Anti-in¯ammatory properties of diclofenac transition metalloelement complexes Maria Konstandinidou a , Angeliki Kourounakis a , Minas Yiangou a , Lygeri Hadjipetrou a, * , Dimitra Kovala-Demertzi b , Sotiris Hadjikakou b , Mavroudis Demertzis b a Department of Genetics, Development and Molecular Biology, School of Biology, Science, Aristotle's University of Thessaloniki, 54006 Thessaloniki, Greece b Inorganic and Analytical Chemistry, Department of Chemistry, University of Ioannina, 45100 Ioannina, Greece Received 3 June 1997; received in revised form 6 January 1998; accepted 9 January 1998 Abstract As part of our research into understanding drug-metalloelement interactions, we have prepared complexes of Cu(II), Co(II), Ni(II), Mn(II), Fe(II), Fe(III), and Pd(II) with Diclofenac, in order to investigate their anti-in¯ammatory activity. Their inhibitory eects on rat or mouse paw edema induced by Carrageenan, Con-A, Nystatin, and Baker's yeast were compared with those of Di- clofenac. Furthermore, the action of Diclofenac's metalloelement complexes on phagocytosis of yeast by rat peritoneal cells, as well as the capacity of some of the metalloelement complexes to inhibit lipid peroxidation of liver microsomal membranes was also in- vestigated. These complexes exhibited a strong inhibitory eect on Carrageenan-, ConA-, and Nystatin-induced edemas (35±80% inhibition) comparable to the inhibition caused by Diclofenac (61±76% inhibition). Furthermore, complexes with Co(II), Ni(II), Pd(II), and Mn(II) were found to have an anti-in¯ammatory pro®le (35±50% inhibition) superior to diclofenac (17% inhibition) when inhibiting in¯ammations due to Baker's yeast, the mechanism of which involves mainly the activation of lipoxygenase and/ or complement system. Complexes of Ni(II) and Pd(II), which showed signi®cant inhibition of induced-edemas in rats, were also tested in mice at lower and higher doses and showed a signi®cant dose-dependent inhibition of edemas in mice. Some of these com- plexes also interfere with in vitro phagocytosis. The most active anti-in¯ammatory complexes Co(II), Pd(II), and Ni(II), also oered signi®cant protection against lipid peroxidation in vitro, acting as antioxidant compounds, properties that are not demonstrated by Diclofenac. Finally, it is noted that almost all metalloelement complexes of Diclofenac showed high anti-in¯ammatory activity at molecular concentrations much lower than that of Diclofenac. From the present study it is suggested that the anti-in¯ammatory activity of Diclofenac is enhanced by the formation of coordination complexes with transition metalloelements. Ó 1998 Elsevier Science Inc. All rights reserved. Keywords: Diclofenac; Metalloelement complexes; Phlogistics; Anti-in¯ammatory 1. Introduction Diclofenac sodium, (2-[2,6-dichlorophenylami- no]phenylacetate) (Fig. 1) is a potent non-steroidal an- ti-in¯ammatory drug (NSAID), therapeutically used in in¯ammatory and painful conditions of rheumatic and non-rheumatic origin [1]. Diclofenac was found to inhibit cyclooxygenase enzyme activity in vitro with no signi®cant eect on phospholipase A2 or on lipoxygenase enzymes [2]. In vitro inhibition of cyclooxygenase does not translate to in vivo inhibition, but it is suggested that like other NSAIDs, Diclofenac interacts in vivo with the arachidonic acid cascade at the level of cyclooxygenase since it is also found to de- crease prostaglandins in synovial ¯uid in humans and in urine and renal medula in rats and pigs [2]. Diclofenac is highly protein bonded in plasma [1]. It has been found to suppress adjuvant-induced arthritis in rats [3], rheu- matoid arthritis in humans [4], monocyte superoxide production in vitro, and the respiratory burst of human peripheral blood leucocytes with no eect on phagocyto- sis [5]. Journal of Inorganic Biochemistry 70 (1998) 63±69 * Corresponding author. Tel.: +30 31 99 83 95; fax: +30 31 99 83 19; e-mail: hadjipel@bio.auth.gr. 0162-0134/98/$19.00 Ó 1998 Elsevier Science Inc. All rights reserved. PII: S 0 1 6 2 - 0 1 3 4 ( 9 8 ) 0 0 0 1 5 - 4