Blocking of responses to endotoxin by E5564 in healthy volunteers with experimental endotoxemia.

Abstract

E5564 is a second-generation synthetic analogue of the lipid A component of endotoxin (lipopolysaccharide [LPS]). The ability of E5564 to block the toxic activity of LPS was assessed in a double-blind, placebo-controlled study. A bolus infusion of endotoxin (4 ng/kg) was administered to healthy subjects to induce a mild transient syndrome similar to clinical sepsis. Single E5564 doses of 50-250 microg ameliorated or blocked all of the effects of LPS in a dose-dependent manner. All E5564 dose groups had statistically significant reductions in elevated temperature, heart rate, C-reactive protein levels, white blood cell count, and cytokine levels (tumor necrosis factor-alpha and interleukin-6), compared with placebo (P<.01). In doses of > or = 100 microg, E5564 acted as an LPS antagonist and completely eliminated these signs. E5564 also blocked or ameliorated LPS-induced fever, chills, headache, myalgia, and tachycardia (P<.01). These results demonstrate that E5564 blocks the effects of LPS in a human model of clinical sepsis and indicate its potential in the treatment and/or prevention of clinical sepsis.

• Authors: Melvyn Lynn, Daniel P Rossignol, Janice L Wheeler, Richard J Kao, Carlos A Perdomo, Robert Noveck, Ramon Vargas, Tony D'Angelo, Sandra Gotzkowsky, F Gilbert McMahon
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 187 Issue 4 Pg. 631-9 (Feb 15 2003) ISSN: 0022-1899 [Print] United States
• PMID: 12599080 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial)

Chemical References

• Cytokines
• E5564
• Lipid A
• Lipopolysaccharides

Topics

• Adolescent
• Adult
• Cytokines (blood)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Endotoxemia (blood, chemically induced, drug therapy)
• Humans
• Infusions, Intravenous
• Lipid A (administration & dosage, analogs & derivatives, therapeutic use)
• Lipopolysaccharides (antagonists & inhibitors)
• Male
• Middle Aged