Effective dosing of lipid A analogue E5564 in rats depends on the timing of treatment and the route of Escherichia coli infection.

Abstract

BACKGROUND:

E5564, a competitive lipid A antagonist, inhibits endotoxin-stimulated inflammation and is under study in patients with sepsis.

METHODS:

We tested whether clinically relevant variables, including the timing of treatment and the route of infection, influenced the effective dosing of E5564 in Escherichia coli-challenged rats.

RESULTS:

All E5564 doses (0.3, 1.0, 2.0, and 3.0 mg/kg intravascular bolus followed by 10% of the bolus dose infused hourly for 24 h) administered 1 h before intravascular E. coli challenge similarly reduced the risk of death. Delaying the start of E5564 to 1 or 3 h after intravascular E. coli challenge significantly reduced the beneficial effect of the doses tested. However, increasing the dose of E5564 reversed some loss of efficacy for delayed treatment (P=.004, for increasing benefit with increasing dose at 1 h). During intrabronchial or intraperitoneal (extravascular) E. coli challenge, the pattern of effective E5564 dosing was the inverse of that for intravascular E. coli challenge (P=.001, for the interaction)--lower doses of E5564 were beneficial and higher doses were not (0.03, 0.3, 1.0, 2.0, and 3.0 mg/kg bolus followed by infusion) (P=.05, for decreasing benefit with increasing dose at 1 h).

CONCLUSION:

These findings suggest that, for maximal clinical benefit, E5564 should be given early and that dosing should be adjusted upward for intravascular infection and downward for extravascular infection.

• Authors: Steven B Solomon, Xizhong Cui, Eric Gerstenberger, Robert L Danner, Yvonne Fitz, Steven M Banks, Charles Natanson, Peter Q Eichacker
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 193 Issue 5 Pg. 634-44 (Mar 01 2006) ISSN: 0022-1899 [Print] United States
• PMID: 16453258 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• E5564
• Endotoxins
• Lipid A
• Lipopolysaccharides
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Blood Chemical Analysis
• Blood Circulation (physiology)
• Colony Count, Microbial
• Disease Models, Animal
• Endotoxins (analysis)
• Escherichia coli Infections (blood, drug therapy, physiopathology)
• Leukocyte Count
• Lipid A (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Lipopolysaccharides (antagonists & inhibitors)
• Lung (pathology)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Sepsis (blood, drug therapy, physiopathology)
• Survival Analysis
• Time Factors
• Tumor Necrosis Factor-alpha (analysis)