Extended in vivo pharmacodynamic activity of E5564 in normal volunteers with experimental endotoxemia [corrected].
E5564 (alpha-D-glucopyranose) is a synthetic antagonist of bacterial endotoxin that has been shown to completely block human endotoxin response. Low doses of E5564 (0.35-3.5 mg) have a long pharmacokinetic half-life, but a surprisingly short ex vivo and in vivo pharmacodynamic half-life (generally less than several hours). To determine whether extended antagonistic activity can be achieved in vivo, this study assesses the pharmacodynamic activity of 4- and 72-h infusions of E5564 into normal volunteers. Administration of 3.5 mg of E5564/h x 72 h completely blocked effects of endotoxin challenge at the end of dosing (72 h), and at 48 and 72 h postdosing. Similarly, a 4-h infusion of E5564, 3 mg/h completely blocked endotoxin administered 8 h postdosing. A lower dose of E5564, 0.5 mg/h x 4 h, ameliorated but did not block most effects of endotoxin 8 h postdosing (p <0.05). Finally, the effect of varying plasma lipoprotein content on E5564 activity was studied in subjects having high or low cholesterol levels (>180 or <140 mg/dl) after 72-h infusion of 252 mg of E5564. No differences were observed. These results demonstrate that E5564 blocks the effects of endotoxin 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 Inc., Glenpointe Centre West, Teaneck, New Jersey 07666-6741, USA. melvyn_lynn@eisai.com
Wong
Y Nancy
YN
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
Wasan
Kishor M
KM
Rossignol
Daniel P
DP
D000293:Adolescent; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D002097:C-Reactive Protein / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D004731:Endotoxins; D006801:Humans; D007962:Leukocytes / Q000187:drug effects; D008050:Lipid A / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D013610:Tachycardia / Q000139:chemically induced
D016207:Cytokines; C404742:E5564; D004731:Endotoxins; D008050:Lipid A; D008070:Lipopolysaccharides; D002097:C-Reactive Protein