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

Abstract

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.

Biodistribution of64Cu in rats after topical application of two lipophilic anti-inflammatory Cu(II) formulations

“…Evidence was adduced [4][5][6] that this third possibility was unlikely to account for all the anti-inflammatory activity observed in these pharmacological assays. The second proposal was deemed to be unlikely because of the rapid manifestation of anti-inflammatory activity and in the light of data obtained with adrenalectomized animals [4,5].…”

“…In previous communications [4][5][6], we reported the anti-inflammatory/anti-oedemic efficacy of lipophilic copper(II) formulations applied to the shaved dorsal skin of rats treated with acute inflammagens (including sodium carrageenan, zymosan and hydroxylapatite) or suffering from chronic adjuvant-induced polyarthritis.…”

“…This communication reports an investigation of the first proposal, namely that copper(II) can rapidly penetrate the dermis if presented in a lipophilic formulation with an appropriate ligand/cupriphore. The cupriphores employed in the present study were salicylate [4] and phenylbutazone [6].…”

Modulation of polymorphonuclear leukocyte responsiveness by copper (II)2 (niflumate)4

“…Since tetrakis-g-2-[3-trifluoromethyl)phenyl] aminonicotinatodicopper (II) [Cu(II)2 (niflumate)4] is known to be a more effective anti-inflammatory agent [1,4] and analgesic agent [5] than niflumic acid and Cu(II)2(niflumate)4 is an effective antiulcer agent [1,2,6] unlike niflumic acid, which is ulcerogenic, the question arose as to the difference in mechanistic effectiveness of these compounds in modulating polymorphonuclear leukocyte (PMNL) reactivity in response to inflammation.…”

Corrosion Chemistry of Copper: Formation of Potentially Skin-Diffusible Compounds

“…Such information is based on clinical observations of remedial action in infl ammatory diseases, describing therapeutic effects [48][49][50] , and qualitative observation by spectroscopic methods [51; Warner R.R., pers. commun.…”