ANTIINFLAMMATORY PROPERTIES OF DICLOFENAC TRANSITION METALLOELEMENT COMPLEXES

As part of our research into understanding drug-metalloelement interac tions, we have prepared complexes of Cu(II), Co(II), Ni(II), Mn(II), F e(II), Fe(III), and Pd(II) with Diclofenac, in order to investigate th eir anti-inflammatory activity. Their inhibitory effects on rat or mou se paw edema induced by Carrageenan, Con-A, Nystatin, and Baker's yeas t were compared with those of Diclofenac. Furthermore, the action of D iclofenac's metalloelement complexes on phagocytosis of yeast by rat p eritoneal cells, as well as the capacity of some of the metalloelement complexes to inhibit lipid peroxidation of liver microsomal membranes was also investigated. These complexes exhibited a strong inhibitory effect on Carrageenan-, ConA-, and Nystatin-induced edemas (35-80% inh ibition) comparable to the inhibition caused by Diclofenac (61-76% inh ibition). Furthermore, complexes with Co(II), Ni(II), Pd(II), and Mn(I T) were found to have an anti-inflammatory profile (35-50% inhibition) superior to diclofenac (17% inhibition) when inhibiting inflammations due to Baker's yeast, the mechanism of which involves mainly the acti vation of lipoxygenase and/ or complement system. Complexes of Ni(II) and Pd(II), which showed significant inhibition of induced-edemas in r ats, were also tested in mice at lower and higher doses and showed a s ignificant dose-dependent inhibition of edemas in mice. Some of these complexes also interfere with in vitro phagocytosis. The most active a nti-inflammatory complexes Co(II), Pd(II), and Ni(II), also offered si gnificant protection against lipid peroxidation in vitro, acting as an tioxidant compounds, properties that are not demonstrated by Diclofena c. Finally, it is noted that almost all metalloelement complexes of Di clofenac showed high anti-inflammatory activity at molecular concentra tions much lower than that of Diclofenac. From the present study it is suggested that the anti-inflammatory activity of Diclofenac is enhanc ed by the formation of coordination complexes with transition metalloe lements. (C) 1998 Elsevier Science Inc. All rights reserved.