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

Sponsor

Radboud University Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT01091571

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

4.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Endotoxemia	Drug: Dipyridamole Drug: Placebo Other: LPS	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Prevention

Official Title:

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

Study Start Date :

Mar 1, 2010

Actual Primary Completion Date :

Oct 1, 2010

Actual Study Completion Date :

Oct 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
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 Names: 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 Names: 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 Names: Human endotoxemia

Arm

Intervention/Treatment

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 Names:

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 Names:

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 Names:

Human endotoxemia

Outcome Measures

Primary Outcome Measures

Circulating cytokines [24 hours after LPS administration]
TNFx, IL6, IL10, IL1RA

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 35 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

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.