RT Journal Article
SR Electronic
T1 Extended in Vivo Pharmacodynamic Activity of E5564 in Normal Volunteers with Experimental Endotoxemia
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 175
OP 181
DO 10.1124/jpet.103.056531
VO 308
IS 1
A1 Melvyn Lynn
A1 Y. Nancy Wong
A1 Janice L. Wheeler
A1 Richard J. Kao
A1 Carlos A. Perdomo
A1 Robert Noveck
A1 Ramon Vargas
A1 Tony D'Angelo
A1 Sandra Gotzkowsky
A1 F. Gilbert McMahon
A1 Kishor M. Wasan
A1 Daniel P. Rossignol
YR 2004
UL http://jpet.aspetjournals.org/content/308/1/175.abstract
AB E5564 (α-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 × 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 × 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. The American Society for Pharmacology and Experimental Therapeutics