CN115209886A - 治疗腹泻或肠道炎性病状的方法 - Google Patents
治疗腹泻或肠道炎性病状的方法 Download PDFInfo
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- CN115209886A CN115209886A CN202180016338.4A CN202180016338A CN115209886A CN 115209886 A CN115209886 A CN 115209886A CN 202180016338 A CN202180016338 A CN 202180016338A CN 115209886 A CN115209886 A CN 115209886A
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Abstract
一种治疗受试者的腹泻或肠道炎性病状的方法,其包括向有需要的受试者施用治疗有效量的β‑羟基‑β‑甲基丁酸(HMB)或其盐。一种治疗受试者的分泌性腹泻的方法,其包括向表现出以下症状中的一种或多种的受试者施用治疗有效量的HMB或其盐:肠道流体流失、肠道电解质流失、脱水或肠道炎症。
Description
发明领域
本发明涉及通过将治疗有效量的β-羟基-β-甲基丁酸(HMB)或其盐施用给有需要的受试者来治疗腹泻或肠道炎性病状的方法。本发明还涉及通过施用治疗有效量的HMB或其盐来治疗分泌性腹泻的方法。
发明背景
腹泻是一种常见的病状,其特征是频繁的稀便、水样便。腹泻可能有多种原因,包括细菌、病毒、真菌或寄生虫感染、药物、食物过敏、手术和各种消化系统病症。腹泻的副作用通常包括稀便、水样便、腹部绞痛、腹痛、发烧、腹胀、恶心、大便有血和粘液、电解质流失、脱水和急需排便。在严重的情况下,腹泻可导致营养不良、电解质失衡和严重脱水。事实上,腹泻导致的电解质流失是全世界发病率和死亡率的主要原因,其中最危险的人群是幼儿和老年人。美国疾病控制与预防中心指出,每天大约有2,195名儿童死于腹泻,并且多达九分之一的儿童死于腹泻,这使得腹泻成为5岁以下儿童死亡的第二大原因。
虽然慢性腹泻可持续4周或更长时间,但在大多数情况下,急性腹泻会在几天内自行消退。然而,患有腹泻的个体可以通过如下方式来缓解症状:食用清淡的食物、服用非处方止泻药以及/或者大量饮用流体来保持水分。可用的抗腹泻治疗和药物包括口服补液溶液、益生菌、抗生素以及/或者针对肠蠕动或流体分泌的抗蠕动药物。不幸的是,口服补液溶液通常不会减少流体流失、减少腹泻排出量或对腹泻持续时间有影响。相反,这些溶液仅用于治疗脱水。抗生素可有效减轻各种腹泻症状并缩短感染性腹泻的持续时间,但起效延迟,因此无法防止立即脱水。抗蠕动药物可用于治疗非感染性腹泻,但它们在感染性腹泻的情况下会产生严重的副作用。因此,需要一种解决上述腹泻症状中的每一种症状的治疗。
在一些情况下,个体可能患有慢性腹泻。慢性腹泻是肠易激病症(IBD)的常见症状,最常见的形式是克罗恩病(Crohn’s disease)和溃疡性结肠炎。IBD的特征是肠炎症并且患有IBD的人不仅会出现腹泻,还会出现腹部绞痛、血便、肠梗阻、发烧、体液流失、食欲不振、极度体重减轻和贫血。因此,IBD对患有它的那些人的日常生活产生了重大影响。目前的治疗选择包括抗生素、止泻药、改变生活方式,并且在某些情况下还包括手术。因此,需要一种可以帮助缓解慢性腹泻症状和治疗肠炎症的营养干预。
非感染性腹泻病例也可能与药物(特别是某些癌症治疗和HIV治疗剂)的副作用相关联。例如,化疗剂往往会加剧胃肠毒性,从而导致腹泻。事实上,据报道,多达50%的接受呈单剂的5-氟尿嘧啶(5-FU)的结直肠癌患者会出现化疗诱导的腹泻,而在多达40%的接受联合疗法的患者中会出现严重的化疗诱导的腹泻。(Lee,Chun Seng,“Gastro-IntestinalToxicity of Chemotherapeutics in Colorectal Cancer:The Role of Inflammation,”World Journal of Gastroenterology,第20卷,第14期,2014年4月14日,第3751-3761页)。腹泻也可由癌症本身引起,一些例子包括神经内分泌肿瘤(例如类癌综合征和Zollinger-Ellison综合征)、结肠癌、淋巴瘤、甲状腺髓样癌和胰腺癌。患有与癌症、癌症治疗、HIV治疗剂或其他药物相关联的腹泻的个体,只能通过膳食管理、非处方止泻药以及/或者大量饮用流体来保持水分来治疗腹泻症状。
如上所指出的,可用的止泻治疗和药物包括口服补液溶液、益生菌、抗生素和/或抗蠕动药物,但是这些治疗选项中的每一种都有缺点。进一步地,预防方法限于适当的洗手、提供安全的水和适当的卫生设施、适当的人类废物处理和疫苗接种。因此,需要改进的预防由腹泻引起的脱水和治疗腹泻和其他肠道炎性病状的方法。还需要一种可以帮助解决与现有腹泻治疗相关的上述限制的营养干预。
发明概述
在一个实施方案中,本发明涉及一种治疗受试者的腹泻或肠道炎性病状的方法,其包括向有需要的受试者施用治疗有效量的β-羟基-β-甲基丁酸(HMB)或其盐。
在另一个实施方案中,本发明涉及治疗受试者的分泌性腹泻的方法,其包括向表现出以下一种或多种症状的受试者施用治疗有效量的β-羟基-β-甲基丁酸(HMB)或其盐:肠道流体流失、肠道电解质流失、脱水或肠炎症。
根据本发明的治疗腹泻和肠道炎性病状的方法是有利的,因为它们能够减少从肠细胞分泌的流体和/或电解质的流失、恢复因腹泻而流失的电解质、降低患有腹泻的受试者脱水的风险、防止立即脱水、减少受试者腹泻的持续时间以及/或者减少受试者腹泻的持续时间。这在儿科和老年人群中特别有利,因为这些群体特别容易因腹泻而脱水。根据下面的详细描述,本发明的这些和附加的目的和优点将更加明显。
附图说明
在附图中阐述的实施方案说明了本发明的某些方面并且在本质上是示例性的,并且不旨在限制由权利要求书限定的本发明,在附图中:
图1A和1B例示了在用毛喉素、烟酸和不同浓度的HMB处理表达GPR109A的细胞时HMB对结肠细胞中细胞内cAMP水平的影响,其中cAMP水平通过荧光测量,如实施例1中所述。
图2A和2B例示了在用毛喉素、烟酸和不同浓度的HMB处理表达GPR109A的细胞时HMB对结肠细胞中细胞内cAMP水平的影响,其中cAMP水平通过放射免疫测定测量,如实施例1中所述。
图3例示了HMB对经HMB处理和经烟酸处理的GPR109A/NCM460D细胞中的ERK磷酸化的影响,如实施例2中所述。
图4例示了使用荧光激活细胞分选(FACS)分析的HMB对CD4+T细胞群中的CD4+FoxP3+细胞(Tregs)形成的影响,如示例3中所述。
图5例示了HMB对调节性T细胞磷酸化的影响,如实施例3中所述。
具体实施方式
本文描述了本发明的特定实施方案。然而,本发明可以许多不同形式来实施并且不应被解读为局限于本文中所阐述的实施方案。相反,提供这些实施方案以向本领域技术人员说明本发明的某些方面的更具体的特征。
如本文所阐述的术语仅用于描述实施方案,并且不应被解释为总体上限制本公开。除非在进行引用的上下文中相反地明确指示或清楚说明,否则本公开的单一特征或限制的所有引用应包括对应的多个特征或限制,并且反之亦然。除非另有说明,否则“一个/种”、“该/所述”和“至少一个/种”可互换使用。此外,如在说明书和所附权利要求书中使用的,单数形式“一个/种”和“该/所述”包括它们的复数形式,除非上下文另有明确指示。
就在本说明书或权利要求书中使用术语“包括(includes)”或“包括(including)”来说,其意图以与术语“包含(comprising)”在权利要求中用作过渡词时所解释的类似的方式包括附加元件或步骤。此外,就所采用的术语“或”(例如,A或B)来说,其意图指“A或B或两者”。当意图“仅A或B而不是两者”时,那么采用术语“仅A或B而不是两者”。因此,在本文中术语“或”的使用是包括性的,而不是排他性的使用。当术语“和”以及“或”一起使用时,如在“A和/或B”中,这指示A或B以及A和B。
本公开中所述的方法可包含如本文所述的任何要素和步骤,由如本文所述的任何要素和步骤组成或基本上由如本文所述的任何要素和步骤组成。
本文所公开的所有范围和参数(包括但不限于百分比、份数和比率)应理解为涵盖其中包含的任何和所有子范围以及各端点之间的每个数字。例如,所陈述的“1至10”的范围应被认为包括以最小值1或更大开始并且以最大值10或更小结束的任何和所有子范围(例如1至6.1,或2.3至9.4),并且被认为包含在所述范围内的每个整数(1、2、3、4、5、6、7、8、9和10)。
除非在进行引用组合的上下文中相反地另有说明或清楚暗指,否则如本文所用的方法或工艺步骤的任何组合可按任何顺序进行。
除非另外指示,否则所有百分比均为重量百分比。
除非另有说明,否则如本文使用的术语“脱水”是指体液(主要是水)的流失量超过摄入量的情况。经历脱水的受试者可能会经历包括但不限于以下的症状:口干、泪液产生减少、缺乏汗水、肌肉痉挛、恶心、呕吐、心悸、头晕和虚弱。
除非另有说明,否则如本文使用的术语“HMB钙”是指β-羟基-β-甲基丁酸(也称为β-羟基-3-甲基丁酸、β-羟基异戊酸或HMB)的钙盐,该钙盐最典型地是一水合物形式。除非另有说明,否则如本文中用于表征HMB钙的所有重量、百分比和浓度均基于HMB钙一水合物的重量。
除非另有说明,否则如本文使用的术语“HMB”是指β-羟基-β-甲基丁酸(也称为β-羟基-3-甲基丁酸、β-羟基异戊酸)及其来源。如本文中用于表征HMB的所有重量、百分比和浓度均基于HMB的重量,除非另有规定,否则如本文中用于表征HMB的所有重量、百分比和浓度均基于HMB的重量。
除非另外指明,否则本文使用的术语“脂肪”和“油”可互换用于指从植物或动物中提取或加工的脂质材料。这些术语还包括合成脂质材料,只要此类合成材料适合于口服施用于人类。
除非另有说明,否则如本文所用的术语“营养粉”是指通常为可流动颗粒且可被水性液体重构且适合于对人口服给药的营养粉。
除非另有说明,否则如本文所用的术语“营养液”是指即饮液体形式的营养产品和通过在使用前重构本文所述的营养粉制成的营养液。
除非另有说明,否则如本文使用的术语“营养产品”和“营养组合物”是指营养液和营养粉,后者可重构形成营养液,并且适合人类口服食用。
除非另有说明,否则如本文所用的术语“治疗有效量”是指足以达到治疗腹泻或肠道炎性病状的预期目的的量的HMB。就本发明而言,治疗腹泻或肠道炎性病状包括减少肠道流体流失、减少肠道电解质流失、减少腹泻排出量、降低发生脱水的风险、恢复流失的电解质、减少肠道炎症、在结肠中诱发肿瘤抑制作用、减少腹泻的持续时间,或它们的组合。
β-羟基-β-甲基丁酸(HMB)是一种已知可用于各种营养产品和补充剂的天然存在的氨基酸代谢物。HMB是必需氨基酸亮氨酸的代谢物,并且已被证明可调节蛋白质周转和抑制蛋白水解。HMB钙是HMB在被配制成口服营养产品时常用的HMB形式,该产品包括片剂、胶囊、可重构粉剂、营养液和乳剂。可重构粉末在这方面特别有用,因为即使在与多种成分(如氨基酸、碳水化合物、蛋白质和脂肪)一起配制时,此类粉末常常也比其液体对应物更能长期保存。
虽然HMB通常用于营养产品中以帮助在选定个体中建立或维持健康的肌肉,但本发明人惊奇地发现HMB也可用于治疗腹泻和肠道的炎性病状。更具体地,本发明人发现HMB可有效缓解腹泻和肠道炎症的几种症状,包括减少肠道流体和/或电解质的流失、降低发生脱水的风险、恢复流失的电解质、减少肠道炎症、在结肠中诱发肿瘤抑制作用,以及/或者减少腹泻持续时间。
根据腹泻的原因(即感染性或非感染性),现有的治疗方法包括通过口服补液溶液、抗生素或针对肠蠕动或流体分泌的药物(即抗蠕动药物)来补充流失的流体和/或电解质。然而,如上所提到的,口服补液溶液不能减少流体流失、腹泻排出量和腹泻持续时间。当用于治疗感染性腹泻时,抗蠕动药物具有严重的副作用。抗生素尽管能有效减少腹泻的症状和持续时间,但由于其起效延迟,无法防止立即脱水。因此,需要一种可以帮助减少腹泻期间,特别是分泌性腹泻期间的流体和电解质流失,从而降低发生脱水的风险并且缩短腹泻病状的持续时间的营养干预。
羟基羧酸受体2(HCAR2),也称为烟酸受体1(NIACR1)或GPR109A,是人类HCAR2基因编码的G蛋白偶联受体。它的活化尤其与脂解活性的抑制、真皮血流增加、烟酸诱导的潮红的介导、烟酸的抗脂解和抗动脉粥样硬化作用的介导以及烟酸诱导的潮红的介导有关。(Colletti SL等人,Hydroxy carboxylic acid receptors(2019.4版),见IUPHAR/BPSGuide to Pharmacology Database。IUPHAR/BPS Guide to Pharmacology CITE.2019;2019(4).)
GPR109A是一种众所周知的B复合维生素烟酸的细胞表面受体,并且存在于许多细胞上,该细胞包括例如肠和结肠细胞、脂肪细胞、朗格汉皮肤细胞(langerhan skin cell)、肾细胞、单核细胞和巨噬细胞。GPR109A的生理激动剂是非结肠细胞中的酮体β-羟基丁酸(β-HB)和结肠细胞中的丁酸。GPR109A在肠和结肠上皮细胞的面向管腔的顶端膜中表达,并且其表达水平在空肠-结肠轴中增加。最大的GPR109A表达在结肠中,在那里它充当丁酸的受体,该丁酸是结肠细菌的膳食纤维发酵物在结肠管腔内产生的细菌代谢产物。结肠中GPR109A的激活会引起深远的抗炎作用和肿瘤抑制作用。此外,肠细胞中GPR109A的激活会导致细胞内cAMP水平降低,这可能对电解质分泌到管腔中产生显着影响。(Ganapathy,V.等人(2013)Current Opinion in Pharmacology 13:869-874;Sivaprakasam,S.等人(2017)Nutrients 9:E856;Singh,,N.等人.Immunity 40:128-139(2014))。诸如霍乱弧菌和大肠杆菌的细菌病原体通过增加肠和结肠上皮细胞中cAMP的细胞水平而引起腹泻。因此,可降低肠和结肠细胞中细胞内cAMP水平的剂将有助于减轻分泌性腹泻。
此外,已经证明GPR109A作为结肠中的炎症的抑制因子发挥着重要作用。与抑制结肠炎症相关的机制涉及抗原呈递树突细胞中GPR109A的激活,其增强了初始T细胞向免疫抑制性调节性T细胞(Tregs)的转化(Singh,N.等人(2014)。Immunity,40(1),128-139)。因此,可诱导初始T细胞转化为Treg的剂适合于减少肠炎症,这对于治疗各种肠道炎性病状(包括例如克罗恩病和溃疡性结肠炎)有益。
鉴于上述情况,希望有一种这样的剂,该剂能降低肠和结肠上皮细胞中的细胞内cAMP水平并且/或者诱导初始T细胞转化为Treg以治疗腹泻和/或肠道的肠炎症。
在一个实施方案中,提供了一种治疗受试者的腹泻或肠道炎性病状的方法。所述方法包括向有需要的受试者施用治疗有效量的HMB或其盐。在具体实施方案中,治疗腹泻或肠道炎性病状包括减少肠道流体流失、减少肠道电解质流失、减少腹泻排出量、降低发生脱水的风险、恢复流失的电解质、减少肠道炎症、在结肠中诱发肿瘤抑制作用、减少腹泻的持续时间,或它们的组合。
在进一步的具体实施方案中,所述方法是用于治疗选自炎性肠病、乳糜泻、肠易激综合征、急性自限性结肠炎和结肠癌的肠道炎性病状。在某些实施方案中,肠道的炎性病状是选自克罗恩病和溃疡性结肠炎的炎性肠病。
在本发明的另一个实施方案中,提供了一种治疗受试者分泌性腹泻的方法。所述方法包括向表现出以下一种或多种症状的受试者施用治疗有效量的HMB或其盐:肠道流体流失、肠道电解质流失、脱水或肠道炎症。在具体的实施方案中,治疗分泌性腹泻包括减少肠道流体流失、减少肠道电解质流失、减少腹泻排出量、降低发生脱水的风险、恢复流失的电解质、减少肠道炎症、减少受试者分泌性腹泻的持续时间,或它们的组合。
在进一步的具体实施方案中,受试者是人。
HMB的合适来源包括呈以下形式的HMB:游离酸、盐(包括无水盐)、酯、内酯,或以其他方式提供HMB的生物可利用形式的其他产品形式。在本发明的进一步具体实施方案中,施用给受试者的HMB或其盐选自由以下组成的组:HMB钠、HMB钾、HMB镁、HMB铬、HMB钙、HMB碱金属、HMB碱土金属、HMB内酯,以及它们的组合。在特定实施方案中,施用给受试者的HMB或其盐是作为HMB钙一水合物提供的。
在进一步的实施方案中,以约0.1至约10g的日剂量向受试者施用HMB或其盐。在具体实施方案中,以约0.25至5g的日剂量向受试者施用HMB或其盐。在更具体的实施方案中,HMB或其盐以约1.5至约3g的日剂量施用给受试者。
在本发明的另一个实施方案中,HMB或其盐以营养组合物的形式施用给受试者。营养组合物通过添加HMB(最典型地是钙一水合物)来配制,或者以其他方式被制备成在成品中含有HMB。只要成品含有HMB,任何HMB来源都适用于此类组合物中。在具体实施方案中,此种来源是HMB钙并且最通常在配制期间以原样被添加到营养产品中。
在具体实施方案中,营养组合物包含基于营养组合物的重量从约0.01重量%至约10重量%的HMB或其盐。在另一个实施方案中,所述组合物包含基于营养组合物的重量从约0.1重量%至约5重量%的HMB或其盐。
营养组合物可提供从约0.1克/天至约10克/天的HMB。因此,营养组合物可提供每份约0.5至约2.5克(包括约1.0至约1.7克,包括约1.5克)的HMB,其中一份可以是约240ml即食营养液或约240ml经重构的营养固体。在一个具体实施方案中,HMB以每240ml约1.58克的水平提供。可以以每天一份、每天两份、每天三份或每天四份或更多份向个体施用,以使个体从营养组合物接收所需量的HMB。
在本发明的其他具体实施方案中,HMB或其盐以营养组合物的形式被施用给受试者,并且该营养组合物进一步包含蛋白质、碳水化合物和/或脂肪。多种来源和类型的蛋白质、碳水化合物和脂肪可用于本文所述的营养组合物的实施方案中。在一个具体实施方案中,营养组合物包含蛋白质、碳水化合物和脂肪。
在进一步的具体实施方案中,营养组合物中的蛋白质包括乳清蛋白浓缩物、乳清蛋白分离物、乳清蛋白水解物、酸酪蛋白、酪蛋白酸钠、酪蛋白酸钙、酪蛋白酸钾、酪蛋白水解物、乳蛋白浓缩物、乳蛋白分离物、乳蛋白水解物、脱脂奶粉、浓缩脱脂乳、大豆蛋白浓缩物、大豆蛋白分离物、大豆蛋白水解物、豌豆蛋白浓缩物、豌豆蛋白分离物、豌豆蛋白水解物、胶原蛋白、胶原蛋白分离物、大米蛋白、马铃薯蛋白、蚯蚓蛋白、昆虫蛋白,或它们中的两种或更多种的组合。
在其他具体实施方案中,营养组合物中的碳水化合物包括人乳寡糖(HMO)、麦芽糖糊精、水解淀粉、葡萄糖聚合物、玉米糖浆、玉米糖浆固体、大米衍生的碳水化合物、蔗糖、葡萄糖、乳糖、蜂蜜、糖醇、异麦芽酮糖、蔗糖酮糖醇(sucromalt)、普鲁兰多糖(pullulan)、马铃薯淀粉、低聚半乳糖、燕麦纤维、大豆纤维、玉米纤维、阿拉伯胶、羧甲基纤维素钠、甲基纤维素、瓜尔豆胶、结冷胶、刺槐豆胶、魔芋粉、羟丙基甲基纤维素、黄蓍胶、刺梧桐胶、阿拉伯树胶、壳聚糖、阿拉伯半乳糖血凝素(arabinoglactins)、葡甘露聚糖、黄原胶、藻酸盐、果胶、低甲氧基果胶、高甲氧基果胶、谷类β-葡聚糖、角叉菜胶、洋车前子、菊粉、低聚果糖或它们中的两种或更多种的组合。碳水化合物可以包括抗消化的碳水化合物,例如抗消化的麦芽糖糊精和抗消化的淀粉、可缓慢消化的碳水化合物。
在进一步的具体实施方案中,脂肪包括椰子油、分馏椰子油、大豆油、玉米油、橄榄油、红花油、中链甘油三酯油(MCT油)、高γ亚麻酸(GLA)红花油、葵花油、棕榈油、棕榈仁油、棕榈油精、菜籽油、海洋油、鱼油、藻油、琉璃苣油、棉籽油、真菌油、二十碳五烯酸(EPA)、二十二碳六烯酸(DHA)、花生四烯酸(ARA)、共轭亚油酸(CLA)、α-亚麻酸、互酯化油(interesterified oil)、转酯油(transesterified oil)、结构化脂质以及它们中的两种或更多种的组合。
在营养组合物的具体实施方案中,蛋白质占营养组合物的约1重量%至约30重量%。在更具体的实施方案中,蛋白质占营养组合物的约1重量%至约25重量%,包括占营养组合物的约1重量%至约20重量%、约1重量%至约15重量%、约1重量%至10重量%、约5重量%至约10重量%,或约10重量%至约20重量%。在另外的具体实施方案中,蛋白质占营养组合物的约1重量%至约5重量%。在另外的具体实施方案中,蛋白质占营养组合物的约20重量%至约30重量%。
在营养组合物的具体实施方案中,碳水化合物以营养组合物的约5重量%至约75重量%的量存在。在更具体的实施方案中,碳水化合物以营养组合物的约5重量%至约70重量%(包括营养组合物的约5重量%至约65重量%、约5重量%至约50重量%、约5重量%至约40重量%、约5重量%至约30重量%、约5重量%至约25重量%、约10重量%至约65重量%、约20重量%至约65重量%、约30重量%至约65重量%、约40重量%至约65重量%,或约15重量%至约25重量%)的量存在。
在具体实施方案中,营养组合物包含营养组合物的约0.5重量%至约30重量%的量的脂肪。在某些具体实施方案中,脂肪占营养组合物的约1重量%至约30重量%,包括占营养组合物的约1重量%至约20重量%、约1重量%至约15重量%、约1重量%至约10重量%、约1重量%至约5重量%、约3重量%至约30重量%、约5重量%至约30重量%、约5重量%至约25重量%、约5重量%至约20重量%、约5重量%至约10重量%,或约10重量%至约20重量%。
在本发明的另一个实施方案中,营养组合物进一步包含选自由维生素、矿物质和微量矿物质组成的组的营养素。营养组合物的具体实施方案可包含维生素和/或相关营养素,其非限制性实例包括维生素A、维生素B12、维生素C、维生素D、维生素E、维生素K、硫胺素、核黄素、吡哆醇、烟酸、叶酸、泛酸、生物素、胆碱、肌醇和/或其盐和衍生物,以及它们的组合。
营养组合物的具体实施方案包含矿物质,其非限制性实例包括钙、磷、镁、锌、锰、钠、钾、钼、铬、铁、铜和/或氯化物,以及它们的组合。
根据具体实施方案,营养组合物是液体或粉末形式并且/或者通过肠内或肠胃外施用。
营养液中HMB的浓度范围可高达营养液的约10重量%(包括约0.01重量%至约10重量%,并且还包括约0.1重量%至约5.0重量%,并且还包括约0.3重量%至约2重量%,并且还包括约0.4重量%至约1.5重量%,并且还包括约0.3重量%至约0.6重量%)。在一个具体实施方案中,HMB以营养液的约0.67重量%的量存在于营养液中。
营养粉中HMB钙的总浓度范围可高达营养粉的约10重量%(包括约0.1重量%至约8重量%,并且还包括约0.2重量%至约5.0重量%,并且还包括约0.3重量%至约3重量%,并且还包括约0.3重量%至约1.5重量%,并且还包括约0.3重量%至约0.6重量%)。
在具体实施方案中,当营养组合物是例如由粉末重构或制成即饮产品的液体时,一份范围为约1ml至约500ml,包括约110ml至约500ml、约110ml至约417ml、约120ml至约500ml、约120ml至约417ml、约177ml至约417ml、约207ml至约296ml、约230ml至约245ml、约110ml至约237ml、约120ml至约245ml、约110ml至约150ml和约120ml至约150ml。在具体实施方案中,一份为约1ml,或约100ml,或约225ml,或约237ml,或约500ml。
在具体实施方案中,当营养组合物是粉末时,例如,一份为待以粉末形式施用或待被重构成约1ml至约500ml(诸如约225ml),或约230ml至约245ml液体的约40g至约60g(诸如45g,或48.6g,或50g)。
额外的具体实施方案,营养组合物包含一种或多种用于修饰营养组合物的物理、化学、美学或加工特性或者用作额外营养组分的组分。额外组分的非限制性实例包括防腐剂;乳化剂(例如卵磷脂);缓冲剂;甜味剂;包括人造甜味剂(例如糖精、阿斯巴甜、乙酰舒泛K、三氯蔗糖);着色剂;调味剂;增稠剂;稳定剂等。
以下实施例展现本发明的各个方面。
实施例
实施例1:HMB对结肠细胞中细胞内cAMP水平的影响
该实施例描述了使用过表达人GPR109A的结肠细胞系来监测HMB对作为GPR109A激活的替代标志物的细胞内cAMP水平的影响。烟酸是GPR109A受体的最强效的激动剂,用作阳性对照。
GI偶联受体(如GPR109A)的活性通常通过证明经毛喉素处理的细胞中的cAMP细胞水平的降低来评估。这通常使用可商购获得的试剂盒cAMP-GloTM Assay完成。毛喉素是一种从印度锦紫苏植物中分离出来的半日花烷二萜类(labdane diterpenoid),作用于Gs蛋白并且激活腺苷酸环化酶以增加细胞内cAMP水平。当经毛喉素处理的细胞中的GI偶联受体被激活时,cAMP水平会上升。
如图1A和1B所例示,用毛喉素处理表达GPR109A的细胞使cAMP水平提高了多于10倍。然而,当这些细胞在存在毛喉素的情况下用烟酸(25μM)或HMB处理时,cAMP的细胞水平显著降低。如上所指出的,烟酸用作GPR109A激活的阳性对照。0.5mM浓度的HMB对GPR109A的影响与烟酸的最大效果相当(烟酸的EC50约为1μM)。HMB激活GPR109A受体的EC50值为亚毫摩尔浓度,即0.25-2.5mM。虽然这些值表明亲和力低,但此类浓度可以通过HMB口服给药在肠管腔中轻松实现,因为HMB的管腔浓度与存在于肠和结肠上皮细胞的面向管腔的顶部膜中的GPR109A的激活相关。
重复上述实验,并且通过放射免疫测定法测量cAMP水平,如图2A和B所例示。同样,对照毛喉素提高了cAMP的细胞水平。在毛喉素存在的情况下,烟酸和HMB降低了cAMP的细胞水平,这证实了HMB对通过下调腺苷酸环化酶来降低肠道上皮细胞中cAMP的细胞水平的影响。因此,结果表明HMB起到GPR109A的激动剂的作用。与通过使用诸如烟酸的药物相反,通过营养组合物施用的HMB降低cAMP的能力是有利的。
实施例2:HMB对结肠细胞中的ERK磷酸化的影响
本实施例描述了使用过表达人GPR109A的结肠细胞系来监测HMB对作为GPR109A激活的替代标志物的ERK磷酸化的影响。烟酸是GPR109A受体最强效的激动剂,再次用作阳性对照。测量了HMB对过表达GPR109A的细胞中作为第二信使系统的ERK的磷酸化的影响。
已知GPR109A的激活导致ERK的磷酸化。如图3所例示,HMB增加了ERK的磷酸化。HMB没有明显的剂量响应。似乎即使在0.25mM的HMB浓度下也会发生ERK磷酸化的增加。类似于上述实施例1,因此结果表明HMB起到GPR109A的激动剂的作用。
实施例3:HMB对调节性T细胞产生的影响
本实施例描述了使用源自对照小鼠和GPR109A敲除小鼠的免疫细胞(结肠树突细胞)来监测HMB对影响小肠和大肠中Treg形成的作用。
GPR109A作为结肠中的炎症的抑制因子发挥着重要作用,部分是通过激活抗原呈递树突细胞中的GPR109A,从而增强初始T细胞向免疫抑制性Treg的转化。如上所指出的,将源自对照小鼠和源自GPR109A敲除小鼠的结肠树突细胞用HMB处理。浓度在250-500μM之间的HMB以GPR109A依赖性方式增强了Tregs的产生,如图4-5所例示。关于图4所示,每个FACS分选面板中的矩形标识了CD4+FoxP3+细胞(Treg)。这些细胞在总CD4+T细胞群体中的百分比示出在各个矩形的顶部。
具体来说,在500μM和100μM下的HMB处理显示来自野生型小鼠的Fox93+Treg细胞增加,但GPR109A-/-敲除老鼠则未能如此。这表明HMB通过激活GPR109A影响肠中Tregs的形成来抑制肠管中的炎症。这再次证实了HMB与GPR109A相互作用并激活了GPR109A。
本文描述的具体实施方案和实施例仅是示例性的并且不限制由权利要求书限定的本发明。
Claims (21)
1.一种治疗受试者的腹泻或肠道炎性病状的方法,其包括:
向有需要的受试者施用治疗有效量的β-羟基-β-甲基丁酸(HMB)或其盐。
2.如利要求1所述的方法,其中所述治疗包括减少肠道流体流失、减少肠道电解质流失、减少腹泻排出量、降低发生脱水的风险、减少肠道炎症、在结肠中诱发肿瘤抑制作用、减少腹泻的持续时间,或它们的组合。
3.如权利要求2所述的方法,其中所述治疗包括减少肠道流体流失、减少肠道电解质流失、减少肠道炎症,或它们的组合。
4.如权利要求1-3中任一项所述的方法,其中所述肠道炎性病状选自由炎性肠病、乳糜泻、肠易激综合征、急性自限性结肠炎和结肠癌组成的组。
5.如权利要求4所述的方法,其中所述肠道炎性病状是选自克罗恩病和溃疡性结肠炎的炎性肠病。
6.一种治疗受试者的分泌性腹泻的方法,其包括:
向表现出以下症状中的一种或多种的受试者施用治疗有效量的β-羟基-β-甲基丁酸(HMB)或其盐:肠道流体流失、肠道电解质流失、脱水或肠道炎症。
7.如权利要求6所述的方法,其中所述治疗包括减少肠道流体流失、减少肠道电解质流失、减少腹泻排出量、降低发生脱水的风险、减少肠道炎症、减少所述受试者中分泌性腹泻的持续时间,或它们的组合。
8.如前述权利要求中任一项所述的方法,其中施用给所述受试者的HMB或其盐选自由以下组成的组:HMB钠、HMB钾、HMB镁、HMB铬、HMB钙、HMB碱金属、HMB碱土金属、HMB内酯,以及它们的组合。
9.如权利要求8所述的方法,其中施用给所述受试者的所述HMB或其盐是作为HMB钙一水合物提供的。
10.如前述权利要求中任一项所述的方法,其中所述HMB或其盐以约0.25至5g的日剂量施用给所述受试者。
11.如权利要求10所述的方法,其中所述HMB或其盐以约1.5至3g的日剂量施用给所述受试者。
12.如前述权利要求中任一项所述的方法,其中所述HMB或其盐以营养组合物施用给所述受试者。
13.如权利要求12所述的方法,其中所述组合物包含基于所述营养组合物的重量的约0.01重量%至约10重量%的HMB或其盐。
14.如权利要求13所述的方法,其中所述组合物包含基于所述营养组合物的重量的约0.1重量%至约5重量%的HMB或其盐。
15.如权利要求11-14中任一项所述的方法,其中所述营养组合物进一步包含蛋白质、碳水化合物和/或脂肪。
16.如权利要求15所述的方法,其中所述蛋白质包括乳清蛋白浓缩物、乳清蛋白分离物、乳清蛋白水解物、酸酪蛋白、酪蛋白酸钠、酪蛋白酸钙、酪蛋白酸钾、酪蛋白水解物、乳蛋白浓缩物、乳蛋白分离物、乳蛋白水解物、脱脂奶粉、浓缩脱脂乳、大豆蛋白浓缩物、大豆蛋白分离物、大豆蛋白水解物、豌豆蛋白浓缩物、豌豆蛋白分离物、豌豆蛋白水解物、胶原蛋白、胶原蛋白分离物、大米蛋白、马铃薯蛋白、蚯蚓蛋白、昆虫蛋白,或它们中的两种或更多种的组合。
17.如权利要求15或权利要求16所述的方法,其中所述碳水化合物包括人乳寡糖(HMO)、麦芽糖糊精、水解淀粉、葡萄糖聚合物、玉米糖浆、玉米糖浆固体、大米来源的碳水化合物、蔗糖、葡萄糖、乳糖、蜂蜜、糖醇、异麦芽酮糖、蔗糖酮糖醇、普鲁兰多糖、马铃薯淀粉、低聚半乳糖、燕麦纤维、大豆纤维、玉米纤维、阿拉伯胶、羧甲基纤维素钠、甲基纤维素、瓜尔豆胶、结冷胶、刺槐豆胶、魔芋粉、羟丙基甲基纤维素、黄蓍胶、刺梧桐胶、阿拉伯树胶、壳聚糖、阿拉伯半乳糖血凝素、葡甘露聚糖、黄原胶、藻酸盐、果胶、低甲氧基果胶、高甲氧基果胶、谷类β-葡聚糖、角叉菜胶、洋车前子、菊粉、低聚果糖或它们中的两种或更多种的组合。
18.如权利要求15-17中任一项所述的方法,其中脂肪包括椰子油、分馏椰子油、大豆油、玉米油、橄榄油、红花油、中链甘油三酯油(MCT油)、高γ亚麻酸(GLA)红花油、葵花油、棕榈油、棕榈仁油、棕榈油精、菜籽油、海洋油、鱼油、藻油、琉璃苣油、棉籽油、真菌油、二十碳五烯酸(EPA)、二十二碳六烯酸(DHA)、花生四烯酸(ARA)、共轭亚油酸(CLA)、α-亚麻酸、互酯化油、转酯油、结构化脂质以及它们中的两种或更多种的组合。
19.如权利要求15-18中任一项所述的方法,其中所述营养组合物进一步包含选自由维生素、矿物质和微量矿物质组成的组的营养素。
20.如权利要求12-19中任一项所述的方法,其中所述营养组合物通过肠内或肠胃外施用。
21.如前述权利要求中任一项所述的方法,其中所述受试者是人。
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