Effect of Selective iNOS Inhibition During Human Endotoxemia

This study has been completed.
Sponsor:
Information provided by:
Radboud University
ClinicalTrials.gov Identifier:
NCT00184990
First received: September 12, 2005
Last updated: April 14, 2008
Last verified: April 2008
  Purpose

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 Intervention Phase
Endotoxemia
Drug: Aminoguanidine
Drug: endotoxin
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Effect of Selective iNOS Inhibition During Human Endotoxemia

Resource links provided by NLM:


Further study details as provided by Radboud University:

Primary Outcome Measures:
  • Hemodynamics [ Time Frame: 24 hrs after LPS administration ]
  • Markers of Inflammation [ Time Frame: 24 hrs after LPS administration ]
  • Cytokines [ Time Frame: 24 hrs after LPS administration ]
  • Markers of Renal Injury [ Time Frame: 24 hrs after LPS administration ]
  • Inducible NO synthase expression [ Time Frame: 24 hrs after LPS administration ]
  • NO-metabolites [ Time Frame: 24 hrs after LPS administration ]
  • Mediators of Vascular reactivity [ Time Frame: 24 hrs after LPS administration ]
  • Sensitivity to norepinephrine [ Time Frame: 24 hrs after LPS administration ]
  • Endothelial-dependent vasorelaxation [ Time Frame: 24 hrs after LPS administration ]

Enrollment: 7
Study Start Date: January 2005
Study Completion Date: September 2005
Primary Completion Date: September 2005 (Final data collection date for primary outcome measure)
  Eligibility

Ages Eligible for Study:   18 Years to 35 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy volunteers

Exclusion Criteria:

  • tendency towards fainting
  • alcohol abuse
  • nicotine abuse
  • drugs abuse
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00184990

Locations
Netherlands
Radboud University Nijmegen Medical Centre
Nijmegen, Gelderland, Netherlands, 6500HB
Sponsors and Collaborators
Radboud University
Investigators
Principal Investigator: Peter Pickkers, PhD Radboud University
  More Information

No publications provided

ClinicalTrials.gov Identifier: NCT00184990     History of Changes
Other Study ID Numbers: PP01
Study First Received: September 12, 2005
Last Updated: April 14, 2008
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Radboud University:
Endotoxemia
Aminoguanidine

Additional relevant MeSH terms:
Endotoxemia
Bacteremia
Sepsis
Infection
Toxemia
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Pimagedine
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 23, 2014