Ranolazina en cardiopatía isquémica crónica: un factor protector frente a la fibrilación auricular de novo / Ranolazine in chronic ischaemic heart disease: a protective factor against de novo atrial fibrillation

Resumen Introducción: en pacientes con cardiopatía isquémica crónica, ranolazina se ha mostrado eficaz ante casos de angina. Estudios recientes la valoran como fármaco para prevenir la fibrilación auricular poscardioversión eléctrica, posquirúrgica o posinfarto. Objetivos: valorar la presencia a largo plazo de episodios de fibrilación auricular de novo en pacientes con cardiopatía isquémica crónica y nuevo episodio de angina inestable que inician ranolazina 350 o 500 mg/12 h, en comparación con el tratamiento habitual. Métodos: estudio observacional retrospectivo que compara la incidencia de fibrilación auricular de novo en 77 pacientes consecutivos, con diagnóstico de cardiopatía isquémica no revascularizable y nuevo ingreso por síndrome coronario agudo durante el año 2013, en comparación con los que iniciaron ranolazina frente a tratamiento convencional, en los 12 meses siguientes al evento. La detección de fibrilación auricular se basó en su presencia en un primer registro electrocardiográfico. Resultados: de 77 pacientes, 38 iniciaron ranolazina, sin diferencias en cuanto a las características basales de las dos poblaciones, con similares tasas de factores de riesgo cardiovascular clásicos, datos ecocardiográficos como tamaño auricular, o tratamiento previo empleado. Se observó una tasa de fibrilación auricular de novo del 5,3% en los pacientes tratados con ranolazina, frente al 23,1% en el grupo sin ranolazina (p<0,001). Al analizar el subgrupo de pacientes que presentó fibrilación auricular en su seguimiento, únicamente es significativa la no toma de ranolazina (p<0,001). Conclusión: el uso de ranolazina en pacientes con cardiopatía isquémica crónica no revascularizable podría suponer un efecto protector para el desarrollo de fibrilación auricular durante un seguimiento de al menos doce meses.

Abstract Introduction: Ranolazine has shown to be effective in cases of angina in patients with chronic ischaemic heart disease. Recent studies have evaluated it as a drug to prevent electrical post-cardioversion, post-surgical or post-infarction atrial fibrillation. Objectives: To perform a long-term evaluation of de novo atrial fibrillation episodes in patients with chronic ischaemic heart disease and a new episode of unstable angina that are taking 350 or 500 mg/12 h of ranolazine, in comparison with usual treatment. Methods: An observational, retrospective study was performed to compare the incidence of de novo atrial fibrillation in 77 consecutive patients with a diagnosis of non-revascularisable ischaemic heart disease and a new hospital admission due to acute coronary syndrome during the year 2013. These were compared with those that started with ranolazine and those on conventional treatment in the 12 months following the event. The detection of atrial fibrillation was based on its presence in a first electrocardiographic register. Results: Of the 77 patients, 38 were started on ranolazine, with no differences as regards the baseline characteristics of the two populations. They had similar rates of classic cardiovascular risk factors, echocardiographic data, such as atrial size, or previous treatment employed. A de novo atrial fibrillation rate of 5.3% was observed in the patients treated with ranolazine, compared to 23.1% in the non-ranolazine group (P<.001). On analysing the sub-group of patients that had an atrial fibrillation in their follow-up, only not taking of ranolazine was significant (P<.001). Conclusion: The use of ranolazine in patients with non-revascularisable ischaemic heart disease could have a protective effect against the development of atrial fibrillation during a 12 months follow-up.

Ações Transmurais Inotrópicas e Antiarrítmicas da Ranolazina em um Modelo Celular da Síndrome do QT Longo Tipo 3 / Inotropic and Antiarrhythmic Transmural Actions of Ranolazine in a Cellular Model of Type 3 Long QT Syndrome

Resumo A Ranolazina (RANO), conhecida na clínica como Ranexa, é um fármaco que previne a arritmia cardíaca através da inibição da corrente de sódio tardia (INaT). Um gradiente de voltagem transmural do canal Nav1.5 encontra-se na parede ventricular esquerda do coração. Assim, investigamos os efeitos da RANO em cardiomiócitos saudáveis e em modelo celular da Síndrome do QT longo tipo 3 (SQTL tipo 3). Usamos células isoladas do endocárdio (ENDO) e do epicárdio (EPI) e um software de medição com detecção de bordas por vídeo e microscopia de fluorescência para monitorar os transientes de cálcio. A RANO (0,1, 1, 10 e 30 uM, a 25OC) em uma série de frequências de estimulação teve impacto pouco significativo sobre ambos os tipos de células, mas a RANO (30uM) a 35OC minimizou o encurtamento dos sarcômeros em ~21% para células do endocárdio. Em seguida, para simular a SQTL tipo 3, as células do ENDO e EPI foram expostas à toxina ATX-II da anêmona do mar, que aumenta a INaT. As arritmias celulares induzidas por ATX-II foram suprimidas com o uso da RANO (30 µM) a 35OC. Com base nesses resultados, podemos concluir que a RANO tem um impacto pouco significativo sobre o encurtamento dos sarcômeros de células saudáveis do ENDO e EPI. Além disso, ela suprime as arritmias induzidas por INaT para níveis semelhantes nas células do ENDO e EPI.

Abstract Ranolazine (RANO) prevents cardiac arrhythmia by blocking the late sodium current (INaL). A transmural gradient of Nav1.5 is found in the left ventricular wall of the heart. Thus, we investigated the effects of RANO in healthy cardiomyocytes and in a cellular model of type 3 long QT syndrome (LQT3). We used isolated endocardium (ENDO) and epicardium (EPI) cells and a video edge detection system and fluorescence microscopy to monitor calcium transients. RANO (0.1, 1, 10 and 30 uM, at 25oC) at a range of pacing frequencies showed a minor impact on both cell types, but RANO at 30uM and 35oC for ENDO cells attenuated sarcomere shortening by~21%. Next, to mimic LQT3, we exposed ENDO and EPI cells to anemone toxin II (ATX-II), which augments INaL. Cellular arrhythmias induced by ATX-II were abrogated by RANO (30 µM) at 35oC. Based on our results we can conclude that RANO has a minor impact on sarcomere shortening of healthy ENDO and EPI cells and it abrogates arrhythmias induced by INaLto a similar level in ENDO and EPI cells.

Effect of ranolazine on HbA1c and blood glucose levels in diabetic patients with chronic angina

Background: Diabetes mellitus is the fifth leading cause of death worldwide and is one of the common co-morbid conditions associated with coronary artery disease (CAD). The overall prevalence of CAD is 7.4% but the prevalence of CAD in diabetics is 9%. Hence treatment of hyperglycemia is a key goal of secondary preventive therapy with a target of reducing HbA1c to <7%. The risk of CAD has been reported to occur 2 to3 decades prior in diabetics compared to non-diabetics. Hence discovery of drugs with potential role in both diabetes and CAD seems to be necessary. Ranolazine is a novel oral anti anginal drug known to reduce HbA1c and fasting blood glucose levels in angina patients with diabetes. The objective of this study is to show the effect of ranolazine (antianginal drug) on HbA1c and fasting blood glucose levels in diabetic patients with chronic angina.Methods: Patients were divided into: Group 1 continued with previous antidiabetic drugs and antianginal drugs. Group 2 were prescribed Tab ranolazine 1000mg b.d (orally) as add on therapy along with previous antidiabetic drugs and antianginal drugs.Results: There was a significant reduction in HbA1c and FBS levels in Group 2 patients who were on ranolazine. Reduction of HbA1c in group1 and Group 2 was 0.21�65% and 1.30�16% respectively. Reduction of FBS in group1 and group2 was 10.66�.80mg/dl and 29.97�.49mg/dl respectively.Conclusions: From the present study we can conclude that ranolazine, an antianginal drug when given at a dose of 1000mg bd in diabetic patients with chronic angina reduces HbA1c and FBS levels.

Effect of anti-inflammatory activity of ranolazine in rat model of inflammation

Background & objectives: Inflammatory processes are a recognized feature of atherosclerotic lesions. Ranolazine inhibits the inflammatory markers such as C-reactive protein, interleukins-1 and -6 and tumour necrosis factor-alpha. The present study was planned to evaluate the effect of anti-inflammatory activity of ranolazine in acute and sub-acute models of inflammation in rats and compare the same with that of control (gum acacia 1%) and aspirin (standard anti-inflammatory drug). Methods: Adult male Wistar rats (150-180 g) were used for the study. They were divided into three groups (n=6). One per cent gum acacia (control), aspirin (200 mg/kg body weight) and ranolazine (180 mg/kg body weight) were given orally. Acute inflammation was induced by injecting carrageenan in the left hind paw. Paw oedema volume and percentage inhibition were measured. Subacute inflammation was induced by implanting foreign bodies subcutaneously. Percentage inhibition of granuloma dry weight and haematoxylin and eosin stained sections of granulation tissue were studied. Results: In acute and subacute model study, ranolazine significantly (P <0.01) decreased the paw oedema volume and granuloma dry weight as compared to control and it was comparable to that of aspirin and histopathological sections showed a decrease in granulation tissue formation as compared to control. Interpretation & conclusions: Ranolazine demonstrated significant anti-inflammatory activity in acute and subacute models of inflammation and needs further evaluation for its use in reducing atherosclerosis.

Protective effects of ranolazine preconditioning on myocardial ischemia reperfusion injury in rats / 心血管康复医学杂志

Objective:To study protective effects of ranolazine preconditioning on myocardial ischemia reperfusion in-jury(MIRI)in rats.Methods:A total of 32 SD rats were randomly and equally divided into sham operation group, ischemia/reperfusion(I/R)group,low dose ranolazine group(low dose group)and high dose ranolazine group (high dose group).HR,SBP,DBP,left ventricular systolic pressure(LVSP),left ventricular diastolic pressure (LVDP),left ventricular pressure maximum rate of rise(+dp/dtmax),left ventricular pressure maximum rate of de-cline(-dp/dtmax),levels of CK-MB,LDH and cTnI,severity of myocardial infarction and ATP concentration were measured and compared among all groups.Results:Compared with sham operation group,there were significant re-ductions in LVSP[(119.35 ± 5.00)mmHg vs.(92.68 ± 2.95)mmHg vs.(100.60 ± 3.12)mmHg vs.(112.22 ± 3.69)mmHg],LVDP[(24.78 ± 1.71)mmHg vs.(17.26 ± 1.69)mmHg vs.(19.25 ± 1.05)mmHg vs.(22.18 ± 1.55)mmHg],+dp/dtmax[(3736 ± 102.37)mmHg/s vs.(3115 ± 112.72)mmHg/s vs.(3338 ± 51.88)mmHg/s vs.(3446 ± 37.99)mmHg/s],-dp/dtmax[(3634 ± 102.51)mmHg/s vs.(3015 ± 127.00)mmHg/s vs.(3239 ±37.36)mmHg/s vs.(3349 ± 45.49)mmHg/s]and ATP concentration[(22.54 ± 1.52)nmol/mg vs.(14.08 ± 1.80) nmol/mg vs.(16.88 ± 0.74)nmol/mg vs.(19.34 ± 0.88)nmol/mg],and significant rise in levels of CK-MB [(490.88 ± 168.04)U/L vs.(1259.0 ± 78.02)U/L vs.(1127.9 ± 127.23)U/L vs.(956.62 ± 105.22)U/L], LDH[(1494.9 ± 174.84)U/L vs.(2657.6 ± 104.33)U/L vs.(2293.9 ± 99.58)U/L vs.(1932.6 ± 134.25)U/L]and cTnI[(1.03 ± 0.14)ng/ml vs.(10.62 ± 1.34)ng/ml vs.(6.97 ± 1.32)ng/ml vs.(4.87 ± 0.79)ng/ml] in I/R group,low dose group and high dose group,P<0.01 all.Compared with I/R group,there were significant rise in LVSP,LVDP,+ dp/dtmax,-dp/dtmaxand ATP concentration,and significant reductions in levels of CK-MB,LDH and cTnI and MI severity[(0.5289 ± 0.0223)vs.(0.4887 ± 0.0089)vs.(0.4438 ± 0.0154)]in low dose group and high dose group(P<0.05 or <0.01),and those of high dose group were significantly better than those of low dose group(P< 0.05 or < 0.01).Conclusion:Ranolazine preconditioning possesses significant protective effect on MIRI,and it's dose-dependent.

Ranolazina como terapia antianginosa adicional en pacientes con enfermedad coronaria estable sintomática / Ranolazine as an additional antianginal therapy in patients with stable symptomatic coronary artery disease

INTRODUCCIÓN: La enfermedad coronaria estable posee varios tratamientos con beneficio probado tanto en mortalidad como en incidencia de eventos agudos. Sin embargo, el control de los síntomas, especialmente en aquellos que no responden a terapia de primera línea, sigue siendo controvertido. Este resumen pretende evaluar el papel de la ranolazina como terapia adicional al tratamiento antianginoso estándar en pacientes que persisten sintomáticos a pesar de éste. MÉTODOS: Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos cuatro revisiones sistemáticas que en conjunto incluyeron 16 estudios primarios, todos correspondientes a ensayos aleatorizados, de los cuales cuatro son atingentes para la pregunta específica. Concluimos que en pacientes con enfermedad coronaria estable que persisten sintomáticos a pesar de terapia antianginosa estándar, el tratamiento adicional con ranolazina podría disminuir los episodios de angina semanales pero aumentando la incidencia de efectos adversos, y resulta en poca o nula diferencia en el riesgo de muerte o infarto agudo al miocardio.

INTRODUCTION: There are several effective therapeutic alternatives for stable coronary artery, in terms of prevention of cardiovascular morbidity and mortality. However, the best way to achieve symptomatic control is a matter of debate, particularly in those who do not respond to first-line therapy. This summary aims to evaluate the role of ranolazine as an additional therapy to standard antianginal treatment in patients with persistent symptoms. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified four systematic reviews including 16 studies overall, all of which were randomized trials. We concluded additional treatment with ranolazine might decrease the frequency of anginal episodes but increase adverse effects. It probably has no effect on the risk of death or acute myocardial infarction.

Nuevos enfoques farmacológicos en el manejo de la angina de pecho estable / New pharmacological approaches in the management of stable angina

RESUMEN En años recientes han sido introducidos nuevos antianginosos al mercado con mecanismos de acción novedosos, complementarios a los del arsenal farmacoterapéutico existente. Aunque el tratamiento de primera línea continúan siendo los betabloqueadores, antagonistas de canales de calcio y nitratos, el descubrimientos de nuevos aspectos fisiopatológicos de la enfermedad permitieron el desarrollo de blancos terapéuticos innovadores a nivel celular y molecular. El nicorandil, la trimetazidina, la ivabradina y la ranolazina se consideran nuevos fármacos antianginosos y constituyen la segunda línea de tratamiento de la angina de pecho estable; están indicados en pacientes que persisten sintomáticos a pesar del manejo de primera línea o en aquellos que presentan intolerancia o contraindicación a los betabloqueadores o antagonistas de canales de calcio. La trimetazidina, a través de su mecanismo de acción metabólico, mejora la tolerancia al ejercicio y puede ser útil en pacientes con falla cardíaca y contraindicación al uso de digitales; la ivabradina tiene un efecto cronotrópico negativo sin afectar el inotropismo ni la tensión arterial por lo que se puede usar en pacientes con taquiarritmias o falla cardíaca concomitante; en contraste, la ranolazina no afecta el cronotropismo por lo que se usa en pacientes con bradiarritmias aunque puede generar prolongación del intervalo QTc. La elección de alguno de estos medicamentos antianginosos de primera o segunda línea debe ser individualizado para cada paciente y se basa en las comorbilidades, contraindicaciones y preferencias del paciente. MÉD.UIS. 2016;29(3):79-93.

ABSTRACT In recent years, new antianginal agents with novel mechanisms of action have been launched to the market, as a complement to the existing therapeutic arsenal. Even though the beta-blockers, calcium channel blockers and nitrates continue to be the first line of treatment, recent discoveries of pathophysiological aspects of the disease led to the development of innovative therapeutic targets on both cellular and molecular level. Nicorandil, trimetazidine, ivabradine and ranolazine are novel antianginal drugs and constitute the second line of treatment of stable angina; these drugs are indicated for those patients who persist symptomatic despite treatment with first line agents or in those with contraindication or intolerance to beta-blockers o calcium channel blockers. Trimetazidine, through its metabolic mechanism of action, improves exercise tolerance and might be useful in patients with concomitant heart failure and contraindication to digitalis; ivabradine can be used in patients with concomitant tachyarrhythmias due to its negative chronotropic effect without affecting inotropism or blood pressure; in contrast, ranolazine doesn't affect chronotropism and can be used in patients with bradyarrhythmias, however, it might cause prolongation of the QTc interval. The choice of treatment with either of the first line or second line antianginal agents must be individualized for each patient and based on comorbidities, contraindications and patient's preference. MÉD.UIS. 2016;29(3):79-93.

Reduced immunoreactivities of B-type natriuretic peptide in pulmonary arterial hypertension rats after ranolazine treatment / 대한해부학회지

Pulmonary arterial hypertension (PAH) is a severe pulmonary vascular disease characterized by sustained increase in the pulmonary arterial pressure and excessive thickening and remodeling of the distal small pulmonary arteries. During disease progression, structural remodeling of the right ventricular (RV) impairs pump function, creates pro-arrhythmic substrates and triggers for arrhythmias. Notably, RV failure and lethal arrhythmias are major contributors to cardiac death in PAH that are not directly addressed by currently available therapies. Ranolazine (RAN) is an anti-anginal, anti-ischemic drug that has cardioprotective effects of heart dysfunction. RAN also has anti-arrhythmic effects due to inhibition of the late sodium current in cardiomyocytes. Therefore, we hypothesized that RAN could reduce the mal-adaptive structural remodeling of the RV, and prevent triggered ventricular arrhythmias in the monocrotaline-induced rat model of PAH. RAN reduced ventricular hypertrophy, reduced levels of B-type natriuretic peptide, and decreased the expression of fibrosis. In addition, RAN prevented cardiovascular death in rat model of PAH. These results support the notion that RAN can improve the functional properties of the RV, highlighting its potential benefits in the setting of heart impairment.

Novel analytical method development for some amide group containing drugs using Bougainvillea spectabilis bract extracts

OBJECTIVE@#To develop and validate a simple, accurate and precise colorimetric method using Bougainvillea spectabilis (B. spectabilis) bract color previously not exploited for estimation of amide group containing drugs i.e. lidocaine and ranolazine in pharmaceutical formulations.@*METHODS@#Methanolic extract of B. spectabilis was prepared and evaluated for stability of its color at different pH and temperature for a period of 3 weeks. The accuracy and reliability of the proposed method was ascertained by evaluating various validation parameters like linearity, precision, limit of detection, limit of quantitation and specificity according to International Conference on Harmonization guidelines. About 0.5% of B. spectabilis bract color was added to the working standard solutions of the drugs separately and after formation of color complex, and absorbances were noted at 418 nm.@*RESULTS@#For color complexes of lidocaine and ranolazine, linearity was found to be in the range of 4 to 24 and 5 to 25 μg/mL respectively. The % relative standard deviation was found to be within specification limits. Presence of lone pair of electron on nitrogen of amide group of both drugs shows basic nature, contributed in formation of color complex between amide and the color pigment obtained from B. spectabilis bracts.@*CONCLUSIONS@#It can be concluded that the method is simple, accurate, economic, and rapid hence can be employed for routine analysis.

Novel analytical method development for some amide group containing drugs using Bougainvillea spectabilis bract extracts

Objective: To develop and validate a simple, accurate and precise colorimetric method using Bougainvillea spectabilis (B. spectabilis) bract color previously not exploited for estimation of amide group containing drugs i.e. lidocaine and ranolazine in pharmaceutical formulations. Methods: Methanolic extract of B. spectabilis was prepared and evaluated for stability of its color at different pH and temperature for a period of 3 weeks. The accuracy and reliability of the proposed method was ascertained by evaluating various validation parameters like linearity, precision, limit of detection, limit of quantitation and specificity according to International Conference on Harmonization guidelines. About 0.5% of B. spectabilis bract color was added to the working standard solutions of the drugs separately and after formation of color complex, and absorbances were noted at 418 nm. Results: For color complexes of lidocaine and ranolazine, linearity was found to be in the range of 4 to 24 and 5 to 25 μg/mL respectively. The % relative standard deviation was found to be within specification limits. Presence of lone pair of electron on nitrogen of amide group of both drugs shows basic nature, contributed in formation of color complex between amide and the color pigment obtained from B. spectabilis bracts. Conclusions: It can be concluded that the method is simple, accurate, economic, and rapid hence can be employed for routine analysis.

Pharmacokinetic study of ranolazine in Chinese healthy volunteers / 中国药学杂志

OBJECTIVE: To study pharmacokinetics after administration of ranolazine sustained release tablets at a single and multiple dose to healthy Chinese volunteers. METHODS: This is a double-blind, random research. All volunteers were assigned to 7 cohorts according their enrollment sequence to receive ranolazine at dose levels of 500, 1000, 1500, 2000, 2500, 3000 mg; and one cohort has been given 500 mg ranolazine by multiple time. The plasma ranolazinecon centration was determined with a validated LC-MS/MS assay. RESULTS: The calibration curve was linear within the range of 5-4000 ng·mL-1. The LLOQ was 5 ng·mL-1 and RSDs of intra and inter day were less than 15%. After single dose, the main parameters in doses: 500, 1000, 1500, 2000, 2500, 3000 mgare: AUC0-t: (4876±1030), (9135±3796), (17562±8249), (14401±6848), (19410±10678), (26170±9896) ng·mL-1·h-1, respectively; MRT0-t: (10.17±1.94), (11.39±4.19), (12.35±3.87), (12.71±3.22), (8.39±3.16), (12.48±4.78) h, respectively; t1/2: (4.74±1.29), (5.35±2.21), (5.53±2.82), (8.64±5.22), (3.97±1.24), (11.64±6.40) h, respectively ;pmax: (471.78±132.84), (856.00±241.33), (1265.01±501.10), (1378.72±900.85), (1980.65±802.75), (3075.78±1516.90) ng·mL-1, respectively; CL: (106.34±24.33), (145.70±121.72), (103.29±48.25), (165.28±81.50), (158.69±77.85), (110.11±31.20) L·h-1, respectively; after the 1st dose in multiple dose, the parameters are: AUC0-t: (5593±4592) ng·mL-1·h-1, MRT0-t: (10.23±3.22) h, t1/2: (6.39±2.84) h, pmax: (527.42±340.15) ng·mL-1; CL: (155.19±133.14) L·h-1; after 106 dose, the parameters are: AUC0-t: (12318±7353) ng·nL-1 ·h-1; MRT0-∞: (11.56±2.14) h, t1/2: (5.11±1.19) h, pmax: (1007.78±455.95) ng·mL-1, pmin: (357.03±268.34) μg·mL-1, ρavg: (654.29±341.59) ng·mL-1, CLss: (82.89±50.42) L·h-1, Flu (109.04±29.93)%, accumulation: (1.25±0.12). There is no accumulation between single and multiple dose given. CONCLUSION: The main pharmacokinetics parameter of-anolazine in different doses we restudied in this research. Compared with the reference, the pharmacokinetics of this research is similar, vith the other study.

Oral ranolazine in the conversion of paroxysmal and initial onset atrial fibrillation.

Background: Atrial fibrillation (AF) is the most common arrhythmia requiring treatment. High-dose oral anti-arrhythmics (mainly class 1C or quinidine) are used as “pill in the pocket” approach to convert recent onset AF. However pro-arrhythmic risk has limited the application of this approach in many patients. Ranolazine, an antianginal agent, which inhibits abnormal late Na+ channel currents, decreases sodium-calcium overload, potentially inhibits after-depolarisations which have been implicated in the initiation and propagation of AF. Methods: Two gramme ranolazine was given orally to 40 patients with new (first detected episode of AF, 16 patients) or paroxysmal (3 hours to 72 hours duration, 24 patients) AF. Twenty-four patients were in hospital, 6 in office, and 10 at home at the time of ranolazine administration. Age, sex, associated health condition, structural heart disease (SHD) and echocardiographic criteria were recorded. Treatment for other related conditions was also given. Successful conversion was defined as restoration of sinus rhythm within 6 hours of ranolazine administration. Results: Twenty-six of 40 patients (65%) converted to sinus rhythm. No pro-arrhythmic effects, haemodynamic instability, adverse effects, or perceived intolerance were noted. Conclusion: High-dose oral ranolazine shows utility as a possible safe agent to convert new or paroxysmal AF.

Development of Sustain Release Matrix Tablet of Ranolazine Based on Methocel K4M CR: In Vitro Drug Release and Kinetic Approach.

In this study an attempt was made to design and evaluate oral sustained release matrix tablets of ranolazine using Methocel K4M CR as the retardant polymer. Tablets were prepared by conventional wet granulation technique. Tablets were evaluated for parameters such as weight variation, hardness, friability and drug content. All the formulations showed compliance with pharmacopieal standards. In vitro release studies were performed using USP type II apparatus (paddle method) in 900 mL of 0.1N HCl at 50 rpm for 8 hours. The release kinetics was analyzed using the zero-order, first order, Higuchi, Hixson-Crowell and Korsmeyer-Peppas equations to explore and explain the mechanism of drug release from the matrix tablets. In vitro release studies revealed that percent drug release decreased with increase of polymer loading. Based on the dissolution data comparison with innovator brand F-5 formulation (16% Methocel K4M CR w/w of drug) was elected as the best formulation. The drug release profile of the best formulation was well controlled and uniform throughout the dissolution studies. The drug release of optimized formulation follows the Higuchi kinetic model (R2 = 0.99) and the mechanism is found to be non-Fickian/anomalous according to Korsmeyer–Peppas equation. All the formulations were checked for stability as per ICH guidelines and formulations were found stable during the study.

Effect of ranolazine on the fast sodium channel current in rabbit atrial myocytes and use-dependent blockade / 西安交通大学学报(医学版)

Objective To explore the effect of ranolazine on the fast sodium channel current (INa) in rabbit atrial myocytes and the existence of use-dependent blockade. Methods Standard whole cell patch clamp technique was used to study the effect of ranolazine on the fast sodium channel current and the use-dependent blockade caused with different frequencies (1Hz, 3.3Hz and 5Hz) to stimulate the cells. Results The 30μmol/L ranolazine significantly reduced INa with an IC_(50) value of (25.6±1.8)μmmol/L and produced a frequency-dependent inhibitory effect on INa with obvious use-dependence. Conclusion Ranolazine can inhibit the fast sodium channel current in rabbit atrial myocytes and indeed has a use-dependent effect.

Effect of ranolazine postconditioning on the reperfusion injurysalvage kinase and mitochondrial permeability transition pore against ischemia-reperfusion injury in isolated rat heart / 中国药理学通报

Aim To investigate the effect of ranolazine postconditioning on myocardial apoptosis, the reperfusion injurysalvage kinase and the opening of MPTP in isolated rat hearts subjected to ischemia and reperfusion.Methods The langendorff mode was set up.Fifty-five SD rat hearts were randomly divided into 8 groups (n=7): ischema and reperfusion (I/R group),20 μmol·L~(-1) ranolazine postconditioning group(RPostC),ranolazine and the specific MPTP opener atractyloside group (RA), ranolazine and the specific ERK1/2 inhibitor PD98059 group (RP), ranolazine and the specific PI3K inhibitor PD98059 wortmannin group(RW), atractyloside group(A), PD98059 group (P) and wortmannin group (W). The isolated hearts were subjected to 30 minutes ischemia,10minutes drug postconditioning and 5 mitutes K-H buffer reperfusion.Myocardial apoptosis (TUNEL-positive cells), apoptotic index (AI), the opening of MPTP (spectrophotometry) and the The expression of p-AKT and p-ERK1/2 protein were measured at the end of reperfusion in each group.Results Compared with IR group, Myocardial AI and opening of MPTP were decreased in RPostC groups (P<0.05), the expression of p-AKT, p-ERK1/2 protein were increased in RPostC, RA, RP, and RW groups (P<0.05).There were no significant differences in other groups(P>0.05). Compared with RPostC group, Myocardial AI and opening of MPTP were increased in RA, RP, RW, A, P and W groups (P<0.05), and the expression of p-AKT、p-ERK1/2 protein were decreased in RP, RW, A, P and W groups (P<0.05). There were no significant differences of the expressions of p-AKT,p-ERK1/2 protein in RA groups (P>0.05). Compared with RA group, there were no significant differences in myocardial AI and opening of MPTP (P>0.05) and the expression of p-AKT and p-ERK1/2 protein were decreased in RP, RW, A, P and W groups (P<0.05).Conclusions Ranolazine postconditioning can attenuate myocardial apoptosis in isolated rat hearts subjected to ischemia and reperfusion via activation RISK pathway and inhibition of the opening of MPTP.

Optimization of Preparation Technology and In Vitro Dissolution Rate of Ranolazine Sustained Release Tablets / 中国药房

OBJECTIVE:To study the preparation method of ranolazine sustained release tablets and to optimize the preparation technology conditions for these preparations. METHODS: The preparation technology conditions were optimized by orthogonal design with the amounts of HPMCP, MC, PH101 and the hardness of ranolazine sustained release tablets as indexes. The optimized results were verified and the in vitro release of ranolazine sustained release tablets was determined. RESULTS: The optimum preparation technology conditions of ranolazine sustained release tablets were as follows: the amounts of HPMCP, MC, PH101 and the hardness were 150mg, 75mg, 30mg, and 10kg, respectively; and the in vitro release rates at 2, 6, and 12h were (29.33?1.05)%, (59.9?1.53)% and (95.60?1.31)%, respectively. CONCLUSION: The delayed release effect of ranolazine sustained release tablets coincided with the predictive value on the whole, and the preparation technology was reproducible. The in vitro accumulated drug release was in conformity with the requirements.

Determination of the Metabolites of Ranolazine in Rats by LC-MS~n / 中国药房

OBJECTIVE:To determinate the metabolites of ranolazine in rats by LC-MSn.METHODS:Rats were given 80 mg?kg-1 ranolazine by i.g.During 0～24 h after intragastrical administration,the sample of urine was collected and extracted by solid phase column.Extracts were determined by LC-MSn.The mobile phase consisted of acetonitrile,10 mmol?L-1ammonium acetate and glacial acetic acid at a flow rate of 0.5 mL?min-1.Fragmentation ions of ranolazine and its metabolites were determined in positive electrospray ionization by using MS,MS2 and MS3 full scans.RESULTS:Twelve phaseⅠ metabolites (O-demethylation,O-dearylation,hydroxylation,N-dealkylation and amide hydrolysis) and nine phase Ⅱ metabolites(O-glucuronidation and sulfation) were found in the sample.CONCLUSION:Ranolazine is extensively metabolized in rats.