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{{short description|Chemical compound}}
{{Drugbox
{{Use dmy dates|date=December 2019}}
| Verifiedfields = changed
{{Not to be confused with|penicillin}}
| verifiedrevid = 408792792
{{Infobox drug
| IUPAC_name = (2''S'')-2-amino-3-methyl-3-sulfanyl-butanoic acid
| Watchedfields = changed
| image = Penicillamine structure.png
| verifiedrevid = 456485077
| image2 = D-Penicillamine-3D-balls.png
| image = Penicillamine structure.svg
| width2 = 190px
| width = 150
| image2 = D-penicillamine-from-xtal-3D-bs-17.png


<!--Clinical data--> <!--Clinical data-->
| tradename = Cuprimine | tradename = Cuprimine, Cuprenyl, Depen, others
| synonyms = {{ubl|<small>D</small>-penicillamine|(–)-penicillamine}}
| Drugs.com = {{drugs.com|monograph|penicillamine}} | Drugs.com = {{drugs.com|monograph|penicillamine}}
| MedlinePlus = a618021
| pregnancy_category = D <sub>(Aust.)</sub>
| DailyMedID = Penicillamine
| legal_status = Prescription
| pregnancy_AU = D
| routes_of_administration = Oral
| routes_of_administration = ] (])
| ATC_prefix = M01
| ATC_suffix = CC01
| ATC_supplemental =

| legal_US = Rx-only
| legal_status = Rx-only


<!--Pharmacokinetic data--> <!--Pharmacokinetic data-->
| bioavailability = Variable | bioavailability = Variable
| protein_bound = | protein_bound =
| metabolism = Hepatic | metabolism = ]
| elimination_half-life = 1 hour | elimination_half-life = 1 hour
| excretion = Renal | excretion = ]


<!--Identifiers--> <!--Identifiers-->
| IUPHAR_ligand = 7264
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 52-67-5 | CAS_number = 52-67-5
| ATC_prefix = M01
| ATC_suffix = CC01
| ATC_supplemental =
| PubChem = 5852 | PubChem = 5852
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
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| KEGG_Ref = {{keggcite|correct|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00496 | KEGG = D00496
| ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 7959 | ChEBI = 7959
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
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<!--Chemical data--> <!--Chemical data-->
| IUPAC_name = (2''S'')-2-amino-3-methyl-3-sulfanylbutanoic acid
| C=5 | H=11 | N=1 | O=2 | S=1
| C=5 | H=11 | N=1 | O=2 | S=1
| molecular_weight = 149.212 g/mol
| smiles = CC(C)((C(=O)O)N)S | smiles = CC(C)((C(=O)O)N)S
| InChI = 1/C5H11NO2S/c1-5(2,9)3(6)4(7)8/h3,9H,6H2,1-2H3,(H,7,8)/t3-/m0/s1
| InChIKey = VVNCNSJFMMFHPL-VKHMYHEABH
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C5H11NO2S/c1-5(2,9)3(6)4(7)8/h3,9H,6H2,1-2H3,(H,7,8)/t3-/m0/s1 | StdInChI = 1S/C5H11NO2S/c1-5(2,9)3(6)4(7)8/h3,9H,6H2,1-2H3,(H,7,8)/t3-/m0/s1
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| StdInChIKey = VVNCNSJFMMFHPL-VKHMYHEASA-N | StdInChIKey = VVNCNSJFMMFHPL-VKHMYHEASA-N
}} }}
<!-- Definition and medical uses -->
'''Penicillamine''' is a ] of the ] class. It is sold under the trade names of '''Cuprimine''' and '''Depen'''. The pharmaceutical form is ''D''-penicillamine, as ''L''-penicillamine is toxic (it inhibits the action of ]). It is a ] of ], although it has no ] properties.
'''Penicillamine''', sold under the brand name of '''Cuprimine''' among others, is a ] primarily used for the treatment of ].<ref name=AHFS2016/> It is also used for people with ] who have ], ], and various ]s.<ref name=AHFS2016>{{cite web|title=Penicillamine|url=https://www.drugs.com/monograph/penicillamine.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161221002647/https://www.drugs.com/monograph/penicillamine.html|archive-date=21 December 2016}}</ref><ref name=WHO2008/> It is taken by mouth.<ref name=WHO2008/>


<!-- History and culture -->
==Uses==
Penicillamine was approved for medical use in the United States in 1970.<ref name=AHFS2016/> It is on the ].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO }}</ref>
Penicillamine is used as a form of ] to treat ]. It works by reducing numbers of ]s, inhibiting ] function, decreasing ], decreasing ], and preventing ] from cross-linking.


==Medical uses==
It is used as a ]:
It is used as a chelating agent:
* In ], a rare genetic disorder of ] metabolism, penicillamine treatment relies on its binding to accumulated copper and elimination through ].
* In ], a rare genetic disorder of ] metabolism, penicillamine treatment relies on its binding to accumulated copper and elimination through urine.<ref name="xl2">{{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 }}</ref>
* In ], a hereditary disorder featuring formation of ] stones, penicillamine binds with ] to yield a mixed ] which is more ] than cystine.
* Penicillamine was the second line treatment for ], after ] (BAL).<ref>{{cite journal | vauthors = Peterson RG, Rumack BH | title = <small>D</small>-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 }}</ref> It is no longer recommended.<ref>{{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 }}</ref>
* Penicillamine has been used to treat ]

* Penicillamine is the second line treatment for arsenic poisoning, after ] (BAL)
In ], a hereditary disorder in which high urine cystine levels lead to the formation of ] stones, penicillamine binds with cysteine to yield a mixed ] which is more ] than cystine.<ref name="xl4">{{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 }}</ref>

Penicillamine has been used to treat ].<ref>{{cite journal | vauthors = Steen VD, Medsger TA, Rodnan GP | title = <small>D</small>-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 }}</ref>

Penicillamine can be used as a ] (DMARD) to treat severe active rheumatoid arthritis in patients who have failed to respond to an adequate trial of conventional therapy,<ref name="PI">{{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}}</ref> although it is rarely used today due to availability of ]s and other agents, such as ] and ]. Penicillamine works by reducing numbers of ]s, inhibiting ] function, decreasing ], decreasing ], and preventing ] from cross-linking.


==Adverse effects== ==Adverse effects==
Adverse effects include: <!-- Side effects and mechanism -->
Common side effects include rash, loss of appetite, nausea, diarrhea, and ].<ref name=AHFS2016/> Other serious side effects include ], ], and ].<ref name=AHFS2016/> It is not recommended in people with ].<ref name=WHO2008/> Use during ] may result in harm to the baby.<ref name=WHO2008>{{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 }}</ref> Penicillamine works by ]; the resulting penicillamine–metal complexes are then removed from the body in the ].<ref name=AHFS2016/>
*] <ref name=Kumar8-5> Table 14-2 in: {{cite book |author=Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson |title=Robbins Basic Pathology|publisher=Saunders |location=Philadelphia |year= |pages= |isbn=1-4160-2973-7 |oclc= |doi=}} 8th edition. </ref>

*Aplastic anemia (idiosyncratic) <ref>Robbins and Cotran, Pathological Basis of Disease 8th Edition, Kumar et al</ref>
], ], ], ], and ] are the most common ]s, occurring in ~20–30% of the patients treated with penicillamine.<ref name="xl3">{{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 }}</ref><ref>{{cite journal | vauthors = Grasedyck K | title = <small>D</small>-penicillamine--side effects, pathogenesis and decreasing the risks | journal = Zeitschrift für Rheumatologie | volume = 47 | pages = 17–19 | year = 1988 | issue = Suppl 1 | pmid = 3063003 }}</ref>
*Antibody-mediated ], which may persist even after its withdrawal

*Drug-induced systemic lupus erythematosus
Other possible adverse effects include:
*Elastosis perforans serpiginosa <ref>{{cite book |author=Bolognia, Jean; et al | title=Dermatology|publisher=Elsevier|location=Philadelphia|year=2007|pages=|isbn=1416029990|oclc=|doi=}}2nd edition.</ref>
* ]<ref name="xl4" /><ref name="xl3" />
*Toxic myopathies<ref>{{cite book|last=Underwood|first=J. C. E.|title=General and systemic Pathology|year=2009|publisher=Elsevier Limited|isbn=9780443068898}}</ref>
* ]<ref name="xl" />
* ]<ref name=Kumar8-5>{{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}}</ref>
* ] (idiosyncratic)<ref name="xl">{{cite journal | vauthors = Fishel B, Tishler M, Caspi D, Yaron M | title = Fatal aplastic anaemia and liver toxicity caused by <small>D</small>-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 }}</ref>
* Antibody-mediated ]<ref name="xl3" /> and ], which may persist even after its withdrawal
* Drug-induced ]<ref>{{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 }}</ref>
* ]<ref>{{cite book | vauthors = Bolognia J | title=Dermatology|publisher=Elsevier|location=Philadelphia|year=2007|isbn=978-1-4160-2999-1|display-authors=etal}}2nd edition.</ref>
* Toxic ]<ref>{{cite book| vauthors = Underwood JC |title=General and Systemic Pathology|year=2009|publisher=Elsevier Limited|isbn=978-0-443-06889-8}}</ref>
* Unwanted breast growth (])<ref>{{cite journal | vauthors = Taylor PJ, Cumming DC, Corenblum B | title = Successful treatment of <small>D</small>-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 }}</ref>
* ]

==Chemistry==
{{multiple image
| width = 150
| image1 = D-Penicillamine.svg
| caption1 = <small>D</small>-(–)-(''S'')-Penicillamine<br>(antiarthritic)
| image2 = L-Penicillamine.svg
| caption2 = <small>L</small>-(+)-(''R'')-Penicillamine<br>(toxic)
}}

Penicillamine is a tri] organic compound, consisting of a ], an ], and a ]. It is an ] structurally similar to ], but with ] dimethyl ]s α to the thiol. Like most amino acids, it is a colorless solid that exists in the ]ic form at ].

Penicillamine is a ] with one ]; the two ]s have distinctly different ] effects. (''S'')-penicillamine (<small>D</small>-penicillamine, having (–) ]) is antiarthritic.<ref>{{Cite book| vauthors = Ariens EJ |title=Chiral Separations by HPLC|publisher=Ellis Horwwod, Chichester|year=1989|location=Chichester|pages=31–68}}</ref> (''R'')-penicillamine (<small>L</small>-penicillamine, having (+) optical rotation) is toxic because it inhibits the action of ] (also known as ]).<ref>{{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}}</ref> That enantiomer is a ] of ] but has no ] properties itself.<ref name="sb">{{cite journal | vauthors = Parker CW, Shapiro J, Kern M, Eisen HN | title = Hypersensitivity to penicillenic acid derivatives in human beings with penicillin allergy | journal = The Journal of Experimental Medicine | volume = 115 | issue = 4 | pages = 821–838 | date = April 1962 | pmid = 14483916 | pmc = 2137514 | doi = 10.1084/jem.115.4.821 }}</ref> A variety of penicillamine–copper complex structures are known.<ref>{{cite journal | vauthors = Birker PJ, Freeman HC | title = Structure, properties, and function of a copper(I)-copper(II) complex of <small>D</small>-penicillamine: pentathallium(I) μ<sub>8</sub>-chloro-dodeca(<small>D</small>-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 }}</ref>


==History== ==History==
Dr. John Walshe (1956) first described the use of penicillamine in Wilson's disease.<ref name=Walshe1956>{{cite journal |author=Walshe JM |title=Wilson's disease; new oral therapy |journal=Lancet |volume=267 |issue=6906 |pages=25–6 |year=1956 |month=January |pmid=13279157 |doi=10.1016/S0140-6736(56)91859-1}}</ref> He had discovered the compound in the urine of patients (including himself) who had taken ], and experimentally confirmed that it increased urinary copper excretion by ]. He had initial difficulty convincing several world experts of the time (Drs 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 ] 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 ], 2HCl, and ].<ref>{{cite journal |author=Walshe JM |title=The story of penicillamine: a difficult birth |journal=Mov. Disord. |volume=18 |issue=8 |pages=853–9 |year=2003 |month=August |pmid=12889074 |doi=10.1002/mds.10458}}</ref> John Walshe first described the use of penicillamine in Wilson's disease in 1956.<ref name=Walshe1956>{{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 }}</ref> He had discovered the compound in the urine of patients (including himself) who had taken ], and experimentally confirmed that it increased urinary copper excretion by ]. 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 ] should be used as a chelator. Later studies confirmed both the copper-centered theory and the efficacy of <small>D</small>-penicillamine. Walshe also pioneered other chelators in Wilson's such as ] and ].<ref>{{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 }}</ref>


Penicillamine was first synthesized by ] under supervision of ].<ref>{{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 }}</ref>
==References==

Penicillamine has been used in rheumatoid arthritis since the first successful case in 1964.<ref>{{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 }}</ref>

== Cost ==
In the United States, ] raised the cost of the medication from about US$500 to US$24,000 per month in 2016.<ref>{{cite news| vauthors = Petersen M |title=How 4 drug companies rapidly raised prices on life-saving drugs|work=]|url=https://www.latimes.com/business/la-fi-senate-drug-price-study-20161221-story.html|access-date=27 March 2019}}</ref>

== References ==
{{reflist}} {{reflist}}


==External links== == External links ==
* {{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 }}
* - Medlineplus.org
* - Medicinenet.com


{{Antirheumatic products}} {{Antirheumatic products}}
{{Chelating agents}} {{Chelating agents}}
{{Non-proteinogenic amino acids}}
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