PROTECTIVE EFFECT OF SK-AND-F 86002, A NOVEL DUAL INHIBITOR OF ARACHIDONIC-ACID METABOLISM, IN MURINE MODELS OF ENDOTOXIN-SHOCK - INHIBITION OF TUMOR NECROSIS FACTOR AS A POSSIBLE MECHANISM OF ACTION

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  • 1 January 1989
    • journal article
    • research article
    • Vol. 27  (1) , 51-61
Abstract
The effect of a new, structurally novel, dual inhibitor of arachidonic acid (AA) metabolism, SK&F 86002, was studied in two murine models of endotoxin shock. The first model was the injection of C57BL/6 mice with lipopolysaccharide (LPS) in combination with D-galactosamine (D-gal), which resulted in death within 6-48 hr. Treatment of these mice with SK&F 86002 (100 mg/kg, p.o.) 30 min to 2 hr prior to the administration of D-gal and LPS protected the animals from mortality. Protection was also provided by treatment with the corticosteroid dexamethasone, whereas only partial protection was afforded by the dual inhibitor of AA metabolism phenidone and the cyclooxygenase inhibitors naproxen and indomethacin. In a similar dosing protocol, SK&F 86002 also protected mice in a seocnd endotoxin shock model in which mice sensitized with Propionibacterium acnes received LPS 10 days later. Moreover, partial protection was obtained when SK&F 86002 was administered therapeutically after LPS injection. The administration of SK&F 86002 to P. acnes/LPS-treated mice decreased serum levels of tumor necrosis factor (TNF), which was not observed following naproxen or indomethacin treatment. Consistent with the role of TNF in this model of endotoxin shock was the observation that treatment with antibodies against TNF also prevented or reduced mortality.