A Possible Therapeutic Role for Adenosine During Inflammation

NCT00513110 | Completed Phase 1

• 2 other identifiers: 2007/099CMO 2007/099
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

Brief 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?

Conditions

Endotoxemia

Keywords

Endotoxin; Adenosine; Caffeine; AMPD1 polymorphism

Outcome Measures

Primary Outcomes (11)

• Hemodynamics; heart rate variability

  24 hrs after LPS administration

• Markers of Inflammation

  24 hrs after LPS administration

• Cytokines

  24 hrs after LPS administration

• Sensitivity to norepinephrine

  24 hrs after LPS administration

• Endothelial-dependent and independent vasorelaxation

  24 hrs after LPS administration

• Mediators of Vascular reactivity

  24 hrs after LPS administration

• Markers of endothelial damage and circulating endothelial cells

  24 hrs after LPS administration

• Urinary excretion of markers of renal injury

  24 hrs after LPS administration

• Neurologic testing

  24 hrs after LPS administration

• Adenosine and related nucleotide concentrations.

  24 hrs after LPS administration

• 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

Study Arms (3)

1

EXPERIMENTAL

Endotoxin and AMPD1 polymorphism

Genetic: AMPD1 polymorphism

2

EXPERIMENTAL

Endotoxin and intervention with caffeine

Drug: Caffeine infusion

3

PLACEBO COMPARATOR

Endotoxin combined with placebo

Drug: placebo

Interventions

AMPD1 polymorphism GENETIC

Endotoxin 2ng/kg to subjects with a AMPD1 polymorphism

1

Caffeine infusion DRUG

Endotoxin 2ng/kg combined with caffeine. Caffeine (4mg/kg) is used as an adenosine receptor antagonist.

2

placebo DRUG

Endotoxin 2ng/kg combined with saline infusion (0.9%)

3

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy male volunteers

You may not qualify if:

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

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (1)

Radboud University Nijmegen Medical Centre

Nijmegen, Gelderland, 6500 HB, Netherlands

Location

Related Publications (2)

• Ramakers BP, Riksen NP, van den Broek P, Franke B, Peters WH, van der Hoeven JG, Smits P, Pickkers P. Circulating adenosine increases during human experimental endotoxemia but blockade of its receptor does not influence the immune response and subsequent organ injury. Crit Care. 2011;15(1):R3. doi: 10.1186/cc9400. Epub 2011 Jan 6.

  PMID: 21211004 DERIVED

• 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. doi: 10.1186/cc9001. Epub 2010 May 5.

  PMID: 20444270 DERIVED

MeSH Terms

Conditions

Endotoxemia

Condition Hierarchy (Ancestors)

Bacteremia; Sepsis; Infections; Toxemia; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Peter Pickkers, MD,PhD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: August 7, 2007
• First Posted: August 8, 2007
• Study Start: August 1, 2007
• Primary Completion: August 1, 2008
• Study Completion: August 1, 2008
• Last Updated: October 1, 2009

Record last verified: 2007-08

Locations

NL (1)