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OpenTrials
Completed

NCT Number: NCT00246714

Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans

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.

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Key information

Conditions

Endotoxemia Bacteremia Infections Inflammation Pathologic Processes Pathological Conditions, Signs and Symptoms Sepsis Systemic Inflammatory Response Syndrome Toxemia

Age range

18 year–35 year

Sex eligibility

Male

Study type

Interventional

Phase

Phase 1

Primary location

Radboud University Nijmegen Medical Center

Nijmegen, Gelderland, 6500HB, Netherlands

About this study

See protocol

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Healthy male volunteers

Exclusion criteria

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

Treatment and study plan

repeated injections of endotoxin during 5 days

Drug

Primary outcomes

  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

Sponsors and collaborators

Lead sponsor

Radboud University Medical Center

Other

Registry information

Important dates

Study start
2005
Primary completion
2007
Study completion
2007
First posted
Oct 31, 2005
Registry last updated
Apr 15, 2008

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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