Completed studies

Safety en tolerability of Adrecizumab (2018)

Aim and methods: To investigate the safety, tolerability, pharmacodynamics and pharmacokinetics of the adrenomedullin-binding antibody Adrecizumab during experimental human endotoxemia in a randomized, double-blind, placebo-controlled manner in 24 healthy human volunteers.

Conclusion: Administration of Adrecizumab was safe and well tolerated in the presence of systemic inflammation. These findings pave the way for further investigation of Adrecizumab in sepsis patients.

Link: https://www.ncbi.nlm.nih.gov/pubmed/29856470

Aspirin and systemic inflammation (2018)

Aim and methods: To investigate immunostimulatory effects of acetylsalicylic acid (aspirin) during systemic inflammation and endotoxin tolerance. Healthy volunteers were randomized to receive either 80mg acetylsalicylic acid or placebo and subsequently challenged with endotoxin twice, at a 1-week interval.

Conclusion: Treatment with low-dose acetylsalicylicacid partially reverses endotoxin tolerance in humans in vivo by shifting response toward a proinflammatory phenotype.

Link: https://journals.lww.com/ccmjournal/Abstract/onlinefirst/Treatment_With_Acetylsalicylic_Acid_Reverses.96065.aspx

Hypoxia and the cytokine response (2018)

Aim and methods: In vitro and animal studies have shown different, opposing effects of hypoxia on the innate immune response. Meanwhile, there is a trend towards  more conservative oxygen strategies in patients in the Emergency Department and Intensive Care Unit with acute inflammatory diseases such as sepsis. We studied the effect of short term hypoxia (SpO2 80-85% for 3.5 hours) on the cytokine response after endotoxin administration in healthy subjects.

Conclusion: Short term hypoxia results in a strong, early augmentation of the anti-inflammatory interleukin-10 and a subsequent attenuation of pro-inflammatory cytokines.

Link: https://www.ebiomedicine.com/article/S2352-3964(18)30228-7/abstract

Ticagrelor, clopidogrel and immunomodulation (2017)

Aim and methods: In post-hoc analysis from randomized controlled trials, sepsis-related mortality appears to be lower in post-myocardial infarction patients treated with ticagrelor when compared to those treated with clopidogrel.  We investigated whether ticagrelor, when compared to clopidogrel, both in combination with acetylsalicylic acid, has immunomodulating effects that may explain these differences. Healthy volunteers were treated with placebo, monotherapy acetylsalicylic acid, ticagrelor-acetylsalicylic acid or clopidogrel-acetylsalicylic acid. At day 7 a cytokine response was induced by endotoxin administraton.
Conclusion: Monotherapy acetylsalicylic acid augmented the pro-inflammatory cytokine response compared to placebo. There was no relevant effect on the cytokine response of neither ticagrelor nor clopidogrel.

Link: https://www.thieme-connect.com/products/ejournals/abstract/10.1160/TH16-10-0799

Vasopressors and the innate immune response (2016)

Aim and methods: To ascertain the effects of vasopressors on the innate immune response in vivo, 40 healthy male volunteers were randomized to receive a 5-hour infusion of either noradrenaline (0.05µg/kg/min), phenylephrine (0.5µg/kg/min), vasopressin (0.04 IU/min) or placebo (NaCl 0.9%) in a double blinded manner. 1 hour after the start of the vasopressor infusion they were given an LPS bolus (2ng/kg) to elicit a systemic inflammatory response.

Conclusion: Both noradrenaline and phenylephrine induced significantly higher circulating levels of the anti-inflammatory cytokine IL-10, and significantly lower levels of pro-inflammatory chemokines MIP-1β and CXCL-10, compared to placebo. Vasopressin did not significantly influence the cytokine levels in this trial, compared to placebo. Noradrenaline and phenylephrine shift the balance towards an anti-inflammatory phenotype during human experimental endotoxemia in vivo.

Link: https://www.atsjournals.org/doi/full/10.1164/rccm.201604-0862CP


The model

During experimental human endotoxemia, we challenge healthy human subjects intravenously with purified endotoxin (lipopolysaccharide (LPS)). read more

The model

During experimental human endotoxemia, we challenge healthy human subjects with purified endotoxin (lipopolysaccharide (LPS)) 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.

The model has proven to be safe, well-tolerated and without any known long-term health risks for the participating subjects. Intravenous endotoxin administration elicits a transient and controlled systemic inflammatory response, clinically characterized by an increase in core temperature of approximately 1.5–2 °C, flu-like symptoms (such as headache, chills, fatigue, myalgia, backache, and nausea) during 2–4 h, as well as hemodynamic alterations (tachycardia, tachypnea, and decrease in blood pressure).