Inhibition of p38 mitogen-activated protein kinase: dose-dependent suppression of leukocyte and endothelial response after endotoxin challenge in humans.
Crit Care Med
; 30(4): 841-5, 2002 Apr.
Article
en En
| MEDLINE
| ID: mdl-11940756
ABSTRACT
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 MAINRESULTS:
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piridinas
/
Activación Neutrófila
/
Proteínas Quinasas Activadas por Mitógenos
/
Endotelio
/
Endotoxinas
/
Inhibidores Enzimáticos
/
Imidazoles
Tipo de estudio:
Clinical_trials
/
Observational_studies
Límite:
Adult
/
Humans
/
Male
Idioma:
En
Revista:
Crit Care Med
Año:
2002
Tipo del documento:
Article
País de afiliación:
Países Bajos