Biodistribution of 64Cu in inflamed rats following administration of two anti-inflammatory copper complexes.

64Cu was administered in two anti-inflammatory formulations to normal rats and to rats with 2 forms of local inflammation, namely (a) an acute paw oedema (elicited with carrageenan) or (b) a chronic granulomatous response to an implanted irritant (Mycobacterium tuberculosis in a polyurethane sponge). The copper formulations used were (i) a slow release one consisting of Cu(II) salicylate applied dermally with ethanol/DMSO and (ii) short acting hydrophilic complex (Cu(I)Cu(II)-penicillamine)5- given subcutaneously. Three types of changes in copper biodistribution with these forms of inflammation were discerned based on determination of 64Cu and copper content in the following organs: inflammatory locus (foot or sponge implant), kidney, liver, spleen, adrenals, brain, blood, thymus, heart, and skin (site of application). The most evident changes were in the kidneys, liver, spleen, adrenals, thymus and serum from animals with chronic granulomatous inflammation. In contrast, a short term acute inflammatory stress (carrageenan paw oedema) had little effect. While copper D-penicillamine (applied subcutaneously) appeared to move as a bolus through the animals, the results with the percutaneous copper salicylate formulation are consistent with it providing a slow release source of copper(II). Exogenous 64Cu from both formulations was sequestered at inflammatory sites (relative to serum). This may partly explain how applied copper complexes can be anti-inflammatory.

Biodistribution of 64Cu in rats after topical application of two lipophilic anti-inflammatory Cu(II) formulations.

64Cu(II) is extensively absorbed and excreted, mainly in the faeces, when applied to the skin of rats as complexes with (a) salicylate in ethanol with dimethylsulphoxide and glycerol or (b) phenylbutazone in dimethyl sulphoxide and glycerol, previously found to be anti-inflammatory. 64Cu distribution paralleled that observed after administering aqueous 64Cu-salicylate i.m. It is concluded that copper(II) can pass rapidly through the dermal barriers when applied with an appropriate cupriphore and presented in a medium with low water content.

Lipophilic copper(II) formulations: some correlations between their composition and anti-inflammatory/anti-arthritic activity when applied to the skin of rats.

Copper complexes of phenols related to salicylic acid were prepared in DMSO and applied to the shaved dorsal skin of rats. The following activities were assayed: (i) suppression of the carrageenan or hydroxylapatite paw oedemas; (ii) reduction of chronic inflammation in established adjuvant arthritis; (iii) local skin toxicity. Cu(II) was an essential component. Some limited structure-activity correlations were made among alternative cupriphores. DMSO solutions of copper complexes were more potent than their solutions in ethanol. Glycerol was a beneficial additive. Reducing the acidity of some copper salicylate formulations also reduced their potency. Niflumic acid and phenylbutazone were effective non-salicylate transcutaneous cupriphores.

Dermal copper drugs: the copper bracelet and cu(II) salicylate complexes.

A review is presented of both published work and unpublished observations concerned with: a) the 'efficacy' of copper bracelets for arthritis; b) the bio-reactivity of metallic copper (especially with human sweat); c) permeation of the skin by Cu(II) when complexed with certain ligands (such as salicylates); d) the pharmacological and clinical activity of AlcusalR and DermcusalR, two formulations of copper salicylate with ethanol and dimethyl sulphoxide respectively that can be applied to the skin. Topical application promises to be a superior alternative to orally ingested drugs.

Anti-inflammatory activity of a dermally applied copper salicylate preparation (Alcusal).

In rats, dermal (dorsum) application of an ethanolic copper salicylate complex (ECS) in ethanol with glycerol (Alcusal) effectively suppressed established polyarthritis, carrageenan-induced paw oedema and the inflammatory response to hydroxylapatite microcrystals. These responses appear to be due to some degree of synergism between the copper(II) and salicylate, i.e. not solely due to either species alone. Evidence for transdermal absorption of 64Cu from 64Cu-ECS is provided. Some safety aspects of this novel drug are discussed.