CN104039318A - 改善认知 - Google Patents
改善认知 Download PDFInfo
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- CN104039318A CN104039318A CN201280065552.XA CN201280065552A CN104039318A CN 104039318 A CN104039318 A CN 104039318A CN 201280065552 A CN201280065552 A CN 201280065552A CN 104039318 A CN104039318 A CN 104039318A
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Abstract
本发明涉及—种组合物,其在(前驱症状的)阿尔茨海默病患者,特别是未经药物治疗的(前驱症状的)阿尔茨海默病患者,更特别是简易精神状态检查得分为20-30的受试者中,用于治疗或预防认知功能障碍,和/或用于改善认知。
Description
技术领域
本发明涉及用于治疗或预防认知功能障碍,和/或用于改善认知的组合物,优选用于(前驱症状的)阿尔茨海默病患者,特别是未经药物治疗的(前驱症状的)阿尔茨海默病患者,更特别是简易精神状态检查得分为20-30的受试者。
背景技术
记忆缺陷是许多人的严重缺陷,尤其是患有阿尔茨海默病的人和/或老年人。这类缺陷常具有严重后果,例如生活质量下降、进行日常生活活动有困难、行为问题、有可能导致住院治疗或机构治疗。
已经有一些疗法被建议用于改善受试者中的记忆功能。然而,极少被证实有效。此外,也曾建议过给予某些营养成分。
WO2009/002166A1描述了一种组合物,其包含(a)尿苷或尿苷磷酸盐;和(b)DHA和/或EPA,用于改善MMSE为24-26的受试者的延迟回忆功能。
发明内容
本发明涉及一种组合物,其包含:
a.一种或多种ω3脂肪酸,其选自二十二碳六烯酸(DHA)、二十碳五烯酸(EPA)和二十二碳五烯酸(DPA);和
b.一种尿苷源,其选自尿苷、脱氧尿苷、尿苷磷酸盐、尿嘧啶、酰化尿苷和胞苷,
用于改善认知和/或用于治疗或预防受试者的受损的认知功能。
本发明还可被称为包含(a)和(b)的组合物用于制造用于改善认知和/或用于治疗或预防受试者的受损的认知功能的产品的用途,其中(a)为一种或多种ω3脂肪酸,其选自二十二碳六烯酸(DHA)、二十碳五烯酸(EPA)和二十二碳五烯酸(DPA);并且(b)为一种尿苷源,其选自尿苷、脱氧尿苷、尿苷磷酸盐、尿嘧啶、酰化尿苷和胞苷。
本发明还可被称作(a)和(b)用于制造用于改善认知和/或用于治疗或预防受试者的受损的认知功能的组合物的用途,其中(a)为一种或多种ω3脂肪酸,其选自二十二碳六烯酸(DHA)、二十碳五烯酸(EPA)和二十二碳五烯酸(DPA);并且(b)为一种尿苷源,其选自尿苷、脱氧尿苷、尿苷磷酸盐、尿嘧啶、酰化尿苷和胞苷。
优选地,所述组合物包含EPA和/或DHA,和一种选自尿苷、脱氧尿苷、尿苷磷酸盐、尿嘧啶、酰化尿苷和胞苷的尿苷源。
更优选地,所述组合物每日剂量或优选每100ml组合物包含至少500mg的DHA,优选至少600mg的DHA,和至少50mg的尿苷,优选至少100mg的尿苷。甚至更优选地,所述组合物每日剂量或优选每100ml组合物包含至少500mg的DHA,优选至少600mg的DHA,和至少50mg的UMP,优选至少100mg的UMP。
优选地,所述组合物还包含胆碱、或者其盐或酯。具体地,所述组合物每日剂量或优选每100ml组合物包含200-600mg胆碱,更优选300-400mg胆碱。
优选地,所述组合物还包含磷脂。
优选地,所述组合物还包含维生素E;特别是以α-生育酚的形式。
优选地,所述组合物还包含硒。
优选地,所述组合物还包含叶酸。
优选地,所述组合物还包含维生素B12。
优选地,所述组合物还包含维生素B6。
特别优选地,除了所述ω3脂肪酸和所述尿苷源之外,所述组合物还包含一种或多种选自磷脂、维生素E、维生素C、硒、维生素B12、维生素B6和叶酸的组分/成分。优选地,所述组合物每日剂量或优选每100ml组合物包含50-1000mg磷脂、0.5-3mg维生素B6、50-500μg叶酸和1-30μg维生素B12。
优选地,所述组合物每日剂量或优选每100ml组合物包含20-60mg维生素E(优选以α生育酚的形式),和60-100mg维生素C。
根据一个优选实施方案,所述组合物每日剂量或优选每100ml组合物包含:
100-500mg,优选200-400mg EPA,
1000-1500mg,优选1100-1300mg DHA,
50-600mg,优选60-200mg磷脂,
200-600mg,优选300-500mg胆碱,
400-800mg,优选500-700mg UMP(尿苷一磷酸),
20-60mg,优选30-50mg维生素E(α-TE),
60-100mg,优选70-90mg维生素C,
40-80μg,优选50-70μg硒,
1-5μg,优选2-4μg维生素B12,
0.5-3mg,优选0.5-2mg维生素B6,和
200-600μg,优选300-500μg叶酸。
优选地,所述组合物每日剂量或优选每100ml组合物具有50-130kcal的能量含量,1-10g的蛋白质含量,1-5g的脂质含量,和4-20g的消化性碳水化合物。
优选地,所述受试者具有一种或多种阿尔茨海默病、轻度认知缺陷、年龄相关的记忆缺陷、多发性硬化、血管性痴呆、额颞痴呆、语义性痴呆或路易体痴呆的症状。更优选地,所述受试者为(前驱症状的)痴呆和/或(前驱症状的)阿尔茨海默病患者。甚至更优选地,所述受试者为痴呆和/或阿尔茨海默病患者。并且甚至更优选地,所述受试者为阿尔茨海默病患者(即具有/患有阿尔茨海默病)。
优选地,所述受试者的简易精神状态检查(MMSE)得分为20-30,特别为20-26,更特别为24-26。
优选地,所述受试者为未经药物治疗的。
优选地,将所述组合物肠内给予所述患者每天至少1次,持续至少12周,优选至少13周,更优选至少14、15、16、17、18、19、20、21、22、23或24周。
本发明还涉及用于改善认知或用于治疗或预防受试者的受损的认知功能的方法,所述方法包括给予所述受试者包含以下组分的组合物:
a.一种或多种ω3脂肪酸,其选自二十二碳六烯酸(DHA)、二十碳五烯酸(EPA)和二十二碳五烯酸(DPA);和
b.一种尿苷源,其选自尿苷、脱氧尿苷、尿苷磷酸盐、尿嘧啶、酰化尿苷和胞苷。
优选地,所述受试者为未经药物治疗的。
优选地,在本发明的方法中,所述受试者的简易精神状态检查(MMSE)得分为20以上,特别为20-26,更特别为24-26。
特别地,所述受试者患有或具有一种或多种阿尔茨海默病、轻度认知缺损、年龄相关的记忆缺陷、多发性硬化、血管性痴呆、额颞痴呆、语义性痴呆或路易体痴呆的症状。
优选地,本发明的方法为在治疗上治疗或预防受试者的认知功能障碍的方法,所述受试者特别是患有阿尔茨海默病、轻度认知缺损、年龄相关的记忆缺陷、多发性硬化、血管性痴呆、额颞痴呆、语义性痴呆或路易体痴呆的受试者,所述方法包括:
-给予一种组合物,所述组合物包含(a)一种或多种ω3脂肪酸,其选自二十二碳六烯酸(DHA)、二十碳五烯酸(EPA)和二十二碳五烯酸(DPA);和(b)一种尿苷源,其选自尿苷、脱氧尿苷、尿苷磷酸盐、尿嘧啶和酰化尿苷,和
-包括对所述受试者进行监测或评估,通过以下神经学测试中的一种或多种测试进行:
-RAVLT-认知,
-RBANS-认知,和
-CVLT-认知。
本发明人通过临床研究惊奇地发现,给予含有(a)二十二碳六烯酸(DHA)和/或二十碳五烯酸(EPA)和/或二十二碳五烯酸(DPA);和(b)尿苷和/或尿苷磷酸盐的组合物,显示出对MMSE为20以上(即20-30)的阿尔茨海默病患者的认知功能有显著的改善。顺应性和耐受性非常高,并且副作用相对较低。特别惊人的是,本发明的临床数据显示出对认知记忆功能的实质性改善,而不仅仅是使认知记忆功能下降的速度降低。临床研究的结果在实施例部分中概述。
附图说明
图1表示本发明组合物对记忆的效应。“原始平均值:对照”24周后记忆区域z-得分从基线的变化为0.09,与此相比,“原始平均值:活性”示出了24周后记忆区域z-得分从基线的变化为0.18,证明对记忆具有改善效应(p=0.032)。
图2表示本发明组合物对认知的效应。“原始平均值从基线的变化:对照”24周后负变化约为-0.2,与此相比,“原始平均值从基线的变化:活性”示出了24周后RAVLT-认知的变化约为0.9,证明对认知具有非常显著的改善效应(p=0.010)。
具体实施方式
本发明涉及一种组合物,其包含:
a.二十二碳六烯酸(DHA)和/或二十碳五烯酸(EPA)和/或二十二碳五烯酸(DPA);和
b.一种尿苷源,其选自尿苷、脱氧尿苷、尿苷磷酸盐、尿嘧啶、酰化尿苷和胞苷,
用于改善认知和/或用于治疗或预防受试者的受损的认知功能。
受试者
优选地,在本发明中,所述受试者为未经药物治疗的受试者。具体地,所述受试者在被给予本发明组合物之前,尚未被给予任何用于记忆改善和/或用于阿尔茨海默病的药物。
优选地,本发明中使用的术语“未经药物治疗的”是指受试者未摄取胆碱酯酶抑制剂、N-甲基-D-天冬氨酸(NMDA)拮抗物和银杏中的一种或多种。
作为一个优选实施方案,例如在本文中所述的临床研究中,发现本发明组合物在未经药物治疗的受试者中非常有效,所述受试者未使用:含有ω-3脂肪酸的添加物;每周多于两次的鱼油;多于200%RDI(参考日摄入量)的维生素B、C和/或E;高能量和高蛋白质的营养补充物/医疗食品;其他研究用产品;多奈哌齐(donepezil);卡巴拉汀(rivastigmine);加兰他敏(galantamine);和/或美金刚(memantine)。
所述受试者优选为人,优选为老年人,优选年龄至少为50岁。
优选地,在本发明中,所述受试者的简易精神状态检查(MMSE)的得分为20-30,更优选20-26,甚至更优选24、25或26。
简易精神状态检查(MMSE)是用于评估认知的简单的30-分问卷测试。在约10分钟的时间段内,对包括记忆和定向的多种功能进行取样。MMSE测试包括很多领域内的简单的问题(questions andproblems):测试的时间和地点,重复词语列表、语言使用和理解,以及基本的运动技能。
虽然27以上(非30)的得分通常被解释为实际上正常,但不允许得出这样的结论:所述受试者不患有阿尔茨海默病、轻度认知缺损、年龄相关的记忆缺陷、多发性硬化、血管性痴呆、额颞痴呆、语义性痴呆或路易体痴呆(或具有上述疾病的一种或多种症状)。
20-26的得分表示轻度/早期痴呆;10-19表示中度痴呆,以及低于10表示重度痴呆。
MMSE为标准化的测试。由于版权的原因,发明人不能将问卷的副本包括在申请中,但是其可轻易地在互联网上获得,以及通过版权所有人Psychological Assessment Resources(PAR)获得。其由Folstein etal.(Psych Res12:189,1975)首次提出,并经过小的修改而广泛用来评估认知。
优选地,在本发明中接受治疗的受试者的简易精神状态检查得分为20-30,优选20-26,甚至更优选24、25或26。
优选地,所述受试者具有20-30,优选20-26,甚至更优选24、25或26的MMSE得分,并且未曾接受/摄取用于记忆缺陷和/或用于阿尔茨海默病的药物,甚至更优选为未经药物治疗的受试者。对于该亚组的治疗特别令人感兴趣,因为在这些受试者中,药物干预的副作用和益处之间的平衡仍是负的。由于相对缺少消极的副作用,需要向这些受试者提供营养治疗。对于这些未经药物治疗的受试者,特别重要的是开发一种能够延迟必须给予具有消极的副作用的药物的时间点的疗法。
或者,所述受试者具有20-30,优选20-26,甚至更优选24、25或26的MMSE得分,并且具有(或患有)阿尔茨海默病、轻度认知缺损(MCI)、年龄相关的记忆缺陷(AAMI)、多发性硬化、血管性痴呆、额颞痴呆、语义性痴呆或路易体痴呆,更优选具有(或患有)阿尔茨海默病。
在患有轻度/早期形式的阿尔茨海默病的患者中尤其需要通过营养治疗来改善认知。如果观察到明显的改善,那么可以减少甚至延迟使用具有消极的副作用的药物进行的药物干预。
更优选地,所述受试者具有20-30,优选20-26,甚至更优选24、25或26的MMSE得分,未经药物治疗,并且具有(或患有)阿尔茨海默病、轻度认知缺损(MCI)、年龄相关的记忆缺陷(AAMI)、多发性硬化、血管性痴呆、额颞痴呆、语义性痴呆或路易体痴呆,更特别地具有(或患有)阿尔茨海默病。
甚至更优选地,在本发明中接受治疗的受试者具有20-26的MMSE得分,未经药物治疗,并且患有阿尔茨海默病。
前驱症状的痴呆和/或阿尔茨海默病患者被定义为在以下标准中的至少一个、优选至少两个、更优选至少三个标准的评分为正的人:
-每升脑脊液(CSF)中总tau(Total-tau)蛋白的水平高于350ng;
-CSF中Aβ-42/磷酸-tau-181的重量比小于6.5;
-内侧颞叶(MTL)萎缩的存在,海马体、内嗅皮质或扁桃体的体积损失的存在,其用磁共振成像(MRI)通过视觉评分的定性分级(参照用年龄标准良好表征的人群)或感兴趣的区域的定量体积分析(参照用年龄标准良好表征的人群)显示;
-额颞叶(FTL)萎缩的存在,其用MRI通过定性分级或定量体积分析显示;
-每mL CSF中F2-异前列烷(F2-1soP,异前列烷8,12-异-iPF2α-VI)的水平高于25pg。
关于CSF中T-tau、P-tau181、Aβ42和F2-异前列烷的浓度对于阿尔茨海默病的未来发病的意义,更多的解释可见于:Hansson O,Zetterberg H,Buchhave P,Londos E,Blennow K,Minthon L(2006)Association Between CSF biomarkers and incipient Alzheimer’s diseasein patients with mild cognitive impairment:a follow-up study.LancetNeurol5:228-234中;以及Pratico D,Clark CM,Liun F,Lee VYM,Troj anowski JQ(2002)Increase in brain oxidative stress in mildcognitive impairment:a possible predictor of Alzheimer disease.ArchNeurol59:972-976中。
在一个优选实施方案中,前驱症状的痴呆和/或阿尔茨海默病患者的鉴定至少包括前两个标准(总tau和Aβ-42/P-tau-181比值)。更优选地,还应用另外三个标准(MTL萎缩、FTL萎缩、F2-IsoP)之一。
除了上述标准中一个或多个以外,或者代替上述标准中一个或多个,可有利地使用以下标准:
-脑中两侧颞部顶骨区域中葡萄糖代谢的降低,这可通过正电子发射断层成像术(PET)检测到;
-后扣带回皮质(posterior cingulate cortex)中葡萄糖代谢的降低,这可通过PET检测到;
-脑中血流量受损,这可通过应用单光子发射计算机断层摄影术(SPECT),例如通过应用放射性同位素99m Tc-HMPAO来测量;
-脑中葡萄糖代谢受损,这可通过应用SPECT测量;
-内侧颞叶或下颞叶的组织学异常(其可通过MRI确定)或葡萄糖利用率异常;
-颞顶叶皮层或后扣带回皮质中组织学异常或葡萄糖利用率异常。
脑或其部分的情况异常可以通过以健康情形下的人自身条件为参照而确定,或者当这不可获得时,通过以代表组的平均条件(例如年龄匹配)为参照来确定。后者的使用最为频繁。通过将患者的条件与参照情形和平均情形比较,当病理状态已发展至最大程度时,临床医生能辨认出前驱症状阶段。特别是患者表现出与健康个体的数值向病理状态的方向偏差x%的中间情形时,用于本发明的目的,被认为是前驱症状患者。当在进食和运动方面的标准化条件下进行测定时,对于血流和葡萄糖代谢的测定,x的值为20%。
认知
特别地发现在阿尔茨海默病患者,特别是未经药物治疗的阿尔茨海默病患者中,所述认知功能有所改善。
本发明涉及用于(i)改善认知和/或(ii)治疗和/或预防受损的认知功能的组合物。
或者,本发明提供用于在有所需要的受试者中(i)改善认知和/或(ii)治疗和/或预防受损的认知功能的方法,所述方法包括将本发明组合物给予所述受试者。特别地,本发明涉及治疗或预防受损的认知功能。
已经发现,当将本发明组合物给予所述受试者时,认知功能确实有所改善。
人类受试者的认知功能可通过使用以下测试的一种或多种来适当地测定:RAVLT-认知、“可重复的成套神经心理状态测量(RepeatableBattery for the Assessment of Neuropsychological Status)”或“加利福尼亚言语学习测试(California Verbal Learning Test)”。
优选地,在本发明的上下文中,术语“认知”和术语“认知记忆”是同义词,是指记忆的子范畴。优选地,两个术语都是指辨认之前遇到的事件、物体或人的能力;和当重新经历之前经历过的事件、人或物品时,该环境内容与储存的记忆表现(memory representation)相匹配,从而引起匹配信号。认知被认为包括回忆(recellection)(也被称为记起(remembering),被视为缓慢的受控制的搜索过程)和熟悉(也被称为认识(knowing),被看作快速的自动过程)。
认知(记忆)并不限制在视觉领域,可包括五种传统感觉形态(即视觉、听觉、触觉、嗅觉和味觉)中的每一个。虽然大多数神经科学研究集中于视觉认知,但是也有与听觉(聆听)、嗅觉(闻)、味觉(尝)和触觉(摸)相关的研究(本领域已知)。
优选地,本发明组合物用于改善听觉(或聆听(hearing),或言语)认知和/或视觉认知,更优选地用于改善言语认知和视觉认知二者。
在这些被给予本发明组合物的受试者中,所述(即时和/或延迟)回忆功能也有所改善。
即时回忆功能可例如使用WMS-VPA即时测试来测量。
延缓回忆功能可通过在方案中延迟设定之后的散文回忆任务(proserecall task)来测量。
因此,本发明组合物还可有利地帮助受试者改善所述回忆功能。因此,在一个优选实施方案中,本发明提供了用于改善回忆和认知功能,和/或治疗和/或预防受损的回忆功能和受损的认知功能的组合物或方法。
测试
所述神经心理学测试是特别设计的任务,用于例如实施例部分中所述的临床试验中,以测量与具体的脑结构或通路相联系的已知的心理功能。测试用于研究脑功能,以及在临床环境中用于诊断缺陷。其经常包括在正式的环境中系统性给予具有明确定义的流程,并且其与个人的、人与人之间的和语境的因素一起形成进行神经心理学评估的方法的核心组成(来源:http://en.wikipedia.org/wiki/Neuropsychological_test)。
用于回忆和认知的莱氏听觉言语学习测试(RAVLT)
莱氏听觉言语学习测试是对即时的和延迟的情景言语学习和记忆的测量方法。所述测试为‘情景’,是因为词语列表的阅读在受试者的记忆中表现为情景。
RAVLT在评价言语学习和记忆方面——包括前摄抑制、倒摄抑制、记忆、编码与检索和主观组织——很有用。因为该测试简短、直接、易于理解,并且适用于年龄为7-89岁的儿童、青少年和成年人,因此其得到了广泛接纳(来源:http://www.annarbor.co.uk/index.php?main_page=index&cPath=249_303)。
例如,在即时回忆部分(RAVLT-即时)中,向受试者读出词语,然后在测试给予者读完列表之后,受试者需要尽其所能回忆这些词语。将该第一个词语列表(列表A)——具有例如15个词语——读若干次例如总共3、4或5次,并记录每个试验的词语回忆情况。通过观察重复听到词语列表后回忆是否有所进步,可以测定学习速度。
列表A的试验之后,向受试者读出第二个列表(列表B)——其具有例如15个词语。记录对列表B的回忆,然后受试者再次被要求回忆列表A的词语。设计给予列表B以干扰对列表A的回忆以使回忆更加困难。
对于延迟回忆部分(RAVLT-延迟),在测试的这个最后阶段之后延迟间隔例如10-30分钟,受试者被要求回忆列表A的词语。
在测试的最后阶段,与认知部分(RAVLT-认知)相当,受试者被要求从书面词语列表中分辨列表A的词语。该列表由掺杂着新的‘错误选择’词语的最初列表A词语组成,例如列表A的15个词语掺杂着15个新的‘错误选择’词语。认知记忆任务的表现一般超过词语回忆,因此是对记忆可能受损的个体的研究的有用补充。
来自韦克斯勒记忆量表-修订(WMS-R)的口头配对相关(VPA)测试
配对相关学习测试需要受试者在记忆中联系两个项目。一些具有该范例特征的任务需要受试者联系颜色和形状,或者联系物体和空间位置。
VPA要求受试者在记忆中联系两个词语。大声读出若干个词语配对(例如8对词语),一些(例如4个)语义上相关的‘容易的’配对,例如‘婴儿-哭’或‘金属-铁’和一些(例如4个)需要在语义上不相关的词语配对之间建立联系的‘困难的’配对,例如‘压碎-黑暗’。词语配对以听觉呈现,然后通过让测试给予者说出每个配对的第一个词语作为线索,来测试即时回忆。受试者必须回应线索而说出配对的词语。所有受试者进行若干次全部配对的测试(例如3次测试),每次正确回答就得到1分(WMS-VPA即时)。
该测试包括延迟回忆情况,例如即时回忆测试后的1-30分钟(WMS-VPA延迟),并试图鼓励高水平的延迟回忆,未得到即时回忆的最高得分(例如在3次试验中8分)的研究参与者随后进行另一次试验(例如第4次、第5次和如果需要的话第6次试验)。如果在例如3次试验或任何连续试验中达到完美表现,就终止即时回忆部分。如果未达到,就给予另一次试验(例如最多6次试验)。在延迟回忆下,呈现所有线索词语(例如8个)并要求受试者提供正确的配对词语。即时回忆产生的得分包括0至配对数×试验次数(例如0至8对×3次试验=24),并且延迟回忆产生的得分包括0至配对数(例如0-8个)。在两种情况下得分越高表明表现越好。
可重复的成套神经心理状态测量(RBANS),如例如Randolf1998年所著的RBANS手册中所述,可用于对认知表现进行评分(RBANS-认知),从而评估或监测认知功能。
加利福尼亚言语学习测试(CVLT),参见例如Delis,D.C.,Kramer,J.H.,Kaplan,E.,&Ober,B.A.(2000),可用于对认知表现(CVLT-认知)进行评分,从而评估或监测认知功能。
如本领域所熟知,所有这些不同测试都可被修改。
尿苷
优选地,本发明的待给予的组合物包含选自尿苷、脱氧尿苷、尿苷磷酸盐、尿嘧啶、酰化尿苷和胞苷的尿苷来源。
在人体内被转化成尿苷的膳食胞苷可被认为是本发明的上下文中的尿苷来源。因此,本发明的待给予的组合物可包含胞苷、脱氧胞苷、胞苷磷酸盐、胞嘧啶和/或酰化胞苷作为尿苷来源。
优选地,本发明组合物包含尿苷和/或尿苷磷酸盐,更优选包含尿苷磷酸盐。
特别地,本发明组合物包含一种或多种选自尿苷一磷酸(UMP)、尿苷二磷酸(UDP)和尿苷三磷酸(UTP)的尿苷磷酸盐,更优选UMP。
最优选地,本发明组合物包含UMP。优选本发明组合物中的尿苷的至少50重量%由UMP提供,更优选至少75重量%,最优选至少95重量%。本发明方法优选包括以0.08-3g/天,优选0.1-2g/天,更优选0.2-1g/天的量(尿苷、脱氧尿苷、尿苷磷酸盐、尿嘧啶和酰化尿苷衍生物的累积量)给予尿苷。本发明方法优选包括以0.08-3g UMP/100ml液体产品,优选0.1-2g UMP/100ml液体产品,更优选0.2-1g/100ml液体产品的量给予包含尿苷的组合物。优选每天给予1-37.5mg UMP/千克体重。基于重量的等效物的所需剂量可由UMP的剂量通过等摩尔量使用等效物和UMP的分子量计算出来,UMP的分子量为324道尔顿。
二十二碳六烯酸、二十碳五烯酸和/或二十二碳五烯酸
本发明组合物优选至少包含二十二碳六烯酸(22:6ω-3;DHA)和/或二十碳五烯酸(20:5ω-3;EPA)和/或二十二碳五烯酸(22:5ω-3;DPA),优选DHA和/或EPA,更优选DHA和EPA。
DHA、EPA和/或DPA优选以甘油三酯、甘油二酯、甘油一酯、游离脂肪酸或它们的盐或酯、磷脂、溶血磷脂、甘油醚、脂蛋白、神经酰胺、糖脂或其结合物的形式提供。更优选地,本发明组合物至少包含甘油三酯的形式的DHA。
优选地,本发明组合物包含的DHA和EPA的量足以给予400-5000mg(DHA+EPA)/天,优选500-3000mg/天,最优选1000-2500mg/天。所述组合物中存在的总脂肪酸中(DHA+EPA)的比例优选为5-50重量%,更优选10-45重量%,最优选15-40重量%。
更优选地,本发明组合物包含的DHA的量足以以300-4000mg/天,更优选500-2500mg/天的量给予DHA。
本发明组合物优选含有非常低量的花生四烯酸(AA)。优选本发明组合物中DHA/AA的重量比至少为5,优选至少10,更优选至少15,优选最高达例如30或甚至最高达60。
本发明方法优选包括给予一种组合物,所述组合物包含基于总脂肪酸计少于5重量%的花生四烯酸,更优选低于2.5重量%,例如低达0.5重量%。
本发明产品中ω-6/ω-3脂肪酸的比率优选为低于0.5,更优选低于0.2,例如低达0.05或0.01。本发明产品中ω-6/ω-3脂肪酸(C20以上)的比率优选为低于0.3,更优选低于0.15,例如低达0.06或0.03。
本文所述的每天的量意指本发明的组合物提供的日剂量单位中的量。所述日剂量单位可为单一剂量,但其也可分成2或3个,或甚至更多个每日份。如果优选实施方案的组合物意欲作为单一单位给予,则本文所述的每天的量优选为组合物单位(优选包装的)中存在的量。
治疗优选地包括每天给予1次、2次或3次,更优选每天1次,持续至少3周,优选持续至少12周,更优选持续至少13周,更优选持续至少14、15、16、17、18、19、20、21、22或23周,甚至更优选持续至少24周。
本发明组合物优选包含基于总脂肪酸计1-40重量%的DHA,优选基于总脂肪酸计3-36重量%的DHA,更优选基于总脂肪酸计10-30重量%的DHA。本发明组合物优选包含基于总脂肪酸计0.5-20重量%的EPA,优选基于总脂肪酸计2-10重量%的EPA,更优选基于总脂肪酸计5-10重量%的EPA。上述量考虑并优化了几个方面,包括味道(例如过高的LCP水平降低味觉,从而导致顺应性降低)。
本发明组合物优选含有至少一种选自鱼油、藻油和卵脂质的油。优选地,本发明组合物含有包含DHA和EPA的鱼油。
饱和的和单不饱和的脂肪酸
本发明组合物优选包含饱和的和/或单不饱和的脂肪酸。饱和脂肪酸的量优选为基于总脂肪酸计6-60重量%,优选12-40重量%,更优选基于总脂肪酸计20-40重量%。特别地,C14:0(肉豆蔻酸)+C16:0(棕榈酸)的量基于总脂肪酸计优选为5-50重量%,优选8-36重量%,更优选15-30重量%。单不饱和脂肪酸——例如油酸和棕榈油酸——的总量优选为5-40重量%,更优选15-30重量%。发现具有这些优选的量的组合物非常有效。
磷脂
优选地,本发明组合物优选包含磷脂,优选基于脂质的总重量计0.1-50重量%的磷脂,更优选0.5-20重量%,更优选1-10重量%,最优选基于脂质的总重量计1-5重量%。脂质的总量优选为干物质的10-30重量%,和/或2-10g脂质/100ml液体组合物。所述组合物优选包含0.01-1克卵磷脂/100ml,更优选0.05-0.5克卵磷脂/100ml。发现具有这些优选的量的组合物非常有效。
胆碱
优选地,本发明组合物含有胆碱和/或磷脂酰胆碱。本发明方法优选包括给予多于50mg胆碱/天,优选80-2000mg胆碱/天,更优选120-1000mg胆碱/天,最优选150-600mg胆碱/天。本发明组合物优选包含50mg-3g胆碱/100ml液体配方物,优选200mg-1000mg胆碱/100ml。
维生素
所述组合物可有利地含有维生素,优选维生素C、维生素E和B族维生素,更优选维生素C、维生素E、维生素B6、维生素B12和叶酸。有利地,包含维生素B12和叶酸。本发明组合物优选每100ml液体产品包含50-1000μg叶酸,更优选150-750μg,最优选200-500μg叶酸。本发明方法优选包括给予50-1000μg叶酸/天,更优选150-750μg,最优选200-500μg叶酸/天。本发明组合物优选每100ml液体产品包含0.5-15μg维生素B12,更优选1-10μg,最优选1.5-5μg维生素B12。本发明方法优选包括给予0.5-15μg维生素B12/天,更优选1-10μg,最优选1.5-5μg维生素B12/天。
有利地,本发明组合物每100ml液体产品包含0.5-3mg,优选0.5-2mg维生素B6。
优选地,包含维生素B6、维生素B12和叶酸。
产品
优选地,本发明组合物包含:
-一种或多种ω3脂肪酸,其选自二十二碳六烯酸(DHA)、二十碳五烯酸(EPA)和二十二碳五烯酸(DPA);和
-一种尿苷源,其选自尿苷、脱氧尿苷、尿苷磷酸盐、尿嘧啶、酰化尿苷和胞苷。
优选地,所述组合物还包含胆碱。
优选地,所述组合物还包含磷脂、维生素E、维生素C、硒、维生素B12、维生素B6和叶酸中的一种或多种。
更优选地,所述组合物包含DHA、EPA、尿苷源(优选UMP)、磷脂、胆碱、维生素E、维生素C、硒、维生素B12、维生素B6和叶酸。
本发明的优选组合物每日剂量或每100ml组合物包含:
-100-500mg,优选200-400mg EPA,
-900-1500mg,优选950-1300mg DHA,
-50-600mg,优选60-200mg磷脂,
-200-600mg,优选300-500mg胆碱,
-400-800mg,优选500-700mg UMP(尿苷一磷酸),
-20-60mg,优选30-50mg维生素E(α-TE),
-60-100mg,优选60-90mg维生素C,
-40-80μg,优选45-65μg硒,
-1-5μg,优选2-4μg维生素B12,
-0.5-3mg,优选0.5-2mg维生素B6,和
-200-600μg,优选300-500μg叶酸。
更优选地,本发明组合物每100ml组合物包含:
-100-500mg,优选200-400mg EPA,
-900-1500mg,优选950-1300mg DHA,
-50-600mg,优选60-200mg磷脂,
-200-600mg,优选300-500mg胆碱,
-400-800mg,优选500-700mg UMP(尿苷一磷酸),
-20-60mg,优选30-50mg维生素E(α-TE),
-60-100mg,优选60-90mg维生素C,
-40-80μg,优选45-65μg硒,
-1-5μg,优选2-4μg维生素B12,
-0.5-3mg,优选0.5-2mg维生素B6,和
-200-600μg,优选300-500μg叶酸。
本发明组合物可为即用液体、固体或半液体产品。优选地,所述组合物为液体,更优选为即用液体。
本发明组合物优选肠内给药,更优选口服。最优选地,本发明组合物通过吸管施用。当其为即用液体时,每日液体量优选为75-200ml/天或75-200ml/单位,最优选90-150ml/天。
可受益于本发明方法和组合物的受试者常常遇到进食的问题。他们的感觉能力和/或肌肉控制力可能受损,而且在某些情况下他们运用适当进食习惯的能力也会受损。吞咽和/或咀嚼可成为问题。因此,本发明组合物优选以能被通过吸管摄取的饮剂形式提供。
本发明组合物优选具有低粘度,优选20℃时100每秒的剪切速率下测量的粘度为1-2000mPa.s,更优选20℃时100每秒的剪切速率下测量的粘度为1-100mPa.s。更优选地,本发明组合物以能被通过吸管摄取的饮剂形式提供,这使得所述产品甚至更易于摄取并改善了顺应性。在一个优选实施方案中,本发明组合物在20℃时100每秒的剪切速率下具有的粘度为1-80mPas,更优选在20℃时100每秒的剪切速率下为1-40mPas。这些粘度测量可例如使用板锥式几何体(plate and conegeometry)进行。
为了被受试者最佳接受,本发明组合物优选具有300-800mOsm/kg的重量克分子渗透压浓度(osmolality)。然而,产品的能量密度优选不要高到其干扰正常进食习惯。当为液体形式时,本发明产品优选含有0.2-3kcal/ml,更优选0.5-2、0.7-1.5kcal/ml。
有利地,本发明组合物含有消化性碳水化合物。本发明组合物优选含有1-50克消化性碳水化合物/100ml的液体产品,更优选5-30克/100ml。更优选10-30克碳水化合物/100ml。消化性碳水化合物的总量优选为以干物质计25-80重量%,优选以干物质计40-80重量%。
本发明组合物还可包含蛋白质,优选0.5-10克蛋白质/100ml,更优选1-6克蛋白质/100ml,最优选2-6克蛋白质/100ml。优选地,本发明组合物含有以总蛋白质计至少80重量%来自乳的蛋白质(例如乳清和/或酪蛋白)。蛋白质使得能够制造可口的产品——特别是对于虚弱老年人来说。
实施例
实施例1:
包装的组合物每125ml包含:
能量125kcal;蛋白质3.9g;碳水化合物16.5g;脂肪4.9g。
脂肪包括1.5g的DHA+EPA,和106mg磷脂(大豆卵磷脂);胆碱400mg;UMP(尿苷一磷酸)625mg;维生素E40mgα-TE;维生素C80mg;硒60μg;维生素B123μg;维生素B61mg;叶酸400μg。
矿物质和微量元素:钠125mg;钾187.5mg;氯离子156.3mg;钙100mg;磷87.5mg;镁25mg;铁2mg;锌1.5mg;铜225μg;锰0.41mg;钼12.5μg;铬8.4μg;碘16.3μg。维生素:维生素A200μg-RE;维生素D30.9Pg;维生素K6.6Pg;硫胺(B1)0.19mg;核黄素(B2)0.2mg;烟酸(B3)2.25mg-NE;泛酸(B5)0.66mg;生物素5μg。
实施例2
临床研究
在患有轻度AD(MMSE20-26)的未经药物治疗的患者中进行的概念验证研究(proof-of-concept study)表明,本发明组合物(特别是实施例1中描述的组合物)每天摄入一次是安全的,并且在12周——所述研究的共同主要终末点(co-primary endpoint)——后改善了受试者的延迟回忆功能(见Scheltens et al.,“Efficacy of a medical food in mildAlzheimer′sd isease:A randomized controlled trial”Alzheimer‘s&Dementia6(2010),1-10.)。
设计本发明研究以确定在患有轻度AD的未经药物治疗的患者中所述组合物对记忆的效应,以及通过24周的更长干预期和通过利用神经心理成套测验(NTB)的全部记忆区域z-得分来扩展调查研究。
设计本发明研究以调查在患有轻度AD的未经药物治疗的患者中在24周的干预过程中所述组合物对记忆表现的效应。第二个目的是调查所述干预的安全性和耐受性,以及评估对整体认知、功能能力和脑电图(EEG)的效应。
材料和方法
本发明研究为随机对照双盲研究,在6个欧洲国家(荷兰、德国、法国、比利时、意大利和西班牙)的27个研究中心进行。对患有轻度AD(MMSE得分≥20)并根据NINCDS-ADRDA标准诊断为可能患有AD的未经药物治疗的患者随机分配(1∶1)实施例1的组合物或等热量的对照产品。干预的持续时间为24周。
与实施例1的组合物相比,对照产品缺少以下组分:EPA、DHA、磷脂、胆碱、UMP、维生素E(α-TE)、维生素C、硒、维生素B12、维生素B6和叶酸。
神经生理成套测验(NTB)的记忆区域得分为主要结果参数。该记忆复合得分来自莱氏听觉言语学习测试(RAVLT:即时回忆、延时回忆和认知表现)和韦克斯勒记忆量表(WMS)口头配对相关测试(即时和延迟回忆)。
从HTB产生的第二个结果为执行功能区域、总复合得分和单个项目得分。其他NTB项目为WMS数字广度、连线测试A和B部分、分类流畅性、受控字词联想测试、阿尔茨海默病评估量表认知部分(ADAS-cog)定向任务和字母数字替代测试。主要研究参数在基线、第12周和第24周评估。对于数据的统计学分析,使用重复测量混合模型。试验在ICMJE允许的www.trialregister.nl进行了登记(NTR1975)。
结果
随机分配总共259个未经药物治疗的受试者(2.6%筛选失败)。在全部研究人群中注意到研究组之间在基线特征方面没有差别。平均年龄为73.8(±7.7)岁,平均筛选MMSE为25.0(±2.8)并且51%为男性。进行预先指定的盲间断分析以检查计算的样本大小是否足够和是否已出现安全问题,以及进行独立的数据监测委员会推荐的不经修改的连续试验。所述259个随机分配的受试者中,238个受试者(91.9%)完成了研究。5个受试者由于(严重的)不良事件((S)AE)而未完成研究;所述组中的3个已经接受了所述组合物,对照组中的2个已经接受了所述组合物,并且注意到研究组之间在(S)AE的发生方面没有差别。注意到血液安全参数方面没有临床相关的差别。在24周期间平均顺应性非常高——97%,并且各组之间没有差别。高顺应性通过顺应性的(营养的)生物标记物——例如红细胞膜中的二十二碳六烯酸和血浆同型半胱氨酸——的显著和明显的变化来确定。
在24周的时间内,本发明组合物与对照产品相比显著改善了主要终末点记忆表现(由NTB得到的复合记忆区域z-得分)(重复测量混合模型,p=0.025)。对记忆表现产生的显著效应通过NTB记忆区域的单个任务确定。
在NTB记忆区域中,得到的认知结果(RAVLT-认知得分)特别显著(见图2)。在24周期间,本发明组合物与对照产品相比显著改善了认知表现(重复测量混合模型,p=0.010)。
Claims (15)
1.一种组合物,其包含:
a.一种或多种ω3脂肪酸,其选自二十二碳六烯酸(DHA)、二十碳五烯酸(EPA)和二十二碳五烯酸(DPA);和
b.一种尿苷源,其选自尿苷、脱氧尿苷、尿苷磷酸盐、尿嘧啶、酰化尿苷和胞苷;
其用于改善认知和/或用于治疗或预防受试者的受损的认知功能。
2.权利要求1的组合物,其中所述受试者具有一种或多种阿尔茨海默病、轻度认知缺损、年龄相关的记忆缺陷、多发性硬化、血管性痴呆、额颞痴呆、语义性痴呆或路易体痴呆的症状。
3.权利要求1或2的组合物,其中所述受试者为前驱症状的痴呆和/或前驱症状的阿尔茨海默病患者。
4.前述权利要求任一项的组合物,其中所述组合物每日剂量或优选每100ml组合物包含至少500mg的DHA,优选至少600mg的DHA,和至少50mg的尿苷,优选至少100mg的尿苷。
5.前述权利要求任一项的组合物,其中所述组合物还包含胆碱,或者其盐或酯。
6.权利要求5的组合物,其中所述组合物每日剂量或优选每100ml组合物包含200-600mg胆碱,更优选300-400mg胆碱。
7.前述权利要求任一项的组合物,其中所述组合物还包含一种或多种选自磷脂、维生素E、维生素C、硒、维生素B12、维生素B6和叶酸的组分/成分。
8.权利要求7的组合物,其中所述组合物每日剂量或优选每100ml组合物包含:
50-1000mg磷脂,
0.5-3mg维生素B6,
50-500μg叶酸,
1-30μg维生素B12。
9.权利要求7或8的组合物,其中所述组合物每日剂量或优选每100ml组合物包含20-60mg维生素E,所述维生素E优选为α生育酚的形式,和60-100mg维生素C。
10.权利要求7-9任一项的组合物,其中所述组合物每日剂量或优选每100ml组合物包含:
100-500mg,优选200-400mg EPA,
1000-1500mg,优选1100-1300mg DHA,
50-600mg,优选60-200mg磷脂,
200-600mg,优选300-500mg胆碱,
400-800mg,优选500-700mg尿苷一磷酸,
20-60mg,优选30-50mg维生素E,优选为α生育酚的形式,
60-100mg,优选70-90mg维生素C,
40-80μg,优选50-70μg硒,
1-5μg,优选2-4μg维生素B12,
0.5-3mg,优选0.5-2mg维生素B6,和
200-600μg,优选300-500μg叶酸。
11.前述权利要求任一项的组合物,其中所述组合物每日剂量或优选每100ml组合物具有50-130kcal的能量含量,1-10g的蛋白质含量,1-5g的脂质含量,和4-20g的消化性碳水化合物含量。
12.前述权利要求任一项的组合物,其中所述受试者的简易精神状态检查(MMSE)得分为20-30,特别为20-26,更特别为24-26。
13.前述权利要求任一项的组合物,其中所述受试者为未经药物治疗的。
14.前述权利要求任一项的组合物,其中将所述组合物肠内给予所述患者每天至少1次,持续至少12周,优选至少13周,更优选至少14、15、16、17、18、19、20、21、22、23或24周。
15.权利要求1、4-11任一项所述的组合物用于制造用于改善认知和/或用于治疗或预防受试者的受损的认知功能的产品的用途。
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WO2018161808A1 (zh) * | 2017-03-07 | 2018-09-13 | 上海泽生科技开发股份有限公司 | 维生素组合物在制备用于预防、治疗或延迟阿尔茨海默病的药物中的用途 |
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JP2014534225A (ja) | 2014-12-18 |
CA2853971C (en) | 2020-03-10 |
BR112014010162A2 (pt) | 2017-06-13 |
EP2773338B1 (en) | 2019-02-06 |
RU2014121891A (ru) | 2015-12-10 |
AU2012331689B2 (en) | 2017-03-30 |
PT2773338T (pt) | 2019-04-30 |
CA2853971A1 (en) | 2013-05-10 |
US20140274938A1 (en) | 2014-09-18 |
HK1201742A1 (zh) | 2015-09-11 |
AU2012331689A1 (en) | 2014-06-05 |
US9763971B2 (en) | 2017-09-19 |
RU2638809C2 (ru) | 2017-12-15 |
EP2773338A1 (en) | 2014-09-10 |
WO2013066151A1 (en) | 2013-05-10 |
PL2773338T3 (pl) | 2019-08-30 |
CN104039318B (zh) | 2018-05-11 |
JP6272766B2 (ja) | 2018-01-31 |
WO2013066165A1 (en) | 2013-05-10 |
ES2720660T3 (es) | 2019-07-23 |
BR112014010162A8 (pt) | 2017-06-20 |
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