In Wilson's disease, a rare genetic disorder of copper metabolism, penicillamine treatment relies on its binding to accumulated copper and elimination through urine.
In cystinuria, a hereditary disorder in which high urine cystine levels lead to the formation of cystine stones, penicillamine binds with cysteine to yield a mixed disulfide which is more soluble than cystine. Penicillamine has been used to treat scleroderma. Penicillamine can be used as a disease-modifying antirheumatic drug to treat severe active rheumatoid arthritis in patients who have failed to respond to an adequate trial of conventional therapy, although it is rarely used today due to availability of TNF inhibitors and other agents, such as tocilizumab and tofacitinib. Penicillamine works by reducing numbers of T-lymphocytes, inhibiting macrophage function, decreasing IL-1, decreasing rheumatoid factor, and preventing collagen from cross-linking.
Adverse effects
, dysgeusia, anorexia, vomiting and diarrhea are the most common side effects, occurring in ~20–30% of the patients treated with penicillamine. Other possible adverse effects include:
Penicillamine is a trifunctional organic compound, consisting of a thiol, an amine, and a carboxylic acid. It is structurally similar to the α-amino acid cysteine, but with geminal dimethyl substituents α to the thiol. Like most amino acids, it is a colorless solid that exists in the zwitterionic form at physiological pH. Of its two enantiomers, L-penicillamine is toxic because it inhibits the action of pyridoxine. That enantiomer is a metabolite of penicillin but has no antibiotic properties itself. A variety of penicillamine–copper complex structures are known.
History
John Walshe first described the use of penicillamine in Wilson's disease in 1956. He had discovered the compound in the urine of patients who had taken penicillin, and experimentally confirmed that it increased urinary copper excretion by chelation. He had initial difficulty convincing several world experts of the time of its efficacy, as they held that Wilson's disease was not primarily a problem of copper homeostasis but of amino acid metabolism, and that dimercaprol should be used as a chelator. Later studies confirmed both the copper-centered theory and the efficacy of D-penicillamine. Walshe also pioneered other chelators in Wilson's such as triethylene tetramine dihydrochloride and tetrathiomolybdate. Penicillamine was first synthesized by John Cornforth under supervision of Robert Robinson. Penicillamine has been used in rheumatoid arthritis since the first successful case in 1964.
