Antagonism of in vivo and ex vivo response to endotoxin by E5564, a synthetic lipid A analogue.

Abstract

E5564, a synthetic lipid A analogue, is a selective, highly active antagonist of endotoxin-mediated activation of immune cells. Preclinical research has indicated that E5564 can block endotoxin-mediated induction of cytokines and endotoxin or Gram-negative bacterial-induced death in animal models. Recent phase I clinical trials have focused on the ability of E5564 to block responsiveness to endotoxin. This was done in two ways: in vivo challenge of human volunteers with 4 ng/kg endotoxin, and by use of an ex vivo assay which utilizes blood drawn from volunteers administered E5564 and challenged with endotoxin at concentrations that ranged from 50 pg/ml to 10 ng/ml. In vivo, > or = 100 microg of E5564 completely blocked signs, symptoms and cytokines induced by concomitantly-administered endotoxin. In contrast, subjects receiving a 50 microg dose of E5564 demonstrated a graded response; cytokines were inhibited > or = 95%, but many signs and symptoms of endotoxemia were still evident. E5564 demonstrated a long pharmacokinetic half-life (> 30 h); however, ex vivo analysis indicated that while single doses of 350 microg induced a nearly complete block of the effects of 1 ng/ml endotoxin immediately upon E5564 administration, antagonistic activity declined rapidly (t(1/2) < 1 h). Similar results were obtained in vivo using a delayed endotoxin challenge. These results have driven us to examine antagonistic activity of E5564 in vivo and ex vivo after administration by continuous infusion or twice-daily dosing. Results from these multiple-dose studies indicate that under these conditions of administration, plasma levels of E5564 can be predictive of long-term pharmacodynamic activity.

• Authors: Daniel P Rossignol, Melvyn Lynn
• Journal: Journal of endotoxin research (J Endotoxin Res) Vol. 8 Issue 6 Pg. 483-8 ( 2002) ISSN: 0968-0519 [Print] United States
• PMID: 12697095 (Publication Type: Journal Article)

Chemical References

• Cytokines
• E5564
• Lipid A
• Lipopolysaccharides

Topics

• Animals
• Cell Culture Techniques
• Cytokines (biosynthesis)
• Disease Models, Animal
• Half-Life
• Humans
• Lipid A (administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology)
• Lipopolysaccharides (adverse effects, antagonists & inhibitors)
• Macrophages (immunology)
• Mice