Ranolazine: An anti-anginal drug with further therapeutic potential

Expert Review of Cardiovascular Therapy

Volumn 8, Issue 3, 2010, Pages 319-329

  Reffelmann, Thorsten ^a,b   Kloner, Robert A ^b  

^a UNIVERSITY OF GREIFSWALD   (Germany)

^b UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

Chronic angina pectoris; Ischemic heart disease; Late sodium influx; Ranolazine

Indexed keywords

AMLODIPINE; ATENOLOL; DILTIAZEM; PLACEBO; RANOLAZINE;

ANGINA PECTORIS; ANOREXIA; ANXIETY; ASTHENIA; BLURRED VISION; CALCIUM CELL LEVEL; CLINICAL TRIAL; CONSTIPATION; CONTROLLED CLINICAL TRIAL; CONTROLLED RELEASE FORMULATION; DIASTOLIC DYSFUNCTION; DIZZINESS; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG MEGADOSE; DRUG METABOLISM; DRUG RECEPTOR BINDING; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; DYSURIA; ELECTROCARDIOGRAPHY; EXERCISE; EXTENDED RELEASE FORMULATION; FATIGUE; FATTY ACID OXIDATION; GLUCOSE METABOLISM; HEART ATRIUM FIBRILLATION; HEART HEMODYNAMICS; HEART MUSCLE CELL; HEART MUSCLE ISCHEMIA; HEART MUSCLE POTENTIAL; HEART RATE; HOT FLUSH; HUMAN; HYPERHIDROSIS; HYPOTENSION; HYPOXIA; IC 50; IMMEDIATE RELEASE FORMULATION; INSOMNIA; JOINT SWELLING; MAXIMUM PLASMA CONCENTRATION; NAUSEA; NON ST SEGMENT ELEVATION MYOCARDIAL INFARCTION; PERIPHERAL EDEMA; PHARMACODYNAMICS; PRURITUS; QT INTERVAL; QT PROLONGATION; RANDOMIZED CONTROLLED TRIAL; REVIEW; SIDE EFFECT; SODIUM CELL LEVEL; SODIUM TRANSPORT; SOMNOLENCE; STABLE ANGINA PECTORIS; STOMACH DISCOMFORT; SYNCOPE; TINNITUS; TORSADE DES POINTES; TREMOR; VERTIGO; VOMITING; XEROSTOMIA;

ACETANILIDES; ANGINA PECTORIS; CHRONIC DISEASE; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG ADMINISTRATION SCHEDULE; DRUG APPROVAL; DRUG THERAPY, COMBINATION; FEMALE; FOLLOW-UP STUDIES; HUMANS; MALE; NITROGLYCERIN; PIPERAZINES; RANDOMIZED CONTROLLED TRIALS AS TOPIC; SURVIVAL RATE; TREATMENT OUTCOME; UNITED STATES;

EID: 77949447131     PISSN: 14779072     EISSN: 17448344     Source Type: Journal    
DOI: 10.1586/erc.09.178     Document Type: Review

References (68)

1. Lloyd-Jones D, Adams R, Carnethon M et al. Heart disease and stroke statistics - 2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 119, 480-486 (2009).
2. Fox K, Garcia MA, Ardissino D et al. Guidelines on the management of stable angina pectoris: executive summary: the task force on the management of stable angina pectoris of the European Society of Cardiology. Eur. Heart J. 27, 1341-1381 (2006).
3. Legrand VM, Serruys PW, Unger F et al. Three-year outcome after coronary stenting versus bypass surgery for the treatment of multivessel disease. Circulation 109, 1114-1120 (2004).
4. Boden WE, O'Rourke RA, Teo KK et al. Optimal medical therapy with or without PCI for stable coronary disease. N. Engl. J. Med. 356, 1503-1516 (2007).
5. Weintraub WS, Spertus JA, Kolm P et al. Effect of PCI on quality of life in patients with stable coronary disease. N. Engl. J. Med. 359, 677-687 (2008).
6. Michaelsen A, Knoblauch NT, Lehmann N et al. Effects of lifestyle modification on the progression of coronary atherosclerosis, autonomic function, and angina - the role of GNB3 C825T polymorphism. Am. Heart J. 151, 870-877 (2006).
7. Ahern GP, Hsu SF, Klyachko VA, Jackson MB. Induction of persistent sodium current by exogenous and endogenous nitric oxide. J. Biol. Chem. 275, 28810-28815 (2000).
8. Undrovinas AI, Fleidervish IA, Makielski JC. Inward sodium current at resting potential in single cardiac myocytes induced by the ischemic metabolite lysophosphatidylcholine. Circ. Res. 71, 1231-1241 (1992).
9. Wu J, Corr PB. Palmitoyl carnithine modifies sodium currents and induces transient inward current in ventricular myocytes. Am. J. Physiol. Heart Circ. Physiol. 266, H1034-H1046 (1994).
10. Hale SL, Shryock JC, Belardinelli L, Sweeney M, Kloner RA. Late sodium current inhibition as a new cardioprotective approach. J. Mol. Cell. Cardiol. 44, 954-967 (2008).
11. Gaffney SM. Ranolazine, a novel agent for chronic stable angina. Pharmacotherapy 26, 135-142 (2006).
12. Song Y, Shryock JC, Wagner S et al. Blocking late sodium current reduces hydrogen-peroxide-induced arrhythmogenic activity and contractile dysfunction. J. Pharmacol. Exp. Ther. 318, 214-222 (2006).
13. Song Y, Shryock JC, Wu L et al. Antagonism by ranolazine of the pro-arrhythmic effects of increasing late INa in guinea pig ventricular myocytes. J. Cardiovasc. Pharmacol. 44, 192-199 (2004).
14. Fraser H, Belardinelli L, Wang L, Light PE, McVeigh JJ, Clanachan AS. Ranolazine decreases diastolic calcium accumulation caused by ATX-II or ischemia in rat hearts. J. Mol. Cell. Cardiol. 41, 1031-1038 (2006).
15. Fredj S, Sampson KJ, Liu H et al. Molecular basis of ranolazine block of LQT-3 mutant sodium channels: evidence for site of action. Br. J. Pharmacol. 148, 16-24 (2006).
16. Moos AJ, Zareba W, Schwarz KQ et al. Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome. J. Cardiovasc. Electrophysiol. 19, 1289-1293 (2008).
17. Antzelevitch C, Belardinelli L, Zygmunt AC et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation 110, 904-910 (2004).
18. Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart 92(Suppl. 4), IV6-IV14 (2006).
19. Undrovinas AI, Belardinelli L, Undrovinas NA, Sabbah HN. Ranolazine improves abnormal repolarization and contraction in left ventricular myocytes of dogs with heart failure by inhibiting late sodium current. J. Cardiovasc. Electrophysiol. 17(Suppl. 1), S169-S177 (2006).
20. Wu L, Shryock JC, Song Y, Antzelevitch C, Belardinelli L. Antiarrhythmic effects of ranolazine in a guinea pig in vitro model of long QT-syndrome. J. Pharmacol. Exp. Ther. 310, 599-605 (2004).
21. Wu L, Shryock JC, Song Y, Belardinelli L. An increase in late sodium current potentiates the proarrhythmic activities of low-risk QT-prolonging drugs in female rabbit hearts. J. Pharmcol. Exp. Ther. 316, 718-726 (2006).
22. Gralinski MR, Chi L, Park JL et al. Protective effects of ranolazine on ventricular fibrillation induced by activation of the ATP-dependent potassium channel in the rabbit heart. J. Cardiovasc. Pharmacol. Ther. 1, 141-148 (1996).
23. Scirica BM, Morrow DA, Hod H et al. Effects of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 116, 1647-1652 (2007).
24. Wang P, Fraser H, Lloyd SG, McVeigh JJ, Belardinelli L, Chatham JC. A comparison between ranolazine and CVT-4325, a novel inhibitor of fatty acid oxidation, on cardiac metabolism and left ventricular function in rat isolated perfused heart during ischemia and reperfusion. J. Pharmacol. Exp. Ther. 321, 213-220 (2007).
25. Clarke B, Wyatt KM, McCormack JG. Ranolazine increases active pyruvate dehydrogenase in perfused normoxic rat hearts: evidence for an indirect mechanism. J. Mol. Cell. Cardiol. 28, 341-350 (1996).
26. McCormack JG, Barr RL, Wolff AA, Lopaschuk GD. Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts. Circulation 93, 135-142 (1996).
27. MacInnes A, Fairman DA, Binding P et al. The antianginal agent trimetazidine does not exert its functional benefit via inhibition of mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ. Res. 93, e33-e37 (2003).
28. Timmis AD, Chaitman BR, Crager M. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur. Heart J. 27, 42-48 (2006).
29. Morrow DA, Scirica MB, Chaitman BR et al. Evaluation of the glycometabolic effects of ranolazine in patients with and without diabetes mellitus in the MERLIN-TIMI 36 randomized controlled trial. Circulation 119, 2032-2039 (2009).
30. Létienne R, Vie B, Puech A, Vieu S, Le Grand B, John GW. Evidence that ranolazine behaves as a weak b1 and b2-adrenoceptor antagonist in the rat cardiovascular system. Naunyn- Schmiedeberg's Arch. Pharmacol. 363, 464-471 (2001).
31. Chaitman BR, Skettino SL, Parker JO et al. Anti-ischemic effects and long term survival during ranolazine monotherapy in patients with chronic severe angina. J. Am. Coll. Cardiol. 43, 1375-1382 (2004).
32. Cocco G, Rousseasu MF, Bouvy T et al. Effects of a new metabolic modulator, ranolazine, on exercise tolerance in angina pectoris patients treated with β-blocker or diltiazem. J. Cardiovasc. Pharmacol. 20, 131-138 (1992).
33. Pepine CJ, Wolff AA; Ranolazine Study Group. A controlled trial with a novel anti-ischemic agent, ranolazine, in chronic stable angina pectoris that is responsive to conventional antianginal agents. Am. J. Cardiol. 84, 46-50 (1999).
34. Thadani U, Ezekowitz M, Fenney L et al. Double-blind efficacy and safety study of a novel anti-ischemic agent, ranolazine, versus placebo in patients with chronic stable angina pectoris. Circulation 90, 726-734 (1994).
35. Chaitman BR, Pepine CJ, Parker JO et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina. A randomized controlled trial. JAMA 291, 309-316 (2004).
36. Stone PH, Gratsiansky NA, Blokhin A et al. Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J. Am. Coll. Cardiol. 48, 566-575 (2006).
37. Clarke B, Spedding M, Patmore L, McCormack JG. Protective effects of ranolazine in guinea pig hearts during low-flow ischaemia and their association with increases in pyruvate dehydrogenase. Br. J. Pharmacol. 109, 748-750 (1993).
38. Zacharowski K, Blackburn B, Thiemermann C. Ranolazine, a partial fatty acid oxidation inhibitor, reduced myocardial infarct size and cardiac troponin release in the rat. Eur. J. Pharmacol. 418, 105-110 (2001).
39. Hale SL, Leeka JA, Kloner RA. Improved left ventricular function and reduced necrosis after myocardial ischemia/ reperfusion in rabbits treated with ranolazine, an inhibitor of the late sodium channel. J. Pharmacol. Exp. Ther. 318, 418-423 (2006).
40. Hale SL, Kloner RA. The antianginal agent, ranolazine, reduces myocardial infarct size but does not alter anatomic no-reflow or regional myocardial blood flow in ischemia/reperfusion in the rabbit. J. Cardiovasc. Pharmacol. Ther. 13, 226-232 (2008).
41. Black SC, Gralinski MR, McCormack JG, Driscoll EM, Lucchesi BR. Effects of ranolazine on infarct size in a canine model of regional myocardial ischemia/ reperfusion. J. Cardiovasc. Pharmacol. 24, 921-928 (1994).
42. Hale SL, Kloner RA. Ranolazine, an inhibitor of the late sodium channel current, reduces postischemic myocardial dysfunction in the rabbit. J. Cardiovasc. Pharmacol. Ther. 11, 249-255 (2006).
43. Sabbah HN, Chandler MP, Mishima T et al. Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, improves left ventricular function in dogs with chronic heart failure. J. Card. Fail. 8, 416-422 (2002).
44. Aaker A, McCormack JG, Hirai T, Musch TI. Effects of ranolazine on the exercise capacity of rats with chronic heart failure induced by myocardial infarction. J. Cardiovasc. Pharmacol. 28, 353-362 (1999).
45. Keating GM. Ranolazine. A review of its use in chronic stable angina pectoris. Drugs 68, 2483-2503 (2008).
46. Jerling M. Clinical pharmacokinetics of ranolazine. Clin. Pharmacokinet. 45, 469-491 (2006).
47. Penman AD, Eadie J, Herron WJ et al. The characterization of the metabolism of ranolazine in man by liquid chromatography mass spectroscopy. Rapid Comun. Mass Spectrom. 9, 1418-1430 (1995).
48. Abdallah H, Jerling M. Effect of hepatic impairment on the multiple-dose pharmacokinetics of ranolazine sustained-release tablets. J. Clin. Pharmacol. 45, 802-809 (2005).
49. Jerling M, Abdallah H. Effect of renal impairment on multiple-dose pharmocokinetics of extended-release ranolazine. Clin. Pharmacol. Ther. 78, 288-297 (2005).
50. Jain D, Dasgupta P, Hughes LO, Lahiri A, Raftery EB. Ranolazine (RS-43285): a preliminary study of a new anti-anginal agent with selective effect on ischaemic myocardium. Eur. J. Clin. Pharmacol. 38, 111-114 (1990).
51. Rousseau MF, Pouleur H, Cocco G, Wolf AA. Comparative efficacy of ranolazine versus atenolol for chronic angina pectoris. Am. J. Cardiol. 95, 311-316 (2005).
52. Venkataraman R, Belardinelli L, Blackburn B, Heo J, Iskandrian AE. A study of the effects of ranolazine using automated quantitative analysis of serial myocardial perfusion images. JACC Cardiovasc. Imaging 2, 1301-1309 (2009).
53. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA 297, 1775-1783 (2007).
54. Wilson SR, Scirica BM, Braunwald E et al. Efficacy of ranolazine in patients with chronic angina. J. Am. Coll. Cardiol. 53, 1510-1516 (2009).
55. Wenger NK, Chaitman B, Vetrovec GW. Gender comparison of efficacy and safety of ranolazine for chronic angina pectoris in four randomized clinical trials. Am. J. Cardiol. 99, 11-18 (2007).
56. Koren MJ, Crager MR, Sweeney M. Long-term safety of a novel antianginal agent in patients with severe chronic stable angina: the Ranolazine Open Label Experience (ROLE). J. Am. Coll. Cardiol. 49, 1027-1034 (2007).
57. 2+- exchanger protein levels and diastolic function of failing human myocardium. Circulation 99, 641-648 (1999).
58. Sossalla S, Wagner S, Rasenack ECL et al. Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts - role of late sodium current and intracellular ion accumulation. J. Mol. Cell. Cardiol. 45, 32-43 (2008).
59. Hayashida W, van Eyll C, Rousseau MF, Pouleur H. Effects of ranolazine on left ventricular regional diastolic function in patients with ischemic heart disease. Cardiovasc. Drugs Ther. 8, 741-747 (1994).
60. Moss AJ, Zareba W, Schwarz KQ, Rosero S, McNitt S, Robinson JL. Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long QT syndrome. J. Cardiovasc. Electrophysiol. 19, 1289-1293 (2008).
61. Hwang H, Arcidi JM, Hale SL et al. Ranolazine as a cardioplegia additive improves recovery of diastolic function in isolated rat hearts. Circulation 120, S16-S21 (2009).
62. Hwang H, Arcidi JM, Hale SL et al. Ranolazine as an adjunct to cardioplegia: a potential new therapeutic application. J. Cardiovasc. Pharmacol. Ther. 14, 125-133 (2009).
63. Antzelevich C, Burashnikov A. Atrial-selective sodium channel block as a novel strategy for the management of atrial fibrillation. J. Electrocardiogr. 42(6), 543-548 (2009).
64. Burashnikov A, Di Diego JM, Zygmunt AC, Belardinelli L, Antzelevitch C. Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine. Circulation 116, 1449-1457 (2007).
65. Burashnikov A, Antzelevitch C. Atrial-selective sodium channel blockers: Do they exist? J. Cardiovasc. Pharmacol. 52, 121-128 (2008).
66. Kumar K, Nearing BD, Carvas M et al. Ranolazine exerts potent effects on atrial electrical properties and abbreviates atrial fibrillation duration in the intact porcine heart. J. Cardiovasc. Electrophysiol. 20, 796-802 (2009).
67. Dhalla AK, Wang WQ, Dow J et al. Ranolazine, an antianginal agent, markedly reduces ventricular arrhythmias induced by ischemia and ischemia-reperfusion. Am. J. Physiol. Am. Heart Circ. Physiol. 297(5), H1923-H1929 (2009).
68. Kumar K, Nearing BD, Bartolli CR et al. Effect of ranolazine on ventricular vulnerability and defibrillation threshold in the intact porcine heart. J. Cardiovasc. Electrophysiol. 19, 1073-1079 (2008).