Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans

April 14, 2008 updated by: Radboud University Medical Center

A number of diseases lead to a so called systemic inflammatory response syndrome (SIRS). This excessive response is self-destructive and leads to major complications of the initial disease: dysfunction of the microcirculation, systemic vasodilation, and increased capillary leakage and oedema. Animal studies have shown that pre-treatment with endotoxin (lipopolysaccharide or LPS) suppress the excessive immune response and when rechallenged, the animal survive a normally lethal dose of endotoxin.

Besides a diminished cytokine response, an increased production of leucocytes in the bone marrow and an increased phagocytosis after pre-treatment with endotoxin is seen. The combination of these factors: diminished systemic inflammatory response and increased cellular immunity makes that endotoxin tolerance is a useful tool for preventing the complications after an excessive inflammatory response.

Further, the presence of cross-tolerance has also been shown: Endotoxin tolerant mice survive more after induction of a normally lethal fungal infection. Endotoxin tolerance is also protective for ischemia/reperfusion injury in kidneys, heart and liver. Little data is known about endotoxin tolerance in human.

The purpose of this study is to induce a state of tolerance through 2 different administration schedules and monitor the effect of tolerance on pro- and anti-inflammatory cytokines, other inflammatory parameters and different proteins involved in the signalling pathway. The effects of tolerance on vascular reactivity will be determined. Finally, the effect of tolerance on ischemia-reperfusion injury will be investigated.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

See protocol

Study Type

Interventional

Enrollment (Anticipated)

16

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
    • Gelderland
      • Nijmegen, Gelderland, Netherlands, 6500HB
        • Radboud University Nijmegen Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 35 years (Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  • Healthy male volunteers

Exclusion Criteria:

  • drug-, nicotine-, alcohol abuses
  • tendency towards fainting
  • BMI < 18 kg/m2

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
inducing endotoxin tolerance
Time Frame: 5 days
5 days
Hemodynamics
Time Frame: 5 days
5 days
Markers of Inflammation
Time Frame: 5 days
5 days
Cytokines
Time Frame: 5 days
5 days
Mediators of Vascular reactivity
Time Frame: 5 days
5 days
Sensitivity to norepinephrine
Time Frame: 5 days
5 days
Endothelial-dependent vasorelaxation
Time Frame: 5 days
5 days
Cross tolerance
Time Frame: 6 days
6 days
Ischemia-reperfusion injury
Time Frame: 6 days
6 days
Effects on tissue saturation (measured by NIRS)
Time Frame: 24 hrs after LPS administration
24 hrs after LPS administration

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Radboud University Medical Center

Investigators

  • Principal Investigator: Peter Pickkers, MD PhD, Radboud University Nijmegen Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2005

Primary Completion (Actual)

December 1, 2007

Study Completion (Actual)

December 1, 2007

Study Registration Dates

First Submitted

October 28, 2005

First Submitted That Met QC Criteria

October 28, 2005

First Posted (Estimate)

October 30, 2005

Study Record Updates

Last Update Posted (Estimate)

April 15, 2008

Last Update Submitted That Met QC Criteria

April 14, 2008

Last Verified

April 1, 2008

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PP03

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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