Some non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production or actions of oxygen radicals generated by polymorphonuclear leucocytes (PMNs); this mechanism may contribute towards their anti-inflammatory activity. In the present study, the effects of a new enolcarboxamide NSAID, meloxicam, on oxyradical production by human PMNs exposed to various stimuli in vitro were compared with those of other standard NSAIDs. The various stimuli employed were intended to mimic the likely synergies which occur with cytokines and bacterial production (e.g. f-met-leu-phe (fMLP) peptide) in inflamed tissues and to give an insight into the site and mechanism of action of meloxicam and related drugs on the cellular processes involved in oxyradical generation. The results show that meloxicam is a potent inhibitor of oxyradical production at drug concentrations comparable with those encountered during therapy. Its mechanism of action appears similar to that of other enolcarboxamides and, while relatively complex, involves effects which are stimulus dependent and myeloperoxidase sensitive. They probably do not involve inhibition of fMLP-Gi protein receptor activation but may involve tumour necrosis factor-⇌ post-receptor activation. Enolcarboxamides have variable effects on phorbol myristate acetate-protein kinase C3-mediated oxyradical production.

The effect of diethyldithiocarbamate (DDC) and sodium nitroprusside (SNP) on the killing of endothelial cells and on the release of arachidonate by mixtures of oxidants and membrane-damaging agents was studied in a tissue culture model employing bovine aortic endothelial cells labeled either with 51Chromium or 3arachidonic acid. While exposure to low, subtoxic concentrations of oxidants (reagent H2O2, glucose-oxidase generated peroxide, xanthine xanthine oxidase, AAPH-generated peroxyl radical, menadione-generated oxidants) did not result either in cell death or in the loss of membrane-associated arachidonic acid, the addition of subtoxic amounts of a variety of membrane-damaging agents (streptolysin S, PLA2, histone, taurocholate, wheatgerm agglutinin) resulted in a synergistic cell death. However, no significant amounts of arachidonate were released unless proteinases were also present. The addition to these reaction mixtures of subtoxic amounts of DDC (an SOD inhibitor and a copper chelator) not only very markedly enhanced cell death but also resulted in the release of large amounts of arachidonate (in the complete absence of added proteinases). Furthermore, the inclusion in DDC-containing reaction mixtures of subtoxic amounts of SNP, a generator of NO, further enhanced, in a synergistic manner, both cell killing and the release of arachidonate. Cell killing and the release of arachidonate induced by the DDC and SNP-containing mixtures of agonists were strongly inhibited by catalase, glutathione, N-acetyl cysteine, vitamin A, and by a nonpenetrating PLA2 inhibitor as well as by tetracyclines. A partial inhibition of cell killing was also obtained by 1,10-phenanthroline and by antimycin. It is suggested that DDC might amplify cell damage by forming intracellular, loosely-bound complexes with copper and probably also by depleting antioxidant thiols. It is also suggested that "cocktails" containing oxidants, membrane-damaging agents, DDC, and SNP might be beneficial for killing of tumor cells in vivo and for the assessment of the toxicity of xenobiotics in vitro.