Common side effects include high blood pressure, headache,kidney problems, increased hair growth, and vomiting.[14] Other severe side effects include an increased risk of infection, liver problems, and an increased risk oflymphoma.[14] Blood levels of the medication should be checked to decrease the risk of side effects.[14] Use duringpregnancy may result inpreterm birth; however, ciclosporin does not appear to causebirth defects.[16]
Ciclosporin's main effect is to lower the activity ofT-cells; it does so by inhibitingcalcineurin in thecalcineurin–phosphatase pathway and preventing the mitochondrial permeability transition pore from opening. Ciclosporin binds to the cytosolic proteincyclophilin (immunophilin) oflymphocytes, especially of T cells. This cyclosporin—cyclophilin complex inhibitscalcineurin, which is normally responsible for activating the transcription ofinterleukin 2. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts viacalmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factorNF-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.[17] Ciclosporin, by preventing the dephosphorylation of NF-AT, leads to reducedeffector T-cell function;[33][34][35][36] it does not affectcytostatic activity.[medical citation needed]
Ciclosporin also binds to the cyclophilin D protein that constitutes part of themitochondrial permeability transition pore (MPTP),[34][37] 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,[38][39] leading to cell death. However, brief mitochondrial permeability transition pore openings play an essential physiological role in maintaining healthy mitochondrial homeostasis.[40]
Ciclosporin can induce a remission of proteinuria caused by such diseases as MCD and FSGS.[41] 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.[42]
Ciclosporin is acyclicpeptide of 11amino acids with notable molecular weight (1,202 Da)—achieves oral bioavailability up to ~30% due to its N-methylated cyclic structure, which confers both metabolic stability and a pronouncedchameleonic properties.[43] It contains a singleD-amino acid, which is rarely encountered in nature. Unlike most peptides, ciclosporin is not synthesized by ribosomes.[44]
Ciclosporin is highly metabolized by theCYP3A4 enzyme in humans and animals after ingestion.[45] The metabolites, which include cyclosporin B, C, D, E, H, and L,[46] have less than 10% of ciclosporin's immunosuppressant activity and are associated with higher kidney toxicity.[47]
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 toATQ39432.1) is the polyketide synthase.[52] These genes are associated with an active retrotransposon.[53] Although these sequences are poorly-annotated on GenBank and other databases, 90% similar sequences can be found for the Cyclosporin-producingBeauveria felina (orAmphichorda ~).[54] SimB has two paralogs in the same organism with different but overlapping functions thanks to their low specificity.[55]
In 1970, new strains of fungi were isolated from soil samples taken from Norway and from Wisconsin in the US by employees ofSandoz (nowNovartis) inBasel,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.[56]
The immunosuppressive effect of the natural product ciclosporin was discovered on 31 January 1972[57] in a screening test on immune suppression designed and implemented byHartmann F. Stähelin at Sandoz.[58][56] The chemical structure of cyclosporin was determined in 1976, also at Sandoz.[59][60] The success of the drug candidate ciclosporin in preventingorgan rejection was shown in kidney transplants byR.Y. Calne and colleagues at the University of Cambridge,[61] and inliver transplants performed byThomas Starzl at theChildren's Hospital of Pittsburgh. The first patient, on 9 March 1980, was a 28-year-old woman.[62] In the United States, the Food and Drug Administration (FDA) approved ciclosporin for clinical use in 1983.[63][64][65][66]
Thomas Starzl's 1992 memoir explains through the eyes of a transplant surgeon that ciclosporin was an epoch-making drug for solid organ allotransplantation.[67] It greatly expanded the clinical applicability of such transplantation by substantially advancing the antirejection pharmacotherapy component.[67] 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. Ciclosporin was a major advancement against the rejection part of the challenge.[67]
In July 2024, theCommittee for Medicinal Products for Human Use (CHMP) of theEuropean Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vevizye, intended for the treatment of dry eye disease.[11] The applicant for this medicinal product is Novaliq GmbH.[11] Vevizye was authorized for medical use in the European Union in September 2024.[11]
The natural product was named cyclosporin by the German-speaking scientists who first isolated it[56] and cyclosporine when translated into English. PerInternational Nonproprietary Name (INN) guidelines for drugs,[68] they was replaced withi so that the INN for the medication is spelled ciclosporin.[citation needed]
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 (nowNovartis), 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 newermicroemulsion,[70] 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.[71][72]
Generic ciclosporin preparations have been marketed under various brand names, including Cicloral (by Sandoz/Hexal), Gengraf (byAbbott) and Deximune (byDexcel Pharma). Since 2002, a topicalemulsion of ciclosporin for treating inflammation caused bykeratoconjunctivitis sicca (dry eye syndrome) has been marketed under the brand name Restasis.[8] Ikervis is a similar formulation with a concentration of 0.1%.[73]Inhaled ciclosporin formulations are in clinical development, and include a solution inpropylene glycol andliposome dispersions.[74][75]
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 ofcremophor and ethanol.[76] 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.[77]
Ciclosporin has been investigated as a possibleneuroprotective agent in conditions such astraumatic brain injury, and has been shown inanimal experiments to reducebrain damage associated with injury.[78] Ciclosporin blocks the formation of themitochondrial permeability transition pore, which has been found to cause much of the damage associated withhead injury andneurodegenerative 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.[79] This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making traumatic brain injuries much worse.[80]
Ciclosporin has been used experimentally to treat cardiac hypertrophy[34][81] (an increase in cell volume).
Inappropriate opening of themitochondrial permeability transition pore (MPTP) manifests in ischemia[34] (blood flow restriction to tissue) and reperfusion injury[34] (damage occurring after ischemia when blood flow returns to tissue), after myocardial infarction[35] (heart attack) and when mutations in mitochondrial DNA polymerase occur.[34] The heart attempts to compensate for disease state by increasing the intracellularCa2+ to increase the contractility cycling rates.[37] Constitutively high levels of mitochondrialCa2+ 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.[37][35]
Cyclosporin A has been shown to decrease cardiac hypertrophy by affecting cardiac myocytes in many ways. Cyclosporin A binds tocyclophilin D to block the opening of MPTP, and thus decreases the release of protein cytochrome C, which can cause programmed cell death.[34][37][82] 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 intramitochondrialCa2+ .[37] Decreasing intramitochondrialCa2+ allows for reversal of cardiac hypertrophy caused in the original cardiac response.[37] Decreasing the release of cytochrome C caused decreased cell death during injury and disease.[34] Cyclosporin A also inhibits the phosphatase calcineurin pathway (14).[34][35][83] Inhibition of this pathway has been shown to decrease myocardial hypertrophy.[35][81][83]
The medication is approved in the United States for the treatment ofatopic dermatitis in dogs.[84] 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 calledOptimmune, manufactured byIntervet, which is part ofMerck. It is also used to treatsebaceous adenitis (immune response against thesebaceous glands),pemphigus foliaceus (autoimmune blistering skin disease),Inflammatory bowel disease,perianal fistulas (anal inflammatory disease), andmyasthenia gravis (a neuromuscular disease).[84][85]
^"Ikervis".European Medicines Agency. 17 September 2018.Archived from the original on 13 August 2022. Retrieved27 February 2023.
^abcd"Vevizye EPAR".European Medicines Agency. 25 July 2024. Retrieved27 July 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^"Vevizye PI".Union Register of medicinal products. 23 September 2024. Retrieved27 September 2024.
^World Health Organization (2019).World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization.hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^World Health Organization (2021).World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization.hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
^Reinhard T (2000). "Lokales Cyclosporin A bei Nummuli nach Keratoconjunctivitis epidemica Eine Pilotstudie - Springer".Der Ophthalmologe.97 (11):764–768.doi:10.1007/s003470070025.PMID11130165.S2CID399211.
^Dijkmans BA, van Rijthoven AW, Goei Thè HS, Boers M, Cats A (August 1992). "Cyclosporine in rheumatoid arthritis".Seminars in Arthritis and Rheumatism.22 (1):30–36.doi:10.1016/0049-0172(92)90046-g.PMID1411580.
^Robert N, Wong GW, Wright JM (January 2010). "Effect of cyclosporine on blood pressure".Cochrane Database of Systematic Reviews (1) CD007893.doi:10.1002/14651858.CD007893.pub2.PMID20091657.
^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. Retrieved23 February 2018.
^abcdefghiMott JL, Zhang D, Freeman JC, Mikolajczak P, Chang SW, Zassenhaus HP (July 2004). "Cardiac disease due to random mitochondrial DNA mutations is prevented by cyclosporin A".Biochemical and Biophysical Research Communications.319 (4):1210–5.Bibcode:2004BBRC..319.1210M.doi:10.1016/j.bbrc.2004.05.104.PMID15194495.
^Morciano G, Giorgi C, Bonora M, Punzetti S, Pavasini R, Wieckowski MR, et al. (January 2015). "Molecular identity of the mitochondrial permeability transition pore and its role in ischemia-reperfusion injury".Journal of Molecular and Cellular Cardiology.78:142–53.doi:10.1016/j.yjmcc.2014.08.015.hdl:11392/2149014.PMID25172387.
^Borel JF (June 2002). "History of the discovery of cyclosporin and of its early pharmacological development".Wiener Klinische Wochenschrift.114 (12):433–7.PMID12422576. Some sources list the fungus under an alternative species nameHypocladium 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.PMID15896681. *Sneader W (23 June 2005). "Ciclosporin".Drug Discovery — A History. John Wiley & Sons. pp. 298–299.ISBN978-0-471-89979-2. 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 storyArchived 2005-03-08 at theWayback Machine" (retrieved 19 June 2005). Mark Plotkin states in his bookMedicine Quest, Penguin Books 2001, pages 46-47, that in 1996mycology researcher Kathie Hodgefound that it is in fact a species ofCordyceps.
^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.PMID25497210.
^di Salvo ML, Florio R, Paiardini A, Vivoli M, D'Aguanno S, Contestabile R (January 2013). "Alanine racemase from Tolypocladium inflatum: a key PLP-dependent enzyme in cyclosporin biosynthesis and a model of catalytic promiscuity".Archives of Biochemistry and Biophysics.529 (2):55–65.doi:10.1016/j.abb.2012.11.011.PMID23219598.
^Borel JF, Feurer C, Gubler HU, Stähelin H (July 1976). "Biological effects of cyclosporin A: a new antilymphocytic agent".Agents and Actions.6 (4):468–75.doi:10.1007/bf01973261.PMID8969.S2CID2862779.
^Rüegger A, Kuhn M, Lichti H, Loosli HR, Huguenin R, Quiquerez C, et al. (1976). "[Cyclosporin A, a Peptide Metabolite from Trichoderma polysporum (Link ex Pers.) Rifai, with a remarkable immunosuppressive activity]" [Cyclosporin A, a Peptide Metabolite from Trichoderma polysporum (Link ex Pers.) Rifai, with a remarkable immunosuppressive activity].Helvetica Chimica Acta (in German).59 (4):1075–92.doi:10.1002/hlca.19760590412.PMID950308.
^Calne RY, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC, et al. (1978). "Cyclosporin A in patients receiving renal allografts from cadaver donors".The Lancet.2 (8104–5):1323–7.doi:10.1016/S0140-6736(78)91970-0.PMID82836.S2CID10731038.
^"Ikervis". Santen.Archived from the original on 3 July 2018. Retrieved3 July 2018.
^Clinical trial numberNCT01287078 for "Cyclosporine Inhalation Solution (CIS) in Lung Transplant and Hematopoietic Stem Cell Transplant Recipients for the Treatment of Bronchiolitis Obliterans" atClinicalTrials.gov.
^Trammer B, Amann A, Haltner-Ukomadu E, Tillmanns S, Keller M, Högger P (November 2008). "Comparative permeability and diffusion kinetics of cyclosporine A liposomes and propylene glycol solution from human lung tissue into human blood ex vivo".European Journal of Pharmaceutics and Biopharmaceutics.70 (3):758–64.doi:10.1016/j.ejpb.2008.07.001.PMID18656538.
^Sullivan PG, Thompson M, Scheff SW (February 2000). "Continuous infusion of cyclosporin A postinjury significantly ameliorates cortical damage following traumatic brain injury".Experimental Neurology.161 (2):631–7.doi:10.1006/exnr.1999.7282.PMID10686082.S2CID25190221.
^Uchino H, Elmér E, Uchino K, Lindvall O, Siesjö BK (December 1995). "Cyclosporin A dramatically ameliorates CA1 hippocampal damage following transient forebrain ischaemia in the rat".Acta Physiologica Scandinavica.155 (4):469–71.doi:10.1111/j.1748-1716.1995.tb09999.x.PMID8719269.
^abLim 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.PMID10756124.S2CID10904494.
^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.PMID23182330.
N
Y (what is this?) (verify)
