For the treatment of acute decompensated congestive heart failure, levosimendan (OR1259) is a calcium sensitizer. When traditional treatment is deemed insufficient, levosimendan (OR1259), a dilator, is prescribed for the short-term management of acute decompensated severe chronic heart failure. Levosimendan (OR1259) has demonstrated encouraging first results in a variety of illnesses requiring inotropic support, including as Takotsubo cardiomyopathy, cardiogenic shock, septic shock, and right ventricular failure [1]. Unlike other types of dilators, levosimendan (OR1259) also involves positive energetic and neurohormonal alterations in addition to its distinct drug-receptor interactions for its cardiovascular effects [2]. In adult patients having cardiology and cardiac surgery, levosimendan (OR1259) may lower mortality [3].

Absorption, Distribution and Excretion
The bioavailability of oral levosimendan is 85 ± 6% in healthy volunteers and 84 ± 4% in patients.

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Metabolism / Metabolites
Complete metabolism, with some active metabolites (OR-1855 and OR-1896) possibly extending the drug's haemodynamic effects.

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Biological Half-Life
Eliminination half-life is approximately 1 hour.

Protein Binding
98% bound to plasma protein.

[1]. Levosimendan: current data, clinical use and future development. Heart Lung Vessel, 2013. 5(4): p. 227-245.

[2]. Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol, 2012. 159(2): p. 82-7.

[3]. Effects of levosimendan on mortality and hospitalization. A meta-analysis of randomized controlled studies. Crit Care Med, 2012. 40(2): p. 634-46.

Levosimendan is a hydrazone, a pyridazinone and a nitrile. It has a role as a vasodilator agent, an EC 3.1.4.17 (3',5'-cyclic-nucleotide phosphodiesterase) inhibitor, a cardiotonic drug and an anti-arrhythmia drug.
Levosimendan increases calcium sensitivity to myocytes by binding to troponin C in a calcium dependent manner. This increases contractility without raising calcium levels. It also relaxes vascular smooth muscle by opening adenosine triphosphate sensitive potassium channels. Levosimendan is used to manage acutely decompensated congestive heart failure.
A hydrazone and pyridazine derivative; the levo-form is a phosphodiesterase III inhibitor, calcium-sensitizing agent, and inotropic agent that is used in the treatment of HEART FAILURE.

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Drug Indication
For short term treatment of acutely decompensated severe chronic heart failure (CHF). Also being investigated for use/treatment in heart disease.

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Mechanism of Action
Levosimendan appears to increase myofilament calcium sensitivity by binding to cardiac troponin C in a calcium-dependent manner. This stabilizes the calcium-induced conformational change of troponin C, thereby (1) changing actin-myosin cross-bridge kinetics apparently without increasing the cycling rate of the cross-bridges or myocardial ATP consumption, (2) increasing the effects of calcium on cardiac myofilaments during systole and (3) improving contraction at low energy cost (inotropic effect). Calcium concentration and, therefore, sensitization decline during diastole, allowing normal or improved diastolic relaxation. Levosimendan also leads to vasodilation through the opening of ATP-sensitive potassium channels. By these inotropic and vasodilatory actions, levosimendan increases cardiac output without increasing myocardial oxygen demand. Levosimendan also has a selective phosphodiesterase (PDE)-III inhibitory action that may contribute to the inotropic effect of this compound under certain experimental conditions. It has been reported that levosimendan may act preferentially as a Ca²⁺ sensitizer at lower concentrations, whereas at higher concentrations its action as a PDE-III inhibitor becomes more prominent in experimental animals and humans.

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Pharmacodynamics
Levosimendan is a new Ca²⁺-sensitizing inotropic agent. Ca²⁺ sensitizers represent a new class of inotropic agents, which overcome the disadvantages associated with currently available inotropic agents in as they are not associated with an increased risk of arrhythmias, cell injury and death due to Ca²⁺ overload in myocardial cells; they do not increase the activation energy; and they have the potential to reverse contractile dysfunction under pathophysiologic conditions, such as acidosis or myocardial stunning. Levosimendan has not been approved for use in the U.S. or Canada.

C14H12N6O

280.28

280.107

141505-33-1

3033825

Light yellow to yellow solid powder

1.3±0.1 g/cm3

216-219ºC (dec.)

1.673

0.59

2

6

3

21

549

1

C[C@@H]1CC(=O)NN=C1C2=CC=C(C=C2)NN=C(C#N)C#N

WHXMKTBCFHIYNQ-SECBINFHSA-N

InChI=1S/C14H12N6O/c1-9-6-13(21)19-20-14(9)10-2-4-11(5-3-10)17-18-12(7-15)8-16/h2-5,9,17H,6H2,1H3,(H,19,21)/t9-/m1/s1

2-[[4-[(4R)-4-methyl-6-oxo-4,5-dihydro-1H-pyridazin-3-yl]phenyl]hydrazinylidene]propanedinitrile

Levosimendanum Simdax Levosimendan

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 50 mg/mL (~178.39 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.92 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (8.92 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)