title: 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).
  
  
  CONCLUSIONS
  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.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA. ssolomon@cc.nih.gov
authors.forename: Steven B
authors.initials: SB
authors.lastname: Solomon
authors.forename: Xizhong
authors.initials: X
authors.lastname: Cui
authors.forename: Eric
authors.initials: E
authors.lastname: Gerstenberger
authors.forename: Robert L
authors.initials: RL
authors.lastname: Danner
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Fitz
authors.forename: Steven M
authors.initials: SM
authors.lastname: Banks
authors.forename: Charles
authors.initials: C
authors.lastname: Natanson
authors.forename: Peter Q
authors.initials: PQ
authors.lastname: Eichacker
mesh_terms: D000818:Animals; D001774:Blood Chemical Analysis; D001775:Blood Circulation / Q000502:physiology; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004731:Endotoxins / Q000032:analysis; D004927:Escherichia coli Infections / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D007958:Leukocyte Count; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D008168:Lung / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D016019:Survival Analysis; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: C404742:E5564; D004731:Endotoxins; D008050:Lipid A; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha