Extended in vivo pharmacodynamic activity of E5564 in normal volunteers with experimental endotoxemia [corrected].

Abstract

E5564 (alpha-D-glucopyranose) is a synthetic antagonist of bacterial endotoxin that has been shown to completely block human endotoxin response. Low doses of E5564 (0.35-3.5 mg) have a long pharmacokinetic half-life, but a surprisingly short ex vivo and in vivo pharmacodynamic half-life (generally less than several hours). To determine whether extended antagonistic activity can be achieved in vivo, this study assesses the pharmacodynamic activity of 4- and 72-h infusions of E5564 into normal volunteers. Administration of 3.5 mg of E5564/h x 72 h completely blocked effects of endotoxin challenge at the end of dosing (72 h), and at 48 and 72 h postdosing. Similarly, a 4-h infusion of E5564, 3 mg/h completely blocked endotoxin administered 8 h postdosing. A lower dose of E5564, 0.5 mg/h x 4 h, ameliorated but did not block most effects of endotoxin 8 h postdosing (p <0.05). Finally, the effect of varying plasma lipoprotein content on E5564 activity was studied in subjects having high or low cholesterol levels (>180 or <140 mg/dl) after 72-h infusion of 252 mg of E5564. No differences were observed. These results demonstrate that E5564 blocks the effects of endotoxin in a human model of clinical sepsis and indicate its potential in the treatment and/or prevention of clinical sepsis.

• Authors: Melvyn Lynn, Y Nancy Wong, Janice L Wheeler, Richard J Kao, Carlos A Perdomo, Robert Noveck, Ramon Vargas, Tony D'Angelo, Sandra Gotzkowsky, F Gilbert McMahon, Kishor M Wasan, Daniel P Rossignol
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 308 Issue 1 Pg. 175-81 (Jan 2004) ISSN: 0022-3565 [Print] United States
• PMID: 14566003 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• E5564
• Endotoxins
• Lipid A
• Lipopolysaccharides
• C-Reactive Protein

Topics

• Adolescent
• Adult
• Blood Pressure (drug effects)
• C-Reactive Protein (metabolism)
• Cytokines (metabolism)
• Endotoxemia (chemically induced, metabolism, prevention & control)
• Endotoxins
• Humans
• Leukocytes (drug effects)
• Lipid A (adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Lipopolysaccharides (adverse effects)
• Male
• Middle Aged
• Tachycardia (chemically induced)