Clinical Trial: The Effects of Oral Dipyridamole Treatment on the Innate Immune Response During Human Endotoxemia

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: The Effects of Oral Dipyridamole Treatment on the Innate Immune Response During Human Endotoxemia.

Brief Summary: During sepsis and septic shock the immune response can be overwhelming leading to excessive tissue damage, organ failure and death. Ideally, the inflammatory response is modulated leading to both adequate protection to invading pathogens as well as limitation of an exuberant immune response. In the last few years adenosine is proposed to have a central role in the modulation of inflammation. In unfavorable conditions such as hypoxia, ischemia or inflammation adenosine is quickly up-regulated; with concentrations up to tenfold in septic patients. Many animal studies have shown that adenosine is able to attenuate the inflammatory response and decrease mortality rates. Therefore, pharmacological elevation of the adenosine concentration is an potential target to attenuate inflammation and limit organ injury. Dipyridamole, an adenosine re-uptake inhibitor is able to increase the adenosine concentration and limit ischemia-reperfusion injury. In order to study the effects of dipyridamole on the inflammatory response we aim to use the so called human endotoxemia model. This model permits elucidation of key players in the immune response to a gram negative stimulus in vivo, therefore serving as a useful tool to investigate potential novel therapeutic strategies in a standardized setting.

Detailed Summary:
Sponsor: Radboud University

Current Primary Outcome: Circulating cytokines [ Time Frame: 24 hours after LPS administration ]

TNFx, IL6, IL10, IL1RA


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Hemodynamics [ Time Frame: 24 hours after LPS administration ]
    Continious heart rate and blood pressure measurement
  • Sensitivity to norepinephrine [ Time Frame: 24 hrs after LPS administration ]
    Venous occlusion plethysmography
  • Endothelial-dependent and independent vasorelaxation [ Time Frame: 24 hours after LPS administration ]
    Venous occlusion plethysmography
  • Markers of endothelial damage and circulating endothelial cells [ Time Frame: 24 hrs after LPS administration ]
    circulating adhesion molecules (ICAM, VCAM, E-selectin, P-selectin) circulating endothelial cells
  • Urinary excretion of markers of renal injury [ Time Frame: 24 hrs after LPS administration ]
    GSTAlpha1-1 and GSTPi1-1
  • Adenosine and related nucleotide concentrations [ Time Frame: 24 hrs after LPS administration ]
  • Additional blood samples will be drawn for genetic testing and measurement of: mRNA and proteins part of the adenosine metabolism [ Time Frame: 24 hours after LPS administration ]
  • Oxydative stress [ Time Frame: 24 hours after LPS administration ]
    Thiols, neutrophilic burst, calcium release of neuthrophils, TBARS, Carbonyls, FRAP, Myeloperoxidase, catalase, Griess assay


Original Secondary Outcome: Same as current

Information By: Radboud University

Dates:
Date Received: March 18, 2010
Date Started: March 2010
Date Completion:
Last Updated: November 4, 2010
Last Verified: March 2010