CN101686723A - 用于痴呆前驱症状患者的食品组合物 - Google Patents
用于痴呆前驱症状患者的食品组合物 Download PDFInfo
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Abstract
一种包含(a)一种或多种选自DHA、DPA和EPA的ω-3脂肪酸、(b)尿苷或其等效物、和(c)一种甲基供体的组合物,可用于治疗具有痴呆前驱症状患者的特征的人。所述特征包括例如每升脑脊液(CSF)中总-tau蛋白的水平高于350ng,以及CSF中Aβ-42/磷酸-tau-181的重量比小于6.5。
Description
技术领域
本发明涉及一种包含长链多不饱和脂肪酸的成分以及一种包含核苷酸或其等效物和一种甲基供体的成分用于制备可用于治疗神经前驱症状(prodromal)患者——具体而言为痴呆前驱症状患者——的产品的用途。
背景技术
西方社会中很多人都受神经疾病之苦,如非AD性痴呆、阿耳茨海默病(AD)、帕金森病(PD)或亨延顿舞蹈病(HD)。这些疾病目前由临床医生通过认真解读多种症状而诊断,所述症状如精神障碍病人的诊断和统计手册(Diagnostic and Statistical Manual of Mental Disorders)(第四版,2000-DSM-IV-TR)中或McKhann et al.,Report of theNINCDS-ARDA-workgroup,Neurology 1984,34,939-944中所定义。
观察到患有特定类型的记忆缺陷的人之间存在明显差异。例如,患阿耳茨海默病的人具有神经变性症状,这可能由以下现象造成:淀粉样蛋白斑累积,或者脑中选定区域中的神经原纤维缠结或突触损失或萎缩或者脑室的扩展,或者这些现象的混合。血管性痴呆患者具有记忆功能降低症状,这由脑血流量受损以及缺血和再灌注事件造成。从原因、对脑所造成损害的种类和总体症状方面来说,患有Lewy小体痴呆或反复继发性痴呆的患者的病理学不同于上述痴呆的患者,尽管它们都表现出记忆缺陷。
在痴呆的诊断中,除记忆功能之外,临床医生通常还分析至少其它的认知领域,例如执行运动功能、描述或识别物体的能力,社会性功能以及实施日常生活中被认为正常的活动的能力。
在衰老早期,特别是进入老年(通常60岁以上)后,有时显现脑功能异常的轻微症状或行为。由于所述症状的形式十分分散,因此临床医生的诊断可能只能基于所述患有具体疾病状态的人的在一定程度上公认的客观测验。例如,不满足某些记忆或认知标准、但通常执行日常生活中正常活动并不表现其它病状的人,可被诊断为“轻度认知缺损(MCI)”患者。当损伤以更***性的方式发生并且被认为由于衰老而发生时,可能做出“年龄相关性记忆缺陷”(AAMI)诊断。一些人认为MCI或AAMI为阿耳茨海默病的前驱症状阶段,即在该疾病之前但将要患病的阶段。然而,该类人中仅少于25%并在多数情况下少于20%的人将最终患痴呆。所述“MCI患者”人群中一部分将痊愈而另一部分可能仍为“MCI患者”。
在该方面中,认为本申请中老年人指的是50岁或以上的人、特别是55岁或以上的人、更特别为60岁或以上的人、更特别为65岁或以上的人。这个相当宽的定义考虑到了不同人群之间、在不同大陆上等平均年龄的变化。大多数发达世界国家中公认65岁实足年龄为“老年”或年长的人的定义(与人可开始获得退休金福利的年龄相关),但像许多西化观念一样,这不能较好地适应于例如非洲的情形。在此时,不存在***(UN)标准数字准则,但是经UN同意的截止值为60+岁以指西方世界中的年长人群。老年人的非洲定义与50至65岁的实足年龄相关,这取决于背景、地区和国家。
用于诊断前驱症状患者的区别试验与用于诊断痴呆或类痴呆病症的常规试验并不一致,尽管这些常规试验中一些可能进一步支持神经障碍或疾病的前驱症状患者的诊断。例如,AD前驱症状患者可能在记忆测试中得到令人满意的分数,并将因此不必然为MCI患者,而他们可能在目前用于前驱症状的诊断工具中得到阳性分数。然后做出“痴呆前驱症状患者”诊断。满足“痴呆前驱症状患者”的诊断要求的所述非MCI人群的诊断问题仍不能由Hansson等人2006年2月6日公布于Http://neurology.thelancet.com中的标准进行诊断。未研究在所建议的试验中表现出相同分数的非MCI人群。
将患者诊断为所谓的AAMI或MCI患者将相对频繁地导致该患者将自然而然成为痴呆患者的错误担心。错误的阳性诊断也给社会造成相对高的花费,由于采取不必要的措施来供养这些患者。因此需要开发更好的诊断工具来鉴定人在衰老期间可能患的多种类型的脑疾病或病症并鉴定属于特定临床前阶段的预测。还需要供养唯一一类的痴呆前驱病症患者,以降低他们将患老年痴呆的可能性。
WO 2007/008586公开了一种降低个体体内淀粉状蛋白β肽水平的方法,该方法包括给予二十二碳六烯酸和二十二碳五烯酸ω-6的来源。WO2006/031683公开了尿苷——优选与胆碱结合——用于改善认知或神经功能的用途。WO 2006/127620公开了一种包含DHA和UMP的组合物,其可用于治疗患记忆障碍、学习问题或神经障碍的受试者(如阿耳茨海默病患者)。Wurtman et al.,Brain Research 2006,1088(1),83-92公开了一种胆碱、UMP和DHA的结合物,其能增加沙鼠脑中突触蛋白质和磷脂的量并可潜在用于治疗阿耳茨海默病。WO 03/041701公开了一种包括DHA、EPA、胆碱、甲硫氨酸、维生素B6、叶酸、锌、镁和UMP作为核苷碱基替换物的组合物,其用于治疗帕金森病、癫痫、精神***症、妄想症、抑郁、睡眠障碍、精神病、痴呆、ADHA、记忆功能缺损、慢性疲乏综合征和运动障碍。
然而,在现有技术中无处暗示使用这些成分用于治疗痴呆前驱症状患者,其具有——例如脑中——神经***中特定损害或经历特定生物化学病症。
发明内容
本发明的基础是从不必然最终导致痴呆的病症(如轻度认知缺损(MCI))中较早地区分出在不进行有效治疗的情况下具有高度发展成为神经障碍如痴呆(特别是阿耳茨海默病(AD))的可能性的病症。现已发现可以通过给药一种包含长链多不饱和脂肪酸、核苷酸和甲基供体的产品来治疗所述神经障碍前驱病症患者。所述给药降低了与脑机能障碍相关的更严重问题(如记忆和认知问题、震颤、感受和感觉的强度的降低)的发展,并可降低痴呆的发病率或延缓其发生。
具体实施方式
本发明涉及一种组合物,包含(a)一种或多种ω-3脂肪酸、(b)尿苷或胞苷或其等效物、和(c)一种甲基供体,所述组合物可用于预防或延缓具有痴呆前驱症状患者的特征的人的痴呆发病。
为本发明目的,患有“老年性痴呆”的人被定义为患有一种或多种痴呆。老年性痴呆或痴呆被认为包括阿耳茨海默病(AD)。因此,本发明还涉及一种组合物,包含(a)一种或多种ω-3脂肪酸、(b)尿苷或胞苷或其等效物、和(c)一种甲基供体的组合物,所述组合物可用于预防或延缓具有阿耳茨海默病前驱症状患者的特征的人的阿耳茨海默病发病。
然而,本发明还独立地针对痴呆前驱症状患者和/或阿耳茨海默病前驱症状患者。“痴呆前驱症状患者”为未患有如上所述老年性痴呆、但具有较高的患老年性痴呆可能性的人。同样“阿耳茨海默病前驱症状患者”为未患有AD但具有较高的患AD可能性的人。下面描述了用于将患者归类为前驱症状患者的诊断工具,所述诊断工具其包括脑损伤和生物化学问题的精确诊断以及标准的谨慎设置。
本发明的前驱症状患者被定义为在以下至少一个、优选至少两个、更优选至少三个标准中评分为阳性的人:
-每升脑脊液(CSF)中tau蛋白的总水平高于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容积损失的存在,其用磁共振成像(MRI)通过视觉评分的定性分级(参照年龄相当的经过很好表征的正常人群)或感兴趣区域的定量分析(参照年龄相当的经过很好表征的正常人群)显示;
-额颞叶(FTL)萎缩的存在,其用MRI通过定性分级或定量分析显示;
-每mL CSF中F2-异前列烷(F2-IsoP,异前列烷8,12-异-iPF2α-VI)的水平高于25pg。
关于CSF中总tau、P-tau181、Aβ42和F2-异前列烷的浓度对于阿耳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’sdisease in patients with mild cognitive impairment:a follow-upstudy.Lancet Neurol 5:228-234中;以及Pratico D,Clark CM,LiunF,Lee VYM,Trojanowski JQ(2002)Increase in brain oxidative stressin mild cognitive impairment:a possible predictor of Alzheimerdisease.Arch Neurol 59:972-976中。
在一种优选实施方案中,本发明前驱症状患者的鉴定包括至少前两个标准(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:
-脑中两侧颞顶骨区域中葡萄糖代谢的降低,这可由正电子发射断层成像术(PET)检测到;
-后扣带回皮质中葡萄糖代谢的降低,这可由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)测量,例如通过应用放射性同位素99m Tc-HMPAO);
-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。
脑或其局部的情况异常可或者通过以健康情形下该人的自身情况为参照,或者当这不可获得时,通过以代表人群的平均情况(例如符合年龄的)为参照。通常更多地使用后者。通过将患者的情况与参照情形和平均情形比较,当病理状态已完全发展至最大程度时,临床医生能辨认出前驱症状阶段。特别是当其中患者表现出与健康个体的病理状态方面数值偏差x%的中间情况,为本发明目的被认为是前驱症状患者。当在进食和运动的标准化条件下确定时,用于测定血流量和葡萄糖代谢的x值为20%。
应当注意到,这些前驱症状患者在与情景记忆缺陷有关的试验或其它适于判断神经疾病存在的试验中的评分中不满足诊断严重神经疾病的标准,所述严重神经疾病例如阿耳茨海默病、帕金森病或亨延顿舞蹈病。
LC-PUFA
待用的LCP优选包括至少一种选自二十二碳六烯酸(22:6ω-3;DHA)、二十二碳五烯酸(22:5ω-3;DPA)和二十碳五烯酸(20:5ω-3;EPA)的LCP。优选本发明组合物包含至少DHA,优选DHA和EPA。更优选本发明组合物包含DHA以及至少一种选自EPA和DPA的DHA前体,更优选本发明组合物包含DHA、DPA和EPA。发明人认为只有部分的脑中所包含DHA来自经口摄取的DHA。所有重要部分的脑中所包含的DHA源自于脑中DPA向DHA的转化。在另一方面中,本发明组合物优选含有大量的EPA。EPA被转化为DPA(ω-3),从而提高随后脑中DPA(ω-3)向DHA的转化率。因此,本发明组合物优选还含有大量的EPA,从而进一步刺激活体内的DHA形成。
LCP优选以甘油三酯、甘油二酯、甘油单酯、游离脂肪酸或者其盐或酯、磷脂、溶血磷脂、甘油醚、脂蛋白质、神经酰胺、糖脂或其结合物的形成提供。优选地,本发明组合物至少包含甘油三酯形式的DHA。
本发明方法优选包含给药400-5000mg(DHA+EPA)每天、更优选500-3000mg每天、最优选1000-2500mg每天。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%。本发明方法优选包含给药DHA,以优选300-4000mg每天、更优选500-2500mg每天的量给药。
本发明中所述每天的量意指本发明组合物所提供的日剂量单位。所述日剂量单位可为单剂量,但其也可分成两或三次、或者甚至更多个每日份。如果一个优选实施方案的组合物意欲用于以单个单位形式给药,则本发明中所述每天的量优选为(优选包装的)组合物单位中存在的量。
本发明组合物优选包含基于总脂肪酸1-40重量%的DHA、优选基于总脂肪酸3-36重量%的DHA、更优选基于总脂肪酸10-30重量%的DHA。本发明组合物优选包含基于总脂肪酸0.5-20重量%的EPA、优选基于总脂肪酸2-10重量%的EPA、更优选基于总脂肪酸5-10重量%的EPA。DHA与EPA和DPA(ω-3)的总和的重量比优选大于1.0、更优选为1.2-10、更优选2-8。上述比例和量考虑到并优化了几个方面,包括味道(过高的LCP水平降低味道,从而导致顺应性降低)、DHA及其前体之间的平衡以确保与最大剂量相关的最佳效果以及产品剂型如液体形式、棒剂或胶囊的可能性。
本发明组合物优选包含极低量的花生四烯酸(AA;20:4ω-6)。花生四烯酸被认为消除本发明组合物的效果。本发明受试者通常摄食足够的AA(的前体),并且过量的日剂量可能刺激炎症应答、抑制日常活动。优选本发明组合物中DHA/AA的重量比至少为5、优选至少为10、更优选至少为15、最高达例如100。优选,EPA/AA的重量比为至少2。本发明方法优选包含给药一种包含基于总脂肪酸少于5重量%、更优选低于2.5重量%的花生四烯酸的组合物。本发明产品中ω-6/ω-3脂肪酸的比例有利地低于0.5、优选低于0.2,例如最低达0.05或达0.1。此处ω-3和ω-6脂肪酸的量适用于所有ω-3或ω-6脂肪酸的总和,所述ω-3或ω-6脂肪酸分别具有至少两个双键和至少20个碳原子。本发明产品中ω-6/ω-3脂肪酸(C20及更高)的比例优选低于0.3、更优选低于0.15,例如最低达0.03或达0.06。如果包含C18脂肪酸,则优选的ω-6/ω-3重量比为0.05-1、更优选0.1-0.6、最优选0.15-0.4。
本发明组合物优选包含至少一种选自鱼油、藻油和卵脂类(eggslipids)的油。优选本发明组合物包含含有DHA、EPA并优选DPA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6-60重量%、优选12-40重量%、更优选基于总脂肪酸12-40重量%。特别地C14:0(肉豆蔻酸)+C16:0(棕榈酸)的量基于总脂肪酸优选为5-50重量%、优选8-36、更优选15-30重量%。单不饱和脂肪酸——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%。包含饱和的和/或单不饱和的脂肪酸提供了能量来源,从而有助于前驱症状受试者的活动。
磷脂
优选,本发明组合物优选包含磷脂,优选基于脂质总量0.1-50重量%的磷脂、更优选0.5-2重量%、更优选基于脂质总量1-5重量%。脂质的总量优选为10-30重量的干物质、和/或2-6g脂质每100ml液体组合物。包含磷脂有益地改善了膜功能,从而使得改善前驱症状受试者体内可能受到影响的脑不同部分的运行成为可能。此外,磷脂改善了本发明产品的稳定性。磷脂还使得能够制造可口的产品。同样,磷脂为胆碱的来源并且预防了运动后血浆胆碱水平的降低。胆碱对于形成乙酰胆碱、学***就能够实现上述优点。
核苷酸
优选本发明组合物包含核苷及其等效物。等效物包括核苷酸、核碱基、核苷以及磷酸化和/或酰化形式。所有所述等效物能提高身体、组织(如血液、肝和脑)内核苷活性形式的内源水平。可用的成分包括植物、动物、藻或发酵物质的提取物,以及合成化合物。
本发明组合物优选包含尿苷和/或其等效物,优选至少一种选自尿苷(即核糖基尿嘧啶)、脱氧尿苷(脱氧核糖基尿嘧啶)、尿苷磷酸盐(UMP、dUMP、UDP、UTP)、核碱基尿嘧啶和酰化尿苷衍生物的尿苷或其等效物。优选本发明组合物包含一种选自尿苷一磷酸(UMP)、尿苷二磷酸(UDP)和尿苷三磷酸(UTP)的尿苷磷酸盐。最优选本发明组合物包含UMP,因为UMP能被身体最有效地吸收。因此,本发明产物中包含UMP能以最低的剂量和/或最低量给药于受试者获得最高效果。优选本发明组合物中尿苷的至少50重量%由UMP提供、更优选至少75重量%、最优选至少95重量%。本发明方法优选包含以0.08-3g每天、优选0.1-2g每天、更优选0.2-1g每天的量给药尿苷(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)。
本发明方法优选包含以0.08-3g UMP每100ml液体产品、优选0.1-2g UMP每100ml液体产品、更优选0.2-1g UMP每100ml液体产品的量给药包含尿苷的组合物。优选每天给药1-37.5mg UMP每千克体重。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。核苷酸或核苷和衍生物的量优选为3-115μmol、优选5-35μmol每kg体重每天、或0.25-9mmol、优选0.3-6、最优选0.45-2.8mmol每天。尿苷衍生物,如可容易由饮食UMP形成的UDP,对于在细胞中输送糖蛋白和糖脂以及其在胞质溶胶和质膜中的利用度而言看起来是重要的。
优选尿苷与胞苷的重量比大于1.0、更优选至少2.0、最优选高于5.0。本发明中所用术语尿苷涉及如上解释的尿苷和/或其等效物。本发明中所用术语胞苷涉及胞苷和/或其等效物。尽管胞苷是尿苷的前体,其通过血脑屏障,但在本发明组合物中包含尿苷更有效力和有效果。
在一个进一步优选实施方案中,本发明组合物优选不包含高量的其它核苷酸。因此,优选本发明组合物中腺苷/尿苷的重量比低于0.1、更优选低于0.01、最优选0。优选本发明组合物中鸟苷/尿苷的重量比低于0.1、更优选低于0.01、最优选0。优选本发明组合物中肌苷与尿苷的重量比低于0.1、更优选低于0.01、最优选0。
尿苷和LCP的结合
发明人发现所定义的核苷酸等效物以及特别是所定义的尿苷源对于支持和/或增强如上定义的脂质成分的日常活动效果而言是重要的。本发明的结合——特别是(i)尿苷以及(ii)DHA和/或EPA的结合——令人惊奇地有效。在生物化学水平上,这可通过膜中神经酰胺代谢的改善以及特别是以存在简单神经酰胺为代价的糖脂的增加而观察到。
甲基供体
优选本发明组合物包含甲基供体。甲基供体为那些当被给药至个体体内后能提供甲基、亚甲基或甲酰基基团的食品级化合物。本发明组合物中包含的甲基供体优选选自丝氨酸、甲硫氨酸、胆碱、甜菜碱、二甲基甘氨酸和肌氨酸及其衍生物。甲基供体可以纯化合物本身、以其盐以及以化合物的形式包含于配方中,其中该甲基供体共价结合至氨基酸,并且其具有小于600道尔顿的分子量。
优选本发明组合物包含胆碱和/或磷酸卵磷酯。本发明方法优选包含给药多于50mg胆碱每天、优选80-2000mg胆碱每天、更优选120-1000mg胆碱每天、最优选150-600mg胆碱每天。本发明组合物优选包含50mg至3g胆碱每100ml液体配方、优选200mg-1000mg胆碱/100ml。其它甲基供体的剂量可通过如对于胆碱所限定的等摩尔量计算出来并用那个甲基供体的分子量进行修正。
用饮食补充胆碱提高了血浆胆碱并从而预防了膜破裂。使用选定的甲基供体将提高对该疗法响应的患者的数目。尤其是老年人——特别是虚弱的老年人——受益于包含选定的甲基供体。
矿物质&微量元素
本发明组合物可通过包含一种或多种矿物质而得以进一步改善。优选本发明组合物包含至少一种选自锌、镁、铜、锰和钼的矿物质。优选本发明组合物包含锰和钼。
锰
饮食中包含锰对于改善细胞的膜功能——特别是神经细胞的膜功能——而言是重要的。尤其是那些营养不良的或者具有涉及赋予生成鞘磷脂和/或有关化合物如脂类和糖基化神经酰胺的代谢能力的遗传或代谢紊乱的人,受益于包含矿物质成分。
每天锰的给药量优选多于0.1mg、更优选0.1-1mg。优选本发明方法包含给药含0.05-2mg锰每100ml、优选0.1-1mg锰每100ml的(液体)组合物。
钼
另外的钼被强优选使辅因子适当作用,钼似乎对于生成合适的膜组成——例如其脂类含量——而言十分重要,并特别确保了神经细胞的正常功能。此外,包含适当量的钼延缓了部分老年人在衰老期间的脑皱缩。本发明方法优选包含给药含0.1-100mg钼每100ml、优选1-50mg钼每100ml的组合物。
锌
还优选包含另外的锌于上述的含脂质或核苷酸成分的产品中,以稳定脑中的蛋白质并预防其聚集,这可能赋予日常生活活动。本发明方法优选包含给药含0.05-25mg锌每100ml、优选0.1-10mg锌每100ml的组合物。
维生素
组合物可有利地包含维生素,如维生素C、维生素E和B族维生素。有利地,包含维生素B12和叶酸盐,因为低血浆B12/叶酸盐水平为出现AD的危险度因子。
本发明组合物优选包含50-1000μg叶酸、更优选150-750μg、最优选200-500μg叶酸每100g液体产品。本发明方法优选包含给药50-1000μg叶酸每天、更优选150-750μg、最优选200-500μg叶酸每天。本发明组合物优选包含0.5-15μg维生素B12、更优选1-10μg、最优选1.5-5μg维生素B12每100g液体产品。本发明方法优选包含给药0.5-15μg维生素B12每天、更优选1-10μg、最优选1.5-5μg维生素B12每天。
产品
本发明组合物优选为即用液体、固体或半液体产品。也可为适于溶解或稀释或者适于强化另一种产品目的的浓缩形式。制品可为饮剂、乳剂、分散剂、药丸或胶囊、块、粒化或未粒化的粉剂、布丁、调味料、凝胶、冰淇淋、汤、饼干、棒糖、甜的糕饼或其它本领域已知的形式。本发明组合物优选肠内给药、更优选口服。最优选本发明组合物通过吸管给药。产品优选用作补充物,其具有优选10-50、更优选15-35g的日剂量单位的干重。当其为即用液体时,日液体量优选为75-200ml每天或每单位、最优选90-150ml/天。
可受益于本发明方法和组合物的受试者(例如阿耳茨海默病前驱病症患者、痴呆前驱症状患者以及老年人、特别是65岁以上的人)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正确进食习惯的能力也会受损。吞咽和/或咀嚼可能成为问题。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。
根据本发明使用的组合物优选具有较低粘度、优选20℃下以100sec-1的剪切率测得的1-2000mPa.s的粘度。更优选,本发明组合物优选以能被通过吸管摄取的饮剂形式提供,这样使得产品更易于摄取并且改善了顺应性。在一个优选实施方案中,本发明组合物具有20℃下100每秒剪切率的1-80mPas的粘度、更优选20℃下100每秒剪切率的1-40mPas的粘度。为了被患者最佳接受,本发明组合物优选具有300-800mOsm/kg的重量克分子渗透压浓度。
受试者(阿耳茨海默病前驱病症患者、痴呆前驱症状患者以及老年人、特别是65岁以上的人)中的另外很多体验到了食欲的普遍下降和/或变得营养不良。因此,在本发明组合物中包含其它营养素是有利的。然而,产品的能量密度优选不要高到干扰正常进食习惯。当以液体形式存在时,本发明产品优选包含0.2-3kcal/ml、更优选0.5-2、0.7-1.5kcal/ml。
有利地本发明组合物包含可消化的碳水化合物。可消化的碳水化合物对受试者的操作能力产生积极影响,并对含LCP和/或尿苷的本发明组合物具有有利效果并超过其效果。本发明组合物优选含有1-50g可消化的碳水化合物每100ml液体产品、更优选5-30g每100ml、更优选10-30g碳水化合物/100ml。可消化的碳水化合物的总量优选为基于干物质25-80重量%、基于干物质40-80重量%。
本发明组合物可还包含蛋白质、优选0.5-10g蛋白质每100ml、更优选1-6g蛋白质每100ml、最优选2-6g蛋白质/100ml。优选本发明组合物包含基于总蛋白质至少80重量%的奶源蛋白质(例如乳清和/或酪蛋白)。蛋白质使得可生产可口产品、尤其是对于虚弱的老年人而言。
合适地,本发明产品具有产品的总干质量的至少20、优选40-90、更优选45-80重量%的累积量的尿苷和脂质以及甲基供体(胆碱)。所述产品尤其适用,因为所述产品不扰乱受试者的标准进食模式。另外这些产品可能也使得对第二道菜或第二餐进行有利的强化。所述产品的合适形式为粉末和凝胶。
受神经病变或神经学问题之苦的人常常遇到进食的问题。他们的感觉能力和/或肌肉控制力已受损,而且在某些情况下他们运用正确进食习惯的能力也已受损。这些患者中的部分可能体验到了食欲的普遍下降并且该患者群中的相对较大部分变得营养不良。优选营养不良人所用的产品具有1.6-4.5kcal每g产品的能量密度。
实施例
实施例1:
用于被诊断为痴呆前驱症状患者的患者的胶囊
将可缓慢溶解的聚合物材料包衣包围一种液相,其中液体重1.1g并且其包含:
0.8g一种植物油和海洋生物油(marine oil)的脂质混合物,其脂肪酸分布如下:
饱和脂肪酸34g
油酸15g
二十碳五烯酸7g
二十二碳六烯酸27g
亚油酸2.6g
α-亚油酸0.6g
其它脂肪酸补足100g脂肪酸
200mg尿苷一磷酸
50mg胆碱
50mg其它组分(包括叶酸、维生素B12、维生素B6、矿物质、微量元素)。
实施例2
用于补充第二道菜的凝胶
该凝胶以以下量含有脂质成分、核苷酸成分、甲基供体和矿物质成分:
每10g:
-100mg DHA
-100mg UMP
-50mg胆碱
-40μg叶酸
-50mg天冬氨酸钾镁。
该凝胶可被加入汤或肉调味料中以作为热菜的补充。对于易于出现痴呆的老年人的生活中的日常活动的支持,可通过给药该产品优选至少2周后测量进行这些活动的难易性确定。
实施例3:带有包装的补充物
经包装的组合物每125ml包含:
能量125kcal;蛋白质3.9g;碳水化合物16.5g;脂肪4.9g。
脂肪包含1.5g DHA+EPA,以及106mg磷脂(大豆卵磷脂);胆碱400mg;UMP(尿苷一磷酸)625mg;维生素E 40mgα-TE;维生素C 80mg;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A 200μg-RE;维生素D30.9μg;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。
该包装物表明该组合物改善了日常生活的活动。该组合物适于给药于使用上述试验确定的痴呆前驱症状患者、阿耳茨海默病前驱病症患者以及老年人。推荐剂量为一、二或三包每天。
实施例4:饮食导致的阿耳茨海默病前驱病症模型中神经变性改变
使幼小的雌性APP/PS1转基因小鼠及其野生型同窝出生仔畜对照组或进食食物A(对照食物)或进食具有如表1中所示添加剂的食物C。在开始饮食干预后三个月,处死小鼠并收集脑。在该阶段,小鼠仅6个月大,它们未表现出行为障碍或认知缺陷的迹象。只有在10月大时,第一记忆缺失在这些小鼠中变得明显[Oksman等人Neurobiology of Disease23(2006)563-572]。使用氨基铜银染色(Amino Cupric Silver staining)来使脑各部分中的神经变性过程可见。使用图像分析和体视学来量化新皮质中的神经变性。
表1:加入常规鼠食物中以得到食物C的具体营养素的量的概况。食物A代表常规鼠食物。各食物被做得具有等热量。
添加剂(g/100g食物) | 食物A | 食物C |
DHAEPAUMP胆碱卵磷脂维生素E维生素C硒叶酸盐维生素B6维生素B12 | ----------- | 0.7570.1891.0000.3130.4120.1570.1600.00011100.00070000.00270000.0000011 |
食物C导致了幼小的APP/PS1转基因小鼠及其野生型同窝出生仔畜的新皮质中的神经变性均显著降低。数据列于表1中。所存在的数据表明该饮食干预可用于减少阿耳茨海默病发展之前的神经变性进程。此外,幼小的APP/PS1转基因小鼠中的神经变性在开始行为或认知改变之前降低,而且在野生型对照组小鼠中亦如此,这突出了用于阿耳茨海默病前驱病征阶段的饮食干预的关联性。
Claims (8)
1.一种组合物,包含(a)一种或多种选自DHA、DPA和EPA的ω-3脂肪酸、(b)尿苷或其等效物、和(c)一种甲基供体,所述组合物可用于预防或延缓具有痴呆前驱症状患者的特征的人的痴呆发病。
2.权利要求1的组合物,其中所述特征包括以下特征中的两个或多个:
-每升脑脊液(CSF)中总-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;
-内侧颞骨叶(MTL)萎缩的存在,海马体、内嗅皮质或扁桃体的容积损失的存在,通过磁共振成像(MRI)显示;
-额颞骨叶(FTL)萎缩的存在,用MRI通过定性分级或定量分析显示;
-每mL CSF中F2-异前列烷(F2-IsoP,异前列烷8,12-异-iPF2α-VI)的水平高于25pg;
-脑中两侧颞顶骨区域中葡萄糖代谢的降低,这可由正电子发射断层成像术(PET)检测到;
-后扣带回皮质中葡萄糖代谢的降低,这可由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)测量,例如通过应用放射性同位素99m Tc-HMPAO);
-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或葡萄糖利用率异常,所述组织学异常可通过MRI确定;
-颞顶叶皮层或后扣带回皮质中组织学异常或葡萄糖利用的异常。
3.权利要求1或2的组合物,其中该组合物包含0.1-2g尿苷,以尿苷一磷酸的形式计算,每日剂量单位。
4.权利要求1-3中任一项的组合物,其中该组合物包含400-4000mg的DHA、DPA和EPA的总和每日剂量单位。
5.前述权利要求中任一项的组合物,其中该组合物包含300-3600mg DHA每日剂量单位。
6.前述权利要求中任一项的组合物,其中DHA与花生四烯酸之间的重量比为至少5.0。
7.前述权利要求中任一项的组合物,其中甲基供体为胆碱,并且以80-2000mg的每日量使用。
8.前述权利要求中任一项的组合物,其中该组合物还包含一种或多种B族维生素。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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PCT/NL2007/050310 WO2009002148A1 (en) | 2007-06-27 | 2007-06-27 | Food composition for prodromal dementia patients |
NLPCT/NL2007/050310 | 2007-06-27 | ||
PCT/NL2008/050408 WO2009002164A1 (en) | 2007-06-27 | 2008-06-20 | Food composition for prodromal dementia patients |
Publications (1)
Publication Number | Publication Date |
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CN101686723A true CN101686723A (zh) | 2010-03-31 |
Family
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Family Applications (1)
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CN200880022198A Pending CN101686723A (zh) | 2007-06-27 | 2008-06-20 | 用于痴呆前驱症状患者的食品组合物 |
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US (1) | US8445458B2 (zh) |
EP (2) | EP2412250B1 (zh) |
JP (1) | JP5906014B2 (zh) |
CN (1) | CN101686723A (zh) |
AT (1) | ATE524077T1 (zh) |
AU (1) | AU2008269726B2 (zh) |
BR (1) | BRPI0813912B1 (zh) |
CA (1) | CA2704906C (zh) |
DK (1) | DK2412250T3 (zh) |
ES (2) | ES2551237T3 (zh) |
FI (1) | FI2170104T4 (zh) |
HU (1) | HUE028126T2 (zh) |
IL (1) | IL202967A (zh) |
MX (1) | MX2009014217A (zh) |
NZ (1) | NZ582265A (zh) |
PL (2) | PL2412250T3 (zh) |
PT (2) | PT2170104E (zh) |
RU (1) | RU2487557C2 (zh) |
WO (2) | WO2009002148A1 (zh) |
ZA (1) | ZA200909227B (zh) |
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CN109689041A (zh) * | 2016-09-29 | 2019-04-26 | 雀巢产品技术援助有限公司 | 作为未患痴呆患者的神经保护剂的ω-3脂肪酸和胆碱 |
CN110475553A (zh) * | 2017-04-11 | 2019-11-19 | 雀巢产品有限公司 | 减轻未患痴呆的个体的认知衰老的组合物和方法 |
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-
2007
- 2007-06-27 WO PCT/NL2007/050310 patent/WO2009002148A1/en active Application Filing
-
2008
- 2008-06-20 FI FIEP08766831.5T patent/FI2170104T4/fi active
- 2008-06-20 PL PL11181091T patent/PL2412250T3/pl unknown
- 2008-06-20 JP JP2010514660A patent/JP5906014B2/ja active Active
- 2008-06-20 EP EP11181091.7A patent/EP2412250B1/en not_active Revoked
- 2008-06-20 HU HUE11181091A patent/HUE028126T2/en unknown
- 2008-06-20 DK DK11181091.7T patent/DK2412250T3/en active
- 2008-06-20 BR BRPI0813912A patent/BRPI0813912B1/pt active IP Right Grant
- 2008-06-20 CN CN200880022198A patent/CN101686723A/zh active Pending
- 2008-06-20 EP EP08766831.5A patent/EP2170104B2/en active Active
- 2008-06-20 AU AU2008269726A patent/AU2008269726B2/en active Active
- 2008-06-20 CA CA2704906A patent/CA2704906C/en active Active
- 2008-06-20 AT AT08766831T patent/ATE524077T1/de active
- 2008-06-20 RU RU2010102526/13A patent/RU2487557C2/ru active
- 2008-06-20 MX MX2009014217A patent/MX2009014217A/es active IP Right Grant
- 2008-06-20 PT PT08766831T patent/PT2170104E/pt unknown
- 2008-06-20 NZ NZ582265A patent/NZ582265A/en unknown
- 2008-06-20 PT PT111810917T patent/PT2412250E/pt unknown
- 2008-06-20 PL PL08766831T patent/PL2170104T3/pl unknown
- 2008-06-20 ES ES11181091.7T patent/ES2551237T3/es active Active
- 2008-06-20 US US12/666,617 patent/US8445458B2/en active Active
- 2008-06-20 ES ES08766831T patent/ES2373001T3/es active Active
- 2008-06-20 WO PCT/NL2008/050408 patent/WO2009002164A1/en active Application Filing
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109689041A (zh) * | 2016-09-29 | 2019-04-26 | 雀巢产品技术援助有限公司 | 作为未患痴呆患者的神经保护剂的ω-3脂肪酸和胆碱 |
CN110475553A (zh) * | 2017-04-11 | 2019-11-19 | 雀巢产品有限公司 | 减轻未患痴呆的个体的认知衰老的组合物和方法 |
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