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 variabilityMarkers 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
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