Ciclosporin

Source: Wikipedia, the free encyclopedia.
(Redirected from
Cyclosporine
)
Not to be confused with cyclobenzaprine or cephalosporin.

Ciclosporin
Clinical data
Pronunciation/ˌsaɪkləˈspɔːrɪn/[1]
Trade namesNeoral, Sandimmune, Restasis, Gengraf, other
Other namescyclosporin, ciclosporin A,[2] cyclosporine A, cyclosporin A (CsA), cyclosporine (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa601207
License data
Pregnancy
category
  • AU: C
Calcineurin inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailabilityvariable
MetabolismLiver CYP3A4
Elimination half-lifevariable (about 24 hours)
ExcretionBile duct
Identifiers
  • (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-Ethyl-33-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexen-1-yl]-6,9,18,24-tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone
JSmol)
  • CC[C@H]1C(=O)N(CC(=O)N([C@H](C(=O)N[C@H](C(=O)N([C@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N1)[C@@H]([C@H](C)C/C=C/C)O)C)C(C)C)C)CC(C)C)C)CC(C)C)C)C)C)CC(C)C)C)C(C)C)CC(C)C)C)C
  • InChI=1S/C62H111N11O12/c1-25-27-28-40(15)52(75)51-56(79)65-43(26-2)58(81)67(18)33-48(74)68(19)44(29-34(3)4)55(78)66-49(38(11)12)61(84)69(20)45(30-35(5)6)54(77)63-41(16)53(76)64-42(17)57(80)70(21)46(31-36(7)8)59(82)71(22)47(32-37(9)10)60(83)72(23)50(39(13)14)62(85)73(51)24/h25,27,34-47,49-52,75H,26,28-33H2,1-24H3,(H,63,77)(H,64,76)(H,65,79)(H,66,78)/b27-25+/t40-,41+,42-,43+,44+,45+,46+,47+,49+,50+,51+,52-/m1/s1 checkY
  • Key:PMATZTZNYRCHOR-CGLBZJNRSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Ciclosporin, also spelled cyclosporine and cyclosporin, is a

keratoconjunctivitis sicca (dry eyes).[14]

Common side effects include high blood pressure, headache,

birth defects.[15]

Ciclosporin is believed to work by decreasing the function of

lymphocytes.[13] It does this by forming a complex with cyclophilin to block the phosphatase activity of calcineurin, which in turn decreases the production of inflammatory cytokines by T-lymphocytes.[16]

Ciclosporin was isolated in 1971 from the

generic medication.[22]

Medical uses

Ciclosporin is

Sjögren's syndrome and meibomian gland dysfunction.[9]

In addition to these indications, ciclosporin is also used in severe

systemic mastocytosis, and posterior or intermediate uveitis with noninfective cause.[citation needed] It is also used, albeit infrequently, in severe rheumatoid arthritis and related diseases.[citation needed][25]

Ciclosporin has also been used in people with acute severe

steroids.[26]

Side effects

Side effects of ciclosporin can include

high blood pressure, potassium retention (possibly leading to hyperkalemia), kidney and liver dysfunction,[27] burning sensations at finger tips, and an increased vulnerability to opportunistic fungal and viral infections. Ciclosporin causes hypertension by inducing vasoconstriction in the kidneys and increasing sodium reabsorption. The increase in blood pressure can cause cardiovascular events; it is thus recommended that the lowest effective dose for people requiring long-term treatment be used.[28]

Ciclosporin use after a kidney transplantation is associated with

glomerular filtration rate,[citation needed] which leads to uric acid retention. Use of azathioprine as an alternative has shown to reduce the incidence of gouty arthritis.[medical citation needed
]

Ciclosporin is listed as an

squamous cell skin cancer and non-Hodgkin lymphoma.[31]

Pharmacology

Mechanism of action

Ciclosporin's main effect is to lower the activity of

cytostatic activity.[medical citation needed
]

Ciclosporin also binds to the cyclophilin D protein that constitutes part of the mitochondrial permeability transition pore (MPTP),[33][36] thus preventing MPTP opening. The MPTP is found in the mitochondrial membrane of cardiac muscle cells. MPTP opening signifies a sudden change in the inner mitochondrial membrane permeability, allowing protons and other ions and solutes of a size up to ~1.5 kDa to go through the inner membrane. This change of permeability is considered a cellular catastrophe,[37][38] leading to cell death. However, brief mitochondrial permeability transition pore openings play an essential physiological role in maintaining healthy mitochondrial homeostasis.[39]

Ciclosporin can induce a remission of proteinuria caused by such diseases as MCD and FSGS. [40] Ciclosporin blocks the calcineurin-mediated dephosphorylation of synaptopodin, a regulator of Rho GTPases in podocytes, thereby preserving the phosphorylation-dependent synaptopodin-14-3-3 beta interaction. Preservation of this interaction, in turn, protects synaptopodin from cathepsin L-mediated degradation. Altogether, the antiproteinuric effect of Ciclosporin results, at least in part, from the maintenance of synaptopodin protein abundance in podocytes, which, in turn, is sufficient to maintain the integrity of the glomerular filtration barrier and to safeguard against proteinuria. [41]

Pharmacokinetics

Ciclosporin is a cyclic peptide of 11 amino acids; it contains a single D-amino acid, which is rarely encountered in nature. Unlike most peptides, ciclosporin is not synthesized by ribosomes.[42]

Ciclosporin is highly metabolized in humans and animals after ingestion. The metabolites, which include cyclosporin B, C, D, E, H, and L,[43] have less than 10% of ciclosporin's immunosuppressant activity and are associated with higher kidney toxicity.[44] Individual ciclosporin metabolites have been isolated and characterized but do not appear to be extensively studied.[medical citation needed]

Biosynthesis

Cyclosporin biosynthesis. Bmt = butenyl-methyl-threonine, Abu = L-alpha-aminobutyric acid, Sar = sarcosine

Cyclosporin is synthesized by a

S-adenosyl methionine. The cyclization step releases cyclosporin from the enzyme.[47] Amino acids such as D-Ala and butenyl-methyl-L-threonine (Bmt) indicate cyclosporin synthetase requires the action of other enzymes. The racemization of L-Ala to D-Ala by alanine racemase is pyridoxal phosphate-dependent. The formation of butenyl-methyl-L-threonine is performed by a Bmt polyketide synthase that uses acetate/malonate as its starting material.[48]

Gene cluster

Tolypocladium inflatum, the species currently used for mass production of Cyclosporin, has the biosynthetic genes arranged into a 12-gene cluster. Of these 12 genes, SimA (Q09164) is the cyclosporin synthetase, SimB (CAA02484.1) is the alanine racemase, and SimG (similar to ATQ39432.1) is the polyketide synthase.[49] These genes are associated with an active retrotransposon.[50] Although these sequences are poorly-annotated on GenBank and other databases, 90% similar sequences can be found for the Cyclosporin-producing Beauveria felina (or Amphichorda ~).[51] SimB has two paralogs in the same organism with different but overlapping functions thanks to their low specificity.[52]

History

In 1970, new strains of fungi were isolated from soil samples taken from Norway and from Wisconsin in the US by employees of

Tolypocladium inflatum Gams, was later used for the large scale fermentation of ciclosporin.[53]

The immunosuppressive effect of the natural product ciclosporin was discovered on 31 January 1972

R.Y. Calne and colleagues at the University of Cambridge,[58] and in liver transplants performed by Thomas Starzl at the Children's Hospital of Pittsburgh. The first patient, on 9 March 1980, was a 28-year-old woman.[59] In the United States, the Food and Drug Administration (FDA) approved ciclosporin for clinical use in 1983.[60][61][62][63]

Thomas Starzl's 1992 memoir explains through the eyes of a transplant surgeon that ciclosporin was an epoch-making drug for solid organ allotransplantation.[64] It greatly expanded the clinical applicability of such transplantation by substantially advancing the antirejection pharmacotherapy component.[64] Put simply, the biggest limits of applying such transplantation more widely were not cost or surgical skill (as formidable as those are) but rather the problem of allograft rejection and the scarcity of donor organs. Ciclopsporin was a major advancement against the rejection part of the challenge.[64]

Society and culture

Name

The natural product was named cyclosporin by the German-speaking scientists who first isolated it

International Nonproprietary Name (INN) guidelines for drugs,[65] the y was replaced with i so that the INN for the medication is spelled ciclosporin.[citation needed
]

Ciclosporin is the INN and the British Approved Name (BAN), while cyclosporine is the United States Adopted Name (USAN) and cyclosporin is a former BAN.[66]

Available forms

Ciclosporin exhibits very poor solubility in water, and, as a consequence, suspension and emulsion forms of the medication have been developed for oral administration and for injection. Ciclosporin was originally brought to market by Sandoz (now Novartis), under the brand name Sandimmune, which is available as soft gelatin capsules, an oral solution, and a formulation for intravenous administration. These are all nonaqueous compositions.[8] A newer microemulsion,[67] orally-administered formulation, Neoral,[7] is available as a solution and as soft gelatin capsules. Compositions of Neoral are designed to form microemulsions in contact with water.[68][69]

Generic ciclosporin preparations have been marketed under various brand names, including Cicloral (by Sandoz/Hexal), Gengraf (by

keratoconjunctivitis sicca (dry eye syndrome) has been marketed under the brand name Restasis.[9] Ikervis is a similar formulation with a concentration of 0.1%.[70] Inhaled ciclosporin formulations are in clinical development, and include a solution in propylene glycol and liposome dispersions.[71][72]

Research

Neuroprotection

Ciclosporin is in a phase II/III (adaptive) clinical study in Europe to determine its ability to ameliorate neuronal cellular damage and reperfusion injury (phase III) in traumatic brain injury. This multi-center study is being organized by NeuroVive Pharma and the European Brain Injury Consortium using NeuroVive's formulation of ciclosporin called Neurostat (also known by its cardioprotection brand name of Ciclomulsion). This formulation uses a lipid emulsion base instead of

cremophor and ethanol.[73] NeuroSTAT was compared to Sandimmune in a phase I study and found to be bioequivalent. In this study, NeuroSTAT did not exhibit the anaphylactic and hypersensitivity reactions found in cremophor- and ethanol-based products.[74]

Ciclosporin has been investigated as a possible

brain damage associated with injury.[75] Ciclosporin blocks the formation of the mitochondrial permeability transition pore, which has been found to cause much of the damage associated with head injury and neurodegenerative diseases. Ciclosporin's neuroprotective properties were first discovered in the early 1990s when two researchers (Eskil Elmér and Hiroyuki Uchino) were conducting experiments in cell transplantation. An unintended finding was that cyclosporin A was strongly neuroprotective when it crossed the blood–brain barrier.[76] This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making traumatic brain injuries much worse.[77]

Cardiac disease

Ciclosporin has been used experimentally to treat cardiac hypertrophy[33][78] (an increase in cell volume).

Inappropriate opening of the mitochondrial permeability transition pore (MPTP) manifests in ischemia[33] (blood flow restriction to tissue) and reperfusion injury[33] (damage occurring after ischemia when blood flow returns to tissue), after myocardial infarction[34] (heart attack) and when mutations in mitochondrial DNA polymerase occur.[33] The heart attempts to compensate for disease state by increasing the intracellular Ca2+
 to increase the contractility cycling rates.[36] Constitutively high levels of mitochondrial Ca2+
 cause inappropriate MPTP opening leading to a decrease in the cardiac range of function, leading to cardiac hypertrophy as an attempt to compensate for the problem.[36][34]

Cyclosporin A has been shown to decrease cardiac hypertrophy by affecting cardiac myocytes in many ways. Cyclosporin A binds to

cyclophilin D to block the opening of MPTP, and thus decreases the release of protein cytochrome C, which can cause programmed cell death.[33][36][79] CypD is a protein within the MPTP that acts as a gate; binding by cyclosporin A decreases the amount of inappropriate opening of MPTP, which decreases the intramitochondrial Ca2+
.[36] Decreasing intramitochondrial Ca2+
 allows for reversal of cardiac hypertrophy caused in the original cardiac response.[36] Decreasing the release of cytochrome C caused decreased cell death during injury and disease.[33] Cyclosporin A also inhibits the phosphatase calcineurin pathway (14).[33][34][80] Inhibition of this pathway has been shown to decrease myocardial hypertrophy.[34][78][80]

Veterinary use

The medication is approved in the United States for the treatment of

sebaceous glands), pemphigus foliaceus (autoimmune blistering skin disease), Inflammatory bowel disease, anal furunculosis (anal inflammatory disease), and myasthenia gravis (a neuromuscular disease).[81][82]

References

  1. ^ "cyclosporin". Dictionary.com Unabridged. Random House. n.d. Archived from the original on 18 November 2010. Retrieved 13 July 2011.
  2. PMID 7074504
    .
  3. FDA
    . Retrieved 22 October 2023.
  4. ^ "Regulatory Decision Summary for Restasis Multidose". Drug and Health Product Register. 23 October 2014. Archived from the original on 7 June 2022. Retrieved 7 June 2022.
  5. ^ "Regulatory Decision Summary for Verkazia". Drug and Health Product Register. 23 October 2014. Archived from the original on 7 June 2022. Retrieved 7 June 2022.
  6. ^ "Health product highlights 2021: Annexes of products approved in 2021". Health Canada. 3 August 2022. Retrieved 25 March 2024.
  7. ^ a b c d "Neoral- cyclosporine capsule, liquid filled Neoral- cyclosporine solution". DailyMed. Archived from the original on 5 July 2013. Retrieved 3 February 2022.
  8. ^ a b c "Sandimmune- cyclosporine capsule, liquid filled Sandimmune- cyclosporine injection Sandimmune- cyclosporine solution". DailyMed. Archived from the original on 21 April 2014. Retrieved 3 February 2022.
  9. ^ a b c "Restasis- cyclosporine emulsion". DailyMed. Archived from the original on 30 March 2014. Retrieved 3 February 2022.
  10. ^ "Vevye- cyclosporine ophthalmic solution solution/ drops". DailyMed. 26 May 2023. Archived from the original on 29 August 2023. Retrieved 29 August 2023.
  11. ^ "Ikervis". European Medicines Agency. 17 September 2018. Archived from the original on 13 August 2022. Retrieved 27 February 2023.
  12. ISBN 9789241547659
    .
  13. ^ a b c d e "Cyclosporine". The American Society of Health-System Pharmacists. Archived from the original on 17 October 2016. Retrieved 8 December 2016.
  14. ^ "Cyclosporine eent". The American Society of Health-System Pharmacists. Archived from the original on 13 January 2016. Retrieved 8 December 2016.
  15. ^ "Cyclosporine Use During Pregnancy". Drugs.com. Archived from the original on 14 September 2017. Retrieved 20 December 2016.
  16. ^
    PMID 10878286. Archived from the original
    (PDF) on 11 August 2017. Retrieved 4 March 2018.
  17. ISBN 978-0-19-922999-4. Archived
    from the original on 5 November 2017.
  18. hdl:10665/325771
    . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  19. hdl:10665/345533
    . WHO/MHP/HPS/EML/2021.02.
  20. ^ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  21. ^ "Cyclosporine - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  22. ^ "FDA Approves First Generic of Restasis". U.S. Food and Drug Administration (FDA) (Press release). 2 February 2022. Archived from the original on 2 February 2022. Retrieved 3 February 2022.
  23. S2CID 399211
    .
  24. S2CID 28546053. Archived
    (PDF) from the original on 21 January 2022. Retrieved 11 October 2021.
  25. PMID 1411580
    .
  26. PMID 8196726
    .
  27. PMID 19218475. Archived
    (PDF) from the original on 20 July 2018. Retrieved 20 April 2018.
  28. PMID 20091657
    .
  29. PMID 2296276
    .
  30. ^ Agents Classified by the IARC Monographs, Volumes 1–110 Archived 25 October 2011 at the Wayback Machine
  31. ^ IARC Working Group on the Evaluation of Carcinogenic Risk to Humans (2012). Ciclosporin. International Agency for Research on Cancer. Archived from the original on 28 August 2021. Retrieved 23 February 2018.
  32. ISBN 978-0-07-144040-0
    .
  33. ^
    PMID 15194495
    .
  34. ^
    S2CID 9181082
    .
  35. PMID 6238408
    .
  36. ^
    PMID 20890047
    .
  37. S2CID 54470812. Archived
    (PDF) from the original on 21 January 2022. Retrieved 2 August 2021.
  38. PMID 25172387
    .
  39. PMID 24987008
    .
  40. S2CID 35867347
    .
  41. PMID 18724379
    .
  42. ISBN 978-0-471-89979-2.
    However, the name, "Beauveria nivea", also appears in several other articles including in a 2001 online publication by Harriet Upton entitled "Origin of drugs in current use: the cyclosporin story Archived 2005-03-08 at the Wayback Machine" (retrieved 19 June 2005). Mark Plotkin states in his book Medicine Quest, Penguin Books 2001, pages 46-47, that in 1996 mycology researcher Kathie Hodge found Archived 10 March 2006 at the Wayback Machine that it is in fact a species of Cordyceps
    .
  43. PMID 2568911
    .
  44. PMID 2137384
    .
  45. PMID 25497210
    .
  46. PMID 8300618
    .
  47. S2CID 33075098.[permanent dead link
    ]
  48. ^ Dewick, P. (2001) Medicinal Natural Products. John Wiley & Sons, Ltd. 2nd ed.
  49. PMID 30279281
    .
  50. PMID 23818858
    .
  51. PMID 29396588
    .
  52. PMID 23219598
    .
  53. ^
    ISBN 978-1-4615-9846-6. Archived
    from the original on 5 November 2017.
  54. S2CID 39502677
    .
  55. S2CID 2862779
    .
  56. PMID 950308
    .
  57. S2CID 24662504
    .
  58. S2CID 10731038
    .
  59. PMID 7017414
    .
  60. PMID 17776314
    . On 2 September (1983), the Food and Drug Administration approved cyclosporin, a new drug that suppresses the immune system.
  61. ^ Gottesman J (20 March 1988). "Milestones in Cardiac Care". Los Angeles Times. Archived from the original on 26 February 2017.
  62. ^ "First Successful Pediatric Heart Transplant [9 June 1984]". Columbia University Medical Center, Dept. of Surgery, Cardiac Transplant Program. Archived from the original on 1 March 2017. It [cyclosporine] gained FDA approval at the end of 1983, ...
  63. ^ "Drugs@FDA: FDA Approved Drug Products [Click on "Approval Date(s) and History]". United States Food and Drug Administration. Archived from the original on 1 March 2017. Drug Name(s): Sandimmune (Cyclosporine), Company: Novartis, Action Date: 11/14/1983, Action Type: Approval, Submission Classification: Type 1 - New Molecular Entity, Review Priority: Priority
  64. ^
    ISBN 978-0-8229-3714-2
    .
  65. ^ "Guidelines on the Use of International Nonproprietary Names (INNs) for Pharmaceutical Substances". World Health Organization. 1997. To facilitate the translation and pronunciation of INN, "f" should be used instead of "ph", "t" instead of "th", "e" instead of "ae" or "oe", and "i" instead of "y"; the use of the letters "h" and "k" should be avoided.[dead link]
  66. ^ "The Cyclosporine Story". www.davidmoore.org.uk. January 2013. Archived from the original on 22 October 2022. Retrieved 24 October 2022.
  67. S2CID 28468973. Archived
    from the original on 5 March 2018. Retrieved 4 March 2018.
  68. PMID 9157923.{{cite journal}}: CS1 maint: DOI inactive as of February 2024 (link
    )
  69. ^ "Neoral" (PDF). FDA Data Dashboard. Food and Drug Administration (FDA); Novartis. September 2009. Archived (PDF) from the original on 20 October 2022. Retrieved 24 October 2022.
  70. ^ "Ikervis". Santen. Archived from the original on 3 July 2018. Retrieved 3 July 2018.
  71. ^ Clinical trial number NCT01287078 for "Cyclosporine Inhalation Solution (CIS) in Lung Transplant and Hematopoietic Stem Cell Transplant Recipients for the Treatment of Bronchiolitis Obliterans" at ClinicalTrials.gov.
  72. PMID 18656538
    .
  73. ^ Administrator. "Hem - NeuroVive Pharmaceutical AB". neurovive.com. Archived from the original on 6 January 2014.
  74. PMID 23179472. Archived
    (PDF) from the original on 26 October 2018. Retrieved 26 October 2018.
  75. S2CID 25190221
    .
  76. PMID 8719269
    .
  77. PMID 21142667
    .
  78. ^
    PMID 9811897
    .
  79. PMID 20798784
    .
  80. ^
    S2CID 10904494
    .
  81. ^
    PMID 24341787
    .
  82. PMID 23182330
    .

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Ciclosporin&oldid=1218849135"