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NCT Number: NCT01091571

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

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.

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Key information

Conditions

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

Age range

18 year–35 year

Sex eligibility

Male

Study type

Interventional

Phase

Phase 4

Primary location

Radboud University Nijmegen Medical Centre

Nijmegen, 6500 HB, Netherlands

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

dipyridamole

Drug

Oral treatment with dipyridamole 200 mg twice daily during seven consecutive days

Other names: Persantin retard

Placebo

Drug

Placebo twice daily during seven consecutive days

LPS

Other

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 names: Human endotoxemia

Primary outcomes

  1. Circulating cytokines

    Time frame: 24 hours after LPS administration

    TNFx, IL6, IL10, IL1RA

Secondary outcomes

  1. Hemodynamics

    Time frame: 24 hours after LPS administration

    Continious heart rate and blood pressure measurement

  2. Sensitivity to norepinephrine

    Time frame: 24 hrs after LPS administration

    Venous occlusion plethysmography

  3. Endothelial-dependent and independent vasorelaxation

    Time frame: 24 hours after LPS administration

    Venous occlusion plethysmography

  4. Markers of endothelial damage and circulating endothelial cells

    Time frame: 24 hrs after LPS administration

    circulating adhesion molecules (ICAM, VCAM, E-selectin, P-selectin) circulating endothelial cells

  5. Urinary excretion of markers of renal injury

    Time frame: 24 hrs after LPS administration

    GSTAlpha1-1 and GSTPi1-1

  6. Adenosine and related nucleotide concentrations

    Time frame: 24 hrs after LPS administration

  7. 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

  8. Oxydative stress

    Time frame: 24 hours after LPS administration

    Thiols, neutrophilic burst, calcium release of neuthrophils, TBARS, Carbonyls, FRAP, Myeloperoxidase, catalase, Griess assay

Sponsors and collaborators

Lead sponsor

Radboud University Medical Center

Other

Registry information

Official study title

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

Important dates

Study start
2010
Primary completion
2010
Study completion
2010
First posted
Mar 24, 2010
Registry last updated
Nov 5, 2010

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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