TY - JOUR 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 SP - 175 LP - 181 DO - 10.1124/jpet.103.056531 VL - 308 IS - 1 AU - Melvyn Lynn AU - Y. Nancy Wong AU - Janice L. Wheeler AU - Richard J. Kao AU - Carlos A. Perdomo AU - Robert Noveck AU - Ramon Vargas AU - Tony D'Angelo AU - Sandra Gotzkowsky AU - F. Gilbert McMahon AU - Kishor M. Wasan AU - Daniel P. Rossignol Y1 - 2004/01/01 UR - http://jpet.aspetjournals.org/content/308/1/175.abstract N2 - 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 ER -