Targeting adrenomedullin in sepsis

Contains fulltext : 201197.pdf (publisher's version ) (Open Access)Radboud University, 15 maart 2019Promotor : Pickkers, P. Co-promotor : Kox, M

The mechanism of action of the adrenomedullin-binding antibody adrecizumab

Contains fulltext : 196331.pdf (publisher's version ) (Open Access

Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis

Contains fulltext : 196399.pdf (publisher's version ) (Open Access)Sepsis remains a major medical challenge, for which, apart from improvements in supportive care, treatment has not relevantly changed over the last few decades. Vasodilation and vascular leakage play a pivotal role in the development of septic shock, with vascular leakage being caused by disrupted endothelial integrity. Adrenomedullin (ADM), a free circulating peptide involved in regulation of endothelial barrier function and vascular tone, is implicated in the pathophysiology of sepsis. ADM levels are increased during sepsis, and correlate with extent of vasodilation, as well as with disease severity and mortality. In vitro and preclinical in vivo data show that administration of ADM exerts anti-inflammatory, antimicrobial, and protective effects on endothelial barrier function during sepsis, but other work suggests that it may also decrease blood pressure, which could be detrimental for patients with septic shock. Work has been carried out to negate ADMs putative negative effects, while preserving or even potentiating its beneficial actions. Preclinical studies have demonstrated that the use of antibodies that bind to the N-terminus of ADM results in an overall increase of circulating ADM levels and improves sepsis outcome. Similar beneficial effects were obtained using coadministration of ADM and ADM-binding protein-1. It is hypothesized that the mechanism behind the beneficial effects of ADM binding involves prolongation of its half-life and a shift of ADM from the interstitium to the circulation. This in turn results in increased ADM activity in the blood compartment, where it exerts beneficial endothelial barrier-stabilizing effects, whereas its detrimental vasodilatory effects in the interstitium are reduced. Up till now, in vivo data on ADM-targeted treatments in humans are lacking; however, the first study in septic patients with an N-terminus antibody (Adrecizumab) is currently being conducted

Vascular Effects of Adrenomedullin and the Anti-Adrenomedullin Antibody Adrecizumab in Sepsis

Sepsis remains a major scientific and medical challenge, for which, apart from significant refinements in supportive therapy, treatment has barely changed over the last few decades. During sepsis, both vascular tone and vascular integrity are compromised, and contribute to the development of shock. The free circulating peptide adrenomedullin (ADM) is involved in the regulation of the endothelial barrier function and tone of blood vessels. Several animal studies have shown that ADM administration improves outcome of sepsis. However, in higher dosages, ADM administration may cause hypotension, limiting its clinical applicability. Moreover, ADM has a very short half-life and easily adheres to surfaces, further hampering its clinical use. The non-neutralizing anti-ADM antibody Adrecizumab (HAM8101) which causes a long-lasting increase of plasma ADM has shown promising results in animal models of systemic inflammation and sepsis; it reduced inflammation, attenuated vascular leakage, and improved hemodynamics, kidney function, and survival. Combined with an excellent safety profile derived from animal and phase I human studies, Adrecizumab represents a promising candidate drug for the adjunctive treatment of sepsis. In this review, we first provide a brief overview of the currently available data on the role of adrenomedullin in sepsis and describe its effects on endothelial barrier function and vasodilation. Furthermore, we provide a novel hypothesis concerning the mechanisms of action through which Adrecizumab may exert its beneficial effects in sepsis

Experimental human endotoxemia as a model of systemic inflammation

Systemic inflammation plays a pivotal role in a multitude of conditions, including sepsis, trauma, major surgery and burns. However, comprehensive analysis of the pathophysiology underlying this systemic inflammatory response is greatly complicated by variations in the immune response observed in critically ill patients, which is a result of inter-individual differences in comorbidity, comedication, source of infection, causative pathogen, and onset of the inflammatory response. During experimental human endotoxemia, human subjects are challenged with purified endotoxin (lipopolysaccharide) intravenously which induces a short-lived, well-tolerated and controlled systemic inflammatory response, similar to that observed during sepsis. The human endotoxemia model can be conducted in a highly standardized and reproducible manner, using a carefully selected homogenous study population. As such, the experimental human endotoxemia model does not share the aforementioned clinical limitations and enables us to investigate both the mechanisms of systemic inflammation, as well as to evaluate novel (pharmacological) interventions in humans in vivo. The present review provides a detailed overview of the various designs, organ-specific changes, and strengths and limitations of the experimental human endotoxemia model, with the main focus on its use as a translational model for sepsis research

Letter to the Editor: Vitamin D deficiency in COVID-19: Mixing up cause and consequence

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Effects of the humanized anti-adrenomedullin antibody adrecizumab (HAM8101) on vascular barrier function and survival in rodent models of systemic inflammation and sepsis

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Bioactive Adrenomedullin, Organ Support Therapies, and Survival in the Critically Ill: Results from the French and European Outcome Registry in ICU Study

Contains fulltext : 214081.pdf (Publisher’s version ) (Closed access

Preclinical safety evaluation of the adrenomedullin-binding antibody Adrecizumab in rodents, dogs and non-human primates

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