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| Trade names | Simdax |
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| Routes of administration | IV |
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| Pharmacokinetic data | |
| Bioavailability | 85% (oral) |
| Protein binding | 97–98% |
| Metabolism | Extensivehepatic |
| Eliminationhalf-life | ~1 hour (levosimendan), 75–80 hours (metabolites) |
| Excretion | urine (54%), feces (44%) |
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| ECHA InfoCard | 100.189.828 |
| Chemical and physical data | |
| Formula | C14H12N6O |
| Molar mass | 280.291 g·mol−1 |
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Levosimendan (INN)/ˌliːvoʊsaɪˈmɛndən/ is acalcium sensitizer used in the management ofacutely decompensated congestive heart failure. It is marketed under thetrade nameSimdax (Orion Corporation). Overall the drug has a two fold mechanism of action. It leads to greaterinotropy by increasing the calcium sensitivity as it binds totroponin and this results in a greater positive inotrophic force. Secondly, the drug is able to openATP-sensitive potassium channels invascular smooth muscle cells, and the vascular dilatory effects of the drug lead to a decreasedpreload andafterload, putting less work on the heart. This drug is in the process of review by theFDA but has not been approved for use in the United States yet.
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 positiveinotropic effect by increasing calcium sensitivity ofmyocytes by binding to cardiactroponin C in a calcium-dependent manner. It also has avasodilatory effect, by openingadenosine triphosphate (ATP)-sensitivepotassium channels in vascularsmooth muscle to cause smooth muscle relaxation. The combined inotropic and vasodilatory actions result in an increased force of contraction, decreasedpreload and decreasedafterload. Moreover, by opening also the mitochondrial (ATP)-sensitive potassium channels in cardiomyocytes, the drug exerts a cardioprotective effect.[1]
Levosimendan is indicated for inotropic support in acutely-decompensated severecongestive 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]
TheOrion Corporation originally developed levosimendan and applied for anew drug application in 1998 in the U.S. However theFood 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]
The use of levosimendan is contraindicated in patients with moderate-to-severekidney impairment, severeliver impairment, severeventricular filling or outflow obstruction, verylow blood pressure andfast heart rate, and/or history of theabnormal heart rhythmtorsades de pointes.[7]
Commonadverse drug reactions (≥1% of patients) associated with levosimendan therapy include: headache, hypotension,arrhythmias (atrial fibrillation,extrasystoles,Atrial tachycardia,ventricular tachycardia),myocardial ischaemia,hypokalaemia and/or nausea (Rossi, 2006).
Levosimendan is marketed as a 2.5 mg/mL concentrated solution for IV infusion. The concentrate is diluted withglucose 5% solution before infusion.