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环孢素

维基百科，自由的百科全书
（重定向自Cyclosporine）
维基百科中的醫學内容仅供参考，並不能視作專業意見。如需獲取醫療幫助或意見，请咨询专业人士。詳見醫學聲明。
环孢素
臨床資料
读音/ˌsaɪkləˈspɔːrɪn/[1]
商品名（英语：Drug nomenclature）Sandimmune及其他
其他名稱cyclosporin、ciclosporin A,[2]cyclosporine A及cyclosporin A (CsA), cyclosporine (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa601207
核准狀況
懷孕分級
  • 澳: C
给药途径口服給藥, 靜脈注射，眼藥水
藥物類別（英语：Drug class）鈣調磷酸酶抑制劑
ATC碼
法律規範狀態
法律規範
藥物動力學數據
生物利用度並非固定
药物代谢肝臟 CYP3A4
生物半衰期並非固定 (約24小時)
排泄途徑膽管
识别信息
  • (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
CAS号59865-13-3  checkY
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB配體ID
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)
ECHA InfoCard100.119.569 編輯維基數據鏈接
化学信息
化学式C62H111N11O12
摩尔质量1,202.64 g·mol−1
3D模型（JSmol（英语：JSmol））
  • CC[C@H]1C(=O)N(CC(=O)N([C@H](C(=O)N[C@H](C(=O)N([C@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N1)[C@@H]([C@H](C)C/C=C/C)O)C)C(C)C)C)CC(C)C)C)CC(C)C)C)C)C)CC(C)C)C)C(C)C)CC(C)C)C)C
  • 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 checkY
  • Key:PMATZTZNYRCHOR-CGLBZJNRSA-N checkY

環孢素（英語：ciclosporin，也有cyclosporine及cyclosporin的拼寫法），是一種鈣調磷酸酶抑制劑，作為免疫抑制劑之用，以治療類風濕性關節炎、乾癬、克隆氏症、腎病症候群、濕疹，以及作為器官移植後長期服用之藥物，防止移植器官受到排斥。[13][14]此藥物透過口服或是靜脈注射方式給藥，也製成眼藥水形式以治療乾眼症。[15]

使用後常見的副作用有高血壓、頭痛、腎臟問題、毛髮生長增加和嘔吐。[14]嚴重的副作用有感染風險增加、肝臟問題和罹患淋巴瘤風險增加。[14]使用後應持續檢查藥物的血藥濃度以降低副作用風險。[14]個體於懷孕期間使用可能會導致早產，但此藥物似乎不會造成胎兒的先天性障礙。[16]

環孢素被認為是透過降低淋巴球的功能來發揮作用。[14]它與親環蛋白（英语：cyclophilin）形成複合物來阻斷鈣調磷酸酶的磷酸酶活性，而減少T細胞產生促炎性細胞因子。[17]

環孢素於1971年從名為膨大彎頸霉的真菌分離出，並於1983年取得核准用於醫療用途。[18]它已列入世界衛生組織基本藥物標準清單之中。[19][20]此藥物在美國於2022年最常使用處方藥中排名第185，開立的處方箋數量超過200萬張。[21][22]市面上有其通用名藥物流通。[23]

醫療用途

環孢素用於治療和預防造血幹細胞移植（又稱骨髓移植）的移植物對抗宿主疾病，並預防宿主對於移植而來的腎臟、心臟和肝臟的排斥反應。[7][6]此藥物也在美國被批准用於治療類風濕性關節炎和乾癬、腺病毒性角結膜炎（英语：Adenoviral keratoconjunctivitis）後出現的持續性錢幣狀角膜炎（英语：nummular keratitis），[24][6]以及作為治療乾燥症和瞼板腺功能障礙引起的乾眼症之用的眼藥水。[8]

環孢素除這些適應症外，也用於治療嚴重的異位性皮膚炎，[25]及嚴重的類風濕性關節炎及相關疾病。[26]

環孢素也用於治療對類固醇治療無反應的急性嚴重潰瘍性結腸炎和蕁麻疹患者。[27]

副作用

使用環孢素產生的副作用有牙齦腫大（英语：Gingival enlargement）、毛髮生長增加、抽搐、消化性潰瘍、胰腺炎、發燒、嘔吐、腹瀉、精神錯亂、膽固醇升高、呼吸困難、麻木和刺痛（尤其是嘴唇）、搔癢、高血壓、鉀滯留（可能導致高血鉀症）、腎臟和肝功能障礙、[28]指尖灼熱感，以及容易受到黴菌和病毒感染。環孢素會誘導腎臟血管收縮和增加鈉重吸收，而引起高血壓。血壓升高會引發心血管問題，因此建議需要使用此藥物進行長期治療的人只使用最低的有效劑量。[29]

腎臟移植後使用環孢素與血液中尿酸濃度升高有關，在某些情況下也會導致痛風。[30]

環孢素被列為國際癌症研究機構一類致癌物（即有足夠的證據表明對人類具有致癌性），[31]特別是會導致皮膚鱗狀細胞癌和非霍奇金氏淋巴瘤。[32]

藥理學

作用機轉

環孢素的主要作用是降低T細胞的活性，它透過抑制鈣調磷酸酶-磷酸酶途徑中的鈣調磷酸酶，並阻止粒線體通透性轉變孔（英语：mitochondrial permeability transition pore）（MPTP）打開來達成。環孢素藉由阻止活化T細胞核因子去磷酸化，導致效應性T細胞功能降低[33][34][35][36]

環孢素是一種免疫抑制劑，除抑制免疫反應外，還能與線粒體膜上的粒線體通透性轉變孔結合。[34][37]MPTP是細胞能量工廠（線粒體）上的一各通道，其開閉程度直接影響細胞的能量供應。環孢素能穩定MPTP的狀態，防止其過度開啟，而保護細胞免受能量耗竭的損害。[38]

環孢素可減緩腎臟微小病變和局灶節段性腎小球硬化症等疾病引起的蛋白尿。其機制為：環孢素保護足細胞中的突觸足蛋白（英语：synaptopodin），使其不被分解，進而維持腎小球基底膜的完整性，減少蛋白質流失。[39]

藥物動力學

環孢素是一種由11個胺基酸組成的環肽，它有單一的D-氨基酸，在自然界中很少見。環孢素並非由核糖體合成，與大多數的肽不同。[40]

環孢素經攝入後會在人類和動物體內充分代謝。代謝物包括環孢素B、C、D、E、H和L，[41]代謝物的免疫抑制活性不到原形環孢素的10%，且與較高的腎毒性（英语：Nephrotoxicity）有關聯。[42]

生物合成

環孢素的生物合成過程。Bmt（butenyl-methyl-threonine，丁烯基甲基蘇氨酸），Abu（L-alpha-aminobutyric acid，L-α-氨基丁酸），Sar（sarcosine，肌氨酸）。

非核糖體肽（英语：nonribosomal peptide）合成酶經由活化、連接和修飾胺基酸，逐步合成環孢素。[43]

基因簇

目前用於大量生產環孢素的物種 - 膨大彎頸霉 - 的生物合成基因排列，形成一個12個基因的簇。這12基因簇是此黴菌生產環孢素的重要遺傳基礎，基因間相互協作，共同完成環孢素的合成過程。[44][45][46][47]

歷史

於瑞士巴塞爾桑多茲集團公司（英语：Sandoz）（現已併入諾華製藥）服務的科學家於1970年從挪威和美國威斯康辛州採集的土壤樣本中分離出新的真菌菌株。兩種菌株都會產生一系列稱為環孢素的天然產物，均具有抗真菌活性的成分。來自挪威的菌株 - 膨大彎頸霉 - 後來被用於大規模生產環孢素。[48]

天然環孢素的免疫抑制作用於1972年1月31日[49]被於桑多茲集團服務的藥理學家哈特曼·F·斯塔赫林（英语：Hartmann F. Stähelin）發現。[50][48]環孢素的化學結構於1976年也為桑多茲集團確定。[51][52]後來英國外科醫師羅伊·約克·卡恩爵士（英语：Roy Calne）及其劍橋大學的同事在1978年進行的腎臟移植手術中[53]以及美國外科醫師托馬斯·斯塔爾茲（英语：Thomas Starzl）於1980年在匹茲堡大學醫療中心兒童醫院（英语：UPMC Children's Hospital of Pittsburgh）進行的肝臟移植手術中[54]均成功確定環孢素具有預防移植排斥的作用。 美國食品藥物管理局（FDA）於1983年核准環孢素用於醫療用途。[55][56][57][58]

托馬斯·斯塔爾茲在其撰述的回憶錄中解釋環孢素是實體器官同種異體移植的劃時代藥物，[59]其具有的良好抗排斥治療成分，大幅擴展移植手術的臨床適用性。[59]簡而言之，廣泛應用這種移植的最大限制不是成本或手術技術，而是同種異體移植排斥以及捐贈器官來源稀缺的問題。環孢素則在處理排斥方面獲得重大進展。[59]

社會與文化

法律地位

歐洲藥品管理局人用藥品委員會（英语：Committee for Medicinal Products for Human Use）（CHMP）於2024年7月採納正面意見，建議授予用於治療乾眼症藥品Vevizye的上市許可。藥品的申請者是設於德國的Novaliq GmbH。[11]Vevizye於2024年9月取得歐盟核准用於醫療用途。[11]

名稱

這種天然產物被首先分離出來的科學家命名為cyclosporin，[48]而在翻譯成英文後將名稱改寫為cyclosporine。根據國際非專有藥名 (INN) 命名指南，藥物名稱再進而改為ciclosporin。[60]

INN和英國批准名稱（英语：British Approved Name） (BAN)均採用Ciclosporin名稱，而美國採用名稱 (USAN)，則使用cyclosporin 。[61]

銷售配方

環孢素的水溶解度非常差，因此藥廠開發出的是供口服和注射用的懸浮液和乳液形式。桑多茲集團最初推出產品的商品名為Sandimmune，有軟明膠膠囊、口服溶液和靜脈注射製劑等形式。[7]一種較新的微乳液（英语：microemulsion）[62]口服製劑<Neoralref name="Neoral FDA label" />為溶液和軟明膠膠囊形式。 [63][64]

此藥物的通用名藥物已有各種品牌名稱於市面出現，包括 Cicloral、Gengraf和Deximune。一種用於治療乾燥性角結膜炎（乾眼症）引起發炎的環孢素外用乳劑於2002年以Restasis品牌上市。 吸入式的環孢素製劑正在臨床開發中。[65][66]

研究

神經保護

環孢素正在歐洲進行一項II/III期（適應性）臨床研究，以確定其對創傷性腦損傷中改善神經元細胞損傷和缺血再灌流傷害（III期）的能力。

環孢素已被研究作為腦外傷等情況下可能的神經保護劑，並在動物實驗中顯示可減少與損傷所造成的相關腦損傷。[67]

心臟病

環孢素已在實驗中用於治療心臟肥大（細胞體積增加）。[34][68]

環孢素已被證明可透過多種方式影響心肌細胞來減少心臟肥大。

獸醫用途

該藥物在美國被批准用於治療狗的異位性皮膚炎。狗身上使用的劑量較人類為少，表示此藥物可作為免疫調節劑，並且比發生在人類身上的副作用更少。本產品有助於減少控制病情所需的藥物種類。也有含環孢素的狗用眼藥膏（Optimmune）及用於治療狗的皮脂腺炎（英语：sebaceous adenitis）、落葉型天皰瘡、發炎性腸道疾病、肛門癤病和重症肌無力的環孢素藥物。[69][70]

參考文獻

  1. ^ cyclosporin. Dictionary.com Unabridged. Random House. n.d. [13 July 2011]. （原始内容存档于18 November 2010）. 
  2. ^ Laupacis A, Keown PA, Ulan RA, McKenzie N, Stiller CR. Cyclosporin A: a powerful immunosuppressant. Canadian Medical Association Journal. May 1982, 126 (9): 1041–6. PMC 1863293 可免费查阅. PMID 7074504. 
  3. ^ Regulatory Decision Summary for Restasis Multidose. Drug and Health Product Register. 2014-10-23 [2022-06-07]. （原始内容存档于2022-06-07）. 
  4. ^ Regulatory Decision Summary for Verkazia. Drug and Health Product Register. 2014-10-23 [2022-06-07]. （原始内容存档于2022-06-07）. 
  5. ^ Health product highlights 2021: Annexes of products approved in 2021. Health Canada. 2022-08-03 [2024-03-25]. 
  6. ^ 6.0 6.1 6.2 Neoral- cyclosporine capsule, liquid filled Neoral- cyclosporine solution. DailyMed. [2022-02-03]. （原始内容存档于2013-07-05）. 
  7. ^ 7.0 7.1 7.2 Sandimmune- cyclosporine capsule, liquid filled Sandimmune- cyclosporine injection Sandimmune- cyclosporine solution. DailyMed. [2022-02-03]. （原始内容存档于2014-04-21）. 
  8. ^ 8.0 8.1 Restasis- cyclosporine emulsion. DailyMed. [2022-02-03]. （原始内容存档于2014-03-30）. 
  9. ^ Vevye- cyclosporine ophthalmic solution solution/ drops. DailyMed. 2023-05-26 [2023-08-29]. （原始内容存档于2023-08-29）. 
  10. ^ Ikervis. European Medicines Agency. 2018-09-17 [27 February 2023]. （原始内容存档于13 August 2022）. 
  11. ^ 11.0 11.1 11.2 Vevizye EPAR. European Medicines Agency. 25 July 2024 [2024-07-27].  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  12. ^ Vevizye PI. Union Register of medicinal products. 2024-09-23 [2024-09-27]. 
  13. ^ World Health Organization. Stuart MC, Kouimtzi M, Hill SR , 编. WHO Model Formulary 2008. World Health Organization. 2009: 221. ISBN 9789241547659. hdl:10665/44053 可免费查阅. 
  14. ^ 14.0 14.1 14.2 14.3 14.4 Cyclosporine. The American Society of Health-System Pharmacists. [2016-12-08]. （原始内容存档于2016-10-17）. 
  15. ^ Cyclosporine eent. The American Society of Health-System Pharmacists. [2016-12-08]. （原始内容存档于2016-01-13）. 
  16. ^ Cyclosporine Use During Pregnancy. Drugs.com. [2016-12-20]. （原始内容存档于2017-09-14）. 
  17. ^ Matsuda S, Koyasu S. Mechanisms of action of cyclosporine (PDF). Immunopharmacology. May 2000, 47 (2–3): 119–25 [2018-03-04]. PMID 10878286. doi:10.1016/S0162-3109(00)00192-2. （原始内容 (PDF)存档于2017-08-11）. 
  18. ^ Watts R, Clunie G, Hall F, Marshall T. Rheumatology. Oxford University Press. 2009: 558. ISBN 978-0-19-922999-4. （原始内容存档于2017-11-05）. 
  19. ^ World Health Organization. World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. hdl:10665/325771 可免费查阅. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  20. ^ World Health Organization. World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. hdl:10665/345533 可免费查阅. WHO/MHP/HPS/EML/2021.02. 
  21. ^ The Top 300 of 2022. ClinCalc. [2024-08-30]. （原始内容存档于2024-08-30）. 
  22. ^ Cyclosporine Drug Usage Statistics, United States, 2013 - 2022. ClinCalc. [2024-08-30]. 
  23. ^ FDA Approves First Generic of Restasis. U.S. Food and Drug Administration (FDA) (新闻稿). 2022-02-02 [2022-02-03]. （原始内容存档于2022-02-02）. 
  24. ^ Reinhard T. Lokales Cyclosporin A bei Nummuli nach Keratoconjunctivitis epidemica Eine Pilotstudie - Springer. Der Ophthalmologe. 2000, 97 (11): 764–768. PMID 11130165. S2CID 399211. doi:10.1007/s003470070025. 
  25. ^ Paolino A, Alexander H, Broderick C, Flohr C. Non-biologic systemic treatments for atopic dermatitis: Current state of the art and future directions. Clinical and Experimental Allergy. May 2023, 53 (5): 495–510. PMID 36949024. doi:10.1111/cea.14301 可免费查阅. 
  26. ^ Dijkmans BA, van Rijthoven AW, Goei Thè HS, Boers M, Cats A. Cyclosporine in rheumatoid arthritis. Seminars in Arthritis and Rheumatism. August 1992, 22 (1): 30–36. PMID 1411580. doi:10.1016/0049-0172(92)90046-g. 
  27. ^ Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. The New England Journal of Medicine. June 1994, 330 (26): 1841–5. PMID 8196726. doi:10.1056/NEJM199406303302601 可免费查阅. 
  28. ^ Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clinical Journal of the American Society of Nephrology (PDF) http://cjasn.asnjournals.org/content/4/2/481.full.pdf |url=缺少标题 (帮助). February 2009, 4 (2): 481–508 [2018-04-20]. PMID 19218475. doi:10.2215/CJN.04800908 可免费查阅. （原始内容存档 (PDF)于2018-07-20）. 
  29. ^ Robert N, Wong GW, Wright JM. Effect of cyclosporine on blood pressure. Cochrane Database of Systematic Reviews. January 2010, (1): CD007893. PMID 20091657. doi:10.1002/14651858.CD007893.pub2. 
  30. ^ Figg WD. Cyclosporine-induced hyperuricemia and gout. The New England Journal of Medicine. February 1990, 322 (5): 334–336. PMID 2296276. doi:10.1056/NEJM199002013220514 可免费查阅. 
  31. ^ Agents Classified by the IARC Monographs, Volumes 1–110 互联网档案馆的存檔，存档日期2011-10-25.
  32. ^ IARC Working Group on the Evaluation of Carcinogenic Risk to Humans. Ciclosporin. International Agency for Research on Cancer. 2012 [2018-02-23]. （原始内容存档于2021-08-28）. 
  33. ^ Ganong WF. 27. Review of medical physiology有限度免费查阅，超限则需付费订阅 22nd. New York: McGraw-Hill Medical. 2005: 530. ISBN 978-0-07-144040-0. 
  34. ^ 34.0 34.1 34.2 Mott JL, Zhang D, Freeman JC, Mikolajczak P, Chang SW, Zassenhaus HP. Cardiac disease due to random mitochondrial DNA mutations is prevented by cyclosporin A. Biochemical and Biophysical Research Communications. July 2004, 319 (4): 1210–5. PMID 15194495. doi:10.1016/j.bbrc.2004.05.104. 
  35. ^ Youn TJ, Piao H, Kwon JS, Choi SY, Kim HS, Park DG, Kim DW, Kim YG, Cho MC. 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. December 2002, 4 (6): 713–8. PMID 12453541. S2CID 9181082. doi:10.1016/S1388-9842(02)00120-4 可免费查阅. 
  36. ^ Handschumacher RE, Harding MW, Rice J, Drugge RJ, Speicher DW. Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science. November 1984, 226 (4674): 544–7. Bibcode:1984Sci...226..544H. PMID 6238408. doi:10.1126/science.6238408. 
  37. ^ 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. Cyclophilin D controls mitochondrial pore-dependent Ca(2+) exchange, metabolic flexibility, and propensity for heart failure in mice. Journal of Clinical Investigation. October 2010, 120 (10): 3680–7. PMC 2947235 可免费查阅. PMID 20890047. doi:10.1172/JCI43171. 
  38. ^ Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiological Reviews. July 2014, 94 (3): 909–50. PMC 4101632 可免费查阅. PMID 24987008. doi:10.1152/physrev.00026.2013. 
  39. ^ Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J, Mundel P. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nature Medicine. 2008, 14 (9): 931–938. PMC 4109287 可免费查阅. PMID 18724379. doi:10.1038/nm.1857. 
  40. ^ Borel JF. History of the discovery of cyclosporin and of its early pharmacological development. Wiener Klinische Wochenschrift. June 2002, 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. Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discovery Today. May 2005, 10 (10): 688–91. PMID 15896681. doi:10.1016/S1359-6446(05)03395-7. 
    * Sneader W. Ciclosporin. Drug Discovery — A History有限度免费查阅，超限则需付费订阅. John Wiley & Sons. 2005-06-23: 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 互联网档案馆的存檔，存档日期2005-03-08." (retrieved 19 June 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.
  41. ^ Wang CP, Hartman NR, Venkataramanan R, Jardine I, Lin FT, Knapp JE, Starzl TE, Burckart GJ. Isolation of 10 cyclosporine metabolites from human bile. Drug Metabolism and Disposition. 1989, 17 (3): 292–6. PMC 3154783 可免费查阅. PMID 2568911. 
  42. ^ Copeland KR, Yatscoff RW, McKenna RM. Immunosuppressive activity of cyclosporine metabolites compared and characterized by mass spectroscopy and nuclear magnetic resonance. Clinical Chemistry. February 1990, 36 (2): 225–9. PMID 2137384. doi:10.1093/clinchem/36.2.225 可免费查阅. 
  43. ^ Lawen A. Biosynthesis of cyclosporins and other natural peptidyl prolyl cis/trans isomerase inhibitors. Biochimica et Biophysica Acta (BBA) - General Subjects. October 2015, 1850 (10): 2111–20. PMID 25497210. doi:10.1016/j.bbagen.2014.12.009. 
  44. ^ Yang X, Feng P, Yin Y, Bushley K, Spatafora JW, Wang C. Tolypocladium inflatum Benefits Fungal Adaptation to the Environment. mBio. October 2018, 9 (5). PMC 6168864 可免费查阅. PMID 30279281. doi:10.1128/mBio.01211-18. 
  45. ^ Bushley KE, Raja R, Jaiswal P, Cumbie JS, Nonogaki M, Boyd AE, Owensby CA, Knaus BJ, Elser J, Miller D, Di Y, McPhail KL, Spatafora JW. The genome of tolypocladium inflatum: evolution, organization, and expression of the cyclosporin biosynthetic gene cluster. PLOS Genetics. June 2013, 9 (6): e1003496. PMC 3688495 可免费查阅. PMID 23818858. doi:10.1371/journal.pgen.1003496 可免费查阅. 
  46. ^ Xu L, Li Y, Biggins JB, Bowman BR, Verdine GL, Gloer JB, Alspaugh JA, Bills GF. Identification of cyclosporin C from Amphichorda felina using a Cryptococcus neoformans differential temperature sensitivity assay. Applied Microbiology and Biotechnology. March 2018, 102 (5): 2337–2350. PMC 5942556 可免费查阅. PMID 29396588. doi:10.1007/s00253-018-8792-0. 
  47. ^ di Salvo ML, Florio R, Paiardini A, Vivoli M, D'Aguanno S, Contestabile R. Alanine racemase from Tolypocladium inflatum: a key PLP-dependent enzyme in cyclosporin biosynthesis and a model of catalytic promiscuity. Archives of Biochemistry and Biophysics. January 2013, 529 (2): 55–65. PMID 23219598. doi:10.1016/j.abb.2012.11.011. 
  48. ^ 48.0 48.1 48.2 Borel JF, Kis ZL, Beveridge T. The history of the discovery and development of Cyclosporin (Sandimmune). Merluzzi VJ, Adams J (编). The search for anti-inflammatory drugs case histories from concept to clinic. Boston: Birkhäuser. 1995: 27–63. ISBN 978-1-4615-9846-6. （原始内容存档于2017-11-05）. 
  49. ^ Cheng M. Hartmann Stahelin (1925-2011) and the contested history of cyclosporin A. Clinical Transplantation. 2013, 27 (3): 326–329. PMID 23331048. S2CID 39502677. doi:10.1111/ctr.12072. 
  50. ^ Borel JF, Feurer C, Gubler HU, Stähelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents and Actions. July 1976, 6 (4): 468–75. PMID 8969. S2CID 2862779. doi:10.1007/bf01973261. 
  51. ^ Rüegger A, Kuhn M, Lichti H, Loosli HR, Huguenin R, Quiquerez C, von Wartburg A. [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. 1976, 59 (4): 1075–92. PMID 950308. doi:10.1002/hlca.19760590412 （德语）. 
  52. ^ Heusler K, Pletscher A. The controversial early history of cyclosporin. Swiss Medical Weekly. June 2001, 131 (21–22): 299–302. PMID 11584691. S2CID 24662504. doi:10.4414/smw.2001.09702 可免费查阅. 
  53. ^ Calne RY, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC, Craddock GN, Pentlow BD, Rolles K. Cyclosporin A in patients receiving renal allografts from cadaver donors. The Lancet. 1978, 2 (8104–5): 1323–7. PMID 82836. S2CID 10731038. doi:10.1016/S0140-6736(78)91970-0. 
  54. ^ Starzl TE, Klintmalm GB, Porter KA, Iwatsuki S, Schröter GP. Liver transplantation with use of cyclosporin a and prednisone. The New England Journal of Medicine. July 1981, 305 (5): 266–9. PMC 2772056 可免费查阅. PMID 7017414. doi:10.1056/NEJM198107303050507. 
  55. ^ Kolata G. FDA speeds approval of cyclosporin. Science. September 1983, 221 (4617): 1273. Bibcode:1983Sci...221.1273K. PMID 17776314. doi:10.1126/science.221.4617.1273-a. On 2 September (1983), the Food and Drug Administration approved cyclosporin, a new drug that suppresses the immune system. 
  56. ^ Gottesman J. Milestones in Cardiac Care. Los Angeles Times. 1988-03-20. （原始内容存档于2017-02-26）. 
  57. ^ First Successful Pediatric Heart Transplant [ 1984-06-09]. Columbia University Medical Center, Dept. of Surgery, Cardiac Transplant Program. （原始内容存档于2017-03-01）. It [cyclosporine] gained FDA approval at the end of 1983, ... 
  58. ^ Drugs@FDA: FDA Approved Drug Products [Click on "Approval Date(s) and History]. United States Food and Drug Administration. （原始内容存档于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 
  59. ^ 59.0 59.1 59.2 Starzl, Thomas E. The Puzzle People: Memoirs Of A Transplant Surgeon. University of Pittsburgh Press. 1992. ISBN 978-0-8229-3714-2. doi:10.2307/j.ctt9qh63b. 
  60. ^ 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. [失效連結]
  61. ^ The Cyclosporine Story. www.davidmoore.org.uk. January 2013 [2022-10-24]. （原始内容存档于2022-10-22）. 
  62. ^ Gibaud S, Attivi D. Microemulsions for oral administration and their therapeutic applications. Expert Opinion on Drug Delivery. August 2012, 9 (8): 937–51 [2018-03-04archive-date=2018-03-05]. PMID 22663249. S2CID 28468973. doi:10.1517/17425247.2012.694865. （原始内容存档于使用|archiveurl=需要含有|archivedate= (帮助)）. 
  63. ^ Min DI. Neoral: a microemulsion cyclosporine. Journal of Transplant Coordination. March 1996, 6 (1): 5–8. PMID 9157923. doi:10.7182/prtr.1.6.1.f04016025hh795up (不活跃 2024 -11-11). 
  64. ^ Neoral (PDF). FDA Data Dashboard. Food and Drug Administration (FDA); Novartis. September 2009 [2022-10-24]. （原始内容存档 (PDF)于2022-10-20）. 
  65. ^ 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 .
  66. ^ Trammer B, Amann A, Haltner-Ukomadu E, Tillmanns S, Keller M, Högger P. 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. November 2008, 70 (3): 758–64. PMID 18656538. doi:10.1016/j.ejpb.2008.07.001. 
  67. ^ Sullivan PG, Thompson M, Scheff SW. Continuous infusion of cyclosporin A postinjury significantly ameliorates cortical damage following traumatic brain injury. Experimental Neurology. February 2000, 161 (2): 631–7. PMID 10686082. S2CID 25190221. doi:10.1006/exnr.1999.7282. 
  68. ^ Mende U, Kagen A, Cohen A, Aramburu J, Schoen FJ, Neer EJ. 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 //www.ncbi.nlm.nih.gov/pmc/articles/PMC24952 |PMC=缺少标题 (帮助). November 1998, 95 (23): 13893–8. Bibcode:1998PNAS...9513893M. PMC 24952 可免费查阅. PMID 9811897. doi:10.1073/pnas.95.23.13893 可免费查阅. 
  69. ^ Archer TM, Boothe DM, Langston VC, Fellman CL, Lunsford KV, Mackin AJ. Oral cyclosporine treatment in dogs: a review of the literature. Journal of Veterinary Internal Medicine. 2014, 28 (1): 1–20. PMC 4895546 可免费查阅. PMID 24341787. doi:10.1111/jvim.12265. 
  70. ^ Palmeiro BS. Cyclosporine in veterinary dermatology. Veterinary Clinics of North America: Small Animal Practice. January 2013, 43 (1): 153–71. PMID 23182330. doi:10.1016/j.cvsm.2012.09.007. 

外部連結

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