Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans
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|ClinicalTrials.gov Identifier: NCT00246714|
Recruitment Status : Completed
First Posted : October 30, 2005
Last Update Posted : April 15, 2008
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|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||16 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|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|
- inducing endotoxin tolerance [ Time Frame: 5 days ]
- Hemodynamics [ Time Frame: 5 days ]
- Markers of Inflammation [ Time Frame: 5 days ]
- Cytokines [ Time Frame: 5 days ]
- Mediators of Vascular reactivity [ Time Frame: 5 days ]
- Sensitivity to norepinephrine [ Time Frame: 5 days ]
- Endothelial-dependent vasorelaxation [ Time Frame: 5 days ]
- Cross tolerance [ Time Frame: 6 days ]
- Ischemia-reperfusion injury [ Time Frame: 6 days ]
- Effects on tissue saturation (measured by NIRS) [ Time Frame: 24 hrs after LPS administration ]
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 ClinicalTrials.gov identifier (NCT number): NCT00246714
|Radboud University Nijmegen Medical Center|
|Nijmegen, Gelderland, Netherlands, 6500HB|
|Principal Investigator:||Peter Pickkers, MD PhD||Radboud University Nijmegen Medical Center|