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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/02/12 15:21:14」(JST)
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"Cyclosporin" redirects here. For other types of cyclosporin, see Cyclosporins.
| Systematic (IUPAC) 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-undecone | |
| 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 CYP3A4 |
| Half-life | Variable (about 24 hours) |
| Excretion | Biliary |
| Identifiers | |
| CAS number | 59865-13-3 Y |
| ATC code | L04AD01 S01XA18 |
| PubChem | CID 5284373 |
| DrugBank | DB00091 |
| ChemSpider | 4447449 Y |
| UNII | 83HN0GTJ6D Y |
| KEGG | D00184 Y |
| ChEMBL | CHEMBL160 Y |
| Chemical data | |
| Formula | C62H111N11O12 |
| Mol. mass | 1202.61 g/mol |
|
SMILES
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InChI
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| N (what is this?) (verify) | |
Ciclosporin (INN/BAN) (pronounced /ˌsaɪkləˈspɔrɪn/);[1] cyclosporine (USAN); cyclosporin (former BAN); or ciclosporin A,[citation needed] cyclosporine A, or cyclosporin A (often shortened to CsA) 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 (Beauveria nivea), found in a soil sample obtained in 1969 from Hardangervidda, Norway, by Dr. Hans Peter Frey, a Sandoz biologist.[4] 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.[5]
Contents
- 1 Medical uses
- 1.1 Cardiac disease
- 2 Adverse effects
- 3 Mechanism of action
- 4 Metabolism and metabolite activity
- 5 Biosynthesis
- 6 Formulations
- 7 See also
- 8 References
- 9 External links
Medical uses[edit]
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 R.Y. Calne and colleagues at the University of Cambridge,[6] 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.[7] Ciclosporin was subsequently approved for use in 1983. Since then, it has been used to prevent and treat graft-versus-host reactions in bone-marrow transplantation and to prevent rejection of kidney, heart, and liver transplants.[8]
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.[8] 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.[9] This drug is also used as a treatment of posterior or intermediate uveitis with noninfective etiology. Ciclosporin is a drug currently used to experimentally treat cardiac hypertrophy[10][11] (an increase in cell volume).
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.[12] 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.[13] This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making traumatic brain injuries much worse.[14] Cyclosporine is currently in a phase II/III (adaptive) clinical study in Europe to determine its ability to ameliorate neuronal cellular damage 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 cyclosporine called NeuroSTAT®.[15]
Cardiac disease[edit]
Inappropriate opening of the mitochondrial permeability transition pore (MPTP) manifests in ischemia[10] (blood flow restriction to tissue) and reperfusion injury[10] (damage occurring after ischemia when blood flow returns to tissue), after myocardial infarction[16] (heart attack) and when mutations in mitochondrial DNA polymerase occur.[10] The heart attempts to compensate for disease state by increasing the intracellular Ca2+
to increase the contractility cycling rates.[17] 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.[16][17]
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.[10][17][18] 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+
.[17] Decreasing intramitochondrial Ca2+
allows for reversal of cardiac hypertrophy caused in the original cardiac response.[17] Decreasing the release of cytochrome C caused decreased cell death during injury and disease.[10] CsA also inhibits the phosphatase calcineurin pathway (14).[10][16][19] Inhibition of this pathway has been shown to decrease myocardial hypertrophy.[11][16][19]
In addition to its well-known immunosuppressive capabilities, the one-time administration of cyclosporine at the time of percutaneous coronary intervention (PCI) has been found to deliver a 40 percent reduction in infarct size in a small group proof of concept study of human patients with reperfusion injury published in The New England Journal of Medicine in 2008.[20]
Adverse effects[edit]
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 possibly leading to hyperkalemia, kidney and liver dysfunction (nephrotoxicity[21] and hepatotoxicity), burning sensations at finger tips and an increased vulnerability to opportunistic fungal and viral infections.In short, it is nephrotoxic, neurotoxic, causes hypertension (due to renal vasoconstriction and increased sodium reabsorption), increases the risk of squamous cell carcinoma and infections. It also causes gingival hypertrophy and hirsutism which is not seen with tacrolimus (another calcineurin inhibitor).
An alternate form of the drug, cyclosporin G (OG37-324), has been found to be much less nephrotoxic than the standard ciclosporin (cyclosporin A).[22] Cyclosporin G (molecular mass 1217) differs from cyclosporin A in the amino acid 2 position, where an L-norvaline replaces the α-aminobutyric acid.[23]
| Identifiers | |
|---|---|
| OPM superfamily | 174 |
| OPM protein | 1cwa |
Ciclosporin is listed as IARC Group 1 carcinogens (sufficient evidence of carcinogenicity in humans).
Mechanism of action[edit]
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 dephosphorylation of NF-AT by binding to cyclophilin.[24] 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),[10][17] and by inhibiting the calcineurin phosphatase pathway.[10][16][25] The MPTP is found in the mitochondrial membrane of cardiac myocytes (heart muscle cells) and moves calcium ions (Ca2+
) into the mitochondria.[10][17] 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.[17] To allow for normal contraction, intracellular Ca2+
increases, and the MPTP in turn opens, shuttling Ca2+
into the mitochondria.[17] Calcineurin is a Ca2+
-activated phosphatase (enzyme that removes a phosphate group from substrate) that regulates cardiac hypertrophy.[11][16][19] 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.[11][16]
Metabolism and metabolite activity[edit]
Ciclosporin is highly metabolized in humans and animals after ingestion. The resulting metabolites include cyclosporin B, C, D, E, H, L, and others.[26] Ciclosporin metabolites have been found to have lower immunosuppressant activity than CsA (approximately <10%), and are associated with higher nephrotoxicity.[27] Individual ciclosporin metabolites have been isolated and characterized but do not appear to be extensively studied.
Biosynthesis[edit]
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 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, glycine, 2-aminobutyric acid, 4-methylthreonine, and D-alanine, which is the starting amino acid in the biosynthetic process.[28] 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.[29] 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.[30]
Figure 2: Butenyl-methyl-L-threonine biosynthesis
Formulations[edit]
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.[31] A newer microemulsion,[32] orally-administered formulation, Neoral,[33] is available as a solution and as soft gelatin capsules (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 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.
A new formulation of cyclosporine called NeuroSTAT (also known by its cardiorprotection trade name of CicloMulsion) by NeuroVive Pharma[15] uses a lipid emulsion base instead of cremophor and ethanol and is undergoing clinical trials for traumatic brain injury (phase II/III) and reperfusion injury (phase III).[15] NeuroSTAT was recently compared to Sandimmune in a phase I study and found to be bioequivalent.[34] One notable finding was that the NeuroSTAT did not exhibit the anaphylactic and hypersensitivity reactions found in cremophor- and ethanol-based products.[34]
See also[edit]
- Cremophor EL (additive in Sandimmune)
- Castor oil (additive in Sandimmune)
- Alcohol (additive in Sandimmune and Neoral)
- Discovery and development of mTOR inhibitors
- Voclosporin, an analog of ciclosporin
References[edit]
- ^ "cyclosporin". Dictionary.com Unabridged. Random House. [n.d.] 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.
- ^ Svarstad, H; Bugge, HC; Dhillion, SS (2000). "From Norway to Novartis: Cyclosporin from Tolypocladium inflatum in an open access bioprospecting regime". Biodiversity and Conservation 9 (11): 1521–1541. doi:10.1023/A:1008990919682.
- ^ 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).
- 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.
- ^ 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.
- ^ a b Report on Carcinogens, Tweltfh Edition. Known To Be Human Carcinogens: U.S. Department of Health and Human Services. 2011. pp. 125–127.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Uchino, H., Elmér, E., Uchino, K., Lindvall, O., Siesjo, B.K.. Cyclosporin A dramatically ameliorates CA1 hippocampal damage following transient forebrain ischaemia in the rat. Acta Physiologica Scandinavica. 1995; Dec;155(4):469–471.
- ^ Sullivan, P., Sebastian, A., Hall, E. "Therapeutic window analysis of the neuroprotective effects of cyclosporine A after traumatic brain injury." Journal of Neurotrauma 2011; Feb;28:311–318.
- ^ a b c http://www.neurovive.com
- ^ 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.
- ^ 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. Cite uses deprecated parameters (help) - ^ 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.
- ^ 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.
- ^ Piot C., Croiselle P., Staat P. et al. "Effect of Cyclosporine on Reperfusion Injury in Acute Myocardial Infaction." New England Journal of Medicine 359 (5): 473-481 2008.
- ^ 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.
- ^ Wang, Paul C. et. al. "Isolation of 10 Cyclosporine Metabolites from Human Bile." Drug Metabolism and Disposition 17.3 (1989): 292-96. Nih.gov. Web. 28 Oct. 2013.
- ^ Copeland, Kenneth R. "Immunosuppressive Activity of Cyclosporine Metabolites Compared and Characterized by Mass Spectrometry and Nuclear Magnetic Resonance."Clinical Chemistry 36.2 (1990): 225-29. Web. 28 Oct. 2013.
- ^ Dittmann J, Wenger RM, Kleinkauf H, Lawen A (January 1994). "Mechanism of cyclosporin A biosynthesis. Evidence for synthesis via a single linear undecapeptide precursor". J. Biol. Chem. 269 (4): 2841–6. PMID 8300618.
- ^ 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.
- ^ Dewick, P. (2001) Medicinal Natural Products. John Wiley & Sons, Ltd. 2nd ed.
- ^ Sandimmune Prescribing Information
- ^ Gibaud, S. P.; Attivi, D. (2012). "Microemulsions for oral administration and their therapeutic applications". Expert Opinion on Drug Delivery: 1. doi:10.1517/17425247.2012.694865. edit
- ^ Neoral Prescribing Information
- ^ a b Ehinger, K. H. J., Hansson, J. J., Sjovall, F., Elmer, E. "Bioequivalence and Tolerability Assessment of a Novel Intravenous Ciclosporin Lipid Emulsion Compared to Branded Ciclosporin in Cremophor EL." Clinical Drug Investigation 2012 Nov. 22 Epub ahead of print.
External links[edit]
- 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
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UpToDate Contents
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- 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. 肺移植後の免疫抑制の維持 maintenance immunosuppression following lung transplantation
- 3. シェーグレン症候群におけるドライアイの治療 treatment of dry eyes in sjogrens syndrome
- 4. シクロスポリンおよびタクロリムスの腎毒性 cyclosporine and tacrolimus nephrotoxicity
- 5. 小児におけるステロイド抵抗性特発性ネフローゼ症候群 steroid resistant idiopathic nephrotic syndrome in children
English Journal
- The effects of Cyclosporine A and azathioprine on human T cells activated by different costimulatory signals.
- Leitner J, Drobits K, Pickl WF, Majdic O, Zlabinger G, Steinberger P.SourceInstitute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
- Immunology letters.Immunol Lett.2011 Oct 30;140(1-2):74-80. Epub 2011 Jul 2.
- Immunosuppression is an important treatment modality in transplantation and human diseases that are associated with aberrant T cell activation. There are considerable differences regarding the cellular processes targeted by the immunosuppressive drugs that are in clinical use. Drugs like azathioprin
- PMID 21756939
Japanese Journal
- 小児科領域における研究と治療の進歩(8)川崎病の急性期治療の現状と新たな試み
- 濱田 洋通
- 東京女子医科大学雑誌 81(4), 227-230, 2011-08-25
- 小児の血管炎である川崎病の治療に焦点をあて、歴史的変遷と現在の標準治療・残された課題への取り組みを概説した.川崎病は自然解熱する急性熱性疾患であるが、血管炎が遷延して冠動脈病変を残すと虚血性心疾患のリスクとなり、一生にわたり管理が必要となる.川崎病は未だに原因が不明であり、モデル動物もいないことから、急性期治療法の開発は試行錯誤の連続であった.初期に試みられたステロイド治療、アスピリンの時代、19 …
- NAID 110008604386
Related Links
- 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 ...
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★リンクテーブル★
| リンク元 | 「シクロスポリン」「Neoral」「ciclosporin」「シクロスポリンA」「CsA」 |
| 関連記事 | 「cyclosporin」「A」「Ad」 |
「シクロスポリン」
- 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。
「Neoral」
「ciclosporin」
シクロス・リン
「シクロスポリンA」
- 英
- cyclosporin A、cyclosporine A、CsA、CYA
- 関
- シクロスポリン
「CsA」
[★] シクロスポリンA、cyclosporin A、cyclosporine A
「cyclosporin」
シクロス・リン
「A」