Penicillamine

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Penicillamine
Penicillamine structure.svg
D-penicillamine-from-xtal-3D-bs-17.png
Clinical data
Trade names Cuprimine, Cuprenyl, Depen, others
Other namesD-penicillamine
AHFS/Drugs.com Monograph
MedlinePlus a618021
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
Bioavailability Variable
Metabolism Liver
Elimination half-life 1 hour
Excretion Kidney
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 InfoCard 100.000.136 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C5H11NO2S
Molar mass 149.21 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 Yes check.svgY
  • Key:VVNCNSJFMMFHPL-VKHMYHEASA-N Yes check.svgY
   (verify)

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]

Contents

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

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. [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

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

Penicillamine enantiomers Penicillamine enantiomers.png
Penicillamine enantiomers

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 and exist as a pair of enantiomers. Refer the image for the structure of penicillamine enantiomers. The (S)-enantiomer, the eutomer, is antiarthritic while the distomer (R)-penicillamine is extremely toxic. [18] Of its two enantiomers, L-penicillamine (having R absolute configuration) 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]

Related Research Articles

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<span class="mw-page-title-main">Rheumatoid arthritis</span> Type of autoimmune arthritis

Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involved, with the same joints typically involved on both sides of the body. The disease may also affect other parts of the body, including skin, eyes, lungs, heart, nerves, and blood. This may result in a low red blood cell count, inflammation around the lungs, and inflammation around the heart. Fever and low energy may also be present. Often, symptoms come on gradually over weeks to months.

<span class="mw-page-title-main">Wilson's disease</span> Genetic multisystem copper-transport disease

Wilson's disease is a genetic disorder in which excess copper builds up in the body. Symptoms are typically related to the brain and liver. Liver-related symptoms include vomiting, weakness, fluid build-up in the abdomen, swelling of the legs, yellowish skin, and itchiness. Brain-related symptoms include tremors, muscle stiffness, trouble in speaking, personality changes, anxiety, and psychosis.

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<span class="mw-page-title-main">Disease-modifying antirheumatic drug</span> Category of drugs

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<span class="mw-page-title-main">Cystinuria</span> Amino acid metabolic disorder involving cystine stones forming in the kidneys, ureter, and bladder

Cystinuria is an inherited autosomal recessive disease characterized by high concentrations of the amino acid cystine in the urine, leading to the formation of cystine stones in the kidneys, ureters, and bladder. It is a type of aminoaciduria. "Cystine", not "cysteine," is implicated in this disease; the former is a dimer of the latter.

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<span class="mw-page-title-main">Tiopronin</span> Chemical compound

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Biological response modifiers (BRMs) are substances that modify immune responses. They can be endogenous or exogenous, and they can either enhance an immune response or suppress it. Some of these substances arouse the body's response to an infection, and others can keep the response from becoming excessive. Thus they serve as immunomodulators in immunotherapy, which can be helpful in treating cancer and in treating autoimmune diseases, such as some kinds of arthritis and dermatitis. Most BRMs are biopharmaceuticals (biologics), including monoclonal antibodies, interleukin 2, interferons, and various types of colony-stimulating factors. "Immunotherapy makes use of BRMs to enhance the activity of the immune system to increase the body's natural defense mechanisms against cancer", whereas BRMs for rheumatoid arthritis aim to reduce inflammation.

<span class="mw-page-title-main">Belimumab</span> Pharmaceutical drug

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References

  1. 1 2 3 4 5 6 "Penicillamine". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  2. 1 2 3 4 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. 1 2 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). Archived (PDF) from the original on 8 September 2015. Retrieved 29 April 2016.
  10. 1 2 3 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. 1 2 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. Archived 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) mu8-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.
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