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Adrecizumab, a non-neutralizing anti-adrenomedullin antibody, improves haemodynamics and attenuates myocardial oxidative stress in septic rats

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,...

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Autores principales: Blet, Alice, Deniau, Benjamin, Geven, Christopher, Sadoune, Malha, Caillard, Anaïs, Kounde, Paul-Robert, Polidano, Evelyne, Pickkers, Peter, Samuel, Jane-Lise, Mebazaa, Alexandre
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520420/
https://www.ncbi.nlm.nih.gov/pubmed/31093784
http://dx.doi.org/10.1186/s40635-019-0255-0
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author Blet, Alice
Deniau, Benjamin
Geven, Christopher
Sadoune, Malha
Caillard, Anaïs
Kounde, Paul-Robert
Polidano, Evelyne
Pickkers, Peter
Samuel, Jane-Lise
Mebazaa, Alexandre
author_facet Blet, Alice
Deniau, Benjamin
Geven, Christopher
Sadoune, Malha
Caillard, Anaïs
Kounde, Paul-Robert
Polidano, Evelyne
Pickkers, Peter
Samuel, Jane-Lise
Mebazaa, Alexandre
author_sort Blet, Alice
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40635-019-0255-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-65204202019-06-05 Adrecizumab, a non-neutralizing anti-adrenomedullin antibody, improves haemodynamics and attenuates myocardial oxidative stress in septic rats Blet, Alice Deniau, Benjamin Geven, Christopher Sadoune, Malha Caillard, Anaïs Kounde, Paul-Robert Polidano, Evelyne Pickkers, Peter Samuel, Jane-Lise Mebazaa, Alexandre Intensive Care Med Exp Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40635-019-0255-0) contains supplementary material, which is available to authorized users. Springer International Publishing 2019-05-15 /pmc/articles/PMC6520420/ /pubmed/31093784 http://dx.doi.org/10.1186/s40635-019-0255-0 Text en © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Research
Blet, Alice
Deniau, Benjamin
Geven, Christopher
Sadoune, Malha
Caillard, Anaïs
Kounde, Paul-Robert
Polidano, Evelyne
Pickkers, Peter
Samuel, Jane-Lise
Mebazaa, Alexandre
Adrecizumab, a non-neutralizing anti-adrenomedullin antibody, improves haemodynamics and attenuates myocardial oxidative stress in septic rats
title 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_short 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
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520420/
https://www.ncbi.nlm.nih.gov/pubmed/31093784
http://dx.doi.org/10.1186/s40635-019-0255-0
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