Effect of Selective iNOS Inhibition During Human Endotoxemia

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.

Study Overview

• Status: Completed
• Conditions: Endotoxemia
• Intervention / Treatment: Drug: endotoxin; Drug: Aminoguanidine

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6500HB
      • Radboud University Nijmegen Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy volunteers

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Peter Pickkers, PhD, Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start: January 1, 2005
• Primary Completion (Actual): September 1, 2005
• Study Completion (Actual): September 1, 2005

Study Registration Dates

• First Submitted: September 12, 2005
• First Submitted That Met QC Criteria: September 12, 2005
• First Posted (Estimate): September 16, 2005

Study Record Updates

• Last Update Posted (Estimate): April 15, 2008
• Last Update Submitted That Met QC Criteria: April 14, 2008
• Last Verified: April 1, 2008

More Information

Terms related to this study

• Keywords: Endotoxemia; Aminoguanidine
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Bacteremia; Toxemia; Endotoxemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Pimagedine
• Other Study ID Numbers: PP01