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

NCT01091571 | Completed Phase 4 DMC

• 1 other identifier: 2009/347
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

Endotoxemia

Keywords

Adenosine; Endotoxin; Innate Immunity; Dipyridamole

Outcome Measures

Primary Outcomes (1)

• Circulating cytokines

  TNFx, IL6, IL10, IL1RA

  24 hours after LPS administration

Secondary Outcomes (8)

• Hemodynamics

  24 hours after LPS administration

• Sensitivity to norepinephrine

  24 hrs after LPS administration

• Endothelial-dependent and independent vasorelaxation

  24 hours after LPS administration

• Markers of endothelial damage and circulating endothelial cells

  24 hrs after LPS administration

• Urinary excretion of markers of renal injury

  24 hrs after LPS administration

Study Arms (2)

Endotoxemia placebo

PLACEBO COMPARATOR

Endotoxin combined with placebo

Drug: Placebo; Other: LPS

Endotoxemia Dipyridamole

EXPERIMENTAL

Endotoxin combined with Dipyridamol treatment

Drug: Dipyridamole; Other: LPS

Interventions

Dipyridamole DRUG

Oral treatment with dipyridamole 200 mg twice daily during seven consecutive days

Also known as: Persantin retard

Endotoxemia Dipyridamole

Placebo DRUG

Placebo twice daily during seven consecutive days

Endotoxemia placebo

LPS OTHER

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.

Also known as: Human endotoxemia

Endotoxemia Dipyridamole; Endotoxemia placebo

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age ≥ 18 and ≤ 35 years
• Male
• Healthy

You may not qualify if:

• 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.

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (1)

Radboud University Nijmegen Medical Centre

Nijmegen, 6500 HB, Netherlands

Location

Related Publications (1)

• 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.

  PMID: 22129171 DERIVED

MeSH Terms

Conditions

Endotoxemia

Interventions

Dipyridamole

Condition Hierarchy (Ancestors)

Bacteremia; Sepsis; Infections; Toxemia; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Bart P Ramakers, MD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: March 18, 2010
• First Posted: March 24, 2010
• Study Start: March 1, 2010
• Primary Completion: October 1, 2010
• Study Completion: October 1, 2010
• Last Updated: November 5, 2010

Record last verified: 2010-03

Locations

NL (1)