Penicillamine

It is used as a chelating agent:

• In Wilson's disease, a rare genetic disorder of copper metabolism, penicillamine treatment relies on its binding to accumulated copper and elimination through urine.{{cite journal | vauthors = Peisach J, Blumberg WE | title = A mechanism for the action of penicillamine in the treatment of Wilson's disease | journal = Molecular Pharmacology | volume = 5 | issue = 2 | pages = 200–209 | date = March 1969 | pmid = 4306792 | doi = 10.1016/S0026-895X(25)14659-2 }} Succimer (dimercaptosuccinic acid) is increasingly used in place of penicillamine.{{cite journal | vauthors = Aaseth J, Skaug MA, Cao Y, Andersen O | title = Chelation in metal intoxication--Principles and paradigms | journal = Journal of Trace Elements in Medicine and Biology | volume = 31 | pages = 260–266 | date = 2015 | pmid = 25457281 | doi = 10.1016/j.jtemb.2014.10.001 | bibcode = 2015JTEMB..31..260A }}
• Penicillamine was the second line treatment for arsenic poisoning, after dimercaprol (BAL).{{cite journal | vauthors = Peterson RG, Rumack BH | title = D-penicillamine therapy of acute arsenic poisoning | journal = The Journal of Pediatrics | volume = 91 | issue = 4 | pages = 661–666 | date = October 1977 | pmid = 908992 | doi = 10.1016/S0022-3476(77)80528-3 }} It is no longer recommended.{{cite journal | vauthors = Hall AH | title = Chronic arsenic poisoning | journal = Toxicology Letters | volume = 128 | issue = 1–3 | pages = 69–72 | date = March 2002 | pmid = 11869818 | doi = 10.1016/S0378-4274(01)00534-3 }}

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.{{cite journal | vauthors = Rosenberg LE, Hayslett JP | title = Nephrotoxic effects of penicillamine in cystinuria | journal = JAMA | volume = 201 | issue = 9 | pages = 698–699 | date = August 1967 | pmid = 6071831 | doi = 10.1001/jama.1967.03130090062021 }}

Penicillamine has been used to treat scleroderma.{{cite journal | vauthors = Steen VD, Medsger TA, Rodnan GP | title = D-Penicillamine therapy in progressive systemic sclerosis (scleroderma): a retrospective analysis | journal = Annals of Internal Medicine | volume = 97 | issue = 5 | pages = 652–659 | date = November 1982 | pmid = 7137731 | doi = 10.7326/0003-4819-97-5-652 }}

Penicillamine can be used as a disease-modifying antirheumatic drug (DMARD) to treat severe active rheumatoid arthritis in patients who have failed to respond to an adequate trial of conventional therapy,{{cite web|title=Cuprimine (penicillamine) Capsules for Oral Use. U.S. Full Prescribing Information|url=http://www.valeant.com/Portals/25/Pdf/PI/Cuprimine-PI.pdf|access-date=29 April 2016|url-status=live|archive-url=https://web.archive.org/web/20150908074509/http://www.valeant.com/Portals/25/Pdf/PI/Cuprimine-PI.pdf|archive-date=8 September 2015}} 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.

Common side effects include rash, loss of appetite, nausea, diarrhea, and low white blood cell levels. Other serious side effects include liver problems, obliterative bronchiolitis, and myasthenia gravis. It is not recommended in people with lupus erythematosus. Use during pregnancy may result in harm to the baby.{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | pages = 64, 592| publisher = World Health Organization }} Penicillamine works by binding heavy metals; the resulting penicillamine–metal complexes are then removed from the body in the urine.

Bone marrow suppression, dysgeusia, anorexia, vomiting, and diarrhea are the most common side effects, occurring in ~20–30% of the patients treated with penicillamine.{{cite journal | vauthors = Camp AV | title = Penicillamine in the treatment of rheumatoid arthritis | journal = Proceedings of the Royal Society of Medicine | volume = 70 | issue = 2 | pages = 67–69 | date = February 1977 | pmid = 859814 | pmc = 1542978 | doi = 10.1177/003591577707000201 }}{{cite journal | vauthors = Grasedyck K | title = D-penicillamine--side effects, pathogenesis and decreasing the risks | journal = Zeitschrift für Rheumatologie | volume = 47 | pages = 17–19 | year = 1988 | issue = Suppl 1 | pmid = 3063003 }}

Other possible adverse effects include:

• Nephropathy
• Hepatotoxicity
• Membranous glomerulonephritis{{cite book|chapter=Table 14-2 | vauthors = Mitchell RS, Kumar V, Abbas AK, Fausto N |title=Robbins Basic Pathology|publisher=Saunders |location=Philadelphia |year= 2007|isbn=978-1-4160-2973-1 |edition=8th}}
• Aplastic anemia (idiosyncratic){{cite journal | vauthors = Fishel B, Tishler M, Caspi D, Yaron M | title = Fatal aplastic anaemia and liver toxicity caused by D-penicillamine treatment of rheumatoid arthritis | journal = Annals of the Rheumatic Diseases | volume = 48 | issue = 7 | pages = 609–610 | date = July 1989 | pmid = 2774703 | pmc = 1003826 | doi = 10.1136/ard.48.7.609 }}
• Antibody-mediated myasthenia gravis and Lambert–Eaton myasthenic syndrome, which may persist even after its withdrawal
• Drug-induced systemic lupus erythematosus{{cite journal | vauthors = Chalmers A, Thompson D, Stein HE, Reid G, Patterson AC | title = Systemic lupus erythematosus during penicillamine therapy for rheumatoid arthritis | journal = Annals of Internal Medicine | volume = 97 | issue = 5 | pages = 659–663 | date = November 1982 | pmid = 6958210 | doi = 10.7326/0003-4819-97-5-659 }}
• Elastosis perforans serpiginosa{{cite book | vauthors = Bolognia J, Rapini RP, Jorizzo JL, Jorizzo JL, Schaffer JV | title= Dermatology|publisher=Elsevier|location=Philadelphia|year=2007|isbn=978-1-4160-2999-1 | edition = 2nd }}
• Toxic myopathies{{cite book| vauthors = Underwood JC |title=General and Systemic Pathology|year=2009|publisher=Elsevier Limited|isbn=978-0-443-06889-8}}
• Unwanted breast growth (macromastia){{cite journal | vauthors = Taylor PJ, Cumming DC, Corenblum B | title = Successful treatment of D-penicillamine-induced breast gigantism with danazol | journal = British Medical Journal | volume = 282 | issue = 6261 | pages = 362–363 | date = January 1981 | pmid = 6780026 | pmc = 1504185 | doi = 10.1136/bmj.282.6261.362-a }}
• Oligospermia

Penicillamine is a trifunctional organic compound, consisting of a thiol, an amine, and a carboxylic acid. It is an amino acid structurally similar to 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.

Penicillamine is a chiral molecule with one stereogenic center; the two enantiomers have distinct physiological effects. {{nowrap|(S)-penicillamine}} ({{nowrap|D-penicillamine}}, having (–) optical rotation) is used as aa drug (a chiral drug).{{Cite book| vauthors = Ariens EJ |title=Chiral Separations by HPLC|publisher=Ellis Horwwod, Chichester|year=1989|location=Chichester|pages=31–68}} {{nowrap|(R)-penicillamine}} ({{nowrap|L-penicillamine}}, having (+) optical rotation) is toxic because it inhibits the action of pyridoxine (also known as vitamin B₆).{{cite book| vauthors = Aronson JK |title=Meyler's Side Effects of Analgesics and Anti-inflammatory Drugs|date=2010|publisher=Elsevier Science|location=Amsterdam|isbn=9780080932941|page=613|url=https://books.google.com/books?id=2WxotnWiiWkC&pg=PA613|url-status=live|archive-url=https://web.archive.org/web/20170910174855/https://books.google.com/books?id=2WxotnWiiWkC&pg=PA613|archive-date=2017-09-10}} {{nowrap|D-penicillamine}} is a metabolite of penicillin but has no antibiotic properties itself. A variety of penicillamine–copper complexes are known.{{cite journal | vauthors = Birker PJ, Freeman HC | title = Structure, properties, and function of a copper(I)-copper(II) complex of D-penicillamine: pentathallium(I) μ₈-chloro-dodeca(D-penicillaminato)-octacuprate(I)hexacuprate(II) n-hydrate | journal = Journal of the American Chemical Society | volume = 99 | issue = 21 | pages = 6890–6899 | date = October 1977 | pmid = 903530 | doi = 10.1021/ja00463a019 }}

John Walshe first described the use of penicillamine in Wilson's disease in 1956.{{cite journal | vauthors = Walshe JM | title = Wilson's disease; new oral therapy | journal = Lancet | volume = 270 | issue = 6906 | pages = 25–26 | date = January 1956 | pmid = 13279157 | doi = 10.1016/S0140-6736(56)91859-1 }} He had discovered the compound in the urine of patients (including himself) 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 (Denny-Brown and Cumings) 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 and tetrathiomolybdate.{{cite journal | vauthors = Walshe JM | title = The story of penicillamine: a difficult birth | journal = Movement Disorders | volume = 18 | issue = 8 | pages = 853–859 | date = August 2003 | pmid = 12889074 | doi = 10.1002/mds.10458 | s2cid = 11406561 }}

Penicillamine was first synthesized by John Cornforth under supervision of Robert Robinson.{{cite book | vauthors = Oakes EH |title=Encyclopedia of World Scientists |date=2007 |publisher=Infobase Publishing |isbn=9781438118826 |page=156 |url=https://books.google.com/books?id=uPRB-OED1bcC&pg=PA156 }}

Penicillamine has been used in rheumatoid arthritis since the first successful case in 1964.{{cite journal | vauthors = Jaffe IA | title = Rheumatoid Arthritis with Arteritis; Report of a Case Treated with Penicillamine | journal = Annals of Internal Medicine | volume = 61 | pages = 556–563 | date = September 1964 | pmid = 14218939 | doi = 10.7326/0003-4819-61-3-556 }}

{{reflist}}

• {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/rn/52-67-5 | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Penicillamine }}

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