Plasma kallikrein | 460738-38-9

• 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 - 肽模拟物
• 英文名称: Plasma kallikrein
• 英文别名: (2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(1R,2aS,4S,5aS,8aS,11aR,13S,14aS,16S,17aS,19S,20aS,22S,23aS,25S,26aS,28S,29aS,31R,32aS,35aS,36R,38aS,39S,41aS,42S,44aS,45S,48R,50aS,51S,53aS,54S,56aS,57S,59aS,60S,63S,66S,69S,72S,75S,78S,84S,87R,96S,99S)-22,42,45-tris(4-aminobutyl)-31-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-carboxybutanoyl]amino]propanoyl]amino]-4-methylsulfanylbutanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-3-phenylpropanoyl]amino]-29a,72,78-tris(2-amino-2-oxoethyl)-14a,75-bis(3-amino-3-oxopropyl)-2a,23a,25,32a,35a,66-hexabenzyl-26a,99-bis[(2S)-butan-2-yl]-17a,41a,59a,69-tetrakis(3-carbamimidamidopropyl)-5a,8a,51,54,63,84-hexakis(2-carboxyethyl)-13,16-bis(carboxymethyl)-20a-[(1R)-1-hydroxyethyl]-60-(hydroxymethyl)-96-[(4-hydroxyphenyl)methyl]-50a-(1H-imidazol-5-ylmethyl)-38a-(1H-indol-3-ylmethyl)-19,28,53a,56a-tetramethyl-57-(2-methylpropyl)-39-(2-methylsulfanylethyl)-1a,3,4a,7a,9,10a,12,13a,15,16a,18,19a,21,22a,24,25a,27,28a,30,31a,34a,37a,38,40a,41,43a,44,47,49a,50,52a,53,55a,56,58a,59,61a,62,65,68,71,74,77,80,83,86,89,92,95,98-pentacontaoxo-33,34,63a,64a,67a,68a-hexathia-a,2,3a,6a,8,9a,11,12a,14,15a,17,18a,20,21a,23,24a,26,27a,29,30a,33a,36a,37,39a,40,42a,43,46,48a,49,51a,52,54a,55,57a,58,60a,61,64,67,70,73,76,79,82,85,88,91,94,97-pentacontazapentacyclo[85.74.4.448,111.04,8.0144,148]nonahexacontahectane-36-carbonyl]amino]-3-hydroxybutanoyl]amino]-5-carbamimidamidopentanoyl]amino]butanedioic acid
• CAS: 460738-38-9
• 化学式: C₃₀₅H₄₄₂N₈₈O₉₁S₈
• 分子量: 7054.0
• InChiKey: VBGWSQKGUZHFPS-FHVLXVBRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -27.9
• 重原子数：
  492
• 可旋转键数：
  133
• 环数：
  17.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  3120
• 氢给体数：
  100
• 氢受体数：
  110

ADMET

毒理性

• 毒性总结

识别和使用：Ecallantide，一种基于人类组织因子途径抑制剂第一个Kunitz结构域的生物合成蛋白，是血浆激肽释放酶的可逆和选择性抑制剂。Ecallantide是一种清澈、无色的溶液。Ecallantide用于治疗12岁及以上患者的遗传性血管性水肿（HAE）的急性发作。 人类暴露和毒性：目前还没有关于Ecallantide过量的报告。HAE患者在单次静脉注射高达90毫克的剂量下，没有出现剂量相关的毒性证据。在接受Ecallantide治疗的病人中，可能会发生潜在的严重超敏反应，包括过敏性休克。在临床研究中，接受静脉或皮下注射Ecallantide的255名遗传性血管性水肿（HAE）患者中，有10名患者（4%）经历了过敏性休克。在187名接受皮下注射Ecallantide的患者亚组中，有5名患者（3%）经历了过敏性休克。与这些反应相关的症状包括胸痛、潮红、咽部水肿、瘙痒、流涕、打喷嚏、鼻塞、喉咙刺激、荨麻疹、喘息和低血压。这些反应在给药后第一个小时内发生。 其他表明超敏反应的副作用包括：瘙痒（5%）、皮疹（3%）和荨麻疹（2%）。 动物研究：在大鼠中进行了为期两年的研究，以评估Ecallantide的致癌潜力。在大鼠中，没有观察到在每三天皮下注射一次高达10毫克/千克的剂量下的肿瘤生成（大约是最大推荐人类剂量（MRHD）的两倍，基于AUC）。在大鼠中，静脉注射的Ecallantide剂量大约是最大推荐人类剂量的13倍（以母体剂量15毫克/千克/天计算，基于毫克/千克）时，在轻微母体毒性存在的情况下，导致早期吸收数量和每窝吸收的胚胎比例增加。在大鼠中，静脉注射的剂量大约是MRHD的8倍（以母体剂量10毫克/千克/天计算）时，没有观察到发育毒性。在大鼠中，皮下注射的Ecallantide剂量高达MRHD的大约2.4倍（以母体剂量20毫克/千克/天计算），在兔中，静脉注射的剂量高达MRHD的大约6倍（以母体剂量5毫克/千克/天计算）时，对胚胎胎儿发育没有不良影响。在大鼠中，皮下注射的Ecallantide剂量高达25毫克/千克/天（大约是MRHD的21倍）时，对生育和生殖性能没有影响。

IDENTIFICATION AND USE: Ecallantide, a biosynthetic protein based on the first Kunitz domain of human tissue factor pathway inhibitor, is a reversible and selective inhibitor of plasma kallikrein. Ecallantide is a clear, colorless solution. Ecallantide is indicated for treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older. HUMAN EXPOSURE AND TOXICITY: There have been no reports of overdose with ecallantide. HAE patients have received single doses up to 90 mg intravenously without evidence of dose-related toxicity. Potentially serious hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with ecallantide. In 255 hereditary angioedema (HAE) patients treated with intravenous or subcutaneous ecallantide in clinical studies, 10 patients (4%) experienced anaphylaxis. For the subgroup of 187 patients treated with subcutaneous ecallantide, 5 patients (3%) experienced anaphylaxis. Symptoms associated with these reactions have included chest discomfort, flushing, pharyngeal edema, pruritus, rhinorrhea, sneezing, nasal congestion, throat irritation, urticaria, wheezing, and hypotension. These reactions occurred within the first hour after dosing. Other adverse reactions indicative of hypersensitivity reactions included the following: pruritus (5%), rash (3%), and urticaria (2%). ANIMAL STUDIES: A two-year study was conducted in rats to assess the carcinogenic potential of ecallantide. No evidence of tumorigenicity was observed in rats at doses up to 10 mg/kg administered subcutaneously every three days (approximately 2-fold greater than the maximum recommended human dose (MRHD) on an AUC basis). In rats, intravenous ecallantide at a dose approximately 13 times the maximum recommended human dose (MRHD) (on a mg/kg basis at a maternal dose of 15 mg/kg/day in rats) caused increased numbers of early resorptions and percentages of resorbed conceptuses per litter in the presence of mild maternal toxicity. No development toxicity was observed in rats that received an intravenous dose approximately 8 times the MRHD (at a maternal dose of 10 mg/kg/day in rats). There were no adverse effects of ecallantide on embryofetal development in rats that received subcutaneous doses up to approximately 2.4 times the MRHD (at a maternal dose of 20 mg/kg/day in rats), and in rabbits that received intravenous doses up to approximately 6 times the MRHD (at a maternal dose of 5 mg/kg/day in rabbits). Ecallantide had no effects on fertility and reproductive performance in rats at subcutaneous doses up to 25 mg/kg/day (approximately 21 times MRDH).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中毒物清除。如果患者停止呼吸，开始人工呼吸，最好使用需求阀复苏器、袋阀面罩装置或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者前倾或置于左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，辅助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预期癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）连续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能够吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的灭菌敷料覆盖皮肤烧伤……。/毒物A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β受体激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注5%葡萄糖（D5W），TKO /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%的生理盐水（NS）或乳酸钠林格氏液（LR）。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。使用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒物A和B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/症状和体征/ Kalbitor 过量使用的报告。遗传性血管性水肿（HAE）患者单次静脉注射剂量高达90毫克，没有剂量相关毒性的证据。

/SIGNS AND SYMPTOMS/ There have been no reports of overdose with Kalbitor. Hereditary angioedema (HAE) patients have received single doses up to 90 mg intravenously without evidence of dose-related toxicity.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在一项健康个体的药代动力学研究中，ecallantide的峰值血浆浓度在大约30毫克ecallantide通过皮下注射给药后2-3小时达到；报告显示，皮下给药的生物利用度大约为90%。

In a pharmacokinetic study in healthy individuals, peak plasma concentrations of ecallantide were achieved at approximately 2-3 hours following a 30 mg dose of ecallantide administered by subcutaneous injection; an approximate bioavailability of 90% was reported with subcutaneous administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Ecallantide 是通过尿液排出的；然而，由于该药物是一种小蛋白，代谢分解（或降解）也是一个可能的消除过程。

Ecallantide is eliminated in urine; however, since the drug is a small protein, metabolic catabolism (or degradation) is also a likely elimination process.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

尚不清楚ecallantide是否经人乳排泄。

It is not known whether ecallantide is excreted in human milk.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

用途

艾卡拉肽（商品名：Kalbitor）用于治疗遗传性血管水肿（HAE）突发或致命性的积液。艾卡拉肽是继另一种药物之后，在美国上市的第二种专门针对HAE发作的治疗方法。

制备

将150克艾卡拉肽线性粗肽溶解于150升缓冲体系中，该缓冲体系为0.1 mM醋酸铵、3倍量（物质的量）DTT的水溶液，pH值调整至7.8。随后敞口置于室温下搅拌36小时，并添加冰乙酸调节pH至3～5以淬灭反应，得到艾卡拉肽粗肽溶液。接着，通过参照实施例12的方法进行纯化和冻干处理，最终获得了白色精肽固体35.7克，环化收率为23.8%，质谱检测结果显示其信号值为8387.654。