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.
Animals ; Arrhythmias, Cardiac ; Arterial Pressure ; Death ; Disease Progression ; Fibrosis ; Heart ; Heart Ventricles ; Hypertension* ; Hypertrophy ; Models, Animal ; Myocytes, Cardiac ; Natriuretic Peptide, Brain* ; Pulmonary Artery ; Rats* ; Sodium ; Vascular Diseases ; Ranolazine

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 I_KATP 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.
Rabbits ; Animals ; Quinidine/therapeutic use* ; Mexiletine/therapeutic use* ; Pinacidil/therapeutic use* ; Sodium ; Ranolazine/therapeutic use* ; Electrophysiologic Techniques, Cardiac ; Arrhythmias, Cardiac/drug therapy*

OBJECTIVETo determine the contents of the residual solvents, methanol, ethanol, toluene, dichloromethane and dioxane in ranolazine raw material.

METHODSHeadspace gas chromatography was used to analyze the residual solvents quantitatively. Samples were analyzed on an HP-INNOWAX column with column temperature at 45 degrees Celsius; using water as solvent.

RESULTSFive residual solvents were completely separated. The liner range and recoveries were satisfied. RSD of precision and accuracy was less than 8% with average recoveries between 87.1% and 105.6%.

CONCLUSIONThe method could be used for the quality control of ranolazine raw material.

Acetanilides ; analysis ; Chromatography, Gas ; methods ; Drug Contamination ; prevention & control ; Enzyme Inhibitors ; analysis ; Ethanol ; analysis ; Methanol ; analysis ; Piperazines ; analysis ; Ranolazine ; Reproducibility of Results ; Solvents ; analysis ; Toluene ; analysis

INTRODUCTION: Cardiovascular diseases and diabetes mellitus (DM) are two disease entities that commonly coexist in a single patient. Ranolazine is an active piperazine derivative approved by FDA in 2006 as an anti-anginal medication. It was noted to have HbA1c lowering effects in the trials on angina. The proposed mechanism of action is the inhibition of glucagon secretion by blocking the Na v1.3 isoform of sodium channels in pancreatic alpha cells leading to glucagon- and glucose-lowering effects. HbA1c lowering to a target of 6.5% in type 2 diabetes patients has been shown to reduce risk of microvascular complications. The objective of this study is to determine the efficacy and safety of Ranolazine in HbA1c lowering as an add-on therapy to existing anti-diabetic regimen.

METHODS: A comprehensive literature search in PubMed, The Cochrane Central Register of Controlled Trials, the ClinicalTrials.gov website, Google Scholar databases and EMBASE databases were made using the search terms "Randomized controlled trial", "Ranolazine," "HbA1c," and "glycosylated hemoglobin", as well as various combinations of these, was done to identify randomized control trials. No restriction on language and time were done. The authors extracted data for characteristics, quality assessment and mean change in HbA1c after at least eight weeks of treatment with ranolazine. The program RevMan 5.3 was used to generate the statistical analysis of the data.

RESULTS: Six RCTs were included to make up a total of 1,650 diabetic patients. Five studies had moderate risk of bias assessment while one had low risk of bias assessment and hence was not included in the analysis. The overall analysis showed an HbA1c reduction of 0.35% 0.68 to -0.03, p-value=0.03) however, the population was heterogenous (I2=100%). The heterogeneity was not eliminated by sensitivity analysis.

DISCUSSION: The results showed a statistically significant lowering of HbA1c with ranolazine. However, the population was heterogenous. The sources of heterogeneity could be the (1) differences in the level of glycemic control among subjects as indicated by baseline HbA1c levels, (2) the current anti-diabetic regimen of the study patients, i.e. whether or not they are on insulin therapy, (3) the presence or absence of ischemic heart disease and (5) duration of ranolazine therapy, and (4) the presence or absence of chronic kidney disease. When the analysis excluded the population with combination insulin therapy and ranolazine, the effect becomes non-significant. Thus, the HbA1c lowering effect may have been from the insulin therapy rather than the ranolazine.

CONCLUSION: Ranolazine as anti-diabetic therapy shows statistically significant HbA1c lowering effect. It can be a potential treatment option for patients with both DM and angina pectoris. However, well-designed, prospective trials are still recommended to determine the effect on a less heterogenous population. Likewise, more studies are needed to determine its safety.

Human ; Hemoglobin A, Glycosylated ; Glucagon ; Glucagon-secreting Cells ; Diabetes Mellitus, Type 2 ; Ranolazine ; Insulin ; Language ; Prospective Studies ; Blood Glucose ; Angina Pectoris ; Coronary Artery Disease ; Myocardial Ischemia ; Renal Insufficiency, Chronic ; Pubmed ; Sodium Channels ; Protein Isoforms

The objectives of this study were to investigate the effects of veratridine (VER) on persistent sodium current (I(Na.P)), Na(+)/Ca(2+) exchange current (I(NCX)), calcium transients and the action potential (AP) in rabbit ventricular myocytes, and to explore the mechanism in intracellular calcium overload and myocardial contraction enhancement by using whole-cell patch clamp recording technique, visual motion edge detection system, intracellular calcium measurement system and multi-channel physiological signal acquisition and processing system. The results showed that I(Na.P) and reverse I(NCX) in ventricular myocytes were obviously increased after giving 10, 20 μmol/L VER, with the current density of I(Na.P) increasing from (-0.22 ± 0.12) to (-0.61 ± 0.13) and (-2.15 ± 0.14) pA/pF (P < 0.01, n = 10) at -20 mV, and that of reverse I(NCX) increasing from (1.62 ± 0.12) to (2.19 ± 0.09) and (2.58 ± 0.11) pA/pF (P < 0.05, n = 10) at +50 mV. After adding 4 μmol/L tetrodotoxin (TTX), current density of I(Na.P) and reverse I(NCX) returned to (-0.07 ± 0.14) and (1.69 ± 0.15) pA/pF (P < 0.05, n = 10). Another specific blocker of I(Na.P), ranolazine (RAN), could obviously inhibit VER-increased I(Na.P) and reverse I(NCX). After giving 2.5 μmol/L VER, the maximal contraction rate of ventricular myocytes increased from (-0.91 ± 0.29) to (-1.53 ± 0.29) μm/s (P < 0.01, n = 7), the amplitude of contraction increased from (0.10 ± 0.04) to (0.16 ± 0.04) μm (P < 0.05, n = 7), and the baseline of calcium transients (diastolic calcium concentration) increased from (1.21 ± 0.08) to (1.37 ± 0.12) (P < 0.05, n = 7). After adding 2 μmol/L TTX, the maximal contraction rate and amplitude of ventricular myocytes decreased to (-0.86 ± 0.24) μm/s and (0.09 ± 0.03) μm (P < 0.01, n = 7) respectively. And the baseline of calcium transients reduced to (1.17 ± 0.09) (P < 0.05, n = 7). VER (20 μmol/L) could extend action potential duration at 50% repolarization (APD(50)) and at 90% repolarization (APD(90)) in ventricular myocytes from (123.18 ± 23.70) to (271.90 ± 32.81) and from (146.94 ± 24.15) to (429.79 ± 32.04) ms (P < 0.01, n = 6) respectively. Early afterdepolarizations (EADs) appeared in 3 out of the 6 cases. After adding 4 μmol/L TTX, APD(50) and APD(90) were reduced to (99.07 ± 22.81) and (163.84 ± 26.06) ms (P < 0.01, n = 6) respectively, and EADs disappeared accordingly in 3 cases. It could be suggested that: (1) As a specific agonist of the I(Na.P), VER could result in I(Na.P) increase and intracellular Na(+) overload, and subsequently intracellular Ca(2+) overload with the increase of reverse I(NCX). (2) The VER-increased I(Na.P) could further extend the action potential duration (APD) and induce EADs. (3) TTX could restrain the abnormal VER-induced changes of the above-mentioned indexes, indicating that these abnormal changes were caused by the increase of I(Na.P). Based on this study, it is concluded that as the I(Na.P) agonist, VER can enhance reverse I(NCX) by increasing I(Na.P), leading to intracellular Ca(2+) overload and APD abnormal extension.
Acetanilides ; pharmacology ; Action Potentials ; Animals ; Calcium ; metabolism ; Myocardial Contraction ; Myocytes, Cardiac ; cytology ; drug effects ; Patch-Clamp Techniques ; Piperazines ; pharmacology ; Rabbits ; Ranolazine ; Sodium-Calcium Exchanger ; metabolism ; Tetrodotoxin ; pharmacology ; Veratridine ; pharmacology

Ranolazine and metabolites in dog urine were identified by LC-MS(n). Dog urine samples were collected after ig 30 mg x kg(-1) ranolazine, then the samples were enriched and purified through solid-phase extraction cartridge. The purified samples were analyzed by LC-MS(n). The possible metabolites were discovered by comparing the full scan and SIM chromatograms of the test samples with the corresponding blanks. Seventeen phase I metabolites and fourteen phase II metabolites were identified in dog urine. Three metabolites were identified by comparing with the control article. The metabolites were formed via the following metabolic pathways: O-demethylation, O-dearylation, hydroxylation, N-dealkylation, amide hydrolysis, glucuronidation and sulfation. The LC-MS(n) method is suitable for the rapid identification of drug and its metabolites in biologic samples.
Acetanilides ; administration & dosage ; metabolism ; urine ; Administration, Oral ; Animals ; Chromatography, Liquid ; Dogs ; Female ; Male ; Piperazines ; administration & dosage ; metabolism ; urine ; Ranolazine ; Solid Phase Extraction ; Spectrometry, Mass, Electrospray Ionization ; Tandem Mass Spectrometry

Ranolazine hydrochloride sustained-release tablet (RH-ST) was prepared and its release behavior in vitro was studied. The pharmacokinetic characteristics and bioavailability in six Beagle dogs after oral administration of RH-ST and ranolazine hydrochloride common tablets (RH-CT) as reference were compared. Three kinds of matrix, hydroxypropylmethylcellulose (HPMC K4M), ethylcellulose (EC 100cp) and acrylic resins (Eudragit RL100) were selected as functional excipients to keep ranolazine hydrochloride (RH) release for 12 hours. Through orthogonal designs, the polymers were quantified and the optimized cumulative release profile was obtained. The single oral dose of RH-ST 500 mg and RH-CT 333.3 mg was given to six dogs using a two way crossover design. Plasma levels were determined by LC-MS and the absorption fractions were calculated according to Loo-Riegelman formula. The steady-state concentration of RH in plasma of six dogs and its pharmacokinetics behaviors after continuous oral administration of RH-ST and RH-CT at different time intervals were studied by LC-MS. The steady-state pharmacokinetic parameters were computed by software program BAPP2.0. With the increase of the amount of the matrix, the drug release was decreased. The most important factor influencing drug release is the quantity of HPMC K4M. Drug release within the period (from 0 h to 12 h) fitted well into Higuchi model. The correlation coefficient (r) between the dissolution in vitro in release media of the distilled water and the absorptin fraction in vivo was 0.9550. To compare with RH-CT, RH-ST in vivo has a steady and slow release behavior, Tmax was obviously delayed (3.00 +/- 0.50) h and the relative bioavailability was over 80 percentage. The combined use of multiple polymers can decrease the tablet weight effectively, and the drug release rate can be decreased both in vitro and in vivo.
Acetanilides ; administration & dosage ; pharmacokinetics ; Acrylic Resins ; chemistry ; Administration, Oral ; Animals ; Area Under Curve ; Biological Availability ; Cellulose ; analogs & derivatives ; chemistry ; Cross-Over Studies ; Delayed-Action Preparations ; Dogs ; Excipients ; Female ; Hypromellose Derivatives ; Male ; Methylcellulose ; analogs & derivatives ; chemistry ; Piperazines ; administration & dosage ; pharmacokinetics ; Ranolazine ; Tablets