cyclo[Abu-Sar-N(Me)Leu-Val-N(Me)Leu-Ala-D-Ala-N(Me)Leu-N(Me)Leu-N(Me)Val-DL-N(Me)Bmt(E)]

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: cyclo[Abu-Sar-N(Me)Leu-Val-N(Me)Leu-Ala-D-Ala-N(Me)Leu-N(Me)Leu-N(Me)Val-DL-N(Me)Bmt(E)]
• 英文别名: (3S,6S,9S,12R,15S,18S,21S,24S,30S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone
• 化学式: C₆₂H₁₁₁N₁₁O₁₂
• 分子量: 1202.6
• InChiKey: PMATZTZNYRCHOR-FVTPFZBWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.5
• 重原子数：
  85
• 可旋转键数：
  15
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  279
• 氢给体数：
  5
• 氢受体数：
  12

ADMET

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：环孢霉素的浓度在不同的案例报告和系列中变化很大。这种可变性似乎部分是由于报告中采样时间的不一致，可能与采样时乳汁中的脂肪含量有关。在典型的母体环孢霉素血药水平下，完全母乳喂养的婴儿通常不会接受超过母亲体重调整剂量的约2%，或者是儿科移植维持剂量的2%，并且通常低于1%。在大多数母乳喂养的婴儿中，血液中检测不到环孢霉素；然而，偶尔婴儿的血液中会有可检测到的水平，即使乳汁水平和婴儿剂量看起来很低。 许多婴儿在母亲使用环孢霉素期间被母乳喂养，通常同时使用皮质类固醇，有时还同时使用硫唑嘌呤。至少有两位母亲在成功母乳喂养第一个婴儿后，又成功母乳喂养了第二个婴儿。没有关于对婴儿生长、发育或肾脏功能产生不良影响的报告，尽管并没有总是进行或报告彻底的随访检查。美国和欧洲的专家指南、国家移植妊娠登记处和其他专家认为在母乳喂养期间使用环孢霉素可能是安全的，尽管其他人表达了关切。如果在此期间使用该药物，应监测母乳喂养的婴儿，可能包括测量血清水平以排除毒性。 由于眼部吸收有限，眼用环孢霉素不应在母乳喂养的婴儿中引起任何不良反应。为了在使用眼药水后显著减少到达母乳中的药物量，应在眼角处对泪点施加压力1分钟或更长时间，然后用吸收性纸巾去除多余的溶液。 ◉ 对母乳喂养婴儿的影响：一名婴儿被母乳喂养，随访显示婴儿保持健康和正常。 一名母亲每天两次服用3毫克/千克的环孢霉素，完全母乳喂养她的婴儿直到断奶，部分母乳喂养持续到14个月。婴儿的肾脏功能稳定，两岁时身体健康。这位母亲还用同样的药物治疗母乳喂养了第二个婴儿。 在7名婴儿中，母乳喂养了4到12个月，期间母亲使用了环孢霉素和泼尼松（其中6名还使用了硫唑嘌呤），婴儿的肾功能未受影响，他们正常生长。 一名母亲在环孢霉素、硫唑嘌呤和泼尼松使用期间部分母乳喂养她的婴儿。没有随访数据报告。 一名婴儿在母亲每天两次使用环孢霉素300毫克、硫唑嘌呤和泼尼松期间，完全母乳喂养了10.5个月。部分母乳喂养持续了2年。婴儿在12个月时生长正常。这位母亲还用同样的药物方案母乳喂养了第二个孩子。 四名婴儿在母亲使用环孢霉素期间被母乳喂养。其中三人随访时临床上未发现不良反应，其中一人血清肌酐和尿素氮（BUN）测量正常。第四个婴儿没有随访报告。 报告了两名母亲在使用环孢霉素并母乳喂养的婴儿。一位母亲每天服用环孢霉素200毫克以及硫唑嘌呤、泼尼松、地尔硫卓和叶酸。第二位母亲每天服用环孢霉素120毫克以及甲基多巴、泼尼松和钙三醇。两位母亲最初都完全母乳喂养她们的婴儿，并分别持续了5个月和14个月。婴儿据报道健康，肾功能正常。 一名孕妇在怀孕26周开始每天服用环孢霉素5毫克/千克，并在母乳喂养期间继续服用。她广泛地母乳喂养她的婴儿，3个月大时婴儿健康。 国家移植妊娠登记处报告了1991年至2011年间收集的母亲在器官移植后母乳喂养婴儿的数据。共有43名移植母亲（大多数是肾脏）在母乳喂养总共49名婴儿期间使用了环孢霉素。哺乳期从1周到2年不等，对儿童的随访从几周到16年不等。一名婴儿出现了轻度血小板计数升高和与年龄不符的异常白蛋白/球蛋白比率；16个月时，实验室数值正常。其余婴儿或儿童没有问题报告。截至2013年12月，共有43位母亲母乳喂养了55名婴儿，最长达24个月，婴儿没有出现明显的不良反应。 一名妇女每天服用环孢霉素200毫克治疗银屑病，同时完全母乳喂养她的婴儿6个月。在12个月大时，婴儿发育正常，没有发现药物在乳汁中的明显不良反应。 一名患有肾病综合症的妇女在怀孕和哺乳期间服用了环孢霉素、泼尼松和羟氯喹。在哺乳期间，她每天早上服用环孢霉素125毫克，晚上服用100毫克（总计每天3毫克/千克），羟氯喹200毫克和泼尼松30毫克。她的双胞胎婴儿在出生后第7天开始部分母乳喂养（70到80%的母乳），她继续哺乳了几个月。婴儿在一个月时体重正常增长，在出生后三个月内没有不良反应。 ◉ 对哺乳和母乳的影响：截至修订日期，未找到相关的已发布信息。

◉ Summary of Use during Lactation:Cyclosporine levels vary considerably in several case reports and series. This variability seems to be partially due to inconsistent sampling times among the reports and probably related to the fat content of the milk at the time of sampling. With typical maternal cyclosporine blood levels, a completely breastfed infant would usually receive no more than about 2% of the mother's weight-adjusted dosage or pediatric transplantation maintenance dosage, and often less than 1%. In most breastfed infants, cyclosporine is not detectable in blood; however, occasionally infants have had detectable blood levels, even when milk levels and infant dosage were apparently low. Numerous infants have been breastfed during maternal cyclosporine use, usually with a concurrent corticosteroid and sometimes with concurrent azathioprine. At least 2 mothers successfully breastfed a second infant after successfully breastfeeding the first infant. No reports of adverse effects on infants’ growth, development or kidney function have been reported, although thorough follow-up examinations have not always been performed or reported. United States and European expert guidelines, the National Transplantation Pregnancy Registry and other experts consider cyclosporine to be probably safe to use during breastfeeding, although others have expressed concern.Breastfed infants should be monitored if this drug is used during lactation, possibly including measurement of serum levels to rule out toxicity if there is a concern. Because absorption from the eye is limited, ophthalmic cyclosporine would not be expected to cause any adverse effects in breastfed infants. To substantially diminish the amount of drug that reaches the breastmilk after using eye drops, place pressure over the tear duct by the corner of the eye for 1 minute or more, then remove the excess solution with an absorbent tissue. ◉ Effects in Breastfed Infants:One infant was breastfed and follow-up showed that the infant remained healthy and normal. A mother who was taking cyclosporine 3 mg/kg twice daily completely breastfed her infant until weaning with partial breastfeeding until 14 months. The infant's kidney function was stable and she was healthy at 2 years of age. This mother also breastfed a second infant. In 7 infants breastfed for 4 to 12 months during maternal cyclosporine and prednisolone (plus azathioprine in 6 of the 7), infant renal function was unaffected, and they grew normally. One mother partially breastfed her infant during cyclosporine, azathioprine and prednisone use. No follow-up data were reported. One infant was exclusively breastfed for 10.5 months during maternal use of cyclosporine 300 mg twice daily, azathioprine and prednisone. Partial breastfeeding continued for 2 years. The infant thrived with normal growth at 12 months. The mother also breastfed a second child while on the same drug regimen. Four infants breastfed during maternal cyclosporine use. In three, no adverse effects were noted clinically on follow-up and one of these had normal serum creatinine and urea nitrogen (BUN) measured. No follow-up was reported on the fourth infant. Two cases were reported of infants whose mothers were taking cyclosporine and breastfeeding. One mother was taking cyclosporine 200 mg daily as well as azathioprine, prednisone, diltiazem, and folate. The second mother was taking cyclosporine 120 mg daily as well as methyldopa, prednisone, and calcitriol. Both mothers exclusively breastfed their infants initially and continued for 5 and 14 months, respectively. The infants were reportedly healthy and had normal renal function. A woman with severe ulcerative colitis during pregnancy received cyclosporine 5 mg/kg daily from 26 weeks of pregnancy and continued while breastfeeding. She extensive breastfed her infant and at 3 months of age the infant was healthy. The National Transplantation Pregnancy Registry reported data gathered from 1991 to 2011 on mothers who breastfed their infants following organ transplantation. A total of 43 mothers with transplants (mostly kidney) used cyclosporine while breastfeeding a total of 49 infants. Duration of nursing ranged from 1 week to 2 years and follow-up of the children ranged from weeks to 16 years. One infant experienced mildly elevated platelet count and an abnormal albumin/globulin ratio for age; at 16 months, laboratory values were normal. There were no reports of problems in the remainder of the infants or children. As of December 2013, a total of 43 mothers had breastfed 55 infants for as long as 24 months with no apparent adverse effects in infants. A woman took cyclosporine 200 mg daily for psoriasis while exclusively breastfeeding her infant for 6 months. At 12 months of age, the infant was developing normally and had no discernible adverse effects from the drug in milk. A woman with nephrotic syndrome took cyclosporine, prednisone, and hydroxychloroquine during pregnancy and lactation. While breastfeeding she took cyclosporine 125 mg in the morning and 100 mg at night (total of 3 mg/kg daily), hydroxychloroquine 200 mg daily and prednisone 30 mg daily. Her twin infants began partially breastfeeding (70 to 80% breastmilk) on day 7 postpartum and she continued to breastfeed for several months. The infants gained weight normally at one month of age and had no adverse reactions in the first three months postpartum. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

文献信息

• Therapeutic methods using cyclosporine components
  申请人：Allergan, Inc.

  公开号：US10736936B2

  公开（公告）日：2020-08-11

  Methods of treating humans or animals having various conditions are disclosed which include administering a cyclosporine component. Among the conditions treated are dry mouth syndrome, verruciform xanthoma, achlorhydria, mucous cysts, oral submucous fibrosis, oral nevi, cancer of the oral mucosa, maloplakia of the genito-urinary tract, vulvovaginitis, helicobacter pylori infection, duodenal ulcers, peptic ulcers, conditions affecting the uterus and appendicitis.

  本研究公开了治疗人类或动物各种疾病的方法，其中包括施用环孢素成分。治疗的病症包括口干综合征、疣状黄瘤、无色素性贫血、粘液囊肿、口腔粘膜下纤维化、口腔痣、口腔粘膜癌、泌尿生殖道恶性肿瘤、外阴阴道炎、幽门螺杆菌感染、十二指肠溃疡、消化性溃疡、影响子宫的病症和阑尾炎。
• Suspension compositions of cyclosporin A for subconjunctival and periocular injection
  申请人：Allergan, Inc.

  公开号：US10780048B2

  公开（公告）日：2020-09-22

  The present disclosure relates to suspension formulations and systems for the treatment of ocular conditions. The suspension formulations can include cyclosporin A and in some embodiments, Form 1 or Form 2 cyclosporin A. A delivery system can be provided that includes two parts, a first part containing particles of cyclosporin and a second part containing other components that can be combined with the first part to make a suspension formulation. The suspension can be injected into the subconjunctival or other periocular space to treat ocular conditions, such as dry eye disease.

  本公开涉及用于治疗眼部疾病的悬浮制剂和系统。悬浮制剂可包括环孢素 A，在某些实施方案中，可包括 1 型或 2 型环孢素 A。可提供一种递送系统，该系统包括两部分，第一部分含有环孢素颗粒，第二部分含有可与第一部分结合制成悬浮制剂的其他成分。悬浮液可注射到结膜下或其他眼周空间，以治疗眼部疾病，如干眼症。
• Methods and compositions for the treatment of hair loss
  申请人：Aneira Pharma, Inc.

  公开号：US10987355B2

  公开（公告）日：2021-04-27

  Compositions and methods for the treatment of hair growth and the prevention of hair loss.

  治疗生发和预防脱发的组合物和方法。
• METHODS OF TREATING BLEPHAROSPASM USING CYCLOSPORINE COMPONENTS
  申请人：BRIN MITCHELL F.

  公开号：US20070191266A1

  公开（公告）日：2007-08-16

  Methods of treating humans or animals afflicted with primary blepharospasm, for example, benign essential blepharospasm, or secondary blepharospasm not caused by an ocular surface disease or condition, are component to a human or animal so afflicted.
• Methods of providing therapeutic effects using cyclosporin compontnts
  申请人：Acheampong Andrew

  公开号：US20070299004A1

  公开（公告）日：2007-12-27

  Methods of treating an eye of a human or animal include administering to an eye of a human or animal a composition in the form of an emulsion including water, a hydrophobic component and a cyclosporin component in a therapeutically effective amount of less than 0.1% by weight of the composition. The weight ratio of the cyclosporin component to the hydrophobic component is less than 0.8.