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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

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?

Condition or disease Intervention/treatment Phase
Endotoxemia Genetic: AMPD1 polymorphism Drug: Caffeine infusion Drug: placebo Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 33 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: A Possible Therapeutic Role for Adenosine During Inflammation
Study Start Date : August 2007
Actual Primary Completion Date : August 2008
Actual Study Completion Date : August 2008

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Caffeine
Drug Information available for: Adenosine

Arm Intervention/treatment
Experimental: 1
Endotoxin and AMPD1 polymorphism
Genetic: AMPD1 polymorphism
Endotoxin 2ng/kg to subjects with a AMPD1 polymorphism

Experimental: 2
Endotoxin and intervention with caffeine
Drug: Caffeine infusion
Endotoxin 2ng/kg combined with caffeine. Caffeine (4mg/kg) is used as an adenosine receptor antagonist.

Placebo Comparator: 3
Endotoxin combined with placebo
Drug: placebo
Endotoxin 2ng/kg combined with saline infusion (0.9%)

Primary Outcome Measures :
  1. Hemodynamics; heart rate variability [ Time Frame: 24 hrs after LPS administration ]
  2. Markers of Inflammation [ Time Frame: 24 hrs after LPS administration ]
  3. Cytokines [ Time Frame: 24 hrs after LPS administration ]
  4. Sensitivity to norepinephrine [ Time Frame: 24 hrs after LPS administration ]
  5. Endothelial-dependent and independent vasorelaxation [ Time Frame: 24 hrs after LPS administration ]
  6. Mediators of Vascular reactivity [ Time Frame: 24 hrs after LPS administration ]
  7. Markers of endothelial damage and circulating endothelial cells [ Time Frame: 24 hrs after LPS administration ]
  8. Urinary excretion of markers of renal injury [ Time Frame: 24 hrs after LPS administration ]
  9. Neurologic testing [ Time Frame: 24 hrs after LPS administration ]
  10. Adenosine and related nucleotide concentrations. [ Time Frame: 24 hrs after LPS administration ]
  11. 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 ]

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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Healthy male volunteers

Exclusion Criteria:

  • Drug-, nicotine-, alcohol abuses
  • Tendency towards fainting
  • Relevant medical history

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00513110

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Radboud University Nijmegen Medical Centre
Nijmegen, Gelderland, Netherlands, 6500 HB
Sponsors and Collaborators
Radboud University
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Principal Investigator: Peter Pickkers, MD,PhD Radboud University
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: P.Pickkers MD PhD, Radboud University Nijmegen Medical Centre Identifier: NCT00513110    
Other Study ID Numbers: 2007/099
CMO 2007/099
First Posted: August 8, 2007    Key Record Dates
Last Update Posted: October 1, 2009
Last Verified: August 2007
Keywords provided by Radboud University:
AMPD1 polymorphism
Additional relevant MeSH terms:
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Pathologic Processes
Systemic Inflammatory Response Syndrome
Central Nervous System Stimulants
Physiological Effects of Drugs
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Purinergic P1 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents