Non-steroidal anti-inflammatory drug-copper complex modulation of polymorphonuclear leukocyte migration

These studies were intended to compare the effects of aspirin, 3,5-diisopropysalicylic acid (3,5-DIPS), and indomethacin with those of their copper complexes: Cu(II)2(aspirinate)4, Cu(II)2(3,5-DIPS)4, and Cu(II)2(indomethacinate)4 as well as Cu(II)2(acetate)4 on polymorphonuclear leukocyte (PMNL) random and directional migration, in addition to their anti-inflammatory activities. Experiments were performed both in vivo and in vitro. In vitro modifications of PMNL migration were measured with the Boyden chamber using N-formyl-methionyl-leucyl-phenylalanine (fMLP) as the chemoattractant and in the agarose assay using fMLP and serum chemotactic derivatives of complement as chemoattractants. In vivo anti-inflammatory activities of these compounds were determined after induction of a serum-induced pleurisy in the rat, and measurement of exudate volume and number of exudative cells 4 hr later. Copper complexes of non-steroidal anti-inflammatory drugs (NSAIDs) were found to be more effective in decreasing random migration and chemotaxis of PMNLs than their parent drugs or Cu(II)2(acetate)4 in in vitro studies. Only chemotaxis was found to be reduced significantly for PMNLs obtained from pleuritic rats after in vivo treatment and the order of copper complex effectiveness was: Cu(II)2(indomethacinate)4 greater than Cu(II)2(3,5-DIPS)4 greater than Cu(II)2(aspirinate)4. All doses of Cu(II)2(acetate)4 administered in vivo failed to affect chemotactic activity. Copper complexes of NSAIDs were also more effective than their parent drugs as anti-inflammatory agents, and Cu(II)2(acetate)4 had no anti-inflammatory activity in this model of inflammation. The order of anti-inflammatory activity was: Cu(II)2(indomethacinate)4 greater than Cu(II)2(3,5-DIPS)4 greater than Cu(II)2(aspirinate)4.