Common side effects include high blood pressure, headache, kidney problems, increased hair growth, and vomiting. Other severe side effects include an increased risk of infection, liver problems, and an increased risk of lymphoma. Blood levels of the medication should be checked to decrease the risk of side effects. Use during pregnancy may result in preterm birth; however, ciclosporin does not appear to cause birth defects.
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. Ciclosporin, by preventing the dephosphorylation of NF-AT, leads to reduced effector T-cell function; it does not affect cytostatic activity.[medical ]
Ciclosporin also binds to the cyclophilin D protein that constitutes part of the mitochondrial permeability transition pore (MPTP), 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, leading to cell death. However, brief mitochondrial permeability transition pore openings play an essential physiological role in maintaining healthy mitochondrial homeostasis.
Ciclosporin is highly metabolized in humans and animals after ingestion. The metabolites, which include cyclosporin B, C, D, E, H, and L, have less than 10% of ciclosporin's immunosuppressant activity and are associated with higher kidney toxicity. Individual ciclosporin metabolites have been isolated and characterized but do not appear to be extensively studied.[medical ]
Cyclosporin biosynthesis. Bmt = butenyl-methyl-threonine, Abu = L-alpha-aminobutyric acid, Sar = sarcosine
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. These genes are associated with an active retrotransposon. 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 ~). SimB has two paralogs in the same organism with different but overlapping functions thanks to their low speficity.
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.
The immunosuppressive effect of the natural product ciclosporin was discovered in December 1971 in a screening test on immune suppression designed and implemented by Hartmann F. Stähelin at Sandoz. The chemical structure of cyclosporin was determined in 1976, also at Sandoz. 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, and in liver transplants performed by Thomas Starzl at the University of Pittsburgh Hospital. The first patient, on 9 March 1980, was a 28-year-old woman. In the United States, the Food and Drug Administration (FDA) approved ciclosporin for clinical use in 1983.
Society and culture
The natural product was named cyclosporin by the German speaking scientists who first isolated it and cyclosporine when translated into English. Per International Nonproprietary Name (INN) guidelines for drugs, the y was replaced with i so that the INN for the medication is spelled ciclosporin.
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. A newer microemulsion, orally-administered formulation, Neoral, is available as a solution and as soft gelatin capsules. The Neoral compositions are designed to form microemulsions in contact with water.[medical ]
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. NeuroSTAT was recently 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.
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. 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 CsA was strongly neuroprotective when it crossed the blood-brain barrier. This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making traumatic brain injuries much worse.
Ciclosporin has been used experimentally to treat cardiac hypertrophy (an increase in cell volume).
Inappropriate opening of the mitochondrial permeability transition pore (MPTP) manifests in ischemia (blood flow restriction to tissue) and reperfusion injury (damage occurring after ischemia when blood flow returns to tissue), after myocardial infarction (heart attack) and when mutations in mitochondrial DNA polymerase occur. The heart attempts to compensate for disease state by increasing the intracellular to increase the contractility cycling rates. Constitutively high levels of mitochondrial 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.
CsA (cyclosporin A) has been shown to decrease cardiac hypertrophy by affecting cardiac myocytes in many ways. CsA 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. CypD is a protein within the MPTP that acts as a gate; binding by CsA decreases the amount of inappropriate opening of MPTP, which decreases the intramitochondrial . Decreasing intramitochondrial allows for reversal of cardiac hypertrophy caused in the original cardiac response. Decreasing the release of cytochrome C caused decreased cell death during injury and disease. CsA also inhibits the phosphatase calcineurin pathway (14). Inhibition of this pathway has been shown to decrease myocardial hypertrophy.
^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.
^Lin H, Rocher LL, McQuillan MA, Schmaltz S, Palella TD, Fox IH (February 1990). "Cyclosporine-induced hyperuricemia and gout". The New England Journal of Medicine. 322 (5): 334-6. doi:10.1056/NEJM199002013220514. PMID2296276.
^ 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. doi:10.1016/j.bbrc.2004.05.104. PMID15194495.
^Morciano G, Giorgi C, Bonora M, Punzetti S, Pavasini R, Wieckowski MR, Campo G, Pinton P (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. PMID25172387.
^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. PMID2137384.
^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.
^Rüegger A, Kuhn M, Lichti H, Loosli HR, Huguenin R, Quiquerez C, von Wartburg A (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.
^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.
^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.