CN108478580A - 依鲁替尼在制备抗重症肝炎药物中的应用 - Google Patents

依鲁替尼在制备抗重症肝炎药物中的应用 Download PDF

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CN108478580A
CN108478580A CN201810178422.6A CN201810178422A CN108478580A CN 108478580 A CN108478580 A CN 108478580A CN 201810178422 A CN201810178422 A CN 201810178422A CN 108478580 A CN108478580 A CN 108478580A
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ibrutinib
serious hepatitis
shandong
serious
buddhist nun
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郑敏
叶炳珏
刘艳宁
楼国华
周承
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Zhejiang University ZJU
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Abstract

本发明的目的是提供依鲁替尼(Ibrutinib)在制备抗重症肝炎药物中的应用，所述Ibrutinib的化学名为1‑[(3R)‑3‑[4‑氨基‑3‑(4‑苯氧基苯基)‑1H‑吡唑并[3,4‑d]嘧啶‑1‑基]‑1‑哌啶基]‑2‑丙烯‑1‑酮。本发明利用ConA介导的小鼠重症肝炎模型来验证Ibrutinib在肝功能及肝脏病理上的抑制作用，在细胞水平上利用内毒素(LPS)来验证Ibrutinib的抑炎效果。经体内外实验证实，其在重症肝炎发生发展中具有较强的抑制作用。并具有明确的靶点，且已经有适应症可用于临床，可用于作为治疗重症肝炎的药物。本发明开拓了依鲁替尼(Ibrutinib)新的医药用途，为治疗重症肝炎提供新的手段。

Description

依鲁替尼在制备抗重症肝炎药物中的应用
技术领域
本发明涉及药物用途领域，涉及抗肿瘤药物依鲁替尼(Ibrutinib)新的药物用途，具体涉及Ibrutinib在制备重症肝炎药物中的用途。
背景技术
重症肝炎是由肝细胞大量坏死而出现严重功能损害的一种临床综合征，病情严重、临床症状复杂、病死率高，是肝病患者病故的主要原因之一，严重危害人类健康。引起重型肝炎的原因很多，包括乙型肝炎病毒(HBV)，药物中毒，慢性酒精性肝损害等，在我国，乙型肝炎病毒感染是其主要的病因。重症肝炎的发病机制较为复杂，对该病的治疗是医学领域中亟待解决的难题。目前临床上对重症肝炎的治疗主要采用以支持和对症疗法为基础的综合性治疗为主，但治疗效果不佳，常需要人工肝支持系统治疗或肝移植。尽管人工肝支持系统有较好的疗效，但因为血浆供应紧张及对开展人工肝支持治疗医院要求较高，使人工肝治疗受到很大的限制。肝移植虽然是治疗终期肝病的最佳选择，但因供肝来源短缺、术后免疫排斥反应严重、费用高昂等因素制约了其在重症肝炎中的应用。因此寻找有效的免疫调节剂来加强重症肝炎的防治是来重要的研究方向。
BTK蛋白是非受体型蛋白酪氨酸激酶Tec家族的一员，广泛表达于除了T细胞外的其他造血细胞，尤其是B细胞。BTK在Toll样受体介导的信号通路等固有免疫过程中起到重要作用：参与调节自然杀伤(NK)细胞的活化，BTK基因缺陷的NK细胞IFN-γ表达减少，细胞毒性降低；由NK细胞介导的急性肝损伤在BTK基因敲除小鼠或用BTK抑制剂处理的小鼠模型中明显减轻。这些均提示BTK可作为抗重症肝炎治疗的新靶点。
依鲁替尼(Ibrutinib)是一种目前已在临床上运用的BTK抑制剂，其通过选择性地与BTK活性中心的第481个半胱氨酸残基共价结合，从而发挥其对第223个酪氨酸残基的磷酸化过程的不可逆的抑制作用。目前，Ibrutinib已经被FDA批准用于治疗慢性淋巴细胞白血病(chronic lymphocytic leukemia,CLL)，套细胞淋巴瘤(mantle cell lymphoma,MCL)以及华氏巨球蛋白血症(Waldenstrom’s macroglobulinemia,WM)，但其在重症肝炎治疗中的作用未见报道。
发明内容
本发明的目的是提供依鲁替尼(Ibrutinib)在制备治疗重症肝炎药物中的应用。所述Ibrutinib的化学名为1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮，其化学结构式如下：
本发明利用ConA介导的小鼠重症肝炎模型来验证Ibrutinib在肝功能及肝脏病理上的抑制作用，在细胞水平上利用内毒素(LPS)来验证Ibrutinib的抑炎效果。
本发明经体内实验、体外实验，证实其在重症肝炎发生发展中具有较强的抑制作用。并具有明确的靶点，且已经有适应症可用于临床，可用于作为治疗重症肝炎的药物。
附图说明
图1显示了本发明的Ibrutinib对ConA介导的小鼠重症肝炎外周血清中肝功能的保护作用。
图2显示了本发明的Ibrutinib对ConA介导的小鼠重症肝炎肝脏的保护作用。
图3显示了本发明的Ibrutinib对LPS刺激的人外周单核细胞细分泌炎症因子的抑制作用。
具体实施方式
为了便于理解，以下将通过具体的附图和实施例对本发明的Ibrutinib进行详细地描述。需要特别指出的是，具体实例和附图仅是为了说明，显然本领域的普通技术人员可以根据本文说明，在本发明的范围内对本发明做出各种各样的修正和改变，这些修正和改变也纳入本发明的范围内。
实施例1
1、在动物实验中，Ibrutinib对ConA介导的小鼠重症肝炎外周血清中肝功能存在保护作用
利用20mg/kg的ConA可在C57小鼠上模拟重症肝炎，Ibrutinib以10mg/kg剂量灌胃预处理小鼠半小时后再利用上述剂量的ConA建立小鼠重症肝炎模型，留取24小时的小鼠外周血的血清检测谷丙转氨酶(ALT)及谷草转氨酶(AST)。
如图1所示，Ibrutinib对ConA介导的小鼠重症肝炎外周血清中ALT与AST有着明显的抑制作用，差异存有统计学意义。
2、肝脏病理HE染色显示Ibrutinib对ConA介导的小鼠重症肝炎存有保护作用
利用20mg/kg的ConA可在C57小鼠上模拟重症肝炎，Ibrutinib以10mg/kg剂量灌胃预处理小鼠半小时后再利用上述剂量的ConA建立小鼠重症肝炎模型，留取24小时的小鼠肝脏，福尔马林固定，石蜡包裹切片，进行HE染色。
结果如图2所示，A为造模组，B为Ibrutinib用药组，C为正常组。可见，与阳性对照组相比，Ibrutinib明显减少ConA介导的肝细胞坏死，对小鼠肝脏有着明显的保护作用。
3、在体外实验中，Ibrutinib对炎症因子存在明显的抑制作用
LPS可在体外细胞实验中模拟细胞炎症模型。分离正常人的外周血单核细胞在体外培养过夜后，用Ibrutinib(5nM)和/或LPS(100ng/ml)(治疗组Ibrutinib预处理半小时)刺激6小时，利用ELISA检测其培养上清中炎症因子(TNF-α，IL-1β，IL-6，IL-10)的水平。
如图3所示，在原代细胞上，Ibrutinib能有效减少LPS引起的TNF-α，IL-1β，IL-6，IL-10等炎症因子水平，结果具有统计学意义。
数据分析：采用SPSS19.0统计分析软件进行非配对t检验，NS表示没有差异，*表示p<0.05,**表示p<0.01。

Claims (2)

1.依鲁替尼在制备抗重症肝炎药物中的应用，所述依鲁替尼的化学名为1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮。
2.根据权利要求1所述的应用，其特征在于，所述药物由1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮与辅料制成。
CN201810178422.6A 2018-03-05 2018-03-05 依鲁替尼在制备抗重症肝炎药物中的应用 Pending CN108478580A (zh)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120053189A1 (en) * 2010-06-28 2012-03-01 Pharmacyclics, Inc. Btk inhibitors for the treatment of immune mediated conditions
CN103917545A (zh) * 2011-07-19 2014-07-09 默沙东公司 Btk抑制剂
CN105848680A (zh) * 2013-10-25 2016-08-10 药品循环有限责任公司 使用布鲁顿酪氨酸激酶抑制剂和免疫疗法的治疗

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120053189A1 (en) * 2010-06-28 2012-03-01 Pharmacyclics, Inc. Btk inhibitors for the treatment of immune mediated conditions
CN103917545A (zh) * 2011-07-19 2014-07-09 默沙东公司 Btk抑制剂
CN105848680A (zh) * 2013-10-25 2016-08-10 药品循环有限责任公司 使用布鲁顿酪氨酸激酶抑制剂和免疫疗法的治疗

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
孟靓靓 等 主编: "《肝胆胰腺疾病药食宜忌》", 31 August 2016 *

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