M. Marrella

Copper and zinc body levels in inflammation: An overview of the data obtained from animal and human studies

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 inflammed 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.

Review: Copper and inflammation — a possible rationale for the pharmalogical manipulation of inflammatory discorders

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 thein 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.

Copper and zinc status in rats with acute inflammation: focus on the inflamed area.

Status of copper and zinc in plasma, blood cells, liver and hind paws (sectioned at the tibio-tarsal joint) were evaluated in rats with carrageenan-induced paw-oedema; moreover, concentrations of copper and zinc in the supernatant and cell fractions obtained from exudates pooled from rats with carrageenan-induced pleurisy were also determined.The evaluation of copper and zinc status in the blood and in the liver of rats with carrageenan-induced paw oedema, showed that only minor variations differentiated this experimental pathology from the previously studied carrageenan-induced pleurisy in rat.In inflammatory exudates withdrawn from pleural cavity, copper concentrations were found to be higher than the basal values measured in the whole paw, whereas zinc concentrations were found to be dramatically lower.Thus the induction of the carrageenan paw-oedema determined an increase in copper and a decrease in zinc concentrations in the inflamed paw; however, in the inflamed paw, the total amounts of both copper and zinc were found to be significantly increased.

Copper and zinc status during acute inflammation: studies on blood, liver and kidneys metal levels in normal and inflamed rats

The concentrations of copper and zinc in plasma, blood cells, liver and kidneys were determined in a study performed on normal female rats, and in female rats with carrageenan induced pleurisy. In the normal rat, the total amount of both metals increases, from 51 to 79 days of age, in all the compartments examined. This increase was mostly, and in some case exclusively, dependent upon the growth of the animal, although high individual and day to day variations in both copper and zinc values were observed in all the compartments studied. In the blood of inflamed rats a statistically significant increase in copper was measured during the crucial hours of the experiment (i.e. from 6 to 72 h); over 90% of the increase found was attributable to variations in plasma copper concentration values. In the liver of inflamed rats a statistically significant increase in zinc was measured at 6, 22 and 48 h after the carrageenan injection. The induction of the acute non-infective inflammatory process did not cause quantitative changes of both copper and zinc in all the other compartments considered in the present study. These results seem to suggest that, during acute inflammation, the organism increases its requirement for copper and zinc, and that this demand is fulfilled by enhanced intestinal absorption and/or decreased intestinal excretion of both metals.

Comparison of the effects of the antimetastatic compound ImH[trans-RuCl4(DMSO)Im] (NAMI-A) on the arthritic rat and on MCa mammary carcinoma in mice.

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 compund on extracellular matrix and tumor blood vessels.

Copper and zinc status in adjuvant-arthritic rat: studies on blood, liver, kidneys, spleen and inflamed paws

The status of copper and zinc in plasma, blood cells, kidneys, spleen and hind paws was evaluated in tail-injected adjuvant-arthritic rats, during both the asymptomatic (3 and 7 days after the inoculum) and symptomatic (14, 21 and 30 days after the inoculum) phases of the experimental disease. During the symptomatic phase, inflamed rats were studied divided into two groups on the basis of their arthritic scores (low-score L.S. and high-score H.S. arthritic rats).Copper (both in concentration and total amount) was found significantly increased in plasma, blood cells, liver, spleen and arthritic paws, whereas, in the kidneys, it was found to be lower than normal.Zinc was found to be remarkably increased in the liver. In blood, zinc was found to be decreased in plasma, but almost unchanged in the cellular fraction. Zinc total amount (but not concentration) was increased in the spleen, most likely because of a significant increase in spleen weight. As previously described in the case of acute inflammation, zinc concentration was found to be significantly decreased in arthritic paws, whereas the total amount of the metal present in these inflamed tissues was higher than normal.The status of copper and zinc may well differentiate L.S. from H.S. arthritic rats, especially during the latest phase of the experimental disease, and particularly because of a normalization of the considered parameters in the low-score group.Many of the changes observed in the status of both metals were seen prior the appearance of arthritis.The overall accumulation of copper and zinc which is induced in rat by the development of adjuvant arthritis, is suggested to further sustain the hypotesis of increased body requirements for both metals during inflammation.

Synthesis and anti-inflammatory effects of some bis(2-benzimidazolyl)thioethers and their copper(II) chelates, orally administered to rats

Abstract A series of bis(2-benzimidazolyl)thioethers and their copper(II) chelates has been prepared and tested. All the ligands and copper(II) complexes synthesized were orally assayed in the rat for anti-inflammatory activity in both acute (carrageenan edema) and chronic (adjuvant arthritis) models of inflammation. Some compounds were also examined for gastric-irritancy potential. Among tested molecules, the copper complex with the unsubstituted lead structure (NSN) showed the best pharmacological activities, which seem to be dependent upon the presence and bioavailability of some intact complex in the gastrointestinal tract after oral administration. The compound did not exhibit any capacity to elicit significant lesion development of the gastric mucosa of stress-sensitized rats. Structure—activity relationships of the copper complexes are discussed.

Oral zinc sulphate as primary therapeutic intervention in a child with Wilson disease

An 8-year-old boy with an hepatic form of Wilson disease was treated with oral zinc sulphate as the primary and sole therapy. After 4 months, liver function had dramatically improved, and the parameters characterizing copper metabolism had also normalized.

Oral zinc as initial therapy in Wilson's disease: two years of continuous treatment in a 10-year-old child

Two years of continuous therapy promoted a significant overall amelioration in a 10‐year‐old boy affected by an hepatic form of Wilsons disease in which zinc sulphate was the sole therapy. In particular, liver function returned to normal and hepatic histology also improved. The parameters characterizing copper metabolism were kept under good control, and a decrease in copper concentration was found in both erythrocytes and liver. The copper balance study performed during the 25th month of treatment showed that oral zinc was still efficiently inhibiting the intestinal absorption of copper. No side effects have been reported so far.

Concerning the potential therapeutic value of zinc in rheumatoid and psoriatic arthritis

Although less extensively studied than copper, the metabolism of zinc has also been shown to be affected by rheumatoid arthritic conditions, a decrease of plasma zinc concentration being the change most frequently observed.