A Possible Therapeutic Role for Adenosine During Inflammation

Radboud University Medical Center

Status and phase: Completed; Phase 1

Conditions: Endotoxemia

Treatments: Genetic: AMPD1 polymorphism; Drug: placebo; Drug: Caffeine infusion

Study type: Interventional

Funder types: Other

Identifiers

NCT00513110

2007/099

CMO 2007/099

Details and patient eligibility

About

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?

Enrollment: 33 estimated patients

Sex: Male

Ages: 18 to 35 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Healthy male volunteers

Exclusion criteria

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

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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33 participants in 3 patient groups, including a placebo group

1

Experimental group

Description:

Endotoxin and AMPD1 polymorphism

Treatment:

Genetic: AMPD1 polymorphism

2

Experimental group

Description:

Endotoxin and intervention with caffeine

Treatment:

Drug: Caffeine infusion

3

Placebo Comparator group

Description:

Endotoxin combined with placebo

Treatment:

Drug: placebo