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Serelaxin

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Serelaxin
Clinical data
Trade namesReasanz
Pregnancy
category
  • N/A
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
  • Investigational
Identifiers
  • 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
ChemSpider
  • none
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC256H408N74O74S8
Molar mass5963.00 g·mol−1

Serelaxin (brand name Reasanz; developmental code name RLX-030) is a medication which is marketed in Russia for the treatment of acute heart failure (AHF), targeting the relaxin receptor.[1] It was also under development in other places in the world, including in the United States, Europe, and Asia, but ultimately was not marketed in these areas.[1]

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,[2][3] such as increased blood output of the heart and blood flow in the kidney.[4] Human-relaxin-2 mediates vasodilation (widening of blood vessels) by increasing the production of nitric oxide (NO), a potent vasodilator.[5] 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.[6] Relaxin can also bind to a secondary receptor, endothelial B receptor,[clarification needed] which is upregulated as a result of the previous pathway.[7] Relaxin binding to endothelial B receptor on endothelial cells also induces vasodilation.[8]

Relaxin causes vasodilation by an indirect mechanism, where it inhibits the potent vasoconstrictors angiotensin II and endothelin.[9] In addition to vasodilation, the effects of relaxin are also seen in the kidneys, by significantly increasing creatinine clearance,[10] which is a measure of kidney function, as well as increased renal blood flow.[8] Relaxin also functions as a cardiac stimulant.[6] Studies have demonstrated that relaxin increases calcium sensitivity of cardiac myofilaments as well as increasing phosphorylation of the myofilaments by protein kinase C (PKC).[11] These modifications both function to increase the force generated by the myofilaments without increasing the energy consumption of the cardiac myocytes.[11] 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 has undergone clinical trials in patients with acute heart failure,[12] conducted by Novartis. Serelaxin has completed several clinical trials as a therapy for AHF. Phase I trials examined safety and tolerability,[13] 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.[8] In phase III the RELAX-AHF trial gave a 48hr intravenous infusion of the same dose.[14] 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.[12][15] The FDA granted serelaxin "breakthrough therapy" designation, meant to expedite the development and review of drugs for life-threatening conditions.[16] On 22 March 2017, Novartis announced that the global Phase III study of serelaxin in patients with acute heart failure did not meet its primary endpoints.[17]

References

  1. ^ a b "Serelaxin - Novartis". Adis Insight. Springer Nature Switzerland AG.
  2. ^ Spreitzer H (4 March 2013). "Neue Wirkstoffe – Serelaxin". Österreichische Apothekerzeitung (in German) (5/2013): 36.
  3. ^ Einecke D (23 November 2012). "Schwangerschaftshormon gegen Herzschwäche" [Pregnancy hormone against heart failure]. Ärzte-Zeitung (in German).
  4. ^ Conrad KP (August 2011). "Maternal vasodilation in pregnancy: the emerging role of relaxin". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 301 (2): R267-75. doi:10.1152/ajpregu.00156.2011. PMC 3154715. PMID 21613576.
  5. ^ Tousoulis D, Kampoli AM, Tentolouris C, Papageorgiou N, Stefanadis C (January 2012). "The role of nitric oxide on endothelial function". Current Vascular Pharmacology. 10 (1): 4–18. doi:10.2174/157016112798829760. PMID 22112350.
  6. ^ a b Bathgate RA, Halls ML, van der Westhuizen ET, Callander GE, Kocan M, Summers RJ (January 2013). "Relaxin family peptides and their receptors". Physiological Reviews. 93 (1): 405–80. doi:10.1152/physrev.00001.2012. PMID 23303914.
  7. ^ Miyares MA, Davis KA (October 2013). "Serelaxin, a 'breakthrough' investigational intravenous agent for acute heart failure". P & T. 38 (10): 606–11. PMC 3875246. PMID 24391379.
  8. ^ a b c Teichman SL, Unemori E, Teerlink JR, Cotter G, Metra M (June 2010). "Relaxin: review of biology and potential role in treating heart failure". Current Heart Failure Reports. 7 (2): 75–82. doi:10.1007/s11897-010-0010-z. PMC 2875472. PMID 20424993.
  9. ^ Teichman SL, Unemori E, Dschietzig T, Conrad K, Voors AA, Teerlink JR, et al. (December 2009). "Relaxin, a pleiotropic vasodilator for the treatment of heart failure". Heart Failure Reviews. 14 (4): 321–9. doi:10.1007/s10741-008-9129-3. PMC 2772950. PMID 19101795.
  10. ^ Ponikowski P, Mitrovic V, Ruda M, Fernandez A, Voors AA, Vishnevsky A, et al. (February 2014). "A randomized, double-blind, placebo-controlled, multicentre study to assess haemodynamic effects of serelaxin in patients with acute heart failure". European Heart Journal. 35 (7): 431–41. doi:10.1093/eurheartj/eht459. PMC 3924183. PMID 24255129.
  11. ^ a b Shaw EE, Wood P, Kulpa J, Yang FH, Summerlee AJ, Pyle WG (July 2009). "Relaxin alters cardiac myofilament function through a PKC-dependent pathway". American Journal of Physiology. Heart and Circulatory Physiology. 297 (1): H29-36. doi:10.1152/ajpheart.00482.2008. PMID 19429819.
  12. ^ Du XJ, Hewitson TD, Nguyen MN, Samuel CS (2014). "Therapeutic effects of serelaxin in acute heart failure". Circulation Journal. 78 (3): 542–52. doi:10.1253/circj.cj-14-0014. PMID 24451687.
  13. ^ King A (January 2013). "Heart failure. Promising data for serelaxin". Nature Reviews. Cardiology. 10 (1): 3. doi:10.1038/nrcardio.2012.174. PMID 23165078. S2CID 2399731.
  14. ^ Filippatos G, Teerlink JR, Farmakis D, Cotter G, Davison BA, Felker GM, et al. (April 2014). "Serelaxin in acute heart failure patients with preserved left ventricular ejection fraction: results from the RELAX-AHF trial". European Heart Journal. 35 (16): 1041–50. doi:10.1093/eurheartj/eht497. PMC 3992428. PMID 24316514.
  15. ^ "FDA grants breakthrough designation to Novartis' serelaxin (RLX030) for acute heart failure". Novartis Global. Archived from the original on 2 March 2014.
  16. ^ "Novartis provides update on Phase III study of RLX030 (serelaxin) in patients with acute heart failure". Global Novartis News Archive. Archived from the original on 10 July 2018.

Template:Protein and peptide receptor modulators

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