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Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans

R

Radboud University Medical Center

Status and phase

Completed
Phase 1

Conditions

Endotoxemia

Treatments

Drug: repeated injections of endotoxin during 5 days

Study type

Interventional

Funder types

Other

Identifiers

Details and patient eligibility

About

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.

Full description

See protocol

Enrollment

16 estimated patients

Sex

Male

Ages

18 to 35 years old

Volunteers

Accepts Healthy Volunteers

Inclusion criteria

  • Healthy male volunteers

Exclusion criteria

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

Trial design

Primary purpose

Diagnostic

Allocation

Non-Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

Trial contacts and locations

1

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Data sourced from clinicaltrials.gov

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