Effects of some non-steroidal anti-inflammatory drug copper complexes on polymorphonuclear leukocyte oxidative metabolism

Abstract

Interaction between anti-inflammatory drugs and reactive oxygen metabolites must be considered in the course of pharmacological studies intended to develop new compounds. Effects of indomethacin, aspirin, and 3,5-diisopropylsalicylic acid (3,5-DIPS) and their copper complexes on PMNL oxidative metabolism and the evolution of an acute inflammatory reaction were studied in the rat. Experiments were performed in vitro by assessment of superoxide generation and reduction of chemiluminescence by PMNLs incubated or not (control) in medium containing various concentrations of these compounds. A dose-related decrease of these parameters was observed, however, copper complexes were found to be more effective than their parent drugs or Cu gluconate. Copper complexes were also more effective anti-inflammatory agents than their parent ligands or Cu gluconate when the volume of exudate and number of exudate PMNLs were assessed after induction of pleurisy in rats by injection of isologous serum. It is concluded that modulation of the PMNL oxidative burst by copper complexes offers an accounting for the anti-inflammatory activity of these compounds.

Modulation of polymorphonuclear leukocyte responsiveness by copper (II)2 (niflumate)4

“…Results reported by Nilsson also provide mechanistic understanding in accounting for the modulation of chemotaxis and metabolic burst by copper complexes either after in vitro or in vivo treatment [7,8]. These observations have been confirmed and extended by others using electron spin resonance and NBT reduction in hydroxyl radical generating systems [35], CL of either non-stimulated [26] or phorbol diester stimulated [37] human PMNLs, as well as hematoporphorin and light stimulated systems [36].…”

“…They are also more effective than their parent ligands in modulating rat PMNL chemotaxis and products of the respiratory burst as well as decreasing pleural inflammation [7,8].…”

“…The effect exerted by NSAIDs on these cells in the early phase of the inflammatory response is of major importance in the development of phlogistic and repair processes. It is generally understood that mechanisms of action of the NSAIDs include their inhibition of PMNL functions [7][8][9][10][11].…”

Nutritional supplementation with copper in the rat. I. Effects on adjuvant arthritis development and on some in vivo- and ex vivo-markers of blood neutrophils

“…2) Different synthetic organic or biologically derived copper containing molecules, ceruloplasmin and yeast Cu(I)-thionein included, can decrease some rat or human neutrophil functions such as the chemotactic response [15,16], the superoxide anion generation [17][18][19][20] and the endothelial adhesion [19]. In contrast, the exposure of human polymorphonuclear leukocytes to Cu(II) chloride enhances the fMLP-induced cell migration [21].…”

Piroxicam-copper complexes: Inhibition of polymorphonuclear leukocyte migration toPseudomonas aeruginosa chemotactinsin vivo and superoxide dismutase-like activityin vitro

“…Moreover, mortality induced by lethal P. aeruginosa challenge was prevented in a dose-related fashion by piroxicam treatment [5]. The mechanisms involved in protection were attributed primarily to the inhibition of PMNL recruitment to the lungs induced by the NSAIA, although other less understood mechanisms related to antioxidant activity may be involved [7,8]. Using pulse radiolysis to generate superoxide, it was shown that Cu 2+-complexes of certain small molecules, including NSAIA, are able to dismutate superoxide, thus inactivating this important tissue damaging intermediate [9].…”