| Revision as of 11:53, 23 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,074 edits Saving copy of the {{drugbox}} taken from revid 456685007 of page Levosimendan for the Chem/Drugbox validation project (updated: 'DrugBank'). |
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{{Short description|Pharmaceutical drug}} |
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{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}} |
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{{Drugbox |
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{{Drugbox |
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| verifiedrevid = 462091419 |
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| Watchedfields = changed |
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| IUPAC_name = 2-phenyl]hydrazinylidene]propanedinitrile |
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| verifiedrevid = 407613581 |
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| IUPAC_name = ({4-phenyl}hydrazono)propanedinitrile |
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| image = Levosimendan.svg |
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| image = Levosimendan.svg |
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| width = 200 |
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| width = 250 |
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| image2 = Levosimendan ball-and-stick.png |
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<!--Clinical data--> |
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<!--Clinical data--> |
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| tradename = |
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| tradename = Simdax |
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| Drugs.com = {{drugs.com|international|levosimendan}} |
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| Drugs.com = {{drugs.com|international|levosimendan}} |
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| pregnancy_category = no data |
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| pregnancy_category = |
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| legal_status = Prescription only. Not marketed in the U.S. |
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| legal_status = Rx-only |
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| routes_of_administration = ] |
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| routes_of_administration = ] |
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<!--Pharmacokinetic data--> |
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<!--Pharmacokinetic data--> |
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| bioavailability = 85% (oral) |
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| bioavailability = 85% (oral) |
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| protein_bound = 97–98% |
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| metabolism = ] |
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| metabolism = Extensive ] |
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| elimination_half-life = 1 hour |
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| elimination_half-life = ~1 hour (levosimendan), 75–80 hours (metabolites) |
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| excretion = ] |
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| excretion = urine (54%), feces (44%) |
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<!--Identifiers--> |
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<!--Identifiers--> |
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| PubChem = 3033825 |
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| PubChem = 3033825 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = DB00922 |
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| DrugBank = DB00922 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 2298414 |
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| ChemSpiderID = 2298414 |
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| UNII_Ref = {{fdacite|changed|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = C6T4514L4E |
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| UNII = C6T4514L4E |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D04720 |
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| KEGG = D04720 |
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| ChEBI_Ref = {{ebicite|changed|EBI}} |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEBI = 50567 |
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| ChEBI = 50567 |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = 313136 |
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<!--Chemical data--> |
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<!--Chemical data--> |
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| C=14 | H=12 | N=6 | O=1 |
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| C=14 | H=12 | N=6 | O=1 |
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| molecular_weight = 280.28 |
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| smiles = O=C2N/N=C(/c1ccc(N/N=C(\C#N)C#N)cc1)(C)C2 |
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| smiles = O=C2N/N=C(/c1ccc(N/N=C(\C#N)C#N)cc1)(C)C2 |
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| InChI = 1/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 |
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| InChIKey = WHXMKTBCFHIYNQ-SECBINFHBZ |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 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 |
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| StdInChI = 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 |
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| StdInChIKey = WHXMKTBCFHIYNQ-SECBINFHSA-N |
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| StdInChIKey = WHXMKTBCFHIYNQ-SECBINFHSA-N |
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}} |
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'''Levosimendan''' (]) {{IPAc-en|ˌ|l|iː|v|oʊ|s|aɪ|ˈ|m|ɛ|n|d|ən}} is a ] sensitizer used in the management of ]. It is marketed under the ] '''Simdax''' (]). Overall the drug has a two fold mechanism of action. It leads to greater ] by increasing the calcium sensitivity as it binds to ] and this results in a greater positive inotrophic force. Secondly, the drug is able to open ] sensitive potassium channels in ] cells, and the vascular dilatory effects of the drug lead to a decreased ] and ], putting less work on the heart. This drug is in the process of review by the ] but has not been approved for use in the United States yet. |
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== Mechanism of action == |
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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 ] effect by increasing calcium sensitivity of ]s by binding to cardiac ] in a calcium-dependent manner. It also has a ] effect, by opening ] (ATP)-sensitive ] channels in vascular ] to cause smooth muscle relaxation. The combined inotropic and vasodilatory actions result in an increased force of contraction, decreased ] and decreased ]. Moreover, by opening also the mitochondrial (ATP)-sensitive potassium channels in cardiomyocytes, the drug exerts a cardioprotective effect.<ref name = "Papp">{{cite journal | vauthors = Papp Z, Édes I, Fruhwald S, De Hert SG, Salmenperä M, Leppikangas H, Mebazaa A, Landoni G, Grossini E, Caimmi P, Morelli A, Guarracino F, Schwinger RH, Meyer S, Algotsson L, Wikström BG, Jörgensen K, Filippatos G, Parissis JT, González MJ, Parkhomenko A, Yilmaz MB, Kivikko M, Pollesello P, Follath F | display-authors = 6 | title = Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan | journal = International Journal of Cardiology | volume = 159 | issue = 2 | pages = 82–7 | date = August 2012 | pmid = 21784540 | doi = 10.1016/j.ijcard.2011.07.022 | url = http://transmed.almazovcentre.ru/jour/article/view/72 }}</ref> |
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== Clinical use == |
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=== Indications === |
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Levosimendan is indicated for inotropic support in acutely-] severe ] in situations where conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate. |
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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.<ref name = "Nieminen">{{cite journal | vauthors = Nieminen MS, Fruhwald S, Heunks LM, Suominen PK, Gordon AC, Kivikko M, Pollesello P | title = Levosimendan: current data, clinical use and future development | journal = Heart, Lung and Vessels | volume = 5 | issue = 4 | pages = 227–45 | date = 2013 | pmid = 24364017 | pmc = 3868185 }}</ref> |
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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.<ref name = "Mebazaa">{{cite journal | vauthors = Mebazaa A, Nieminen MS, Packer M, Cohen-Solal A, Kleber FX, Pocock SJ, Thakkar R, Padley RJ, Põder P, Kivikko M | display-authors = 6 | title = Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial | journal = JAMA | volume = 297 | issue = 17 | pages = 1883–91 | date = May 2007 | pmid = 17473298 | doi = 10.1001/jama.297.17.1883 | doi-access = free }}</ref> 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.<ref name = "Böhm">{{cite journal | vauthors = Böhm M, Link A, Cai D, Nieminen MS, Filippatos GS, Salem R, Cohen Solal A, Huang B, Padley RJ, Kivikko M, Mebazaa A | display-authors = 6 | title = Beneficial association of β-blocker therapy on recovery from severe acute heart failure treatment: data from the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support trial | journal = Critical Care Medicine | volume = 39 | issue = 5 | pages = 940–4 | date = May 2011 | pmid = 21283007 | doi = 10.1097/CCM.0b013e31820a91ed | s2cid = 1396039 }}</ref> |
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=== Licensing status === |
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The ] originally developed levosimendan and applied for a ] in 1998 in the U.S. However the ] (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.<ref>{{cite web|last=Orion|title=Simdax (levosimendan) Fact Sheet|url=http://www.orion.fi/Documents/Publications%20and%20Media%20main%20file/Presentation%20materials%20PDF/Simdax%20Fact%20Sheet.pdf|publisher=Orion|access-date=16 February 2013|url-status=dead|archive-url=https://web.archive.org/web/20120528223937/http://orion.fi/Documents/Publications%20and%20Media%20main%20file/Presentation%20materials%20PDF/Simdax%20Fact%20Sheet.pdf|archive-date=28 May 2012}}</ref> 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).<ref>{{cite web|last=Tenax Therapeutics|title=Levosimendan - Tenax Therapeutics|url=http://www.tenaxthera.com/pipeline/levosimendan/|publisher=Tenax Therapeutics|access-date=27 November 2022}}</ref> |
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=== Contraindications === |
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The use of levosimendan is contraindicated in patients with moderate-to-severe ], severe ] impairment, severe ] filling or outflow obstruction, very ] and ], and/or history of the ] ].<ref>{{cite book | veditors = Rossi S | title = ] | date = 2006 | location = Adelaide | publisher = Australian Medicines Handbook }}</ref> |
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=== Adverse effects=== |
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Common ]s (≥1% of patients) associated with levosimendan therapy include: headache, hypotension, ]s (], ], ], ]), ], ] and/or nausea (Rossi, 2006). |
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=== Formulations === |
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Levosimendan is marketed as a 2.5 mg/mL concentrated solution for IV infusion. The concentrate is diluted with ] 5% solution before infusion. |
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== References == |
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{{reflist}} |
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{{Cardiac stimulants excluding cardiac glycosides}} |
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] |
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] |
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] |