Copper complexes: a physiologic approach to the treatment of ‘inflammatory diseases’

Copper is an ‘essential’ metalloelement and as such it is required for life. Since none of the essential metalloelements can be synthesized in vivo it is required that they be obtained in the diet, If, following absorption, copper is not utilized immediately in the synthesis of copper-dependent enzymes it is either stored in the liver or excreted in a homeostatic fashion. It is well established that copper-dependent enzymes are required for cellular utilization of oxygen; dismutation of superoxide; cross-linking of collagen and elastin; synthesis of dihydroxyphenylalanine, melanin, norepinephrine, and epinephrine; metabolism of monoamines; and mobilization of stored iron for hematopoeisis. Other biochemical processes which are less well understood concerning the involvement of copper are: modulation of prostaglandin synthesis, lysosomal membrane permeability, modulation of histamine activity, angiogenesis, enhancement of synaptic vesicle attachment to neuronal plasma membranes, uptake and release of monoamines by synaptosomes, and activation of brain adenylate cyclase. A 2 to 3 fold increase in plasma or serum copper concentration is observed as a general response to infectious, inflammatory, and stress related diseases. It is well documented that blood copper concentrations increase in arthritic diseases, seizures, and neoplastic diseases and it is likely that there is a similar elevation with ulcers and diabetes. These elevations are viewed as a general acute phase physiologic response which facilitates remission. In the event that this physiologic response is impaired remission does not occur. Copper-containing components in blood are: ceruloplasmin which contains 6 atoms of copper and has a molecular weight of 132,000, a copper-albumin complex with a molecular weight of 69,000, and a variety of amino acid complexes with molecular weights in the range of 300 to 400. While there is always a highly significant correlation between the plasma copper increase and the increase in ceruloplasmin, further studies are needed to determine the relative change in concentration of each of the copper-containing components in the physiologic response to disease. This same increase in plasma copper concentration occurs in a variety of animal models of inflammation. Since treatment of these inflammations with exogenous low-molecular-weight copper complexes produces antiinfammatory effects the use of copper complexes may be viewed as a physiological approach to treatment. Low-molecular-weight copper complexes have been shown to have antiarthritic effects in man. In addition to being effective antiinflammatory agents copper complexes have been shown to be effective antiulcer, anticonvulsant, anticancer, and antidiabetic agents. This seeming diverse variety of pharmacologic effects are unified with the hypothesis that copper complexes facilitate or promote tissue repair processes involving copper-dependent enzymes and that arthritis, ulcers, seizures, neoplasia, and diabetes are diseases of specific tissues in disrepair. The corollary to this hypothesis is that the loss or reduction of copper-dependent enzyme mediated processes leads to tissue disfunction which may be re-established with copper complex therapy. Evidence will be presented to show that non-toxic doses of copper complexes have antiinflammatory activity in recognized models of inflammation and that copper complexes of antiinflammatory drugs are more effective than the parent drugs. Data will also be presented to show that copper complexes have antiulcer activity and that copper complexes of antiinflammatory drugs, which are well known ulcerogens, are also potent antiulcer agents. This observation supports the view that copper complexes of antiinflammatory drugs are less toxic than the parent drugs and suggests that complexation may have a role in ulcerogenesis. Anticonvulsant activity of copper complexes in two recognized models of seizure will be presented to show that complexes of non-anticonvulsant and convulsant ligands are effective anticonvulsant agents. In addition, data obtained with a copper complex of an antiepileptic drug suggests that the active form of these drugs may be their copper complexes. Recognition that neoplastic cells have reduced superoxide dismutase (SOD) activity and that copper complexes have SOD-like activity lead to the investigation of copper complexes as anticancer agents. Data will be presented to show that small molecular weight copper complexes inhibit solid Ehrlich tumor growth and increase survival. Following the observation that SOD inhibited streptozotocin-induced diabetes, small molecular weight copper complexes were studied and found to inhibit streptozotocin-induced diabetes as well. This observation will be presented in support of a possible role for copper complexes in the treatment of diabetes.