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

This study has been completed.
Sponsor:
Information provided by:
Radboud University
ClinicalTrials.gov Identifier:
NCT01091571
First received: March 18, 2010
Last updated: November 4, 2010
Last verified: March 2010

March 18, 2010
November 4, 2010
March 2010
October 2010   (final data collection date for primary outcome measure)
Circulating cytokines [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
TNFx, IL6, IL10, IL1RA
Same as current
Complete list of historical versions of study NCT01091571 on ClinicalTrials.gov Archive Site
  • Hemodynamics [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
    Continious heart rate and blood pressure measurement
  • Sensitivity to norepinephrine [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
    Venous occlusion plethysmography
  • Endothelial-dependent and independent vasorelaxation [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
    Venous occlusion plethysmography
  • Markers of endothelial damage and circulating endothelial cells [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    GSTAlpha1-1 and GSTPi1-1
  • Adenosine and related nucleotide concentrations [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Oxydative stress [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
    Thiols, neutrophilic burst, calcium release of neuthrophils, TBARS, Carbonyls, FRAP, Myeloperoxidase, catalase, Griess assay
Same as current
Not Provided
Not Provided
 
The Effects of Oral Dipyridamole Treatment on the Innate Immune Response During Human Endotoxemia
The Effects of Oral Dipyridamole Treatment on the Innate Immune Response During Human Endotoxemia.

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.

Not Provided
Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Prevention
Endotoxemia
  • Drug: Dipyridamole
    Oral treatment with dipyridamole 200 mg twice daily during seven consecutive days
    Other Name: Persantin retard
  • Drug: Placebo
    Placebo twice daily during seven consecutive days
  • Other: LPS
    The LPS derived from E. coli O:113 2ng/kg iv will be injected in 1 minute at a dosage of 2 ng/kg body weight.
    Other Name: Human endotoxemia
  • Placebo Comparator: Endotoxemia placebo
    Endotoxin combined with placebo
    Interventions:
    • Drug: Placebo
    • Other: LPS
  • Experimental: Endotoxemia Dipyridamole
    Endotoxin combined with Dipyridamol treatment
    Interventions:
    • Drug: Dipyridamole
    • Other: LPS
Ramakers BP, Riksen NP, Stal TH, Heemskerk S, van den Broek P, Peters WH, van der Hoeven JG, Smits P, Pickkers P. Dipyridamole augments the antiinflammatory response during human endotoxemia. Crit Care. 2011;15(6):R289. doi: 10.1186/cc10576. Epub 2011 Nov 30.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
30
October 2010
October 2010   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Age ≥ 18 and ≤ 35 years
  • Male
  • Healthy

Exclusion Criteria:

  • Use of any medication.
  • History of allergic reaction to dipyridamole
  • Bleeding disorder.
  • Smoking.
  • Previous spontaneous vagal collapse.
  • History, signs or symptoms of cardiovascular disease.
  • Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complex bundle branch block.
  • Hypertension (defined as RR systolic > 160 or RR diastolic > 90).
  • Hypotension (defined as RR systolic < 100 or RR diastolic < 50).
  • Renal impairment (defined as plasma creatinin >120 μmol/l).
  • Liver enzyme abnormalities or positive hepatitis serology.
  • Positive HIV serology or any other obvious disease associated with immune deficiency.
  • Febrile illness in the week before the LPS challenge.
  • Participation in another drug trial or donation of blood 3 months prior to the planned LPS challenge.
Male
18 Years to 35 Years
Yes
Contact information is only displayed when the study is recruiting subjects
Netherlands
 
NCT01091571
2009/347
Yes
P. Pickkers MD, PhD, Radboud University Nijmegen Medical Centre
Radboud University
Not Provided
Principal Investigator: Bart P Ramakers, MD Radboud University
Radboud University
March 2010

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP