CN101765427A - 在简易精神状态检查值为24-26的受试者中改善记忆 - Google Patents

在简易精神状态检查值为24-26的受试者中改善记忆 Download PDF

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CN101765427A
CN101765427A CN200880100603A CN200880100603A CN101765427A CN 101765427 A CN101765427 A CN 101765427A CN 200880100603 A CN200880100603 A CN 200880100603A CN 200880100603 A CN200880100603 A CN 200880100603A CN 101765427 A CN101765427 A CN 101765427A
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vitamin
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memory
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P·J·G·H·坎普伊斯
M·格罗南迪克
A·邦格尔斯
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Nutricia NV
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Priority claimed from PCT/NL2007/050307 external-priority patent/WO2009002146A1/en
Priority claimed from PCT/NL2007/050306 external-priority patent/WO2009002145A1/en
Priority claimed from PCT/NL2007/050310 external-priority patent/WO2009002148A1/en
Priority claimed from PCT/NL2008/050124 external-priority patent/WO2009082203A1/en
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Abstract

本发明因此涉及一种包含：(a)尿苷或磷酸尿苷；以及(b)二十二碳六烯酸和/或二十碳五烯酸的组合物用于在简易精神状态检查值为24-26的受试者中改善记忆以及/或者治疗或预防记忆功能损伤的用途，其中所述组合物经肠内给予所述受试者。在MMSE测验中，(30中)27或更大的任何得分实际上是正常的。在痴呆患者中，20-26指示轻度痴呆，10-19指示中度痴呆，低于10指示重度痴呆。本发明人相信，在20-26的组中，24-26的亚组中的记忆损伤甚至是可逆转的，这是因为病理通路只是刚刚开始形成。在该受试者亚组中病理通路只是刚刚开始形成。临床研究显示了对该亚组的优良结果。

Description

在简易精神状态检查值为24-26的受试者中改善记忆
技术领域
本发明涉及一种组合物用于在简易精神状态检查值(mini-mentalstate examination)为24-26的受试者中改善记忆功能的用途。
背景技术
记忆损伤是发生许多人中的一种严重缺陷，特别是那些患有阿尔茨海默氏病的人和/或老年人。这种损伤经常有严重的后果，例如生活质量下降，进行日常活动困难，有可能导致住院或进入疗养院。
已经提出几种治疗法用于在受试者中改善记忆功能。但是，这些治疗法几乎均被证明是无效的。而且，还已经建议给予几种营养成分。
发明内容
营养治疗特别适宜于具有相对轻的记忆损伤症状的受试者，即简易精神状态检查值(MMSE)为24-26的受试者。本发明人已认识到，在该特定亚组中记忆改善对于受试者日常生活活动和生活质量有巨大的影响。该受试者亚组的特殊之处在于病理通路只是刚刚开始形成。在MMSE测验中，(30中)27或更大的任何得分实际上是正常的。在痴呆患者中，20-26指示轻度痴呆，10-19指示中度痴呆，低于10指示重度痴呆。本发明人相信，在20-26的组中，24-26的亚组中的记忆损伤甚至是可逆转的，这是因为病理通路只是刚刚开始形成。高度希望改善该亚组的受试者的记忆功能，这是因为这可延缓对药物治疗的需要或者降低药物治疗的剂量。而且，在MMSE为24-26的受试者中的改善可推迟受试者需要住院或进入疗养院的时间，使得独立生活的时间更长，改善生活质量或者提高进行日常活动的能力。
MMSE值为24-26的受试者亚组包含两类人群。第一，它包含那些未接受记忆损伤的药物治疗的受试者，即未用药受试者。特别优选对该亚组进行治疗，这是因为在这些受试者中在药物介入的副作用和有益作用之间权衡的结果仍是负面的。由于相对无负面的副作用，希望为这些受试者提供营养治疗。对于MMSE为24-26的未用药受试者，开发一种延缓必须给药的时间点的疗法是特别重要的。
第二，MMSE值为24-26的受试者亚组包含具有很轻形式的阿尔茨海默氏病的受试者群。具有很轻形式的阿尔茨海默氏病的受试者特别需要通过营养疗法来改善记忆。如果记忆功能能够得到改善，那么药物介入在出现显著改善的情况下可能被减少或者甚至被推迟。
然而，发现一种这样的(营养)组合物是特别困难的，即该组合物在MMSE为24-26的组中能够有效地改善记忆功能，因为病理通路只是刚刚开始形成并且症状较轻。检测对照和治疗组之间的差异是特别困难的，因此有效的治疗需要强化的测验。
本发明人通过临床研究意外地发现，给予包含(a)尿苷或磷酸尿苷；以及(b)二十二碳六烯酸和/或二十碳五烯酸的组合物在MMSE为24-26的受试者中显示了显著的记忆功能改善。顺应性和耐受性很高并且副作用相对较低。特别意外地是，本发明的临床数据显示了真正的记忆功能改善，而不是仅记忆功能的下降率降低。另外发现，在该亚组中延迟回忆功能被显著改善。临床研究的结果总结于实施例中。
具体实施方式
本发明因此涉及一种包含：
a.尿苷或磷酸尿苷；以及
b.二十二碳六烯酸和/或二十碳五烯酸
的组合物用于在简易精神状态检查值为24-26的受试者中改善记忆以及/或者治疗或预防记忆功能损伤的用途，其中将所述组合物经肠内给予所述受试者。
受试者
本发明涉及简易精神状态检查值为24、25或26(即24-26)的受试者。简易精神状态检查(MMSE)是一项用于评价认知的30条的简短问卷测验。它在约10分钟的时间段内对包括记忆和方位的多种功能进行采样。MMSE测验包括多个方面的简单问答题和解答题(questions and problems)：时间和位置的测验、重复词串、语言的使用和理解以及基本的运动技能。(30中)27或更大的任何得分实际上是正常的；20-26指示轻度痴呆；10-19指示中度痴呆；低于10指示重度痴呆。MMSE是一种标准的测验。由于版权的原因本发明人不能在本说明书中包含该问卷的副本，但该问卷易于在互联网上获得并且可容易地通过版权所有人Psychological AssessmentResources(PAR)获取。它最初由Folstein等人(Psych Res 12：189，1975)提出，并经小改动被广泛用于评价认知。
本发明中治疗的受试者的简易精神状态检查值为24-26，并且优选地是未用药的和/或患有很轻形式的阿尔茨海默氏病，优选的事具有很轻的阿尔茨海默氏病和MMSE为24-26的未用药受试者。本发明中使用的术语“未用药的”是指未摄入一种或多种的胆碱酯酶抑制药、N-甲基-D-天冬氨酸(NMDA)拮抗药和银杏提取物(ginkgo biloba)的受试者。在本文给出的临床研究中发现，本发明的组合物对于未用药的受试者有效。受试者优选地为人，优选地为老年人，优选年龄为至少50岁。
记忆
本发明涉及本发明的组合物用于(i)改善记忆以及/或者(ii)治疗和/或预防记忆功能损伤的用途。或者，本发明提供了一种用于在需要的受试者中(i)改善记忆以及/或者(ii)治疗和/或预防记忆功能损伤的方法，所述方法包括将本发明的组合物给予所述受试者。具体而言，本发明涉及对记忆功能损伤的治疗。已经发现，当将本发明的组合物给予受试者时记忆功能被真正改善。人受试者的记忆功能可使用(修改的)阿尔茨海默病评定量表-认知部分(ADAS-cog)、韦氏记忆量表-修订版(Wechsler Memory Scale，WMS revised)来适当地确定。
具体地发现，在这些受试者中延迟回忆功能得到改善。延迟回忆功能可通过30分钟延迟期的散文回忆任务(prose recall task30-minute delay interval)进行测量。散文段落的延迟回忆不是一种能对很轻阿尔茨海默氏型痴呆和正常衰老进行清晰区分的量度。因此，本发明的组合物还可有利地帮助(目前)未患阿尔茨海默氏病的受试者来改善延迟回忆功能。因此，在一个优选的实施方案中，本发明提供了一种用于改善延迟回忆以及/或者治疗和/或预防延迟回忆功能损伤的方法。
尿苷
优选地，本发明的组合物含有尿苷和/或磷酸尿苷。优选地，本发明的组合物含有选自单磷酸尿苷(UMP)、二磷酸尿苷(UDP)和三磷酸尿苷(UTP)的一种或多种磷酸尿苷。
最优选地，本发明的组合物含有UMP。优选地，本发明的组合物中至少50重量％，更优选至少75重量％，最优选至少95重量％的尿苷是由UMP提供。本发明的方法优选地包括以每天0.08-3g，优选每天0.1-2g，更优选每天0.2-1g的量给予尿苷(尿苷、脱氧尿苷、磷酸尿苷、尿嘧啶和酰化的尿苷衍生物的累积量)。本发明的方法优选地包括给予这样的一种组合物，该组合物包括每100ml液体产品含有0.08-3g UMP，优选每100ml液体产品含0.1-2g UMP，更优选每100ml液体产品含0.2-1g的尿苷。优选地，每千克体重每天给予1-37.5mg UMP。通过使用等价物分子量和UMP分子量(后者为324道尔顿)取等摩尔的量，可从UMP的剂量计算以重量计的所需的等价物剂量。
二十二碳六烯酸和/或二十碳五烯酸
本发明的组合物优选地至少含有二十二碳六烯酸(22：6ω-3；DHA)和/或二十碳五烯酸(20：5ω-3；EPA)，优选地含有DHA和EPA。所提供的DHA和/或EPA的形式优选被为甘油三酯、甘油二酯、甘油单酯、游离脂肪酸或者它们的盐或酯、磷脂、溶血磷脂、甘油醚、脂蛋白、神经酰胺、糖脂或它们的结合物。优选地，本发明的组合物至少含有甘油三酯形式的DHA。
本发明的方法优选地包括，每天给予400-5000mg(DHA+EPA)，更优选每天500-3000mg，最优选每天1000-2500mg。总脂肪酸中(DHA+EPA)的比例优选地为5-50重量％，更优选10-45重量％，最优选15-40重量％。本发明的方法优选包括给予DHA，优选每天300-4000mg，更优选每天500-2500mg的量。本发明的方法优选地包括给予DHA，优选的量为每天300-4000mg，更优选的量为每天500-2500mg。
本发明的组合物优选含有很低量的花生四烯酸(AA)。优选地，本发明的组合物中DHA/AA的重量比为至少5，优选至少10，更优选至少15，优选地上至例如60或上至30。本发明的方法优选地包括给予这样一种组合物，该组合物含有以总脂肪酸计至少5重量％的花生四烯酸，更优选低于2.5重量％，例如下至0.5重量％。本发明的产品中ω-6/ω-3脂肪酸比优选地低于0.5，更优选地低于0.2，例如下至0.05或至0.1。本发明的产品中ω-6/ω-3脂肪酸(C 20及更高)比优选地低于0.3，更优选地低于0.15，例如下至0.03或至0.06。
本文所述的每日量是指本发明的组合物所提供的日剂量单位中的量。这样的日剂量单位可以是单剂量，但它也可以被细分为2个、3个甚或更多个日常份量(daily servings)。根据一个优选的实施方案，如果意欲将所述组合物作为单个单位给药，那么本文描述的每日量优选地是在(优选地是被包装的)组合物单位中存在的量。治疗优选地涉及每天给药一次、两次或三次，更优选每天一次，持续至少3周的时间。
本发明的组合物优选地含有以总脂肪酸计1-40重量％的DHA，优选以总脂肪酸计3-36重量％的DHA，更优选以总脂肪酸计10-30重量％的DHA。本发明的组合物优选地含有以总脂肪酸计0.5-20重量％的EPA，优选以总脂肪酸计2-10重量％的EPA，更优选以总脂肪酸计5-10重量％的EPA。上述的量考虑并优化多个方面，包括口感(太高的LCP水平会降低口感，导致顺应性降低)。
本发明的组合物优选包含选自鱼油、海藻油和卵脂质的至少一种油。优选地，本发明的组合物含有包括DHA和EPA的鱼油。
饱和脂肪酸和单不饱和脂肪酸
本发明的组合物优选地含有饱和脂肪酸和/或单不饱和脂肪酸。饱和脂肪酸的量优选地为以总脂肪酸计6-60重量％，优选12-40重量％，更优选以总脂肪酸计20-40重量％。具体而言，C14:0(豆蔻酸)+C16:0(棕榈酸)的量优选地为以总脂肪酸计5-50重量％，优选8-36重量％，更优选15-30重量％。不饱和脂肪酸例如油酸和棕榈油酸的总量优选地为5-40重量％，更优选地为15-30重量％。具有这些优选的量的组合物被发现很有效。
磷脂
优选地，本发明的组合物优选地含有磷脂，优选以脂质总重量计0.1-50重量％的磷脂，更优选0.5-20重量％，更优选1-10重量％，最优选以脂质总重量计1-5重量％。脂质总重量优选地为干物质的10-30重量％，和/或每100ml液体组合物含2-10g脂质。所述组合物优选地包括每100ml含有0.01-1克卵磷脂，更优选每100ml含0.05-0.5克卵磷脂。具有这些优选的量的组合物被发现很有效。
胆碱
优选地，本发明的组合物含有胆碱和/或磷脂酰胆碱。本发明的方法优选地包括每天给予超过50mg胆碱，优选每天80-2000mg胆碱，更优选每天120-1000mg胆碱，最优选每天150-600mg胆碱。本发明的组合物优选地包括每100ml本发明的液体配方含有50mg-3克胆碱，优选200mg-1000mg胆碱/100ml。
维生素
本组合物可有利地含有维生素，优选维生素C、维生素E和B这些维生素，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，可含有维生素B12和叶酸。本发明的组合物优选地包括每100ml液体产品含有50-1000μg叶酸，更优选150-750μg叶酸，最优选200-500μg叶酸。本发明的方法优选地包括每天给予50-1000μg叶酸，更优选每天150-750μg叶酸，最优选每天200-500μg叶酸。本发明的组合物优选地包括每100ml液体产品含有0.5-15μg维生素B12，更优选1-10μg维生素B12，最优选1.5-5μg维生素B12。本发明的方法优选地包括每天给予0.5-15μg维生素B12，更优选每天1-10μg维生素B12，最优选每天1.5-5μg维生素B12。
优选地，本发明的组合物含有磷脂、胆碱、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，更优选磷脂、胆碱、维生素E、维生素C、硒、维生素B12、维生素B6和叶酸。
产品
本发明的组合物优选地为一种即用型液体、固体或半液体产品。本发明的组合物优选地经肠内，更优选经口服给药。最优选地，本发明的组合物为通过吸管给药。如果它是一种即用型液体，那么该日液体量优选地为每日或每个单位75-200ml，最优选90-150ml/天。
可受益于本发明的方法和组合物的受试者经常出现与进食有关的问题。已经赋予了他们感觉能力和/或对肌肉的控制，并且在一些情况下他们对应用正确的进食习惯的愿望也得以实现。吞咽和/或咀嚼经常很是问题。因此，所提供的本发明的组合物的形式优选地为一种能够通过吸管摄入的饮料。
本发明优选地具有一个较低的粘度，优选在20℃和每秒100的剪切率下的测量粘度为1-2000mPas，更优选在20℃和每秒100的剪切率下的测量粘度为1-100mPas的粘度。更优选地，所提供的本发明的组合物的形式为能够通过吸管摄入的饮料，这使得该产品可更容易地被摄入并可改善顺应性。在一个优选的实施方案中，本发明的组合物在20℃和每秒100的剪切率下的粘度为1-80mPas，更优选在20℃和每秒100的剪切率下的粘度1-40mPas。这些粘度的测量例如可使用盘状及锥形几何体进行。
为了最能使患者接受，本发明的组合物优选地具有300-800mOsm/kg的重量克分子渗透压浓度。然而，所述产品的能量密度优选地不高至干扰正常进食习惯的程度。如果是液体形式，那么本发明的产品的能量密度优选地为0.2-3kcal/ml，更优选地为0.5-2、0.7-1.5kcal/ml。
本发明的组合物可有利地含有可消化的碳水化合物。本发明的组合物优选地为每100ml液体产品含有1-50克可消化的碳水化合物，更优选每100ml含5-30克，更优选每100ml含10-30克碳水化合物。可消化的碳水化合物的总量优选地是干物质的25-80重量％，优选以干物质计40-80重量％。
本发明的组合物还可含有蛋白质，优选地每100ml含0.5-10克蛋白质，更优选地每100ml含1-6克蛋白质，最优选2-6克蛋白质/100ml。优选地，本发明的组合物含有以总蛋白质计至少80重量％的乳来源的蛋白质(例如乳清和/或酪蛋白)。蛋白质使得能够制造出美味的产品，尤其是为虚弱的老年人。
实施例
实施例1：
经包装的组合物每125ml含有：
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 DHA+EPA和106mg磷脂(大豆卵磷脂)；胆碱400mg；UMP(单磷酸尿苷)625mg；维生素E 40mgα-TE；维生素C 80mg；60μg；维生素B12 3μg；维生素B6 1mg；叶酸400μg。
矿物和微量元素：钠125mg；钾187.5mg；氯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A 200μg-RE；维生素D3 0.9μg；维生素K 6.6μg；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
越来越多的证据表明营养在具有记忆功能损伤的受试者中的作用。进行本研究以评价医学食物的介入对患有很轻的阿尔茨海默氏病(AD)的未经用药受试者记忆的影响。将MMSE为24-26的患有很轻AD的未经用药受试者随机地分配在一项双盲12周研究中，每天一次接受125ml(125kcal)含如下成分的奶基饮料：(a)根据实施例1的配方(活性产品)或者(b)根据实施例1的等能量的对照饮料，但是无EPA、DHA、磷脂、胆碱、UMP、维生素E、维生素C、硒、维生素B12、维生素B6和叶酸(对照产品)。
结果测量为(延迟)词句记忆任务(源自韦氏记忆量表-修订版)。
结果：
在基线水平，在活性产品处理组和对照产品处理组之间没有显著差异。然而，这两组之间在以下方面有显著差异，即延迟词句记忆任务(源自韦氏记忆量表-修订版(WMS-r))在基线水平和经12周处理后之间的变化。在源自WMS-r的延迟词句记忆量表上，接受对照产品的组(n＝66)平均下降-0.164分，包含0的95％置信区间(-0.938至0.610)，而接受活性产物的组(n＝60)平均提高0.983分，0之上的95％置信区间(0.214至1.752)。
该研究可证明，以活性产品介入12周可改善记忆，特别是改善MMSE为24-26的受试者的延迟回忆功能(参见表1)。
表1
  组  MMSE为24-26的受试者  延迟词句记忆得分(WMS-r)
  对照   66   -0.164
  处理   60   +0.983

Claims (7)

1.一种组合物，该组合物包含：
a.尿苷或磷酸尿苷；以及
b.二十二碳六烯酸和/或二十碳五烯酸，
所述组合物用于在简易精神状态检查值为24-26的受试者中改善记忆以及/或者治疗或预防记忆功能损伤，其中将所述组合物经肠内给予所述受试者。
2.根据权利要求1的组合物，用于在简易精神状态检查值为24-26的受试者中(i)改善延迟回忆功能以及/或者(ii)治疗和/或预 防延迟回忆功能损伤。
3.根据权利要求1或2的组合物，其中所述组合物含有磷脂、胆碱、维生素E、维生素C、硒、维生素B12、维生素B6和叶酸。
4.根据前述权利要求任一项的组合物，其中将所述组合物经肠内给予所述受试者每天至少一次，持续至少3周的时间。
5.根据前述权利要求任一项的组合物，每个日剂量单位含有按照单磷 酸尿苷形式计算的0.1-2g尿苷，并且每个日剂量单位含有400-5000mg的DHA和EPA之和。
6.根据前述权利要求任一项的组合物，每100ml包含1-50克的可消化碳水化合物、每100ml含0.5-10g蛋白质，以及0.2-3kcal/ml的能量。
7.根据前述权利要求任一项的组合物，是一种液体产品，在20℃和每秒100的剪切率下的测量粘度为1-100mPas。
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