CN110638854A - 一种胸腺路径预防或/和治疗阿尔兹海默症的药物或保健食品 - Google Patents
一种胸腺路径预防或/和治疗阿尔兹海默症的药物或保健食品 Download PDFInfo
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Abstract
本发明公开了一种胸腺路径预防或/和治疗阿尔兹海默症的药物或保健食品,其特征在于,所述胸腺路径是:衰老→胸腺萎缩→免疫功能下降→阿尔兹海默病发展,鲜墨旱莲汁→胸腺恢复→免疫功能提高→中断或逆转阿尔兹海默病发展;所述药物或保健食品由鲜墨旱莲取汁,其鲜墨旱莲汁中墨旱莲多酚类黄酮含量在5.00‑30.00%,噻吩类含量为1.00‑10.00%,蟛蜞菊内酯类含量在0.5‑10.00%。本发明在病原体感染鼻腔、口腔、肠道、肝脏阶段,终止持续进行性炎性反应,沿特殊通道进入中枢神经系统,防止阿尔兹海默病的发生;和/或/并在进化的病毒,或免疫逃避修饰的毒素进入中枢神经系统阶段,终止持续性神经炎反应,中断阿尔兹海默病理级联反应,治疗早中期阿尔兹海默病。
Description
技术领域
本发明属于生物医药技术领域,具体涉及为一种胸腺路径预防或/和治疗阿尔兹海默症的药物或保健食品。
背景技术
阿尔茨海默症(Alzheimer’s Disease,AD)是21世纪的公共健康危机,被誉为最难突破的领域之一。《2018年世界阿尔茨海默病报告》指出:2018年,全球共有5000万人罹患痴呆症,该数据预计于2030年达到8200万人,于2050年达到1.52亿;据估计,2018年因痴呆症带来的总体费用为1万亿美元,到2030年,这一数字将增至2万亿美元。美国阿尔茨海默病协会发布的2019年阿尔茨海默病事实和数据报告,美国患有阿尔茨海默病的人总数达到580万,阿尔茨海默病已成为美国的第六大死因,据估计,到2050年,阿尔茨海默病人将增加近三倍,达到1380万。中国更严重,我国65岁以上人群,将从2013年的一亿三千万上升到2030年的4亿,中国痴呆的发病率达6%,其中AD占痴呆总数的65%,现在,中国的AD患病人群已经达到一千万,轻度认知障碍有两千四百万,其中三分之一会发展成痴呆,仅在2015年,中国AD的支出,就已经达到了11562亿人民币。该病严重影响患者的生活质量,对患者家庭以及社会和经济可持续发展带来了巨大负担,目前仍没有有效的治疗途径。随着全球范围内人均寿命的延长和该疾病的复杂性,对大量老年人产生严重危害,成为全球优先关注的重大公共卫生和公共健康难题,被认为是21世纪的公共健康危机。
截至目前,全球累计研发投入超过6000亿美元,临床试验失败药物有320余个,失败率高达99.6%。2019年3月21日,百健及其合作伙伴日本卫材对两项靶向Aβ的抗体治疗药物Aducanumab(BIIB037)的3期临床试验的宣停,标志着单一靶向Aβ干预策略的局限。有关Tau拮抗的多个药物处于临床的不同研究阶段,如TRx0237、RO7105705、C2N 8E12、BIIB092等,然而降低Tau蛋白能否有效治疗AD,以及降低其含量是否能导致其他的病理状态,目前尚存在巨大争议,这些均极大地挑战了传统“一药一靶”的AD治疗策略。
目前尚无特效药物治疗阿尔茨海默症,只有两类改善症状药物:胆碱酯酶抑制剂和N-甲基-D-天冬氨酸受体抑制剂,都是治标不治本的药物。目前比较公认的解释是人类大脑中积累了太多β-淀粉样蛋白(Aβ),形成沉淀核心,产生神经毒性,诱导神经系统炎症和细胞坏死。另一种假说是微管相关蛋白tau蛋白结构异化导致其在神经细胞内积累,阻碍神经系统的正常功能。据此,药企和研究机构纷纷以β-淀粉样蛋白或tau蛋白为靶点研发治疗阿尔茨海默症的新药,其中不乏辉瑞、强生、礼来这样的国际巨头,可惜纷纷折戟沉沙,未能从三期临床试验脱颖而出。美国药品研究与制造商协会(PhRMA)发布报告称:仅2000~2012年间,244个处于临床阶段的阿尔茨海默症药物,只有一个用于加强认知能力的药物被美国FDA批准。在1998-2017年期间,全球已有146个AD药物在临床中遭遇失败,仅有1个药物成功上市,也只是改善症状,不能改变疾病进展。2019年的9月14日,制药公司百健与其合作伙伴卫材,刚宣布停止一种“BACE抑制剂”对早期AD的临床研究,这是百健在今年年初,颇有希望的“β淀粉样蛋白单抗”的研究被终止。
阿尔茨海默病药物发现基金会(Alzheimer’s Drug Discovery Foundation,ADDF)发布了2018年阿尔茨海默病临床试验报告(2018 Alzheimer’s Clinical TrialsReport):目前有超过220个治疗AD的临床研究,包括102种改变疾病进程的潜在治疗方法。74%的潜在疗法聚焦于Aβ和tau蛋白以外的创新靶点。有关AD患者的神经营养性因子疗法、代谢增强剂、细胞膜调节剂、抗毒抗炎治疗、抗淀粉样蛋白、基因治疗与神经细胞移植等治疗方法也越来越引起人们的关注,但均未取得良好疗效。
AD病因及相关致病机制复杂:衰老会导致炎症水平升高,自噬活动和清除错误折叠蛋白能力的下降,线粒体和新陈代谢障碍,神经突触丢失和功能失常,以及心血管障碍和表观遗传学变化等多种身体变化。能治疗AD的药物,必须同时满足从减少酶的裂变,到减少胰岛素降解,再到增加抗炎因子等等36个条件,单一靶点的候选药物均面临研发失败的风险,与衰老生物学(aging biology)相关的针对AD多种靶点的药物研发才是合理的选择。
“体质(免疫力)疗法”:AD病症是大脑神经元持续性死亡,tau蛋白是导致细胞死亡的原因。而AD的潜伏期有10-40年(在病症出现10-40年之前),病理变化已经开始了,而tau蛋白的出现却在疾病后期。临床发现,癌症病人治愈后,有四分之一到三分之一的人,又被AD击中,而癌症和AD一样,原因是多方面的,但本质都是体质衰弱的结果。所以现在癌症治疗方式由针对“癌”变成围绕“人的体质(免疫力)”。AD也应如此,不能只针对“AD病”,关键要围绕“人的体质(免疫力)”,通过抗衰老改善病人的体质(免疫力),中断或逆转AD的进程。
2019年5月14日世界卫生组织(WHO)发布《降低认知衰退和痴呆症风险指南》:针对痴呆症的12个相关问题,采取减轻体重可以改善葡萄糖耐量、胰岛素敏感性、血压、氧化应激和炎症等各种与认知障碍、痴呆有关的代谢因素;抑郁症可能在痴呆症中具有前驱作用,比如认知障碍可能是老年人抑郁的主要症状,与去甲肾上腺素能变化、白质病变之间的关联等可能是潜在机制。听力损失也是全球人口残疾的第四大原因,与认知能力下降或痴呆的风险增加有关。
芬兰的FINGER临床试验,对1200个痴呆病人进行了2年血管护理、饮食、锻炼、认知训练等立体化的,多维度的治疗,认知功能提高了25%,达到期望效果。目前许多国家都开展安全经济高效健康方式,组成了World Wide FINGERS跨学科全球网络进行协作研究。美国国家老龄化研究所(NIA,隶属于美国国立卫生研究院(NIH))授权阿尔茨海默病协会开展一项针对阿尔茨海默病的开创性临床试验 (U.S. POINTER):研究通过饮食、运动、认知刺激和健康指导等干预保护脑健康、降低患病风险,维持已有痴呆症风险的人记忆的大型临床研究,旨在保护60-79岁之间、认知下降风险逐年增高的老年人的认知功能。美国加利福尼亚大学伯克利分校2019年7月29日宣布获得了美国国立卫生研究院(简称NIH)国家老龄化研究所(NIA)总计4700万美元的五年资助,用于将先进的脑影像纳入阿尔茨海默病协会的开创性临床试验 (U.S. POINTER)。
未来AD治疗最好的也是唯一的办法:早发现、早干预、全干预的多靶点“体质疗法”。
开创性计划的实质也是“体质疗法”:通过改变人体的“体质”方式,达到大脑相关的整体健康,抵抗阿尔茨海默病、血管性痴呆。未来AD治疗最好的也是唯一的办法:早发现、早干预、全干预的多靶点“体质疗法”。
现有防治阿尔茨海默病的同类技术:
、“今得瑞”胶囊(国食健字G20130093,价格 ¥996.00/ 300 mg/粒*60粒/瓶*3瓶)
多功能组合:低聚肽→海洋生物活性肽,能够降低Aβ蛋白的合成,改善脑细胞的微环境,滋养大脑记忆中枢-海马区的脑细胞,改善海马神经元活性,调节突触的可塑性,促进脑源性神经营养因子(BDNF)的表达;人参皂苷→祖国传统中药人参的最主要的活性成分,其中的单体成分Rg1为主要功效成分,提高乙酰胆碱的合成与释放,增强神经可塑性,上调BDNF的表达,抑制tau蛋白发生磷酸化,减缓神经纤维缠结的形成;茶多酚→植物,天然抗氧化剂,抑制异常蛋白累积、抗氧化应激、调节细胞信号通路等多环节、多功能神经保护、神经修复作用。
以中国食品发酵工业研究院的复合偶联酶解和多级膜分离技术提取“海洋生物活性肽”、人参皂苷天然动植物成分,加上药食同源的高效抗氧化绿茶提取物功能因子-组合,首都医科大学宣武医院国家老年疾病临床医学研究中心-中国AD临床前期联盟对SCD(主观认知下降)人群脑功能与结构的影响的人体试验,安全、具有明显地辅助改善记忆、抗氧化功能。
、代代花制备治疗阿尔茨海默病药物或食品
代代花粉末主要含有多糖、氨基酸、微量元素、果胶、腺苷、黄酮类活性成分、单萜类活性成分、二倍半萜类活性成分和三萜类活性成分,具有改善记忆功能减退的功能疗效或改善睡眠障碍的功能疗效或治疗阿尔茨海默病的功能疗效或抗血管性老年痴呆的功能疗效。
代代花粉碎成粗粉,用0-100%乙醇浸泡0.5-2小时,4-12倍量溶剂加热回流提取2-4次,每次1-3小时,过滤,合并滤液。用冷冻干燥法或喷雾干燥进行干燥,收集冻干粉或喷雾干燥粉。
植物生物活性物质,包括药食同源的绿茶多酚、姜黄素、白藜芦醇。绿茶多酚(greentea polyphenols, GTP)是从绿茶中提取的多羟基酚类化合物的总称,主要包括儿茶素、槲皮素、山萘酚、芦丁、酚酸、茶氨酸等,其中儿茶素含量最为丰富,占茶叶干重的30%以上。衰老机体各组织器官的氧化应激增加神经退行性疾病,绿茶多酚因其极强的抗氧化能力在防治神经退行性疾病方面具有极大的潜力。人参皂苷、知母皂甙:人参(Panax ginseng)是人类认识和应用最早的保健佳品之一,其药用价值也早已为世界所公认。国内外的大量研究证实人参具有增强免疫力、改善记忆力、抗肿瘤、抗衰老、抗辐射、抗疲劳等多种生物活性,可有效改善AD相关症状如记忆障碍及增龄性记忆减退等,并对不同方式学习记忆的获得、保留与再现都有着不同程度的异化作用。海洋胶原肽(Marine Collagen Peptide, MCP):海洋生物活性肽具有抗菌、抗氧化、降血压、抗肿瘤、调节免疫等特殊的生理功能。
、BrAD-R13有望成为一种能够延缓疾病进程和保护神经的新型AD药物。
张江药谷企业上海博芮健制药有限公司宣布,公司在研项目阿尔茨海默病创新药BrAD-R13(治疗阿尔茨海默病的1.1类新药)已于2019年5月10日获得美国FDA临床试验默示许可。该款新药是全球首个获批进入临床试验的小分子TrkB(Trk:酪氨酸激酶)受体激动剂,拟用于治疗轻中度阿尔茨海默病。通过细胞生存交叉筛选法得到世界上第一个小分子TrkB激动剂——7,8-二羟基黄酮(7,8-DHF:。对细胞凋亡的保护作用,EC50为35nM,其相对于黄酮类儿茶素(100nM)、松脂素(100nM)和香叶木素(500nM)的效力更大。)本身是一种天然产物活性分子,可以特异性结合TrkB受体细胞外结构域,并选择性地激活TrkB受体,还抑制BACE1(β-分泌酶)表达并降低Aβ40和Aβ42的水平,给药结果显示没有明显毒性。博芮健制药通过化学修饰得到的候选药物BrAD-R13,相比天然产物7,8-DHF具有更好血脑屏障穿透性,明显改善了生物利用度和脑组织暴露水平。药效试验表明,5XFAD转基因模型小鼠长期口服BrAD-R13后,脑内TrkB及其下游信号通路被激活,产生包括减少突触丢失和改善电生理等神经保护作用,同时与AD相关的biomarker(Aβ、Tau等)也都有所降低,最终在行为学检测中表现出学习与记忆能力的提升。BrAD-R13有望成为一种能够延缓疾病进程和保护神经的新型AD药物,对其他神经退行性疾病,包括但不限于抑郁症(Depression)、精神分裂症(Schizophrenia)、帕金森症(Parkinson’s Disease)、肌萎缩侧索硬化(即渐冻人症,ALS)、亨廷顿病(即舞蹈症,Huntington’s Disease)、孤独症(又名自闭症,Austim)、Rett综合症等也具有良好的治疗效果。【PCT/US13/67972;7,8-Dihydoxyflavone and 7,8-Substituted Flavone Derivatives, Compositions, and Methods Related Thereto;USissued Patent US9682948B2;中国:授权专利 ZL201380062367.X】。
2019年9月6日,中国科学院上海药物研究所耿美玉课题组联合上海绿谷制药有限公司等研究团队在《Cell Research》杂志上发表《Sodium oligomannate therapeuticallyremodels gut microbiota and suppresses gut bacterial amino acids-shapedneuroinflammation to inhibit Alzheimer’s disease progression》揭示了GV-971的作用机理:研究发现在AD的进程中,肠道菌群失衡导致外周血中苯丙氨酸和异亮氨酸的异常增加,进而诱导外周促炎性Th1细胞的分化和增殖,并促进其脑内侵润。侵润入脑的Th1细胞和脑内固有的M1型小胶质细胞共同活化,导致AD相关神经炎症的发生。原创新药GV-971通过重塑肠道菌群平衡、降低外周相关代谢产物苯丙氨酸/异亮氨酸的积累,减轻脑内神经炎症,进而改善认知障碍,达到治疗AD的效果。历程21年的抗阿尔茨海默症(AD)的原创新药GV-971成功完成临床3期试验,为AD的治疗带来“中国方案”,填补AD治疗领域内全世界17年没有新药上市的空白。
圣地亚哥精准医疗领军企业索元生物,2019年6月18日宣布已从芬兰奥立安集团(Orion Corporation)获得治疗阿尔茨海默症(老年痴呆症)新药ORM-12741(索元生物命名为DB105)的授权,获得ORM-12741的开发、制造及商业化的全球权利。ORM-12741是一种选择性强的高效、全新的靶标为α-2C肾上腺素受体(AR)的拮抗剂,可能对阿尔茨海默病、精神分裂症和抑郁症等精神类疾病有效。原为芬兰奥立安集团开发治疗阿尔茨海默病的创新药。迄今为止,在11项临床研究中,有540多名患者服用ORM-12741,证实该药物的安全性及耐受性良好。ORM-12741的一项IIa期研究结果曾在第65届美国神经病学学会(AAN)年会上公布。该研究结果表明,使用ORM-12741的患者12周时记忆评分改善了4%,而安慰剂组恶化了33%。ORM-12741对情景记忆的作用明显。
美国生物科技公司Cortexyme的研究团队与路易斯维尔大学牙科学院教授简·波滕帕团队展开合作,从阻断龈卟啉单胞菌从口腔到大脑的转移路径入手,针对牙龈单胞菌的主要毒素,利用对应酶实施阻断,并开发出一种试验药物——COR388。在小鼠实验中,服药后的实验鼠脑中β-淀粉样蛋白产量降低,神经退化的情况也有所缓解。目前,COR388正处于阿尔兹海默病的1期临床试验阶段。
总之目前尚无特效药物治疗阿尔茨海默症,只有改善症状药物,都是治标不治本。
发明内容
本发明的目的在于提供一种胸腺路径预防或/和治疗阿尔兹海默症的药物或保健食品。为纯天然植物制成,通过逆转胸腺年老退变路径,提高免疫功能,中断病原体传导途径,抑制和抵抗炎症级联反应和细胞氧化应激过程,从而逆转或中断阿尔兹海默病的进展,达到治疗阿尔茨海默症的目的。
本发明采用的技术方案是:一种胸腺路径预防或/和治疗阿尔兹海默症的药物或保健食品。其特征在于,所述胸腺路径是:衰老→胸腺萎缩→免疫功能下降→阿尔兹海默病发展,鲜墨旱莲汁→胸腺恢复→免疫功能提高→中断或逆转阿尔兹海默病发展;所述药物或保健食品由鲜墨旱莲取汁,其鲜墨旱莲汁中墨旱莲多酚类黄酮含量在5.00-30.00%,噻吩类含量为1.00-10.00%,蟛蜞菊内酯类含量在0.5-10.00%。
所述墨旱莲制成包括如下过程:鲜墨旱莲钠化→破碎制浆→压榨取汁,得鲜墨旱莲汁。
所述鲜墨旱莲汁进一步按照常规的配方和制备技术制成习惯上可以接受的保健食品类型,包括不限于饮料、口服液。
所述鲜墨旱莲汁进行干燥后,进一步按照常规的配方和制备技术制成习惯上可以接受的保健食品类型,包括不限于糕点、含片、口服液、饮料。
所述鲜墨旱莲汁,进一步按照药品的常规制备技术制成药学上可以接受的药物剂型,包括不限于滴剂、颗粒剂、片剂、丸剂、胶囊、口服液、注射剂。
本发明以上任一所述的一种胸腺路径预防或/和治疗阿尔兹海默症的药物或保健食品,应用于预防或/和治疗阿尔兹海默症。
本发明研究发现:阿尔兹海默病是脑部长期处于进行型慢性炎症状态,使得脑部微环境改变,导致血脑屏障通透性异常,致使神经退行性病变。进程为:病原体【病毒(人类疱疹病毒 6A (HHV-6A) 和 7 (HHV-7))、病菌(肠道病菌、口腔病菌)、毒素(创伤性脑损伤毒性代谢产物、肝脏病素、细胞病素、牙龈菌蛋白酶)】→感染鼻腔、口腔、肠道、肝脏→引起免疫反应(适量的炎症反应发生保护中枢神经系统免受感染)→持续进行性炎性反应(衰老使细胞免疫活力降低:免疫失衡状态)→病毒进化或毒素免疫逃避修饰→进化的病毒(或免疫逃避修饰的毒素)沿嗅觉神经系统、三叉神经系统、肝脑血液循环系统、肠-脑神经轴、淋巴—脑脊液循环系统等特殊通道进入中枢神经系统→引发神经胶质细胞持续活化和持续神经炎性反应→触发阿尔兹海默病理级联反应(正常情况下Aβ的产生和清除处于动态平衡)→产生淀粉样蛋白-β(Aβ)沉积于细胞外和过度磷酸化tau蛋白沉积于细胞内及神经原纤维缠结→循环加重阿尔兹海默病理改变→阿尔兹海默病。用鲜墨旱莲汁,通过逆转胸腺年老退变路径,提高免疫功能,中断病原体传导途径,抑制和抵抗炎症级联反应和细胞氧化应激过程,逆转或中断阿尔兹海默病的进展,保护神经的药物和保健食品的开发路线是可行。
本发明的有益效果是:
本发明一种胸腺路径预防或/和治疗阿尔兹海默症的药物或保健食品,治疗费用比现有疗法低50%,有效率高30%,安全(墨旱莲是“亦蔬亦药”植物),可靠性高。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,下面结合具体实施例对本发明做出进一步详细说明。本领域的技术人员应当理解的是,所述实施例只用于解释本发明,并非用于限定本发明的范围。在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换,但这些修改和替换均在本发明的保护范围。下述实施例中所使用的试验方法如无特殊说明,均为常规方法;所使用的材料、试剂等,如无特殊说明,为可从商业途径得到的试剂和材料。
实施例1:墨旱莲的毒性试验
选用健康Wistar大鼠,雌雄各半,分别为空白对照组(灌胃给予等体积蒸馏水)、墨旱莲汁高、中、低剂量组[按实施例1制备,水混悬后灌胃,剂量分别为50.0、30.0、10.0g/kg/d(相当鲜墨旱莲草1000g、600g、200g kg/d)。每组50只Wistar大鼠,雌雄各25只,每日灌胃一次,每周给药7天,连续8周。试验期间对大鼠的外观、行为、体重、摄食量等各项指标进行检测,并分别于给药结束和恢复期结束进行血液学及血液生化学各项指标检测和病理组织学检查。
结果:100天灌胃:给予墨旱莲汁50.0 g/kg/d(相当鲜墨旱莲草1000g/kg/d)剂量组,LD50为35.0g/kG±3.0g/kg(相当鲜墨旱莲草500g/kg/d),安全系数为 700~750倍。遗传毒性试验、小鼠骨髓细胞微核试验和小鼠精子畸形试验,结果均为阴性,未显示有致突变性;无毒。30.0、10.0g/kg/d(相当鲜墨旱莲草600g、200g/kg/d)剂量组大鼠活动正常,所有体征与对照组比较未见差别和异常改变,摄食量与同期对照组比较,未见毒理学意义的异常变化。对体重无负面影响。血液学和血液生化学指标与同期对照组比较,均未见毒理学意义的异常改变。各组动物器官组织均无肉眼可见的病理改变。所有脏器重量及脏器系数亦均无毒理学意义的异常变化。所有镜检脏器均未发现与药物相关的病理改变。恢复期未见延迟性毒性反应,亦未见与药物有关的延迟性病理改变。结果表明,本发明墨旱莲汁具有较大的安全空间,可以长期使用。
实施例2:墨旱莲汁的制备
将墨旱莲100kg加盐1-5kg,破碎、压榨收集药汁,药渣加入1倍量的水,搅拌5~30min,再次压榨取汁,合并两次压榨药汁,100~200目筛过滤,浓缩至20千毫升,即得本发明的鲜墨旱莲汁。
实施例3:墨旱莲膏的制备
将墨旱莲100kg加盐1-5kg,破碎、压榨收集药汁,药渣加入1倍量的水,搅拌5~30min,再次压榨取汁,合并两次压榨药汁,100~200目筛过滤,浓缩至10千毫升,加山梨酸钾,即得本发明的墨旱莲膏。
实施例4:墨旱莲干粉的制备
将墨旱莲100kg加盐1-5kg,破碎、压榨收集药汁,药渣加入1倍量的水,搅拌5~30min,再次压榨取汁,合并两次压榨药汁,100~200目筛过滤, 40~75℃减压浓缩,超声波干燥(或喷雾干燥:进风口温度为90~140℃,出风口温度为70~110℃),收集干燥物,粉碎后过60~100目筛,即得本发明的墨旱莲干粉5-6kg。
实施例5:墨旱莲颗粒的制备
将墨旱莲100kg加盐1-5kg,破碎、压榨收集药汁,药渣加入1倍量的水,搅拌5~30min,再次压榨取汁,合并两次压榨药汁,100~200目筛过滤,浓缩至10千毫升;加山梨醇、甜味素,在流化沸腾制粒机中使物料粉末在自上而下的热空气流作用下保持悬浮的流化状态,喷入黏合剂液体使粉末聚结成颗粒
/或在高速搅拌制粒机中,与黏合剂溶液混合后粉碎成大小适宜的类球形颗粒
/或在喷雾干燥制粒机中,与辅料混合成浆状物,通过高压喷嘴喷入喷雾干燥器中,在热空气流中雾化成大小适宜的液滴并瞬间干燥成类球形颗粒。
实施例6:墨旱莲口含片的制备
将实施例4制备的墨旱莲干粉1份,及必要辅料0.3份,混匀后用单冲压片机/或多冲旋转压片机压片即得。
实施例7:墨旱莲糕点制备。
取面粉10kg、将实施例4制备的墨旱莲干粉8kg、果糖粉1kg进行混合,搅拌均匀,制得混合粉;将混合粉在热锅中炒熟,然后将1.2kg的火麻仁油、1kg的果葡糖浆与炒熟的混合粉一起搅拌,拌匀后在紫外线灯下照射40min进行杀菌,杀菌后按要求手工压制成糕点。
实施例8:墨旱莲口服液(饮料)的制备
取实施例2制备的鲜墨旱莲汁10kg,加入姜汁3kg,过滤,加入适量保鲜剂,装瓶、按所需重量装瓶密封,每瓶质量10-50毫升,检验合格,成品。
实施例9:墨旱莲饮料的制备
取实施例2制备的鲜墨旱莲汁10kg、姜汁3kg、食糖5kg、纯净水80kg,加入适量保鲜剂,装瓶、按所需重量装瓶密封,每瓶质量250-500毫升,检验合格,成品。
实施例10:墨旱莲注射液的制备
将鲜墨旱莲100kg,加盐2.5-5kg,破碎、压榨收集药汁,药渣加入1倍量的水,搅拌5~30min,再次压榨取汁,合并两次压榨药汁,100~200目筛过滤,浓缩至10千毫升;加浓度60~70%乙醇,沉淀除去杂质和不溶物。2次加入乙醇75%~80%乙醇,放置12小时到24小时,沉淀除去杂质和不溶物/或用醋酸纤维膜(CA膜)、聚砜膜(PS膜)高分子膜过滤,提高注射液的澄明度。浓缩制成每ml含旱莲草10.0g的注射液。每天肌注2-3次,每次4ml;可用注射液4ml加入50% 葡萄糖20ml中静注,每天2-3次,用药时间一般为7-10天。
实施例11:鲜墨旱莲汁逆转胸腺萎缩作用
方法:用D-半乳糖至胸腺萎缩,建立法衰老模型组、鲜墨旱莲汁组。
每天经背部皮下注射1%D-半乳糖40mg/(kg.d)30d。空白对照组注射等最生理盐水。
分组及用药:将30只小鼠随即分成空白对照组、衰老模型组、鲜墨旱莲汁组,每组10只,雌雄鼠分笼喂养,鲜墨旱莲汁组分别给予鲜墨旱莲汁口服液每鼠50g/(kg.d)分别灌胃60d。空白对照组、衰老摸型组每天灌胃等量白开水,最后一次用药2h后断头处死小鼠,解剖取脑、胸腺称重,福尔马林固定,石蜡包埋切片,HE染色,镜检。
结果:墨旱莲对胸腺组织的影响:
以胸胞重量(mg)与体重(g)之比作为小鼠胸腺指数,胸腺指数,胸腺皮质原度,胸腺皮质细胞数,各组间的差异显著,可见鲜墨旱莲汁逆转胸腺萎缩作用显著。见表1。
表1鲜墨旱莲汁逆转胸腺萎缩作用
实施例12:墨旱莲汁对APP/PS1小鼠海马IL-1β、IL-6、TNF-α含量的影响
实验方法:
检测海马1-1B和TN一a:采用双抗体夹心法测定海马白介素-1β(IL-1β)和肿瘤坏死因子-α(TNF-α)含量:称取小鼠体重,冰台上将小鼠断头,迅速取脑组织海马,匀浆,4℃静置,TGL-16G台式离心机3000r·min-1进行离心20min,取上清,分装EP小管中,-20℃冰箱保存备用。按IL-1β和TNF-α酶联免试剂盒说明书,使用6100型RT-雷杜酶标仪进行操作,450nm波长处测定各孔吸光度(A),根据标准曲线求出方程,计算IL-1β和TNF-α的含量。
结果:与空白组相比,模型组小鼠海马IL-1β、IL-6、TNF-α含量显著增加(P<0.01);与模型组相比,墨旱莲汁组小鼠海马IL-1β、IL-6、TNF-α含量显著减少(P<0.01);墨旱莲汁组与多奈哌齐组也有显著差异(P>0.05),见表2。
表2墨旱莲汁对APP/PS1小鼠海马IL-1β、IL-6、TNF-α含量的影响 (n=3)
注:与空白组比较,*P<0.05;#表示P<0.05;**表示P<0.01;与模型组比较,##表示P<0.01。
结论:结果表明,模型组与对照组比较小鼠海马IL-1β和TNF-α含量升高,提示模型组海马IL-1β和TNF-α明显升高,产生明显的炎症反应,免疫衰退水平明显,引发AD疾病。而经过墨旱莲汁治疗后,显示APP/Ps1双转基因小鼠海马IL-1β和TNF-α降低,说明墨旱莲汁改善APPs1双转基因小鼠海马IL-1β和TNF-α水平,而此时 APP/PSI双转基因小鼠的学习记忆能力得到改善,显示降低海马IL-1β和TNF-α水平与改善小鼠学习记忆能力相关,进一步提示墨旱莲汁通过降低APPs1双转基因小鼠海马IL-1β和TNF-α水平来改善小鼠的学习记忆能力。显示墨旱莲汁可以通过抑制IL-1β和TNF-α来治疗AD。
实施例13:墨旱莲汁对APP/PS1小鼠海马Aβ含量、APP和P-Tau的影响
实验方法:
检测海马Aβ、APP和P-Tau:将小鼠快速断头,迅速在冰上剥离海马组织放于EP管中,于-80℃液氮罐中储存备用。将每组小鼠的海马用10倍体积的RIPA组织/细胞裂解液(ml/g湿重组织)在冰上进行超声粉碎、匀浆,然后用离心机在4℃14000rpm 下离心40min,吸取上清液。按试剂盒说明书测定Aβ含量、APP和P-Tau表达情况。
结果见表3,与空白组相比,模型组小鼠海马Aβ含量显著增加(P<0.01);与模型组相比,墨旱莲汁组多和奈哌齐组小鼠海马Aβ含量显著减少 (P<0.01);墨旱莲汁组和多奈哌齐组没有显著差异(P>0.05)。与空白组相比,模型组APP、P-Tau表达显著增加 (P<0.01),与模型组相比,墨旱莲汁组和奈哌齐组APP,P-Tau表达显著减少(P<0.01);墨旱莲汁组比与多奈哌齐组也有显著差异 (P>0.05)。见表3。
表3、墨旱莲汁提取物对APP/PS1小鼠海马Aβ含量、APP和P-Tau表达的影响 (n=3)
注:与空白组比较,*P<0.05、**表示P<0.01;与模型组比较,#P<0.05、##表示P<0.01。
实施例14:墨旱莲汁滴鼻预防或/和治疗“嗅觉障碍+阿尔茨海默病”
对20例经医院确诊为嗅觉障碍+轻度认知功能障碍的AD患者进行临床治疗:10例(50%)鼻腔气动喷射雾化吸入布地奈德混悬液,口服阿瑞斯(盐酸多奈哌齐片),治疗用量5mg/次(一日1次),每晚睡前口服,服用一个月。10例(50%)每天6次(1次/2小时)每次50IU鼻内喷射雾化墨旱莲汁,口服阿瑞斯(盐酸多奈哌齐片),治疗用量5mg/次(一日1次),每晚睡前口服,服用一个月。墨旱莲汁组的嗅觉障碍、记忆、语言表达能力和注意力等认知功都能得到改善,其中7例(70%)明显改善,2例(20%)改善,1例(10%)稍有改善,总有效率达100%。检测墨旱莲汁对AD患者的认知功能、大脑葡萄糖的代谢水平以及相关的血液生物标志物的影响,结果墨旱莲汁能够降低Aβ42的水平和tau蛋白/ Aβ42比例,结合正电子发射断层显像检查,结果表明墨旱莲汁能够提高大脑颞顶叶、额叶、楔叶等区域的代谢水平,增强这些区域的大脑功能,提高受试者的认知功能。鼻腔气动喷射雾化吸入布地奈德混悬液组,5例(50%)明显改善,3例(30%)稍有改善,2例无效;总有效率达80%。无效者检测葡萄糖代谢水平以、血液生物标志物,相关的FGF2、IGF-1R、Ki67表达明显减少,使嗅感觉神经元的再生能力减弱,发生嗅觉障碍。见表4。
表4:两组疗效比较
实施例15:口含墨旱莲片预防或/和治疗牙周炎+阿尔茨海默病(三叉神经路径)
经医院确诊为牙周炎+轻度老年痴呆病例30例;分为治疗组15例和对照组15例。治疗组男10例,女5例;年龄50~65岁;病程6个月~3年;牙周炎15例(100%),记忆减退15例(100%),判断能力下降12例(80%),情感淡漠、反应迟钝5例(33%)。对照组男10例,女5例;年龄50~65岁;病程6个月~3年;牙周炎15例(100%),记忆减退15例(100%),判断能力下降12例(80%),情感淡漠、反应迟钝4例(30%)。
方法:墨旱莲含片组口含墨旱莲片,治疗用量5mg/次(1次/2小时);口服阿瑞斯(盐酸多奈哌齐片),治疗用量5mg/次(一日1次),每晚睡前口服,服用3个月。对照组每天口服阿瑞斯(盐酸多奈哌齐片),治疗用量5mg/次(一日1次),每晚睡前口服,服用3个月。
治疗结束后2周内到医院进行复查。疗效判断标准:(1)显效:以上症状全部消失,记忆力明显增强,能够对事件进行分析、思考、判断,对外界刺激有相应的情感反应,开始关注周围发生时事,反应敏捷;(2)有效:以上症状明显改善,记忆力、判断能力、情感和行动反应都有了明显改善;(3)无效:以上症状不减轻或加重,记忆严重受损,丧失判断能力,情感由淡漠变为急躁不安,常走动不停,可见尿失禁。显效率+有效率=总有效率。见表5。
表5:两组疗效比较
实施例16:口服墨旱莲膏预防或/和治疗肝功能异常+阿尔兹海默症(肝酶、酪氨酸酶。肝-脑轴(gut-liver-brain axis)路径。)
经医院确诊为肝功能异常+轻度老年痴呆病例30例;分为治疗组15例和对照组15例。治疗组男10例,女5例;年龄50~65岁;病程6个月~3年;肝功能异常15例(100%),记忆减退15例(100%),判断能力下降12例(80%),情感淡漠、反应迟钝5例(33%)。对照组男10例,女5例;年龄50~65岁;病程6个月~3年;肝功能异常15例(100%),记忆减退15例(100%),判断能力下降12例(80%),情感淡漠、反应迟钝4例(30%)。
方法:墨旱莲膏组口服含墨旱莲膏,治疗用量30-50ml/次(1次/2小时);口服阿瑞斯(盐酸多奈哌齐片),治疗用量5mg/次(一日1次),每晚睡前口服,服用3个月。对照组每天口服阿瑞斯(盐酸多奈哌齐片),治疗用量5mg/次(一日1次),每晚睡前口服,服用3个月。
治疗结束后2周内到医院进行复查。疗效判断标准:(1)显效:以上症状全部消失,记忆力明显增强,能够对事件进行分析、思考、判断,对外界刺激有相应的情感反应,开始关注周围发生时事,反应敏捷;(2)有效:以上症状明显改善,记忆力、判断能力、情感和行动反应都有了明显改善;(3)无效:以上症状不减轻或加重,记忆严重受损,丧失判断能力,情感由淡漠变为急躁不安,常走动不停,可见尿失禁。显效率+有效率=总有效率。见表6。
表6:两组疗效比较
实施例17:口服墨旱莲膏预防或/和治疗糖尿病+阿尔兹海默症(肠-脑轴(gut-liver-brain axis)胰岛素抵抗或胰岛素降解酶(insulin degrading enzyme, IDE)路径)。
经医院确诊为肝功能异常+轻度老年痴呆病例30例;分为治疗组15例和对照组15例。治疗组男10例,女5例;年龄50~65岁;病程6个月~3年;II型糖尿病15例(100%),记忆减退15例(100%),判断能力下降12例(80%),情感淡漠、反应迟钝5例(33%)。对照组男10例,女5例;年龄50~65岁;病程6个月~3年;II型糖尿病15例(100%),记忆减退15例(100%),判断能力下降10例(70%),情感淡漠、反应迟钝3例(20%)。
方法:墨旱莲膏组口服含墨旱莲膏,治疗用量30-50ml/次(1次/2小时);口服阿瑞斯(盐酸多奈哌齐片),治疗用量5mg/次(一日1次),每晚睡前口服,服用3个月。对照组每天口服阿瑞斯(盐酸多奈哌齐片),治疗用量5mg/次(一日1次),每晚睡前口服,服用3个月。
治疗结束后2周内到医院进行复查。疗效判断标准:(1)显效:治疗后空腹血糖<7.0mmol/L,或餐后2h血糖<7.8mmol/L,或降糖幅度较治疗前下降30%以上;记忆力明显增强,能够对事件进行分析、思考、判断,对外界刺激有相应的情感反应,开始关注周围发生时事,反应敏捷;(2)有效:治疗后空腹血糖<8.3mmol/L,或餐后2h血糖<11.0mmol/L,或降糖幅度较治疗前下降10%~30%;记忆力、判断能力、情感和行动反应都有了明显改善;(3)无效:治疗后血糖下降未达上述标准;记忆严重受损,丧失判断能力,情感由淡漠变为急躁不安,常走动不停,可见尿失禁。显效率+有效率=总有效率。见表7。
表7:两组疗效比较
实施例18:口服墨旱莲膏预防或/和治疗牙周病+糖尿病+阿尔兹海默症(肠-脑轴(gut-liver-brain axis),TNF-α→胰岛素抵抗路径)。
经医院确诊为牙周炎+糖尿病+轻度老年痴呆病例60例;分为治疗组30例和对照组30例。治疗组男20例,女10例;年龄50~65岁;病程6个月~3年;牙周炎、II型糖尿病30例(100%),记忆减退30例(100%),判断能力下降20例(65%),情感淡漠、反应迟钝10例(33%)。对照组男20例,女10例;年龄50~65岁;病程6个月~3年;牙周炎、II型糖尿病30例(100%),记忆减退30例(100%),判断能力下降20例(65%),情感淡漠、反应迟钝10例(33%)。
方法:墨旱莲膏组口服含墨旱莲膏,治疗用量30-50ml/次(1次/2小时);口服盐酸美金刚片,治疗第一周的剂量为每日5mg(半片,晨服),第二周每天10mg(每次半片,每日两次),第三周每天15mg(早上服一片,下午服半片),第4周开始以后维持剂量每天20mg(每次一片,每日两次),治疗3个月。对照组每天口服口服盐酸美金刚片,治疗第一周的剂量为每日5mg(半片,晨服),第二周每天10mg(每次半片,每日两次),第三周每天15mg(早上服一片,下午服半片),第4周开始以后维持剂量每天20mg(每次一片,每日两次),治疗3个月。
治疗结束后2周内到医院进行复查。疗效判断标准:(1)显效:治疗后空腹血糖<7.0mmol/L,或餐后2h血糖<7.8mmol/L,或降糖幅度较治疗前下降30%以上;记忆力明显增强,能够对事件进行分析、思考、判断,对外界刺激有相应的情感反应,开始关注周围发生时事,反应敏捷;(2)有效:治疗后空腹血糖<8.3mmol/L,或餐后2h血糖<11.0mmol/L,或降糖幅度较治疗前下降10%~30%;记忆力、判断能力、情感和行动反应都有了明显改善;(3)无效:治疗后血糖下降未达上述标准;记忆严重受损,丧失判断能力,情感由淡漠变为急躁不安,常走动不停,可见尿失禁。显效率+有效率=总有效率。见表8。
表8:两组疗效比较
结果:经过积极治疗后,墨旱莲膏组的显效率和总有效率均明显高于对照组。
实施例19:口服墨旱莲膏预防或/和治疗肠道微生物代谢紊乱+阿尔兹海默症(肠-肠道微生物-脑AD路径)。
经医院确诊为肠代谢紊乱+轻度老年痴呆病例30例;分为治疗组15例和对照组15例。治疗组男10例,女5例;年龄50~65岁;病程6个月~3年;肠代谢紊乱15例(100%),记忆减退15例(100%),判断能力下降12例(80%),情感淡漠、反应迟钝5例(33%)。对照组男10例,女5例;年龄50~65岁;病程6个月~3年;肠代谢紊乱15例(100%),记忆减退15例(100%),判断能力下降10例(70%),情感淡漠、反应迟钝3例(20%)。
方法:墨旱莲膏组口服含墨旱莲膏,治疗用量30-50ml/次(1次/2小时);口服阿瑞斯(盐酸多奈哌齐片),治疗用量5mg/次(一日1次),每晚睡前口服,服用3个月。对照组每天口服阿瑞斯(盐酸多奈哌齐片),治疗用量5mg/次(一日1次),每晚睡前口服,服用3个月。
治疗结束后2周内到医院进行复查。疗效判断标准:(1)显效:治疗后肠代谢正常;记忆力明显增强,能够对事件进行分析、思考、判断,对外界刺激有相应的情感反应,开始关注周围发生时事,反应敏捷;(2)有效:治疗后肠代谢基本正常;记忆力、判断能力、情感和行动反应都有了明显改善;(3)无效:治疗后肠代谢紊乱明显;记忆严重受损,丧失判断能力,情感由淡漠变为急躁不安,常走动不停,可见尿失禁。显效率+有效率=总有效率。见表9。
表9:两组疗效比较
肠道微生物变化:采用高通量测序仪测序分析16s rRNA,结果显示治疗组肠道微生物的多样性显著增加。
实施例20:墨旱莲静脉注射预防或/和治疗动脉粥样硬化(atherosclerosis, AS)+阿尔兹海默症(血液循环-BBB路径)
《中药大辞典》:治疗肺结核咯血:取旱莲草全草、白茅根茎制成注射液,每毫升含旱莲草0.5克,白茅根0.5克。每天肌注2~3次,每次4毫升;对大咯血患者,可用注射液4毫升加入50%葡萄糖20毫升中静注,每天2~3次。用药时间一般为4~5天或稍长些。副作用偶有寒战、高烧,待出汗后即消失,多为制剂不纯所致。
经医院确诊为动脉粥样硬化(atherosclerosis, AS)+轻度老年痴呆病例30例;分为治疗组15例和对照组15例。治疗组男10例,女5例;年龄50~65岁;病程6个月~3年;动脉粥样硬化(atherosclerosis, AS)15例(100%),记忆减退15例(100%),判断能力下降12例(80%),情感淡漠、反应迟钝5例(33%)。对照组男10例,女5例;年龄50~65岁;病程6个月~3年;动脉粥样硬化(atherosclerosis, AS)15例(100%),记忆减退15例(100%),判断能力下降10例(70%),情感淡漠、反应迟钝3例(20%)。
方法:静脉注射实施例10制备的墨旱莲注射液,治疗用量30-60ml/次(3次/天);口服阿瑞斯(盐酸多奈哌齐片),治疗用量5mg/次(一日1次),每晚睡前口服,服用3个月。对照组每天口服阿瑞斯(盐酸多奈哌齐片),治疗用量5mg/次(一日1次),每晚睡前口服,服用3个月。
治疗结束后2周内到医院进行复查。疗效判断标准:(1)显效:治疗后舒张压下降10mmHg并下降到正常或下降20mmHg以上,收缩压降到正常;记忆力明显增强,能够对事件进行分析、思考、判断,对外界刺激有相应的情感反应,开始关注周围发生时事,反应敏捷;(2)有效:治疗后舒张压下降未达到10mmHg,但己降到正常范围,或下降10-19mmHg,如为收缩期高血压,收缩压下降30mmHg;记忆力、判断能力、情感和行动反应都有了明显改善;(3)无效:治疗后血压下降未达到有效标准;记忆严重受损,丧失判断能力,情感由淡漠变为急躁不安,常走动不停,可见尿失禁。显效率+有效率=总有效率。见表10。
表10:两组疗效比较
实施例21:脑脊液注射墨旱莲(注射液)预防或/和治疗阿尔兹海默症
实验方法:
实验动物 健康成年昆明种小白鼠,体重20-25g雌雄各半,实验前小鼠适应性喂养一周。
实验试剂及药品
人工脑脊液(ACSF)组成(mM):NaCL 126,KCL3.5,MgCL2·6H2O1.3,CaCL2 2.0,NaH2PO4·2H2O1.2,NaHCO3 25,Glucose 11,Ph7.4。
TP粉末:购于安徽红星药业有限公司,临用前用双蒸水配成1g/L的溶液。
MK801:购于Sigma公司,用双蒸水配成3mM的溶液,4℃保存。
Glu:购于Sigma公司,用双蒸水配成25mM的溶液,4℃保存。
2,3,5-三苯基四氮唑(TTC):购于Sigma公司,用双蒸水配成 20g/L的溶液,常温避光保存。
乌拉坦:购于医药集团上海化学试剂公司,用双蒸水配成的200g/L溶液,常温保存。
LDH试剂盒:购于南京建成公司。
其它化学试剂均为分析纯。
仪器和设备
组织切片机:The Micklelaboratory engineering Co. LTD,美国。
振动切片机:MA752 Motorised Advance Vibroslice,美国。
酶标仪:Cenios TECAN公司,奥地利。
ph计:DELTA320,梅特勒—托利多仪器(上海)有限公司。
恒温水槽:SSW型,上海博讯实业有限公司医疗设备厂。
将全脑组织固定于振动切片机上,冠状切片,脑片厚400μm之后,脑片移至持续通混合气体(95%O2+5%CO2)的含葡萄糖ACSF中,室温下预孵育60min,以利脑片从切片时产生的机械性损伤中恢复活性。
来自同一动物的脑片被随机分到装有3ml ACSF(含镁离子或无镁离子)的孵育瓶中,每瓶含脑片5片,保持脑片不重叠,并持续通95%O2+5%CO2,在35℃水浴槽中孵育30min。之后,脂多糖损伤组加入3mM 的脂多糖,继续孵育72h。空白对照组在相同条件下孵育72h,但不加入脂多糖。脂多糖损伤之后,各组每瓶孵育液均换成3ml新鲜的含镁离子ACSF,持续通95%O2+5%CO2,继续培养72h。
墨旱莲注射液组在加入3mM脂多糖同时,保持整个孵育期间墨旱莲注射液浓度为10g/L。
检测脑片的IL-6/IL-10和损伤率%:空白组、模型组、墨旱莲注射液组IL-6/IL-10分别为0.96、0.43和1.86。空白组、模型组、墨旱莲注射液组损伤率分别为17.24%、82.57%和 25.30%。见表11。
表11
以上所述实施例仅表达了本发明的几种实施方式,实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,只要这些变形和改进与上述技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围,也将属本发明权利要求的保护范围。
Claims (6)
1.一种胸腺路径预防或/和治疗阿尔兹海默症的药物或保健食品,其特征在于,所述胸腺路径是:衰老→胸腺萎缩→免疫功能下降→阿尔兹海默病发展,鲜墨旱莲汁→胸腺恢复→免疫功能提高→中断或逆转阿尔兹海默病发展;所述药物或保健食品由鲜墨旱莲取汁,其鲜墨旱莲汁中墨旱莲多酚类黄酮含量在5.00-30.00%,噻吩类含量为1.00-10.00%,蟛蜞菊内酯类含量在0.1-6.00%。
2.根据权利要求1所述的一种预防或/和治疗阿尔兹海默症的药物或保健食品,其特征在于,所述墨旱莲制成包括如下过程:鲜墨旱莲钠化→破碎制浆→压榨取汁,最后得鲜墨旱莲汁。
3.根据权利要求2所述的一种预防或/和治疗阿尔兹海默症的药物或保健食品,其特征在于,所述鲜墨旱莲汁进一步按照常规的配方和制备技术制成习惯上可以接受的保健食品类型,包括不限于饮料、口服液。
4.根据权利要求2所述的一种预防或/和治疗阿尔兹海默症的药物或保健食品,其特征在于,所述鲜墨旱莲汁进行干燥后,进一步按照常规的配方和制备技术制成习惯上可以接受的保健食品类型,包括不限于糕点、含片、口服液、饮料。
5.根据权利要求2所述的一种预防或/和治疗阿尔兹海默症的药物或保健食品,其特征在于,所述鲜墨旱莲汁,进一步按照药品的常规制备技术制成药学上可以接受的药物剂型,包括不限于滴剂、颗粒剂、片剂、丸剂、胶囊、口服液、注射剂。
6.根据权利要求1-5任一所述的一种预防或/和治疗阿尔兹海默症的药物或保健食品,其特征在于,应用于预防或/和治疗阿尔兹海默症。
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