CN107635551A - 改善膀胱功能的方法 - Google Patents
改善膀胱功能的方法 Download PDFInfo
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- CN107635551A CN107635551A CN201680028041.9A CN201680028041A CN107635551A CN 107635551 A CN107635551 A CN 107635551A CN 201680028041 A CN201680028041 A CN 201680028041A CN 107635551 A CN107635551 A CN 107635551A
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- vitamin
- bladder
- pufa
- uridine
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Abstract
本发明涉及尿苷和/或其等同物和n3‑PUFA在制备用于恢复或改善受试者,特别是患有脊髓损伤的患者的膀胱功能的产品中的用途。
Description
本发明为药学营养领域,更具体地涉及用于改善膀胱功能的组合物。在优选的方面,本发明涉及改善患有神经障碍的患者的膀胱功能。
背景技术
受损的膀胱功能、膀胱功能障碍或尿失禁是常见且严重的问题,其可能会对人的生命产生深远的影响。受损的膀胱功能的主要原因是膀胱的受损的神经功能,其通常与神经障碍例如脑损伤、脊髓损伤、骶髓损伤和外周神经损伤相关。这些神经障碍可能会干扰膀胱的神经功能。由于排尿中枢之间需要进行协调,任何这些部位的损伤常常会导致神经源性膀胱功能障碍。
由于神经系统原因受损的膀胱功能还可称为“神经源性膀胱”。神经系统例如在大脑水平、脊髓、骶髓或外周神经处任何类型的病变,可能是膀胱功能障碍的原因。
正常的膀胱功能由膀胱的逼尿肌和括约肌的协同作用调节。它们通常具有两个功能,即收集尿液和保持控制,并在必要的时候清空膀胱,而不残留尿液。逼尿肌由可以收缩以促进膀胱排空的平滑肌纤维组成。当膀胱壁被拉伸时,这将向副交感神经系统发出膀胱充满的信号,因此需要逼尿肌收缩以排出过量的尿。内外尿道括约肌通常收缩以阻止膀胱排空,并将舒张以使得尿液通过。内括约肌是自主控制的,而外括约肌可以有意控制。逼尿肌和括约肌均可呈放松或收缩的状态。
膀胱功能障碍主要可分为2类:无法存储和不能排空。无法存储主要是反射亢进的逼尿肌或反射消失的括约肌的结果。不能排空主要是由于反射消失的逼尿肌和反射亢进的括约肌。
在副交感神经中,膀胱受起源于骶髓S2-S4的传出神经供应神经支配,通过使用骨盆神经向膀胱传导。副交感神经刺激会导致逼尿肌收缩,因此膀胱的收缩导致排尿。在交感神经中,传出神经起源于T11-L2并通过使用腹下神经向膀胱和尿道传导。膀胱内的B-肾上腺素能受体会引起平滑肌细胞的松弛,而膀胱和尿道基底中的A-受体会引起这些细胞的收缩。躯体输出源于骶髓的S1-S4并穿过阴部神经,支配可有意控制的外部尿道括约肌。
膀胱和括约肌-逼尿肌功能的协调发生在大脑中,在脑桥的排尿中枢中,其在被激活时促进了尿道括约肌的松弛。该中枢与骶骨排尿中枢具有直接通路,以协调排尿,这需要括约肌的松弛和逼尿肌的收缩。当膀胱拉伸时(即发出膀胱充满的信号),骶骨的排尿中枢接收信号并触发反射性排尿。脑桥的排尿中枢随着儿童年龄的增长而逐渐成熟,所以人们能够控制排尿而不是反射性排尿。内侧额叶和胼胝体控制排尿的有意控制。
迄今为止,尚未能有效治疗神经受损的膀胱功能。
在过去的十年间,尿苷、胆碱和n-3脂肪酸如DHA作为治疗认知功能障碍和与年龄相关的记忆障碍(AAMI)的活性成分已经引起注意,参见例如WO2007/089703(麻省理工学院)和WO 2009/002165(N.V.Nutricia)。这些化合物是膜磷脂合成的限速前体。根据上述出版物,通过改善膜磷脂合成,相信可以改善认知或记忆功能。对膜磷脂的作用与特异性突触前和突触后蛋白质的增强有关。
WO 2013/066165和WO 2013/066167(N.V.Nutricia)公开了一种产品,其包含(i)尿苷和胞苷,或其盐、磷酸酯、酰基衍生物或其酯的一种或多种,和(ii)脂质部分,其包含二十二碳六烯酸(22:6;DHA)、二十碳五烯酸(20:5;EPA)和二十二碳五烯酸(22:5;DPA)或其酯的至少一种。可以通过给药组合物,特别是向阿尔茨海默病或痴呆患者给药组合物来改善识别和执行功能,例如信息处理速度、认知和心理灵活性、注意力、浏览和认知定势转换。WO2012/125020公开了一种类似的产品,其用于预防或治疗神经外伤、创伤性脑损伤、脑瘫和脊髓损伤,重点在于神经元存活。同样的产品也被证明可以在阿尔茨海默病(AD)患者的临床试验中增强膜形成和功能(Scheltens等人,Alzheimer′s&Dementia 2010,6,1-10和J.Alzheimers Dis.2012,31,225-236)。
脊髓损伤(SCI)影响全世界的大量患者。尽管由于应急药物治疗方案的进展而使得存活率增加,但没有神经保护或神经再生治疗,并且许多SCI患者患有终身运动和感觉缺失。这对患者的生活质量和预期寿命有重大影响,也代表了公共卫生费用负荷。
n-3脂肪酸在管理和改善脊髓损伤方面的疗效由Michael-Titus等人(在Trendsin Neurosciences,2014,37,30-38中)综述。Figueroa等人(在J.Neurotrauma,2013,30,853-868中)描述了预防性的n-3 PUFA给药改善脊髓损伤后膀胱功能的功能恢复。
发明内容
发明人惊奇地发现,包含尿苷和/或其等同物以及n-3 PUFA的组合物在改善膀胱功能方面,特别是改善患有正在患有神经障碍、正在从神经障碍中恢复和/或已经患有神经障碍的患者的膀胱功能是有效的。不囿于理论,相信尿苷和n-3 PUFA的混合物可以通过支持例如脊髓损伤后发生的再生过程来改善膀胱的神经功能,以及膀胱与大脑之间的连接。实施例显示本发明的组合物确实显著改善膀胱功能。在给药本发明的组合物时,膀胱功能恢复得明显更快。
因此,本发明涉及一种用于恢复或改善受试者膀胱功能的方法,其包括向受试者给药包含(i)尿苷和/或其等同物和(ii)n-3 PUFA的组合物。本发明还可以表述为(i)尿苷和/或其等同物和(ii)n-3 PUFA用于制备用于恢复或改善受试者膀胱功能的组合物的用途。
换句话说,本发明涉及用于恢复或改善受试者膀胱功能的组合物,所述组合物包含(i)尿苷和/或其等同物和(ii)n-3 PUFA。本发明还涉及(i)尿苷和/或其等同物和(ii)n-3 PUFA的结合物用于恢复或改善受试者膀胱功能。
在第一优选实施方案中,如本发明上下文所述的尿苷和/或其等同物是尿苷一磷酸。在第二优选实施方案中,n-3 PUFA选自EPA和/或DHA,优选至少DHA。在第三优选实施方案中,组合物还包含一种或多种胆碱、B族维生素,所述B族维生素优选包含或至少是叶酸,更优选至少叶酸和维生素B6,以及抗氧化剂。在第四优选实施方案中,组合物至少包含胆碱。在最优选的实施方案中,组合物还包含胆碱、叶酸、维生素B6、抗氧化剂和磷脂。在第五优选实施方案中,受试者是正在患有神经障碍、正在从神经障碍中恢复和/或已经患有神经障碍的患者,优选脊髓损伤的患者。在第六优选实施方案中,每100mL组合物包含:(i)400-800mg UMP;(ii)n-3 PUFA,其包含(a)100-500mg EPA和(b)900-1500mg DHA;(iii)50-600mg磷脂;(iv)200-600mg胆碱;(v)维生素B,其包含(a)1-5μg维生素B12,(b)0.5-3mg维生素B6和(c)200-600μg叶酸;和(vi)抗氧化剂,其包含(a)20-60mg维生素E(α-TE),(b)60-100mg维生素C和(c)40-80μg硒。在第七优选实施方案中,组合物是液体或与液体可复水(reconstitutable)的固体。
具体实施方式
本发明涉及一种用于改善受试者(受损的)膀胱功能的方法,其中所述方法包括向所述受试者给药组合物,所述组合物包含(i)尿苷和/或其等同物和(ii)n-3 PUFA。优选地,本发明的组合物还包含选自胆碱和B族维生素中的一种或多种,且优选还包含抗氧化剂,更优选还包含磷脂。
或者,本发明还涉及用于改善受试者(受损的)膀胱功能的组合物,所述组合物的特征如上并在下文提供更多细节。此外,本发明涉及(i)尿苷和/或其等同物和(ii)n-3PUFA在制备用于改善受试者(受损的)膀胱功能的组合物中的用途,所述组合物的特征如上并在下文提供更多细节。
组分(i)和(ii)以治疗有效量存在。
组合物
根据本发明使用的方法或用途或组合物包括给药本发明的组合物。本发明的组合物可以用作药物产品或营养产品。
一方面,本发明的组合物可以用作包含一种或多种药学上可接受的载体材料的药物产品。这样的产品可以以一个或多个剂量单位包含如下定义的日剂量。剂量单位可以是液体形式或固体形式,其中在后一种情况下,日剂量可以以如在一个或多个胶囊或片剂中的一个或多个固体剂量单位来提供。药物产品,优选用于肠内给药,可以是固体或液体盖仑制剂。固体盖仑制剂的实例是含有活性成分以及常规盖仑制剂载体的片剂、胶囊剂(例如硬壳或软壳明胶胶囊)、丸剂、囊剂、粉剂、颗粒剂等。可以使用任何常规载体材料。载体材料可以是适于口服给药的有机或无机惰性载体材料。合适的载体包括水、明胶、阿拉伯树胶、乳糖、淀粉、硬脂酸镁、滑石、植物油等。此外,可以根据接受的药物配合实践添加添加剂如调味剂、防腐剂、稳定剂、乳化剂、缓冲剂等。尽管单独的活性成分可合适地以单一的组合物给药,但也可以以单独的剂量单位给药。
在优选的方面,本发明的组合物可以用作营养产品,例如用作营养补充剂,例如作为正常饮食的添加剂、作为添加到正常饮食中的增强剂,或作为完全营养品。营养产品优选包含至少一种选自脂肪、蛋白质和碳水化合物的组分,优选所有组分。应当理解,营养产品与药物产品的不同在于存在向给药组合物的受试者提供营养的营养物,特别是蛋白质、脂肪、可消化的碳水化合物和膳食纤维。它还可以含有如矿物质、维生素、有机酸和调味剂的成分。虽然术语“营养产品”通常用于文献中,但它表示具有药物成分或药物目的的营养产品。因此,本发明的营养组合物也可用于营养产品中。
在一个实施方案中,产品包含脂质成分以及碳水化合物和蛋白质中的至少一种,其中脂质组合物提供食品的20至50能量%。在一个实施方案中,食品是含有0.8-1.4kcal/ml的液体组合物。
本发明的组合物通常是肠内组合物,即用于口服给药。优选以液体形式给药。优选地,组合物包含其他组分溶解或悬浮于其中的水。
因此,组合物优选为液体,或与液体,优选与水可复水以获得液体组合物的固体(通常为粉末或片剂,优选粉末)。以下定义的组分的剂量可以例如为日剂量或每100mL的浓度。后一种定义也适用于可复水固体,应与液体复水后确定。
尿苷
本发明的组合物包含(i)尿苷和/或其等同物。尿苷等同物是本领域已知的,通常包括脱氧尿苷(脱氧核糖基尿嘧啶)、尿苷磷酸盐(UMP、dUMP、UDP、UTP)、核碱基尿嘧啶、酰化尿苷衍生物(例如,C1-6酰化尿苷)和/或酯(例如,C1-6链烷酸酯)。组合物优选包含选自以下的组分(i):尿苷(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、酰化尿苷衍生物及其混合物,更优选选自以下的尿苷磷酸:尿苷一磷酸(UMP)、尿苷二磷酸(UDP)和尿苷三磷酸(UTP)。最优选地,组合物包含UMP,因为UMP最有效地被身体吸收。因此,在本发明组合物中包含UMP使得能够以向受试者给药最低剂量和/或给药低体积而具有高效力。
优选由UMP提供至少50重量%的组分(i),更优选至少75重量%,最优选至少95重量%。待给药的剂量方便地以UMP的形式给出。因此,以相当于UMP量的摩尔当量方便地计算尿苷来源的量。
本发明的方法优选包括以以下量来给药尿苷(累积量的尿苷及其等同物):(a)0.1至6g/天,优选0.2至3g/天,更优选0.4至2g/天,和/或(b)0.1至6g/100ml(液体)组合物,优选0.2至3g/100ml(液体)组合物,更优选0.4至2g/100ml(液体)组合物。基于组合物的总重量计,尿苷优选以至少0.1%、更优选以至少0.7重量%、最优选以至少2.5重量%,和/或以至多5重量%、更优选以最多3重量%、最优选以至多2.5重量%存在。
胞苷
除了尿苷之外或替代尿苷,组合物还可以含有胞苷和/或其等同物。胞苷等同物是本领域已知的,通常包括脱氧胞苷(脱氧核糖基胞嘧啶),胞苷磷酸(UMP、dUMP、UDP、UTP)、核碱基胞嘧啶、酰化胞苷衍生物(例如,C1-6酰化胞苷)和/或酯(例如,C1-6链烷酸酯)。在一个实施方案中,组合物包含选自胞苷、胞苷磷酸盐(CMP、CDP、CTP,优选CMP)中的一种或多种,还可以采用胞磷胆碱(CDP-胆碱)。
本发明的方法优选包括以以下量来给药胞苷(累积量的胞苷及其等同物):(i)0.1至6g/天,优选0.2至3g/天,更优选0.4至2g/天,和/或(ii)0.1至6g/100ml(液体)组合物,优选0.2至3g/100ml(液体)组合物,更优选0.4至2g/100ml(液体)组合物。基于组合物的总重量计,胞苷优选以至少0.1%、更优选以至少0.7重量%、最优选以至少2.5重量%,和/或以至多5重量%、更优选以至多3重量%、最优选以至多2.5重量%存在。
n-3 PUFA
本发明的组合物包含(ii)n-3多不饱和脂肪酸(PUFA),优选n-3 LC-PUFA。在本发明的上下文中,LC-PUFA(长链PUFA)的链长为18个或更多个碳原子。
组分(ii)优选选自二十二碳六烯酸(22:6;DHA)、二十碳五烯酸(20:5;EPA)、二十二碳五烯酸(22:5ω-3;DPA)及其混合物,优选DHA和EPA的至少一种。优选地,本发明组合物至少含有DHA,更优选含有DHA和EPA。EPA转化为DPA(ω-3),以增加随后的DPA至DHA的转化率。因此,本发明的组合物优选含有显著量的EPA,从而一步刺激体内DHA形成。组分(ii),优选DHA和/或EPA,优选以甘油三酯、甘油二酯、甘油单酯、游离脂肪酸或其盐或酯、磷脂、溶血磷脂、甘油醚、脂蛋白、神经酰胺、糖脂或其组合来提供。优选地,本发明组合物至少包含甘油三酯形式的DHA。合适的n-3 PUFA、n-3 LC-PUFA和/或DHA来源包括金枪鱼油、(其他)鱼油、富含DHA的烷基酯、藻油、蛋黄或富含n-3 LC-PUFA的磷脂,例如磷脂酰丝氨酸-DHA。
DHA优选以每天500至5000mg,更优选每天750至4000mg,最优选每天1000至3000mg的量给药。本发明的组合物中的DHA含量优选使得患者的每日DHA摄入量为患者每千克总体重50-1000mg DHA,更优选100-800mg/kg,更优选250-700mg/kg,最优选350-600mg/kg。如果有的话,EPA优选以每天500-5000mg,更优选每天750-4000mg,最优选1000-3000mg的量给药。如果单独使用或优选与DHA组合使用,则使用这些量的EPA。
如果同时存在DHA和EPA,则DHA与EPA的重量比优选大于1,更优选2∶1至10∶1,更优选3∶1至8∶1。在日剂量方面,本发明的方法优选包括每天给药500-5000mg n-3 LC-PUFA(更优选DHA+EPA+DPA,最优选DHA+EPA),更优选每天给药750-4000mg,最优选每天1000-3000mg。
在单位剂量方面,总脂肪酸的n-3 LC-PUFA(更优选DHA+EPA+DPA,最优选DHA+EPA)的比例优选为5-95重量%,更优选为10-80重量%,最优选为15-70重量%。本发明的组合物优选包含基于总脂肪酸的5-95重量%的DHA,优选基于总脂肪酸的10-75重量%的DHA,更优选基于总脂肪酸的10-60重量%的DHA。本发明的组合物优选包含基于总脂肪酸的5-95重量%的EPA,优选10-75重量%的EPA,最优选15-60重量%,基于总脂肪酸计。
基于组合物的总重量计,n-3 PUFA优选以至少0.1重量%、更优选以至少0.8重量%、最优选以至少1.4重量%,和/或以至多5重量%、更优选以至多3重量%、最优选以至多2.5重量%存在。基于组合物的总重量计,DHA优选以0.25-5重量%,更优选0.5-2.4重量%,最优选0.9-1.5重量%存在。基于组合物的总重量计,EPA优选以0.05-2.5重量%,更优选以0.2-1.0重量%,最优选以0.35-0.8重量%存在。
上述比例和量考虑并优化了几个方面,包括味道(过高的LC-PUFA水平降低味道,导致降低的顺应性)、DHA及其前体之间的平衡,以确保最佳效果,同时保持低体积配方。
算他脂质成分
除了n-3 PUFA之外,组合物优选还包含其他脂质,例如n-6PUFA或n-6LC-PUFA(例如α-亚麻酸(ALA)、亚油酸(LA))和磷脂。
优选组合物的ALA含量保持在低水平。虽然该组合物对于脊髓损伤患者特别有益,但是由于过氧化PUFA的作用,即使已经观察到ALA的体内供应在神经外伤中是神经保护性的,但认为高度不饱和脂肪酸的过量供应会导致对损伤组织的损伤风险进一步增加(King等人,J.Neurosci.(26)17:4672-4680)。ALA浓度优选保持在小于2.0重量%,更优选低于1.5重量%,特别是低于1.0重量%的水平,基于所有脂肪酸的重量计。
LA浓度可以维持在正常水平,即20至30重量%,基于所有脂肪酸的重量计,但在一个实施方案中,LA浓度也显著降低至低于15重量%,甚至小于10重量%的量,基于总脂肪酸计。LA浓度优选为脂肪酸的至少1重量%。
在一个实施方案中,在本发明的组合物中,重量比n-3 PUFA∶n-6 PUFA优选在0.3至7的范围内,优选在1.4∶1至5.9∶1的范围内,更优选在3∶1至5.5∶1的范围内,最优选在3∶1至5∶1、特别是小于5∶1的范围内。n-6LC-PUFA的量优选小于50重量%,优选在5至40重量%,更优选8至30重量%的范围内,基于组合物中脂肪酸的总重量计。
本发明的组合物还可以包含磷脂。优选地,一种或多种磷脂存在于本发明的组合物中。所述一种或多种磷脂选自磷脂酸(PA)、磷脂酰乙醇胺(PE)、磷脂酰胆碱(PC)、磷脂酰丝氨酸(PS)和磷酸肌醇(PI)。本发明的组合物优选每100ml包含0.01至1g,更优选每100ml包含0.05至0.5g,最优选每100ml包含80至600mg的量的至少一种磷脂。所述至少一种磷脂优选由卵磷脂提供。
算他组分
本发明的组合物可以包含其他组分,例如选自胆碱和B族维生素的一种或多种,优选两者,更优选还包含抗氧化剂。优选存在胆碱、B族维生素(特别是叶酸和维生素B6)以及抗氧化剂(特别是维生素C和/或E)中的一种或多种,优选全部,因为已经启示脊髓损伤导致这些组分的营养缺乏(Fraser 2014)。因此,胆碱、B族维生素(尤其是维生素B12)和抗氧化剂(特别是硒、维生素C和/或E)的存在可能有助于脊髓损伤患者的一般健康。
胆碱
本发明的组合物优选包含胆碱。胆碱可以原样存在,或作为以例如盐或酯形式,或其任何组合的胆碱等同物存在。胆碱盐优选选自氯化胆碱、重酒石酸胆碱或硬脂酸胆碱。胆碱酯优选选自磷脂酰胆碱和溶血磷脂酰胆碱。
本发明的方法优选包括每天给药超过50mg胆碱,优选每天给药80至3000mg胆碱,更优选每天给药100至2000mg胆碱,最优选每天给药150至1000mg胆碱。本发明的组合物优选每100ml液体组合物包含80mg至3000g胆碱,优选每100ml组合物包含100mg至2000mg胆碱,优选每100ml组合物包含200至1000mg胆碱,最优选每100ml组合物包含200mg至600mg胆碱。以上数字是基于胆碱计,考虑到相当于胆碱的摩尔当量,可以计算胆碱等同物或来源的量。
B族维生素
本发明的组合物可进一步包含一种或多种B族维生素。维生素B选自维生素B1(硫胺素)、维生素B2(核黄素)、维生素B3(烟酸或烟酰胺)、维生素B5(泛酸)、维生素B6(吡哆素、吡哆醛或吡哆胺,或吡哆素盐酸盐)、维生素B7(生物素)、维生素B9(叶酸)和维生素B12(各种钴胺素)。功能等同物包含在这些术语中。术语“维生素B12”包含本领域已知的所有钴胺素等同物。优选地,本发明上下文中的B族维生素包含选自维生素B6、维生素B12和维生素B9中的至少一种,更优选至少两种。更优选地,组合物至少包含维生素B6和/或B9,最优选维生素B6、B9和B12。
维生素B以有效剂量给药,其剂量取决于所用维生素B的类型。根据经验,可以基于已知的饮食建议,例如根据美国国家科学院的医学研究所(IOM)或由食品科学委员会(EU的科学委员会)所建议的,本文公开的信息和可选的有限量的常规测试来选择合适的最小或最大剂量。最小剂量可以基于估计平均需要值(EAR),尽管较低剂量可能已经有效。如IOM所建议,最大剂量通常不超过可接受的上限摄入水平(UL)。
当存在于本发明的组合物中时,维生素B6通常以提供0.1至100mg,特别是0.5至25mg,更特别是0.5至5mg的日剂量的量存在。本发明的组合物优选每100g(液体)产品包含0.1至100mg维生素B6,更优选每100g(液体)产品包含0.5至5mg维生素B6,更优选每100g(液体)产品包含0.5至5mg维生素B6。
当存在于营养组合物或药物中时,维生素B9通常以提供50至5000μg,特别是100至1000μg,更特别是200至800μg的日剂量的量存在。本发明的组合物优选每100g(液体)产品包含50至5000μg维生素B9,更优选每100g(液体)产品包含100至1000μg维生素B9,更优选每100g(液体)产品包含200至800μg叶酸。维生素B9可以以叶酸的形式存在,其包括叶酸,亚叶酸,甲基化、亚甲基化和甲酰化形式的叶酸,其盐或酯(例如C1-6烷基酯),以及它们与一种或多种谷氨酸的衍生物,并且全部为还原或氧化形式。优选地,维生素B9以叶酸的形式提供。
当存在于本发明的组合物中时,维生素B12通常以提供0.5至100μg,特别是1至10μg,更特别是1.5至5μg的日剂量的量存在。本发明的组合物优选每100g(液体)产品包含0.5至100μg维生素B12,更优选每100g(液体)产品包含1至10μg维生素B12,更优选每100g(液体)产品包含1.5至5μg维生素B12。
抗氧化剂
本发明的组合物还可以包含抗氧化剂,其优选选自维生素C、维生素E和硒。特别优选的是,组合物同时包含维生素C和维生素E,最优选本发明的组合物包含维生素C、维生素E和硒。抗氧化剂优选包括在本发明的组合物中,因为它们可以防止由膳食PUFA产生的损伤部位的氧化损伤。
维生素C包括其功能等同物,并且可以以提供20至2000mg,特别是30至500mg,更特别是75至150mg的日剂量的量存在。在一个实施方案中,维生素C以每100ml组合物20至2000mg,特别是30至500mg,更特别是75至150mg的量存在。
维生素E是指本领域已知的具有维生素E活性的化合物,通常是生育酚和/或其等同物。维生素E可以以提供10至300mg,特别是30至200mg,更特别是35至100mg的日剂量的量存在。这样量的维生素E防止由本发明的组合物中存在的膳食PUFA引起的损伤部位的氧化损伤。在一个实施方案中,生育酚和/或等同物以每100ml组合物10至300mg,特别是30至200mg,更特别是35至100mg的量存在。本说明书中使用的术语“生育酚和/或其等同物”包括生育酚(例如α-生育酚和γ-生育酚)、生育三烯酚、其药学和/或营养可接受的衍生物及其任何组合。以上数字是基于本领域公认的α-生育酚等同物(α-TE)计。
本发明的组合物优选含有硒。硒的抗氧化活性有利于预防和/或抑制对脑区的损害。优选地,组合物每100ml液体产品包含0.01和5mg硒,优选每100ml液体产品包含0.02和0.1mg硒。每日给药的硒的量优选为0.01mg以上,更优选为0.01至0.5mg。
鉴于上述,本发明的组合物优选包含尿苷和/或其等同物,上述任何形式的n-3LC-PUFA DHA和EPA、磷脂、胆碱、叶酸、维生素B12和维生素B6,其等同物或衍生物。组合物优选包含上述任何形式的尿苷和/或UMP,n-3 LC-PUFA DHA和EPA、磷脂、胆碱、叶酸、维生素B12、维生素B6、维生素C、维生素E和硒,其等价物或衍生物。
在特别优选的实施方案中,本发明的组合物每日剂量或每125ml液体包含:
(i)400-1000mg,优选500-700mg,更优选约625mg UMP,
(ii-a)100-500mg,优选200-400mg,更优选约300mg EPA,
(ii-b)900-2000mg,优选950-1300mg,更优选约1200mg DHA,
(iii)50-600mg,优选60-200mg,更优选约106mg磷脂,
(iv)200-800mg,优选300-500mg,更优选约400mg胆碱,
(v-a)1-5μg,优选2-4μg,更优选约3μg维生素B12,
(v-b)0.5-3mg,优选0.5-2mg,更优选约1mg维生素B6,
(v-c)200-800μg,优选300-500μg,更优选约400μg叶酸。
(vi-a)20-80mg,优选30-50mg,更优选约40mg维生素E
(α-生育酚等同物(α-TE)),
(vi-b)60-150mg,优选60-90mg,更优选约80mg维生素C,和
(vi-c)40-100μg,优选45-65μg,更优选约60μg硒。
在特别优选的实施方案中,本发明的组合物每日剂量或每125ml液体包含:
(i)600-1500mg,优选700-1050mg,更优选约940mg UMP,
(ii-a)150-750mg,优选320-600mg,更优选约450mg EPA,
(ii-b)1000-3000mg,优选1400-2000mg,更优选约1800mg DHA,
(iii)75-900mg,优选110-300mg,更优选约160mg磷脂,
(iv)300-120mg,优选450-750mg,更优选约600mg胆碱,
(v-a)1.5-7.5μg,优选4-6μg,更优选约4.5μg维生素B12,
(v-b)0.75-4.5mg,优选1.2-3mg,更优选约1.5mg维生素B6,
(v-c)300-1200μg,优选450-750μg,更优选约600μg叶酸。
(vi-a)30-120mg,优选45-75mg,更优选约60mg维生素E(α-生育酚等同物(α-TE)),
(vi-b)70-225mg,优选90-135mg,更优选约120mg维生素C,和(vi-c)50-150μg,优选65-100μg,更优选约80μg硒。
应用
本发明的组合物用于恢复或改善受试者(受损的)膀胱功能或改善受试者膀胱功能的恢复。本用途也可以被称为刺激(恢复)膀胱功能或膀胱控制,改善膀胱功能或膀胱控制的恢复,改善自主膀胱功能,治疗和/或预防尿失禁,治疗和/或预防渗漏膀胱。在本发明的上下文中,“预防”也可以被称为“降低风险或减少发生”。在本发明的上下文中,受损的膀胱功能可以为任何形式,例如失禁(例如欲望性尿失禁、充溢性尿失禁)、痉挛性膀胱、尿潴留、弱收缩性膀胱、尿频、夜尿症、膀胱过度活动症、减少或丧失(充满的)膀胱感觉、排尿后增加残留尿。
受损的膀胱功能优选与神经障碍相关或由神经障碍引起。在优选的实施方案中,受损的膀胱功能与脊髓损伤或创伤性脑损伤相关或由脊髓损伤或创伤性脑损伤引起,最优选由脊髓损伤引起。换句话说,本发明的组合物用于在脊髓损伤或创伤性脑损伤之后,最优选在脊髓损伤之后改善(受损的)膀胱功能。换句话说,本发明的组合物用于改善正在患有神经障碍、正在从神经障碍中恢复和/或已经患有神经障碍,特别是脊髓损伤或创伤性脑损伤,最优选脊髓损伤的患者(受损的)膀胱功能。
在优选的实施方案中,受试者是正在患有神经障碍、正在从神经障碍中恢复和/或已经患有神经障碍的患者,优选正在患有神经障碍的患者。在该实施方案的上下文中,所述用途也可以称为“治疗和/或预防神经源性膀胱功能障碍”或“治疗和/或预防神经源性膀胱”。
神经障碍可以是患者神经系统中的任何种类的损伤,例如脑损伤、脊髓损伤、骶髓损伤和外周神经损伤。由于排尿中枢之间需要进行协调,任何这些部位的损伤常常会导致神经源性膀胱功能障碍。在特别优选的实施方案中,患者正在患有脊髓损伤、正在从脊髓损伤中恢复和/或已经患有脊髓损伤,优选患者正在患有脊髓损伤。
脑损伤(位于脑桥或更高处的病变部位)可能导致受损或破坏的脑桥排尿中枢控制,从而引起排泄失控。原始的排尿通常会是未受损的,人们会成为急迫性尿失禁。由脑损伤引起的受损的膀胱控制通常以急迫性尿失禁和痉挛性膀胱的形式。任何类型的脑损伤可能引起受损的膀胱功能,所述脑损伤优选选自中风、脑肿瘤、创伤性脑损伤、帕金森病、脑积水、脑瘫和夏-德综合征。
脊髓损伤(脑桥和骶骨脊髓之间的病变部位)通常抑制(完全或部分)中枢神经系统,并且其再激活可能导致受影响器官的过度刺激和痉挛状态。在骶髓上方的脊髓水平的损伤将导致脑桥排尿中枢与骶骨排尿中枢之间的信息传递损失,通常导致与脑桥上部病变将导致的相同类型的失禁。然而,在脊髓损伤后的初期,患者将经常处于脊髓休克状态,这导致反射性神经系统停止和无反射性逼尿肌。因此,在头几个星期,人们无法排泄,如果不处理,这可能是威胁生命的状况。6-8周后,由于与骶骨排尿中枢的连接仍然完好无损,所以人们将能够反射性排泄。这导致急迫性尿失禁。此外,神经系统的再激活可导致受影响的器官的过度刺激和痉挛,导致括约肌和逼尿肌之间的痉挛性膀胱和协同动作障碍。由脊髓损伤引起的受损的膀胱控制通常为急迫性尿失禁和痉挛性膀胱的形式。任何类型的脊髓损伤都可能引起受损的膀胱功能,脊髓损伤优选选自创伤性脊髓损伤、截瘫、四肢麻痹、多发性硬化和脊髓脊膜突出。
骶髓损伤(骶骨脊髓和/或神经根部的病变部位)可引起难以感觉甚至不能感觉膀胱充满(感觉神经源性膀胱),并且当感觉到膀胱充满时难以排除尿液(运动神经源性膀胱)。在骶髓水平的损伤通常导致不能感觉到膀胱壁被拉伸。没有有意或反射性的排尿,导致不能收缩膀胱。因此,一个人将不能排尿,除非有充溢性尿失禁(当膀胱内的压力较高,使得可以维持括约肌的压力以保持控制)。由骶髓损伤引起的受损的膀胱控制通常为充溢性尿失禁和尿潴留的形式。任何类型的骶髓损伤都可能引起受损的膀胱功能,所述骶髓损伤优选选自骶髓肿瘤、椎间盘突出、骨盆骨折、腰椎板切除术、根治性子宫切除术、经腹会阴直肠切除术和脊髓栓系综合征。
外周神经损伤(外周神经中的病变部位)可能引起膀胱损伤或甚至破坏至膀胱的神经,而这又可导致膀胱充盈感消失。神经支配膀胱的外周神经水平的损伤将导致膀胱不能接收到信号和发出信号。不再有膀胱充盈的感觉,或不再有反射性或有意排泄的能力。通常,患者不能收缩逼尿肌(运动神经源性膀胱)。由外周神经损伤引起的受损的膀胱控制通常为充溢性尿失禁、尿潴留和弱收缩性膀胱的形式。任何类型的外周神经损伤都可能引起受损的膀胱功能,所述外周神经损伤优选选自糖尿病、糖尿病性膀胱病、脊髓灰质炎、格-巴二氏综合征(Guillain-Barrésyndrome)、疱疹,带状疱疹、恶性贫血和神经梅毒(脊髓痨)。
在优选的实施方案中,神经障碍选自截瘫、四肢麻痹、多发性硬化和脊髓脊膜突出、帕金森病、中风、创伤性脊髓损伤或创伤性脑损伤。在优选的实施方案中,神经障碍是创伤性损伤,优选创伤性脑损伤或创伤性脊髓损伤,更优选创伤性脊髓损伤。特别是脊髓损伤患者受益于本发明的组合物,因为完全从脊髓损伤中恢复是几乎不可能的,并且症状在整个寿命期间持续存在。这些患者的受损的梯式控制(ladder control)的不适最重。
如上所述的组合物可以用作营养治疗、营养支持、医疗食品、特殊医疗用途的食物或营养补充剂。这种产品可以以每天50-250mL的一份、两份或三份的剂量消耗,在本发明的损伤的情况下,恢复和/或康复期间通常为每天125mL。优选的日剂量在100至500mL范围内,更优选为125至375mL,最优选为200至300mL。
优选地,组合物是肠内给药的。优选地,每天给药至少一次,尽管可以从这些数值计算出替代剂量方案。
实施例
实施例1
在本方案中使用雌性成年Sprague-Dawley大鼠(~250g)。所有动物的脊髓使用静态挤压模型(Nystrom等人,Acta Neurologica Scandinavica,1998,78,460-6;Huang等人,European Journal of Neuroscience,2007,23,273-8)在胸部水平T12(T12)受损。手术后,定期监测大鼠的任何不良反应,并在损伤后的前两周每天称重,然后每周称重两次。术后第一周,每天检查膀胱两次,并在需要时手动进行按压,之后每天一次,直至排泄反射重新建立。
手术前将大鼠随机分配到对照饮食组和本发明的饮食组。对照组中的大鼠接受常规的基于AIN-93M的大鼠食物(N=9),而本发明组中的大鼠喂食含有补充有日剂量450mg/kg(N=9)的相同的大鼠食物的本发明饮食4周。两种饮食是等能量的,并满足所有基本的饮食要求。它们含有标准维生素混合物(AIN-93-VX)和矿物质混合物(AIN-93-MX)。两种饮食的组成不同之处在于使用的脂肪混合物以及一些补充的营养物质,包括胆碱、B-维生素、抗氧化剂、尿苷一磷酸(UMP)和卵磷脂。饮食的详细组成如表1和表2所示。为了防止脂质氧化,所有饮食储存在-20℃下直到使用。饮食以硬丸的形式给予动物。来自两个治疗组的所有大鼠每天接受新鲜的饮食丸剂。将大鼠放回它们的饲养笼后,从手术中恢复后立即开始饮食治疗,每个笼子最多容纳4只大鼠。每天监测每笼中食用的食物量。所有治疗组的平均日摄入量相似。
表1:饮食组成(以g/100g组合物计)
表2:脂肪酸分布(以g/100g组合物计)
使用GraphPad Prism版本6(GraphPad Software Inc.,San Diego,CA,USA)进行统计测试。数据集用Student氏t(Student′s t)检验或双向重复测量ANOVA进行分析,随后在适当情况下使用Bonferroni的事后比较检验进行事后分析。所有数据以平均值±S.E.M给出。P<0.05被认为具有统计学意义。
将喂食本发明的饮食的大鼠组与喂食标准维持饮食的大鼠组进行比较显示:用本发明的饮食治疗的大鼠,膀胱排泄能力的恢复明显更快(膀胱恢复的天数(对照饮食)=8.8±1.8;(本发明的饮食)=3.9±1.1,P<0.05)。在本发明的饮食组中,七只大鼠中的四只在手术后第2天已经恢复了对它们的膀胱的完全控制,并且所有大鼠在第8天前恢复了膀胱功能。在对照组中,六只大鼠中只有两只在手术后第10天恢复了膀胱排泄,所有大鼠在第12天前恢复了膀胱功能。
实施例2
本发明的液体组合物,其每125mL份包含:
Claims (13)
1.一种用于恢复或改善受试者膀胱功能的方法,其包括向受试者给药包含(i)尿苷和/或其等同物和(ii)n-3 PUFA的组合物。
2.权利要求1所述的方法,其中所述受试者为正在患有神经障碍、正在从神经障碍中恢复和/或已经患有神经障碍的患者,优选脊髓损伤的患者。
3.权利要求1或2所述的方法,其中n-3 PUFA选自EPA和/或DHA。
4.前述权利要求中任一项所述的方法,其中每天给药500-5000mg DHA。
5.前述权利要求中任一项所述的方法,其中所述组合物还包含胆碱,优选还包含B族维生素。
6.前述权利要求中任一项所述的方法,其中所述组合物还包含磷脂、胆碱、B族维生素和抗氧化剂。
7.权利要求5或6所述的方法,其中所述组合物包含胆碱、维生素B6和叶酸。
8.前述权利要求中任一项所述的方法,其中所述尿苷和/或其等同物为尿苷一磷酸。
9.前述权利要求中任一项所述的方法,其中所述组合物每125mL或每日剂量包含:
(i)400-800mg UMP;
(ii)n-3 PUFA,其包含(a)100-500mg EPA和(b)900-1500mg DHA;
(iii)50-600mg磷脂;
(iv)200-600mg胆碱;
(v)维生素B,其包含(a)1-5μg维生素B12、(b)0.5-3mg维生素B6和(c)200-600μg叶酸;以及
(vi)抗氧化剂,其包含(a)20-60mg维生素E(α-TE)、(b)60-100mg维生素C和(c)40-80μg硒。
10.前述权利要求中任一项所述的方法,其中所述组合物为液体或与液体可复水的固体。
11.一种用于恢复或改善受试者膀胱功能的组合物,其包含(i)尿苷和/或其等同物和(ii)n-3 PUFA。
12.(i)尿苷和/或其等同物和(ii)n-3 PUFA用于制备用于恢复或改善受试者膀胱功能的组合物的用途。
13.权利要求11使用的所述组合物或权利要求12所述的用途,其中所述受试者为正在患有神经障碍、正在从神经障碍中恢复和/或已经患有神经障碍的患者,优选脊髓损伤的患者。
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