A Possible Therapeutic Role for Adenosine During Inflammation

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?

Conditions

• Endotoxemia

Interventions

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%)

Sponsors & Collaborators

• Radboud University Medical Center

  lead OTHER

Principal Investigators

• Peter Pickkers, MD,PhD · Radboud University Medical Center

Study Design

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

35 Years

Sex

MALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2007-08-31

Primary Completion

2008-08-31

Completion

2008-08-31

Countries

• Netherlands

Study Locations