Blocking of responses to endotoxin by E5564 in healthy volunteers with experimental endotoxemia.
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.
Lynn
Melvyn
M
Eisai Medical Research, Teaneck, New Jersey 07666-6741, USA. melvyn_lynn@eisai.com
Rossignol
Daniel P
DP
Wheeler
Janice L
JL
Kao
Richard J
RJ
Perdomo
Carlos A
CA
Noveck
Robert
R
Vargas
Ramon
R
D'Angelo
Tony
T
Gotzkowsky
Sandra
S
McMahon
F Gilbert
FG
D000293:Adolescent; D000328:Adult; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D019446:Endotoxemia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D006801:Humans; D007262:Infusions, Intravenous; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged
D016207:Cytokines; C404742:E5564; D008050:Lipid A; D008070:Lipopolysaccharides