Levosimendan: From basic science to clinical trials

Recent Patents on Cardiovascular Drug Discovery

Volumn 6, Issue 1, 2011, Pages 9-15

  Rognoni, Andrea ^a,b   Lupi, Alessandro ^a,b   Lazzero, Maurizio ^a,b   Bongo, Angelo S ^a,b   Rognoni, Giorgio ^a,b  

^a University Hospital Maggiore della Carita   (Italy)

^b Sant'Andrew Hospital   (Italy)

Author keywords

Calcium sensitizer; Heart failure; Levosimendan

Indexed keywords

BETA ADRENERGIC RECEPTOR BLOCKING AGENT; DIGOXIN; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; DOBUTAMINE; FUROSEMIDE; LEVOSIMENDAN; N [4 (1,4,5,6 TETRAHYDRO 4 METHYL 6 OXO 3 PYRIDAZINYL)PHENYL]ACETAMIDE; PHOSPHODIESTERASE INHIBITOR; PLACEBO; SPIRONOLACTONE;

ACUTE CORONARY SYNDROME; ACUTE HEART FAILURE; ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; ARTICLE; ATRIOVENTRICULAR BLOCK; BRADYCARDIA; CARDIOGENIC SHOCK; CLINICAL TRIAL; CONGENITAL HEART DISEASE; CONTINUOUS INFUSION; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG INDUCED HEADACHE; DRUG MECHANISM; DRUG METABOLISM; DRUG SAFETY; DRUG TOLERABILITY; HEART ATRIUM FIBRILLATION; HEART DISEASE; HEART FAILURE; HEART FUNCTION; HEART LEFT VENTRICLE FAILURE; HEART MUSCLE CELL; HEART PERFORMANCE; HEART PROTECTION; HEART RIGHT VENTRICLE FUNCTION; HEART VENTRICLE ARRHYTHMIA; HEART VENTRICLE REMODELING; HEART VENTRICLE TACHYCARDIA; HUMAN; HYPERTENSION; HYPOTENSION; INOTROPISM; LOADING DRUG DOSE; MORTALITY; OXYGEN CONSUMPTION; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); SEPTIC SHOCK; ST SEGMENT ELEVATION MYOCARDIAL INFARCTION; VASODILATATION;

ACUTE DISEASE; ANIMALS; CALCIUM CHANNELS; CARDIOVASCULAR AGENTS; CHRONIC DISEASE; EVIDENCE-BASED MEDICINE; HEART FAILURE; HUMANS; HYDRAZONES; MYOCARDIAL CONTRACTION; MYOCARDIUM; OXYGEN CONSUMPTION; POTASSIUM CHANNELS; PYRIDAZINES; TRANSLATIONAL RESEARCH; TREATMENT OUTCOME; VENTRICULAR FUNCTION;

EID: 79551665671     PISSN: 15748901     EISSN: None     Source Type: Journal    
DOI: 10.2174/157489011794578455     Document Type: Article

References (60)

1. Bleumink GS, Knetsch AM, Sturkenboom MC. Quantifying the heart failure epidemic: Prevalence, incidence rate, lifetime risk and prognosis of heart failure. The Rotterdam Study. Eur Heart J 2004; 25: 1614-1619.
2. The Study Group on Diagnosis of the Working Group on Heart Failure of The European Society of Cardiology. Increasing awareness and improving the management of heart failure in Europe: The improvement of HF initiative. Eur Heart Fail 1999; 1: 139-144.
3. Nieminenen MS, Bohm M, Cowie MR. Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: The task force on acute heart failure of the European Society of cardiology. Eur Heart J 2005; 26: 384-416.
4. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson KD. Short - term risk of death after treatment with nesiritide for decompensated heart failure: A pooled analysis of randomized controlled trials. JAMA 2005; 293: 1900-1905.
5. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005; 111: 1487-1491.
6. Thackray S, Easthaugh J, Freemantle N, Cleland JG. The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure: A meta - regression analysis. Eur Hear Fail 2002; 4: 515-529.
7. Burger AJ, Horton DP, LeJemtel T. Effect of nesiritide (B - type natriuretic peptide) and dobutamine on ventricular arrhythmias in the treatment of patients with acutely decompensated congestive heart failure: The precedent study. Am Heart J 2002; 144: 1102-1108.
8. Antila S, Sundberg S, Lehtonen LA. Clinical pharmacology of levosimendan. Clin Pharmacokinet 2007; 46: 535-532.
9. Innes CA, Wagstaff AJ. Levosmendan: A review of its use in the management of acute decompensated heart failure. Drugs 2003; 63: 2651-2671.
10. Slawky MT, Colucci WS, Gottlieb SS. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Circulation 2000; 102: 2222-2227.
11. Nieminen MS, Akkila J, Hasenfuss G. Hemodynamic and neurohumoral effects of continous infusion of levosimendan in patients with congestive heart failure. J Am Coll Cardiol 2000; 36: 1903-1912.
12. Mebazaa A, Nieminen MS, Packer M, Cohen-Solal A, Kleber FX, Pocock SJ, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: The SURVIVE Randomized Trial. JAMA 2007; 297: 1487-1491.
13. Cleland JG, Freemantle N, Coletta AP, Clark AL. Clinical trials update from the American Heart Association: REPAIR - AMI, ASTAMI, JELIS, MEGA, REVIVE II, SURVIVE and PROACTIVE. Eur Heart Fail 2006; 8: 105-110.
14. Kivikko M, Antila S, Eha J, Lehtonen L, Pentikäinen PJ. Pharmacokintics of levosimendan and its metabolites during and after a 24 - hour continous infusion in patients with severe heart failure. Int J Clin Pharmacol Ther 2002; 40: 465-471.
15. + channel in rat arterial myocites. Eur J Pharmacol 1997; 333: 249-259.
16. + channels. J Pharmacol Sci 2007; 104: 1-5.
17. Szilagyi S, Pollesello P, Levijoki J, Kaheinen P, Haikala H, Edes I, et al. The effects of levosimendan and OR - 1896 on isolated hearts, myocyte - sized preparatios and phosphodiesterase enzymes of the guinea pig. Eur J Pharmacol 2004; 486: 67-74.
18. Haikala H, Kaivola J, Nissenen E, Wall P, levijoki J, Linden IB. Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan. J Mol Cell Cardiol 1995; 27: 1859-1866.
19. Hasenfuss G, Pieske B, Castell M, Kretschmann B, Maier LS, Just H. Influence if the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation 1998; 98: 2141-2147.
20. Kristof E, Szigeti G, Papp Z, Bodi A, Ball NA, Walsh RA, et al. The effects of levosimendan on the left ventricular function and protein phosphorylation in post - ischemic guinea pig - heart. Basic Res Cardiol 1999; 94: 223-230.
21. De Luca L, Proietti P, Celotto A, Bucciarelli-Ducci C, Benedetti G, Di Roma A, et al. Levosimendan improves hemodynamics and coronary flow reserve after percutaneous coronary intervention in patients with acute myocardial infarctionand left ventricular dysfunction. Am Heart J 2005; 150: 563-568.
22. Ukkonen H, Saraste M, Akkila J, Knuuti MJ, Lehikoinen P, Någren K, et al. Myocardial efficency during calcium sensitization with levosimendan: A non - invasive study with positron emission tomography and echocardiography in healthy volunteers. Clin Pharmacol Ther 1997; 61: 596-607.
23. Michaels AD, McKeown B, Kostal M, Kalpesh T, Vakharia BA, Mark VJ, et al. effects of intravenous levosimendan on human coronary vasomotor regulation, left ventricular wall stress, and myocardial oxygen uptake. Circulation 2005; 111: 1504-1509.
24. Brown BG, Bolson EL, Dodge HT. Dynamic mechanisms in human coronary stenosis. Circulation 1984; 70: 917-922.
25. Lilleberg J, Nieminen MS, Akkila J, Heikkilä L, Kuitunen A, Lehtonen L, et al. Effects of a new calcium sensitizer, levosimendan, haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting. Eur Heart J 1998; 19: 660-668.
26. Marin-Garcia J, Goldenthal MJ. Mitochondrial centrality in heart failure. Heart Fail Rev 2008; 13: 137-150.
27. Louhelainen M, Vahtola E, Kaheinen P, Leskinen H, Merasto S, Kytö V, et al. Effects of levosimendan on cardiac remodelling and cardiomyocyte apoptosis in hypertensive Dahl/Rapp rats. Br J Pharmacol 2007; 150: 851-861.
28. Okuyama M, Yamaguchi S, Nozaki N, Yamaoka M, Shirakabe M, Tomoike H. Serum levels of soluble form of Fas molecule in patients with congestive heart failure. Am J Cardiol 1997; 79: 1698-1701.
29. Yamaguchi S, Yamaoka M, Okuyama M, Nitoube J, Fukui A, Shirakabe M, et al. Elevated circulating levels and cardiac secretion PF soluble Fas ligand in patients with congestive heart failure. Am J Cardiol 1999; 83: 1500-1503.
30. Nieminen MS, Seandell EP. Consideraitons on the efficacy and safety of levosimendan in ischemic heart heart failure. Ital Heart J 2003; 4 (Suppl 2): 39S-44S.
31. Sonntag S, Sundberg S, Lwhtonen L, Kleber FX. The calciumsensitizer levosimendan improves the function of stunned myocardium after percutenaous transluminal coronary angioplasty in acute myocardial ischemia. J Am Coll Cardiol 2004; 43: 2177-2182.
32. Mclean A, Huang S, Stewart D, Nalos M, Tang B. Efficacy of levosimendan in shock. (Abstract). Crit Care 2004; 6: P83.
33. Samimi-Fard S, Garcia-Gonzalez MJ, Dominguez-Reodriguez A, Abreu-Gonzalez P. Effects of levosimendan versus dobutamine on long - term survival of patients with cardiogenic shock after primary coronary angioplasty. Int J Cardiol 2008; 127: 284-287.
34. Tsagalou EP, Kanakakis J, Anastasiou-Nana MI, Drakos SG, Ntalis AS, Milliaras K, et al. Hemodynamic effects of levosimendan in acute myocardial infarction complicated by cardiogenic shock and high systemic vascular resistance. Acute Card Care 2009; 11: 99-106.
35. Scheiermann P, Ahluwalia D, Hoegl S, dolfen A, Revvermann M, Zwissler B, et al. Effects of intravenous and inhaled levosimendan in severe rodent sepsis. Intensive Care Med 2009; 35: 1412-1419.
36. Braun JP, Schneider M, Kastrup M, Liu J. Treatment of acute heart failure in an infant after cardiac surgery using levosimendan. Eur J Cardiothorac Surg 2004; 26: 228-230.
37. Turanlathi M, Boldt T, Palkama T, Antila S, Lehtonen L, Pesonen E. Pharmacokinetics of levosimendan in pediatric patients evaluated for cardiac surgery. Pediatr Crit Care Med 2004; 5: 457-462.
38. Duyugu H, Ozerkan F, Zoghi M, Nalbantgil S, Yildiz A, Akilli A, et al. Effect of levosimendan on right ventricular systolic and diastolic functions in patients with ischaemic heart failure. Int J Clin Pract 2008; 62: 228-233.
39. Kasikcioglu HA, Uyrel H, Tartan Z, Kasikcioglu E, Ozturk R, Carn A. Do calcium sensitizer effect right ventricular funciotns in patients with chronic heart failure? Int J Cardiol 2007; 118: 246-248.
40. Adamopoulos S, Parissis JT, Iliodromitis EK, Paraskevaidis I, Tsiapras D, Farmakis D, et al. Effects of levosimendan versus dobutamine in inflammatory and apoptotic pathways in acutely decompensated chronic heart failure. Am J Cardiol 2006; 98: 102-106.
41. Moiseyev VS, Poder P, Andrejevs N, Ruda MY, Golikov AP, Lazebnik LB, et al. Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. A randomized placebo -controlled, double - blind study (RUSSLAN). Eur Heart J 2002; 23: 1422-1432.
42. Zairis MN, Apostolatos C, Anastasiadis P, Mytas D, Katsaris C, Kouris N, et al. The effects of a calcium sensitizer or an inotrope or none in chronic low output decompesated heart failure: Results from the Calcum Sensitizer or Inotrope or None in Low Output Heart Failure Study (CASINO). J Am Coll Cardiol 2004; 43 (Suppl A): 206A-207A.
43. Follath F, Cleland JG, Just H, Papp JG, Scholz H, Peuhkurinen K, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low - output heart failure (the LIDO stud): A randomized double-blind trial. Lancet 2002; 360: 196-202.
44. Garratt C, Packer M, Colucci W, Fisher L, Massie B, Teerlink J, et al. Development of a comprehensive new end - point for the evaluation of new treatments for acute decompensated heart failure: Results with levosimendan in the revive I study. Crit Care 2004; 8 (Suppl 1): 89.
45. Packer M. REVIVE II: multicenter placebo - controlled trial of levosimendan on clinical status in acutely decompensated heart failure. Circulation 2005; 112: 3363.
46. Delaney A, Bradford C, McCaffrey J, Bagshaw SM, Lee R. Levosimendan for the treatment of acute severe heart failure: A meta - analysis of randomised controlled trials. Int J Cardiol 2010; 138 (3): 282-289.
47. Landoni G, Mizzi A, Biondi-Zoccai G, Bruno G, Bignami E, Corno L, et al. Reducing mortality in cardiac surgery with levosimendan: A meta - analysin of randomized controlled trials. J Cardiothorac Vasc Anesth 2009; 24: 51-57.
48. Landoni G, Mizzi A, Biondi-Zoccai G, Bignami E, Prati P, Ajello V, et al. Levosimendan reduces mortality in critically ill patients. A meta-analysis of randomized controlled trials. Minerva Anestesiol 2010; 76 (4): 276-286.
49. Parissis JT, Karavidas A, Bistola V, Arapi S, Paraskevaidis IA, Farmakis D, et al. Effects of levosimendan on flow - mediated vasodilation and soluble adhesion molecules in patients with advanced chronic heart failure. Atherosclerosis 2008; 197: 278-282.
50. Tokuda Y, Grant PW, Wolfenden HD, Manganas C, Lyon WJ, Murala JSK. Levosimendan for patients with impaired left ventricular function undergoing cardiac surgery. Interact Cardiovasc Thorac Surg 2006; 5: 322-326.
51. Morelli A, Teboul JL, Maggiore SM, Vieillard-Baron A, Rocco M, Conti G, et al. Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: A pilot study. Crit Care Med 2006; 34: 2287-2293.
52. Kerbaul F, Rondelet B, Demester JP, Fesler P, Huez S, Naeije R, et al. Effects of levosimendan versus dobutamine on pressure load -induced right ventricular failure. Crit Care Med 2006; 34: 2814-2819.
53. Missant C, Rex S, Segers P, Wouters PF. Levosimendan improves right ventriculovascular coupling in a porcine model of right ventricular dysfunction. Crit Care Med 2007; 35: 707-715.
54. Schwarte LA, Picker O, Bornstein SR, Fournell A, Scheeren TW. Levosimendan is superior to milrinone and dobutamine in selectively incresing microvascular gastric mucosal oxygenation in dogs. Crit Care Med 2005; 33: 135-142.
55. Archan S, Toller W. Levosimendan: Current status and future prospects. Curr Opin Anaesthesiol 2008; 21: 78-84.
56. Poeder, P. Treatment of acute myocardial infarction by simultaneous, separate or sequential administration, of amount of thrombolytic agent and levosimendan or their salt to patients. CA2474430 (2010).
57. Poeder, P., Haikala, H. Use of levosimendan and beta - adrenergic receptor antagonist useful for the treatment of heart failure. CA2450915C (2010).
58. Krivonosov, D.S., Tarasov, N.I. Method of treating patients with myocardial infarction ensured by primary transcutaneous transluminal coronary angioplasty with myocardial unload with beta - blocker Carvedolol. RU2381795 (2010).
59. Levijoki, J. Use of combination of levosimendan or its salt, calcium ion source and/or an intracellular calcium increasing agent for treating heart failure. DE60235965C0 (2010).
60. Lehtonen, L., Pentikainen, P., Lilleberg, J. Use of levosimendan or its salt for manufacture for treatment of erectile dysfunction has calcium dependent binding to troponin. CA2431125 (2002)