A Possible Therapeutic Role for Adenosine During Inflammation

Endotoxemia Clinical Trial

Official title:

A Possible Therapeutic Role for Adenosine During Inflammation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00513110
• Other study ID #: 2007/099
• Secondary ID: CMO 2007/099
• Status: Completed
• Phase: Phase 1
• First received: August 7, 2007
• Last updated: September 30, 2009
• Start date: August 2007
• Est. completion date: August 2008

Study information

• Verified date: August 2007
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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?

Recruitment information / eligibility

• Status: Completed
• Enrollment: 33
• Est. completion date: August 2008
• Est. primary completion date: August 2008
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 35 Years

Eligibility

Inclusion Criteria:

• Healthy male volunteers

Exclusion Criteria:

• Drug-, nicotine-, alcohol abuses

• Tendency towards fainting

• Relevant medical history

Study Design

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

Related Conditions & MeSH terms

• Endotoxemia

Intervention

Genetic:
• AMPD1 polymorphism
Endotoxin 2ng/kg to subjects with a AMPD1 polymorphism

Drug:
• Caffeine infusion
Endotoxin 2ng/kg combined with caffeine. Caffeine (4mg/kg) is used as an adenosine receptor antagonist.
• placebo
Endotoxin 2ng/kg combined with saline infusion (0.9%)

Locations

Country	Name	City	State
Netherlands	Radboud University Nijmegen Medical Centre	Nijmegen	Gelderland

Sponsors (1)

Lead Sponsor	Collaborator
Radboud University

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Hemodynamics; heart rate variability		24 hrs after LPS administration	No
Primary	Markers of Inflammation		24 hrs after LPS administration	No
Primary	Cytokines		24 hrs after LPS administration	No
Primary	Sensitivity to norepinephrine		24 hrs after LPS administration	No
Primary	Endothelial-dependent and independent vasorelaxation		24 hrs after LPS administration	No
Primary	Mediators of Vascular reactivity		24 hrs after LPS administration	No
Primary	Markers of endothelial damage and circulating endothelial cells		24 hrs after LPS administration	No
Primary	Urinary excretion of markers of renal injury		24 hrs after LPS administration	No
Primary	Neurologic testing		24 hrs after LPS administration	No
Primary	Adenosine and related nucleotide concentrations.		24 hrs after LPS administration	No
Primary	Additional blood samples will be drawn for measurement of: TLR-expression, Genetics; micro array analyses and determination of intercellular signalling pathways.		24 hrs after LPS administration	No