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

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, 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.

Study Overview

• Status: Completed
• Conditions: Endotoxemia
• Intervention / Treatment: Drug: Placebo; Other: LPS; Drug: Dipyridamole

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 4

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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	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; Drug: Dipyridamole; Oral treatment with dipyridamole 200 mg twice daily during seven consecutive days; Other Names: Persantin retard

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Bart P Ramakers, MD, Radboud University Medical Center

Publications and helpful links

General Publications

• 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. doi: 10.1186/cc10576. Epub 2011 Nov 30.

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: March 18, 2010
• First Submitted That Met QC Criteria: March 23, 2010
• First Posted (Estimate): March 24, 2010

Study Record Updates

• Last Update Posted (Estimate): November 5, 2010
• Last Update Submitted That Met QC Criteria: November 4, 2010
• Last Verified: March 1, 2010

More Information

Terms related to this study

• Keywords: Adenosine; Endotoxin; Innate Immunity; Dipyridamole
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Bacteremia; Toxemia; Endotoxemia; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Phosphodiesterase Inhibitors; Dipyridamole
• Other Study ID Numbers: 2009/347

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No