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NCT Number: NCT00513110

A Possible Therapeutic Role for Adenosine During Inflammation

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?

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Key information

Conditions

Endotoxemia Bacteremia Infections Inflammation Pathologic Processes Pathological Conditions, Signs and Symptoms Sepsis Systemic Inflammatory Response Syndrome Toxemia

Age range

18 year–35 year

Sex eligibility

Male

Study type

Interventional

Phase

Phase 1

Primary location

Radboud University Nijmegen Medical Centre

Nijmegen, Gelderland, 6500 HB, Netherlands

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Healthy male volunteers

Exclusion criteria

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

Treatment and study plan

AMPD1 polymorphism

Genetic

Endotoxin 2ng/kg to subjects with a AMPD1 polymorphism

Caffeine infusion

Drug

Endotoxin 2ng/kg combined with caffeine. Caffeine (4mg/kg) is used as an adenosine receptor antagonist.

Placebo

Drug

Endotoxin 2ng/kg combined with saline infusion (0.9%)

Primary outcomes

  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

Sponsors and collaborators

Lead sponsor

Radboud University Medical Center

Other

Registry information

Important dates

Study start
2007
Primary completion
2008
Study completion
2008
First posted
Aug 8, 2007
Registry last updated
Oct 1, 2009

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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