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Autoimmune diseases, including myasthenia gravis, occur in patients treated with D-penicillamine. Because D-penicillamine might induce autoantibodies by the mechanism of antigenic alteration, we studied the reaction of D-penicillamine with purified acetylcholine receptor from Torpedo californica. We found that brief exposure to D-penicillamine resulted in its covalent attachment to two receptor subunits, alpha (40,000 daltons) and gamma (59,000 Daltons), presumably by reduction and formation of mixed disulfides. Furthermore, D-penicillamine treatment resulted in a dramatic modification of the equilibrium acetylcholine binding properties of both purified receptor and receptor-rich membrane fragments.

A series of mercaptan compounds were studied with respect to their ability to inhibit the growth of poliovirus in cultured cells. Of the compounds tested only d-penicillamine possessed antiviral activity. There was no direct effect on the virus itself, nor were the processes of adsorption, penetration and uncoating, or virus-induced “shut-off” of host cell protein synthesis inhibited. At concentrations where there was no effect on host cell RNA or protein synthesis, d-penicillamine caused a marked inhibition of virus-specific RNA and protein synthesis. Although much reduced, the relative concentrations of single-stranded and double-stranded viral RNA synthesized in the presence of d-penicillamine was unchanged. Similarly, all apparent precursor and cleavage product proteins could be synthesized in the presence of the drug. The inhibitory effect was reversible, after a lag of 1.5 to 2 h after removal of the drug, and normal yields of virus could be obtained. The structural and functional properties of d-penicillamine are discussed in relation to requirements for anti-polioviral activity.

Neutrophilic agranulocytosis developed in two patients with rheumatoid arthritis within the first five weeks of administration of penicillamine (D-penicillamine). One patient died from sepsis, the other recovered after discontinuation of the drug which was resumed at a lower dose without resultant untoward effects. The characteristic hematological findings were compared with those occurring in the course of agranulocytosis caused by other unrelated drugs. In the light of the pathological and laboratory findings, a cytotoxic effect and not an immunologic mechanism was responsible for the neutrophilic agranulocytosis in the patients described. Previous therapy with adrenal corticosteroids in both patients, leading to adrenal cortical insufficiency, may have played a role in the development of the hematological [ill]oxicity.