Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002962 (angina)
 21,142 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ranolazine inhibits the late Na current and is proposed to reduce angina by decreasing [Na]i during ischemia, thereby reducing Ca influx via Na/Ca exchange (NCX). We sought to test this hypothesis and to determine whether oxidative stress during simulated-demand ischemia activates the late Na current. We measured [Ca]i and [Na]i in rabbit ventricular myocytes by flow cytometry during metabolic inhibition (MI) with 2 mM cyanide and 0 mM glucose at 37 degrees C plus pacing (P) at 0.5 Hz (P-MI), and in P-MI + 1, 10, or 50 microM ranolazine. In the clinically relevant concentration range (1-10 microM), ranolazine decreased Na and Ca loading and the development of myocyte contracture. P-MI caused an increase in fluorescence of the oxidative radical probe CM-H2DCFDA, which was inhibited by the radical scavenger Tiron 20 mM. The NCX inhibitor KB-R7943 (10 microM) and Tiron 20 mM reduced the rise in [Ca]i during P-MI and eliminated the effect of 10 microM ranolazine on [Ca]i. These results indicate that oxidative stress increases the late Na current during MI. Inhibition of the resulting increase in Na and Ca loading and contracture seems to account for the observed antiischemia effects of ranolazine.
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PMID:Ranolazine inhibits an oxidative stress-induced increase in myocyte sodium and calcium loading during simulated-demand ischemia. 1839 79

Ranolazine, which was approved by the US Food and Drug Administration in January 2006, provides a mechanism of action to treat ischemia that has not hitherto been available. Ranolazine is effective in reducing manifestations of ischemia and angina, and it also holds potential promise to be effective in the management of left ventricular dysfunction, particularly diastolic dysfunction, and arrhythmias. This article provides an update on the available studies concerning the value of ranolazine across the spectrum of cardiovascular disease.
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PMID:Ranolazine: new paradigm for management of myocardial ischemia, myocardial dysfunction, and arrhythmias. 1892 34

Extended-release ranolazine (ranolazine ER) [Ranexa] is a piperazine derivative with a novel mechanism of action that was recently approved in the EU for use as add-on therapy in patients with stable angina pectoris. Ranolazine ER achieves its antianginal effect without affecting heart rate or blood pressure (BP) to a clinically significant extent. Results of well designed, placebo-controlled, short-term studies demonstrate that add-on therapy with ranolazine ER in patients with chronic stable angina improves exercise performance, and reduces anginal frequency and nitroglycerin use. Although longer-term therapy with ranolazine ER did not reduce the incidence of major cardiovascular events in patients with non-ST-elevation acute coronary syndromes, it did reduce the incidence of recurrent ischaemia. Ranolazine ER is a generally well tolerated antianginal agent. Although it is associated with modest dose-related increases in the corrected QT (QTc) interval, ranolazine ER does not appear to be associated with an excess of arrhythmias. Thus, ranolazine ER is a useful new option for patients with chronic stable angina whose symptoms are not controlled with first-line antianginal therapy or who do not tolerate first-line antianginal agents.
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PMID:Ranolazine: a review of its use in chronic stable angina pectoris. 1901 75

Inhibition of the persistent or late Na current (INa) using ranolazine (Ranexa) represents a novel mechanism of action that was approved in the United States in 2006 and only recently in the European Union for use in patients with stable angina pectoris. In general, myocardial ischemia is associated with reduced adenosine triphosphate fluxes and decreased energy supply, resulting in severe disturbances of intracellular ion homeostasis in cardiac myocytes. In the recent years, increased late INa was suggested to contribute to this phenomenon by elevating intracellular Na concentration with subsequent rise in diastolic Ca levels by means of the sarcolemmal Na-Ca exchange system. Ranolazine, a specific inhibitor of late INa, reduces Na influx and hence ameliorates disturbed Na and Ca homeostasis. This is associated with a symptomatic improvement of angina in patients unlike other antianginal drugs without affecting heart rate or systemic blood pressure as shown in placebo-controlled studies. Therefore, ranolazine is a useful new option for patients with chronic stable angina not only as an add-on therapy. New clinical and experimental studies even point to potential antiarrhythmic effects, beneficial effects in diastolic heart failure, and under hyperglycemic conditions. In the present article, the relevant pathophysiological concepts for the role of late INa inhibition are reviewed and the most recent data from basic studies and clinical trials are summarized.
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PMID:A novel mechanism for the treatment of angina, arrhythmias, and diastolic dysfunction: inhibition of late I(Na) using ranolazine. 1933 33

Ranolazine, a piperazine derivative, is currently approved for the treatment of chronic angina. However, its ionic mechanisms in other types of cells remain unclear, although it is thought to be a selective blocker of late Na(+) current. This study was conducted to evaluate the possible effects of ranolazine on Na(+) current (I(Na)), L-type Ca(2+) current (I(Ca,L)), inwardly rectifying K(+) current (I(K(IR))), delayed-rectifier K(+) current (I(K(DR))), and Ca(2+)-activated K(+) current (I(K(Ca))) in pituitary tumor (GH(3)) cells. Ranolazine depressed the transient and late components of I(Na) with different potencies. This drug exerted an inhibitory effect on I(K(IR)) with an IC(50) value of 0.92 microM, while it slightly inhibited I(K(DR)) and I(K(Ca)). It shifted the steady-state activation curve of I(K(IR)) to more positive potentials with no change in the gating charge of the channel. Ranolazine (30 microM) also reduced the activity of large-conductance Ca(2+)-activated K(+) channels in HEK293T cells expressing alpha-hSlo. Under current-clamp conditions, low concentrations (e.g., 1 microM) of ranolazine increased the firing of action potentials, while at high concentrations (>or=10 microM), it diminished the firing discharge. The exposure to ranolazine also suppressed I(Na) and I(K(IR)) effectively in NG108-15 neuronal cells. Our study provides evidence that ranolazine could block multiple ion currents such as I(Na) and I(K(IR)) and suggests that these actions may contribute to some of the functional activities of neurons and endocrine or neuroendocrine cells in vivo.
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PMID:Effects of ranolazine, a novel anti-anginal drug, on ion currents and membrane potential in pituitary tumor GH(3) cells and NG108-15 neuronal cells. 1960 66

More than 6 million people in the United States are affected by chronic angina. On January 27, 2006, the US Food and Drug Administration (FDA) approved a new medication for the treatment of chronic stable angina called ranolazine (Ranexa). This is the first angina drug approved by the FDA in over a decade. The unique thing about this drug is that it falls into a new class of therapies in that it works at the level of cellular metabolism in decreasing demand on the cardiac tissue. There are many factors to consider when prescribing this medication including past studies, dosing, and education. There is also evidence that this drug may also benefit diabetic patients with glycemic control.
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PMID:Chronic angina and the treatment with ranolazine: facts and recommendations. 1973 66

(1) Betablockers such as atenolol are the first-line symptomatic treatment for stable angina. Calcium channel blockers such as verapamil and amlodipine are second-line alternatives; (2) Ranolazine is now authorized for symptomatic adjuvant treatment of angina in patients who are poorly controlled by a betablocker and/or a calcium channel blocker. Its mechanism of action is poorly understood; (3) In two randomised double-blind trials in respectively 565 and 823 patients treated for 7 and 12 weeks, ranolazine (500 mg to 1000 mg twice a day), added to ongoing amlodipine therapy only provided a limited benefit, preventing less than one angina attack per week; (4) Comparative trials failed to show whether ranolazine has a clear-cut impact on mortality; (5) Ranolazine prolongs the QT interval in a dose-dependent manner and thus exposes patients to the risk of torsades de pointes. It is also associated with gastrointestinal disorders (constipation, nausea, vomiting) and dizziness; (6) Ranolazine is metabolised by the cytochrome P450 isoenzymes CYP 3A4 and CYP 2D6 and is also a P-glycoprotein substrate. There is therefore a high risk of pharmacokinetic interactions. There is also a risk of pharmacodynamic interactions with drugs that prolong the QT interval; (7) In practice, the efficacy of ranolazine in the prevention of angina attacks does not outweigh the risk of severe adverse effects.
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PMID:Ranolazine: new drug. Stable angina: not worth the risk. 1974 43

The increasing and unmet social and economic burden of ischemic heart disease calls for new antianginal therapies. Ranolazine, a new antianginal agent, has a different mode of action from existing therapies, which act by decreasing indices of cardiac work. Ranolazine mainly affects the late sodium current across the membrane of cardiomyocytes, inducing a cascade of electrophysiologic and metabolic effects with the potential to reduce the cardiac ischemic burden without significantly changing blood pressure and heart rate. In clinical trials, ranolazine has been demonstrated to exert antianginal and anti-ischemic effects in chronic angina. It improves exercise performance, and decreases angina frequency and nitroglycerin use. Ranolazine is well tolerated at therapeutic doses. Larger studies are needed to explore the effects on hard end-points of morbidity and mortality.
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PMID:Ranolazine, a new antianginal drug. 1980 44

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and a major cause of morbidity. In the past decade, there have been significant advances in the nonpharmacologic management of AF. However, despite these advances there continues to be a great need for antiarrhythmic drugs to suppress AF. Existing medications have moderate efficacy for AF termination and suppression and have significant associated side effects, limiting their use. The need for new therapies has spawned the growth of several exciting drugs at various stages of development for the medical management of AF. Some agents are derivatives of currently available compounds, whereas others have been newly developed to focus on novel ion current targets. Dronedarone is the first antiarrhythmic agent in a decade to be recommended for approval by the US Food and Drug Administration for the management of AF. It is expected to a have a dramatically improved side effect profile, which likely will be the key factor in its prominence in our armamentarium in the future; however, dronedarone appears to have only moderate efficacy. Other novel agents are in various stages of development. Vernakalant, an "atrial selective" compound, will be useful in the acute chemical cardioversion of AF but not atrial flutter. Although vernakalant is similar in efficacy to ibutilide, it carries a significantly reduced risk of torsades de pointes. Ranolazine, initially developed for treating chronic angina, has important effects on ion currents potentially useful in arrhythmia management. Clinical trials specifically studying AF suppression will need to be performed before the utility of ranolazine can be extended. It is hoped that as our understanding of the pathophysiology of AF improves, innovative targets for pharmacologic therapy will emerge. However, the challenge of proving efficacy and safety in large randomized controlled trials will remain for any promising new agent.
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PMID:New and emerging antiarrhythmic drugs for atrial fibrillation: what may become available to the clinician in the near future. 1984 35

Ranolazine sustained-release tablets were recently approved in the EU for chronic stable angina as add-on therapy when symptoms are not controlled with first-line agents. The mechanism of action is thought to involve inhibition of late sodium influx in the heart, which can reduce abnormalities of contractility and repolarisation associated with ischaemia. Ranolazine increases the exercise capacity, reduces angina, and diminishes the use of nitroglycerine. The drug has an excellent safety profile and may be a valuable addition to the treatment of chronic stable angina.
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PMID:[Ranolazine--new treatment of chronic stable angina pectoris]. 2000 68


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