Effect of tirilazad mesylate (U74006F) on eicosanoid and tumor necrosis factor generation in healthy and endotoxemic neonatal calves

Abstract

The effects of a 21-aminosteroid, tirilazad mesylate (U74006F; The Upjohn Co., Kalamazoo, MI), developed for treatment of central nervous system trauma in human beings, on eicosanoid and tumor necrosis factor (TNF) generation were evaluated in both healthy and endotoxin-challenged neonatal calves. Endotoxemia was induced in 24 neonatal calves by intravenous infusion of Escherichia coli lipopolysaccharide (3.25 micrograms/kg) over 3 hr. Group I calves received the endotoxin infusion alone; group II calves received an infusion of 0.9% saline and were treated with tirilazad mesylate (1.5 mg/kg) 1 hr after the infusion was started, group III and IV calves were treated with tirilazad mesylate 1 hr after or before endotoxin infusion was started. Tirilazad mesylate effectively suppressed production of plasma prostacyclin (6-keto-PGF1 alpha) and TNF in endotoxin-challenged neonatal calves. In addition, production of thromboxane B2 was mitigated by treatment with tirilazad mesylate both 1 hr before and 1 hr after initiation of endotoxin infusion. It appears that tirilazad mesylate effectively suppresses eicosanoid and TNF generation induced by endotoxin, and thus may be beneficial in the treatment of endotoxemia and septicemia in neonatal calves.