The development of acute and chronic inflammatory processes induces, in the laboratory animal, a net accumulation of both copper and zinc in many body compartments, the inflamed area included. In rheumatoid arthritis, as well as in animal models, only plasma zinc concentration seems to be significantly correlated with disease severity, while the increase in total plasma copper could be described as an "all or nothing" phenomenon. Moreover, in rheumatoid arthritis, it appears that the disease develops and progresses without being linked to either copper or zinc deficiency conditions. Thus, it seems reasonable to suggest that a rationale for the use of copper and/or zinc in the treatment of inflammatory disorders can only be drawn from the intrinsic pharmacological properties of such trace elements, rather than from the need for their repletion.

The effects of the new molecule ImH[trans-RuCl4(DMSO)Im] (NAMI-A), administered orally or intraperitoneally to adjuvant-arthritic rats or orally to mice bearing s.c. or i.m. implants of MCa mammary carcinoma, were studied. NAMI-A was not able to modify the progression of chronic inflammation in the complete Freund-adjuvant injected animals. Histology indicated a significant worsening of the inflammatory process, characterised by an increased infiltration of inflammatory cells, as well as by a remarkable deposition of connective tissue fibres around the blood vessels and alveolar walls. NAMI-A had no effect on primary i.m. implanted MCa mammary carcinoma growth and its lung metastasis formation, but significantly interfered with the cell cycle of primary tumor cells following bolus oral administration. On the contrary, NAMI-A caused a significant inhibition of lung metastasis accompanied by a dramatic deposition of connective tissue fibres around the primary tumor mass, when given as medicated food to mice implanted s.c. with MCa tumor. These data indicated that NAMI-A is well absorbed after oral administration although there is no connection between lung concentration and the antimetastatic activity. Conversely, the marked deposition of connective tissues in NAMI-A treated animals is in agreement with the reported effects of the compound on extracellular matrix and tumor blood vessels.

No abstract

Acute and chronic inflammations are characterized, among other features, by changes in the metabolism of copper and by a widespread responsiveness to the therapy with copper-containing molecules. The exact map of inflammation-induced copper movements as well as the role played by the metal in the pathogenesis of inflammatory disorders are, however, far from being clear, and this is especially true in the case of chronic processes. Nevertheless the present knowledge suggests that the "copper approach' may provide a new way for coping with the problem of anti-inflammatory/anti-arthritic therapies. The administration of exogenous copper, and the in vivo manipulation of the endogenous metal levels are proposed as two possible therapeutic strategies, not necessarily mutually exclusive. For a better understanding of the value of such an approach, further research work is needed, especially to attain a more detailed know-how on the involved chemical forms, distribution and functions of copper in both normal as well as inflamed organisms.

The concentration of copper in serum and liver was determined by atomic absorption spectrophotometry in a study performed on normal rats of either sex and in female rats with carrageenan‐induced pleurisy. In the normal animal, total serum copper concentration is significantly higher in female rats, and appears to be higher in mature animals in females. In normal rats of either sex, liver copper concentration undergoes daily variations which are inversely related to the weight of the organ and which leave constant the total amount of metal in the liver. Moreover a day to day non‐cyclic variability of liver copper concentration and liver weight was observed. This first set of data showed that comparison with time control was essential. In the inflamed rat, a significant rise of total serum copper at 22, 48 and 72 h after the induction of inflammation was observed. From 96 h up to 240 h post‐injection no significant differences were evident. Total liver copper content did not change in the inflamed rats. During acute inflammation in the rat, the copper needed for the increased synthesis of caeruloplasmin is supplied without depletion of liver copper stores.