CN116549466A - 一种毛蕊花糖苷化合物在制备抗动脉血栓形成的药物中的应用 - Google Patents
一种毛蕊花糖苷化合物在制备抗动脉血栓形成的药物中的应用 Download PDFInfo
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- CN116549466A CN116549466A CN202310662191.7A CN202310662191A CN116549466A CN 116549466 A CN116549466 A CN 116549466A CN 202310662191 A CN202310662191 A CN 202310662191A CN 116549466 A CN116549466 A CN 116549466A
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- acid
- acteoside
- pharmaceutically acceptable
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- blood flow
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Abstract
本申请提供一种毛蕊花糖苷化合物在制备抗动脉血栓形成的药物中的应用，应用于生物医药技术领域。其中，应用FeCl3诱导的颈动脉血栓模型，通过大鼠激光散斑与血流测定，应用激光散斑仪检测放置FeCl3滤片后不同时间点的血流情况(0min、5min、10min、15min、20min和25min)，并采集原始散斑图像，毛蕊花糖苷和OFFE在放置滤片前10min经尾静脉注射给药。给予富含毛蕊花糖苷的OFFE亦可缓解FeCl3引起的血流减低的现象，其在10mg/kg剂量下，在贴敷滤片后20min和25min时的血流百分比为0min时的66.7±12.3和60.5±12.5(与模型组相比，p值均小于0.01)，证实毛蕊花糖苷对FeCl3诱发的颈总动脉血栓形成有抑制作用，这对其在动脉血栓形成、缺血性脑卒中等血栓相关病症的治疗作用具有重要的研究价值和应用前景。
Description
技术领域
本申请涉及生物医药技术领域，具体涉及一种毛蕊花糖苷化合物在制备抗动脉血栓形成的药物中的应用。
背景技术
缺血性脑卒中是由于脑血管原位血栓形成或栓子栓塞所导致的脑血液循环障碍性疾病，约占所有脑卒中病例的87％。
在缺血性脑卒中发生发展过程中，缺血/缺氧可引起一系列复杂的病理生理反应，包括能量代谢紊乱、谷氨酸兴奋毒性作用、氧化应激损伤、炎症和细胞凋亡等。其中，缺血缺氧可引起动脉血管内皮细胞损伤，暴露内皮下胶原；血小板通过胶原-血管性血友病因子-血小板糖蛋白Ib轴可促进血小板活化以及血小板糖蛋白Ib/IIa的功能上调，促使血小板聚集；同时，凝血因子XII通过血小板活化后所暴露出的带负电荷的无机聚磷酸盐表面，转为有活性的FXIIa，进而启动内源性凝血级联通路，促进血栓形成。FXIIa的形成可激活血浆激肽释放酶(PK)，后者一方面正反馈的激活FXII，进而促进内源性凝血级联通路，一方面促进炎症介质缓激肽的生成，激活后续的信号通路，加重内皮细胞损伤，上调炎性因子表达。
目前，关于缺血性脑卒中的治疗，除了机械取栓外，目前的药物治疗以t-PA的溶栓为主。t-PA是一种纤溶酶原激活剂，可在缺血性脑卒中发作后的早期给予患者静脉溶栓。它通过促进血栓溶解来恢复脑血流，从而减轻脑部组织的缺血和损伤。t-PA溶栓治疗通常在发病后的3小时内进行，被称为溶栓时间窗。在特定情况下，可以在3～4.5小时内进行扩展的溶栓时间窗。由于其时间窗口窄，出血风险大，t-PA的临床应用受到极大限制。实际上，一些天然产物可以针对性地干预脑卒中相关的各种病理生理过程，包括氧化应激、炎症和神经元凋亡等。因此，从天然产物中开发高效、低毒、安全经济的活性物质，对于增加脑卒中患者的治疗选择具有重要意义。
毛蕊花糖苷(Acteoside；A01)是一种苯乙醇苷类化合物，常见于地黄、车前子、桂花等植物中。毛蕊花糖苷已被广泛研究，并发现具有多种生物学效应。
(1)抗炎作用：毛蕊花糖苷被发现具有抗炎作用。它可以抑制炎症反应中一些炎性介质的产生，如肿瘤坏死因子-α(TNF-α)和白细胞介素-1β(IL-1β)，从而减轻炎症反应和组织损伤；
(2)抗肿瘤作用：研究表明，毛蕊花糖苷对某些肿瘤细胞具有抗增殖和抗转移的作用。它可以抑制肿瘤细胞的增殖和侵袭，并诱导肿瘤细胞凋亡。此外，毛蕊花糖苷还可以调节一些与肿瘤发生和发展相关的信号通路。
(3)抗病原微生物作用：毛蕊花糖苷被发现对多种病原微生物具有抑制作用。它可以抑制细菌、真菌和病毒的生长和复制，对于一些感染性疾病的治疗可能具有潜在的效果。
除了上述作用，毛蕊花糖苷还具有一些其他生物学效应，如抗氧化、保护神经系统、调节免疫反应等。然而，需要进一步的研究来全面了解其作用机制和潜在的临床应用。目前，不同的天然活性物质针对不同凝血因子的抗血栓效用均有所研究，现有技术CN115607557A公开了毛蕊花糖苷在制备血浆型激肽释放酶抑制剂中的应用，证明了毛蕊花糖苷对血浆型激肽释放酶具有明显抑制作用，但仅对一种诱导因子有抑制作用，无法证明在临床治疗中能否起到抗血栓功效。基于此，本领域仍然需要寻找出一种高效、低毒、安全经济的活性物质以满足临床治疗的需求。
发明内容
有鉴于此，本发明探究毛蕊花糖苷化合物在制备抗动脉血栓形成的药物中的应用。
本发明在第一方面提供了一种毛蕊花糖苷化合物在制备抗动脉血栓形成的药物中的应用。
优选的，所述毛蕊花糖苷化合物的浓度为1mg/kg～10mg/kg。
本发明在第二方面提供一种毛蕊花糖苷化合物药学上可接受的盐在制备抗动脉血栓形成的药物中的应用。
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。
本发明在第三方面提供了一种富含毛蕊花糖苷的桂花水提物在制备抗动脉血栓形成的药物中的应用。
优选的，所述桂花水提物含45％毛蕊花糖苷。
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",JournalofPharmaceutical Science66:1 19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,WileyVCH,2002)。
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：本发明发现毛蕊花糖苷化合物在制备抗动脉血栓形成的药物中的应用。
附图说明
图1是毛蕊花糖苷对FeCl3诱发的颈总动脉血流变化的作用。静脉给予毛蕊花糖苷(A01；1mg/kg和5mg/kg)或OFFE(10mg/kg)，10min后在大鼠颈总动脉贴敷12％的FeCl3，应用激光散斑仪观察贴敷后不同时间点动脉血流的变化。N＝6/组。数据以均值±标准误表示。统计学分析采用重复测定的双因素方差分析；组间比较应用Fisher LSD检验。**，P<0.01。
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。
实施例中所用的毛蕊花糖苷购自成都超九八生物科技有限公司，批号：wkq20042004；纯度≥98％(HPLC)。
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；激光散斑仪：RFLSI III型，深圳瑞沃德公司。
应用FeCl3诱导的颈动脉血栓模型，观察毛蕊花糖苷对动脉血栓形成的影响。
实验共分为四组：生理盐水组、毛蕊花糖苷(A01；1mg/kg)组、毛蕊花糖苷(A01；5mg/kg)组和富含A01的桂花水提物(含45％毛蕊花糖苷，OFFE；10mg/kg)组。
大鼠激光散斑与血流测定：
健康雄性Wistar大鼠24只(体重250-280g),购自上海斯莱克实验动物有限公司。实验动物生产许可证号为：SCXK(沪)2017-0005；使用许可证号为：SYXK(沪)2014-0018。实验动物自由饮水摄食。
动物适应性喂养1周。动物以60mg/kg的戊巴比妥钠经腹腔注射麻醉，后置于仰卧位，经颈部正中皮肤切口，游离右侧颈总动脉。将滤片(10mm x5mm)置于12％FeCl3溶液里5sec后取出，放置在颈总动脉上(其下放置Parafilm以保护周边组织)。应用激光散斑仪检测放置FeCl3滤片后不同时间点的血流情况(0min、5min、10min、15min、20min和25min)，并采集原始散斑图像。毛蕊花糖苷和OFFE在放置滤片前10min经尾静脉注射给药。
血流变化情况以基础值的百分比(％of baseline at 0min)表示。
数据分析：
数据以均值±标准误差表示。使用Sigma Stat2.03软件进行实验数据的统计学处理；统计学分析采用单因素方差分析；组间比较应用Fisher LSD检验。P<0.05为有显著性差异。
技术效果：
FeCl3可诱发颈总动脉血栓形成，引起动脉血流的减低，在贴敷滤片后15min、20min和25min时的血流百分比为0min时的70.4±12.6、26.6±2.0以及27.0±1.8；而给予毛蕊花糖苷可缓解FeCl3引起的血流减低的现象，在1mg/kg剂量下，其在贴敷滤片后20min和25min时的血流百分比为0min时的63.1±11.4和69.6±12.0(与模型组相比，p值均小于0.01)；而在5mg/kg剂量下，毛蕊花糖苷组动物在贴敷滤片后20min和25min时的血流百分比为0min时的76.7±11.2和66.6±9.9(与模型组相比，p值均小于0.01)。
给予富含毛蕊花糖苷的OFFE亦可缓解FeCl3引起的血流减低的现象，其在10mg/kg剂量下，在贴敷滤片后20min和25min时的血流百分比为0min时的66.7±12.3和60.5±12.5(与模型组相比，p值均小于0.01)。
毛蕊花糖苷对FeCl3诱发的颈总动脉血流变化的作用如图1所示：毛蕊花糖苷对FeCl3诱发的颈总动脉血流变化的作用。静脉给予毛蕊花糖苷(A01；1mg/kg和5mg/kg)或OFFE(10mg/kg)，10min后在大鼠颈总动脉贴敷12％的FeCl3，应用激光散斑仪观察贴敷后不同时间点动脉血流的变化。N＝6/组。数据以均值±标准误表示。统计学分析采用重复测定的双因素方差分析；组间比较应用Fisher LSD检验。**，P<0.01。
综上，毛蕊花糖苷对FeCl3诱发的颈总动脉血栓形成有抑制作用，这对其在动脉血栓形成、缺血性脑卒中等血栓相关病症的治疗作用具有重要的研究价值和应用前景。
Claims (8)
1.一种毛蕊花糖苷化合物在制备抗动脉血栓形成的药物中的应用。
2.如权利要求1所述的应用，其特征在于，所述毛蕊花糖苷化合物的浓度为1mg/kg～10mg/kg。
3.一种毛蕊花糖苷化合物药学上可接受的盐在制备抗动脉血栓形成的药物中的应用。
4.如权利要求3所述的应用，其特征在于，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。
5.如权利要求3所述的应用，其特征在于，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。
6.一种富含毛蕊花糖苷的桂花水提物在制备抗动脉血栓形成的药物中的应用。
7.如权利要求6所述的应用，其特征在于，所述桂花水提物含45％毛蕊花糖苷。
8.如权利要求1～7任一项所述的应用，其特征在于，所述药物还进一步包含药学上可接受的赋形剂。
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