Inhibition of p38 mitogen-activated protein kinase: dose-dependent suppression of leukocyte and endothelial response after endotoxin challenge in humans.
OBJECTIVE
We studied the activity of a single oral dose of RWJ-67657, a synthetic p38 mitogen-activated protein kinase inhibitor, in preventing dual leukocyte/endothelial activation after endotoxin infusion in healthy volunteers.


METHODS
Prospective placebo-controlled study.


METHODS
Intensive care unit at a university medical center.


METHODS
Twenty-one healthy male volunteers.


METHODS
Endotoxin (4 ng/kg) as a 1-min infusion. According to randomization, the volunteers received placebo (n = 6) or 1400 mg (n = 4), 700 mg (n = 6), or 350 mg (n = 5) of RWJ-67657.


RESULTS
Neutrophil activation was investigated by analyzing the extent of membrane expression of adhesion markers by calibrated flow cytometry. Circulating intercellular adhesion molecule-1 and E-selectin were measured by enzyme-linked immunosorbent assays. The endotoxin-induced shedding of L-selectin was diminished in a dose-dependent manner (p <.0001). High-dose RWJ-67657 prevented up-regulation of the integrins CD11b (p <.01) and CD 66b (p <.01) on neutrophils. The endotoxin-induced increase in circulating intercellular adhesion molecule-1 and circulation E-selectin was almost completely prevented by high-dose RWJ-67657.


CONCLUSIONS
A single oral dose of RWJ-67657 prevented neutrophil and endothelial activation after endotoxin infusion.
Fijen
Jan Willem
JW
Intensive and Respiratory Care Unit, Department of Internal Medicine, University Hospital Groningen, The Netherlands.
Tulleken
Jaap E
JE
Kobold
Anneke C Muller
AC
de Boer
Peter
P
van der Werf
Tjip S
TS
Ligtenberg
Jack J M
JJ
Spanjersberg
Rob
R
Zijlstra
Jan G
JG
D000328:Adult; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000032:analysis; D004727:Endothelium / Q000187:drug effects*; D004731:Endotoxins / Q000008:administration & dosage*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D019041:L-Selectin / Q000032:analysis; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D018375:Neutrophil Activation / Q000187:drug effects*; D011446:Prospective Studies; D011725:Pyridines / Q000008:administration & dosage*; D048051:p38 Mitogen-Activated Protein Kinases
D019040:E-Selectin; D004731:Endotoxins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; C400277:RWJ 67657; D018799:Intercellular Adhesion Molecule-1; D019041:L-Selectin; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases