Penicillamine

Penicillamine

Clinical data
Trade names	Cuprimine
AHFS/Drugs.com	Monograph
Pregnancy category	AU: D US: D (Evidence of risk)
Routes of administration	Oral (capsules)
ATC code	M01CC01 (WHO)
Legal status
Legal status	US: ℞-only ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	Variable
Metabolism	Hepatic
Biological half-life	1 hour
Excretion	Renal
Identifiers
IUPAC name (2S)-2-amino-3-methyl-3-sulfanylbutanoic acid
CAS Number	52-67-5
PubChem (CID)	5852
IUPHAR/BPS	7264
DrugBank	DB00859
ChemSpider	5643
UNII	GNN1DV99GX
KEGG	D00496
ChEBI	CHEBI:7959
ChEMBL	CHEMBL1430
ECHA InfoCard	100.000.136
Chemical and physical data
Formula	C5H11NO2S
Molar mass	149.212 g/mol
3D model (Jmol)	Interactive image
SMILES CC(C)([C@H](C(=O)O)N)S
InChI InChI=1S/C5H11NO2S/c1-5(2,9)3(6)4(7)8/h3,9H,6H2,1-2H3,(H,7,8)/t3-/m0/s1 Key:VVNCNSJFMMFHPL-VKHMYHEASA-N
(verify)

Penicillamine, sold under the trade names of Cuprimine, Cuprenyl and Depen, is a medication of the chelator class.^[1] It is D-penicillamine, as L-penicillamine is toxic (it inhibits the action of pyridoxine, also known as vitamin B₆).^[2] It is an α-amino acid metabolite of penicillin, although it has no antibiotic properties.^[3]

It is on the World Health Organization's List of Essential Medicines, the most important medication needed in a basic health system.^[4]

Medical uses

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.^[1]
• 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.^[5]
• Penicillamine has been used to treat scleroderma.^[6]
• Penicillamine was the second line treatment for arsenic poisoning, after dimercaprol (BAL).^[7] It is no longer recommended.^[8]

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,^[9] 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

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:

• Nephropathy^[5][10]
• Hepatotoxicity^[12]
• Membranous glomerulonephritis^[13]
• Aplastic anemia (idiosyncratic)^[12]
• Antibody-mediated myasthenia gravis^[10] and Lambert–Eaton myasthenic syndrome, which may persist even after its withdrawal
• Drug-induced systemic lupus erythematosus^[14]
• Elastosis perforans serpiginosa^[15]
• Toxic myopathies^[16]
• Unwanted breast growth^[17]

History

John Walshe first described the use of penicillamine in Wilson's disease in 1956.^[18] 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.^[19]

Penicillamine has been used in rheumatoid arthritis since the first successful case in 1964.^[20] Cuprimine remains in production (2016) by Aton Pharma.^[21]

References

1. 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.
2. Aronson, J. K. (2010). Meyler's Side Effects of Analgesics and Anti-inflammatory Drugs. Amsterdam: Elsevier Science. p. 613. ISBN 9780080932941.
3. 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.
4. "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
5. 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.
6. 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.
7. 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.
8. Hall, A. H. (2002). "Chronic arsenic poisoning". Toxicology Letters. 128 (1–3): 69–72. doi:10.1016/S0378-4274(01)00534-3. PMID 11869818.
9. "Cuprimine (penicillamine) Capsules for Oral Use. U.S. Full Prescribing Information" (PDF). Retrieved 29 April 2016.
10. 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.
11. Grasedyck, K. (1988). "D-Penicillamine—side effects, pathogenesis and decreasing the risks". Zeitschrift für Rheumatologie. 47 Suppl 1: 17–19. PMID 3063003.
12. 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.
13. 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.
14. 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.
15. Bolognia, Jean; et al. (2007). Dermatology. Philadelphia: Elsevier. ISBN 1-4160-2999-0.2nd edition.
16. Underwood, J. C. E. (2009). General and Systemic Pathology. Elsevier Limited. ISBN 978-0-443-06889-8.
17. Taylor; Cumming; Corenblum (January 31, 1981). "Successful treatment of D-penicillamine-induced breast gigantism with danazol". 282. Br Med J: 362–3. doi:10.1136/bmj.282.6261.362-a. PMC 1504185. PMID 6780026.
18. Walshe, J. M. (Jan 1956). "Wilson's disease; new oral therapy". Lancet. 267 (6906): 25–6. doi:10.1016/S0140-6736(56)91859-1. PMID 13279157.
19. 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.
20. 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.
21. http://www.cuprimine.com/

External links

• Cuprimine (penicillamine) Official Site
• Penicillamine (Systemic) — Medlineplus.org
• Penicillamine and Arthritis — Medicinenet.com