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Muscle & Nerve Oct 2020The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1... (Review)
Review
The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications.
Topics: Acetazolamide; Age of Onset; Carbonic Anhydrase Inhibitors; Chloride Channels; Electrodiagnosis; Electromyography; Fatigue; Genetic Testing; Humans; Lamotrigine; Mexiletine; Muscle Weakness; Muscle, Skeletal; Myalgia; Myotonia Congenita; Myotonic Disorders; NAV1.4 Voltage-Gated Sodium Channel; Practice Guidelines as Topic; Ranolazine; Sodium Channel Blockers; Voltage-Gated Sodium Channel Blockers
PubMed: 32270509
DOI: 10.1002/mus.26887 -
Cardiology 2018Ischaemic heart disease is a major cause of death and disability worldwide, while angina represents its most common symptom. It is estimated that approximately 9 million... (Review)
Review
Ischaemic heart disease is a major cause of death and disability worldwide, while angina represents its most common symptom. It is estimated that approximately 9 million patients in the USA suffer from angina and its treatment is challenging, thus the strategy to improve the management of chronic stable angina is a priority. Angina might be the result of different pathologies, ranging from the "classical" obstruction of a large coronary artery to alteration of the microcirculation or coronary artery spasm. Current clinical guidelines recommend antianginal therapy to control symptoms, before considering coronary artery revascularization. In the current guidelines, drugs are classified as being first-choice (beta-blockers, calcium channel blockers, and short-acting nitrates) or second-choice (ivabradine, nicorandil, ranolazine, trimetazidine) treatment, with the recommendation to reserve second-line modifications for patients who have contraindications to first-choice agents, do not tolerate them, or remain symptomatic. However, such a categorical approach is currently questioned. In addition, current guidelines provide few suggestions to guide the choice of drugs more suitable according to the underlying pathology or the patient comorbidities. Several other questions have recently emerged, such as: is there evidence-based data between first- and second-line treatments in terms of prognosis or symptom relief? Actually, it seems that newer antianginal drugs, which are classified as second choice, have more evidence-based clinical data that are more contemporary to support their use than what is available for the first-choice drugs. It follows that actual guidelines are based more on tradition than on evidence and there is a need for new algorithms that are more individualized to patients, their comorbidities, and pathophysiological mechanism of chronic stable angina.
Topics: Adrenergic beta-Antagonists; Angina, Stable; Calcium Channel Blockers; Cardiovascular Agents; Chest Pain; Humans; Ivabradine; Nicorandil; Patient Selection; Practice Guidelines as Topic; Ranolazine; Treatment Outcome; Trimetazidine
PubMed: 29874661
DOI: 10.1159/000487936 -
Nutrients Jan 2020Type 2 diabetes mellitus (T2DM) is a risk factor for cognitive impairment. Ranolazine, an anti-ischemic drug used in the treatment of angina pectoris, has been shown to...
Type 2 diabetes mellitus (T2DM) is a risk factor for cognitive impairment. Ranolazine, an anti-ischemic drug used in the treatment of angina pectoris, has been shown to possess hypoglycemic properties in pre-clinical and clinical studies. The aim of this study was to evaluate the effects of ranolazine on glucose metabolism and cognitive function in a T2DM model of Wistar rats. Diabetes was induced by a high fat diet (HFD) and streptozotocin (STZ). The control group received a normal caloric diet (NCD) and sodium citrate buffer. Metformin, an effective hypoglycemic drug, was employed as a positive control. Animals were divided into the following groups: HFD/STZ + Ranolazine, HFD/STZ + Metformin, HFD/STZ + Vehicle, NCD + Vehicle, NCD + Ranolazine, and NCD + Metformin. Rats received ranolazine (20 mg/kg), metformin (300 mg/kg), or water, for 8 weeks. At the end of the treatments, all animals underwent to an intraperitoneal glucose tolerance test (IPGTT) and behavioral tests, including passive avoidance, novel object recognition, forced swimming, and elevate plus maze tests. Interleukin-6 plasma levels in the six treatment groups were assessed by Elisa assay. Body mass composition was estimated by nuclear magnetic resonance (NMR). Glucose responsiveness significantly improved in the HFD/STZ + Ranolazine ( < 0.0001) and HFD/STZ + Metformin ( = 0.003) groups. There was a moderate effect on blood glucose levels in the NCD + Ranolazine and NCD + Metformin groups. Lean body mass was significantly increased in the HFD/STZ + Ranolazine and HFD/STZ + Metformin animals, compared to HFD/STZ + Vehicle animals. Ranolazine improved learning and long-term memory in HFD/STZ + Ranolazine compared to HFD/STZ + Vehicle ( < 0.001) and ameliorated the pro-inflammatory profile of diabetic mice. These results support the hypothesis of a protective effect of ranolazine against cognitive decline caused by T2DM.
Topics: Animals; Behavior, Animal; Blood Glucose; Cognition; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Glucose Tolerance Test; Hypoglycemic Agents; Maze Learning; Metformin; Ranolazine; Rats; Rats, Wistar; Streptozocin
PubMed: 32023991
DOI: 10.3390/nu12020382 -
Circulation Jun 2021SGLT2 (sodium/glucose cotransporter 2) inhibitors exert robust cardioprotective effects against heart failure in patients with diabetes, and there is intense interest to...
BACKGROUND
SGLT2 (sodium/glucose cotransporter 2) inhibitors exert robust cardioprotective effects against heart failure in patients with diabetes, and there is intense interest to identify the underlying molecular mechanisms that afford this protection. Because the induction of the late component of the cardiac sodium channel current (late-) is involved in the etiology of heart failure, we investigated whether these drugs inhibit late-.
METHODS
Electrophysiological, in silico molecular docking, molecular, calcium imaging, and whole heart perfusion techniques were used to address this question.
RESULTS
The SGLT2 inhibitor empagliflozin reduced late- in cardiomyocytes from mice with heart failure and in cardiac Nav1.5 sodium channels containing the long QT syndrome 3 mutations R1623Q or ΔKPQ. Empagliflozin, dapagliflozin, and canagliflozin are all potent and selective inhibitors of HO-induced late- (half maximal inhibitory concentration = 0.79, 0.58, and 1.26 µM, respectively) with little effect on peak sodium current. In mouse cardiomyocytes, empagliflozin reduced the incidence of spontaneous calcium transients induced by the late- activator veratridine in a similar manner to tetrodotoxin, ranolazine, and lidocaine. The putative binding sites for empagliflozin within Nav1.5 were investigated by simulations of empagliflozin docking to a three-dimensional homology model of human Nav1.5 and point mutagenic approaches. Our results indicate that empagliflozin binds to Nav1.5 in the same region as local anesthetics and ranolazine. In an acute model of myocardial injury, perfusion of isolated mouse hearts with empagliflozin or tetrodotoxin prevented activation of the cardiac NLRP3 (nuclear-binding domain-like receptor 3) inflammasome and improved functional recovery after ischemia.
CONCLUSIONS
Our results provide evidence that late- may be an important molecular target in the heart for the SGLT2 inhibitors, contributing to their unexpected cardioprotective effects.
Topics: Animals; Benzhydryl Compounds; Glucosides; Humans; Male; Mice; Sodium Channels; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 33832341
DOI: 10.1161/CIRCULATIONAHA.121.053350 -
Cell Feb 2019Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to...
Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to cardiac chamber specification and platform versatility can be overcome. We describe here a scalable tissue-cultivation platform that is cell source agnostic and enables drug testing under electrical pacing. The plastic platform enabled on-line noninvasive recording of passive tension, active force, contractile dynamics, and Ca transients, as well as endpoint assessments of action potentials and conduction velocity. By combining directed cell differentiation with electrical field conditioning, we engineered electrophysiologically distinct atrial and ventricular tissues with chamber-specific drug responses and gene expression. We report, for the first time, engineering of heteropolar cardiac tissues containing distinct atrial and ventricular ends, and we demonstrate their spatially confined responses to serotonin and ranolazine. Uniquely, electrical conditioning for up to 8 months enabled modeling of polygenic left ventricular hypertrophy starting from patient cells.
Topics: Action Potentials; Cell Differentiation; Cells, Cultured; Electrophysiological Phenomena; Humans; Induced Pluripotent Stem Cells; Models, Biological; Myocardium; Myocytes, Cardiac; Pluripotent Stem Cells; Tissue Culture Techniques; Tissue Engineering
PubMed: 30686581
DOI: 10.1016/j.cell.2018.11.042 -
Clinical Cardiology Mar 2016Ranolazine utilization in the management of refractory angina has been established by multiple randomized clinical studies. However, there is growing evidence showing an... (Review)
Review
Ranolazine utilization in the management of refractory angina has been established by multiple randomized clinical studies. However, there is growing evidence showing an evolving role in the field of cardiac arrhythmias. Multiple experimental and clinical studies have evaluated the role of ranolazine in prevention and management of atrial fibrillation, with ongoing studies on its role in ventricular arrhythmias. In this review, we will discuss the pharmacological, experimental, and clinical evidence behind ranolazine use in the management of various cardiac arrhythmias.
Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Heart Conduction System; Heart Rate; Humans; Kinetics; Ranolazine; Sodium Channel Blockers; Sodium Channels; Treatment Outcome
PubMed: 26459200
DOI: 10.1002/clc.22476 -
Nature Metabolism Sep 2023Resistance of melanoma to targeted therapy and immunotherapy is linked to metabolic rewiring. Here, we show that increased fatty acid oxidation (FAO) during prolonged...
Resistance of melanoma to targeted therapy and immunotherapy is linked to metabolic rewiring. Here, we show that increased fatty acid oxidation (FAO) during prolonged BRAF inhibitor (BRAFi) treatment contributes to acquired therapy resistance in mice. Targeting FAO using the US Food and Drug Administration-approved and European Medicines Agency-approved anti-anginal drug ranolazine (RANO) delays tumour recurrence with acquired BRAFi resistance. Single-cell RNA-sequencing analysis reveals that RANO diminishes the abundance of the therapy-resistant NGFR neural crest stem cell subpopulation. Moreover, by rewiring the methionine salvage pathway, RANO enhances melanoma immunogenicity through increased antigen presentation and interferon signalling. Combination of RANO with anti-PD-L1 antibodies strongly improves survival by increasing antitumour immune responses. Altogether, we show that RANO increases the efficacy of targeted melanoma therapy through its effects on FAO and the methionine salvage pathway. Importantly, our study suggests that RANO could sensitize BRAFi-resistant tumours to immunotherapy. Since RANO has very mild side-effects, it might constitute a therapeutic option to improve the two main strategies currently used to treat metastatic melanoma.
Topics: United States; Animals; Mice; Ranolazine; Melanoma; Immunotherapy; Protein Kinase Inhibitors; Methionine
PubMed: 37563469
DOI: 10.1038/s42255-023-00861-4 -
Monaldi Archives For Chest Disease =... Sep 2021Ranolazine derives from piperazine and has been approved as a drug for the therapy of chronic stable angina. It acts by selectively inhibiting the late sodium inward... (Review)
Review
Ranolazine derives from piperazine and has been approved as a drug for the therapy of chronic stable angina. It acts by selectively inhibiting the late sodium inward current. Moreover, ranolazine has other metabolic features which makes it effective in other diseases as well as coronary artery ones. In this paper I make an updated review of all possible therapeutic roles of ranolazine: through cardiology and beyond.
Topics: Acetanilides; Heart; Humans; Piperazines; Ranolazine
PubMed: 34498453
DOI: 10.4081/monaldi.2021.1806