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The American Journal of Cardiology Dec 2023Heart failure is a complex clinical syndrome with a detrimental impact on mortality and morbidity. Energy substrate utilization and myocardial ion channel regulation... (Review)
Review
Heart failure is a complex clinical syndrome with a detrimental impact on mortality and morbidity. Energy substrate utilization and myocardial ion channel regulation have gained research interest especially after the introduction of sodium-glucose co-transporter 2 inhibitors in the treatment of heart failure. Ranolazine or N-(2,6-dimethylphenyl)-2-(4-[2-hydroxy-3-(2-methoxyphenoxy) propyl] piperazin-1-yl) acetamide hydrochloride is an active piperazine derivative which inhibits late sodium current thus minimizing calcium overload in the ischemic cardiomyocytes. Ranolazine also prevents fatty acid oxidation and favors glycose utilization ameliorating the "energy starvation" of the failing heart. Heart failure with preserved ejection fraction is characterized by diastolic impairment; according to the literature ranolazine could be beneficial in the management of increased left ventricular end-diastolic pressure, right ventricular systolic dysfunction and wall shear stress which is reflected by the high natriuretic peptides. Fewer data is evident regarding the effects of ranolazine in heart failure with reduced ejection fraction and mainly support the control of the sodium-calcium exchanger and function of sarcoendoplasmic reticulum calcium adenosine triphosphatase. Ranolazine's therapeutic mechanisms in myocardial ion channels and energy utilization are documented in patients with chronic coronary syndromes. Nevertheless, ranolazine might have a broader effect in the therapy of heart failure and further mechanistic research is required.
Topics: Humans; Ranolazine; Piperazines; Acetanilides; Heart Failure; Sodium
PubMed: 37844876
DOI: 10.1016/j.amjcard.2023.09.066 -
Pacing and Clinical Electrophysiology :... Sep 2016Ranolazine is an antianginal medication originally granted approval by the U.S. Food and Drug Administration for therapeutic use in 2006. Since its introduction into the... (Review)
Review
Ranolazine is an antianginal medication originally granted approval by the U.S. Food and Drug Administration for therapeutic use in 2006. Since its introduction into the U.S. market, there have been multiple trials and clinical case reports that demonstrate ranolazine may be effective in the prevention and treatment of both atrial and ventricular arrhythmias, including postoperative atrial fibrillation following coronary artery bypass graft (CABG) surgery. More recently, the combination of dronedarone with ranolazine has demonstrated in initial studies to have a synergistic effect in the reduction of burden of atrial fibrillation. This article will review the basic pharmacology of ranolazine, the studies demonstrating use of ranolazine in atrial and ventricular arrhythmias, the limitations to the use of ranolazine as antiarrhythmic therapy, and explore the synergistic effect with other agents in the suppression of arrhythmias.
Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dose-Response Relationship, Drug; Drug Administration Schedule; Evidence-Based Medicine; Humans; Ranolazine; Treatment Outcome
PubMed: 27358212
DOI: 10.1111/pace.12905 -
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 -
The Annals of Pharmacotherapy May 2016To review the antihyperglycemic effect of ranolazine in type 2 diabetes mellitus (T2DM). (Review)
Review
OBJECTIVE
To review the antihyperglycemic effect of ranolazine in type 2 diabetes mellitus (T2DM).
DATA SOURCES
An EMBASE search was conducted between January 1966 through December 2015 using the search termsranolazine, diabetes, andhemoglobin A1C(A1C). Additional references were identified from a review of literature citations. A search of clinicaltrials.gov was conducted to identify unpublished studies assessing ranolazine in diabetes.
STUDY SELECTION AND DATA EXTRACTION
All English-language observational and randomized controlled trials assessing the effects of ranolazine on A1C were evaluated.
DATA SYNTHESIS
Four published and 3 unpublished trials were identified. In all except 1 study, ranolazine 750 to 1000 mg twice daily was associated with a statistically significant decrease in A1C compared with placebo (placebo-corrected change in A1C: -0.28 to -0.7). In the trial in which a significant difference was not observed, patients assigned to ranolazine received a lower maintenance metformin dose compared with patients not assigned to ranolazine. A greater percentage of patients randomized to ranolazine achieved an A1C<7% compared with the placebo group (41.2%-59% vs 25.7%-49%). Ranolazine was not associated with an increase in the incidence of hypoglycemia and was well tolerated overall. The mechanism for lowering of A1C has not been determined.
CONCLUSIONS
Ranolazine therapy may decrease A1C among patients with T2DM without an increase in hypoglycemia. For patients with T2DM and chronic stable angina, ranolazine may be of use given its utility in cardiovascular disease and benefit in A1C lowering.
Topics: Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Randomized Controlled Trials as Topic; Ranolazine
PubMed: 26917816
DOI: 10.1177/1060028016631757 -
The Cochrane Database of Systematic... Feb 2017Stable angina pectoris is a chronic medical condition with significant impact on mortality and quality of life; it can be macrovascular or microvascular in origin.... (Review)
Review
BACKGROUND
Stable angina pectoris is a chronic medical condition with significant impact on mortality and quality of life; it can be macrovascular or microvascular in origin. Ranolazine is a second-line anti-anginal drug approved for use in people with stable angina. However, the effects of ranolazine for people with angina are considered to be modest, with uncertain clinical relevance.
OBJECTIVES
To assess the effects of ranolazine on cardiovascular and non-cardiovascular mortality, all-cause mortality, quality of life, acute myocardial infarction incidence, angina episodes frequency and adverse events incidence in stable angina patients, used either as monotherapy or as add-on therapy, and compared to placebo or any other anti-anginal agent.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase and the Conference Proceedings Citation Index - Science in February 2016, as well as regional databases and trials registers. We also screened reference lists.
SELECTION CRITERIA
Randomised controlled trials (RCTs) which directly compared the effects of ranolazine versus placebo or other anti-anginals in people with stable angina pectoris were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Two authors independently selected studies, extracted data and assessed risk of bias. Estimates of treatment effects were calculated using risk ratios (RR), mean differences (MD) and standardised mean differences (SMD) with 95% confidence intervals (CI) using a fixed-effect model. Where we found statistically significant heterogeneity (Chi² P < 0.10), we used a random-effects model for pooling estimates. Meta-analysis was not performed where we found considerable heterogeneity (I² ≥ 75%). We used GRADE criteria to assess evidence quality and the GRADE profiler (GRADEpro GDT) to import data from Review Manager 5.3 to create 'Summary of findings' tables.
MAIN RESULTS
We included 17 RCTs (9975 participants, mean age 63.3 years). We found very limited (or no) data to inform most planned comparisons. Summary data were used to inform comparison of ranolazine versus placebo. Overall, risk of bias was assessed as unclear.For add-on ranolazine compared to placebo, no data were available to estimate cardiovascular and non-cardiovascular mortality. We found uncertainty about the effect of ranolazine on: all-cause mortality (1000 mg twice daily, RR 0.83, 95% CI 0.26 to 2.71; 3 studies, 2053 participants; low quality evidence); quality of life (any dose, SMD 0.25, 95% CI -0.01 to 0.52; 4 studies, 1563 participants; I² = 73%; moderate quality evidence); and incidence of non-fatal acute myocardial infarction (AMI) (1000mg twice daily, RR 0.40, 95% CI 0.08 to 2.07; 2 studies, 1509 participants; low quality evidence). Add-on ranolazine 1000 mg twice daily reduced the fervour of angina episodes (MD -0.66, 95% CI -0.97 to -0.35; 3 studies, 2004 participants; I² = 39%; moderate quality evidence) but increased the risk of non-serious adverse events (RR 1.22, 95% CI 1.06 to 1.40; 3 studies, 2053 participants; moderate quality evidence).For ranolazine as monotherapy compared to placebo, we found uncertain effect on cardiovascular mortality (1000 mg twice daily, RR 1.03, 95% CI 0.56 to 1.88; 1 study, 2604 participants; low quality evidence). No data were available to estimate non-cardiovascular mortality. We also found an uncertain effect on all-cause mortality for ranolazine (1000 mg twice daily, RR 1.00, 95% CI 0.81 to 1.25; 3 studies, 6249 participants; low quality evidence), quality of life (1000 mg twice daily, MD 0.28, 95% CI -1.57 to 2.13; 3 studies, 2254 participants; moderate quality evidence), non-fatal AMI incidence (any dose, RR 0.88, 95% CI 0.69 to 1.12; 3 studies, 2983 participants; I² = 50%; low quality evidence), and frequency of angina episodes (any dose, MD 0.08, 95% CI -0.85 to 1.01; 2 studies, 402 participants; low quality evidence). We found an increased risk for non-serious adverse events associated with ranolazine (any dose, RR 1.50, 95% CI 1.12 to 2.00; 3 studies, 947 participants; very low quality evidence).
AUTHORS' CONCLUSIONS
We found very low quality evidence showing that people with stable angina who received ranolazine as monotherapy had increased risk of presenting non-serious adverse events compared to those given placebo. We found low quality evidence indicating that people with stable angina who received ranolazine showed uncertain effect on the risk of cardiovascular death (for ranolazine given as monotherapy), all-cause death and non-fatal AMI, and the frequency of angina episodes (for ranolazine given as monotherapy) compared to those given placebo. Moderate quality evidence indicated that people with stable angina who received ranolazine showed uncertain effect on quality of life compared with people who received placebo. Moderate quality evidence also indicated that people with stable angina who received ranolazine as add-on therapy had fewer angina episodes but increased risk of presenting non-serious adverse events compared to those given placebo.
Topics: Angina, Stable; Cardiovascular Agents; Cause of Death; Humans; Incidence; Middle Aged; Myocardial Infarction; Quality of Life; Randomized Controlled Trials as Topic; Ranolazine
PubMed: 28178363
DOI: 10.1002/14651858.CD011747.pub2 -
European Journal of Pharmacology Mar 2022Ranolazine was approved by the US Food and Drug Administration as an antianginal drug in 2006, and has been used since in certain groups of patients with stable angina.... (Review)
Review
Ranolazine was approved by the US Food and Drug Administration as an antianginal drug in 2006, and has been used since in certain groups of patients with stable angina. The therapeutic action of ranolazine was initially attributed to inhibitory effects on fatty acids metabolism. As investigations went on, however, it developed that the main beneficial effects of ranolazine arise from its action on the late sodium current in the heart. Since late sodium currents were discovered to be involved in various heart pathologies such as ischemia, arrhythmias, systolic and diastolic dysfunctions, and all these conditions are associated with heart failure, ranolazine has in some way been tested either directly or indirectly on heart failure in numerous experimental and clinical studies. As the heart continuously remodels following any sort of severe injury, the inhibition by ranolazine of the underlying mechanisms of cardiac remodeling including ion disturbances, oxidative stress, inflammation, apoptosis, fibrosis, metabolic dysregulation, and neurohormonal impairment are discussed, along with unresolved issues. A projection of pathologies targeted by ranolazine from cellular level to clinical is provided in this review.
Topics: Heart Failure; Humans; Ranolazine; Sodium Channel Blockers
PubMed: 35114190
DOI: 10.1016/j.ejphar.2022.174787 -
American Journal of Cardiovascular... Sep 2021Coronary microvascular dysfunction (CMD) is defined as a mismatch of myocardial blood supply and oxygen consumption due to a dysfunction of the coronary microvessels. Up... (Review)
Review
Coronary microvascular dysfunction (CMD) is defined as a mismatch of myocardial blood supply and oxygen consumption due to a dysfunction of the coronary microvessels. Up to 20-30% of patients with CMD have progressive worsening of symptoms with significant impairment of quality of life. Large-scale randomized studies of the pharmacologic treatment of CMD are lacking. Classic anti-ischemic drugs are the initial form of treatment, but efficacy is often limited. Ranolazine has a unique mechanism of action that does not affect blood pressure or heart rate. When added to existing anti-anginal agents, ranolazine improved at least one domain in eight of ten studies in which a questionnaire was used to assess patient health status. Five studies evaluated coronary arterial flow reserve (CFR), reporting that patients with low values had significant improvement in CFR and suggesting that those with more severe CMD respond more favorably to ranolazine. In two studies, exercise duration and time to myocardial ischemia were significantly increased after treatment with ranolazine. Data are lacking for ranolazine use as the sole agent for CMD treatment. Some questions remain to be answered regarding ranolazine use for CMD. Larger studies of longer duration are needed to verify the effectiveness of ranolazine in the treatment of CMD.
Topics: Cardiovascular Agents; Humans; Myocardial Ischemia; Ranolazine
PubMed: 33438139
DOI: 10.1007/s40256-020-00462-6 -
Cardiovascular & Hematological Agents... 2015Ranolazine, a newly introduced, FDA-approved antianginal agent, has more recently been shown to have additional beneficial antiarrhythmic actions attributed to its... (Review)
Review
Ranolazine, a newly introduced, FDA-approved antianginal agent, has more recently been shown to have additional beneficial antiarrhythmic actions attributed to its inhibitory effect on both peak and late sodium current. The first clinical evidence of ranolazine's antiarrhythmic efficacy has been provided by the MERLIN-TIMI 36 trial, which showed that ranolazine may suppress both supraventricular and ventricular arrhythmias in patients with non-ST-segment elevation acute coronary syndrome. An interesting observation of available studies is that ranolazine seems to be more effective in pathological conditions, such as heart failure, ischemia, tachyarrhythmias or long QT3 syndrome, and has little effect on normal myocytes. Importantly, the drug may have an antiarrhythmic effect without causing proarrhythmia. The mechanisms involved in the antiarrhythmic action of ranolazine, experimental and clinical data for its antiarrhythmic efficacy in suppressing atrial fibrillation and ventricular tachyarrhythmias, are herein reviewed. Current data from small randomized trials indicate that further larger randomized controlled trials are needed that will examine the antiarrhythmic effects of ranolazine and its potential use in patients with arrhythmias.
Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Trials as Topic; Humans; Ranolazine
PubMed: 26245658
DOI: 10.2174/187152571301150730113903 -
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 -
Expert Opinion on Investigational Drugs Jun 2015Atrial fibrillation (AF) is a frequent occurrence with advancing age and is associated with increased morbidity and mortality. Unfortunately, the currently available AF... (Review)
Review
INTRODUCTION
Atrial fibrillation (AF) is a frequent occurrence with advancing age and is associated with increased morbidity and mortality. Unfortunately, the currently available AF therapies have a great deal of side effects.
AREAS COVERED
In this review, the authors discuss the evidence upon which the use of Ranolazine as an anti-arrhythmic drug is based. Specifically, the authors review the Phase I-III trials that studied ranolazine as potential treatment for AF. They also discuss the efficacy, safety, tolerability and side effects and compare the MERLIN TIMI 36, HARMONY and ROLE trials.
EXPERT OPINION
Although ranolazine is considered an anti-angina drug, it may also be, according to the available data, used in patients with AF. Ranolazine has anti-AF efficacy, both alone or in combination with other drugs such as amiodarone and dronedarone. Indeed, its efficacy has been demonstrated in various settings such as the termination of paroxysmal AF, the facilitation of AF electrical cardioversion, and postoperative AF prevention. Although there is a great deal of evidence from pioneering experimental studies, the clinical evidence of the AF-suppressing effect of ranolazine is derived from studies with small sample size or from secondary analyses. A better understanding of the role of ranolazine as an anti-AF drug will be obtained through larger, prospective, placebo-controlled clinical trials in different populations.
Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; Humans; Ranolazine
PubMed: 25872749
DOI: 10.1517/13543784.2015.1036984