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Neurochemical Research May 2016Using the mouse maximal electroshock test, the reference model of tonic-clonic seizures, the aim of the present study was to determine the type of interaction between...
Using the mouse maximal electroshock test, the reference model of tonic-clonic seizures, the aim of the present study was to determine the type of interaction between mexiletine (a class IB antiarrhythmic drug) and classical antiepileptics: valproate, carbamazepine, phenytoin, and phenobarbital. Isobolographic analysis of obtained data indicated antagonistic interactions between mexiletine and valproate (for fixed ratio combinations of 1:1 and 3:1). Additivity was observed between mexiletine and valproate applied in proportion of 1:3 as well as between mexiletine and remaining antiepileptics for the fixed ratios of 1:3, 1:1, and 3:1. Neither motor performance nor long-term memory were impaired by mexiletine or antiepileptic drugs regardless of whether they were administered singly or in combination. Mexiletine did not significantly affected brain concentrations of carbamazepine, phenobarbital or phenytoin. In contrast, the antiarrhythmic drug decreased by 23 % the brain level of valproate. This could be, at least partially, the reason of antagonistic interaction between the two drugs. In conclusion, the observed additivity suggests that mexiletine can be safely applied in epileptic patients treated with carbamazepine, phenytoin or phenobarbital. Because of undesirable pharmacodynamics and pharmacokinetic interactions with valproate, mexiletine should not be used in such combinations.
Topics: Animals; Anticonvulsants; Avoidance Learning; Brain; Carbamazepine; Drug Interactions; Electroshock; Male; Memory, Long-Term; Mexiletine; Mice; Motor Activity; Phenobarbital; Phenytoin; Seizures; Tissue Distribution; Valproic Acid
PubMed: 26738990
DOI: 10.1007/s11064-015-1812-x -
Biomedicines May 2024A sodium current (I) reduction occurs in the setting of many acquired and inherited conditions and is associated with cardiac conduction slowing and increased arrhythmia...
A sodium current (I) reduction occurs in the setting of many acquired and inherited conditions and is associated with cardiac conduction slowing and increased arrhythmia risks. The sodium channel blocker mexiletine has been shown to restore the trafficking of mutant sodium channels to the membrane. However, these studies were mostly performed in heterologous expression systems using high mexiletine concentrations. Moreover, the chronic effects on I in a non-diseased cardiomyocyte environment remain unknown. In this paper, we investigated the chronic and acute effects of a therapeutic dose of mexiletine on I and the action potential (AP) characteristics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) of a healthy individual. Control hiPSC-CMs were incubated for 48 h with 10 µM mexiletine or vehicle. Following the wash-out of mexiletine, patch clamp analysis and immunocytochemistry experiments were performed. The incubation of hiPSC-CMs for 48 h with mexiletine (followed by wash-out) induced a significant increase in peak I of ~75%, without any significant change in the voltage dependence of (in)activation. This was accompanied by a significant increase in AP upstroke velocity, without changes in other AP parameters. The immunocytochemistry experiments showed a significant increase in membrane Na1.5 fluorescence following a 48 h incubation with mexiletine. The acute re-exposure of hiPSC-CMs to 10 µM mexiletine resulted in a small but significant increase in AP duration, without changes in AP upstroke velocity, peak I density, or the I voltage dependence of (in)activation. Importantly, the increase in the peak I density and resulting AP upstroke velocity induced by chronic mexiletine incubation was not counteracted by the acute re-administration of the drug. In conclusion, the chronic administration of a clinically relevant concentration of mexiletine increases I density in non-diseased hiPSC-CMs, likely by enhancing the membrane trafficking of sodium channels. Our findings identify mexiletine as a potential therapeutic strategy to enhance and/or restore I and cardiac conduction.
PubMed: 38927420
DOI: 10.3390/biomedicines12061212 -
F1000Research 2015To determine the exact role of sodium channel proteins in migration, invasion and metastasis and understand the possible anti-invasion and anti-metastatic activity of... (Review)
Review
OBJECTIVE
To determine the exact role of sodium channel proteins in migration, invasion and metastasis and understand the possible anti-invasion and anti-metastatic activity of repurposed drugs with voltage gated sodium channel blocking properties.
MATERIAL AND METHODS
A review of the published medical literature was performed searching for pharmaceuticals used in daily practice, with inhibitory activity on voltage gated sodium channels. For every drug found, the literature was reviewed in order to define if it may act against cancer cells as an anti-invasion and anti-metastatic agent and if it was tested with this purpose in the experimental and clinical settings.
RESULTS
The following pharmaceuticals that fulfill the above mentioned effects, were found: phenytoin, carbamazepine, valproate, lamotrigine, ranolazine, resveratrol, ropivacaine, lidocaine, mexiletine, flunarizine, and riluzole. Each of them are independently described and analyzed.
CONCLUSIONS
The above mentioned pharmaceuticals have shown anti-metastatic and anti-invasion activity and many of them deserve to be tested in well-planned clinical trials as adjunct therapies for solid tumors and as anti-metastatic agents. Antiepileptic drugs like phenytoin, carbamazepine and valproate and the vasodilator flunarizine emerged as particularly useful for anti-metastatic purposes.
PubMed: 27408684
DOI: 10.12688/f1000research.6789.1 -
Palliative Medicine Dec 2017Rectal tenesmus is a distressing symptom in patients with advanced cancer and challenging to treat. There is lack of consensus on the appropriate management of tenesmus... (Review)
Review
BACKGROUND
Rectal tenesmus is a distressing symptom in patients with advanced cancer and challenging to treat. There is lack of consensus on the appropriate management of tenesmus in this patient population.
AIM
To identify and examine the effectiveness of interventions to palliate rectal tenesmus caused by advanced cancer when surgery, radiotherapy or chemotherapy are no longer treatment options.
DESIGN
A systematic review of the literature following standard systematic review methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance.
DATA SOURCES
A comprehensive search of the electronic databases MEDLINE, EMBASE and the Cochrane Library was conducted from date of inception to April 2016. PubMed 'related articles' search, grey literature search and hand-searches of the bibliographies of relevant papers and textbooks were also performed. Non-cancer patients were excluded. Any studies involving surgery or radiotherapy to treat tenesmus were excluded. Studies involving interventions to treat pelvic pain syndromes without specific outcome measures on severity of tenesmus were excluded. The quality of the studies was assessed using a National Institute for Health and Clinical Excellence-recommended quality assessment tool.
RESULTS
From 861 studies, 9 met full criteria and were selected. All were case series investigating the use of pharmacological interventions (diltiazem, nifedipine, methadone, mexiletine hydrochloride, lidocaine and bupivacaine), anaesthetic interventions (lumbar sympathectomy, neurolytic superior hypogastric plexus block), and endoscopic laser interventions. The included studies showed substantial heterogeneity, and therefore, a meta-analysis was not feasible.
CONCLUSION
From this review, we identified a significant gap in research into the palliation of rectal tenesmus. A multimodal approach may be necessary due to the complexity of the pathophysiology of tenesmus. Future research should focus on randomised controlled trials of drug therapies whose potential effectiveness is suggested by case series.
Topics: Anesthesia; Anesthetics; Calcium Channel Blockers; Humans; Laser Therapy; Neoplasms; Palliative Care; Rectal Diseases
PubMed: 28590211
DOI: 10.1177/0269216317697897 -
Value in Health : the Journal of the... Jul 2021Mexiletine is a long-known drug used for the treatment of arrhythmias and repurposed in the 1980s for patients with nondystrophic myotonia (NDM). Recently, the price of...
OBJECTIVES
Mexiletine is a long-known drug used for the treatment of arrhythmias and repurposed in the 1980s for patients with nondystrophic myotonia (NDM). Recently, the price of mexiletine in Europe increased significantly after registration as an orphan drug for NDM. This led to international discussions on affordability and willingness to reimburse mexiletine in the absence of background information that would justify such a price. Our objective was to calculate a cost-based price for mexiletine for adult patients with NDM based on detailed information on development costs.
METHODS
We calculated a fair price based on a cost-based pricing model for commercial mexiletine to treat adults with NDM using a recent European drug-pricing model as a framework to include actual costs incurred. Three scenarios were applied: 1 with minimum estimated costs, 1 with maximum estimated costs, and 1 with costs as if mexiletine was innovative.
RESULTS
The calculated fair price of mexiletine per patient per year (PPPY) is €452 for the minimum scenario and €1996 for the maximum scenario. By using hypothetical R&D costs used for innovative drugs, the price would be €6685 PPPY. In Europe, the list price of mexiletine ranges from €30 707-60 730 PPPY, based on 600 mg daily.
CONCLUSIONS
The current list price for mexiletine in Europe is manifold higher than any scenario of the cost-based models. Accounting for the reduced costs for clinical development in a repurposing scenario, the cost-based pricing model provides a fair commercial price range, which can be used as benchmark for pricing negotiations and/or reimbursement decisions.
Topics: Anti-Arrhythmia Agents; Commerce; Drug Repositioning; Europe; Humans; Mexiletine; Myotonia; Orphan Drug Production
PubMed: 34243835
DOI: 10.1016/j.jval.2021.02.004 -
Cardiology 2019The uptake of sacubitril/valsartan since the PARADIGM study confirmed its beneficial effects on outcomes over enalapril in chronic systolic heart failure has inevitably...
The uptake of sacubitril/valsartan since the PARADIGM study confirmed its beneficial effects on outcomes over enalapril in chronic systolic heart failure has inevitably led to potential interactions with co-prescribed medications in real-world patients. We report two cases that raise the possibility of an interaction between sacubitril/valsartan and the class Ib anti-arrhythmic mexiletine resulting in proarrhythmic effects. We discuss the pharmacokinetics of both agents and posit potential mechanistic interactions that suggest caution should be used and careful monitoring for (ventricular) arrhythmias applied in patients receiving sacubitril/valsartan and mexiletine.
Topics: Aged; Aminobutyrates; Angiotensin Receptor Antagonists; Arrhythmias, Cardiac; Biphenyl Compounds; Drug Combinations; Drug Interactions; Female; Heart Failure, Systolic; Humans; Male; Mexiletine; Tetrazoles; Valsartan
PubMed: 30852576
DOI: 10.1159/000497071 -
Kardiologia Polska 2017Antiarrhythmic treatment of patients with recurrent ventricular tachyarrhythmia, in whom catheter ablation and amiodarone treatment were ineffective or contraindicated,...
BACKGROUND
Antiarrhythmic treatment of patients with recurrent ventricular tachyarrhythmia, in whom catheter ablation and amiodarone treatment were ineffective or contraindicated, is an unsolved clinical problem.
AIM
The study aims to evaluate the efficacy and tolerability of mexiletine in patients with recurrent ventricular tachyarrhythmias and/or electrical storm events, in whom standard treatment strategies failed to prevent ventricular tachyarrhythmia.
METHODS
We performed a retrospective cohort analysis of all patients treated with mexiletine for recurrent ventricular tachycardia and/or ventricular fibrillation in our institution between January 2011 and September 2015. The primary endpoints were total number of electrical storm events and ventricular tachycardia/ventricular fibrillation (VT/VF) episodes after the beginning of mexiletine therapy. Secondary endpoints were total number of implantable cardioverter-defibrillator (ICD) therapies and discontinuation of the therapy. Events were compared with a matched duration period before initiating mexiletine. Patients served as self-controls.
RESULTS
Seventeen patients were included in the study; 11 patients were males. Mean age was 64.2 ± 15.4 years. The median time of mexiletine treatment was eight months (interquartile range [IR]: 1-22 months). The mexiletine dose was 600 mg/day in 13 patients and 400 mg/day in four patients. In four patients the dose was modified during treatment in a range from 400 to 600 mg/day depending on clinical decision. Treatment with mexiletine significantly reduced the number of electrical storm events (14 episodes vs. two episodes; median and IR for 17 patients: 1 [0-1] vs. 0 [0-0], p = 0.0010), VT/VF episodes (285 vs. 74 episodes; median and IR for 17 patients: 7 [5-27] vs. 0 [0-5], p = 0.0115), and ICD interventions (317 interven-tions vs. nine interventions; median and IR for 17 patients: 10 [5-25] vs. 0 [0-2], p = 0.0006), in comparison with a matched period before initiation of treatment. In 14 out of 17 patients (82%) sufficient tolerability of mexiletine was observed. Only in three (18%) patients severe side effects of mexiletine treatment occurred requiring discontinuation of therapy.
CONCLUSIONS
Mexiletine was a sufficiently tolerated antiarrhythmic drug in short-term treatment of ventricular tachyarrhyth-mias in the studied population. Mexiletine may be effective in the treatment of recurring ventricular tachyarrhythmias or electrical storm events.
Topics: Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Combined Modality Therapy; Defibrillators, Implantable; Drug Tolerance; Humans; Male; Mexiletine; Middle Aged; Recurrence; Retrospective Studies; Treatment Outcome; Ventricular Fibrillation
PubMed: 29057449
DOI: 10.5603/KP.2017.0189 -
The Cochrane Database of Systematic... Aug 2015Coronary artery disease is a major public health problem affecting both developed and developing countries. Acute coronary syndromes include unstable angina and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Coronary artery disease is a major public health problem affecting both developed and developing countries. Acute coronary syndromes include unstable angina and myocardial infarction with or without ST-segment elevation (electrocardiogram sector is higher than baseline). Ventricular arrhythmia after myocardial infarction is associated with high risk of mortality. The evidence is out of date, and considerable uncertainty remains about the effects of prophylactic use of lidocaine on all-cause mortality, in particular, in patients with suspected myocardial infarction.
OBJECTIVES
To determine the clinical effectiveness and safety of prophylactic lidocaine in preventing death among people with myocardial infarction.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 3), MEDLINE Ovid (1946 to 13 April 2015), EMBASE (1947 to 13 April 2015) and Latin American Caribbean Health Sciences Literature (LILACS) (1986 to 13 April 2015). We also searched Web of Science (1970 to 13 April 2013) and handsearched the reference lists of included papers. We applied no language restriction in the search.
SELECTION CRITERIA
We included randomised controlled trials assessing the effects of prophylactic lidocaine for myocardial infarction. We considered all-cause mortality, cardiac mortality and overall survival at 30 days after myocardial infarction as primary outcomes.
DATA COLLECTION AND ANALYSIS
We performed study selection, risk of bias assessment and data extraction in duplicate. We estimated risk ratios (RRs) for dichotomous outcomes and measured statistical heterogeneity using I(2). We used a random-effects model and conducted trial sequential analysis.
MAIN RESULTS
We identified 37 randomised controlled trials involving 11,948 participants. These trials compared lidocaine versus placebo or no intervention, disopyramide, mexiletine, tocainide, propafenone, amiodarone, dimethylammonium chloride, aprindine and pirmenol. Overall, trials were underpowered and had high risk of bias. Ninety-seven per cent of trials (36/37) were conducted without an a priori sample size estimation. Ten trials were sponsored by the pharmaceutical industry. Trials were conducted in 17 countries, and intravenous intervention was the most frequent route of administration.In trials involving participants with proven or non-proven acute myocardial infarction, lidocaine versus placebo or no intervention showed no significant differences regarding all-cause mortality (213/5879 (3.62%) vs 199/5848 (3.40%); RR 1.02, 95% CI 0.82 to 1.27; participants = 11727; studies = 18; I(2) = 15%); low-quality evidence), cardiac mortality (69/4184 (1.65%) vs 62/4093 (1.51%); RR 1.03, 95% CI 0.70 to 1.50; participants = 8277; studies = 12; I(2) = 12%; low-quality evidence) and prophylaxis of ventricular fibrillation (76/5128 (1.48%) vs 103/4987 (2.01%); RR 0.78, 95% CI 0.55 to 1.12; participants = 10115; studies = 16; I(2) = 18%; low-quality evidence). In terms of sinus bradycardia, lidocaine effect is imprecise compared with effects of placebo or no intervention (55/1346 (4.08%) vs 49/1203 (4.07%); RR 1.09, 95% CI 0.66 to 1.80; participants = 2549; studies = 8; I(2) = 21%; very low-quality evidence). In trials involving only participants with proven acute myocardial infarction, lidocaine versus placebo or no intervention showed no significant differences in all-cause mortality (148/2747 (5.39%) vs 135/2506 (5.39%); RR 1.01, 95% CI 0.79 to 1.30; participants = 5253; studies = 16; I(2) = 9%; low-quality evidence). No significant differences were noted between lidocaine and any other antiarrhythmic drug in terms of all-cause mortality and ventricular fibrillation. Data on overall survival 30 days after myocardial infarction were not reported. Lidocaine compared with placebo or no intervention increased risk of asystole (35/3393 (1.03%) vs 14/3443 (0.41%); RR 2.32, 95% CI 1.26 to 4.26; participants = 6826; studies = 4; I(2) = 0%; very low-quality evidence) and dizziness/drowsiness (74/1259 (5.88%) vs 16/1274 (1.26%); RR 3.85, 95% CI 2.29 to 6.47; participants = 2533; studies = 6; I(2) = 0%; low-quality evidence). Overall, safety data were poorly reported and adverse events may have been underestimated. Trial sequential analyses suggest that additional trials may not be needed for reliable conclusions to be drawn regarding these outcomes.
AUTHORS' CONCLUSIONS
This Cochrane review found evidence of low quality to suggest that prophylactic lidocaine has very little or no effect on mortality or ventricular fibrillation in people with acute myocardial infarction. The safety profile is unclear. This conclusion is based on randomised controlled trials with high risk of bias. However (disregarding the risk of bias), trial sequential analysis suggests that additional trials may not be needed to disprove an intervention effect of 20% relative risk reduction. Smaller risk reductions might require additional higher trials.
Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bradycardia; Humans; Lidocaine; Myocardial Infarction; Randomized Controlled Trials as Topic; Ventricular Fibrillation
PubMed: 26295202
DOI: 10.1002/14651858.CD008553.pub2 -
Biological & Pharmaceutical Bulletin 2022Evaluation of drug-induced cardiotoxicity is still challenging to avoid adverse effects, such as torsade de pointes (TdP), in non-clinical and clinical studies. Numerous...
Evaluation of drug-induced cardiotoxicity is still challenging to avoid adverse effects, such as torsade de pointes (TdP), in non-clinical and clinical studies. Numerous studies have suggested that human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a useful platform for detecting drug-induced TdP risks. Comprehensive in vitro Proarrhythmia Assay (CiPA) validation study suggested that hiPSC-CMs can assess clinical TdP risk more accurately than the human ether-a-go-go-related assay and QT interval prolongation. However, there were still some outliers, such as bepridil, mexiletine, and ranolazine, among the CiPA 28 compounds in the CiPA international multi-site study using hiPSC-CMs. In this study, we assessed the effects of the positive compound dofetilide, the negative compound aspirin, and several CiPA compounds (bepridil, mexiletine, and ranolazine) on the electromechanical window (E-M window), which were evaluated using multi-electrode array assay and motion analysis, in hiPSC-CMs. Similar to previous in vivo studies, dofetilide, which has a high TdP risk, decreased the E-M window in hiPSC-CMs, whereas aspirin, which has a low TdP risk, had little effect. Bepridil, classified in the high TdP-risk group in CiPA, decreased the E-M window in hiPSC-CMs, whereas ranolazine and mexiletine, which are classified in the low TdP-risk group in CiPA, slightly decreased or had little effect on the E-M window of hiPSC-CMs. Thus, the E-M window in hiPSC-CMs can be used to classify drugs into high and low TdP risk.
Topics: Aspirin; Bepridil; DNA-Binding Proteins; Humans; Induced Pluripotent Stem Cells; Mexiletine; Myocytes, Cardiac; Ranolazine; Risk Assessment
PubMed: 35786601
DOI: 10.1248/bpb.b22-00268 -
Expert Review of Neurotherapeutics Oct 2016Motor neuron hyperexcitability appears linked to the process of neurodegeneration in amyotrophic lateral sclerosis (ALS). As such, therapies that inhibit neuronal... (Review)
Review
INTRODUCTION
Motor neuron hyperexcitability appears linked to the process of neurodegeneration in amyotrophic lateral sclerosis (ALS). As such, therapies that inhibit neuronal hyperexcitability may prove effective in arresting the progression of ALS.
AREA COVERED
We searched MEDLINE and ClinicalTrials.gov and selected randomised controlled trials that covered neuroprotective therapy. Riluzole has been established to reduce neuronal hyperexcitability. More recently, initial studies of Na(+) channel blockers (mexiletine and flecainide) have been trialled. Separately, a trial of a K(+) channel activator (retigabine) is underway, while edaravone is currently being considered for licensing by drug approval agencies based on a hypothesis that the elimination of free radicals may lead to protection of motor neurones. Expert commentary: Initial clinical trials with Na(+) channel blockers have not yet established efficacy in ALS. Currently, retigabine is under evaluation as a potential therapy. Edaravone has recently been approved as a new therapeutic option for ALS in Japan.
Topics: Amyotrophic Lateral Sclerosis; Antipyrine; Edaravone; Humans; Motor Neurons; Neuroprotective Agents; Riluzole
PubMed: 27314534
DOI: 10.1080/14737175.2016.1197774