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环孢素

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环孢素
临床资料
读音/ˌsaɪkləˈspɔːrɪn/[1]
商品名（英语：Drug nomenclature）Sandimmune及其他
其他名称cyclosporin、ciclosporin A,[2]cyclosporine A及cyclosporin A (CsA), cyclosporine (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa601207
核准状况
怀孕分级
  • 澳: C
给药途径口服给药, 静脉注射，眼药水
药物类别（英语：Drug class）钙调磷酸酶抑制剂
ATC码
法律规范状态
法律规范
药物动力学数据
生物利用度并非固定
药物代谢肝脏 CYP3A4
生物半衰期并非固定 (约24小时)
排泄途径胆管
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配体ID
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)
ECHA InfoCard100.119.569 编辑维基数据链接
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

环孢素（英语：ciclosporin，也有cyclosporine及cyclosporin的拼写法），是一种钙调磷酸酶抑制剂，作为免疫抑制剂之用，以治疗类风湿性关节炎、干癣、克隆氏症、肾病症候群、湿疹，以及作为器官移植后长期服用之药物，防止移植器官受到排斥。[13][14]此药物透过口服或是静脉注射方式给药，也制成眼药水形式以治疗干眼症。[15]

使用后常见的副作用有高血压、头痛、肾脏问题、毛发生长增加和呕吐。[14]严重的副作用有感染风险增加、肝脏问题和罹患淋巴瘤风险增加。[14]使用后应持续检查药物的血药浓度以降低副作用风险。[14]个体于怀孕期间使用可能会导致早产，但此药物似乎不会造成胎儿的先天性障碍。[16]

环孢素被认为是透过降低淋巴球的功能来发挥作用。[14]它与亲环蛋白（英语：cyclophilin）形成复合物来阻断钙调磷酸酶的磷酸酶活性，而减少T细胞产生促炎性细胞因子。[17]

环孢素于1971年从名为膨大弯颈霉的真菌分离出，并于1983年取得核准用于医疗用途。[18]它已列入世界卫生组织基本药物标准清单之中。[19][20]此药物在美国于2022年最常使用处方药中排名第185，开立的处方笺数量超过200万张。[21][22]市面上有其通用名药物流通。[23]

医疗用途

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环孢素用于治疗和预防造血干细胞移植（又称骨髓移植）的移植物对抗宿主疾病，并预防宿主对于移植而来的肾脏、心脏和肝脏的排斥反应。[7][6]此药物也在美国被批准用于治疗类风湿性关节炎和干癣、腺病毒性角结膜炎（英语：Adenoviral keratoconjunctivitis）后出现的持续性钱币状角膜炎（英语：nummular keratitis），[24][6]以及作为治疗干燥症和睑板腺功能障碍引起的干眼症之用的眼药水。[8]

环孢素除这些适应症外，也用于治疗严重的异位性皮肤炎，[25]及严重的类风湿性关节炎及相关疾病。[26]

环孢素也用于治疗对类固醇治疗无反应的急性严重溃疡性结肠炎和荨麻疹患者。[27]

副作用

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使用环孢素产生的副作用有牙龈肿大（英语：Gingival enlargement）、毛发生长增加、抽搐、消化性溃疡、胰腺炎、发烧、呕吐、腹泻、精神错乱、胆固醇升高、呼吸困难、麻木和刺痛（尤其是嘴唇）、搔痒、高血压、钾滞留（可能导致高血钾症）、肾脏和肝功能障碍、[28]指尖灼热感，以及容易受到霉菌和病毒感染。环孢素会诱导肾脏血管收缩和增加钠重吸收，而引起高血压。血压升高会引发心血管问题，因此建议需要使用此药物进行长期治疗的人只使用最低的有效剂量。[29]

肾脏移植后使用环孢素与血液中尿酸浓度升高有关，在某些情况下也会导致痛风。[30]

环孢素被列为国际癌症研究机构一类致癌物（即有足够的证据表明对人类具有致癌性），[31]特别是会导致皮肤鳞状细胞癌和非霍奇金氏淋巴瘤。[32]

药理学

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作用机转

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环孢素的主要作用是降低T细胞的活性，它透过抑制钙调磷酸酶-磷酸酶途径中的钙调磷酸酶，并阻止线粒体通透性转变孔（英语：mitochondrial permeability transition pore）（MPTP）打开来达成。环孢素借由阻止活化T细胞核因子去磷酸化，导致效应性T细胞功能降低[33][34][35][36]

环孢素是一种免疫抑制剂，除抑制免疫反应外，还能与线粒体膜上的线粒体通透性转变孔结合。[34][37]MPTP是细胞能量工厂（线粒体）上的一各通道，其开闭程度直接影响细胞的能量供应。环孢素能稳定MPTP的状态，防止其过度开启，而保护细胞免受能量耗竭的损害。[38]

环孢素可减缓肾脏微小病变和局灶节段性肾小球硬化症等疾病引起的蛋白尿。其机制为：环孢素保护足细胞中的突触足蛋白（英语：synaptopodin），使其不被分解，进而维持肾小球基底膜的完整性，减少蛋白质流失。[39]

药物动力学

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环孢素是一种由11个氨基酸组成的环肽，它有单一的D-氨基酸，在自然界中很少见。环孢素并非由核糖体合成，与大多数的肽不同。[40]

环孢素经摄入后会在人类和动物体内充分代谢。代谢物包括环孢素B、C、D、E、H和L，[41]代谢物的免疫抑制活性不到原形环孢素的10%，且与较高的肾毒性（英语：Nephrotoxicity）有关联。[42]

生物合成

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环孢素的生物合成过程。Bmt（butenyl-methyl-threonine，丁烯基甲基苏氨酸），Abu（L-alpha-aminobutyric acid，L-α-氨基丁酸），Sar（sarcosine，肌氨酸）。

非核糖体肽（英语：nonribosomal peptide）合成酶经由活化、连接和修饰氨基酸，逐步合成环孢素。[43]

基因簇

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目前用于大量生产环孢素的物种 - 膨大弯颈霉 - 的生物合成基因排列，形成一个12个基因的簇。这12基因簇是此霉菌生产环孢素的重要遗传基础，基因间相互协作，共同完成环孢素的合成过程。[44][45][46][47]

历史

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于瑞士巴塞尔桑多兹集团公司（英语：Sandoz）（现已并入诺华制药）服务的科学家于1970年从挪威和美国威斯康辛州采集的土壤样本中分离出新的真菌菌株。两种菌株都会产生一系列称为环孢素的天然产物，均具有抗真菌活性的成分。来自挪威的菌株 - 膨大弯颈霉 - 后来被用于大规模生产环孢素。[48]

天然环孢素的免疫抑制作用于1972年1月31日[49]被于桑多兹集团服务的药理学家哈特曼·F·斯塔赫林（英语：Hartmann F. Stähelin）发现。[50][48]环孢素的化学结构于1976年也为桑多兹集团确定。[51][52]后来英国外科医师罗伊·约克·卡恩爵士（英语：Roy Calne）及其剑桥大学的同事在1978年进行的肾脏移植手术中[53]以及美国外科医师托马斯·斯塔尔兹（英语：Thomas Starzl）于1980年在匹兹堡大学医疗中心儿童医院（英语：UPMC Children's Hospital of Pittsburgh）进行的肝脏移植手术中[54]均成功确定环孢素具有预防移植排斥的作用。 美国食品药物管理局（FDA）于1983年核准环孢素用于医疗用途。[55][56][57][58]

托马斯·斯塔尔兹在其撰述的回忆录中解释环孢素是实体器官同种异体移植的划时代药物，[59]其具有的良好抗排斥治疗成分，大幅扩展移植手术的临床适用性。[59]简而言之，广泛应用这种移植的最大限制不是成本或手术技术，而是同种异体移植排斥以及捐赠器官来源稀缺的问题。环孢素则在处理排斥方面获得重大进展。[59]

社会与文化

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法律地位

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欧洲药品管理局人用药品委员会（英语：Committee for Medicinal Products for Human Use）（CHMP）于2024年7月采纳正面意见，建议授予用于治疗干眼症药品Vevizye的上市许可。药品的申请者是设于德国的Novaliq GmbH。[11]Vevizye于2024年9月取得欧盟核准用于医疗用途。[11]

名称

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这种天然产物被首先分离出来的科学家命名为cyclosporin，[48]而在翻译成英文后将名称改写为cyclosporine。根据国际非专有药名 (INN) 命名指南，药物名称再进而改为ciclosporin。[60]

INN和英国批准名称（英语：British Approved Name） (BAN)均采用Ciclosporin名称，而美国采用名称 (USAN)，则使用cyclosporin 。[61]

销售配方

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环孢素的水溶解度非常差，因此药厂开发出的是供口服和注射用的悬浮液和乳液形式。桑多兹集团最初推出产品的商品名为Sandimmune，有软明胶胶囊、口服溶液和静脉注射制剂等形式。[7]一种较新的微乳液（英语：microemulsion）[62]口服制剂<Neoralref name="Neoral FDA label" />为溶液和软明胶胶囊形式。 [63][64]

此药物的通用名药物已有各种品牌名称于市面出现，包括 Cicloral、Gengraf和Deximune。一种用于治疗干燥性角结膜炎（干眼症）引起发炎的环孢素外用乳剂于2002年以Restasis品牌上市。 吸入式的环孢素制剂正在临床开发中。[65][66]

研究

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神经保护

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环孢素正在欧洲进行一项II/III期（适应性）临床研究，以确定其对创伤性脑损伤中改善神经元细胞损伤和缺血再灌流伤害（III期）的能力。

环孢素已被研究作为脑外伤等情况下可能的神经保护剂，并在动物实验中显示可减少与损伤所造成的相关脑损伤。[67]

心脏病

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环孢素已在实验中用于治疗心脏肥大（细胞体积增加）。[34][68]

环孢素已被证明可透过多种方式影响心肌细胞来减少心脏肥大。

兽医用途

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该药物在美国被批准用于治疗狗的异位性皮肤炎。狗身上使用的剂量较人类为少，表示此药物可作为免疫调节剂，并且比发生在人类身上的副作用更少。本产品有助于减少控制病情所需的药物种类。也有含环孢素的狗用眼药膏（Optimmune）及用于治疗狗的皮脂腺炎（英语：sebaceous adenitis）、落叶型天疱疮、发炎性肠道疾病、肛门疖病和重症肌无力的环孢素药物。[69][70]

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