同: CsA

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/06/20 21:28:32」(JST)

wiki en

"Cyclosporin" redirects here. For other types of cyclosporin, see Cyclosporins.

Ciclosporin (INN/BAN) (pronounced /ˌsaɪkləˈspɔrɪn/),^[1] cyclosporine (USAN), cyclosporin (former BAN), or cyclosporin A is an immunosuppressant drug widely used in organ transplantation to prevent rejection. It reduces the activity of the immune system by interfering with the activity and growth of T cells.^[2]^[3] It was initially isolated from the fungus Tolypocladium inflatum, found in a soil sample obtained by Sandoz scientists at Hardangervidda, Norway, in 1969.^{[citation needed]} Most peptides are synthesized by ribosomes, but ciclosporin is a cyclic nonribosomal peptide of 11 amino acids and contains a single D-amino acid, which are rarely encountered in nature.^[4]

Medical uses

The immunosuppressive effect of ciclosporin was discovered on 31 January 1972 by employees of Sandoz (now Novartis) in Basel, Switzerland, in a screening test on immune suppression designed and implemented by Hartmann F. Stähelin, M.D. The success of ciclosporin in preventing organ rejection was shown in kidney transplants by Calne and colleagues at the University of Cambridge,^[5] and in liver transplants performed by Dr. Thomas Starzl at the University of Pittsburgh Hospital. The first patient, on 9 March 1980, was a 28-year-old woman.^[6] Ciclosporin was subsequently approved for use in 1983.

In addition to transplants, ciclosporin is also used in psoriasis, severe atopic dermatitis, pyoderma gangrenosum, chronic autoimmune urticaria, and, infrequently, in rheumatoid arthritis and related diseases, although it is only used in severe cases. It is commonly prescribed in the US as an ophthalmic emulsion for the treatment of dry eyes. It has been investigated for use in many other autoimmune disorders, and is sometimes prescribed in veterinary cases, particularly in extreme cases of immune-mediated hemolytic anemia. Inhaled ciclosporin has been investigated to treat asthma and is being studied as a preventive therapy for chronic rejection of the lungs. Ciclosporin has also been used to help treat patients with acute severe ulcerative colitis that do not respond to treatment with steroids.^[7] This drug is also used as a treatment of posterior or intermediate uveitis with noninfective etiology.

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.^[8] 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 is a drug currently used to experimentally treat cardiac hypertrophy^[9]^[10] (an increase in cell volume).

Cardiac disease

Inappropriate opening of the mitochondrial permeability transition pore (MPTP) manifests in ischemia^[9] (blood flow restriction to tissue) and reperfusion injury^[9] (damage occurring after ischemia when blood flow returns to tissue), after myocardial infarction^[11] (heart attack) and when mutations in mitochondrial DNA polymerase occur.^[9] The heart attempts to compensate for disease state by increasing the intracellular Ca²⁺ to increase the contractility cycling rates.^[12] 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.^[11]^[12]

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.^[9]^[12]^[13] 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⁺.^[12] Decreasing intramitochondrial Ca²⁺ allows for reversal of cardiac hypertrophy caused in the original cardiac response.^[12] Decreasing the release of cytochrome C caused decreased cell death during injury and disease.^[9] CsA also inhibits the phosphatase calcineurin pathway (14).^[9]^[11]^[14] Inhibition of this pathway has been shown to decrease myocardial hypertrophy.^[10]^[11]^[14]

Adverse effects

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

ADRs can include gingival hyperplasia, convulsions, peptic ulcers, pancreatitis, fever, vomiting, diarrhea, confusion, hypercholesterolemia, dyspnea, numbness and tingling particularly of the lips, pruritus, high blood pressure, potassium retention, and possibly hyperkalemia, kidney and liver dysfunction (nephrotoxicity^[15] and hepatotoxicity), burning sensations at finger tips and an increased vulnerability to opportunistic fungal and viral infections.

An alternate form of the drug, cyclosporin G (OG37-324), has been found to be much less nephrotoxic than the standard ciclosporin (cyclosporin A).^[16] Cyclosporin G (molecular mass 1217) differs from cyclosporin A in the amino acid 2 position, where an L-norvaline replaces the α-aminobutyric acid.^[17]

Ciclosporin is listed as IARC Group 1 carcinogens (sufficient evidence of carcinogenicity in humans).

Mechanism of action

In medicine, the most important effect of ciclosporin is to lower the activity of T cells and their immune response.

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 dephosphorlyation of NF-AT by binding to cyclophilin.^[18] 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 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),^[9]^[12] and by inhibiting the calcineurin phosphatase pathway.^[9]^[11]^[19] The MPTP is found in the mitochondrial membrane of cardiac myocytes (heart muscle cells) and moves calcium ions (Ca²⁺) into the mitochondria.^[9]^[12] 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.^[12] To allow for normal contraction, intracellular Ca²⁺ increases, and the MPTP in turn opens, shuttling Ca²⁺ into the mitochondria.^[12] Calcineurin is a Ca²⁺-activated phosphatase (enzyme that removes a phosphate group from substrate) that regulates cardiac hypertrophy.^[10]^[11]^[14] 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.^[10]^[11]

Biosynthesis

Figure 1: Ciclosporin biosynthesis. Bmt = butenyl-methyl-threonine, Abu = L-alpha-aminobutyric acid, Sar = sarcosine

Ciclosporin is synthesized by a nonribosomal peptide synthetase, ciclosporin synthetase. The enzyme contains an adenylation domain, a thiolation domain, a condensation domain, and an N-methyltransferase^{[disambiguation needed ]} 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. Ciclosporin synthetase substrates include L-valine, L-leucine, L-alanine, L-glycine, 2-aminobutyric acid, 4-methylthreonine, and D-alanine. With the adenylation domain, ciclosporin 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 ciclosporin from the enzyme.^[20] Amino acids such as D-Ala and butenyl-methyl-L-threonine indicate ciclosporin 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.^[21]

Figure 2: Butenyl-methyl-L-Threonine biosynthesis

Formulations

The drug exhibits very poor solubility in water, and, as a consequence, suspension and emulsion forms of the drug 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.^[22] A newer microemulsion, orally-administered formulation, Neoral,^[23] is available as a solution and as soft gelatin capsules. 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 drug 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 drug, 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.

References

^ "cyclosporin". Dictionary.com Unabridged. Random House. [n.d.]. http://dictionary.reference.com/browse/cyclosporin. Retrieved 2011-07-13.
^ Henry J. Kaminski (26 November 2008). Myasthenia Gravis and Related Disorders. Springer. p. 163. "Cyclosporine is derived from a fungus and is a cyclic undecapeptide with actions directed exclusively on T cells."
^ Cantrell DA, Smith KA (1984). "The interleukin-2 T-cell system: a new cell growth model". Science. 224 (4655): 1312–1316. DOI:10.1126/science.6427923. PMID 6427923.
^
Borel JF (2002). "History of the discovery of cyclosporin and of its early pharmacological development". Wien. Klin. Wochenschr. 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 (2005). "Sourcing a chemical succession for cyclosporin from parasites and human pathogens". Drug Discov. Today 10 (10): 688–91. DOI:10.1016/S1359-6446(05)03395-7. PMID 15896681.
- "Ciclosporin". Drug Discovery — A History. John Wiley & Sons. pp. 298–299 (refs. page 315).
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" (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 that it is in fact a species of Cordyceps.
^ Calne RY, White DJG, Thiru S, Evans DB, McMaster P, Dunn DC, et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. The Lancet 1978/II:1323-1327
^ Starzl TE, Klintmalm GB, Porter KA, Iwatsuki S, Schröter GP (1981). "Liver transplantation with use of cyclosporin a and prednisone". N. Engl. J. Med. 305 (5): 266–9. DOI:10.1056/NEJM198107303050507. PMC 2772056. PMID 7017414. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2772056.
^ Lichtiger S, Present DH, Kornbluth A, et al. (1994). "Cyclosporine in severe ulcerative colitis refractory to steroid therapy". N. Engl. J. Med. 330 (26): 1841–5. DOI:10.1056/NEJM199406303302601. PMID 8196726.
^ Sullivan PG, Thompson M, Scheff SW (2000). "Continuous infusion of cyclosporin A postinjury significantly ameliorates cortical damage following traumatic brain injury". Exp. Neurol. 161 (2): 631–7. DOI:10.1006/exnr.1999.7282. PMID 10686082.
^ ^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". Biochem. Biophys. Res. Commun. 319 (4): 1210–5. DOI:10.1016/j.bbrc.2004.05.104. PMID 15194495. http://linkinghub.elsevier.com/retrieve/pii/S0006291X04010952.
^ ^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". Proc. Natl. Acad. Sci. U.S.A. 95 (23): 13893–8. DOI:10.1073/pnas.95.23.13893. PMC 24952. PMID 9811897. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9811897.
^ ^a ^b ^c ^d ^e ^f ^g Youn TJ, Piao H, Kwon JS, et al. (December 2002). "Effects of the calcineurin dependent signaling pathway inhibition by cyclosporin A on early and late cardiac remodeling following myocardial infarction". Eur. J. Heart Fail. 4 (6): 713–8. DOI:10.1016/S1388-9842(02)00120-4. PMID 12453541. http://eurjhf.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12453541.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Elrod JW, Wong R, Mishra S, et al. (October 2010). "Cyclophilin D controls mitochondrial pore-dependent Ca²⁺ exchange, metabolic flexibility, and propensity for heart failure in mice". J. Clin. Invest. 120 (10): 3680–7. DOI:10.1172/JCI43171. PMC 2947235. PMID 20890047. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2947235.
^ Wilkinson ST, Johnson DB, Tardif HL, Tome ME, Briehl MM (2010). "Increased cytochrome c correlates with poor survival in aggressive lymphoma". Oncol Lett 1 (2): 227–230. DOI:10.3892/ol_00000040. PMC 2927837. PMID 20798784. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2927837.
^ ^a ^b ^c Lim HW, De Windt LJ, Mante J, et al. (April 2000). "Reversal of cardiac hypertrophy in transgenic disease models by calcineurin inhibition". J. Mol. Cell. Cardiol. 32 (4): 697–709. DOI:10.1006/jmcc.2000.1113. PMID 10756124. http://linkinghub.elsevier.com/retrieve/pii/S0022-2828(00)91113-1.
^ Naesens M, Kuypers DR, Sarwal M (2009). "Calcineurin inhibitor nephrotoxicity". Clin. J. Am. Soc. Nephrol. 4 (2): 481–509. DOI:10.2215/CJN.04800908. PMID 19218475.
^ Henry ML, Elkhammas EA, Davies EA, Ferguson RM (1995). "A clinical trial of cyclosporine G in cadaveric renal transplantation". Pediatr. Nephrol. 9 (Suppl): S49–51. DOI:10.1007/BF00867684. PMID 7492487.
^ Calne RY, White DJ, Thiru S, Rolles K, Drakopoulos S, Jamieson NV (1985). "Cyclosporin G: immunosuppressive effect in dogs with renal allografts". Lancet 1 (8441): 1342. DOI:10.1016/S0140-6736(85)92844-2. PMID 2860538.
^ William F. Ganong. Review of medical physiology, 22nd edition, Lange medical books, chapter 27, page 530. ISBN 0-07-144040-2
^ 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. http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=6238408.
^ Hoppert M, Gentzsch C, Schörgendorfer K (October 2001). "Structure and localization of cyclosporin synthetase, the key enzyme of cyclosporin biosynthesis in Tolypocladium inflatum". Arch. Microbiol. 176 (4): 285–93. DOI:10.1007/s002030100324. PMID 11685373. http://link.springer.de/link/service/journals/00203/papers/1176004/11760285.pdf.
^ Dewick, P. (2001) Medicinal Natural Products. John Wiley & Sons, Ltd. 2nd ed.
^ http://www.pharma.us.novartis.com/product/pi/pdf/sandimmune.pdf
^ http://www.pharma.us.novartis.com/product/pi/pdf/neoral.pdf

External links

U.S. National Library of Medicine: Drug Information Portal — Ciclosporin
Neoral U.S. Prescribing Information
Sandimmune U.S. Prescribing Information
Atopica brand (for atopic dermatitis in dogs)
Restasis brand
ChemSub Online : Ciclosporin A

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. シクロスポリンおよびタクロリムスの薬理作用および副作用 pharmacology and side effects of cyclosporine and tacrolimus
2. シクロスポリンおよびタクロリムスの腎毒性 cyclosporine and tacrolimus nephrotoxicity
3. 成人の腎移植における免疫抑制維持療法 maintenance immunosuppressive therapy in renal transplantation in adults
4. 移植片対宿主病の予防および治療に使用される免疫抑制剤の概要 overview of immunosuppressive agents used for prevention and treatment of graft versus host disease
5. 成人におけるステロイド抵抗性およびステロイド依存性の潰瘍性大腸炎に対するアプローチ approach to adults with steroid refractory and steroid dependent ulcerative colitis

English Journal

Potential modulation on P-glycoprotein and CYP3A by soymilk and miso: In vivo and ex-vivo studies.

Yu CP, Hsieh YW, Lin SP, Chi YC, Hariharan P, Chao PD, Hou YC.Author information School of Pharmacy, China Medical University, Taichung 404, Taiwan, ROC.AbstractP-glycoprotein (P-gp) and CYP3A4 both play very important roles in drug bioavailability, resistance and interactions. Our in vitro studies indicated that P-gp function was activated by many isoflavones. This study investigated the in vivo effects of soymilk and miso, isoflavone-rich soy foods, on P-gp and CYP3A by tracing the pharmacokinetics of cyclosporine (CSP), a probe drug of P-gp. Rats were orally administered CSP with and without soymilk or miso. A specific monoclonal fluorescence polarisation immunoassay was used to determine the blood concentration of CSP. The results showed that soymilk and miso significantly decreased the Cmax of CSP by 64.5% and 78.3%, and reduced the AUC0-540 by 64.9% and 78.3%, respectively. Mechanism studies revealed that the activities of P-gp and CYP3A4 were induced by soymilk and miso. In conclusion, ingestion of soymilk and miso significantly activated the functions of P-gp and CYP3A.
Food chemistry.Food Chem.2014 Apr 15;149:25-30. doi: 10.1016/j.foodchem.2013.10.058. Epub 2013 Oct 23.
P-glycoprotein (P-gp) and CYP3A4 both play very important roles in drug bioavailability, resistance and interactions. Our in vitro studies indicated that P-gp function was activated by many isoflavones. This study investigated the in vivo effects of soymilk and miso, isoflavone-rich soy foods, on P-
PMID 24295672

CRAC channel inhibition produces greater anti-inflammatory effects than glucocorticoids in CD8 cells from COPD patients.

Grundy S, Kaur M, Plumb J, Reynolds S, Hall S, House D, Begg M, Ray D, Singh D.Author information *University of Manchester NIHR Translational Research Facility, Manchester Academic Health Science Centre, University Hospital of South Manchester Foundation Trust, Manchester M23 9LT, U.K.AbstractThere are increased numbers of pulmonary CD8 lymphocytes in COPD (chronic obstructive pulmonary disease). CRAC (calcium release-activation calcium) channels play a central role in lymphocyte activation though the regulation of the transcription factor NFAT (nuclear factor of activated T-cells). We studied the expression of NFAT in lungs from COPD patients compared with controls, and evaluated the effects of CRAC channel inhibition compared with corticosteroids on NFAT activation and cytokine production in CD8 cells from COPD patients. The effects of the corticosteroid dexamethasone, the calcineurin inhibitor cyclosporin and the CRAC channel inhibitor Synta 66 were studied on cytokine production and NFAT activation using peripheral blood and isolated pulmonary CD8 cells. NFAT1 and CD8 co-expression in the lungs was compared in COPD patients and controls using combined immunohistochemistry and immunofluorescence. NFAT inhibition with either cyclosporin or Synta 66 resulted in significantly greater maximal inhibition of cytokines than dexamethasone in both peripheral blood and pulmonary CD8 cells [e.g. >95% inhibition of IFNγ (interferon γ) production from pulmonary CD8 cells using cyclosporin and Synta 66 compared with <50% using dexamethasone]. The absolute number of pulmonary CD8 cells co-expressing NFAT1 was significantly raised in lungs from COPD patients compared with controls, but the percentage of CD8 cells co-expressing NFAT1 was similar between COPD patients and controls (80.7% compared with 78.5% respectively, P=0.3). Inhibition of NFAT using the CRAC channel Synta 66 produces greater anti-inflammatory effects on CD8 cells from COPD patients than corticosteroids. NFAT is expressed at a high level in pulmonary CD8 cells in COPD.
Clinical science (London, England : 1979).Clin Sci (Lond).2014 Feb;126(3):223-32. doi: 10.1042/CS20130152.
There are increased numbers of pulmonary CD8 lymphocytes in COPD (chronic obstructive pulmonary disease). CRAC (calcium release-activation calcium) channels play a central role in lymphocyte activation though the regulation of the transcription factor NFAT (nuclear factor of activated T-cells). We s
PMID 23905758

An update on drug-drug interactions with biologics for the treatment of moderate-to-severe psoriasis.

Gupta R, Levin E, Wu JJ, Koo J, Liao W.Author information Keck School of Medicine of University of Southern California , Los Angeles, CA , USA.AbstractObjective: Moderate-to-severe psoriasis is a chronic skin condition that often requires systemic therapy and biologics are the newest systemic treatment available. A favorable aspect of biologics is that they are thought to have minimal risks for drug-drug interactions compared to oral systemic medications such as cyclosporine and methotrexate. However, this assumption has not been recently or adequately reviewed. We reviewed the literature to identify possible drug-drug interactions with biologics and other medications. Methods: We searched PubMed for published case reports, clinical studies, reviews, and Food and Drug Administration (FDA) labels discussing possible drug-drug interactions with biologics for the treatment of moderate-to-severe psoriasis. Results: There were only a small number of published articles describing drug-drug interactions with biologics. Our review identified two case reports, five clinical studies, and three pharmacokinetics reviews. The majority of articles did not observe clinically relevant drug-drug interactions with biologics. FDA labels do suggest a possible relationship between tumor necrosis factor (TNF)-alpha inhibitors and cytochrome P450 (CYP) activity. Conclusion: The paucity of information regarding drug-drug interactions reaffirms the idea that biologics have limited susceptibility to drug-drug interactions compared to other oral medications. Further studies are needed to adequately assess drug-drug interactions with biologics.
The Journal of dermatological treatment.J Dermatolog Treat.2014 Feb;25(1):87-9. doi: 10.3109/09546634.2013.825041. Epub 2013 Aug 27.
Objective: Moderate-to-severe psoriasis is a chronic skin condition that often requires systemic therapy and biologics are the newest systemic treatment available. A favorable aspect of biologics is that they are thought to have minimal risks for drug-drug interactions compared to oral systemic medi
PMID 23855593

Japanese Journal

臨床研究小児造血幹細胞移植におけるシクロスポリン持続静注法と1日2回3時間静注法の有効性と安全性の比較検討

納富誠司郎,梅田雄嗣,松原央 [他]
臨床血液 53(11), 1891-1897, 2012-11
NAID 40019507205

各種局所療法や羊膜移植が有用であった粘膜類天疱瘡の3例

越後岳士,折戸秀光,濱口儒人 [他]
日本皮膚科学会雑誌 = The Japanese journal of dermatology 122(11), 2647-2654, 2012-11
NAID 40019469779

Related Pictures

★リンクテーブル★

リンク元	「シクロスポリン」「免疫抑制薬」「慢性間質性腎炎」「Neoral」「ciclosporin」
拡張検索	「cyclosporine toxicity」
関連記事	「cyclosporin」

「シクロスポリン」

Identifiers
Symbol
OPM superfamily	174
OPM protein	1cwa

Ciclosporin
Systematic (IUPAC) name
	(E)-14,17,26,32-tetrabutyl-5-ethyl-8-(1-hydroxy-2-methylhex-4-enyl) -1,3,9,12,15,18,20,23,27-nonamethyl-11,29-dipropyl-1,3,6,9,12,15,18,21,24,27,30- undecaazacyclodotriacontan-2,4,7,10,13,16,19,22,25,28,31-undecaone
Clinical data
Trade names	Neoral, Sandimmune
AHFS/Drugs.com	monograph
MedlinePlus	a601207
Pregnancy cat.	C (AU) C (US)
Legal status	Prescription Only (S4) (AU) POM (UK) ℞-only (US)
Routes	oral, IV, ophthalmic
Pharmacokinetic data
Bioavailability	variable
Metabolism	hepatic
Half-life	variable (about 24 hours)
Excretion	biliary
Identifiers
CAS number	59865-13-3
ATC code	L04AD01 S01XA18
PubChem	CID 5284373
DrugBank	DB00091
ChemSpider	4447449
UNII	83HN0GTJ6D
KEGG	D00184
ChEMBL	CHEMBL160
Chemical data
Formula	C62H111N11O12
Mol. mass	1202.61
	InChI 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 ; Key:PMATZTZNYRCHOR-CGLBZJNRSA-N ;
(what is this?) (verify);

　　[★]

英: cyclosporine, CyA, CsA, ciclosporin
同: シクロスポリンA cyclosporine A cyclosporin A、サイクロスポリン、サイクロスポリンA
商: アマドラ、サンディミュン Sandimmun、シクポラール、ネオーラル Neoral、パピロックミニ
関: 免疫抑制薬、

シクロスポリンはシクロスポリンA、CsAともよばれ、1976年にT細胞を介する免疫抑制剤であり、臓器移植を可能にした薬剤である。
1970年代初めにノルウェーの土壌中の真菌(Tolypocladium inflatum)の培養液から分離された、分子量1202の環状ポリペプチドで環状部分は10個のアミノ酸から構成される。
C62H111N11O12の分子式で表される。
拒絶反応抑制効果が強く、1980年代になって副腎皮質ステロイドとの併用によって、従来の肝移植の1年生存率25％が80％に上昇し、臓器移植が現在のように医療として定着することに貢献した。
宿主の移植片に対する反応のみならずGVH反応にも有効であるとされる。
シクロスポリンは活性化T細胞のIL-2産生を抑制する。
IL-2はT細胞により自己分泌/傍分泌されT細胞の活性化と増殖を起こす。
細胞質に存在するリン酸化された転写因子NFAT(nuclear factor of activated T cells)は、活性型のカルシニューリン(Ca2+とカルモジュリンが結合した形)により脱リン酸化されると、活性化したNFATとなる。
活性化したNFATは核内に移行しIL-2の転写しIL-2 mRNAが産生され、結果としてIL-2合成に繋がる。
さて、細胞内に入ったシクロスポリン(CsA)はシクロフィリン(cyclophilin)と結合する。
CsA-cyclophilin複合体はカルシニューリンに結合し、結果としてカルシニューリンを不活化して、脱リン酸化活性を抑制する。
副作用として、腎毒性、高血圧、脂質異常症、神経毒性、肝毒性がある。
シクロスポリンの腎毒性は、シクロスポリンがTGF-β産生を刺激することと関係があるらしい。
TGF-βは細胞外基質の産生を促し、間質の線維化を来す。
ヘルパーT細胞の作用を抑制するがサプレッサーT細胞には影響しない。
移植当日から10～15mg/kgで投与開始し，次第に4mg/kg程度に減量する。
トラフ値は50-250ng/mlが目標となる。
肝・腎移植後は150-250ng/mlで維持されるが、最終的には100ng/ml以下まで減量される。
骨髄移植では150-250ng/ml、再生不良性貧血では250ng/ml以下、ネフローゼ症候群では150ng/ml以下で維持される。
自己免疫疾患では血中濃度と効果の相関は、明確ではないが、一般的にBehcet病・乾癬では50-200ng/mlに維持される。
もともとのシクロスポリンは腸管からの吸収が悪く，マイクロエマルジョン化したサンディミュンやネオーラルはこの問題を軽減した。
代謝は肝臓でP450によって行われるので，この酵素に関与する薬剤との併用時には血中濃度に注意する。

「免疫抑制薬」

　　[★]

英: immunosuppressive drug, immunosuppressant
関

免疫抑制薬

作用機序

シクロスポリン、タクロリムス

56kDa immunophilinに結合 (GOO.1596)

56kDa immunophilinはHSP70, HSP90と共にglucocorticoid receptosに結合している。

再生不良性貧血に対する治療薬として

抗ヒト胸腺細胞抗体

副作用

感染症

リスクの上がる病原微生物

https://www.jpn-geriat-soc.or.jp/publications/other/pdf/clinical_practice_of_geriatrics_48_5_461.pdf

	量と投与期間	病原微生物	予防薬
ステロイド	プレドニン10mgで8週間以上投与予定	Pneumocystis jirovecii	ST合剤
	リンデロン1mg以上を1カ月以上投与	Pneumocystis jirovecii	ST合剤
	プレドニン15mg以上を2～3週間以上	結核	感染予防はなし，潜在結核治療としてはイソニアジド
	ステロイド全般	ノカルジア？	ST合剤？（ただし，投与下での発症あり）
TNFα阻害薬	インフリキシマブ、エタネルセプト	Pneumocystis jirovecii	ST合剤
TNFα阻害薬	インフリキシマブ、エタネルセプト	結核	新規感染予防はなし，潜在結核治療としてはイソニアジド