CN114222502A - 用于预防血管性痴呆的作为佐剂使用的食品补充剂 - Google Patents
用于预防血管性痴呆的作为佐剂使用的食品补充剂 Download PDFInfo
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Abstract
一种包括假马齿苋的干提取物、虾青素、维生素E、L‑茶氨酸和积雪草的干提取物的组合,在预防血管性痴呆中用作佐剂,因为其能够减少血管性认知障碍(VCI)的主要可改变风险因素。
Description
技术领域
本发明涉及一种口服制剂,特别是作为佐剂用于预防血管性痴呆,特别是用于减少血管性认知障碍(VCI)的主要可改变风险因素。
背景技术
血管性痴呆(VaD)是老年人痴呆最常见的原因之一,占所有痴呆病例的8-10%,仅次于阿尔茨海默病(AD)1。早在2002年,意大利老龄化纵向研究(ILSA)估计在65-84岁的意大利人口中痴呆症的患病率在女性中为7.2%,在男性中为5.3%。根据同一项研究,依照欧洲数据,在意大利,对于总计约150,000例流行病例,血管形式占痴呆症的22%2。
VaD的一种轻度形式是血管性认知障碍(VCI)。从临床的角度来看,已经看到VCI患者在执行功能与相对记忆力节省方面存在缺陷2,3,4直至更晚期,其中经常出现假性延髓影响(构音障碍、吞咽困难)和尿失禁。近一半的血管性认知障碍(VCI)的患者在首次疾病诊断五年后出现血管性痴呆VaD。因此,尽快识别和管理在VCI病例中发挥作用的风险因素的需求,对于预防血管损伤和改善患者的生活质量至关重要5。除了高龄,血管性痴呆的风险因素还包括:高血压、动脉粥样硬化、糖尿病、心脏病和中风。还可以看出,因为脑损伤而出现谷氨酸的大量释放,其具有神经毒性并促进氧化应激,从而促进神经元的炎症6,7。
目前缺乏针对血管性痴呆的有效药物干预。标准治疗主要侧重于通过使用例如抗高血压药、阿司匹林、他汀类药物(statins)、抗糖尿病药以及生活方式改变等识别和控制心血管和脑血管风险的症状管理和预防进一步的脑损伤。几类抗AD药剂没被临床试验认可地用于血管性痴呆的症状管理。胆碱酯酶(ChE)抑制剂(多奈哌齐(donepezil)、加兰他敏(galantamine)和卡巴拉汀(rivastigmine))和NMDA受体拮抗剂(美金刚)在改善认知功能方面显示出一些适度的短期临床益处;然而,这些研究中的大多数未能证明综合功能、日常生活活动和生活质量有显著改善。迄今为止进行的大多数研究持续时间相对较短(5-6个月);因此,这些血管性痴呆干预的长期益处和安全性尚未得到验证7。
关于氧化应激引起的神经元损伤,通常与如中风等神经血管问题有关,应该注意大脑是一个极易受到氧化应激影响的器官,因为这些组织中的代谢活动更强烈,因此对能量的需求更大,并产生更多的自由基。这是氧化磷酸化过程所固有的,并且代表了从线粒体本身开始的细胞破坏的潜在风险。所产生的自由基很容易通过抗氧化机制(超氧化物歧化酶、谷胱甘肽、过氧化氢酶)的作用而失活。在任何情况下,由于没有酶防御系统是100%有效的,因此整套抗氧化酶不能完全中和由线粒体产生的活性氧。由于许多因素,抗氧化机制实际上会遭受危机,因此不再能够补偿由细胞产生的自由基。在这种情况下会发生氧化应激:自由基与生物分子(脂肪、蛋白质、核酸)反应,导致结构和功能改变并激活炎症系统。随着时间的推移,基于自由基的衰老理论已经演变为基于线粒体自由基的衰老理论8-9。该理论断言,对线粒体的整体氧化损伤,由内源性代谢过程和/或外源性氧化影响加剧10,导致线粒体效率逐渐降低。实质性损伤可归因于穿过膜的电子,这会损伤线粒体并导致能量产生降低。它引发了涉及功能损伤和能量产生减少的恶性循环。线粒体逐渐失去其功能完整性,因此到达它们的越来越多比例的氧分子被转化为ROS。在中风的情况下,线粒体的贡献可能是决定性的:在缺血发作期间,神经和神经胶质线粒体中产生的大量ROS可能对脑组织是毁灭性的11。基于血管的神经元可塑性的降低也是对进一步调节神经发生至关重要的营养因子的血管内皮细胞分泌受损的结果12。血流减少的代谢影响可能会通过毛细血管壁的转运改变而加剧。除了影响血管的结构和功能外,衰老还会降低微血管可塑性,因此毛细血管对神经元活动的增加较少地响应,尽管可以保留对促进血管生成的其他因素的响应。血管可塑性的丧失肯定会影响神经元可塑性,因为成人大脑中的神经元更新与毛细血管及其生长有关。内皮细胞产生的营养因子是成人海马体内的神经发生的重要的额外调节因子,这些因子分泌的障碍可能会对老年人大脑产生影响。因此,微血管结构和可塑性的与年龄相关的变化促使认知功能下降,伴随着多种方式的大脑衰老。为了抵消由血管问题引起的认知损伤,应用旨在尽可能减少该问题根源的可改变风险因素的策略是合理的。
主要可改变风险因素是:
-神经炎症氧化应激:氧自由基的增加导致神经炎症激活,对神经元功能产生负面影响;
-氧供应的改变和神经元营养的改变:神经元水平的血流量减少不可避免地导致营养性痛苦和缺氧,从而导致神经元的可塑性降低;
-胆碱能神经传递的改变:记忆和认知功能的下降总是与乙酰胆碱介导的神经传递的效率降低有关。
因此,为了在全球范围内减少血管性认知障碍(VCI),人们应该:
1.减少氧化应激和神经炎症;
2.诱导神经小动脉的血管舒张,促进营养和氧供应
3.促进乙酰胆碱的突触后积累,维持电信号的高效传输
本发明的目的是提供一种或多种活性成分,其能够:
1.防止神经元炎症和氧化应激
2.改善认知和记忆能力
3.促进神经元可塑性。
L-茶氨酸是一种存在于茶类植物(Camelia sinensis)的叶子、更广为人知的是茶树或绿茶中的天然物质。L-茶氨酸与谷氨酸的结构相似性意味着它对谷氨酸受体具有高亲和性。L-茶氨酸是一种谷氨酸拮抗剂,可与促离子型谷氨酸受体如AMPA、红藻氨酸和NMDA受体结合,在保护神经元免受过量谷氨酸侵害方面可发挥重要作用。除了作用于谷氨酸受体外,动物研究还表明,L-茶氨酸影响大脑中多巴胺和血清素的浓度,并可能通过抑制皮质神经元的兴奋而具有抗应激作用。最近的研究还显示出,L-茶氨酸不仅减少焦虑,还减轻具有高压力反应的成年人的血压升高。谷氨酸的拮抗机制和应激性高血压的降低导致L-茶氨酸保护神经元免受导致认知缺陷和痴呆的氧化和炎症损伤13-15。
积雪草是一种常用于阿育吠陀和中药中的药草,其由于主要由萜烯类组成的植物复合物(phytocomplex)而具有抗氧化、抗炎和抗细胞凋亡的特性。所有这些特性都可以解释为什么积雪草不仅增强血管,而且对大脑可塑性也有积极的影响。体内研究显示出,积雪草增加了树突的长度,也改善了受神经退行性疾病影响的小鼠的CA3海马体的神经树突树枝状化5。体外研究显示出,积雪草提取物在改善认知功能方面的有效性是与其胆碱能特性相关的,事实上它抑制乙酰胆碱酯酶(AChE)的作用,其是阿尔茨海默病(AD)发病机制中的关键酶。积雪草还具有抗氧化和抗炎特性,对神经元细胞的体外研究证实了积雪草皂苷对通过因缺血缺氧引起的乳酸脱氢酶过度产生而受损的神经元膜的完整性具有保护效果。细胞上清液中乳酸脱氢酶的增加显示出与细胞膜的脂质过氧化有关。结果进一步证实,积雪草皂苷还可以直接抑制膜的脂质过氧化,从而减少神经元坏死并保护神经细胞16-18。
负责假马齿苋药理作用的成分包括生物碱类、皂苷类、甾醇类。一些成分(生物碱婆罗门(brahmin)和疱疹素(herpestin)、皂苷类、D-甘露醇、酸A、莫尼埃林(monnierin))是40多年前在印度分离出来的。随后已鉴定出其他活性成分,包括白桦脂酸(betullicacid)、豆甾醇、β-谷甾醇以及一些假马齿苋皂苷(bacosides)和假马齿苋皂苷(bacosaponins)。负责认知作用的成分被认为是假马齿苋皂苷A和B,后者仅在光学活性上不同,并且可能是假马齿苋皂苷A分离过程中产生的人工产物。三萜类皂苷及其假马齿苋皂苷负责假马齿苋属(Bacopa)的增加神经脉冲传递的能力。假马齿苋皂苷通过增加蛋白激酶活性、促进神经元合成、有助于恢复突触活动和改善神经脉冲传递来帮助修复受损的神经元。基于动物模型研究的结果,可以说假马齿苋皂苷在海马体、额叶皮层和纹状体中发挥抗氧化活性。假马齿苋提取物在动物模型和体外离体动脉中:通过从内皮释放一氧化氮来降低血压,对血管平滑肌Ca2+体内平衡具有额外效果;静脉注射,在不干扰心率的情况下降低收缩压和舒张压,诱导离体动脉的血管舒张。假马齿苋被定义为益智成分,因为它通过减少乙酰胆碱酯酶促进胆碱能神经递质的释放及其突触后浓度19-27。
在许多特性中,虾青素具有抗炎和抗氧化作用,并保护细胞质膜和线粒体双膜,改善其功能,从而提高线粒体产生能量的能力28-30。
维生素E的生物作用是由于其抗氧化能力:它通过隔离过氧脂质自由基来防止多不饱和脂肪酸(PUFA)氧化的扩散。这是维生素E在动物组织中、特别是在细胞膜中的基本功能,其中生育酚与磷脂中的PUFA有关。
CN 107 789 429 A(SHANDONG YZANDER MEDICAL TECHNOLOGY CO)(XP002798468)描述了一种用于治疗血管性痴呆的含有皂苷的假马齿苋的提取物。
KR 2012 0051458 A(XP002798476)描述了一种通过将磷脂酰丝氨酸和虾青素与源自磷虾(Krill)的磷脂结合来制备用于预防血管性痴呆的组合物的方法。
CN 105 287 985 A(XP002798477)描述了一种用于治疗老年性痴呆的组合物,其中该组合物除其他活性成分外还包含维生素E。
JP 2000 229854 A (XP002798469)将茶氨酸描述为用于治疗和预防血管性痴呆的活性物质。
CN 102 389 437(XP002798470)描述了一种用于预防和治疗血管性痴呆的含有积雪草三萜类的组合物。
WO 03/003981 A2描述了通过包含假马齿苋、二十二碳六烯酸和维生素E等的组合物来增强精神功能。
CN 109 419 800 A(XP002798471)描述了一种用于治疗血管性痴呆的组合物,其包含DHA和维生素E以及其他活性成分。
WO 2013/066151 Al描述了一种用于治疗阿尔茨海默病痴呆的组合物,其包含二十二碳六烯酸和维生素E等。
Mingyuan T.等人“Curcumin Induces ABCA1 Expression and ApolipoproteinA-I-Mediated Cholesterol Transmembrane in the Chronic Cerebral HypoperfusionAging rats”The American Journal of Chinese Medicine”World Scientific US,第41卷,第1027-1042页-XP009519445描述了使用姜黄素作为一种新的、不同的脑血管疾病治疗方法,这是因为其调节大脑中的跨膜胆固醇转运的能力。
发明内容
申请人现在发现了一种活性成分的组合,其可以减少血管性认知障碍(VCI)的主要可改变风险因素,因此可以用作治疗血管性痴呆的佐剂。
因此,本发明的目的是上述组合,其由以下组成:假马齿苋的干提取物、虾青素、维生素E、L-茶氨酸和积雪草的干提取物以及任选地选自以下活性成分中的至少一种:棕榈酰乙醇酰胺(PEA)、五加属(eleutherococcus)、可可(Theobroma cacao),所述组合在预防血管性痴呆中用作佐剂,其中所述组合以口服制剂、优选片剂的形式给药,其作为唯一活性成分与合适的赋形剂和/或稀释剂结合被包含,并且在所述口服制剂中:
·假马齿苋的含量为70-200mg、更优选100mg,其中假马齿苋皂苷的最低滴度为10%、优选20%;
·虾青素在所述组合中的最低含量为1mg、优选2mg;
·维生素E,优选维生素醋酸酯,在所述组合中的最大含量为60mg、优选30mg;
·L-茶氨酸在所述组合中的含量范围为150-300mg、更优选200mg;
·积雪草的存在量为75-250mg、更优选150mg,其中总萜烯(作为积雪草皂苷)的最低滴度为10%。
附图说明
图1显示了在时间T0,即研究开始时和3个月后的时间T1,对总共35名轻度VCI患者进行的MoCa测试(蒙特利尔认知评估测试)的结果,其中:20名代表对照组,而其余15名代表治疗组,将补充剂每天一次以片剂形式给予治疗组,所述补充剂的组成在实施例1中给出。
图2显示了14名每天一次服用片剂形式的补充剂的患者在研究开始时的时间T0和3个月后的时间T1的老年抑郁量表(GDS)测试的结果,所述补充剂的组成在实施例中示出。
图3显示了在研究开始时的时间T0和3个月后的时间T1对9名每天一次服用片剂形式的补充剂的患者进行的连线(Trail Making)A(TMTA)测试的结果,所述补充剂的组成在实施例中示出。
具体实施方式
为了本发明的目的,定义“包含”不排除在此定义之后,存在除了在此定义之后明确列出的那些之外的其它组分的可能性;相反,定义“由……组成”排除存在除了在此定义之后明确列出的那些之外的其它组分的可能性。
根据本发明使用目的的组合的一个优选方案,该组合由前述4种活性物质假马齿苋、虾青素、维生素E、L-茶氨酸和积雪草的干提取物组成。
根据另一特别优选的方案,除上述活性成分外,根据本发明使用的组合不仅由上述四种活性成分组成,还有任选地选自以下活性成分中的至少一种:棕榈酰乙醇酰胺(PEA)、五加属、可可。
根据本发明使用的该组合以口服制剂的形式给药,该组合作为唯一活性成分与合适的赋形剂和/或稀释剂结合被包含。
更优选地,所述口服制剂是食品补充剂。
还更优选地,所述口服制剂或食品补充剂是片剂形式。
根据本发明使用的口服制剂,优选片剂形式,含有作为唯一活性成分的上述组合,其中:
·假马齿苋的干提取物的含量为70-200mg、更优选100mg,其中假马齿苋皂苷的最低滴度为10%、优选20%;
·虾青素在所述组合中的最低含量为1mg、优选5mg;
·维生素E,优选维生素E醋酸酯,在所述组合中的最大含量为60mg、优选30mg;
·L-茶氨酸在所述组合中的含量范围为150-300mg、更优选200mg;
·积雪草的干提取物的存在量为75-250mg、更优选150mg,其中总萜烯(作为积雪草皂苷)的最低滴度为10%。
虾青素优选包含在雨生红球藻(Haematococcus pluvialis Flotow)藻类的干提取物中,其中最低虾青素滴度为2%、更优选5%。
优选地,含有根据本发明使用的组合作为唯一活性成分的片剂每天给药1或2次。
包含根据本发明使用的组合作为唯一活性成分的、片剂形式的食品补充剂的组合物,出于说明的目的下面在实施例1中显示,实施例2显示了证实片剂抗VCI并因而预防血管性痴呆的功效的临床研究,所述片剂的组成在实施例1中报道。
实施例1-包衣片剂形式的食品补充剂配方
实施例2-临床研究
本研究的目的是验证以每天一次的可吞服片剂的形式给药的本发明的补充剂对象,是否可以促进患有血管性认知障碍(VCI)的受试者的认知功能和记忆力,预防神经元损伤的恶化。
测试的患者数量和纳入/排除标准。
分析了来自35名患有VCI以及原始MoCA测试分数在15-24之间(受教育<13年+1分)的患者的数据(这些数据可以根据与血管疾病(小血管疾病、动脉性高血压、动脉粥样硬化、微中风或轻度中风等)和/或代谢疾病的共病进行假设),并与看护人会谈以证明认知功能和记忆的变化。患者男女不限,且年龄均超过60岁。
35名患者中,15名属于服用本发明补充剂对象的组,20名患者属于未服用补充剂的对照组。
曾因中风和出血性中风住院治疗的患者,患有足以解释认知障碍的如多发性硬化症、帕金森综合症、脑炎和阿尔茨海默病等其他原发性神经系统疾病的患者,患有脑肿瘤和严重抑郁症等足够严重疾病的患者,积极诊断为药物或酒精滥用/依赖的患者,肾病患者,已经接受药物治疗以控制认知障碍和痴呆的患者,接受苯二氮卓类药物和神经松弛药物治疗的患者、已知或疑似对产品的至少一种成分不耐受的患者全部被排除在试验之外。
剂量:1片/天(饱腹时)。
连续3个月的观察数据
-T0→基线
-T1→观察三个月后
通过对治疗组与未治疗对照组的MOCA问卷的分析,评估本发明的补充剂对象的功效:
-蒙特利尔认知评估量表(MoCA):它是一种相当快速的工具,用于筛查通常以血管性为基础的轻度认知障碍。它允许验证不同的功能区域:注意力(attention)、专注度(concentration)、执行功能、记忆力、语言、视觉构建技能、抽象、计算、定向。评分范围:0-30分(0最坏情况,30无认知障碍(CI))
-GDS测试(老年抑郁量表):测定老年受试者抑郁情绪的问卷。它的分数范围从最低的“0”(不存在障碍)到最高的“30”(最严重的障碍)。因此,郁症的严重程度表示如下:0-10不存在,11-16轻度/中度抑郁,17以上重度抑郁。
-连线A(TMT-A)测试评估视觉运动类型任务中空间规划的能力。受试者必须用铅笔顺序连接数字1-25。任务必须尽快完成。检查者必须立即纠正错误。
结果
三个测试获得的结果分别如图1、2和3所示。
图1(MoCA测试)显示了在用本发明的补充剂对象治疗的组中,在早期的三个月内的分数从19上升到21。这些数据表明本发明的补充剂在一季度中的影响作用;相反,对照组有轻微恶化。
图2:对14名患者进行的GDS测试显示了,情绪障碍已从轻度/中度(12)变为不存在(10)。
图3:对9名患者进行的TMT-A测试显示了,T0时81秒的平均执行时间减少到大约70秒。再次,本发明的补充剂对象在一季度中起到积极作用。
结论
具体来说,它改善了对通过MoCA测试调查的全局记忆状态测试的响应(注意力、专注度、执行功能、记忆力、语言、视觉构建技能、抽象、计算、定向),它还改善了视觉运动类型任务(TMT-A)中空间规划的能力。受试者对心理/体液健康(GDS)有更高的感知。
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Claims (6)
1.一种组合,其由以下组成:假马齿苋的干提取物、虾青素、维生素E、L-茶氨酸和积雪草的干提取物以及任选地选自以下活性成分中的至少一种:棕榈酰乙醇酰胺(PEA)、五加属、可可,所述组合在预防血管性痴呆中用作佐剂,
其中:所述组合以口服制剂、优选片剂的形式给药,其作为唯一活性成分与合适的赋形剂和/或稀释剂结合被包含,并且在所述口服制剂中:
·假马齿苋的含量为70-200mg、更优选100mg,其中假马齿苋皂苷的最低滴度为10%、优选20%;
·虾青素在所述组合中的最低含量为1mg、优选2mg;
·维生素E,优选维生素醋酸酯,在所述组合中的最大含量为60mg、优选30mg;
·L-茶氨酸在所述组合中的含量范围为150-300mg、更优选200mg;
·积雪草的存在量为75-250mg、更优选150mg,其中总萜烯(作为积雪草皂苷)的最低滴度为10%。
2.一种组合,其由以下组成:假马齿苋、虾青素、维生素E、L-茶氨酸和积雪草以及任选地选自以下活性成分中的至少一种:棕榈酰乙醇酰胺(PEA)、五加属、可可,所述组合用于减少血管性认知障碍(VCI)的主要可改变风险因素,其中所述组合以口服制剂、优选片剂的形式给药,其作为唯一活性成分与合适的赋形剂和/或稀释剂结合被包含,并且在所述口服制剂中:
·假马齿苋的含量为70-200mg、更优选100mg,其中假马齿苋皂苷的最低滴度为10%、优选20%;
·虾青素在所述组合中的最低含量为1mg、优选2mg;
·维生素E,优选维生素醋酸酯,在所述组合中的最大含量为60mg、优选30mg;
·L-茶氨酸在所述组合中的含量范围为150-300mg、更优选200mg;
·积雪草的存在量为75-250mg、更优选150mg,其中总萜烯(作为积雪草皂苷)的最低滴度为10%。
3.根据权利要求2使用的组合,其中所述主要风险因素是:由于氧化应激引起的神经炎症、氧供应的改变和神经元营养改变、乙酰胆碱介导的神经传递的改变。
4.根据权利要求1-3中任一项使用的组合,其由:假马齿苋的干提取物、虾青素、维生素E、L-茶氨酸和积雪草的干提取物组成。
5.根据权利要求1-4中任一项使用的组合,其中所述口服制剂是食品补充剂。
6.根据权利要求1-5中任一项使用的口服组合,其中所述口服制剂、优选片剂每天给药一次或两次。
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