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Radboud University |
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Information provided by: | Radboud University |
ClinicalTrials.gov Identifier: | NCT00513110 |
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?
Condition | Intervention | Phase |
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Endotoxemia |
Genetic: AMPD1 polymorphism Drug: Caffeine infusion Drug: placebo |
Phase I |
Study Type: | Interventional |
Study Design: | Prevention, Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment, Pharmacokinetics/Dynamics Study |
Official Title: | A Possible Therapeutic Role for Adenosine During Inflammation |
Estimated Enrollment: | 33 |
Study Start Date: | August 2007 |
Estimated Study Completion Date: | August 2008 |
Arms | Assigned Interventions |
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1: Experimental
Endotoxin and AMPD1 polymorphism
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Genetic: AMPD1 polymorphism
Endotoxin 2ng/kg to subjects with a AMPD1 polymorphism
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2: Experimental
Endotoxin and intervention with caffeine
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Drug: Caffeine infusion
Endotoxin 2ng/kg combined with caffeine. Caffeine (4mg/kg) is used as an adenosine receptor antagonist.
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3: Placebo Comparator
Endotoxin combined with placebo
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Drug: placebo
Endotoxin 2ng/kg combined with saline infusion (0.9%)
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Ages Eligible for Study: | 18 Years to 35 Years |
Genders Eligible for Study: | Male |
Accepts Healthy Volunteers: | Yes |
Inclusion Criteria:
Exclusion Criteria:
Netherlands, Gelderland | |
Radboud University Nijmegen Medical Centre | Recruiting |
Nijmegen, Gelderland, Netherlands, 6500 HB | |
Contact: Peter Pickkers, MD, PhD p.pickkers@ic.umcn.nl | |
Principal Investigator: Peter Pickkers, MD, PhD |
Principal Investigator: | Peter Pickkers, MD,PhD | Radboud University |
Study ID Numbers: | 2007/099, CMO 2007/099 |
Study First Received: | August 7, 2007 |
Last Updated: | August 7, 2007 |
ClinicalTrials.gov Identifier: | NCT00513110 |
Health Authority: | Netherlands: The Central Committee on Research Involving Human Subjects (CCMO) |
Endotoxin Adenosine Caffeine AMPD1 polymorphism |
Caffeine citrate Systemic Inflammatory Response Syndrome Sepsis Bacteremia Caffeine |
Endotoxemia Adenosine Toxemia Inflammation |
Vasodilator Agents Molecular Mechanisms of Pharmacological Action Physiological Effects of Drugs Central Nervous System Stimulants Enzyme Inhibitors Cardiovascular Agents Infection Pharmacologic Actions |
Pathologic Processes Phosphodiesterase Inhibitors Sensory System Agents Therapeutic Uses Analgesics Peripheral Nervous System Agents Anti-Arrhythmia Agents Central Nervous System Agents |