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. 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 opposed 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 attractive 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
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.

Primary objective: The primary objective of the study is to determine the
effect of oral dipyridamole treatment on the innate immune response induced by
a lipopolysaccharide (LPS) challenge. Various pro- and anti-inflammatory
cytokines will be measured for this purpose.

Secondary Objective(s): There are three secondary objectives:
1. To determine if the attenuated vascular response to endothelium dependent
vasodilators and vasoconstrictors during endotoxemia can be prevented by oral
dipyridamole treatment.
2. To determine if dipyridamole can attenuate (subclinical) renal damage known
to occur during human endotoxemia, markers of proximal and distal tubular
damage will be measured at various time points.
3. To measure the dipyridamole-induced increase of adenosine after LPS
challenge.

Randomized double-blind placebo-controlled parallel intervention study in
healthy human volunteers during experimental endotoxemia.

Subjects will receive dipyridamole (five day treatment with 200 mg twice daily
n=15) or placebo (n=15). The day of the experiment, prehydration will be
performed by infusion of 1.5 L 2.5% glucose/0.45% saline (moeten we niet naar
een 0,9% NaCL oplossing toe?) solution in 1 hour before LPS administration. LPS
derived from E coli O:113 will be injected (2 ng/kg i.v., infusion rate; 1
minute).

A medical interview and physical examination are part of this study.
Dipyridamole can cause a headache after ingestion of the first dosages. Other
side effects are mild and are described in the investigators brochure. The day
of the experiment, volunteers will be monitored on the research unit of our
intensive care and receive an arterial line (a. brachialis) to facilitate blood
pressure monitoring, drug infusion during venous occlusion plethysmography and
blood sampling. The arterial line will be placed under local anaesthesia using
2% lidocaine. Furthermore a venous cannula will be placed for the
administration of saline/glucose.
The administration of LPS induces flu-like symptoms for approximately 4 hrs.
This model of systemic inflammation has been applied for many years in research
centres all over the world. Endotoxin administration is considered safe and no
long term effects have ever been documented.
At the Radboud University Nijmegen Medical Centre, over 150 volunteers have
received over 250 injections of lipopolysaccharide. Therefore, there is
sufficient experience with this model at this centre.
In total, approximately 350 ml blood will be drawn during the experiment and
urine will be collected.