Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans

Endotoxemia Clinical Trial

Official title:

Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00246714
• Other study ID #: PP03
• Status: Completed
• Phase: Phase 1
• First received: October 28, 2005
• Last updated: April 14, 2008
• Start date: October 2005
• Est. completion date: December 2007

Study information

• Verified date: April 2008
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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.

Description:

See protocol

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: December 2007
• Est. primary completion date: December 2007
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 35 Years

Eligibility

Inclusion Criteria:

• Healthy male volunteers

Exclusion Criteria:

• drug-, nicotine-, alcohol abuses

• tendency towards fainting

• BMI < 18 kg/m2

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Endotoxemia

Intervention

Drug:
• repeated injections of endotoxin during 5 days

Locations

Country	Name	City	State
Netherlands	Radboud University Nijmegen Medical Center	Nijmegen	Gelderland

Sponsors (1)

Lead Sponsor	Collaborator
Radboud University

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	inducing endotoxin tolerance		5 days	No
Primary	Hemodynamics		5 days	No
Primary	Markers of Inflammation		5 days	No
Primary	Cytokines		5 days	No
Primary	Mediators of Vascular reactivity		5 days	No
Primary	Sensitivity to norepinephrine		5 days	No
Primary	Endothelial-dependent vasorelaxation		5 days	No
Primary	Cross tolerance		6 days	No
Primary	Ischemia-reperfusion injury		6 days	No
Primary	Effects on tissue saturation (measured by NIRS)		24 hrs after LPS administration	No