Levosimendan

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Levosimendan
IV
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability85% (oral)
Protein binding97–98%
MetabolismExtensive hepatic
Elimination half-life~1 hour (levosimendan), 75–80 hours (metabolites)
Excretionurine (54%), feces (44%)
Identifiers
  • 2-[[4-[(4R)-4-methyl-6-oxo-4,5-dihydro-1H-pyridazin-3-yl]phenyl]hydrazinylidene]propanedinitrile
JSmol)
  • O=C2N/N=C(/c1ccc(N/N=C(\C#N)C#N)cc1)[C@H](C)C2
  • 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 checkY
  • Key:WHXMKTBCFHIYNQ-SECBINFHSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Levosimendan (

FDA
but has not been approved for use in the United States yet.

Mechanism of action

Levosimendan is a calcium sensitizer — it increases the sensitivity of the heart to calcium, thus increasing cardiac contractility without a rise in intracellular calcium. Levosimendan exerts its positive

myocytes by binding to cardiac troponin C in a calcium-dependent manner. It also has a vasodilatory effect, by opening adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle to cause smooth muscle relaxation. The combined inotropic and vasodilatory actions result in an increased force of contraction, decreased preload and decreased afterload. Moreover, by opening also the mitochondrial (ATP)-sensitive potassium channels in cardiomyocytes, the drug exerts a cardioprotective effect.[1]

Clinical use

Indications

Levosimendan is indicated for inotropic support in acutely-

congestive heart failure
in situations where conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate.

Some of the Phase III studies in the extensive clinical program including the trials LIDO (200 patients), RUSSLAN (500), REVIVE-I (100), REVIVE-II (600) and SURVIVE (1350). In total, the clinical data base includes more than 3500 patients in Phase IIb and III double-blind randomized studies.[2]

In the SURVIVE study, despite a reduction in plasma B-type natriuretic peptide level in patients in the levosimendan group compared with patients in the dobutamine group, levosimendan did not significantly reduce all-cause mortality at 180 days.[3] However, in a retrospective subgroup analysis, Levosimendan was superior to dobutamine for treating patients with a history of CHF or those on beta-blocker therapy when they were hospitalized with acute decompensations.[4]

Licensing status

The

new drug application in 1998 in the U.S. However the Food and Drug Administration (FDA) requested further trials be conducted and Orion withdrew the application in November 1999. Initially, Orion obtained the approval to market the drug in Sweden in 2000.[5] Since then 60 countries worldwide have approved the drug for acute cardiac care, but it remains unapproved in North America, where it is currently in Phase III development by Tenax Therapeutics for reduction in morbidity in patients with Pulmonary Hypertension derived from Heart Failure with preserved Ejection Faction (PH-HFpEF).[6]

Contraindications

The use of levosimendan is contraindicated in patients with moderate-to-severe

abnormal heart rhythm torsades de pointes.[7]

Adverse effects

Common

hypokalaemia
and/or nausea (Rossi, 2006).

Formulations

Levosimendan is marketed as a 2.5 mg/mL concentrated solution for IV infusion. The concentrate is diluted with glucose 5% solution before infusion.

References

  1. PMID 21784540
    .
  2. PMID 24364017
    .
  3. PMID 17473298
    .
  4. S2CID 1396039
    .
  5. ^ Orion. "Simdax (levosimendan) Fact Sheet" (PDF). Orion. Archived from the original (PDF) on 28 May 2012. Retrieved 16 February 2013.
  6. ^ Tenax Therapeutics. "Levosimendan - Tenax Therapeutics". Tenax Therapeutics. Retrieved 27 November 2022.
  7. ^ Rossi S, ed. (2006). Australian Medicines Handbook. Adelaide: Australian Medicines Handbook.
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