CN108472278A - 用于降低pku患者的苯丙氨酸水平的营养产品 - Google Patents
用于降低pku患者的苯丙氨酸水平的营养产品 Download PDFInfo
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- CN108472278A CN108472278A CN201680075853.9A CN201680075853A CN108472278A CN 108472278 A CN108472278 A CN 108472278A CN 201680075853 A CN201680075853 A CN 201680075853A CN 108472278 A CN108472278 A CN 108472278A
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Abstract
本发明涉及一种组合物,其包括(i)选自DHA、DPA和EPA的一种或多种ω‑3脂肪酸,和(ii)选自尿苷源和胞苷源的一种或多种嘧啶衍生物,其用于降低或正常化PKU患者的血液中苯丙氨酸水平或用于对PKU患者的血液中苯丙氨酸水平进行饮食控制。
Description
发明背景
本发明涉及用于治疗PKU患者的组合物。进一步,本发明涉及包括蛋白质、脂质和碳水化合物的营养组合物,所述组合物提供不同于苯丙氨酸的至少所有必需氨基酸。
苯丙酮尿症(PKU)的遗传突变特征损害苯丙氨酸羟化酶(PAH)的正常功能,其通常将苯丙氨酸(Phe)转化为酪氨酸(Tyr)。该突变导致Phe在血液和大脑中累积至毒性水平。另外,由于Tyr是神经递质多巴胺和去甲肾上腺素的前体,Tyr合成的降低会破坏这些儿茶酚胺的生物合成。同时,Phe与Tyr和色氨酸(Trp,5-羟色胺的前体)在穿过血脑屏障(BBB)的氨基酸转运体上竞争,因此高血Phe浓度还导致入脑的Tyr和Trp的降低,进一步影响神经元中神经递质和蛋白质生物合成对它们的可获得性。
多巴胺和5-羟色胺的可获得性至关重要,因为这些神经递质参与各种功能,尤其是在作为高级认知功能的主要位点的前额皮质(PFC)中。有人提出,在仍然控制饮食且血浆Phe浓度落入由此推荐水平的PKU患者中,多巴胺和5-羟色胺的代谢均有缺陷,正如脑脊液检测显示这些神经递质的低水平代谢物。同时,对于早先和持续治疗的患有PKU的儿童的研究表明了执行功能包括策略处理、处理速度、问题解决、非语言性智力、工作记忆和注意灵活性方面的缺陷。
PKU病理生理学的关键是血液中的Phe水平的升高。目前荷兰对PKU的治疗特点是将儿童(0-12岁)的这些水平控制在120μmol/l到360μmol/l之间并在12岁后将其控制在120μmol/l到600μmol/l之间。如果不治疗,Phe水平可升至1000到2000μmol/l。由于患者常常在控制节食上存在困难,因此该水平随时会处于之前提到的水平之间。
目前PKU的营养治疗着重于降低饮食中苯丙氨酸的摄入。这样的饮食应终身保持,但在儿童和青春期中尤其重要。许多研究已经显示完全消耗饮食中的苯丙氨酸几乎不可能。患者总是想吃除作为蛋白质来源的基于氨基酸的当前医疗食品以外的食物。鉴于血液中苯丙氨酸水平几乎总是高于推荐值,需要一种能够降低PKU患者血液中苯丙氨酸水平的产品来解决PKU患者的饮食控制中的实际问题。
本发明的目的是提供一种用于治疗PKU患者的组合物,其中该组合物包括两种或更多活性成分的组合,当PKU患者的饮食中含有大量Phe时,该成分的组合能有效降低或正常化患者血液中苯丙氨酸水平,或将血液中的苯丙氨酸水平有效保持在非病理范围内。
本发明的另一个目的是提供可用于降低血液中苯丙氨酸水平的改良饮食产品。
发明内容
发明人惊讶地发现这样的组合物,其包含选自DHA、DPA和EPA的ω-3脂肪酸和选自尿苷源和胞苷源的嘧啶衍生物、尤其是DHA和UMP,可降低血液中的苯丙氨酸浓度。该发现是一项科学认可的PKU小鼠模型研究的完全意外的结果。将这些接受基于DHA和UMP的饮食(用不同氨基酸苯丙氨酸水平补充)或接受没有DHA和UMP的对照饮食的PKU小鼠(C57/Bl6enu2)与接受对照饮食的野生型(WT)小鼠进行比较。饮食治疗从出生后第31天开始并持续三个月。令人惊讶地发现接受DHA和UMP饮食的PKU小鼠相比接受对照饮食的PKU小鼠具有更低的血液苯丙氨酸水平。(见图1)。
因此,本发明涉及一种组合物,其包括(i)选自DHA、DPA和EPA的一种或多种ω-3脂肪酸,和(ii)选自尿苷源和胞苷源的一种或多种嘧啶衍生物,其用于降低或正常化PKU患者的血液中苯丙氨酸水平或用于PKU患者的血液中苯丙氨酸水平进行饮食控制。
根据本发明,选自DHA、DPA和EPA的一种或多种ω-3脂肪酸和/或选自尿苷源和胞苷源的一种或多种嘧啶衍生物通常在所述组合物中用作活性成分。所述组合物可包括一种或多种其它成分,其可对于本发明的预期用途具有有益效果,尤其是维生素B、甲基供体(如胆碱)、磷脂或抗氧化剂(如维生素C、硒、维生素E)。
所述组合物可以是含有根据本发明用途的所述活性成分和一种或多种药学上可接受的赋形剂的药物组合物。优选地,根据本发明用途的所述活性成分作为营养组合物的一部分或与营养组合物联合给予。
因此,本发明还涉及一种营养组合物,其包含蛋白质、脂质和碳水化合物,其中蛋白质至少提供不同于苯丙氨酸的所有必需氨基酸,并任选地提供苯丙氨酸,如果存在,苯丙氨酸浓度为0-10mg/克蛋白质;脂质包含基于总脂质含量的总浓度为至少0.05重量%的选自DHA、DPA和EPA的一种或多种ω-3脂肪酸;以及选自尿苷源和胞苷源的一种或多种嘧啶衍生物。所述选自尿苷源和胞苷源的一种或多种嘧啶衍生物通常以至少1
μmol/100千卡营养组合物的总浓度存在。这样的营养组合物特别适用于本发明的用途。
发明详述
本发明涉及包含一种或多种ω-3脂肪酸、尿苷或胞苷或其等同物的组合物,及其用于降低或正常化PKU患者的血液中的苯丙氨酸水平的用途。
如本文所使用的,除非另有说明或上下文另有规定,术语“或”还意味着“和”。因此,“选项A或B”是指任何选项A、B和A和B。
除非另有说明,此处使用的术语“一种”或“一个”意思是“至少一种/至少一个”。
除非另有说明,当指代单数名词(例如,化合物、添加剂等)时,包括复数。
除非另有说明,当在此提及酸如脂肪酸、氨基酸或叶酸时,该术语意指包括所述酸的共轭碱(例如叶酸盐)、所述酸的盐和所述酸的衍生物(例如脂肪酸酯,如甘油三酯),它们能被身体转化为所述酸。
出于清楚和简洁的目的,各特征在本发明中被描述为相同或单独的实施方式的一部分,然而,应理解本发明的范围可包括具有所有或一些所述特征的组合的实施方式。
蛋白质
术语“蛋白质”定义为由一种或多种氨基酸构成的任何化合物;该术语尤其包括游离氨基酸、其盐、肽、水解蛋白质和完整蛋白质。
与没有PKU的人相比,PKU患者必须降低苯丙氨酸(Phe)的摄入量以保持血液和脑中的Phe水平在正常范围内。因此,在有利的实施方式中,根据本发明(的用途)的组合物基本不含苯丙氨酸或具有相对低的苯丙氨酸水平。因此,所述组合物有利地包含0-10mg Phe/克蛋白质,尤其是0-1mg Phe/克蛋白质,优选地为0-0.1mg Phe/克蛋白质。
低水平通常意味着Phe的含量低于相当的(营养)组合物,例如不打算给予PKU患者的相同类型的(营养)产品。
在优选的实施方式中,根据本发明的(用途的)组合物包括酪蛋白-糖-巨肽(caseino-glyco-macropeptide)(cGMP)。除cGMP蛋白质源以外,优选添加不同于Phe的补充型必需氨基酸作为作为蛋白质源,以补偿GMP蛋白质中少量存在的氨基酸。与游离氨基酸相比,使用cGMP作为营养产品的蛋白质源的优点是cGMP具有更好的口味、低渗透压和平衡的氨基酸分布。而且,cGMP没有Phe或Phe含量低(例如,牛cGMP的氨基酸序列没有Phe单元,但可商业获得的获得自牛奶的cGMP可能包含来自其它牛奶蛋白质组分的微量的Phe)。这使得该蛋白质理想地适用于PKU患者的饮食。蛋白质源优选地包括约30重量%到约70重量%的酪蛋白-糖-巨肽和约70重量%到约30重量%的补充型游离氨基酸。
优选地,根据本发明的(用途的)所述组合物提供过量的Tyr以补充PKU患者将Phe代谢为Tyr的能力缺陷。优选地,根据本发明的(用途的)组合物的Tyr含量为7-15重量%总氨基酸含量,甚至优选地为8-13重量%以及甚至优选地为9-12重量%总氨基酸含量。
优选地,蛋白质源提供根据本发明的(用途的)组合物的干重的约7%到约80%,更优选7-20%,最优选7-13%。在一个适用于婴幼儿配方的优选的实施方式中,蛋白质源提供根据本发明的(用途的)组合物的能量的约7%到约13%。能量百分比可基于组合物的成分对卡路里值的通常已知的贡献来确定;对于蛋白质和可消化的碳水化合物,卡路里值通常为4千卡/克,对于脂肪,为9千卡/克。
优选地,根据本发明的(用途的)营养组合物包括不同于苯丙氨酸的所有必需氨基酸,即缬氨酸、苏氨酸、色氨酸、甲硫氨酸、亮氨酸、异亮氨酸、赖氨酸和组氨酸。在另一个实施方式中,所述营养组合物包括所有必需氨基酸,包括苯丙氨酸。
对特定类型的营养组合物而言,合适的氨基酸分布是本领域已知的,并且可基于PKU患者的已知的营养配方,例如PKU Anamix Junior、PKU Lophlex Advance或PKU AnamixInfant(均可获得自纽迪希亚先进医学营养公司(Nutricia Advanced MedicalNutrition))。
而且,根据本发明的(用途的)营养组合物可基于例如WO
2011/078677中描述的任何适于PKU患者的组合物,其关于那些组合物的含量通过引用被纳入本文,尤其是表2和3,限制条件是根据本发明的(用途的)组合物可包括Phe并且包括所述嘧啶衍生物和所述ω-3脂肪酸。
而且,根据本发明的营养组合物可基于例如WO 2013/133711中描述的任何适于PKU患者的组合物,其关于那些组合物的含量通过引用被纳入本文,尤其是表1、2a和2b,限制条件是根据本发明的(用途的)组合物可包括Phe并且包括所述嘧啶衍生物和所述ω-3脂肪酸。
而且,根据本发明的营养组合物可基于例如WO 2015/002537中描述的任何适于PKU患者的组合物,其关于那些组合物的含量通过引用被纳入本文,尤其是实施例1-10的组合物,限制条件是根据本发明的(用途的)组合物可不含Phe或可以包含较低量(优选小于10mg/g蛋白质)的Phe,并且包含所述嘧啶衍生物和ω-3脂肪酸。
而且,雀巢(Nestlé[Engl])2010;68:58–69表2的内容通过引用结合于此,其提供PKU患者日常蛋白质、能量和Phe摄入量的指南。
尤其,根据本发明的(用途的)营养组合物包括一种或多种氨基酸,优选地至少是不同于苯丙氨酸的必需氨基酸,更优选表1中给出的相对量的所有氨基酸。
表1
氨基酸 | 优选的范围 |
g/100g干重 | |
丙氨酸 | 0.5-4.0 |
精氨酸 | 1.0-7.0 |
天冬氨酸 | 0.8-6.5 |
半胱氨酸 | 0.4-3.5 |
谷胺酰胺 | 1.0-5.0 |
甘氨酸 | 0.8-6.0 |
组氨酸 | 0.5-4 |
异亮氨酸 | 0.5-6.0 |
亮氨酸 | 1.5-10 |
赖氨酸 | 1-7 |
甲硫氨酸 | 0.2-2 |
苯丙氨酸 | 0-0.3 |
脯氨酸 | 1-8 |
丝氨酸 | 0.5-5 |
苏氨酸 | 0.6-6 |
色氨酸 | 0.2-2.5 |
酪氨酸 | 1.0-9.0 |
缬氨酸 | 1.0-7.0 |
脂质
术语脂质包括通常在食品中被认为是脂肪或油的任何可食用脂肪物质,包括甘油三酯、脂肪酸和磷脂。
脂质的总量优选为干物质的10到30重量%,和/或液体组合物的每100ml 2到6g脂质。
长链多不饱和脂肪酸(LCP)
根据本发明的(用途的)组合物中的LCP包含选自二十二碳六烯酸(22:6ω-3;DHA)、二十二碳五烯酸(22:5ω3;DPA)和二十碳五烯酸(20:5ω-3;EPA)的至少一种LCP。
本发明的组合物优选至少含有DHA。
所述组合物优选包括DHA、和选自EPA和DPA的至少一种DHA前体,更优选DHA和EPA。本发明的组合物更优选包括DHA、DPA和EPA。
LCP优选地作为选自甘油三酯、甘油二酯、单甘酯、游离脂肪酸、脂肪酸的盐、脂肪酸的酯(甘油酯除外)、磷脂、溶血磷脂(lysophospholipid)、甘油醚、脂蛋白、神经酰胺、糖脂的一种或多种化合物提供。优选地,本发明的组合物包括甘油三酯形式的DHA。
优选给予所述组合物以提供每天(一共)400-5000mg选自DHA、EPA和DPA的ω-3脂肪酸,更优选每天500-3000mg,最优选每天1000-2500mg。本发明的用途优选包括DHA的给予,优选以每天300-4000mg的量,更优选每天500-2500mg。
如本文所述的每天的量是指由本发明的组合物提供的日剂量单位中的量。这种日剂量单位可以是单一剂量,也可以分成两次或三次,或甚至更多每日份。
本发明的组合物优选包括基于总脂肪酸的0.1-40重量%DHA,优选地基于总脂肪酸的0.3-36重量%DHA,更优选基于总脂肪酸的1.0-30重量%DHA。本发明的组合物优选包括基于总脂肪酸的0.05-20重量%EPA,优选地基于总脂肪酸的0.2-10重量%EPA,更优选基于总脂肪酸的0.5-10重量%EPA。DHA的重量与EPA和DPA(ω-3)之和的比例优选大于1.0,更优选为1.2-10,更优选为2-8。上述比例和量考虑并优化了几个方面,包括口味(过高的LCP水平会降低口味评价,导致降低的依从性)、DHA与其前体之间的平衡,以确保最大剂量与产品配方(如液体形式、条棒或胶囊)的可能性相关的最佳效果。
本发明的组合物中的具有至少20个碳原子的ω-6脂肪酸和具有至少20个碳原子的ω-3脂肪酸的重量与重量之比有利地低于0.5,优选地低于0.2。具有至少18个碳原子的ω-6脂肪酸与具有至少18个碳原子的ω-3脂肪酸优选的重量与重量之比为0.05-1,更优选0.1-0.6,最优选0.15-0.4。
本发明的组合物优选含有选自海洋油和蛋类脂质的至少一种油。海洋油优选选自鱼油和藻油。本发明的组合物优选包含含有DHA、EPA和优选DPA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包括饱和脂肪酸和/或单不饱和脂肪酸。饱和脂肪酸的量优选基于总脂肪酸为6-60重量%,优选12-40重量%,更优选基于总脂肪酸为20-40重量%。尤其,基于总脂肪酸,C14:0(肉豆蔻酸)+C16:0(棕榈酸)的量优选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到40重量%,更优选15到30重量%。包括饱和脂肪酸和/或单不饱和脂肪酸提供能量来源,协助前驱对象的活动。
磷脂
磷脂是胆碱的来源,并且可以防止运动后血浆胆碱水平的下降。胆碱是参与学习和记忆以及肌肉活化的神经递质乙酰胆碱的形成所必需的。这些优势已经在相对低的磷脂水平下实现。因此,在胆碱之外,根据本发明的组合物可包括一种或多种磷脂。
优选地,本发明的组合物包括一种或多种磷脂,优选基于脂质总重的0.1-50重量%磷脂,更优选0.5-20重量%,更优选基于脂质总重的1到5重量%。
如果使用,总磷脂日剂量通常在50到5000mg的范围内,尤其是100到2000mg的范围内,更特别150到1200mg的范围内。
如本文所使用,术语磷脂包括溶血磷脂、脱酰磷脂和甘油磷脂。尤其,所述磷脂选自磷脂酰胆碱(PC)、磷脂酰乙醇胺(PE)、磷脂酰丝氨酸(PS)、磷脂酸(phosphatidate)、磷酸肌醇(如磷脂酰肌醇(PI)、磷脂酰肌醇磷酸、磷脂酰肌醇二磷酸、磷脂酰肌醇三磷酸)和鞘磷脂。在特定的实施方式中,所述组合物包括选自磷脂酰丝氨酸、磷脂酰肌醇、磷脂酰胆碱和磷脂酰乙醇胺的至少两种不同的磷脂。卵磷脂、例如大豆卵磷脂是可商业获得的磷脂源。牛奶脂肪也可用作磷脂源,例如以磷脂浓缩物的形式。
嘧啶衍生物
根据本发明的(用途的)组合物包括选自尿苷源和胞苷源的嘧啶衍生物。当向人体给予时,可通过分别提供尿苷等同物、胞苷等同物的任何化合物来提供这些源。术语“核苷等同物”(一般用于核苷),分别为尿苷等同物或胞苷等同物(用于这些特定的核苷),通常在本领域中用于如下化合物,包括核碱基(如核碱基本身)、核苷、单核苷酸(核苷的单磷酸酯、二磷酸酯或三磷酸酯)、寡核苷酸、多核苷酸及其生理学上可接受的衍生物,其可以在体内转化为核苷或核苷酸本身。
这样的衍生物的实例包括各种酯。酰基可以是任何生理上可接受的有机酸残基,特别是C2-C24有机酸残基。嘧啶源的优选酰基化形式是其中(脱氧)核糖已被乙酸、正己酸、辛酸或正癸酸酰基化的那些,因为这些增加了尿苷或胞苷源的生物利用度。使这些中链脂肪酸与核苷反应、例如与核苷的5'位反应的方法本身在本领域中是已知的,并包括常规的酰基化方法。在另一种实施方式中,用PUFA(例如ω-3PUFA)来酰基化尿苷源。WO 2002/088159涉及尿苷酯,其可根据本发明使用。该公开关于(脱氧)尿苷酯的内容通过引用并入本文。(其它)合成的化合物也可合适地作为核苷源(例如核苷的酰基化衍生物、例如三乙酰尿苷)而含有。
这样的等同物能够增加体内(例如血液、肝和脑等组织)核苷的活性形式的内源水平。有用的成分包括植物、动物、细菌、藻类或酵母材料的提取物,以及合成的化合物。
本发明的组合物优选地包括尿苷和/或其等同物,优选选自尿苷(即核糖基尿嘧啶)、脱氧尿嘧啶(脱氧核糖基尿嘧啶)、尿苷磷酸盐(UMP、dUMP、UDP、dUDP、UTP、dUTP)、核碱基尿嘧啶的至少一种尿苷或其等同物,其中任选地所述核苷酸的(脱氧)核糖的一个或多个羟基部分被酰基化。
合适的胞苷源特别包括胞苷、脱氧胞苷和衍生的(脱氧)胞苷。衍生的脱(氧化)胞苷优选地选自CMP、CDP、CTP dCMP、dCDP和dCTP,其中任选地所述核苷酸的(脱氧)核糖的一个或多个羟基部分被酰基化。
本发明的组合物优选包括选自单磷酸尿苷(UMP)、二磷酸尿苷(UDP)和三磷酸尿苷(UTP)的尿苷磷酸盐。本发明的组合物最优选包括UMP,因为UMP最有效地被身体吸收。因此,在本产品中包含UMP使得能够在最低剂量和/或向受试者给予少量的情况下得到高效率。优选地,本发明的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%。本发明的组合物优选地被用于一种包括以每天0.08-3g的量给予嘧啶衍生物(尿苷源和胞苷源的累积量)的方法,优选地每天0.1-2g,更优选每天0.2-1g。
组合物的用途优选包括使用以0.4mg-3000mg的浓度提供尿苷源的组合物(以UMP/100千卡计算),优选0.6mg-2000mg(以UMP/100千卡计算),更优选-1mg–1000mg(以UMP/100千卡计算)。
优选每天给予1-37.5mg,尿苷等同物(以UMP/千克体重计算)。重量基准的等同物的所需的剂量可由使用等同物的分子量和UMP的分子量(后者为324道尔顿)得到的等摩尔量的UMP的剂量计算出。
如果存在,胞苷源的含量通常为0.4到3000mg,以单磷酸胞苷/100千卡组合物计算。
选自尿苷源和胞苷源的嘧啶衍生物优选以至少1.2μmol/100千卡组合物的量存在于根据本发明的组合物中,更优选1.2μmol/100千卡--9.26mmol/100千卡组合物,更优选1.8μmol/100千卡-6.173mmol/100千卡,更优选3μmmol/100千卡-3.1mmol/100千卡的所述嘧啶衍生物(尿苷/胞苷)单元。
尽管胞苷是尿苷的前体,在本发明的组合物中包括一种或多种尿苷等同物将更有效和高效。因此,优选60-100重量%、尤其是90-100%的嘧啶衍生物含量由一种或多种尿苷源构成。
甲基供体
由于PKU患者的蛋白质缺乏型饮食,经常存在于如肉类、鱼类和乳制品中的甲基供体的摄入量可能会减少,使得它们不能被PKU患者足量摄入。因此,本发明的组合物优选含有显著的量的甲基供体。
甲基供体是给予人类个体体内时可提供甲基、亚甲基或甲酰基的食品级化合物。本发明的组合物中包括的甲基供体优选选自丝氨酸、蛋氨酸、胆碱、甜菜碱、二甲基甘氨酸和肌氨酸及其衍生物。甲基供体可以作为纯化合物(如其盐和化合物形式)本身包括在其中,其中甲基供体与氨基酸共价结合,并且其分子量小于600道尔顿。
胆碱是指含有N,N,N-三甲基乙醇铵阳离子的各种季铵盐。更具体地,胆碱选自碱阳离子、胆碱盐或酯(如氯化胆碱、胆碱酒石酸盐、胆碱硬脂酸盐等),或分离出胆碱的化合物(如甘磷酸胆碱、鞘磷脂、胞苷-二磷酸-胆碱或胞磷胆碱或CDP-胆碱),酰基甘油磷酸胆碱例如卵磷脂、溶血卵磷脂、甘油磷脂酰胆碱和其任何混合物。本发明的组合物优选包括胆碱盐,尤其是氯化胆碱和/或磷脂酰胆碱。
本发明的方法优选包括每天给予多于50mg的胆碱,更优选每天80-2000mg胆碱,更优选每天120-1000mg胆碱,最优选每天150-600mg胆碱。本发明的根据本发明的(用途的)组合物优选每100千卡包括10-2000mg胆碱。优选至少10mg/100千卡,更优选至少20、30、40、50、60、70、80、90、100mg/100千卡。上述下限的优选上限是2000mg/100千卡,更优选1750、1500、1250或1000mg/100千卡。
甲基供体的总日剂量可通过对胆碱定义等摩尔量并校正该甲基供体的分子量来计算。总日剂量优选至少为0.48mmol甲基供体/天,更优选至少0.77mmol/天,更优选至少1.15mmol/天,最优选至少1.22mmol/天。总日剂量优选20mmol或更少,更优选10mmol或更少,最优选10mmol或更少。在组合物为液体产品的情况下,本方面的组合物优选每100ml包含0.48-30mmol甲基供体,优选1.9-10mmol甲基供体/100ml。
如实施例1和2所示,包含选定的甲基供体可能会使PKU患者受益。
维生素B
在一实施方式中,根据本发明的(用途的)组合物包括选自维生素B6、维生素B9和维生素B12的至少一种维生素B。维生素B6包括吡哆醇、吡哆醛、吡哆胺和吡哆醇盐例如盐酸盐或磷酸盐。维生素B9也称为叶酸或叶酸盐。维生素B12也被称为钴胺素。
尤其,包含维生素B6、维生素B12和维生素B9的组合可实现良好的结果。
应当注意,维生素B家族的一种或多种其它维生素可存在于根据本发明的(用途的)组合物中。这样的其它维生素B包括维生素B1(硫胺素)、维生素B2(核黄素)、维生素B3(烟酸或烟碱胺)、维生素B5(泛酸)、和维生素B7(生物素)。
维生素B以有效量给予,该量取决于所使用的维生素B的类型。作为经验法则,合适的最小或最大剂量可基于已知的饮食推荐进行选择,例如美国国家科学院医学研究所(IOM)和科学食品委员会的(欧盟的一个科学委员会)推荐,本文公开的信息以及可选的有限量的常规测试。最小剂量可以基于估计的平均需要量(EAR),尽管较低的剂量可能已经有效。正如IOM所建议的,最大剂量通常不会超过容许的上限摄入量(UL)。
如果存在,维生素B6通常以0.5到10mg的日剂量提供,特别在0.75到5mg的范围,更特别在0.9到2.5mg。如果根据本发明的组合物中存在,维生素B6浓度通常为0.05-10mg维生素B6/100千卡,优选地0.1-1mg/100千卡。如果存在,根据本发明的组合物(用途)中的维生素B12含量通常为0.05–5μg维生素B12/100千卡,优选0.1到2.5μg/100千卡,甚至更优选0.2到2.0μg/100千卡。如果存在,维生素B9通常以50到5000μg的日剂量提供,特别是150到1000μg的范围,更特别是200到1000μg的范围。
(v)抗氧化剂
根据本发明的组合物可包括选自维生素C、维生素E和硒的抗氧化剂。维生素C可作为游离酸(抗坏血酸)或盐存在,例如抗坏血酸钠或抗坏血酸钾。维生素E的合适来源包括(α-)生育酚和生育三烯酚。硒的合适来源包括硒酸盐和亚硒酸盐。
抗氧化剂将以有效剂量施用。作为经验法则,合适的最小或最大剂量可基于已知的饮食推荐进行选择,例如美国国家科学院医学研究所(IOM)和科学食品委员会的(欧盟的一个科学委员会)推荐,本文公开的信息以及可选的有限量的常规测试。最小剂量可以基于估计的平均需要量(EAR),尽管较低的剂量可能已经有效。正如IOM所建议的,最大剂量通常不会超过容许的上限摄入量(UL)。如果在组合中存在,维生素C通常以20到1,200mg的日剂量提供,特别是30到400mg的范围,更特别是35到120mg的范围。如果在根据本发明的营养或药物组合物中存在,维生素E通常以8到200mg的日剂量提供,特别是20到140mg的范围,更特别是35到100mg的范围。
如果在根据本发明的营养或药物组合物中存在,硒通常以40到400μg的日剂量提供,特别是50到200μg的范围,更特别是55到80μg的范围。
任选地,可以存在一种或多种的(v)选自维生素C、维生素E和硒的抗氧化剂之外的抗氧化剂。
其它组分
此外,根据本发明的(用途的)组合物可包括一种或多种其它微量营养物,例如选自(其它)维生素、矿物质和微量元素、牛磺酸和肌醇的一种或多种微量营养物。尤其,在一个优选实施方式中,所述组合物包括维生素A和/或维生素D。此外,所述组合物可包含膳食纤维。
营养组合物
根据本发明的组合物优选是包括碳水化合物、脂质和蛋白质的营养组合物。优选地,所述组合物还包括维生素、胆碱、抗氧化剂和/或矿物质(尤其是上述定义的那些)。根据要求保护的发明,营养组合物中优选含有(通常由正常蛋白质来源,如乳制品和肉类提供的)维生素A和D,脂质优选包含选自EPA、DHA和DPA的多不饱和脂肪酸。根据本发明的营养组合物还包括选自尿苷源和胞苷源的嘧啶衍生物,优选尿苷和/或其等同物,优选选自尿苷(即核糖基尿嘧啶)、脱氧尿嘧啶(脱氧核糖基尿嘧啶)、尿苷磷酸盐(UMP、dUMP、UDP、UTP)、核碱基尿嘧啶和酰基化尿苷衍生物的至少一种尿苷或其等同物,最优选地单磷酸尿苷。
在特定的实施方式中,所述营养组合物提供完全的营养,即提供以提供健康的营养摄入的合适的量提供维生素,矿物质,和碳水化合物、蛋白质、和脂肪形式的食物能量的营养。有利地,完全的营养还包括膳食纤维和/或益生菌。用于完全营养的合适组合物在本领域中是已知的,并且本发明的营养组合物可基于特殊医疗用食品法规(FSMP,EC,http://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX:31999L0021),条件是根据本发明的(用途的)营养组合物包含一种或多种所述嘧啶衍生物和一种或多种所述ω-3脂肪酸。
PKU患者的治疗
根据本发明的(用途的)组合物、尤其是营养组合物特别适于PKU患者的治疗。当Phe高于理想浓度、或最大程度地接近理想浓度时,其可降低患者血液中的Phe水平。因此,组合物也可用于将Phe浓度正常化至正常(非病理性)水平。然而,本发明对于PKU患者血液中Phe水平的营养控制(饮食控制)也非常有用。PKU患者的营养控制目标是保持血浆phe浓度,以支持健康的成长、发育和心理功能,同时提供营养完全的饮食。Erin L.MacLeod和Denise M.NeyAnn描述了如何在雀巢[Engl]2010;68:58-69中进行PKU患者的营养控制。原则上,待治疗的对象可以是任何PKU患者,尽管本发明特别有利于具有升高的Phe水平的PKU患者,更特别是具有毒性水平的Phe的患者、或者特别有利于治疗通常因不符合无Phe或或Phe限制饮食而具有增加的暴露于过高量的Phe的PKU患者。
被认为具有毒性的血液中最低的Phe水平在一定程度上取决于患者,特别是患者的年龄。此外,不同国家在血液中Phe水平的推荐指南方面存在一些差异。通常,血液中约1500μmol/l的水平被认为是有毒性的,但毒性可能会出现在相当低的水平中,这取决于患者的年龄等因素。
下表显示了某些国家不同患者组血液中推荐的Phe水平。
根据本发明的血液中Phe水平的正常化尤其指将Phe浓度从高于推荐的最高水平的值降低到推荐的范围内的浓度。饮食控制旨在将血液中的Phe浓度保持在推荐范围内。
典型地,所述组合物用于将血液中的苯丙氨酸水平降低、将血液中的苯丙氨酸水平正常化、或将血液中的苯丙氨酸水平保持在低于1200μM的浓度,尤其是低于900μmol/l,更尤其低于600μmol/l。
通常,0-10岁年龄的人类儿童的根据本发明的(用途的)组合物的治疗旨在将患者血液中的苯丙氨酸浓度降低、正常化或维持在40-360μmol/l,优选120-360μmol/l的范围内。
通常,10-12岁年龄的人类儿童的根据本发明的(用途的)组合物的治疗旨在将患者血液中的苯丙氨酸浓度降低、正常化或维持在低于900μmol/l,尤其是低于600μmol/l,优选低于480μmol/l,更优选120-360μmol/l。
通常,12-20岁年龄的人类儿童的根据本发明的(用途的)组合物的治疗旨在将患者血液中的苯丙氨酸浓度降低、正常化或维持在900μmol/l,尤其低于600μmol/l,优选低于480μmol/l,更优选在120-600μmol/l的范围内。
通常,20岁以上年龄的人类的根据本发明的(用途的)组合物的治疗旨在将患者血液中的苯丙氨酸浓度降低、正常化或维持在低于1200μmol/l,尤其是低于900μmol/l,具体低于700μmol/l,更具体600μmol/l或更低。范围的下限可以是0,尤其是120μmol/l。
在妊娠的情况下,治疗通常旨在将患者血液中苯丙氨酸浓度降低,正常化或维持在120-360μmol/l浓度的范围内。
尽管在用根据本发明的(用途的)组合物进行治疗时,建议将Phe的每日摄入量限制为低于通常对未患有PKU的受试者推荐的每日摄入量,但本发明降低了含有大量Phe的食品消耗的不利影响的风险。
该组合物通常经口给予,尽管另一种给予方式如管饲或作为栓剂是可行的。
接下来,通过许多实施例来说明本发明。
实施例1 PKU小鼠模型(C57Bl/6 Pahenu2)中的营养产品的Phe降低作用
材料与方法
小鼠模型
在该实验中,使用C57Bl/6 Pahenu2小鼠模型。从自行育种中获得雄性和雌性纯合(PKU)小鼠和野生型(WT)同窝仔畜。在相同的12:12光照/黑暗周期、温度和湿度条件下,将雄性和雌性小鼠饲养在不同的房间中。将60个PKU个体和10个WT小鼠细分为7个实验组,接受不同饮食。所有饮食的基本配方是AIN93G(Research Diet Services,Wijk bijDuurstede)。
饮食
WT个体接受正常食物,Phe含量为8.8g/kg。当补充Fortasyn(N.V.Nutricia)成分且三种不同Phe含量随机化时,产生了六组PKU小鼠。(FC)是营养物的组合,包括抗氧化剂(硒、维生素E)、尿苷-5'-单磷酸、胆碱、维生素B12和B6、叶酸、磷脂、二十二碳六烯酸(DHA)和二十碳五烯酸。
这产生了以下的组。如之前对WT个体所述,前两组接受相同的AIN93G正常食物(Phe含量8.8g/kg)。其中一组接受没有FC的饮食(对照),另一组接受含有FC的该饮食,这些组分别被称为:“Phe8.8”和“Phe8.8+FC”。与FC组相比,对照组接受较少量的Se、维生素E、胆碱、维生素B12、B6和叶酸。另外,FC组接受EPA/DHA/UMP和磷脂(卵磷脂),而对照组不补充这些成分。两组接受低Phe饮食。这种饮食含有4.0g/kg Phe并且无或有FC,分别称为“Phe4.0”和“Phe4.0+FC”。最后,创建两个中Phe含量组,其中Phe水平被设定在高Phe和低Phe组之间。中Phe饮食含量为6.4g/kg,无FC(Phe6.4)和有FC(Phe6.4+FC)。所有的饮食都符合实验动物的最低营养要求。这些动物可随意获得这些饮食和水12周。在实验开始时(出生后第28天(PND 28)),将动物断奶并通过尾静脉穿刺取血样。在PND 31,将动物暴露于圆形露天场地并后续增加不同饮食持续12周。在实验的第一周(PND 31~PND 38)中每天在16:00-18:00之间对每只动物称重,此后每周一次。每天测量食物的摄入。在这12周内,在PND59和87进行采血。在PND115,通过心脏穿刺实施安乐死以收集血液,然后灌注。本研究中关于动物的所有处理均由荷兰格罗宁根大学伦理委员会批准。
血液收集
用三种不同的技术采集血样。在PND 28,收集一小块尾部组织用于基因分型。在此过程之后立即从尾部尖端的伤口采集血液样品。在PND 59和87,通过尾静脉采样收集血样。在两种技术中,在将血液转移至滤纸之前,使用Na-肝素化的微血细胞比容管(VITREX,ISO12772,REF 161313)来采集血液。在PND115,通过腹膜内(ip)注射戊巴比妥来麻醉动物。当后爪反射不再存在时,进行心脏穿刺。将收集的血液储存在用肝素锂(Sarstedt,REF41.1393.005)准备的微管中,然后在4℃以12800rpm离心血液样品10分钟。分析前收集血浆并保存在-80℃。
氨基酸分析
在干血斑中,使用高效液相色谱串联质谱法定量苯丙氨酸和酪氨酸。将血液收集在滤纸上并风干至少24小时。用直径4毫米的干血斑进行撮取,并留在含有氘化苯丙氨酸和酪氨酸作为内标的甲醇中洗脱。使用Nexera LC30(Shimadzu,日本东京)进行液相色谱分析。使用API-3000(AB-Sciex,弗雷明汉,美国)进行质谱分析。
为了测量全血浆中的氨基酸(除色氨酸外),将样品涡旋并以20.800rcf离心4分钟。离心后,将85μl上清液移液至胶囊中。加入磺基水杨酸中的正亮氨酸作为内标(1:1v/v)。通过高效液相色谱法(HPLC)测量氨基酸浓度,然后在Biochrom 30分析仪(法玛西亚生物技术公司(Pharmacia Biotech),剑桥,英国)上进行柱后茚三酮衍生化。
统计学分析
使用Shapiro-Wilk正态性检验测试血液苯丙氨酸值的正态性。只有WT个体和Phe4.0组没有正态分布值。尽管有这些发现,但进行单因素方差分析,用Bonferonni作为事后检验。使用Shapiro-Wilk正态性检验测试血液苯丙氨酸摄入值的正态性。WT个体表现出非正态分布(p=0.0482)。尽管所有其他组都显示正态分布的数据,但我们使用Bonferonni事后检验进行了单因素方差分析。用Pearson相关来检验绝对Phe-摄入和血液中Phe水平之间的相关性。通过Fisher r-到-z变换,探索了相关性之间的显著差异。
PKU病理生理学的关键是血液中的Phe水平的升高。目前的荷兰的PKU治疗方案的特点是将儿童(0-12岁)的这些水平控制在120μmol/L到360μmol/L,12岁起控制在120μmol/l到600μmol/l之间。若不治疗,Phe水平可升高至1000和2000μmol/l。由于患者经常难以维持该饮食,其水平可能随时处于前面提到的水平之间。在目前的实验中,不同的Phe含量被提供给动物以在某种程度上模拟这些不同的患者组。
图1A-1E中的结果显示血液中Phe水平随着Phe摄入量的减少而下降,但令人惊讶的是,两组中Phe摄入量最高的测试组别(Phe8和Phe6)在统计学上显著低于安慰剂组。这表明FC组中的其他成分能够降低血液中的Phe水平。
图1B描述了血液中的Phe水平,单向方差分析揭示了PKU小鼠中Phe8.8和Phe8.8+FC以及Phe6.4和Phe6.4+FC之间的显著差异,如星号所示。
实施例2 PKU小鼠模型(BTBR PKU小鼠)中的营养产品的Phe降低作用
在第二组实验中,进行相同的操作,但实施例2进行了以下修改:使用的小鼠具有相同的突变(Pahenu2),但遗传背景是BTBR上而不是C57Bl/6。另外,现在有6个组别:接受正常食物的野生型(WT),WT+FC,接受正常食物的PKU(Phe 6.2),接受正常食物+FC的PKU,接受低Phe(2.2)的PKU和接受低Phe+FC的PKU。
在四月龄时,在将血液转移到滤纸上并在如上所述分析Phe水平之前,通过尾静脉采样将血液收集到Na-肝素化的微量血细胞比容管(VITREX,ISO 12772,REF 161313)中。
图2描述了血液中的Phe水平,单因素方差分析揭示了PKU小鼠中高Phe和高Phe+FC之间的显著差异,如星号所示。
实施例3根据本发明的(用途的)示例性组合物
表2
Claims (23)
1.一种组合物,其包括(i)选自DHA、DPA和EPA的一种或多种ω-3脂肪酸,和(ii)选自尿苷源和胞苷源的一种或多种嘧啶衍生物,其用于降低或正常化PKU患者的血液中苯丙氨酸水平或用于对PKU患者的血液中苯丙氨酸水平进行饮食控制。
2.如权利要求1所述用途的组合物,其中,所述组合物还包括胆碱和/或磷脂。
3.如权利要求2所述用途的组合物,其中,所述组合物以提供0.1-5g胆碱的日剂量的量给予。
4.如前述权利要求中任一项所述用途的组合物,其中,所述组合物还包括蛋白质并且所述组合物包括0-10mg苯丙氨酸/g蛋白质,优选0-1mg/g蛋白质,更优选0-0.1mg/g蛋白质。
5.如前述权利要求中任一项所述用途的组合物,其中,所述组合物是包括脂质、可消化的碳水化合物、蛋白质的营养组合物,以基于该组合物的干重的浓度计为1-15重量%脂质,5-60重量%碳水化合物,和1-40重量%蛋白质,并进一步包括根据EC委员会指令1999/21/EC中FSMP规定所规定的维生素和矿物质。
6.如前述权利要求中任一项所述用途的组合物,其中,所述组合物包括基于该组合物的总脂质含量计的0.1-40重量%DHA,以及0.4到3000mg尿苷源,计算为单磷酸尿苷/100千卡组合物。
7.如前述权利要求中任一项所述用途的组合物,其中,其还包括选自维生素B6、维生素B12和维生素B9的至少一种维生素B。
8.如前述权利要求中任一项所述用途的组合物,其中,其还包括选自维生素C、维生素E和硒的抗氧化剂。
9.如前述权利要求中任一项所述用途的组合物,其中,所述组合物用于使人PKU患者的血液的苯丙氨酸水平降低至、使人PKU患者的血液的苯丙氨酸水平正常化至或将人PKU患者的血液的苯丙氨酸水平保持在低于1200μmol/l的浓度,优选低于600μmol/l。
10.如权利要求9所述用途的组合物,其中,PKU患者是0-10岁的人类儿童并且血液中苯丙氨酸水平被降低至、正常化至或保持在40-360μmol/l的浓度范围,尤其在120-360μmol/l的范围。
11.如权利要求9所述用途的组合物,其中,PKU患者是10-20岁的人类并且血液中苯丙氨酸水平被降低至、正常化至或保持在600μmol/l或更低的浓度范围,优选120-600μmol/l的范围,尤其是120-360μmol/l的范围。
12.如权利要求9所述用途的组合物,其中,PKU患者是20岁或以上的人类并且血液中苯丙氨酸水平被降低至、正常化至或保持在低于1200μmol/l的浓度,具体为700μmol/l或更低,优选是120-600μmol/l的范围。
13.如权利要求9所述用途的组合物,其中,PKU患者在孕期且并且血液中苯丙氨酸水平被降低至、正常化至或保持在120-360μmol/l的浓度范围。
14.如前述权利要求中任一项所述用途的组合物,其中,所述组合物经口给予。
15.一种营养组合物,其包括蛋白质、脂质和碳水化合物,其中蛋白质提供不同于苯丙氨酸的至少所有必需氨基酸,和任选的苯丙氨酸,如果存在,其以苯丙氨酸浓度0-10mg/克蛋白质存在;脂质包括选自DHA、DPA和EPA的一种或多种ω-3脂肪酸,其总浓度基于总脂质含量至少为0.05重量%;以及选自尿苷源和胞苷源的一种或多种嘧啶衍生物,每100千卡组合物提供0.4-3000mg尿苷源,计算为单磷酸尿苷/100千卡组合物,和/或0.4-3000mg胞苷源,计算为单磷酸胞苷/100千卡组合物。
16.如权利要求15所述的营养组合物,其中所述组合物包含总含量为0.001-9.26mmol/100千卡,优选0.0018-6.173mmol/100g/100千卡,更优选0.003-3.1mmol/100千卡的一种或多种嘧啶衍生物。
17.如权利要求15或16所述的营养组合物,其中所述组合物包含1-15重量%的脂质,5-60重量%的可消化的碳水化合物和1-14重量%的蛋白质,其均以所述组合物的干重计。
18.如权利要求15、16或17所述的营养组合物,其包含胆碱。
19.如权利要求15-18中任一项所述的营养组合物,其包含:
i)DHA和EPA
ii)尿苷和/或单磷酸尿苷
iii)选自维生素B6、维生素B9和维生素B12的至少一种维生素B
iv)磷脂酰胆碱和/或一种或多种其他磷脂;和
v)选自维生素C、维生素E和硒的抗氧化剂。
20.如权利要求19所述的营养组合物,其中所述组合物包含维生素B6、维生素B12、维生素B9、维生素C、维生素E、硒和选自氯化胆碱和甘磷酸胆碱的至少一种胆碱。
21.如权利要求15-20中任一项所述的营养组合物,其中,所述组合物包含选自磷脂酰丝氨酸、磷脂酰肌醇、磷脂酰胆碱和磷脂酰乙醇胺的至少两种不同的磷脂。
22.如权利要求15-21中任一项所述的营养组合物,其包含维生素A和/或维生素D。
23.如权利要求15-22中任一项所述的营养组合物,其用于如权利要求1-14中任一项的用途。
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WO2011078654A1 (en) | 2009-12-24 | 2011-06-30 | N.V. Nutricia | Low-caloric high-protein nutritional composition for the stimulation of muscle protein synthesis |
WO2012125020A1 (en) * | 2011-03-14 | 2012-09-20 | N.V. Nutricia | Method for treating neurotrauma |
WO2013129914A1 (en) * | 2012-03-02 | 2013-09-06 | N.V. Nutricia | Method for improving functional synaptic connectivity |
WO2013133691A1 (en) * | 2012-03-09 | 2013-09-12 | N.V. Nutricia | Liquid nutritional composition comprising free amino acids |
WO2015002527A1 (en) | 2013-07-05 | 2015-01-08 | N.V. Nutricia | Amino acid composition for use in the treatment of a pdd |
WO2015115885A1 (en) * | 2014-01-31 | 2015-08-06 | N.V. Nutricia | Method for reducing white matter lesions, white matter hyperintensities (wmh), leukoaraiosis or periventricular white matter disease in elderly |
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2015
- 2015-10-23 WO PCT/NL2015/050738 patent/WO2017069611A1/en active Application Filing
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2016
- 2016-10-24 EP EP16798577.9A patent/EP3364963A1/en active Pending
- 2016-10-24 US US15/770,444 patent/US20180303144A1/en not_active Abandoned
- 2016-10-24 CN CN201680075853.9A patent/CN108472278A/zh active Pending
- 2016-10-24 BR BR112018008022A patent/BR112018008022A2/pt not_active Application Discontinuation
- 2016-10-24 RU RU2018118799A patent/RU2740905C2/ru active
- 2016-10-24 WO PCT/NL2016/050729 patent/WO2017069629A1/en active Application Filing
Patent Citations (2)
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WO2014171813A1 (en) * | 2013-04-17 | 2014-10-23 | N.V. Nutricia | Nutritional composition for improving brain function in phenylketonuria |
CN104012659A (zh) * | 2014-06-26 | 2014-09-03 | 中恩(天津)营养科技有限公司 | 一种用于苯丙酮尿症儿童的配方粉及其制备方法 |
Non-Patent Citations (1)
Title |
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ERIN L. MACLEOD ET AL.: "Nutritional Management of Phenylketonuria", 《ANNALES NESTLE》 * |
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RU2018118799A3 (zh) | 2020-01-21 |
RU2740905C2 (ru) | 2021-01-21 |
BR112018008022A2 (pt) | 2018-10-23 |
RU2018118799A (ru) | 2019-11-25 |
WO2017069629A1 (en) | 2017-04-27 |
US20180303144A1 (en) | 2018-10-25 |
WO2017069611A1 (en) | 2017-04-27 |
EP3364963A1 (en) | 2018-08-29 |
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