CN107261144A - 治疗阿尔茨海默病的新疗法 - Google Patents
治疗阿尔茨海默病的新疗法 Download PDFInfo
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- CN107261144A CN107261144A CN201710347219.2A CN201710347219A CN107261144A CN 107261144 A CN107261144 A CN 107261144A CN 201710347219 A CN201710347219 A CN 201710347219A CN 107261144 A CN107261144 A CN 107261144A
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Abstract
本发明涉及治疗阿尔茨海默病的新疗法。具体地,本发明涉及用于治疗阿尔茨海默病及相关病症的组合物和方法。更具体地,本发明涉及阿尔茨海默病及相关病症的新的组合疗法。本发明具体涉及单独或者组合起来可以有效调节突触功能和/或血管生成和/或细胞应激反应的化合物。本发明还涉及制备用于治疗阿尔茨海默病的药物或药物组合的方法和治疗阿尔茨海默病或其相关病症的方法。
Description
本申请为国际申请PCT/EP2010/066510于2012年7月3日进入中国国家阶段、申请号为201080060454.8、发明名称为“治疗阿尔茨海默病的新疗法”的分案申请。
技术领域
本发明涉及治疗阿尔茨海默病(Alzheimer’s disease,AD)和相关病症的组合物和方法。更具体而言,本发明涉及阿尔茨海默病和相关病症的新的组合疗法。本发明具体涉及单独或者组合起来可以有效地调节突触功能和/或血管生成和/或细胞应激反应的化合物。本发明还涉及选择治疗阿尔茨海默病的药物或药物组合的方法与治疗阿尔茨海默病或相关病症的方法。
背景技术
AD为典型皮质性痴呆,其特征为皮质相关区域受累造成的记忆减退,并伴随言语困难(语言病症,其中存在说话和言语理解受损)、运动障碍(在没有运动或感觉损伤的情况下不能协调和执行某些有意的动作和姿势)和失认(认知物体、人、声音、形状或气味的能力)。还会涉及诸如痉挛性下肢轻瘫(影响下肢的虚弱症)等特殊症状(1-4)。
阿尔茨海默病的发病随着年龄急剧增长。目前AD是痴呆症的最常见原因,它的临床特征在于认知功能总体下降,其发展缓慢并使晚期患者卧床、失禁且依赖于监护。平均来说,死亡发生在诊断后9年(5)。
AD的发病率随着年龄急剧增长。据联合国人口规划项目估计,到2050年80岁以上的人数将达到3.7亿。目前,据估计,50%的85岁以上老人患有AD。因此,50年内世界上将有超过1亿人患有痴呆症。需要长久护理和其他服务的巨额人数将严重影响医疗、财政和人力资源(6)。
记忆损伤是该疾病的早期特点且涉及情景记忆(对于日常事件的记忆)。在该疾病的晚期涉及语义记忆(对于言语和视觉意义的记忆)。相反,直到晚期还保持工作记忆(涉及用于短期存储和处理信息的结构和过程的短期记忆)和程序记忆(无意识记忆,即技巧和程序的长期记忆)。随着疾病进展,显现出语言损伤、视觉感知和空间缺损、失认和失用的其他特点。
阿尔茨海默病的经典情况具有足够的特征性,允许鉴别约80%的病例(7)。然而,确实存在着临床异质性,这不仅对于临床管理来说是重要的,而且为不同的功能形式提供了进一步的特定药物治疗启示(8)。
AD的病理标志物包括含有β-淀粉样蛋白(Aβ)的淀粉样斑块、含有τ的神经元纤维缠结(NFT)以及神经元和突触功能障碍和丧失(9-11)。最近十年,关于AD的病因已经提出了两种主要假说:“淀粉样蛋白级联假说”,其认为神经退行性过程是由淀粉样蛋白前体蛋白(APP)的异常加工所触发的一系列事件(12),以及“神经元细胞骨架退化假说”(13),其提出细胞骨架改变是触发事件。解释AD发展的最广为接受的理论仍然是淀粉样蛋白级联假说(14-16),并且AD研究人员主要集中于确定潜藏在与Aβ蛋白质相关的毒性之后的机制。相反地,由于基础和实践两方面的考虑,τ蛋白所受到的制药工业的关注比淀粉样蛋白少得多。此外,与其它两者相比,突触密度改变是与认知受损最相关的病变。研究显示,淀粉样蛋白病变似乎以神经递质特异性方式发展,其中胆碱能末梢表现得最易受损,其次是谷氨酸能末梢,最后是GABA能末梢(11)。
发明内容
本发明的目的是提供治疗AD和相关病症的新的治疗方法。
发明人已经鉴定出若干药物,其单独或者组合起来可以有效地影响参与AD的途径,并且可以代表治疗AD和相关病症的新的有效的疗法。
因此,本发明提供治疗AD病和相关病症的新的组合物和方法。
更具体而言,本发明涉及用于治疗阿尔茨海默病或相关病症的组合物,其包括选自下列至少两种化合物的组合:氨基己酸、阿坎酸盐、氨氯地平、阿加曲班、巴氯芬、西洛他唑、西那卡塞、氯吡格雷、二羟丙茶碱、非诺多泮、来氟米特、米帕林、甲巯咪唑、苯乙双胍、丙胺卡因、利福布汀、磺胺异噁唑、他达拉非、特比萘芬、桂利嗪、环匹罗司、依普利酮、甘珀酸、舒洛地特、乙胺嗪(carbamazine)、异戊巴比妥、头孢替坦、丁四硝酯、甲氯噻嗪、利塞膦酸盐、恩丙茶碱、胆茶碱、甲乙双酮、头孢甲肟、安搏律定、依托咪酯、米格列奈、贝尼地平、左西孟旦和唑尼沙胺、或者其盐或药物前体或衍生物或缓释制剂。
本发明的另一个目的涉及用于同时、分别或顺序给药的组合物,其包括选自下列至少两种化合物的组合:氨基己酸、阿坎酸盐、氨氯地平、阿加曲班、巴氯芬、西洛他唑、西那卡塞、氯吡格雷、二羟丙茶碱、非诺多泮、来氟米特、米帕林、甲巯咪唑、苯乙双胍、丙胺卡因、利福布汀、磺胺异噁唑、他达拉非、特比萘芬、桂利嗪、环匹罗司、依普利酮、甘珀酸、舒洛地特、乙胺嗪、异戊巴比妥、头孢替坦、丁四硝酯、甲氯噻嗪、利塞膦酸盐、恩丙茶碱、胆茶碱、甲乙双酮、头孢甲肟、安搏律定、依托咪酯、米格列奈、贝尼地平、左西孟旦和唑尼沙胺、或者其盐或药物前体或衍生物或缓释制剂。
最优选的药物组合包括2、3、4或5种不同的药物,进而更优选2或3种。此外,以上药物组合还可以用于与目前被用于AD的其他药物或治疗进一步组合。
本发明还涉及治疗阿尔茨海默病或相关病症的方法,该方法包括对有需要的对象同时、分别或顺序施用上面所公开的药物组合。
本发明的另一目的是治疗阿尔茨海默病或相关病症的方法,该方法包括对有需要的对象同时、分别或顺序施用调节突触功能的药物组合和/或调节血管生成的药物和/或调节细胞应激反应的药物。
本发明的另一目的在于制备用于治疗阿尔茨海默病或相关病症的药物的方法,该方法包括检测候选药物对于突触功能和血管生成以及细胞应激反应的活性和选择改善突触功能、减轻血管生成调节异常和调节细胞应激反应的候选药物的步骤。
本发明还涉及制备用于治疗阿尔茨海默病或相关病症的组合物的方法,该方法包括制备调节突触功能的药物和/或减轻血管生成调节异常的药物和/或调节细胞应激反应的药物的组合,用于向有需要的对象同时、分别或顺序给药。
附图说明
图1:在β-淀粉样蛋白中毒的大鼠原代皮质神经元培养物中所选药物对轴突生长的影响。p<0.01;p<0.00001:与介质差异显著。*:p<0.05;****:p<0.0001:与Aβ25-35差异显著。双侧student’s t检验。20μM Aβ25-35产生显著中毒,比用介质处理的神经元高25%。阿坎酸盐(图1A)或唑尼沙胺(图1B)显著阻止这种中毒。
图2:在β-淀粉样蛋白中毒的大鼠原代皮质神经元培养物中苯乙双胍对轴突生长的影响。p<0.01:与介质差异显著。**:p<0.001:与Aβ25-35差异显著。双侧student’s t检验。20μM Aβ25-35产生显著中毒,比用介质处理的神经元高25%。苯乙双胍显著阻止这种中毒。
图3:所选药物对于β-淀粉样肽对从大鼠脑内皮细胞释放LDH的毒性的保护作用。p<0.05:与介质差异显著。**:p<0.01;***:p<0.0001;****:p<0.00001:与Aβ25-35差异显著。双侧student’s t检验。30μM Aβ25-35产生中度但显著的中毒(图3A至D)。来氟米特(图3A)、特比萘芬(图3B)、磺胺异噁唑(图3C)或巴氯芬(-)(图3D)显著阻止这种中毒。此外,来氟米特和特比萘芬不仅阻止淀粉样损害作用,而且也减少培养基中的自发性细胞死亡。
图4:在β-淀粉样蛋白中毒的中毒后,所选药物对NGF所分化的PC12的存活率的影响。p<0.00001:与介质差异显著。**:p<0.01;***:p<0.0001:与Aβ25-35差异显著。双侧student’s t检验。10μM Aβ25-35产生显著中毒,比用介质处理的神经元高25%(图4A和4B)。丙胺卡因(Prilocain)(Fig4A)或氨氯地平(Fig4B)显著阻止这种中毒。
图5:在β-淀粉样蛋白中毒的大鼠原代皮质神经元培养物中,所选药物对于LDH释放的影响。p<0.000001:与介质差异显著。*:p<0.05;***:p<0.001:与Aβ25-35差异显著。双侧student’s t检验。20μM Aβ25-35产生显著中毒,比用介质处理的神经元高25%。(图5A和B)。唑尼沙胺(图5A)或磺胺异噁唑(图5B)或来氟米特(图5C)显著阻止这种中毒。
图6:在HBMEC中所选药物预处理对人Aβ1-42损伤的影响。A)用于药物筛选的实验模型的验证:10nm VEGF预处理1小时显著保护毛细血管网免受这种淀粉样损伤(与淀粉样中毒相比+78%毛细血管网)。*:p<0.05:与对照(没有中毒)差异显著。p<0.05:与淀粉样中毒差异显著(ANOVA+Dunett Post-Hoc检验)。如图6B、图6C、图6D、图6E、图6F、图6G、图6H中的剂量-响应实验分别所示,磺胺异噁唑、左西孟旦、特比萘芬、巴氯芬、氨基己酸、舒洛地特或非诺多泮显著阻止该中毒。p<0.05:与下一剂量差异显著。*:p<0.05:与淀粉样中毒差异显著(ANOVA+Dunett Post-Hoc检验)。
图7:在人Aβ1-42对大鼠原代皮质细胞的毒性中,所选药物预处理对LDH释放的影响。A)用于药物筛选的实验模型的验证:BDNF(50ng/ml)预处理1小时显著保护神经元免受该淀粉样损伤(-62%),其被作为神经保护的阳性对照。*:p<0.05:与对照(没有中毒)差异显著。p<0.05:与淀粉样中毒差异显著(ANOVA+Dunett Post-Hoc检验)。对于所有实验,与用介质处理的神经元相比,Aβ1-42产生显著中毒。巴氯芬(-86%)(B)、磺胺异噁唑(-42%)(C)、左西孟旦(-133%)(D)、依托咪酯(-50%)(E)、甘珀酸(-39%)(F)和桂利嗪(-50%)(G)显著阻止这种中毒。对于所有实验,p<0.05:与Aβ1-42中毒差异显著(ANOVA+Dunett Post-Hoc检验)。
图8:在β-淀粉样蛋白中毒的HBMEC培养物中,磺胺异噁唑和左西孟旦组合治疗对毛细血管网总长度的影响。p<0.05,与Aβ1-42差异显著。*:p<0.05与介质差异显著。ANOVA+Dunett Post-Hoc检验。聚集的人淀粉样肽(2.5μM Aβ1-42)产生显著中毒,比用介质处理的神经元高40%。磺胺异噁唑和左西孟旦的组合显著阻止这种中毒(A),而在那些浓度下,左西孟旦(B)和磺胺异噁唑(C)单独使用对中毒没有显著影响。
图9:在β-淀粉样蛋白中毒的HBMEC培养物中,磺胺异噁唑和特比萘芬组合治疗对毛细血管网总长度的影响。p<0.05,与Aβ1-42差异显著。*:p<0.05,与介质差异显著。ANOVA+Dunett Post-Hoc检验。聚集的人淀粉样肽(2.5μM Aβ1-42)产生显著中毒,比用介质处理的神经元高40%。磺胺异噁唑和左西孟旦的组合显著阻止这种中毒(A),而在那些浓度下,磺胺异噁唑(B)和特比萘芬(C)单独使用对中毒没有显著影响。
图10:在β-淀粉样蛋白中毒的HBMEC培养物中,巴氯芬和左西孟旦组合治疗对毛细血管网总长度的影响。p<0.05,与Aβ1-42差异显著。*:p<0.05,与介质差异显著。ANOVA+Dunett Post-Hoc检验。聚集的人淀粉样肽(2.5μM Aβ1-42)产生显著中毒,比用介质处理的神经元高40%。巴氯芬和左西孟旦的组合显著阻止这种中毒(A),而在那些浓度下,左西孟旦(B)和巴氯芬(C)单独使用对中毒没有显著影响。
图11:在β-淀粉样蛋白中毒的HBMEC培养物中,特比萘芬和氨基己酸组合治疗对毛细血管网总长度的影响。p<0.05,与Aβ1-42差异显著。*:p<0.05,与介质差异显著。ANOVA+Dunett Post-Hoc检验。聚集的人淀粉样肽(2.5μM Aβ1-42)产生显著中毒,比用介质处理的神经元高40%。特比萘芬和氨基己酸的组合显著阻止这种中毒(A),而在那些浓度下,氨基己酸(B)和特比萘芬(C)单独使用对中毒没有显著影响。
图12:在β-淀粉样蛋白中毒的HBMEC培养物中,氨基己酸和左西孟旦组合治疗对毛细血管网总长度的影响。p<0.05,与Aβ1-42差异显著。*:p<0.05,与介质差异显著。ANOVA+Dunett Post-Hoc检验。聚集的人淀粉样肽(2.5μM Aβ1-42)产生显著中毒,比用介质处理的神经元高40%。左西孟旦和氨基己酸的组合显著阻止这种中毒(A),而在那些浓度下,氨基己酸(B)和左西孟旦(C)单独使用对中毒没有显著影响。
图13:在β-淀粉样蛋白中毒的HBMEC培养物中,特比萘芬和左西孟旦组合治疗对毛细血管网总长度的影响。p<0.05,与Aβ1-42差异显著。*:p<0.05,与介质差异显著。ANOVA+Dunett Post-Hoc检验。聚集的人淀粉样肽(2.5μM Aβ1-42)产生显著中毒,比用介质处理的神经元高40%。特比萘芬和氨基己酸的组合显著阻止这种中毒(A),而在那些浓度下,特比萘芬(B)和左西孟旦(C)单独使用对中毒没有显著影响。
发明详述
本发明提供治疗AD和相关病症的新疗法。本发明公开了药物或药物组合的新用途,其允许有效矫治这些疾病并可以用于患者治疗。
术语“AD相关病症”包括AD型老年痴呆(SDAT)、帕金森病、路易体痴呆、血管性痴呆、轻度认知损伤(MCI)、年龄相关记忆损伤(AAMI)和与衰老有关的问题、脑炎后帕金森综合症、肌萎缩性侧索硬化(ALS)、多发性硬化(MS)和唐氏综合症。
如本文所用,病症的“治疗”包括由病症引发的症状的治疗、阻止、预防、延迟或减少。术语治疗具体包括控制疾病发展和相关症状。
术语“改善”,当涉及突触功能时,包括与对象的现有功能相比突触功能的任何提高。这样的改善可以包括恢复、即达到正常水平,或者较低的但仍足以改善患者状况的提高。如在实验部分中所描述的,这样的改善可以使用已知的生物学检验评估或验证。
术语“增加”,当涉及血管生成时,包括与对象的现有水平相比血管生成的任何增加。这样的改善可以包括包括恢复、即达到正常水平,或者较低的但仍足以改善患者状况的增加。如在实验部分中所描述的,这样的改善可以使用已知的生物学检验评估或验证。
术语“抑制”,当涉及细胞应激反应(“CSR”)时,包括与对象的现有活性相比CSR的任何减少。这样的减少包括足以改善患者状况的部分减少、如5-20%,以及更大量的减少,如20-50%或更完全的抑制,如50%以上。如在实验部分中所描述的,这样的抑制可以使用已知的生物学检验评估或验证。
此外,在本发明的情形中,具体化合物的指定意在不仅包括具体指出的分子,而且也包括其任何纯度的药用可接受的盐、水合物、酯、醚、异构体、外消旋体、结合物或前体药物。
术语“组合或组合治疗/疗法”指向对象共同施用至少两种或更多种药物以产生生物学效应的治疗。在根据本发明的组合治疗中,所述至少两种药物可以一起或分别、同时或顺序施用。此外,所述至少两种药物可以通过不同途径或方案施用。因此,虽然其可以配制在一起,但组合的药物也可以分别配制。
如上所述,本发明涉及使用改善突触功能和/或增加血管生成和/或抑制细胞应激反应的特定药物或药物组合,对于有需要的对象治疗阿尔茨海默病和相关病症的组合物和方法。
通过全面整合包括描述阿尔茨海默病的不同方面的细胞生物学研究、表达谱实验和遗传关联性研究结果的实验数据,以及细胞信号转导和功能途径中存在的联系,发明人已经发现,突触功能、血管生成和细胞应激反应代表在患有AD的对象中发生改变的重要机制。通过进一步的实验研究,如实施例中所述,发明人已经选出有效改变这些途径且有效改善AD的药物或药物组合。因而这些药物和组合代表治疗AD和相关病症的新方法。
用下述标准选择位于所述功能网络中并且牵涉阿尔茨海默病的基因:
(1)-与作为病因造成阿尔茨海默病的家族性病例的基因(APP、ApoE、早老素、τ蛋白)直接相互作用,
(2)-用标准(1)选出的基因的功能性配偶体,
(3)-用标准(2)选出的基因的最接近的功能性配偶体。
通过该方法,发明人已经确定,负责突触功能、血管生成和细胞应激反应的网络是影响阿尔茨海默病的主要功能性网络。
发明人已经更具体地确定,突触丧失是阿尔茨海默病的功能相关标志,其最终导致进行性认知衰退、记忆丧失和痴呆症。重要的是,与在神经原纤维缠结的形成或淀粉样斑块的沉积中所出现的其他AD特异性细胞病变标志相比,突触丧失与阿尔茨海默病状的特征性认知缺损的相关性更好。因此,突触组织和突触塑性代表了在阿尔茨海默病情况下的治疗干预的重要靶点。
APP蛋白是由轴突转运并在突触前末梢中加工的,其导致Aβ在突触中高度积累。Aβ42的寡聚体以及淀粉样斑块本身对于抑制长期加深来说是重要的,并且是造成AD患者的记忆损伤的主要原因。
我们的数据整合过程揭示出一组基因,其牵涉AD中的突触变形,并且在形式上可以分为三个主要的功能组:参与突触后致密物(“PSD”)的组织和突触后膜处神经信号正确传递的蛋白质;确保神经递质释放的蛋白质;以及参与轴突生长和突触结构发育成熟的蛋白质。
因此,在具体实施方案中,本发明认识到,对于AD的有效治疗,重要的是改善参与突触后致密物的蛋白质的活性。
在我们的分析所鉴别出的基因中,DLG2基因代表特别的目标,其编码MAGUK家族的蛋白质且在成簇的膜结合受体、细胞粘合分子和基于肌动蛋白的细胞骨架之间产生界面(17-18)。发明人已经鉴别出一大族离子型/代谢型谷氨酸和生长因子受体,其与在兴奋性突触处的DLG2蛋白或DLG2/PSD95蛋白复合体直接相互作用,并且因此可以被作为治疗阿尔茨海默病的治疗靶点。
因此,在另一个具体实施方案中,本发明还认识到,对于AD的有效治疗,重要的是改善参与调节突触前膜处神经递质释放的蛋白质的活性。
神经递质在突触前质膜的受限的且高度特化的活性区域处的释放由动作电位触发,并且受到电压依赖性钙CaV通道、Maxik/BK通道(大电导钙激活钾通道)和cGMP依赖性PRKG蛋白激酶的组合作用的控制,如我们的分析所表明的,所述因素全部与阿尔茨海默病的发展密切相关。除了这些涉及神经递质释放的功能模块外,发明人已经确定了另外一组蛋白质,其与阿尔茨海默病进程中的突触神经递质失调有关,负责突触小泡(例如,STX2、STXBP6、BIN1、RAB3B、UNC13C和RIMS1/2骨架蛋白)的成熟、停靠和融合。因此,这些功能途径被优先列为治疗阿尔茨海默病的合适的治疗靶点。
在另一种具体实施方案中,本发明进一步认识到,对于AD的有效治疗,重要的是改善参与调节轴突生长和导向的蛋白质的活性。
参与调节轴突生长和导向的蛋白质允许神经元前体细胞和轴突向适合的目的地迁移,从而确保正确的定位和连接;它们也参与新形成的突触的发育成熟以及AD病中轴突和突触的降解。这些过程对于认知功能的执行发挥了重要作用,并且似乎对Aβ沉积的毒性效应极为易感。
轴突生长和导向的连续步骤受到细胞外或膜连接的导蛋白、脑信号蛋白、肝配蛋白、DLL和Slit分子与其各自的功能受体的组合作用的紧密控制,它们中大多数是通过我们的数据挖掘过程揭示出来的。大部分轴突生长受体的激活的功能性结果与其差异性调节小GTPase RhoA、Rac1和Cdc42的活性的能力、与主要负责轴突退缩和生长锥萎陷的RhoAGTPase密切相关(19)。这些信号途径已经被认为是治疗阿尔茨海默病的合适的治疗靶点。
因此,本发明认识到,对于AD的有效治疗,重要的是通过调节上述靶基因和蛋白质,改善在阿尔茨海默病和其他神经发生障碍中所改变的突触功能。
通过数据挖掘过程,发明人也已经确定,负责血管生成的网络代表在阿尔茨海默病中被影响的另一主要功能网络。
血管生成在确保组织稳态和对环境和生理挑战、如缺氧或伤口愈合的适应性响应中发挥了重要作用;其功能障碍促成从心血管并发症到肿瘤生长和转移的众多和不同病变的发病机理。
虽然阿尔茨海默病传统上被认为是伴随侧枝血管病变的神经退行性病症,但我们的分析允许重新评定血管失调的发病机理影响,并认为血管生成途径在这种疾病的病因中有重要的且可能为病因性的作用。发明人已经发现调节血管生成的基因在牵涉阿尔茨海默病的信号网络中极度富集。这一结论对于预防和治疗阿尔茨海默病具有深远意义,并为这种复杂的神经退行性疾病的组合治疗提供了新的指导方针。
在密切牵涉与阿尔茨海默病有关的血管重塑的信号途径中,已经鉴别出由VEGFR1、ErbB4、Notch、DCC、CD44、肝配蛋白受体和钙粘蛋白所介导的若干功能模块。
如我们的数据挖掘过程所揭示的,可能参与形成在阿尔茨海默病中所出现的血管缺陷的其他靶蛋白包括IL20R、LEPTR、NRP1与NRP2、以及内皮素EDNRA受体、参与胞外基质的组织和重塑的蛋白质(THBS2、LAMA1、COL4A2、ADAMTS12和ADAM10)或者在诸如催乳素、生长激素和胎盘催乳素等公知的血管生成调节因子的功能加工中发挥重要作用的蛋白质(例如TLL2)(20)。
此外,我们还发现了,与阿尔茨海默病有关的若干基因代表被AMP激活的激酶的上游调节因子和下游效应子、血管系统的重要调节子(例如,瘦素和CNTF受体、凝血酶信号途径、CAMKK2β和LKB1激酶)(21-24)。这一发现允许我们将AMPK介导的信号网络确定为治疗阿尔茨海默病的合理治疗靶点。
磷脂酸(PA)、溶血磷脂酸(LPA)和鞘氨醇1-磷酸(S1P)是具有强信号特点的天然磷脂。值得注意的是,这些磷脂生长因子对于内皮细胞的血管生成潜力显示出不同作用(25)。利用我们的数据挖掘过程,我们鉴别出了参与LPA代谢或通过LPA信号进行调节并且与阿尔茨海默病的发展潜在相关的许多基因(MTR、MAT2B、CUBN、ATP10A、THEM2、PITPNC1、ENPPG、SGPP2、AGPAT、DGKH、DGKB、MGST2、PLD2和DRD2)。因此,我们推断该信号网络代表治疗阿尔茨海默病的合适的治疗靶点。
本发明还强调了通过调节上述靶基因和蛋白质,增强在阿尔茨海默病和其他神经退行性疾病中被改变的血管生成的重要性。
最后,我们已经确定,负责细胞应激反应的网络是在阿尔茨海默病中被影响的第三主要功能网络。
我们已经更具体确定,细胞应激反应是阿尔茨海默病的功能相关标志。如上所述,发明人已经在细胞应激反应网络中鉴别出三个蛋白质家族,其与阿尔茨海默病的发生和控制在功能上相关,并且代表组合治疗的有价值的靶点。更具体而言,这些蛋白质组是参与钙稳态、蛋白质折叠和执行细胞凋亡的蛋白质。
在具体实施方案中,本发明更具体涉及利用调节参与钙稳态的蛋白质的活性的药物组合的组合物和方法。
钙是最重要的胞内信使之一,其在神经元和内皮细胞中介导细胞过程的多效性,包括突触可塑性、血管生成和细胞凋亡。
胞内钙水平是由质膜和内质网中的一系列钙通透性通道、钙泵和钙交换体的协同作用精确调节的(26-27)。我们已经鉴别出牵涉钙稳态途径的基因网络,其功能可以被突变的早老蛋白或阿尔茨海默病进程中的毒性β-淀粉样蛋白改变。其中,IP3R(ITPR1)和RYR3受体、在ER水平调节钙稳态的ATP2A3(SERCA3 Ca2+ATPase)、从真核细胞中逆浓度梯度驱出钙离子的质膜ATPase ATP2B1和电压门控Na+通道代表治疗阿尔茨海默病的潜在治疗靶点的特别目标。
在另一个具体实施方案中,本发明更具体涉及利用调节参与蛋白质折叠或聚集的蛋白质的活性的药物组合的组合物和方法。
蛋白质聚集是AD的主要细胞病理现象。阿尔茨海默病的两个主要细胞标志出现在神经原纤维缠结(NFTs)的形成和淀粉样斑块的沉积中,其分别由聚集的超磷酸化τ蛋白和APP蛋白的Aβ片段构成。容易聚集的另一个蛋白质——α-突触核蛋白更被认为是帕金森病的特殊标志物,但是,在散发性或家族性形式的阿尔茨海默病的大多数病例中,其可以在淀粉样斑块中被检测出来。
我们已经确定牵涉调节折叠、翻译后修饰和阿尔茨海默病相关蛋白聚集体的每个主要成分的加工的若干基因,作为治疗阿尔茨海默病的适当的治疗靶点,——例如与APP相互作用并调节其稳定性和功能的APBA1和APBA2BP蛋白,或者牵涉α-突触核蛋白的清除的PARK2泛素-蛋白连接酶(28)。同样地,在阿尔茨海默病的进程中GSK-3β激酶可能在蛋白质错折叠的病变中发挥尤其重要的作用。我们的发现,即调节GSK-3β激酶活性的一些信号模块及其与τ蛋白-WWOX(29)、透明质酸(hyaluronan)CD44受体、Wnt受体Fz2/ROR2和胰岛素受体/PTPRG磷酸酶复合体(30)的相互作用与阿尔茨海默病的进展有关,增强了这一结论。
在另一个具体实施方案中,本发明涉及利用抑制细胞凋亡的药物组合的组合物和方法,在阿尔茨海默病中所述细胞凋亡被认为是负责细胞丧失的主要细胞机制。
如我们的分析所鉴别出的,阿尔茨海默病情况下的细胞凋亡最有可能是通过典型的p53依赖性途径而进行的。
可以通过翻译后修饰和通过与正和负调节因子的相互作用调控p53蛋白。我们已经鉴别出了若干这样的调节蛋白-WWOX、MDM1、HIPK2和PML,这证实了关于在阿尔茨海默病中p53蛋白在执行细胞死亡中的关键作用的提议(31-33)。
在可能直接并具体涉及诱导阿尔茨海默病情况下的细胞凋亡的受体系统中,参与轴突导向和血管生成的UNC5C(Unc-5同系物C)和DCC(在结肠癌中缺失)导蛋白受体代表具体目标。这些受体被认为是推定的条件性肿瘤抑制子,因为,在不存在其配体时,它们作为诱导细胞凋亡的导蛋白依赖性受体起作用(34)。导蛋白-1与这些受体的结合抑制依赖p53的细胞凋亡,而p53直接参与导蛋白-1与其受体的转录调节(33)。此外,已知DCC受体是由早老素加工,这表明了其在阿尔茨海默病发展中的重要作用(35)。因此,我们的数据挖掘表明,除了由被破坏的钙稳态和过量ROS生产所激发的更为非特异性的促凋亡程序外,导蛋白受体依赖性和p53介导的程序性细胞死亡也可能是牵涉阿尔茨海默病情况下的病理性细胞丧失的特异性促凋亡途径之一。
在具体实施方案中,本发明更具体涉及利用抑制参与钙稳态、蛋白质折叠和执行细胞凋亡的至少两种不同蛋白质的活性的药物组合的组合物和方法。
在优选的实施方案中,本发明提出了新的组合物,其通过调节上述靶基因和蛋白质,可以用于抑制阿尔茨海默病和其他神经退行性疾病中所引发的细胞应激反应。
如上所述,本发明涉及对于有需要的对象治疗阿尔茨海默病或相关病症的组合物和方法,其利用改善突触功能和/或增加血管生成和/或抑制细胞应激反应的药物的组合。
更具体地,发明人已经选出并检验了许多改变一种或者优选全部上述途径的药物或药物组合。如实施例中所公开的,这些药物组合对于阿尔茨海默病具有强烈作用,并且代表该病的新疗法。这些药物组合尤其有利,因为它们影响不同的途径并因而更加有效。此外,由于其有效性和作用模式,可以低剂量使用该药物组合,这是另一个非常重要的优势。
以下表1中列出了最优选的药物。
表1
在这方面,本发明的优选的目的涉及组合物,其包括选自氨基己酸、阿坎酸盐、氨氯地平、阿加曲班、巴氯芬、西洛他唑、西那卡塞、氯吡格雷、二羟丙茶碱、非诺多泮、来氟米特、米帕林、甲巯咪唑、苯乙双胍、丙胺卡因、利福布汀、磺胺异噁唑、他达拉非、特比萘芬、桂利嗪、环匹罗司、依普利酮、甘珀酸、舒洛地特、乙胺嗪、异戊巴比妥、头孢替坦、丁四硝酯、甲氯噻嗪、利塞膦酸盐、恩丙茶碱、胆茶碱、甲乙双酮、头孢甲肟、安搏律定、依托咪酯、米格列奈、贝尼地平、左西孟旦和唑尼沙胺的至少两种化合物、或者其任何纯度的盐或药物前体或衍生物或者其缓释制剂的组合,用于同时、分别或顺序给药。
在具体实施方案中,本发明涉及组合物,其包括选自氨基己酸、桂利嗪、环匹罗司、依普利酮、甘珀酸、舒洛地特、乙胺嗪、异戊巴比妥、头孢替坦、丁四硝酯、甲氯噻嗪、利塞膦酸盐、恩丙茶碱、胆茶碱、甲乙双酮、头孢甲肟、安搏律定、依托咪酯、米格列奈、贝尼地平和左西孟旦的至少一种化合物、或者其盐或前体药物或衍生物或缓释制剂,与选自阿坎酸盐、氨氯地平、阿加曲班、巴氯芬、西洛他唑、西那卡塞、氯吡格雷、二羟丙茶碱、非诺多泮、来氟米特、米帕林、甲巯咪唑、苯乙双胍、丙胺卡因、利福布汀、磺胺异噁唑、他达拉非、特比萘芬和唑尼沙胺的至少一种化合物、或者其盐或前体药物或衍生物或缓释制剂组合,用于同时、分别或顺序给药。
如实施例中所公开的,使用以上所列药物中至少2种的组合疗法致使阿尔茨海默病的有效矫治。
根据本发明的疗法可以单独或作为药物组合进行。
在优选的实施方案中,以用于合并、分别或顺序给药的组合使用本发明的药物,从而提供最有效的作用。在这方面,根据本发明的治疗阿尔茨海默病的组合物使用改善突触功能的药物和减轻血管生成的药物和/或抑制细胞应激反应的药物。
更具体而言,为了用于治疗阿尔茨海默病或相关病症,根据本发明的组合物可以选自包括下列药物组合中至少一种的组合物:
-AMPK的调节剂(优选苯乙双胍)和钠通道SCN1A的抑制剂与BK通道的激活剂(优选唑尼沙胺)或者BK通道的调节剂(优选甲氯噻嗪),
-AMPK的调节剂(优选苯乙双胍)和GABA能和谷氨酸能受体活性的调节剂(优选选自阿坎酸盐、依托咪酯和安搏律定),
-AMPK的调节剂(优选苯乙双胍)和EDNRA内皮素受体的拮抗剂(优选磺胺异噁唑),
-钠通道SCN1A的抑制剂与BK通道的激活剂(优选唑尼沙胺)或BK通道的调节剂(优选甲氯噻嗪)以及RYR3兰尼碱受体的调节剂(优选丙胺卡因),
-GABBR2受体的调节剂(优选巴氯芬)和RHOA的调节剂(优选选自特比萘芬和利塞膦酸盐),
-GABBR2受体的调节剂(优选巴氯芬)和EDNRA内皮素受体的拮抗剂(优选磺胺异噁唑),
-GABBR2受体的调节剂(优选巴氯芬)和钠通道SCN1A的抑制剂与BK通道的激活剂(优选唑尼沙胺)或BK通道的调节剂(优选甲氯噻嗪),
-GABBR2受体的调节剂(优选巴氯芬)和HAS1-3透明质酸合成酶的调节剂(优选来氟米特),
-钠通道SCN1A的抑制剂与BK通道的激活剂(优选唑尼沙胺)或BK通道的调节剂(优选甲氯噻嗪)以及腺苷受体ADORA1/2/3的调节剂(优选二羟丙茶碱),
-钠通道SCN1A的抑制剂与BK通道的激活剂(优选唑尼沙胺)或BK通道的调节剂(优选甲氯噻嗪)以及EDNRA内皮素受体的拮抗剂(优选磺胺异噁唑)
-RHOA的调节剂(优选选自特比萘芬和利塞膦酸盐)和EDNRA内皮素受体的拮抗剂(优选磺胺异噁唑),
-RHOA的调节剂(优选选自特比萘芬和利塞膦酸盐)和磷脂酶PLA1A和PLA2的抑制剂(优选米帕林),
-RHOA的调节剂(优选选自特比萘芬和利塞膦酸盐)和GABA能和谷氨酸能受体活性的调节剂(优选选自阿坎酸盐、依托咪酯和安搏律定),
-RHOA的调节剂(优选选自特比萘芬和利塞膦酸盐)和化学伴侣(优选利福布汀),
-AMPK的调节剂(优选苯乙双胍)和PDE11A与PDE4A、PDE5A磷酸二酯酶的抑制剂(优选选自他达拉非、恩丙茶碱和胆茶碱),
-钠通道SCN1A的抑制剂与BK通道的激活剂(优选唑尼沙胺)或BK通道的调节剂(优选甲氯噻嗪)以及凝血酶受体F2R信号转导的调节剂(优选阿加曲班和头孢甲肟),
-AMPK的调节剂(优选苯乙双胍)和嘌呤能受体P2RY1和P2RY12的调节剂(优选氯吡格雷),
-GABA能和谷氨酸能受体活性的调节剂(优选选自阿坎酸盐、依托咪酯和安搏律定)和CASR的调节剂(优选西那卡塞),
-EDNRA内皮素受体的拮抗剂(优选磺胺异噁唑)和CASR的调节剂(优选西那卡塞),
-RHOA的调节剂(优选选自特比萘芬和利塞膦酸盐)和凝血酶受体F2R信号转导的调节剂(优选选自阿加曲班和头孢甲肟),
-GABBR2受体的调节剂(优选巴氯芬)和嘌呤能受体P2RY1和P2RY12的调节剂(优选氯吡格雷),
-RHOA的调节剂(优选选自特比萘芬和利塞膦酸盐)和嘌呤能受体P2RY1和P2RY12的调节剂(优选氯吡格雷),
-钠通道SCN1A的抑制剂与BK通道的激活剂(优选唑尼沙胺)或BK通道的调节剂(优选甲氯噻嗪)和电压门控钙CACNA通道的拮抗剂(优选选自桂利嗪、贝尼地平、甲乙双酮和氨氯地平),
-GABA能和谷氨酸能受体活性的调节剂(优选选自阿坎酸盐、依托咪酯和安搏律定)和电压门控钙CACNA通道的拮抗剂(优选选自桂利嗪、贝尼地平、甲乙双酮和氨氯地平),
-钠通道SCN1A的抑制剂与BK通道的激活剂(优选唑尼沙胺)或BK通道的调节剂(优选甲氯噻嗪)和HIF1A信号转导的调节剂(优选环匹罗司),
-GABA能和谷氨酸能受体的调节剂(优选选自阿坎酸盐、依托咪酯和安搏律定)和HIF1A信号转导的调节剂(优选环匹罗司),
-EDNRA内皮素受体的拮抗剂(优选磺胺异噁唑)和氧化磷酸化作用的调节剂(优选选自异戊巴比妥和甲巯咪唑),
-钠通道SCN1A的抑制剂与BK通道的激活剂(优选唑尼沙胺)或BK通道的调节剂(优选甲氯噻嗪)和氧化磷酸化作用的调节剂(优选选自异戊巴比妥和甲巯咪唑),
-EDNRA内皮素受体的拮抗剂(优选磺胺异噁唑)和维生素K代谢的调节剂(优选头孢替坦),
-钠通道SCN1A的抑制剂与BK通道的激活剂(优选唑尼沙胺)或BK通道的调节剂(优选甲氯噻嗪)和维生素K代谢的调节剂(优选头孢替坦),
-GABA能和谷氨酸能受体活性的调节剂(优选选自阿坎酸盐、依托咪酯和安搏律定)和PRKG1的调节剂(优选丁四硝酯),
-钠通道SCN1A的抑制剂与BK通道的激活剂(优选唑尼沙胺)或BK通道的调节剂(优选甲氯噻嗪)和PRKG1的调节剂(优选丁四硝酯),
-EDNRA内皮素受体的拮抗剂(优选磺胺异噁唑)和PRKG1的调节剂(优选丁四硝酯),
-KCNJ11的调节剂(优选选自米格列奈和左西孟旦)和PRKG1的调节剂(优选丁四硝酯),
-KCNJ11的调节剂(优选选自米格列奈和左西孟旦)和-钠通道SCN1A的抑制剂与BK通道的激活剂(优选唑尼沙胺)或BK通道的调节剂(优选甲氯噻嗪),
-KCNJ11的调节剂(优选选自米格列奈和左西孟旦)和-RHOA的调节剂(优选选自特比萘芬和利塞膦酸盐)。
在最优选的实施方案中,本发明涉及选自氨基己酸、阿坎酸盐、氨氯地平、阿加曲班、巴氯芬、西洛他唑、西那卡塞、氯吡格雷、二羟丙茶碱、非诺多泮、来氟米特、米帕林、甲巯咪唑、苯乙双胍、丙胺卡因、利福布汀、磺胺异噁唑、他达拉非、特比萘芬、桂利嗪、环匹罗司、依普利酮、甘珀酸、舒洛地特、乙胺嗪、异戊巴比妥、头孢替坦、丁四硝酯、甲氯噻嗪、利塞膦酸盐、恩丙茶碱、胆茶碱、甲乙双酮、头孢甲肟、安搏律定、依托咪酯、米格列奈、贝尼地平、左西孟旦和唑尼沙胺的化合物、或者其盐或药物前体或衍生物或缓释制剂的任何组合,用于治疗阿尔茨海默病或相关病症。
在具体的实施方案中,用于治疗阿尔茨海默病或相关病症的本发明的组合物包括选自氨基己酸、桂利嗪、环匹罗司、依普利酮、甘珀酸、舒洛地特、乙胺嗪、异戊巴比妥、头孢替坦、丁四硝酯、甲氯噻嗪、利塞膦酸盐、恩丙茶碱、胆茶碱、甲乙双酮、头孢甲肟、安搏律定、依托咪酯、米格列奈、贝尼地平和左西孟旦的至少一种化合物、或者其盐或药物前体或衍生物或缓释制剂,与选自阿坎酸盐、氨氯地平、阿加曲班、巴氯芬、西洛他唑、西那卡塞、氯吡格雷、二羟丙茶碱、非诺多泮、来氟米特、米帕林、甲巯咪唑、苯乙双胍、丙胺卡因、利福布汀、磺胺异噁唑、他达拉非、特比萘芬和唑尼沙胺的至少一种化合物、或者其盐或药物前体或衍生物或缓释制剂相组合。
本发明的另一个特别优选的实施方案涉及用于对有需要的对象治疗阿尔茨海默病(AD)或相关病症的组合物,其至少包括氨基己酸、或者其盐或药物前体或衍生物或缓释制剂。在具体的实施方案中,将氨基己酸与优选选自阿坎酸盐、氨氯地平、阿加曲班、巴氯芬、西洛他唑、西那卡塞、氯吡格雷、二羟丙茶碱、非诺多泮、来氟米特、米帕林、甲巯咪唑、苯乙双胍、丙胺卡因、利福布汀、磺胺异噁唑、他达拉非、特比萘芬、桂利嗪、环匹罗司、依普利酮、甘珀酸、舒洛地特、乙胺嗪、异戊巴比妥、头孢替坦、丁四硝酯、甲氯噻嗪、利塞膦酸盐、恩丙茶碱、胆茶碱、甲乙双酮、头孢甲肟、安搏律定、依托咪酯、米格列奈、贝尼地平、左西孟旦和唑尼沙胺的至少一种其他化合物、或者其盐或药物前体或衍生物或缓释制剂组合使用,用于合并、分别或顺序给药。
本发明的优选组合物包括氨基己酸、或者其盐或药物前体或衍生物或缓释制剂,和选自巴氯芬、磺胺异噁唑、特比萘芬和左西孟旦的至少一种其他化合物、或者其盐或药物前体或衍生物或缓释制剂,用于合并、分别或顺序给药。这样的组合物本身也代表了本发明的具体目的。
本发明还涉及对有需要的对象治疗阿尔茨海默病(AD)或相关病症的方法,其包括向所述对象施用有效量的氨基己酸、或者其盐或药物前体或衍生物或缓释制剂,优选如上所述组合施用。
本发明的另一个特别优选的实施方案涉及用于对有需要的对象治疗阿尔茨海默病(AD)或相关病症的组合物,其至少包括左西孟旦、或者其盐或药物前体或衍生物或缓释制剂。在具体的实施方案中,将左西孟旦与优选选自氨基己酸、阿坎酸盐、氨氯地平、阿加曲班、巴氯芬、西洛他唑、西那卡塞、氯吡格雷、二羟丙茶碱、非诺多泮、来氟米特、米帕林、甲巯咪唑、苯乙双胍、丙胺卡因、利福布汀、磺胺异噁唑、他达拉非、特比萘芬、桂利嗪、环匹罗司、依普利酮、甘珀酸、舒洛地特、乙胺嗪、异戊巴比妥、头孢替坦、丁四硝酯、甲氯噻嗪、利塞膦酸盐、恩丙茶碱、胆茶碱、甲乙双酮、头孢甲肟、安搏律定、依托咪酯、米格列奈、贝尼地平和唑尼沙胺的至少一种另外的化合物、或者其盐或药物前体或衍生物或缓释制剂组合使用,用于合并、分别或顺序给药。
本发明的优选的组合物包括左西孟旦、或者其盐或药物前体或衍生物或缓释制剂,和选自氨基己酸、巴氯芬、磺胺异噁唑和特比萘芬的至少一种另外的化合物、或者其盐或药物前体或衍生物或缓释制剂,用于合并、分别或顺序给药。这样的组合物本身也代表了本发明的具体目的。
本发明还涉及对有需要的对象治疗阿尔茨海默病(AD)或相关病症的方法,其包括向所述对象施用有效量的左西孟旦、或者其盐或药物前体或衍生物或缓释制剂,优选如上所述组合施用。
本发明的另一个特别优选的实施方案涉及用于对有需要的对象治疗阿尔茨海默病(AD)或相关病症的组合物,该组合物至少包括依普利酮、甘珀酸、舒洛地特、桂利嗪或乙胺嗪、或者其盐或药物前体或衍生物或缓释制剂。
在具体的实施方案中,将依普利酮、甘珀酸、舒洛地特、桂利嗪或乙胺嗪与优选选自左西孟旦、氨基己酸、阿坎酸盐、氨氯地平、阿加曲班、巴氯芬、西洛他唑、西那卡塞、氯吡格雷、二羟丙茶碱、非诺多泮、来氟米特、米帕林、甲巯咪唑、苯乙双胍、丙胺卡因、利福布汀、磺胺异噁唑、他达拉非、特比萘芬、桂利嗪、环匹罗司、依普利酮、甘珀酸、舒洛地特、乙胺嗪、异戊巴比妥、头孢替坦、丁四硝酯、甲氯噻嗪、利塞膦酸盐、恩丙茶碱、胆茶碱、甲乙双酮、头孢甲肟、安搏律定、依托咪酯、米格列奈、贝尼地平和唑尼沙胺的至少一种另外的化合物、或者其盐或药物前体或衍生物或缓释制剂组合使用,用于合并、分别或顺序给药。
本发明的优选的组合物包括依普利酮、甘珀酸、舒洛地特、桂利嗪或乙胺嗪、或者其盐或药物前体或衍生物或缓释制剂,和选自左西孟旦、氨基己酸、巴氯芬、磺胺异噁唑和特比萘芬的至少一种另外的化合物、或者其盐或药物前体或衍生物或缓释制剂,用于合并、分别或顺序给药。这样的组合物本身也代表了本发明的具体目的。
本发明还涉及对有需要的对象治疗阿尔茨海默病(AD)或相关病症的方法,其包括向所述对象施用有效量的依普利酮、甘珀酸、舒洛地特、桂利嗪或乙胺嗪、或者其盐或药物前体或衍生物或缓释制剂,优选如上所述组合施用。
最优选地,为了对有需要的对象组合治疗阿尔茨海默病(AD)或相关病症,本发明的组合物包括用于合并、分别或顺序给药的下列药物组合中的至少一种:
-苯乙双胍和唑尼沙胺,
-苯乙双胍和甲氯噻嗪,
-苯乙双胍和阿坎酸盐,
-苯乙双胍和磺胺异噁唑,
-巴氯芬和氨基己酸,
-巴氯芬和左西孟旦,
-巴氯芬和特比萘芬,
-巴氯芬和利塞膦酸盐,
-巴氯芬和磺胺异噁唑,
-巴氯芬和唑尼沙胺,
-巴氯芬和甲氯噻嗪,
-巴氯芬和磺胺异噁唑,
-巴氯芬和来氟米特,
-氨基己酸和磺胺异噁唑,
-氨基己酸和特比萘芬,
-氨基己酸和左西孟旦,
-左西孟旦和磺胺异噁唑,
-左西孟旦和特比萘芬,
-唑尼沙胺和二羟丙茶碱,
-甲氯噻嗪和二羟丙茶碱,
-唑尼沙胺和丙胺卡因,
-甲氯噻嗪和丙胺卡因,
-唑尼沙胺和磺胺异噁唑,
-苯乙双胍和氯吡格雷
-阿坎酸盐和西那卡塞
-磺胺异噁唑和西那卡塞
-特比萘芬和阿加曲班,
-特比萘芬和头孢甲肟,
-巴氯芬和氯吡格雷
-特比萘芬和氯吡格雷
-利塞膦酸盐和氯吡格雷,
-唑尼沙胺和桂利嗪
-阿坎酸盐和丁四硝酯
-磺胺异噁唑和丁四硝酯
-米格列奈或左西孟旦和丁四硝酯,
-米格列奈或左西孟旦和唑尼沙胺,
-米格列奈或左西孟旦和特比萘芬,
-米格列奈或左西孟旦和利塞膦酸盐.
-米格列奈或左西孟旦和甲氯噻嗪,
-甲氯噻嗪或唑尼沙胺和磺胺异噁唑,
-特比萘芬或利塞膦酸盐和磺胺异噁唑,
-特比萘芬或利塞膦酸盐和米帕林,
-特比萘芬或利塞膦酸盐和阿坎酸盐,
-特比萘芬或利塞膦酸盐和利福布汀,
-他达拉非或恩丙茶碱或胆茶碱和苯乙双胍,
-唑尼沙胺或甲氯噻嗪和阿加曲班或头孢甲肟,
-利塞膦酸盐和阿加曲班或头孢甲肟,
-唑尼沙胺或甲氯噻嗪和桂利嗪或贝尼地平或甲乙双酮或氨氯地平,
-阿坎酸盐和桂利嗪或贝尼地平或甲乙双酮或氨氯地平,
-唑尼沙胺或甲氯噻嗪和环匹罗司,
-磺胺异噁唑和异戊巴比妥,
-唑尼沙胺或甲氯噻嗪和异戊巴比妥,
-磺胺异噁唑和头孢替坦,
-唑尼沙胺或甲氯噻嗪和头孢替坦,
-唑尼沙胺或甲氯噻嗪和丁四硝酯。
本发明的优选组合物的具体实例包括用于合并、分别或顺序给药的下列药物组合中的一种:
-巴氯芬和氨基己酸,
-巴氯芬和左西孟旦,
-氨基己酸和磺胺异噁唑,
-氨基己酸和特比萘芬,
-氨基己酸和左西孟旦,
-左西孟旦和磺胺异噁唑,
-左西孟旦和特比萘芬,
-依普利酮和左西孟旦,
-依普利酮和磺胺异噁唑,
-依普利酮和非诺多泮,
-舒洛地特和左西孟旦,
-舒洛地特和磺胺异噁唑,
-舒洛地特和非诺多泮,或
-依普利酮和舒洛地特。
如实验部分所描述的,至少包括氨基己酸或左西孟旦的组合物提供了显著的治疗和生物作用从而改善人类对象中的阿尔茨海默病。这些组合物有效阻止了淀粉样b蛋白或肽对人类细胞的毒性效应,并代表了治疗这种疾病的新的强效的方法。
在另一个优选实施方案中,为了同时、分别或顺序给药以对有需要的对象组合治疗阿尔茨海默病(AD)或相关病症,根据本发明的组合物包括至少三种化合物、或者其任何纯度的盐或药物前体或衍生物、或者缓释制剂的组合。
根据本发明的治疗方法可以单独使用药物或使用与其他靶向相同途径或作用方式不同的治疗联合的药物组合。
在具体实施方案中,本发明的组合物还可以包括已经存在或者可能被开发的药物,其与由选自以下的基因所编码的蛋白质结合或者调节其活性:ABAT、ABCA1、ABI1、ABL1、ACAT、ACC2、ACCN1、ADAMTS12、ADCY2、ADIPOQ、ADIPOR1/R2、ADORA1/2A/2B、ADRA1A/2、ADRB1/2、AGPAT5、AIP4、AKAP2、AKR1C2、AKT、ALDH2、ALOX12、ALOX5、ANG2、ANK1、ANKRA、ANXA1、APBA1、APBA2BP、APOA1、APOER2、ARHGAP17、ARHGAP26、ATG5/7/12、ATM、ATP10A、ATP1A1、ATP2A3、ATP2B1、ATP6V1C1、ATR、AUH、BACE1、BAD、BAI3、BASSOON、BAX、BCAR1、BCL2、BDNF、BECLIN1、BIN1、BK通道(KCNMA1、KCNMB1)、BMP3A、BRCA1、CA10、CACNA1C/2D3/2D4、CADPS2、CALM1-5(钙调素)、CAMK1D、CAMKK2、CASK、CASR、CAST、CBL、CD36、CD44、CDC2、CDC42、CDC42BPB、CDC42EP3、CDH1/2/13、CDK5、CDKN1A、CHAT、CHK1、CHRM1-5、CHRNA1-7/9/10、CIT(枸橼)、CK1、CNGB3、CNTFR、COL4A2、CPT、CRAM、CREB、CRMP、CSH1、CTNNA2、CTNNB1、CTTN(皮层肌动蛋白)、CUBN、CULLIN1、CYP7B1、CYSLTR1/R2、DAB1、DCC、DEPDC2、DGKB/H/Z、DHCR7、DHFR、DLG2/4、DNAJB9、DOCK3、DRD2/5、DYN1/3、EDG1-8、EDN1/2、EDNRA/B、EFNA1/2/4/5/7(肝配蛋白A)、EFNB1/2/3(肝配蛋白B)、EHHADH、ELAVL2、ENPP2(自分泌运动因子)、ENPP6、EPHA3、EPHBR1/2/3/4/6、ERBB2/4、ERK1/2、ESRRG、ETFA、EZR、F2、F2R、FAS、FDPS、FES、FGF1/2、FKBP12/12.6、FLNA、FLT1(VEGFR1)、FLT4、FOXO1/3A、FRAP(MTOR)、FTO、FYN、FZ2、GABBR1/2、GABRA2/G2、GADD45、GAT1、GATA3、GH1、GIPC1/2、GLRA1、GLUD1、GNA12/13、GNPTAB、GPC5、GPHN(桥尾蛋白)、GRIA2/3、GRID1/2、GRIK1/2、GRIN2B/3A、GRIP1/2、GRK2/5、GRM3/5/6/7/8、GRP170、GSK3B、HAPLN1、HAS1-3、HCRTR2、HIF1A、HIPK2、HK2、HMOX1、HOMER1/2/3、HSD11B1、HSP90B1、HSPA5、HTR1A/1B/1D、HYAL1/2/3、IDE、IL20RA/B、IL6ST、IL8、IMPDH1/2、INS、INSR、IRF1、ITB1、ITGA1/6、ITGB1、ITPR1、JNK1、KALRN(钾蛋白)、KCNA2/D2、KCNH2、KCNIP1/2、KCNJ11、KCNJ12、KCNJ3、KCNMA1、KCNMB1-4、KDR(VEGFR2)、KTN1、KYNU、LAMA1、LDLR、LEP(瘦素)、LEPR、LIFR、LIN7A/B/C(VELI1/2/3)、LIPL2、LKB1、LRP1、LRP2(巨蛋白)、LTBP2、LYN、MAD1L1、MAML3、MAOA/B、MAT2B、MCC1、MDM1、ME1、MET、MGST2、MINT1、MLLT4(丝状肌动蛋白结合蛋白)、MMP2、MMP9、MOESIN、MTR、MUC1、MUNC13/18A、MYO6、MYOL、NADPH氧化酶、NAV1、NBEA、NCAM1、NCK1/2、NEDD9、NF2(merlin)、NFKB1、NFKBIB、NGEF(ephexin)、NGF、NGFR、NHERF、NIL16、NLGN1、NOC2、NOS1/2A/3、NOTCH1/2/3、NPC1/2、NPIST、NR1I2、NR3C1、NR3C2、NRG1/3、NRP1/2、NRX3、NTF3/5、NTN1(导蛋白1)、NTRK2(TRKB)、NWASP、OPCML、OPRK1、OPRM、OPRS1、OSBPL3/10、P2RY1、P2RY 12、PAELR、PAI1/2、PAK1/6/7、PALLD、PAP1、PARK2、PC、PCAF、PCTP、PDE11A、PDE1A、PDE3A/3B、PDE4A/4B/4D、PDE5A、PDE6D、PDGFA/B、PDGFRA/B、PI3K、PIAS1、PICALM、PICK1、PIK3C3、PIP5K、PITPNC1、PKCA、PKCD、PLA1A/2、PLAT、PLAU、PLCB1、PLD1/2、PLEXA1、PLG、PLN、PLXDC2、PML、POP2、PPARA、PPARD、PPARG、PPARGC1B、PPFIBP1、PPP1CA、PPP3CA(神经钙蛋白)、PRDX5/6、PRKAA(AMPK)、PRKACA、PRKG1、PRL、PTGER1、PTGFR、PTGS2、PTN、PTP1B、PTPN11、PTPRF、PTPRG、PTPRM、PVRL1、PXN(桩蛋白)、PYK2、RAB3B、RAC1、RACK1、RAP1、RASGRF2、RBPJ、RDX(根蛋白)、RELN、RGNEF、RHEB、RHOA、RHOG、RIM2、RIMS1/2、ROBO2、ROCK1/2、ROR2、RPH3A(Rab亲和蛋白)、RPH3AL、RPS6KA1、RPS6KB2、RTN1、RXR/RAR、RYR3、SACM1L、SAPAP、SAPK3、SCARB1、SCHIP1、SCN1A/1B、SCNN1D/1G、SEC24D、SEMA3A/3C/3E/4C、SGPP2、SH3BP5、SIAH1A、SIL1、SLC12A1/2/5、SLC1A2、SLC25A21、SLC6A1/A18、SLC8A1/A2/A3、SLC9A1、SLIT1、SLN、SMAD3/4、SNAP25、SNCA、SNCAIP、SORBS2、SORCS2、SPLA2、SPOCK1、SPP1(骨桥蛋白)、SRC、SRD5A1、SREBF1/F2、SRGAP3、STAT3、STX1A/2(突触融合蛋白)、STXBP6、SUM1、SV2C、SYN1、SYNJ1/2(突触伸蛋白)、SYT12、SYTL4(粒亲蛋白)、TACE、TACR1、TBR1、TBXA2R、TGFBR1/R2/R3、THBS1/2、THEM2、THRA/B、TIAM1、TIMP2、TLL2、TOP2A、TP53、TP63、TRIO、TRPC3/4/5、TSC1/2、TSPO、UBE2A、ULK4、UNC13C、UNC5C、VAMP2/5、VCL(VINCULIN)、VDAC1、VEGFA/C、VEGFR1、VMAT、VPS15、WASPIP、WAVE、WNT1A/5A、WWOX、XANTHINE氧化酶、YAP和YES1。
以上所列的所有基因和蛋白质的序列可以从基因文库中获得,并且可以用本领域已知技术分离。也可以用本领域已知技术评定这些基因或蛋白质的活性。
本发明也描述了可以用于调节靶基因和蛋白质的这些辅助药物。我们已经鉴别出单独或者组合起来调节上述途径且可以用于治疗阿尔茨海默病或相关病症的具体药物。
在优选的实施方案中,本发明的组合物可以进一步包括选自以下的至少一种药物:抑制剂ABAT,(优选氨己烯酸),和/或抑制剂ABL1(优选伊马替尼),和/或ACAT的抑制剂(优选橙皮素),和/或ADCY2的调节剂(优选阿糖腺苷),和/或腺苷ADORA1/2A/3受体的调节剂(优选选自氯法拉滨和去纤苷酸),和/或肾上腺素能ADRA受体的调节剂(优选选自哌氰嗪、甲氧异丁嗪、美芬丁胺和地匹福林),和/或肾上腺素能ADRB受体的调节剂(优选选自胍乙啶、苄二甲胍、比托特罗和丙卡特罗),和/或ALOX5/12的抑制剂(优选选自二乙基乙胺嗪和马索罗酚),和/或ATP1A1的抑制剂(优选去乙酰毛花苷和奥美拉唑),和/或自噬作用的激活剂(优选海藻糖),和/或CA10的抑制剂(优选醋甲唑胺),和/或钙化作用的调节剂(优选选自膦甲酸钠、硝酸镓、钙二醇、降钙素、钙三醇、氯瞵酸、二氢速甾醇、依降钙素、依替膦酸、伊普黄酮和醋酸特立帕肽),和/或CALM1的调节剂(钙调素)(优选安搏律定),和/或CD44的调节剂(优选选自依氟鸟氨酸和苯溴马隆),和/或化学伴侣(优选选自阿拉伯糖醇和甘露醇),和/或毒蕈碱CHRM受体的调节剂(优选选自环喷托酯、羟苯环嘧、曲司胺和异氟磷),和/或不能穿过血脑屏障的烟碱乙酰胆碱CHRNA受体的拮抗剂(优选选自泮库溴铵、哌库溴铵、瑞库溴铵、罗库溴铵、琥珀胆碱、维库溴胺、阿曲库铵、顺阿曲库铵、杜什库铵、美加明、美多寇林、美维库铵和新霉素),和/或CNGB3的抑制剂(优选阿米洛利),和/或CYSLTR1/2、PTGER1、PTGFR和TBXA2R类十二烷酸受体的调节剂(优选选自曲伏前列素、孟鲁司特、西路斯特、氨来呫诺、卡前列素氨基丁三醇、比马前列素和利多瑞尔),和/或DHFR的抑制剂(优选乙胺嘧啶和三氨蝶呤),和/或多巴胺DRD2受体的调节剂(优选选自双氢麦角胺和卡麦角林),和/或多巴胺受体DRD5的激动剂(优选非诺多泮),和/或EDNRA的抑制剂(优选选自磺胺甲恶唑和庆大霉素),和/或ENPP2(自分泌运动因子)的调节剂(优选L-组氨酸),和/或ERBB2的抑制剂(优选拉帕替尼),和/或F2凝血酶的调节剂(优选选自舒洛地特、希美加曲、华法林、苯丙香豆醇、依诺肝素、阿他肝素、磺达肝癸、拉氧头孢、杆菌肽、噻氯匹定和厄多司坦),和/或FDPS的抑制剂(优选阿仑唑奈),和/或GABRA2的调节剂(优选选自苯巴比妥、美索比妥、头孢替安、氯美噻唑、硫喷妥、鲁比前列酮和氨曲南),和/或GRIK1的拮抗剂(优选托吡酯),和/或GSK3B活性的调节剂(优选选自沙丁胺醇和间羟胺),和/或HIF1A信号的调节剂(优选选自美洛昔康、托泊替康、去铁胺、地衣酸、肼苯哒嗪、去铁酮、二苯甲酰甲烷、阿伏苯宗、地诺前列酮、依前列醇、2-酮戊二酸和含羞草碱),和/或HK2(己糖激酶II)的抑制剂(优选选自奎宁、加贝酯、联苯苄唑和克霉唑),和/或HMOX1的调节剂(优选选自金诺芬、血色素/血晶质和精氨酸血红素),和/或HTR1B/1D受体的调节剂(优选选自麦角胺和依立曲坦),和/或IMPDH1和IMPDH2的抑制剂(优选硫鸟嘌呤),和/或整合素ITGA/B的调节剂(优选雷贝拉唑),和/或KCND2钾通道的抑制剂(优选利多卡因),和/或KCNH2钾通道的抑制剂(优选伊布利特),和/或KCNMA1的调节剂(优选选自色甘酸盐、炔己蚁胺、托康唑、氯唑沙宗、乌诺前列酮、橙皮素、苄氟噻嗪、苯噻嗪、氯噻嗪、环噻嗪、氯甲苯噻嗪、氢氟甲噻、喹乙宗和三氯甲噻嗪),和/或MGST2的调节剂(优选巴柳氮),和/或MMP2和MMP9的调节剂(优选坎沙曲),和/或线粒体通透性转换孔形成的调节剂(优选选自甘珀酸和环丙沙星),和/或MTOR的抑制剂(优选雷帕霉素),和/或NOS1/2A/3的调节剂(优选选自丙基硫尿嘧啶、硫乙拉嗪和酮替芬),和/或NR3C1受体信号的调节剂(优选选自甲吡酮和莫米松),和/或NR3C2受体的调节剂(优选选自依普利酮和氟氢可的松),和/或NRP2的抑制剂(优选哌加他尼),和/或OPCML的调节剂(优选阿芬太尼),和/或OPRK1和OPRS1的调节剂(优选选自丁丙诺啡和戊唑辛),和/或OPRM(优选烯丙左吗喃),和/或氧化磷酸化作用的调节剂(优选选自阿米三嗪、红霉素、卡那霉素和浅蓝菌素),和/或P2RY1和/或P2RY12受体的抑制剂(优选替罗非班),和/或PDE11A、PDE4A和PDE5A磷酸二酯酶的抑制剂(优选选自松叶菊碱、米利酮和阿那格雷),和/或PDE3A/3B和PDE4A/4B磷酸二酯酶的抑制剂和BK通道的激活剂(优选西洛他唑),和/或PDGFRA/B受体的调节剂(优选选自贝卡普勒明、链霉素、花翠素、花青素和烟曲霉素),和/或PLA2的调节剂(优选选自尼氟酸、氢可他酯和奈替米星),和/或PLAT的调节剂(优选苯丁酸钠),和/或PLD2的调节剂(优选安立生坦),和/或PLG的抑制剂(优选氨基己酸),和/或PPARD的调节剂(优选二十碳五烯酸),和/或PPARG的调节剂(优选丁酸苯酯),和/或PRKG1的调节剂(优选选自硝普盐、硝化甘油和帕立骨化醇),和/或PTP1B的抑制剂(优选替鲁膦酸盐),和/或RHOA/RAC的调节剂(优选选自氯噻酮、氢氯噻嗪、氯莫环素、赖甲环素、游霉素、两性霉素B、头孢氨苄、头孢噻啶、头孢呋辛、双氯西林),和/或RXR/RAR的调节剂(优选他佐罗汀),和/或SCN1A/B钠通道的拮抗剂(优选磷苯妥英),和/或SLC12A1的抑制剂(优选布美他尼),和/或SLC6A1的抑制剂(优选噻加宾),和/或SLC9A1的调节剂(优选布克利嗪),和/或SRD5A1的抑制剂(优选度他雄胺),和/或TACR1的拮抗剂(优选选自阿瑞吡坦和伐普肽),和/或TGFB信号的调节剂(优选阿利吉仑),和/或THRA/B的调节剂(优选选自碘塞罗宁),和/或TOP2A的抑制剂(优选硫蒽酮),和/或TSPO的调节剂(优选选自氟硝基安定和羟基安定),和/或VDAC1的调节剂(优选二羟基铝),和/或VEGFR1的抑制剂(优选苏尼替尼),和/或维生素K代谢的调节剂(优选选自头孢美唑、头孢孟多和头孢哌酮),和/或VMAT的抑制剂(优选选自四苯喹嗪、地舍平和尼替西农),和/或电压门控钙通道(CACNA)的抑制剂(优选选自乐卡地平、普加巴林、米拉地尔、阿雷地平、巴米地平(bamidipine)、苄环烷、苄普地尔、克仑硫卓、依福地平、依高地平、依他苯酮、芬地林、氟桂嗪、加洛帕米、依拉地平、拉西地平、利多氟嗪、洛美利嗪、马尼地平、尼卡地平、尼伐地平、尼莫地平、尼索地平、尼群地平、哌克昔林、普尼拉明、司莫第尔和特罗地林),和/或YES1、SRC和EPHA3的抑制剂(优选达沙替尼)。
与根据本发明的药物或药物组合联合使用的其他治疗可以包括改善阿尔茨海默病症状的一种或多种药物或者可以用于阿尔茨海默病的姑息性治疗的药物。优选地,所述一种或多种药物选自3APS、AAB-001、ABT-089、ABT-126、AC-3933、ACC-001、对乙酰氨基酚、AFFITOPE AD01、AFFITOPE AD02、α-硫辛酸、α-生育酚、AN1792、抗Aβ、AQW051、阿立哌唑、阿托西汀、阿托伐他汀、AVE1625、AVP-923、AZD0328、AZD3480、巴品珠单抗、BAY94-9172(ZK6013443)、Bifeprunox、黑胡椒素、BMS-708163、BRL-049653、苔藓虫素、CAD106、塞来昔布、CERE-110、脑活素、CHF 5074、胆碱、Circadin、西酞普兰、辅酶Q、铜、CTS21166、姜黄素、CX516(安帕来斯)、CX717、Cyclophosphamate、DCB-AD1、右旋安非他命、DHA(二十二碳六烯酸)、地高辛、Dimebon(Latrepirdine)、双丙戊酸钠、DMXB-A、多奈哌齐、多西环素、Egb 761、EHT 0202tazolate、ELND005(鲨肌醇)、EPAX 1050TG、甲磺酸二氢麦角碱、表没食子儿茶素没食子酸酯、异地普伦、雌二醇、雌激素、依那西普、EVP-6124、EVT101、艾斯能、鱼油、FK962、florpiramine F 18、叶酸+维生素B6+维生素B21、加巴喷丁、加兰他敏、吉非罗齐、银杏(Ginkgo biloba)提取物(例如EGb 761或CP401)、银杏的改良提取物(例如活性成分富集的或污染物减少的)或者含有银杏提取物的药物(例如达纳康或静可福t)、葡萄糖、L-谷氨酸、GSI 136、GSI-953、GSK239512、GSK933776A、氟哌丁苯、HF0220、石杉碱A、氢可酮/APAP、布洛芬、IFN-α2A、吲哚美辛、胰岛素、静脉用免疫球蛋白、Ketasyn、乐考唑坦、亮丙瑞林、左旋多巴、硫辛酸、锂、劳拉西泮、洛伐他汀、叶黄素、LY2062430(索拉珠单抗)、LY2811376、LY450139、LY451395、MABT5102A、苹果酸盐、马赛替尼(AB1010)、甲孕酮、褪黑素、MEM 1003、MEM 3454、美金刚、亚甲基蓝、哌醋甲酯、米非司酮、MK0249、MK0677、MK0952、MK0952、MK3328、莫达非尼、MPC-7869、NADH、萘普生、奈非西坦、海王磷虾油、奈拉美生、NIC5-15、Nicoderm贴片、烟酰胺(维生素B3)、Novasoy、NP031112、NS 2330、NSA-789、NSAIDs、奥氮平、ω-3多不饱和脂肪酸(EPA+DHA)、ONO-2506PO、羟丁酸盐、人参、PAZ-417、PBT2、羟哌氯丙嗪、PF-04360365、PF-04447943、PF-04494700、苯羟基丙氨酸、磷脂酰丝氨酸、匹伐他汀、Posiphen、PPI-1019(APAN)、帕伐他汀、哌唑嗪、泼尼松、黄体酮、PRX-03140、PYM50028、喹硫平、R1450、雷洛昔芬、雷米普利、雷沙吉兰、加兰他敏、白藜芦醇、利福霉素、利哌利酮、利凡斯的明、RN1219、RO5313534、罗非考昔、罗西格列酮、洋苏草(鼠尾草)、SAM-315、SAM-531、SAM-760、SB-742457、硒、舍曲林、SGS-742、辛伐他汀、SK-PC-B70M、索拉珠单抗、SR57667B、SRA-333、SRA-444、SSR180711C、ST101、T-817MA、塔克林、Tarenflurbil、睾酮、Tramiprosate(3APS)、曲唑酮、TRx0014(亚甲基蓝)、色氨酸、V950、丙戊酸盐、瓦尼克林、维生素C、维生素E、VP4896、扎利落登、玉米黄质、唑吡坦、和ZT-1(DEBIO-9902 SR)。
本发明还涉及治疗阿尔茨海默病或相关病症的方法,该方法包括向有需要的对象同时、分别或顺序施用如上所述的药物组合。
本发明的另一个目的是治疗阿尔茨海默病或相关病症的方法,该方法包括向有需要的对象同时、分别或顺序施用调节突触功能的药物和/或调节血管生成的药物和/或调节细胞应激反应的药物的组合。
本发明的另一个目的在于选择用于组合治疗阿尔茨海默病或相关病症的药物的方法,该方法包括检测候选药物对于突触功能和/或血管生成和/或细胞应激反应的活性并选择改善突触功能、减轻血管生成调节异常和调节细胞应激反应的药物的步骤。
在另一个实施方案中,本发明涉及选择用于治疗阿尔茨海默病或相关病症的组合物的方法,该方法包括制备改善突触功能的药物和/或减轻血管生成调节异常的药物和/或调节细胞应激反应的药物的组合,用于向有需要的对象同时、分别或顺序施用。
在另一个优选实施方案中,本发明涉及治疗阿尔茨海默病或相关病症的方法,该方法包括向有需要的对象同时、分别或顺序施用调节突触功能的药物和/或调节血管生成的药物和/或调节细胞应激反应的药物。
可以向所述对象重复施用本发明的组合物。
本发明的组合物通常包括一种或若干种可药用的载体或赋形剂。治疗的持续时间取决于受治疗的疾病的阶段、所使用的组合物、患者的年龄和状况、以及患者对治疗的反应。可以独立地控制组合中各种成分的施用剂量、频率和方式。例如,可以口腔施用一种药物而肌内施用第二种药物。可以采用包括休息期间的间歇式周期(on-and-off cycle)给予组合治疗,使得患者的身体有机会从尚且无法预见的副作用中恢复。还可以将药物配制在一起,使得一次给药可以给予全部药物。
可以用任何合适的方法施用组合中的各种药物,所述方法致使药物的浓度与其他成分组合起来能够矫治AD中所牵涉途径的发挥功能。
虽然有可能将组合中的活性成分作为纯化学品施用,但优选将其作为药物组合物提供,这种情形下也称为药物制剂。可能的组合物包括适合于经口、直肠、局部(包括透皮、经颊和舌下)、或胃肠外(包括皮下、肌内、静脉内和真皮内)给药的组合物。
更通常,将这些药物制剂以“患者包”的形式开给患者,所述患者包在单个包装、通常为泡罩包装中含有一定数量的剂量单位或者用于以计量的单位剂量给药的其它方式,以供在一个明确的治疗阶段期间使用。与药剂师从整体供给品中分出患者的药物供应的传统处方相比,患者包的优势在于,患者总是能够得到患者包中含有的包装说明书,而这在传统处方中通常是没有的。包含包装说明书已经显示出可以改善患者对医生指导的遵从性。因此,本发明还包括本文前述的药物制剂,其与适合于所述制剂的包装材料组合。在这样的患者包中,可以从说明书、能力、条件、适应症和/或其他手段推断出用于组合治疗的制剂的预期使用方法,有助于以最适合于治疗的方式使用制剂。这样的措施使患者包特别适合于和适用于使用本发明的组合的治疗。
药物可以任何合适的量包含在任何合适的载体物质中,并且可以组合物总重量的1-99重量%的量存在。可以用适合于经口、胃肠外(例如静脉内、肌内)、直肠、皮肤、鼻、阴道、吸入、皮肤(贴片)或眼给药途径的剂型提供该组合物。因此,组合物可以是例如片剂、胶囊、丸剂、粉剂、颗粒、悬浮剂、乳液、溶液、包括水凝胶在内的凝胶剂、糊剂、软膏、霜剂、膏药、饮剂、渗透给药装置、栓剂、灌肠剂、注射剂、植入剂、喷雾剂或气雾剂的形式。
可以按照常规制药实践(例如参见《Remington:制药科学与实践》(第20版),A.R.Gennaro主编,Lippincott Williams&Wilkins,2000与《制药技术全书》,J.Swarbrick和J.C.Boylan主编,1988-1999,Marcel Dekker,纽约)配制药物组合物。
可以将本发明的药物组合物配制为在给药时基本立即或者在给药后的任何预定时间或时期内释放活性药物。
控释制剂包括(i)在较长时期内在体内产生基本恒定的药物浓度的制剂;(ii)在预定的延迟时间后在较长时期内在体内产生基本恒定的药物浓度的制剂;(iii)通过在体内维持相对恒定、有效的药物水平同时使与活性药物物质的血浆水平波动相关的不良副作用最小化,在预定的时期内维持药物作用的制剂;(iv)通过例如将控释组合物在空间上置于患病组织或器官附近或其中,使药物作用局部化的制剂;以及(v)通过使用载体或化学衍生物将药物递送到特定的目的细胞类型从而使药物作用定向的制剂。
在下述情况下尤其优选施用控释制剂形式的药物,所述情况中具有(i)狭窄的治疗指数(即产生有害副作用或毒性反应的血浆浓度与产生治疗效果的血浆浓度之间的差异小;一般而言,将治疗指数TI定义为半数致死剂量(LD50)与半数有效剂量(ED50)的比值);(ii)狭窄的胃肠道吸收窗;或(iii)非常短的生物半衰期,使得为了将血浆水平维持在治疗水平需要在一天中频繁用药。
为了达到所研究药物的释放速率超过代谢速率的控制释放,可以采取许多策略中的任何策略。可以通过适当选择各种配制参数和成分、包括例如各种类型的控释组合物和包衣来达到控制释放。因此,使用合适的赋形剂将药物配制成为在给药时以受控方式释放药物的药物组合物(单个或多个单位的片剂或胶囊组合物、油溶液、悬浮液、乳液、微胶囊、微球、纳米颗粒、贴片和脂质体)。
用于经口使用的固体剂型
用于经口使用的制剂包括含有活性成分与无毒性的药用可接受的赋形剂的混合物的片剂。这些赋形剂可以是例如惰性稀释剂或填充剂(例如蔗糖、微晶纤维素、包括马铃薯淀粉在内的淀粉、碳酸钙、氯化钠、磷酸钙、硫酸钙或磷酸钠);造粒剂和崩解剂(例如包括微晶纤维素在内的纤维素衍生物、包括马铃薯淀粉在内的淀粉、交联羧甲基纤维素钠、藻酸盐或藻酸);粘合剂(例如阿拉伯树胶、藻酸、藻酸钠、明胶、淀粉、预胶化淀粉、微晶纤维素、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、聚乙烯吡咯烷酮或聚乙二醇);以及润滑剂、助流剂和抗粘附剂(例如硬脂酸、二氧化硅或滑石粉)。其他药用可接受的赋形剂可以是着色剂、调味剂、增塑剂、保湿剂、缓冲剂等。
片剂可以是未包衣的,或者它们可以用已知技术包衣,以任选延迟在胃肠道中的崩解和吸收,从而在较长时期内提供持续作用。可以使包衣适应于以预定方式释放活性药物物质(例如为了获得控释制剂)或者可以使其适应于直到通过胃之后才释放活性药物物质(肠溶包衣)。包衣可以是糖包衣、薄膜包衣(例如基于羟丙基甲基纤维素、甲基纤维素、甲基羟乙基纤维素、羟丙基纤维素、羧甲基纤维素、丙烯酸酯共聚物、聚乙二醇、和/或聚乙烯吡咯烷酮)或肠溶包衣(例如基于甲基丙烯酸共聚物、乙酸邻苯二甲酸纤维素、邻苯二甲酸羟丙基甲基纤维素、乙酸琥珀酸羟丙基甲基纤维素、邻苯二甲酸聚乙酸乙烯酯、虫胶和/或乙基纤维素)。可以使用延时材料,例如单硬脂酸甘油酯或二硬脂酸甘油酯)。
固体片剂组合物可以包括适合于保护组合物免于不想要的化学变化(例如在释放活性药物物质前的化学降解)的包衣。可以采用与《制药技术全书》中所描述的相似方式将包衣涂覆在固体剂型上。
若干种药物可以在片剂中混合在一起,或者可以是分开的。例如,在片剂的里面含有第一种药物,而第二种药物在外面,使得在释放第一种药物之前释放相当部分的第二种药物。
经口使用的制剂也可以提供成为可咀嚼片剂,或者其中活性成分与惰性固体稀释剂(例如马铃薯淀粉、微晶纤维素、碳酸钙、磷酸钙或高岭土)混合的硬明胶胶囊,或者其中活性成分与水或油介质例如液体石蜡或橄榄油混合的软明胶胶囊。可以使用上述片剂和胶囊中的成分以常规方式制备粉剂或颗粒。
可以将经口使用的控释组合物构建成为例如通过控制活性药物物质的溶解和/或扩散来释放活性药物。
可以通过药物的片剂、胶囊、丸剂或颗粒制剂的适当包衣,或者通过将药物掺入到适当的基质中,从而实现溶解或扩散控释。控释包衣可以包括上述一种或多种包衣物质,和/或例如虫胶、蜂蜡、glycowax、蓖麻蜡、巴西棕榈蜡、硬脂醇、单硬脂酸甘油酯、二硬脂酸甘油酯、棕榈酸硬脂酸甘油酯、乙基纤维素、丙烯酸类树脂、dl-聚乳酸、乙酸丁酸纤维素、聚氯乙烯、聚乙酸乙烯酯、乙烯吡咯烷酮、聚乙烯、聚甲基丙烯酸酯、甲基丙烯酸甲酯、2-羟基甲基丙烯酸酯、甲基丙烯酸酯水凝胶、1,3-丁二醇、甲基丙烯酸乙二醇酯和/或聚乙二醇。在控释基质制剂中,基质材料还可以包括例如水合甲基纤维素、巴西棕榈蜡和硬脂醇、卡巴浦尔934、有机硅、三硬脂酸甘油酯、丙烯酸甲酯-甲基丙烯酸甲酯、聚氯乙烯、聚乙烯和/或卤代氟烃。
含有所宣称的组合中的一种或多种药物的控释组合物还可以采用漂浮片剂或胶囊的形式(即在经口给药时,在胃内容物顶部漂浮一定时期的片剂或胶囊)。可以通过将药物与赋形剂和20-75%w/w的水胶体诸如羟乙基纤维素、羟丙基纤维素或羟丙基甲基纤维素的混合物造粒从而制备药物的漂浮片制剂。然后可以将所获得的颗粒压制成片剂。在与胃液接触时,片剂在其表面周围形成基本上不透水的凝胶屏障。这种凝胶屏障参与维持密度小于1,从而允许片剂保持漂浮在胃液中。
用于经口给药的液体
适合于通过添加水制备水混悬剂的粉剂、可分散粉剂或颗粒是用于经口给药的便利剂型。作为混悬剂的制剂提供了活性成分与分散或湿润剂、助悬剂和一种或多种防腐剂的混合物。合适的助悬剂是例如羧甲基纤维素钠、甲基纤维素、藻酸钠等。
胃肠外组合物
药物组合物也可以通过以剂型、制剂或借助含有常规的无毒的可药用的载体和佐剂的合适给药装置或植入物的形式通过注射、输注、或植入(静脉内、肌内、皮下等)进行胃肠外给药。这样的组合物的配制和制备对于药物制剂领域的技术人员来说是公知的。
胃肠外使用的组合物可以提供成单位剂量形式(例如单剂安瓿甁)或者含有若干剂并且可以添加合适的防腐剂(参见下文)的小瓶。组合物可以采用溶液、混悬剂、乳液、输注装置或用于植入的递送装置的形式,或者将其作为干粉提供,以在使用前用水或其他合适的介质复溶。除了活性药物外,组合物还可以包括合适的胃肠外可接受的载体和/或赋形剂。可以为了受控释放将活性药物掺入到微球、微胶囊、纳米颗粒、脂质体等中。组合物可以包括助悬剂、增溶剂、稳定剂、pH调节剂和/或分散剂。
根据本发明的药物组合物可以采用适合于无菌注射的形式。为了制备这样的组合物,将合适的活性药物溶解或悬浮在胃肠外可接受的液体介质中。在可以使用的可接受介质和溶剂中包括水、通过加入适量盐酸、氢氧化钠或合适的缓冲剂调整到合适pH的水、1,3-丁二醇、林格液和等渗氯化钠溶液。水性制剂也可以含有一种或多种防腐剂(例如对羟基苯甲酸的甲酯、乙酯或正丙酯)。在一种药物仅仅少量或微溶于水的情况下,可以加入溶解增强剂或助溶剂,或者溶剂可以包括10-60%w/w的丙二醇等。
控释胃肠外组合物可以采用水性混悬剂、微球、微胶囊、磁性微球、油溶液、油混悬剂或乳液的形式。或者,可以将活性药物掺入生物相容的载体、脂质体、纳米颗粒、植入物或输注装置中。用于制备微球和/或微胶囊的材料是例如可生物降解/可生物侵蚀的聚合物,如丙交酯乙交酯共聚物、聚(氰基丙烯酸异丁酯)、聚(2-羟基乙基-L-谷氨酰胺)。在配制控释胃肠外制剂时可以使用的生物相容载体是碳水化合物类(例如葡聚糖)、蛋白质(例如白蛋白)、脂蛋白或抗体。用于植入物的材料可以是不可生物降解的(例如聚二甲基硅氧烷)或可生物降解的(例如聚己内酯、聚乙醇酸、或聚原酸酯)。
直肠组合物
对于直肠应用,组合物的合适的剂型包括栓剂(乳液或混悬液型)和直肠明胶胶囊(溶液或混悬液)。在典型的栓剂制剂中,将活性药物与适当的药用可接受的栓剂基质诸如可可酯、酯化的脂肪酸、甘油化的明胶和各种水溶性的或水可分散的基质如聚乙二醇组合。可以掺入各种添加剂、增强剂或表面活性剂。
经皮和局部组合物
药物组合物也可以作为含有常规的无毒的可药用的载体和赋形剂的剂型或制剂局部施用在皮肤上,用于经皮吸收,所述载体和赋形剂包括微球和脂质体。所述制剂包括霜剂、软膏、洗液、搽剂、凝胶、水凝胶、溶液、混悬剂、药棒、喷雾剂、糊剂、膏药或其他类型的经皮药物递送系统。可药用的载体或赋形剂可以包括乳化剂、抗氧化剂、缓冲剂、防腐剂、保湿剂、渗透增强剂、螯合剂、凝胶形成剂、软膏基质、香料和护肤剂。
乳化剂可以是天然存在的树胶(例如阿拉伯树胶或黄耆树胶)
防腐剂、保湿剂、渗透增强剂可以是对羟苯甲酸酯,例如对羟基苯甲酸的甲酯或丙酯,以及苯扎氯铵、甘油、丙二醇、脲等。
上述用于局部施用在皮肤上的药物组合物也可以用于局部施用在身体待治疗部分上或其附近的情况下。组合物可以适用于直接应用或利用专门的药物递送装置诸如敷料或者石膏、衬垫、海绵、条或其他适合的柔性材料形式进行应用。
治疗的剂量和持续时间
应该理解,组合的药物可以在相同或不同的药物制剂中同时施用或者顺序施用。如果是顺序施用,施用第二种(或者另外的)活性成分的延后不应当导致丧失活性成分组合的有效作用的益处。对于根据本发明的组合的最低要求是,该组合应当旨在以具有活性成分组合的有效作用的益处来组合使用。组合的预期使用可以通过能力、条件、适应症和/或有助于使用本发明的组合的其他方式推断出来。
虽然本发明的活性药物可以分剂施用,例如每日两次或三次,但是优选组合中的每种药物每日单次剂量,最优选单一药物组合物(单位剂量形式)中的所有药物每日单次剂量。
术语“单位剂量形式”指适合作为人类对象的单位剂量的物理上分立的单位(如胶囊、片剂或装药的注射器筒),每个单位含有根据计算能够产生所需疗效的预定量的活性物质以及所需的药物载体。
给药可以每日一次至几次,持续几天至几年,甚至可以是患者终生。在多数情况下表明需要长期或至少定期重复地长期给药。
此外,关于特定患者的药物基因组学(基因型对治疗的药物动力学、药效学或疗效情况的影响)信息可以影响所使用的剂量。
除了对于特别受损害的AD病例可能需要较高剂量来产生响应之外,组合中每种药物的优选剂量通常在不超过长期维持治疗的通常处方剂量或者在3期临床研究中被证明安全的剂量范围内。
本发明的一个显著优点是,在组合治疗中可以低剂量使用每种化合物,同时组合起来对患者产生显著的临床益处。在化合物单独没有显著作用的剂量下,组合治疗确实是有效的。因此,本发明的特殊优点在于使用各种化合物的亚适剂量的能力,所述亚适剂量即低于通常所开出的治疗剂量的剂量,优选治疗剂量的1/2,更优选1/3、1/4、1/5,或者甚至更优选治疗剂量的1/10至1/100。在这样的亚适剂量下,化合物单独基本没有活性,而根据本发明的组合完全有效。
优选的剂量相当于长期维持治疗的通常处方剂量的1%直至50%的量。
最优选的剂量相当于长期维持治疗的通常处方剂量的1%直至10%的量。
以下提供本发明中所使用的药物剂量的具体实例:
-氨基己酸每天约0.05至15g
-左西孟旦每天约0.05至4mg
-口服氨氯地平每天约0.05至1mg
-口服氯吡格雷每天约0.75至7.5mg,
-口服他达拉非每天约0.05至0.5mg,
-口服西洛他唑每天约1至10mg,
-口服特比萘芬约2.5至25mg,每天一次或两次,
-口服来氟米特每天约0.25至2.5mg,
-口服西那卡塞每天约0.3至3mg,
-口服阿坎酸盐约7至70mg,每天三次,
-口服甲巯咪唑每天约0.05至1.5mg
-口服米帕林每天约3至30mg,
-口服苯乙双胍每天约0.5至5mg,
-口服巴氯芬每天约0.4至8mg,分二或三剂服用,
-口服利福布汀每天约6至60mg,
-口服异戊巴比妥每天约0.06至15mg,
-口服头孢替坦每天约0.01至0.4mg,
-口服二羟丙茶碱每天约6至60mg,分2或3剂,
-口服甲氯噻嗪每天约0.025至1mg,
-口服利塞膦酸盐每天约0.05至3mg,
-口服依托咪酯每天约0.6至6mg,
-口服唑尼沙胺每天约1至40mg.
应该理解,实际施用的药物的量将由医生根据相关情况包括所治疗的病症、所施用的具体组合物、个体患者的年龄、体重和反应、患者症状的严重性以及所选择的给药途径决定。因此,上述剂量范围旨在为本文的教导提供一般性指导和支持,而不是限制本发明的范围。
具体实施方式
给出以下实施例,其是用于说明的目的而不是限制。
实施例
I.化合物与其组合物预防Aβ25-35肽的毒性
在这第一系列实验中,已经检测了候选化合物对于预防或减轻Aβ25-35肽的毒性作用的能力。首先单个检测药物,随后检测其组合作用。在多种细胞类型上测定其作用,从而进一步说明化合物的活性。
在AD中,APP蛋白形成纤维状Aβ蛋白(淀粉样蛋白)的不溶性β折叠层的聚集体。从可溶性到纤维状形态的构象变化似乎是随Aβ浓度升高而增加的自发事件,因此任何大于正常量的Aβ的产生(或者较大的、较难溶形态的Aβ的产生)会导致斑块形成增加。一旦开始形成Aβ斑块,其它分子可以与新生的斑块相互作用从而最终产生成熟的斑块和相关的神经细胞死亡区域。考虑到这一点,我们已经优先检测药物对暴露于淀粉样β蛋白的细胞的存活率的影响。
I.1对抗Aβ25-35肽对皮质神经元的毒性的保护作用
细胞培养
按照Singer等1999的描述培养原代大鼠皮质神经元。简单来说,将妊娠15天的雌性大鼠通过颈椎脱位处死(Rats Wistar;Janvier),并从子宫中取出胎畜。取出皮质并置于用冰冷的含有1%青霉素-链霉素(PS;Invitrogen)和1%牛血清白蛋白(BSA;Sigma)的Leibovitz培养基(L15;Invitrogen)中。在37℃下用在不含钙和镁的PBS中稀释的胰蛋白酶(胰蛋白酶EDTA 1X;Invitrogen)处理20分钟使皮质解离。通过加入含有II级DNAase I(0.1mg/ml;Roche Diagnostic)和10%胎牛血清(FCS;Invitrogen)的Dulbecco改良Eagle培养基(DMEM;Invitrogen)终止反应。然后通过使细胞3次通过10mg移液管使细胞机械脱开。然后将细胞在10℃下以180x g离心10分钟。舍弃上清液,将细胞团重新悬浮在指定培养基中,所述培养基由补充有B27(2%;Invitrogen)、L-谷氨酰胺(0.2mM;Invitrogen)、1%PS溶液和10ng/ml脑源神经营养因子(BDNF,Pan Biotech)的神经元基础培养基(Invitrogen)组成。在Neubauer细胞计数器上使用锥虫蓝排斥实验对活细胞进行计数。将细胞以30000细胞/孔的密度接种在96孔板(孔用聚L-赖氨酸(10μg/ml;Sigma)预包覆)中,并在37℃下在潮湿空气(95%)/CO2(5%)气氛下培养,
培养6天后,将细胞与药物(5种浓度)温育。1小时后,在不含BDNF但具有药物的指定培养基中用20μMβ-淀粉样蛋白(25-35;Sigma)使细胞中毒。使皮质神经元中毒2天。每种条件进行两份独立的培养物,每种条件6个孔。
轴突长度定量
用冷的乙醇(95%)和乙酸(5%)溶液将细胞固定10分钟。将细胞用0.1%皂角苷通透化之后,用含有10%山羊血清的PBS阻断2小时。然后将细胞与针对微管相关蛋白2(MAP-2;Sigma)的单克隆抗体温育。该抗体特异性地显现出细胞体和轴突。所使用的二级抗体是Alexa Fluor 488山羊抗小鼠IgG(分子探针)。用荧光染料(Hoechst溶液,SIGMA)显示神经元的核。使用InCell AnalyzerTM 1000(GE Healthcare),以20×放大倍数对每个孔拍摄20张照片。在相同条件下拍摄全部照片。使用Developer软件(GE Healthcare)定量轴突长度。
结果
图1中所显示的结果是从两个独立的培养物中提取出来的,每种条件6个孔。所有值均表示为平均值±平均值标准误差。对原始数据进行了双侧student's t检验分析。结果表示为与对照(介质)相比的轴突长度百分比。
在持续2天的20μM Aβ25-35中毒之前,将药物与大鼠原代皮质神经元温育1小时(36)。
在该温育2天后,对反映轴突细胞生长的轴突长度的网络进行定量。结果表明被检测药物明显发挥出对抗Aβ25-35中毒的神经保护作用(图1和图2)。
I.2对抗Aβ25-35肽对脑内皮细胞的毒性的保护作用
细胞培养
对0代大鼠脑内皮细胞的原代培养物(Vect-Horus SAS,Marseille)进行培养。在汇合时,用胰蛋白酶EDTA(Pan Biotech编号:P10-023100)使内皮细胞松解。将细胞以25000细胞/孔的密度接种在96孔板(孔预先包覆30μL 1.5mg/ml的I型大鼠胶原蛋白,Vect-HorusSAS,Marseill)中,并在补充有1%微管生长补充物(MVGS,S-005-25,Invitrogen)的MCBD131培养基(M-131-500,Invitrogen)中培养细胞。在37℃下在潮湿空气(95%)/CO2(5%)气氛下培养细胞。隔日将一半培养基用新鲜培养基更换。
4天后,将溶解在0.1%DMSO或水中的药物以不同浓度添加到细胞培养基中。在含有Dulbecco改良Eagle培养基(DMEM,Pan Biotech编号:P04-03600)、补充有2%胎牛血清(FBS;Invitrogen编号16000-036)、1%L谷氨酰胺(Pan Biotech编号P04-80100)、1%青霉素-链霉素(PS;Pan Biotech编号P06-07100)、0.1mg/ml肝素(Sigma)、10ng/ml内皮生长因子(EGF,Invitrogen)和10ng/ml血管内皮生长因子(VEGF,PHG0146,Invitrogen)的培养基中,进行1小时预温育。
然后,在相同培养基中用30μMβ-淀粉样蛋白(25-35;Sigma)和药物一起使细胞中毒。接着使细胞中毒3天。
乳酸脱氢酶(LDH)活性测定
中毒3天后,对于每个培养物收集上清液并用细胞毒性检测试剂盒(LDH,RocheApplied Sciences)进行分析。这种细胞死亡定量的比色法测定是基于测定从受损细胞的细胞溶质中释放到上清液中的乳酸脱氢酶(LDH)的活性。用分光光度计在492nm波长处采用多次扫描装置(Thermo,Ref Ascent)评定光密度(DO)。
结果
图3中所显示的结果是从两个独立的培养物中提取出来的,每种条件6个孔。所有值均表示为平均值±平均值标准误差。对原始数据进行了双侧student's t检验分析。结果表示为与对照(介质)相比的细胞存活率的百分比。
在持续3天的30μM Aβ25-35中毒之前,将药物与大鼠原代脑内皮细胞温育1小时。
该温育后3天,对反映细胞死亡水平的培养基中的LDH释放进行定量。
所显示的结果清楚表明所检测的化合物发挥出对抗这种Aβ25-35中毒的有力保护作用(图3)。
I.3对抗Aβ25-35肽对嗜铬细胞瘤细胞的毒性的保护作用
PC12细胞培养
在37℃水中将来自ATCC(ATCC CRL-1721)的PC12(大鼠嗜铬细胞瘤,ATCC编号:CRL-1721)细胞迅速解冻。立即将上清液放入含有Dulbecco改良Eagle培养基DMEM-F12(PanBiotech编号:P04-41450)与15%热灭活马血清(nvitrogen编号:16050-130)、2.5%胎牛血清(FBS;Invitrogen编号:16000-036)、1%10.000U/ml的青霉素和10mg/ml的链霉素(PS;Pan Biotech编号:P06-07100)以及1%200mM的L-谷氨酰胺(Pan Biotech编号:P04-80100)的9mL PC12增殖培养基中。
将细胞离心(800转/分,4℃,5分钟)并将其加入5ml PC12增殖培养基中,用Malassez细胞采用中性红排斥检测(Sigma)对活细胞进行计数。
然后将细胞以每cm23.104细胞接种到PC12增殖培养基中,所述培养基在用聚L-赖氨酸(10μg/ml,Sigma编号:P2636)预包覆的75cm2塑料瓶(Greiner编号:658175)中。
隔日更换培养基。培养3天后,当细胞达到80%汇合时,将其在没有钙和镁的HBSS(Pan Biotech编号:P06-33500)中清洗,并在胰蛋白酶EDTA(0.05%,Pan Biotech编号:P10-023100)中温育。用添加了0.5mg/ml 2级DNAse 1(Pan Biotech编号:T60-37780100)的PC12增殖培养基终止酶反应。然后,将PC12离心(800转/分,4℃,10分钟),并将细胞以2.9104/cm2的密度接种到用聚L-赖氨酸预包覆的175cm2培养瓶中(Greiner编号:661195)。
中毒和MTT存活率测定
将PC12细胞(#2代)以3300细胞/cm2的基准接种到96孔板(Greiner编号655 180)上,所述96孔板被用含有B27(2%,Invitrogen,编号21103049)、青霉素(50U/ml)-链霉素(50μg/ml)和谷氨酰胺(1%)以及50ng/ml的NGF(Sigma编号N1408)的聚L-赖氨酸(Sigma)神经元基础培养基(Invitrogen,编号21103049)预包覆。NGF允许PC12分化为交感(sympatic)神经元样细胞。
培养5天后,将培养基更换为添加了NGF(50ng/ml)、没有抗氧化剂的B27、谷氨酰胺和抗生素的神经元基础培养基。24小时后,将细胞与5种浓度的药物温育1小时,每种条件6孔。预温育1小时后,在细胞培养基中用10μMβ-淀粉样蛋白(25-35;Sigma)和药物使细胞中毒。24小时后,用PBS(Pan Biotech,编号P04-36100)将细胞清洗一次,并用MTT(3,[4,5-二甲基噻唑-2-基]-2,5二苯基溴化四唑)存活率检验评价PC12细胞的存活率。
皮质神经元细胞培养
如Singer等1999所述培养原代大鼠皮质神经元。简单来说,将妊娠15天的雌性大鼠通过颈椎脱位(Rats Wistar;Janvier)处死,并从子宫中取出胎畜。取出皮质并置于用冰冷的含有1%青霉素-链霉素(PS;Invitrogen)和1%牛血清白蛋白(BSA;Sigma)的Leibovitz培养基(L15;Invitrogen)中。在37℃下用在不含钙和镁的PBS中稀释的胰蛋白酶(胰蛋白酶EDTA 1X;Invitrogen)处理20分钟使皮质松解。通过加入含有II级DNAase I(0.1mg/ml;Roche Diagnostic)和10%胎牛血清(FCS;Invitrogen)的Dulbecco改良Eagle培养基(DMEM;Invitrogen)终止反应。然后通过使细胞3次通过10mg移液管使细胞机械脱开。然后在10℃下以180×g离心10分钟。舍弃上清液,将细胞团重新悬浮在指定培养基中,所述培养基由补充有B27(2%;Invitrogen)、L-谷氨酰胺(0.2mM;Invitrogen)、1%PS溶液和10ng/ml脑源神经营养因子(BDNF,Pan Biotech)的神经元基础培养基(Invitrogen)组成。在Neubauer细胞计数器上使用锥虫蓝排斥实验对活细胞进行计数。将细胞以30000细胞/孔接种在96孔板(孔用聚L-赖氨酸(10μg/ml;Sigma)预包覆)中,并在37℃下在潮湿空气(95%)/CO2(5%)气氛下培养,
培养6天后,将细胞与药物(5种浓度)温育。1小时后,用在不含BDNF但具有药物的指定培养基中的20μMβ-淀粉样蛋白(25-35;Sigma)使细胞中毒。使皮质神经元中毒2天。
乳酸脱氢酶(LDH)活性测定
培养2天后,收集上清液并用细胞毒性检测试剂盒(LDH,Roche AppliedSciences)进行分析。这种细胞死亡定量的比色法测定是基于测定从受损细胞的细胞溶质中释放到上清液中的乳酸脱氢酶(LDH)的活性。采用多次扫描装置(Thermo,编号Ascent)在492nm波长处用分光光度计测定光密度(DO)。结果表示为与阴性对照(介质)相比较的细胞存活率的百分比。
结果
图4和图5中所显示的结果是从两个独立的培养物中提取出来的,每种条件6个孔。所有值均表示为平均值±平均值标准误差。对原始数据进行了双侧student's t检验分析。结果表示为与对照(介质)比较的轴突长度的百分比。
在持续24小时的10μM Aβ25-35中毒之前1小时,将NGF分化的PC12细胞与药物温育。
在该温育1天后,使用MTT测定法对NGF分化的PC12的存活率进行定量。结果清楚表明丙胺卡因(pilocain)和氨氯地平发挥出对抗这种Aβ25-35中毒的强烈的神经保护作用(图4)。
在持续2天的10μM Aβ25-35中毒之前1小时,还将大鼠原代皮质神经元与本发明的化合物进行温育。在该温育两天后,对培养基中反应细胞死亡水平的LDH释放进行定量。所显示的结果表明本发明中所使用的化合物发挥出对于这种Aβ25-35中毒的显著保护作用(图5)。
I.4药物组合的活性
还用调节突触功能和/或血管生成和/或细胞应激反应的若干药物组合进行了体外测定。
在如上所述的相同试验条件下将药物进行温育(参见I.1-I.3部分)。表2中总结了作用于目标的最有效的药物组合。
表2
+表明对于Aβ25-35中毒的正性神经保护作用。
II.预防人Aβ1-42毒性的化合物
在该另一系列实验中,已经检测了候选化合物预防或降低人Aβ1-42毒性作用的能力。人Aβ1-42是构成在罹患AD的人类患者的活检组织中发现的聚集体的全长肽。首先单个检测药物,随后检测其组合作用。在多种细胞类型上测定作用,从而进一步说明化合物的活性。
II.1对抗Aβ1-42肽对人脑微血管内皮细胞模型的毒性的保护作用
使用人脑微血管内皮细胞培养物研究候选化合物对于Aβ1-42毒性所提供的保护。
在+37℃水浴中将人脑微血管脑内皮细胞(HBMEC,ScienCell编号:1000,在第10代冷冻)迅速解冻。立即将上清液放入9ml含有10%胎牛血清(FCS;GIBCO编号10270-106)的Dulbecco改良Eagle培养基(DMEM;Pan Biotech编号:P04-03600)中。在+4℃下将细胞悬浮液以180×g离心10分钟并且将沉淀团悬浮在有1.6%无血清Rocketfuel(Cell System,编号:SF-4Z0-500-R,批次54102)、2%10.000U/ml的青霉素和10mg/ml的链霉素(PS;PanBiotech编号:P06-07100批次133080808)的CSC无血清培养基((CSC无血清,Cell System,编号:SF-4Z0-500-R,批次51407-4)中,并将其以每孔20000个细胞的密度和100μL的终体积接种在96孔板(基质凝胶层生物涂层血管生成系统,BD,编号354150,Batch A8662)中。在基质凝胶支持物上,脑内皮细胞自发启动毛细血管网形态发生的过程(47)。
每种条件进行3个独立的培养物,每种条件6孔。
候选化合物与人淀粉样蛋白-β1-42处理
简单来说,在20μM(母液)的指定培养基中复溶Aβ1-42肽(Bachem,编号:H1368,批次1010533),并为了聚集在37℃下和黑暗中将其缓慢震荡3天。在相同条件下制备对照培养基。
3天后,对于在对照培养基中稀释的2.5μM的HBMEC使用该聚集的人淀粉样肽(最佳温育时间)。在HBMEC接种到基质凝胶上后2小时将Aβ1-42肽加入,进行18小时温育。
在HBMEC接种到基质凝胶上后1小时,将待测化合物和VEGF-165溶解在培养基(+0.1%DMSO)中,然后在施加Aβ1-42前将其与HBMEC预温育1小时(每个培养孔的终体积为100μL)。待测化合物或VEGF温育后1小时(细胞接种到基质凝胶上后2小时),在有待测化合物或VEGF(总体积200μL/孔)存在下加入100μL Aβ1-42肽,直到终浓度为在对照培养基中稀释的2.5μM,以避免进一步的药物稀释。
培养板的组织
在该研究中对于所有实验使用已知为VEGF-A的促血管生成异构体的VEGF-165作为参照化合物。VEGF-165是参与血管生成的最丰富的VEGF异构体。使用10nM VEGF作为参照待测化合物。
评价以下条件:
●阴性对照:单独的培养基+0.1%DMSO
●中毒:淀粉样蛋白-β1-4.2.(2.5μM)18小时
●阳性对照:VEGF-165(10nM)(1参照化合物/培养)在加入Aβ1-42(2.5μM)前1hr,温育时间18h。
●待测化合物:待测化合物在加入Aβ1-42(2.5μM)前1hr,温育时间18h。
毛细血管网定量
对于每个孔,在光透射下使用InCell AnalyzerTM 1000(GE Healthcare)用4×镜头拍摄2张照片。在相同条件下拍摄全部图像。用Developer软件(GE Healthcare)完成血管生成网的分析。评定毛细血管网的总长度。
数据处理
所有值表示为3个培养物的平均值±平均值标准误差(每种条件n=6)。对不同条件执行ANOVA,然后在允许的情况下进行Dunnett检验(Statview软件5.0版),来完成统计分析。图片上插入的值(作为%)显示淀粉样蛋白毒性发展。事实上,将淀粉样蛋白毒性作为100%,将待测化合物的作用计算为该淀粉样蛋白毒性的%。
结果
图6和表3中显示了结果,它们表明药物单独产生了对于Aβ肽1-42所导致的毒性的显著保护作用。
-低剂量、例如160nM的氨基己酸单独产生强烈的保护作用;
-低至8nM剂量的左西孟旦产生强烈的保护作用。
II.2对抗Aβ1-42对原代皮质神经元细胞的毒性的保护作用
待测化合物和人淀粉样蛋白-β1-42处理
如前所述培养原代大鼠皮质神经元。
简单来说,在40μM(母液)的指定培养基中复溶Aβ1-42肽,并且在+37℃下在黑暗中缓慢震荡3天以聚集。在相同条件下制备对照培养基。
3天后,如下将该溶液用于原代皮质神经元:
神经元培养10天后,将药物溶解在培养基(+0.1%DMSO)中,然后在应用Aβ1-42(每个培养孔的终体积为100μL)前与神经元预温育1小时。药物温育后1小时加入100μL Aβ1-42肽,使得终浓度在有药物存在下稀释为10μM,从而避免进一步的药物稀释。使皮质神经元中毒24小时。每种条件进行3个独立的培养物,每种条件6孔。
用BDNF(50ng/ml)和雌二醇-β(100和150nM)分别作为阳性对照和参照化合物。每种条件进行3个独立的培养物,每个条件12孔。
培养板的组织
用100和150nM的雌二醇-β作为参照待测化合物,用50ng/ml的BDNF作为阳性对照。
将BDNF和雌二醇-β溶解在培养基中,在应用聚集的Aβ1-42前预温育1h。
评价以下条件:
-1对照板:12孔/条件
●阴性对照:单独培养基+0.1%DMSO
●中毒:淀粉样蛋白-β1-4.2.(10μM)24小时
●阳性对照:BDNF(50ng/ml)1小时,随后淀粉样蛋白-β1-42(10μM)24小时。
●参照化合物:雌二醇(150nM)1小时,随后淀粉样蛋白-β1-42(10μM)24小时。
-1药物板:6孔/条件
●阴性对照:单独培养基+0.1%DMSO
●中毒:淀粉样蛋白-β1-4.2.(10μM)24小时
●药物1:药物1-1小时,随后淀粉样蛋白-β1-42(10μM)24小时。
●药物2:药物2-1小时,随后淀粉样蛋白-β1-42(10μM)24小时。
乳酸脱氢酶(LDH)活性测定
中毒24小时后,去掉上清液并且用细胞毒性检测试剂盒(LDH,Roche AppliedScience,编号:11644793001,批次:11800300)分析。用于定量细胞毒性的这种比色法是基于测定从死亡细胞的细胞溶质释放到上清液的乳酸脱氢酶(LDH)的活性。
数据处理
所有值表示为3个培养物的平均值±平均值标准误差(每种条件n=6)。对不同条件进行统计分析(ANOVA,然后在允许的情况下进行Dunnett检验,Statview软件5.0版)。
结果
表3和图7中显示了在对于原代皮质神经元细胞的毒性测定中所获得的每个所选药物的结果。
表3
II.3组合治疗对抗人Aβ1-42肽对人HBME细胞的毒性的作用
在人类细胞上评估本发明的药物组合的疗效。在这些测定中所使用的方案与以上II.1部分中所述的相同。
结果
在人类大脑微血管内皮细胞上检测了下列药物组合:
-巴氯芬和氨基己酸,
-巴氯芬和左西孟旦,
-氨基己酸和磺胺异噁唑,
-氨基己酸和特比萘芬,
-氨基己酸和左西孟旦,
-左西孟旦和磺胺异噁唑,
-左西孟旦和特比萘芬,
-依普利酮和左西孟旦,
-依普利酮和磺胺异噁唑,
-依普利酮和非诺多泮,
-舒洛地特和左西孟旦,
-舒洛地特和磺胺异噁唑,
-舒洛地特和非诺多泮,或
-依普利酮和舒洛地特。
如下表中所示和图8-13中所示例的,全部所检测的药物组合在HBMEC模型中显示出对抗人Aβ1-42肽的毒性的保护作用。
表4
III.左西孟旦和磺胺异噁唑组合治疗有效保护神经元对抗人Aβ1-42毒性
在该实施例中,评价使用左西孟旦和磺胺异噁唑的组合治疗预防或降低人Aβ1-42毒性作用的能力。
在实施例II.1中所公开的实验条件下检测所述组合治疗。如II.1中所公开的,使用人脑微血管内皮细胞培养物,并且将其与药物组合同时或顺序温育。
图8中显示了结果,其清楚表明,聚集的人淀粉样肽(Aβ1-42,2.5μM)产生显著的中毒作用,比用介质处理的神经元高40%。磺胺异噁唑和左西孟旦的组合显著预防这种中毒作用(图8A),而在那些浓度下,左西孟旦(图8B)和磺胺异噁唑(图8C)单独对于中毒作用没有显著影响。
IV.特比萘芬和磺胺异噁唑组合治疗有效保护神经元对抗人Aβ1-42毒性
在该实施例中,评价使用特比萘芬和磺胺异噁唑的组合治疗预防或降低人Aβ1-42毒性作用的能力。
在实施例II.1中所公开的实验条件下检测所述组合治疗。如II.1中所公开的,使用人脑微血管内皮细胞培养物,并且将其与药物组合同时或顺序温育。
图9中显示了结果,其清楚表明,聚集的人淀粉样肽(Aβ1-42,2.5μM)产生显著的中毒作用,比用介质处理的神经元高40%。特比萘芬和磺胺异噁唑的组合显著预防这种中毒作用(图9A),而在那些浓度下,磺胺异噁唑(图9B)和特比萘芬(图9C)单独对于中毒作用没有显著影响。
V.左西孟旦和巴氯芬组合治疗有效保护神经元对抗人Aβ1-42毒性
在该实施例中,评价使用左西孟旦和巴氯芬的组合治疗预防或降低人Aβ1-42毒性作用的能力。
在实施例II.1中所公开的实验条件下检测所述组合治疗。如II.1中所公开的,使用人脑微血管内皮细胞培养物,并且将其与药物组合同时或顺序温育。
图10中显示了结果。其清楚表明,聚集的人淀粉样肽(Aβ1-42,2.5μM)产生显著的中毒作用,比用介质处理的神经元高40%。左西孟旦和巴氯芬的组合显著预防这种中毒作用(图10A),而在那些浓度下,左西孟旦(图10B)和巴氯芬(图10C)单独对于中毒作用没有显著影响。
VI.氨基己酸和特比萘芬组合治疗有效保护神经元对抗人Aβ1-42毒性
在该实施例中,评价使用氨基己酸和特比萘芬的组合治疗预防或降低人Aβ1-42毒性作用的能力。
在实施例II.1中所公开的实验条件下检测所述组合治疗。如II.1中所公开的,使用人脑微血管内皮细胞培养物,并且将其与药物组合同时或顺序温育。
图11中显示了结果。其清楚表明,聚集的人淀粉样肽(Aβ1-42,2.5μM)产生显著的中毒作用,比用介质处理的神经元高40%。氨基己酸和特比萘芬的组合显著预防这种中毒作用(图11A),而在那些浓度下,氨基己酸(图11B)和特比萘芬(图11C)单独对于中毒作用没有显著影响。
VII.氨基己酸和左西孟旦组合治疗有效保护神经元对抗人Aβ1-42毒性
在该实施例中,评价使用氨基己酸和左西孟旦的组合治疗预防或降低人Aβ1-42毒性作用的能力。
在实施例II.1中所公开的实验条件下检测所述组合治疗。如II.1中所公开的,使用人脑微血管内皮细胞培养物,并且将其与药物组合同时或顺序温育。
图12中显示了结果。其清楚表明,聚集的人淀粉样肽(Aβ1-42,2.5μM)产生显著的中毒作用,比用介质处理的神经元高40%。氨基己酸和左西孟旦的组合显著预防这种中毒作用(图12A),而在那些浓度下,氨基己酸(图12B)和左西孟旦(图12C)单独对于中毒作用没有显著影响。
VIII.特比萘芬和左西孟旦组合治疗有效保护神经元对抗人Aβ1-42毒性
在该实施例中,评价使用特比萘芬和左西孟旦的组合治疗预防或降低人Aβ1-42毒性作用的能力。
在实施例II.1中所公开的实验条件下检测所述组合治疗。如II.1中所公开的,使用人脑微血管内皮细胞培养物,并且将其与药物组合同时或顺序温育。
图13中显示了结果。其清楚表明,聚集的人淀粉样肽(Aβ1-42,2.5μM)产生显著的中毒作用,比用介质处理的神经元高40%。特比萘芬和左西孟旦的组合显著预防这种中毒作用(图13A),而在那些浓度下,特比萘芬(图13B)和左西孟旦(图13C)单独对于中毒作用没有显著影响。
IX.体内活性
在阿尔茨海默病的体内模型中检测在体外检测中有活性的化合物与其组合物。在许多研究中,在充当AD病模型的转基因小鼠的大脑中,与阿尔茨海默病相关的突变的人类淀粉样β蛋白前体(APP)转基因的过表达已经是促进Aβ沉积的最可靠的方法。当它们衰老时,这些突变APP小鼠形成稳固的淀粉样蛋白病变和其他AD样特点,包括突触密度降低、反应性神经胶质增生和一些认知缺陷。许多突变APP小鼠模型很少显示出明显的神经元丧失和神经元纤维缠结(NFT)病变的迹象。对于该BRI-Aβ42转基因为半合子的小鼠能够存活并可生育,具有正常寿命。转基因的BRI-Aβ42mRNA以小鼠朊病毒蛋白启动子的特征性模式表达;在小脑颗粒细胞和海马中检测出最高的转基因表达水平,其次是皮质、脑桥、丘脑和中脑。在转基因融合蛋白中,在弗林蛋白酶样切割位点处将Aβ1-42融合到BRI蛋白C末端,使得切割导致有效分泌Aβ1-42到细胞腔和细胞外空间中。因此,这些小鼠特异性地表达Aβ1-42异构体。半合子的BRI-Aβ42小鼠随年龄积累不能用去污剂溶解的淀粉样蛋白-β,并早在3月龄时就在小脑中形成有核斑块,随后发生前脑病变的形成,直到12月龄时细胞外Aβ斑块才一致地出现在海马和内嗅/梨状皮质中。早在3个月时在转基因小鼠的小脑分子层中就可以观察到淀粉样蛋白β沉积(有核斑块),其随年龄变得更加明显;在6月龄时,在内嗅/梨状皮质和海马中看到了偶发的细胞外斑块,但是直到>12月龄时才能一致地发现。最老的小鼠在小脑、皮质、海马和嗅球中显示出广泛分布的有核且弥散斑块的病变。细胞外淀粉样斑块显示出致密的淀粉样蛋白核心,并具有辐射状的纤丝;在这些斑块周围观察到了许多束营养不良的轴突。反应性神经胶质增生与斑块有关。
药物处理
已经从Jackson实验室(http://jaxmice.jax.org/strain/007002.html)获得转基因Tg(Prnp-ITM2B/APP695*42)A12E mc小鼠(37)。已经在混合的B6C3背景上维持被发现具有最高的Aβ42血浆水平的小鼠,BRI-Aβ42A(12e)系。成年雄性转基因小鼠可以自由接近食物和水。按照得到批准的研究动物护理和使用委员会议定书,将小鼠称重并腹膜内注射或强喂对照溶液(安慰剂)或制备成不同剂量的本发明的药物或表2的药物组合,每日一次,连续进行10到20周。
存活率分析
使用Kaplan–Meier方法分析存活率。对于所有成对多重比较检验使用了Holm–Sidak方法(事后)。对无关的死亡进行检查。所有比较在同窝仔畜间进行,从而限定来自背景种系差异的任何潜在的混杂效应。
行为测试
按照由若干作者发表的方法(38-41)设计和进行行为测试。
Morris水迷宫(MWW)中的空间学习和记忆
在直径90cm、由白色塑料制成并装填有乳白色水的圆形水池中进行本实验。将直径8cm的由透明塑料制成的逃离平台浸没在水平面下0.5cm。视觉线索由印刷成A4大小的字母的不同几何形状提供,并放置在周围的四个壁上(距离水池50到70cm)。在4天内,每天对每只小鼠进行四次试验(试验之间的间隔为5到7分钟,总共16次试验)。从四个不同起始点之一进行每个试验。使用Videotrack软件(View Point)监测小鼠的运动。测定了找到逃离平台所花费的时间(逃离潜伏期,最高60秒)。在找到平台后,允许小鼠在其上停留15秒。将不能在60秒内找到平台的小鼠引导到平台,并允许其在上面停留15秒。对于这种情况,在记录中输入逃离潜伏期为60秒。除了第1天的第一次试验之外,对每天的所有四次试验进行平均,用于统计学分析。在第9天(最后一次训练后5天),对小鼠进行60秒的探索试验,其中将平台去除并让小鼠搜寻它。记录每只动物在每个象限中花费的时间(象限搜索时间)。使用了3、7、10和12月龄的若干组雄性小鼠。
少数一些小鼠表现出强烈干扰测试的僵滞行为(例如,不动地躺在水中且拒绝游泳),从数据分析中排除这些动物。在安静和弱光环境下进行所有行为实验。
辐射臂水迷宫中的工作记忆测试
由在直径100cm、装有水的水池(也用于Morris水迷宫和平台识别任务)中安装有铝制插件以产生6个辐射状分布的游泳臂所组成的装置的帮助下,获得了这种基于认知的工作记忆灵敏性测定。测试由每天5次1分钟的试验、持续9-12天构成。在每天的测试开始时,将透明的被浸没的平台放置在6个游泳臂之一的末端(随机选择、每天改变)。对于前四次习得试验中的每次,将动物置于一个不含有平台的臂中(随机顺序),并允许其搜寻平台。在60秒试验期间,每次动物进入另一个不含平台的臂,则将其轻轻放回到其起始位置并记录错误。在4次试验后,允许动物休息30分钟,然后进行第5次(记忆力)试验,其从最后的不含平台的游泳臂开始。对于每个试验,记录错误(臂选择不正确)的次数和逃离潜伏期(到达平台的时间,最多60秒)。
在圆形平台测试中的空间参照学习和记忆
在由直径69cm的圆形平台沿圆周等距离间隔地有16个“逃离”孔所组成的装置的帮助下进行基于认知的任务测试。将逃离庇护区安装在一个孔的下方,并用黑色幕帘围住平台,幕帘上放置有各种视觉提示。在单次5分钟试验开始时,将动物置于平台中央并提供令其厌恶的刺激(亮光、鼓风)。记录错误(头伸入非逃离孔)的总次数和逃离潜伏期(到达逃离孔的时间)。
在平台认知测试中的认知能力
这种基于认知的搜索任务评估物体分辨和认识能力。目标物体由直径9cm、安装有10cm×40cm黑旗的圆形平台组成,其位于直径100cm的圆形水池的水面上方0.8cm处。测试由每天4次60s的试验、连续进行4天构成。在每一天,对于每次试验,将目标物体置于水池的不同象限中,对于所有4次试验,在沿着水池圆周的相同位置处释放动物。对于每次试验记录总潜伏期(最多60s)。
修改的Irwin检测
使用了从Irwin修改的全面筛选来测定任何小鼠是否表现出与其基因型相关的生理、行为或感觉运动障碍。为了调查运动技能、协调性和肌肉力量,将小鼠置于紧系在两个30cm高的柱子之间的线上,并评估它们在线上的平衡能力。此外,测定了它们用四只爪子握紧并悬挂在线上至少5秒和爬回到线上的能力。
血管淀粉样蛋白沉积的定量
为了对脑淀粉样蛋白血管病变(CAA)进行定量,在4℃下用生物素化-Ab9抗体(抗Aβ1-16,1:500)将以30μm间隔贯穿顶叶或小脑皮质软脑膜的5μm的石蜡包埋切片免疫染色过夜(每个年龄组每种基因型n=5-7只小鼠,每只小鼠n=6个切片)。用修改的Vonsattel评分系统(42)目测评估阳性染色的血管。通过将CAA血管数量乘以CAA严重性等级计算CAA严重性分值。
组织学:免疫组织化学和免疫荧光
将3到12月龄的Tg和WT小鼠麻醉,并用0.9%NaCl和4%多聚甲醛的0.1mol/L磷酸缓冲盐水(PBS)(pH 7.4)溶液、或10%福尔马林和4%多聚甲醛的0.1mol/L PBS(pH 7.4)溶液相继进行穿过心脏的灌注。取出脑和脊髓,并储存在4%多聚甲醛中。将一些样品包埋在石蜡中,并在滑动切片机上以10μm的厚度切片。在低温恒温器上切出冷冻切片(14μm),并安放在铬钒包被的载玻片上。通过用含有0.3%H2O2的甲醇处理切片30分钟,淬灭内源性过氧化物酶。将切片在10%马血清中阻断。在4℃下在有1%马血清存在下使用第一抗体温育过夜。所有生物素化或荧光素偶联、德克萨斯红偶联和AMCA偶联的二级抗体、荧光染料、ABC试剂盒和作为过氧化物酶活性的发色团的3,3'-二氨基联苯胺都来自Vetor Laboratories公司。与二级抗体的温育在室温下持续1小时。使用磷酸缓冲盐水(0.1mol/L PBS,pH7.4)或Tris缓冲盐水(0.1mol/L Tris,0.15mol/L NaCl,pH7.4)进行所有清洗步骤(3-10分钟)和抗体稀释。按照制造商的手册进行与ABC复合物的温育和用3,3'-二氨基联苯胺的检测。按照标准步骤进行苏木精复染色。每次测定使用每种基因型、年龄和性别的小鼠至少3只(43)。
脑提取物的制备
在最后一次注射后90到120分钟之间,将大脑快速收获在冰上并在-80℃下冷冻。在冷冻后称重来自每只小鼠的右侧脑半球。采用中值绝对偏差的半球质量分析允许我们排除与组中其他样品相比超过4个中值绝对偏差的样品。将脑半球匀浆化,并按照制造商的说明书制备含有全部蛋白的细胞裂解物,用于酶测定试剂盒(R&D Systems,Inc.)。简单来说,将脑皮质在800μL含有低盐的1×提取缓冲液(R&D试剂盒)中匀浆化,并在冰上温育10分钟。然后将匀浆液在4℃下以13,000g离心15分钟。按照源自双缩脲的测定法(Pierce)估算每种样品中的蛋白浓度。用Western免疫印迹和夹心ELISA技术测定APP、Aβ40和Aβ42的水平。此外,从相同的提取物中测定α、β-和γ-分泌酶的活性。
小鼠脑皮质提取物中总APP水平的测定
在每块凝胶中上样相等蛋白量的脑提取物,每种样品每道30μg。每块凝胶包含8种处理:对照;17.5mg/kg剂量的药物1;若干种剂量的药物2。为了使得凝胶内偏差最小化,每块凝胶包括三套所有处理组。用22C11抗体探测每个印迹。还用β-肌动蛋白抗体探测每个印迹,以对转移效率进行归一化。将APP条带信号的强度用β-肌动蛋白的强度进行归一化。将两个“对照”样品上样在每个凝胶/印迹中,以测试印迹之间的偏差。用两种方法进行印迹分析:逐个印迹(n=3),以测试凝胶间偏差;以及如(38-39)中所述的组合印迹(n=9或10)。使用n=3进行的逐个印迹分析与使用n=9或10进行的最终分析显示出相同的趋势。提供了组合分析的结果。
Aβ夹心ELISA
对于脑AβELISA来说,独立地测定了前脑和后脑的Aβ水平,且分析中不包含嗅球。对于血浆Aβ分析来说,在心脏穿刺后将血液收集在EDTA涂层的管中。在4℃下将血样以3000rpm离心10分钟,并将血浆分成等份并在使用前储存在-80℃下。用末端特异性夹心ELISA测定Aβ水平,用Ab9(抗Aβ1-16Ab)作为Aβ40的捕获Ab,用13.1.1-HRP(抗Aβ35-40Ab)作为Aβ40的检测Ab,且用Ab9-HRP作为Aβ42的检测Ab(每个年龄组中每种基因型n=5-7个小鼠)。如(46)中所述,用相同小鼠组作为内部对照,将Aβ水平针对以前的结果归一化,从而使可能的ELISA变异性最小化。
Western印迹
在含有1%蛋白酶抑制剂混合物(Roche)的放射免疫沉淀测定(RIPA)缓冲液(Boston BioProducts,Worcester,MA)中将速冻的前脑样品匀浆。在4℃下将匀浆液以100,000×g离心1h。用BCA蛋白测定法(Pierce)测定上清液中的蛋白浓度。在Bis-Tris 12%XT凝胶或Bis-Tris 4–12%凝胶(Bio-Rad,Hercules,CA)上运行蛋白样品(20μg),并将其转移到0.2μm的硝酸纤维素膜上。如(46)中所述,将印迹在0.1M PBS中微波处理2分钟,共两次,并用Ab 82E1(抗Aβ1-16,1:1000;IBL,Gunma,日本)和抗APP C末端20个氨基酸的抗体(1:1000)进行探测。将印迹切成条,并用抗β-肌动蛋白抗体(1:1000;Sigma)作为上样对照重新探测。使用ImageJ软件计算相对条带强度。
实质淀粉样蛋白沉积的定量
将半脑在10%福尔马林中浸泡固定并进行石蜡包埋处理。将脑组织切片(5μm)用抗总Aβ抗体(Ab)进行免疫染色。将切片用苏木精复染色。将每个脑的通过海马、梨状皮质(前囱,-1.70到-2.80mm)或小脑(副绒球、crus ansifrom和简单小叶;前囱-5.40到-6.36mm)的6个切片用于定量(每个年龄组每种基因型n=5-7只小鼠)。使用MetaMorph软件(Molecular Devices,Palo Alto,CA)测定Aβ斑块负荷。对于有核斑块的定量,将那些用于Aβ负荷分析的连续切片用硫黄素S(ThioS)染色,并对海马、内嗅/梨状皮质或小脑中的硫黄素阳性斑块的数量进行计数。以不知情方式进行所有上述分析。
体内数据的统计学分析
使用STATISTICA 8.0(Statsoft)分析来自所有实验的结果。使用ANOVA以及Holm-Sidak事后多重比较检验或双尾Student's t检验分析Aβ水平、淀粉样斑块负荷和CAA严重性。如果数据组不满足参数检验假设,则执行Kruskal–Wallis检验然后是Dunn's事后多重比较或Mann–Whitney秩和检验。为了检验双转基因小鼠中的Aβ水平是否与单转基因同窝仔畜中的Aβ水平的累加和一致,使用了不含截距检验的多重线性回归。所有的比较在同窝仔畜间进行。排除对照(0mg/kg)样品后进行药物反应模拟。ED50对应于在实验中诱导出最大药物诱导反应的50%所需的剂量(mg/kg)。它是使用用于ED50对数的Hill方程模型来计算。
对于候选药物组合进行体内实验。以下表5中列出了学习和空间记忆的阳性结果。
表5
药物 | Morris水迷宫实验中的结果 |
特比萘芬和左西孟旦 | + |
特比萘芬和磺胺异噁唑 | + |
巴氯芬和左西孟旦 | + |
磺胺异噁唑和左西孟旦 | + |
氨基己酸和左西孟旦 | + |
氨基己酸和特比萘芬 | + |
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Claims (6)
1.包含以下的药物组合之一或其盐或缓释制剂的组合物在制备用于治疗阿尔茨海默病的药物中的应用,每个组合用于合并、分别或顺序给药:
-左西孟旦和巴氯芬,
-左西孟旦和氨基己酸,
-左西孟旦和磺胺异噁唑,或
-左西孟旦和特比萘芬。
2.权利要求1的应用,所述组合物还包括选自以下的至少一种药物:氨己烯酸,伊马替尼,橙皮素,阿糖腺苷,氯法拉滨,去纤苷酸,哌氰嗪,甲氧异丁嗪,美芬丁胺,地匹福林,胍乙啶,苄二甲胍,比托特罗,丙卡特罗,二乙基乙胺嗪,马索罗酚,去乙酰毛花苷,奥美拉唑,海藻糖,醋甲唑胺,膦甲酸钠,硝酸镓,钙二醇,降钙素,钙三醇,氯瞵酸,二氢速甾醇,依降钙素,依替膦酸,伊普黄酮,醋酸特立帕肽,安搏律定,依氟鸟氨酸,苯溴马隆,阿拉伯糖醇,甘露醇,环喷托酯,羟苯环嘧,曲司胺,异氟磷,泮库溴铵,哌库溴铵,瑞库溴铵,罗库溴铵,琥珀胆碱,维库溴胺,阿曲库铵,顺阿曲库铵,杜什库铵,美加明,美多寇林,美维库铵,新霉素,阿米洛利,曲伏前列素,孟鲁司特,西路斯特,氨来呫诺,卡前列素氨基丁三醇,比马前列素,利多瑞尔,乙胺嘧啶,三氨蝶呤,双氢麦角胺,卡麦角林,非诺多泮,磺胺甲恶唑,庆大霉素,L-组氨酸,拉帕替尼,舒洛地特,希美加曲,华法林,苯丙香豆醇,依诺肝素,阿他肝素,磺达肝癸,拉氧头孢,杆菌肽,噻氯匹定,厄多司坦,阿仑唑奈,苯巴比妥,美索比妥,头孢替安,氯美噻唑,硫喷妥,鲁比前列酮,氨曲南,托吡酯,沙丁胺醇,间羟胺,美洛昔康,托泊替康,去铁胺,地衣酸,肼苯哒嗪,去铁酮,二苯甲酰甲烷,阿伏苯宗,地诺前列酮,依前列醇,2-酮戊二酸,含羞草碱,奎宁,加贝酯,联苯苄唑,克霉唑,金诺芬,血色素/血晶质,精氨酸血红素,麦角胺,依立曲坦,硫鸟嘌呤,雷贝拉唑,利多卡因,伊布利特,色甘酸盐,炔己蚁胺,托康唑,氯唑沙宗,乌诺前列酮,橙皮素,苄氟噻嗪,苯噻嗪,氯噻嗪,环噻嗪,氯甲苯噻嗪,氢氟甲噻,喹乙宗,三氯甲噻嗪,巴柳氮,坎沙曲,甘珀酸,环丙沙星,雷帕霉素,丙基硫尿嘧啶,硫乙拉嗪,酮替芬,甲吡酮,莫米松,依普利酮,氟氢可的松,哌加他尼,阿芬太尼,丁丙诺啡,戊唑辛,烯丙左吗喃,阿米三嗪,红霉素,卡那霉素,浅蓝菌素,替罗非班,松叶菊碱,米利酮,阿那格雷,西洛他唑,贝卡普勒明,链霉素,花翠素,花青素,烟曲霉素,尼氟酸,氢可他酯,奈替米星,苯丁酸钠,安立生坦,氨基己酸,二十碳五烯酸,丁酸苯酯,硝普盐,硝化甘油,帕立骨化醇,替鲁膦酸盐,氯噻酮,氢氯噻嗪,氯莫环素,赖甲环素,游霉素,两性霉素B,头孢氨苄,头孢噻啶,头孢呋辛,双氯西林,他佐罗汀,磷苯妥英,布美他尼,噻加宾,布克利嗪,度他雄胺,阿瑞吡坦,伐普肽,阿利吉仑,碘塞罗宁,硫蒽酮,氟硝基安定,羟基安定,二羟基铝,苏尼替尼,头孢美唑,头孢孟多,头孢哌酮,四苯喹嗪,地舍平,尼替西农,乐卡地平,普加巴林,米拉地尔,阿雷地平,巴米地平,苄环烷,苄普地尔,克仑硫卓,依福地平,依高地平,依他苯酮,芬地林,氟桂嗪,加洛帕米,依拉地平,拉西地平,利多氟嗪,洛美利嗪,马尼地平,尼卡地平,尼伐地平,尼莫地平,尼索地平,尼群地平,哌克昔林,普尼拉明,司莫第尔,特罗地林,达沙替尼。
3.包括左西孟旦或者其盐或缓释制剂作为活性成分的组合物在制备用于在患有阿尔茨海默病的对象中保护神经元或脑内皮细胞对抗Aβ毒性的药物中的应用。
4.权利要求1,2或3的应用,所述组合物还包括可药用的载体或赋形剂。
5.权利要求1,2或3的应用,其中所述组合物反复向患者给药。
6.包含以下的药物组合之一或其盐或缓释制剂的组合物,每个组合用于合并、分别或顺序给药:
-左西孟旦和巴氯芬,
-左西孟旦和氨基己酸,
-左西孟旦和磺胺异噁唑,或
-左西孟旦和特比萘芬。
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EA (1) | EA024465B1 (zh) |
ES (1) | ES2800311T3 (zh) |
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EP3797767A1 (en) | 2021-03-31 |
ES2800311T3 (es) | 2020-12-29 |
EP2496226A1 (en) | 2012-09-12 |
MX2012005131A (es) | 2012-05-29 |
CN102834095A (zh) | 2012-12-19 |
JP2015157841A (ja) | 2015-09-03 |
EP3650021A1 (en) | 2020-05-13 |
AR078846A1 (es) | 2011-12-07 |
EA024465B1 (ru) | 2016-09-30 |
IL219412A (en) | 2017-05-29 |
CA3065614A1 (en) | 2011-05-12 |
BR112012010470A2 (pt) | 2016-03-08 |
JP2013510114A (ja) | 2013-03-21 |
US20120270836A1 (en) | 2012-10-25 |
EP2496226B1 (en) | 2020-03-04 |
EA201200686A1 (ru) | 2013-05-30 |
CA2779070A1 (en) | 2011-05-12 |
WO2011054759A1 (en) | 2011-05-12 |
JP5977172B2 (ja) | 2016-08-24 |
JP6062995B2 (ja) | 2017-01-18 |
EP2322163A1 (en) | 2011-05-18 |
IL219412A0 (en) | 2012-06-28 |
CA2779070C (en) | 2020-02-25 |
US8809302B2 (en) | 2014-08-19 |
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