The Effects of Oral Dipyridamole Treatment on the Innate Immune Response During Human Endotoxemia

This study has been completed.
Sponsor:
Information provided by:
Radboud University
ClinicalTrials.gov Identifier:
NCT01091571
First received: March 18, 2010
Last updated: November 4, 2010
Last verified: March 2010
  Purpose

During sepsis and septic shock the immune response can be overwhelming leading to excessive tissue damage, organ failure and death. Ideally, the inflammatory response is modulated leading to both adequate protection to invading pathogens as well as limitation of an exuberant immune response. In the last few years adenosine is proposed to have a central role in the modulation of inflammation. In unfavorable conditions such as hypoxia, ischemia or inflammation adenosine is quickly up-regulated; with concentrations up to tenfold in septic patients. Many animal studies have shown that adenosine is able to attenuate the inflammatory response and decrease mortality rates. Therefore, pharmacological elevation of the adenosine concentration is an potential target to attenuate inflammation and limit organ injury. Dipyridamole, an adenosine re-uptake inhibitor is able to increase the adenosine concentration and limit ischemia-reperfusion injury. In order to study the effects of dipyridamole on the inflammatory response we aim to use the so called human endotoxemia model. This model permits elucidation of key players in the immune response to a gram negative stimulus in vivo, therefore serving as a useful tool to investigate potential novel therapeutic strategies in a standardized setting.


Condition Intervention Phase
Endotoxemia
Drug: Dipyridamole
Drug: Placebo
Other: LPS
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Prevention
Official Title: The Effects of Oral Dipyridamole Treatment on the Innate Immune Response During Human Endotoxemia.

Resource links provided by NLM:


Further study details as provided by Radboud University:

Primary Outcome Measures:
  • Circulating cytokines [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
    TNFx, IL6, IL10, IL1RA


Secondary Outcome Measures:
  • Hemodynamics [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
    Continious heart rate and blood pressure measurement

  • Sensitivity to norepinephrine [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
    Venous occlusion plethysmography

  • Endothelial-dependent and independent vasorelaxation [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
    Venous occlusion plethysmography

  • Markers of endothelial damage and circulating endothelial cells [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
    circulating adhesion molecules (ICAM, VCAM, E-selectin, P-selectin) circulating endothelial cells

  • Urinary excretion of markers of renal injury [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
    GSTAlpha1-1 and GSTPi1-1

  • Adenosine and related nucleotide concentrations [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
  • Additional blood samples will be drawn for genetic testing and measurement of: mRNA and proteins part of the adenosine metabolism [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
  • Oxydative stress [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
    Thiols, neutrophilic burst, calcium release of neuthrophils, TBARS, Carbonyls, FRAP, Myeloperoxidase, catalase, Griess assay


Estimated Enrollment: 30
Study Start Date: March 2010
Study Completion Date: October 2010
Primary Completion Date: October 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Endotoxemia placebo
Endotoxin combined with placebo
Drug: Placebo
Placebo twice daily during seven consecutive days
Other: LPS
The LPS derived from E. coli O:113 2ng/kg iv will be injected in 1 minute at a dosage of 2 ng/kg body weight.
Other Name: Human endotoxemia
Experimental: Endotoxemia Dipyridamole
Endotoxin combined with Dipyridamol treatment
Drug: Dipyridamole
Oral treatment with dipyridamole 200 mg twice daily during seven consecutive days
Other Name: Persantin retard
Other: LPS
The LPS derived from E. coli O:113 2ng/kg iv will be injected in 1 minute at a dosage of 2 ng/kg body weight.
Other Name: Human endotoxemia

  Eligibility

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

Inclusion Criteria:

  • Age ≥ 18 and ≤ 35 years
  • Male
  • Healthy

Exclusion Criteria:

  • Use of any medication.
  • History of allergic reaction to dipyridamole
  • Bleeding disorder.
  • Smoking.
  • Previous spontaneous vagal collapse.
  • History, signs or symptoms of cardiovascular disease.
  • Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complex bundle branch block.
  • Hypertension (defined as RR systolic > 160 or RR diastolic > 90).
  • Hypotension (defined as RR systolic < 100 or RR diastolic < 50).
  • Renal impairment (defined as plasma creatinin >120 μmol/l).
  • Liver enzyme abnormalities or positive hepatitis serology.
  • Positive HIV serology or any other obvious disease associated with immune deficiency.
  • Febrile illness in the week before the LPS challenge.
  • Participation in another drug trial or donation of blood 3 months prior to the planned LPS challenge.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01091571

Locations
Netherlands
Radboud University Nijmegen Medical Centre
Nijmegen, Netherlands, 6500 HB
Sponsors and Collaborators
Radboud University
Investigators
Principal Investigator: Bart P Ramakers, MD Radboud University
  More Information

No publications provided by Radboud University

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: P. Pickkers MD, PhD, Radboud University Nijmegen Medical Centre
ClinicalTrials.gov Identifier: NCT01091571     History of Changes
Other Study ID Numbers: 2009/347
Study First Received: March 18, 2010
Last Updated: November 4, 2010
Health Authority: Netherlands: Medical Ethics Review Committee (METC)

Keywords provided by Radboud University:
Adenosine
Endotoxin
Innate Immunity
Dipyridamole

Additional relevant MeSH terms:
Endotoxemia
Bacteremia
Sepsis
Infection
Toxemia
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Dipyridamole
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Platelet Aggregation Inhibitors
Hematologic Agents
Therapeutic Uses
Vasodilator Agents
Cardiovascular Agents

ClinicalTrials.gov processed this record on July 26, 2014