CN100411620C - 潘生丁或单哌潘生丁在制备用于治疗及预防血纤维蛋白依赖性微循环障碍药物中的用途 - Google Patents

潘生丁或单哌潘生丁在制备用于治疗及预防血纤维蛋白依赖性微循环障碍药物中的用途 Download PDF

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CN100411620C
CN100411620C CNB008146756A CN00814675A CN100411620C CN 100411620 C CN100411620 C CN 100411620C CN B008146756 A CNB008146756 A CN B008146756A CN 00814675 A CN00814675 A CN 00814675A CN 100411620 C CN100411620 C CN 100411620C
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mopidamol
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沃尔夫冈·艾瑟特
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Abstract

本发明公开了用于治疗人类或非人类动物体的方法，以治疗血纤维蛋白依赖性微循环障碍，例如由代谢疾病、发炎反应或自体免疫疾病引起的微循环障碍，进一步治疗外周微循环障碍或与增加细胞断裂相关的微循环障碍，该方法包含给药需此治疗的人类或非-人类动物体有效剂量的医药组合物，该组合物包含选自潘生丁，单哌潘生丁的嘧啶并-嘧啶和其医药可接受盐类，及该嘧啶并-嘧啶于制备相应医药组合物的用途。

Description

潘生丁或单哌潘生丁在制备用于治疗及预防血纤维蛋白依赖性微循环障碍药物中的用途
发明领域
本发明是关于使用潘生丁或单哌潘生丁为活性成份治疗血纤维蛋白-依赖性微循环障碍的方法，其提供治疗状况下持续改善微循环，及用于制备相应医药组合物的潘生丁或单哌潘生丁的用途。
发明背景
潘生丁{2，6-二(二乙醇氨基)-4，8-二哌啶基-嘧啶并[5，4-d]嘧啶}，接近相关取代的嘧啶并-嘧啶及其制剂已公开在例如美国专利3,031,450中。进一步相关取代的嘧啶并-嘧啶及其制剂已公开于例如英国专利1,051,218中，特别是化合物单哌潘生丁{2，6-二(二乙醇氨基)-4-哌啶基嘧啶并[5，4-d]嘧啶}。在1960年代早期二吡嗒摩被当作冠状动脉扩张剂。其也以抑制腺苷摄取的血小板凝集抑制剂特性而著名。接着，在兔子模型的脑动脉循环研究上显示潘生丁能够降低血栓形成。这些研究引导其用作抗血栓剂；很快成为如应用在中风预防、维持冠状动脉旁路开放及瓣膜置换的选择治疗，以及冠状动脉血管造形术之前治疗上。
进一步，在欧洲中风预防研究2(the European Stroke Prevention Study 2，ESPS-2；神经科学期刊(J Neurol Sci.)1996；143：1-13；神经学(Neurology)1998；51：17-19)证明经单独使用潘生丁的治疗可如低剂量阿斯匹林一样有效降低中风危险，并且潘生丁和阿斯匹林的结合疗法比单独使用阿斯匹林效力超过二倍。
潘生丁经数个机制抑制血栓形成。早期研究显示其抑制内生性有效抗血栓化合物-腺苷的摄取。也显示潘生丁抑制环状AMP磷酸二酯酶，因此增加细胞内c-AMP。
实验室模型模拟血管复杂生理学显示血管系统并不是被动管道，在血管受伤后经复杂的检测和平衡系统和血液产生深远交互作用以保护其完整性。因此内皮产生前列环素，一种强力凝集抑制剂。正常内皮不具血栓形成性并且会预防血小板附着。不同刺激剂促使内皮-驱动的松弛因子(EDRF)释放，其可抑制血小板附着和凝集。同时，给药硝基化合物后细胞内增加cGMP显示能够松弛平滑肌细胞。因此内皮可以经由二个分开机制抑制血栓形成，一是经由前列环素和c-AMP介导，另一是用EDRF和c-GMP介导。潘生丁显示会增强这二者血管壁抗血栓机制，此外还有腺苷-节制效力。其经由增加细胞内cAMP浓度刺激前列环素产生，并且经由增加cGMP提高强力抗血栓形成的氧化氮系统。
潘生丁也具有抗氧化剂特性(自由基生物医学(Free Radic.Biol.Med.)1995；18：239-247)，其有助于抗血栓形成作用。当低密度脂蛋白氧化后会被巨噬细胞清除受体识别，此被认为是动脉硬化发展过程必要步骤。(医学年评(Ann.Rev.Med.)1992；43：219-25)。
在实验性肝硬化中发现用潘生丁抑制自由基形成能抑制纤维化(肝脏学(Hepatology)1996；24：855-864)并且在氨基酸-核苷酸肾病的实验动物中能抑制氧自由基和蛋白尿(欧洲临床研究期刊(Eur.J.Clin.Invest.)1998；28：877-883；肾生理学(Renal Physiol.)1984；7：218-226)。在人类非瘤肺组织中也观察到对脂肪过氧化的抑制(普通药理学(Gen.Pharmacol.)1996；27：855-859)。
单哌潘生丁已知具有抗血栓形成以及其他抗转移特性。
发明概要
令人惊讶地发现潘生丁和单哌潘生丁对血管壁具有保护作用，因此强力影响血管壁和凝血系统中血纤维蛋白路径的交互作用，结果在刺激血块形成后产生血纤维蛋白聚集的基本降低。
由于已知凝血酶原酶复合体定位在带负电荷细胞膜的磷脂时显著地转变为更具活性使得血管损伤会加速血纤维蛋白聚集。用稳定细胞膜，使较少负电荷的磷脂酰丝氨酸可转而曝露在细胞膜外层，对凝血酶原酶复合体提供较少机会与磷脂结合，因此预防凝血酶原酶复合体在其全转换率下操作将凝血酶原转变成为凝血酶，其负责将血纤维蛋白原转换成血纤维蛋白。
血小板积聚和血纤维蛋白积聚是包含在血块形成中的基本路径。而且显示此二种路径的时程有本质上的不同(血栓形成与止血(Thromb.Haemost.)1993；69(摘要)：569)，证明此二个机制并不如预期地密切结合。其实已知潘生丁和单哌潘生丁作为血小板凝集抑制剂的活性，而更新发现指出此二药剂是由稳定血管壁细胞膜的能力调节的额外血纤维蛋白聚集抑制剂。这效力对小血管或微血管特别重要因为血管壁表面积对血液体积的比值高，并且对血纤维蛋白-依赖性微循环障碍的治疗和预防提供新的方法。因此潘生丁和单哌潘生丁具有治疗多种疾病包含渐进式中小尺寸血管失调疾病的潜力。
对较大血管和短期治疗情况或预防急性状况，一般认为已知潘生丁血管扩张活性更为重要。已知使用潘生丁当作应激反应测试剂时，用短期高剂量潘生丁输液使得血管自我调节迟滞落后，因此显现不相称灌注。经核子显影或超音波心脏动态诊断，此可用来区别血流在后期-狭窄区域的较少增加和在循环的健康部位的较大增加。在长期口服治疗血浆中潘生丁以及相关腺苷浓度增加超过数小时期间允许自我调节系统产生补偿作用，因此在“应激反应测试”状况下潘生丁血浆浓度以及腺苷浓度在四分钟内达到巅峰。已经发现根据本发明的治疗对小或微血管可提供持续性效果，因此持续性改善微循环。
发现潘生丁和单哌潘生丁经由血管壁和细胞膜稳定效应对血纤维蛋白聚集具有显著抑制活性，也为与其它抗血栓形成剂结合治疗提供理论方法，其他抗血栓形成剂有如血小板凝集抑制剂例如乙酸水杨酸(ASA)、氯砒格雷或噻氯匹定或其医药可接受的盐类，血纤维蛋白原接受体拮抗剂(阿伯西森马伯(Abciximab)，RDGS-肽、合成静脉注射或口服血纤维蛋白原拮抗剂，例如，伐达菲奔(fradafiban)、拉伐达菲奔(lefradafiban)或其医药可接受盐类)，肝素和类肝素或抗凝血酶，或为结合治疗使用额外心血管疗法如使用ACE抑制剂，血管紧张素II拮抗剂，钙-拮抗剂或降脂剂如史塔廷(statins)。
ASA经由直接作用在血小板来抑制凝集，更详细地说，用不可逆地乙酰化血小板环氧合酶，而抑制具强力血栓形成的血栓烷产生。然而，阿斯匹林在高剂量时会穿过进入内皮细胞(新英格兰医学杂志(N.Eng.J.Med.1984；311：1206-1211)，中断天然有效血小板凝集抑制剂和“花生四烯酸(arachidonic cascade))”副产物-前列环素生成。(新英格兰医学杂志1979；300：1142-1147)。这些观察引导出以低剂量ASA抗血小板治疗的概念将血栓烷抑制增至最大，同时将前列环素损失减至最小(柳叶刀(Lancet)1981；1：969-971)。根据本发明结合潘生丁或单哌潘生丁和低剂量ASA概念优选。
本发明一方面提供治疗或预防人类或非-人类动物体，优选哺乳动物血纤维蛋白-依赖性微循环障碍或包含微循环障碍的疾病状态的方法，该方法包含给药该动物体有效量的药物组合物，该组合物包含选自潘生丁、单哌潘生丁和其医药可接受盐，优选潘生丁的嘧啶并-嘧啶，任选结合一或多种其它抗血栓形成剂。
本发明另一方面提供选自潘生丁、单哌潘生丁和其医药可接受盐，优选潘生丁的嘧啶并-嘧啶，任选结合一或多种其它抗血栓剂的用途，其用于制备治疗或预防人类或非-人类动物体，优选哺乳动物血纤维蛋白-依赖性微循环障碍或包含微循环障碍的疾病状态的医药组合物。
发明详述
本发明提供治疗和预防与进行性的中小尺寸血管失调有关的的血纤维蛋白-依赖性微循环障碍的新方法，包含给药须要此治疗的人士有效量的含有选自潘生丁、单哌潘生丁和其医药可接受盐类的嘧啶并-嘧啶的医药组合物。
血纤维蛋白-依赖性微循环障碍意指其中血纤维蛋白沉积的疾病包含病理发生或中或小尺寸血管机能障碍的进行导致种种临床症状。已知代谢疾病如糖尿病会引起该微循环障碍，然而，发炎反应也会引起微循环障碍，起因于从组织发炎部位释放出血纤维蛋白原。进一步认为微循环障碍也可能起因于自体免疫反应。
应该了解“血纤维蛋白-依赖性微循环障碍”征候以非-限定方式包含代谢疾病引起的其中血管受损的微循环障碍包括：
如糖尿病血管病，特别是糖尿病微血管病，例如糖尿病坏疽、糖尿病视网膜病变、糖尿病神经病变或小腿溃疡，
发炎反应引起的微循环障碍，
如克罗恩疾病(morbus crohn，局部性回肠炎)
自体免疫疾病引起的微循环障碍，
如自体免疫慢性-活性肝炎(特发性肝炎)，原发性-胆汁性硬变或(自体免疫相关)多发性硬化症，
外周性微循环障碍，
如雷那德疾病(Raynaud′s disease)，耳鸣或突发性失聪，
与增加细胞断裂有关的微循环障碍，
如肿瘤疾病或血栓形成血小板减少紫癜(TTP)，
或其他症候，
肾硬化，
肾前性高血压，
溶血性尿毒症征综合症(HUS)，
动脉高血压，
血管性痴呆，
阿滋海默症(Alzheimer′s disease)
沙德克氏萎缩病(Sudeck′s disease)
眼睛中央-静脉血栓，
缺血性视神经病，
高半胱氨基酸-诱导的血管病，
缺血性或冠状动脉心脏病，
预防心肌梗塞或再梗塞和治疗或预防动脉硬化。
“血纤维蛋白-依赖性微循环障碍”征候也包括相应的心肌病症。因此本发明提供给须要此治疗的人士，例如遭受缺血性或冠状动脉心脏疾病，改善心肌血流供应的方法以及预防心肌梗塞或再梗塞的方法。
而且本发明也提供治疗或预防动脉硬化的方法以给药潘生丁和单哌潘生丁支持或帮助改善或恢复满足血管的微循环。
本文中已指出潘生丁，单哌潘生丁或其医药可接受的盐类可以单独使用于单一制剂或与其它抗血栓形成剂结合治疗血纤维蛋白-依赖性微循环障碍。
潘生丁和单哌潘生丁血浆浓度宜维持在约0.2至5微摩尔/升，优选约0.4至5微摩尔/升，更优选约0.5至2微摩尔/升或最优选约0.8至1.5微摩尔/升。达到此效果可使用任何市售潘生丁口服迟缓型、即时型或非经肠道型制剂，优选迟缓型制剂，例如可购得的商标名潘生
Figure C0081467500081
Figure C0081467500082
或者与低剂量ASA结合治疗，使用下列可购得的商标名阿散 或阿葛挪克斯制剂。潘生丁迟缓型制剂已公开在EP-A-0032562，即时型制剂公开在EP-A-0068191，而且ASA和潘生丁的结合公开在EP-A-0257344，这些文献引入本说明书作为参考文献。单哌潘生丁也有口服迟缓型、即时型或非经肠道型制剂可供使用，例如公开在GB 1,051,218或公开在EP-A-0,108,898，优选为迟缓型配方。
潘生丁和单哌潘生丁可口服给药，每日剂量25至450毫克，优选50至240毫克，最优选75至200毫克。在长期治疗上，宜每日三或四次给药重复剂量如25毫克潘生丁迟缓型剂量或任何其它即时释放制剂。对于非经肠道给药，潘生丁在24小时期间通过缓慢静脉输注(不可超过0.2毫克/分钟)给药0.5至5毫克/公斤体重的剂量，优选1至3.5毫克/公斤体重。
潘生丁和单哌潘生丁与低剂量ASA的结合可以口服合并给药，每日10至30毫克ASA和50至300毫克潘生丁和单哌潘生丁，优选80至240毫克潘生丁和单哌潘生丁，例如重量比介于1比5和1比12之间，最优选重量比为1比8，例如25毫克ASA和200毫克潘生丁或单哌潘生丁。
其它抗血栓化合物可给与0.1至10倍，优选0.3至5.0倍，最优选0.3至2.0倍于临床记述剂量(例如罗特
Figure C0081467500087
1999；伐达菲奔、拉伐达菲奔：EP-A-0483667，结合潘生丁或单哌潘生丁每日剂量25至450毫克，优选50至240毫克，最优选75至200毫克。
对于结合的治疗，使用潘生丁和单哌潘生丁和ACE抑制剂，本技术领域中已知的任何ACE抑制剂都可适用，例如贝那秦普利(benazepril)，卡托普利(captopril)，西洛普利(ceronapril)，恩那普利(enalapril)，福森普利(fosinopril)，咪哒普利(imidapril)，赖诺普利(lisinopril)，摩依洗普利(moexi pril)，喹那普利(quinapril)，雷米普利(ramipril)、川多普利(trandolapril)或哌道普利(perindopril)，使用本技术领域中已知剂量，例如罗特
Figure C0081467500088
1999所述，Editio Cantor Verlag Aulendorf。
对于结合治疗，使用潘生丁或单哌潘生丁和血管紧张剂II拮抗剂，本技术领域中已知任何血管紧张剂II拮抗剂都可适用，例如沙腾(sartan)如肯德沙腾(candesartan)，依波沙腾(eprosartan)、艾尔宾沙腾(irbesartan)、露沙腾(losartan)、帖尔米沙腾(telmisartan)、凡尔沙腾(valsartan)、欧尔媚沙腾(olmesartan)、或泰松沙腾(tasosartan)，使用本技术领域已知剂量，例如罗特
Figure C0081467500091
1999所述，Editio Cantor Verlag Aulendorf。
对于结合治疗，使用潘生丁和单哌潘生丁和钙-拮抗剂，本技术领域已知任何钙-拮抗剂都可适用，例如硝苯地平(nifedipine)，硝群地平(nitrendipine)，尼索地平(nisoldipine)、尼尔伐地平(nilvadipine)、伊拉地平(isradipine)、费乐地平(felodipine)、或拉西地平(lacidipine)，使用本技术领域已知剂量，例如罗特
Figure C0081467500092
1999所述，Editio Cantor Verlag Aulendorf。
对于结合治疗，使用潘生丁和单哌潘生丁和史塔延(statin)，本技术领域已知史塔廷都可适用，例如洛伐史塔廷(lovastatin)、喜伐史塔廷(simvastatin)，使用本技术领域已知剂量，例如罗特
Figure C0081467500093
1999所述，Editio Cantor VerlagAulendorf。
值得注意与增加细胞断裂有关的微循环障碍，如上所述，特别会加速血纤维蛋白积聚，起因于具潜在游离细胞膜区域活化凝血酶原酶复合体。这些微循环障碍，例如肿瘤疾病或血栓形成血小板减少紫癜，优选治疗使用高剂量潘生丁或单哌潘生丁。意指潘生丁或单哌潘生丁血浆浓度达约0.2至50微摩尔/升，优选约0.5至20微摩尔/升，特别是约0.5至10微摩尔/升，优选以缓速静脉输液来维持。针对这些征候的口服治疗，潘生丁或单哌潘生丁可给药每日剂量约150至1000毫克，优选约200至800毫克，最优选约200至600毫克。
与增加细胞断裂有关的微循环障碍也可用潘生丁或单哌潘生丁和低剂量ASA的结合来治疗，使用上述高剂量潘生丁或单哌潘生丁，和每日口服剂量约10至30毫克ASA，优选约25毫克ASA。
为了研究以潘生丁抑制血纤维蛋白堆积，以下列实验进行：
在体内使用放射性标记的血小板和血纤维蛋白原的研究
将使用99Tc放射性标记的血小板和使用123I放射性标记的血纤维蛋白原研究潘生丁和肝素的效力。方法在物理研究中的核子仪器和方法(NuclearInstruments and Methods in Physics Research)A.1994，353：448-452中描述。放置能量-敏感固相放射探测器包围兔子颈动脉。经气囊血管造形术诱发损伤后，监测血小板和血纤维蛋白原的积聚达4小时。发现血小板和血纤维蛋白原积聚具有不同时程。在受损后放射性标记的血小板注射达30分钟时没有检测到积聚现象；显然血管造形术部位已被内生性血小板附着所钝化。反之，血纤维蛋白原积聚在对照组和治疗组动物上甚至在四小时后尚未达到平稳状态，所以指出受损后在不同时间点由不同刺激或促进因子调节血纤维蛋白原(图1)。以肝素治疗降低血小板和血纤维蛋白原二者的积聚。以潘生丁治疗也会产生血小板凝聚的降低，同于肝素所见；然而，对血纤维蛋白原积聚的降低用潘生丁远大于用肝素的效果(图2)。
图解：
图1；在兔子颈总动脉的血管造形术后每分钟间隔99Tc-标记的血小板和123I-标记的血纤维蛋白原的同步检测。对照(无治疗)组(N＝6)显示在受损后血小板快速增加和血纤维蛋白原逐渐增加。以肝素治疗(100U/公斤大剂量后接续25U/公斤/小时输液)显示血小板以及血纤维蛋白积聚的降低。没有损伤时测量显现恒定放射活性。
图2：以潘生丁(0.25毫克/公斤接着0.45毫克/公斤/小时)治疗后在血管造形术位置放射活性标记的血小板(99Tc)和血纤维蛋白(123I)的沉积。血小板沉积降低，但是在血管造形术后第一个四小时期间血纤维蛋白原积聚几乎完全被阻断。

Claims (4)

1. 选自潘生丁、单哌潘生丁和其医药可接受的盐的药物在制备用于治疗疾病的口服药用组合物中的用途，该口服药物组合物含有该药物作为唯一的有效化合物，能提供每日剂量25至450毫克的该药物，其中所述的疾病选自：糖尿病坏疽、糖尿病神经病变以及小腿溃疡。
2. 根据权利要求1的用途，其中该药用组合物为口服迟缓型或即时型制剂。
3. 选自潘生丁、单哌潘生丁和其医药可接受的盐的药物与一种或多种其他抗血栓形成剂的组合或者选自潘生丁、单哌潘生丁和其医药可接受的盐的药物与ACE抑制剂、血管紧张素II拮抗剂、Ca-拮抗剂或降脂剂的组合在制备用于治疗或预防人类或非人类动物体中选自糖尿病坏疽、糖尿病神经病变以及小腿溃疡的疾病的药物组合物中的用途，其中该抗血栓形成剂选自乙酰水杨酸、氯砒格雷或噻氯匹定或其医药可接受的盐类、血纤维蛋白原受体拮抗剂、肝素和类肝素，
其中，当与选自氯砒格雷或噻氯匹定或其医药可接受的盐类、血纤维蛋白原受体拮抗剂、肝素和类肝素的一种或多种其他抗血栓形成剂组合时，或与ACE抑制剂、血管紧张素II拮抗剂、Ca-拮抗剂或降脂剂组合时，该组合物能提供每日口服剂量25至450毫克的潘生丁、单哌潘生丁或其医药可接受的盐，以及
当与乙酰水杨酸组合时，该组合物能提供每日口服剂量50至300毫克的潘生丁、单哌潘生丁或其医药可接受的盐，和每日口服剂量10至30毫克的乙酰水杨酸。
4. 根据权利要求1～3中任一项的用途，其特征是该药物是潘生丁或其医药可接受的盐类。
CNB008146756A 1999-10-22 2000-10-14 潘生丁或单哌潘生丁在制备用于治疗及预防血纤维蛋白依赖性微循环障碍药物中的用途 Expired - Fee Related CN100411620C (zh)

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Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1093814A1 (en) * 1999-10-22 2001-04-25 Boehringer Ingelheim Pharma KG Use of dipyridamole or mopidamol in the manufacture of a medicament for the treatment and prevention of fibrin-dependent microcirculation disorders
US7064130B2 (en) * 2001-04-20 2006-06-20 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of radical-scavenging compounds for treatment and prevention of NO-dependent microcirculation disorders
DE10119680A1 (de) * 2001-04-20 2002-11-14 Boehringer Ingelheim Pharma Verwendung von Radikalfänger-Verbindungen zur Behandlung und Verhinderung von no-abhängigen Störungen der Mikrozirkulation
RU2322984C2 (ru) 2001-10-05 2008-04-27 Комбинаторкс, Инкорпорейтед Комбинации для лечения иммуновоспалительных расстройств
MY131170A (en) * 2002-03-28 2007-07-31 Nissan Chemical Ind Ltd Therapeutic agent for glomerular disease
DE10335027A1 (de) * 2003-07-31 2005-02-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verwendung von Angiotensin II Rezeptor Antagonisten
CA2515266A1 (en) * 2003-02-07 2004-08-19 Boehringer Ingelheim International Gmbh Use of dipyridamole or mopidamole for treatment and prevention of mmp-9-dependent disorders
DE10306179A1 (de) * 2003-02-13 2004-08-26 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verwendung von Dipyridamol in Kombination mit Acetylsalicylsäure und einem Angiotensin II-Antagonisten zur Schlaganfall-Prophylaxe
KR20060007034A (ko) * 2003-04-24 2006-01-23 베링거 인겔하임 인터내셔날 게엠베하 혈전색전증 질환 및 트롬빈의 과형성 및/또는 트롬빈수용체의 상승된 발현에 의해 유발된 질환 및 장애를치료하고 예방하기 위한, 디피리다몰 또는 모피다몰의 용도
JP2005060359A (ja) * 2003-08-13 2005-03-10 Boehringer Ingelheim Pharma Gmbh & Co Kg 血管系病態の治療及び予防のためのジピリダモール、アセチルサリチル酸及びアンギオテンシンｉｉ拮抗薬の使用
TW200517114A (en) * 2003-10-15 2005-06-01 Combinatorx Inc Methods and reagents for the treatment of immunoinflammatory disorders
RU2006143838A (ru) 2004-05-13 2008-06-20 БЕРИНГЕР ИНГЕЛЬХАЙМ ИНТЕРНАЦИОНАЛЬ ГмбХ (DE) Применение дипиридамола для лечения устойчивости к ингибиторам тромбоцитов
JP4880591B2 (ja) 2004-06-04 2012-02-22 テバ ファーマシューティカル インダストリーズ リミティド イルベサルタンを含む医薬組成物
ATE390138T1 (de) * 2006-02-09 2008-04-15 Teva Pharma Dipyridamol enthaltende zusammensetzungen mit verlängerter freisetzung und verfahren zu deren herstellung
US20100062066A1 (en) * 2006-11-14 2010-03-11 Acusphere, Inc Formulations of Tetrahydropyridine Antiplatelet Agents for Parenteral or Oral Administration
EP2991634A1 (en) 2013-04-30 2016-03-09 Otitopic Inc. Dry powder formulations and methods of use
TW201503900A (zh) * 2013-07-29 2015-02-01 ren-zheng Lin 增強治療急性中風之抗血小板藥物之遞送方法及其組合物
AU2016212527B2 (en) * 2015-01-28 2019-03-07 Realinn Life Science Limited Compounds for enhancing PPARgamma expression and nuclear translocation and therapeutic use thereof
KR101736832B1 (ko) 2017-02-28 2017-05-17 초당약품공업 주식회사 디피리다몰을 유효 성분으로 함유하는 신장 질환 치료용 의약 조성물
CN114432451B (zh) * 2018-12-21 2024-02-09 广州市妇女儿童医疗中心 胃肠道疾病的免疫机制及治疗药物
CN111346228B (zh) * 2018-12-21 2022-01-14 广州市妇女儿童医疗中心 胃肠道疾病的免疫机制及治疗药物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1685450A1 (ru) * 1989-03-10 1991-10-23 Московский медицинский стоматологический институт им.Н.А.Семашко Способ лечени скаленус-синдрома при шейном остеохондрозе
EP0457671A2 (en) * 1990-05-14 1991-11-21 FIDIA S.p.A. Dipyridamide for the treatment of diseases of the central or peripheral nervous system
CN1111985A (zh) * 1994-05-06 1995-11-22 王志刚 阿司匹林与潘生丁复方多层片的制备方法
CN1152436A (zh) * 1995-12-22 1997-06-25 王介明 一种治疗缺血性脑血管病和脑血栓的康复液及其制法
CN1227100A (zh) * 1999-01-26 1999-09-01 广东药学院 一种治疗、预防血栓形成及中风的复方制剂及其制备方法

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3031450A (en) * 1959-04-30 1962-04-24 Thomae Gmbh Dr K Substituted pyrimido-[5, 4-d]-pyrimidines
DE2735830A1 (de) * 1977-08-09 1979-03-01 Thomae Gmbh Dr K Antithrombotische arzneimittelkombination und verfahren zu ihrer herstellung
DE3000979A1 (de) * 1980-01-12 1981-07-23 Dr. Karl Thomae Gmbh, 7950 Biberach Neue dipyridamol-retardformen und verfahren zu ihrer herstellung
DE3124090A1 (de) * 1981-06-19 1983-01-05 Dr. Karl Thomae Gmbh, 7950 Biberach Neue orale dipyridamolformen
DE3237575A1 (de) * 1982-10-09 1984-04-12 Dr. Karl Thomae Gmbh, 7950 Biberach Neue orale mopidamolformen
JPS6153271A (ja) * 1984-08-24 1986-03-17 Kaken Pharmaceut Co Ltd ローダニン誘導体
ATE50497T1 (de) * 1984-07-21 1990-03-15 Hoechst Ag Kombinationspraeparat aus pyrimido-pyrimidinen und o-acetylsalicylsaeure bzw. deren pharmakologisch vertraeglichen salzen und dessen verwendung.
DE3627423A1 (de) * 1986-08-13 1988-02-18 Thomae Gmbh Dr K Arzneimittel enthaltend dipyridamol oder mopidamol und o-acetylsalicylsaeure bzw. deren physiologisch vertraegliche salze, verfahren zu ihrer herstellung und ihre verwendung zur bekaempfung der thrombusbildung
US5242921A (en) * 1988-04-27 1993-09-07 Yale University Compositions and methods for treating cutaneous hyperproliferative disorders
US5639482A (en) * 1993-11-10 1997-06-17 Crary; Ely J. Composition for control and prevention of diabetic retinopathy
US5498613A (en) * 1994-06-07 1996-03-12 The University Of Southern California Dipyridamole and analogs thereof in preventing adhesion formation
US5968983A (en) * 1994-10-05 1999-10-19 Nitrosystems, Inc Method and formulation for treating vascular disease
US5620409A (en) * 1995-09-15 1997-04-15 The Research Foundation Of State University Of New York Method for inhibiting clot formation
KR20010013413A (ko) * 1997-06-05 2001-02-26 피터 지. 스트링거 혈전성 질환의 치료 방법
CA2378257A1 (en) * 1999-08-10 2001-02-15 William E. Sponsel Method for increasing optic nerve, choroidal and retinal blood flow to facilitate the preservation of sight
EP1093814A1 (en) * 1999-10-22 2001-04-25 Boehringer Ingelheim Pharma KG Use of dipyridamole or mopidamol in the manufacture of a medicament for the treatment and prevention of fibrin-dependent microcirculation disorders
DE10011482B4 (de) * 2000-03-09 2004-06-09 Fresenius Hemocare Gmbh Verfahren zum Herstellen eines Adsorbens zum Absenken der Konzentration von Fibrinogen und/oder Fibrin, Adsorbens und Verwendung des Adsorbens zur Herstellung eines Adsorbers
US6979462B1 (en) * 2000-10-03 2005-12-27 Mutual Pharmaceutical Co., Inc. Stabilization of solid drug formulations
US7064130B2 (en) * 2001-04-20 2006-06-20 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of radical-scavenging compounds for treatment and prevention of NO-dependent microcirculation disorders
US20020187187A1 (en) * 2001-04-21 2002-12-12 Toshimitsu Ohki Fast disintegrating meloxicam tablet
US7064103B2 (en) * 2002-01-04 2006-06-20 Becton, Dickinson And Company Binding protein as biosensors
US20030180282A1 (en) * 2002-03-25 2003-09-25 Victor Serebruany Method of treatment of thrombotic events
CA2515266A1 (en) * 2003-02-07 2004-08-19 Boehringer Ingelheim International Gmbh Use of dipyridamole or mopidamole for treatment and prevention of mmp-9-dependent disorders
KR20060007034A (ko) * 2003-04-24 2006-01-23 베링거 인겔하임 인터내셔날 게엠베하 혈전색전증 질환 및 트롬빈의 과형성 및/또는 트롬빈수용체의 상승된 발현에 의해 유발된 질환 및 장애를치료하고 예방하기 위한, 디피리다몰 또는 모피다몰의 용도

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1685450A1 (ru) * 1989-03-10 1991-10-23 Московский медицинский стоматологический институт им.Н.А.Семашко Способ лечени скаленус-синдрома при шейном остеохондрозе
EP0457671A2 (en) * 1990-05-14 1991-11-21 FIDIA S.p.A. Dipyridamide for the treatment of diseases of the central or peripheral nervous system
CN1111985A (zh) * 1994-05-06 1995-11-22 王志刚 阿司匹林与潘生丁复方多层片的制备方法
CN1152436A (zh) * 1995-12-22 1997-06-25 王介明 一种治疗缺血性脑血管病和脑血栓的康复液及其制法
CN1227100A (zh) * 1999-01-26 1999-09-01 广东药学院 一种治疗、预防血栓形成及中风的复方制剂及其制备方法

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