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

Endotoxemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01091571
• Other study ID #: 2009/347
• Status: Completed
• Phase: Phase 4
• First received: March 18, 2010
• Last updated: November 4, 2010
• Start date: March 2010
• Est. completion date: October 2010

Study information

• Verified date: March 2010
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: Medical Ethics Review Committee (METC)
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: October 2010
• Est. primary completion date: October 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 35 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Endotoxemia

Intervention

Drug:
• Dipyridamole
Oral treatment with dipyridamole 200 mg twice daily during seven consecutive days
• 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.

Locations

Country	Name	City	State
Netherlands	Radboud University Nijmegen Medical Centre	Nijmegen

Sponsors (1)

Lead Sponsor	Collaborator
Radboud University

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Circulating cytokines	TNFx, IL6, IL10, IL1RA	24 hours after LPS administration	No
Secondary	Hemodynamics	Continious heart rate and blood pressure measurement	24 hours after LPS administration	No
Secondary	Sensitivity to norepinephrine	Venous occlusion plethysmography	24 hrs after LPS administration	No
Secondary	Endothelial-dependent and independent vasorelaxation	Venous occlusion plethysmography	24 hours after LPS administration	No
Secondary	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	No
Secondary	Urinary excretion of markers of renal injury	GSTAlpha1-1 and GSTPi1-1	24 hrs after LPS administration	No
Secondary	Adenosine and related nucleotide concentrations		24 hrs after LPS administration	No
Secondary	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	No
Secondary	Oxydative stress	Thiols, neutrophilic burst, calcium release of neuthrophils, TBARS, Carbonyls, FRAP, Myeloperoxidase, catalase, Griess assay	24 hours after LPS administration	No