A Possible Therapeutic Role for Adenosine During Inflammation - Full Text View

Sponsor:	Radboud University
Information provided by:	Radboud University
ClinicalTrials.gov Identifier:	NCT00513110

Purpose

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
Endotoxemia	Genetic: AMPD1 polymorphism Drug: Caffeine infusion Drug: placebo	Phase I

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Pharmacokinetics/Dynamics Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Prevention
Official Title:	A Possible Therapeutic Role for Adenosine During Inflammation

Resource links provided by NLM:

Genetics Home Reference related topics: Help Me Understand Genetics

MedlinePlus related topics: Caffeine

Drug Information available for: 3,7-Dihydro-1,3,7-trimethyl-1H-purine-2,6-dione Adenosine

U.S. FDA Resources

Further study details as provided by Radboud University:

Primary Outcome Measures:

Hemodynamics; heart rate variability [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
Markers of Inflammation [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
Cytokines [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
Sensitivity to norepinephrine [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
Endothelial-dependent and independent vasorelaxation [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
Mediators of Vascular reactivity [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
Markers of endothelial damage and circulating endothelial cells [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
Urinary excretion of markers of renal injury [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
Neurologic testing [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
Adenosine and related nucleotide concentrations. [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]

Estimated Enrollment:	33
Study Start Date:	August 2007
Study Completion Date:	August 2008
Primary Completion Date:	August 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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%)

Eligibility

Ages Eligible for Study:	18 Years to 35 Years
Genders Eligible for Study:	Male
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Healthy male volunteers

Exclusion Criteria:

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00513110

Locations

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

Sponsors and Collaborators

Radboud University

Investigators

Principal Investigator:

Peter Pickkers, MD,PhD

Radboud University

More Information

No publications provided by Radboud University

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

van den Boogaard M, Ramakers BP, van Alfen N, van der Werf SP, Fick WF, Hoedemaekers CW, Verbeek MM, Schoonhoven L, van der Hoeven JG, Pickkers P. Endotoxemia-induced inflammation and the effect on the human brain. Crit Care. 2010;14(3):R81. Epub 2010 May 5.

Responsible Party:	P.Pickkers MD PhD, Radboud University Nijmegen Medical Centre
ClinicalTrials.gov Identifier:	NCT00513110 History of Changes
Other Study ID Numbers:	2007/099, CMO 2007/099
Study First Received:	August 7, 2007
Last Updated:	September 30, 2009
Health Authority:	Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Radboud University:

Endotoxin
Adenosine
Caffeine
AMPD1 polymorphism

Additional relevant MeSH terms:

Inflammation
Endotoxemia
Pathologic Processes
Bacteremia
Sepsis
Infection
Toxemia
Systemic Inflammatory Response Syndrome
Adenosine
Caffeine
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs

Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Anti-Arrhythmia Agents
Cardiovascular Agents
Vasodilator Agents
Central Nervous System Stimulants
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Purinergic P1 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents

ClinicalTrials.gov processed this record on February 09, 2012