H-2Nal-Cys(1)-Tyr-D-Trp-Lys-Val-Cys(1)-Thr-NH2 | 108736-35-2

• 物质功能分类: 生物化工 - 多肽
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: H-2Nal-Cys(1)-Tyr-D-Trp-Lys-Val-Cys(1)-Thr-NH2
• 英文别名: (4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-N-[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2S)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide
• CAS: 108736-35-2
• 化学式: C₅₄H₆₉N₁₁O₁₀S₂
• 分子量: 1096.3
• InChiKey: PUDHBTGHUJUUFI-PURAGXGVSA-N

物化性质

• 沸点：
  1508.2±65.0 °C(Predicted)
• 密度：
  1.40±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  77
• 可旋转键数：
  17
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  406
• 氢给体数：
  13
• 氢受体数：
  14

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

轻度的、短暂的、无症状的血清转氨酶水平升高出现在接受奥曲肽治疗的小部分患者中，并且在一些个体中，这种升高是持久的，并且随着时间的推移可能会恶化，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，并且随着剂量较高，损伤可能更频繁。与奥曲肽治疗相关的肝损伤的大多数病例是无症状和非黄疸的，以血清ALT和AST显著升高为特征，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。尚未有急性肝衰竭或消失胆管综合征与奥曲肽相关的实例，并且这种损伤的特征是停止注射或输注后迅速改善。在连续输注高剂量奥曲肽治疗的新生儿和婴儿中，已经报告了几例转氨酶显著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抑制和胆汁分泌减少，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%到65%的患者通过超声检查发现胆结石，并且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，胆固醇结石也可能在胆总管和肝内胆管中形成，导致症状、败血症发作和需要部分肝切除。尽管熊去氧胆酸治疗可能有所帮助，但它似乎并不能预防奥曲肽治疗期间的胆结石形成。奥曲肽还与急性胰腺炎有关，这可能是由于其抑制胃肠激素释放的作用，尽管其他病例可能是由于胆结石通过和胰腺导管阻塞的继发结果。 可能性评分：C（临床上明显肝损伤的可能原因）。

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，高达29%，但高于正常上限5倍的升高是罕见的（ 帕西瑞肽会导致胆囊收缩力抑制和胆汁分泌减少，长期治疗与胆结石形成的高发生率相关。在前瞻性研究中，接受维持帕西瑞肽治疗的肢端肥大症患者中，有20%至30%的患者在一到两年内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防止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

• WGK Germany：
  3

制备方法与用途

兰瑞肽概述

兰瑞肽是一种用于治疗肢端肥大症及神经内分泌肿瘤引发的综合征的药物。它与奥曲肽类似，是长效生长激素抑制素类似物。该药品由易普森公司制造，并以索马杜林的商品名销售。2002年3月14日中国批准了该药上市。

用途

兰瑞肽不仅可用于治疗肢端肥大症和神经内分泌肿瘤引发的综合征，也可用于有关呋喃、酚类、亚硝基芳烃和硫代苯类等化学物质的统计结构警报的研究。此外，在多肽合成中也有应用价值。

药理学

兰瑞肽是一种人工合成的生长激素抑制素类似物，能对多种激素产生抑制作用，包括生长激素、促甲状腺激素（TSH）、胰岛素和胰高血糖素等。与生长激素抑制素相似，兰瑞肽通过受体发挥作用，并对外周生长抑素受体具有更高的亲和力，活性相近但中枢神经系统的影响较弱。虽然生长激素抑制素在体内数分钟内便会分解，但兰瑞肽的半衰期更长，因此能产生长效作用。

副作用

兰瑞肽的主要副作用包括注射部位轻度疼痛以及胃肠道扰乱，例如腹泻、恶心和呕吐等。长期使用可能会导致胆结石。

科学研究

自2009年以来，关于生长激素抑制素对多囊肝的研究已有超过17篇发表。其中，涉及兰瑞肽的有约7至8篇论文，研究者来自荷兰、比利时和美国等地。

2019年4月22日，荷兰拉德堡德大学医学中心消化内科发表了最新的一个兰瑞肽临床试验结果（Gastroenterology 2019 Apr22）。该试验旨在检测兰瑞肽能否缓解多囊肝的囊肿增长。共有305位常染色体显性遗传性多囊肾病患者参与，其中175位患者合并多囊肝且肝脏体积磁共振显示超过2000毫升。这175名患者中有95人接受了每四周一次皮下注射兰瑞肽120毫克的治疗。

经过120周后，接受兰瑞肽治疗组患者的肝脏体积减少了1.99%，而对照组则增加了3.92%。因此与对照组相比，兰瑞肽使肝体积减小了5.91%；而在最后一次注射4个月后的检测中，肝体积的增长依然降低了7.18%。

目前，兰瑞肽尚未用于多囊肝的治疗，仍处于临床试验阶段。

生物活性

Lanreotide（拉洛特丁、安吉奥佩汀、BIM 23014、德米普汀、伊普蒂尔、ITM-014、索马杜林、Somatuline、兰雷托丁）是一种天然生长激素抑制素肽的类似物，作为生长激素（GH）的生理抑制剂具有生物活性。此外，它还具备抗肿瘤作用。

靶点

Target	Value
growth hormone (GH)	()

参考质量标准

• 外观：白色粉末
• 纯度（HPLC）≥98.0%
• 单杂≤1.0%
• 醋酸根含量5.0%～12.0%
• 水分含量≤10.0%