CN112716948A - 二氢小檗碱在制备治疗溃疡性结肠炎的药物中的应用 - Google Patents
二氢小檗碱在制备治疗溃疡性结肠炎的药物中的应用 Download PDFInfo
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Abstract
Description
技术领域
本发明属于医药领域,特别涉及二氢小檗碱在制备治疗溃疡性结肠炎的药物中的应用。
背景技术
溃疡性结肠炎(Ulcerative colitis,UC)属于炎症性肠病(Inflammatory BowelDisease,IBD)的一种亚型,是一种慢性难治性的炎症性疾病,临床表现为腹痛、腹泻、便血、体重减轻。此外,这种顽固性胃肠道疾病严重损害健康和生活质量,并在IBD患者中形成结直肠癌的高风险。流行病学报告显示,UC的发病率和患病率随着时间的推移在全球范围内不断增加,尤其是在发展中国家。由于UC病程迁延不愈,反复无常,不但给患者造成精神和肉体上的痛苦,而且给家庭和社会带来沉重的经济负担。UC的发病机制尚不十分明确,可能与炎症、免疫功能紊乱、肠黏膜损伤、肠道微生物群失调和遗传易感性等因素有关。目前对溃疡性结肠炎尚无特效药物,已被世界卫生组织列为现代难治性疾病之一。
目前临床治疗溃疡性结肠炎的药物主要有以下5种:氨基水杨酸类(如柳氮磺胺砒啶)、皮质类固醇类、免疫抑制类药物(如硫唑嘌呤)、生物制剂(如TNF-α)及益生菌。这些药物虽能缓解一定症状,但存在副作用显著、易复发、耐药、价格昂贵等问题,阻碍了其临床应用。因此,探究治疗UC的有效、安全新药及其效应机制已成为临床研究的热点,而天然化合物具有靶点多、副作用少等特点,具有广泛应用于治疗溃疡性结肠炎的突出潜力。
传统中药黄连为中医治疗湿热痢疾要药,具有“清热解毒,燥湿止痢”的功效,长于入中焦与大肠以治泻痢。小檗碱为黄连的主要活性成分,广泛用作治疗肠道感染、腹泻和痢疾的非处方药。小檗碱因其具有抗炎、抗氧化、抗结肠炎、抗菌、降血脂等多种生物活性而日益受到人们的关注。然而,由于其生物利用度低、溶解性差、肠上皮吸收困难,阻碍了小檗碱在治疗溃疡性结肠炎中的应用。
因此,针对小檗碱所存在的缺陷和不足,希望研究和开发出一种对治疗溃疡性结肠炎更有效的药物。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此,本发明提出一种二氢小檗碱在制备治疗溃疡性结肠炎的药物中的应用,本发明指出二氢小檗碱可显著改善溃疡性结肠炎小鼠的一般症状,改善病理变化,减少髓过氧化物酶活力,抑制促炎细胞因子的含量,增加结肠紧密连接蛋白的表达,从而提高肠黏膜屏障功能,治疗溃疡性结肠炎效果显著。
二氢小檗碱在制备治疗溃疡性结肠炎的药物中的应用,所述二氢小檗碱的结构式为式(Ⅰ):
二氢小檗碱的分子式为C20H19NO4,分子量为337.37。本发明的研究结果显示,二氢小檗碱具有治疗溃疡性结肠炎作用,其机制与其降低结肠组织中髓过氧化氢酶(MPO)活力及促炎细胞因子的水平,增加结肠组织中紧密连接蛋白的表达,从而改善肠黏膜屏障功能相关,并具有良好的肠道吸收率。二氢小檗碱的这种作用可以用于制备治疗溃荡性结肠炎的药物,特别是以腹痛、持续性腹泻、血便、发热、腹胀为主要临床表现的溃疡性结肠炎。
一种治疗溃疡性结肠炎的药物,以二氢小檗碱作为活性成分,还包括药学上可接受的辅料。
优选的,所述药学上可接受的辅料包括溶剂、填充剂、润滑剂、崩解剂、缓冲剂、助溶剂、抗氧剂、抑菌剂、乳化剂、粘合剂或助悬剂中的至少一种。
优选的,所述药物的制剂形式为片剂、颗粒剂、胶囊剂、滴丸、栓剂或口服液。
优选的,所述药物的给药方式为口服或直肠给药。
实验表明,二氢小檗碱能有效改善实验性溃疡性结肠炎小鼠的包括体重下降、腹泻、血便和精神状态等多方面的一般状态,明显改善病理变化、显著减轻炎症反应、降低结肠组织中促炎细胞因子的水平,增加紧密连接蛋白含量,提高肠黏膜屏障功能,显示出二氢小檗碱具有明显的抗溃疡性结肠炎作用,且其抗溃疡性结肠炎作用显著优于小檗碱。
相对于现有技术,本发明的有益效果如下:
(1)与现有的治疗溃疡性结肠炎的药物相比,二氢小檗碱保护肠道粘膜的机制有所不同,具备良好的治疗效果,也为治疗溃疡性结肠炎提供了一种新的药物选择;
(2)二氢小檗碱抗溃疡性结肠炎的优点在于作用迅速、疗效确切且药效良好。二氢小檗碱为黄连中天然来源的单体成分,在实验过程中未见明显副作用及毒性反应,揭示二氢小檗碱是一种高效、安全的抗溃疡性结肠炎药物。因此,从安全角度二氢小檗碱的每日施用剂量不受严格的限制,使用时可根据临床实际情况进行调整,保证了二氢小檗碱的疗效,具有很好的推广应用前景。
附图说明
图1表示二氢小檗碱对DSS诱导的溃疡性结肠炎小鼠症状的影响;(A)实验设计示意图;(B)小鼠临床症状;(C)每日体重变化;(D)DAI评分;其中##为与CON组比较P<0.01,*为与DSS组比较P<0.05,**为与DSS组比较P<0.01,&为与BBR组比较P<0.05。
图2表示二氢小檗碱对DSS诱导的溃疡性结肠炎小鼠结肠长度和重量的影响;(A)小鼠结肠长度差异的条形图;(B)小鼠结肠重量变化条形图;其中##为与CON组比较P<0.01,*为与DSS组比较P<0.05,**为与DSS组比较P<0.01。
图3表示二氢小檗碱对DSS诱导的溃疡性结肠炎小鼠结肠组织病理学损伤的影响;(A)病变典型显微照片(放大200倍,箭头为炎症细胞浸润);(B)组织学评分;其中##为与CON组比较P<0.01,*为与DSS组比较P<0.05,**为与DSS组比较P<0.01,&为与BBR组比较P<0.05。
图4表示二氢小檗碱对DSS诱导的溃疡性结肠炎小鼠结肠组织中髓过氧化酶(Myeloperoxidase,MPO)的影响;其中##为与CON组比较P<0.01,*为与DSS组比较P<0.05。
图5表示二氢小檗碱对DSS诱导的溃疡性结肠炎小鼠结肠组织中促炎性细胞因子水平的影响;(A)TNF-α、(B)IL-6、(C)IL-1β、(D)IL-17、(E)IFN-γ;其中##为与CON组比较P<0.01,*为与DSS组比较P<0.05,**为与DSS组比较P<0.01。
图6表示二氢小檗碱对DSS诱导的溃疡性结肠炎小鼠结肠组织中紧密连接蛋白(ZO-1、ZO-2、Occludin、JAM-A和Claudin-1)表达的影响。其中##为与CON组比较P<0.01,*为与DSS组比较P<0.05,**为与DSS组比较P<0.01,&为与BBR组比较P<0.05。
以上各图中CON为正常组,DSS为模型组,DHBB为二氢小檗碱组,BBR为小檗碱组。
具体实施方式
为了让本领域技术人员更加清楚明白本发明所述技术方案,现列举以下实施例进行说明。需要指出的是,以下实施例仅为本发明的优选实施例,对本发明要求的保护范围不构成限制作用,任何未违背本发明的精神实质和原理下所做出的修改、替代、组合,均包含在本发明的保护范围内。
以下实施例中所用的原料、试剂或装置如无特殊说明,均可从常规商业途径得到,或者可以通过现有已知方法得到。
实验动物及药品:6-8周SPF级雄性Balb/C小鼠(20-23g),购于广东省医学实验动物中心;许可证号:SYXK(YUE)2013-0034。实验期间,动物的饲养条件为:温度:22±2℃,相对湿度:50±10%,每天12小时光照和12小时黑夜的环境中适应性饲养7天。期间,小鼠喂以标准小鼠饲料并可自由饮水。
供试药品:二氢小檗碱购于成都植标化纯生物技术有限公司。硫唑嘌呤购于AspenPharmacare Australia Pty Ltd.(Leonards,New South Wales,Australia)。葡聚糖硫酸钠(DSS,MW:36000-50000)购于美国MP Biomedicals公司。
实验分组:实验开始前,记录BALB/c小鼠称重,并按体重随机分组为6组:正常组(CON),模型组(DSS),硫唑嘌呤组(AZA,13mg/kg),二氢小檗碱低剂量组(12.5mg/kg),二氢小檗碱中剂量组(25mg/kg),二氢小檗碱高剂量组(50mg/kg),小檗碱组(BBR,50mg/kg),每组10只小鼠。
溃疡性结肠炎造模的建立:BALB/c小鼠自由饮用3%DSS水溶液8天,诱导溃疡性结肠炎模型。模型建立的同时,各组小鼠给予相应的药物进行治疗,其中正常组、模型组则给予治疗药物的相应溶剂(0.5%CMC-Na水溶液)。持续给药8天。第9天,所有小鼠颈椎脱臼致死。
效果实施例1:小鼠疾病活动指数(Disease activity index,DAI)评分
实验方法:
实验过程中,每天观察记录小鼠体重变化、活动状况、粪便性状、血便情况。DAI评分按照以下标准进行:
体重变化评分:下降小于1%,0分;下降1-5%,1分;下降5-10%,2分;下降10-15%,3分;下降大于15%,4分。
大便性状评分:正常,0分;粪便较软,1分;粪便湿软,2分;半稀便,3分;稀便,4分。
便潜血评分:无血便,0分;便血检测阳性+,1分;便血检测阳性++,2分;便血检测阳性+++,3分;明显血便,4分。
DAI=(体重下降分数+大便性状分数+血便分数)/3。
实验结果:如图1所示,在整个试验周期内,正常小鼠摄食饮水正常,毛发干净有光泽;动作灵敏、活跃,体重保持稳定趋势。给予DSS造模后,模型组小鼠毛发稀疏、竖起、无光泽,小鼠常静卧蜷缩,小鼠血便情况严重,体重下降明显,DAI评分显著增加。而二氢小檗碱组(12.5、25和50mg/kg)、小檗碱组(50mg/kg)和阳性药硫唑嘌呤组(13mg/kg)等各给药处理组均可明显改善DSS诱导的小鼠体重下降和便血情况,并显著减低DAI评分,且二氢小檗碱减低体重下降和DAI评分效果显著优于小檗碱(P<0.05)。
实验结论:二氢小檗碱可显著改善DSS诱导的溃疡性结肠炎小鼠模型小鼠体重下降,降低DAI评分。
效果实施例2:实验小鼠的结肠观察
实验方法:
实验第9天,将小鼠颈椎脱白处死,剖取结肠,然后测量结肠长度并拍照比较。
实验结果:如图2所示,与正常组相比,模型组小鼠结肠显著缩短;而给予二氢小檗碱(12.5、25和50mg/kg)治疗后情况有明显改善,小鼠结肠长度均较模型组显著增长。
实验结论:二氢小檗碱可显著增加DSS诱导的溃疡性结肠炎小鼠的结肠长度,具有抗溃疡性结肠炎的作用。
效果实施例3:实验小鼠结肠H&E染色观察
实验方法:
实验第9天处死小鼠,剖取结肠。每只小鼠取1cm左右的结肠置于4%多聚甲醛中固定、石蜡包埋,用于H&E染色。
H&E染色:脱蜡(二甲苯I 20min-二甲苯II 20min-无水乙醇I 5min-无水乙醇II5min-75%乙醇5min-蒸馏水洗);苏木素染3-5min;流水冲洗苏木素液,切片依次入85%、95%的梯度乙醇脱水各5min,伊红染5min,蒸馏水稍洗;脱水封片(无水乙醇I 5min-无水乙醇II 5min-无水乙醇Ⅲ5min-二甲苯I 5min-二甲苯II 5min,中性树胶封片);显微镜观察,拍照。
实验结果:如图3所示,与正常组相比,DSS诱导的结肠炎黏膜结构破坏严重,其特征包括上皮损伤严重、杯状细胞减少、隐窝或肠腺基本消失、黏膜下层或肌层水肿严重、黏膜下层炎症细胞浸润明显,导致较高的组织病理学评分。然而,与模型组相比,二氢小檗碱(12.5、25和50mg/kg)处理组以剂量依赖方式显著恢复隐窝结构并减少结肠黏膜上皮坏死,改善黏膜下层水肿程度,并减少炎性细胞浸润。
效果实施例4:实验小鼠结肠MPO活性的测定
实验方法:
实验第9天,将小鼠颈椎脱白处死,迅速取出结肠,并在预冷的PBS溶液中彻底清洗结肠,然后放在-80℃冰箱中待用。取出储存在中的结肠组织,按重量体积比为1:19加入MPO试剂盒中的相关试剂,制备成5%的组织匀浆液,继而严格按照试剂盒说明书操作计算MPO活力。
实验结果:溃疡性结肠炎小鼠结肠组织中MPO的活性越大,说明中性粒细胞的浸润越多,组织损伤的越严重。如图4所示,结肠组织中MPO活性与正常组相比,模型组MPO活性显著增加;而二氢小檗碱(12.5、25和50mg/kg)处理组以剂量依赖方式显著降低MPO活性。
效果实施例5:ELISA测定结肠组织的炎症细胞因子(TNF-α、IL-6、IL-1β、IL-17、IFN-γ)
实验方法:
取出储存在-80℃中的结肠组织,按重量体积比为1:9加入预冷的PBS溶液,匀浆,3500g,4℃离心15min后,取上清液,严格按照ELISA试剂盒说明书操作,分别测定炎症因子TNF-α、IL-6、IL-1β、IL-17和IFN-γ的含量。
实验结果:如图5所示,相较于正常对照组,DSS诱导的结肠炎模型组小鼠结肠组织中促炎细胞因子(TNF-α、IL-1β、IL-6、IL-17和IFN-γ)显著升高(P<0.05)。然而,与模型组相比,二氢小檗碱(50mg/kg)处理组显著减少上述5种抗炎细胞因子的水平(P<0.05),表明二氢小檗碱可通过有效抑制DSS诱导的溃疡性结肠炎小鼠炎症蛋白水平来改善溃疡性结肠炎症状。
效果实施例6:Western blot分析结肠组织的紧密连接蛋白(ZO-1、ZO-2、Claudin-1、JAM-A、Occludin)
实验方法:
组织总蛋白的提取:取出储存在-80℃中的结肠组织,按100mg:1mL比例加入裂解液(RIPA裂解液:Cocktail:PMSF:磷酸酶抑制剂A:磷酸酶抑制剂B=100:2:1:1:1),冰上匀浆,冰上孵育20min(期间偶尔涡旋);14000g,4℃离心10min后,取上清于1.5mL EP管中,并用BCA试剂盒,测定相应蛋白浓度。
提取的蛋白上清液以1:4加入5x loading buffer后,100℃变性5min,分装保存于-80℃。
制备8%或10%聚丙烯酰胺分凝胶(SDS-PAGE)和5%浓缩胶,待浓缩胶聚合完全后,加满电泳缓冲液。用微量进样器上样等量样品且同时在泳道两侧加marker(5μL)指示蛋白质分子量,80V恒压电泳30min后调120V恒压电泳,待溴酚蓝线泳至距胶边缘处时,停止电泳,切下分离胶所需部分,湿法转膜到PVDF膜上。将膜用5%脱脂奶粉室温封闭1小时,将PVDF膜浸于TBST中,洗膜3次,每次10min。取出PVDF膜,并与下列一种抗体在4℃下孵育过夜:ZO-1(1:500)、ZO-2(1:500)、Claudin-1(1:500)、JAM-A(1:500)、Occludin(1:500)、β-actin(1:2000)在4℃孵育过夜,并与辣根酶标记的二抗(1:2000)室温孵育2小时,使用ECL化学发光液显影蛋白质条带,使用Image J软件分析目的条带灰度值,以β-actin内参,计算目标蛋白的相对表达量。
实验结果:如图6所示,与正常对照组相比,DSS处理的结肠炎模型组小鼠中紧密连接蛋白(ZO-1、ZO-2、Claudin-1、JAM-A和Occludin)的表达显著减少(P<0.05),表明肠黏膜屏障结构被破坏。然而,与DSS诱导的结肠炎模型组相比,二氢小檗碱(50mg/kg)处理组显著增加紧密连接蛋白的含量,显示其可明显改善肠黏膜屏障功能。
以上所有的测试中,数据统计分析方法为,实验结果以均数±标准误表示。采用SPSS17.0软件进行统计学分析,各组间差异比较采用单因素方差分析(One-Way Analysisof ANOVA),若组间方差齐则用LSD分析,若不齐则用Dunnett’s T3分析。P<0.05或P<0.01表示组间差异有统计学意义。
综合所述,二氢小檗碱能有效改善实验性溃疡性结肠炎小鼠的包括体重下降、腹泻、血便和精神状态等多方面的一般状态,明显改善病理变化、显著减轻炎症反应、降低结肠组织中促炎细胞因子的水平,增加紧密连接蛋白含量,提高肠黏膜屏障功能,显示出二氢小檗碱具有明显的抗溃疡性结肠炎作用,且其抗溃疡性结肠炎作用显著优于小檗碱。
药物制备例1:片剂
取二氢小檗碱500g,加入乳糖480g、淀粉754g混合均匀,用7%的淀粉浆350g作为粘合剂,湿法制粒,烘干,加入硬脂酸镁16g混匀,压制成每片含二氢小檗碱50mg的片剂10000片,每片净重0.21g。口服,用于治疗溃疡性结肠炎。症见:腹痛、腹泻、便血、体重减轻等。
药物制备例2:胶囊剂
取二氢小檗碱500g,加入乳糖980g、淀粉1254g混合均匀,用7%的淀粉浆350g作为粘合剂,湿法制粒,烘干,加入硬脂酸镁16g混匀,填充至1号胶囊制成10000粒,每粒胶囊内含二氢小檗碱50mg,每粒净重0.31g。口服,用于治疗溃疡性结肠炎。症见:腹痛、腹泻、便血、体重减轻等。
药物制备例3:颗粒剂
称取100g二氢小檗碱加入到适量β-环糊精中制成包合物,加入适量蔗糖粉、微晶纤维素、淀粉浆,混合均匀,逐渐加入乙醇和水,制成颗粒,进行分装。规格为每包含二氢小檗碱50mg的颗粒剂,每包净重7g。开水冲服,口服,用于治疗溃疡性结肠炎。症见:腹痛、腹泻、便血、体重减轻等。
药物制备例4:滴丸
取二氢小檗碱300g,加入适量硬脂酸钠作为基质,适量液体石蜡为冷却剂;滴制法制成含有每丸含二氢小檗碱6mg的滴丸,每丸净重30mg。口服,用于治疗溃疡性结肠炎。症见:腹痛、腹泻、便血、体重减轻等。
药物制备例5:栓剂
取二氢小檗碱100g,加入可可豆脂等辅料,配置成含二氢小檗碱50mg的栓剂。直肠给药,用于治疗溃疡性结肠炎。症见:腹痛、腹泻、便血、体重减轻等。
药物制备例5:口服液
称取100g二氢小檗碱,加入增溶剂泊洛沙姆,和一定比例的乙醇,充分搅匀;然后加入蔗糖、山梨酸钾等适宜附加剂(如矫味剂、抑菌剂、抗氧化剂、着色剂),溶解均匀,滤过澄清,将内容物装入口服液玻璃瓶中,灭菌。规格为每瓶含二氢小檗碱50mg的口服液,每瓶净含量10mL。口服,用于治疗溃疡性结肠炎。症见:腹痛、腹泻、便血、体重减轻等。
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