DIFFERENTIATION IN-VIVO OF CLASSICAL NONSTEROIDAL ANTIINFLAMMATORY DRUGS FROM CYTOKINE SUPPRESSIVE ANTIINFLAMMATORY DRUGS AND OTHER PHARMACOLOGICAL CLASSES USING MOUSE-TUMOR 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 i n vivo, to examine the biochemistry and pharmacology of inflammatory c ytokine production. It appears that classical nonsteroidal antiinflamm atory drugs (NSAIDs) (prostaglandin H synthase 1 (PGHS-1) inhibitors) do not inhibit but instead stimulate cytokine production. in the curre nt study, the authors utilized LPS-induced TNF alpha production in the Balb/c mouse to evaluate the activity of a classical NSAID, a mixed i nhibitor, and SmithKline Beecham cytokine suppressive antiinflammatory drugs (CSAID(TM)). The results corroborated the stimulation of TNF al pha production by NSAIDs (indomethacin, naproxen, ibuprofen) and indic ated 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 i nhibit 5-lipoxygenase, cyclooxygenase and cytokine production, also st imulated TNF alpha production while the 5-lipoxygenase inhibitor, phen idone, was inactive. The CSAID(TM) (exemplified by SK&F 86002, SK&F 10 5809 and SK&F 104351), strongly inhibited TNF alpha production in this model system (ED(50)s of 32, 48, and 34 mg/kg p.o., respectively). Th ese results clearly differentiate CSAID(TM) from the other compounds t ested and suggest that CSAID(TM) are relatively weak inhibitors of PGH S 1 while being potent inhibitors of inflammatory cytokine production.