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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ranolazine is a new, orally active pharmacologic agent that experimentally has been shown to favorably affect myocardial metabolism during myocardial ischemia. It has no direct action on myocardial hemodynamics but appers to improve ventricular functioning by blocking uptake of free fatty acids by the heart while shifting metabolism to anaerobic glycolysis during myocardial ischemia. Preliminary clinical studies suggest a dose-dependent antianginal, and anti-ischemic effect and an excellent safety profile for this unique drug. However, the results of a recent double-blind efficacy and safety study showed no antianginal effect of ranolazine (30--120 mg thrice daily) when compared to placebo.
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PMID:Ranolazine: A New Anti-Ischemic Drug Which Affects Myocardial Energetics. 1185 Jun 61

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

Ranolazine is a metabolic modulator developed by Syntex (Roche) and is in phase III clinical trials as an anti-anginal agent and for the treatment of peripheral arterial disease, particularly intermittent claudication. It allows maintenance of energy output by muscle cells under hypoxic conditions. Ranolazine may be especially useful in angina patients in whom other therapies are ineffective. The licensee, CV Therapeutics (CVT), began a pivotal placebo-controlled, phase III clinical trial of ranolazine in October 1997 enrolling 150 angina patients [265551]. CVT plans to begin a second phase III trial in 350 to 400 angina patients receiving other anti-anginal medications during 1998 [279177]. 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 modulation of the activities of L-type calcium channels. This is achieved without reducing heart rate or blood pressure, or impairing pumping ability [253375,247228]. Ranolazine has been tested in more than 1300 US and European patients in phase I and phase II clinical trials, and is now being evaluated in a placebo-controlled, double-blind multicenter study to determine its effectiveness in treating stable angina. Phase II trials, in over 1200 patients with ischemic heart disease, were completed by Syntex. They demonstrated increased exercise times to onset of angina or electrocardiographic change associated with insufficient blood flow to the heart with three times daily dosing of ranolazine [224364]. Roche Bioscience claims that in the US and Western Europe approximately 1.4 million angina patients are not adequately treated with existing therapies and some 5 million patients suffer from intermittent claudication [166817]. In August 1998, CV Therapeutics signed an agreement with Catalytica Pharmaceuticals, which will manufacture specified quantities of ranolazine</ulink> for use in clinical trials [293333].
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PMID:Ranolazine Roche Bioscience. 1619 83

One of the first signs of ischemic heart disease may manifest as chronic stable angina, a mismatch between oxygen supply and demand. With more than approximately 16.5 million people each year having stable angina, development of new therapies to help control this disease state are warranted. Ranolazine, a novel agent exerting its effect through a partial fatty oxidase inhibitor, is one of the first new drugs in more than 20 years to be developed for chronic stable angina. Working through enzymatic modulation, instead of altering myocardial hemodynamics, ranolazine appears to be effective. An overview of chronic stable angina is provided, the American College of Cardiology-American Heart Association (ACC-AHA) current pharmacologic treatment guidelines are reviewed, and the mechanism of action of ranolazine is explored. Finally, the major clinical trials supporting its place in medical therapy are discussed. Additional clinical trials are under way to further elucidate ranolazine's exact role in the treatment of chronic stable angina. From results of the existing phase III clinical trials, however, the most beneficial potential role of ranolazine in the treatment algorithm of chronic stable angina appears to be as adjunctive therapy to the recommended ACC-AHA treatment modalities.
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PMID:Ranolazine, a novel agent for chronic stable angina. 1650 55

Ranolazine (Ranexa), a piperazine derivative, is a new antianginal agent approved for the treatment of chronic stable angina pectoris for use as combination therapy when angina is not adequately controlled with other antianginal agents. While the exact mechanism of action of ranolazine is not known, its antianginal and anti-ischaemic effects do not appear to depend upon changes in blood pressure or heart rate. An extended-release (ER) oral formulation of ranolazine has been developed to facilitate twice-daily administration whilst maintaining therapeutically effective plasma concentrations. In patients with chronic stable angina, ranolazine ER monotherapy was shown to improve exercise duration at trough plasma drug concentration in a dose-dependent manner compared with placebo. The drug was effective as adjunctive therapy in patients with chronic stable angina whose condition was not controlled adequately with conventional antianginal therapy. In randomised clinical trials, ranolazine ER was well tolerated, with no overt effects on cardiovascular haemodynamics or conduction, apart from a modest increase in corrected QT (QTc) interval (but no torsades de pointes). Importantly, the efficacy and tolerability of ranolazine ER were not affected by comorbid conditions, including old age, heart failure (HF) or diabetes mellitus. Comparative trials of ranolazine ER with other antianginal agents and trials examining its effects on long-term morbidity and mortality in patients with ischaemic heart disease are required to determine with greater certainty the place of the drug in current antianginal therapy. Nevertheless, ranolazine ER may well prove to be a useful alternative and adjunct to conventional haemodynamic antianginal therapy in the treatment of chronic stable angina.
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PMID:Ranolazine: a review of its use in chronic stable angina pectoris. 1662 Jan 47

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

Ranolazine (Ranexa), a piperazine derivative, is a new antianginal agent approved for the treatment of chronic stable angina pectoris for use as combination therapy when angina is not adequately controlled with other antianginal agents. While the exact mechanism of action of ranolazine is not known, its antianginal and anti-ischemic effects do not appear to depend upon changes in BP or heart rate. An extended-release (ER) oral formulation of ranolazine has been developed to facilitate twice-daily administration whilst maintaining therapeutically effective plasma concentrations. In patients with chronic stable angina, ranolazine ER monotherapy was shown to improve exercise duration at trough plasma drug concentration in a dose-dependent manner compared with placebo. The drug was effective as adjunctive therapy in patients with chronic stable angina whose condition was not controlled adequately with conventional antianginal therapy. In randomized clinical trials, ranolazine ER was well tolerated, with no overt effects on cardiovascular hemodynamics or conduction, apart from a modest increase in corrected QT interval (but no torsades de pointes). Importantly, the efficacy and tolerability of ranolazine ER were not affected by old age and co-morbid conditions (heart failure or diabetes mellitus). Comparative trials of ranolazine ER with other antianginal agents and trials examining its effects on long-term morbidity and mortality in patients with ischemic heart disease are required to determine with greater certainty the place of the drug in current antianginal therapy. Nevertheless, ranolazine ER may well prove to be a useful alternative and adjunct to conventional hemodynamic antianginal therapy in the treatment of chronic stable angina.
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PMID:Spotlight on ranolazine in chronic stable angina pectoris. 1708 71

The modulation of cardiac metabolism with Trimetazidine is very important for the control of myocardial ischemia and for the preservation of left ventricular function. The optimization of cardiac metabolism should also include improvement of cardiac insulin resistance with insulin sensitizer agents and the optimization of Kreb's Cycle with essential amino acids. Regarding new drugs that may act inhibiting free fatty acid oxidation we have to underline that to date it is not clear whether Ranolazine has an effect on cardiac metabolism. We agree instead that metabolic agents like Dichloroacetate, Perhexiline and Etomoxir have an antiischemic effect, while their administration requires adjustment of dose and careful monitoring of side effects.
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PMID:Metabolic agents in the management of diabetic coronary patients: a new era. 1756 Dec 87

Chronic Angina resistant to medical treatment with hemodynamically acting agents is a major problem in clinical setup. For such patients, large number of clinical trials have documented the beneficial effect of Ranolazine. It acts as an anti-anginal agent that controls myocardial ischemia through intracellular metabolic changes. Ranolazine is a partial fatty acid oxidation inhibitor which shifts cardiac energy metabolism 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. Other possible mechanism by which Ranolazine could act is by reducing the formation of reactive oxygen species (ROS) and improves reperfusion mechanical function. Ranolazine has been approved by US FDA for the treatment of chronic angina pectoris in combination with amlodipine, beta-blockers or nitrates in patients who do not show adequate response to other anti-anginals. 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. Ranolazine is available as brand name 'Ranexa' as extended release oral tablets. This review focuses on the clinical effects, the mechanism of actions, drug interactions and beneficial effects of Ranolazine in chronic angina and other cardiometabolic disorders.
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PMID:Ranolazine, a partial fatty acid oxidation inhibitor, its potential benefit in angina and other cardiovascular disorders. 1822 Nov 1

William Heberden in 1772 published "some account of the disorder of the breast" which contains the essential elements of angina pectoris as we understand it today. The number of existing cases in the U.S. population today is 6.4 million. Myocardial ischemia manifested by angina pectoris can be either acute or chronic. Patients with chronic stable angina will be the focus of this supplement. The majority of patients are symptomatic but approximately 25% can be asymptomatic. The clinical manifestations of myocardial ischemia generally are chest discomfort, arrhythmias, and LV dysfunction. Myocardial ischemia is a result of imbalance between myocardial oxygen supply and myocardial oxygen demand. High grade coronary stenosis are the usual cause of decreased oxygen supply. The classic hemodynamic factors increasing myocardial oxygen demand include hypertension and increased heart rate due to tachyarrhythmias of any etiology. Exertion is the usual precipitating cause of chronic myocardial ischemia. New information has come forward indicating that myocardial ischemia is associated with disruption of cellular sodium and calcium homeostasis. Ischemia results in a rise of intracellular sodium concentration and thus sodium overload which then activates the sodium calcium exchanger and leads to increased intracellular calcium. When this occurs there is electrical instability and mechanical dysfunction which increases oxygen demand and decreases oxygen supply. The compound Ranolazine is thought to selectively inhibit the late sodium current and attenuates the abnormalities of ventricular repolarization and contractility associated with myocardial ischemia. This compound is the first new class of anti-anginal medication approved in 25 years which may provide physicians with additional therapy for chronic stable angina along with the other anti-angina agents, beta blockers, calcium antagonists and nitrates.
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PMID:Re-thinking angina. 1837 24


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