Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans - Full Text View

Sponsored by:	Radboud University
Information provided by:	Radboud University
ClinicalTrials.gov Identifier:	NCT00246714

Purpose

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	Intervention	Phase
Endotoxemia	Drug: repeated injections of endotoxin during 5 days	Phase I

Drug Information available for: Proline

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Diagnostic, Non-Randomized, Open Label, Active Control, Parallel Assignment, Pharmacokinetics/Dynamics Study
Official Title:	Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans

Further study details as provided by Radboud University:

Primary Outcome Measures:

inducing endotoxin tolerance [ Time Frame: 5 days ] [ Designated as safety issue: No ]
Hemodynamics [ Time Frame: 5 days ] [ Designated as safety issue: No ]
Markers of Inflammation [ Time Frame: 5 days ] [ Designated as safety issue: No ]
Cytokines [ Time Frame: 5 days ] [ Designated as safety issue: No ]
Mediators of Vascular reactivity [ Time Frame: 5 days ] [ Designated as safety issue: No ]
Sensitivity to norepinephrine [ Time Frame: 5 days ] [ Designated as safety issue: No ]
Endothelial-dependent vasorelaxation [ Time Frame: 5 days ] [ Designated as safety issue: No ]
Cross tolerance [ Time Frame: 6 days ] [ Designated as safety issue: No ]
Ischemia-reperfusion injury [ Time Frame: 6 days ] [ Designated as safety issue: No ]
Effects on tissue saturation (measured by NIRS) [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]

Estimated Enrollment:	16
Study Start Date:	October 2005
Study Completion Date:	December 2007
Primary Completion Date:	December 2007 (Final data collection date for primary outcome measure)

Detailed Description:

See protocol

Eligibility

Ages Eligible for Study:	18 Years to 35 Years
Genders Eligible for Study:	Male
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Healthy male volunteers

Exclusion Criteria:

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00246714

Locations

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

Sponsors and Collaborators

Radboud University

Investigators

Principal Investigator:

Peter Pickkers, MD PhD

Radboud University Nijmegen Medical Center

More Information

Responsible Party:	Radboud University Medical Centre ( P.Pickkers )
Study ID Numbers:	PP03
Study First Received:	October 28, 2005
Last Updated:	April 14, 2008
ClinicalTrials.gov Identifier:	NCT00246714
Health Authority:	Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Radboud University:

endotoxin tolerance
humans
cross-tolerance
pro and anti-inflammatory cytokines

Study placed in the following topic categories:

Systemic Inflammatory Response Syndrome
Sepsis
Bacteremia

Endotoxemia
Toxemia
Inflammation

Additional relevant MeSH terms:

Pathologic Processes
Infection

ClinicalTrials.gov processed this record on January 16, 2009