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Neuromuscular Disorders : NMD Feb 2023Although mexiletine effectively treats myotonia, supply disruptions affected Europe between 2008-2018. MyoPath was a mixed-methods, cross-sectional, market research...
Although mexiletine effectively treats myotonia, supply disruptions affected Europe between 2008-2018. MyoPath was a mixed-methods, cross-sectional, market research survey conducted January-June 2018 to evaluate consequences of limited access to/awareness of mexiletine in people with myotonia. Part A: qualitative structured interviews (clinicians; advocates for adult patients); Part B: quantitative online questionnaire completed by people with self-reported history of myotonia. Part A: Interviews (clinicians, n=12; patient advocates, n=5; 12 countries) indicated poor mexiletine awareness among general neurologists. Patients chose between living with myotonia (other treatments were generally unsatisfactory) or importing mexiletine. Part B: Questionnaire respondents, myotonic dystrophy (DM)1, n=213; DM2, n=128; non-dystrophic myotonia (NDM), n=41; other n=8; (11 countries). Of the respondents, 76/390 (20%) people with awareness of/access to mexiletine described profound improvements in myotonia and health-related quality of life following treatment. Respondents with NDM had greatest mexiletine experience (n=28/41). Mexiletine was associated with fewer falls, less muscle stiffness, increased mobility. Treatment interruptions worsened myotonia and were associated with fatigue, pain, dysphagia, breathing difficulty, impaired digestion, poor sleep. However, 36/54 (67%) of currently treated people expressed anxiety about mexiletine's availability: this finding was expected (MyoPath was undertaken before mexiletine's approval in NDM). MyoPath provides the largest European exploration of patients' views regarding impact of mexiletine on myotonia. Anticipated effects of mexiletine differ between people with different myotonic disorders: myotonia is the main symptom in NDM but one of many potential symptoms affecting those with DM. Nevertheless, findings indicate substantial harm caused to people with myotonia when mexiletine awareness/access is limited.
Topics: Adult; Humans; Mexiletine; Myotonia; Quality of Life; Cross-Sectional Studies; Myotonic Dystrophy; Surveys and Questionnaires
PubMed: 36706619
DOI: 10.1016/j.nmd.2022.12.008 -
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 -
Drug Discovery Today Mar 2023The beginning of the 20th decade has witnessed an increase in drug development programs for myotonic dystrophy type 1 (DM1). We have collected nearly 20 candidate drugs... (Review)
Review
The beginning of the 20th decade has witnessed an increase in drug development programs for myotonic dystrophy type 1 (DM1). We have collected nearly 20 candidate drugs with accomplished preclinical and clinical phases, updating our previous drug development pipeline review with new entries and relevant milestones for pre-existing candidates. Three interventional first-in-human clinical trials got underway with distinct drug classes, namely AOC 1001 and DYNE-101 nucleic acid-based therapies, and the small molecule pitolisant, which joins the race toward market authorization with other repurposed drugs, including tideglusib, metformin, or mexiletine, already in clinical evaluation. Furthermore, newly disclosed promising preclinical data for several additional nucleic-acid therapeutic candidates and a CRISPR-based approach, as well as the advent into the pipeline of novel therapeutic programs, increase the plausibility of success in the demanding task of providing valid treatments to patients with DM1.
Topics: Humans; Myotonic Dystrophy; Drug Development
PubMed: 36634841
DOI: 10.1016/j.drudis.2023.103489 -
HeartRhythm Case Reports Nov 2022
PubMed: 36618596
DOI: 10.1016/j.hrcr.2022.08.003 -
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 -
Heart Rhythm Apr 2023Drug-induced QT prolongation (DI-QTP) is a clinical entity in which administration of a human ether-à-go-go-related gene/rapid delayed rectifier potassium current...
BACKGROUND
Drug-induced QT prolongation (DI-QTP) is a clinical entity in which administration of a human ether-à-go-go-related gene/rapid delayed rectifier potassium current blocker such as dofetilide prolongs the cardiac action potential duration (APD) and the QT interval on the electrocardiogram. Inhibition of serum and glucocorticoid regulated kinase-1 (SGK1) reduces the APD at 90% repolarization (APD90) in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) derived from patients with congenital long QT syndrome.
OBJECTIVE
Here, we test the efficacy of 2 novel SGK1 inhibitors-SGK1-I1 and SGK1-I2-in iPSC-CM models of dofetilide-induced APD prolongation.
METHODS
Normal iPSC-CMs were treated with dofetilide to produce a DI-QTP iPSC-CM model. SGK1-I1's and SGK1-I2's therapeutic efficacy for shortening the dofetilide-induced APD90 prolongation was compared to mexiletine. The APD90 values were recorded 4 hours after treatment using a voltage-sensing dye.
RESULTS
The APD90 was prolonged in normal iPSC-CMs treated with dofetilide (673 ± 8 ms vs 436 ± 4 ms; P < .0001). While 10 mM mexiletine shortened the APD90 of dofetilide-treated iPSC-CMs from 673 ± 4 to 563 ± 8 ms (46% attenuation; P < .0001), 30 nM of SGK1-I1 shortened the APD90 from 673 ± 8 to 502 ± 7 ms (72% attenuation; P < .0001). Additionally, 300 nM SGK1-I2 shortened the APD90 of dofetilide-treated iPSC-CMs from 673 ± 8 to 460 ± 7 ms (90% attenuation; P < .0001).
CONCLUSION
These novel SGK1-Is substantially attenuated the pathological APD prolongation in a human heart cell model of DI-QTP. These preclinical data support the development of this therapeutic strategy to counter and neutralize DI-QTP, thereby increasing the safety profile for patients receiving drugs with torsadogenic potential.
Topics: Humans; Mexiletine; Action Potentials; Long QT Syndrome; Sulfonamides; Myocytes, Cardiac
PubMed: 36610526
DOI: 10.1016/j.hrthm.2022.12.036 -
Biological & Pharmaceutical Bulletin 2023The negative inotropic effects of nine Vaughan Williams class I antiarrhythmic drugs were examined in guinea pig ventricular tissue preparations. The drugs decreased the...
The negative inotropic effects of nine Vaughan Williams class I antiarrhythmic drugs were examined in guinea pig ventricular tissue preparations. The drugs decreased the contractile force of papillary muscles with different potencies: the potency order was propafenone > aprindine > cibenzoline > flecainide > ranolazine > disopyramide > pilsicainide > mexiletine > GS-458967. The potency of drugs correlated with the reported IC values to block the L-type Ca channel rather than the Na channel. The effects of drugs were roughly the same when examined under a high extracellular K solution, which inactivates the Na channel. Furthermore, the attenuation of the extracellular Ca-induced positive inotropy was strong with propafenone, moderate with cibenzoline, and weak with pilsicainide. These results indicate that the negative inotropic effects of class I antiarrhythmic drugs can be largely explained by their blockade of the L-type Ca channel.
Topics: Guinea Pigs; Animals; Anti-Arrhythmia Agents; Propafenone; Myocardium; Lidocaine; Papillary Muscles
PubMed: 36596522
DOI: 10.1248/bpb.b22-00644 -
Circulation. Arrhythmia and... Jan 2023Macroscopic T wave alternans (macro-TWA) often heralds the onset of Torsades de Pointes in patients with QT prolongation. However, the mechanisms underlying macro-TWA...
BACKGROUND
Macroscopic T wave alternans (macro-TWA) often heralds the onset of Torsades de Pointes in patients with QT prolongation. However, the mechanisms underlying macro-TWA remain unclear. We examined the cellular and ionic basis for macro-TWA in rabbits with left ventricular hypertrophy (LVH).
METHODS
The renovascular hypertension model was used to induce LVH in rabbits. Action potentials were simultaneously recorded from epicardium and endocardium together with a transmural ECG and isometric contractility in arterially perfused left ventricular wedges. Late sodium current (I) was recorded in single-isolated left ventricular myocytes with the whole cell patch-clamp technique.
RESULTS
Macro-TWA and accompanied mechanical alternans occurred spontaneously in 8 of 33 LVH rabbits (<0.05, versus 0/15 in controls) and were induced by an I enhancer ATX-II at 1 to 3 nM in additional 7. Macro-TWA and mechanical alternans occurred discordantly, that is, that longer QT interval and larger T wave were associated with weaker isometric contvractility. Alternating early afterdepolarizations in the endocardium caused macro-TWA in 12 of 15 LVH rabbits and, therefore, early afterdepolarization-dependent R-from-T extrasystoles and Torsades de Pointes always originated from the beats with longer QT and larger T wave during macro-TWA. I density was significantly larger in LVH myocytes than that of control myocytes. Macro-TWA, mechanical alternans, R-from-T extrasystoles, and Torsades de Pointes were all abolished by I blocker ranolazine or mexiletine.
CONCLUSIONS
LVH enhances I density and promotes alternating early afterdepolarizations in the left ventricular endocardium that manifest as macro-TWA with discordant mechanical alternans. I blockade abolishes macro-TWA, mechanical alternans, early afterdepolarization-dependent R-from-T extrasystoles, and Torsades de Pointes.
Topics: Animals; Rabbits; Torsades de Pointes; Bradycardia; Arrhythmias, Cardiac; Heart Ventricles; Long QT Syndrome; Cardiac Complexes, Premature; Electrocardiography; Action Potentials
PubMed: 36595630
DOI: 10.1161/CIRCEP.122.011453 -
Membranes Dec 2022A 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...
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 (VSD), whereas MEX stabilizes the activated state of VSD. 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 S6, S6 and P1. In both ensembles, the ligand NH 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 VSD shifted helices S4-S5, S5, S6 and S6 and tightened the TB site. In a model with activated VSD 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 S5, P1, S6 and S6. 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 VSD.
PubMed: 36557159
DOI: 10.3390/membranes12121252 -
Current Opinion in Pharmacology Feb 2023Skeletal muscle ion channelopathies are rare genetic diseases mainly characterized by myotonia (muscle stiffness) or periodic paralysis (muscle weakness). Here, we... (Review)
Review
Skeletal muscle ion channelopathies are rare genetic diseases mainly characterized by myotonia (muscle stiffness) or periodic paralysis (muscle weakness). Here, we reviewed the available therapeutic options in non-dystrophic myotonias (NDM) and periodic paralyses (PP), which consists essentially in drug repositioning to address stiffness or weakness attacks. Empirical use followed by successful randomized clinical trials eventually led to the orphan drug designation and marketing authorization granting of mexiletine for NDM and dichlorphenamide for PP. Yet, these treatments neither consider the genetic cause of the diseases nor address the individual variability in drug response. Thus, ongoing research aims at the identification of repurposed drugs alternative to mexiletine and dichlorphenamide to allow personalization of treatment. This review highlights how drug repurposing may represent an efficient strategy in rare diseases, allowing reduction of drug development time and costs in a context in which the return on investment may be particularly challenging.
Topics: Humans; Drug Repositioning; Channelopathies; Mexiletine; Dichlorphenamide; Muscle, Skeletal; Paralyses, Familial Periodic; Myotonic Disorders; Mutation
PubMed: 36512979
DOI: 10.1016/j.coph.2022.102329