THE DEVELOPMENT OF SCREENING TESTS FOR D-PENICILLAMINE-LIKE ANTIRHEUMATIC ACTIVITY BASED ON IN VIVO INTERACTIONS WITH COPPER

Abstract

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 dis-mutation of superoxide anion.