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Clinical data
Pronunciation /ˌskləˈspɔːrɪn/[2]
Trade names Neoral, Sandimmune, others
Synonyms cyclosporin, ciclosporin A,[1] cyclosporine A, cyclosporin A (CsA), cyclosporine (USAN US)
AHFS/ Monograph
MedlinePlus a601207
License data
  • AU: C
  • US: C (Risk not ruled out)
Routes of
By mouth, IV, eye drops
Drug class immunosuppressant
calcineurin inhibitor
eye medication
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability Variable
Metabolism liver CYP3A4
Biological half-life Variable (about 24 hours)
Excretion biliary
CAS Number
PubChem CID
ECHA InfoCard 100.119.569
Chemical and physical data
Formula C62H111N11O12
Molar mass 1202.61 g/mol
3D model (JSmol)
 NYesY (what is this?)  (verify)
Symbol N/A
OPM superfamily 174
OPM protein 1cwa

Ciclosporin, also spelled cyclosporine and cyclosporin, is an immunosuppressant medication and natural product.[3] It is used by mouth and injection into a vein for rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, and in organ transplants to prevent rejection.[3][4] It is also used as eye drops for keratoconjunctivitis sicca (dry eyes).[5]

Common side effects include high blood pressure, headache, kidney problems, increased hair growth, and vomiting.[4] Other severe side effects include an increased risk of infection, liver problems, and an increased risk of lymphoma.[4] Blood levels of the medication should be checked to decrease the risk of side effects.[4] Use during pregnancy may result in preterm birth; however, it does not appear to cause birth defects.[6]

Ciclosporin is believed to work by decreasing the function of lymphocytes.[4] It does this by forming a complex with cyclophilin to block the phosphatase activity of calcineurin that in turn decreases the production of inflammatory cytokines by T‐lymphocytes.[7]

Ciclosporin was isolated in 1971 from the fungus Tolypocladium inflatum and came into medical use in 1983.[8] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[9] The wholesale cost in the developing world is about US$106.50 a month.[10] In the United Kingdom it costs the NHS about GB£121.25 per month.[11] The wholesale price in the United States is about US$172.95 per month.[12]

Medical uses[edit]

Ciclosporin is approved by the FDA to prevent and treat graft-versus-host disease in bone-marrow transplantation and to prevent rejection of kidney, heart, and liver transplants.[13][14] It is also approved in the US for the treatment of rheumatoid arthritis and psoriasis,[14] as an ophthalmic emulsion for the treatment of dry eyes[15] (a common symptom of Sjögren's syndrome), and as a treatment for persistent nummular keratitis following adenoviral keratoconjunctivitis.[16]

In addition to these indications, ciclosporin is also used in severe atopic dermatitis, Kimura disease, pyoderma gangrenosum, chronic autoimmune urticaria, acute systemic mastocytosis, and, infrequently, in rheumatoid arthritis and related diseases, although it is only used in severe cases.[citation needed]

Ciclosporin has also been used to help treat people with acute severe ulcerative colitis and autoimmune urticaria that do not respond to treatment with steroids.[17] This medication is also used as a treatment of posterior or intermediate uveitis with noninfective cause.[citation needed]

Side effects[edit]

Treatment may be associated with a number of potentially serious adverse drug reactions (ADRs).

ADRs can include enlargement of the gums, convulsions, peptic ulcers, pancreatitis, fever, vomiting, diarrhea, confusion, hypercholesterolemia, dyspnea, numbness and tingling particularly of the lips, pruritus, high blood pressure, potassium retention possibly leading to hyperkalemia, kidney and liver dysfunction (nephrotoxicity[18] and hepatotoxicity), burning sensations at finger tips, and an increased vulnerability to opportunistic fungal and viral infections. In short, it is nephrotoxic, neurotoxic, increases the risk of squamous cell carcinoma and infections, and often causes hypertension (due to renal vasoconstriction and increased sodium reabsorption). The latter may result in serious adverse cardiovascular events; thus it is recommended that prescribers find the lowest effective dose for people requiring long term treatment.[19] Ciclosporin also causes enlargement of the gums and increased hair growth which is not seen with tacrolimus (another calcineurin inhibitor).

Use of ciclosporin in post renal transplantation is associated with hyperuricemia and, in some cases, gout.[20] This is due to the decrease in glomerular filtration rate induced by ciclosporin leading to retention of uric acid. Use of azathioprine as an alternative has shown to reduce the incidence of gouty arthritis.

It is listed as IARC Group 1 carcinogens (sufficient evidence of carcinogenicity in humans).[21]

Mechanism of action[edit]

The most important effect of ciclosporin is to lower the activity of T cells and their immune response. It does this by binding to cyclophilin, a multifunctional protein that facilitates protein folding, acts as a protein chaperone, and regulates the activity of other proteins. The resulting ciclosporin/cyclophilin complex inhibits the phosphatase activity of calcineurin which in turn is required for the activation of transcription factors that up regulate the expression of inflammatory cytokines.[7]

Ciclosporin binds to the cytosolic protein cyclophilin (immunophilin) of lymphocytes, especially T cells. This complex of ciclosporin and cyclophilin inhibits calcineurin, which, under normal circumstances, is 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 nuclear factor of activated T-cells (NFATc), which moves to the nucleus of the T-cell and increases the activity of genes coding for IL-2 and related cytokines. Ciclosporin prevents the dephosphorylation of NF-AT by binding to cyclophilin.[22] It also inhibits lymphokine production and interleukin release and, therefore, leads to a reduced function of effector T-cells. It does not affect cytostatic activity.

Ciclosporin affects mitochondria by preventing the mitochondrial permeability transition pore from opening, thus inhibiting cytochrome c release, a potent apoptotic stimulation factor. This is not the primary mechanism of action for clinical use, but is also an important effect for research on apoptosis.

Ciclosporin binds to the cyclophilin D protein (CypD) that constitutes part of the mitochondrial permeability transition pore (MPTP),[23][24] and by inhibiting the calcineurin phosphatase pathway.[23][25][26] The MPTP is found in the mitochondrial membrane of cardiac myocytes (heart muscle cells) and moves calcium ions (Ca2+
) into the mitochondria.[23][24] When open, Ca2+
enters the mitochondria, disrupting transmembrane potential (the electric charge across a membrane). If unregulated, this can contribute to mitochondrial swelling and dysfunction.[24] To allow for normal contraction, intracellular Ca2+
increases, and the MPTP in turn opens, shuttling Ca2+
into the mitochondria.[24] Calcineurin is a Ca2+
-activated phosphatase (enzyme that removes a phosphate group from substrate) that regulates cardiac hypertrophy.[25][27][28] Regulation occurs through NFAT (nuclear factor of activated T-cells) activation, which, when dephosphorylated, binds to GATA and forms a transcription factor (protein that can bind DNA and alter the expression of DNA) with ability to control the hypertrophic gene (2). Activation of calcineurin causes increases in hypertrophy.[25][27]


Most peptides are synthesized by ribosomes, but cyclosporin is a cyclic nonribosomal peptide of 11 amino acids and contains a single D-amino acid, which is rarely encountered in nature.[29]

Ciclosporin is highly metabolized in humans and animals after ingestion. The resulting metabolites include cyclosporin B, C, D, E, H, L, and others.[30] Ciclosporin metabolites have been found to have lower immunosuppressant activity than CsA (approximately <10%), and are associated with higher nephrotoxicity.[31] Individual ciclosporin metabolites have been isolated and characterized but do not appear to be extensively studied.


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

Cyclosporin is synthesized by a nonribosomal peptide synthetase, cyclosporin synthetase.[32] 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.[33] 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.[34] Amino acids such as D-Ala and butenyl-methyl-L-threonine indicate cyclosporin synthetase requires the action of other enzymes such as a D-alanine racemase. The racemization of L-Ala to D-Ala is pyridoxal phosphate-dependent. The formation of butenyl-methyl-L-threonine is performed by a butenyl-methyl-L-threonine polyketide synthase that uses acetate/malonate as its starting material.[35]

Butenyl-methyl-L-threonine biosynthesis


In 1970, new strains of fungi were isolated from soil samples taken from Norway and from Wisconsin in the USA 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.[36]

The immunosuppressive effect of the natural product cyclosporin was discovered in December 1971 in a screening test on immune suppression designed and implemented by Hartmann F. Stähelin at Sandoz.[37][36] The chemical structure of cyclosporin was determined in 1976, also at Sandoz.[38][39] 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,[40] 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.[41] In the United States, the Food and Drug Administration (FDA) approved ciclosporin for clinical use in 1983.[42][43][44][45]


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, as an oral solution, and as a formulation for intravenous administration. These are all nonaqueous compositions.[46] A newer microemulsion,[47] orally-administered formulation, Neoral,[48] is available as a solution and as soft gelatin capsules (10 mg, 25 mg, 50 mg and 100 mg). The Neoral compositions are designed to form microemulsions in contact with water. Generic ciclosporin preparations have been marketed under various trade names, including Cicloral (Sandoz/Hexal), Gengraf (Abbott) and Deximune (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 (0.05%). Inhaled ciclosporin formulations are in clinical development, and include a solution in propylene glycol and liposome dispersions.

The medication is also available in a dog preparation manufactured by Novartis Animal Health called Atopica. Atopica is indicated for the treatment of atopic dermatitis in dogs. 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.


The natural product was named cyclosporin by the German speaking scientists who first isolated it[36] and cyclosporine when translated into English. Per International Nonproprietary Name (INN) guidelines for drugs,[49] the "y" was replaced with "i" so that the INN for the medication is spelled ciclosporin.

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



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.[50] 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.[51]

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.[52] 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.[53] This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making traumatic brain injuries much worse.[54]

Cardiac disease[edit]

Ciclosporin has been used experimentally to treat cardiac hypertrophy[23][27] (an increase in cell volume).

Inappropriate opening of the mitochondrial permeability transition pore (MPTP) manifests in ischemia[23] (blood flow restriction to tissue) and reperfusion injury[23] (damage occurring after ischemia when blood flow returns to tissue), after myocardial infarction[25] (heart attack) and when mutations in mitochondrial DNA polymerase occur.[23] The heart attempts to compensate for disease state by increasing the intracellular Ca2+
to increase the contractility cycling rates.[24] 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.[24][25]

CsA 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.[23][24][55] 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 Ca2+
.[24] Decreasing intramitochondrial Ca2+
allows for reversal of cardiac hypertrophy caused in the original cardiac response.[24] Decreasing the release of cytochrome C caused decreased cell death during injury and disease.[23] CsA also inhibits the phosphatase calcineurin pathway (14).[23][25][28] Inhibition of this pathway has been shown to decrease myocardial hypertrophy.[25][27][28]

Veterinary use[edit]

The medication is approved in the United States for the treatment of atopic dermatitis in dogs.[56] 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).[56][57]

It is sometimes prescribed for extreme cases of immune-mediated hemolytic anemia.[57]

See also[edit]


  1. ^ 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 1863293Freely accessible. PMID 7074504. 
  2. ^ "cyclosporin". Unabridged. Random House. n.d. Archived from the original on 2010-11-18. Retrieved 2011-07-13. 
  3. ^ a b WHO Model Formulary 2008 (PDF). World Health Organization. 2009. p. 221. ISBN 9789241547659. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016. 
  4. ^ 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. 
  5. ^ "Cyclosporine eent". The American Society of Health-System Pharmacists. Archived from the original on 13 January 2016. Retrieved 8 December 2016. 
  6. ^ "Cyclosporine Use During Pregnancy". Archived from the original on 14 September 2017. Retrieved 20 December 2016. 
  7. ^ a b Matsuda S, Koyasu S (May 2000). "Mechanisms of action of cyclosporine". Immunopharmacology. 47 (2–3): 119–25. doi:10.1016/S0162-3109(00)00192-2. PMID 10878286. 
  8. ^ Watts R, Clunie G, Hall F, Marshall T (2009). Rheumatology. Oxford University Press. p. 558. ISBN 978-0-19-922999-4. Archived from the original on 2017-11-05. 
  9. ^ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016. 
  10. ^ "Ciclosporin". International Drug Price Indicator Guide. Retrieved 8 December 2016. 
  11. ^ British national formulary: BNF 69 (69th ed.). British Medical Association. 2015. p. 632. ISBN 978-0-85711-156-2. 
  12. ^ "NADAC as of 2016-12-07 |". Centers for Medicare and Medicaid Services. Archived from the original on 21 December 2016. Retrieved 20 December 2016. 
  13. ^ SandImmune Label Archived 2014-04-21 at the Wayback Machine.
  14. ^ a b "DailyMed - NEORAL- cyclosporine capsule, liquid filled NEORAL- cyclosporine solution". Archived from the original on 2013-07-05. 
  15. ^ "DailyMed - RESTASIS - cyclosporine emulsion". Archived from the original on 2014-03-30. 
  16. ^ Reinhard T (2000). "Lokales Cyclosporin A bei Nummuli nach Keratoconjunctivitis epidemica Eine Pilotstudie - Springer". Der Ophthalmologe. 97 (11): 764–768. doi:10.1007/s003470070025. 
  17. ^ Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S (June 1994). "Cyclosporine in severe ulcerative colitis refractory to steroid therapy". The New England Journal of Medicine. 330 (26): 1841–5. doi:10.1056/NEJM199406303302601. PMID 8196726. 
  18. ^ Naesens M, Kuypers DR, Sarwal M (February 2009). "Calcineurin inhibitor nephrotoxicity". Clinical Journal of the American Society of Nephrology. 4 (2): 481–508. doi:10.2215/CJN.04800908. PMID 19218475. 
  19. ^ 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. PMID 20091657. 
  20. ^ 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. PMID 2296276. 
  21. ^ Agents Classified by the IARC Monographs, Volumes 1–110 Archived 2011-10-25 at the Wayback Machine.
  22. ^ Ganong WF (2005). "27". Review of medical physiology (22nd ed.). New York: McGraw-Hill Medical. p. 530. ISBN 978-0-07-144040-0. 
  23. ^ a b c d e f g h i j Mott 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. PMID 15194495. 
  24. ^ a b c d e f g h i Elrod JW, Wong R, Mishra S, Vagnozzi RJ, Sakthievel B, Goonasekera SA, Karch J, Gabel S, Farber J, Force T, Brown JH, Murphy E, Molkentin JD (October 2010). "Cyclophilin D controls mitochondrial pore-dependent Ca(2+) exchange, metabolic flexibility, and propensity for heart failure in mice". Journal of Clinical Investigation. 120 (10): 3680–7. doi:10.1172/JCI43171. PMC 2947235Freely accessible. PMID 20890047. 
  25. ^ a b c d e f g Youn TJ, Piao H, Kwon JS, Choi SY, Kim HS, Park DG, Kim DW, Kim YG, Cho MC (December 2002). "Effects of the calcineurin dependent signaling pathway inhibition by cyclosporin A on early and late cardiac remodeling following myocardial infarction". European Journal of Heart Failure. 4 (6): 713–8. doi:10.1016/S1388-9842(02)00120-4. PMID 12453541. Archived from the original on 2013-04-15. 
  26. ^ Handschumacher RE, Harding MW, Rice J, Drugge RJ, Speicher DW (November 1984). "Cyclophilin: a specific cytosolic binding protein for cyclosporin A". Science. 226 (4674): 544–7. doi:10.1126/science.6238408. PMID 6238408. 
  27. ^ a b c d Mende U, Kagen A, Cohen A, Aramburu J, Schoen FJ, Neer EJ (November 1998). "Transient cardiac expression of constitutively active Galphaq leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways". Proceedings of the National Academy of Sciences of the United States of America. 95 (23): 13893–8. doi:10.1073/pnas.95.23.13893. PMC 24952Freely accessible. PMID 9811897. 
  28. ^ a b c Lim HW, De Windt LJ, Mante J, Kimball TR, Witt SA, Sussman MA, Molkentin JD (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. 
  29. ^ Borel JF (June 2002). "History of the discovery of cyclosporin and of its early pharmacological development". Wiener klinische Wochenschrift. 114 (12): 433–7. PMID 12422576. 
    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. "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 Archived 2005-03-08 at the Wayback Machine." (retrieved June 19, 2005). Mark Plotkin states in his book Medicine Quest, Penguin Books 2001, pages 46-47, that in 1996 mycology researcher Kathie Hodge found Archived 2006-03-10 at the Wayback Machine. that it is in fact a species of Cordyceps.
  30. ^ Wang CP, Hartman NR, Venkataramanan R, Jardine I, Lin FT, Knapp JE, Starzl TE, Burckart GJ (1989). "Isolation of 10 cyclosporine metabolites from human bile". Drug Metabolism and Disposition. 17 (3): 292–6. PMC 3154783Freely accessible. PMID 2568911. 
  31. ^ 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. PMID 2137384. 
  32. ^ Lawen A (October 2015). "Biosynthesis of cyclosporins and other natural peptidyl prolyl cis/trans isomerase inhibitors". Biochimica et Biophysica Acta. 1850 (10): 2111–20. doi:10.1016/j.bbagen.2014.12.009. PMID 25497210. 
  33. ^ Dittmann J, Wenger RM, Kleinkauf H, Lawen A (January 1994). "Mechanism of cyclosporin A biosynthesis. Evidence for synthesis via a single linear undecapeptide precursor". Journal of Biological Chemistry. 269 (4): 2841–6. PMID 8300618. 
  34. ^ Hoppert M, Gentzsch C, Schörgendorfer K (October 2001). "Structure and localization of cyclosporin synthetase, the key enzyme of cyclosporin biosynthesis in Tolypocladium inflatum" (PDF). Archives of Microbiology. 176 (4): 285–93. doi:10.1007/s002030100324. PMID 11685373. [permanent dead link]
  35. ^ Dewick, P. (2001) Medicinal Natural Products. John Wiley & Sons, Ltd. 2nd ed.
  36. ^ a b c Borel JF, Kis ZL, Beveridge T (1995). "The history of the discovery and development of Cyclosporin (Sandimmune®)". In Merluzzi VJ, Adams J. The search for anti-inflammatory drugs case histories from concept to clinic. Boston: Birkhäuser. pp. 27–63. ISBN 978-1-4615-9846-6. Archived from the original on 2017-11-05. 
  37. ^ 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. PMID 8969. 
  38. ^ 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. PMID 950308. 
  39. ^ Heusler K, Pletscher A (June 2001). "The controversial early history of cyclosporin". Swiss Medical Weekly. 131 (21–22): 299–302. PMID 11584691. Archived from the original on 2017-09-02. 
  40. ^ Calne RY, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC, Craddock GN, Pentlow BD, Rolles K (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. PMID 82836. 
  41. ^ Starzl TE, Klintmalm GB, Porter KA, Iwatsuki S, Schröter GP (July 1981). "Liver transplantation with use of cyclosporin a and prednisone". The New England Journal of Medicine. 305 (5): 266–9. doi:10.1056/NEJM198107303050507. PMC 2772056Freely accessible. PMID 7017414. 
  42. ^ Kolata G (September 1983). "FDA speeds approval of cyclosporin". Science. 221 (4617): 1273. doi:10.1126/science.221.4617.1273-a. PMID 17776314. On 2 September (1983), the Food and Drug Administration approved cyclosporin, a new drug that suppresses the immune system. 
  43. ^ Gottesman J (20 March 1988). "Milestones in Cardiac Care". Los Angeles Times. Archived from the original on 26 February 2017. 
  44. ^ "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, ... 
  45. ^ "Drugs@FDA: FDA Approved Drug Products [Click on "Approval Date(s) and History]". United States Food and Drug Administration. Archived from the original on 2017-03-01. 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 
  46. ^ Sandimmune Prescribing Information Archived 2004-07-19 at the Wayback Machine.
  47. ^ Gibaud S, Attivi D (August 2012). "Microemulsions for oral administration and their therapeutic applications". Expert Opinion on Drug Delivery. 9 (8): 937–51. doi:10.1517/17425247.2012.694865. PMID 22663249. 
  48. ^ Neoral Prescribing Information Archived 2007-07-28 at the Wayback Machine.
  49. ^ "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. 
  50. ^ Administrator. "Hem - NeuroVive Pharmaceutical AB". Archived from the original on 2014-01-06. 
  51. ^ Ehinger KH, Hansson MJ, Sjövall F, Elmér E (January 2013). "Bioequivalence and tolerability assessment of a novel intravenous ciclosporin lipid emulsion compared to branded ciclosporin in Cremophor ® EL". Clinical Drug Investigation. 33 (1): 25–34. doi:10.1007/s40261-012-0029-x. PMC 3586182Freely accessible. PMID 23179472. 
  52. ^ 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. PMID 10686082. 
  53. ^ 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. PMID 8719269. 
  54. ^ Sullivan PG, Sebastian AH, Hall ED (February 2011). "Therapeutic window analysis of the neuroprotective effects of cyclosporine A after traumatic brain injury". Journal of Neurotrauma. 28 (2): 311–8. doi:10.1089/neu.2010.1646. PMC 3037811Freely accessible. PMID 21142667. 
  55. ^ 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 2927837Freely accessible. PMID 20798784. 
  56. ^ 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 4895546Freely accessible. PMID 24341787. 
  57. ^ a b 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. 

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