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.
Design. Prospective placebo-controlled study.
Setting: Intensive care unit at a university medical center.
Subjects. Twenty-one healthy male volunteers.
Interventions., 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.
Measurements and Main 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.
Conclusion: A single oral dose of RWJ-67657 prevented neutrophil and endothelial activation after endotoxin infusion.
|Number of pages||5|
|Journal||Critical Care Medicine|
|Publication status||Published - Apr-2002|
|Event||13th Annual Congress of the European-Society-of-Intensive-Care-Medicine - ROME, Italy|
Duration: 1-Oct-2000 → 4-Oct-2000
- adhesion molecules
- leukocyte activation
- p38 mitogen-activated protein kinase