14-3-3. Inhibiting 14-3-3 also shifted the channel activation toward hyperpolarized voltages in the presence of the four drugs studied and slowed the recovery of inactivation in the presence of quinidine. Our results demonstrated that the protein 14-3-3 and Na1.5 coupling could impact the effects of AADs. Therefore, 14-3-3 and Na1.5 coupling are new mechanisms to consider in the development of drugs targeting Na1.5. SIGNIFICANCE STATEMENT: The cardiac sodium channel Na1.5 is a target of commonly used antiarrhythmic drugs, and Na1.5 function is regulated by the protein 14-3-3. The present study demonstrated that the regulation of Na1.5 by 14-3-3 influences Na1.5's response to antiarrhythmic drugs. This study provides detailed information about how 14-3-3 differentially regulated Na1.5 functions under the influence of different drug subtypes. These findings will guide future molecular studies investigating Na1.5 and antiarrhythmic drugs outcomes.
Topics: Humans; Anti-Arrhythmia Agents; Mexiletine; 14-3-3 Proteins; Quinidine; HEK293 Cells; Lidocaine; Sodium Channels
PubMed: 36460339
DOI: 10.1124/jpet.122.001407 -
Journal of Pharmacological and... 2019Voltage-sensitive optical (VSO) sensors offer a minimally invasive method to study the time course of repolarization of the cardiac action potential (AP). This...
INTRODUCTION
Voltage-sensitive optical (VSO) sensors offer a minimally invasive method to study the time course of repolarization of the cardiac action potential (AP). This Comprehensive in vitro Proarrhythmia Assay (CiPA) cross-platform study investigates protocol design and measurement variability of VSO sensors for preclinical cardiac electrophysiology assays.
METHODS
Three commercial and one academic laboratory completed a limited study of the effects of 8 blinded compounds on the electrophysiology of 2 commercial lines of human induced pluripotent stem-cell derived cardiomyocytes (hSC-CMs). Acquisition technologies included CMOS camera and photometry; fluorescent voltage sensors included di-4-ANEPPS, FluoVolt and genetically encoded QuasAr2. The experimental protocol was standardized with respect to cell lines, plating and maintenance media, blinded compounds, and action potential parameters measured. Serum-free media was used to study the action of drugs, but the exact composition and the protocols for cell preparation and drug additions varied among sites.
RESULTS
Baseline AP waveforms differed across platforms and between cell types. Despite these differences, the relative responses to four selective ion channel blockers (E-4031, nifedipine, mexiletine, and JNJ 303 blocking I, I, I, and I, respectively) were similar across all platforms and cell lines although the absolute changes differed. Similarly, four mixed ion channel blockers (flecainide, moxifloxacin, quinidine, and ranolazine) had comparable effects in all platforms. Differences in repolarisation time course and response to drugs could be attributed to cell type and experimental method differences such as composition of the assay media, stimulated versus spontaneous activity, and single versus cumulative compound addition.
DISCUSSION
In conclusion, VSOs represent a powerful and appropriate method to assess the electrophysiological effects of drugs on iPSC-CMs for the evaluation of proarrhythmic risk. Protocol considerations and recommendations are provided toward standardizing conditions to reduce variability of baseline AP waveform characteristics and drug responses.
PubMed: 31319140
DOI: 10.1016/j.vascn.2019.106612 -
Journal of Neurology May 2021Non-dystrophic myotonias (NDM) are heterogeneous diseases caused by mutations in CLCN1 and SCN4A. The study aimed to describe the clinical and genetic spectrum of NDM in...
INTRODUCTION
Non-dystrophic myotonias (NDM) are heterogeneous diseases caused by mutations in CLCN1 and SCN4A. The study aimed to describe the clinical and genetic spectrum of NDM in a large German cohort.
METHODS
We retrospectively identified all patients with genetically confirmed NDM diagnosed in our center. The following data were analyzed: demographics, family history, muscular features, cardiac involvement, CK, EMG, genotype, other tested genes, treatment perceived efficacy.
RESULTS
70 patients (age 40.2 years ± 14.9; 52.8% males) were included in our study (48 NDM-CLCN1, 22 NDM-SCN4A). The most frequent presenting symptoms were myotonia (NDM-CLCN1 83.3%, NDM-SCN4A 72.2%) and myalgia (NDM-CLCN1 57.4%, NDM-SCN4A 52.6%). Besides a more prominent facial involvement in NDM-SCN4A and cold-sensitivity in NDM-CLCN1, no other significant differences were observed between groups. Cardiac arrhythmia or conduction defects were documented in sixNDM-CLCN1 patients (three of them requiring a pacemaker) and one patient with NDM-SCN4A. CK was normal in 40% of patients. Myotonic runs in EMG were detected in 89.1% of CLCN1 and 78.9% of SCN4A. 50% of NDM-CLCN1 patients had the classic c.2680C>T (p.Arg894*) mutation. 12 new genetic variants are reported. About 50% of patients were not taking any anti-myotonic drug at the last follow-up. The anti-myotonic drugs with the best patient's perceived efficacy were mexiletine and lamotrigine.
CONCLUSION
This study highlights the relevant clinical overlap between NDM-CLCN1 and NDM-SCN4A patients and warrants the use of early and broad genetic investigation for the precise identification of the NDM subtype. Besides the clinical and genetic heterogeneity, the limited response to current anti-myotonic drugs constitutes a continuing challenge.
Topics: Adult; Chloride Channels; Female; Humans; Male; Mutation; Myotonia; Myotonia Congenita; NAV1.4 Voltage-Gated Sodium Channel; Retrospective Studies
PubMed: 33263785
DOI: 10.1007/s00415-020-10328-1 -
International Journal of Molecular... Oct 2023Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in...
Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in young individuals without heart structural issues. It increases the risk of sudden cardiac death, and its characteristic feature is an abnormal ST segment elevation on the ECG. While BrS has diverse genetic origins, a subset of cases can be conducted to mutations in the gene, which encodes for the Nav1.5 sodium channel. Our study focused on three novel mutations (p.A344S, p.N347K, and p.D349N) found in unrelated BrS families. Using patch clamp experiments, we found that these mutations disrupted sodium currents: p.A344S reduced current density, while p.N347K and p.D349N completely abolished it, leading to altered voltage dependence and inactivation kinetics when co-expressed with normal channels. We also explored the effects of mexiletine treatment, which can modulate ion channel function. Interestingly, the p.N347K and p.D349N mutations responded well to the treatment, rescuing the current density, while p.A344S showed a limited response. Structural analysis revealed these mutations were positioned in key regions of the channel, impacting its stability and function. This research deepens our understanding of BrS by uncovering the complex relationship between genetic mutations, ion channel behavior, and potential therapeutic interventions.
Topics: Humans; Brugada Syndrome; NAV1.5 Voltage-Gated Sodium Channel; Arrhythmias, Cardiac; Mutation
PubMed: 37894777
DOI: 10.3390/ijms242015089 -
Neurochemical Research Oct 2018The aim of the study was to evaluate precisely the type of interactions between mexiletine (an antiarrhythmic drug) and four new generation antiepileptic drugs:...
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 ED 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.
Topics: Animals; Anticonvulsants; Avoidance Learning; Brain; Drug Interactions; Drug Therapy, Combination; Electroshock; Lamotrigine; Male; Memory, Long-Term; Mexiletine; Mice; Oxcarbazepine; Pregabalin; Topiramate
PubMed: 30117096
DOI: 10.1007/s11064-018-2606-8 -
International Journal of... 2021As adrenaline, serotonin and norepinephrine are two other vasoconstrictors and both of which have been proved to increase the quality and duration of local anesthetics... (Comparative Study)
Comparative Study
As adrenaline, serotonin and norepinephrine are two other vasoconstrictors and both of which have been proved to increase the quality and duration of local anesthetics when added as adjuvants. However, the difference in the improvement of the nociception of local anesthetics between the two adjuvants remains unclear. The purpose of this study was to assess the cutaneous nociception of mexiletine by coadministration with serotonin and norepinephrine. Subcutaneous injection of drugs or combinations includes mexiletine 0.6, 1.8, 6.0 μmol, serotonin 1.6500 μmol, noradrenaline 0.8895 nmol, saline, mexiletine 1.8 and 6.0 μmol, respectively combined with serotonin 0.4125, 0.8250, 1.6500 μmol and noradrenaline 0.0356, 0.1779, 0.8895 nmol, with each injection dose of 0.6 ml. The nociception of mexiletine alone and mexiletine coadministered with serotonin and norepinephrine was assessed after subcutaneous injection. Subcutaneous injections of mexiletine elicited dose-related cutaneous antinociception ( < 0.05, 0.01, or 0.001). Compared with mexiletine (1.8 μmol), adding norepinephrine (except for lowest dose) and serotonin to mexiletine (1.8 μmol) solutions for skin nociceptive block potentiated and prolonged the action ( < 0.01 or 0.001). Mexiletine (6.0 μmol) combined with norepinephrine and serotonin extended the duration of cutaneous antinociception when compared with mexiletine (6.0 μmol) alone ( < 0.05, 0.01, or 0.001). Both serotonin and norepinephrine improve the sensory block and enhances the nociceptive block duration of mexiletine, and serotonin is superior to that of norepinephrine.
Topics: Analgesics; Anesthetics, Local; Animals; Dose-Response Relationship, Drug; Drug Combinations; Male; Mexiletine; Norepinephrine; Pain; Rats, Sprague-Dawley; Serotonin; Skin; Rats
PubMed: 33998312
DOI: 10.1177/20587384211016129 -
Journal of Neurology, Neurosurgery, and... Mar 2021The management of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform... (Comparative Study)
Comparative Study Meta-Analysis
INTRODUCTION
The management of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) remains challenging in view of the paucity of data and evidence-based treatment recommendations are missing.
METHODS
In this single-centre, non-randomised, prospective open-label study, we evaluated and compared the efficacy of oral and parenteral treatments for SUNCT and SUNA in a real-world setting. Additionally, single-arm meta-analyses of the available reports of SUNCT and SUNA treatments were conducted.
RESULTS
The study cohort comprised 161 patients. Most patients responded to lamotrigine (56%), followed by oxcarbazepine (46%), duloxetine (30%), carbamazepine (26%), topiramate (25%), pregabalin and gabapentin (10%). Mexiletine and lacosamide were effective in a meaningful proportion of patients but poorly tolerated. Intravenous lidocaine given for 7-10 days led to improvement in 90% of patients, whereas only 27% of patients responded to a greater occipital nerve block. No statistically significant differences in responders were observed between SUNCT and SUNA. In the meta-analysis of the pooled data, topiramate was found to be significantly more effective in SUNCT than SUNA patients. However, a higher proportion of SUNA than SUNCT was considered refractory to medications at the time of the topiramate trial, possibly explaining this isolated difference.
CONCLUSIONS
We propose a treatment algorithm for SUNCT and SUNA for clinical practice. The response to sodium channel blockers indicates a therapeutic overlap with trigeminal neuralgia, suggesting that sodium channels dysfunction may be a key pathophysiological hallmark in these disorders. Furthermore, the therapeutic similarities between SUNCT and SUNA further support the hypothesis that these conditions are variants of the same disorder.
Topics: Administration, Oral; Adolescent; Adult; Aged; Analgesics; Anesthetics, Local; Anticonvulsants; Female; Humans; Infusions, Parenteral; Male; Middle Aged; Prospective Studies; SUNCT Syndrome; Young Adult
PubMed: 33361408
DOI: 10.1136/jnnp-2020-323999 -
Journal of Veterinary Cardiology : the... Feb 2017A 6-year-old, male, mongrel dog was presented for acute onset of dyspnea and cough. At admission, the dog was cachectic and severely depressed. The electrocardiogram...
A 6-year-old, male, mongrel dog was presented for acute onset of dyspnea and cough. At admission, the dog was cachectic and severely depressed. The electrocardiogram showed a sinus rhythm conducted with left bundle truncular branch block and interrupted by frequent multiform ventricular ectopic beats organized in allorhythmias. Thoracic radiographs revealed a marked cardiomegaly with perihilar edema, whereas transthoracic echocardiography revealed a dilated cardiomyopathy with segmental dyskinesis. Furosemide, enalapril, pimobendan, and mexiletine were prescribed, and a Holter was scheduled after resolution of congestive heart failure. Three days later, the dog died suddenly during sleep. Histopathology revealed diffuse myocyte hypertrophy with multifocal hemorrhages, alternating to areas of severe replacement fibrosis and lymphoplasmocytic infiltrates. Immunohystochemistry stains were strongly positive for T-lymphocyte infiltration (CD3) and weakly positive for B-lymphocytes (CD79). Polymerase chain reaction was positive for Bartonella spp. Based on these results, a post-mortem diagnosis of bacterial inflammatory cardiomyopathy was made.
Topics: Animals; Bartonella; Bartonella Infections; Cardiomyopathy, Dilated; Dogs; Male; Myocarditis
PubMed: 27847165
DOI: 10.1016/j.jvc.2016.07.005 -
Cureus May 2020Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder involving abnormal motility. The patients are commonly started on symptom control management for...
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder involving abnormal motility. The patients are commonly started on symptom control management for IBS - diarrhea subtype by prescribing antimotility agents, usually having opioid agonist activity, and newer medications have been emerging for this as well. Patients sometimes self-medicate themselves to exceedingly high doses of these medications to achieve symptoms control. There are only a few cases of opioid-induced arrhythmia in the literature, primarily loperamide being used as a drug substitute by substance abusers. Still, it has been rarely reported to cause arrhythmia in a patient with IBS. We present a case of a 33-year-old female with a past medical history of hypertension and depression who presented to the emergency department for evaluation of syncope. She had wide complex tachycardia on electrocardiogram (EKG) with prolonged rate-corrected QT interval (QTc). Her medications, including eluxadoline, Lomotil, and loperamide, were held and she was discharged on mexiletine with normal QTc. She did not have any more incidences of arrhythmia. This case highlights the importance of not overdosing on opioid agonist medications prescribed to treat IBS as these can lead to potentially fatal complications. Physicians have to be judicious in promptly determining that the cause of arrhythmia can also be over-the-counter (OTC) medications.
PubMed: 32467816
DOI: 10.7759/cureus.8243