Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We assessed ranolazine's potential to reduce myocardial injury resulting from 90-min occlusion and 18-h reperfusion of left circumflex coronary artery (LCX) in anesthetized dogs. Ranolazine, a putative antianginal agent, has exhibited positive results in a variety of experimental models associated with the ischemic myocardium. Previous studies demonstrated that ranolazine possesses a mechanism of action involving increases in the amount of active pyruvate dehydrogenase during ischemia, suggesting that the compound may act to promote glucose utilization. Ranolazine was administered as a bolus of 3.3 mg/kg, followed by a constant infusion of 7.2 mg/kg/h for 20 h. The loading dose was administered 30 min before LCX occlusion. Control animals received appropriate volumes of vehicles (loading and infusion). Hemodynamics were unchanged between ranolazine and vehicle groups. Three animals in each group were excluded because of ventricular fibrillation (VF). There was no difference in degree of ST segment change between control and ranolazine-treated groups at any time during LCX occlusion. The area at risk (AAR) of infarct was 40.1 +/- 1.7 and 38.9 +/- 1.3% in control-treated (n = 13) and randolazine-treated (n = 8) animals, respectively (p = 0.631). Myocardial infarct size (IS) was 31.7 +/- 5.2 and 36.6 +/- 8.5% in control and ranolazine-treated animals, respectively (p = 0.603). No significant changes were observed in plasma content of enzymatic markers at 0.5, 2.0, and 18.0 h of reperfusion. The results of this in vivo study indicate that ranolazine did not provide protection from injury to regionally ischemic and reperfused myocardium despite its reported antiischemic activity.
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PMID:Effect of ranolazine on infarct size in a canine model of regional myocardial ischemia/reperfusion. 789 75

1. Ranolazine shifts ATP production away from fatty acid oxidation toward glucose oxidation. 2. Because more oxygen is required to phosphorylate a given amount of ATP during fatty acid oxidation than during carbohydrate oxidation, the ranolazine-induced shift in substrate selection reduces the cell's demand for oxygen without decreasing its ability to do work. The shift also maintains coupling of glycolysis to glucose oxidation during ischemia, thus reducing tissue acidosis. 3. This unique, non-hemodynamic mechanism offers the potential to treat angina without reducing blood pressure, heart rate or myocardial contractility. 4. At least three double-blind, randomized, placebo-controlled clinical trials have yielded data consistent with this hypothesis.
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PMID:Ranolazine: a novel metabolic modulator for the treatment of angina. 955 12

Ranolazine is a novel antianginal agent currently under investigation as monotherapy and adjunct therapy for the treatment of chronic stable angina. Although 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. Because 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 does not significantly affect blood pressure, heart rate, or cardiac conduction. 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 and 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 remain to be determined.
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PMID:Ranolazine: a potential new treatment for chronic stable angina. 1197 3

Trimetazidine acts as an effective antianginal clinical agent by modulating cardiac energy metabolism. Recent published data support the hypothesis that trimetazidine selectively inhibits long-chain 3-ketoacyl CoA thiolase (LC 3-KAT), thereby reducing fatty acid oxidation resulting in clinical benefit. The aim of this study was to assess whether trimetazidine and ranolazine, which may also act as a metabolic modulator, are specific inhibitors of LC 3-KAT. We have demonstrated that trimetazidine and ranolazine do not inhibit crude and purified rat heart or recombinant human LC 3-KAT by methods that both assess the ability of LC 3-KAT to turnover specific substrate, and LC 3-KAT activity as a functional component of intact cellular beta-oxidation. Furthermore, we have demonstrated that trimetazidine does not inhibit any component of beta-oxidation in an isolated human cardiomyocyte cell line. Ranolazine, however, did demonstrate a partial inhibition of beta-oxidation in a dose-dependent manner (12% at 100 micromol/L and 30% at 300 micromol/L). Both trimetazidine (10 micromol/L) and ranolazine (20 micromol/L) improved the recovery of cardiac function after a period of no flow ischemia in the isolated working rat heart perfused with a buffer containing a relatively high concentration (1.2 mmol/L) of free fatty acid. In summary, both trimetazidine and ranolazine were able to improve ischemic cardiac function but inhibition of LC 3-KAT is not part of their mechanism of action. The full text of this article is available online at http://www.circresaha.org.
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PMID:The antianginal agent trimetazidine does not exert its functional benefit via inhibition of mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. 1286 92

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.
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PMID:Ranolazine. A metabolic modulator for the treatment of chronic stable angina. 1594 56

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.
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PMID:Ranolazine (Roche Bioscience). 1611 67

Myocardial ischemia is a metabolic problem involving reduced delivery of oxygen to cardiac mitochondria, resulting in less ATP formation, acceleration of glycolysis and production of lactate and H+ by the cell. Traditional therapies for ischemia aim at restoring the balance between mitochondrial ATP production and breakdown by reducing the need for ATP via suppression of heart rate, blood pressure and cardiac contractility, or by increasing oxygen delivery via increased myocardial blood flow. Despite optimal treatment with traditional hemodynamically oriented drugs (beta-adrenergic receptor antagonist, Ca2+ channel antagonist and nitrates), many patients continue to suffer from angina. Thus, there is a need for anti-anginal drugs that act directly on cardiomyocytes to lessen the metabolic abnormalities induced by ischemia and reduce the symptoms (chest pain and exercise intolerance). Ranolazine has been demonstrated to improve exercise time to angina or 1 mm of ST-segment depression in a manner similar to currently approved drugs, but without any significant effects on heart rate or blood pressure at rest or during exercise. In two Phase III trials, ranolazine improved exercise tolerance and reduced the frequency of angina attacks in chronic severe angina patients when administered either as monotherapy or on a background of atenolol, amlodinine or diltiazem. At present, ranolazine is under review for US Food and Drug Administration approval and, if approved, it will represent the first drug of its class in the USA.
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PMID:Ranolazine: new approach for the treatment of stable angina pectoris. 1618 Oct 27

Reactive oxygen species (ROS), including H2O2, cause intracellular calcium overload and ischemia-reperfusion damage. The objective of this study was to examine the hypothesis that H2O2-induced arrhythmic activity and contractile dysfunction are the results of an effect of H2O2 to increase the magnitude of the late sodium current (late INa). Guinea pig and rabbit isolated ventricular myocytes were exposed to 200 microM H2O2. Transmembrane voltages and currents and twitch shortening were measured using the whole-cell patch-clamp technique and video edge detection, respectively. [Na+]i and [Ca2+]i were determined by fluorescence measurements. H2O2 caused a persistent late INa that was almost completely inhibited by 10 microM tetrodotoxin (TTX). H2O2 prolonged the action potential duration (APD), slowed the relaxation rate of cell contraction, and induced early afterdepolarizations (EADs) and aftercontractions. H2O2 also caused increases of [Na+]i and [Ca2+]i. Ranolazine (10 microM), a novel inhibitor of late INa, attenuated H2O2-induced late INa by 51+/-9%. TTX (2 microM) or 10 microM ranolazine attenuated H2O2-induced APD prolongation and suppressed EADs. Ranolazine accelerated the twitch relaxation rate in the presence of H2O2 and abolished H2O2-induced aftercontractions. Pretreatment of myocytes with ranolazine delayed and reduced the increases of APD, [Na+]i, and [Ca2+]i caused by H2O2. In conclusion, the results confirm the hypothesis that an increase in late INa during exposure of ventricular myocytes to H2O2 contributes to electrical and contractile dysfunction and suggest that inhibition of late INa may offer protection against ROS-induced Na+ and Ca2+ overload.
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PMID:Blocking late sodium current reduces hydrogen peroxide-induced arrhythmogenic activity and contractile dysfunction. 1656 63

Ranolazine is an inhibitor of the late sodium current and, via this mechanism, decreases sodium-dependent intracellular calcium overload during ischemia and reperfusion. Ranolazine reduces angina, but there is little information on its effects in acute myocardial infarction. The aim of this study was to test the effects of ranolazine on left ventricular (LV) function and myocardial infarct size after ischemia/reperfusion in rabbits. Ten minutes before coronary artery occlusion (CAO), anesthetized rabbits were assigned to vehicle (n=15) or ranolazine (2 mg/kg i.v. bolus plus 60 microg/kg/min i.v. infusion; n=15). Hearts received 60 min of CAO and 3 h of reperfusion. CAO caused LV dysfunction associated with necrosis. However, at the end of reperfusion, rabbits treated with ranolazine had better global LV ejection fraction (0.42+/-0.02 versus 0.33+/-0.02; p<0.007) and stroke volume (1.05+/-0.08 versus 0.78+/-0.07 ml; p<0.01) compared with vehicle. The fraction of the LV wall that was akinetic or dyskinetic was significantly less in the ranolazine group at 0.23+/-0.03 versus 0.34+/-0.03 in vehicle-treated group; p<0.02. The ischemic risk region was similar in both groups; however, infarct size was significantly smaller in the treated group (44+/-5 versus 57+/-4% vehicle; p<0.04). There were no significant differences among groups in heart rate, arterial pressure, LV end-diastolic pressure, or maximum-positive or -negative first time derivative of LV pressure (dP/dt). In conclusion, the results of this study show that ranolazine provides protection during acute myocardial infarction in this rabbit model of ischemia/reperfusion. Ranolazine treatment led to better ejection fraction, stroke volume and less wall motion abnormality after reperfusion, and less myocardial necrosis.
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PMID:Improved left ventricular function and reduced necrosis after myocardial ischemia/reperfusion in rabbits treated with ranolazine, an inhibitor of the late sodium channel. 1661 68

Because intracellular sodium and calcium overload play a key role in both mechanical and electrical dysfunction during myocardial ischemia, inhibition of the late sodium current would be expected to decrease the intracellular sodium and calcium overloads and thereby reduce their undesirable effects. Ranolazine selectively inhibits late sodium current relative to peak sodium current, and attenuates the abnormalities of ventricular repolarization and contractility associated with ischemia. This is the currently proposed mechanism (hypothesis) of action of the effects of ranolazine during myocardial ischemia.
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PMID:Inhibition of sodium-dependent calcium overload to treat myocardial ischemia. 1664 21


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