Effect of Selective iNOS Inhibition During Human Endotoxemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00184990
Recruitment Status : Completed
First Posted : September 16, 2005
Last Update Posted : April 15, 2008
Information provided by:
Radboud University

Brief Summary:
Sepsis or endotoxemia is manifested by hypotension, resistance to vasopressors, myocardial depression,and altered organ blood flow distribution. The mechanisms underlying the cardiovascular dysfunction during sepsis are complex; however, they are partially mediated by an uncontrolled production of NO by inducible NO synthase (iNOS).Control subjects received 2 ng/kg E. coli endotoxin, whereas the active intervention group received endotoxin in the presence of selective iNOS-inhibitor aminoguanidine. Hemodynamics, vascular responses to norepinephrine, acetylcholine and sodium nitroprusside, as well as circulating cytokines and other mediators of inflammation were measured. We tested the hypothesis that inhibition of NO-synthesis prevented the LPS-mediated insensitivity to noradrenalin and endothelial-dependent vasorelaxation. Furthermore, we tested whether NO participates in occurrence of the endotoxin tolerance in humans by using the iNOS inhibitor aminoguanidine on healthy volunteers with endotoxemia. At 0; 2 and 4 hours after the LPS challenge whole blood was stimulated with five TLR agonists in vitro and pro- and anti-inflammatory cytokines were measured.

Condition or disease Intervention/treatment Phase
Endotoxemia Drug: Aminoguanidine Drug: endotoxin Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 7 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Effect of Selective iNOS Inhibition During Human Endotoxemia
Study Start Date : January 2005
Actual Primary Completion Date : September 2005
Actual Study Completion Date : September 2005

Primary Outcome Measures :
  1. Hemodynamics [ Time Frame: 24 hrs after LPS administration ]
  2. Markers of Inflammation [ Time Frame: 24 hrs after LPS administration ]
  3. Cytokines [ Time Frame: 24 hrs after LPS administration ]
  4. Markers of Renal Injury [ Time Frame: 24 hrs after LPS administration ]
  5. Inducible NO synthase expression [ Time Frame: 24 hrs after LPS administration ]
  6. NO-metabolites [ Time Frame: 24 hrs after LPS administration ]
  7. Mediators of Vascular reactivity [ Time Frame: 24 hrs after LPS administration ]
  8. Sensitivity to norepinephrine [ Time Frame: 24 hrs after LPS administration ]
  9. Endothelial-dependent vasorelaxation [ Time Frame: 24 hrs after LPS administration ]

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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Healthy volunteers

Exclusion Criteria:

  • tendency towards fainting
  • alcohol abuse
  • nicotine abuse
  • drugs abuse

Information from the National Library of Medicine

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 identifier (NCT number): NCT00184990

Radboud University Nijmegen Medical Centre
Nijmegen, Gelderland, Netherlands, 6500HB
Sponsors and Collaborators
Radboud University
Principal Investigator: Peter Pickkers, PhD Radboud University Identifier: NCT00184990     History of Changes
Other Study ID Numbers: PP01
First Posted: September 16, 2005    Key Record Dates
Last Update Posted: April 15, 2008
Last Verified: April 2008

Keywords provided by Radboud University:

Additional relevant MeSH terms:
Systemic Inflammatory Response Syndrome
Pathologic Processes
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action