Serelaxin: Difference between revisions

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Serelaxin
Clinical data
Pregnancy; category	N/A;
Routes of; administration	Intravenous
ATC code	C01DX21 (WHO) ;
Legal status
Legal status	Investigational;
Identifiers
	IUPAC name L-Serine, L-α-aspartyl-L-seryl-L-tryptophyl-L-methionyl-L-α-glutamyl-L-α-glutamyl-L-valylL-isoleucyl-L-lysyl-L-leucyl-L-cysteinylglycyl-L-arginyl-L-α-glutamyl-L-leucyl-L-valyl-L- arginyl-L-alanyl-L-glutaminyl-L-isoleucyl-L-alanyl-L-isoleucyl-L-cysteinylglycyl-L- methionyl-L-seryl-L-threonyl-L-tryptophyl-, cyclic (11→11'),(23→24')-bis(disulfide) with 5-oxo-L-prolyl-L-leucyl-L-tyrosyl-L-seryl-L-alanyl-L-leucyl-L-alanyl-L-asparaginyl-L-lysyl-L- cysteinyl-L-cysteinyl-L-histidyl-L-valylglycyl-L-cysteinyl-L-threonyl-L-lysyl-L-arginyl-L- seryl-L-leucyl-L-alanyl-L-arginyl-L-phenylalanyl-L-cysteine cyclic (10'→15')-disulfide;
CAS Number	99489-94-8;
ChemSpider	NA ;
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
Formula	C256H408N74O74S8
Molar mass	5963 g/mol

VisualWikitext

Revision as of 14:23, 23 July 2014

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

Overview

Serelaxin (RLX030) is an investigational drug for the treatment of acute heart failure (AHF), targeting the relaxin receptor. Serelaxin is a recombinant form of human relaxin-2, a hormone that (among other functions) is produced during pregnancy and mediates the haemodynamic changes that occur during this time, such as increased blood output of the heart and blood flow in the kidney. Human-relaxin-2 mediates vasodilation (widening of blood vessels) by increasing the production of nitric oxide (NO), a potent vasodilator. Activation of the relaxin receptor RXFP1 activates several enzymes in a phosphorylation cascade that eventually results in the activation of NO synthase in endothelial cells and the subsequent production of NO. Relaxin can also bind to a secondary receptor, endothelial B receptor, which is upregulated as a result of the previous pathway. Relaxin binding to endothelial B receptor on endothelial cells also induces vasodilation.

Relaxin causes vasodilation by an indirect mechanism, where it inhibits the potent vasoconstrictors angiotensin II and endothelin. In addition to vasodilation, the effects of relaxin are also seen in the kidneys, by significantly increasing creatinine clearance, which is a measure of kidney function, as well as increased renal blood flow. Relaxin also functions as a cardiac stimulant. Studies have demonstrated that relaxin increases calcium sensitivity of cardiac myofilaments as well as increasing phosphorylation of the myofilaments by protein kinase C (PKC). These modifications both function to increase the force generated by the myofilaments without increasing the energy consumption of the cardiac myocytes. Thus relaxin and serelaxin can increase stroke volume, the amount of blood pumped per heart beat, without increasing the energy demand on the already strained heart of acute heart failure patients.

Acute heart failure

Serelaxin is currently undergoing clinical trials in patients with acute heart failure, and is being developed by Novartis. Serelaxin has completed several clinical trials as a therapy for AHF. Phase I trials examined safety and tolerability, while phase II trials evaluated its haemodynamic effects and symptom relief. The Pre-RELAX-AHF phase II trial administered a dose of 30 µg/kg/day and showed a decrease in blood pressure, improved dyspnoea, and increased renal blood flow. In phase III the RELAX-AHF trial gave a 48hr intravenous infusion of the same dose. It significantly improved patients' dyspnoea, resulted in a 30% reduction in worsening of heart failure symptoms, a decreased hospital stay and a reduction in signs and symptoms of congestion. The FDA has granted serelaxin "breakthrough therapy" designation, meant to expedite the development and review of drugs for life threatening conditions and is set to be reviewed in February 2014.

References

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 | molecular_weight = 5963 g/mol
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+__NOTOC__
+{{SI}}
+{{CMG}}; {{AE}} {{KS}}
-'''Serelaxin''' ('''RLX030''') is an investigational drug for the treatment of acute [[heart failure]] (AHF), targeting the [[relaxin receptor]]. Serelaxin is a recombinant form of human [[relaxin]]-2, a hormone that (among other functions) is produced during pregnancy and mediates the haemodynamic changes that occur during this time,<ref name="Spreitzer" /><ref name="aerztezeitung" /> such as increased blood output of the heart and blood flow in the kidney.<ref name="pmid21613576" />  Human-relaxin-2 mediates vasodilation (widening of blood vessels) by increasing the production of [[nitric oxide]] (NO), a potent [[vasodilator]].<ref name="Tousoulis" />  Activation of the relaxin receptor [[RXFP1]] activates several enzymes in a [[phosphorylation cascade]] that eventually results in the activation of NO synthase in endothelial cells and the subsequent production of NO.<ref name="Bathgate" />  Relaxin can also bind to a secondary receptor, endothelial B receptor,{{Clarify|date=March 2014}} which is upregulated as a result of the previous pathway.<ref name="Miyares" />  Relaxin binding to endothelial B receptor on endothelial cells also induces vasodilation.<ref name="Teichman1" />
+==Overview==
-Relaxin causes vasodilation by an indirect mechanism, where it inhibits the potent vasoconstrictors angiotensin II and endothelin.<ref name="Teichman2" />
+'''Serelaxin''' ('''RLX030''') is an investigational drug for the treatment of acute [[heart failure]] (AHF), targeting the [[relaxin receptor]]. Serelaxin is a recombinant form of human [[relaxin]]-2, a hormone that (among other functions) is produced during pregnancy and mediates the haemodynamic changes that occur during this time, such as increased blood output of the heart and blood flow in the kidney.  Human-relaxin-2 mediates vasodilation (widening of blood vessels) by increasing the production of [[nitric oxide]] (NO), a potent [[vasodilator]].  Activation of the relaxin receptor [[RXFP1]] activates several enzymes in a [[phosphorylation cascade]] that eventually results in the activation of NO synthase in endothelial cells and the subsequent production of NO. Relaxin can also bind to a secondary receptor, endothelial B receptor, which is upregulated as a result of the previous pathway.  Relaxin binding to endothelial B receptor on endothelial cells also induces vasodilation.
-In addition to vasodilation, the effects of relaxin are also seen in the kidneys, by significantly increasing [[creatinine]] clearance,<ref name="Ponikowski" /> which is a measure of kidney function, as well as increased renal blood flow.<ref name="Teichman1" />
-Relaxin also functions as a cardiac stimulant.<ref name="Bathgate" />  Studies have demonstrated that relaxin increases calcium sensitivity of cardiac [[myofilament]]s as well as increasing phosphorylation of the myofilaments by [[protein kinase C]] (PKC).<ref name="Shaw" />  These modifications both function to increase the force generated by the myofilaments without increasing the energy consumption of the cardiac myocytes.<ref name="Shaw" />  Thus relaxin and serelaxin can increase [[stroke volume]], the amount of blood pumped per heart beat, without increasing the energy demand on the already strained heart of acute heart failure patients.
+Relaxin causes vasodilation by an indirect mechanism, where it inhibits the potent vasoconstrictors angiotensin II and endothelin.
+In addition to vasodilation, the effects of relaxin are also seen in the kidneys, by significantly increasing [[creatinine]] clearance, which is a measure of kidney function, as well as increased renal blood flow.
+Relaxin also functions as a cardiac stimulant. Studies have demonstrated that relaxin increases calcium sensitivity of cardiac [[myofilament]]s as well as increasing phosphorylation of the myofilaments by [[protein kinase C]] (PKC).  These modifications both function to increase the force generated by the myofilaments without increasing the energy consumption of the cardiac myocytes. Thus relaxin and serelaxin can increase [[stroke volume]], the amount of blood pumped per heart beat, without increasing the energy demand on the already strained heart of acute heart failure patients.
 ==Acute heart failure==
-Serelaxin is currently undergoing clinical trials in patients with acute heart failure,<ref name="Teerlink" /> and is being developed by [[Novartis]].  Serelaxin has completed several clinical trials as a therapy for AHF.  Phase I trials examined safety and tolerability,<ref name="Du" /> while phase II trials evaluated its haemodynamic effects and symptom relief.  The Pre-RELAX-AHF phase II trial administered a dose of 30&nbsp;µg/kg/day and showed a decrease in blood pressure, improved [[dyspnoea]], and increased renal blood flow.<ref name="Teichman1" />  In phase III the RELAX-AHF trial gave a 48hr intravenous infusion of the same dose.<ref name="King" />  It significantly improved patients' dyspnoea, resulted in a 30% reduction in worsening of heart failure symptoms, a decreased hospital stay and a reduction in signs and symptoms of congestion.<ref name="Teerlink" /><ref name="Filippatos" />  The FDA has granted serelaxin "breakthrough therapy" designation, meant to expedite the development and review of drugs for life threatening conditions and is set to be reviewed in February 2014.<ref name="Novartis" />
+Serelaxin is currently undergoing clinical trials in patients with acute heart failure, and is being developed by Novartis.  Serelaxin has completed several clinical trials as a therapy for AHF.  Phase I trials examined safety and tolerability, while phase II trials evaluated its haemodynamic effects and symptom relief.  The Pre-RELAX-AHF phase II trial administered a dose of 30&nbsp;µg/kg/day and showed a decrease in blood pressure, improved [[dyspnoea]], and increased renal blood flow.  In phase III the RELAX-AHF trial gave a 48hr intravenous infusion of the same dose.  It significantly improved patients' dyspnoea, resulted in a 30% reduction in worsening of heart failure symptoms, a decreased hospital stay and a reduction in signs and symptoms of congestion. The FDA has granted serelaxin "breakthrough therapy" designation, meant to expedite the development and review of drugs for life threatening conditions and is set to be reviewed in February 2014.
 == References ==
-{{reflist|35em|refs=
+{{reflist|2}}
-<ref name="Teerlink">{{cite journal|last=Teerlink|first=John R|coauthors=Cotter, Gad; Davison, Beth A; Felker, G Michael; Filippatos, Gerasimos; Greenberg, Barry H; Ponikowski, Piotr; Unemori, Elaine; Voors, Adriaan A; Adams, Kirkwood F; Dorobantu, Maria I; Grinfeld, Liliana R; Jondeau, Guillaume; Marmor, Alon; Masip, Josep; Pang, Peter S; Werdan, Karl; Teichman, Sam L; Trapani, Angelo; Bush, Christopher A; Saini, Rajnish; Schumacher, Christoph; Severin, Thomas M; Metra, Marco|title=Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial|journal=The Lancet|date=1 November 2012|doi=10.1016/S0140-6736(12)61855-8|url=http://www.sciencedirect.com/science/article/pii/S0140673612618558}}</ref>
-<ref name="Spreitzer">{{cite journal| author = H. Spreitzer| date = 4 March 2013| title = Neue Wirkstoffe – Serelaxin| journal = Österreichische Apothekerzeitung| issue = 5/2013| page = 36| language = German}}</ref>
-<ref name=Tousoulis>{{cite journal|last=Tousoulis|first=D|coauthors=Kampoli, A., Papageorgiou, C., Stefanadis, C.|title=The role of nitric oxide on endothelial function|journal=Curr Vasc Pharmacol|year=2012|volume=10|pages=4–18}}</ref>
-<ref name="aerztezeitung">{{cite web|url=http://www.aerztezeitung.de/medizin/krankheiten/herzkreislauf/herzinsuffizienz/article/826906/fortschritt-sicht-schwangerschaftshormon-herzschwaeche.html?sh=1&h=-655181939|journal=ÄrzteZeitung|date=23 November 2012|title=Schwangerschaftshormon gegen Herzschwäche|trans_title=Pregnancy hormone against heart failure|author=Dirk Einecke}}</ref>
-<ref name="pmid21613576">{{cite journal | author = Conrad KP | title = Maternal vasodilation in pregnancy: the emerging role of relaxin | journal = Am. J. Physiol. Regul. Integr. Comp. Physiol. | volume = 301 | issue = 2 | pages = R267–75 |date=August 2011 | pmid = 21613576 | pmc = 3154715 | doi = 10.1152/ajpregu.00156.2011 }}</ref>
-<ref name="Bathgate">{{cite journal|last=Bathgate|first=R.|coauthors=Halls, M., van der Westhuizen, E., Callander, G., Kocan, M. et al|title=The Relaxin family peptides and their receptors|journal=Physiol Rev|year=2013|volume=93|pages=405–480}}</ref>
-<ref name="Miyares">{{cite journal|last=Miyares|first=M|coauthors=Davis, K.|title=Serelaxin, a breakthrough investigational intravenous agent for acute heart failure|journal=P.T|year=2013|volume=38|pages=606–611}}</ref>
-<ref name="Teichman1">{{cite journal|last=Teichman|first=S|coauthors=Unemori, E., Teerlink, J., Cotter, G., Metra, M.|title=Relaxin, review of biology and potential role in treating heart failure|journal=Curr Heart Fail Rep|year=2010|volume=75|pages=75–82}}</ref>
-<ref name="Teichman2">{{cite journal|last=Teichman|first=S|coauthors=Unemori, E., Dschietzig, T., Conrad, K., Voors, A. et al|title=Relaxin, a pleiotropic vasodilator for the treatment of heart failure|journal=Heart Fail Rev|year=2009|volume=14|pages=321–329}}</ref>
-<ref name="Ponikowski">{{cite journal|last=Ponikowski|first=P.|coauthors=Mitroic, V., Rude, M., Fernandez, A., Voors, A. et al|title=A randomized, double-blind, placebo controlled, multicentre study to assess haemodynamic effects of serelaxin in patients with acute heart failure|journal=Eur Heart J|year=2014|volume=35|pages=431–441}}</ref>
-<ref name="Shaw">{{cite journal|last=Shaw|first=E.|coauthors=Wood, P., Kulpa, J., Yang, F., Summerlee, A. et al|title=Relaxin alters cardiac myofilament function through a PKC-dependent pathway|journal=Am J Physiol Heart Circ Physiol|year=2009|volume=297|pages=29–36}}</ref>
-<ref name="Du">{{cite journal|last=Du|first=X.|coauthors=Hewitson, T., Nguyen, M., Samuel, C.|title=Therapeutic effects of Serelaxin in acute heart failure|journal=Circ J|year=2014|volume=12|pages=6–19}}</ref>
-<ref name="King">{{cite journal|last=King|first=A|title=Heart failure-promising data for Serelaxin|journal=Nat Rev Cardiol|year=2013|volume=10|page=3}}</ref>
-<ref name="Filippatos">{{cite journal|last=Filippatos|first=G.|coauthors=Teerlink, J., Farmakis, D., Cotter, G., Davison, B. et al|title=Serelaxin in acute heart failure patients with preserved left ventricular ejection fraction: results from the RELAX-AHF trial|journal=Eur Heart|year=2014|volume=89|pages=90–103}}</ref>
-<ref name="Novartis">{{cite web|last=Novartis Global|title=FDA grants breakthrough designation to Novartis' serelaxin (RLX030) for acute heart failure|url=http://www.novartis.com/newsroom/media-releases/en/2013/1711047.shtml|publisher=Novartis Global}}</ref>
-}}
 {{Vasodilators used in cardiac diseases}}

v t e Vasodilators used in cardiac diseases (C01D)
Nitrates	Glyceryl trinitrate • Isosorbide dinitrate • Isosorbide mononitrate • Molsidomine • Pentaerythritol tetranitrate
Quinolone vasodilators	Flosequinan
Others	Itramin tosilate • Prenylamine • Oxyfedrine • Benziodarone • Carbocromen • Hexobendine • Etafenone • Heptaminol • Imolamine • Dilazep • Trapidil • Molsidomine • Efloxate • Cinepazet • Cloridarol • Nicorandil • Linsidomine • Nesiritide • Gapicomine

Clinical data
Pregnancy category	N/A
Routes of administration	Intravenous
ATC code	C01DX21 (WHO)
Legal status
Legal status	Investigational
Identifiers
IUPAC name L-Serine, L-α-aspartyl-L-seryl-L-tryptophyl-L-methionyl-L-α-glutamyl-L-α-glutamyl-L-valylL-isoleucyl-L-lysyl-L-leucyl-L-cysteinylglycyl-L-arginyl-L-α-glutamyl-L-leucyl-L-valyl-L- arginyl-L-alanyl-L-glutaminyl-L-isoleucyl-L-alanyl-L-isoleucyl-L-cysteinylglycyl-L- methionyl-L-seryl-L-threonyl-L-tryptophyl-, cyclic (11→11'),(23→24')-bis(disulfide) with 5-oxo-L-prolyl-L-leucyl-L-tyrosyl-L-seryl-L-alanyl-L-leucyl-L-alanyl-L-asparaginyl-L-lysyl-L- cysteinyl-L-cysteinyl-L-histidyl-L-valylglycyl-L-cysteinyl-L-threonyl-L-lysyl-L-arginyl-L- seryl-L-leucyl-L-alanyl-L-arginyl-L-phenylalanyl-L-cysteine cyclic (10'→15')-disulfide
CAS Number	99489-94-8
ChemSpider	NA^Y
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
Formula	C₂₅₆H₄₀₈N₇₄O₇₄S₈
Molar mass	5963 g/mol

Serelaxin: Difference between revisions

Revision as of 14:23, 23 July 2014

Overview

Acute heart failure

References

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