Ranolazine Group Research Articles

Comparative effects of ranolazine and trimetazidine on cardiac structure and exercise capacity in a healthy rat model: a new doping agent?

Abstract Background/Introduction Anti-anginal drugs that have been shown to improve myocardial energy use include ranolazine and trimetazidine [1]. An inquiry is warranted into their ability to impact cardiac functions and exercise capacity. Purpose This study aims to evaluate the effects of ranolazine; and trimetazidine as a positive control group on cardiac structure and exercise capacity in a rodent model in comparison with the control group. Methods In a randomized, controlled trial, 24 Sprague-Dawley rats were divided into three groups: control, ranolazine, and trimetazidine. Rats were given daily doses of ranolazine (50 mg/kg/1 ml) [2], trimetazidine (10 mg/kg/1 ml) [3], or saline (control) via gastric gavage for 30 days. At the beginning of the trial, as well as on the 15th and 30th days, the rats were weighed, placed on rotarod, and assessed using transthoracic echocardiography (Figure 1). The rats underwent 21 days of forced swimming testing. According to the guidelines for rat exercise testing [4], signs of exhaustion, lack of coordinated movements, and failure to surface for three seconds following submersion in the water were designated as grounds for terminating the test. Weight, rotarod durations, M-mode and Doppler measurements, and forced swimming test durations were recorded on the 0th, 15th, and 30th days. Results No discernible differences were found between the groups in the initial evaluations. By using echocardiography, the left ventricular masses expanded in all three, indicating the emergence of an athlete's heart. In comparison to the control group, the ranolazine and trimetazidine groups showed considerable increases in their ability to exercise. In particular, the swimming times of the trimetazidine group and the ranolazine group improved to a mean of 1889 seconds by the 21st session, 1700 seconds in the trimetazidine group, and 1548 seconds in the control group (Figure 2), respectively, indicating enhanced cardiac performance. Conclusion(s) Ranolazine exhibits significant potential to enhance exercise capacity and cardiac efficiency in rats, surpassing the effects observed with trimetazidine. Trimetazidine is already registered as a doping agent in WADA [5]. These findings highlight the potential use of ranolazine as a performance enhancing agent in healthy subjects for a malicious purpose of creating unfair advantages in professional sports. Further studies in human subjects are needed.Figure 1Figure 2

Neuroprotective effect of ranolazine in mice's model of Alzheimer's disease

Background. Alzheimer's disease is a neurodegenerative disorder that worsens over time as more brain regions are affected and symptoms increase. It usually starts slowly and advances permanently. Ranolazine is a piperazine derivative used as a second-line treatment for people with chronic aortic stenosis who are unresponsive to other medications and have steady or ineffectively-managed angina pectoris. This study is intended to look into the possible neuroprotective effects of ranolazine scopolamine-induced Alzheimer's illness-like features in a mouse model. Methods. This is a randomized controlled animal study that has been carried out in Department of Pharmacology from College of Medicine of Al-Nahrain University. Mice were separated into five groups equally (each group with 10); a control group, and an induction group (mice were administered scopolamine 1 mg per kg intraperitoneally every 24 hr for seven days to induce features similar to Alzheimer's disease). The mice in the remaining three treatment groups were given tested medications prophylactically for 14 days, then the induction was carried out with scopolamine 1 mg/kg i.p. once daily while the tested medication dosages were continued for an additional 7 days; these treatment groups included: donepezil group (5 mg/Kg/d), ranolazine group (40 mg/Kg/d), and combination groups - donepezil (5 mg/Kg/d) with ranolazine (40 mg/Kg/d); all were administrated i.p. once daily. Behavioral parameters including the Y maze test and novel object recognition test were assessed for inflammatory cytokines and oxidative stress parameters. Result. Ranolazine exhibits significant improvement in behavior and memory, oxidative stress parameter level, as well as inflammatory cytokines. When the scopolamine induction group was compared to the control group, the spontaneous alteration considerably decreased (p ≤0.001). However, compared to the induction group, all three donepezil, ranolazine, and combination (donepezil + ranolazine) groups had a highly significant increase in the spontaneous alteration and when compared with the control group, there were no statistically significant changes (p >0.05). In comparison with a control group, the scopolamine (induction group) revealed a highly significant reduction (p ≤0.001) in the recognition index. In contrast to the induction group, all three donepezil, ranolazine, and combination (donepezil + ranolazine) groups demonstrated a highly statistically significant improvement in the recognition index. When compared with the control group, there were no statistically significant changes (p >0.05). Conclusion. The current investigation demonstrated ranolazine's neuroprotective action against scopolamine-induced AD-like characteristics in mouse models. The present work has demonstrated the considerable antioxidant and anti-inflammatory benefits of ranolazine, which may account for these positive results.

Efficacy of nicorandil and ranolazine in prevention of contrast-induced nephropathy in patients with mild-to-moderate renal dysfunction: a randomized controlled trial.

Contrast-induced nephropathy (CIN) is a common complication after percutaneous coronary intervention (PCI). There is conflicting evidence regarding efficacy of nicorandil in CIN prevention. With respect to ranolazine, there is physiological possibility as well as data in animal study regarding its protective effect against CIN; there is, however, no human data till date. To assess the efficacy of nicorandil and ranolazine in preventing CIN. The secondary endpoint was to measure difference in postprocedure acute kidney injury (AKI) incidence across groups. Also, patients were followed up till 6 months for major adverse events. This single-center randomized controlled study included 315 patients of coronary artery disease with mild-to-moderate renal dysfunction undergoing elective PCI. Eligible patients were assigned to either nicorandil (n = 105), ranolazine (n = 105) or control group (n = 105) in 1 : 1 : 1 ratio by block randomization. All enrolled patients were given intravenous sodium chloride at rate of 1.0 mL/kg/h (0.5 mL/kg/h for patients with left ventricular ejection fraction <45%) from 6 h before procedure till 12 h after procedure. Iso-osmolar contrast agent (iodixanol) was used for all patients. In addition to hydration, patients in nicorandil group received oral nicorandil (10 mg, 3 times/d) and those in ranolazine group received oral ranolazine (1000 mg, 2 times/d) 1 day before procedure and for 2 days after PCI. Patients in control group received only hydration. Total number of CIN was 34 (10.7%), which included 19 (18.1%) in control, 8 (7.6%) in nicorandil and 7 (6.6%) in ranolazine group. There was significant association of CIN reduction across groups ( P = 0.012). On pairwise comparison also, there was significant benefit across control and ranolazine as well as control and nicorandil ( P < 0.025). There was numerically higher incidence of AKI in controls; the difference, however, did not reach statistical significance after applying Bonferroni correction ( P = 0.044). Over 6-month follow-up, adverse events were similar across groups. While this study adds to existing literature that supports role for nicorandil in CIN prevention, the efficacy of ranolazine in protecting against CIN has been demonstrated in humans for the first time.

Association between Ranolazine, Ischemic Preconditioning, and Cardioprotection in Patients Undergoing Scheduled Percutaneous Coronary Intervention.

Background and Objectives: Remote ischemic preconditioning (RIPC) has demonstrated efficacy in protecting against myocardial ischemia-reperfusion injury when applied before percutaneous coronary revascularization. Ranolazine, an anti-ischemic drug, has been utilized to minimize ischemic events in chronic angina patients. However, there is a lack of trials exploring the combined effects of ranolazine pretreatment and RIPC in patients undergoing percutaneous coronary interventions (PCIs). Materials and Methods: The present study is a prospective study which enrolled 150 patients scheduled for nonemergent percutaneous coronary revascularization. Three groups were formed: a control group undergoing only PCIs, an RIPC group with RIPC applied to either upper limb before the PCI (preconditioning group), and a group with RIPC before the PCI along with prior ranolazine treatment for stable angina (ranolazine group). Statistical analyses, including ANOVAs and Kruskal-Wallis tests, were conducted, with the Bonferroni correction for type I errors. A repeated-measures ANOVA assessed the changes in serum enzyme levels (SGOT, LDH, CRP, CPK, CK-MB, troponin I) over the follow-up. Statistical significance was set at p < 0.05. Results: The ranolazine group showed (A) significantly lower troponin I level increases compared to the control group for up to 24 h, (B) significantly lower CPK levels after 4, 10, and 24 h compared to the preconditioning group (p = 0.020, p = 0.020, and p = 0.019, respectively) and significantly lower CPK levels compared to the control group after 10 h (p = 0.050), and (C) significantly lower CK-MB levels after 10 h compared to the control group (p = 0.050). Conclusions: This study suggests that combining RIPC before scheduled coronary procedures with ranolazine pretreatment may be linked to reduced ischemia induction, as evidenced by lower myocardial enzyme levels.

The efficacy of ranolazine in improving glycemic parameters in patients with type 2 diabetes mellitus: a meta-analysis

Ranolazine is an anti-anginal drug that mediates its effects by inhibition of cardiac late sodium current. Although it is not indicated for the treatment of type 2 diabetes mellitus (T2DM), several clinical trials have shown that ranolazine was associated with a reduction in HbA1c. The objective of this meta-analysis is to determine the efficacy and safety of ranolazine in improving glycemic control in patients with T2DM. A total of five randomized controlled trials involving 2,680 patients were included in the analysis. The pooled analysis showed that ranolazine may improve glycemic control with a modest decrease in HbA1c and FBS. The difference in HbA1c was -0.38% (95% CI -0.59 to -0.17), favoring ranolazine. Sensitivity analysis showed a difference of HbA1c of -0.49% (CI -0.67, -0.31), still favoring the ranolazine group. There was also a statistically significant difference in fasting glucagon, favoring the ranolazine group (-2.70 pg/ml: 95% CI -5.24 to -0.16). The risk of hypoglycemia with ranolazine was comparable with placebo (RR 1.27 95% CI 0.84 to 1.91). Overall, ranolazine appears to be a safe and effective option for improving glycemic control in patients with T2DM, with a modest decrease in HbA1c and FBS, and a lower risk of hypoglycemia compared to placebo. However, further studies are needed to confirm these findings and to investigate the long-term safety and efficacy of ranolazine in this patient population.

Efficacy of Ranolazine to Improve Diastolic Performance in Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-analysis.

This article evaluates the efficacy of using ranolazine to improve diastolic performance and exercise capacity in heart failure with preserved ejection fraction. A comprehensive literature review found eight trials where there are no significant difference in peak O2 (p=0.09) and exercise duration (p=0.18) between ranolazine and placebo. The ranolazine group had significantly higher and better diastolic parameters compared to placebo, with a mean difference of 0.45 (95% CI [27.18-39.50]). There were no significant differences for haemodynamic parameters (blood pressure and heart rate) and electrocardiography (QT interval) between ranolazine and placebo. The review found that ranolazine has good wefficacy to improve diastolic performance among heart failure with preserved ejection fraction patients and it does not affect blood pressure, heart rate and rate of ventricular repolarisation (shortening of the QT interval).

Impact of late sodium current inhibition on cardiac electrophysiology parameters and ventricular arrhythmias in isolated Langendorff perfused rabbit hearts with short QT interval

Objective: To determine the electrophysiological effects and related mechanisms of late sodium current inhibitors on hearts with short QT intervals. Methods: The electrophysiological study was performed on isolated Langendorff perfused rabbit hearts. A total of 80 New Zealand White rabbits were used and 34 hearts without drug treatment were defined as control group A, these hearts were then treated with IKATP opener pinacidil, defined as pinacidil group A. Then, 27 hearts from pinacidil group A were selected to receive combined perfusion with sodium channel inhibitors or quinidine, a traditional drug used to treat short QT syndrome, including ranolazine combined group (n=9), mexiletine combined group (n=9), and quinidine combined group (n=9). Nineteen out of the remaining 46 New Zealand rabbits were selected as control group B (no drug treatments, n=19), and then treated with pinacidil, defined as pinacidil group B (n=19). The remaining 27 rabbits were treated with sodium inhibitors or quinidine alone, including ranolazine alone group (n=9), mexiletine alone group (n=9), and quinidine alone group (n=9). Electrocardiogram (ECG) physiological parameters of control group A and pinacidil group A were collected. In control group B and pinacidil group B, programmed electrical stimulation was used to induce ventricular arrhythmias and ECG was collected. ECG physiological parameters and ventricular arrhythmia status of various groups were analyzed. The concentrations of pinacidil, ranolazine, mexiletine and quinidine used in this study were 30, 10, 30 and 1 μmol/L, respectively. Results: Compared with control group A, the QT interval, 90% of the repolarization in epicardial and endocardial monophasic action potential duration (MAPD90-Epi, MAPD90-Endo) was shortened, the transmural dispersion of repolarization (TDR) was increased, and the effective refractor period (ERP) and post-repolarization refractoriness (PRR) were reduced in pinacidil group A (all P<0.05). Compared with the pinacidil group A, MAPD90-Epi, MAPD90-Endo, QT interval changes were reversed in quinidine combined group and mexiletine combined group (all P<0.05), but not in ranolazine combined group. All these three drugs reversed the pinacidil-induced increases of TDR and the decreases of ERP and PRR. The induced ventricular arrhythmia rate was 0 in control group B, and increased to 10/19 (χ2=13.6, P<0.05) in pinacidil group B during programmed electrical stimulation. Compared with the pinacidil group B, incidences of ventricular arrhythmia decreased to 11% (1/9), 11% (1/9) and 0 (0/9) (χ2=4.5, 4.5, 7.4, P<0.05) respectively in ranolazine group, mexiletine group and quinidine group. Conclusions: Inhibition of late sodium current does not increase but even decreases the risk of malignant arrhythmia in hearts with a shortened QT interval. The antiarrhythmic mechanism might be associated with the reversal of the increase of TDR and the decrease of refractoriness (including both ERP and PRR) of hearts with shortened QT interval.

Effect of ranolazine on Tp-e interval, Tp-e/QTc, and P-wave dispersion in patients with stable coronary artery disease.

IntroductionRanolazine 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).MethodsThis 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.ResultsThere 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, P < .001), Tp‐e/QT (0.22 ± 0.04 vs. 0.23 ± 0.03; P = .03), Tp‐e/QTc (0.21 ± 0.04 vs. 0.22 ± 0.04 P = .001), and PWD (39.2 ± 13.7 vs. 43.5 ± 12.9 P = .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, Pmax, and PWD were found significantly in ranolazine group again.ConclusionTp‐e/QTc ratio, QTc, Pmax, 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.

Antinociceptive effect of ranolazine and trimetazidine

ABSTRACT Background:Ranolazine and trimetazidine are piperazine derivatives used in antianginal therapy. There are data on the use of these drugs in the treatment of neuropathic pain. In this study, it was aimed to evaluate the antinociceptive effects of ranolazine and trimetazidine. Methods: Sixty patients who were started on trimetazidine or ranolazine treatment were included in the study. The patients were evaluated with Seattle Angina Questionnaire (SAQ), Visual Analog Scale (VAS) and State-Trait Anxiety Inventory (STAI) on the first day of treatment and at the first month follow-up. Results: The SAQ scores of the patients given ranolazine were statistically significantly higher than the patients given trimetazidine. The most significant increase was observed in terms of treatment satisfaction (53.03 ± 8.11 vs. 72.88 ± 5.29, p < 0.001) and quality of life (49.79 ± 8.62 vs. 68.01 ± 0.65, p = 0.016). The decrease in VAS (p = 0.001) and the decrease in STAI scores (p = 0.002) after treatment in the ranolazine group were significantly higher than in the trimetazidine group. Conclusions: Ranolazine and trimetazidine are two effective drugs in antianginal treatment. While both drugs are effective on general systemic musculoskeletal pain and anxiety, the efficacy of ranolazine is more pronounced.

Role of Ranolazine in the Prevention and Treatment of Atrial Fibrillation in Patients with Left Ventricular Systolic Dysfunction: A Meta-Analysis of Randomized Clinical Trials.

Background: Ranolazine has the potential to prevent atrial fibrillation (AF) and plays a role in rhythm control strategy for atrial fibrillation in various clinical settings. However, data on the use of ranolazine in patients with left ventricular (LV) systolic dysfunction are limited. The aims of this meta-analysis of randomized clinical trials are to investigate the efficacy and safety of ranolazine in AF patients with LV systolic dysfunction. PubMed and the Cochrane Database of Systematic Reviews were searched until July 2020. The efficacy outcomes included the incidence of new-onset AF, the rate of sinus rhythm restoration, and the time until sinus rhythm restoration. Safety endpoints were at death, and any adverse events were reported in the enrolled studies. We initially identified 204 studies and finally retrieved 5 RCTs. Three studies were analyzed in the meta-analysis. Among AF patients with LV systolic dysfunction, our meta-analysis showed that the combination of ranolazine to amiodarone significantly increased the sinus rhythm restoration rate compared to amiodarone alone (risk ratio (RR) 2.87, 95% confidence interval (CI) 2.48–3.32). Moreover, the time to sinus rhythm restoration was 2.46 h shorter in the ranolazine added to amiodarone group (95% CI: 2.27–2.64). No significant adverse events and proarrhythmias in the ranolazine group were identified. In conclusion, in AF patients with LV systolic dysfunction, ranolazine as an add-on therapy to amiodarone potentiates and accelerates the conversion of AF to sinus rhythm. Moreover, ranolazine shows good safety profiles. Further studies to investigate the effectiveness of ranolazine in the prevention of new-onset AF among patients with LV systolic dysfunction are needed.

Microvascular Assessment of Ranolazine in Non-Obstructive Atherosclerosis: The MARINA Randomized, Double-Blinded, Controlled Pilot Trial.

Microvascular dysfunction is known to play a key role in patients with angina and nonobstructive coronary artery disease. We investigated the impact of ranolazine among patients with angina and nonobstructive coronary artery disease. In this randomized, double-blinded, placebo-controlled pilot trial, 26 patients with angina once weekly or more, abnormal stress test, and nonobstructive coronary artery disease (<50% stenosis by angiography and fractional flow reserve >0.80) were randomized 1:1 to ranolazine or placebo for 12 weeks. Primary end point was ΔSeattle Angina Questionnaire (SAQ) angina frequency score. Baseline and 3 months follow-up SAQ, Duke Activity Status Index scores along with invasive fractional flow reserve, coronary flow reserve (CFR), hyperemic myocardial resistance, and cardiopulmonary exercise testing measurements were performed. No significant differences in ΔSAQ angina frequency scores (P=0.53) or Duke Activity Status Index (P=0.76) were observed between ranolazine versus placebo, although patients on ranolazine had lesser improvement in SAQ physical limitation scores (P=0.02) compared with placebo at 3 months. There were no significant differences in ΔCFR or Δhyperemic myocardial resistance between ranolazine and placebo groups. Patients treated with ranolazine, compared with placebo, had no significant improvement in maximum rate of oxygen consumption measured during incremental exercise (VO2 max) and peak metabolic equivalents of task. Interestingly, in the ranolazine group, patients with baseline CFR<2.0 demonstrated greater gain in CFR compared with those with baseline CFR≥2.0 (P=0.02). Ranolazine did not demonstrate improvement in SAQ angina frequency score, invasive microvascular function, or peak metabolic equivalent compared with placebo at 3 months. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02147067.

Ranolazine Improves Right Ventricular Function in Patients With Precapillary Pulmonary Hypertension: Results From a Double-Blind, Randomized, Placebo-Controlled Trial

IntroductionA major outcome determinant in patients with precapillary pulmonary hypertension (PH) is right ventricular (RV) function. We studied the effect of ranolazine on RV function over 6 months using cardiovascular magnetic resonance (CMR) imaging in patients with precapillary PH (groups I, III, and IV). Methods and ResultsWe enrolled patients with PH and RV dysfunction (CMR imaging ejection fraction [EF] of <45%) in a longitudinal, randomized, double-blinded, placebo controlled, multicenter study of ranolazine treatment. All enrolled patients were on stable PH-specific therapy. Enrolled patients were assessed using CMR imaging, New York Heart Association functional class, N-terminal pro brain natriuretic peptide, 6-minute walk test, and quality of life health outcomes at baseline and repeated at the end of treatment. The primary outcome was change in RVEF after 6 months of treatment. Analysis of covariance was used to analyze the longitudinal changes taking into account baseline values, age, and sex, based on per protocol population. Twenty-two patients were enrolled, and 9 patients completed follow-up CMR imaging after ranolazine treatment and 6 completed placebo treatment. There was significant increase in RVEF at end of treatment compared with baseline in the ranolazine group adjusted for baseline values, age, and sex. There were no statistically significant changes in secondary outcomes such as changes in New York Heart Association functional class, 6-minute walk distance, N-terminal pro brain natriuretic peptide, or quality of life measures. Ranolazine treated patients experienced a higher number of adverse events, but only one was discontinued owing to side effects. ConclusionsRanolazine may improve RV function in patients with precapillary PH. Larger studies are needed to confirm the beneficial effects of ranolazine.

Ranolazine protects against diabetic cardiomyopathy by activating the NOTCH1/NRG1 pathway

AimsDiabetic cardiomyopathy (DCM) is a common diabetes complication that can cause arrhythmia, heart failure, and even sudden death. Ranolazine is an antianginal agent used to treat chronic stable angina and has been demonstrated as an effective treatment for many cardiovascular diseases. However, the mechanism by which ranolazine alleviates DCM is unclear, motivating this study investigating the effects of ranolazine in DCM. Materials and methodsDCM rats were treated with one of three doses of ranolazine (10, 30, and 90 mg/kg/day) for 12 weeks. B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), cysteinyl aspartate specific proteinase-3 (Caspase-3), Notch homolog 1 (NOTCH1), and Neuregulin 1 (NRG1) expression was assayed using western blot and qRT-PCR. Cardiac changes were assayed using echocardiography, CT, HE staining, and Masson's trichrome staining. TUNEL staining and flow cytometry were used to detect cell apoptosis. NOTCH1 inhibitor (DAPT) was used to explore the mechanism of ranolazine. Key findingsCompared with the DCM group, the ranolazine groups had no obvious weight loss and significantly decreased blood glucose levels. Ranolazine prevented diabetes-caused cardiac injury. Ranolazine also decreased the number of apoptotic cells and altered the expression of apoptosis-related mRNAs and proteins. Ranolazine-induced NOTCH1 activated NRG1 and inhibited the downstream apoptosis-related pathway, while DAPT partially inhibited ranolazine-induced NOTCH1 and NRG1 expression. SignificanceTo our knowledge, this study is the first to demonstrate that ranolazine protects against DCM-induced apoptosis by activating the NOTCH1/NRG1 signaling pathway. Moreover, our study identified new mechanisms involved in DCM.

P1001Efficacy of ranolazine for the prevention of atrial fibrillation in high-risk patients with chronic coronary syndrome and hypertension

Abstract Background Ranolazine currently is used to relief angina symptoms in patients with chronic coronary syndrome (CCS). Additional its anti-angina effect it has been showing antiarrhythmic effect by predominantly inhibiting late sodium and rapid potassium rectifier current. We aimed to assess the efficacy of ranolazine for the prevention of atrial fibrillation (AF) in high-risk patients older than 60 years with CCS at least &amp;gt;5 years and hypertension. Methods 264 older high-risk patients (&amp;gt;60 years) with CCS and hypertension were prospectively enrolled (mean age was 66 ± 11.5 years, male 48%). Among them 132 patients have received additional ranolazine to the standard therapy while control group patients (n = 132) have received only standard therapy. Mean follow-up period was 5.0 ± 4.6 years. All statistical analyzes was performed using one sample student t-test. Results Initial baseline characteristics of patients were not statistically different. During the follow-up period in 8.3 % (n = 11) of patents have occurred MACE (AMI, PCI, CABG, death) in ranolazine group vs. in 9.8% (n = 13) of patients in the control group (P &amp;gt; 0.05). During the follow-up AF (paroxysmal and persistent) was developed significantly lower in ranolizine group than standard group (respectively: 13.6 % vs.18 percentage; P &amp;lt; 0.05). Sinus rhythm was recovered in the higher percent of patients in ranolazine group than standard group after cardioversion (89% vs. 79%, P &amp;lt; 0.05). Conclusion: Adding ranolazine to the standard treatment seems to have a beneficial role for the prevention of AF in high-risk patients with CCS and hypertension.

P427Influence of ranolazine on cardioversion rate in patients with new onset atrial fibrillation and ischemic disease of the heart

Abstract Background Ranolazine is a piperazine derivative, mainly used as antianginal drug in patients with ischemic disease of the heart (IDH). Despite its antianginal effect, it has an antiarrhythmic effect by inhibiting of late sodium and rapid potassium rectifier current. Aim of the study was to assess the additional antiarrhythmic efficacy of ranolazine in patients with new onset atrial fibrillation (AF) and IDH. Material and Methods 168 eligible patients with IDH and short duration of new onset AF were enrolled in this study. Among them, 92 were treated additionally ranolazine to the standart therapy – Group I while 76 only with standart therapy – Group II. The choice of antiarrhythmic drug for cardioversion was either amiodarone or propafenone at the discretion of the doctor. Primary endpoint was recovering of sinus rhythm. All statistical analysis were performed using student t-test. Results Mean age of patients was 66 ± 11.5 years, male 48% in ranolazine group (Group I) and 64.5 ± 12.0 years, male 46% in Group II, and there were no statistically significant differences between two groups. Both groups of patients were characterized by median AF episode duration of 12 (4; 24) hours. Amiadoron was administered in 70 % (n = 65) of patients in Group I and in 77% (n = 59); propafenon in 30% (n = 17) of patients in Group I and 23% (n = 17) in Group II. Cardioversion rate was significantly higher in Group I than Group II (87% vs. 74%, P &amp;lt; 0.05;). There were not observed safety endpoints in Group I whereas 3 safety endpoints (severe bradycardia and arterial hypotension) were observed in Group II (P &amp;gt; 0.05). Conclusion Adding ranolazine to the standard therapy in patients with IDH seems to have a beneficial role in restoring sinus rhythm in recent new onset AF.

Protective effects of Ranolazine on testicular torsion and detorsion injury in rats.

Ranolazine is a drug used in refractory chronic stable angina. In this study, it was aimed to evaluate the protective effect of ranolazine in a testis torsion model in light of objective biochemical and pathological data. A total of 24 pre-pubertal male Wistar albino rats were separated into three groups of 8 as the sham group, control group and ranolazine group. Testis torsion was applied for 3hr to all the rats in Group Control and Group Ranolazine. In Group Control, 0.9% NaCl was applied 1hr after the torsion. In Group Ranolazine, ranolazine 30mg/kg was dissolved in a 0.9% NaCl solution and was administered intraperitoneally 1hr after torsion. Histopathological evaluation was made using the Cosentino score. As a result of the objective biochemical and pathological criteria used in this study, this protective effect of ranolazine was observed in testis torsion. The results obtained in this study may suggest that ranolazine is a drug that could be applied after detorsion to patients diagnosed with torsion.

Effect of ranolazine on symptom and quality of life in patients with angina in the absence of obstructive coronary artery disease: A case control study

BackgroundMore than 20% of patients presenting to the catheterization lab have no significant obstructive coronary artery disease (CAD) despite having angina. Several occult coronary abnormalities, including endothelial dysfunction, microvascular dysfunction (MVD), and/or a myocardial bridge (MB), may explain their symptoms. We studied the effect of ranolazine on symptoms and quality of life (QOL) in these patients. MethodsWe retrospectively studied 53 patients prescribed with ranolazine, matched on sex and age, with 106 patients on standard of care who underwent comprehensive invasive testing. Endothelial dysfunction was defined as a decrease in luminal diameter of >20% after intracoronary acetylcholine, MVD as an index of microvascular resistance ≥25, and a MB as an echolucent half-moon sign and/or ≥10% systolic compression on intravascular ultrasound. A Seattle Angina Questionnaire (SAQ) and SF-12 questionnaire were completed at baseline and follow-up. ResultsMedian follow-up was 1.9 (1.7–2.2) years. Endothelial dysfunction was present in 109 (69%), MVD in 36 (23%), and an MB in 86 (54%). Both groups had significant improvement in all dimensions of the SF-12 and SAQ with the exception of treatment satisfaction. We found no significant difference in change in SAQ and SF-12 scores between the groups, although the ranolazine group had significantly lower baseline SAQ scores. ConclusionIn patients with angina and no obstructive CAD, ranolazine is no different than standard of care in symptomatic and QOL improvement. Further randomized trials are warrented to confirm our findings and identify novel medical therapies in this patient population.

Effects of ranolazine on cardiac function in rats with heart failure.

To investigate the effects of ranolazine on the cardiac function and myocardial apoptosis in rats with heart failure and its possible mechanisms. Thirty Wistar rats were randomly divided into sham operation (negative control; NC), chronic heart failure (CHF), and ranolazine groups. Suprarenal abdominal aortic coarctation was used to induce CHF in rats. Five weeks later, rats in the ranolazine group received ranolazine (50 mg/kg) daily, whereas those in the CHF group received normal saline. After 4 weeks, changes in hemodynamic parameters, cardiac structure and pathology, myocardial apoptosis, and protein expression were assessed. The left ventricular end-diastolic pressure (LVEDP) significantly increased in the CHF group; whereas the maximal rate of left ventricular pressure rise and fall (±dp/dtmax) decreased, compared to those in the NC group. Ranolazine significantly reduced LVEDP and increased ±dp/dtmax (p<0.01), compared to those in the CHF group. Severe impairment of cardiomyocytes was observed in the CHF group with evident inflammation; however, ranolazine reversed these deficits. Rats in the CHF group exhibited an increase in TUNEL-positive cells, which was inhibited by ranolazine, where the apoptotic index significantly decreased in ranolazine-treated rats (p<0.01). Also, ranolazine downregulated caspase-9 expression and upregulated pAKT and Bcl-2 expression in rat cardiomyocytes. Moreover, ranolazine significantly inhibited myocardial apoptosis and caspase-9 expression, promoted AKT phosphorylation, and upregulated pAKT and Bcl-2 expression in vitro, compared to those in the control group (p<0.001). LY294002 inhibited ranolazine-induced suppression of myocardial apoptosis (p<0.001). Ranolazine improved cardiac function and inhibited myocardial apoptosis in rats with CHF, which could be attributed to the regulation of AKT phosphorylation.

Effectiveness of Ranolazine to Prevent Myocardial Injury During Elective Percutaneous Coronary Intervention

Background: Ranolazine is a novel antianginal drug that reduces intracellular accumulation of calcium ion in ischemic myocardium. A pilot randomized study (n=70) has shown that pretreatment with ranolazine 1000mg twice daily for 7days significantly reduced periprocedural myocardial injury (PMI) in elective Percutaneous coronary intervention (PCI). Our objective was to detect whether similar effect could be obtained by ranolazine pretreatment through an interventional study.&#x0D; Materials &amp; Methods: 110 patients with chronic stable angina scheduled for elective PCI were enrolled in an interventional study. For 7 days before the procedure, 55 patients were allocated to receive ranolazine 1000 mg twice daily (ranolazine group) and 55 patients didn't receive ranolazine (control group). Serum creatinine kinase-MB (CK-MB) and Troponin I levels were measured at baseline and 24 hours post procedure.&#x0D; Results: Periprocedural myocardial injury [i.e. an elevation of serum biomarkers (preferably cardiac troponins) above the 99th percentile of upper reference limit (URL)] was detected less commonly after PCI in ranolazine than in control group (11% vs. 27%, p=0.0001). Also, PCI-related myocardial infarction [i.e., post procedural increase in CK-MB&gt;3 times above the URL] tended to be lower in the ranolazine versus placebo group: 1.8% versus 5.45%, P=0.0002. 24 hours post procedural levels of cardiac markers were also significantly lower in the ranolazine versus control group (CK-MB: 2.42±2.05 versus 7.02±9 ng/ml, P=0.001; Troponin 1: 0.447±0.74 versus 1.18±1.6 ng/ml, P=0.004). No significant adverse effect of the drug was reported.&#x0D; Conclusion: So, we have concluded that ranolazine was effective in significantly reducing the periprocedural myocardial injury in elective PCI.&#x0D; Anwer Khan Modern Medical College Journal Vol. 10, No. 1: Jan 2019, P 43-49

Antianginal Efficacy and Tolerability of Ranolazine as an Add-on Drug to Concomitant Medications Primarily Metoprolol in Chronic Stable Angina Patients: A Prospective, Open-Label Study.

Objective:To evaluate the efficacy and tolerability of ranolazine as an add-on drug in chronic stable angina patients and the impact of ranolazine on the quality of life in chronic stable angina patients receiving other antianginal medications.Materials and Methods:It was a prospective, open-label, hospital-based study involving 144 patients with chronic stable angina. First group received either metoprolol 12.5 or 25 mg/day or other antianginal medications; if the symptoms persist, the dose of metoprolol was increased to 50 mg/day, and to the second group, ranolazine 500 mg BD or 1 g OD was added along with metoprolol or others if the anginal attacks were not subsiding. The patients were followed up to 6 months with electrocardiography, treadmill test, and quality of life questionnaire. Adverse events were recorded at each visit during the study.Results:There was a statistically significant reduction in weekly anginal frequency (P < 0.001) and improvement in an exercise tolerance in both the groups, but more in the ranolazine group. Adverse events reported were mild, infrequent.Conclusion:Ranolazine is could be used as an add-on drug in chronic angina patients not improved with metoprolol or antianginal medications.