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Penicillamine

January 01, 1970

Not to be confused with penicillin.

Penicillamine, sold under the brand name 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, and various heavy metal poisonings.[1][2] It is taken by mouth.[2]

Penicillamine
Clinical data
Trade namesCuprimine, Cuprenyl, Depen, others
Other names
  • D-penicillamine
  • (–)-penicillamine
AHFS/Drugs.comMonograph
MedlinePlusa618021
License data
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
  • 52-67-5 Y
PubChem CID
  • 5852
IUPHAR/BPS
  • 7264
DrugBank
  • DB00859 Y
ChemSpider
  • 5643 Y
UNII
  • GNN1DV99GX
KEGG
  • D00496 Y
ChEBI
  • CHEBI:7959 Y
ChEMBL
  • ChEMBL1430 Y
CompTox Dashboard (EPA)
  • DTXSID6037069
ECHA InfoCard100.000.136
Chemical and physical data
FormulaC5H11NO2S
Molar mass149.21 g·mol−1
3D model (JSmol)
  • Interactive image
  • 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 Y
  • Key:VVNCNSJFMMFHPL-VKHMYHEASA-N Y
  (verify)

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.[3]

Medical uses edit

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.[4]
  • Penicillamine was the second line treatment for arsenic poisoning, after dimercaprol (BAL).[5] It is no longer recommended.[6]

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.[7]

Penicillamine has been used to treat scleroderma.[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 edit

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; 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 edit

 
D-(–)-(S)-Penicillamine
(antiarthritic)
 
L-(+)-(R)-Penicillamine
(toxic)

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 edit

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 edit

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

References edit

  1. ^ a b c d e f "Penicillamine". The American Society of Health-System Pharmacists. from the original on 21 December 2016. Retrieved 8 December 2016.
  2. ^ a b c d World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. pp. 64, 592. hdl:10665/44053. ISBN 9789241547659.
  3. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.{{cite book}}: CS1 maint: location missing publisher (link)
  4. ^ Peisach J, Blumberg WE (March 1969). "A mechanism for the action of penicillamine in the treatment of Wilson's disease". Molecular Pharmacology. 5 (2): 200–209. PMID 4306792.
  5. ^ Peterson RG, Rumack BH (October 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.
  6. ^ Hall AH (March 2002). "Chronic arsenic poisoning". Toxicology Letters. 128 (1–3): 69–72. doi:10.1016/S0378-4274(01)00534-3. PMID 11869818.
  7. ^ a b Rosenberg LE, Hayslett JP (August 1967). "Nephrotoxic effects of penicillamine in cystinuria". JAMA. 201 (9): 698–699. doi:10.1001/jama.1967.03130090062021. PMID 6071831.
  8. ^ Steen VD, Medsger TA, Rodnan GP (November 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. ^ "Cuprimine (penicillamine) Capsules for Oral Use. U.S. Full Prescribing Information" (PDF). (PDF) from the original on 8 September 2015. Retrieved 29 April 2016.
  10. ^ a b c Camp AV (February 1977). "Penicillamine in the treatment of rheumatoid arthritis". Proceedings of the Royal Society of Medicine. 70 (2): 67–69. doi:10.1177/003591577707000201. 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. ^ a b Fishel B, Tishler M, Caspi D, Yaron M (July 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 RS, Kumar V, Abbas AK, Fausto N (2007). "Table 14-2". Robbins Basic Pathology (8th ed.). Philadelphia: Saunders. ISBN 978-1-4160-2973-1.
  14. ^ Chalmers A, Thompson D, Stein HE, Reid G, Patterson AC (November 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 J, et al. (2007). Dermatology. Philadelphia: Elsevier. ISBN 978-1-4160-2999-1.2nd edition.
  16. ^ Underwood JC (2009). General and Systemic Pathology. Elsevier Limited. ISBN 978-0-443-06889-8.
  17. ^ Taylor PJ, Cumming DC, Corenblum B (January 1981). "Successful treatment of D-penicillamine-induced breast gigantism with danazol". British Medical Journal. 282 (6261): 362–363. doi:10.1136/bmj.282.6261.362-a. PMC 1504185. PMID 6780026.
  18. ^ Ariens EJ (1989). Chiral Separations by HPLC. Chichester: Ellis Horwwod, Chichester. pp. 31–68.
  19. ^ Aronson JK (2010). Meyler's Side Effects of Analgesics and Anti-inflammatory Drugs. Amsterdam: Elsevier Science. p. 613. ISBN 9780080932941. from the original on 10 September 2017.
  20. ^ Parker CW, Shapiro J, Kern M, Eisen HN (April 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.
  21. ^ Birker PJ, Freeman HC (October 1977). "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. doi:10.1021/ja00463a019. PMID 903530.
  22. ^ Walshe JM (January 1956). "Wilson's disease; new oral therapy". Lancet. 270 (6906): 25–26. doi:10.1016/S0140-6736(56)91859-1. PMID 13279157.
  23. ^ Walshe JM (August 2003). "The story of penicillamine: a difficult birth". Movement Disorders. 18 (8): 853–859. doi:10.1002/mds.10458. PMID 12889074. S2CID 11406561.
  24. ^ Oakes EH (2007). Encyclopedia of World Scientists. Infobase Publishing. p. 156. ISBN 9781438118826.
  25. ^ Jaffe IA (September 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.
  26. ^ Petersen M. "How 4 drug companies rapidly raised prices on life-saving drugs". Los Angeles Times. Retrieved 27 March 2019.

External links edit

  • "Penicillamine". Drug Information Portal. U.S. National Library of Medicine.

January 01, 1970
penicillamine, confused, with, penicillin, sold, under, brand, name, cuprimine, among, others, medication, primarily, used, treatment, wilson, disease, also, used, people, with, kidney, stones, have, high, urine, cystine, levels, rheumatoid, arthritis, various. Not to be confused with penicillin Penicillamine sold under the brand name 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 and various heavy metal poisonings 1 2 It is taken by mouth 2 PenicillamineClinical dataTrade namesCuprimine Cuprenyl Depen othersOther namesD penicillamine penicillamineAHFS Drugs comMonographMedlinePlusa618021License dataUS DailyMed PenicillaminePregnancycategoryAU DRoutes ofadministrationBy mouth capsules ATC codeM01CC01 WHO Legal statusLegal statusUS only In general Prescription only Pharmacokinetic dataBioavailabilityVariableMetabolismLiverElimination half life1 hourExcretionKidneyIdentifiersIUPAC name 2S 2 amino 3 methyl 3 sulfanylbutanoic acidCAS Number52 67 5 YPubChem CID5852IUPHAR BPS7264DrugBankDB00859 YChemSpider5643 YUNIIGNN1DV99GXKEGGD00496 YChEBICHEBI 7959 YChEMBLChEMBL1430 YCompTox Dashboard EPA DTXSID6037069ECHA InfoCard100 000 136Chemical and physical dataFormulaC 5H 11N O 2SMolar mass149 21 g mol 13D model JSmol Interactive imageSMILES CC C C H C O O N SInChI InChI 1S C5H11NO2S c1 5 2 9 3 6 4 7 8 h3 9H 6H2 1 2H3 H 7 8 t3 m0 s1 YKey VVNCNSJFMMFHPL VKHMYHEASA N Y verify 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 3 Contents 1 Medical uses 2 Adverse effects 3 Chemistry 4 History 5 Cost 6 References 7 External linksMedical uses editIt 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 4 Penicillamine was the second line treatment for arsenic poisoning after dimercaprol BAL 5 It is no longer recommended 6 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 7 Penicillamine has been used to treat scleroderma 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 editCommon 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 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 Nephropathy 7 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 OligospermiaChemistry edit nbsp D S Penicillamine antiarthritic nbsp L R Penicillamine toxic 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 a 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 editJohn 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 editIn the United States Valeant raised the cost of the medication from about US 500 to US 24 000 per month in 2016 26 References edit 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 a b c d World Health Organization 2009 Stuart MC Kouimtzi M Hill SR eds WHO Model Formulary 2008 World Health Organization pp 64 592 hdl 10665 44053 ISBN 9789241547659 World Health Organization 2019 World Health Organization model list of essential medicines 21st list 2019 Geneva hdl 10665 325771 WHO MVP EMP IAU 2019 06 License CC BY NC SA 3 0 IGO a href Template Cite book html title Template Cite book cite book a CS1 maint location missing publisher link Peisach J Blumberg WE March 1969 A mechanism for the action of penicillamine in the treatment of Wilson s disease Molecular Pharmacology 5 2 200 209 PMID 4306792 Peterson RG Rumack BH October 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 Hall AH March 2002 Chronic arsenic poisoning Toxicology Letters 128 1 3 69 72 doi 10 1016 S0378 4274 01 00534 3 PMID 11869818 a b Rosenberg LE Hayslett JP August 1967 Nephrotoxic effects of penicillamine in cystinuria JAMA 201 9 698 699 doi 10 1001 jama 1967 03130090062021 PMID 6071831 Steen VD Medsger TA Rodnan GP November 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 Cuprimine penicillamine Capsules for Oral Use U S Full Prescribing Information PDF Archived PDF from the original on 8 September 2015 Retrieved 29 April 2016 a b c Camp AV February 1977 Penicillamine in the treatment of rheumatoid arthritis Proceedings of the Royal Society of Medicine 70 2 67 69 doi 10 1177 003591577707000201 PMC 1542978 PMID 859814 Grasedyck K 1988 D penicillamine side effects pathogenesis and decreasing the risks Zeitschrift fur Rheumatologie 47 Suppl 1 17 19 PMID 3063003 a b Fishel B Tishler M Caspi D Yaron M July 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 Mitchell RS Kumar V Abbas AK Fausto N 2007 Table 14 2 Robbins Basic Pathology 8th ed Philadelphia Saunders ISBN 978 1 4160 2973 1 Chalmers A Thompson D Stein HE Reid G Patterson AC November 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 Bolognia J et al 2007 Dermatology Philadelphia Elsevier ISBN 978 1 4160 2999 1 2nd edition Underwood JC 2009 General and Systemic Pathology Elsevier Limited ISBN 978 0 443 06889 8 Taylor PJ Cumming DC Corenblum B January 1981 Successful treatment of D penicillamine induced breast gigantism with danazol British Medical Journal 282 6261 362 363 doi 10 1136 bmj 282 6261 362 a PMC 1504185 PMID 6780026 Ariens EJ 1989 Chiral Separations by HPLC Chichester Ellis Horwwod Chichester pp 31 68 Aronson JK 2010 Meyler s Side Effects of Analgesics and Anti inflammatory Drugs Amsterdam Elsevier Science p 613 ISBN 9780080932941 Archived from the original on 10 September 2017 Parker CW Shapiro J Kern M Eisen HN April 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 Birker PJ Freeman HC October 1977 Structure properties and function of a copper I copper II complex of D penicillamine pentathallium I m8 chloro dodeca D penicillaminato octacuprate I hexacuprate II n hydrate Journal of the American Chemical Society 99 21 6890 6899 doi 10 1021 ja00463a019 PMID 903530 Walshe JM January 1956 Wilson s disease new oral therapy Lancet 270 6906 25 26 doi 10 1016 S0140 6736 56 91859 1 PMID 13279157 Walshe JM August 2003 The story of penicillamine a difficult birth Movement Disorders 18 8 853 859 doi 10 1002 mds 10458 PMID 12889074 S2CID 11406561 Oakes EH 2007 Encyclopedia of World Scientists Infobase Publishing p 156 ISBN 9781438118826 Jaffe IA September 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 Petersen M How 4 drug companies rapidly raised prices on life saving drugs Los Angeles Times Retrieved 27 March 2019 External links edit Penicillamine Drug Information Portal U S National Library of Medicine Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Penicillamine amp oldid 1221470134, wikipedia, wiki, book, books, library,

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