CN116585334A - 芍药新苷在制备治疗炎症性肠病的药物中的应用 - Google Patents
芍药新苷在制备治疗炎症性肠病的药物中的应用 Download PDFInfo
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Abstract
本发明提供了芍药新苷在制备治疗溃疡性结肠炎的药物中的应用。本发明研究发现,芍药新苷作为对溃疡性结肠炎具有治疗作用,并能够显著抑制炎症诱导的结肠上皮细胞焦亡。进一步实验发现,芍药新苷抑制结肠上皮细胞焦亡的具体机制是激活过氧化物酶体增殖剂激活受体γ相关信号通路来实现的。因此,芍药新苷能显著减少DSS诱导的结肠炎动物模型的肠道损伤,是治疗溃疡性结肠炎等炎症性疾病的潜在药物。本发明为炎症性肠病患者的治疗提供了新的用药选择,且药物来源广泛,成分和用量明确,用药安全,无明显副作用。
Description
技术领域
本发明属于中医药技术领域,具体地说是芍药新苷在制备治疗溃疡性结肠炎中的应用。
背景技术
炎症性肠病(Inflammatory bowel disease,IBD)作为一种自身免疫性疾病在全球的发病率仍在上升。溃疡性结肠炎(Ulcerative colitis,UC)是IBD的主要类型之一,是一种慢性复发性炎症性疾病,其特征是黏膜上皮损伤和肠道菌群紊乱。虽然有各种研究报道遗传背景、环境因素和免疫功能障碍是UC的发病原因,但其发生和发展的确切机制尚未完全阐明。此外,UC患者通常在肠外组织中(肝脏、肺、皮肤、眼睛、关节和血管系统)也有不同程度的炎症。并且,UC患者还具有较高的结直肠癌风险(Wei YY,Fan YM,Ga Y,Zhang YN,Han JC,Hao ZH.Shaoyao decoction attenuates DSS-induced ulcerative colitis,macrophage and NLRP3inflammasome activation through the MKP1/NF-κBpathway.Phytomedicine.2021Nov;92:153743.)。
2000年以前,UC的治疗选择仅限于皮质类固醇、氨基水杨酸、硫嘌呤和钙调磷酸酶抑制剂。2000年后,针对肿瘤坏死因子(Tumor necrosis factor,TNF)的生物疗法被用于治疗UC,随后,针对不同生物通路的其他分子也作为治疗UC的靶点而成为临床治疗手段(Harbord M,Eliakim R,Bettenworth D,et al.Third European evidence-basedconsensus on diagnosis and management of ulcerative colitis.Part 2:currentmanagement.J Crohns Colitis 2017;11:769–84.)。在英夫利昔单抗被欧洲药品管理局和美国食品药品管理局批准用于UC。仅仅20年后,三类生物疗法(抗TNF-α、抗整合素和白细胞介素抑制剂[(Interleukin,IL)-12和IL-23])和首批小分子(Janus激酶抑制剂)已被批准用于治疗中重度溃疡性结肠炎。此外,来自这些类别和其他类别的新药物(如鞘氨醇1-磷酸受体1[S1P1]调节剂)将很快进入临床前研究,并获得三期临床试验的阳性数据(Sabino J,Verstockt B,Vermeire S,Ferrante M.New biologics and small molecules ininflammatory bowel disease:an update.Therap Adv Gastroenterol 2019;12:1756284819853208.)。
尽管近年来UC的治疗取得了进展,但治疗UC的药物对部分患者存在无应答是常见的现象,导致大量患者没有可用的治疗方案。因此,开发新的靶点药物是目前研究者关注的关键问题。
UC的发病机制复杂,先天免疫是识别感染和启动病原体清除和组织修复过程的第一道防线,其中发挥关键作用的是NOD样受体热蛋白结构域相关蛋白-3(NOD-likereceptor thermal protein domain associated protein 3,NLRP3)炎症小体,炎症小体导致下游含半胱氨酸的天冬氨酸蛋白水解酶-1(Cysteinyl aspartate specificproteinase,Caspase-1)的蛋白水解激活,触发成孔蛋白(Gasdermin D,GSDMD)的活化以及促炎细胞因子IL-1β和IL-18的激活与分泌。许多临床研究表明,结肠组织和巨噬细胞分泌的IL-1β与UC的严重程度密切相关。此外,临床前研究也证明IL-18也是UC的关键致病因子(Zhen Y,Zhang H.NLRP3 Inflammasome and Inflammatory Bowel Disease.FrontImmunol.2019Feb 28;10:276.)。细胞焦亡是UC发生发展的一个重要分子机制,抑制细胞焦亡,尤其是抑制肠上皮细胞焦亡将成为治疗UC的有效策略。
据文献报道,UC患者的肠黏膜中PPARγ表达显著降低(Cao H,Liu J,Shen P,CaiJ,Han Y,Zhu K,Fu Y,Zhang N,Zhang Z,Cao Y.Protective Effect of Naringin onDSS-Induced Ulcerative Colitis in Mice.J Agric Food Chem.2018Dec 19;66(50):13133-13140.)。PPARγ的激活增加了细胞的抗氧化与抗炎功能。PPARγ激活可以抑制巨噬细胞的M1极化以及树突细胞的激活。此外,激活PPARγ可以通过抑制核因子κB(Nuclearfactor kappa-B,NF-κB)的活性减少细胞焦亡的发生(Liu J,Yao Q,Xie X,Cui Q,JiangT,Zhao Z,Du X,Lai B,Xiao L,Wang N.Procyanidin B2 Attenuates Nicotine-InducedHepatocyte Pyroptosis through a PPARγ-Dependent Mechanism.Nutrients.2022Apr22;14(9):1756.)。另一项研究指出PPARγ通过与NLRP3结合,破坏NLRP3炎性小体复合物的组装,从而抑制NLRP3炎性小体的激活,而这可能是PPARγ抑制细胞焦亡的另一个机制(LiuJ,Yao Q,Xie X,Cui Q,Jiang T,Zhao Z,Du X,Lai B,Xiao L,Wang N.Procyanidin B2Attenuates Nicotine-Induced Hepatocyte Pyroptosis through aPPARγ-DependentMechanism.Nutrients.2022Apr 22;14(9):1756.)。值得注意的是,PPARγ还能诱导微卫星稳定的结直肠癌细胞中程序性死亡配体-1(programmed death ligand-1,PD-L1)的表达,并且,PPARγ激动剂能够增强淋巴因子激活的杀伤细胞的杀伤作用,显著抑制肠癌细胞的增殖与生存活力(Gutting T,Hauber V,Pahl J,Klapproth K,Wu W,Dobrota I,HerweckF,Reichling J,Helm L,Schroeder T,Li B,Weidner P,Zhan T,Eckardt M,Betge J,Belle S,Sticht C,Gaiser T,Boutros M,Ebert MPA,Cerwenka A,Burgermeister E.PPARγinduces PD-L1 expression in MSS+colorectal cancercells.Oncoimmunology.2021May 5;10(1):1906500.)。提示PPARγ激动剂不仅可以治疗UC,还可能对结肠癌还有预防作用。
实验研究和临床应用表明,芍药汤对UC有治疗作用,表明芍药中含有一种或多种能够治疗溃疡性结肠炎的活性成分。在TCMSP数据库(TCMSP-Traditional ChineseMedicine Systems Pharmacology Database and Analysis Platform(tcmsp-e.com))中分析芍药的活性成分,通过设置筛选条件为口服利用率>40%,类药性>0.6,水分配系数<0得到的活性物质为芍药苷(paeoniflorin,Pae)、芍药新苷(Lactiflorin,Lac)。芍药苷作为芍药中含量最高的成分,其药理作用得到了广泛的研究。目前,有少量的文献报道了芍药苷对UC的治疗作用(Zheng K,Jia J,Yan S,Shen H,Zhu P,Yu J.Paeoniflorinameliorates ulcerative colitis by modulating the dendritic cell-mediatedTH17/Treg balance.Inflammopharmacology.2020Dec;28(6):1705-1716.;Lu P,Herdtweck E,Bach T.Intramolecular[2+2]photocycloaddition reactions as anentry to the2-oxatricyclo[4.2.1.0(4,9)]nonan-3-one skeleton oflactiflorin.Chem Asian J.2012Aug;7(8):1947-58.)。芍药新苷作为来自天然植物芍药的活性成分之一,其植物提取与全合成技术目前都有被报道(Gu P,Zhu L,Liu Y,Zhang L,Liu J,Shen H.Protective effects of paeoniflorin on TNBS-induced ulcerativecolitis through inhibiting NF-kappaB pathway and apoptosis in mice.IntImmunopharmacol.2017Sep;50:152-160.)。但其药理作用一直未充分研究,基本处于空白状态。从结构分析可知,芍药新苷的极性弱于芍药苷,水溶性更好,具有更好的生物利用度。
发明内容
基于现有技术提示,芍药汤治疗溃疡性结肠炎的主要有效成分是芍药苷。但芍药新苷是芍药苷的结构类似物,也是芍药根中的主要活性成分,是否也具有芍药苷类似的甚至更强的治疗作用还是未知的。对此,本发明研究了芍药新苷的毒理,药代动力学及药效学,并与芍药苷做了比较。发现芍药新苷与芍药苷均是安全有效的药物,且芍药新苷具有更好的药代动力学特征,成药潜力更强。最重要的是,在治疗溃疡性结肠炎的药效学研究中我们发现芍药新苷具有远优于芍药苷的疗效。芍药新苷能够显著抑制炎症诱导的结肠上皮细胞焦亡,维持结肠粘膜屏障的完整性,是治疗溃疡性结肠炎的潜在药物。并且进一步研究发现芍药新苷与与美沙拉嗪复配具有协同效果。基于此,本发明填充了芍药新苷在药理学研究方面的空白,同时也给UC提供了有效的治疗手段。
本发明首先探索了芍药新苷的毒理与药代动力学数据,然后运用DSS诱导UC动物模型,验证芍药新苷的疗效;继而在体外运用电子显微镜、分子对接、蛋白免疫印迹等技术揭露芍药新苷的分子机制。
基于此,本发明的目的在于提供芍药新苷在制备治疗溃疡性结肠炎(UC)的药物中的应用。主要用于治疗炎症免疫性疾病中的UC,核心治疗作用是抑制结肠上皮细胞焦亡,维护结肠黏膜屏障的完整性。
本发明提供芍药新苷,或芍药新苷与美沙拉嗪复配在制备治疗炎症性肠病的药物中的应用,其特征在于,所述的炎症性肠病为溃疡性结肠炎。
具体地,所述药物用于缓解炎症诱导的结肠损伤。
更具体地,所述药物用于抑制结肠上皮细胞焦亡。进一步地,所述药物用于调节结肠上皮中PPAR-γ的表达。尤其是,所述药物用于靶向PPAR-γ蛋白并激活PPAR-γ。
优选地,所述药物包含芍药新苷和药物学上可接受的辅料,所述芍药新苷的剂量为所述芍药新苷的人体给药剂量为4mg/kg-7mg/kg,优选为所述芍药新苷的人体给药剂量为4.17mg/kg-6.84mg/kg。当涉及芍药新苷与美沙拉嗪复配时,两者比例为0.8-1.2:1,优选地其比例为1:1,具有明显的协同效应。
更具体地,所述药物的剂型为颗粒剂、胶囊剂、片剂、溶液剂、丸剂、粉末剂。
本发明提供芍药新苷,或芍药新苷与美沙拉嗪复配在缓解炎症诱导的结肠损伤具有协同增效的效果。在制备抑制结肠上皮细胞焦亡的药物中的应用。
本发明进一步提供芍药新苷,或芍药新苷与美沙拉嗪复配在制备调节结肠上皮中PPAR-γ的表达的药物中的应用。
本发明还提供芍药新苷,或芍药新苷与美沙拉嗪复配在制备靶向PPAR-γ蛋白而激活PPAR-γ的药物中的应用。
与已有技术相比,本发明的有益效果体现在:本发明从治疗UC有效的传统中药汤剂芍药汤中遴选高效活性单体,并与芍药汤中含量最高的成分进行疗效对比,能够确保遴选出的活性单体的高效性;通过毒理学、药代动力学和药效学实验表明,本发明的芍药新苷疗效显著,吸收好,安全性高。且芍药新苷的单体获取有全合成以及植提法两种方式,原料获取灵活。
分子生物学实验结果表明,芍药新苷作为一个天然来源的活性小分子,可能具有多个活性靶点,但其对肠上皮细胞焦亡的抑制作用极其显著,疗效确切。
综上,本发明创新性地发现,芍药新苷能有效保护DSS诱导的UC动物的结肠粘膜完整性,减轻DSS对结肠组织的损伤,维持模型小鼠的健康状态。同时,本发明创新性的发现芍药新苷显著改善结肠上皮细胞结构与功能完整性,抑制炎症诱导的结肠上皮细胞焦亡的发生。本发明还探索了芍药新苷的作用机制以及关键靶点,证明芍药新苷治疗作用具有一定PPARγ依赖性。因此,芍药新苷能显著改善UC动物结肠损伤,临床上可用于治疗UC。本发明为UC患者的治疗提供了新的用药选择,且药物来源广泛,成分和用量明确,用药安全无明显副作用。并且进一步研究发现芍药新苷与与美沙拉嗪复配具有协同效果,其应用价值更大。
附图说明
图1、DSS诱导小鼠实验性结肠炎模型及Lac作用的研究概况。其中,A:体重波动曲线;B:疾病活动指数(**P<0.01DSS vs.Control,##P<0.01Lac(20mg)vs.DSS,Mean±SD,n=5)。
图2、各组小鼠结肠损伤情况的代表性图片。
图3、HT-29电镜图像。
图4、GSDMD-N的蛋白免疫印迹条带。
图5、GSDMD-N的蛋白免疫印迹条带灰度值统计图。(***P<0.001DSS vs.Controlgroup;###P<0.001DSS vs.LPS+ATP group)
图6、芍药新苷与1ZGY(PPARγ)的分子对接结果。
图7、芍药新苷对HT-29细胞中PPAR-γ与GSDMD-N表达影响的蛋白免疫印迹条带。
图8、PPAR-γ与GSDMD-N的蛋白免疫印迹条带灰度值统计图。(*P<0.05LPS+ATPvs.Control group;#P<0.05LPS+ATP+Lac vs.LPS+ATP group;$P<0.05,$$P<0.01LPS+ATP+siRNA(PPAR-γ)vs.Control group;&P<0.05,&&P<0.01LPS+ATP+siRNA(PPAR-γ)+Lac vs.Control group)。
具体实施方式
下面,通过实施例对本发明再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1:芍药新苷急性毒性研究
昆明种小鼠单次灌胃给予芍药新苷(3g/kg)后,或者单次静脉注射芍药新苷(600mg/kg),每天观察2次,观察二周无一例死亡。观察期内未发现灌胃和尾静脉给药组观察期间无竖毛,体表颜色改变,运动正常,无痉挛、运动失调等现象,无惊厥,机体反射正常,皮毛光滑、眼、鼻、口腔未见异常分泌物,粪便和尿液对比对照组正常,无明显的缩、扩瞳,眼球突出等眼检指征均正常。观察14d内,所有分组均无小鼠死亡情况。测量给药前及给药后第1,3,5,7,9,11,14d小鼠体质量,小鼠随着饲养的时间增加,体质量也有不同程度的增长,未见明显异常。观察期结束后处死小鼠,解剖肉眼观察记录结果显示,灌胃和尾静脉给药组小鼠的心、肝、脾、肺、肾等主要的组织器官未见明显异常。主要组织病理学染色结果显示给药组肝小叶细胞结构形态正常,未有病变或异常、脾脏中的生发中心、边缘区和红白髓交界均未见异常,同时给药组的脾脏组织结构基本同对照组、肺组织结构清晰,无水肿和积液,肺泡结构正常,肺泡间隔纤细无增宽、肾小球和肾单位细胞结构正常。
实施例2:单次灌胃给芍药苷与芍药新苷的药物代谢动力学研究
分别按照三种给药剂量(25mg·kg-1、50mg·kg-1、100mg·kg-1)给小鼠灌胃芍药新苷,然后分别在给药前后的5、10、30、45、60、90、120、240、360min等时间点依次取血,血浆样本经处理后,用UPLC-MS进行色谱分析,测得各组各时间点色谱峰面积,折算成血药浓度用DAS(drug and statistics for windows)ver 2.0软件进行房室模型的判别,并计算出药代动力学参数,其主要药动学参数结果见表1和表2。经计算,芍药新苷的口服绝对生物利用度约为49%,与TCMSP数据库记录的结果相一致。由表1、表2可知,芍药新苷吸收速度较快,吸收程度较好,体内分布较为广泛。
表1小鼠单次灌胃芍药新苷与芍药苷药动学参数
表2小鼠单次静脉注射芍药新苷与芍药苷药动学参数
实施例3:芍药新苷对DSS诱导小鼠结肠炎模型的影响
C57BL/6鼠,雄小鼠60只,雄性,体重20±2g。实验时,除正常组外,DSS溶液自由饮用一周,正常组饮用清水作为对照。一周后进行小鼠疾病活动度评分(DAI),质量下降(%)、粪便性状、便血情况,从而反映炎症程度。十天后将小鼠脱颈处死,取出结肠组织,清洗干净后测量其长度,并观测其结肠糜烂程度。
实验动物随机分为9组,分别为:正常组、模型组、阳性对照组、芍药苷组(25,50,100mg·kg-1)、芍药新苷组(25,50,100mg·kg-1)。用药方案:自造模前5日起,按0.1ml/10g体积分别灌胃给予不同剂量的药物,每日1次,连续5日,正常组和模型组给予相应体积的羧甲基纤维素钠(CMC-Na),实验结果见图1,2。与模型组相比较,阳性对照药柳氮磺胺吡啶(Sulfasalazin,SASP)组与芍药新苷(Lactiflorin,Lac)各剂量组对DSS诱导的结肠炎症均有明显的抑制作用。芍药苷(Paeoniflorin,Pae)的中剂量和大剂量组对结肠炎症状也有一定程度的改善。与阳性对照药组相比,芍药新苷组小鼠状态更好,表现出了一定的优越性。
整个实验期间,所有造模组小鼠均出现程度不同的活动减少,萎靡不振、毛色无光泽、肛门周围见脓血便等改变。本次实验中,DSS组小鼠最早于造模开始后第3日出现明显的体重下降,至第7日结束时每只小鼠体重平均减少将近基础体重的20%。DSS组小鼠于实验第2日即可检测出粪便潜血阳性,伴随粪便松软等性状改变;至第5日DSS组小鼠全部出现肉眼脓血便等溃疡性结肠炎表现。而芍药新苷组小鼠变化不明显,与对照组接近同时芍药新苷组小鼠脓血便症状出现较迟、程度较轻。实验全部结束后,按照记录的疾病活动评分和体重记录、绘制体重变化曲线和疾病活动评分曲线(图1)。
实验结束后解剖提取各组小鼠结肠(自盲肠至肛门段),测量后与对照组小鼠比较,实验组小鼠结肠可见不同程度的缩短,肠壁增厚,弹性丧失,剖开肠腔可见明显肠粘膜糜烂、出血,不同面积的溃疡形成。芍药苷组小鼠的结肠损伤也较为严重。而芍药新苷组小鼠结肠缩短程度较轻(图2),肠道出血不明显。在肠粘膜溃疡表现形态上,DSS组小鼠表现为连续性大面积粘膜溃疡,芍药新苷组小鼠表现为散在分布的肠粘膜红斑或者浅表溃疡。
实施例4:芍药新苷对肠上皮细胞焦亡的影响
(1)从武汉普诺赛生命科技有限公司购进HT-29细胞株,用即用型完全培养基制备HT-29细胞悬液(1×107/ml),铺24孔培养板,爬片。每孔加入40μl HT-29细胞悬液(终浓度为5×105/ml)及460μl完全培养基,体外分别给予LPS(提前24小时)+ATP(提前1小时)诱导结肠上皮细胞焦亡,并分别给予芍药苷(10-6Mol/L,提前20小时)以及芍药新苷(10-6Mol/L,提前20小时)处理。然后,对各组细胞进行脱水处理,具体方法为35%乙醇(10分钟)—50乙醇(10分钟)—75%乙醇(10分钟)—95%乙醇(10分钟,2次)—无水乙醇(10分钟,2次)—六亚甲基二胺氨基甲酸盐与无水乙醇的混合液(1:2)20分钟—六亚甲基二胺氨基甲酸盐与无水乙醇的混合液(2:1)20分钟—六亚甲基二胺氨基甲酸盐(20分钟,2次),随后在通风橱中风干。送至安徽医科大学电镜中心镀金拍摄,结果如图3。扫面电子显微镜的结果表明,在LPS+ATP的作用下,结肠上皮细胞失去固有形态,变为圆形,且细胞膜多有破裂。芍药苷组结肠上皮细胞焦亡特征减弱,但仅仅只是延缓了细胞焦亡的进程。芍药新苷组结肠上皮细胞细胞膜完整,结构立体,基本观测不到焦亡的形态学特征,与对照组相似。
(2)对不同处理的细胞进行提蛋白,然后用Western blot方法检测不同处理的HT-29细胞中GSDMD-N的表达水平,结果如图4。蛋白免疫印迹结果表明,LPS与ATP处理结肠上皮细胞能够显著上调焦亡标志蛋白GSDMD-N的表达水平,芍药新苷能够逆转这种上调。与之相反,芍药苷在该方面的作用较弱,甚至接近于无。
实施例5:芍药新苷对肠上皮细胞中PPARγ功能的影响
(1)分子对接实验表明芍药新苷与PPAR-γ亲和力较强:
使用Discovery Studio 2.1(DS 2.1;Accelrys Software Inc.)程序对芍药新苷与PPAR-γ蛋白(PDB ID:1ZGY)进行对接模拟。使用DS 2.1中基于分子动力学(MD)模拟退火的C-DOCKER算法模块,根据BSAI模型活性位点口袋周围产生的PPAR-γ重要氨基酸残基,定义10°活性位点和球体。如前所述,蛋白质和底物的结构在DS 2.1中使用哈佛大学大分子力学力场的化学方法进行能量最小化,然后进行全电位最终最小化。基于C-DOCKER,检索底物的能量对接构象进行对接后分析。分子对接实验表明芍药新苷与PPAR-γ的分子间相互作用力如氢键、范德华力较强,如图5所示,芍药新苷与PPAR-γ亲和力较强。
(2)小干扰实验验证芍药新苷治疗作用的PPAR-γ依赖性。如图6所示:
当HT-29细胞密度为50-60%时,根据制造商的方案,使用Lipofectamine 3000转染siRNA-PPARγ或空载体。提取细胞全蛋白,Western blot检测PPAR-γ与GSDMD-N的表达,以β-actin作为内参。如图6所示,LPS+ATP+siRNA-PPARγ组GSDMD-N的表达明显增高,LPS+ATP+siRNA-PPARγ+Lac组Lac抑制焦亡的作用几乎消失,GSDMD-N表达增高。小干扰实验验证芍药新苷的治疗作用具有PPAR-γ依赖性。
根据蛋白免疫印迹结果分析,芍药新苷对LPS+ATP引起的HT-29细胞焦亡具有抑制作用,但这种抑制作用是PPAR-γ依赖性的。
上述结果表明,芍药新苷能显著改善溃疡性结肠炎动物模型结肠损伤,可用于治疗溃疡性结肠炎。
实施例6:芍药新苷与美沙拉嗪配合的作用。
建立LPS诱导的HT-29细胞炎症模型,研究芍药新苷、美沙拉嗪和两者配伍,对LPS诱导分泌炎症介质NO、COX-2以及PGE的影响。首先通过calcusyn软件计算芍芍新苷、美沙拉嗪单用及其配伍对炎症介质NO、COX-2以及PGE影响的Dm浓度(中效浓度),并根据Dm浓度计算芍药新苷和美沙拉嗪配伍的协同指数(CI)。根据NO的测定结果,运用calcusyn软件处理得出美沙拉嗪与芍药新苷的配比1:1时的Dm为0.025mg/ml,均小于美沙拉嗪、芍药新苷单独使用时的Dm(0.035mg/ml、0.274mg/ml)并得到芍药新苷和美沙拉嗪配伍的协同指数CI曲线,CI=D1/DX1+D2/DX2(式中D1、D2为美沙拉嗪和芍药新苷联合作用的中效浓度Dm,Dx1、Dx2为美沙拉嗪和芍药新苷单独作用时的中效浓度Dm)协同指数CI为0.429,CI<1,说明芍药新苷和美沙拉嗪具有协同作用;芍药新苷和美沙拉嗪配伍对COX-2和PGE的抑制效果强于单独用药效果。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对以上实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (10)
1.芍药新苷,或芍药新苷与美沙拉嗪复配在制备治疗炎症性肠病的药物中的应用,其特征在于,所述的炎症性肠病为溃疡性结肠炎。
2.如权利要求1所述的应用,其特征在于,所述药物用于缓解炎症诱导的结肠损伤。
3.如权利要求1所述的应用,其特征在于,所述药物用于抑制结肠上皮细胞焦亡。
4.如权利要求1所述的应用,其特征在于所述药物用于调节结肠上皮中PPAR-γ的表达。
5.如权利要求1所述的应用,其特征在于,所述药物用于靶向PPAR-γ蛋白并激活PPAR-γ。
6.如权利要求1至5任一项所述应用,其特征在于,所述药物包含芍药新苷和药物学上可接受的辅料,所述芍药新苷的剂量为所述芍药新苷的人体给药剂量为4mg/kg-7 mg/kg,优选为所述芍药新苷的人体给药剂量为4.17mg/kg-6.84mg/kg;当涉及芍药新苷与美沙拉嗪复配时,两者比例为0.8-1.2:1,优选地其比例为1:1。
7.如权利要求6所述的应用,其特征在于,所述药物的剂型为颗粒剂、胶囊剂、片剂、溶液剂、丸剂、粉末剂。
8.芍药新苷,或芍药新苷与美沙拉嗪复配在缓解炎症诱导的结肠损伤具有协同增效的效果。在制备抑制结肠上皮细胞焦亡的药物中的应用。
9.芍药新苷,或芍药新苷与美沙拉嗪复配在制备调节结肠上皮中PPAR-γ的表达的药物中的应用。
10.芍药新苷,或芍药新苷与美沙拉嗪复配在制备靶向PPAR-γ蛋白而激活PPAR-γ的药物中的应用。
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