Differentiation in vivo of classical non-steroidal antiinflammatory drugs from cytokine suppressive antiinflammatory drugs and other pharmacological classes using mouse tumour necrosis factor alpha production.
The stimulation of tumour necrosis factor alpha (TNF alpha) production by lipopolysaccharide (LPS) has been widely used, both in vitro and in vivo, to examine the biochemistry and pharmacology of inflammatory cytokine production. It appears that classical nonsteroidal antiinflammatory drugs (NSAIDs) (prostaglandin H synthase 1 (PGHS-1) inhibitors) do not inhibit but instead stimulate cytokine production. In the current study, the authors utilized LPS-induced TNF alpha production in the Balb/c mouse to evaluate the activity of a classical NSAID, a mixed inhibitor, and SmithKline Beecham cytokine suppressive antiinflammatory drugs (CSAID). The results corroborated the stimulation of TNF alpha production by NSAIDs (indomethacin, naproxen, ibuprofen) and indicated that the stimulation rank-ordered with the potency of inhibition of PGHS-1. Neither acetaminophen nor nabumetone was found to stimulate TNF alpha production significantly. Tenidap, a compound reported to inhibit 5-lipoxygenase, cyclooxygenase and cytokine production, also stimulated TNF alpha production while the 5-lipoxygenase inhibitor, phenidone, was inactive. The CSAID (exemplified by SK&F 86002, SK&F 105809 and SK&F 104351), strongly inhibited TNF alpha production in this model system (ED50s of 32, 48, and 34 mg/kg p.o., respectively). These results clearly differentiate CSAID from the other compounds tested and suggest that CSAID are relatively weak inhibitors of PGHS 1 while being potent inhibitors of inflammatory cytokine production.
Department of Inflammation/Respiratory Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
D E
DE
Griswold
L M
LM
Hillegass
J J
JJ
Breton
K M
KM
Esser
J L
JL
Adams
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D004347:Drug Interactions; D007093:Imidazoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011355:Prodrugs / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007093:Imidazoles; D008070:Lipopolysaccharides; D011355:Prodrugs; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C057655:SK&F 104351; C067914:SK&F 105809; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole