somatostatin | 51110-01-1

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 其它
• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 英文名称: somatostatin
• 英文别名: somatostatin-14；Dtxcid6026793；(4R,7S,10S,13S,16S,19S,22S,25S,28S,31S,34S,37R)-19,34-bis(4-aminobutyl)-31-(2-amino-2-oxoethyl)-37-[[2-[[(2S)-2-aminopropanoyl]amino]acetyl]amino]-13,25,28-tribenzyl-10,16-bis(1-hydroxyethyl)-7-(hydroxymethyl)-22-(1H-indol-3-ylmethyl)-6,9,12,15,18,21,24,27,30,33,36-undecaoxo-1,2-dithia-5,8,11,14,17,20,23,26,29,32,35-undecazacyclooctatriacontane-4-carboxylic acid
• CAS: 51110-01-1
• 化学式: C₇₆H₁₀₄N₁₈O₁₉S₂
• 分子量: 1637.9
• InChiKey: NHXLMOGPVYXJNR-UYURUMNQSA-N

物化性质

• 溶解度：
  H2O：1 mg/mL
• 稳定性/保质期：
  遵照规定使用和储存，则不会发生分解。

计算性质

• 辛醇/水分配系数(LogP)：
  -3.1
• 重原子数：
  115
• 可旋转键数：
  26
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  664
• 氢给体数：
  22
• 氢受体数：
  24

ADMET

毒理性

• 肝毒性

在预注册的兰瑞肽研究中，血清酶水平没有显著变化，并且没有报告出现临床上明显的急性肝损伤。综合分析报告称，在治疗期间血清ALT、AST或碱性磷酸酶水平没有整体变化，也没有出现具有临床意义的升高。与其它生长抑素类似物一样，长期使用兰瑞肽治疗与胆泥和胆石症的高发生率相关，这可能是由于抑制胆囊收缩力和减少胆汁分泌所致。在长期研究中，20%到33%的使用兰瑞肽治疗的患者发生了胆石症。在某些情况下，会出现有症状的胆囊炎，这可能会伴有血清酶和胆红素的轻至中度升高。然而，大多数与兰瑞肽相关的胆结石是无症状的。与奥曲肽不同，兰瑞肽和其他长效生长抑素类似物并未与临床上明显的肝损伤病例相关联，这种损伤独立于胆石症或胆泥之外，尽管它们的使用范围较窄，并未在许多使用奥曲肽治疗的情况中使用（如门脉高压、静脉曲张出血和患有先天性高胰岛素血症的婴儿）。

In preregistration studies of lanreotide, serum enzyme levels did not change appreciably and there were no reports of clinically apparent acute liver injury. Pooled analyses reported that there were no overall changes in serum ALT, AST or alkaline phosphatase levels during therapy or instances of clinically meaningful elevations with treatment. Prolonged therapy with lanreotide, as with other somatostatin analogues, was associated with a high rate of biliary sludge and cholelithiasis, probably due to inhibition of gall bladder contractility and decrease in bile secretion. In long term studies, cholelithiasis developed in 20% to 33% of lanreotide treated patients. In some instances, symptomatic cholecystitis occurred which can be accompanied by mild-to-moderate elevations in serum enzymes and bilirubin. However, most lanreotide associated gallstones were asymptomatic. Unlike octreotide, lanreotide and other long acting somatostatin analogues have not been liked to cases of clinically apparent liver injury, independent of cholelithiasis or biliary sludge, although they have had more limited use and have not been used in many of the clinical situations that were treated with octreotide (portal hypertension, variceal hemorrhage and infants with congenital hyperinsulinemia).

来源:LiverTox

毒理性

• 肝毒性

轻微的、短暂的、无症状的血清转氨酶水平升高发生在接受奥曲肽治疗的小部分患者中，有些人转氨酶水平升高持续存在，并随着时间的推移而恶化，可能需要停药。此外，已经描述了几例归因于奥曲肽的急性、临床上明显的肝损伤。发病通常在开始治疗后的1到6个月内，并且随着剂量增加，损伤可能更频繁。与奥曲肽治疗相关的肝损伤大多数是无症状和非黄疸的，特点是血清ALT和AST显著升高，血清碱性磷酸酶、GGT和胆红素正常或接近正常。然而，在某些情况下，尤其是重新用药后，出现了黄疸。尚未有与奥曲肽相关的急性肝衰竭或消失胆管综合征的实例，其损伤的特征是停止注射或输注后迅速改善。已经报告了几例新生儿和婴儿在连续输注高剂量奥曲肽治疗先天性高胰岛素血症时，出现显著转氨酶升高并在停止治疗后迅速改善的情况。 奥曲肽导致胆囊收缩力和胆汁分泌减少，长期治疗与胆结石形成的高发生率相关。在前瞻性研究中，接受维持奥曲肽治疗的肢端肥大症患者中，有25%至65%的患者通过超声检查发现胆结石，其中一部分患者发展为有症状的胆石症，需要住院和胆囊切除术。即使在胆囊切除术后，胆总管和肝内胆管也可能形成胆固醇结石，导致症状、败血症发作和需要部分肝切除。使用熊去氧胆酸治疗似乎不能预防奥曲肽治疗期间的胆结石形成，尽管可能有帮助。奥曲肽还与急性胰腺炎有关，这可能是由于它对胃肠道激素释放的抑制作用，尽管其他病例可能是由于胆结石通过和胰腺导管阻塞。 可能性评分：C（可能是临床上明显肝损伤的病因）。

Mild, transient, asymptomatic elevations in serum aminotransferase levels occur in a small proportion of patients receiving octreotide, and in some individuals the elevations are persistent and worsen over time and may require drug discontinuation. In addition, several instances of acute, clinically apparent liver injury attributable to octreotide have been described. The onset is generally within 1 to 6 months of starting therapy and injury may be more frequent with higher doses. Most cases of liver injury associated with octreotide therapy have been asymptomatic and anicteric, and marked by prominent elevations in serum ALT and AST with normal or near normal serum alkaline phosphatase, GGT and bilirubin. In some instances, however, jaundice has arisen, particularly with rechallenge. There have been no instances of acute liver failure or vanishing bile duct syndrome associated with octreotide, and a characteristic feature of the injury is the rapidity of improvement upon stopping the injections or infusions. Several instances of marked aminotransferase elevations with rapid improvements on stopping have been reported in newborns and infants with congenital hyperinsulinemia who were treated with continuous infusions of high doses of octreotide. Octreotide causes inhibition of gall bladder contractility and decrease in bile secretion, and long term therapy is associated with a high rate of cholesterol gallstone formation. In prospective studies, between 25% and 65% of patients with acromegaly treated with maintenance octreotide developed gallstones detected by ultrasonography and a proportion developed symptomatic cholelithiasis requiring hospitalization and cholecystectomy. Even after cholecystectomy, cholesterol stones may form in the common bile duct and intrahepatic ducts causing symptoms, episodes of sepsis and need for partial hepatic resection. Therapy with ursodiol does not appear to prevent gallstone formation during octreotide therapy, although it may help. Octreotide has also been associated with acute pancreatitis, which may be due to its inhibitory effect on gastrointestinal hormone release, although other cases may be secondary to passage of gall bladder stones and pancreatic duct obstruction. Likelihood score: C (probable cause of clinically apparent liver injury).

来源:LiverTox

毒理性

• 肝毒性

轻度的、短暂的、无症状的血清转氨酶水平升高在接受帕西瑞肽LAR治疗的患者中发生率为高达29%，但超过正常上限5倍以上的升高是罕见的（ 帕西瑞肽会导致胆囊收缩能力的抑制和胆汁分泌的减少，长期治疗与胆结石形成的高发生率有关。在前瞻性研究中，接受维持帕西瑞肽治疗一年到两年的肢端肥大症患者中，有20%到30%的患者通过超声检查发现胆结石，其中一部分患者发展为有症状的胆石症，需要住院并进行胆囊切除术。即使在胆囊切除术后，胆固醇结石也可能在奥曲肽治疗期间在胆总管和肝内胆管中形成，这可能导致症状和肝功能测试异常。使用熊去氧胆酸治疗似乎并不能预防与奥曲肽治疗相关的胆结石形成，尽管它可能有所帮助。 可能性评分：E*（未经证实但疑似罕见的临床明显肝胆损伤原因）。

Mild, transient, asymptomatic elevations in serum aminotransferase levels occur in up to 29% of patients receiving pasireotide LAR, but elevations above 5 times the upper limit of normal are rare ( Pasireotide causes inhibition of gall bladder contractility and a decrease in bile secretion, and long term therapy is associated with a high rate of cholesterol gallstone formation. In prospective studies, between 20% and 30% of patients with acromegaly treated with maintenance pasireotide for one to two years developed gallstones detected by ultrasonography and a proportion developed symptomatic cholelithiasis requiring hospitalization and cholecystectomy. Even after cholecystectomy, cholesterol stones may form in the common bile duct and intrahepatic ducts during somatostatin analogue therapy which can cause symptoms and liver test abnormalities. Therapy with ursodiol does not appear to prevent gallstone formation related to somatostatin analogue therapy, although it may help. Likelihood score: E* (unproven but suspected rare cause of clinically apparent hepatobiliary injury).

来源:LiverTox

安全信息

• 危险品标志：
  Xi
• 安全说明：
  S26,S36
• 危险类别码：
  R36/37/38
• WGK Germany：
  3

制备方法与用途

从提供的信息中，我们可以总结出生长抑素（Somatostatin）的主要内容如下：

药物概述

• 作用机制：通过抑制胰岛素和胰高血糖素的分泌来影响血糖水平；还能减少消化液的分泌和胃肠道运动。
• 适应症：
  • 控制出血，例如胃溃疡、十二指肠溃疡等引起的急性大出血。
  • 治疗严重的腹腔内感染导致的低血压。
  • 帮助治疗胰瘘、胆瘘、肠瘘的情况。

给药方式

• 主要通过静脉给药。
• 根据不同的适应症，剂量和使用时间不同。例如用于出血控制时通常为250μg/h；用于糖尿病酮症酸中毒时则可高达100～500μg/h等。

不良反应

• 包括但不限于恶心、呕吐、腹痛、腹泻等症状。
• 可能会导致血糖水平短暂下降，需要密切监测患者血糖变化并适时调整胰岛素用量。

注意事项与禁忌

• 用药期间需要注意持续给药，并且避免中断。
• 对本品过敏者或孕妇及哺乳期妇女禁用。
• 使用时需注意药物相互作用，特别是与其他镇痛剂的作用可能相抵触。

药物安全性

• 属于高毒性物质类别，在使用过程中必须严格遵守操作规范以防止中毒事故的发生。同时，该药物具有可燃性，因此储存和运输中需要注意防火安全措施。
• 使用时应配备适当的灭火器（如水、二氧化碳、干粉或砂土等），以应对可能发生的火灾风险。

综上所述，生长抑素是一种重要的临床用药，但也存在一定的毒性和使用限制。在实际应用过程中，医生需要根据患者的具体情况进行合理选择和调整，并密切观察可能出现的不良反应。

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• [EN] PSMA-TARGETING AMANITIN CONJUGATES<br/>[FR] CONJUGUÉS D'AMANITINE CIBLANT LE PSMA
  申请人：HEIDELBERG PHARMA RES GMBH

  公开号：WO2019057964A1

  公开（公告）日：2019-03-28

  The invention relates to a PSMA-targeting conjugate comprising (a) an amatoxin; (b) a small molecule PSMA-targeting moiety; and (c) optionally a linker linking said amatoxin and said small molecule PSMA-targeting moiety. The invention furthermore relates to a pharmaceutical composition comprising such conjugate.

  这项发明涉及一种PSMA靶向共轭物，包括(a)阿马毒素；(b)小分子PSMA靶向基团；以及(c)可选地连接所述阿马毒素和所述小分子PSMA靶向基团的连接剂。此外，该发明还涉及包含这种共轭物的药物组合物。
• NOVEL GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME
  申请人：Ryono Denis E.

  公开号：US20080009465A1

  公开（公告）日：2008-01-10

  Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure wherein is a heteroaryl ring; R 4 is —(CH 2 ) n -Z-(CH 2 ) m —PO(OR 7 )(OR 8 ), —(CH 2 ) n Z-(CH 2 ) m —PO(OR 7 )R g , —(CH 2 ) n -Z-(CH 2 ) m —OPO(OR 7 )R g , —(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10 ), or —(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10 ); R 5 and R 6 are independently selected from H, alkyl and halogen; Y is R 7 (CH 2 ) s or is absent; and X, n, Z, m, R 4 , R 5 , R 6 , R 7 , and s are as defined herein; or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.

  提供了磷酸酯和磷酸酯激活剂，因此在治疗糖尿病和相关疾病方面非常有用，并具有以下结构： 其中 是杂环芳基环； R 4 为—(CH 2 ) n -Z-(CH 2 ) m —PO(OR 7 )(OR 8 )、—(CH 2 ) n Z-(CH 2 ) m —PO(OR 7 )R g 、—(CH 2 ) n -Z-(CH 2 ) m —OPO(OR 7 )R g 、—(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10) 或—(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10) ； R 5 和R 6 分别选择自H、烷基和卤素； Y为R 7 (CH 2 ) s 或不存在；以及 X、n、Z、m、R 4 、R 5 、R 6 、R 7 和s如本文所定义；或其药用盐。 还提供了一种利用上述化合物治疗糖尿病和相关疾病的方法。
• THIOL-ENE CLICK CHEMISTRY FOR DRUG CONJUGATES
  申请人：SYSCHEM, INC.

  公开号：US20130323169A1

  公开（公告）日：2013-12-05

  The present invention relates to linker molecules that readily conjugate cellular recognition ligand at one end and drug payload at the other, and are useful in treating or preventing cancer, an autoimmune disease, an inflammatory condition, a central nervous system disorder or an infection. The linker inker molecules of the invention are represented by Formula I, II and III; Linker-Drug compounds represented by Formula IV, V and VI; and Ligand-Linker-Drug conjugates represented by Formula VII, VIII and IX:

  本发明涉及易于在一端结合细胞识别配体和在另一端结合药物载荷的连接分子，并且在治疗或预防癌症、自身免疫疾病、炎症症状、中枢神经系统紊乱或感染方面具有用处。该发明的连接分子由公式I、II和III表示；由公式IV、V和VI表示的连接-药物化合物；以及由公式VII、VIII和IX表示的配体-连接-药物共轭物。
• CYTOTOXIC PEPTIDES AND ANTIBODY DRUG CONJUGATES THEREOF
  申请人：PFIZER INC.

  公开号：US20130129753A1

  公开（公告）日：2013-05-23

  The present invention is directed to cytotoxic pentapeptides, to antibody drug conjugates thereof, and to methods for using the same to treat cancer.

  本发明涉及细胞毒性五肽，其抗体药物偶联物，以及使用它们治疗癌症的方法。