CN116850173A - 一种二氢杨梅素在制备凝血X因子FXa抑制剂的药物中的应用 - Google Patents
一种二氢杨梅素在制备凝血X因子FXa抑制剂的药物中的应用 Download PDFInfo
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- CN116850173A CN116850173A CN202310666578.XA CN202310666578A CN116850173A CN 116850173 A CN116850173 A CN 116850173A CN 202310666578 A CN202310666578 A CN 202310666578A CN 116850173 A CN116850173 A CN 116850173A
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- dihydromyricetin
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Abstract
本申请提供一种二氢杨梅素在制备凝血X因子FXa抑制剂的药物中的应用，应用于生物医药技术领域，其中，通过将不同浓度的DHM与FXa(终浓度2nM)混合，37℃条件下在低离子强度标准缓冲液体系内孵育5min(20mM Hepes,150mM NaCl,2mM CaCl2,0.1mM EDTA,0.1％PEG8000；pH 7.4)，然后加入特异性荧光底物(S2765；终浓度200μM)，应用全波长扫描式多功能读数仪)，波长340nm进行检测荧光强度(激发光波长为280nm)，DHM的终浓度(mg/mL)为：0.039，0.078，0.156，0.312，0.625，1.250，2.500，5.000，10.000。DHM抑制FXa活性的IC50(mg/mL)为4.09±1.11，Hill Slope为1.208±0.158，证明二氢杨梅素(DHM)对FXa活性具有抑制作用。
Description
技术领域
本发明涉及生物医药领域，具体涉及制备凝血X因子FXa抑制剂的药物中的应用。
背景技术
凝血因子Xa(FXa)是一种丝氨酸蛋白酶，是X因子经活化后释放出来的一种由一条重链和一条轻链经二硫键连结而成的肽段；该肽段主要有四个活性位点，分别是S1、S2、S3和S4，在凝血级联反应扮演重要角色。FXa可以与FVa、磷脂和Ca2+形成促凝血酶复合物，通过激活内源性和外源性凝血中凝血酶原产生凝血酶，在凝血酶的作用下纤维蛋白原转化成纤维蛋白单体进而形成纤维蛋白凝块，导致血栓形成。凝血级联反应是一个逐级放大的过程。研究表明，每活化1分子的凝血因子X，就会有1000多个凝血酶分子被激活。FXa在凝血级联反应中位于凝血酶上游，抑制FXa而不是凝血酶可以更有效地减少凝血级联反应进一步放大，从而可有效抑制血栓形成。此外，抑制FXa具有较低的出血风险，因为它能够减少凝血酶的进一步生成，但不影响预先存在凝血酶的水平。FXa已成为新型抗凝药物研发的最佳靶点。
目前，美国食品药品监督管理局已批准四种口服FXa抑制剂：利伐沙班、阿哌沙班、依度沙班和贝曲沙班，这些药物通过高度选择性地直接作用于FXa活性中心，竞争性地抑制游离的或结合的FXa，进而阻断内源性和外源性凝血途径，抑制凝血酶活性和血栓形成，但对凝血酶诱导的血小板聚集无直接作用。与传统抗凝剂相比，这些新型FXa抑制剂表现出生物利用度高、特异性高以及与其他药物和食物相互作用少的特点。
但是，FXa抑制剂的临床应用也有其不足之处。第一，一些FXa抑制剂可能对其他凝血因子也有一定的抑制作用，这可能导致进一步的凝血异常。虽然这种交叉反应的风险相对较低，但仍需要密切监测患者的凝血参数。第二，FXa抑制剂可能与其他药物相互作用，影响它们的疗效或增加副作用的发生。特别是一些需要通过CYP代谢的药物可能与FXa抑制剂发生相互作用，导致药物浓度升高或降低。在使用FXa抑制剂时，医生需要考虑患者正在使用的其他药物，并监测可能的相互作用。第三，目前，对于FXa抑制剂的过量使用或出血的逆转剂选择有限。与直接凝血酶抑制剂(如达比加群酶)不同，尚未开发出特定的逆转剂来快速逆转FXa抑制剂的抗凝作用。这在紧急情况下可能会导致治疗上的挑战。第四，出血风险：FXa抑制剂的主要不足之处是增加了患者出血的风险。由于FXa是凝血过程中的重要组分，抑制其活性可能导致凝血功能降低，从而增加出血的风险。这需要密切监测患者的凝血功能，并在必要时采取措施来控制出血。第五，FXa抑制剂的临床适应症确实有限。例如，在严重肾和肝损伤的患者以及植入机械心脏瓣膜的患者中，使用FXa抑制剂可能具有一定的风险。肾和肝脏功能受损可能影响药物的代谢和清除，增加药物在体内的浓度，从而增加出血的风险。机械心脏瓣膜患者使用FXa抑制剂时，由于机械瓣膜本身具有血栓形成的风险，抗凝治疗选择需要特别慎重考虑。
二氢杨梅素(Dihydromyricetin，DHM)是一种二氢黄酮醇类黄酮化合物，广泛存在于蛇葡萄科蛇葡萄属植物中，在藤茶茎叶中DHM含量可以达到30％；DHM也存在于杨梅科、杜鹃科、藤黄科、大戟科、橄榄科、豆科、山榄科及柳科等植物中。DHM是白色针状结晶，分子式C15H12O8，易溶于甲醇、乙醇及丙酮，DHM主要通过与多种血管收缩相关的受体结合来发挥作用，包括血管收缩素受体和5-羟色胺受体。它具有直接收缩颅内和外周血管的作用，从而减少血管扩张和炎症反应，减轻头痛症状。DHM具有抗氧化、抗肿瘤、抗炎、解酒保肝、抗病原微生物及调血脂等多方面的药理作用。此外，二氢杨梅素还具有抗高血压、抑制体内血栓形成、降血糖等生物活性。
因此，需要进一步开发新的、更安全的FXa抑制剂来满足临床应用。
发明内容
有鉴于此，本发明应用商业化的FXa和其特异性的荧光底物，观察DHM对FXa活性的影响。
本发明提供了一种二氢杨梅素或其药物上可接受的盐在制备凝血X因子FXa抑制剂的药物中的应用。
优选的，所述二氢杨梅素或其药物上可接受的盐与凝血X因子在低离子强度标准缓冲液中孵育，所述低离子强度标准缓冲液包括Hepes、NaCl、CaCl2、EDTA或PEG8000。
本发明中，所述药学上可接受的盐通过药学上可接受的碱加成制备，所述药学上可接受的碱加成盐包括：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐或二乙醇胺盐。
本发明中，所述的药学上可接受的盐通过药学上可接受的酸加成制备，所述药学上可接受的酸包括无机酸或有机酸，所述无机酸包括：盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸或硫酸；所述有机酸包括：乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸或氨基酸。
本发明中，所述药物还进一步包含药学上可接受的赋形剂。
本发明中，所述化合物或其药学上可接受的盐可以任何合适的途径给予受试者，例如口服。
本发明中，所述化合物可通过抑制颈总动脉血栓形成治疗相关疾病。
所述化合物或其药学上可接受的盐可以制成各种合适的剂型，例如，片剂、胶囊剂、静脉注射剂、腹腔注射剂、吸入剂、雾化剂、冻干剂、贴剂、凝胶剂、喷雾剂或栓剂。
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的原型接触的方式获得碱加成盐。当本发明的化合物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal ofPharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts：Properties、Selection，and Use(P.Heinrich Stahl and Camille G.Wermuth，ed.，Wiley-VCH,2022)。
术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本方面发现二氢杨梅素对凝血因子FXa活性具有抑制作用，这对在开发新的、更安全的凝血因子FXa抑制剂具有重要的研究价值和应用前景。
附图说明
为了更清楚地说明本申请实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本申请的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其它的附图。
图1为二氢杨梅素对凝血因子FXa活性抑制曲线。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例中所用的人X因子购自Haematologic Technologies Inc公司，批号：EE1102；二氢杨梅素(DHM)购自上海源叶生物科技有限公司，批号：Y08J12K136911；特异性荧光底物S2765购自Instrucmentatio Laboratory Company公司，批号：N1159417。
实施例中所用的仪器设备购自以下厂商：
电子天平：BT25S，赛多利斯；多功能酶标仪：Flash型，ThermoScientific公司。
应用商业化的FXa和其特异性的荧光底物，观察DHM对FXa活性的影响。
将不同浓度的DHM与FXa(终浓度2nM)混合，37℃条件下在低离子强度标准缓冲液体系内孵育5min(20mM Hepes,150mM NaCl,2mM CaCl2,0.1mM EDTA,0.1％ PEG8000；pH7.4)，然后加入特异性荧光底物(S2765；终浓度200μM)，应用全波长扫描式多功能读数仪)，波长340nm进行检测荧光强度(激发光波长为280nm)。DHM的终浓度(mg/mL)为：0.039，0.078，0.156，0.312，0.625，1.250，2.500，5.000，10.000。
数据分析：
对FXa活性抑制百分比按下列公式计算：
抑制率(％)＝(A空白-A测定)*100％/A空白。
数据以均值±标准误表示。曲线拟合应用GraphPad Prism 8.0.1软件进行。
技术效果：
DHM对FXa活性抑制曲线如图1所示：二氢杨梅素(DHM)可剂量依赖性的抑制FXa活性。DHM抑制FXa活性的IC50(mg/mL)为4.09±1.11，Hill Slope为1.208±0.158。N＝3/剂量。
综上所述，二氢杨梅素(DHM)对FXa活性具有抑制作用。本发明提出DHM对FXa活性的抑制作用，这对开发新的、更安全的FXa抑制剂具有重要的研究价值和应用前景。
Claims (3)
1.一种二氢杨梅素或其药物上可接受的盐在制备凝血X因子FXa抑制剂的药物中的应用。
2.如权利要求1所述的应用，其特征在于，所述二氢杨梅素或其药物上可接受的盐与凝血X因子在低离子强度标准缓冲液中孵育，所述低离子强度标准缓冲液包括Hepes、NaCl、CaCl2、EDTA或PEG8000。
3.如权利要求1～2任一项所述的应用，其特征在于，所述凝血X因子FXa抑制剂药物还进一步包含药学上可接受的赋形剂。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101023942A (zh) * | 2007-03-20 | 2007-08-29 | 广西中医学院 | 二氢杨梅素治疗心血管疾病的用途 |
| CN104173313A (zh) * | 2014-08-25 | 2014-12-03 | 杭州朱养心药业有限公司 | 利伐沙班片剂药物组合物 |
| CN108567772A (zh) * | 2018-07-24 | 2018-09-25 | 广西师范大学 | 二氢杨梅素的新用途 |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101023942A (zh) * | 2007-03-20 | 2007-08-29 | 广西中医学院 | 二氢杨梅素治疗心血管疾病的用途 |
| CN104173313A (zh) * | 2014-08-25 | 2014-12-03 | 杭州朱养心药业有限公司 | 利伐沙班片剂药物组合物 |
| CN108567772A (zh) * | 2018-07-24 | 2018-09-25 | 广西师范大学 | 二氢杨梅素的新用途 |
Non-Patent Citations (2)
| Title |
|---|
| 潘照斌;李棐朝;廖月娥;林晓崧;: "二氢杨梅素抗血栓形成的作用研究", 中医药导报, vol. 16, no. 11, pages 92 - 94 * |
| 谭胜蓝;陈磊;何桂霞;颜苗;邓阳;罗娟;: "二氢杨梅素心血管保护作用的研究进展", 中南药学, vol. 15, no. 03, pages 339 - 343 * |
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