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Wikipedia

Ciclosporin

February 15, 2024

Not to be confused with cyclobenzaprine or cephalosporin.

Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, eczema, and in organ transplants to prevent rejection.[11][12] It is also used as eye drops for keratoconjunctivitis sicca (dry eyes).[13]

Ciclosporin
Clinical data
Pronunciation/ˌsaɪkləˈspɔːrɪn/[1]
Trade namesNeoral, Sandimmune, Restasis, other
Other namescyclosporin, ciclosporin A,[2] cyclosporine A, cyclosporin A (CsA), cyclosporine (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa601207
License data
Pregnancy
category
  • AU: C
Routes of
administration		by mouth, intravenous (IV), eye drops
Drug classCalcineurin 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
CAS Number
  • 59865-13-3 Y
PubChem CID
  • 5284373
IUPHAR/BPS
  • 1024
DrugBank
  • DB00091 N
ChemSpider
  • 4447449 Y
UNII
  • 83HN0GTJ6D
KEGG
  • D00184 Y
ChEBI
  • CHEBI:4031
ChEMBL
  • ChEMBL160 Y
PDB ligand
  • PRD_000142 (PDBe, RCSB PDB)
CompTox Dashboard (EPA)
  • DTXSID0020365
ECHA InfoCard100.119.569
Chemical and physical data
FormulaC62H111N11O12
Molar mass1202.635 g·mol−1
3D model (JSmol)
  • Interactive image
  • 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 Y
  • Key:PMATZTZNYRCHOR-CGLBZJNRSA-N Y
 NY (what is this?)  (verify)

Common side effects include high blood pressure, headache, kidney problems, increased hair growth, and vomiting.[12] Other severe side effects include an increased risk of infection, liver problems, and an increased risk of lymphoma.[12] Blood levels of the medication should be checked to decrease the risk of side effects.[12] Use during pregnancy may result in preterm birth; however, ciclosporin does not appear to cause birth defects.[14]

Ciclosporin is believed to work by decreasing the function of lymphocytes.[12] 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.[15]

Ciclosporin was isolated in 1971 from the fungus Tolypocladium inflatum and came into medical use in 1983.[16] It is on the World Health Organization's List of Essential Medicines.[17][18] In 2020, it was the 212th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[19][20] It is available as a generic medication.[21]

Medical uses edit

Ciclosporin is indicated to treat and prevent graft-versus-host disease in bone marrow transplantation and to prevent rejection of kidney, heart, and liver transplants.[7][6] It is also approved in the US for treating of rheumatoid arthritis and psoriasis, persistent nummular keratitis following adenoviral keratoconjunctivitis,[22][6] and as eye drops for treating dry eyes caused by Sjögren's syndrome and meibomian gland dysfunction.[8]

In addition to these indications, ciclosporin is also used in severe atopic dermatitis,[23] Kimura disease, pyoderma gangrenosum, chronic hives, acute 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][24]

Ciclosporin has also been used in people with acute severe ulcerative colitis and hives that do not respond to treatment with steroids.[25]

Side effects edit

Side effects of ciclosporin can include gum enlargement, increased hair growth, convulsions, peptic ulcers, pancreatitis, fever, vomiting, diarrhea, confusion, increased cholesterol, trouble breathing, numbness and tingling (particularly of the lips), itchiness, high blood pressure, potassium retention (possibly leading to hyperkalemia), kidney and liver dysfunction,[26] 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.[27]

Ciclosporin use after a kidney transplantation is associated with increased levels of uric acid in the blood and, in some cases, gout.[28] This is due to the decrease in 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 IARC Group 1 carcinogen (i.e. there is sufficient evidence of carcinogenicity in humans),[29] specifically leading to squamous cell skin cancer and non-Hodgkin lymphoma.[30]

Pharmacology edit

Mechanism of action edit

Ciclosporin's main effect is to lower the activity of T-cells; it does so by inhibiting calcineurin in the calcineurin–phosphatase pathway and preventing the mitochondrial permeability transition pore from opening. Ciclosporin binds to the cytosolic protein cyclophilin (immunophilin) of lymphocytes, especially of T cells. This cyclosporin—cyclophilin complex inhibits calcineurin, which is normally responsible for activating the transcription of interleukin 2. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor NF-AT (nuclear factor of activated T-cells), which moves to the T-cell nucleus and increases the transcription of genes for IL-2 and related cytokines.[15] Ciclosporin, by preventing the dephosphorylation of NF-AT, leads to reduced effector T-cell function;[31][32][33][34] it does not affect cytostatic activity.[medical citation needed]

Ciclosporin also binds to the cyclophilin D protein that constitutes part of the mitochondrial permeability transition pore (MPTP),[32][35] 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,[36][37] leading to cell death. However, brief mitochondrial permeability transition pore openings play an essential physiological role in maintaining healthy mitochondrial homeostasis.[38]

Ciclosporin can induce a remission of proteinuria caused by such diseases as MCD and FSGS. [39] 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. [40]

Pharmacokinetics edit

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.[41]

Ciclosporin is highly metabolized in humans and animals after ingestion. The metabolites, which include cyclosporin B, C, D, E, H, and L,[42] have less than 10% of ciclosporin's immunosuppressant activity and are associated with higher kidney toxicity.[43] Individual ciclosporin metabolites have been isolated and characterized but do not appear to be extensively studied.[medical citation needed]

Biosynthesis edit

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

Cyclosporin is synthesized by a nonribosomal peptide synthetase, cyclosporin synthetase.[44] The enzyme contains an adenylation domain, a thiolation domain, a condensation domain, and an N-methyltransferase domain. The adenylation domain is responsible for substrate recognition and activation, whereas the thiolation domain covalently binds the adenylated amino acids to phosphopantetheine, and the condensation domain elongates the peptide chain. Cyclosporin synthetase substrates include L-valine, L-leucine, L-alanine, glycine, 2-aminobutyric acid, 4-methylthreonine, and D-alanine, which is the starting amino acid in the biosynthetic process.[45] With the adenylation domain, cyclosporin synthetase generates the acyl-adenylated amino acids, then covalently binds the amino acid to phosphopantetheine through a thioester linkage. Some of the amino acid substrates become N-methylated by S-adenosyl methionine. The cyclization step releases cyclosporin from the enzyme.[46] 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.[47]

Gene cluster edit

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.[48] These genes are associated with an active retrotransposon.[49] 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 ~).[50] SimB has two paralogs in the same organism with different but overlapping functions thanks to their low specificity.[51]

History edit

In 1970, new strains of fungi were isolated from soil samples taken from Norway and from Wisconsin in the US by employees of Sandoz (now Novartis) in Basel, Switzerland. Both strains produced a family of natural products called cyclosporins. Two related components that had antifungal activity were isolated from extracts from these fungi. The Norwegian strain, Tolypocladium inflatum Gams, was later used for the large scale fermentation of ciclosporin.[52]

The immunosuppressive effect of the natural product ciclosporin was discovered on 31 January 1972[53] in a screening test on immune suppression designed and implemented by Hartmann F. Stähelin at Sandoz.[54][52] The chemical structure of cyclosporin was determined in 1976, also at Sandoz.[55][56] The success of the drug candidate ciclosporin in preventing organ rejection was shown in kidney transplants by R.Y. Calne and colleagues at the University of Cambridge,[57] 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.[58] In the United States, the Food and Drug Administration (FDA) approved ciclosporin for clinical use in 1983.[59][60][61][62]

Thomas Starzl's 1992 memoir explains through the eyes of a transplant surgeon that ciclosporin was an epoch-making drug for solid organ allotransplantation.[63] It greatly expanded the clinical applicability of such transplantation by substantially advancing the antirejection pharmacotherapy component.[63] 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.[63]

Society and culture edit

Name edit

The natural product was named cyclosporin by the German-speaking scientists who first isolated it[52] and cyclosporine when translated into English. Per International Nonproprietary Name (INN) guidelines for drugs,[64] 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.[65]

Available forms edit

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.[7] A newer microemulsion,[66] orally-administered formulation, Neoral,[6] is available as a solution and as soft gelatin capsules. Compositions of Neoral are designed to form microemulsions in contact with water.[67][68]

Generic ciclosporin preparations have been marketed under various trade names, including Cicloral (by Sandoz/Hexal), Gengraf (by Abbott) and Deximune (by Dexcel Pharma). Since 2002, a topical emulsion of ciclosporin for treating inflammation caused by keratoconjunctivitis sicca (dry eye syndrome) has been marketed under the trade name Restasis.[8] Ikervis is a similar formulation with a concentration of 0.1%.[69] Inhaled ciclosporin formulations are in clinical development, and include a solution in propylene glycol and liposome dispersions.[70][71]

Research edit

Neuroprotection edit

Ciclosporin is currently 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 trade name of CicloMulsion). This formulation uses a lipid emulsion base instead of cremophor and ethanol.[72] 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.[73]

Ciclosporin has been investigated as a possible neuroprotective agent in conditions such as traumatic brain injury, and has been shown in animal experiments to reduce brain damage associated with injury.[74] 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.[75] This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making traumatic brain injuries much worse.[76]

Cardiac disease edit

Ciclosporin has been used experimentally to treat cardiac hypertrophy[32][77] (an increase in cell volume).

Inappropriate opening of the mitochondrial permeability transition pore (MPTP) manifests in ischemia[32] (blood flow restriction to tissue) and reperfusion injury[32] (damage occurring after ischemia when blood flow returns to tissue), after myocardial infarction[33] (heart attack) and when mutations in mitochondrial DNA polymerase occur.[32] The heart attempts to compensate for disease state by increasing the intracellular Ca2+
 to increase the contractility cycling rates.[35] 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.[35][33]

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.[32][35][78] 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+
.[35] Decreasing intramitochondrial Ca2+
 allows for reversal of cardiac hypertrophy caused in the original cardiac response.[35] Decreasing the release of cytochrome C caused decreased cell death during injury and disease.[32] Cyclosporin A also inhibits the phosphatase calcineurin pathway (14).[32][33][79] Inhibition of this pathway has been shown to decrease myocardial hypertrophy.[33][77][79]

Veterinary use edit

The medication is approved in the United States for the treatment of atopic dermatitis in dogs.[80] Unlike the human form of the medication, the lower doses used in dogs mean the drug acts as an immunomodulator and has fewer side effects than in humans. The benefits of using this product include the reduced need for concurrent therapies to bring the condition under control. It is available as an ophthalmic ointment for dogs called Optimmune, manufactured by Intervet, which is part of Merck. It is also used to treat sebaceous adenitis (immune response against the sebaceous glands), pemphigus foliaceus (autoimmune blistering skin disease), Inflammatory bowel disease, anal furunculosis (anal inflammatory disease), and myasthenia gravis (a neuromuscular disease).[80][81]

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    Some sources list the fungus under an alternative species name Hypocladium inflatum gams such as Pritchard and Sneader in 2005:
    * Pritchard DI (May 2005). "Sourcing a chemical succession for cyclosporin from parasites and human pathogens". Drug Discovery Today. 10 (10): 688–91. doi:10.1016/S1359-6446(05)03395-7. PMID 15896681.
    * Sneader W (23 June 2005). "Ciclosporin". Drug Discovery — A History. John Wiley & Sons. pp. 298–299. 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 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 10 March 2006 at the Wayback Machine that it is in fact a species of Cordyceps.
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External links edit

  • Cyclosporine at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  • "Cyclosporine". Drug Information Portal. U.S. National Library of Medicine.
  • ChemSub Online: Cyclosporin A

February 15, 2024
ciclosporin, confused, with, cyclobenzaprine, cephalosporin, also, spelled, cyclosporine, cyclosporin, calcineurin, inhibitor, used, immunosuppressant, medication, taken, orally, intravenously, rheumatoid, arthritis, psoriasis, crohn, disease, nephrotic, syndr. Not to be confused with cyclobenzaprine or cephalosporin Ciclosporin also spelled cyclosporine and cyclosporin is a calcineurin inhibitor used as an immunosuppressant medication It is taken orally or intravenously for rheumatoid arthritis psoriasis Crohn s disease nephrotic syndrome eczema and in organ transplants to prevent rejection 11 12 It is also used as eye drops for keratoconjunctivitis sicca dry eyes 13 CiclosporinClinical dataPronunciation ˌ s aɪ k l e ˈ s p ɔːr ɪ n 1 Trade namesNeoral Sandimmune Restasis otherOther namescyclosporin ciclosporin A 2 cyclosporine A cyclosporin A CsA cyclosporine USAN US AHFS Drugs comMonographMedlinePlusa601207License dataEU EMA by INN US DailyMed CyclosporinePregnancycategoryAU CRoutes ofadministrationby mouth intravenous IV eye dropsDrug classCalcineurin inhibitorATC codeL04AD01 WHO S01XA18 WHO Legal statusLegal statusAU S4 Prescription only CA only 4 5 UK POM Prescription only US WARNING 3 Rx only 6 7 8 9 EU Rx only 10 In general Prescription only Pharmacokinetic dataBioavailabilityvariableMetabolismLiver CYP3A4Elimination half lifevariable about 24 hours ExcretionBile ductIdentifiersIUPAC name 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 undeconeCAS Number59865 13 3 YPubChem CID5284373IUPHAR BPS1024DrugBankDB00091 NChemSpider4447449 YUNII83HN0GTJ6DKEGGD00184 YChEBICHEBI 4031ChEMBLChEMBL160 YPDB ligandPRD 000142 PDBe RCSB PDB CompTox Dashboard EPA DTXSID0020365ECHA InfoCard100 119 569Chemical and physical dataFormulaC 62H 111N 11O 12Molar mass1202 635 g mol 13D model JSmol Interactive imageSMILES 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 CInChI 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 YKey PMATZTZNYRCHOR CGLBZJNRSA N Y N Y what is this verify Common side effects include high blood pressure headache kidney problems increased hair growth and vomiting 12 Other severe side effects include an increased risk of infection liver problems and an increased risk of lymphoma 12 Blood levels of the medication should be checked to decrease the risk of side effects 12 Use during pregnancy may result in preterm birth however ciclosporin does not appear to cause birth defects 14 Ciclosporin is believed to work by decreasing the function of lymphocytes 12 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 15 Ciclosporin was isolated in 1971 from the fungus Tolypocladium inflatum and came into medical use in 1983 16 It is on the World Health Organization s List of Essential Medicines 17 18 In 2020 it was the 212th most commonly prescribed medication in the United States with more than 2 million prescriptions 19 20 It is available as a generic medication 21 Contents 1 Medical uses 2 Side effects 3 Pharmacology 3 1 Mechanism of action 3 2 Pharmacokinetics 4 Biosynthesis 4 1 Gene cluster 5 History 6 Society and culture 6 1 Name 6 2 Available forms 7 Research 7 1 Neuroprotection 7 2 Cardiac disease 8 Veterinary use 9 References 10 External linksMedical uses editCiclosporin is indicated to treat and prevent graft versus host disease in bone marrow transplantation and to prevent rejection of kidney heart and liver transplants 7 6 It is also approved in the US for treating of rheumatoid arthritis and psoriasis persistent nummular keratitis following adenoviral keratoconjunctivitis 22 6 and as eye drops for treating dry eyes caused by Sjogren s syndrome and meibomian gland dysfunction 8 In addition to these indications ciclosporin is also used in severe atopic dermatitis 23 Kimura disease pyoderma gangrenosum chronic hives acute 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 24 Ciclosporin has also been used in people with acute severe ulcerative colitis and hives that do not respond to treatment with steroids 25 Side effects editSide effects of ciclosporin can include gum enlargement increased hair growth convulsions peptic ulcers pancreatitis fever vomiting diarrhea confusion increased cholesterol trouble breathing numbness and tingling particularly of the lips itchiness high blood pressure potassium retention possibly leading to hyperkalemia kidney and liver dysfunction 26 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 27 Ciclosporin use after a kidney transplantation is associated with increased levels of uric acid in the blood and in some cases gout 28 This is due to the decrease in 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 IARC Group 1 carcinogen i e there is sufficient evidence of carcinogenicity in humans 29 specifically leading to squamous cell skin cancer and non Hodgkin lymphoma 30 Pharmacology editMechanism of action edit Ciclosporin s main effect is to lower the activity of T cells it does so by inhibiting calcineurin in the calcineurin phosphatase pathway and preventing the mitochondrial permeability transition pore from opening Ciclosporin binds to the cytosolic protein cyclophilin immunophilin of lymphocytes especially of T cells This cyclosporin cyclophilin complex inhibits calcineurin which is normally responsible for activating the transcription of interleukin 2 In T cells activation of the T cell receptor normally increases intracellular calcium which acts via calmodulin to activate calcineurin Calcineurin then dephosphorylates the transcription factor NF AT nuclear factor of activated T cells which moves to the T cell nucleus and increases the transcription of genes for IL 2 and related cytokines 15 Ciclosporin by preventing the dephosphorylation of NF AT leads to reduced effector T cell function 31 32 33 34 it does not affect cytostatic activity medical citation needed Ciclosporin also binds to the cyclophilin D protein that constitutes part of the mitochondrial permeability transition pore MPTP 32 35 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 36 37 leading to cell death However brief mitochondrial permeability transition pore openings play an essential physiological role in maintaining healthy mitochondrial homeostasis 38 Ciclosporin can induce a remission of proteinuria caused by such diseases as MCD and FSGS 39 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 40 Pharmacokinetics edit 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 41 Ciclosporin is highly metabolized in humans and animals after ingestion The metabolites which include cyclosporin B C D E H and L 42 have less than 10 of ciclosporin s immunosuppressant activity and are associated with higher kidney toxicity 43 Individual ciclosporin metabolites have been isolated and characterized but do not appear to be extensively studied medical citation needed Biosynthesis edit nbsp Cyclosporin biosynthesis Bmt butenyl methyl threonine Abu L alpha aminobutyric acid Sar sarcosineCyclosporin is synthesized by a nonribosomal peptide synthetase cyclosporin synthetase 44 The enzyme contains an adenylation domain a thiolation domain a condensation domain and an N methyltransferase domain The adenylation domain is responsible for substrate recognition and activation whereas the thiolation domain covalently binds the adenylated amino acids to phosphopantetheine and the condensation domain elongates the peptide chain Cyclosporin synthetase substrates include L valine L leucine L alanine glycine 2 aminobutyric acid 4 methylthreonine and D alanine which is the starting amino acid in the biosynthetic process 45 With the adenylation domain cyclosporin synthetase generates the acyl adenylated amino acids then covalently binds the amino acid to phosphopantetheine through a thioester linkage Some of the amino acid substrates become N methylated by S adenosyl methionine The cyclization step releases cyclosporin from the enzyme 46 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 47 Gene cluster edit 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 48 These genes are associated with an active retrotransposon 49 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 50 SimB has two paralogs in the same organism with different but overlapping functions thanks to their low specificity 51 History editIn 1970 new strains of fungi were isolated from soil samples taken from Norway and from Wisconsin in the US by employees of Sandoz now Novartis in Basel Switzerland Both strains produced a family of natural products called cyclosporins Two related components that had antifungal activity were isolated from extracts from these fungi The Norwegian strain Tolypocladium inflatum Gams was later used for the large scale fermentation of ciclosporin 52 The immunosuppressive effect of the natural product ciclosporin was discovered on 31 January 1972 53 in a screening test on immune suppression designed and implemented by Hartmann F Stahelin at Sandoz 54 52 The chemical structure of cyclosporin was determined in 1976 also at Sandoz 55 56 The success of the drug candidate ciclosporin in preventing organ rejection was shown in kidney transplants by R Y Calne and colleagues at the University of Cambridge 57 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 58 In the United States the Food and Drug Administration FDA approved ciclosporin for clinical use in 1983 59 60 61 62 Thomas Starzl s 1992 memoir explains through the eyes of a transplant surgeon that ciclosporin was an epoch making drug for solid organ allotransplantation 63 It greatly expanded the clinical applicability of such transplantation by substantially advancing the antirejection pharmacotherapy component 63 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 63 Society and culture editName edit The natural product was named cyclosporin by the German speaking scientists who first isolated it 52 and cyclosporine when translated into English Per International Nonproprietary Name INN guidelines for drugs 64 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 65 Available forms edit 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 7 A newer microemulsion 66 orally administered formulation Neoral 6 is available as a solution and as soft gelatin capsules Compositions of Neoral are designed to form microemulsions in contact with water 67 68 Generic ciclosporin preparations have been marketed under various trade names including Cicloral by Sandoz Hexal Gengraf by Abbott and Deximune by Dexcel Pharma Since 2002 a topical emulsion of ciclosporin for treating inflammation caused by keratoconjunctivitis sicca dry eye syndrome has been marketed under the trade name Restasis 8 Ikervis is a similar formulation with a concentration of 0 1 69 Inhaled ciclosporin formulations are in clinical development and include a solution in propylene glycol and liposome dispersions 70 71 Research editNeuroprotection edit Ciclosporin is currently 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 trade name of CicloMulsion This formulation uses a lipid emulsion base instead of cremophor and ethanol 72 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 73 Ciclosporin has been investigated as a possible neuroprotective agent in conditions such as traumatic brain injury and has been shown in animal experiments to reduce brain damage associated with injury 74 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 Elmer 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 75 This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making traumatic brain injuries much worse 76 Cardiac disease edit Ciclosporin has been used experimentally to treat cardiac hypertrophy 32 77 an increase in cell volume Inappropriate opening of the mitochondrial permeability transition pore MPTP manifests in ischemia 32 blood flow restriction to tissue and reperfusion injury 32 damage occurring after ischemia when blood flow returns to tissue after myocardial infarction 33 heart attack and when mutations in mitochondrial DNA polymerase occur 32 The heart attempts to compensate for disease state by increasing the intracellular Ca2 to increase the contractility cycling rates 35 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 35 33 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 32 35 78 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 35 Decreasing intramitochondrial Ca2 allows for reversal of cardiac hypertrophy caused in the original cardiac response 35 Decreasing the release of cytochrome C caused decreased cell death during injury and disease 32 Cyclosporin A also inhibits the phosphatase calcineurin pathway 14 32 33 79 Inhibition of this pathway has been shown to decrease myocardial hypertrophy 33 77 79 Veterinary use editThe medication is approved in the United States for the treatment of atopic dermatitis in dogs 80 Unlike the human form of the medication the lower doses used in dogs mean the drug acts as an immunomodulator and has fewer side effects than in humans The benefits of using this product include the reduced need for concurrent therapies to bring the condition under control It is available as an ophthalmic ointment for dogs called Optimmune manufactured by Intervet which is part of Merck It is also used to treat sebaceous adenitis immune response against the sebaceous glands pemphigus foliaceus autoimmune blistering skin disease Inflammatory bowel disease anal furunculosis anal inflammatory disease and myasthenia gravis a neuromuscular disease 80 81 References edit cyclosporin Dictionary com Unabridged Random House n d Archived from the original on 18 November 2010 Retrieved 13 July 2011 Laupacis A Keown PA Ulan RA McKenzie N Stiller CR May 1982 Cyclosporin A a powerful immunosuppressant Canadian Medical Association Journal 126 9 1041 6 PMC 1863293 PMID 7074504 FDA sourced list of all drugs with black box warnings Use Download Full Results and View Query links nctr crs fda gov FDA Retrieved 22 October 2023 Search Page Drug and Health Product Register 23 October 2014 Archived from the original on 7 June 2022 Retrieved 7 June 2022 Search Page Drug and Health Product Register 23 October 2014 Archived from the original on 7 June 2022 Retrieved 7 June 2022 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 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 a b c Restasis cyclosporine emulsion DailyMed Archived from the original on 30 March 2014 Retrieved 3 February 2022 Vevye cyclosporine ophthalmic solution solution drops DailyMed 26 May 2023 Archived from the original on 29 August 2023 Retrieved 29 August 2023 Ikervis European Medicines Agency 17 September 2018 Archived from the original on 13 August 2022 Retrieved 27 February 2023 World Health Organization 2009 Stuart MC Kouimtzi M Hill SR eds WHO Model Formulary 2008 World Health Organization p 221 hdl 10665 44053 ISBN 9789241547659 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 Cyclosporine eent The American Society of Health System Pharmacists Archived from the original on 13 January 2016 Retrieved 8 December 2016 Cyclosporine Use During Pregnancy Drugs com Archived from the original on 14 September 2017 Retrieved 20 December 2016 a b Matsuda S Koyasu S May 2000 Mechanisms of action of cyclosporine PDF Immunopharmacology 47 2 3 119 25 doi 10 1016 S0162 3109 00 00192 2 PMID 10878286 Archived from the original PDF on 11 August 2017 Retrieved 4 March 2018 Watts R Clunie G Hall F Marshall T 2009 Rheumatology Oxford University Press p 558 ISBN 978 0 19 922999 4 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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 Wang CP Hartman NR Venkataramanan R Jardine I Lin FT Knapp JE et al 1989 Isolation of 10 cyclosporine metabolites from human bile Drug Metabolism and Disposition 17 3 292 6 PMC 3154783 PMID 2568911 Copeland KR Yatscoff RW McKenna RM February 1990 Immunosuppressive activity of cyclosporine metabolites compared and characterized by mass spectroscopy and nuclear magnetic resonance Clinical Chemistry 36 2 225 9 doi 10 1093 clinchem 36 2 225 PMID 2137384 Lawen A October 2015 Biosynthesis of cyclosporins and other natural peptidyl prolyl cis trans isomerase inhibitors Biochimica et Biophysica Acta BBA General Subjects 1850 10 2111 20 doi 10 1016 j bbagen 2014 12 009 PMID 25497210 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Bibcode 1998PNAS 9513893M doi 10 1073 pnas 95 23 13893 PMC 24952 PMID 9811897 Wilkinson ST Johnson DB Tardif HL Tome ME Briehl MM March 2010 Increased cytochrome c correlates with poor survival in aggressive lymphoma Oncology Letters 1 2 227 230 doi 10 3892 ol 00000040 PMC 2927837 PMID 20798784 a b Lim HW De Windt LJ Mante J Kimball TR Witt SA Sussman MA et al April 2000 Reversal of cardiac hypertrophy in transgenic disease models by calcineurin inhibition Journal of Molecular and Cellular Cardiology 32 4 697 709 doi 10 1006 jmcc 2000 1113 PMID 10756124 S2CID 10904494 a b Archer TM Boothe DM Langston VC Fellman CL Lunsford KV Mackin AJ 2014 Oral cyclosporine treatment in dogs a review of the literature Journal of Veterinary Internal Medicine 28 1 1 20 doi 10 1111 jvim 12265 PMC 4895546 PMID 24341787 Palmeiro BS January 2013 Cyclosporine in veterinary dermatology Veterinary Clinics of North America Small Animal Practice 43 1 153 71 doi 10 1016 j cvsm 2012 09 007 PMID 23182330 External links editCyclosporine at the U S National Library of Medicine Medical Subject Headings MeSH Cyclosporine Drug Information Portal U S National Library of Medicine ChemSub Online Cyclosporin A Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Ciclosporin amp oldid 1205702653, wikipedia, wiki, book, books, library,

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