Levosimendan

The determinants of calcium sensitivity, ie, the curve relating the shortening of cardiac myofibrils to the cytoplasmic calcium concentration, are incompletely understood, but several types of drugs can be shown to affect calcium sensitivity in vitro. Levosimendan is the most recent example of a drug that increases calcium sensitivity (it may also inhibit phosphodiesterase) and reduces symptoms in models of heart failure. 

Kivikko M, Lehtonen L. Levosimendan a new inodila-tory drug for the treatment of decompensated heart failure. Curr Pharm Des. 2005 11 43 5—455. 

Mebazaa A, Barraud D, Welschbillig S. Randomized clinical trials with levosimendan. AmJ Cardiol. 2005 96 74G-79G. 

Levosimendan is widely used in recent years as an inotrope with very favorable properties. It has actually been shown to be beneficial in ischemia-reperfusion in the isolated heart,243 in distinct contrast to dobutamine which by itself has an unfavorable effect.244... 

In the setting of cardial surgery, levosimendan given preoperatively would also be a consideration. Of the various antoxidants, desferrioxamine could be a candidate. Erythropoietin would be another strong candidate it is already widely used in heart failure. 

E. F. Du Toit, C. A. Muller, J. McCarthy, L. H. Opie, Levosimendan effects of a calcium sensitizer on function and arrhythmias and cyclic nucleotide levels during ischemia/reperfusion in the Langcndorff-perfused guinea pig heart, J Pharmacol Exp Ther 290, 505-14 (1999). 

Stehr SN, Christ T, Rasche B et al (2007) The effects of Levosimendan on myocardial function in ropivacaine toxicity in isolated Guinea pig heart preparations. Anesth Analg 105(3) 641-647... 

It has recently become possible to alter the relation between force and [Ca +ji in myocardium, a useful trick in congestive heart failure. Pimobendan modestly increases the affinity of cardiac Tn C (cTn) for Ca +, thereby increasing the activation of contraction at any given [Ca +]i. The more potent levosimendan binds to the N-terminal region of cTn C in a Ca -dependent manner, and amplifies the effect of Ca +, perhaps by increasing the stability of the Ca +-induced conformational change in cTn C or by enhancing cooperativity in the thin filament. 

Complete structure analysis of OR-1746. Pollesello and Nore reported the elucidation of the complex structure formed by the condensation of two molecules of levosimendan in the presence of ethanol. The condensation product, which contains a number of clusters of protonated and unprotonated nitrogens could not be confirmed on the basis of conventional 2D NMR data long-range HMBC data were necessary to... 

Levosimendan is a novel inotropic calcium-sensitizing drug. In advanced congestive heart failure, it improves cardiac contractility by sensitizing troponin C to calcium. It has been used recently in a porcine model of endotoxin-induced septic shock, in which pretreatment with levosimendan improved cardiac output and systemic and gut oxygen delivery." There are currently two ongoing clinical trials of levosimendan in septic shock. The role of levosimendan in the supportive management of circulatory failure in sepsis remains to be determined. 

Oldner A, Konrad D, Weitzberg E, et al. Effects of levosimendan, a novel inotropic calcium-sensitizing drug, in experimental septic shock. Crit Care Med 2001 29 2185-2193. 

KF-15232, Levosimendan, ORG 20494 (181), Pimobendan (182), Siguazodan (183), SK F 95654, Indolidan (184) and MCI-154 the increased activity seen with the 5-methyl-4,5-dihydro-3(2F/)-pyridazinone PDE III inhibitors is associated with the 5-methyl configuration. Some pyridazinones, such as Zardaverine (185), show combined PDE III and PDE IV inhibitory activity and have been investigated for the treatment of asthma as they may show combined bronchodilatory and antiinflammatory activities. Yet further PDE inhibition, this time of PDE V, is shown by phthalazines like MY 5445 (186). 

Relatively few pyridazine derivatives occur in natur, e.g. the quaternary salt pyridazinomycin 20. Some pyridazine derivatives show biological activity and are applied as herbicides and anthelmintics, e.g. maleic hydrazide 18 and the chlorinated pyridazinones 21 (pyrazon)/22 (pyridaben). The tetrahydro-pyridazinone derivative levosimendan 23 is an innovative myofilament calcium sensitizer applied as cardiotonic in treatment of heart failure. 

Orthostatic hypotension occurred when levosimendan was given with isosorbide mononitrate. The haemodynamic effects of levosimendan were not significantly altered by captopiil, carvedilol or other unnamed beta blockers, or felodipine. Levosimendan does not alter the effects of warfarin. Itraconazole does not alter the pharmacokinetics of levosimendan. Levosimendan appears not to interact adversely with alcohoL... 

A double-blind, randomised, crossover study in 12 healthy subjects given oral alcohol 0.8 g/kg with intravenous levosimendan 1 mg found no clinically significant pharmacokinetic or pharmacodynamic interactions. ... 

In 12 healthy subjects carvedilol 25 mg twice daily for 7 to 9 days did not alter the effeets of a single 2-mg intravenous dose of levosimendan on cardiac contractility. In addition, the heart rate and diastolic blood pressure responses were not altered, but the systolie blood pressure response was blunted. In a study to eompare levosimendan with dobutamine in patients with severe, low-output heart failure, 33 of the 102 patients receiving levosimendan were also given unnamed beta bloekers. The use of a beta blocker was shown not to reduee the haemodynamie effeets of levosimendan. The authors say this suggests that there may be a place for levosimendan in the management of exaeerbations of heart failure not eontrolled by beta bloekers. ... 

Captopril, in doses of up to 50 mg twiee daily, did not ehange the haemodynamie effeets of a single 1- or 2-mg intravenous dose of levosimendan in 24 patients with heart failure. No additional deerease in blood pressure was observed. No speeial preeautions appear to be required if levosimendan is given to patients taking eaptopril. 

A study of the use of oral levosimendan 500 mierograms four times daily and felodipine 5 mg onee daily in 24 men with eoronary heart disease found that eoneurrent use was well tolerated. The felodipine did not antagonise the positive inotropie effeets of the levosimendan and had no effect on exercise capaeity. Both drugs inereased the heart rate during exereise, and there was a slight additional effeet with the eombination (5 to 8 bpm... 

In an open, randomised, crossover study, 10 healthy subjects were given a single 25-mg oral dose of warfarin both before and on day 4 of a 9-day course of oral levosimendan 500 micrograms four times daily. No clinically relevant changes in the anticoagulant effects of the warfarin were seen, and levosimendan alone had no effect on blood coagulation. In addition, there was no important pharmacokinetic interaction between warfarin and levosimendan. No interactions would therefore be expected if both drugs are used concurrently. ... 

Antila S, Jarvinen A, Akkila J, Honkanen T, Karlsson M, Lehtonen L. Studies on psychomo-toric effects and pharmacokinetic interactions of the new calcium sensitizing drug levosimendan and ethanol. Arzneimittelforschmg (1997) 47, 816-20. 

Lehtonen L, Sundberg S. The contractility enhancing effect of the calcium sensitiser levosimendan is not attenuated by carvedilol in healthy subjects. EurJClin Pharmacol (2002) 58, 449-52. 

Follath F, Cleland JGF, Just H, Papp JGY, Scholz H, Peuhkurinen K, Harjola VP, MItrovic V, AbdallaM, SandellE-P, LehtonenL, for die Steering Committee and Investigators of the Levosimendan Infusion versus Dobutamine (LIDO) Study. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO stucty) a randomised double-blind trial. Lancet (2002) 360,196-202. 

Antila S, Eha J, Heinpalu M, Lehtonen L, Loogna I, Mesikepp A, Planken U, Sandell E-P. Haemodynamic interactions of a new calcium sensitizing drug levosimendan and cqjtopril. EurJClin Pharmacol (1996) 49,451-8. 

Sundberg S, Lehtonen L. Haemottynamic interactions between the novel calcium sensitiser levosimendan and isosorhide-S-manonitoate in healthy subjects. EurJ Clin Pharm[Pg.896]

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