A Possible Therapeutic Role for Adenosine During Inflammation

September 30, 2009 updated by: Radboud University Medical Center

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?

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Anticipated)

33

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
    • Gelderland
      • Nijmegen, Gelderland, Netherlands, 6500 HB
        • Radboud University Nijmegen Medical Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 35 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  • Healthy male volunteers

Exclusion Criteria:

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / 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%)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Markers of Inflammation
Time Frame: 24 hrs after LPS administration
24 hrs after LPS administration
Cytokines
Time Frame: 24 hrs after LPS administration
24 hrs after LPS administration
Mediators of Vascular reactivity
Time Frame: 24 hrs after LPS administration
24 hrs after LPS administration
Sensitivity to norepinephrine
Time Frame: 24 hrs after LPS administration
24 hrs after LPS administration
Hemodynamics; heart rate variability
Time Frame: 24 hrs after LPS administration
24 hrs after LPS administration
Endothelial-dependent and independent vasorelaxation
Time Frame: 24 hrs after LPS administration
24 hrs after LPS administration
Markers of endothelial damage and circulating endothelial cells
Time Frame: 24 hrs after LPS administration
24 hrs after LPS administration
Urinary excretion of markers of renal injury
Time Frame: 24 hrs after LPS administration
24 hrs after LPS administration
Neurologic testing
Time Frame: 24 hrs after LPS administration
24 hrs after LPS administration
Adenosine and related nucleotide concentrations.
Time Frame: 24 hrs after LPS administration
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
24 hrs after LPS administration

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Radboud University Medical Center

Investigators

  • Principal Investigator: Peter Pickkers, MD,PhD, Radboud University Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2007

Primary Completion (Actual)

August 1, 2008

Study Completion (Actual)

August 1, 2008

Study Registration Dates

First Submitted

August 7, 2007

First Submitted That Met QC Criteria

August 7, 2007

First Posted (Estimate)

August 8, 2007

Study Record Updates

Last Update Posted (Estimate)

October 1, 2009

Last Update Submitted That Met QC Criteria

September 30, 2009

Last Verified

August 1, 2007

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2007/099
  • CMO 2007/099

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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