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Adrecizumab, a non-neutralizing anti-adrenomedullin antibody, improves haemodynamics and attenuates myocardial oxidative stress in septic rats
Intensive Care Medicine Experimental Pub Date : 2019-05-15 , DOI: 10.1186/s40635-019-0255-0
Alice Blet 1, 2 , Benjamin Deniau 1, 2, 3 , Christopher Geven 4 , Malha Sadoune 2 , Anaïs Caillard 1, 2, 3 , Paul-Robert Kounde 1, 2, 3 , Evelyne Polidano 2 , Peter Pickkers 4 , Jane-Lise Samuel 2 , Alexandre Mebazaa 1, 2, 3
Affiliation  

BackgroundSepsis 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.MethodsFor 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.ResultsA 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).ConclusionsIn 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.

中文翻译:

Adrecizumab 是一种非中和性抗肾上腺髓质素抗体,可改善脓毒症大鼠的血流动力学并减轻心肌氧化应激

背景脓毒症仍然是一个主要的健康问题,具有持续的高发病率和死亡率。在败血症期间经常发生心血管功能障碍。肾上腺髓质素已被确定为血管张力调节的关键介质。非中和抗肾上腺髓质素抗体 Adrecizumab 可改善小鼠模型中盲肠结扎和穿刺引起的感染性休克期间的血流动力学功能障碍。我们的目的是确定 Adrecizumab 在败血症大鼠模型中对血流动力学的作用。方法为了诱导败血症,在 Wistar 雄性大鼠中进行盲肠结扎和穿刺。手术后 24 小时静脉注射单盲 Adrecizumab (2 mg/kg) 或安慰剂,并输注去甲肾上腺素作为护理标准。每组有> 7只动物。在 Adrecizumab 注射后 3 小时评估侵入性血压和心脏功能(通过超声心动图)。 结果在脓毒症大鼠中单次治疗性注射 Adrecizumab 可迅速改善血液动力学,脓毒症 Adrecizumab 大鼠与未治疗的脓毒症大鼠相比收缩压升高。 p = 0.049)。未治疗的脓毒症组和脓毒症-Adrecizumab 组之间的缩短分数没有差异。然而,与未治疗的败血症大鼠相比,单剂量 Adrecizumab 后 3 小时内心输出量增加(p = 0.006)。单剂量的 Adrecizumab 导致与连续给药去甲肾上腺素相似的血流动力学。单次注射 Adrecizumab 3 小时后,脓毒症大鼠心脏的炎症表型(TNFα,IL-10)没有变化。相比之下,单次 Adrecizumab 注射后 3 小时,与未治疗的败血症大鼠相比,败血症-Adrecizumab 的心脏中自由基的产生减少(p < 0.05)。结论在败血症大鼠模型中,单次治疗性注射 Adrecizumab 迅速恢复血流动力学参数并减弱心肌氧化应激。目前,正在对感染性休克和循环生物肾上腺髓质素浓度升高的患者进行概念验证和剂量探索 II 期试验 (Adrenoss-2)。
更新日期:2019-05-15
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