CN1768735A - 糖尿病性合并症和神经障碍用的药剂及其应用 - Google Patents
糖尿病性合并症和神经障碍用的药剂及其应用 Download PDFInfo
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Abstract
通过将餐后血糖降低剂作为有效成分使用，提供了在糖尿病性合并症的预防、改善、治疗等中优秀的药剂和神经障碍的预防、改善、治疗等中优秀的药剂。特别是，那格列奈等D－苯基丙氨酸衍生物、ミチグリニド等琥珀酸苄基酯衍生物和瑞格列奈等苯甲酸衍生物作为口服给药剂期待很大。通过本发明，由于提供了这些等优秀的药剂及其使用方法(为进行前述治疗等的对生物体内的给药方法等)或，为制造该药剂的餐后血糖降低剂的应用等，通过将降压剂、末梢循环改善剂和高血脂症治疗药的至少1种进一步在该药剂中混合，或与该餐后血糖降低剂组合并用、使用，可进一步提高前述合并症的预防、改善、治疗等的效果。
Description
本申请是申请号为CN01806731.X(国际申请日为2001年3月15日)、发明名称为“糖尿病性合并症和神经障碍用的药剂及其应用”的进入国家阶段的PCT申请的分案申请。
技术领域
本发明涉及适用于糖尿病性合并症或神经障碍的新的药剂，更详细地说，涉及含有餐后血糖降低剂的适用于糖尿病性合并症的预防、改善和/或治疗的药剂，和含有餐后血糖降低剂的适用于神经障碍的预防、改善和/或治疗药用的药剂，以及这些药剂的使用(为了前述糖尿病性合并症、或神经障碍的预防、改善和/或治疗的该药剂的使用等)或为制造前述药剂的前述餐后血糖降低剂的使用等。
背景技术
糖尿病是以持续慢性高血糖为主要特征的疾病。虽然糖尿病患者的数量在世界中不断增加，但是通过胰岛素、抗生素等，糖尿病性昏睡，感染症的危险大大减少了。但是，即使是现在，糖尿病导致作为细小血管症带来的神经障碍、视网膜症和肾病的所谓三大合并症的频率也很高，因此患者的日常生活或社会活动被显著限制，被强迫进行不自由的生活。另外，已知其是促进可被称为大血管病原因的动脉硬化的危险因子，即使发作糖尿病，也不使之导致这些等血管合并症的发病或发展，已成为现代糖尿病治疗的重要课题、目标。
发明的课题
现在的状况是，还没有适用于这些等合并症的预防、改善、治疗方法中的优秀的药剂。
虽然在DCCT研究或UKPDS研究报导了通过注射胰岛素或磺酰脲剂(氯磺丙脲、优降糖、吡磺环己脲等)严格的血糖控制可减轻合并症的发病、发展危险，但是，即使具有这些等也不能完全控制合并症的发病。另外，作为慢性合并症治疗药现在用于临床的口服给药制剂只有醛糖还原酶抑制剂，而且其有效性也可以说是有限的，因此期待开发特别是作为口服制剂的优秀的其它药剂。
另一方面，神经障碍是中枢和末梢神经功能异常引起的障碍，除了知觉、感觉异常，运动障碍以外，还包含很多神经症状，有糖尿病引起的(作为合并症)，但是不是糖尿病引起的也很多，适用于这样的障碍的，即在神经障碍的预防、改善、治疗中必要的优秀药剂还没有。
在上述情况下，需要开发对糖尿病性合并症或神经障碍有效的药剂。在本发明应解决的课题是，开发、提供这样的药剂。
发明的公开
本发明者为解决上述课题，反复积极研究的结果发现，餐后血糖降低剂可改善作为糖尿病模型动物已知的Goto-Kakizaki大鼠(以下称为“GK大鼠”)的运动神经传导速度的降低，因此可作为糖尿病性合并症的预防、改善和治疗用药剂使用，而且还可作为非糖尿病引起的神经障碍的预防、改善和治疗用药剂使用。
另外，本发明者等，在GK大鼠中发现，餐后血糖降低剂可抑制作为神经障碍指标的神经内Na+/K+-ATP酶活性的降低，抑制作为血管障碍指标的血中vWF浓度的上升，并降低作为动脉硬化、大血管障碍危险因子的血中脂质。
基于这些等各种发现，完成了本发明。
即，本发明，作为一个形态是存在于药剂或药品中，作为其代表性的物质可列举：
(1)以含有餐后血糖降低剂为特征的糖尿病性合并症的预防、改善和/或治疗用药剂；
(2)以含有餐后血糖降低剂为特征的神经障碍的预防、改善和/或治疗用药剂，和
(3)在以含有降压剂、末梢循环改善剂和高血脂症治疗药中的至少一种和餐后血糖降低剂，或组合为特征的糖尿病性合并症的预防、改善和/或治疗用药剂中适用的，或可使用的药品。
前述糖尿病性合并症的预防、改善和/或治疗用药剂，可通过在其中进一步混合降压剂、末梢循环改善剂和高血脂症治疗药的至少一种(以合剂等同一制剂形态)，和/或与这些等组合使用，可进一步提高其效果。组合使用时，可以不同的制剂(多种制剂)的形态，同时或设定适当的时间给药。此时，对于给药顺序没有特别的限制。
本发明是，作为一个形态是面向这些等的药剂、药品，将这些等合并总称为“本发明药剂”。
下面，本发明作为另外的形态存在于在该药剂的使用中，作为代表性的物质可列举：
(4)具有以餐后血糖降低剂为有效成分对生物体给药为特征的糖尿病性合并症的预防、改善和/或治疗方法；和
(5)具有以餐后血糖降低剂为有效成分对生物体给药为特征的神经障碍的预防、改善和/或治疗方法。
另外，作为本发明的其它形态，还有餐后血糖降低剂在前述本发明药剂制备中的应用，作为代表可列举：
(6)为制造糖尿病性合并症的预防、改善和/或治疗用药剂的餐后血糖降低剂的应用；
(7)为制造神经障碍的预防、改善和/或治疗用药剂中的餐后血糖降低剂的应用；和
(8)为制造糖尿病性合并症的预防、改善和/或治疗用药剂的，与降压剂、末梢循环改善剂和高血脂症治疗药的至少一种一起的餐后血糖降低剂的应用。
另外，在上述糖尿病性合并症的预防、改善和/或治疗方法中，通过使用降压药、末梢循环改善剂和高血脂症治疗药的至少一种对该生物体给药，可进一步提高其效果。此时，对于并用给药的方法没有特别的限制，例如，可使用前述各个多个制剂在时间上同时给药，也可以是多个制剂在不同的时间对同一生物体给药。对于其给药顺序没有特别的限制。
另外，在上述为制造糖尿病性合并症的预防、改善和/或治疗用药剂的餐后血糖降低剂的应用中，与前述相同，可将降压药、末梢循环改善剂和高血脂症治疗药的至少一种在该餐后血糖降低剂中混合使用，可以与降压药、末梢循环改善剂和高血脂症治疗药的至少一种组合的形态使用该餐后血糖降低剂，通过这些等的方法，可进一步提高其效果。但是对于该组合的方法，与前述同样，没有特别的限制。
附图的简要说明
[图1]
图1是实施例1中，显示通过动物实验的运动神经传导速度的测定结果图。
[图2]
图2是实施例3中，显示通过动物实验的血浆中总胆固醇浓度的测定结果随时间变化的图。
◇：GK，病态对照组；■：GK，优降糖组；▲：GK，那格列奈(ナテグリニド)组；和×：正常对照组。
实施方案
下面对本发明的实施形态进行说明。
本发明是，如前所述的特定药剂、药品(本发明的药剂)，这些等药剂的使用(使用方法、给药方法等)，或为制造这些等药剂的餐后血糖降低剂的使用等，由于可以说该药剂是本发明中共同的重要要素(构成要素)，因此下面对以该药剂为中心的本发明进行以下说明。
本发明的药剂，可以是作为目的的药剂本身、药品本身，对于其给药场合的对象没有特别的限制，但是可代表性列举需要糖尿病性合并症或神经障碍的预防、改善、治疗等的患者。对于必需这些等药剂的生物体、特别是哺乳动物，通常是人(患者)，应用其有效量。该药剂的适用方法(给药方法)与在本发明中的糖尿病性合并症、或神经病的预防、改善和/或治疗方法相对应。另一方面，将下述详细描述的餐后血糖降低剂作为前述药剂的必须有效成分使用，即，含有实质上与其等同的该餐后血糖降低剂作为必须有效成分的状态的药剂与在本发明中为制造糖尿病性合并症、或神经障碍的预防、改善和/或治疗用药剂的餐后血糖降低剂的使用相对应。
本发明药剂中使用的必须有效成分是餐后血糖降低剂，只要是可以该目的(使餐后的血糖降低的目的)被使用，或具有这样的效果的物质都可以，对此没有特别的限制。因此，选择在本发明中作为改善餐后血糖值的物质被使用的，或可使用的化合物，可作为本发明药剂的必须有效成分使用。也可以使用今后被开发的化合物。餐后血糖降低剂是否合适的判断没有特别的困难，例如，使用用餐负荷前应予评价的药剂给药，测定餐后2小时的血糖值，相对于不使用该药剂时评价血糖上升抑制效果的方法，可进行在本发明可使用的餐后血糖降低剂是否合适的认定。另外，已经作为其它的药剂被开发的物质，例如下述详细描述的那格列奈等作为该餐后血糖降低剂在本发明药剂成分中的利用也是简便的。
作为在本发明中可使用的餐后血糖降低剂的具体例，可列举具有例如激素和新陈代谢研究誌，27卷，263-266页(1995年)中作为氯茴苯酸类所示化合物那样活性(改善餐后血糖值)的物质，更具体地可列举下述通式(1)所示的(-)-N-(反式-4-异丙基环己烷羰基)-D-苯基丙氨酸(称为“那格列奈”)等的D-苯基丙氨酸衍生物(参见特公平4-15221号公报、专利第2508949号公报和特开平10-194969号公报等)，ミチグリニド(KAD-1229)等琥珀酸苄基酯衍生物，瑞格列奈等苯甲酸衍生物。
上述餐后血糖降低剂中，在经口服给药显示优秀效果方面优选包含在氯茴苯酸类的化合物。更优选可列举那格列奈等D-苯基丙氨酸衍生物，ミチグリニド等琥珀酸苄基酯衍生物和瑞格列奈等苯甲酸衍生物，其中更优选那格列奈。
对于本发明药剂对人等给药时的给药方式没有特别的限制。因此，可采用口服给药、非口服给药(静脉给药等)各种给药形式，对于本发明药剂必须的有效成分的获得如前所述，在从已知作为餐后降血糖剂的物质中选择本发明的有效成分时，或者即使在别的用途中采用本发明中使用的药剂成分时，可选择、使用口服给药、非口服给药等给药形式毫无疑问地具有餐后血糖降低作用的化合物，但是可口服给药的药剂是简便的。
在糖尿病合并症中使用本发明药剂时，例如，为了预防、改善和/或治疗糖尿病性合并症给药该药剂时，对于该合并症的种类没有特别的限制，可广泛应用于肾病、视网膜病、神经障碍和血管障碍等。另一方面，在将前述药剂在神经障碍的治疗中使用时，只要是神经障碍就可以，可广泛应用于各种神经障碍。
在本发明的药剂中，可与其它药剂成分(药物活性物质)一起，例如，混合或组合后使用，只要是以这样的本发明目的的含有前述必须有效成分为目的的显示前述药理活性的物质，都包含在本发明的药剂中。
另外，其它的药剂成分可以是盐、或衍生物，在本发明与作为目的的前述必须的有效成分成的盐，或即使是化合物，只要是可显示作为目的的前述药理活性的物质都包括在本发明的药剂中。
作为这样的药剂成分，可列举例如，显示降血糖作用的胰岛素或リスプロ，glargine等胰岛素衍生物，甲苯磺丁脲、格列齐特、格列本脲、格列美脲等磺酰脲剂，阿卡波糖、伏格列波糖、米格列醇等α糖苷酶抑制剂，甲福明、苯乙福明等双胍剂，吡格列酮、ロジグリタゾン、曲格列酮等噻唑烷类或含有GI-262570、JTT-501、YM-440、NN-622、KRP-297等非噻唑烷骨架的PPARγ激动剂、拮抗剂的胰岛素抵抗性改善剂，AJ-9677等肾上腺素β3受体激动剂，CLX-0901等胰岛素样激动药，GLP-1、Exendin-4、NN-2211等GLP-1激动剂，DPP-728A等DPPIV抑制剂、T-1095等SGLT抑制剂等。另外，也可列举可以说对合并症有效果的依帕司他、フィダレスタット、渐那司他、ミナレスタツト等醛糖还原酶抑制剂或甲钴胺或メキシチレン、Y-128等神经障碍治疗剂，α-硫辛酸或普罗布可等抗氧化剂。
特别是，将抑制血管障碍的餐后血糖降低剂和使血压降低的降压剂，例如，卡托普利、地拉普利、阿拉普利、悦宁定、赖诺普利、西拉普利、贝那普利、咪达普利、替莫普利、喹那普利、群多普利、培哚普利等血管紧张素转移酶抑制剂，氯沙坦、カンデサルタン、イルベサルタン、缬纱坦等血管紧张素II受体拮抗剂，ポピンドロ一ル、吲哚洛尔、卡替洛尔、心得安、纳多洛尔、尼普地洛、醋丁洛尔、塞里洛尔、美多心安、阿替洛尔、ピソプロロ一ル、ベキタソロ一ル、拉贝洛尔、卡维地洛、贝凡洛尔、氨磺洛尔、阿罗洛尔等β阻断剂、哌唑嗪、布那唑嗪、特拉唑嗪、多沙唑嗪、乌拉地尔等α1阻断剂，硝苯地平、尼卡地平、尼伐地平、尼群地平、尼索地平、马尼地平、贝尼地平、バルジニピン、氨氯地平、依福地平、非洛地平、西尼地平、阿雷地平、地尔硫卓等钙拮抗剂，环戊噻嗪、三氯噻嗪、氢氯噻嗪、氢氟噻嗪、苄基氢氯噻嗪、甲氯噻嗪、吲达帕胺、氯噻酮、曲帕胺、美替克仑、美托拉宗、美夫西特、阿佐塞米、利尿酸、吡咯他尼、布美他尼、速尿、螺内酯、氨苯喋啶等利尿剂等组合并用或以合剂形式使用，在糖尿病性合并症、特别是肾、神经、视网膜等细小血管障碍中是有效的。
同样，将抑制血管障碍的餐后血糖降低剂和末梢循环改善剂，例如，贝前列腺素、前列地尔等前列腺素衍生物、制剂或酮色林、沙格雷酯、AT-1015等血清素受体拮抗剂，西洛匹林等磷酸二酯酶抑制剂、各种抗血小板药(例如阿斯匹林等)COX抑制剂，奥扎格雷等血栓合成酶抑制剂，塞氯匹定或氯吡格雷等ADP受体抑制剂，除此以外，己酮可可碱、二十五碳烯酸、烟碱酸生育酚等组合并用或作为合剂使用，在糖尿病性合并症、特别是肾、神经、视网膜等细小血管障碍中是有效的。
进一步，将使血中脂质降低的餐后血糖降低剂和高血脂症治疗药，例如，谱伐他汀、辛伐他汀、氟伐他汀、セリバスタチン、アトルバスタチン、イタバスタチン等HMG-CoA还原酶抑制剂或双贝特、氯贝丁酯、克利贝特、苯扎贝特、非诺贝特等フィブラ一ト类药剂，コレスチミド、消胆胺等阴离子交换树脂、尼可莫尔、戊四烟酯等烟碱酸制剂等组合并用或作为合剂使用，在糖尿病性合并症、特别是基于动脉硬化引起的大血管障碍、心肌梗塞、闭塞性动脉硬化症等中是有效的。
此外，可含有药理学上可允许的各种制剂用物质(作为补助剂)(以下，也称为“制剂学上允许的载体)。制剂用物质可根据制剂的剂型适当选择，可列举例如，赋形剂、稀释剂、添加剂、崩解剂、粘合剂、被覆剂、润滑剂、滑走剂、亮滑剂、矫味剂、甜味剂、可溶化剂等。如果进一步具体例示制剂用物质的话，可列举碳酸镁、二氧化钛、乳糖、甘露醇和其它糖类、滑石、牛乳蛋白、明胶、淀粉、纤维素及其衍生物，动物和植物油，聚乙二醇，和溶剂，例如无菌水和一元或多元醇，例如甘油。
本发明的药剂，可制成如前所述公知的或将来被开发的各种药物制剂的形态，例如，口服给药、腹腔内给药、透皮给药、吸入给药等各种给药形态。为将本发明的药剂调制成这些等各种药物制剂，可适当采用公知的或将来被开发的方法。
作为这些等各种药物制剂的形态，可列举例如，适当的固形或液体制剂形态，例如，颗粒、粉剂、包衣片剂、片剂、(微)胶囊、栓剂、糖浆、果汁、悬浮液、乳浊液、滴液剂、注射用溶液、延长活性物质释放的制剂。
存在于以上所示制剂形态中的本发明的药剂中，当然应含有达到药效的有效量的前述成分(餐后血糖降低剂)。
对于本发明药剂中使用的餐后血糖降低剂(有效成分)的给药量，可根据餐后血糖降低剂的种类、合并症的种类、合并症或神经障碍症状的程度、制剂的形态、有无副作用或其程度等适当选择。例如，将那格列奈作为有效成分的制剂，经口服给药，患者每天用那格列奈的净重量表示可给药优选10mg～10g左右，更优选30mg～1g左右，进一步优选90～270mg左右。对于给药的次数、时间，可以是几天1次，或1天1次，但通常是1天几次，例如分2～4次，优选饭前给药。另外，在静脉给药等非经口服给药时，与上述经口服给药相比可以十～二十分之一左右的给药量给药。
从上述说明也可容易地理解在本发明的糖尿病合并症或神经障碍的预防、改善和/或治疗方法中使用时的本发明药剂的使用方法。
更简便地，作为本发明中使用的餐后血糖降低剂，可使用作为餐后血糖降低剂或具有该效果的药剂已经被开发的，或在开发途中等已知的药剂，作为这样的药剂的种类或、各个药剂的有效量，可采用合适的使用量或给药量。关于这样的药剂的种类或其使用方法，给药量等记载的内容，全部作为本申请说明书的一部分作为参考被引入。
如前所述，在本发明药剂中使用的必须成分(餐后血糖降低剂)以外，可进一步使用其它药剂成分，即使在该情况下，可利用基于前述说明或已知的制剂技术，且根据各种剂型可制备必要的制剂。当然，作为其使用量，只要是作为前述其它药剂成分使用达到效果的有效量的药剂(前述其它药剂)就可以，在此条件下在与前述餐后血糖降低剂并用其它药剂成分(通过混合、组合等)时，对于该其它药剂成分的给药量没有特别的限制。例如，可根据必须成分的餐后血糖降低剂的种类、合并症等的种类、合并症等或神经障碍的症状的程度、制剂的形态、有无副作用或其程度进行适当选择。
特别是，例如，混合或组合降压剂、末梢循环改善剂和高血脂症治疗药的至少1种使用时，对于这些等药剂的给药或使用量，作为该降压剂、末梢循环改善剂或高血脂症治疗药，或具有其效果的药剂，作为已经开发的，或在开发途中等其它已知的各种药剂的有效量，可采用合适的使用量或给药量。因此，关于这样的已知的降压剂、末梢循环改善剂或高血脂症治疗药，或具有其效果的药剂的种类或其使用方法，给药量记载的内容，全部作为本申请说明书的一部分作为参考被引入。
优选的实施方式
下面，基于实施例对本发明进行详细说明。在该实施例中使用的％，没有特别的说明时表示重量％。
(实施例1)
通过动物试验测定运动神经传导速度，研究对合并症的影响(改善效果)。
(试验方法)
动物试验用下述4组构成进行，将那格列奈和格列苯脲在0.5％甲基纤维素(MC)中悬浮制成给药液。
| 试验组 | 动物 | 给药药物 | 试验个数 |
| 病态对照组 | GK大鼠 | 0.5％MC | 8 |
| 格列苯脲组 | GK大鼠 | 格列苯脲1mg/kg | 8 |
| 那格列奈组 | GK大鼠 | 那格列奈50mg/kg | 9 |
| 正常对照组 | ウイスタ一大鼠 | 0.5％MC | 9 |
(试验动物)
将作为糖尿病自然发病模型的GK大鼠(雄性)和正常ウイスタ一大鼠(雄性)在6周龄导入。
从7周龄开始在光调整下(暗期：上午7点～下午7点，明期：下午7点～第二天早晨7点)，以6小时的间隔，1天2次，分别只有1小时(上午9点～10点，下午3点～4点)控制喂食的条件下饲养。
从14周龄开始，连续每天，在控制喂食前以6小时的间隔，1天2次(上午9点，下午3点)，分别用0.5％MC、格列苯脲(1mg/kg)、那格列奈(50mg/kg)，强制口服给药。
(运动神经传导速度的测定)
在开始给药后第23周(37周龄)，为研究对糖尿病合并症的影响，按照キヤメロン等糖尿病ロジア誌，39卷，1047-1054页(1996年)的方法使用尾神经测定运动神经传导速度。结果如图1所示。
(评价结果)
图1的结果表明，在作为糖尿病自然发病模型的GK大鼠(病态对照组)与正常对照组相比，可确认作为糖尿病性合并症指标之一的运动神经传导速度显著降低(病态对照组48.2±1.3m/sec、正常对照组55.2±1.8m/sec)。
在作为口服糖尿病治疗药通常被使用的磺酰脲剂的格列苯脲给药组，看到的有些改善(52.3±0.9m/sec)。与此相对，使用那格列奈给药的GK大鼠保持了与正常大鼠同等的运动神经传导速度(55.9±1.3m/sec)，对于神经障碍的发病、进展，那格列奈显示了显著的预防、改善、治疗效果。
(实施例2)
(神经内Na+/K+-ATP酶活性的测定)
对于在前述实施例1分组、饲养、给药的动物，在开始给药后第23周(37周龄)剖检，按照グリ一ン等，ジャ一ナルオブクリニカルインベスティグ一ション誌，72卷，1058-1063页(1983年)的方法，测定坐骨神经中的Na+/K+-ATP酶活性。
(评价结果)
在GK大鼠(病态对照组)中，与正常对照组相比，确认了作为神经功能指标之一的Na+/K+-ATP酶活性显著降低(病态对照组87.6±9.8μmol ADP/g/hr，正常对照组110.5±7.7μmol ADP/g/hr)。
与此相对，使用那格列奈给药的GK大鼠抑制了Na+/K+-ATP酶活性的降低(99.5±7.6μmol ADP/g/hr)，对于神经障碍的发病、进展，那格列奈显示了显著的预防、改善、治疗效果。
(实施例3)
(血中总胆固醇浓度的测定)
对于在前述实施例1中分组、饲养、给药的动物，在开始给药1周前(13周龄)、开始给药第4周(18周龄)、第14周(28周龄)、第23周(37周龄)绝食17小时后，从锁骨下静脉采血，使用富士ドライケムアナライザ一用胆固醇氧化酶法测定血浆中总胆固醇浓度。结果如图2所示。
(评价结果)
从图2的结果可知，在GK大鼠(病态对照组)中，与正常对照组相比，无论在任何测定时期，可确认作为动脉硬化、大血管障碍的危险因子的血浆中总胆固醇浓度显著增加。
在作为口服糖尿病治疗药通常被使用的磺酰脲剂的格列苯脲给药组，确认胆固醇值没有变化。与此相对，在使用那格列奈给药的GK大鼠中，血浆总胆固醇浓度显著降低，对于糖尿病性合并症、特别是动脉硬化、大血管障碍的发病、进展，那格列奈显示了显著的预防、改善、治疗效果。
(实施例4)
(试验方法)
如果在绝食下对GK大鼠用脂肪输液(引身力补、2g/kg)强制口服给药，可确认给药后2小时达到峰值的血浆中甘油三酯的上升。使用10只该餐后高血脂症模型大鼠，用交叉试验法，研究药物对血浆中甘油三酯浓度的影响(餐后高血脂症抑制效果)。即，在脂肪输液负荷前使用那格列奈(50mg/kg)或作为对照的糖吸收延迟剂的伏格列波糖(0.2mg/kg)口服给药，到给药后4小时为止，随时间从尾静脉采血。
(血浆中甘油三酯浓度的测定)
使用富士ドライケムアナライザ一进行测定。
(评价结果)
到负荷后4小时为止的甘油三酯曲线下面积增加(ΔAUC)在伏格列波糖组为164±17mg·h/dl。与此相对，那格列奈给药组的ΔAUC为81±22mg·h/dl，显著降低了。
(在Zucker Fattty大鼠的评价结果)
在其它病态动物模型的Zucker Fatty大鼠也进行同样的研究。Zucker Fattty大鼠在脂肪输液负荷上比GK大鼠显示显著的餐后高血脂症，到负荷后4小时为止的甘油三酯的曲线下面积增加(ΔAUC)在伏格列波糖组为501±112mg·h/dl。与此相对，那格列奈给药组的ΔAUC为15±69mg·h/dl，显著降低了。
通过琼脂糖电泳进行脂蛋白划分的结果是，含有称为乳糜微粒、VLDL的可以说与血管障碍、动脉硬化相关的异常组分的原点和プレβ组分的增加是显著的，在那格列奈给药组该上升被抑制，暗示在糖尿病性合并症、特别是动脉硬化、大血管障碍的发病、进展，那格列奈显示了预防、改善、治疗效果。
(实施例5)
(血清中vWF浓度的测定)
在给药开始后第23周(37周龄)从下大静脉采集在前述实施例1分组、饲养、给药的动物的血液，通过使用抗人vWF抗体(DAKO社制)的ELISA法测定血清中的vWF浓度。
(评价结果)
GK大鼠(病态对照组)与正常对照组相比，可确认作为血管内皮障碍指标之一的血清中vWF浓度的显著上升(将正常对照组作为100(±22.7)％，在病态对照组是184.8±24.3％)。
与此相对，那格列奈给药的GK大鼠血清中vWF浓度的上升被抑制了(124.5±21.5％)，暗示对于血管障碍的发病、进展，那格列奈显示了预防、改善、治疗效果。
如上述结果表明的那样，确认通过那格列奈的给药，可显著改善糖尿病大鼠的神经传导速度的降低，暗示了那格列奈作为糖尿病性合并症药剂的有效成分是优秀的，同时，也可作为糖尿病性合并症以外的神经障碍的预防、改善、治疗用药剂的有效成分，可期待分作为别面向它们的药剂。
进一步，由于通过那格列奈的给药改善糖尿病大鼠神经中的Na+/K+-ATP酶活性低下，血清中vWF浓度的上升，血中总胆固醇的上升，因此可强烈期待那格列奈作为糖尿病性合并症和神经障碍的预防、改善、治疗用药剂的有效成分。
发明效果
按照本发明，可提供在糖尿病性合并症的预防、改善、治疗等中有用的药剂和在神经障碍的预防、改善、治疗等中有用的药剂，其使用方法(它们等为治疗等的给药方法)，或为了该目的的餐后血糖降低剂在该药剂制造中的应用等。
特别是，作为餐后血糖降低剂，那格列奈等D-苯基丙氨酸衍生物、ミチグリニド等琥珀酸苄基酯衍生物和瑞格列奈等苯甲酸衍生物作为口服给药剂期待很大。
进一步，在前述必须成分的餐后血糖降低剂中，通过混合(以同一制剂形态)或组合(以多个制剂形态)1种或多个降压剂、末梢循环改善剂、高血脂症治疗剂等，可进一步提高前述糖尿病性合并症的预防、改善、治疗效果。
Claims (14)
1.糖尿病性合并症的预防、改善和/或治疗用药剂，其特征在于含有氯茴苯酸类化合物，也可含有制剂学上可允许的载体。
2.权利要求1记载的药剂，其中合并症是肾病、视网膜症、神经障碍和血管障碍的至少1种。
3.权利要求1记载的药剂，其中氯茴苯酸类化合物是ミチグリニド。
4.权利要求1记载的药剂，其中氯茴苯酸类化合物是瑞格列奈。
5.权利要求1～4任一项中记载的药剂，其是口服给药用的。
6.神经障碍的预防、改善和/或治疗用药剂，其特征在于含有氯茴苯酸类化合物，也可含有制剂学上可允许的载体。
7.权利要求1记载的药剂，含有降压剂、末梢循环改善剂和高血脂症治疗药的至少1种。
8.权利要求1的药剂，与降压剂、末梢循环改善剂和高血脂症治疗药的至少1种组合使用。
9.在糖尿病性合并症的预防、改善和/或治疗用药剂中适用，或可使用的药品，其特征在于含有降压剂、末梢循环改善剂和高血脂症治疗药的至少1种和氯茴苯酸类化合物，或者组合了降压剂、末梢循环改善剂和高血脂症治疗药的至少1种和氯茴苯酸类化合物，也可含有制剂学上可允许的载体。
10.氯茴苯酸类化合物在制造用于糖尿病性合并症的预防、改善和/或治疗的药剂中的应用。
11.氯茴苯酸类化合物在制造用于神经障碍的预防、改善和/或治疗的药剂中的应用。
12.权利要求10记载的应用，该氯茴苯酸类化合物是以与降压剂、末梢循环改善剂和高血脂症治疗药的至少1种混合的状态被使用的。
13.权利要求10记载的应用，与降压剂、末梢循环改善剂和高血脂症治疗药的至少1种组合使用。
14.降压剂、末梢循环改善剂和高血脂症治疗药的至少1种与氯茴苯酸类化合物在制造糖尿病性合并症的预防、改善和/或治疗用药剂中的应用。
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- 2001-03-15 AU AU2001241168A patent/AU2001241168B2/en not_active Ceased
- 2001-03-15 MX MXPA02009130A patent/MXPA02009130A/es unknown
- 2001-03-15 EP EP01912425A patent/EP1283054A4/en not_active Withdrawn
- 2001-03-15 RU RU2002127804/15A patent/RU2281764C2/ru active
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- 2001-03-15 KR KR1020027012193A patent/KR100873585B1/ko not_active IP Right Cessation
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Also Published As
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|---|---|
| HK1055674A1 (en) | 2004-01-21 |
| CN1418109A (zh) | 2003-05-14 |
| NZ521366A (en) | 2005-07-29 |
| AU2001241168B2 (en) | 2005-06-16 |
| ZA200207223B (en) | 2003-09-09 |
| EP1283054A4 (en) | 2006-04-12 |
| EP1283054A1 (en) | 2003-02-12 |
| KR20070104953A (ko) | 2007-10-29 |
| SK14922002A3 (sk) | 2003-04-01 |
| NO20024429D0 (no) | 2002-09-16 |
| NO20024429L (no) | 2002-11-06 |
| CN1234414C (zh) | 2006-01-04 |
| AU4116801A (en) | 2001-09-24 |
| WO2001068136A1 (fr) | 2001-09-20 |
| IL151690A0 (en) | 2003-04-10 |
| HUP0300325A2 (hu) | 2003-07-28 |
| KR20020081459A (ko) | 2002-10-26 |
| KR100873585B1 (ko) | 2008-12-11 |
| PL357719A1 (en) | 2004-07-26 |
| HUP0300325A3 (en) | 2004-08-30 |
| TWI305726B (en) | 2009-02-01 |
| US20030073729A1 (en) | 2003-04-17 |
| CZ20023121A3 (cs) | 2003-05-14 |
| MXPA02009130A (es) | 2003-03-12 |
| CA2403442A1 (en) | 2002-09-17 |
| BR0109336A (pt) | 2003-06-24 |
| RU2281764C2 (ru) | 2006-08-20 |
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