CN110167544A - β-羟基-β-甲基丁酸(HMB)和益生菌的组合物及使用方法 - Google Patents
β-羟基-β-甲基丁酸(HMB)和益生菌的组合物及使用方法 Download PDFInfo
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Abstract
本发明提供包含HMB和至少一种益生菌的组合物。还描述了向动物施用HMB和至少一种益生菌的方法。施用HMB和益生菌以减少炎性细胞因子标志物和/或保持肌肉完整性。
Description
发明背景
本申请要求于2016年10月21日提交的美国临时专利申请第62/411,200号的优先权,并且将该临时申请援引加入本文。
1.领域
本发明涉及包含β-羟基-β-甲基丁酸(β-hydroxy-β-methylbutyrate,HMB)和益生菌的组合物,以及使用该组合物减少炎性细胞因子标志物和/或保持肌肉完整性的方法。
2.背景
HMB
α-酮异己酸(alpha-ketoisocaproate,KIC)是亮氨酸的第一主要活性代谢物。KIC代谢的副产物是β-羟基-β-甲基丁酸(HMB)。已经发现HMB可用于多种应用背景中。具体而言,在美国专利5,360,613(Nissen)中,记载HMB用于降低血液中总胆固醇和低密度脂蛋白胆固醇的水平。在美国专利5,348,979(Nissen等人)中,记载HMB用于促进人体内的氮滞留。美国专利5,028,440(Nissen)中,讨论了HMB对增加动物中瘦组织发育的有用性。并且,在美国专利4,992,470(Nissen)中,记载HMB在增强哺乳动物免疫应答方面是有效的。美国专利6,031,000(Nissen等人)记载了HMB和至少一种氨基酸对治疗疾病相关的消瘦的用途。
HMB抑制蛋白质水解的用途源于亮氨酸具有蛋白质节约的特性的观察结果。必需氨基酸亮氨酸可用于蛋白质合成或转氨成α-酮酸(α-酮异己酸,KIC)。在一个通路中,KIC可以被氧化成HMB,并且这大约占亮氨酸氧化的5%。HMB在增强肌肉质量和力量方面优于亮氨酸。当以HMB钙盐形式给予时在每天3.0g或者每天0.038g/kg体重下可实现HMB的最佳效果,而亮氨酸的最佳效果则需要每天超过30.0g。
一旦产生或摄入,HMB似乎有两种结果。第一种结果为简单的在尿液中***。在食用了HMB后,尿浓度增加,导致HMB约20-50%损失到尿液。另一种结果与HMB到HMB-CoA的活化有关。一旦转化为HMB-CoA,可能发生进一步的代谢,或为HMB-CoA脱水成MC-CoA,或为HMB-CoA直接转化为HMG-CoA,为细胞内胆固醇合成提供底物。几项研究已证明HMB参与到胆固醇合成通路中,并且可成为用于受损细胞膜再生的新细胞膜的来源。人体研究已证明,在最初的48小时内通过补充HMB减少了通过升高的血浆CPK(肌酸磷酸激酶)测定的剧烈运动后的肌肉损伤。在持续日常使用的情况下,HMB的保护作用持续多达三周。许多研究表明作为CaHMB(HMB钙)的HMB的有效剂量为每天3.0g(~38mg·kg体重-1·天-1)。已测试HMB的安全性,显示在健康的年轻人或老年人中没有副作用。HMB与L-精氨酸和L-谷氨酰胺组合,当对AIDS和癌症患者进行补充时也被证明是安全的。
最近,HMB游离酸(新的HMB的递送形式)已经被开发出来。这种新的递送形式已被证明比CaHMB吸收更快并具有更高的组织清除率。在美国专利公开序列号20120053240中记载了这种新的递送形式,其整体援引加入本文。
HMB已被证明可增强高强度运动的恢复和减少高强度运动造成的肌肉损伤。HMB减少TNF-α对蛋白质合成的抑制,并降低与TNF相关的蛋白质降解。
在研究剧烈身体活动而恢复甚微的研究中,例如士兵在持续战斗行动中所遇到的情况,采用补充HMB可减轻与这种身体应力有关的有害影响。据报道,在持续的军事行动中,士兵的体重、力量和体力都有显著下降。这些应力还与炎性细胞因子标志物的显著升高有关。最近的一项实地研究表明,在包括模拟战斗在内的高强度训练中,当士兵补充HMB三周时,炎性反应减少,并伴有肌肉完整性的保持(通过弥散张量成像测定)。这些结果与报道短期(例如4天)和长期(例如12周)的HMB补充可以减少细胞因子对肌肉损伤方案的反应的其它研究一致。
益生菌
近年来,益生菌作为饮食补充剂用于预防和治疗各种疾病变得非常流行。益生菌是活菌,其被认为有助于改善消化健康和免疫功能,同时减少炎症。益生菌(如凝结芽孢杆菌(Bacillus coagulans))被认为可以增强肠道内食物的酶消化,导致更高的营养物的吸收。
令人惊讶且出乎意料地发现,HMB与益生菌组合减少炎性细胞因子标志物并保持肌肉完整性。细胞因子对高强度训练的反应的降低通常被用来表示从高强度训练中更有利的恢复。HMB与益生菌组合具有协同作用,使得与单独施用HMB相比该组合导致增强的HMB的吸收和循环HMB的更大增加。与单独施用HMB的效果相比,改善的炎性细胞因子标志物的减少和肌肉完整性证明HMB与益生菌之间的这种协同作用。
发明概述
本发明的一个目的为提供组合物,其用于保持肌肉完整性。
本发明的另一个目的为提供组合物,其用于减少炎性细胞因子标志物。
本发明的又一个目的为提供施用用于保持肌肉完整性的组合物的方法。
本发明的另外的目的为提供施用用于减少炎性细胞因子标志物的组合物的方法。
本发明的另一个目的为提供改善HMB吸收的方法,所述方法通过向含有HMB的组合物中添加益生菌。
本发明的另外的目的为提供增加HMB在血流中的时间的方法,所述方法通过向含有HMB的组合物中添加益生菌。
参照以下的说明书、附图和权利要求书,本发明的这些目的和其它目的对于本领域技术人员而言会变得显而易见。
本发明旨在克服在此之前遇到的困难。为此,提供包含HMB和益生菌的组合物。该组合物被施用至有此需要的个体。所有的方法包括向动物施用HMB和益生菌。本发明中包括的个体包括人类和非人类哺乳动物。所述组合物被由此需要的个体服用。
附图简述
图1描绘补充四十(40)天后炎性细胞因子反应对高强度军事训练的变化。
图2描绘补充四十(40)天后DTI测量的变化。
发明详述
令人惊讶且出乎意料地发现益生菌与HMB具有协同关系。使用含有HMB和益生菌的组合物导致炎性细胞因子标志物的减少和肌肉完整性的保持,并且发现这些效果比单独施用HMB的效果更明显。HMB与益生菌的组合是协同的,使得与单独施用HMB相比该组合导致增强的HMB的吸收和循环HMB的更大增加。
HMB
β-羟基-β-甲基丁酸或β-羟基-异戊酸可以其游离酸形式(CH3)2(OH)CCH2COOH来表示。术语“HMB”是指具有前述化学式的化合物,可以为游离酸和盐形式,及其衍生物。尽管任何形式的HMB都可以在本发明的范围内使用,但优选HMB选自游离酸、盐、酯和内酯。HMB酯包括甲酯和乙酯。HMB内酯包括异戊酰内酯。HMB盐包括钠盐、钾盐、铬盐、钙盐、镁盐、碱金属盐和碱土金属盐(earth metal salts)。
生产HMB及其衍生物的方法在本领域是公知的。例如,HMB可以通过双丙酮醇的氧化来合成。Coffman等人.,J.Am.Chem.Soc.80:2882-2887(1958)记载了一个合适的操作。如其中所述,HMB是通过双丙酮醇的碱性次氯酸钠氧化来合成的。该产物以游离酸形式回收,可以转化为盐。例如,HMB可以通过类似于Coffman等人(1958)的操作制备为其钙盐,其中HMB的游离酸用氢氧化钙中和,并通过从乙醇水溶液中结晶而回收。HMB的钙盐可从Metabolic Technologies,Ames,Iowa商购获得。
β-羟基-β-甲基丁酸(HMB)钙的补充
二十多年前,HMB的钙盐被开发为人类的营养补充剂。研究证明,每千克体重38mg的CaHMB对于一般的人似乎是有效剂量。
HMB降低蛋白质分解和增加蛋白质合成的分子机制已经被报道。Eley等人进行的体外研究证明HMB通过mTOR磷酸化刺激蛋白质合成。其它研究证明,当肌肉蛋白质分解代谢被蛋白水解诱导因子(PIF)、脂多糖(LPS)和血管紧张素II刺激时,HMB通过减少泛素-蛋白酶体蛋白水解途径的诱导来降低蛋白水解。还有其它研究证明HMB还减少胱天蛋白酶-3和-8蛋白酶的活化。
HMB游离酸形式
在大多数情况下,用于临床研究和作为增补剂销售的HMB为钙盐形式。最近的进展已经使HMB能以游离酸形式制造用作营养补充剂。最近,开发了新的HMB的游离酸形式,其显示出比CaHMB更快被吸收,导致更快和更高的血清HMB峰值水平和改善的组织血清清除率。
因此HMB游离酸可能是比钙盐形式更有效的施用HMB的方法,特别是当直接在剧烈运动之前施用时。然而,本领域的普通技术人员会认识到,本发明包括任何形式的HMB。
任何形式的HMB都可以以一种方式掺入到递送和/或施用形式中,使得导致通常剂量为约0.5g HMB至约30g HMB。
在本发明的范围内可以使用任何合适的HMB剂量。计算合适剂量的方法在本领域中是公知的。HMB的剂量可以用相应的Ca-HMB摩尔量表示。其中可以口服或静脉施用HMB的剂量范围为每24小时每千克体重0.01至0.2克HMB(Ca-HMB)。对于成人,假设体重为约100至200lbs,HMB(基于Ca-HMB)的口服或静脉内剂量可以为每24小时每个个体0.5至30克。
益生菌
益生菌,如凝结芽孢杆菌(BC30),具有很多健康益处,包括改善消化健康和免疫功能以及减少炎症。此外,之前的研究表明BC30可以增强蛋白质的吸收。任何益生菌都适用于本文所述的组合物。本领域技术人员会理解凝结芽孢杆菌的适当的量。本发明的典型组合物在1克剂量制剂中会含有2×105至1010个菌落形成单位的活菌或细菌孢子(在凝结芽孢杆菌的情况下)。在其它实施方式中,细菌的量包括浓度为约1×104至约1×1012活菌的益生菌。凝结芽孢杆菌细菌为孢子、营养细胞或其组合的形式。虽然在实验例中使用了凝结芽孢杆菌,但本发明并不限于这种特定的芽孢杆菌种。任何种类的益生菌都可用于本发明的组合物和方法。
当组合物以可食用形式口服施用时,组合物优选为饮食补充剂、食品或药物介质的形式,更优选为饮食补充剂或食品形式。在本发明的范围内,可以使用任何合适的包含该组合物的饮食补充剂或食品。本领域普通技术人员会明白,不管何种形式(如饮食补充剂、食品或药物介质),组合物可以包括氨基酸、蛋白质、肽、碳水化合物、脂肪、糖、矿物质和/或微量元素。
为了将组合物制备成饮食补充剂或食品,组合物通常会以使组合物在饮食补充剂或食品中基本均匀分布的方式组合或混合。或者,可以将组合物溶解在液体中,如水。
饮食补充剂的组合物可以是粉末、凝胶、液体或可以制成板状或包入胶囊。
尽管在本发明的范围内可以使用包含该组合物的任何合适的药物介质,但优选地该组合物与合适的药物载体(如葡萄糖或蔗糖)组合。
此外,药物介质的组合物可以以任何合适的方式静脉内施用。对于通过静脉内输注施用,组合物优选为水溶性无毒形式。静脉内施用特别适合于正在接受静脉注射(IV)治疗的住院患者。例如,组合物可以溶解于向患者施用的IV溶液(例如生理盐水或葡萄糖溶液)中。而且,组合物可以添加到营养IV溶液中,其可以包括氨基酸、葡萄糖、肽、蛋白质和/或脂质。静脉内施用的组合物的量可以与口服施用中使用的水平类似。静脉输注可能比口服施用更加可控和准确。
计算施用组合物的频率的方法是本领域公知的,并且在本发明的范围内可以使用任何合适的施用频率(例如,每天一次6g剂量或每天两次3g剂量),并且可经任何合适的时间段(例如,可以经五分钟的时间段或经一小时的时间段施用单剂量,或者可选地,可以经长期的时间段施用多剂量)。组合物可以经长期的时间段施用,例如数周、数月或数年。
在本发明的范围内可以使用任何合适的HMB和益生菌剂量。计算合适剂量的方法在本领域中是公知的。
本领域普通技术人员会理解,HMB和益生菌不必以相同的组合物施用以进行要求保护的方法。换句话说,可将益生菌和HMB的单独的胶囊、丸剂、混合物等施用于个体以实施要求保护的方法。
术语施用(administering、administration)包括向哺乳动物提供组合物、服用该组合物及其组合。
实验例
以下实施例会更详细地说明本发明。会容易理解本发明的组合物(如本文实施例中通常描述和说明的)可以以各种制剂和剂型合成。因此,下面本发明的方法、制剂和组合物的目前优选的实施方案的更详细的描述如声明的并不意在限制本发明的范围,而仅是本发明目前优选的实施方案的代表。
方法
受试者
以色列国防军(IDF)精锐战斗部队的26名男性士兵自愿参加了这项双盲平行设计研究。在解释所有程序、风险和益处后,每位受试者都提供了参与研究的知情同意。IDF医疗公司的Helsinki委员会以及Soroka医学中心的医学伦理委员会和Helsinki委员会批准了这项研究。受试者不得使用任何其它饮食补充剂,并且未服用任何雄激素或其它行为增强药物。通过在受试者招募期间完成的健康问卷调查,完成了行为增强药物使用和其它补充的筛查。士兵来自同一部队,并被随机分配至两组中的一组:CaHMB与BC30(CaHMBBC30;n=9;20.5±0.8y;1.75±0.09m;75.4±9.6kg)或CaHMB与安慰剂(CaHMBPL,n=9;19.1±3.4y;1.73±0.05m;71.4±6.4kg)。来自同一部队的第三组受试者对参与本研究感兴趣,但对服用补充剂不感兴趣,他们同意作为对照组(CTL;n=8;20.4±0.7y;1.73±0.05m;68.6±5.3kg)。
研究方案
在40天的干预期间,所有受试者均进行相同的每日方案。在最初的28天中,士兵们在基地驻扎,并参加了同样的高级军事训练任务,包括战斗技能的开发和训练,包括每周五次的90分钟的激烈徒手格斗(krav-maga)训练。身体训练包括平均每周两次5千米的跑步。在第5周和第6周期间,士兵们在野外,背着大约35千克的装备(相当于受试者体重的40%),在困难地形中每晚行进25千米至30千米。行进练习的持续时间为每晚5至8小时。在训练的最后一晚(第40天),士兵们还在行进训练后进行了额外的5千米担架搬运。在最后两周的训练中,士兵每晚睡5到8个小时。所有评估(抽血和磁共振成像[MRI])在最后的补充剂服用(第40天)之前(PRE)和之后约12小时(POST)的一天中进行。所有评估在PRE和POST时均以相同的顺序进行。
补充方案
CaHMBBC30和CaHMBPL的受试者每日三次摄入1.0克CaHMB,每日总服用量为3克。每份由4粒胶囊(250毫克CaHMB)组成,在早晨、中中、晚上用餐期间服用。CaHMB获自代谢技术公司(Ames,IA,USA)。益生菌补充剂(凝结芽孢杆菌GBI-30,6086)由嘉纳登生物技术公司(Mayfield Hts,OH,USA)提供。每份含有2.0×1010菌落形成单位。受试者每日服用一份(早餐)。安慰剂由制造商提供,并且在外观、重量和味道上与活性产品相匹配。安慰剂和活性产品均以粉末形式提供,并在摄入前在水(~250ml)中混合。CaHMBBC30和CaHMBPL的受试者被提供了两份20天的HMB和PL供应品。受试者必须在每20天结束时返回所有已使用和未使用的小包。
血液测量
在每次测试之前获得静息血液样品。在15分钟的平衡期后获得所有血液样品。使用配备有管支架的20号一次性针头(Becton Dickinson,Franklin Lakes,NJ)从肘前臂静脉获得这些血液样品。每位受试者的血液样品是在过夜禁食后的每个阶段的同一时间采集的。将所有血液样品收集至两个管中,一管不含抗凝剂,第二管含K2EDTA。使第一管中的血液在室温下30分钟凝结,并随后与剩余的第二管的全血以3000×g离心15分钟。将所得血浆和血清置于单独的1.8ml微量离心管中,并在-80℃冷冻用于后续分析。
生化分析
根据制造商的说明书,使用市售动力学测定(Sekisui Diagnostics,Charlottetown,PE,Canada;Sigma-Aldrich,St.Louis,MO,USA)分析肌酸激酶(CK)和乳酸脱氢酶(LDH)的血清浓度。使用人细胞因子/趋化因子平板1(EMD Millipore,Billerica,MA,USA),通过多重测定分析细胞因子和趋化因子(包括粒细胞-巨噬细胞集落刺激因子(GM-CSF)、分形趋化因子(CX3CL1)、干扰素γ(INF-γ)、白细胞介素-1β(IL-1β)、白细胞介素-2(IL-2)、白细胞介素-6(IL-6)、白细胞介素-8(IL-8)、白细胞介素-10(IL-10)和肿瘤坏死因子-α(TNF-α))的血浆浓度。此外,血浆HMB浓度通过气相色谱-质谱联用技术分析,并通过代谢技术公司采用上述方法进行测定。将所有样品解冻一次,并由同一名技术人员使用BioTek Eon分光光度计对CK和LDH浓度(BioTek,Winooski,VT,USA)进行分析,并使用MagPix对细胞因子和趋化因子浓度(EMD Millipore)进行分析,一式两份。所有测定的平均测定内变异性低于10%。
磁共振成像(MRI)
使用MRI评估股直肌(RF)和股外侧肌(VL)的肌肉完整性的变化。由于后勤方面(logistical)的考虑(时间因素),先验的确定本研究的首要重点为对比BC30与CaHMB共同给药与仅CaHMB的效果,因此仅对CaHMBBC30和CaHMBPL的士兵进行MRI评估。通过densor张量成像(DTI)测定肌肉完整性。DTI是一种用于评估肌肉损伤的亚临床症状的灵敏的MRI技术。DTI评估基于细胞膜和其它限制水扩散的结构。水运动可以通过测定水扩散的三个正交方向(称为特征向量)及其强度(称为特征值)来评估。从三个特征值(λ1、λ2和λ3),可以计算诸如各向异性分数(FA)和表观扩散系数(ADC)的参数,以评估体素中水扩散的特性。这些测量已被证明可提供有关骨骼肌完整性的信息。
MRI数据采用3.0Tesla全身成像仪(Ingenia,Philips Medical Systems,Best,The Netherlands)获得。在每次测量期间,受试者仰卧在扫描仪中,并使用相控阵表面线圈成像。选择髌骨上方20cm的位置作为图像中心并使用油胶囊标记。所有扫描均按轴向规划,由40片4mm宽的切片组成,足-头覆盖160mm,视野为290×280mm(RL×AP)。进行三次图像采集。T1w DIXON用于解剖参考,T2w Turbo自旋回声用于评估肌肉的任何结构损伤,以及弥散张量成像(DTI)序列用于肌肉纤维跟踪。使用的序列参数先前已公布。
脂肪抑制(SPAIR-光谱选择性绝热反转恢复)用于T2-TSE和DTI扫描。DTI序列为两个包中成像的2D-EPI序列。b值为400秒/mm2,并在15个不同方向上成像。通过使用Philips的‘FiberTrak’软件计算肌纤维跟踪分析。在切片15和25上手动绘制ROI(感兴趣区域)用于RF和VL。然后使该软件使用一种算法描绘肌纤维,如果FA小于0.1,如果角度变化大于27°,或者纤维长度小于10mm,则消除轨迹。同一名研究人员进行所有评估。
统计分析
协方差分析(ANCOVA)用于分析所有MRI和血因变量(肌肉损伤标志物和细胞因子)。PRE和POST值分别用作协变量和因变量。在显著f比率的情况下,采用LSD事后成对比较来检验组间的差异。ANCOVA的结果也转换为PRE的变化。对于所有对比,p≤0.05的α水平被认为是统计学显著的。除非另有说明,否则所有数据均以平均值±SD报告。使用SPSS(IBMStatistics for Windows,23.0版;Armonk,NY:IBM Corp)进行统计分析。
结果
在参与这项试验的26名士兵中,有25人完成了干预。唯一退出本研究的受试者在训练中受伤。在研究期间未报告与补充相关的副作用。根据CaHMB和BC30的服用量(由返回的胶囊和BC-30包的数量决定),两个CaHMB组中补充的依从性为95.0±3.0%。通过分析两个补充剂组中受试者的PRE和POST时的血浆HMB浓度来进行研究依从性的另外的测量。从PRE(3.28±0.73nmol·L-1)到POST(34.1±43.9nmol·L-1)评估,发现血浆HMB浓度显著升高(p=0.010)。
血液数据
炎性细胞因子的循环浓度见表1。此外,图1中描述了组间PRE变化的对比。观察到循环TNF-α浓度变化的显著相互作用(F=6.48,p=0.006)。CaHMBBC30和CaHMBPL的POST时的血浆TNF-α浓度显著低于CTL(分别为p=0.019和p=0.002)。然而,发现CaHMBBC30和CaHMBPL之间无差异(p=0.290)。组间血浆CX3CL1浓度的变化也发现显著的相互作用(F=4.70,p=0.025)。CaHMBBC30和CaHMBPL的CX3CL1浓度的变化显著低于CTL(分别为p=0.044和p=0.011)。发现CaHMBBC30和CaHMBPL之间在CX3CL1浓度上无差异(P=0.687)。显现血浆IL-1β浓度变化的显著相互作用(F=6.93,p=0.006)。与CTL相比,CaHMBBC30和CaHMBPL的IL-1β浓度显著减少(分别为p=0.005和p=0.004)。在CaHMBBC30和CaHMBPL之间观察到无差异(p=0.878)。还发现血浆IL-2浓度的显著相互作用(F=4.96,p=0.019)。与CTL相比,POST时的CaHMBBC30和CaHMBPL的循环IL-2浓度显著减少(分别为p=0.007和p=0.029)。发现CaHMBBC30和CaHMBPL之间无差异(p=0.584)。在血浆IL-6浓度的变化中也观察到显著的相互作用(F=7.99,p=0.005)。与CTL相比,CaHMBBC30和CaHMBPL的血浆IL-6浓度显著减少(分别为p=0.002和p=0.018)。发现CaHMBBC30和CaHMBPL之间的POST时的IL-6反应无差异(p=0.467)。在血浆IL-10浓度的变化中也观察到显著的相互作用(F=3.72,p=0.041)。在CaHMBBC30和CTL之间观察到显著差异(p=0.013)。未发现其它显著差异。对于INF-γ(F=1.25,p=0.31)、IL-8(F=1.49,p=0.25)或GM-CSF(F=0.71,p=0.50)浓度的变化未观察到显著的相互作用。
表1. 40天高强度军事训练对研究组细胞因子浓度的作用。
CaHMBBC30=HMB钙和凝结芽孢杆菌;CaHMBPL=HMB钙和安慰剂;CTL=对照。所有数据均以平均值±SD报告。ANCOVA测试用于评估组间差异。
对肌肉损伤标志物的分析显示,各组的血浆LDH(F=0.15,p=0.86)或CK浓度(F=0.17,p=0.84)之间无显著的相互作用。在组合的组中,从PRE(537.7±86.1IU·L-1)到POST(567.5±87.4IU·L-1)未发现LDH浓度的变化。此外,组合的组中从PRE(225.4±79.8IU·L-1)到POST(377.6±230.2IU·L-1)未发现CK浓度的变化。
DTI
CaHMBBC30和CaHMBPL之间的FA和ADC评估对比见表2。
表2:有和没有益生菌(BC30)的β-羟基-β-甲基丁酸对应高强度军事训练的MRI和DTI测量
表中的所有数据均以平均值±SD报告。配对T检验用于评估两组的随时间的变化。CaHMBBC30=HMB钙和凝结芽孢杆菌;CaHMBPL=HMB钙和安慰剂;CTL=对照。
此外,图2中描绘了组间PRE变化的对比。观察到RF中CaHMBBC30和CaHMBPL的FA无显著差异(F=0.315,p=0.587),但发现两组(collapsed across groups)从PRE至POST有显著下降。发现RF组间ADC有显著差异(F=7.198,p=0.023)。CaHMBBC30的受试者的ADC减少,而CaHMBPL的受试者的ADC增加。VL中发现组间FA(F=2.95,p=0.117)或ADC(F=1.886,p=0.200)无显著差异。
本研究结果表明,在高强度军事训练中,40天的HMB补充(有和没有凝结芽孢杆菌)可以减少炎性细胞因子标志物。与对照相比,该组合似乎减少IL-10的反应。此外,与单独CaHMB相比,CaHMB与BC30的组合在保持肌肉完整性方面提供显著的益处,如通过股直肌(RF)的表观扩散系数(ADC)的降低所表明的。
CaHMBPC30、CaHMBPL和CTL的血浆HMB分别为50.6±15.6nmol·L-1、15.6±28.0nmol·L-1和3.3±0.9nmol·L-1。观察到的CaHMBBC30的更高的HMB浓度表明BC30具有增强吸收能力。
采用DTI对肌肉完整性进行测量,DTI被认为是一种评估肌肉损伤的亚临床症状的灵敏方法。DTI测量水分子的扩散及其在三维肌肉微观结构中的运动方向。在健康组织中,结构的完整性导致扩散障碍。各向异性分数(FA)表示创伤后向组织扩散的增加,而表观扩散系数(ADC)则通过轴长反映肌肉的每个方向上的扩散程度。FA的减小和ADC的增加,代表对肌肉完整性的破坏,表明了更大的扩散。之前,我们报道了仅安慰剂组的RF和半腱肌的FA显著减小,并且补充剂组的VL的ADC可能增加,表明以其游离酸形式提供的HMB可在高强度军事训练中增强肌肉完整性。然而,数据显示,向CaHMB中添加BC30对保持肌肉完整性提供了协同作用,导致比单独CaHMB具有更大程度的肌肉保护。
前述说明书和附图包括本发明的示例性实施方案。本文所述的前述实施方案和方法可基于本领域技术人员的能力、经验和偏好而变化。仅仅以某种顺序列出的方法的步骤并不构成对方法步骤顺序的任何限制。前述说明书和附图仅解释和说明本发明,并且本发明不限于此,除非权利要求有此限制。之前已获得本公开的本领域技术人员可以在不背离本发明的范围的情况下对其进行修改和变更。
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Claims (18)
1.组合物,其包含约0.5g至约30g的β-羟基-β-甲基丁酸(HMB)和至少一种益生菌。
2.如权利要求1所述的组合物,其中所述HMB选自其游离酸形式、其盐、其酯及其内酯。
3.如权利要求1所述的组合物,其中所述HMB为钙盐。
4.如权利要求1所述的组合物,其中HMB为游离酸形式。
5.如权利要求1所述的组合物,其中所述益生菌为凝结芽孢杆菌(Bacilluscoagulans)。
6.在有此需要的动物中减少炎性细胞因子标志物的方法,所述方法包括向所述动物施用协同的组合物,所述组合物对需要减少细胞因子标志物的个体包含约0.5g至约30g的β-羟基-β-甲基丁酸(HMB)和至少一种益生菌。
7.如权利要求6所述的方法,其中所述HMB选自其游离酸形式、其盐、其酯及其内酯。
8.如权利要求6所述的方法,其中所述HMB为钙盐。
9.如权利要求6所述的方法,其中HMB为游离酸形式。
10.如权利要求6所述的方法,其中所述益生菌为凝结芽孢杆菌。
11.在有此需要的动物中保持肌肉完整性的方法,所述方法包括向所述动物施用协同的组合物,所述组合物对需要保持肌肉完整性的个体包含约0.5g至约30g的β-羟基-β-甲基丁酸(HMB)和至少一种益生菌。
12.如权利要求11所述的方法,其中所述HMB为钙盐。
13.如权利要求11所述的方法,其中HMB为游离酸形式。
14.如权利要求11所述的方法,其中所述益生菌为凝结芽孢杆菌。
15.用于改善营养补充剂中HMB功效的方法,所述方法包括以协同有效量向所述补充剂中添加HMB和至少一种益生菌。
16.如权利要求15所述的方法,其中所述HMB为钙盐。
17.如权利要求15所述的方法,其中HMB为游离酸形式。
18.如权利要求15所述的方法,其中所述益生菌为凝结芽孢杆菌。
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PCT/US2017/057549 WO2018075867A1 (en) | 2016-10-21 | 2017-10-20 | COMPOSITIONS AND METHODS OF USE OF β-HYDROXY-β-METHYLBUTYRATE (HMB) AND PROBIOTICS |
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EP (1) | EP3528801B1 (zh) |
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CN (1) | CN110167544A (zh) |
AU (2) | AU2017345598B2 (zh) |
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BR9307035A (pt) | 1992-09-16 | 1999-06-29 | Univ Iowa State Res Found Inc | Processo para redução dos níveis sanguíneos de colesterol total e de colesterol de lipoproteína de baixa densidade |
US5348979A (en) | 1992-12-23 | 1994-09-20 | Iowa State University Research Foundation Inc. | Method of promoting nitrogen retention in humans |
US6031000A (en) | 1998-06-23 | 2000-02-29 | Iowa State University Research Foundation, Inc. | Composition comprising β-hydroxy-β-methylbutyric acid and at least one amino acid and methods of use |
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SG11201507046UA (en) * | 2013-03-15 | 2015-10-29 | Nusirt Sciences Inc | Leucine and nicotinic acid reduces lipid levels |
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AU2023266257A1 (en) | 2023-12-07 |
WO2018075867A1 (en) | 2018-04-26 |
EP3528801B1 (en) | 2024-07-17 |
CA3041520A1 (en) | 2018-04-26 |
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