Sulphasalazine and derivatives, natural killer activity and ulcerative colitis.
The effects of sulphasalazine, 5-aminosalicylic acid (5-ASA), sulphapyridine and azodisalicylic acid (ADS) in vitro on the natural killer (NK) activity of peripheral blood mononuclear cells (MNC) have been examined and compared with those of the lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA) and the cyclooxygenase inhibitor, indomethacin. Sulphasalazine, sulphapyridine and ADS inhibited NK activity with 50% inhibitory concentrations (IC50) of 0.7, 2.5 and 4.0 mmol/l respectively. The effect was rapidly reversible. In contrast, 5-ASA minimally inhibited NK activity at 50 mmol/l only. NDGA potently inhibited NK activity (IC50 27 mumol/l) but this was only partly reversible in short term incubations. Indomethacin had no effect at concentrations less than those inhibiting cyclo-oxygenase activity (1-10 mumol/l) but potently and reversibly inhibited NK activity at or above 25 mumol/l. The inhibitory effects observed were unlikely to be due to direct toxicity of effector cells as 5-ASA, sulphapyridine and ADS had no effect on the viability of peripheral blood MNC, whereas NDGA and indomethacin lysed MNC only at maximal concentrations tested. Though sulphasalazine produced MNC lysis at and above 1 mmol/l, the rapid reversibility of the inhibition of NK activity at 1 mmol/l suggested that lysis of NK cells contributed little to the suppressive effect at this concentration. The disparity of the therapeutic efficacy and effects on NK activity of sulphasalazine and its derivatives in vitro may suggest that NK activity is not a major pathogenic mechanism in ulcerative colitis. Any inhibitory effect on cellular immune function of indomethacin does not necessarily reflect an effect of cyclo-oxygenase inhibition.
Gibson
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Jewell
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D000636:Aminosalicylic Acids / Q000494:pharmacology; D002396:Catechols / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects*; D016859:Lipoxygenase Inhibitors; D009637:Masoprocol; D019804:Mesalamine; D009000:Monocytes / Q000187:drug effects*; D013427:Sulfapyridine / Q000494:pharmacology; D012460:Sulfasalazine / Q000031:analogs & derivatives / Q000494:pharmacology*
D000636:Aminosalicylic Acids; D002396:Catechols; D016859:Lipoxygenase Inhibitors; D012460:Sulfasalazine; D019804:Mesalamine; D009637:Masoprocol; C032587:olsalazine; D007213:Indomethacin; D013427:Sulfapyridine