CN114762688B - 一种含有西洛他唑的组合物在脑血管病中的应用 - Google Patents
一种含有西洛他唑的组合物在脑血管病中的应用 Download PDFInfo
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Abstract
本说明涉及一种含有西洛他唑或其在药学上可接受的盐和右旋莰醇的组合物,在制备治疗脑血管病,特别是缺血性脑血管病的药物中的应用。
Description
技术领域
本发明属于制药领域,涉及西洛他唑和右旋莰醇组合物在制备治疗脑血管病,特别是缺血性脑血管病药物中的应用。
背景技术
脑血管疾病(cerebrovascular disease, CVD)是指由于各种脑血管病变所引起的脑部病变,按其发病进程可分为急性脑血管病(中风)和慢性脑血管病两种。急性脑血管病包括短暂性脑缺血发作、脑血栓形成、脑栓塞、高血压脑病、脑出血和蛛网膜下腔出血等;慢性脑血管病包括脑动脉硬化、脑血管病性痴呆、脑动脉盗血综合症、帕金森氏病等。缺血性脑卒中(Stroke)是指由于脑的供血动脉(颈动脉和椎动脉)狭窄或闭塞、脑供血不足导致的脑组织坏死的总称。脑缺血包括四种类型,分比为短暂性脑缺血发作(TIA)、可逆性神经功能障碍(RIND)、进展性卒中(SIE)和完全性卒中(CS)。TIA无脑梗死存在,而RIND、SIE和CS有不同程度的脑梗死存在。
西洛他唑(vinpocetine)为抗血小板聚集药,最早由日本大冢制药有限公司研制合成,并于1988年在日本上市,1999年5月在美国获得FDA批准,1996年进入我国。西洛他唑是一种选择性磷酸二脂酶3抑制剂(Phosphodiesterase 3,PDE3),西洛他唑与血浆蛋白的结合率约为 95%,而且大多是以比较稳定的原型存在。西洛他唑具有广谱的药理学活性,对于很多疾病,如外周血栓疾病和间歇性跛行等都有临床价值。而且西洛他唑具有抗血小板、舒张血管的功能,从而可以起到防止循环性休克和冠状动脉狭窄再发生的作用。研究表明PDE3 可以抑制循环***内 cAMP 的降解,并增加血小板和血管平滑肌中的 cAMP,对血小板的形成有抑制作用并且有促进血管平滑肌细胞增生的作用。西洛他唑主要通过影响下列各种因素抑制血小板降解:花生四烯酸、二磷酸腺苷、肾上腺素、胶原蛋白、纤维蛋白酶。现在已经有专家认为可以对颈动脉血栓的患者建议行西洛他唑治疗,可以治疗或预防脑缺血。同时 PDE3 可以抑制一氧化氮合成酶(NOS)的生成,从而减少一氧化氮(NO)的产生。
西洛他唑的结构式如下:
(分子式C20H27N5O2;分子量369.47)
天然冰片的主要成分在2015版中国药典中规定天然冰片中右旋莰醇含量不低于96%。右旋莰醇是一种双环单萜类化合物,存在于许多中草药的挥发油中,表现出多种生物活性,如抗炎、抗氧化以及增强GABA受体功能等(Euro J Pharma 2017,811:1-11)。冰片已被美国FDA批准用于食品调味剂或佐剂(21 CFR 172.515)。冰片也是一种用于治疗多种疾病的口服佐剂,成年人天然冰片的推荐口服剂量为0.3–0.9 g/d(中国药典,2015版)。此外,醒脑静注射液(其中含冰片约1 mg/mL,***药品标准中药成方制剂第十七册)临床静脉滴注给药方式为10-20 mL用5%~10%葡萄糖注射液或氯化钠注射液250~500 mL稀释后滴注,由此推算单次静脉滴注冰片用量为10-20 mg。冰片也是冰硼散中重要成分,其含量不低于30 mg/g(3%)(中国药典,2015版)。
本专利发明人发现,大鼠局灶性脑缺血再灌损伤模型尾静脉给予1~18 mg/kg西洛他唑或0.27~5 mg/kg右旋莰醇能够显著改善MCAO大鼠神经功能缺陷和减少脑梗死面积;并且在上述剂量范围内进行复方组合(西洛他唑:右旋莰醇质量比18:1~1:1)获得了意想不到的协同增效作用。小鼠局灶性脑缺血再灌损伤静脉给予10~19.46 mg/kg西洛他唑或0.54~10 mg/kg右旋莰醇能够显著改善MCAO小鼠神经功能缺陷和减少脑梗死面积。
发明内容
本发明目的是提供一种药物组合物在制备治疗脑血管药物中的应用,所述的药物组合物含有西洛他唑或其药学上可接受的盐和右旋莰醇,更进一步地,此药物组合配合使用能协同性增加治疗脑血管病的药效。
上述药物组合物,其特征在于西洛他唑或其药学上可接受的盐:右旋莰醇重量比100:1~1:1,优选的,重量比50:1~1:1,优选的,重量比36:1~1:1;优选的,重量比25:1~1:1;优选的,重量比18:1~1:1和9:1~1:1。
本发明的药物组合可以应用于制备脑血管的药物。其中,脑血管病优选缺血性脑血管病,进一步优选缺血性脑卒中。
本发明的有益效果是:西洛他唑和右旋莰醇两者配伍,根据动物(大鼠、小鼠)药效试验结果,针对脑血管病,两者具有协同性地增加药效的作用。
具体实施方式
下述实施例举例说明本发明,不应被认为是对本发明的限制。
实施例1 西洛他唑和右旋莰醇组合物对局灶性脑缺血再灌损伤的保护作用研究1
1 材料和方法
1.1 实验动物
Sprague-Dawley(SD)大鼠,雄性,SPF级,体重250-280g。
1.2 受试药品
样品名称 | 厂家 | 批号 |
西洛他唑 | 上海阿拉丁生化科技股份有限公司 | K1405071 |
右旋莰醇 | 江苏欧威医药有限公司 | KC20171205-1-2 |
1.3 实验方法
1.3.1 动物分组与给药
实验动物分为西洛他唑组(1 mg/kg)、右旋莰醇组(1 mg/kg)、西洛他唑与右旋莰醇组合物组(2 mg/kg,西洛他唑:右旋莰醇=1:1,西洛他唑1 mg/kg、右旋莰醇1 mg/kg)及模型组,共4组。制备脑缺血模型后,将动物机率均等单盲分配至各组。动物于再灌注后立即静脉给药1次,模型组动物给于等体积的生理盐水。脑缺血后24小时处死动物,取脑,染色,拍照测定脑梗塞范围。
1.3.2 局灶性脑缺血再灌模型的制备
采用颈内动脉线栓法制备大鼠局灶性脑缺血再灌模型。将处于麻醉状态的大鼠用皮筋束紧四肢(后肢固定膝关节以上,前肢固定腕关节以下)及头部,动物仰卧位固定于手术台上,以动物剃毛器自头端向胸部方向剃毛,酒精消毒皮肤。颈部正中切开,钝性分离皮下组织。分离颈前三角表面的薄层筋膜,拨起低边-锁骨舌骨肌下缘,可见与此肌肉平行的纵行搏动的动脉,打开动脉壳,暴露右侧颈动脉分叉,分离右侧颈总动脉、颈外动脉、颈内动脉,轻轻剥离迷走神经,结扎并剪断颈外动脉。夹闭颈总动脉近心端,从颈外动脉的结扎线的远端作一切口,***栓线,经过颈总动脉分叉进入颈内动脉,然后徐徐***至有轻微阻力为止(自分叉处约20 mm),阻断大脑中动脉的所有血供。以丝线在颈外动脉切口下方稍固定栓线,松开颈总动脉近心端夹闭丝线,将浸有消毒生理盐水的纱布覆盖于创面上,将大鼠放置在保温垫上保温。右侧脑缺血2.0 h后,轻轻拔出栓线,恢复血供进行再灌注,用固定栓线的丝线结扎颈外动脉,缝合皮肤,消毒。将大鼠放置干净饲料中,观察一般情况和呼吸直至麻醉苏醒;加食进水,常规饲养。
1.3.3 脑梗塞范围测定
动物神经缺陷症状评价完毕后以CO2处死,断头取脑,去除嗅球、小脑和低位脑干,用生理盐水冲洗大脑表面血迹,吸去表面残留水迹,于-20 ℃放置20 min,取出后立即于视线交叉平面垂直向下作冠状切面,并向后每隔2 mm切一片,将脑片置于1% TTC染液中孵育(37 ℃ 30min),正常脑组织染成深红色,缺血脑组织则呈苍白色,用生理盐水冲洗后,迅速将脑片从前向后按顺序排成一排,吸干表面残留水迹,拍照。
脑梗死面积的计算:照片用Image J软件处理,根据公式计算左脑相应面积以及右脑非梗死灶面积,求出梗死范围百分比。
梗死体积计算法:
V=t (A1+ A2+ A3+ ………+An)
t为切片厚度,A为梗死面积。
%I=100%×(VC-VL)/VC
%I为梗死体积百分比,VC为对照侧(左脑半球)脑体积,VL为梗死侧(右脑半球)非梗死区域体积。
1.3.4 组合物协同性分析
根据金正均公式q= E(a+b) / (Ea+ Eb- Ea×Eb)评价组合物中西洛他唑与右旋莰醇是否有协同作用。式中E(a+b)为合用药物的有效率,Ea、Eb 分别为A 药(西洛他唑)、B药(右旋莰醇)单独用药的有效率。E给药组=(X模型-X给药)/X模型,X为脑梗塞范围值。若q 值在0.85~1.15 范围内,为两药合用单纯相加, q 值>1.15为协同, q 值<0.85 则表示两药合用有拮抗作用。
1.4 数据统计
实验数据以平均值±标准差(Mean±SD)表示。采用单因素方差分析各组之间差异,组间比较采用LSD法检验,P<0.05定义为差异显著。
2 实验结果
对脑梗塞范围的影响见表1,实验结果表明,右旋莰醇1 mg/kg和组合物(西洛他唑1 mg/kg+右旋莰醇1 mg/kg)给药能够显著减小动物脑梗塞范围(p<0.01,p<0.001),西洛他唑1 mg/kg给药有改善脑缺血损伤的趋势,但无统计学差异(p=0.06)。协同性计算结果q=1.24,表明两药联用具有协同作用。
表1 西洛他唑与右旋莰醇复方用药对脑梗范围的影响
组别 | 动物数 | 脑梗死范围(%) |
模型组 | 11 | 39.73±7.62 |
西洛他唑组 | 10 | 33.78 ± 5.74 |
右旋莰醇组 | 11 | 28.28 ±8.06** |
西洛他唑与右旋莰醇组合物1:1组 | 11 | 20.38±9.47*** |
均值±标准差,**p<0.01,*** p<0.001,与模型组相比
实施例2 西洛他唑和右旋莰醇组合物对局灶性脑缺血再灌损伤的保护作用研究2
1 材料和方法
1.1 实验动物
Sprague-Dawley(SD)大鼠,雄性,SPF级,体重250-280g。
1.2 受试药品
西洛他唑和右旋莰醇同实施例1。
1.3 实验方法
实验动物分为西洛他唑组(9 mg/kg)、右旋莰醇组(1mg/kg)、西洛他唑与右旋莰醇组合物组(10mg/kg,西洛他唑:右旋莰醇=9:1,西洛他唑9 mg/kg +右旋莰醇1 mg/kg)及模型组,共4组。制备脑缺血模型后,将动物机率均等单盲分配至各组。动物于再灌注后立即静脉给药1次,模型组动物给于等体积的生理盐水。脑缺血后24小时处死动物,取脑,染色,拍照测定脑梗塞范围。
局灶性脑缺血再灌模型制备、脑梗塞范围测定、组合物协同性分析及数据统计方法同实施例1。
2 实验结果
对脑梗塞范围的影响见表2,实验结果表明,西洛他唑9 mg/kg、右旋莰醇1 mg/kg和组合物(西洛他唑9 mg/kg+右旋莰醇1 mg/kg)给药能够显著减小动物脑梗塞范围(p=0.024,p=0.017,p=0.000)。协同性计算结果q=1.5,表明两药联用具有协同作用。
表2 西洛他唑与右旋莰醇复方用药对脑梗范围的影响
组别 | 动物数 | 脑梗死范围(%) |
模型组 | 11 | 38.25±7.87 |
西洛他唑组 | 11 | 30.00 ± 8.43* |
右旋莰醇组 | 12 | 28.62±9.87* |
西洛他唑与右旋莰醇组合物9:1组 | 12 | 14.64±5.52*** |
均值±标准差,**p<0.05,*** p<0.001,与模型组相比
实施例3 西洛他唑和右旋莰醇组合物对局灶性脑缺血再灌损伤的保护作用研究3
1 材料和方法
1.1 实验动物
Sprague-Dawley(SD)大鼠,雄性,SPF级,体重250-280g。
1.2 受试药品
西洛他唑和右旋莰醇同实施例1。
1.3 实验方法
实验动物分为西洛他唑组(18mg/kg)、右旋莰醇组(1mg/kg)、西洛他唑与右旋莰醇组合物组(19mg/kg,西洛他唑:右旋莰醇=18:1,西洛他唑18 mg/kg +右旋莰醇1 mg/kg)及模型组,共4组。制备脑缺血模型后,将动物机率均等单盲分配至各组。动物于再灌注后立即静脉给药1次,模型组动物给于等体积的生理盐水。脑缺血后24小时处死动物,取脑,染色,拍照测定脑梗塞范围。
局灶性脑缺血再灌模型制备、脑梗塞范围测定、组合物协同性分析及数据统计方法同实施例1。
2 实验结果
对脑梗塞范围的影响见表3,实验结果表明,西洛他唑18 mg/kg、右旋莰醇1 mg/kg和组合物(西洛他唑18 mg/kg+右旋莰醇1 mg/kg)给药能够显著减小动物脑梗塞范围(p=0.001,p=0.002,p=0.000)。协同性计算结果q=1.24,表明两药联用具有协同作用。
表3 西洛他唑与右旋莰醇复方用药对脑梗范围的影响
组别 | 动物数 | 脑梗死范围(%) |
模型组 | 11 | 40.32±7.65 |
西洛他唑组 | 12 | 27.84 ± 7.50** |
右旋莰醇组 | 11 | 29.97±7.02** |
西洛他唑与右旋莰醇组合物18:1组 | 12 | 15.92±7.37*** |
均值±标准差,**p<0.01,*** p<0.001,与模型组相比
实施例4 西洛他唑/右旋莰醇(1:1,3:1,9:1)对局灶性脑缺血再灌损伤的作用
1 材料和方法
1.1 实验动物
Sprague-Dawley(SD)大鼠,雄性,SPF级,体重250-280g。
1.2 受试药品
西洛他唑和右旋莰醇同实施例1。
1.3 实验方法
实验动物分为模型组和西洛他唑/右旋莰醇三个组合物组(分别为1:1组,西洛他唑5 mg/kg +右旋莰醇5 mg/kg;3:1组,西洛他唑7.5 mg/kg +右旋莰醇2.5 mg/kg;9:1组,西洛他唑9 mg/kg +右旋莰醇1 mg/kg。各组合物给药总剂量均为10 mg/kg。),共4组。制备脑缺血模型后,将动物机率均等单盲分配至各组。动物于再灌注后立即静脉给药1次,模型组动物给于等体积的生理盐水。脑缺血后24小时处死动物,取脑,染色,拍照测定脑梗塞范围。
局灶性脑缺血再灌模型制备、脑梗塞范围测定及数据统计方法同实施例1。
2 实验结果
对脑梗塞范围的影响见表4,实验结果表明,西洛他唑/右旋莰醇1:1、3:1和9:1组合给药均能显著减小动物脑梗塞范围(p<0.001)。
表4 西洛他唑/右旋莰醇组合物对脑梗范围的影响
组别 | 动物数 | 脑梗死范围(%) |
模型组 | 13 | 39.23±8.34 |
西洛他唑/右旋莰醇1:1组 | 11 | 22.59 ± 7.12*** |
西洛他唑/右旋莰醇3:1组 | 12 | 23.88±9.50*** |
西洛他唑/右旋莰醇9:1组 | 13 | 17.38±8.39*** |
均值±标准差,*** p<0.001,与模型组相比
实施例5 西洛他唑/右旋莰醇(9:1,18:1,36:1)对局灶性脑缺血再灌损伤的作用
1 材料和方法
1.1 实验动物
Sprague-Dawley(SD)大鼠,雄性,SPF级,体重250-280g。
1.2 受试药品
西洛他唑和右旋莰醇同实施例1。
1.3 实验方法
实验动物分为模型组和西洛他唑/右旋莰醇三个组合物组(分别为9:1组,西洛他唑9mg/kg +右旋莰醇1mg/kg;18:1组,西洛他唑9.47mg/kg +右旋莰醇0.53mg/kg;36:1组,西洛他唑9.73mg/kg +右旋莰醇0.27mg/kg。各组合物给药总剂量均为10mg/kg。),共4组。制备脑缺血模型后,将动物机率均等单盲分配至各组。动物于再灌注后立即静脉给药1次,模型组动物给于等体积的生理盐水。脑缺血后24小时处死动物,取脑,染色,拍照测定脑梗塞范围。
局灶性脑缺血再灌模型制备、脑梗塞范围测定及数据统计方法同实施例1。
2 实验结果
对脑梗塞范围的影响见表5,实验结果表明,西洛他唑/右旋莰醇9:1、18:1和36:1组合给药均能显著减小动物脑梗塞范围(p<0.001)。
表5 西洛他唑/右旋莰醇组合物对脑梗范围的影响
组别 | 动物数 | 脑梗死范围(%) |
模型组 | 13 | 41.08±8.52 |
西洛他唑/右旋莰醇9:1组 | 12 | 18.35 ± 7.86*** |
西洛他唑/右旋莰醇18:1组 | 12 | 23.23±10.97*** |
西洛他唑/右旋莰醇36:1组 | 13 | 23.40±12.11*** |
均值±标准差,*** p<0.001,与模型组相比
实施例6 西洛他唑/右旋莰醇(1:1,3:1,9:1)对小鼠局灶性脑缺血再灌损伤的作用
1 材料和方法
1.1 实验动物
C57BL/6J小鼠,雄性,SPF级,8周龄。
1.2 受试药品
西洛他唑和右旋莰醇同实施例1。
1.3 实验方法
实验动物分为模型组和西洛他唑/右旋莰醇三个组合物组(分别为1:1组,西洛他唑10mg/kg +右旋莰醇10mg/kg;3:1组,西洛他唑15mg/kg +右旋莰醇5mg/kg;9:1组,西洛他唑18mg/kg +右旋莰醇2mg/kg。各组合物给药总剂量均为20mg/kg。),共4组。制备脑缺血模型后,将动物机率均等单盲分配至各组。动物于再灌注后立即静脉给药1次,模型组动物给于等体积的生理盐水。脑缺血后24小时处死动物,取脑,染色,拍照测定脑梗塞范围。
局灶性脑缺血再灌模型的制备:采用颈内动脉线栓法制备小鼠局灶性脑缺血再灌模型。将处于麻醉状态的小鼠仰卧位固定于手术台上。颈部正中切开,钝性分离皮下组织。分离右侧颈总动脉、颈外动脉、颈内动脉。从颈外动脉***栓线,经过颈总动脉分叉进入颈内动脉,然后徐徐***至有轻微阻力为止(自分叉处约10 mm),阻断大脑中动脉的所有血供。右侧脑缺血60min后,轻轻拔出栓线,恢复血供进行再灌注。将小鼠放置干净饲料中,观察一般情况和呼吸直至麻醉苏醒;加食进水,常规饲养。
脑梗塞范围测定及数据统计方法同实施例1。
2 实验结果
对脑梗塞范围的影响见表6,实验结果表明,西洛他唑/右旋莰醇1:1、3:1和9:1组合给药均能显著减小动物脑梗塞范围(p<0.001)。
表6 西洛他唑/右旋莰醇组合物对脑梗范围的影响
组别 | 动物数 | 脑梗死范围(%) |
模型组 | 13 | 36.03±8.29 |
西洛他唑/右旋莰醇1:1组 | 11 | 21.13 ± 10.16*** |
西洛他唑/右旋莰醇3:1组 | 12 | 20.82±10.40*** |
西洛他唑/右旋莰醇9:1组 | 12 | 17.89±8.56*** |
均值±标准差,*** p<0.001,与模型组相比
实施例7 西洛他唑/右旋莰醇(9:1,18:1,36:1)对小鼠局灶性脑缺血再灌损伤的作用
1 材料和方法
1.1 实验动物
C57BL/6J小鼠,雄性,SPF级,8周龄。
1.2 受试药品
西洛他唑和右旋莰醇同实施例1。
1.3 实验方法
实验动物分为模型组和西洛他唑/右旋莰醇三个组合物组(分别为9:1组,西洛他唑18mg/kg +右旋莰醇2mg/kg;18:1组,西洛他唑18.95mg/kg +右旋莰醇1.05mg/kg;36:1组,西洛他唑19.46mg/kg +右旋莰醇0.54mg/kg。各组合物给药总剂量均为20mg/kg。),共4组。制备脑缺血模型后,将动物机率均等单盲分配至各组。动物于再灌注后立即静脉给药1次,模型组动物给于等体积的生理盐水。脑缺血后24小时处死动物,取脑,染色,拍照测定脑梗塞范围。
局灶性脑缺血再灌模型的制备同实施例6,脑梗塞范围测定及数据统计方法同实施例1。
2 实验结果
对脑梗塞范围的影响见表7,实验结果表明,西洛他唑/右旋莰醇9:1、18:1和36:1组合给药均能显著减小动物脑梗塞范围(p<0.001, p<0.001, p<0.01)。
表7 西洛他唑/右旋莰醇组合物对脑梗范围的影响
组别 | 动物数 | 脑梗死范围(%) |
模型组 | 12 | 37.99±8.59 |
西洛他唑/右旋莰醇9:1组 | 12 | 17.97 ± 8.70*** |
西洛他唑/右旋莰醇18:1组 | 13 | 22.56±10.93*** |
西洛他唑/右旋莰醇36:1组 | 12 | 22.49±12.96** |
均值±标准差,** p<0.01,*** p<0.001,与模型组相比。
Claims (1)
1.一种组合物在制备治疗脑血管病药物中的应用,所述组合物含有西洛他唑或其在药学上可接受的盐和右旋莰醇的组合物;
所述西洛他唑或其在药学上可接受的盐和右旋莰醇的重量比为18:1~9:1;
所述脑血管病为缺血性脑卒中。
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