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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 -
Clinical and Translational Science Aug 2022Lamotrigine, approved for use as an antiseizure medication as well as the treatment of bipolar disorder, inhibits sodium channels in the brain to reduce repetitive...
Lamotrigine, approved for use as an antiseizure medication as well as the treatment of bipolar disorder, inhibits sodium channels in the brain to reduce repetitive neuronal firing and pathological release of glutamate. The shared homology of sodium channels and lack of selectivity associated with channel blocking agents can cause slowing of cardiac conduction and increased proarrhythmic potential. The Vaughan-Williams classification system differentiates sodium channel blockers using biophysical properties of binding. As such, Class Ib inhibitors, including mexiletine, do not slow cardiac conduction as measured by the electrocardiogram, at therapeutically relevant exposure. Our goal was to characterize the biophysical properties of Na 1.5 block and to support the observed clinical safety of lamotrigine. We used HEK-293 cells stably expressing the hNa 1.5 channel and voltage clamp electrophysiology to quantify the potency (half-maximal inhibitory concentration) against peak and late channel current, on-/off-rate binding kinetics, voltage-dependence, and tonic block of the cardiac sodium channel by lamotrigine; and compared to clinically relevant Class Ia (quinidine), Ib (mexiletine), and Ic (flecainide) inhibitors. Lamotrigine blocked peak and late Na 1.5 current at therapeutically relevant exposure, with rapid kinetics and biophysical properties similar to the class Ib inhibitor mexiletine. However, no clinically meaningful prolongation in QRS or PR interval was observed in healthy subjects in a new analysis of a previously reported thorough QT clinical trial (SCA104648). In conclusion, the weak Na 1.5 block and rapid kinetics do not translate into clinically relevant conduction slowing at therapeutic exposure and support the clinical safety of lamotrigine in patients suffering from epilepsy and bipolar disorder.
Topics: Anticonvulsants; Flecainide; HEK293 Cells; Humans; Lamotrigine; Mexiletine; Sodium Channel Blockers; Sodium Channels
PubMed: 35579204
DOI: 10.1111/cts.13311 -
Evidence-based Complementary and... 2022This study was intended to identify the shifts in the metabolomics profile of the hepatic tissue damaged by alcohol consumption and verify the potential restorative...
This study was intended to identify the shifts in the metabolomics profile of the hepatic tissue damaged by alcohol consumption and verify the potential restorative action of flos carthami (the flowers of , FC) in the protection of alcohol-induced injury by attenuating the level of identified metabolites. Rats were treated with FC and subsequently subjected to alcohol administration. The serum samples were subjected to liquid chromatography-mass spectrometry (LC-MS)-based metabolomics followed by statistical and bioinformatics analyses. The clustering of the samples showed an obvious separation in the principal component analysis (PCA) plot, and the scores plot of the orthogonal partial least squares-discriminant analysis (OPLS-DA) model allowed the distinction among the three groups. Among the 3211 total metabolites, 1088 features were significantly different between the control and alcohol-treated groups, while 367 metabolites were identified as differential metabolites between the alcohol- and FC-treated rat groups. Time series clustering approach indicated that 910 metabolites in profile 6 were upregulated by alcohol but subsequently reversed by FC treatment; among them, the top 10 metabolites based on the variable importance in projection (VIP) scores were 1-methyladenine, phenylglyoxylic acid, N-acetylvaline, mexiletine, L-fucose, propylthiouracil, dopamine 4-sulfate, isoleucylproline, (R)-salsolinol, and monomethyl phthalate. The Pearson correlation analysis and network construction revealed 96 hub metabolites that were upregulated in the alcohol liver injury model group but were downregulated by FC. This study confirmed the hepatoprotective effects of FC against alcohol-induced liver injury and the related changes in the metabolic profiles, which will contribute to the understanding and the treatment of alcohol-induced acute liver injury.
PubMed: 35547657
DOI: 10.1155/2022/8158699 -
Frontiers in Neurology 2022Non-dystrophic myotonias (NDMs) are skeletal muscle ion channelopathies caused by or mutations. This study aimed to describe the clinical, myopathological, and genetic...
INTRODUCTION
Non-dystrophic myotonias (NDMs) are skeletal muscle ion channelopathies caused by or mutations. This study aimed to describe the clinical, myopathological, and genetic analysis of NDM in a large Chinese cohort.
METHODS
We reviewed the clinical manifestations, laboratory results, electrocardiogram, electromyography, muscle biopsy, genetic analysis, treatment, and follow-up of 20 patients (from 18 families) with NDM.
RESULTS
Cases included myotonia congenita (MC, 17/20) and paramyotonia congenita (PMC, 3/20). Muscle stiffness and hypertrophy, grip and percussion myotonia, and the warm-up phenomenon were frequently observed in MC and PMC patients. Facial stiffness, eye closure myotonia, and cold sensitivity were more common in PMC patients and could be accompanied by permanent weakness. Nine MC patients and two PMC patients had cardiac abnormalities, mainly manifested as cardiac arrhythmia, and the father of one patient died of sudden cardiac arrest. Myotonic runs in electromyography were found in all patients, and seven MC patients had mild myopathic changes. There was no difference in muscle pathology between MC and PMC patients, most of whom had abnormal muscle fiber type distribution or selective muscle fiber atrophy. Nineteen variants were found in 17 MC patients, among which c.795T>G (p.D265E) was a new variant, and two variants were found in three PMC patients. The patients were treated with mexiletine and/or carbamazepine, and the symptoms of myotonia were partially improved.
CONCLUSIONS
MC and PMC have considerable phenotypic overlap. Genetic investigation contributes to identifying the subtype of NDM. The muscle pathology of NDM lacks specific changes.
PubMed: 35350395
DOI: 10.3389/fneur.2022.830707 -
ChemMedChem Apr 2022
PubMed: 35312164
DOI: 10.1002/cmdc.202200131 -
American Journal of Translational... 2021Intersubject variability in drug response, whether related to efficacy or toxicity, is well recognized clinically. Over the years, drug selection from our pharmacologic... (Review)
Review
Intersubject variability in drug response, whether related to efficacy or toxicity, is well recognized clinically. Over the years, drug selection from our pharmacologic armamentarium has moved from providers' preferred choices to more personalized treatments as clinicians' decisions are guided by data from clinical trials. Since the advent of more accessible and affordable pharmacogenomic (PGx) testing, the promise of precise pharmacotherapy has been made. Results have accumulated in the literature with numerous examples demonstrating the value of PGx to improve drug response or prevent drug toxicity. Unfortunately, limited availability of reimbursement policies has dampened the enthusiasm of providers and organizations. The clinical application of PGx knowledge remains difficult for most clinicians under real-world conditions in patients with numerous chronic conditions and polypharmacy. This may be due to phenoconversion, a condition where there is a discrepancy between the genotype-predicted phenotype and the observed phenotype. This condition complicates the interpretation of PGx results and may lead to inappropriate recommendations and clinical decision making. For this reason, regulatory agencies have limited the transfer of information from PGx laboratories directly to consumers, especially recommendations about the use of certain drugs. This mini-review presents cases (mexiletine, propafenone, clopidogrel, warfarin, codeine, procainamide) from historical observations where drug response was modified by phenoconversion. The cases illustrate, from decades ago, that we are still in great need of advanced clinical decision systems that cope with conditions associated with phenoconversion, especially in patients with polypharmacy.
PubMed: 35035679
DOI: No ID Found -
The Application of Clinical Genetics 2021Becker's type myotonia congenita is an autosomal recessive nondystrophic skeletal muscle disorder characterized by muscle stiffness and the inability of muscle...
BACKGROUND
Becker's type myotonia congenita is an autosomal recessive nondystrophic skeletal muscle disorder characterized by muscle stiffness and the inability of muscle relaxation after voluntary contraction. It is caused by mutations in the gene, which encodes for a chloride channel mainly expressed in the striated muscle. Most cases have been reported in the European population, and only mexiletine has demonstrated a randomized placebo-controlled, double-blinded effectiveness.
CASE PRESENTATION
We present two male siblings from Colombia with Latino ancestry, without parental consanguinity, with myotonia during voluntary movements, muscle hypertrophy of lower extremities, transient weakness, and severe muscle fatigue after exercise from three years of age. A genetic panel for dystrophic muscle disorders and a muscle biopsy were both negative. Genetic testing was performed in their second decade of life. Both patients' exomic sequencing test reported the mutation c.1129C >T (p.Arg377*) affecting exon 10 of the , generating a premature stop codon. This mutation was described as pathogenic and observed in only one other patient in the United Kingdom.
CONCLUSION
To our knowledge, these are the first cases of Becker's type myotonia congenita reported in Colombia. Increasing awareness of healthcare providers for this type of disease in the region could lead to the identification of undiagnosed patients. Limited availability of medical geneticists as well as genetic testing may be the cause of the lack of previous description of cases, in addition to the delay in the diagnosis of the patients. Further epidemiological studies can reveal underdiagnosed myotonias in the country and in the Latin-American region.
PubMed: 34938096
DOI: 10.2147/TACG.S323559 -
European Heart Journal. Case Reports Dec 2021Long QT3 syndrome type 3 (LQT3) is a gain of function mutation of the SCN5A gene that is inherited in an autosomal dominant fashion. Long QT3 syndrome type 3 results in...
BACKGROUND
Long QT3 syndrome type 3 (LQT3) is a gain of function mutation of the SCN5A gene that is inherited in an autosomal dominant fashion. Long QT3 syndrome type 3 results in an increase in arrhythmic events during rest, sleep, and bradycardia by extending the QT interval and inducing Torsades de pointes and sudden cardiac death. Attempting to block the sodium channel with Class I anti-arrhythmics or blocking adrenergic tone with beta-blockers especially in women has shown to be beneficial. There have been few large-scale studies on treating patients with LQT3 due to its lethality and underreported number of cases. Specifically, the safety and efficacy of pharmacologic treatment in pregnant LQT3 patients are unknown.
CASE SUMMARY
This case demonstrates the safe use of Mexiletine and Propranolol in a 3rd-trimester pregnant LQT3 patient after a presumed ventricular arrhythmia and device-lead electrical short from therapy rendered her implantable cardioverter defibrillator inoperable in a VVI mode (venticular demand pacing). With appropriate medications, the patient was safely monitored through the remainder of her pregnancy and safely delivered at 36 weeks of pregnancy a healthy baby girl. The daughter, heterozygous for LQT3, showed no evidence of intrauterine growth restriction or other side effects from the medications.
DISCUSSION
There are many variants of the SCN5A gene mutations that can lead to different phenotypes and not all mutations are responsive to the same medications. In this case, Mexiletine and Propranolol, both of which have only recently shown to benefit certain variants or LQT3 respectively, were safely started during the 3rd trimester of pregnancy without harming the foetus.
PubMed: 34926986
DOI: 10.1093/ehjcr/ytab487 -
Case Reports in Medicine 2021Advanced heart failure patients commonly suffer from ventricular arrhythmias which can be managed by antiarrhythmic drugs like mexiletine. These ventricular arrhythmias...
Advanced heart failure patients commonly suffer from ventricular arrhythmias which can be managed by antiarrhythmic drugs like mexiletine. These ventricular arrhythmias can be complicated by illicit drug use which alter outcomes and can potentially impact the patient-physician relationship through countertransference. However, mexiletine can lead to false positive urine drug screen testing for amphetamine, and these false-positive urine drug screen test results can affect the decision-making process. Health care providers should be aware of this fact and should either use confirmatory testing or look for confounding compounds in patients who deny using illicit substances and have a positive urine drug screen. Our patient is 64 years old who arrived at the emergency department after experiencing a shock by his intracardiac defibrillator. The patient tested positive for amphetamine on his urine drug screen and was later ruled out by confirmatory quantitative testing.
PubMed: 34887926
DOI: 10.1155/2021/7134394 -
BMC Neurology Dec 2021Non-dystrophic myotonias (NDMs) comprise muscle chloride and sodium channelopathies due to genetic defects of the CLCN1- and SCN4A-channels. No licensed antimyotonic...
Improving the understanding of how patients with non-dystrophic myotonia are selected for myotonia treatment with mexiletine (NaMuscla): outcomes of treatment impact using a European Delphi panel.
BACKGROUND
Non-dystrophic myotonias (NDMs) comprise muscle chloride and sodium channelopathies due to genetic defects of the CLCN1- and SCN4A-channels. No licensed antimyotonic treatment has been available until approval of mexiletine (NaMuscla®) for adult patients by the EMA in December 2018. This Delphi panel aimed to understand how outcomes of the pivotal phase III Mexiletine study (MYOMEX) translate to real world practice and investigate health resource use, quality of life and the natural history of NDM to support economic modelling and facilitate patient access.
METHODS
Nine clinical experts in treating NDM took part in a two-round Delphi panel. Their knowledge of NDM and previous use of mexiletine as an off-label treatment prior to NaMuscla's approval ensured they could provide both qualitative context and quantitative estimates to support economic modelling comparing mexiletine (NaMuscla) to best supportive care. Consensus in four key areas was sought: healthcare resource utilization (HRU), treatment with mexiletine (NaMuscla), patient quality of life (QoL), and the natural history of disease. Concept questions were also asked, considering perceptions on the feasibility of mapping the validated Individualized Neuromuscular Quality of Life (INQoL) instrument to the generic EQ-5D™, and the potential impact on caregiver QoL.
RESULTS
Consensus was achieved for key questions including the average long-term dosage of mexiletine (NaMuscla) in practice, the criteria for eligibility of myotonia treatment, the clinical importance of QoL outcomes in MYOMEX, the higher proportion of patients with increased QoL, and the reduction in the need for mental health resources for patients receiving mexiletine (NaMuscla). While consensus was not achieved for other questions, the results demonstrated that most experts felt mexiletine (NaMuscla) reduced the need for HRU and was expected to improve QoL. The QoL mapping exercise suggested that it is feasible to map domains of INQoL to EQ-5D. Points of interest for future research were identified, including that mexiletine (NaMuscla) may slow the annual decrease in QoL of patients over their lifetime, and a significant negative impact on QoL for some caregivers.
CONCLUSIONS
This project successfully provided data from an informed group of clinical experts, complementing the currently available clinical trial data for mexiletine (NaMuscla) to support patient access decisions.
Topics: Adult; Channelopathies; Humans; Mexiletine; Myotonia; NAV1.4 Voltage-Gated Sodium Channel; Quality of Life; Treatment Outcome
PubMed: 34852780
DOI: 10.1186/s12883-021-02491-3