The Effects of Oral Dipyridamole Treatment on the Innate Immune Response During Human Endotoxemia - Full Text View

Purpose

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	Intervention	Phase
Endotoxemia	Drug: Dipyridamole Drug: Placebo Other: LPS	Phase 4

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator) Primary Purpose: Prevention
Official Title:	The Effects of Oral Dipyridamole Treatment on the Innate Immune Response During Human Endotoxemia.

Resource links provided by NLM:

Drug Information available for: Dipyridamole

U.S. FDA Resources

Further study details as provided by Radboud University:

Primary Outcome Measures:

Circulating cytokines [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
TNFx, IL6, IL10, IL1RA

Secondary Outcome Measures:

Hemodynamics [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
Continious heart rate and blood pressure measurement
Sensitivity to norepinephrine [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
Venous occlusion plethysmography
Endothelial-dependent and independent vasorelaxation [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
Venous occlusion plethysmography
Markers of endothelial damage and circulating endothelial cells [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
circulating adhesion molecules (ICAM, VCAM, E-selectin, P-selectin) circulating endothelial cells
Urinary excretion of markers of renal injury [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
GSTAlpha1-1 and GSTPi1-1
Adenosine and related nucleotide concentrations [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
Oxydative stress [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
Thiols, neutrophilic burst, calcium release of neuthrophils, TBARS, Carbonyls, FRAP, Myeloperoxidase, catalase, Griess assay

Estimated Enrollment:	30
Study Start Date:	March 2010
Study Completion Date:	October 2010
Primary Completion Date:	October 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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 Name: 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 Name: 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 Name: Human endotoxemia

Eligibility

Ages Eligible for Study:	18 Years to 35 Years
Genders Eligible for Study:	Male
Accepts Healthy Volunteers:	Yes

Criteria

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01091571

Locations

Netherlands
Radboud University Nijmegen Medical Centre
Nijmegen, Netherlands, 6500 HB

Sponsors and Collaborators

Radboud University

Investigators

Principal Investigator:

Bart P Ramakers, MD

Radboud University

More Information

No publications provided by Radboud University

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ramakers BP, Riksen NP, Stal TH, Heemskerk S, van den Broek P, Peters WH, van der Hoeven JG, Smits P, Pickkers P. Dipyridamole augments the antiinflammatory response during human endotoxemia. Crit Care. 2011;15(6):R289. Epub 2011 Nov 30.

Responsible Party:	P. Pickkers MD, PhD, Radboud University Nijmegen Medical Centre
ClinicalTrials.gov Identifier:	NCT01091571 History of Changes
Other Study ID Numbers:	2009/347
Study First Received:	March 18, 2010
Last Updated:	November 4, 2010
Health Authority:	Netherlands: Medical Ethics Review Committee (METC)

Keywords provided by Radboud University:

Adenosine
Endotoxin
Innate Immunity
Dipyridamole

Additional relevant MeSH terms:

Endotoxemia
Bacteremia
Sepsis
Infection
Toxemia
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Dipyridamole

Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Platelet Aggregation Inhibitors
Hematologic Agents
Therapeutic Uses
Vasodilator Agents
Cardiovascular Agents

ClinicalTrials.gov processed this record on June 17, 2013