CN101316594B - 用于预防或治疗胃肠道粘膜损伤的组合物 - Google Patents
用于预防或治疗胃肠道粘膜损伤的组合物 Download PDFInfo
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Abstract
本发明提供一种预防或治疗胃肠道粘膜损伤的组合物，其包含瑞伐普拉赞或其盐及药学上可接受的载体。通过增强胃肠道粘膜中的防御因子，同时作为酸泵拮抗剂，瑞伐普拉赞或其盐对胃肠道粘膜损伤有极好的预防或治疗作用。
Description
技术领域
本发明涉及一种用于预防或治疗胃肠道粘膜损伤的组合物，其包含瑞伐普拉赞(revaprazan)或其盐。
背景技术
瑞伐普拉赞，已知化学名为5，6-二甲基-2-(4-氟苯基氨基)-4-(1-甲基-1，2，3，4-四氢异喹啉-2-基)嘧啶，为下式1表示的化合物，可以酸加成盐(例如盐酸瑞伐普拉赞)的形式获得[PCT公开号WO96/05177]。
式1
瑞伐普拉赞或其盐与存在于胃壁细胞内的质子泵(H+/K+ATP酶)的H+/K+交换位点可逆结合，从而竞争性地抑制H+分泌到胃腔中。瑞伐普拉赞或其盐结合到H+/K+ATP酶的特定位点，从而阻止H+运送以及酸分泌到胃腔中，因此提高了胃内pH。与不可逆质子泵抑制剂例如奥美拉唑不同，瑞伐普拉赞或其盐不受药物的胃酸激活或质子泵的胃酸分泌的影响。基于瑞伐普拉赞或其盐的机理不同于不可逆质子泵抑制剂例如奥美拉唑的机理，将瑞伐普拉赞或其盐归类为酸泵拮抗剂(APA)。
同时，当攻击因子(例如胃酸)增强或防御因子削弱时，会引起胃肠紊乱。质子泵抑制剂(例如奥美拉唑)和酸泵拮抗剂(例如瑞伐普拉赞)都是抑制攻击因子即胃酸分泌的化合物，细胞保护剂(例如硫糖铝、瑞巴派特)是增强防御因子的化合物。
发明内容
本发明者已使用酸泵拮抗剂即瑞伐普拉赞或其盐进行了各种临床试验，发现瑞伐普拉赞或其盐在胃肠道中除了具有质子泵抑制活性外，还具有细胞保护活性。这种令人惊异的发现暗示瑞伐普拉赞或其盐不仅有抑制胃酸(攻击因子)分泌的作用，还有增强防御因子的胃肠道细胞保护作用。
因此，本发明提供一种预防或治疗胃肠道粘膜损伤的组合物，其包含瑞伐普拉赞或其盐。
本发明提供一种预防或治疗胃肠道粘膜损伤的组合物，其包含瑞伐普拉赞或其盐及药学上可接受的载体。
根据本发明的一个方面，提供一种预防或治疗胃粘膜损伤的方法，其包括将药物组合物给予需要上述预防或治疗的人，所述药物组合物包含对于预防或治疗胃粘膜损伤有效量的瑞伐普拉赞或其药学上可接受的盐及药学上可接受的载体。
根据本发明的另一个方面，提供一种预防或治疗药物诱发的胃粘膜损伤的方法，其包括将药物组合物给予需要上述预防或治疗的人，所述药物组合物包含对于预防或治疗药物诱发的胃粘膜损伤有效量的瑞伐普拉赞或其药学上可接受的盐及药学上可接受的载体。
根据本发明的另一个方面，提供一种预防或治疗乙醇诱发的胃粘膜损伤的方法，其包括将药物组合物给予需要上述预防或治疗的人，所述药物组合物包含对于预防或治疗乙醇诱发的胃粘膜损伤有效量的瑞伐普拉赞或其药学上可接受的盐及药学上可接受的载体。
根据本发明的另一个方面，提供一种为接受非甾体类抗炎药(NSAID)的人提供胃粘膜细胞保护的方法，其包括在给予NSAID之前或给予NSAID的同时，将药物组合物给予所述的人，所述药物组合物包含对于细胞保护有效量的瑞伐普拉赞或其药学上可接受的盐及药学上可接受的载体。对于本发明的NSAID没有特殊限制，包括广泛使用的所有NSAID，例如阿斯匹林、吲哚美辛、双氯芬酸、布洛芬、萘普生、吡罗昔康、甲芬那酸、氟芬那酸、夫洛非宁、乙水杨胺、水杨酸钠、二氟尼柳、氯非宗、酮保泰松、保泰松、阿氯芬酸、阿明洛芬、酮洛芬、氟比洛芬、普拉洛芬、洛索洛芬钠、盐酸噻拉米特、柠檬酸哌立索唑、依莫法宗、阿西美辛、马来酸丙谷美辛、布可隆等。
附图说明
通过详细描述本发明的实施方式并参考其附图，本发明上述的和其它的特点和优点将更为清楚：
图1显示瑞伐普拉赞对由幽门螺杆菌(H.pylori)诱发的胃肠道粘膜损伤引起的细胞死亡的抑制作用的MTT分析结果；
图2显示瑞伐普拉赞对由乙醇诱发的胃肠道粘膜损伤引起的细胞死亡的抑制作用的MTT分析结果；
图3A和3B显示瑞伐普拉赞对体内胃肠道损伤的细胞保护作用的图像；
图4显示瑞伐普拉赞对幽门螺杆菌诱发的ERK(细胞外信号调节激酶)激活的抑制作用的Western印迹图像；
图5显示瑞伐普拉赞对幽门螺杆菌诱发的NF-kB激活的抑制作用的电泳迁移率变动分析(EMSA)结果；
图6显示瑞伐普拉赞对促血管生长因子的活性影响的RT-PCR结果；
图7显示瑞伐普拉赞对热休克蛋白的活性影响的Western印迹图像；
图8显示给予吲哚美辛之前，用瑞巴派特、奥美拉唑和瑞伐普拉赞处理对胃粘膜损伤预防作用的对比图像；和
图9显示给予吲哚美辛之后，瑞伐普拉赞对胃粘膜损伤治疗作用的对比图像。
具体实施方式
可根据WO96/05177、WO97/42186和/或WO98/18784公开的方法制备瑞伐普拉赞。瑞伐普拉赞的盐可以是无机酸盐，例如盐酸盐、硫酸盐、磷酸盐和硝酸盐；或有机酸盐，例如酒石酸盐、延胡索酸盐、柠檬酸盐、甲磺酸盐和乙酸盐。优选盐酸瑞伐普拉赞。
本发明的组合物可包含添加剂(例如乳糖或玉米淀粉)、润滑剂(例如硬脂酸镁)、乳化剂、悬浮剂、稳定剂和等张剂。如需要，可添加甜味剂和/或调味剂。
本发明的组合物可通过口服或肠胃外给予，包括静脉内、腹膜内、皮下、直肠和局部给予途径。因此，本发明的组合物可制成各种形式，例如片剂、胶囊剂、水溶液剂或悬浮剂。对于口服用片剂，通常添加载体(例如乳糖、玉米淀粉)和润滑剂(例如硬脂酸镁)。对于口服给予的胶囊剂，可将乳糖和/或干玉米淀粉用作稀释剂。当需口服用的水悬浮剂时，活性成分可与乳化剂和/或悬浮剂混合。如需要，可添加某些甜味剂和/或调味剂。用于肌肉内、腹膜内、皮下和静脉内时，通常制备活性成分的无菌溶液，并应将溶液的pH进行适当地调节和缓冲。用于静脉内时，应控制溶质总浓度以使所述制剂具有等张性。本发明的组合物可以是含有药学上可接受的载体(例如pH7.4的盐溶液)的水溶液剂的形式。通过局部团注可将溶液引入患者的肌内血流中。
可给予需要预防或治疗胃肠道粘膜损伤的患者有效量的瑞伐普拉赞或其盐，所述有效量为约50mg～400mg/天，优选为约100mg～300mg/天，更优选为约150mg～250mg/天，最优选为约200mg/天。当然，可根据患者的年龄、体重、敏感性或症状改变剂量。
在下文中，将通过以下实施例更为具体地描述本发明。然而，以下实施例只为了说明本发明，因此本发明不限于此并且不受其限制。
实施例1幽门螺杆菌(H.pylori)诱发的细胞死亡率的测量(MTT分析-1)
为测定瑞伐普拉赞对幽门螺杆菌感染的细胞保护性质，在幽门螺杆菌感染之前，使用瑞伐普拉赞和瑞巴派特预处理胃粘膜细胞，测量细胞死亡率。将已知具有细胞保护性质的瑞巴派特用作对照药物。
将人胃上皮(AGS，KCLB 21739)细胞以5×104个细胞/ml接种到96孔板上，在补充有100单位/mL的青霉素、100μg/mL的链霉素和10％FBS(胎牛血清)的RPMI 1640(Gibco BRL，格兰德岛，纽约，美国)中培养。将溶解于无菌水的瑞伐普拉赞和瑞巴派特加入AGS细胞中，使最终浓度达到50μM，在37℃下培养细胞16小时。为去除RPMI 1640培养基，将上述96孔板在24℃、3000rpm下离心5分钟，并用PBS(137mMNaCl、2.7mM KCl、10mM Na2HPO4和2mM KH2PO4)洗涤3次。为了接种，将幽门螺杆菌(ATCC 43504)培养液重悬于PBS，并在最终浓度为5×108CFU/ml条件下，与AGS细胞共培养。在37℃下培养48小时后，将培养液在24℃、3000rpm下离心5分钟，除去培养基即RPMI 1640，然后通过MTT(3-[4，5-二甲基-2-噻唑]-2，5-二苯基溴化四唑)分析方法估计活细胞总数。将MTT(Amresco，俄亥俄州，美国)溶解于PBS(137mMNaCl、2.7mM KCl、10mM Na2HPO4和2mM KH2PO4)中制备的1mg/ml的MTT溶液加入每个孔(50μl/孔)中，接着在37℃下培养4小时。然后在24℃、3000rpm下离心5分钟，除去上清液，将活细胞形成的甲
颗粒(formazan grains)溶解于99.5％二甲亚砜(DMSO)(Kanto，东京，日本)(50μl/孔)，使用ELISA读取仪(TECAN，Maennedorf，瑞士)在540nm下测量光强度。
MTT分析结果如图1所示。参照图1，48小时的幽门螺杆菌感染引起显著的胃粘膜细胞毒性。然而，通过瑞巴派特和瑞伐普拉赞的预处理，显著减小了幽门螺杆菌感染引起的胃粘膜细胞毒性。这些结果显示瑞伐普拉赞对幽门螺杆菌诱发的细胞毒性具有等于或高于瑞巴派特的细胞保护作用。
实施例2乙醇诱发的细胞死亡率的测量(MTT分析-2)
将大鼠胃粘膜(RGM-1，RIKEN细胞库，日本)细胞以5×104个细胞/ml接种到96孔板上，在补充有100单位/mL的青霉素、100μg/mL的链霉素和10％FBS(胎牛血清)的DMEM-F12(Gibco BRL，格兰德岛，纽约，美国)中培养。将溶解于无菌水的瑞伐普拉赞和瑞巴派特加入RGM-1细胞，使最终浓度达到50μM，在37℃下培养细胞16小时。为去除DMEM-F12培养基，将上述96孔板在24℃、3000rpm下离心5分钟，并用PBS(137mM NaCl、2.7mM KCl、10mM Na2HPO4和2mMKH2PO4)洗涤3次。然后，将含有乙醇的培养基(含有200mM乙醇的DMEM-F12，其中补充有100单位/mL的青霉素、100μg/mL的链霉素和10％FBS)加入细胞中，在37℃下培养细胞16小时。培养后，将培养液在24℃、3000rpm下离心5分钟，除去培养基，然后通过MTT(3-[4，5-二甲基-2-噻唑]-2，5-二苯基溴化四唑)分析方法估计活细胞总数。将MTT(Amresco，俄亥俄州，美国)溶解于PBS(137mM NaCl、2.7mM KCl、10mM Na2HPO4和2mM KH2PO4)中制备的1mg/ml的MTT溶液加入每个孔(50μl/孔)中，接着在37℃下培养4小时。然后在24℃、3000rpm下离心5分钟，除去上清液，将活细胞形成的甲颗粒溶解于99.5％的二甲亚砜(DMSO)(Kanto，东京，日本)(50μl/孔)，使用ELISA读取仪(TECAN，Maennedorf，瑞士)在540nm下测量光强度。
MTT分析结果如图2所示。参照图2，在仅用乙醇处理组中，诱发了显著的胃粘膜细胞毒性。另一方面，在瑞巴派特/瑞伐普拉赞-乙醇处理组中，胃粘膜细胞毒性显著减小。这些结果显示瑞伐普拉赞具有等于或高于瑞巴派特的细胞保护作用。
实施例3瑞伐普拉赞对体内胃肠道损伤预防作用的评价
实验使用六周龄的无特异病原(SPF)的Sprague-Dawley雄性大鼠(Charles River，东京，日本)。向大鼠喂饲商购的灭菌颗粒饲料(Biogenomics Co.，首尔，韩国)，随意给予无菌水，将其饲养在装有空调装置的生物危害的房间中，光暗周期为12小时光亮期：12小时光暗期。将大鼠分成4组：仅用吲哚美辛处理组、瑞伐普拉赞-吲哚美辛处理组、仅用乙醇处理组和瑞伐普拉赞-乙醇处理组。使大鼠禁食24小时，然后在接触吲哚美辛(40mg/kg，接触时间为12小时)或无水乙醇(6ml/kg，接触时间为1小时)之前，通过口胃管将悬浮于0.5％CMC(羧甲基纤维素)中的瑞伐普拉赞以10mg/kg给予大鼠。
切除属于吲哚美辛处理组的大鼠的胃，观察胃粘膜损伤程度(参见图3A)。参照图3A，在仅用吲哚美辛处理组中，可目视观察到加重的胃粘膜出血性损伤。然而，在给予瑞伐普拉赞之后，使用吲哚美辛处理过的瑞伐普拉赞-吲哚美辛处理组中，吲哚美辛诱发的胃粘膜损伤得到完全抑制。此外，切除属于乙醇处理组的大鼠的胃，观察胃粘膜损伤程度(参见图3B)。参照图3B，在仅用乙醇处理组中，也可目视观察到显著加重的胃粘膜出血性损伤。然而，在给予瑞伐普拉赞之后，使用乙醇处理过的瑞伐普拉赞-乙醇处理组中，乙醇诱发的胃粘膜损伤得到完全抑制。这些结果显示：瑞伐普拉赞的预处理显著减小了非甾体类抗炎药(NSAID)(例如吲哚美辛)诱发的或乙醇诱发的胃粘膜损伤，因此获得了极好的胃肠道粘膜的细胞保护作用。
实施例4诱发幽门螺杆菌介导的细胞毒性的细胞外信号调节激酶(ERK)
活性的评价
幽门螺杆菌诱发的细胞毒性激活MAPK(促***原活化蛋白激酶)，因此导致细胞凋亡。因此，幽门螺杆菌感染造成MAPK的3个主要亚族中ERK磷酸化的增加。
将人胃上皮(AGS，KCLB 21739)细胞以2×106个细胞/100mm2接种于培养皿中，在补充有100单位/mL的青霉素、100μg/mL的链霉素和10％FBS(胎牛血清)的RPMI 1640(Gibco BRL，格兰德岛，纽约，美国)中培养。将溶解于无菌水的瑞伐普拉赞加入AGS细胞中，使最终浓度达到5μM和25μM，在37℃下培养细胞16小时。去除RPMI 1640培养基，然后用PBS(137mM NaCl、2.7mM KCl、10mM Na2HPO4和2mMKH2PO4)洗涤细胞3次。为了接种，将幽门螺杆菌(ATCC 43504)培养液重悬于PBS，并在5×108CFU/ml条件下，与AGS细胞共培养。在37℃下培养30分钟后，将细胞重悬于裂解缓冲液(20mM Tris-Cl(pH7.5)、150mM NaCl、1％Triton X-100、1mM EDTA和蛋白酶抑制剂混合物(Roche，曼海姆，德国))中。使用BIORUPTOR(Cosmo Bio，江东区(Koto-ku)，东京)将悬浮液超声约10秒钟，共4次，在4℃、12000rpm下离心30分钟。将上清液用作蛋白提取物，在10％SDS-PAGE凝胶上进行电泳，使用半干转印***(Hoeffer Pharmacia Biotech，旧金山，加州，美国)将其转移到PVDF膜(Millipore，马萨诸塞州，美国)上。为了防止一抗与该蛋白之间的非特异性结合，用含有5％脱脂乳(Difco，利沃里亚(Livonia)，密西根州，美国)的封闭液(TBST：10mM Tris-Cl，pH8.0；150mM NaCl和0.1％吐温20(v/v))在23℃下封闭PVDF膜1小时。在4℃下，用p-ERK或ERK的一抗的1∶1000稀释液(200ng/ml)培养PVDF膜15小时。在23℃下，用HRP(辣根过氧化物酶)偶联的二抗(Santa Cruz Biotech，加州，美国)的1∶2000稀释液(100ng/ml)培养PVDF膜1小时。使用ECL(增强化学发光)检测试剂盒(Amersham-Pharmacia Biotec，白金汉郡，英国)使免疫复合物得以显示。
幽门螺杆菌感染细胞的未处理组和瑞伐普拉赞处理组的p-ERK的Western印迹结果如图4所示。参照图4，瑞伐普拉赞对ERK的激活显示出显著的、浓度依赖性的抑制作用。
实施例5与幽门螺杆菌感染有关的NF-kB转录因子活性的评价(电泳迁
移率变动分析，EMSA)
使用EMSA评价已知与幽门螺杆菌感染有关的对氧化还原敏感的转录因子NF-kB(核因子-kB)的DNA结合活性。将已知具有细胞保护性质的瑞巴派特(50μM)用作对照药物，瑞伐普拉赞(25μM)用作试验药物。
将人胃上皮(AGS，KCLB 21739)细胞以2×106个细胞/100mm2接种于培养皿中，在补充有100单位/mL的青霉素、100μg/mL的链霉素和10％FBS(胎牛血清)的RPMI 1640(Gibco BRL，格兰德岛，纽约，美国)中培养。将溶解于无菌水的瑞伐普拉赞和瑞巴派特加入AGS细胞中，使最终浓度分别达到25μM和50μM，在37℃下培养细胞16小时。除去培养基，用PBS(137mM NaCl、2.7mM KCl、10mM Na2HPO4和2mMKH2PO4)洗涤细胞2次。为了接种，将幽门螺杆菌(ATCC 43504)培养液重悬于PBS，并在37℃、最终浓度为5×108CFU/ml条件下，与AGS细胞共培养1小时。使用NE-PER核和胞质提取试剂盒(Pierce，罗克福德(Rockford)，伊利诺斯州，美国)制备用于EMSA的核组分。用于NF-kB的EMSA的双链寡核苷酸序列如下：5′-AGT TGA GGG GAC TTTCCC AGG C-3′，用生物素3′端DNA标记试剂盒(Pierce，罗克福德，伊利诺斯州，美国)标记寡核苷酸。用光位移化学发光EMSA试剂盒(Pierce，罗克福德，伊利诺斯州，美国)进行EMSA。
使用EMSA对NF-kB的DNA结合活性的评价结果如图5所示。这些结果表明通过瑞伐普拉赞预处理，NF-kB的活性得到显著抑制，因此获得了等于或高于瑞巴派特的细胞保护作用。
实施例6参与细胞保护的蛋白表达水平的测量(RT-PCR)
为评价瑞伐普拉赞的细胞保护作用，将属于NSAID的舒林酸100μM加入大鼠细胞中，测量促血管生长因子、VEGF(血管内皮生长因子)、白介素-8(IL-8)和COX-2(环氧化酶-2)的表达水平。将已知具有细胞保护性质的瑞巴派特(50μM)用作对照药物，瑞伐普拉赞(25μM)用作试验药物。
将大鼠胃粘膜(RGM-1，RIKEN细胞库，日本)细胞以2×106个细胞/100mm2接种于培养皿中，在补充有100单位/mL的青霉素、100μg/mL的链霉素和10％FBS(胎牛血清)的RPMI 1640(Gibco BRL，格兰德岛，纽约，美国)中培养。将溶解于无菌水的瑞伐普拉赞和瑞巴派特加入RGM-1细胞中，使最终浓度分别达到25μM和50μM，在37℃下培养细胞16小时。除去培养基，用PBS(137mM NaCl、2.7mM KCl、10mMNa2HPO4和2mM KH2PO4)洗涤细胞3次。将舒林酸的DMSO溶液加入细胞中，使最终浓度达到100μM，在37℃下培养细胞8小时。在23℃、3000rpm下离心3分钟，收集培养的细胞，使用TRIzol试剂(Lifetechnologies，米兰，意大利)从细胞中分离总RNA。将灭菌的无核糖核酸酶(RNase)的水加入2μg总RNA和1μl 10pmol/λ寡聚dT中，以获得体积为34μl的反应溶液。在65℃下培养反应溶液5分钟，向其加入10μl 5X的反转录缓冲溶液、5μl10mM的dNTP和1μl的M-MLV反转录酶。在37℃下培养所得溶液1小时，获得cDNA(Promega，麦迪逊分校，威斯康星大学)，通过PCR扩增所述cDNA。使用Premix Ex Taq试剂盒(Takara，千叶县(Chiba)，日本)和如下的特定引物进行PCR：
5′-TGCACCCACGACAGAAGGGGA-3′和
5′-TCACCGCCTTGGCTTGTCACAT-3′(用于VEGF)；
5′-GAAGATAGATTGCCCGA-3′和
5′-CATAGCCTCTCACACATTTC-3′(用于IL-8)；
5′-ATCTGTGTGGGTACAAATTTG-3′和
5′-GTCTCTCATCTGCAATAATGTG-3′(用于COX-2)；
5′-TGAAGGTCGGTGTCAACGGATTTGTC-3′和
5′-CATGTAGGCCATGAGGTCCACCAC-3′(用于GAPDH)。
如上所述，GAPDH用作阳性对照。PCR进行如下：94℃下进行1分钟，60℃(VEGF)、45℃(IL-8)、48℃(COX-2)和55℃(GAPDH)下各自进行1分钟，72℃下进行1分钟，如此进行35个循环(VEGF、IL-8和COX-2)或28个循环(GAPDE)。在1％琼脂糖凝胶上分离PCR产物，用10mg/ml溴化乙锭染色。
瑞巴派特-舒林酸处理组和瑞伐普拉赞-舒林酸处理组中的IL-8、VEGF和COX-2的表达水平如图6所示。参照图6，瑞伐普拉赞-舒林酸处理组中，IL-8、VEGF和COX-2的表达水平远高于瑞巴派特-舒林酸处理组中的表达水平。已知用于解释NSAID诱发的胃粘膜损伤的机理之一与引起胃粘膜再生和局部缺血的VEGF、IL-8和COX-2的减少有关。在此方面，图6显示的瑞伐普拉赞-舒林酸处理组中IL-8、VEGF和COX-2表达水平增加的结果揭示出瑞伐普拉赞对胃肠道粘膜具有良好的细胞保护作用。
实施例7热休克蛋白活性的评价(Western印迹)
为测量热休克蛋白HO-1、HSP27和HSP70的表达，用浓度为5μM、10μM和25μM的瑞伐普拉赞预处理细胞，然后用吲哚美辛(NSAID，0.5μM)处理。
将大鼠胃粘膜(RGM-1，RIKEN细胞库，日本)细胞以2×106个细胞/100mm2接种到培养皿中，在补充有100单位/mL的青霉素、100μg/mL的链霉素和10％FBS(胎牛血清)的DMEM-F12(Gibco BRL，格兰德岛，纽约，美国)中培养。用瑞伐普拉赞(5μM、10μM和25μM)预处理RGM-1细胞，在37℃下培养16小时。除去培养基，用PBS(137mM NaCl、2.7mMKCl、10mM Na2HPO4和2mM KH2PO4)洗涤细胞3次。将吲哚美辛的无菌水溶液加入细胞中，使最终浓度达到0.5μM，在37℃下培养细胞16小时。培养后，将细胞重悬于裂解缓冲液(20mM Tris-Cl(pH7.5)、150mMNaCl、1％Triton X-100、1mM EDTA和蛋白酶抑制剂混合物(Roche，曼海姆，德国))中。使用BIORUPTOR(Cosmo Bio，江东区，东京)将悬浮液超声约10秒钟，共4次，在4℃、12000rpm下离心30分钟。将上清液用作蛋白提取物，将提取的蛋白在10％SDS-PAGE凝胶上进行电泳，使用半干转印***(Hoeffer Pharmacia Biotech，旧金山，加州，美国)将其转移到PVDF膜(Millipore，马萨诸塞州，美国)上。为了防止一抗与该蛋白之间的非特异性结合，用含有5％脱脂乳(Difco，利沃里亚，密西根州，美国)的封闭液(TBST：10mM Tris-Cl，pH8.0；150mMNaCl和0.1％吐温20(v/v))在23℃下封闭PVDF膜1小时。在4℃下，用HO-1、HSP27、HSP70或α-微管蛋白(TU-02)的一抗的1∶1000稀释液(200ng/ml)培养PVDF膜15小时。在23℃下，用HRP(辣根过氧化物酶)偶联的二抗(Santa Cruz Biotech，加州，美国)的1∶2000稀释液(100ng/ml)培养PVDF膜1小时。使用ECL(增强化学发光)检测试剂盒(Amersham-Pharmacia Biotec，白金汉郡，英国)使免疫复合物得以显示(参见图7)。
由图7可看出瑞伐普拉赞通过刺激热休克蛋白的表达显示出细胞保护作用。
实施例8瑞伐普拉赞对NSAID诱发的胃病预防作用的评价
实验使用六周龄的无特异病原(SPF)的Sprague-Dawley雄性大鼠(Charles River，东京，日本)。向大鼠喂饲商购的灭菌颗粒饲料(Biogenomics Co.，首尔，韩国)，随意给予无菌水，将其饲养在装有空调装置的生物危害的房间中，光暗周期为12小时光亮期：12小时光暗期。使大鼠禁食24小时，然后在接触吲哚美辛(40mg/kg，接触时间为12小时)之前，通过口胃管将悬浮于0.5％CMC(羧甲基纤维素)中的瑞伐普拉赞以5mg/kg、10mg/kg、瑞巴派特以30mg/kg以及奥美拉唑以5mg/kg给予大鼠。将磷酸盐缓冲盐水灌注到大鼠胃腔中使胃膨胀。然后，沿较大曲度切割打开胃，计算胃粘膜损伤的总面积以获得损伤的平均尺寸。
对照组和试验组中对胃粘膜损伤预防作用的对比结果如图8所示。参照图8，在对照组、奥美拉唑预处理组和瑞巴派特预处理组中，可观察到出血性损伤，而在瑞伐普拉赞预处理组中几乎观察不到出血性损伤。这些结果显示瑞伐普拉赞对胃粘膜损伤具有极好的预防作用。
实施例9瑞伐普拉赞对NSAID诱发的胃病治疗作用的评价
实验使用六周龄的无特异病原(SPF)的Sprague-Dawley雄性大鼠(Charles River，东京，日本)。向大鼠喂饲商购的灭菌颗粒饲料(Biogenomics Co.，首尔，韩国)，随意给予无菌水，将其饲养在装有空调装置的生物危害的房间中，光暗周期为12小时光亮期：12小时光暗期。使大鼠禁食24小时，然后通过口胃管用1ml吲哚美辛的0.5％CMC(羧甲基纤维素)溶液(40mg/kg)处理大鼠。用吲哚美辛处理8小时后，用1ml瑞伐普拉赞的0.5％CMC溶液(5mg/kg和10mg/kg)处理大鼠1小时，以与实施例8相同的方式确定胃病程度。
仅用吲哚美辛处理组和吲哚美辛-瑞伐普拉赞处理组中的胃粘膜损伤治疗作用的对比结果如图9所示。参照图9，在吲哚美辛-瑞伐普拉赞处理组中，胃粘膜出血性损伤得到显著改善，糜烂和溃疡的数量也减少了。这些结果显示瑞伐普拉赞对胃粘膜损伤有极好的治疗作用。
工业实用性
如上所述，通过增强胃肠道粘膜中的防御因子，同时作为酸泵拮抗剂，瑞伐普拉赞或其盐对胃肠道粘膜损伤有极好的预防或治疗作用。
Claims (5)
1.瑞伐普拉赞或其药学上可接受的盐在生产通过为胃粘膜提供细胞保护作用来预防胃粘膜损伤的药物方面的应用，其中，所述胃粘膜具有乙醇诱发的损伤。
2.根据权利要求1所述的应用，其中所述药学上可接受的盐是盐酸瑞伐普拉赞。
3.根据权利要求1所述的应用，其中所述瑞伐普拉赞或其药学上可接受的盐的有效量为约100mg～300mg/天。
4.根据权利要求1所述的应用，其中所述瑞伐普拉赞或其药学上可接受的盐的有效量为约150mg～250mg/天。
5.根据权利要求1所述的应用，其中所述瑞伐普拉赞或其药学上可接受的盐的有效量为约200mg/天。
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| PCT/KR2006/005044 WO2007064128A1 (en) | 2005-12-01 | 2006-11-28 | Composition for preventing or treating damages of the mucosa in the gastrointestinal tracts |
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| EP (1) | EP1954279A4 (zh) |
| JP (1) | JP5207974B2 (zh) |
| KR (1) | KR100805660B1 (zh) |
| CN (2) | CN102309490A (zh) |
| AU (1) | AU2006321471B2 (zh) |
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| HK (1) | HK1123507A1 (zh) |
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| CA2673536A1 (en) | 2006-12-22 | 2008-07-03 | Yuhan Corporation | Revaprazan-containing solid dispersion and process for the preparation thereof |
| BRPI1013288A2 (pt) | 2009-07-09 | 2016-03-29 | Raqualia Pharma Inc | uso de um composto, método de composição farmacêutica para o tratamento de doenças em que a motilidade gastrointestinal anormal está envolvida, kit e embalagem comercial que compreende uma composição farmacêutica contendo o composto |
| KR101730865B1 (ko) * | 2011-02-11 | 2017-04-27 | 주식회사유한양행 | 레바프라잔-함유 나노입자를 포함하는 경구투여용 약학 조성물 및 그의 제조방법 |
| KR101739818B1 (ko) * | 2011-05-20 | 2017-05-26 | 주식회사유한양행 | 레바프라잔 또는 그의 염을 함유하는 현탁액 형태의 경구투여용 약학 조성물 |
| WO2017018473A1 (ja) | 2015-07-30 | 2017-02-02 | 武田薬品工業株式会社 | 錠剤 |
| CN105998688A (zh) * | 2016-06-22 | 2016-10-12 | 郑亮 | 一种胃粘膜损伤的抑制方法 |
| KR20180107341A (ko) * | 2017-03-16 | 2018-10-02 | 차의과학대학교 산학협력단 | 칼륨 경쟁적 위산분비억제제를 유효성분을 함유하는 장 누수 증후군 치료 및 예방용 조성물 |
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| CA2253906C (en) * | 1996-05-04 | 2002-04-02 | You Wha Hong | Process for preparation of pyrimidine derivatives |
| US6080738A (en) * | 1996-10-25 | 2000-06-27 | Yoshitomi Pharmaceuticals Industries, Ltd. | Heterocyclic amide compounds and medicinal uses thereof |
| TR199900943T2 (xx) | 1996-10-29 | 1999-12-21 | Yuhan Corporation | Pirimidin t�revlerinin haz�rlanma prosesi. |
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Also Published As
| Publication number | Publication date |
|---|---|
| JP2009517462A (ja) | 2009-04-30 |
| EP1954279A4 (en) | 2009-06-03 |
| EP1954279A1 (en) | 2008-08-13 |
| JP5207974B2 (ja) | 2013-06-12 |
| CN101316594A (zh) | 2008-12-03 |
| US20070129391A1 (en) | 2007-06-07 |
| AU2006321471A1 (en) | 2007-06-07 |
| BRPI0619081A2 (pt) | 2011-09-20 |
| MY145406A (en) | 2012-02-15 |
| IL191680A0 (en) | 2009-08-03 |
| CA2631068C (en) | 2011-01-11 |
| CN102309490A (zh) | 2012-01-11 |
| US7776873B2 (en) | 2010-08-17 |
| ZA200805747B (en) | 2009-11-25 |
| CR10018A (zh) | 2008-09-02 |
| ECSP088545A (es) | 2008-08-29 |
| AU2006321471B2 (en) | 2010-07-29 |
| KR20070057663A (ko) | 2007-06-07 |
| WO2007064128A1 (en) | 2007-06-07 |
| KR100805660B1 (ko) | 2008-02-21 |
| HK1123507A1 (en) | 2009-06-19 |
| CA2631068A1 (en) | 2007-06-07 |
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