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

Study Overview
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Brief Summary
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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.

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

Conditions
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Endotoxemia

Intervention / Treatment
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* Drug: Dipyridamole
* Drug: Placebo
* Other: LPS


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Endotoxemia placebo<br>Endotoxin combined with placebo | Drug: Placebo<br>* Placebo twice daily during seven consecutive days<br>Other: LPS<br>* 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.<br>* Other names: Human endotoxemia;|
| Experimental: Endotoxemia Dipyridamole<br>Endotoxin combined with Dipyridamol treatment | Drug: Dipyridamole<br>* Oral treatment with dipyridamole 200 mg twice daily during seven consecutive days<br>* Other names: Persantin retard;Other: LPS<br>* 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.<br>* Other names: Human endotoxemia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Circulating cytokines | TNFx, IL6, IL10, IL1RA | 24 hours after LPS administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemodynamics | Continious heart rate and blood pressure measurement | 24 hours after LPS administration | 
| Sensitivity to norepinephrine | Venous occlusion plethysmography | 24 hrs after LPS administration | 
| Endothelial-dependent and independent vasorelaxation | Venous occlusion plethysmography | 24 hours after LPS administration | 
| Markers of endothelial damage and circulating endothelial cells | circulating adhesion molecules (ICAM, VCAM, E-selectin, P-selectin) circulating endothelial cells | 24 hrs after LPS administration | 
| Urinary excretion of markers of renal injury | GSTAlpha1-1 and GSTPi1-1 | 24 hrs after LPS administration | 
| 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 | Thiols, neutrophilic burst, calcium release of neuthrophils, TBARS, Carbonyls, FRAP, Myeloperoxidase, catalase, Griess assay | 24 hours after LPS administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adenosine, Endotoxin, Innate Immunity, Dipyridamole