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A Possible Therapeutic Role for Adenosine During Inflammation

Information source: Radboud University
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Endotoxemia

Intervention: AMPD1 polymorphism (Genetic); Caffeine infusion (Drug); placebo (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: Radboud University

Official(s) and/or principal investigator(s):
Peter Pickkers, MD,PhD, Principal Investigator, Affiliation: Radboud University

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?

Clinical Details

Official title: A Possible Therapeutic Role for Adenosine During Inflammation

Study design: Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Primary outcome:

Hemodynamics; heart rate variability

Markers of Inflammation

Cytokines

Sensitivity to norepinephrine

Endothelial-dependent and independent vasorelaxation

Mediators of Vascular reactivity

Markers of endothelial damage and circulating endothelial cells

Urinary excretion of markers of renal injury

Neurologic testing

Adenosine and related nucleotide concentrations.

Additional blood samples will be drawn for measurement of: TLR-expression, Genetics; micro array analyses and determination of intercellular signalling pathways.

Eligibility

Minimum age: 18 Years. Maximum age: 35 Years. Gender(s): Male.

Criteria:

Inclusion Criteria:

- Healthy male volunteers

Exclusion Criteria:

- Drug-, nicotine-, alcohol abuses

- Tendency towards fainting

- Relevant medical history

Locations and Contacts

Radboud University Nijmegen Medical Centre, Nijmegen, Gelderland 6500 HB, Netherlands
Additional Information

Starting date: August 2007
Last updated: September 30, 2009

Page last updated: August 20, 2015

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