title: A lipid A analog, E5531, blocks the endotoxin response in human volunteers with experimental endotoxemia.
abstract: BACKGROUND
  Endotoxin (lipopolysaccharide [LPS]) has been associated with sepsis and the high mortality rate seen in septic shock. The administration of a small amount of LPS to healthy subjects produces a mild syndrome qualitatively similar to that seen in clinical sepsis. We used this model to test the efficacy of an endotoxin antagonist, E5531, in blocking this LPS-induced syndrome.
  
  
  METHODS
  In a placebo-controlled, double-blind study, we randomly assigned 32 healthy volunteers to four sequential groups (100, 250, 500, or 1000 microg of E5531). Each group of eight subjects (six assigned to E5531, two assigned to placebo) received a 30-min intravenous infusion of study drug. LPS (4 ng/kg) was administered to all subjects as an intravenous bolus in the contralateral arm at the midpoint of the infusion. Symptoms, signs, laboratory values, and hemodynamics (by echocardiogram) were evaluated at prospectively defined times.
  
  
  RESULTS
  In subjects receiving placebo, LPS caused headache, nausea, chills, and myalgias. E5531 led to a dose-dependent decrease in these symptoms that was statistically significant (p < .05) except for myalgias. The signs of endotoxemia (fever, tachycardia, and hypotension) were consistently inhibited at the three higher doses (250, 500, and 1000 microg, p < .05). Tumor necrosis factor-alpha and interleukin-6 blood levels were both lower in those who received E5531 (p < .0001). The C-reactive protein level and white blood cell count response were decreased at all doses (p < .0001). The hyperdynamic cardiovascular state (high cardiac index and low systemic vascular resistance) associated with endotoxin challenge was significantly inhibited at the higher doses of E5531.
  
  
  CONCLUSIONS
  E5531 blocks the symptoms and signs and cytokine, white blood cell count, C-reactive protein, and cardiovascular response seen in experimental endotoxemia. This agent is a potent inhibitor of endotoxin challenge in humans and may be of benefit in the prevention or treatment of sepsis and septic shock.
authors.affiliation: Division of Cardiovascular Disease and Critical Care Medicine, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612-3833, USA.
authors.forename: E
authors.initials: E
authors.lastname: Bunnell
authors.forename: M
authors.initials: M
authors.lastname: Lynn
authors.forename: K
authors.initials: K
authors.lastname: Habet
authors.forename: A
authors.initials: A
authors.lastname: Neumann
authors.forename: C A
authors.initials: CA
authors.lastname: Perdomo
authors.forename: L T
authors.initials: LT
authors.lastname: Friedhoff
authors.forename: S L
authors.initials: SL
authors.lastname: Rogers
authors.forename: J E
authors.initials: JE
authors.lastname: Parrillo
mesh_terms: D000293:Adolescent; D000328:Adult; D004311:Double-Blind Method; D019446:Endotoxemia / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008050:Lipid A / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D008297:Male
chemical_list: D008050:Lipid A; D008070:Lipopolysaccharides; C092845:E 5531