Adrecizumab, a non-neutralizing anti-adrenomedullin antibody, improves haemodynamics and attenuates myocardial oxidative stress in septic rats
Abstract Background Sepsis still represents a major health issue, with persistent high morbidity and mortality rates. Cardiovascular dysfunction occurs frequently during sepsis. Adrenomedullin has been identified as a key mediator in vascular tone regulation. A non-neutralizing anti-adrenomedullin a...
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doaj-f989ddc660074b0c9d38b3fea6b109442020-11-25T03:16:21ZengSpringerOpenIntensive Care Medicine Experimental2197-425X2019-05-017111310.1186/s40635-019-0255-0Adrecizumab, a non-neutralizing anti-adrenomedullin antibody, improves haemodynamics and attenuates myocardial oxidative stress in septic ratsAlice Blet0Benjamin Deniau1Christopher Geven2Malha Sadoune3Anaïs Caillard4Paul-Robert Kounde5Evelyne Polidano6Peter Pickkers7Jane-Lise Samuel8Alexandre Mebazaa9Department of Anesthesia, Burn and Critical Care, University Hospitals Saint-Louis – Lariboisière, AP-HPDepartment of Anesthesia, Burn and Critical Care, University Hospitals Saint-Louis – Lariboisière, AP-HPDepartment of Intensive Care Medicine, Radboud Center for Infectious Diseases (RCI), Radboud University Medical centerUMR-S 942, InsermDepartment of Anesthesia, Burn and Critical Care, University Hospitals Saint-Louis – Lariboisière, AP-HPDepartment of Anesthesia, Burn and Critical Care, University Hospitals Saint-Louis – Lariboisière, AP-HPUMR-S 942, InsermDepartment of Intensive Care Medicine, Radboud Center for Infectious Diseases (RCI), Radboud University Medical centerUMR-S 942, InsermDepartment of Anesthesia, Burn and Critical Care, University Hospitals Saint-Louis – Lariboisière, AP-HPAbstract Background Sepsis still represents a major health issue, with persistent high morbidity and mortality rates. Cardiovascular dysfunction occurs frequently during sepsis. Adrenomedullin has been identified as a key mediator in vascular tone regulation. A non-neutralizing anti-adrenomedullin antibody, Adrecizumab, may improve haemodynamic dysfunction during caecal ligation and puncture-induced septic shock in a murine model. Our objective was to determine the role of Adrecizumab on haemodynamics in a rat model of sepsis. Methods For the induction of sepsis, caecal ligation and puncture were performed in Wistar male rats. Single blinded administration of Adrecizumab (2 mg/kg) or placebo was injected i.v. 24 h after the surgery, and norepinephrine was infused as the standard of care. There were > 7 animals per group. Invasive blood pressure and cardiac function (by echocardiography) were assessed until 3 h after Adrecizumab injection. Results A single therapeutic injection of Adrecizumab in septic rats induced rapid haemodynamic benefits with an increase in systolic blood pressure in septic-Adrecizumab rats versus untreated-septic rats (p = 0.049). The shortening fraction did not differ between the untreated-septic and septic-Adrecizumab groups. However, cardiac output increased during the 3 h after a single dose of Adrecizumab compared to untreated septic rats (p = 0.006). A single dose of Adrecizumab resulted in similar haemodynamics to the continuous administration of norepinephrine. Three hours after a single injection of Adrecizumab, there was no change in the inflammatory phenotype (TNFα, IL-10) in the hearts of the septic rats. By contrast, 3 h after a single Adrecizumab injection, free-radical production decreased in the hearts of septic-Adrecizumab vs untreated septic rats (p < 0.05). Conclusions In a rat model of sepsis, a single therapeutic injection of Adrecizumab rapidly restored haemodynamic parameters and blunted myocardial oxidative stress. Currently, a proof-of-concept and dose-finding phase II trial (Adrenoss-2) is ongoing in patients with septic shock and elevated concentrations of circulating bio-adrenomedullin.http://link.springer.com/article/10.1186/s40635-019-0255-0 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alice Blet Benjamin Deniau Christopher Geven Malha Sadoune Anaïs Caillard Paul-Robert Kounde Evelyne Polidano Peter Pickkers Jane-Lise Samuel Alexandre Mebazaa |
spellingShingle |
Alice Blet Benjamin Deniau Christopher Geven Malha Sadoune Anaïs Caillard Paul-Robert Kounde Evelyne Polidano Peter Pickkers Jane-Lise Samuel Alexandre Mebazaa Adrecizumab, a non-neutralizing anti-adrenomedullin antibody, improves haemodynamics and attenuates myocardial oxidative stress in septic rats Intensive Care Medicine Experimental |
author_facet |
Alice Blet Benjamin Deniau Christopher Geven Malha Sadoune Anaïs Caillard Paul-Robert Kounde Evelyne Polidano Peter Pickkers Jane-Lise Samuel Alexandre Mebazaa |
author_sort |
Alice Blet |
title |
Adrecizumab, a non-neutralizing anti-adrenomedullin antibody, improves haemodynamics and attenuates myocardial oxidative stress in septic rats |
title_short |
Adrecizumab, a non-neutralizing anti-adrenomedullin antibody, improves haemodynamics and attenuates myocardial oxidative stress in septic rats |
title_full |
Adrecizumab, a non-neutralizing anti-adrenomedullin antibody, improves haemodynamics and attenuates myocardial oxidative stress in septic rats |
title_fullStr |
Adrecizumab, a non-neutralizing anti-adrenomedullin antibody, improves haemodynamics and attenuates myocardial oxidative stress in septic rats |
title_full_unstemmed |
Adrecizumab, a non-neutralizing anti-adrenomedullin antibody, improves haemodynamics and attenuates myocardial oxidative stress in septic rats |
title_sort |
adrecizumab, a non-neutralizing anti-adrenomedullin antibody, improves haemodynamics and attenuates myocardial oxidative stress in septic rats |
publisher |
SpringerOpen |
series |
Intensive Care Medicine Experimental |
issn |
2197-425X |
publishDate |
2019-05-01 |
description |
Abstract Background Sepsis still represents a major health issue, with persistent high morbidity and mortality rates. Cardiovascular dysfunction occurs frequently during sepsis. Adrenomedullin has been identified as a key mediator in vascular tone regulation. A non-neutralizing anti-adrenomedullin antibody, Adrecizumab, may improve haemodynamic dysfunction during caecal ligation and puncture-induced septic shock in a murine model. Our objective was to determine the role of Adrecizumab on haemodynamics in a rat model of sepsis. Methods For the induction of sepsis, caecal ligation and puncture were performed in Wistar male rats. Single blinded administration of Adrecizumab (2 mg/kg) or placebo was injected i.v. 24 h after the surgery, and norepinephrine was infused as the standard of care. There were > 7 animals per group. Invasive blood pressure and cardiac function (by echocardiography) were assessed until 3 h after Adrecizumab injection. Results A single therapeutic injection of Adrecizumab in septic rats induced rapid haemodynamic benefits with an increase in systolic blood pressure in septic-Adrecizumab rats versus untreated-septic rats (p = 0.049). The shortening fraction did not differ between the untreated-septic and septic-Adrecizumab groups. However, cardiac output increased during the 3 h after a single dose of Adrecizumab compared to untreated septic rats (p = 0.006). A single dose of Adrecizumab resulted in similar haemodynamics to the continuous administration of norepinephrine. Three hours after a single injection of Adrecizumab, there was no change in the inflammatory phenotype (TNFα, IL-10) in the hearts of the septic rats. By contrast, 3 h after a single Adrecizumab injection, free-radical production decreased in the hearts of septic-Adrecizumab vs untreated septic rats (p < 0.05). Conclusions In a rat model of sepsis, a single therapeutic injection of Adrecizumab rapidly restored haemodynamic parameters and blunted myocardial oxidative stress. Currently, a proof-of-concept and dose-finding phase II trial (Adrenoss-2) is ongoing in patients with septic shock and elevated concentrations of circulating bio-adrenomedullin. |
url |
http://link.springer.com/article/10.1186/s40635-019-0255-0 |
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