Beneficial effects of SK&F 105809, a novel cytokine-suppressive agent, in murine models of endotoxin shock.

SK&F 105809 is a structurally novel dual inhibitor of lipoxygenase and cyclooxygenase-mediated arachidonic acid (AA) metabolism, which has demonstrated antiinflammatory activity in rodent models of inflammation. In addition, the active metabolite of this compound, SK&F 105561, has been shown in vitro to inhibit the production of the inflammatory cytokine interleukin-1 (IL-1) in human monocytes stimulated with lipopolysaccharide (LPS). We report here that in vitro SK&F 105561 also blocks the production of tumor necrosis factor (TNF) from human monocytes (IC50 0.8-3 microM). Furthermore, in a murine model of endotoxin shock in which animals are injected with LPS in combination with D-galactosamine (D-gal), SK&F 105809 (10, 30, and 100 mg/kg p.o.), delivered 30 min prior to LPS/D-gal, caused a dramatic reduction in serum TNF (40-90%) and protected the animals from the lethal effects of this treatment. Similar results were obtained in a second model of endotoxin shock in which mice were sensitized with Propionibacterium acnes 10 days prior to LPS injection. In this system 100-fold higher levels of serum TNF are elicited than with the LPS/D-gal model. Treatment with SK&F 105809 (30 and 100 mg/kg p.o.) delivered 30 min prior to LPS resulted in 90-100% inhibition of serum TNF. Protection from the lethal effects of LPS was observed at these doses in the P. acnes/LPS model.