cupric-glycinate and copper-bis(histidinate)

Single intra-articular injections of copper II bisglycinate [Cu(II)gly] (30-300 micrograms) into guinea-pig knee joints induce progressive joint degradation which first appears after about 2 weeks and peaks about 12 weeks after injection. The stable complex, copper II bishistidinate (300 micrograms) was without effect. The Cu(II)gly induced syndrome has features more in common with osteoarthritis than rheumatoid arthritis in that erosion occurs in the absence of persistent synovial inflammation. The possibility that the damage may be caused by Cu(II)gly inducing free radical formation within the joint, leading to a self-perpetuating chain reaction is discussed. D-Penicillamine and other drugs were tested for their effects on the histological changes induced 4 weeks after the intra-articular injections of 100 micrograms Cu(II)gly. Few significant effects were observed and these were restricted to D-penicillamine, which caused inconsistent protection, sodium aurothiomalate which protected at a dose causing weight loss and prednisolone which exacerbated joint damage. It is concluded that the variability of the control response will need to be reduced before the model can be used for routine drug evaluation but it may be of value in the study of chronic degradative joint disease.

Topics: Animals; Anti-Inflammatory Agents; Arthritis; Arthritis, Rheumatoid; Disease Models, Animal; Glycine; Guinea Pigs; Histidine; Injections, Intra-Articular; Knee Joint; Male; Organometallic Compounds; Osteoarthritis; Penicillamine

Injections of labile copper complexes such as copper II bisglycinate [Cu(II)gly] induce marked inflammatory responses in rats in contrast to stable copper complexes like copper II bishistidinate which are nonirritant. The antirheumatic drugs D-penicillamine, mercaptopyridoxine, thiola and captopril, inhibit Cu(II)gly-induced cutaneous vascular permeability when given intravenously and show oral cupriuretic activity. Inhibition of Cu(II)gly inflammation alone or cupriuretic activity alone do not appear predictive of clinical antirheumatic activity since L-cysteine methylester and trien, which are active in the former and latter tests, respectively, are devoid of clinical antirheumatic activity. Indomethacin and aspirin are inactive in these tests, thus discounting the concept that such drugs act in part through their copper complexes. The mechanisms by which labile copper induces inflammation and by which D-penicillamine-like drugs modulate the response are discussed. It is suggested that copper can generate free radicals in vivo and that D-penicillamine may act by neutralization of labile copper complexes and/or by formation of copper complexes with the capacity to catalyse the dismutation of superoxide anion.

Topics: Animals; Arthritis, Rheumatoid; Capillary Permeability; Copper; Drug Interactions; Extremities; Female; Glycine; Histidine; Inflammation; Male; Organometallic Compounds; Penicillamine; Rats; Rats, Inbred Strains; Skin; Skin Diseases