Effects of drotrecogin alfa (activated) in human endotoxemia.
In a phase III clinical trial, drotrecogin alfa (activated) was shown to improve survival and promote faster improvement of cardiovascular and respiratory dysfunction in patients with severe sepsis. To further examine mechanisms involved in the action of this drug, a healthy human endotoxin model was used. Healthy volunteers (eight per group) received drotrecogin alfa (activated) or placebo intravenously for 8 h in a randomized, double-blind, controlled manner. After 2 h of study drug infusion, endotoxin (2 ng/kg) was infused and measurement of physiologic responses and biomarkers continued for 24 h. Consistent with results from severe sepsis clinical trials, drotrecogin alfa (activated) improved mean arterial pressure during the period of infusion after endotoxin exposure. In contrast to severe sepsis clinical trials using drotrecogin alfa (activated) but similar to another human endotoxin study, no significant antithrombotic, profibrinolytic, or anti-inflammatory effects were observed. These results suggest a novel role for drotrecogin alfa (activated) in the human endotoxin model.
Kalil
Andre C
AC
UMDNJ-Robert Wood Johnson Medical School, Department of Surgery, New Brunswick, New Jersey 08903, USA.
Coyle
Susette M
SM
Um
John Y
JY
LaRosa
Steven P
SP
Turlo
Mary Ann
MA
Calvano
Steve E
SE
Sundin
David P
DP
Nelson
David R
DR
Lowry
Stephen F
SF
D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000378:metabolism; D019446:Endotoxemia / Q000188:drug therapy* / Q000378:metabolism*; D004731:Endotoxins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005342:Fibrinolysis; D006801:Humans; D007249:Inflammation; D010919:Placebos / Q000378:metabolism; D011486:Protein C / Q000378:metabolism / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology*; D018805:Sepsis / Q000188:drug therapy; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004731:Endotoxins; D010919:Placebos; D011486:Protein C; D011994:Recombinant Proteins; D013917:Thrombin; C421124:drotrecogin alfa activated