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)
Smith
E F
EF
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, plc, King of Prussia, PA 19406.
Slivjak
M J
MJ
Bartus
J O
JO
Esser
K M
KM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003864:Depression, Chemical; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004926:Escherichia coli / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D006400:Hematocrit; D007093:Imidazoles / Q000494:pharmacology*; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D010976:Platelet Count / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013844:Thiazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004731:Endotoxins; D007093:Imidazoles; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole