CN117064940A - 麝香心痛宁在制备治疗缺血性脑卒中药物中的应用 - Google Patents
麝香心痛宁在制备治疗缺血性脑卒中药物中的应用 Download PDFInfo
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Abstract
本发明属于医药技术领域,具体涉及麝香心痛宁在制备治疗缺血性脑卒中药物中的应用。本发明首次报导了麝香心痛宁对缺血性脑卒中治疗的效用,动物实验结果表明,麝香心痛宁片可以大大减小脑梗死病灶的面积,抑制神经元细胞的坏死,显著改善MCAO大鼠神经行为和认知水平。本发明对麝香心痛宁用于治疗缺血性脑卒中具有重要意义。
Description
技术领域
本发明属于医药技术领域,具体涉及麝香心痛宁在制备治疗缺血性脑卒中药物中的应用。
背景技术
缺血性脑卒中(cerebral ischemic stroke)又称脑梗死,在中医中称为卒中或中风。该疾病是由各种原因导致的脑组织血液供应障碍、缺血,引发脑组织缺血缺氧性坏死、软化的综合征,从而产生临床相应的神经缺陷,主要表现为突发局灶性或弥散性的神经功能缺损。
在目前医学上,缺血性卒中具有高发病率、高复发率、高致残率及高死亡率的特点,其预后与神经功能缺损的严重程度、年龄及病因等因素有关,若能及时治疗,部分患者可能恢复部分运动、感觉功能。这种疾病的出现对于人体的健康无形之中造成了伤害。
目前治疗缺血性脑卒中常用药物包括扩张血管、扩充血容量、溶解血栓的药物,或抗凝药物,但扩充血容量药物并不适合心脏疾病人群,一旦服用可能造成心力衰竭;溶解血栓的药物不宜大量服用,可能导致身体出血;抗凝药物的服用药物需要特别注意出现的不良反应。
麝香心痛宁片的主要成分有人工麝香、延胡索(醋炙)、苏合香、川芎、人参、冰片,具体由延胡索(醋炙)220~260份、人工麝香4~12份、苏合香4~12份、川芎100~140份、人参100~140份、冰片6~18份制成。目前用于治疗气滞血瘀型冠心病心绞痛所致胸痛、胸闷、两胁胀痛、气短、心悸等症状,其用于缺血性脑卒中的治疗未见报道。
发明内容
为了解决上述问题,本发明提供了麝香心痛宁在制备治疗缺血性脑卒中药物中的应用。
本发明提供了以下技术方案:
麝香心痛宁在制备治疗脑卒中药物中的应用。
进一步地,脑卒中为缺血性脑卒中。
进一步地,所述药物为药学上可接受的任意剂型,包括片剂、胶囊剂、注射剂、颗粒剂、混悬剂和溶液剂中的至少一种。
进一步地,上述麝香心痛宁的制法如下:
以下六味药:醋炙延胡索239g、人工麝香8g、苏合香8g、川芎119g、人参119g、冰片12g,人工麝香加等量淀粉混合研细;苏合香加微粉硅胶12g,混合研细;冰片研细。延胡索(醋炙)80g粉碎成细粉;其余延胡索(醋炙)159g、人参、川芎加60%乙醇回流提取三次,每次加6倍量,回流2小时,合并提取液,滤过,滤液回收乙醇并浓缩至相对密度1.30-1.32(60℃)的稠膏,加入延胡索(醋炙)细粉及淀粉适量,混匀,制粒,干燥,加入人工麝香、苏合香及冰片细粉,混匀,压片制成1000片,包薄膜衣,即得。
本发明的有益效果包括但不限于:
本发明首次报导了麝香心痛宁在治疗缺血性脑卒中的应用。动物实验结果表明,麝香心痛宁片给药,可以大大减小脑梗死病灶的面积,抑制神经元细胞的坏死,而且,与模型组相比,麝香心痛宁组新物体偏好指数明显升高(P<0.05)说明麝香心痛宁片可以显著改善MCAO大鼠神经行为和认知水平。
通过对麝香心痛宁组方合理性研究,表明其全方具有治疗缺血性脑卒中的作用是君药、臣药、佐使药共同作用的结果,为麝香心痛宁在制备治疗缺血性脑卒中药物中的应用提供了研究基础。
附图说明
此处所说明的附图用来提供对本发明的进一步理解,构成本发明的一部分,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。在附图中:
图1为麝香心痛宁对MCAO大鼠脑梗塞灶面积的影响;
图2为麝香心痛宁片对MCAO大鼠神经元坏死的影响;
图3、图4分别为图1和图2的彩色视图。
具体实施方式
为能清楚说明本方案的技术特点,下面通过具体实施方式,结合附图,对本发明进行详细阐述。本发明的范围并不限于下述实施例。本领域的专业人员能够理解,在不背离本发明的精神和范围的前提下,可以对本发明进行各种变化和修饰。
本发明麝香心痛宁片治疗缺血性脑卒中的应用实验
一、材料
1.1实验动物
SPF级雄性SD大鼠,280g±20g,购于北京维通利华实验动物技术有限公司,实验动物许可证号SCXK(京)2016-0011。
1.2主要仪器
IVC独立通气笼具系统(BCR-RI01-25-C12/PSU型,山东新华医疗器械股份有限公司),多通道小动物麻醉机(R550IE型,深圳瑞沃德生命科技有限公司),Morris水迷宫(深圳瑞沃德生命科技有限公司),十字高架(63009,深圳瑞沃德生命科技有限公司),新物体识别(63008,深圳瑞沃德生命科技有限公司)。
1.3主要药品与试剂
栓线(2838/A4,北京西浓科技有限公司),异氟烷(深圳瑞沃德生命科技有限公司,批号:20220101),麝香心痛宁(山东宏济堂制药集团股份有限公司,批号:2102001)。
1.4产品制法
【成分】延胡索(醋炙)、人工麝香、苏合香、川芎、人参、冰片
【制法】以上六味,人工麝香加等量淀粉混合研细;苏合香加微粉硅胶12g,混合研细;冰片研细。延胡索(醋炙)80g粉碎成细粉;其余延胡索(醋炙)159g、人参、川芎加60%乙醇回流提取三次,每次加6倍量,回流2小时,合并提取液,滤过,滤液回收乙醇并浓缩至相对密度1.30-1.32(60℃)的稠膏,加入延胡索(醋炙)细粉及淀粉适量,混匀,制粒,干燥,加入人工麝香、苏合香及冰片细粉,混匀,压片制成1000片,包薄膜衣,即得。
二、MCAO模型建立
大鼠用异氟烷进行麻醉,颈部备皮、消毒,颈部正中作2cm纵行切口,钝性分离颈部肌肉,暴露并分离右侧颈总动脉(common carotid artery,CCA)、颈内动脉(internalcarotid artery,ICA)、颈外动脉(external carotid artery,ECA)及迷走神经,于CCA远心端和近心端处挂线备用,动脉夹夹闭CCA远心端,CCA近心端结扎,于距CCA分叉部4~5mm处剪一0.2mm的“V”字型切口,将栓线经切口缓慢插入CCA,将栓线沿着ICA缓缓送入大脑中动脉近端,以栓线上特制的黑色标记点刚好到达ICA与ECA分叉处、且进线遇阻力时停止进线;结扎CCA远心端将栓线固定以防其滑脱,剪掉血管外多余栓线,缝合肌肉、皮肤;假手术组只给予剥离血管。
三、药理研究方法
3.1动物分组、给药及处理
动物造模清醒30min后行为学评分,随机分组分为模型组、麝香心痛宁组,每组8只,24h后用药。麝香心痛宁灌胃0.135g/kg.d生药量,5%吐温80稀释。另取8只作为假手术组。模型组及假手术组给予生理盐水灌胃。用药三周后再次行为学评分,模型组、麝香心痛宁组、假手术组随机选取6只心脏灌注后取脑。
3.2行为学检测
每组每周按照改良mNSS神经功能缺损评分标准进行评分,且第一周末进行十字高架迷宫检测大鼠短期记忆,第二周末再次进行十字高架迷宫检测,隔天进行新物体识别实验检测大鼠学习记忆能力,第三周开始连续五天进行Morris水迷宫检测大鼠空间记忆能力。
3.3TTC染色
大鼠取脑后-80℃冰冻约2h,从额极开始切取4张冠状脑片,厚约1.5mm,置于2%TTC溶液中,37℃避光孵育30min。缺血区被染成白色,非缺血区被染成红色。
3.4脑神经元坏死率
常规5μm冠状切片,二甲苯脱蜡,梯度酒精至水洗,苏木素染色,浓氨水洗返蓝,伊红染色,中性树胶封片。以细胞核出现浓染、固缩、碎裂为阳性细胞,高倍镜下(40×)观察大鼠脑皮质及缺血侧海马CA1区。
四、药理研究结果
4.1麝香心痛宁片对MCAO大鼠脑梗塞灶、神经元坏死的影响
结果如图1所示,由图1可知,模型组小鼠较假手术组具有较大面积脑梗死病灶,海马区和皮质区存在大量坏死神经元细胞,麝香心痛宁片给药可以大大减小脑梗死病灶的面积,抑制神经元细胞的坏死。
4.2麝香心痛宁片对MCAO大鼠神经行为学评分、新异物识别的影响
结合下表1和图2,与假手术组比较,模型组神经行为学评分明显升高(P<0.01),与模型组相比,麝香心痛宁组神经行为学评分明显降低(P<0.01);与假手术组相比,模型组新物体偏好指数明显降低(P<0.05),与模型组相比,麝香心痛宁组新物体偏好指数明显升高(P<0.05)。由此说明,麝香心痛宁片可以显著改善MCAO大鼠神经行为和认知功能。
表1麝香心痛宁片对MCAO大鼠神经行为学评分、新异物识别的影响
注:a与假手术组相比,P<0.01,b与模型组相比,P<0.01;#与假手术组相比,P<0.05,*与模型组相比,P<0.05。
4.3麝香心痛宁片对MCAO大鼠十字高架的影响
十字高架:与假手术组相比,模型组开壁时间百分比明显降低(P<0.05),与模型组相比,麝香心痛宁组开壁时间百分比明显升高(p<0.01)。说明:麝香心痛宁片可以显著改善MACO大鼠的焦虑状态。结果如下表2。
表2麝香心痛宁片对MCAO大鼠十字高架的影响
注:a与假手术组相比,P<0.05,b与模型组相比,P<0.01。
4.4麝香心痛宁片对MCAO大鼠水迷宫的影响
水迷宫:与假手术组比较,模型组平台所在时间百分比明显降低(P<0.01),与模型组比较,麝香心痛宁组平台所在时间百分比明显增高(P<0.05);与假手术组比较,模型组穿越平台次数明显降低(P<0.01),与模型组比较,麝香心痛宁组穿越平台次数明显升高(P<0.01)。说明:麝香心痛宁片可以显著改善MACO大鼠的认知水平。结果如下表3。
表3麝香心痛宁片对MCAO大鼠水迷宫的影响
注:a与假手术组相比,P<0.01,b与模型组相比,P<0.05;#与假手术组相比,P<0.01,*与模型组相比,P<0.01。
五、组方合理性研究:
将麝香心痛宁片处方拆为君药组(麝香、延胡索),臣药组(苏合香、川芎),佐使药组(冰片,人参),君药组+臣药组(麝香、延胡索、苏合香、川芎)、君药组+佐使药组(麝香、延胡索、冰片,人参)、臣药组+佐使药组(苏合香、川芎、冰片,人参),按照原处方工艺制成片剂。制作MCAO大鼠模型,观察各组对大鼠神经行为学评分、新异物识别的影响。结果如下表4。
与假手术组比较,模型组神经行为学评分明显升高(P<0.01),与模型组相比,君药组、臣药组、佐使药组神经行为学评分无显著差异;与假手术组相比,模型组新物体偏好指数明显降低(P<0.05),与模型组相比,君药组、臣药组、佐使药组新物体偏好指数无显著变化。说明:麝香心痛宁片全方具有治疗缺血性脑卒中的作用是君药、臣药、佐使药共同作用的结果。
表4君药组、臣药组、佐使药组对MACO大鼠神经行为学评分、新异物识别的影响
注:a与假手术组相比,P<0.01;#与假手术组相比,P<0.05。
为考察每一味药物在处方中的作用,制备麝香阴性样品(处方中除无麝香,其余与麝香心痛宁片相同),延胡索阴性样(处方中除无延胡索,其余与麝香心痛宁片相同),苏合香阴性样品(处方中除无苏合香,其余与麝香心痛宁片相同),川芎阴性样(处方中除无川芎,其余与麝香心痛宁片相同),人参阴性样品(处方中除无人参,其余与麝香心痛宁片相同),冰片阴性样品(处方中除无冰片,其余与麝香心痛宁片相同)。制作MCAO大鼠模型,观察各组对大鼠神经行为学评分、新异物识别的影响。结果如下表5。
表5以上试验药组对MACO大鼠神经行为学评分、新异物识别的影响
注:a与假手术组相比,P<0.01;#与假手术组相比,P<0.05;b与模型组比,P<0.01;*与模型组对比,P<0.05。
由表5可以看出,与假手术组比较,模型组神经行为学评分明显升高(P<0.01);与模型组相比,麝香阴性组、延胡索阴性组、苏合香阴性组、川芎阴性组、人参阴性组、冰片阴性组神经行为学评分均显示出一定程度升高;与假手术组相比,模型组新物体偏好指数明显降低(P<0.05);与模型组相比,麝香阴性组、延胡索阴性组、苏合香阴性组、川芎阴性组、人参阴性组、冰片阴性组新物体偏好指数均发生较为明显变化。由此说明:麝香心痛宁片全方具有治疗缺血性脑卒中的作用是各原料药共同作用的结果,缺一不可。
以上所述,仅为本申请的实施例而已,本申请的保护范围并不受这些具体实施例的限制,而是由本申请的权利要求书来确定。对于本领域技术人员来说,本申请可以有各种更改和变化。凡在本申请的技术思想和原理之内所作的任何修改、等同替换、改进等,均应包含在本申请的保护范围之内。
Claims (3)
1.麝香心痛宁在制备治疗脑卒中药物中的应用。
2.根据权利要求1所述的应用,其特征在于,脑卒中为缺血性脑卒中。
3.根据权利要求1所述的应用,其特征在于,所述药物为药学上可接受的任意剂型,包括片剂、胶囊剂、注射剂、颗粒剂、混悬剂和溶液剂中的至少一种。
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