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Journal of Arrhythmia Aug 2021Ranolazine is an antianginal drug and also exhibits antiarrhythmic effect by affecting action potential time, refractory period, and repolarization reserve. We evaluated...
INTRODUCTION
Ranolazine is an antianginal drug and also exhibits antiarrhythmic effect by affecting action potential time, refractory period, and repolarization reserve. We evaluated the effect of ranolazine therapy on myocardial repolarization parameters (Tp-e, QT, QTc intervals, Tp-e/QT, and Tp-e/QTc ratios), index of cardiac electrophysiological balance (iCEB) (QT/QRS, QTc/QRS) and P-wave dispersion (PWD) in patients with stable coronary artery disease (CAD).
METHODS
This study included 175 patients, aged between 35 and 90 years who were followed with stable CAD for at least 3 months. Ninety patients had been receiving ranolazine for at least 1 month, and 85 patients had never received ranolazine. All patients' basic demographic data, risk factors, medications, and echocardiographic parameters recorded. Myocardial repolarization parameters, P-wave times, and PWD were analyzed from 12 lead electrodes.
RESULTS
There was no variation between the groups in terms of basic demographic parameters and CAD risk factors. Tp-e interval (87.3 ± 14.4 vs. 90.8 ± 12.4 msn, < .001), Tp-e/QT (0.22 ± 0.04 vs. 0.23 ± 0.03; = .03), Tp-e/QTc (0.21 ± 0.04 vs. 0.22 ± 0.04 = .001), and PWD (39.2 ± 13.7 vs. 43.5 ± 12.9 = .028) were significantly lower in the ranolazine group. But iCEB was similar in both groups. In multivariate analysis after adjusted confounding factors such as age and BMI, Tp-e/QTc ratio, QTc, P, and PWD were found significantly in ranolazine group again.
CONCLUSION
Tp-e/QTc ratio, QTc, P, and PWD were significantly lower in stable CAD patients under ranolazine therapy. In stable CAD patients, the prognostic significance of ranolazine for arrhythmic events requires further evaluation of these parameters through long-term follow-up and large-scale prospective studies.
PubMed: 34386127
DOI: 10.1002/joa3.12549 -
Dermatology Reports Mar 2022Dermatoses affecting palms may represent a dermatologic challenge from both the diagnostic, and therapeutic point of view. Patients with supposedly occupational...
Dermatoses affecting palms may represent a dermatologic challenge from both the diagnostic, and therapeutic point of view. Patients with supposedly occupational dermatitis can spend months or even years in a frustrating attempt to avoid contact with possible irritants or allergens. To underline the importance of a thorough unbiased analysis of the patient's history and clinical features, we present the iconic case of a bricklayer affected by a chronic, disabling desquamation of palms which in the end was classified as keratolysis exfoliativa (KE) attributed to ranolazine-intake, an antianginal drug. To the best of our knowledge, this specific adverse effect of druginduced KE of palms has never been reported before in association with ranolazine.
PubMed: 35399369
DOI: 10.4081/dr.2022.9264 -
Research in Pharmaceutical Sciences Jun 2021Diabetic cardiomyopathy is a complication of diabetes defined as cardiac dysfunction without the involvement of pericardial vessels, hypertension, or cardiac valve...
BACKGROUND AND PURPOSE
Diabetic cardiomyopathy is a complication of diabetes defined as cardiac dysfunction without the involvement of pericardial vessels, hypertension, or cardiac valve disorders. Ranolazine, an antianginal drug, acts through blocking of cardiac late sodium channels and/or inhibiting beta-oxidation of fatty acids. With regard to its mechanism of action, the present work has been carried out to investigate the potential useful effects of ranolazine on the systolic and diastolic dysfunctions in an experimental rat model of diabetic cardiomyopathy. Lidocaine, as a sodium channel blocker, was used to have a clearer image of the involved mechanisms.
EXPERIMENTAL APPROACH
Diabetes was induced by streptozocin. After 8 weeks, the effects of cumulative concentrations of ranolazine and lidocaine were evaluated on diabetic and normal hearts by the Langendorff method. Finally, the hearts were isolated from the Langendorff system and adenosine three phosphates (ATP) and adenosine diphosphate (ADP) concentrations were measured to assay the metabolic effect of ranolazine.
FINDINGS/RESULTS
Ranolazine significantly decreased the velocity of systolic contraction (+dP/dt) and the velocity of diastolic relaxation (-dP/dt) and developed pressure in normal and diabetic rat hearts. However, this negative effect was greater in normal hearts compared to diabetics. Ranolazine (100 μM) decreased the ATP level only in normal hearts and the ATP/ADP ratio decreased significantly ( < 0.05) in both groups. This reduction was more prominent in normal hearts.
CONCLUSION AND IMPLICATIONS
It is concluded that in the isolated rat heart preparation, ranolazine has no benefit on diabetic cardiomyopathy and may even worsen it. It seems that these effects are related to the metabolic effects of ranolazine.
PubMed: 34221060
DOI: 10.4103/1735-5362.314825 -
JACC. Clinical Electrophysiology Jun 2022
Topics: Arrhythmias, Cardiac; Humans; Ranolazine; Tachycardia, Ventricular
PubMed: 35738853
DOI: 10.1016/j.jacep.2022.04.010 -
The Journal of Investigative Dermatology Feb 2023Circulating tumor cells are the key link between a primary tumor and distant metastases, but once in the bloodstream, loss of adhesion induces cell death. To identify...
Circulating tumor cells are the key link between a primary tumor and distant metastases, but once in the bloodstream, loss of adhesion induces cell death. To identify the mechanisms relevant for melanoma circulating tumor cell survival, we performed RNA sequencing and discovered that detached melanoma cells and isolated melanoma circulating tumor cells rewire lipid metabolism by upregulating fatty acid (FA) transport and FA beta-oxidation‒related genes. In patients with melanoma, high expression of FA transporters and FA beta-oxidation enzymes significantly correlates with reduced progression-free and overall survival. Among the highest expressed regulators in melanoma circulating tumor cells were the carnitine transferases carnitine O-octanoyltransferase and carnitine acetyltransferase, which control the shuttle of peroxisome-derived medium-chain FAs toward mitochondria to fuel mitochondrial FA beta-oxidation. Knockdown of carnitine O-octanoyltransferase or carnitine acetyltransferase and short-term treatment with peroxisomal or mitochondrial FA beta-oxidation inhibitors thioridazine or ranolazine suppressed melanoma metastasis in mice. Carnitine O-octanoyltransferase and carnitine acetyltransferase depletion could be rescued by medium-chain FA supplementation, indicating that the peroxisomal supply of FAs is crucial for the survival of nonadherent melanoma cells. Our study identifies targeting the FA-based cross-talk between peroxisomes and mitochondria as a potential therapeutic opportunity to challenge melanoma progression. Moreover, the discovery of the antimetastatic activity of the Food and Drug Administration‒approved drug ranolazine carries translational potential.
Topics: Mice; Animals; Carnitine O-Acetyltransferase; Carnitine Acyltransferases; Neoplastic Cells, Circulating; Ranolazine; Oxidation-Reduction; Fatty Acids; Melanoma; Carnitine
PubMed: 36058299
DOI: 10.1016/j.jid.2022.08.038 -
Philosophical Transactions of the Royal... Jun 2023Atrial fibrillation (AF) is frequently associated with β-adrenergic stimulation, especially in patients with structural heart diseases. The objective of this study was...
Atrial fibrillation (AF) is frequently associated with β-adrenergic stimulation, especially in patients with structural heart diseases. The objective of this study was to determine the synergism of late sodium current (late ) and Ca/calmodulin-dependent protein kinase (CaMKII)-mediated arrhythmogenic activities in β-adrenergic overactivation-associated AF. Monophasic action potential, conduction properties, protein phosphorylation, ion currents and cellular trigger activities were measured from rabbit-isolated hearts, atrial tissue and atrial myocytes, respectively. Isoproterenol (ISO, 1-15 nM) increased atrial conduction inhomogeneity index, phospho-Na1.5 and phospho-CaMKII protein levels and late by 108%, 65%, 135% and 87%, respectively, and induced triggered activities and episodes of AF in all hearts studied ( < 0.05). Sea anemone toxin II (ATX-II, 2 nM) was insufficient to induce any atrial arrhythmias, whereas the propensities of AF were greater in hearts treated with a combination of ATX-II and ISO. Ranolazine, eleclazine and KN-93 abolished ISO-induced AF, attenuated the phosphorylation of Na1.5 and CaMKII, and reversed the increase of late ( < 0.05) in a synergistic mode. Overall, late in association with the activation of CaMKII potentiates β-adrenergic stimulation-induced AF and the inhibition of both late and CaMKII exerted synergistic anti-arrhythmic effects to suppress atrial arrhythmic activities associated with catecholaminergic activation. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.
Topics: Animals; Rabbits; Atrial Fibrillation; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Adrenergic Agents; Sodium; Heart Atria; Action Potentials; Calcium
PubMed: 37122215
DOI: 10.1098/rstb.2022.0163 -
Muscle & Nerve Jul 2022Neuronal hyperexcitability (manifested by cramps) plays a pathological role in amyotrophic lateral sclerosis (ALS), and drugs affecting it may help symptomatic...
INTRODUCTION/AIMS
Neuronal hyperexcitability (manifested by cramps) plays a pathological role in amyotrophic lateral sclerosis (ALS), and drugs affecting it may help symptomatic management and slow disease progression. We aimed to determine safety and tolerability of two doses of ranolazine in patients with ALS and evaluate for preliminary evidence of drug-target engagement by assessing muscle cramp characteristics.
METHODS
We performed an open-label dose-ascending study of ranolazine in 14 individuals with ALS in two sequential cohorts: 500 mg (cohort 1) and 1000 mg (cohort 2) orally twice daily. Each had a 2-week run-in period, 4-week drug administration, and 6-week safety follow-up. Primary outcome was safety and tolerability. Exploratory measures included cramp frequency and severity, fasciculation frequency, cramp potential duration, ALS Functional Rating Scale---Revised score, and forced vital capacity.
RESULTS
Six and eight participants were enrolled in cohorts 1 and 2, respectively. There were no serious adverse events. Two subjects in cohort 2 discontinued the drug due to constipation. The most frequent drug-related adverse event was gastrointestinal (40%). Cramp frequency decreased by 54.8% (95% confidence interval [CI], 39%-70.8%) and severity decreased by 46.3% (95% CI, 29.5-63.3%), which appeared to be dose-dependent, with decreased awakening due to cramps. Other outcomes showed no change.
DISCUSSION
Ranolazine was well tolerated in ALS up to 2000 mg/day, with gastrointestinal side effects being the most frequent. Ranolazine reduced cramp frequency and severity, supporting its investigation for muscle cramps in a future placebo-controlled trial.
Topics: Amyotrophic Lateral Sclerosis; Humans; Muscle Cramp; Pilot Projects; Ranolazine
PubMed: 35466411
DOI: 10.1002/mus.27560 -
Hellenic Journal of Cardiology : HJC =... 2023We determined the effect of ranolazine vs. placebo in angina patients on 1) selective measures of the ischemic burden, 2) cardiovascular outcomes, including atrial... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
We determined the effect of ranolazine vs. placebo in angina patients on 1) selective measures of the ischemic burden, 2) cardiovascular outcomes, including atrial fibrillation incidence, 3) the in-treatment glycohemoglobin levels and the permanent discontinuations because of side effects, and 4) the achieved between-arms blood pressure and heart rate difference.
METHODS
PubMed and Cochrane Collaboration Library databases were searched for eligible trials until end of September 2020. Trial quality was assessed by the Rob2 tool. Risk ratios or achieved mean differences during follow-up and 95% confidence interval (CI) of categorical or continuous outcomes, respectively, were calculated (random-effects model). The relationship between discontinuation rates and ranolazine's mean dose was investigated by meta-regression analysis.
RESULTS
We selected 18 trials (n = 12,995 patients in patients with macro or microvascular coronary heart disease. Achieved blood pressure and heart rate at rest were not different between randomized arms. Ranolazine administration compared to placebo was associated with an increase of 1) total exercise duration by 30 seconds (95% CI, 18-42), 2) time to 1 mm ST-segment depression by 44 seconds (95% CI, 30-54), and 3) time to angina onset by 40 seconds (95% CI, 30-54). On average, the incidence of atrial fibrillation was reduced by 25% following ranolazine treatment compared to placebo, while glycohemoglobin showed a mean decrease of 0.4% (95% CI, 0.3-0.5%).
DISCUSSION
Ranolazine remains an effective anti-ischemic drug, increases the angina-free exercise duration, delays the onset of ST-segment depression. The beneficial effects of ranolazine are extended to atrial fibrillation reduction rates and better glycemic control.
Topics: Humans; Ranolazine; Angina, Stable; Atrial Fibrillation; Glycated Hemoglobin; Piperazines; Acetanilides; Coronary Artery Disease
PubMed: 36481415
DOI: 10.1016/j.hjc.2022.12.002 -
International Journal of Molecular... Dec 2022Recent studies suggest a pathogenetic association between metabolic disturbances, including type 2 diabetes (T2DM), and cognitive decline and indicate that T2DM may...
Recent studies suggest a pathogenetic association between metabolic disturbances, including type 2 diabetes (T2DM), and cognitive decline and indicate that T2DM may represent a risk factor for Alzheimer's disease (AD). There are a number of experimental studies presenting evidence that ranolazine, an antianginal drug, acts as a neuroprotective drug. The aim of the present study was to evaluate the effects of ranolazine on hippocampal neurodegeneration and astrocytes activation in a T2DM rat model. Diabetes was induced by a high fat diet (HFD) and streptozotocin (STZ) injection. Animals were divided into the following groups: HFD/STZ + Ranolazine, HFD/STZ + Metformin, HFD/STZ + Vehicle, NCD + Vehicle, NCD + Ranolazine and NCD + Metformin. The presence of neurodegeneration was evaluated in the hippocampal cornus ammonis 1 (CA1) region by cresyl violet staining histological methods, while astrocyte activation was assessed by western blot analysis. Staining with cresyl violet highlighted a decrease in neuronal density and cell volume in the hippocampal CA1 area in diabetic HFD/STZ + Vehicle rats, while ranolazine and metformin both improved T2DM-induced neuronal loss and neuronal damage. Moreover, there was an increased expression of GFAP in the HFD/STZ + Vehicle group compared to the treated diabetic groups. In conclusion, in the present study, we obtained additional evidence supporting the potential use of ranolazine to counteract T2DM-associated cognitive decline.
Topics: Rats; Animals; Diabetes Mellitus, Type 2; Ranolazine; Noncommunicable Diseases; Metformin; Encephalitis; Diet, High-Fat; Streptozocin
PubMed: 36555798
DOI: 10.3390/ijms232416160 -
Frontiers in Oncology 2021Glioblastoma (GBM) is the most aggressive adult glioma with a median survival of 14 months. While standard treatments (safe maximal resection, radiation, and...
Glioblastoma (GBM) is the most aggressive adult glioma with a median survival of 14 months. While standard treatments (safe maximal resection, radiation, and temozolomide chemotherapy) have increased the median survival in favorable O(6)-methylguanine-DNA methyltransferase (MGMT)-methylated GBM (~21 months), a large proportion of patients experience a highly debilitating and rapidly fatal disease. This study examined GBM cellular energetic pathways and blockade using repurposed drugs: the glycolytic inhibitor, namely dicholoroacetate (DCA), and the partial fatty acid oxidation (FAO) inhibitor, namely ranolazine (Rano). Gene expression data show that GBM subtypes have similar glucose and FAO pathways, and GBM tumors have significant upregulation of enzymes in both pathways, compared to normal brain tissue ( < 0.01). DCA and the DCA/Rano combination showed reduced colony-forming activity of GBM and increased oxidative stress, DNA damage, autophagy, and apoptosis . In the orthotopic Gl261 and CT2A syngeneic murine models of GBM, DCA, Rano, and DCA/Rano increased median survival and induced focal tumor necrosis and hemorrhage. In conclusion, dual targeting of glycolytic and FAO metabolic pathways provides a viable treatment that warrants further investigation concurrently or as an adjuvant to standard chemoradiation for GBM.
PubMed: 33854970
DOI: 10.3389/fonc.2021.633210