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A Possible Therapeutic Role for Adenosine During Inflammation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00513110
Recruitment Status : Completed
First Posted : August 8, 2007
Last Update Posted : October 1, 2009
Information provided by:
Radboud University

Tracking Information
First Submitted Date  ICMJE August 7, 2007
First Posted Date  ICMJE August 8, 2007
Last Update Posted Date October 1, 2009
Study Start Date  ICMJE August 2007
Actual Primary Completion Date August 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 7, 2007)
  • Hemodynamics; heart rate variability [ Time Frame: 24 hrs after LPS administration ]
  • Markers of Inflammation [ Time Frame: 24 hrs after LPS administration ]
  • Cytokines [ Time Frame: 24 hrs after LPS administration ]
  • Sensitivity to norepinephrine [ Time Frame: 24 hrs after LPS administration ]
  • Endothelial-dependent and independent vasorelaxation [ Time Frame: 24 hrs after LPS administration ]
  • Mediators of Vascular reactivity [ Time Frame: 24 hrs after LPS administration ]
  • Markers of endothelial damage and circulating endothelial cells [ Time Frame: 24 hrs after LPS administration ]
  • Urinary excretion of markers of renal injury [ Time Frame: 24 hrs after LPS administration ]
  • Neurologic testing [ Time Frame: 24 hrs after LPS administration ]
  • Adenosine and related nucleotide concentrations. [ Time Frame: 24 hrs after LPS administration ]
  • Additional blood samples will be drawn for measurement of: TLR-expression, Genetics; micro array analyses and determination of intercellular signalling pathways. [ Time Frame: 24 hrs after LPS administration ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT00513110 on Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE A Possible Therapeutic Role for Adenosine During Inflammation
Official Title  ICMJE A Possible Therapeutic Role for Adenosine During Inflammation
Brief Summary

The adenosine receptor is known for its anti-inflammatory actions and could therefore be a potential target in the treatment of sepsis and septic shock. Stimulation of the adenosine receptor could potentially lead to a decrease in inflammation and tissue damage.

Under normal conditions adenosine is formed either by an intracellular 5`nucleotidase, which dephosphorylates AMP, or by the hydrolysis of S-adenosylhomcysteine by hydrolase. An alternative pathway of AMP degradations is provided by the cytosolic enzyme AMP deaminase (AMPD), which catalyses the irreversible deamination of AMP to inosine monophosphate and ammonia.

In humans four AMPD isoforms have been described, named after the source from which they were initially purified; M (muscle), L (liver), E1 and E2 (erythrocyte), encoded by AMPD1, AMPD2 and AMPD3. Approximately 15-20% of Caucasian and African American individuals are heterozygous or homozygous for the 34C>T variant of AMPD1.

We hypothesize that healthy volunteers who have the polymorphism for AMPD1 have a less severe inflammatory response to LPS and show less (severe) organ failure. This hypothesis is based on the expected higher levels of adenosine in patients with the AMPD1 polymorphism. This hypothesis is strengthened by the fact that patients with coronary artery disease and the AMPD1 polymorphism show improved cardiovascular survival (Anderson JL et al. J Am Coll Cardiol 2000; 36: 1248-52) possibly based on higher adenosine levels by reduced AMPD activity. Furthermore the polymorphism predicts improved clinical outcome in patients with heart failure (Loh E et al. Circulation 1999) also based on a hypothetical elevation of adenosine.

We hypothesize that:

The C34T-polymorphism of the enzyme AMP-deaminase leads to a decreased inflammatory respons and thereby a decrease of LPS-induced tissue damage.

A second hypothesis is based on the antagonism of the adenosine receptor, by caffeine;

Antagonism of the adenosine receptor by caffeine leads to an increased LPS-induced inflammatory reaction and an increase in (subclinical) tissue damage?

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Condition  ICMJE Endotoxemia
Intervention  ICMJE
  • Genetic: AMPD1 polymorphism
    Endotoxin 2ng/kg to subjects with a AMPD1 polymorphism
  • Drug: Caffeine infusion
    Endotoxin 2ng/kg combined with caffeine. Caffeine (4mg/kg) is used as an adenosine receptor antagonist.
  • Drug: placebo
    Endotoxin 2ng/kg combined with saline infusion (0.9%)
Study Arms  ICMJE
  • Experimental: 1
    Endotoxin and AMPD1 polymorphism
    Intervention: Genetic: AMPD1 polymorphism
  • Experimental: 2
    Endotoxin and intervention with caffeine
    Intervention: Drug: Caffeine infusion
  • Placebo Comparator: 3
    Endotoxin combined with placebo
    Intervention: Drug: placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Estimated Enrollment  ICMJE
 (submitted: August 7, 2007)
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE August 2008
Actual Primary Completion Date August 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Healthy male volunteers

Exclusion Criteria:

  • Drug-, nicotine-, alcohol abuses
  • Tendency towards fainting
  • Relevant medical history
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 35 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00513110
Other Study ID Numbers  ICMJE 2007/099
CMO 2007/099
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party P.Pickkers MD PhD, Radboud University Nijmegen Medical Centre
Study Sponsor  ICMJE Radboud University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Peter Pickkers, MD,PhD Radboud University
PRS Account Radboud University
Verification Date August 2007

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