SK&F 86002 inhibits tumor necrosis factor formation and improves survival in endotoxemic rats

We evaluated the effects of SK&F 86002, a dual 5-lipoxygenase/cyclooxygenase inhibitor, on the responses to 30 mg/kg Escherichia coli endotoxin (bacterial lipopolysaccharides, LPS) in conscious male Sprague-Dawley rats. Injection of LPS increased serum tumor necrosis factor (TNF alpha) activity from 20 U/ml (baseline) to 1,066 +/- 430 and 2,825 +/- 1,155 U/ml (n = 9) at 30 min and 1 h after administration of LPS, respectively (p less than 0.01 as compared with the vehicle control group). This dose of LPS reduced the survival rate to 9% at 48 h (mean survival time 9.7 +/- 2.7 h), increased heart rate (HR) to 494 +/- 18 beats/min, increased the hematocrit to 56 +/- 2 vol%, reduced the circulating platelet count at 6 h to 40% of the initial value, and produced leukopenia of 30% of the initial value at 1 h, with recovery to the initial value at 6 h. Administration of 30 mg/kg SK&F 86002 (intragastric, i.g.) 1 h before injection of LPS reduced serum TNF alpha concentrations to 92 +/- 58 and 184 +/- 117 U/ml at 30 min and 1 h (p less than 0.05), respectively, and also reduced the hemoconcentration. The survival rate was improved to 60% (mean survival time 38.1 +/- 4.3 h; p less than 0.05), although there was no effect on the hemodynamic responses to LPS. SK&F 86002 significantly reduced thrombocytopenia at 30 min and 1 h (p less than 0.05), but not at 3 and 6 h, and had no effect on changes in white blood cell (WBC) count.(ABSTRACT TRUNCATED AT 250 WORDS)