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Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00246714
Recruitment Status : Completed
First Posted : October 30, 2005
Last Update Posted : April 15, 2008
Information provided by:
Radboud University

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Endotoxemia Drug: repeated injections of endotoxin during 5 days Phase 1

Detailed Description:
See protocol

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans
Study Start Date : October 2005
Actual Primary Completion Date : December 2007
Actual Study Completion Date : December 2007

Primary Outcome Measures :
  1. inducing endotoxin tolerance [ Time Frame: 5 days ]
  2. Hemodynamics [ Time Frame: 5 days ]
  3. Markers of Inflammation [ Time Frame: 5 days ]
  4. Cytokines [ Time Frame: 5 days ]
  5. Mediators of Vascular reactivity [ Time Frame: 5 days ]
  6. Sensitivity to norepinephrine [ Time Frame: 5 days ]
  7. Endothelial-dependent vasorelaxation [ Time Frame: 5 days ]
  8. Cross tolerance [ Time Frame: 6 days ]
  9. Ischemia-reperfusion injury [ Time Frame: 6 days ]
  10. Effects on tissue saturation (measured by NIRS) [ Time Frame: 24 hrs after LPS administration ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Healthy male volunteers

Exclusion Criteria:

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00246714

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Radboud University Nijmegen Medical Center
Nijmegen, Gelderland, Netherlands, 6500HB
Sponsors and Collaborators
Radboud University
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Principal Investigator: Peter Pickkers, MD PhD Radboud University Nijmegen Medical Center

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Responsible Party: P.Pickkers, Radboud University Medical Centre Identifier: NCT00246714    
Other Study ID Numbers: PP03
First Posted: October 30, 2005    Key Record Dates
Last Update Posted: April 15, 2008
Last Verified: April 2008
Keywords provided by Radboud University:
endotoxin tolerance
pro and anti-inflammatory cytokines
Additional relevant MeSH terms:
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Systemic Inflammatory Response Syndrome
Pathologic Processes