Penicillamine Explained

Watchedfields:changed
Verifiedrevid:456485077
Width:150
Tradename:Cuprimine, Cuprenyl, Depen, others
Dailymedid:Penicillamine
Pregnancy Au:D
Routes Of Administration:By mouth (capsules)
Atc Prefix:M01
Atc Suffix:CC01
Legal Us:Rx-only
Legal Status:Rx-only
Bioavailability:Variable
Metabolism:Liver
Elimination Half-Life:1 hour
Excretion:Kidney
Iuphar Ligand:7264
Cas Number:52-67-5
Pubchem:5852
Drugbank:DB00859
Chemspiderid:5643
Unii:GNN1DV99GX
Kegg:D00496
Chebi:7959
Chembl:1430
Iupac Name:(2S)-2-amino-3-methyl-3-sulfanylbutanoic acid
C:5
H:11
N:1
O:2
S:1
Smiles:CC(C)([C@H](C(=O)O)N)S
Stdinchi:1S/C5H11NO2S/c1-5(2,9)3(6)4(7)8/h3,9H,6H2,1-2H3,(H,7,8)/t3-/m0/s1
Stdinchikey:VVNCNSJFMMFHPL-VKHMYHEASA-N

Penicillamine, sold under the brand name of Cuprimine among others, is a medication primarily used for the treatment of Wilson's disease. It is also used for people with kidney stones who have high urine cystine levels, rheumatoid arthritis, and various heavy metal poisonings.[1] It is taken by mouth.

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.[2]

Medical uses

It is used as a chelating agent:

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.[6]

Penicillamine has been used to treat scleroderma.[7]

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,[8] 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

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. Use during pregnancy may result in harm to the baby.[9] Penicillamine works by binding heavy metals; the resulting penicillamine–metal complexes are then removed from the body in the urine.[1]

Bone marrow suppression, dysgeusia, anorexia, vomiting, and diarrhea are the most common side effects, occurring in ~20–30% of the patients treated with penicillamine.[10] [11]

Other possible adverse effects include:

Chemistry

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 drug with one stereogenic center; the two enantiomers have distinctly different physiological effects. (S)-penicillamine (D-penicillamine, having (–) optical rotation) is antiarthritic.[18] (R)-penicillamine (L-penicillamine, having (+) optical rotation) is toxic because it inhibits the action of pyridoxine (also known as vitamin B6).[19] That enantiomer is a metabolite of penicillin but has no antibiotic properties itself.[20] A variety of penicillamine–copper complex structures are known.[21]

History

John Walshe first described the use of penicillamine in Wilson's disease in 1956.[22] 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.[23]

Penicillamine was first synthesized by John Cornforth under supervision of Robert Robinson.[24]

Penicillamine has been used in rheumatoid arthritis since the first successful case in 1964.[25]

Cost

In the United States, Valeant raised the cost of the medication from about US$500 to US$24,000 per month in 2016.[26]

External links

Notes and References

  1. Web site: Penicillamine. The American Society of Health-System Pharmacists. 8 December 2016. live. https://web.archive.org/web/20161221002647/https://www.drugs.com/monograph/penicillamine.html. 21 December 2016.
  2. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 21st list 2019 . 2019 . 10665/325771 . World Health Organization . Geneva . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO .
  3. Peisach J, Blumberg WE . A mechanism for the action of penicillamine in the treatment of Wilson's disease . Molecular Pharmacology . 5 . 2 . 200–209 . March 1969 . 4306792 .
  4. Peterson RG, Rumack BH . D-penicillamine therapy of acute arsenic poisoning . The Journal of Pediatrics . 91 . 4 . 661–666 . October 1977 . 908992 . 10.1016/S0022-3476(77)80528-3 .
  5. Hall AH . Chronic arsenic poisoning . Toxicology Letters . 128 . 1–3 . 69–72 . March 2002 . 11869818 . 10.1016/S0378-4274(01)00534-3 .
  6. Rosenberg LE, Hayslett JP . Nephrotoxic effects of penicillamine in cystinuria . JAMA . 201 . 9 . 698–699 . August 1967 . 6071831 . 10.1001/jama.1967.03130090062021 .
  7. Steen VD, Medsger TA, Rodnan GP . D-Penicillamine therapy in progressive systemic sclerosis (scleroderma): a retrospective analysis . Annals of Internal Medicine . 97 . 5 . 652–659 . November 1982 . 7137731 . 10.7326/0003-4819-97-5-652 .
  8. Web site: Cuprimine (penicillamine) Capsules for Oral Use. U.S. Full Prescribing Information. 29 April 2016. live. https://web.archive.org/web/20150908074509/http://www.valeant.com/Portals/25/Pdf/PI/Cuprimine-PI.pdf. 8 September 2015.
  9. Book: WHO Model Formulary 2008 . 2009 . 9789241547659 . ((World Health Organization)) . Stuart MC, Kouimtzi M, Hill SR . 10665/44053 . World Health Organization . 64, 592. World Health Organization .
  10. Camp AV . Penicillamine in the treatment of rheumatoid arthritis . Proceedings of the Royal Society of Medicine . 70 . 2 . 67–69 . February 1977 . 859814 . 1542978 . 10.1177/003591577707000201 .
  11. Grasedyck K . D-penicillamine--side effects, pathogenesis and decreasing the risks . Zeitschrift für Rheumatologie . 47 . 17–19 . 1988 . Suppl 1 . 3063003 .
  12. Book: Table 14-2 . Mitchell RS, Kumar V, Abbas AK, Fausto N . Robbins Basic Pathology. Saunders . Philadelphia . 2007. 978-1-4160-2973-1 . 8th.
  13. Fishel B, Tishler M, Caspi D, Yaron M . Fatal aplastic anaemia and liver toxicity caused by D-penicillamine treatment of rheumatoid arthritis . Annals of the Rheumatic Diseases . 48 . 7 . 609–610 . July 1989 . 2774703 . 1003826 . 10.1136/ard.48.7.609 .
  14. Chalmers A, Thompson D, Stein HE, Reid G, Patterson AC . Systemic lupus erythematosus during penicillamine therapy for rheumatoid arthritis . Annals of Internal Medicine . 97 . 5 . 659–663 . November 1982 . 6958210 . 10.7326/0003-4819-97-5-659 .
  15. Book: Bolognia J . Dermatology. Elsevier. Philadelphia. 2007. 978-1-4160-2999-1. etal. 2nd edition.
  16. Book: Underwood JC . General and Systemic Pathology. 2009. Elsevier Limited. 978-0-443-06889-8.
  17. Taylor PJ, Cumming DC, Corenblum B . Successful treatment of D-penicillamine-induced breast gigantism with danazol . British Medical Journal . 282 . 6261 . 362–363 . January 1981 . 6780026 . 1504185 . 10.1136/bmj.282.6261.362-a .
  18. Book: Ariens EJ . Chiral Separations by HPLC. Ellis Horwwod, Chichester. 1989. Chichester. 31–68.
  19. Book: Aronson JK . Meyler's Side Effects of Analgesics and Anti-inflammatory Drugs. 2010. Elsevier Science. Amsterdam. 9780080932941. 613. live. https://web.archive.org/web/20170910174855/https://books.google.com/books?id=2WxotnWiiWkC&pg=PA613. 2017-09-10.
  20. Parker CW, Shapiro J, Kern M, Eisen HN . Hypersensitivity to penicillenic acid derivatives in human beings with penicillin allergy . The Journal of Experimental Medicine . 115 . 4 . 821–838 . April 1962 . 14483916 . 2137514 . 10.1084/jem.115.4.821 .
  21. Birker PJ, Freeman HC . 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 of the American Chemical Society . 99 . 21 . 6890–6899 . October 1977 . 903530 . 10.1021/ja00463a019 .
  22. Walshe JM . Wilson's disease; new oral therapy . Lancet . 270 . 6906 . 25–26 . January 1956 . 13279157 . 10.1016/S0140-6736(56)91859-1 .
  23. Walshe JM . The story of penicillamine: a difficult birth . Movement Disorders . 18 . 8 . 853–859 . August 2003 . 12889074 . 10.1002/mds.10458 . 11406561 .
  24. Book: Oakes EH . Encyclopedia of World Scientists . 2007 . Infobase Publishing . 9781438118826 . 156 .
  25. Jaffe IA . Rheumatoid Arthritis with Arteritis; Report of a Case Treated with Penicillamine . Annals of Internal Medicine . 61 . 556–563 . September 1964 . 14218939 . 10.7326/0003-4819-61-3-556 .
  26. News: Petersen M . How 4 drug companies rapidly raised prices on life-saving drugs. Los Angeles Times. 27 March 2019.

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