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Journal of Neuromuscular Diseases 2021Skeletal muscle ion channelopathies include non-dystrophic myotonias (NDM), periodic paralyses (PP), congenital myasthenic syndrome, and recently identified congenital...
BACKGROUND
Skeletal muscle ion channelopathies include non-dystrophic myotonias (NDM), periodic paralyses (PP), congenital myasthenic syndrome, and recently identified congenital myopathies. The treatment of these diseases is mainly symptomatic, aimed at reducing muscle excitability in NDM or modifying triggers of attacks in PP.
OBJECTIVE
This systematic review collected the evidences regarding effects of pharmacological treatment on muscle ion channelopathies, focusing on the possible link between treatments and genetic background.
METHODS
We searched databases for randomized clinical trials (RCT) and other human studies reporting pharmacological treatments. Preclinical studies were considered to gain further information regarding mutation-dependent drug effects. All steps were performed by two independent investigators, while two others critically reviewed the entire process.
RESULTS
For NMD, RCT showed therapeutic benefits of mexiletine and lamotrigine, while other human studies suggest some efficacy of various sodium channel blockers and of the carbonic anhydrase inhibitor (CAI) acetazolamide. Preclinical studies suggest that mutations may alter sensitivity of the channel to sodium channel blockers in vitro, which has been translated to humans in some cases. For hyperkalemic and hypokalemic PP, RCT showed efficacy of the CAI dichlorphenamide in preventing paralysis. However, hypokalemic PP patients carrying sodium channel mutations may have fewer benefits from CAI compared to those carrying calcium channel mutations. Few data are available for treatment of congenital myopathies.
CONCLUSIONS
These studies provided limited information about the response to treatments of individual mutations or groups of mutations. A major effort is needed to perform human studies for designing a mutation-driven precision medicine in muscle ion channelopathies.
Topics: Channelopathies; Humans; Hypokalemic Periodic Paralysis; Lamotrigine; Mexiletine; Muscle, Skeletal; Mutation; Myasthenic Syndromes, Congenital; Myotonic Disorders; Precision Medicine; Randomized Controlled Trials as Topic; Sodium Channel Blockers
PubMed: 33325393
DOI: 10.3233/JND-200582 -
Minerva Cardiology and Angiology Dec 2023To evaluate the clinical outcomes of oral mexiletine (oMXT) to treat ventricular tachyarrhythmias (VTAs) in the era of implantable cardioverter-defibrillator (ICD)...
INTRODUCTION
To evaluate the clinical outcomes of oral mexiletine (oMXT) to treat ventricular tachyarrhythmias (VTAs) in the era of implantable cardioverter-defibrillator (ICD) technology.
EVIDENCE ACQUISITION
A systematic search was conducted using PubMed, Embase and Cochrane databases following the PRISMA guidelines to collect literature data reporting oMXT efficacy and safety outcomes in treating VTAs in ICD recipients.
EVIDENCE SYNTHESIS
Final analysis included four studies accounting for a total of 91 patients with recurrent VTAs treated with oMXT. Amiodarone therapy was initially attempted in most patients (91.2%), while catheter ablation was performed in one-third of patients. VTA recurrences were observed in 55/91 patients (60.4%) during oMXT treatment compared to 91/91 (100%) before treatment (P<0.001). Appropriate therapies occurred in 55/88 ICD patients (62.5%) during oMXT treatment compared to 80/88 (90.9%) before treatment (P<0.001). After oMXT introduction, there was a significant reduction of the individual burden of VTA episodes and appropriate ICD therapies per patient, showing Hedges'g values of -1.103 (P=0.002) and -1.474 (P=0.008), respectively. Safety analysis showed a sample-weighted overall side-effect rate of 30%, while 21% of patients required drug reduction or discontinuation. Aggregated meta-regression analysis of the included studies and remote literature revealed a linear correlation between oMXT dosage and the overall side effects rate (r = 0.48; P=0.014).
CONCLUSIONS
Oral mexiletine provides an adjunctive treatment to manage VTAs and reduces appropriate therapies in ICD patients with moderate efficacy and acceptable safety profiles. These observations await confirmation through randomised clinical trials.
Topics: Humans; Mexiletine; Defibrillators, Implantable; Anti-Arrhythmia Agents; Treatment Outcome; Tachycardia, Ventricular
PubMed: 36305779
DOI: 10.23736/S2724-5683.22.06176-2 -
Regional Anesthesia and Pain Medicine Apr 2022In an attempt to aggregate observations from clinical trials, several meta-analyses have been published examining the effectiveness of systemic, non-opioid,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
In an attempt to aggregate observations from clinical trials, several meta-analyses have been published examining the effectiveness of systemic, non-opioid, pharmacological interventions to reduce the incidence of chronic postsurgical pain.
OBJECTIVE
To inform the design and reporting of future studies, the purpose of our study was to examine the quality of these meta-analyses.
EVIDENCE REVIEW
We conducted an electronic literature search in Embase, MEDLINE, and the Cochrane Database of Systematic Reviews. Published meta-analyses, from the years 2010 to 2020, examining the effect of perioperative, systemic, non-opioid pharmacological treatments on the incidence of chronic postsurgical pain in adult patients were identified. Data extraction focused on methodological details. Meta-analysis quality was assessed using the A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) critical appraisal tool.
FINDINGS
Our search yielded 17 published studies conducting 58 meta-analyses for gabapentinoids (gabapentin and pregabalin), ketamine, lidocaine, non-steroidal anti-inflammatory drugs, and mexiletine. According to AMSTAR 2, 88.2% of studies (or 15/17) were low or critically low in quality. The most common critical element missing was an analysis of publication bias. Trends indicated an improvement in quality over time and association with journal impact factor.
CONCLUSIONS
With few individual trials adequately powered to detect treatment effects, meta-analyses play a crucial role in informing the perioperative management of chronic postsurgical pain. In light of this inherent value and despite a number of attempts, high-quality meta-analyses are still needed.
PROSPERO REGISTRATION NUMBER
CRD42021230941.
Topics: Adult; Chronic Pain; Gabapentin; Humans; Ketamine; Pain, Postoperative; Pregabalin
PubMed: 35027479
DOI: 10.1136/rapm-2021-102981 -
International Journal of Cardiology Mar 2019The most common cardiac feature of Kearns-Sayre syndrome (KSS) is atrioventricular block (AVB), and pacemaker implantations (PMIs) are recommended for KSS patients with...
The most common cardiac feature of Kearns-Sayre syndrome (KSS) is atrioventricular block (AVB), and pacemaker implantations (PMIs) are recommended for KSS patients with advanced AVB. However, some KSS patients develop fatal arrhythmias such as polymorphic ventricular tachycardia (PMVT) and ventricular fibrillation (VF) and die suddenly even after PMIs. We report a patient with KSS who developed PMVT, VF, and QT prolongation, and was treated with mexiletine and successfully managed with an implantable cardioverter defibrillator (ICD). We reviewed the literature on arrhythmias in KSS published from 1975 to 2018. There were 112 patients with arrhythmia-associated KSS, 10 died, and 6 died suddenly after the PMI. The first manifestation of an arrhythmia was bundle branch block, then it progressed to AVB, and developed into complete AVB (CAVB) in about half the KSS patients. Ventricular arrhythmias were documented in 12 patients, and 8 were implanted with defibrillators afterwards. One patient after the implantation of a cardiac resynchronization therapy defibrillator (CRT-D) was treated for VF by an appropriate shock. This fact suggested that VF occurred even under proper pacing, and that defibrillators were effective. Pacemakers may suppress early afterdepolarizations (EADs) associated with a QT prolongation due to bradycardia. Similarly, mexiletine may suppress EADs by blocking the late sodium and Ca currents. Ventricular arrhythmias observed under suppression of EADs may be caused by delayed afterdepolarization (DADs) via an increasing intracellular Ca concentration due to mitochondrial dysfunction. Therefore, a PMI alone may not be sufficient to prevent sudden death, and an ICD implantation should be necessary.
Topics: Adolescent; Cardiac Resynchronization Therapy; Death, Sudden, Cardiac; Defibrillators, Implantable; Electrocardiography; Female; Humans; Kearns-Sayre Syndrome; Tachycardia, Ventricular; Ventricular Fibrillation
PubMed: 30642644
DOI: 10.1016/j.ijcard.2018.12.064