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.
Olivera
D L
DL
SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
Esser
K M
KM
Lee
J C
JC
Greig
R G
RG
Badger
A M
AM
D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D005688:Galactosamine / Q000008:administration & dosage; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D011425:Propionibacterium acnes; D012772:Shock, Septic / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D007093:Imidazoles; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C067914:SK&F 105809; D005688:Galactosamine