CN101919868B - 连翘酯苷b的用途 - Google Patents
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Abstract
连翘酯苷B的新用途，提供了连翘酯苷B在制备治疗或预防心血管疾病的药物中的应用，具体涉及连翘酯苷B在制备治疗或预防冠心病、心绞痛或心肌梗塞的药物中的应用。连翘酯苷B能显著降低急性心肌缺血大鼠肢体导联心电图J点的升高、减少缺血面积。
Description
技术领域
本发明涉及一种连翘酯苷B的新用途，具体涉及连翘酯苷B在制备治疗或预防心血管疾病的药物中的应用。
背景技术
连翘酯苷B是从中药独一味中提取获得的，具有抗氧化和抑制脂质过氧化作用[Delazar A，Sabzevari A，Mojarrab M，Nazemiyeh H，Esnaashari S，Nahar L，Razavi SM，Sarker SD.Free radical scavenging principles from Phlomis caucasica.Nat Med(Tokyo)2008，62(4)：464-466.；Martin-Nizard F，Sahpaz S，Furman C，Fruchart JC，Duriez P，BailleulF.Natural phenylpropanoids protect endothelial cells against oxidized LDL-inducedcytotoxicity.Planta Med.2003，69(3)：207-211.]，体外具有抗菌、神经保护作用[Nazemiyeh H，Rahman MM，Gibbons S，Nahar L，Delazar A，Ghahramani MA，Talebpour AH，Sarker SD.Assessment of the antibacterial activity of phenylethanoid glycosides fromPhlomis lanceolata against multiple-drug-resistant strains of Staphylococcusaureus.Nat Med(Tokyo).2008，62(1)：91-95.；Koo KA，Sung SH，Park JH，Kim SH，LeeKY，Kim YC.In vitro neuroprotective activities of phenylethanoid glycosides fromCallicarpa dichotoma.Planta Med.2005，71(8)：778-780.]，抑制脂蛋白诱导的内皮细胞内皮素-1释放[Martin-Nizard F，Sahpaz S，Kandoussi A，Carpentier M，Fruchart JC，Duriez P，Bailleul F.Natural phenylpropanoids inhibit lipoprotein-inducedendothelin-1 secretion by endothelial cells.J Pharm Pharmacol.2004，56(12)：1607-1611.]，抑制COX-2[Sahpaz S，Garbacki N，Tits M，Bailleul F.Isolationand pharmacological activity of phenylpropanoid esters from Marrubium vulgare.JEthnopharmacol.2002 Mar；79(3)：389-92.]。连翘酯苷B对心血管疾病的作用也未见报道，基于此，本发明人通过大量的实验研究，提供了连翘酯苷B在制备治疗或预防心血管疾病的药物中的应用。
发明内容
本发明提供了连翘酯苷B在制备治疗或预防心血管疾病的药物中的应用。
本发明提供了连翘酯苷B在制备治疗或预防缺血性心脏病的药物中的应用。
本发明提供了连翘酯苷B在制备治疗或预防冠心病的药物中的应用。
本发明提供了连翘酯苷B在制备治疗或预防心绞痛或心肌梗塞的药物中的应用。
本发明提供了连翘酯苷B在制备治疗或预防心衰的药物中的应用。
本发明提供的连翘酯苷B在用于上述任一用途时，其注射使用剂量范围为25mg～1000mg，优选剂量范围为25mg～500mg；其灌胃使用剂量范围为100mg～2000mg，优选剂量范围为100mg～1000mg。
本发明提供了以连翘酯苷B为活性成分的药物，其可以以注射剂、片剂、丸剂、颗粒剂、胶囊、糖浆等剂型存在，优选为冻干粉针和胶囊。本发明提供的各种剂型均可以采用药学常规方法制备而成。
具体实施方式
制备例1制备连翘酯苷B
取独一味药材20kg，将其粉碎，过10目筛，加8倍量(V/W)80％乙醇浸泡过夜，回流提取两次，每次2小时，提取液回收乙醇至无醇味，过滤，滤液上处理好聚酰胺柱，水洗6倍柱体积弃去，继续用10％乙醇洗脱4个柱体积，收集洗脱液，上处理好的聚酰胺柱，水洗至流出液无色，再用5％乙醇洗脱4倍柱体积，收集5％乙醇洗脱液，蒸干，得含量为95％的连翘酯苷B。
制备例2制备连翘酯苷B
取独一味药材20kg，将其粉碎，过10目筛，加20倍量(V/W)85％乙醇渗漉提取，提取液回收乙醇至无醇味，过滤，滤液上处理好聚酰胺柱，水洗6倍柱体积弃去，继续用10％乙醇洗脱4个柱体积，收集洗脱液，上处理好的AB-8大孔树脂柱，水洗2倍柱体积弃去，再用20％乙醇洗脱4倍柱体积，收集洗脱液，蒸干，得含量为90％的连翘酯苷B。
制备例3连翘酯苷B冻干粉针制备
取连翘酯苷B 25.0g，加注射用水2000ml使其溶解，，加甘露醇8g，搅拌溶解，超滤，得到无热源的澄清液，灌入10ml西林瓶中，2ml/只，按冻干粉针工艺冻干，制成每支含连翘酯苷25.0mg的冻干粉针。
制备例4连翘酯苷B片剂制备
称取100g连翘酯苷B，35g糖粉，40g乳糖和23g羧甲基淀粉钠充分混合均匀后过100目筛，加入3％PVPK30水溶液适量制软材，20目筛制粒，60℃干燥3小时，18目筛整粒，加入2g硬脂酸镁，混合均匀后浅凹冲压片，调节片重约200mg，即得。
试验例1连翘酯苷B对大鼠心肌缺血损伤的影响
(1)材料：
连翘酯苷B原料按制备例1方法制备，连翘酯苷B静脉注射各组用药根据制备例3制备，连翘酯苷B灌胃给药各组用药根据制备例4制备。
氯化硝基四氮唑蓝(N-BT)，由军事医学科学院药材供应站提供。
实验动物：普通级SD大鼠，雄性，体重280g-350g，雌雄各半，山东绿叶制药有限公司实验动物中心提供，合格证号：SYXK(鲁)20030020。
(2)方法与结果：
动物随机分为模型对照组(生理盐水)、硝苯地平组(6mg/kg)、连翘酯苷B静脉注射组1(2.5mg/kg)、连翘酯苷B静脉注射组2(5mg/kg)、连翘酯苷B静脉注射组3(10mg/kg)、连翘酯苷B静脉注射组4(20mg/kg)、连翘酯苷B静脉注射组5(50mg/kg)、连翘酯苷B静脉注射组6(100mg/kg)、连翘酯苷B灌胃组1(10mg/kg)、连翘酯苷B灌胃组2(50mg/kg)、连翘酯苷B灌胃组3(100mg/kg)、连翘酯苷B灌胃组4(200mg/kg)，每组10只。禁食12小时后，ip.乌拉坦(1.2g/kg)麻醉，测肢体II导联心电图。剪去左胸前皮毛，碘酒及酒精消毒，沿胸骨左缘1cm处，剪开胸壁肌肉及二条肋骨，迅速打开胸腔，暴露心脏，在动脉圆锥与左心耳之间结扎左冠状动脉，立即将心脏放回，排挤出胸腔空气，用止血钳闭合胸腔，造成大鼠急性心肌缺血模型。硝苯地平组在麻醉前灌胃给药，灌胃给药组连续给药3天，于第2天给药后禁食16小时后，第3天给药30分钟后手术，其余各组术后随即静脉注射相应药物。记录给药前及给药后1.5h、3h心电图，测量心电图J点的升高值，6h后取出心脏，以冷生理盐水洗净后，-20℃冰箱冷冻过夜。次日，将冷冻的心脏由结扎处至心尖部等厚切成5片，浸入新鲜配制的0.25％N-BT磷酸缓冲液(pH 7.4)中。37℃水浴振摇10～15min。用滤纸吸干切片表面的染色液，分离染色部分和未染色部分，称重，记算梗死面积。梗死面积(％)＝梗死部分重量/(非梗死部分重量+梗死部分重量)×100％。数据用x±SD表示，以组间t检验进行统计学处理。
结果如表1所示，心肌缺血6小时后，模型组大鼠心肌出现明显的灶状缺血区，达到26％左右。连翘酯苷B静脉注射组1(2.5mg/kg)、连翘酯苷B静脉注射组2(5mg/kg)、连翘酯苷B静脉注射组3(10mg/kg)、连翘酯苷B静脉注射组4(20mg/kg)、连翘酯苷B静脉注射组5(50mg/kg)、连翘酯苷B静脉注射组6(100mg/kg)、连翘酯苷B灌胃组1(10mg/kg)、连翘酯苷B灌胃组2(50mg/kg)、连翘酯苷B灌胃组3(100mg/kg)、连翘酯苷B灌胃组4(200mg/kg)降低肢体导联心电图J点的升高、减少缺血面积(与模型组比较，p＜0.05或p＜0.01)；连翘酯苷B静脉注射组5(50mg/kg)与连翘酯苷B静脉注射组6(100mg/kg)比较，对肢体导联心电图J点的升高及缺血面积无明显差异(p＞0.05)；连翘酯苷B灌胃组3(100mg/kg) 与连翘酯苷B灌胃组4(200mg/kg)比较，对肢体导联心电图J点的升高及缺血面积无明显差异(p＞0.05)。
表1连翘酯苷B对大鼠心肌缺血损伤的影响(n＝10)
与模型对照组比较，*P＜0.05，**P＜0.01。
试验例2连翘酯苷B对慢性心衰大鼠的影响
1.1材料药物
连翘酯苷B原料按制备例1方法制备，连翘酯苷B静脉注射各组用药根据制备例3制备，连翘酯苷B灌胃给药各组用药根据制备例4制备。
盐酸阿霉素针剂，上海华联制药厂，批号040712；卡托普利片，天津飞鹰制药有限公司，批号040213。
仪器 美国BIC 16导生理记录仪(美国BIC公司生产)
动物 Wistar大鼠，雌雄各半，体重180-220g，山东省天然药物工程技术研究中心实验动物中心提供，动物合格证：鲁动质字200106005号
1.2试验方法与结果
大鼠130只，雌雄各半，取120只腹腔注射盐酸阿霉素2mg/kg，每周1次，共6周。随机分为10组，即NS组，卡托普利12.5mg/kg组，连翘酯苷B静脉注射组1(2.5mg/kg)、连翘酯苷B静脉注射组2(5mg/kg)、连翘酯苷B静脉注射组3(10mg/kg)、连翘酯苷B静 脉注射组4(20mg/kg)、连翘酯苷B静脉注射组5(50mg/kg)、连翘酯苷B静脉注射组6(100mg/kg)、连翘酯苷B灌胃组1(10mg/kg)、连翘酯苷B灌胃组2(50mg/kg)、连翘酯苷B灌胃组3(100mg/kg)、连翘酯苷B灌胃组4(200mg/kg)。第6周起连翘酯苷B静脉各药组开始给药，连续给药14天，第5周起连翘酯苷B灌胃给药各组开始给药，连续给药21天。20％乌拉坦1.1g/kg腹腔注射麻醉，手术剥离气管并插管，同时游离出右侧颈总动脉，经其插入自制的心室插管(直径1mm，充满1％肝素)，描记血压曲线；再继续插入，使其通过左侧动脉瓣进入左心室，描记室内压曲线，自动分析处理左室收缩压(LVSP)，心室内压最大上升速率(+dp/dtmax)，心室内压最大下降速率(-dp/dtmax)和实测心肌最大收缩速度(Vpm)等数据。另取10只大鼠作为正常对照组，不给予盐酸阿霉素，其余操作同上述，组间T检验，进行统计学处理。
表1试验结果表明连翘酯苷B静脉注射组1(2.5mg/kg)、连翘酯苷B静脉注射组2(5mg/kg)、连翘酯苷B静脉注射组3(10mg/kg)、连翘酯苷B静脉注射组4(20mg/kg)、连翘酯苷B静脉注射组5(50mg/kg)、连翘酯苷B静脉注射组6(100mg/kg)、连翘酯苷B灌胃组1(10mg/kg)、连翘酯苷B灌胃组2(50mg/kg)、连翘酯苷B灌胃组3(100mg/kg)、连翘酯苷B灌胃组4(200mg/kg)能升高由盐酸阿霉素导致的心衰大鼠的LVSP，+dp/dtmax，-dp/dtmax和Vpm的降低(与NS组比较，P＜0.05或P＜0.01)。连翘酯苷B静脉注射组5与连翘酯苷B静脉注射组6比较，对心衰大鼠的LVSP，+dp/dtmax，-dp/dtmax和Vpm的升高无显著性差异；连翘酯苷B灌胃组3与连翘酯苷B灌胃组4比较，对心衰大鼠的LVSP，+dp/dtmax，-dp/dtmax和Vpm的升高无显著性差异。
表1连翘酯苷B对慢性心衰大鼠心功能的影响(n＝10)
与NS组比较，Δ：P＜0.05；ΔΔ：P＜0.01
Claims (3)
1.连翘酯苷B作为唯一活性成分在制备治疗或预防冠心病的药物中的应用。
2.连翘酯苷B作为唯一活性成分在制备治疗或预防心绞痛或心肌梗塞的药物中的应用。
3.连翘酯苷B作为唯一活性成分在制备治疗或预防心衰的药物中的应用。
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