CN106176778A - 异类叶升麻苷或其药学上可接受的盐的用途 - Google Patents
异类叶升麻苷或其药学上可接受的盐的用途 Download PDFInfo
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- CN106176778A CN106176778A CN201610646844.2A CN201610646844A CN106176778A CN 106176778 A CN106176778 A CN 106176778A CN 201610646844 A CN201610646844 A CN 201610646844A CN 106176778 A CN106176778 A CN 106176778A
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- isoacteoside
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Abstract
异类叶升麻苷或其医药学上可接受的盐被作为一种淀粉样β肽生成、累积或聚集的抑制剂,以预防或治疗与淀粉样β肽相关性疾病或状况。
Description
本申请为2011年6月16日提交的名称为“异类叶升麻苷或其药学上可接受的盐的用途”、申请号为201180029882.9的发明专利申请的分案申请。
技术领域
本发明涉及异类叶升麻苷在抑制淀粉样β肽生成、积累或聚集的抑制剂的新用途,尤其涉及使用异类叶升麻苷预防或治疗与淀粉样β肽相关的疾病或状况的新用途。
背景技术
阿滋海默氏症(Alzheimer’s disease)被认为与一种具有39-43个胺基酸的肽的积累相关,该肽被称为淀粉样β肽(amyloidβpeptides)(简称Aβ),其为类淀粉前体蛋白APP(amyloid precursor protein)的一种水解产物。其中Aβ1-40最为大量且毒性低,而Aβ1-42则对神经元有较高的毒性,且具高度纤维形成性(fibrillogenic),被认为是与阿滋海默氏症的发病最为相关的Aβ形式。Aβ单体可经寡聚化而形成可溶性的Aβ寡聚体(oligomer),进一步聚集于细胞外形成不可溶性的纤维丝或老年斑块(senile plaque)。
一般认为与Aβ相关的疾病或状况包含唐氏症(Down syndrome)、荷兰型遗传性脑出血伴淀粉样变病(Hereditary cerebral hemorrhage with amyloi d(HCHWA)Dutch)、关岛帕金森氏症-失智症复合症(Parkinsonism-dementi a complex on Guam)(ClinicalNeurology and Neurosurgery(1990)92:305-310);大脑淀粉样血管病(J.Neuropath.Exp.Neuro.(2002)61:282-293);包涵体肌炎(Neurology(2006)66:65-68);额颞叶型失智症(Neurorepo rt(2002)13-5:719-723);年龄相关黄斑变性(ExperimentalEye Research(2004)78:243-256);皮克病(Pick’s disease)(Neuroscience Letters(1994)171:63-66)及其它。
所述Aβ相关的疾病或状况一般而言与Aβ的生成、积累或聚集有关, 包括因先天如遗传、或后天如老化或环境等因素而导致生物体中存在不正常的Aβ或Aβ聚集体数量。
一般认为如果能抑制Aβ的生成、积累或聚集,应可作为有效预防或治疗阿滋海默氏症或其它与淀粉样β肽相关的疾病或状况的一种方式。
发明内容
鉴于淀粉样β肽和其聚集体,容易在生物体内引发各种疾病或状况,因此本发明的目的之一是提供一种抑制淀粉样β肽生成、积累或聚集的有效成份,其可作为食品、饮品、咀嚼物、贴片、皮肤保养品或其它添加剂。本发明的另一目的则是提供一种预防或治疗淀粉样β肽相关疾病或状况的药物及方法。
为达到上述目的,本发明揭示了以异类叶升麻苷或其医药学上可接受的盐抑制淀粉样β肽生成、积累或聚集的用途,以及制备预防或治疗淀粉样β肽相关的疾病或状况的药物的用途。
作为优选,上述异类叶升麻苷或其医药学上可接受的盐用以抑制该淀粉样β肽导致神经元的损伤或凋亡,进而保留、改善或恢复学习与记忆能力。
作为优选,上述药物对人类的有效剂量相当于每日每公斤体重0.2毫克至4.0毫克的异类叶升麻苷或其医药学上可接受的盐。
为使本发明的上述目的、特征和优点能更明显易懂,下文特举出实施例,并配合附图作详细说明。
附图的简要说明
图1示出了各井(well)的细胞外Aβ1-40含量百分比,结果显示本发明的异类叶升麻苷(D)具有显著降低Aβ1-40在细胞外积累的极佳活性;
图2示出了各井的细胞内的Aβ1-40含量百分比;
图3示出了各测试样品对APP表现量的影响;
图4示出了各测试样品对Aβ1-40降解的影响;
图5示出了各测试样品对Aβ1-42寡聚化的影响;
图6示意地示出了Aβ的生成、清除与聚集过程;
图7示出了动物试验的时程表;
图8示出了各测试样品对实验大鼠的探索能力影响;
图9示出了各测试样品对实验大鼠的被动回避反应的影响;
图10示出了各测试样品对实验大鼠进行水迷宫空间表现的影响;
图11示出了各测试样品对实验大鼠进行水迷宫参考记忆试验的影响;
图12A-12E示出了实验大鼠的脑部组织染色结果;
图13A示出了实验大鼠脑部皮质区和海马区的乙酰胆碱含量检测结果;
图13B示出了实验大鼠脑部皮质区和海马区的胆碱含量检测结果;
图14A示出了实验大鼠脑部皮质区所测得的乙酰胆碱酯酶活性结果;
图14B示出了实验大鼠脑部海马区所测得的乙酰胆碱酯酶活性结果。
实施发明的最佳方式
许多由淀粉样β肽引发的疾病均具有一种共通的特征,即淀粉样β肽聚集体的形成。这些淀粉样β肽聚集体可以如纤维或斑块的形态出现,并且沉淀在生物体的系统、器官、组织或体液中,进而引发各种疾病或状况。如能有效抑制淀粉样β肽的生成、积累或聚集,应可避免淀粉样β肽形成聚集体而引发的各种疾病或状况,其应可作为有效预防或治疗淀粉样β肽相关疾病或状况的方式之一。
有鉴于此,本发明以具有下式的异类叶升麻苷或其医药学上可接受的盐作为抑制(例如降低或避免)淀粉样β肽生成、积累或聚集的有效成份,尤其是抑制淀粉样β肽于细胞外的生成、积累或聚集。
美国专利7,087,252B2揭示了一种从管花肉苁蓉(Cistanche tubulosa(Schenk)Wight)的肉质茎所制备的含25-50wt%松果菊苷(echinacoside)及5-15wt%类叶升麻苷(acteoside)的制剂,其可用于抗老年痴呆症(senile dementia)。异类叶升麻苷及多种其它苯乙醇苷类(phenylethanoid glycosides)已知被包含于该制剂中。
在本发明中,异类叶升麻苷的水合物或其它溶剂溶合物、前药及代谢 物均被视为异类叶升麻苷的功能上的等同物。所述“前药”指某种前趋化合物可于生物条件(活体内或活体外)下水解、氧化或进行其它反应而产生异类叶升麻苷。所述“代谢物”指异类叶升麻苷于细胞或生物体内被代谢所形成的化合物。
当异类叶升麻苷的“医药学上可接受盐”施予生物体时,其通常可具有与异类叶升麻苷相同或类似的医疗功效,在生理上可忍受,且不会产生过敏或类似反应。所述异类叶升麻苷的医药学上可接受盐可包含但不限于铁盐、钙盐或镁盐等。
所述“预防”指避免或延迟疾病或状况在生物体中出现,而所述“治疗”则指减缓或阻止疾病或状况的发展,或使生物体的状况回复至较佳或正常的状态。
所述“淀粉样β肽相关性疾病或状况”指此疾病或状况的发生通常与淀粉样β肽的生成、积累或聚集相关,尤其指此疾病或状况的发生为淀粉样β肽所导致。而当在具有某种疾病或状况的一定比例的生物体上发现有淀粉样β肽的不正常生成、积累或聚集现象时,也可认为此疾病或状况为淀粉样β肽相关。另外,当淀粉样β肽的聚集处与疾病或状况所发生的病理特征影响位置相近时,亦可认为此疾病或状况为淀粉样β肽相关。
本发明所提供的抑制淀粉样β肽的有效成份,亦可作为食品、饮品等添加剂使用,以达到抑制淀粉样β肽生成、积累或聚集的方便性使用。
本发明所提供的用于治疗淀粉样β肽相关性疾病或状况的药物或医药组合物,包含异类叶升麻苷或其医药学上可接受的盐作为有效成份,并可包含适当的载剂、稀释剂或赋形剂等,以呈现如散剂(powder)、颗粒剂(granule)、锭剂(tablet)、片剂(troche)、丸剂(pill)、胶囊(capsule)、水性或油性溶液(solution)、悬浮液(suspension)、乳膏(cream)、软膏(ointment)、凝胶(gel)、气雾剂(aerosol)、栓剂(suppository)、贴剂(patch)或其它所需形式。上述药物或医药组合物可通过口腔、局部、非经肠、皮肤、鼻、眼、眼内或其它途径给药。
在本文中,所述“或”一般定义为“及/或”,除非另有特别说明。
随着世界人口老龄化的日益严重,与衰老有关的许多疾病例如失智症(dementia)已然成为现今老年疾病的重点医疗研究之一,而在各种失智症中又以阿滋海默氏症最为普遍。阿滋海默氏症是一种慢性的神经退化性疾病,其特征为病人逐渐失去认知能力且出现严重的行为异常,后续也会造成语 言和运动能力的丧失,对病患本身与其家人的生活质量容易造成极大的影响。有鉴于罹患阿滋海默氏症的患者人数有逐渐增加的趋势,造成家庭与社会的严重负担,因此本发明特捡选与阿滋海默氏症较为相关的Aβ进行试验。
在下列实施例中,利用表一所提供的测试样品进行Aβ试验,并且与未加入任何测试样品处理的对照组(Vehicle)进行比较。
表一:进行试验的样品
松果菊苷(Echinacoside)、类叶升麻苷(Acteoside)和异类叶升麻苷(Isoacteoside)分别具有下列结构式:
松果菊苷:
类叶升麻苷:
异类叶升麻苷:
实施例一:神经瘤母细胞株的培养
将原生型(wild type)人类神经瘤母细胞SH-SY5Y培养于Eagle’s Minimumessential Medium(EMEM)/Ham’s F12medium(1:1混合物)(含10%FBS,10units/mlpenicillin,10μg/ml Streptomycin)中,而原生型小鼠神经瘤母细胞Neuro-2a则培养于minimum essential medium(MEM)培养基(含10%FBS,10units/ml penicillin,10μg/mlStreptomycin)中。
实施例二:各样品对Aβ1-40于细胞外的积累测试
将实施例一中的原生型人类神经瘤母细胞SH-SY5Y的培养基置换成化学成份培养基(EMEM/F12medium(Cat.No.12500-062),Hepes 5mM,葡萄糖0.6%,NaHCO3 3mM,麸酰胺2.5mM,胰岛素25μg/ml,Transferin 100μg/ml,Progestrone 20nM,Putrescine 60μM,亚硒酸钠(Sodium selenite)30nM,Heparin 2μg/ml)。每个井(well)具有1x105个SH-SY5Y细胞,而培养基体积为300μl。30分钟后,将表一中所示的测试样品A-D分别以50μg/ml的浓度加入至不同井中处理24小时,接着以Human Aβ1-40Immunoassay kits(Catalog#KHB3482Invitrogen)分析各井的培养基中的Aβ1-40含量。
人类神经瘤母细胞SH-SY5Y会积累Aβ于细胞外的培养基中,而图1示出了SH-SY5Y井分别经各测试样品A-D处理后,Aβ1-40于培养基中的含量百分比,其以未加入任何测试样品处理的对照组为比较基准。结果显示为平均值±标准误差,而对照组和测试样品组间的统计差异标示*表示P<0.05,**表示P<0.01,***表示P<0.001。
参考图1所示,测试样品A(含苯乙醇苷的制剂)和测试样品C(类叶升麻苷)减少培养基中的Aβ1-40含量约20%,而测试样品D(异类叶升麻苷)则减少培养基中的Aβ1-40含量达47.44±16.62%。图1结果显示异类叶升麻苷(D)具有显著降低Aβ1-40于细胞外积累的极佳活性。
实施例三:各测试样品对Aβ1-40于细胞内的积累实验
每个井均具有1x105个SH-SY5Y细胞,而培养基体积为300μl。将各井中的SH-SY5Y细胞以浓度50μg/ml的测试样品A-D处理24小时后,分别将各井中的细胞部份制成细胞均质液,并利用Human Aβ1-40Immunoassay kits(Catalog#KHB3482Invitrogen)分析其Aβ1-40含量。
图2示出了SH-SY5Y井的细胞内的Aβ1-40含量百分比,以未加入任何测试样品处理的对照组为比较基准。如图2所示,测试样品A-D均未明显造成Aβ于细胞中积累。
实施例四:各测试样品对APP在细胞中表现的影响实验
每个井具有1x105个SH-SY5Y细胞,而培养基体积为300μl。将各井中的SH-SY5Y细胞以浓度50μg/ml的测试样品A-D处理24小时后,将细胞部分以均质缓冲液(50mM Hepes pH7.5,1mM EDTA,150mM NaCl,1%NP-40,1mM PMSF,5μg/ml aprotinin,10μg/ml leupeptin)进行均质,利用超高速离心除去不溶物质。将蛋白质以SDS-聚丙烯酰胺胶电泳(polyacrylamide gel electrophoresis)分离,并转渍到PVDF膜后再利用免疫转渍法(immunoblot)(antiAβ1-17,6E10或antiAPP-c端抗体)来检测holoAPP含量。
图3示出了测试样品A-D对APP在细胞中表现的影响,其以百分比表示,并以未加入任何测试样品处理的对照组(Vehicle)为基准。如图3所示,测试样品A-D并未降低APP表现的活性。
实施例五:各测试样品对Aβ1-40于细胞外的降解实验
小鼠神经瘤母细胞neuro-2a会在化学成份培养基中释放出分解Aβ的酵素,但不会在培养基中积累足以侦测的Aβ量。将neuro-2a在培养基中培养24小时,之后将不含细胞的培养基取出,并分别以浓度50μg/ml的测试样品A-D及10ng人工合成的Aβ1-40处理24小时,之后检视各测试样品是否具有可促进培养基中的酵素降解Aβ的活性。利用Human Aβ1-40Immunoassay kits(Catalog#KHB3482Invitrogen)分别检验各井中的Aβ1-40之残留量,其显示为百分比,并以未加入任何测试样品处理的对照组(Vehicle)为比较基准。如图4所示,测试样品D(异类叶升麻苷)并未促进Aβ于细胞外的降解。
实施例六:各测试样品对Aβ1-42寡聚化的实验
将干燥的Human Aβ1-42自从冰箱取出静置至室温,加入1,1,1,3,3,3-Hexa-fluro-2-propanol(HFIP)溶解Aβ1-42至浓度为1mM,然后在室温下静置1小时。以Hamilton注射器将上述Aβ1-42/HFIP容易进行分装,并且以氮气将HFIP吹干,接着存放于-20℃。将HFIP处理后的Aβ1-42以PBS溶解,并分别以浓度50μg/ml的测试样品A-D且于4℃下振荡处理24小时,以制备Aβ1-42的寡聚物(oligomer),并利用thioflavine T结合荧光(Ex=450nm,Em=482nm)以分析Aβ1-42的寡聚化程度。
图5示出了测试样品A-D分别对Aβ1-42寡聚化(oligomerization)的影响,结果以百分比显示,并以未加入任何测试样品处理的对照组为基准。参考图5所示测试样品A(含苯乙醇苷的制剂)、B(松果菊苷)、C(类叶升麻苷)和D(异类叶升麻苷)均具有抑制Aβ1-42寡聚化的活性,其中异类叶升麻苷(D)可抑制Aβ1-42寡聚化程度达98.93±1.70,亦即异类叶升麻苷(D)可有效降低Aβ1-42的寡聚化,进而可抑制Aβ形成纤维丝或老年斑块。
图6示意地示出了Aβ的生成、清除与聚集过程(参考来源:Pharmacology&Therapeutics(2005)108:131)。图6表明培养基中细胞外的Aβ积累(1)会受到Aβ细胞内积累量(2)、APP表现(3)、Aβ降解(4)、Aβ寡聚化(5)以及Aβ生成(6)等影响。根据上述实施例二至六的细胞实验结果,相较于其它测试样品A-C而言,异类叶升麻苷(D)具有降低细胞外Aβ积累(1)的作用,并且对于降低Aβ的寡聚化程度(5)有极佳的效用,应可进一步用以抑制Aβ的聚集。此外,异类叶升麻苷(D)降低Aβ于细胞外积累(1)的作用并非源于异类叶升麻苷增进了Aβ于细胞内的积累(2)、降低了细胞的APP表现(3)、或增进了Aβ于细胞外进行降解(4),因此推测异类叶升麻苷(D)可直接减少Aβ的生成(6)。
综合上述结果,异类叶升麻苷(D)或其医药学上可接受的盐可作为抑制Aβ生成、积累或聚集的有效成份,预计异类叶升麻苷(D)可有效抑制Aβ导致神经元的损伤或凋亡,以进而保留、改善或恢复学习与记忆能力。此外,根据上述结果,异类叶升麻苷(D)或其医药学上可接受盐应可用于预防或治疗Aβ相关疾病或状况,以及用于抑制Aβ的生成、积累或聚集。
所述Aβ相关疾病或状况可包含但不限于阿滋海默氏症、轻度认知障碍、路易氏体失智症、唐氏症、荷兰型类淀粉变性症、关岛帕金森氏症-失智症复合症、大脑淀粉样血管病、包涵体肌炎、额颞叶型失智症、年龄相关性黄斑变性、皮克病以及其它。另外,所述Aβ虽以Aβ中最大量的Aβ1-40 或具有高度纤维形成性的Aβ1-42为例,但也可包含其它胺基酸片段。
在上述测试样品中,异类叶升麻苷(D)具有降低Aβ生成、积累和聚集的最佳效用。下列实施例七至十一中,首先于250~300公克重的雄性SD大鼠(购自乐斯科股份有限公司)的侧脑室内输注Aβ1-42,以造成大鼠的神经损坏,影响大鼠的记忆与学习操作能力,并可诱导大鼠脑中形成似老年斑块的沉积,以作为拟似阿滋海默氏症的动物模式。经Aβ诱导的阿滋海默氏症的动物模式可参考Nabeshima等人的文献数据(Neuroscience Letters(1994)170:63-66)(British Journal of Pharmacology(1999)126:235-244)。
将大鼠麻醉后,在大鼠的左脑室设置输注管,进行缝合后归回饲养笼中照顾。图7示出了动物试验的实验排程,在开始输注Aβ1-42后的第7天进行探索能力(explorationbehavior)评估,第8至9天进行被动回避反应(passive avoidance learning)评估,第10至13天进行水迷宫(water maze)评估,第14天则进行空间性探索实验(probe test)。实验组别设计如表二所示,其中假手术组(Sham)以TFA溶液(64.9%sterile ddH2O,35%acetonitrile,0.1%trifluoroacetic acid)进行处理,而其它实验组则每小时以0.5μl溶解于TFA溶液的Aβ1-42处理,相当于每天给予300pmol/12μl的Aβ1-42(Tocris 1428;MW:4514.08)。整个试验期间,在进行探索能力、被动回避反应以及水迷宫等测试的训练前经口投予测试样品给实验大鼠。表二显示各个实验组别的条件,其中测试样品D为表一中的异类叶升麻苷,而Aricept则为市售用以治疗失智症例如阿滋海默氏症的药物。所有测试样品均以二次蒸馏水每日制备,并以胃管经口灌胃方式给予。
在实施例七至十一中,结果显示为平均值±标准误差,而Aβ1-42对照组和其它实验组间的统计差异标示*表示P<0.05,**表示P<0.01,***表示P<0.001。
最后牺牲所有实验大鼠,取其脑部进行切片和染色,并进行神经传递物质的测定。
表二:动物实验设计
实施例七:探索能力的设备与测定
探索能力测定装置系由一长、宽、高均40cm及一个不锈钢底板所组成,底板上有16个直径3cm的洞,距两侧7cm,各洞的间距为4cm。每只大鼠的测定时间为10分钟,测试大鼠穿洞的次数。
图8示出了根据表二所示的动物探索行为(exploration behavior)的实验结果。如图8所示,Aβ1-42经脑室输注予实验大鼠后,会造成实验大鼠的探索能力低下,而测试样品D(异类叶升麻苷)和Aricept均可有效增进实验大鼠的探索能力,且测试样品D(异类叶升麻苷)在5mg/kg的剂量下优于Aricept 0.75mg/kg的功效。
实施例八:被动回避反应实验
被动回避装置由一明室、一暗室以及一介于两室间的闸门所构成。
将大鼠置入明室,同时开启闸门,以大鼠在90秒内进入暗室者,供做本实验。
训练期:将筛选过的大鼠置入明室,同时开启闸门,待大鼠进入暗室后,关闭闸门,同时将底板通以电流刺激5秒,之后自暗室取出大鼠,归回饲养笼。
于训练后24小时,再将大鼠置入明室,同时开启闸门,记录大鼠在明室之滞留时间(step-through latency,STL)。
图9示出了根据表二所示动物进行被动回避反应的实验结果。参考图9,实验大鼠经脑室输注给予Aβ1-42后,会显著造成实验大鼠的被动回避学习反应的障碍,而经测试样品D(异类叶升麻苷)和Aricept的治疗均可改善实验大鼠因脑室输注Aβ1-42导致实验大鼠被动回避的学习障碍现象。如图9所示,测试样品D(异类叶升麻苷)于2.5mg/kg的剂量下与Aricept 0.75mg/kg的效果相当,而测试样品D(异类叶升麻苷)于5mg/kg的剂量下则优于Aricept 0.75mg/kg的功效。
实施例九:水迷宫实验
本实验将泳池分成四个象限,将隐藏平台固定置于第四象限上,并且置于水面下方1公分处。每一大鼠每天均给予两次训练,两次训练间隔为4小时,每次训练均给予2分钟以找寻隐藏平台。第一次训练为空间表现(spatial performance)试验,每只大鼠最多给予120秒的时间游泳找寻隐藏平台,若大鼠于120秒内成功找到隐藏平台,则让大鼠于平台上休息30秒钟;而若大鼠于时间终止前尚未找到隐藏平台,则将大鼠的分数计为120秒,并将其抓至隐藏平台休息30秒钟。此空间表现试验一共进行4天。于第5天将隐藏平台自水迷宫泳池取走,再将大鼠置于第一象限,并且给予60秒钟的时间游泳,记录大鼠在泳池内原隐藏平台的象限所花的时间,以进行参考记忆试验(probe test)。
图10示出了根据表二所示动物进行空间表现试验结果,而图11示出了根据表二所示动物进行参考记忆试验的实验结果,并与假手术组(Sham)、Aβ1-42对照组和正对照组Aricept的结果作比较。参考图10及图11所示,动物实验结果显示测试样品D和药物Aricept均可改善Aβ1-42诱发水迷宫空间表现和参考记忆缺失的现象,而测试样品D 5mg/kg则优于对照组Aricept 0.75mg/kg的效果。
实施例十:大鼠脑部组织染色结果
将进行水迷宫实验后的大鼠断头,并且快速将脑自头盖骨内移开,进行脑部海马区Aβ1-42免疫组织染色。图12A至12E示出了脑部组织染色结果。在图12B中,在连续输注Aβ1-42的大鼠脑中发现大量的斑块,而在图12C和图12D中,经测试样品D(异类叶升麻苷)2.5mg/kg处理后的大鼠脑中仅发现极少量的斑块,而经测试样品D(异类叶升麻苷)5mg/kg处理后 的大鼠脑中则几乎没有斑块产生。比较图12C至图12E,经测试样品D(异类叶升麻苷)处理后的大鼠脑中,其斑块数量明显小于经药物Aricept处理过后的结果。由此结果可知,测试样品D(异类叶升麻苷)可有效抑制Aβ经聚集而形成斑块,或者可消除斑块。
实施例十一:大鼠大脑皮质区及海马区中的神经传导物质含量
将进行水迷宫实验后的大鼠牺牲掉,并快速将脑自头盖骨内移开,按Glowinski&Iversen的方法,将大脑皮质区及海马区分别取出,分别称重,并加入50mM Na-phosphatebuffer(pH 7.8)进行均质,以供进行神经传递物质浓度及酶含量的测定。
表三和表四分别为根据表二所示实验大鼠于其脑部皮质区和海马区的神经传导物质多巴胺(DA)与其代谢物DOPAC和HVA的含量检测结果。参考表三和表四所示的结果,Aβ1-42造成实验大鼠的皮质区和海马区的DA含量降低,而测试样品D和Aricept均可改善Aβ1-42所造成的实验大鼠皮质区和海马区的DA含量降低的现象。
表三:根据表二所示实验大鼠于其脑部皮质区的神经传导物质多巴胺(DA)与其代谢物DOPAC和HVA的含量检测结果
表四:根据表二所示实验大鼠于其脑部海马区的神经传导物质多巴胺(DA)与其代谢物DOPAC和HVA的含量检测结果
图13A为根据表二所示实验大鼠于其脑部皮质区和海马区的神经传导物质乙酰胆碱(Acetylcholine)的含量检测结果,而图13B则为根据表二所示实验大鼠于其脑部皮质区和海马区的胆碱(Choline)含量检测结果。参考图13A和图13B所示结果,Aβ1-42造成实验大鼠之皮质区和海马区的乙酰胆碱含量降低,而测试样品D和Aricept均可改善Aβ1-42所造成的实验大鼠皮质区和海马区的乙酰胆碱含量降低的现象,且其中以测试样品D(异类叶升麻苷)5mg/kg的结果最佳。
图14A和图14B分别示出了根据表二所示实验大鼠于其脑部皮质区和海马区所测得的乙酰胆碱酯酶(acetylcholinesterase)活性结果。参考图14A和图14B所示结果,Aβ1-42造成实验大鼠皮质区和海马区的乙酰胆碱酯酶活性增加,而测试样品D和Aricept均可改善Aβ1-42所造成的实验大鼠皮质区和海马区的乙酰胆碱酯酶活性增加的现象。
由于Aβ的聚集体会损伤细胞,进而引发各种疾病或状况。根据实施例二至六的细胞试验结果,异类叶升麻苷可有效抑制Aβ的生成、积累或聚集,进而避免Aβ形成聚集体,其可用于预防或治疗阿滋海默氏症以及其它Aβ相关疾病或状况。
根据实施例七至九的动物试验结果,异类叶升麻苷具有显著改善Aβ所致的记忆或学习能力衰退的效果。而根据实施例十所示结果,异类叶升麻苷可有效抑制Aβ经聚集而形成斑块,或者消除斑块。此外,根据实施例十一,异类叶升麻苷可有效改善神经传导物质因Aβ而减少的现象,故可具有改善记忆或学习能力衰退的效果。根据上述细胞和动物试验结果,如将异类叶升麻苷或其医药学上可接受的盐以某种有效治疗量,如相当于约0.2毫克/公斤至4毫克/公斤(即对60公斤成人的建议剂量约为12毫克至240毫克)的异类叶升麻苷的每日剂量投予至某一人类个体,其应可作为预防或 治疗阿滋海默氏症以及其它Aβ相关疾病或状况的方法。
虽然本发明已以数个较佳实施例揭露如上,但其并非用以限定本发明,本领域技术人员在未脱离本发明所揭示的精神下所进行的等效替换或修饰,均应包含在本发明权利要求的范围内。
Claims (7)
1.异类叶升麻苷或其医药学上可接受的盐用于制备预防或治疗与淀粉样β肽相关的疾病或状况的药物的用途,其中,所述与淀粉样β肽相关的疾病或状况为轻度认知障碍、路易氏体失智症、唐氏症、荷兰型类淀粉变性症、关岛帕金森氏症-失智症复合症、大脑淀粉样血管病、包涵体肌炎、额颞叶型失智症、年龄相关性黄斑变性或皮克病。
2.根据权利要求1所述的用途,其中所述疾病或状况与该淀粉样β肽的生成、累积或聚集有关。
3.根据权利要求2所述的用途,其中所述疾病或状况与该淀粉样β肽在细胞外的生成、累积或聚集有关。
4.根据权利要求1至3中任一项所述的用途,其中所述淀粉样β肽为Aβ1-40或Aβ1-42。
5.根据权利要求1所述的用途,其中所述异类叶升麻苷或其医药学上可接受的盐用以抑制所述淀粉样β肽导致神经元的损伤或凋亡,进而保留、改善或恢复学习与记忆能力。
6.根据权利要求1所述的用途,其中,所述药物对人类的一种有效剂量相当于每日每公斤体重0.2毫克至4.0毫克的异类叶升麻苷或其医药学上可接受的盐。
7.异类叶升麻苷或其医药学上可接受的盐作为添加剂在制备食品、饮品、咀嚼物、贴片或皮肤保养品中的用途。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108785320A (zh) * | 2018-04-13 | 2018-11-13 | 浙江大学 | 异毛蕊花糖苷在制备激活Nrf2-ARE信号通路的保健品/药品中的应用 |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2044951A1 (en) * | 2007-10-02 | 2009-04-08 | Merz Pharma GmbH & Co. KGaA | The use of substances for the treatment of loss of eyesight in humans with glaucoma and other degenerative eye diseases |
KR102048289B1 (ko) * | 2011-12-16 | 2020-01-08 | 신파 티엔리 파머슈티컬 컴퍼니 리미티드 (항저우) | 아밀로이드 β 펩타이드 관련 질환 또는 이상을 예방 또는 치료하기 위한 약학적 조성물 |
CN103622980A (zh) * | 2013-12-12 | 2014-03-12 | 宁夏医科大学 | 肉苁蓉苯乙醇苷类化合物作为制备治疗骨质疏松症药物的应用及药物组合物 |
TWI619721B (zh) * | 2014-04-10 | 2018-04-01 | 杏輝藥品工業股份有限公司 | 異類葉升麻苷衍生物及其製造方法與用途 |
TWI650131B (zh) * | 2014-07-03 | 2019-02-11 | 杏輝藥品工業股份有限公司 | 管花肉蓯蓉萃取物之用於製備保護眼部細胞之藥品或食品用途 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20040064830A (ko) * | 2003-01-10 | 2004-07-21 | 주식회사 엘컴사이언스 | 페닐에타노이드 유도체를 포함하는 퇴행성 뇌신경계질환의 예방 및 치료용 조성물 |
EP1736167A2 (en) * | 2005-06-20 | 2006-12-27 | I.R.B. Istituto Di Ricerche Biotecnologiche S.r.l. | Extracts obtained from cell line cultures from plants belonging to the Oleaceae family (e.g. Syringa vulgaris), their preparation and use |
WO2007125351A1 (en) * | 2006-04-27 | 2007-11-08 | Senexis Limited | Pyrimidine derivatives for the treatment of amyloid-related diseases |
CN101264094A (zh) * | 2008-04-16 | 2008-09-17 | 西藏自治区高原生物研究所 | 藏波罗花苯丙素苷组合物及其制备方法和用途 |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100500584B1 (ko) * | 2002-08-12 | 2005-07-12 | 경희대학교 산학협력단 | 신경성장인자와 유사 작용을 갖는 육종용 추출물 및 이를함유하는 조성물 |
TW200416036A (en) * | 2003-02-18 | 2004-09-01 | Sinphar Pharmaceutical Co Ltd | Medicinal preparation containing phenylethanoid glycosides extracted from herbaceous plant, cistanche tubulosa (schenk.) wight, process of making the same, and uses of the same |
CN1268341C (zh) * | 2003-03-04 | 2006-08-09 | 杏辉天力(杭州)药业有限公司 | 来源于管花肉苁蓉的含有苯乙醇苷的制剂及其制备方法和用途 |
JP2006312594A (ja) * | 2005-05-06 | 2006-11-16 | Univ Nihon | 学習・記憶障害予防用組成物 |
JP4936507B2 (ja) * | 2006-01-18 | 2012-05-23 | 学校法人近畿大学 | カンカニクジュヨウの抽出物より得られる強壮剤又は強精剤、配糖体化合物及びそれらの用途 |
CN100446792C (zh) * | 2006-03-21 | 2008-12-31 | 中国海洋大学 | 一种改善记忆的中药 |
JP5410683B2 (ja) * | 2008-02-19 | 2014-02-05 | 学校法人近畿大学 | カンカニクジュヨウから得られる肝保護剤及び抗TNF−α作用剤 |
JP2009196908A (ja) * | 2008-02-20 | 2009-09-03 | Yomeishu Seizo Co Ltd | リパーゼ阻害剤及び飲食品 |
JP2009209063A (ja) * | 2008-03-03 | 2009-09-17 | Univ Kinki | 皮膚外用剤または皮膚化粧料 |
JP2009263279A (ja) * | 2008-04-25 | 2009-11-12 | Oriza Yuka Kk | エラスターゼ阻害剤 |
CN101703125B (zh) * | 2009-12-04 | 2012-07-04 | 中国科学院新疆生态与地理研究所 | 肉苁蓉红茶及其制备方法 |
-
2011
- 2011-06-10 TW TW100120452A patent/TWI486162B/zh active
- 2011-06-15 US US13/160,663 patent/US20120009131A1/en not_active Abandoned
- 2011-06-16 EP EP11170127.2A patent/EP2397144B1/en active Active
- 2011-06-16 CN CN2011800298829A patent/CN103037868A/zh active Pending
- 2011-06-16 JP JP2013514533A patent/JP5968878B2/ja active Active
- 2011-06-16 AU AU2011267724A patent/AU2011267724B2/en active Active
- 2011-06-16 SG SG2012091914A patent/SG186717A1/en unknown
- 2011-06-16 CA CA2802441A patent/CA2802441C/en active Active
- 2011-06-16 KR KR1020137000895A patent/KR101847501B1/ko active IP Right Grant
- 2011-06-16 WO PCT/CN2011/000998 patent/WO2011157059A1/zh active Application Filing
- 2011-06-16 MY MYPI2012005431A patent/MY160878A/en unknown
- 2011-06-16 CN CN201610646844.2A patent/CN106176778A/zh active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20040064830A (ko) * | 2003-01-10 | 2004-07-21 | 주식회사 엘컴사이언스 | 페닐에타노이드 유도체를 포함하는 퇴행성 뇌신경계질환의 예방 및 치료용 조성물 |
EP1736167A2 (en) * | 2005-06-20 | 2006-12-27 | I.R.B. Istituto Di Ricerche Biotecnologiche S.r.l. | Extracts obtained from cell line cultures from plants belonging to the Oleaceae family (e.g. Syringa vulgaris), their preparation and use |
WO2007125351A1 (en) * | 2006-04-27 | 2007-11-08 | Senexis Limited | Pyrimidine derivatives for the treatment of amyloid-related diseases |
CN101264094A (zh) * | 2008-04-16 | 2008-09-17 | 西藏自治区高原生物研究所 | 藏波罗花苯丙素苷组合物及其制备方法和用途 |
Non-Patent Citations (1)
Title |
---|
王建刚: "《临床药理学》", 31 December 2008 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108785320A (zh) * | 2018-04-13 | 2018-11-13 | 浙江大学 | 异毛蕊花糖苷在制备激活Nrf2-ARE信号通路的保健品/药品中的应用 |
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