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

Phase 4

Completed

• Conditions: Endotoxemia
• Interventions: Drug: Placebo; Drug: Dipyridamole; Other: LPS

• Registration Number: NCT01091571
• Lead Sponsor: Radboud University Medical Center

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Status Verified: 2010-03
• Study Start: 2010-03
• Study First Submitted: 2010-03-18
• Study First Submitted QC: 2010-03-23
• Study First Posted: 2010-03-24
• Primary Completion: 2010-10
• Study Completion: 2010-10
• Last Update Submitted: 2010-11-04
• Last Update Posted: 2010-11-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 30

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Endotoxemia placebo	Placebo	Endotoxin combined with placebo
Endotoxemia placebo	LPS	Endotoxin combined with placebo
Endotoxemia Dipyridamole	Dipyridamole	Endotoxin combined with Dipyridamol treatment
Endotoxemia Dipyridamole	LPS	Endotoxin combined with Dipyridamol treatment

Primary Outcome Measures

Name	Time	Method
Circulating cytokines	24 hours after LPS administration	TNFx, IL6, IL10, IL1RA

Secondary Outcome Measures

Name	Time	Method
Hemodynamics	24 hours after LPS administration	Continious heart rate and blood pressure measurement
Sensitivity to norepinephrine	24 hrs after LPS administration	Venous occlusion plethysmography
Endothelial-dependent and independent vasorelaxation	24 hours after LPS administration	Venous occlusion plethysmography
Markers of endothelial damage and circulating endothelial cells	24 hrs after LPS administration	circulating adhesion molecules (ICAM, VCAM, E-selectin, P-selectin) circulating endothelial cells
Urinary excretion of markers of renal injury	24 hrs after LPS administration	GSTAlpha1-1 and GSTPi1-1
Adenosine and related nucleotide concentrations	24 hrs after LPS administration
Additional blood samples will be drawn for genetic testing and measurement of: mRNA and proteins part of the adenosine metabolism	24 hours after LPS administration
Oxydative stress	24 hours after LPS administration	Thiols, neutrophilic burst, calcium release of neuthrophils, TBARS, Carbonyls, FRAP, Myeloperoxidase, catalase, Griess assay

Trial Locations

Locations (1)

Radboud University Nijmegen Medical Centre; 🇳🇱 Nijmegen, Netherlands