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Muscle & Nerve Oct 2022Peripheral neuropathies commonly affect quality of life of patients due to pain, sleep disturbances, and fatigue, although trials have not adequately explored these... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION/AIMS
Peripheral neuropathies commonly affect quality of life of patients due to pain, sleep disturbances, and fatigue, although trials have not adequately explored these domains of care. The aim of this study was to assess the impact of nortriptyline, duloxetine, pregabalin, and mexiletine on pain, sleep, and fatigue in patients diagnosed with cryptogenic sensory polyneuropathy (CSPN).
METHODS
We implemented a Bayesian adaptive design to perform a 12-wk multisite, randomized, prospective, open-label comparative effectiveness study in 402 CSPN patients. Participants received either nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). At prespecified analysis timepoints, secondary outcomes, Patient Reported Outcomes Measurement Information System (PROMIS) surveys including Short Form (SF)-12, pain interference, fatigue, and sleep disturbance, were collected.
RESULTS
Mexiletine had the highest quit rate (58%) due to gastrointestinal side effects, while nortriptyline (38%) and duloxetine (38%) had the lowest quit rates. If tolerated for the full 12 wk of the study, mexiletine had the highest probability (>90%) of positive outcomes for improvements in pain interference and fatigue. There was no significant difference among the medications for sleep disturbance or SF-12 scores. Adverse events and lack of efficacy were the two most common reasons for cessation of therapy.
DISCUSSION
Physicians caring for patients with CSPN should consider mexiletine to address pain and fatigue, although nortriptyline and duloxetine are better medications to trial first since they are better tolerated. Future research should compare other commonly used medications for CSPN to determine evidence-based treatment strategies.
Topics: Activities of Daily Living; Bayes Theorem; Diabetic Neuropathies; Double-Blind Method; Duloxetine Hydrochloride; Fatigue; Humans; Mexiletine; Nortriptyline; Pain; Pregabalin; Prospective Studies; Quality of Life; Sleep; Treatment Outcome
PubMed: 35585718
DOI: 10.1002/mus.27637 -
Drug Discovery Today Jul 2021Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular genetic disease with an estimated prevalence of approximately at least half a million individuals based... (Review)
Review
Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular genetic disease with an estimated prevalence of approximately at least half a million individuals based on its vast ethnic variation. Building upon a well-known physiopathology and several proof-of-concept therapeutic approaches, herein we compile a comprehensive overview of the most recent drug development programs under preclinical and clinical evaluation. Specifically, close to two dozen drug developments, eight of which are already in clinical trials, explore a diversity of new chemical entities, drug repurposing, oligonucleotide, and gene therapy-based approaches. Of these, repurposing of tideglusib, mexiletine, or metformin appear to be therapies with the most potential to receive marketing authorization for DM1.
Topics: Animals; Drug Development; Humans; Myotonic Dystrophy
PubMed: 33798646
DOI: 10.1016/j.drudis.2021.03.024 -
JMIR Cardio Jan 2023Drug-induced prolongation of the corrected QT interval (QTc) increases the risk for Torsades de Pointes (TdP) and sudden cardiac death. Medication effects on the QTc...
BACKGROUND
Drug-induced prolongation of the corrected QT interval (QTc) increases the risk for Torsades de Pointes (TdP) and sudden cardiac death. Medication effects on the QTc have been studied in controlled settings but may not be well evaluated in real-world settings where medication effects may be modulated by patient demographics and comorbidities as well as the usage of other concomitant medications.
OBJECTIVE
We demonstrate a new, high-throughput method leveraging electronic health records (EHRs) and the Surescripts pharmacy database to monitor real-world QTc-prolonging medication and potential interacting effects from demographics and comorbidities.
METHODS
We included all outpatient electrocardiograms (ECGs) from September 2008 to December 2019 at a large academic medical system, which were in sinus rhythm with a heart rate of 40-100 beats per minute, QRS duration of <120 milliseconds, and QTc of 300-700 milliseconds, determined using the Bazett formula. We used prescription information from the Surescripts pharmacy database and EHR medication lists to classify whether a patient was on a medication during an ECG. Negative control ECGs were obtained from patients not currently on the medication but who had been or would be on that medication within 1 year. We calculated the difference in mean QTc between ECGs of patients who are on and those who are off a medication and made comparisons to known medication TdP risks per the CredibleMeds.org database. Using linear regression analysis, we studied the interaction of patient-level demographics or comorbidities on medication-related QTc prolongation.
RESULTS
We analyzed the effects of 272 medications on 310,335 ECGs from 159,397 individuals. Medications associated with the greatest QTc prolongation were dofetilide (mean QTc difference 21.52, 95% CI 10.58-32.70 milliseconds), mexiletine (mean QTc difference 18.56, 95% CI 7.70-29.27 milliseconds), amiodarone (mean QTc difference 14.96, 95% CI 13.52-16.33 milliseconds), rifaximin (mean QTc difference 14.50, 95% CI 12.12-17.13 milliseconds), and sotalol (mean QTc difference 10.73, 95% CI 7.09-14.37 milliseconds). Several top QT prolonging medications such as rifaximin, lactulose, cinacalcet, and lenalidomide were not previously known but have plausible mechanistic explanations. Significant interactions were observed between demographics or comorbidities and QTc prolongation with many medications, such as coronary disease and amiodarone.
CONCLUSIONS
We demonstrate a new, high-throughput technique for monitoring real-world effects of QTc-prolonging medications from readily accessible clinical data. Using this approach, we confirmed known medications for QTc prolongation and identified potential new associations and demographic or comorbidity interactions that could supplement findings in curated databases. Our single-center results would benefit from additional verification in future multisite studies that incorporate larger numbers of patients and ECGs along with more precise medication adherence and comorbidity data.
PubMed: 36662566
DOI: 10.2196/41055 -
International Journal of Molecular... Jan 2023The voltage-gated sodium channels represent an important target for drug discovery since a large number of physiological processes are regulated by these channels. In... (Review)
Review
The voltage-gated sodium channels represent an important target for drug discovery since a large number of physiological processes are regulated by these channels. In several excitability disorders, including epilepsy, cardiac arrhythmias, chronic pain, and non-dystrophic myotonia, blockers of voltage-gated sodium channels are clinically used. Myotonia is a skeletal muscle condition characterized by the over-excitability of the sarcolemma, resulting in delayed relaxation after contraction and muscle stiffness. The therapeutic management of this disorder relies on mexiletine and other sodium channel blockers, which are not selective for the Na1.4 skeletal muscle sodium channel isoform. Hence, the importance of deepening the knowledge of molecular requirements for developing more potent and use-dependent drugs acting on Na1.4. Here, we review the available treatment options for non-dystrophic myotonia and the structure-activity relationship studies performed in our laboratory with a focus on new compounds with potential antimyotonic activity.
Topics: Humans; Mexiletine; Muscle, Skeletal; Myotonia; NAV1.4 Voltage-Gated Sodium Channel; Syndrome; Voltage-Gated Sodium Channel Blockers
PubMed: 36614292
DOI: 10.3390/ijms24010857 -
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 -
Journal of Neuromuscular Diseases 2023Myotonia congenita is the most common form of nondystrophic myotonia and is caused by Mendelian inherited mutations in the CLCN1 gene encoding the voltage-gated chloride...
BACKGROUND
Myotonia congenita is the most common form of nondystrophic myotonia and is caused by Mendelian inherited mutations in the CLCN1 gene encoding the voltage-gated chloride channel of skeletal muscle.
OBJECTIVE
The study aimed to describe the clinical and genetic spectrum of Myotonia congenita in a large pediatric cohort.
METHODS
Demographic, genetic, and clinical data of the patients aged under 18 years at time of first clinical attendance from 11 centers in different geographical regions of Türkiye were retrospectively investigated.
RESULTS
Fifty-four patients (mean age:15.2 years (±5.5), 76% males, with 85% Becker, 15% Thomsen form) from 40 families were included. Consanguineous marriage rate was 67%. 70.5% of patients had a family member with Myotonia congenita. The mean age of disease onset was 5.7 (±4.9) years. Overall 23 different mutations (2/23 were novel) were detected in 52 patients, and large exon deletions were identified in two siblings. Thomsen and Becker forms were observed concomitantly in one family. Carbamazepine (46.3%), mexiletine (27.8%), phenytoin (9.3%) were preferred for treatment.
CONCLUSIONS
The clinical and genetic heterogeneity, as well as the limited response to current treatment options, constitutes an ongoing challenge. In our cohort, recessive Myotonia congenita was more frequent and novel mutations will contribute to the literature.
Topics: Male; Humans; Child; Adolescent; Aged; Infant; Child, Preschool; Female; Myotonia Congenita; Retrospective Studies; Chloride Channels; Mutation; Muscle, Skeletal
PubMed: 37355912
DOI: 10.3233/JND-230046 -
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