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→Medical uses: Recent publications have cited references indicating that penicillamine is effective at reducing serum bilirubin in newborns.
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* In [[cystinuria]], a hereditary disorder featuring formation of [[cystine]] stones, penicillamine binds with [[cysteine]] to yield a mixed [[disulfide]] which is more [[soluble]] than cystine.<ref name="xl4">{{Cite journal | last1 = Rosenberg | first1 = L. E. | last2 = Hayslett | first2 = J. P. | doi = 10.1001/jama.1967.03130090062021 | title = Nephrotoxic Effects of Penicillamine in Cystinuria | journal = JAMA: The Journal of the American Medical Association | volume = 201 | issue = 9 | pages = 698 | year = 1967 | pmid = | pmc = }}</ref>
* In [[cystinuria]], a hereditary disorder featuring formation of [[cystine]] stones, penicillamine binds with [[cysteine]] to yield a mixed [[disulfide]] which is more [[soluble]] than cystine.<ref name="xl4">{{Cite journal | last1 = Rosenberg | first1 = L. E. | last2 = Hayslett | first2 = J. P. | doi = 10.1001/jama.1967.03130090062021 | title = Nephrotoxic Effects of Penicillamine in Cystinuria | journal = JAMA: The Journal of the American Medical Association | volume = 201 | issue = 9 | pages = 698 | year = 1967 | pmid = | pmc = }}</ref>
* Penicillamine has been used to treat [[scleroderma]].<ref>{{Cite journal | last1 = Steen | first1 = V. D. | last2 = Medsger Jr | first2 = T. A. | last3 = Rodnan | first3 = G. P. | 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 | year = 1982 | pmid = 7137731 | doi=10.7326/0003-4819-97-5-652}}</ref>
* Penicillamine has been used to treat [[scleroderma]].<ref>{{Cite journal | last1 = Steen | first1 = V. D. | last2 = Medsger Jr | first2 = T. A. | last3 = Rodnan | first3 = G. P. | 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 | year = 1982 | pmid = 7137731 | doi=10.7326/0003-4819-97-5-652}}</ref>
* Penicillamine was the second line treatment for [[arsenic poisoning]], after [[dimercaprol]] (BAL).<ref>{{Cite journal | last1 = Peterson | first1 = R. G. | last2 = Rumack | first2 = B. H. | doi = 10.1016/S0022-3476(77)80528-3 | title = D-Penicillamine therapy of acute arsenic poisoning | journal = The Journal of Pediatrics | volume = 91 | issue = 4 | pages = 661–666 | year = 1977 | pmid = 908992| pmc = }}</ref> It is no longer recommended.<ref>{{Cite journal | last1 = Hall | first1 = A. H. | title = Chronic arsenic poisoning | doi = 10.1016/S0378-4274(01)00534-3 | journal = Toxicology Letters | volume = 128 | issue = 1–3 | pages = 69–72 | year = 2002 | pmid = 11869818| pmc = }}</ref>
* Penicillamine was the second line treatment for [[arsenic poisoning]], after [[dimercaprol]] (BAL).<ref>{{Cite journal | last1 = Peterson | first1 = R. G. | last2 = Rumack | first2 = B. H. | doi = 10.1016/S0022-3476(77)80528-3 | title = D-Penicillamine therapy of acute arsenic poisoning | journal = The Journal of Pediatrics | volume = 91 | issue = 4 | pages = 661–666 | year = 1977 | pmid = 908992| pmc = }}</ref> It is no longer recommended.<ref>{{Cite journal | last1 = Hall | first1 = A. H. | title = Chronic arsenic poisoning | doi = 10.1016/S0378-4274(01)00534-3 | journal = Toxicology Letters | volume = 128 | issue = 1–3 | pages = 69–72 | year = 2002 | pmid = 11869818| pmc = }}</ref><ref>{{cite journal |last1=Lakatos |first1=L |last2=Kövér |first2=B. |last3=Oroszlán |first3=Gy. |last4=Vekerdy |first4=Zsuzsa |title=D-penicillamine therapy in AB0 hemolytic disease of the newborn infant |journal=European Journal of Pediatrics |date=June 1976 |volume=123 |issue=2 |pages=133-137 |pmid=987908 |url=https://link.springer.com/content/pdf/10.1007/BF00442643.pdf}}</ref>


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,<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|accessdate=29 April 2016|deadurl=no|archiveurl=https://web.archive.org/web/20150908074509/http://www.valeant.com/Portals/25/Pdf/PI/Cuprimine-PI.pdf|archivedate=8 September 2015|df=}}</ref> although it is rarely used today due to availability of [[TNF inhibitor]]s and other agents, such as [[tocilizumab]] and [[tofacitinib]]. Penicillamine works by reducing numbers of [[T cell|T-lymphocyte]]s, inhibiting [[macrophage]] function, decreasing [[Interleukin-1 family|IL-1]], decreasing [[rheumatoid factor]], and preventing [[collagen]] from cross-linking.
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,<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|accessdate=29 April 2016|deadurl=no|archiveurl=https://web.archive.org/web/20150908074509/http://www.valeant.com/Portals/25/Pdf/PI/Cuprimine-PI.pdf|archivedate=8 September 2015|df=}}</ref> although it is rarely used today due to availability of [[TNF inhibitor]]s and other agents, such as [[tocilizumab]] and [[tofacitinib]]. Penicillamine works by reducing numbers of [[T cell|T-lymphocyte]]s, inhibiting [[macrophage]] function, decreasing [[Interleukin-1 family|IL-1]], decreasing [[rheumatoid factor]], and preventing [[collagen]] from cross-linking.

Penicillamine was demonstrated to significantly reduce serum [[bilirubin]] concentration in infants with [[hyperbilirubinemia]] due to AB0 hemolytic disease.<ref>{{cite journal |last1=Lakatos |first1=Lajos |last2=Kövér |first2=B. |last3=Oroszlán |first3=Gy. |last4=Vekerdy |first4=Zsuzsa |title=D-penicillamine therapy in AB0 hemolytic disease of the newborn infant |journal=European Journal of Pediatrics |date=June 1976 |volume=123 |issue=2 |pages=133-137 |pmid=987908 |url=https://link.springer.com/content/pdf/10.1007/BF00442643.pdf}}</ref><ref>{{cite journal |last1=Lakatos |first1=Lajos |last2=Balla |first2=György |last3=Pataki |first3=István |last4=Vekerdy-Nagy |first4=Zsuzsanna |last5=Oroszlán |first5=György |title=D-Penicillamine in the Neonatal Period: Case Reports |journal=International Journal of Medical and Pharmaceutical Case Reports |date=May 2, 2015 |volume=4 |issue=3 |pages=59-63 |doi=10.9734/IJMPCR/2015/17239 |url=http://www.sciencedomain.org/abstract/9069}}</ref><ref>{{cite journal |last1=Mancuso |first1=Cesare |title=Bilirubin and brain: A pharmacological approach |journal=Neuropharmacology |date=May 15, 2017 |volume=118 |pages=113-123 |doi=10.1016/j.neuropharm.2017.03.013 |pmid=28315352 |url=https://www.sciencedirect.com/science/article/pii/S0028390817301053?via%3Dihub}}</ref> In a study of 330 newborns with [[neonatal jaundice]] due to [[hemolysis]], penicillamine significantly reduced serum [[bilirubin]] concentration, and it was more effective than [[phototherapy]] for preterm neonates.<ref>{{cite journal |last1=Lakatos |first1=Lajos |last2=Kövér |first2=B |last3=Vekerdy |first3=S7 |last4=Dvorácsek |first4=E |title=D-penicillamine therapy of neonatal jaundice: comparison with phototherapy. |journal=Acta paediatrica Academiae Scientiarum Hungaricae |date=February 1976 |volume=17 |issue=2 |pages=93-102 |pmid=1036444}}</ref>


==Adverse effects==
==Adverse effects==

Revision as of 10:18, 9 July 2018

Penicillamine
Clinical data
Trade namesCuprimine, Cuprenyl, Depen, others
AHFS/Drugs.comMonograph
Pregnancy
category
  • AU: D
Routes of
administration		by mouth (capsules)
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityVariable
Metabolismliver
Elimination half-life1 hour
Excretionkidney
Identifiers
  • (2S)-2-amino-3-methyl-3-sulfanylbutanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.136 Edit this at Wikidata
Chemical and physical data
FormulaC5H11NO2S
Molar mass149.212 g/mol g·mol−1
3D model (JSmol)
  • CC(C)([C@H](C(=O)O)N)S
  • InChI=1S/C5H11NO2S/c1-5(2,9)3(6)4(7)8/h3,9H,6H2,1-2H3,(H,7,8)/t3-/m0/s1 checkY
  • Key:VVNCNSJFMMFHPL-VKHMYHEASA-N checkY
  (verify)

Penicillamine, sold under the trade names of Cuprimine among others, is a medication primarily used for the treatment of Wilson's disease.[1] It is also used for people with kidney stones who have high urine cystine levels, rheumatoid arthritis, copper poisoning, and lead poisoning.[1][2] It is taken by mouth.[2]

Common side effects include rash, loss of appetite, nausea, diarrhea, and low blood white blood cell levels.[1] Other serious side effects include liver problems, obliterative bronchiolitis, and myasthenia gravis.[1] It is not recommended in people with lupus erythematosus.[2] Use during pregnancy may result in harm to the baby.[2] Penicillamine works by binding heavy metals such that they can be removed from the body in the urine.[1]

Penicillamine was approved for medical use in the United States in 1970.[1] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[3] The wholesale cost in the developing world is about 0.55 to 1.20 USD a dose.[4] In the United States treatment costs more than 200 USD per month.[5]

Medical uses

It is used as a chelating agent:

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,[12] 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.

Penicillamine was demonstrated to significantly reduce serum bilirubin concentration in infants with hyperbilirubinemia due to AB0 hemolytic disease.[13][14][15] In a study of 330 newborns with neonatal jaundice due to hemolysis, penicillamine significantly reduced serum bilirubin concentration, and it was more effective than phototherapy for preterm neonates.[16]

Adverse effects

Bone marrow suppression, dysgeusia, anorexia, vomiting and diarrhea are the most common side effects, occurring in ~20–30% of the patients treated with penicillamine.[17][18]

Other possible adverse effects include:

Chemistry

Penicillamine is a trifunctional organic compound, consisting of a thiol, an amine, and a carboxylic acid. It is very similar chemically to the α-amino acid cysteine, but with geminal methyl groups α to the thiol (SH) group. Like most amino acids, it is a colorless solid that exists in the zwitterionic form. Of its two enantiomers, L-penicillamine is toxic because it inhibits the action of pyridoxine (also known as vitamin B6).[25] L-penicillamine is a metabolite of penicillin. It has no antibiotic properties.[26]

History

John Walshe first described the use of penicillamine in Wilson's disease in 1956.[27] 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, 2 HCl, and tetrathiomolybdate.[28]

Penicillamine was first made by John Cornforth (Somerville College, Oxford) under supervision of Robert Robinson.[29]

Penicillamine has been used in rheumatoid arthritis since the first successful case in 1964.[30] Cuprimine remains in production (2016) by Aton Pharma.[31]

References

  1. ^ a b c d e f "Penicillamine". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  2. ^ a b c d WHO Model Formulary 2008 (PDF). World Health Organization. 2009. pp. 64, 592. ISBN 9789241547659. Archived from the original (PDF) on 13 December 2016. Retrieved 8 December 2016. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  3. ^ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived from the original (PDF) on 13 December 2016. Retrieved 8 December 2016. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  4. ^ "Penicillamine". International Drug Price Indicator Guide. Retrieved 8 December 2016.
  5. ^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 471. ISBN 9781284057560.
  6. ^ Peisach, J.; Blumberg, W. E. (1969). "A mechanism for the action of penicillamine in the treatment of Wilson's disease". Molecular Pharmacology. 5 (2): 200–209. PMID 4306792.
  7. ^ a b Rosenberg, L. E.; Hayslett, J. P. (1967). "Nephrotoxic Effects of Penicillamine in Cystinuria". JAMA: The Journal of the American Medical Association. 201 (9): 698. doi:10.1001/jama.1967.03130090062021.
  8. ^ Steen, V. D.; Medsger Jr, T. A.; Rodnan, G. P. (1982). "D-Penicillamine therapy in progressive systemic sclerosis (scleroderma): A retrospective analysis". Annals of Internal Medicine. 97 (5): 652–659. doi:10.7326/0003-4819-97-5-652. PMID 7137731.
  9. ^ Peterson, R. G.; Rumack, B. H. (1977). "D-Penicillamine therapy of acute arsenic poisoning". The Journal of Pediatrics. 91 (4): 661–666. doi:10.1016/S0022-3476(77)80528-3. PMID 908992.
  10. ^ Hall, A. H. (2002). "Chronic arsenic poisoning". Toxicology Letters. 128 (1–3): 69–72. doi:10.1016/S0378-4274(01)00534-3. PMID 11869818.
  11. ^ Lakatos, L; Kövér, B.; Oroszlán, Gy.; Vekerdy, Zsuzsa (June 1976). "D-penicillamine therapy in AB0 hemolytic disease of the newborn infant" (PDF). European Journal of Pediatrics. 123 (2): 133–137. PMID 987908.
  12. ^ "Cuprimine (penicillamine) Capsules for Oral Use. U.S. Full Prescribing Information" (PDF). Archived from the original (PDF) on 8 September 2015. Retrieved 29 April 2016. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  13. ^ Lakatos, Lajos; Kövér, B.; Oroszlán, Gy.; Vekerdy, Zsuzsa (June 1976). "D-penicillamine therapy in AB0 hemolytic disease of the newborn infant" (PDF). European Journal of Pediatrics. 123 (2): 133–137. PMID 987908.
  14. ^ Lakatos, Lajos; Balla, György; Pataki, István; Vekerdy-Nagy, Zsuzsanna; Oroszlán, György (May 2, 2015). "D-Penicillamine in the Neonatal Period: Case Reports". International Journal of Medical and Pharmaceutical Case Reports. 4 (3): 59–63. doi:10.9734/IJMPCR/2015/17239.
  15. ^ Mancuso, Cesare (May 15, 2017). "Bilirubin and brain: A pharmacological approach". Neuropharmacology. 118: 113–123. doi:10.1016/j.neuropharm.2017.03.013. PMID 28315352.
  16. ^ Lakatos, Lajos; Kövér, B; Vekerdy, S7; Dvorácsek, E (February 1976). "D-penicillamine therapy of neonatal jaundice: comparison with phototherapy". Acta paediatrica Academiae Scientiarum Hungaricae. 17 (2): 93–102. PMID 1036444.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  17. ^ a b c Camp, A. V. (1977). "Penicillamine in the treatment of rheumatoid arthritis". Proceedings of the Royal Society of Medicine. 70 (2): 67–69. PMC 1542978. PMID 859814.
  18. ^ Grasedyck, K. (1988). "D-Penicillamine—side effects, pathogenesis and decreasing the risks". Zeitschrift für Rheumatologie. 47 Suppl 1: 17–19. PMID 3063003.
  19. ^ a b Fishel, B.; Tishler, M.; Caspi, D.; Yaron, M. (1989). "Fatal aplastic anaemia and liver toxicity caused by D-penicillamine treatment of rheumatoid arthritis". Annals of the Rheumatic Diseases. 48 (7): 609–610. doi:10.1136/ard.48.7.609. PMC 1003826. PMID 2774703.
  20. ^ Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson. "Table 14-2". Robbins Basic Pathology (8th ed.). Philadelphia: Saunders. ISBN 1-4160-2973-7.
  21. ^ Chalmers, A.; Thompson, D.; Stein, H. E.; Reid, G.; Patterson, A. C. (1982). "Systemic lupus erythematosus during penicillamine therapy for rheumatoid arthritis". Annals of Internal Medicine. 97 (5): 659–663. doi:10.7326/0003-4819-97-5-659. PMID 6958210.
  22. ^ Bolognia, Jean; et al. (2007). Dermatology. Philadelphia: Elsevier. ISBN 1-4160-2999-0.2nd edition.
  23. ^ Underwood, J. C. E. (2009). General and Systemic Pathology. Elsevier Limited. ISBN 978-0-443-06889-8.
  24. ^ Taylor; Cumming; Corenblum (January 31, 1981). "Successful treatment of D-penicillamine-induced breast gigantism with danazol". Br Med J. 282: 362–3. doi:10.1136/bmj.282.6261.362-a. PMC 1504185. PMID 6780026.
  25. ^ Aronson, J. K. (2010). Meyler's Side Effects of Analgesics and Anti-inflammatory Drugs. Amsterdam: Elsevier Science. p. 613. ISBN 9780080932941. Archived from the original on 2017-09-10. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  26. ^ Parker, C. W.; Shapiro, J.; Kern, M.; Eisen, H. N. (1962). "Hypersensitivity to penicillenic acid derivatives in human beings with penicillin allergy". The Journal of Experimental Medicine. 115 (4): 821–838. doi:10.1084/jem.115.4.821. PMC 2137514. PMID 14483916.
  27. ^ Walshe, J. M. (Jan 1956). "Wilson's disease; new oral therapy". Lancet. 270 (6906): 25–6. doi:10.1016/S0140-6736(56)91859-1. PMID 13279157.
  28. ^ Walshe, J. M. (Aug 2003). "The story of penicillamine: a difficult birth". Mov. Disord. 18 (8): 853–9. doi:10.1002/mds.10458. PMID 12889074.
  29. ^ Oakes, Elizabeth H. (2007). Encyclopedia of World Scientists. Infobase Publishing. p. 156. ISBN 9781438118826.
  30. ^ Jaffe, I. A. (1964). "Rheumatoid Arthritis with Arteritis; Report of a Case Treated with Penicillamine". Annals of Internal Medicine. 61: 556–563. doi:10.7326/0003-4819-61-3-556. PMID 14218939.
  31. ^ "Archived copy". Archived from the original on 2016-01-26. Retrieved 2016-01-19. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)CS1 maint: archived copy as title (link)
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