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PubMed1994

Double-blind efficacy and safety study of a novel anti-ischemic agent, ranolazine, versus placebo in patients with chronic stable angina pectoris. Ranolazine Study Group.

BACKGROUND: Ranolazine modulates the metabolism of ischemic myocardial cells and improves the efficiency of oxygen use. This study was conducted to evaluate the antianginal and anti-ischemic effects and safety of different doses of ranolazine administered three times daily (tid) compared with placebo in patients with stable angina pectoris. METHODS AND RESULTS: Patients with stable angina pectoris took part in the study. Previous antianginal drugs were discontinued under medical supervision. Three hundred nineteen patients received single-blind placebo for up to 18 days, and 318 stopped exercise because of angina of moderate severity, had evidence of myocardial ischemia (> or = 1-mm ST segment depression), and were randomized to one of four study groups in a double-blind manner: ranolazine 30 mg tid (n = 81), ranolazine 60 mg tid (n = 81), ranolazine 120 mg tid (n = 78), and placebo tid (n = 79). After the 4-week double-blind phase, symptom-limited exercise tests were repeated at 1 hour (peak test) and 8 hours (trough test) after the study medication was administered. In addition, patients kept an angina diary throughout the study and wore a Holter monitor for 48 hours. Total exercise duration at baseline (+/- SEM) was 5.9 +/- 0.2 minutes for the placebo group and 6.4 +/- 0.3, 5.9 +/- 0.3, and 6.6 +/- 0.2 minutes for the ranolazine 30-, 60-, and 120-mg groups, respectively (P = NS). After 4 weeks of double-blind therapy, compared with baseline values, at 1 hour after the study medication was administered (peak effect), total exercise duration (+/- SEM) increased by 0.45 +/- 0.2 minutes in the placebo group and by 0.3 +/- 0.2, 0.6 +/- 0.2, and 0.5 +/- 0.2 minutes in the ranolazine 30-, 60-, and 120-mg groups, respectively (placebo versus ranolazine, P = NS). Times to 1-mm ST segment depression at baseline were similar in the four groups and, after 4 weeks of therapy in each group, increased significantly by similar magnitudes at 1 hour after the administration of the medications. Similar changes were seen for the time to onset of angina. Eight hours after administration (trough effect), no differences in total exercise time or any other exercise variables were observed between the placebo and the ranolazine groups. Compared with the baseline values, the number of anginal attacks per week and the number and duration of ischemic episodes per 48 hours during Holter monitoring decreased significantly by similar magnitudes in the placebo and ranolazine groups. CONCLUSIONS: Therapy with ranolazine 30, 60, and 120 mg tid was not superior to placebo. Our study does not support the published beneficial effects of similar doses of ranolazine on either myocardial ischemia or exercise performance or on anginal attacks during daily life in patients with angina pectoris.

Acetanilides↗
PubMed2006

Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial.

OBJECTIVES: The purpose of this study was to determine if ranolazine improves angina in stable coronary patients with persisting symptoms despite maximum recommended dose of amlodipine. BACKGROUND: Ranolazine is a unique antianginal agent that has been effective in stable angina, but it has not been studied in the setting of maximum recommended doses of conventional antianginal agents. METHODS: Stable patients with coronary disease and > or =3 anginal attacks per week despite maximum recommended dosage of amlodipine (10 mg/day) were randomized to 1,000 mg ranolazine or placebo twice a day for 6 weeks. Primary end point was the frequency of angina episodes per week during the double-blind treatment phase. Efficacy was also assessed by nitroglycerin consumption per week and the Seattle Angina Questionnaire (SAQ). Adjustment for multiple testing of secondary end points used a hierarchic closed testing procedure. Efficacy was assessed in subgroups based on baseline angina frequency, concomitant long-acting nitrate use, gender, and age. Safety was assessed by adverse events and electrocardiogram evaluations. RESULTS: A total of 565 patients were randomized: 281 patients to ranolazine and 284 patients to placebo. Baseline characteristics were similar between treatment groups. At baseline, angina frequency averaged 5.63 +/- 0.18 episodes/week, and nitroglycerin consumption averaged 4.72 +/- 0.21 tablets/week. Compared with placebo, ranolazine significantly reduced frequency of angina episodes (2.88 +/- 0.19 on ranolazine vs. 3.31 +/- 0.22 on placebo; p = 0.028) and nitroglycerin consumption (2.03 +/- 0.20 on ranolazine vs. 2.68 +/- 0.22; p = 0.014), with treatment effect that appeared consistent across subgroups. The median angina weekly episode rate at baseline was 4.5 per week. Subgroup analysis showed statistically significant reductions of angina frequency, nitroglycerin use, and SAQ angina frequency for patients with a baseline frequency >4.5 per week but only of angina frequency for those with baseline frequency < or =4.5 per week. Patients with more frequent angina appeared to have a more pronounced treatment effect. No hemodynamic changes were observed. Ranolazine was well tolerated. CONCLUSIONS: Ranolazine significantly reduced frequency of angina and nitroglycerin consumption compared with placebo and was well tolerated. (The ERICA [Efficacy of Ranolazine In Chronic Angina] Trial; http://clinicaltrials.gov; NCT00091429).

Acetanilides↗
PubMed1999

A controlled trial with a novel anti-ischemic agent, ranolazine, in chronic stable angina pectoris that is responsive to conventional antianginal agents. Ranolazine Study Group.

We assessed efficacy and safety of a new anti-ischemic agent, ranolazine, during a randomized, double-blind, placebo-controlled crossover study. In the qualifying phase, we withdrew at least 1 antianginal drug from the drug regimen of 312 patients with chronic stable angina while they took placebo. After exercise time had shortened by > or =1.0 minute, we randomly assigned patients to receive either immediate-release ranolazine in 3 dosing regimens or placebo during each treatment period. After each week of treatment, we measured exercise tolerance and ranolazine plasma concentrations at both peak and trough. All exercise parameters significantly (p< or =0.02) improved (intention-to-treat analysis) with ranolazine (all regimens combined) at mean peak plasma concentrations ranging from 1,576 to 2,492 ng/ml compared with placebo without differences in double product. Although similar trends persisted at mean trough, plasma concentrations (range 275 to 602 ng/ml), only the time to 1.0 mm ST-segment depression remained statistically significant. In conclusion, immediate-release ranolazine is effective and well tolerated. However, this immediate-release short-acting formulation with this dosing regimen is not adequate for continuous protection. Either larger or more frequent doses or a sustained-release formulation would be required for clinical use.

Acetanilides↗
PubMed1999

Ranolazine (Roche Bioscience).

Ranolazine is a metabolic modulator that is being developed by CV Therapeutics (CVT), under license from Roche (formerly Syntex), as a potential treatment for angina. In August 1999, the first of two pivotal phase III clinical trials in patients with stable angina was completed. In August 1999, CVT announced initial results from this trial, designated the MARISA trial, of ranolazine in patients with stable angina. At each of the three doses studied, ranolazine significantly increased patients' treadmill exercise duration compared to placebo, the primary endpoint for this trial. MARISA (monotherapy assessment of ranolazine in stable angina) was a randomized, double-blind, placebo-controlled trial of a sustained release formulation of ranolazine used in 175 patients who were not receiving other anti-anginal drugs. Compared to placebo, ranolazine taken bid at doses of 500, 1000 or 1500 mg significantly increased exercise duration at trough plasma concentrations, which occur at about 12 h after the previous dose. In addition, two key secondary endpoints, exercise time to onset of angina and exercise time to the electrocardiographic appearance of ischemia were also significantly increased by ranolazine compared to placebo at all three doses. The company plans on presenting additional data at a major medical conference, including safety and tolerability data, which are still under analysis. In July 1999 CVT initiated its second phase III trial. The CARISA trial (combination assessment of ranolazine in stable angina) is a randomized, double-blind, placebo-controlled trial of ranolazine used in combination with other anti-anginal drugs, in approximately 450 patients. The primary endpoint for this trial, duration of exercise on a treadmill, is identical to that used in phase II clinical trials. The CARISA trial, along with the pivotal phase III MARISA trial which completed treatment in June 1999, is expected to form the basis of the company's NDA submission to the FDA. In June 1999, results of a randomized, double-blind, placebo-controlled phase II study of ranolazine in chronic stable angina pectoris were published in the July 1, 1999 issue of the American Journal of Cardiology. The study of 312 patients demonstrated that ranolazine may increase exercise time in chronic stable angina patients. The results also indicate that there may be no change in heart rate or blood pressure among any of the ranolazine dosing regimens. In January 1999, CVT received regulatory clearance in Canada, the Czech Republic and Poland and initiated its first pivotal phase III trial for ranolazine in these countries. These new clinical trial centers complement the US centers enrolling American patients. The compound allows maintenance of energy output by muscle cells by improving oxygen metabolism to make the heart pump more efficiently. Ranolazine may be especially useful in angina patients in whom other therapies are ineffective. Clinical studies suggest that ranolazine lowers the heart's demand for oxygen, by increasing its ability to use carbohydrate rather than fat as a fuel. This is thought to be due to activation of pyruvate dehydrogenase, and also by modulating the activities of L-type calcium channels. This is achieved without reducing heart rate or blood pressure, or impairing pumping ability. In August 1998, CVT signed an agreement with Catalytica Pharmaceuticals, which will manufacture specified quantities of ranolazine for use in clinical trials.

Journal Article↗
PubMed2006

Ranolazine in the management of chronic stable angina.

PURPOSE: A review of the pharmacology, pharmacokinetics, clinical trials, safety, and efficacy of ranolazine is presented. SUMMARY: Ranolazine has recently been approved as adjunctive treatment for chronic stable angina (CSA). Data suggest that ranolazine exerts its antiischemic effect through antagonism of the late sodium current and other cardiac ion channels. Peak plasma levels of ranolazine have been observed two to five hours following repeated dosing and are unaffected by food. In placebo-controlled and active-controlled clinical trials conducted with ranolazine, ranolazine has been effective in the treatment of patients with CSA. One trial demonstrated that monotherapy with extended-release ranolazine was effective against angina and ischemia in patients with CSA. Ranolazine improved exercise duration and time to onset of angina. In a trial in which ranolazine was given in combination with atenolol, diltiazem, or amlodipine, ranolazine produced clinically significant improvement in exercise duration and reduced the incidence of anginal attacks compared with placebo. Another trial demonstrated that extended-release ranolazine 1000 mg given twice daily reduced mean weekly angina episodes in patients with chronic angina. Ranolazine is generally well tolerated. In clinical trials, adverse effects were seen more in the ranolazine groups than in the placebo groups. CONCLUSION: Despite a lack of mortality data, ranolazine has demonstrated its efficacy and safety, either as monotherapy or in combination with other antianginal agents, in the management of CSA. Patients who fail optimal therapy with standard-of-care antianginal agents are the best candidates for treatment with ranolazine.

Acetanilides↗
PubMed2006

Clinical pharmacokinetics of ranolazine.

Ranolazine is a compound that is approved by the US FDA for the treatment of chronic angina pectoris in combination with amlodipine, beta-adrenoceptor antagonists or nitrates, in patients who have not achieved an adequate response with other anti-anginals. The anti-anginal effect of ranolazine does not depend on changes in heart rate or blood pressure. It acts through different pharmacological mechanisms where inhibition of the late inward sodium current (reducing calcium overload and thereby left ventricular diastolic tension) is one plausible mechanism of reduced oxygen consumption. Initial studies used an oral solution or an immediate-release (IR) capsule, but subsequently an extended-release (ER) formulation was developed to allow for twice-daily administration with maintained efficacy. Following administration of an oral solution or IR capsule, peak plasma concentrations (C(max)) are observed within 1 hour. After administration of radiolabelled ranolazine, 73% of the dose was excreted in urine, and unchanged ranolazine accounted for <5% of radioactivity in both urine and faeces. The absolute bioavailability ranges from 35% to 50%. Food has no effect on rate or extent of absorption from the ER formulation. Ranolazine protein binding is about 61-64% over the therapeutic concentration range. Volume of distribution at steady state ranges from 85 to 180 L. Ranolazine is extensively metabolised by cytochrome P450 (CYP) 3A enzymes and, to a lesser extent, by CYP2D6, with approximately 5% excreted renally unchanged. Elimination half-life of ranolazine is 1.4-1.9 hours but is apparently prolonged, on average, to 7 hours for the ER formulation as a result of extended absorption (flip-flop kinetics). Elimination occurs through parallel linear and saturable elimination pathways, where the saturable pathway is related to CYP2D6, which is partly inhibited by ranolazine. Oral plasma clearance diminishes with dose from, on average, 45 L/h at 500 mg twice daily to 33 L/h at 1000 mg twice daily. The departure from dose proportionality for this dose range is modest, with increases in steady-state C(max) and area under plasma concentration-time curve (AUC) from 0 to 12 hours of 2.5- and 2.7-fold, respectively. Ranolazine pharmacokinetics are unaffected by sex, congestive heart failure and diabetes mellitus. AUC increases up to 2-fold with advancing degree of renal impairment. Ranolazine is a weak inhibitor of CYP3A, and increases AUC and C(max) for simvastatin, its metabolites and HMG-CoA reductase inhibitor activity <2-fold. Digoxin AUC is increased 40-60% by ranolazine through P-glycoprotein inhibition. Ranolazine AUC is increased by CYP3A inhibitors ranging from 1.5-fold for diltiazem 180 mg once daily to 3.9-fold for ketoconazole 200 mg twice daily. Verapamil increases ranolazine exposure approximately 2-fold. CYP2D6 inhibition has a negligible effect on ranolazine exposure.

Acetanilides↗
PubMed1996

Ranolazine increases active pyruvate dehydrogenase in perfused normoxic rat hearts: evidence for an indirect mechanism.

Ranolazine has shown anti-anginal efficacy in humans and cardiac anti-ischaemic activity in models, but without affecting haemodynamics or baseline contraction. In isolated normoxic rat hearts, Langendorff-perfused for 30 min with 11 mM glucose, 3% albumin, and 0.4 mM or 0.8 mM palmitate, 20 microM ranolazine significantly increased active, dephosphorylated, pyruvate dehydrogenase (PDHa), but not with no palmitate or 1.2 mM palmitate. Dichloroactetate (DCA, 1 mM), a PDHa kinase inhibitor, significantly increased PDHa in hearts perfused with 0, 0.4 or 0.8 mM but not 1.2 mM palmitate. PDHa was significantly increased with 1.2 mM palmitate by DCA plus ranolazine, and additive effects were also seen at 0.8 mM palmitate. Activation of PDH by ranolazine and promotion of glucose oxidation offers a plausible means by which the drug may be anti-ischaemic nonhaemodynamically. Extensive studies with extracted enzymes and isolated rat heart mitochondria failed to demonstrate any effects of ranolazine on PDH kinase or phosphatase, or on PDH catalytic activity, whereas effects of other known effectors (such as DCA) were readily demonstrable, suggesting that ranolazine activates PDH indirectly. Further analyses of the hearts revealed that ranolazine reduced acetyl CoA content under all conditions where fatty acid was present, and +/- DCA which itself had little effect. In the absence of fatty acid, ranolazine and/or DCA raised acetyl CoA. In perfusions where octanoate (+/- albumin) replaced palmitate, ranolazine still decreased acetyl CoA, but not when acetate replaced palmitate. In octanoate-perfused hearts, the contents of the C4, C6 and C8 CoA esters were all increased by ranolazine. This is consistent with ranolazine causing an inhibition of fatty acid beta-oxidation leading to decreased acetyl CoA and activation of PDH.

Acetanilides↗
PubMed1996

Effects of ranolazine on L-type calcium channel currents in guinea-pig single ventricular myocytes.

1. Ranolazine has protective effects against ischaemia as exemplified by a reduction of the associated enzyme release and an attenuation of the fall of ATP and other metabolic changes. It has been suggested that ranolazine may affect GTP-binding proteins involved in the beta-adrenergic protein kinase A (PKA) cascade by interacting with Gs. Calcium channel currents are stimulated by this cascade but the effect of ranolazine upon them is not known. The whole cell patch clamp technique was used to examine the action of ranolazine on basal calcium channel currents and those stimulated by activation at various steps in the PKA cascade. 2. Ranolazine had only a small effect on the basal calcium current (100 microM caused 11.3% inhibition), but markedly attenuated the beta-adrenoceptor stimulated current (20 nM isoprenaline increased current by 2.3 fold, 10 microM ranolazine inhibited this increase by 47.6%). When the PKA cascade was activated downstream to the receptor by either G-protein activation with Gpp[NH]p or adenylate cyclase activation with forskolin, the calcium current showed a sensitivity to ranolazine similar to the basal current. Activation of the PKA cascade via H2 receptors gave rise to currents which showed an intermediate sensitivity to ranolazine. Ranolazine inhibition of ICa persisted during muscarinic attenuation of beta-adrenoceptor activation. 3. The results indicate that ranolazine, at concentrations which have significantly beneficial effects during ischaemic episodes, only greatly affects whole cell calcium current when facilitated by beta-adrenoceptor or histamine receptor activation. Ranolazine would appear to act at the receptor level, rather than at the GTP-binding or Gs/adenylate cyclase level. An additional smaller effect is also present, which may be mediated by a direct effect on the channel, or components closely associated with it.

Acetanilides↗
PubMed2006

Ranolazine, an inhibitor of the late sodium channel current, reduces postischemic myocardial dysfunction in the rabbit.

Ranolazine is a selective inhibitor of the late sodium current relative to peak sodium channel current, and via this mechanism, it may decrease sodium-dependent intracellular calcium overload during ischemia and reperfusion. Ranolazine reduces the frequency of angina attacks, but there is little information on its effects on myocardial stunning after short-term ischemia. The objective of this study was to test the effects of ranolazine on left ventricular (LV) function and myocardial stunning after ischemia/reperfusion in rabbits. Myocardial stunning was induced in rabbits by 15 minutes of coronary artery occlusion (CAO) followed by 3 hours reperfusion. Ten minutes before CAO, rabbits were randomly assigned to vehicle (n = 15) or ranolazine (2 mg/kg bolus plus 60 microg/kg/min infusion, IV, n = 15). Myocardial stunning was assessed by LV 2-dimensional echocardiography using, as a marker of severity, ischemic free-wall fractional thickening (FWft; systolic wall thickness - diastolic wall thickness/diastolic wall thickness). Regional ejection fraction (EF) was also assessed. During CAO, FWft was depressed in both groups, indicating an ischemic insult (FWft was reduced from 0.62 +/- 0.05 at baseline to 0.10 +/- 0.04 in vehicle and from 0.73 +/- 0.05 to 0.26 +/- 0.07 in ranolazine, P < 0.05, ranolazine vs vehicle). After reperfusion, previously ischemic myocardium remained stunned; however, FWft recovered significantly better in ranolazine (0.51 +/- 0.05) than in vehicle (0.35 +/- 0.04, P = .027). Baseline EF was 0.65 +/- 0.02 in the ranolazine and 0.68 +/- 0.02 in vehicle (P = ns). During CAO, EF was reduced by 36% +/- 6% in vehicle versus only 20% +/- 6% in ranolazine (P < .05). At the end of reperfusion, EF remained depressed in both groups, but the reduction in the vehicle group (25% +/- 5%) was significantly worse than in ranolazine (9% +/- 4%, P = .017). Improvement in function was independent of necrosis (negligible) or differences in hemodynamics (no differences between groups). Ranolazine treatment reduced myocardial stunning following brief ischemia/reperfusion suggesting that inhibiting the late sodium channel current may be a novel approach to treating stunning independent of effects on hemodynamics.

Acetanilides↗
PubMed2006

Ranolazine: a new approach to management of patients with angina.

OBJECTIVE: To review the pharmacology, pharmacokinetics, and clinical efficacy of ranolazine for the treatment of chronic stable angina. DATA SOURCES: MEDLINE was searched (1966-February 2006) using the English-language key terms ranolazine and chronic stable angina. Additional studies were identified from the bibliographies of the reviewed literature. STUDY SELECTION AND DATA EXTRACTION: Studies evaluating ranolazine, alone or in combination with other agents, were incorporated in this review. DATA SYNTHESIS: Ranolazine is a metabolic modulator designed to improve cardiac energy availability and cardiac metabolism. It is believed to be a partial fatty acid oxidation inhibitor. Ranolazine has been shown to improve exercise duration and time to anginal attacks without significantly affecting heart rate or blood pressure. Adverse effects of ranolazine are reported to be dose related. The elimination half-life of ranolazine is estimated to be between 1.4 and 1.9 hours for the immediate-release and 7 hours for sustained-release preparations. CONCLUSIONS: Ranolazine has a unique mechanism of action that is different from that of conventional agents. It has been studied as monotherapy or in combination with other commonly prescribed agents. It appears that ranolazine has a promising safety data profile and does not affect hemodynamic parameters. At this point, although ranolazine should not be used in place of conventional therapy, it appears that ranolazine may be considered in the management of symptomatic patients when standard antianginal medications are not tolerated or are ineffective.

Acetanilides↗
PubMed2004

Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial.

CONTEXT: Many patients with chronic angina experience anginal episodes despite revascularization and antianginal medications. In a previous trial, antianginal monotherapy with ranolazine, a drug believed to partially inhibit fatty acid oxidation, increased treadmill exercise performance; however, its long-term efficacy and safety have not been studied in combination with beta-blockers or calcium antagonists in a large patient population with severe chronic angina. OBJECTIVES: To determine whether, at trough levels, ranolazine improves the total exercise time of patients who have symptoms of chronic angina and who experience angina and ischemia at low workloads despite taking standard doses of atenolol, amlodipine, or diltiazem and to determine times to angina onset and to electrocardiographic evidence of myocardial ischemia, effect on angina attacks and nitroglycerin use, and effect on long-term survival in an open-label observational study extension. DESIGN, SETTING, AND PATIENTS: A randomized, 3-group parallel, double-blind, placebo-controlled trial of 823 eligible adults with symptomatic chronic angina who were randomly assigned to receive placebo or 1 of 2 doses of ranolazine. Patients treated at the 118 participating ambulatory outpatient settings in several countries were enrolled in the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial from July 1999 to August 2001 and followed up through October 31, 2002. INTERVENTION: Patients received twice-daily placebo or 750 mg or 1000 mg of ranolazine. Treadmill exercise 12 hours (trough) and 4 hours (peak) after dosing was assessed after 2, 6 (trough only), and 12 weeks of treatment. MAIN OUTCOME MEASURES: Change in exercise duration, time to onset of angina, time to onset of ischemia, nitroglycerin use, and number of angina attacks. RESULTS: Trough exercise duration increased by 115.6 seconds from baseline in both ranolazine groups (pooled) vs 91.7 seconds in the placebo group (P =.01). The times to angina and to electrocardiographic ischemia also increased in the ranolazine groups, at peak more than at trough. The increases did not depend on changes in blood pressure, heart rate, or background antianginal therapy and persisted throughout 12 weeks. Ranolazine reduced angina attacks and nitroglycerin use by about 1 per week vs placebo (P<.02). Survival of 750 patients taking ranolazine during the CARISA trial or its associated long-term open-label study was 98.4% in the first year and 95.9% in the second year. CONCLUSION: Twice-daily doses of ranolazine increased exercise capacity and provided additional antianginal relief to symptomatic patients with severe chronic angina taking standard doses of atenolol, amlodipine, or diltiazem, without evident adverse, long-term survival consequences over 1 to 2 years of therapy.

Acetanilides↗
PubMed2001

Evidence that ranolazine behaves as a weak beta1- and beta2-adrenoceptor antagonist in the rat [correction of cat] cardiovascular system.

The clinical anti-anginal effectiveness of ranolazine is currently being evaluated. However, the mechanism of its anti-ischaemic action is still unclear. The aim of this work was to establish whether ranolazine exerts functional beta-adrenoceptor antagonist activity in the rat cardiovascular system. Radioligand binding studies were performed in rat hearts and guinea-pig lungs for beta1- and beta2-adrenoceptor affinity, respectively. Ranolazine had micromolar affinity for both beta,- and beta2-adrenoceptors (pKi5.8 and 6.3, respectively). Developed tension was measured in isolated rat left atria (electrically driven at 4 Hz) and cumulative concentration/response curves to (+/-)isoprenaline (0.01-1,000 nM) constructed. Ranolazine (0.32-10 microM) surmountably but weakly antagonised isoprenaline-induced positive inotropic responses, with an apparent pA2 of 5.85 (5.69-6.00) and a slope of -0.74 (-0.70 to -0.77). In bivagotomised, atropinised pithed rats, ranolazine per se evoked marked bradycardia at doses above 10 mg/kg i.v. (maximum variation at 80 mg/kg -125+/-15 bpm, n=6, P<0.001) by a mechanism apparently unrelated to blockade of beta1- or beta2-adrenoceptors. Cumulative incremental doses of (+/-)isoprenaline (0.63 ng/kg to 0.16 mg/kg i.v.) administered to pithed rats induced concomitant depressor and chronotropic responses. Animals received either vehicle (saline 0.9% i.v., n=12), atenolol (0.04-2.5 mg/kg i.v., n=6 per dose), ICI 118551 (0.01-0.63 mg/kg i.v., n=6 or 7 per dose), (+/-)propranolol (0.01-0.63 mg/kg i.v., n=6 per dose) or ranolazine (2.5-80 mg/kg i.v., n=6 or 7 per dose) 10 min prior to isoprenaline. Ranolazine dose-dependently and competitively antagonised isoprenaline-induced decreases in diastolic arterial pressure (DAP, dose ratio 12.2 with 80 mg/kg ranolazine) and increases in heart rate (HR, dose ratio 20.3 with 80 mg/kg ranolazine). Collectively, these results demonstrate that ranolazine behaves as a weak beta1- and beta2-adrenoceptor antagonist in the rat cardiovascular system.

Acetanilides↗
PubMed2004

Ranolazine: ion-channel-blocking actions and in vivo electrophysiological effects.

Ranolazine is a novel anti-ischemic drug that prolongs the QT interval. To evaluate the potential mechanisms and consequences, we studied: (i) Ranolazine's effects on HERG and IsK currents in Xenopus oocytes with two-electrode voltage clamp; (ii) effects of ranolazine, compared to d-sotalol, on effective refractory period (ERP), QT interval and ventricular rhythm in a dog model of acquired long QT syndrome; and (iii) effects on selected native currents in canine atrial myocytes with whole-cell patch-clamp technique. Ranolazine inhibited HERG and IsK currents with different potencies. HERG was inhibited with an IC(50) of 106 micromol l(-1), whereas the IC(50) for IsK was 1.7 mmol l(-1). d-Sotalol caused reverse use-dependent ERP and QT interval prolongation, whereas ranolazine produced modest, nonsignificant increases that plateaued at submaximal doses. Neither drug affected QRS duration. d-Sotalol had clear proarrhythmic effects, with all d-sotalol-treated dogs developing torsades de pointes (TdP) ventricular tachyarrhythmias, of which they ultimately died. In contrast, ranolazine did not generate TdP. Effects on I(Kr) and I(Ks) were similar to those on HERG and IsK. Ranolazine blocked I(Ca) with an IC(50) of approximately 300 micromol l(-1). I(Na) was unaffected. We conclude that ranolazine inhibits I(Kr) by blocking HERG currents, inhibits I(Ca) at slightly larger concentrations, and has modest and self-limited effects on the QT interval. Unlike d-sotalol, ranolazine does not cause TdP in a dog model. The greater safety of ranolazine may be due to its ability to inhibit I(Ca) at concentrations only slightly larger than those that inhibit I(Kr), thus producing offsetting effects on repolarization.

Acetanilides↗
PubMed1994

Cardioprotective effects of ranolazine (RS-43285) in the isolated perfused rabbit heart.

OBJECTIVE: The aim was to examine the putative cardioprotective effects of the novel antianginal agent, ranolazine, using an isolated rabbit heart model of ischaemia and reperfusion. METHODS: Hearts from male New Zealand White rabbits were perfused in the Langendorff mode with a recirculating Krebs buffer at a constant flow of 20-25 ml.min-1. After equilibration, hearts were treated with ranolazine (10 or 20 microM) or vehicle control for 10 min before exposure to a 30 min period of global ischaemia and 60 min reperfusion; a normoxic control group was also studied. Haemodynamic variables (left ventricular pressure), myocardial creatine kinase, and potassium release were measured at baseline (preischaemic) and at selected points during reperfusion; tissue calcium and ATP content were also measured and electron microscopy was performed. RESULTS: Left ventricular developed pressure during reperfusion was improved (p < 0.05) in a concentration dependent manner by 10 and 20 microM ranolazine (the baseline value was unaffected) with the latter dose resulting in a return to preischaemic values. The release of creatine kinase and potassium was reduced in the ranolazine groups (p < 0.05). A 2.5-fold increase in tissue calcium content in vehicle treated hearts at the end of reperfusion (compared to normoxic time control) was reduced by 10 microM ranolazine (p < 0.05) and completely prevented by 20 microM ranolazine. Similarly, the decrease in tissue ATP was largely inhibited by ranolazine in a concentration dependent manner. Electron microscopy showed that 20 microM ranolazine prevented the occurrence of many indications of reperfusion injury observed in vehicle treated control hearts, for example, blurring of myofibrillar Z bands, derangement of myofibrillar architecture, disruption of mitochondrial cristae and matrices, and the appearance of electron-dense bodies within them. The deposition of lanthanum chloride, a marker of blood vessel integrity, is also modified in the ranolazine treated hearts. CONCLUSIONS: Ranolazine has impressive cardioprotective properties in an isolated rabbit heart model of ischaemia and reperfusion, suggesting that the drug warrants further research into its precise mechanism of action.

Acetanilides↗
PubMedDate not supplied

Ranolazine. A metabolic modulator for the treatment of chronic stable angina.

Ranolazine is a novel new antianginal agent currently under investigation as monotherapy and adjunct therapy for the treatment of chronic stable angina. While the mechanism of action of ranolazine is not completely understood, it is believed to involve a reduction in fatty acid oxidation, ultimately leading to a shift in myocardial energy production from fatty acid oxidation to glucose oxidation. Since the oxidation of glucose requires less oxygen than the oxidation of fatty acids, ranolazine can help maintain myocardial function in times of ischemia. In addition, ranolazine has minimal effect on blood pressure and heart rate. Ranolazine, by inhibiting cellular ionic channels, prolongs the corrected QT interval. However, ranolazine has not yet been associated with any incidences of ventricular arrhythmia. The clinical data with ranolazine focuses on its use in chronic stable angina, where it has been shown to increase exercise tolerance and decrease angina compared with placebo, as well as in combination with beta-blockers and calcium channel blockers. The use of ranolazine for other cardiac conditions and the effect of ranolazine on morbidity and mortality remains to be determined. Ongoing clinical trials will help further establish the role of ranolazine in the treatment of cardiovascular disorders.

Acetanilides↗
PubMed1996

Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts.

BACKGROUND: Ranolazine is a novel antianginal agent that may reduce symptoms without affecting hemodynamics and has shown cardiac antiischemic effects in in vivo and in vitro models. In one study it increased active pyruvate dehydrogenase (PDHa). Other agents that increase PDHa and so increase glucose and decrease fatty acid (FA) oxidation are beneficial in ischemic-reperfused hearts. Effects of ranolazine on glucose and palmitate oxidation and glycolysis were assessed in isolated rat hearts. METHODS AND RESULTS: Working hearts were perfused with Krebs-Henseleit buffer plus 3% albumin under normoxic conditions and on reperfusion after 30-minute no-flow ischemia and under conditions designed to give either low [low (Ca) (1.25 mmol/L), high [FA] (1.2 mmol/L palmitate; with/without insulin] or high (2.5 mmol/L Ca, 0.4 mmol/L palmitate; with/without pacing) glucose oxidation rates; Langendorff-perfused hearts (high Ca, low FA) were subjected to varying degrees of low-flow ischemia. Glycolysis and glucose oxidation were measured with the use of [5-3H/U-14C]-glucose and FA oxidation with the use of [1-14C]- or [9,10-3H]-palmitate. In working hearts, 10 micromol/L ranolazine significantly increased glucose oxidation 1.5-fold to 3-fold under conditions in which the contribution of glucose to overall ATP production was low (low Ca, high FA, with insulin), high (high Ca, low Fa, with pacing), or intermediate. In some cases, reductions in FA oxidation were seen. No substantial changes in glycolysis were noted with/without ranolazine; rates were approximately 10-fold glucose oxidation rates, suggesting that pyruvate supply was not limiting. Insulin increased basal glucose oxidation and glycolysis but did not alter ranolazine responses. In normoxic Langendorff hearts (high Ca, low FA; 15 mL/min), all basal rates were lower compared with working hearts, but 10 micromol/L ranolazine similarly increased glucose oxidation; ranolazine also significantly increased it during flow reduction to 7, 3, and 0.5 mL/min. Ranolazine did not affect baseline contractile or hemodynamic parameters or O2 use. In reperfused ischemic working hearts, ranolazine significantly improved functional outcome, which was associated with significant increases in glucose oxidation, a reversal of the increased FA oxidation seen in control reperfusions (versus preischemic), and a smaller but significant increase in glycolysis. CONCLUSIONS: Beneficial effects of ranolazine in cardiac ischemia/reperfusion may be due, at least in part, to a stimulation of glucose oxidation and a reduction in FA oxidation, allowing improved ATP/O2 and reduction in the buildup of H+, lactate, and harmful fatty acyl intermediates.

Acetanilides↗
PubMed2005

Studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects.

The interactions of ranolazine, a new antianginal compound, with inhibitors and substrates of the CYP3A isoenzyme family were studied in 1 open-label and 4 double-blind, randomized, multiple-dose studies. In healthy adult volunteers, the authors sought (1) to determine the steady-state pharmacokinetics, safety, and tolerability of immediate- and sustained-release ranolazine with and without ketoconazole, diltiazem, or simvastatin and (2) to evaluate the effect of ranolazine on the pharmacokinetics of diltiazem, simvastatin, simvastatin metabolites, and HMG-CoA reductase activity. Ketoconazole increased ranolazine plasma concentrations and reduced the CYP3A4-mediated metabolic transformation of ranolazine, confirming that CYP3A4 is the primary metabolic pathway for ranolazine. Diltiazem reduced oral clearance of ranolazine in a dose-dependent manner. Simvastatin did not affect ranolazine pharmacokinetics, although ranolazine increased the AUC and C(max) of simvastatin, simvastatin acid, 2 simvastatin metabolites, and HMG-CoA reductase activity by <2-fold. Administration of ranolazine in combination with diltiazem or simvastatin was safe and well tolerated during the interval studied.

Acetanilides↗
PubMed2002

The use of ranolazine in cardiovascular disease.

Ranolazine is a novel drug that has shown promise in the treatment of cardiovascular disease. Ranolazine exerts its effect by shifting myocardial energy metabolism away from free fatty acids and toward glucose as the substrate for production of adenosine triphosphate. Preclinical data have confirmed that ranolazine reduces myocardial ischaemic injury in various animal models. Researchers are continuing to gather clinical data but findings to date support the conclusion that ranolazine has anti-ischaemic effects without inducing the typical reduction in blood pressure and heart rate associated with the use of traditional anti-ischaemic agents. Given the absence of haemodynamic effects associated with ranolazine, it has great promise as a drug that could be added to existing therapy without concern for hypotensive or bradycardic side effects. Ranolazine has been shown to improve exercise-induced myocardial ischaemia and to lessen the severity of angina in the setting of chronic ischaemic heart disease. Early preclinical observations also suggest positive effects of ranolazine in the management of congestive heart failure; however, trials in this area are ongoing. Several recently completed Phase III clinical studies in patients with chronic ischaemic heart disease have confirmed the findings of smaller trials and should satisfy regulatory concerns necessary to place ranolazine on the commercial market in the US. The maker of ranolazine, CV Therapeutics (Palo Alto, California), will file a New Drug Application (NDA) with the US FDA for the approval of ranolazine as an anti-anginal in the near future.

Acetanilides↗