CN104872685A - 改善心脏衰竭症状的营养组合物 - Google Patents
改善心脏衰竭症状的营养组合物 Download PDFInfo
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Abstract
本发明提供一种改善心脏衰竭症状的营养组合物,该营养组合物是由有效治疗高剂量的白胺酸及组胺酸所组成的群组;本发明还提供一种包含该营养组合物的营养补充品,其是为一饮品、日常补充品或食物;本发明更进一步提供一种使用该营养补充品治疗心脏衰竭患者的方法。
Description
技术领域
本发明提供一种用于心血管疾病患者的营养组合物,特别是一种用于急性或慢性心脏衰竭患者的营养组合物。
背景技术
心脏衰竭是一种表现各种心脏疾病终末期的复杂临床综合症状,其可能会造成比很多癌症更不佳的预后。目前心脏衰竭的估计成本是占已开发经济体医疗总开支的1至2%且预期还会持续提升;但尽管如此,短期和长期与心脏衰竭患者有关的再住院率或死亡率仍然居高不下,而目前在治疗皆着重于药物治疗或装置方面(例如是植入性去颤器及心脏再同步化治疗)。然而,这些方法无法「治愈」患者的状态,非真正的缓解心脏衰竭疾病的疾病状态。
心脏衰竭被认为是一种具有多因素的发病机制的疾病,其以一种复杂的方式与外周围循环机能不全、自律神经失调、活化肾素-血管紧张素系统的活化、发炎、氧化压力、免疫系统活化及胰岛素抗性相互关联,这些复杂的因素所引起的代谢异常可能会与长期心肌功能障碍有关。此外,这些代谢异常已经证实会影响其他的器官,包含骨骼肌肉,导致心脏衰竭患者易于疲劳及身体活动功能障碍。再者,例如是贫血、糖尿病、肾功能障碍及心脏恶病质等代谢疾病的并发症还会大幅地影响心脏衰竭患者的预后。
发明内容
据此,目前需要一种用于改善心脏衰竭患者症状的营养支持治疗方式,本发明提供一种营养组合物、含有该营养组合物的营养补充品以及使用该营养补充品治疗心脏衰竭患者的方法。
本发明的一目的是提供一种用于改善心脏衰竭患者症状的营养组合物,其是由有效治疗高剂量的白胺酸(leucine)及组胺酸(histidine)所组成,其中组胺酸与白胺酸的比例是为1:5至1:11,且白胺酸的剂量是介于4.0g至12.0g之间。
在本发明的一实施例中,其中该营养组合物能有效提升该心脏衰竭患者的骨骼肌肉质量、左心室射血分数(left ventricular ejection fraction)、血红蛋白及6-分钟步行距离。
本发明的另一目的是提供一种用于改善心脏衰竭患者症状的营养补充品,其中该营养补充品包含上述的营养组合物。
在本发明的一实施例中,其中该营养补充品进一步包含异白胺酸(isoleucine)及缬胺酸(valine)。
在本发明的一实施例中,其中该营养补充品每日的单位剂量是为33.0%-65.0%(w/w)的营养组合物、6.8%-12.0%(w/w)的异白胺酸及12.5%-23.0%(w/w)的缬胺酸。
在本发明的一实施例中,其中该营养补充品进一步包含至少一选自于由醣类、矿物质、维他命、多酚、L-肉碱、辅酶Q10、烟碱及β-羟基-β-甲基丁酸(β-hydroxy-β-methylbutyrate)所组成的群组。
在本发明的一实施例中,其中该醣类是来自于毛木耳(Auricularia polytricha)及海带的β-葡聚醣样多醣体,或该醣类是为一寡糖,且该寡糖是为果寡糖(fructo-oligosaccharide)。
在本发明的一实施例中,其中该多酚是为白藜芦醇(resveratrol)。
在本发明的一实施例中,其中该矿物质是选自于由钙、镁、锌、铜及硒所组成的群组。
在本发明的一实施例中,其中该维他命是选自于由维他命A、维他命B6、维他命B12、维他命C、维他命D、维他命E、硫胺素、核黄素及叶酸所组成的群组。
在本发明的一实施例中,其中该营养补充品不含中链三酸甘油脂(medium-chain triglycerides)、酪胺酸(tyrosine)、亚精胺(spermidine)、精胺(spermine)或苯丙胺酸(phenylalanine)。
在本发明的一实施例中,其中该营养补充品是选自于粉末、液体及即可使用(ready-to-use)的型式所组成的群组。
本发明的又一目的是提供一种如上述的营养组合物在制备改善心脏衰竭患者症状的营养补充品的用途。
在本发明的一实施例中,其中该营养补充品是为每日口服给予。
在本发明的一实施例中,其中该心脏衰竭患者是为患有急性或慢性心脏衰竭的患者。
在本发明的一实施例中,其中该营养补充品能有效提增该心脏衰竭患者骨骼肌肉质量、左心室射血分数、血红蛋白及6-分钟步行距离。
在本发明的一实施例中,其中该营养补充品每日的单位剂量是为33.0%-65.0%(w/w)的营养组合物、6.8%-12.0%(w/w)的异白胺酸及12.5%-23.0%(w/w)的缬胺酸。
在本发明的一实施例中,其中该营养补充品进一步包含至少一选自于由醣类、矿物质、维他命、多酚、L-肉碱、辅酶Q10、烟碱及β-羟基-β-甲基丁酸(β-hydroxy-β-methylbutyrate)所组成的群组。
在本发明的一实施例中,其中该营养补充品不含中链三酸甘油脂、酪胺酸、亚精胺、精胺或苯丙胺酸。
给予心脏衰竭患者本发明的营养组合物可增加血浆中白胺酸、组胺酸、白蛋白及血红蛋白的含量;还具有6-分钟步行距离、增加骨骼肌肉质量、左心室射血分数以及与心脏衰竭相关的住院率降低。因此,营养支持可视为一种治疗心脏衰竭的新策略。
虽然本发明已以实施例揭露如上,然其并非用以限定本发明,任何所属技术领域中具有通常知识者,在不脱离本发明的精神和范围内,当可作些许的更动与润饰,故本发明的保护范围当事后付的申请专利范围所界定者为准。
附图说明
图1是显示与心脏衰竭相关的无事件存活率(event-free survival rate)的曲线图,其中包含心脏衰竭相关的再住院率。L+H组:患者的饮食额外加入高剂量的白胺酸(8.3±3.2g/天)及组胺酸(1.5±0.5g/天);支链胺基酸(BCAA)组:患者的饮食额外加入支链胺基酸(白胺酸4.3±0.5g/天、异白胺酸2.2±0.3g/天、以及缬胺酸4.4±0.4g/天);控制组:除了日常饮食外没有增加任何的营养素。
具体实施方式
如于本文中所使用数值为近似值,所有临床及实验数据皆表示在20%的范围内,较佳为在10%的范围内,最佳为在5%的范围内。
营养素不是药物,正如近期强调「营养素质非药物治疗」的观念。因为营养方法必须涉及多种因素,以及经由体内的协同效应大多数的营养素是有生物活性的,而使得这个观念极为重要。因此,以代谢物组学为基础的(metabolomics-based)的营养组合物及微量营养素应与具有重度心脏衰竭患者相结合。本发明利用心脏衰竭的代谢途径中复杂相互作用的发现,而设计出专一符合心脏衰竭患者需求的营养组合物。
以代谢物组学为基础的营养组合物对心脏衰竭患者能明显改善症状、生活质量及及疾病状态效果,其与例如是心脏衰竭相关的再住院率降低的较佳预后有关。本发明除了有可减少大部分的心脏衰竭医疗照顾成本外,在代谢物组学为基础上开发的知识还具有极大的科学价值。
截至目前为止,根据心血管危险因素的相关知识仍然无法解释所有心脏衰竭患者的病因。无论是哪一种病因,心脏衰竭的发展与心脏无力是有因果关连,就是心脏无法满足身体的代谢需求。在心脏衰竭患者代谢体学的代谢物改变中,可找出以诊断和预后为目的的心脏衰竭-特定代谢物临床应用方法。目前美国心脏病学会及美国心脏协会(ACC/AHA)基于疾病发展共识制定心脏衰竭的分期以取代致病机制,ACC/AHA的分类系统有四个分级。例如:A级代表有心脏衰竭风险的患者,但尚未出现心脏结构上变化(例如:糖尿病患者,或患有冠心病无先前梗塞的患者)。B级代表具有心脏结构上变化的患者(例如:射血分数下降、左心室肥厚、腔室肥大),但尚无心脏衰竭的症状。C级代表已有心脏衰竭症状。D级代表具有难治性心脏衰竭需要进一步介入治疗(例如:双腔室心跳节律器、左心室辅助装置或心脏移植)的患者。除了ACC/AHA对心脏衰竭分级的定义外,还有另一种定义心脏衰竭功能状态的分级,称为纽约心脏协会(NYHA)功能性分类(第I级至第IV级),此分类是表示患者日常活动症状及生活质量,第I级:身体活动没有限制,日常身体活动不会引起过度疲劳、心悸或呼吸困难(气喘)。第II级:身体活动轻度受限制,休息时会缓解,但是从事日常活动会导致过度疲劳、心悸或呼吸困难。第III级:身体活动明显受限制,休息时会缓解,但是从事轻微日常活动会导致过度疲劳、心悸或呼吸困难。第IV级:从事任何身体活动皆会感到不适,休息时有新功能不全的症状,如果进行任何体力活动,不适的感觉会增加。
实施例1代谢体学(metabolomics-based)为基础的营养评估
在本发明中,利用高通量及开发多种生物标记潜在优势,代谢体学是一种有别于传统因子的检测方式,能分辨心脏衰竭前期至重度心脏衰竭患者状态的代谢信号(metabolic signature)的一个平台。经过深入了解与有关心脏衰竭代谢紊乱(metabolic perturbation),加上营养基因组一起深入研究,而发产出个人化的治疗策略。
依据ACC/AHA的分类系统分类为心脏衰竭C级,C级是表示由于急性或失代偿性(decompensated)慢性心脏衰竭住院的患者,年龄为20至85岁,包含具有收缩性及舒张性心脏衰竭的患者。同时,正常控制组年龄为20至85岁,且无显着全身性疾病,如高血压、糖尿病或冠状动脉疾病,正常控制组未使用任何药物,并且具有大于60%的左心室射血分数(left ventricular ejection fraction)。
不同分级的心脏衰竭患者的代谢产物血浆浓度有显着不同,例如苯丙胺酸(phenylalanine)、鸟胺酸(ornithine)、组胺酸(histidine)、亚精胺(spermidine)、精胺(spermine)、牛磺酸(taurine)及磷酯酰胆盐(phosphatidylcholines)。代谢产物的组合可作为好的生物标记,其与商业上用于诊断的B型排钠利尿胜肽(B-typenatriuretic peptide,BNP)有相同的功效,且对于预后功效更好。另一方面,常见到心脏衰竭患者因不同病因而在代谢产物上有不同的改变,显示出心脏衰竭的病程进展可能涉及普遍性的代谢紊乱。许多途径中,即谷氨酸-鸟胺酸-脯氨酸(glutamate-ornithine-proline)途径、多胺(polyamine)合成、多巴胺途径及磷酯酰胆盐合成,对心脏衰竭的病程进展有特定的影响。
在本发明中,代谢产物的定量以以下方式进行。加入200μL乙腈(acetonitrile,ACN)至50μL的血浆中,将混合物震荡30秒,超声坡处理15分钟,再以10,000g离心25分钟,收集上清液至另一个玻璃试管中。沉淀物以200μL 50%的甲醇再萃取,将甲醇上清液及乙腈合并,并在氮蒸发器中干燥,将残留物保存在-80℃中。进行代谢物分析,将残留物悬浮于100μL 95:5的水/乙腈溶液中,以14,000g离心5分钟,收集澄清的上清液以LC-MC进行分析。
液相色谱分离以100mm×2.1mm Acquity 1.7μL C8管柱(Waters公司,美国)使用AQCUITY TM UPLC系统(Waters公司,美国)。该管柱维持在45℃中,并以1.5mL/分钟的流速进行。以线性梯度从LC管柱冲提样本:1-48%B冲提0-2.5分钟;48-98%B冲提2.5-3分钟;98%B冲提3-4.2分钟;返回到1%B的水平进行再平衡4.3-6分钟,流动相为水溶液中0.1%甲酸(溶剂A)以及在乙腈中0.1%甲酸(溶剂B)。
将冲提液引入至TOF MS系统(SYNAPT G1高解析质谱仪,Waters Corp.,美国)且在ESI-正离子模式下操作,其条件如下:在300℃的温度下去溶剂气体设定为700l/h,锥气体设定为25l/h且源温度(source temperature)设定在80℃;毛细管电压及锥电压分别设定为3,000V及35V;MCP检测器电压设定为1,650V,数据收集速度设定为0.1s及扫描间歇时间为0.02s,以20至990m/z重心模式收集数据。为精确质量收集,以在浓度60ng/ml及流速6l/分钟时磺胺二甲氧嘧啶(sulfadimethoxine)的锁定质量(lock-mass)的条件进行(在ESI-正离子模式[M+H]+在311.0841Da)。
原始质谱数据才使用MassLynx V4.1及MakerLynx软件(Waters Corp.,美国)进行分析。每个质量离子的强度相对于总离子计算以产生包含滞留时间、m/z值及标准化波锋区域的数据矩阵。正确的分子质量数据之后以数据数据库进行收寻,包含内部或使用人类小分子代谢物数据库(HMDB)及京都基因与基因组百科全书(KEGG)数据库。
依据ACC/AHA分类系统分类的心脏衰竭C级与正常控制组之间表现出大量显着不同的关键代谢产物为组胺酸、苯丙胺酸、亚精胺及磷酯酰胆盐C34:4,在心脏衰竭患者中组胺酸及磷酯酰胆盐C34:4显着地减少,但苯丙胺酸及亚精胺显着增加。这些代谢产物绘制于生化途径上,经由这些代谢途径产生的异常流量可表现出重要的致病角色。有趣的是,在病情有进步的患者血中组胺酸及磷酯酰胆盐C34:4的浓度增加,而苯丙胺酸及亚精胺的浓度减少。
代谢体学的结果显示除了诊断外也可用于预后的临床应用,由4个代谢成分组合的代谢组比商业上生物标记BNP具有较佳的预后价值,这种代谢组合含盖不同方面的致病机制。例如,磺胺二甲氧嘧啶/精胺酸总比率代表内皮功能异常;亚精胺可能代表新机的毒性;丁酰基肉碱(butyrylcarnitine)代表脂质代谢异常;以及总必需胺基酸代表营养不良。另外,本发明的发现经由在代谢上的营养支持,提升藉由提供严重心脏衰竭患者辅助性治疗的可能性。
代谢异常表示与心脏衰竭相关的状态,而不是急性的心脏损伤。BNP的表现量在心脏衰竭的急性阶段之后就显着的减少,然后在接下来12个月仍然是相对较低的表现量。在代谢组合图形中,有一个类似的模式,然而,一个有趣的趋势显示,在12个月的代谢组合图形相较于在6个月的代谢组合图形正在持续恶化中,其说明在长期追踪下,临床征状不明显的代谢紊乱恶化是否会先于未来临床恶化。藉由代谢图形以及对前期心脏衰竭阶段或急性或失代偿性慢性心脏衰竭后撤消阶段的患者给予初期营养支持的数值的调查,这些数据进一步支持代谢组合评估对心脏衰竭状态的专一性。
事实上,评估心脏衰竭的代谢图形的数值远远超于诊断,从代谢体学异常得到信息可作为提供给心脏衰竭患者设计出以代谢体学-为基础的营养疗程,以提供具敏感性以代谢体学为基础的代谢组合图形以定义反应任何营养组合物的治疗效果的最佳平台。
实施例2设计以代谢体学-为基础的营养组合物
在本发明中,基于代谢体学的发现,提供一种以代谢体学为基础的营养组合物改善心脏衰竭相关异常、营养状态、功能状态及与健康相关的生活质量及与减少心脏衰竭相关的再住院的发生率。本发明与基础研究到临床试验有关,且将有利于患者的照护及经济效益。
以下列出几种对心脏衰竭患者营养支持不同的疗程:
营养组合物:高剂量的白胺酸(leucine)及组胺酸(histidine),其中组胺酸与白胺酸的比例是为1:5至1:11,且白胺酸的剂量是介于4.0g至12.0g之间。此外,以下为本发明的营养补充品,且本发明的营养组合物及营养补充品是选自于粉末、液体及可使用的型式所组成的群组。
添加物1:异白胺酸(isoleucine)及缬胺酸(valine)。
添加物2:醣类,例如是来自于毛木耳(Auricularia polytricha)及海带的β-葡聚醣样多醣体及果寡糖(fructo-oligosaccharide)。
添加物3:多酚,例如是白藜芦醇(resveratrol)。
添加物4:L-肉碱。
添加物5:辅酶Q10。
添加物6:包含烟碱、钙、镁、锌、铜、硒、维他命A、硫胺素、核黄素、维他命B6、叶酸、维他命B12、维他命C、维他命E及维他命D的微量营养素。
添加物7:β-羟基-β-甲基丁酸(β-hydroxy-β-methylbutyrate,HMB),HMB为白胺酸的代谢产物,HMB还具有增加肌肉产物及抑制肌肉分解。
在本发明中,该营养组合物可分别加入添加物1至7,且还包含一不含有中链三酸甘油脂(medium-chain triglycerides)、酪胺酸(tyrosine)、亚精胺(spermidine)、精胺(spermine)或苯丙胺酸(phenylalanine)的条件。
实施例3高剂量白胺酸及组胺酸改善临床参数、活动功能以及降低与心脏衰竭有关的再住院率
在本发明中,为证实提供高剂量的白胺酸及组胺酸比仅提供支链胺基酸(BCAA),更能增加骨骼肌肉质量、血红蛋白及6-分钟步行距离,以及降低心脏衰竭相关事件的发生率。
本发明以212个心脏衰竭(HF)患者进行临床试验,该些患者的病症包含:(i)具有典型心脏衰竭病征及症状,以及NYHA功能分类为II至IV级(经由Battler etal.分类≧1级),其是排除非心原性的因素之后基于胸腔X光检查诊断为急性心原性肺瘀血住院者;(ii)经由超声波心动图(echocardiograms)纪录有<40%左心室射血分数(left ventricular ejection fraction,LVEF);以及(iii)年龄在20至85之间。排除的条件包含:(1)患有非心脏衰竭在接下来六个月内会影响存活的疾病;(2)超过3个月卧床不起;(3)具有≧3mg/dl血清肌酸酐;(4)在前两个星期内经历过透析;(5)具有严重的冠状动脉疾病没有完整的血运重建治疗(revascularization therapy);以及(6)怀孕。
本发明将212个心脏衰竭患者分为三组:(1)L+H组:患者的饮食额外加入高剂量的白胺酸(8.3±3.2g/天)及组胺酸(1.5±0.5g/天);(2)支链胺基酸(BCAA)组:患者的饮食额外加入支链胺基酸(白胺酸4.3±0.5g/天、异白胺酸2.2±0.3g/天、以及缬胺酸4.4±0.4g/天);以及(3)控制组:除了日常饮食外没有增加任何的营养素。给予患者营养素一个月后,然后再回到患者的日常饮食。
患者接着在血液中的血红蛋白、B型排钠利尿胜肽(BNP)、白蛋白(albumin)、白胺酸、及组胺酸的含量的改变、6-分钟步行距离提升、骨骼肌肉质量以及左心室射血分数(LVEF);BNP是为HF状态的敏感指标(较高的数值表示较差的状态)。此外,临床上随访患者与心脏衰竭相关的再住院。
3.1实验室参数
患者出院前及依规划的每一时间点收集血液样本于含有EDTA的采血管内,BNP的量测是使用Triage BNP测试(Biosite公司,美国)。Triage BNP测试是为一种在血浆样本中定量测定BNP的荧光免疫分析法,采取三次检测的平均值。其他的量测包含血红蛋白及白蛋白的含量是于在基隆长庚医院心脏衰竭中心实验室进行。
3.2身体成分分析
利用Inbody 720多频分析仪(在1、5、50、250、500及1,000kHz)进行每一个患者八极性生物电阻分析(eight-polar bioelectrical impedance analyses)(ModelBios pace In Body 720,韩国)。依制造厂商的操作手册进行,以八个接触电极量测(手掌及拇指两个位置,脚的前部及脚跟另外两个位置),其使本发明分析5个各自独立的身体部分(左与右上肢、躯干、以及左与右下肢)。在BIA进行量测之前指导患者将胃及膀胱排空、避免运动以及卧躺至少5分钟以增加精确度。所有的患者站立并以脚与脚电击接触并握住手电击,将患者的鉴别号、身高、年龄及性别输入分析仪。依据不同的频率电流有不同的穿透力,以这种方式,骨骼肌肉质量能精确地在不同时间点对不同群组的患者进行评估。
3.36-分钟步行距离
为评估不同群组患者的功能程度,经由有经验的研究护士进行6分钟步行距离评估。此评估代表身体状态,还代表不同功能程度的患者对不同营养组合物的反应。
3.4心脏超声波心动图
超声波心动图影像是由患者左侧卧吐气末时以2.5MH进行量测(2-维)获得(飞利浦iE33机器)。基于辛普森法则(Simpson method)计算左心室射血分数(LVEF),利用美国超声波心动图学会(American Society of Echocardiography)建议评估左心室舒张及收缩末期的尺寸以及其他相关构造上的异常,例如是瓣膜病变。
3.5患者的结果
从每个月的医院纪录、与医师的构通、电话访谈及患者的定期回诊获得的随访数据。「再住院」的定义为与心脏衰竭相关的再住院,心脏衰竭相关的再住院是为预后目的而进行的分析。
3.6统计分析
结果对于连续变量以平均值±标准偏差表示,作为分类变量的数目(百分比)。数据经由未配对的t-test、非参数检验、卡方检验、皮尔逊相关(Pearson correlation)或变异数分析(analysis of variance,ANOVA)进行比对,之后有需要时利用Tukey事后比较检定(post-hoc test)。收集如期或最后一次可获得访问的随访数据,利用Kaplan-Meier曲线绘制及分析以比较不同营养组合物用于心脏衰竭患者的效果。所有统计分以双边(two-sided)检定及利用SPSS软件(15版,美国)进行,p值<0.05被认为是显着的。
3.7结果
整体而言,212个住院患者具有参予此研究的资格,三组的基础特性(baselinecharacteristics)列于表1。患者在年龄、性别、LVEF、功能分级、共病(co-morbidity)的发生率、6分钟步行距离或实验室数据。
一个月后在临床上及实验室参数上的改变。在控制组中血浆中的白胺酸的含量显着减少,与BCAA组的含量接近,而在L+H组的白胺酸量明显增加。且在控制组与BCAA组中,血浆中组胺酸的含量相同,而在L+H组的组胺酸的含量明显增加。
在控制组中,6-分钟步行距离有稍微的增加,而在BCAA组及L+H组两组在6-分钟步行距离皆有显着的增加(表2)。此外,L+H组比BCAA组6-分钟步行距离增加更多。
在骨骼肌肉质量方面,在控制组及BCAA组皆没有明显的改变。然而,在L+H组的患者骨骼肌肉质量有显着的增加(表2)。关于LVEF方面,仅有L+H组有显着的改善。在骨骼生长期间,第一周时L+H组因肌肉合成导致血浆中的组胺酸的含量会瞬间降低,故组胺酸为骨骼肌肉质量生长及改善心肌收酸力的重要成分。
在红血蛋白的含量方面,L+H组一个月后有显着的增加,然而,控制组及BCAA组皆有稍微的增加。在血浆中白蛋白的含量方面,三组皆有显着的增加,且三组的增加没有差异。在BNP表现量方面,在一个月后控制组没有显着增加的趋势,而在一个月之后BCAA组及L+H组皆有显着减少。此外,L+H组比BCAA组更显着地减少。且本发明还证实能改善心脏衰竭患者症状的有效治疗高剂量的白胺酸及组胺酸是为每日4.0g至12.0g的白胺酸及0.36g至2.4g的组胺酸,且组胺酸与白胺酸的比例是为1:5至1:11。
再住院率。六个月后追踪所有的患者,如图1所示,三组与心脏衰竭相关的再住院率:控制组为33.1%、BCAA组22.5%以及L+H组12.2%。Kaplan-Meier曲线显示控制组的无事件存活率(event-free survival rate)无明显高于BCAA组,然而,相较于控制组,L+H组的无事件存活率明显更高(log rank=13.7,p=0.001)。
总而言之,基于临床及实验室参数、以及六个月无事件存活率,证实本发明的具有高剂量白胺酸及组胺酸的营养组合物的患者具有较佳的预后。
实施例4提供心脏衰竭患者中链三酸甘油脂会导致血液中乙酰基肉碱(acylcarnitine)提升
给予在35个心脏衰竭患者含中链三酸甘油脂的营养组合物一个月。如表3所示,经由代谢体学分析进行脂肪酸代谢的血液检查,该数据显示血液中大部分乙酰基肉碱的含量(来自于短至长链)提升,其代表心脏衰竭患者的粒线体已有β-氧化作用受损,而导致各种乙酰基肉碱作为废物堆积在血液中。
该数据显示给予心脏衰竭患者含有中链三酸甘油脂的营养添加物是有害的。
实施例5给予心脏衰竭患者小袋包装(含心脏衰竭配方)以评估效果
本发明的一实施例提供一种营养素小袋包装,该营养素小袋包装包含白胺酸(5.25g)、异组胺酸(1.2g)、组胺酸(2.25g)及缬胺酸(1.0g)。患者分为两组:(1)HF配方组(n=12):患者除了日常饮食额外给予前7天每日一包营养素小袋包装服用及之后7天每日两包营养素小袋包装;以及(2)控制组(n=12):未额外给予营养素。
十四天后监控两组患者的实验室参数,包含血浆中白胺酸、组胺酸及3-甲基组胺酸的含量。血浆中甲基组胺酸的含量表示肌肉蛋白质分解量。以LC-MS系统测量这些代谢产物。
在血浆中白胺酸的含量,在14天内控制组没有明显的改变,但有减少的趋势。在第7天时在HF配方组的血浆中白胺酸的含量有增加的趋势,在14天时有明显增加。在本发明的其他实施例中,HF配方组包含28.0%-55.0%(w/w)白胺酸、5.0%-10.0%(w/w)组胺酸、6.8%-12.0%(w/w)异白胺酸及12.5%-23.0%(w/w)缬胺酸,还显示出血浆中的白胺酸及组胺酸有增加的趋势。
关于血浆中组胺酸的含量,在14天内控制组没有显着的差异,然而,在第7天及第14天HF配方组有显着的增加。关于3-甲基组胺酸的含量,在第14天控制组有显着的增加,而在HF配方组在给予含有HF配方的营养素之后第14天3-甲基组胺酸显着的减少。这些发现显示在含有本发明的营养组合物的HF配方能有效降低蛋白质从骨骼肌肉的分解。
实施例6以高剂量的白胺酸改善临床参数及活动功能
在本实施例中,心脏衰竭患者除了日常饮食摄取外分别给予心脏衰竭患者三种不同的营养组合物。组合物#1组:前两周给予一天组胺酸1.0g及白胺酸5.0g以及之后两周给予一天组胺酸2.0g及白胺酸10.0g;组合物#2组:前两周给予一天组胺酸1.0g、白胺酸2.0g、异白胺酸1.0g及缬胺酸2.0g以及之后两周给予一天组胺酸2.0g、白胺酸4.0g、异白胺酸2.0g及缬胺酸4.0g;该组还代表添加组胺酸的支链胺基酸(BCAA);以及组合物#3组:前两周给予一天组胺酸1.0g以白胺酸1.0g以及之后两周给予一天组胺酸2.0g及白胺酸2.0g)。每组患者给予该些额外的营养组合物一个月,然后恢复正常饮食。
给予心脏衰竭患者三种不同的营养组合物。在组合物#1组中,相较于第0个月(M0),患者在营养介入后第一个月(M1)有较高的血浆中白胺酸及组胺酸含量,且其白蛋白及血红蛋白的含量还较高,但BNP的表现量降低;有较长的6-分钟步行距离、骨骼肌肉质量以及左心室射血分数增加(表4)。在组合物#2组中,相较于第0个月(M0),患者在营养介入后第一个月(M1)有较高的血浆中组胺酸的含量,但白胺酸为未有着的增加,且其具有较高的白蛋白的含量,但BNP的表现量降低,然而,血红蛋白的含量未有显着增加;患者在第一个月还有较长的6-分钟步行距离,然而,骨骼肌肉质量及左心室射血分数增加未有明显的增加。此外,相较于组合物#1组,组合物#2组的6-分钟步行距离增加的较少且BNP的表现量降低较少。本发明的具有高剂量的组胺酸及白胺酸的营养组合物能有效改善骨骼肌肉生长质量、血红蛋白的含量及心脏收缩力(表4)。
在组合物#3组中,相较于第0个月(M0),患者在营养介入后第一个月(M1)有较高的血浆中白蛋白的含量,但白胺酸的含量较低,然而,组胺酸、血红蛋白的含量、以及BNP的表现量未有显着改变;患者在第一个月有左心室射血分数改变不明显,然而,6-分钟步行距离及骨骼肌肉质量未有显着改变。此外,相较于组合物#1组,在组合物#3组的组胺酸、6-分钟步行距离、骨骼肌肉质量及左心室射血分数都增加较少(如表4)。
实施例7以高剂量的组胺酸改善临床参数及活动功能
在本实施例中,心脏衰竭患者除了日常饮食摄取外分别给予心脏衰竭患者两种不同的营养组合物。组合物#4组:前两周给予一天组胺酸1.0g及白胺酸5.0g以及之后两周给予一天总量为组胺酸2.0g及白胺酸10.0g;组合物#5组:前两周给予一天组胺酸0.25g及白胺酸5.0g以及之后两周给予一天组胺酸0.5g及白胺酸10.0g);每组患者给予该些额外的营养组合物一个月,然后恢复正常饮食。
在组合物#4组中,相较于第0个月(M0),患者在营养介入后第一个月(M1)有较高的血浆中白胺酸及组胺酸含量,且其白蛋白及血红蛋白的含量还较高,但BNP的表现量降低;有较长的6-分钟步行距离、骨骼肌肉质量以及左心室射血分数增加(如表5)。在组合物#5组中,相较于第0个月(M0),患者在营养介入后第一个月(M1)有较高的血浆中白胺酸的含量,但组胺酸未有显着的改变,且其白蛋白的含量较高,但BNP的表现量降低;然而,血红蛋白的含量未有显着的改变,患者在第一个月还有较长的6-分钟步行距离(如表5)。然而骨骼肌肉质量以或左心室射血分数没有明显改变。再者,相较于组合物#4组,组合物#5组的BNP的表现量降低较少,且6-分钟步行距离增加较少(如表5)。其结果显示出组胺酸能有效改善骨骼肌肉生长质量、血红蛋白的含量及心脏收缩力。
在本发明中,改善心脏衰竭患者有效治疗高剂量的白胺酸及组胺酸是为每日4.0g至12.0g的白胺酸及0.36g至2.4g的组胺酸,组胺酸与白胺酸的比例是为1:5至1:11。
综上所述,本发明提供一种改善心脏衰竭患者症状的营养组合物,其是由有效治疗高剂量的白胺酸及组胺酸所组成的群组。每日口服给予心脏衰竭患者含有4.0g至12.0g的白胺酸及0.36g至2.4g的组胺酸的营养组合物,其中组胺酸与白胺酸的比例是为1:5至1:11。该心脏衰竭患者有良好的预后,例如症状、与疾病有关的生活质量以及在六个月内的再住院率。因此,高剂量的白胺酸及组胺酸可应用于预防及治疗心脏衰竭。本发明还提供一种给予心脏病患者含有该营养组合物的营养补充品,其是为一饮品、日常补充品或食物。
表1.患者出院时的基础特性(n=212)
BCAA组:仅给予支链胺基酸;L+H组:给予高剂量的白胺酸及组胺酸;BNP:B型排钠利尿胜肽;GFR:评估肾丝球滤过率;COPD:慢性阻塞性肺病;LVEF:左心室射血分数;6-分钟步行:6-分钟步行距离。
表2.三组患者在临床上及实验室参数上的改变
BCAA组:仅给予支链胺基酸;L+H组:给予高剂量的白胺酸及组胺酸;M0:起始值;M1:一个月后量测的数据;6-分钟步行:6-分钟步行距离;SMM:骨骼肌肉质量;LVEF:左心室射血分数;BNP:B型排钠利尿胜肽;*:相较于M0的数据;#:BCAA组相较于控制组于M0及M1之间有差异;:L+H组相较于控制组于M0及M1之间有差异。
表3、心脏衰竭患者在给予含有中链三酸甘油脂的营养组合物之前以及一个月后的脂肪代谢分析
数据以平均值±标准偏差表示。
表4、三组患者的临床及实验室数据
「组合物#1组」:前两周给予患者一天组胺酸1.0g及白胺酸5.0g以及后两周给予一天组胺酸2.0g及白胺酸10.0g;「组合物#2组)」:前两周给予患者一天组胺酸1.0g、白胺酸2.0g、异白胺酸1.0g及缬胺酸2.0g以及后两周给予一天组胺酸2.0g、白胺酸4.0g、异白胺酸2.0g及缬胺酸4.0g;以及「组合物#3组」:前两周给予患者一天组胺酸1.0g及白胺酸1.0g以及后两周给予一天组胺酸2.0g及白胺酸2.0g;M0:起始值;M1:营养介入后一个月;6-分钟步行:6-分钟步行距离;SMM:骨骼肌肉质量;LVEF:左心室射血分数;BNP:B型排钠利尿胜肽;*:相较于M0的数据;#:相较于「组合物#1组」,「组合物#2组)」于M0及M1之间有差异;:「组合物#3组」相较于「组合物#1组」在M0及M1之间的差异。
表5、两组患者的临床及实验室数据
「组合物#4组」:前两周给予患者一天组胺酸1.0g及白胺酸5.0g以及之后两周给予一天组胺酸2.0g及白胺酸10.0g;「组合物#5组)」:前两周给予患者一天两次组胺酸0.25g及白胺酸5.0g以及之后两周给予一天组胺酸0.5g及白胺酸10.0g;M0:起始值;M1:营养介入后一个月;6-分钟步行:6-分钟步行距离;SMM:骨骼肌肉质量;LVEF:左心室射血分数;BNP:B型排钠利尿胜肽;*:相较于M0的数据;#:相较于「组合物#4组」,「组合物#5组)」于M0及M1之间有差异。
Claims (20)
1.一种用于改善心脏衰竭患者症状的营养组合物,其特征在于,其由有效治疗高剂量的白胺酸(leucine)及组胺酸(histidine)所组成,其中组胺酸与白胺酸的比例为1:5至1:11,且白胺酸的剂量介于4.0g至12.0g之间。
2.如权利要求1所述的营养组合物,其特征在于,该营养组合物能有效提升该心脏衰竭患者的骨骼肌肉质量、左心室射血分数(left ventricular ejectionfraction)、血红蛋白及6-分钟步行距离。
3.一种用于改善心脏衰竭患者症状的营养补充品,其特征在于,该营养补充品包含如权利要求1所述的营养组合物。
4.如权利要求3所述的营养补充品,其特征在于,该营养补充品进一步包含异白胺酸(isoleucine)及缬胺酸(valine)。
5.如权利要求4所述的营养补充品,其特征在于,该营养补充品每日的单位剂量为33.0%-65.0%(w/w)的营养组合物、6.8%-12.0%(w/w)的异白胺酸及12.5%-23.0%(w/w)的缬胺酸。
6.如权利要求3所述的营养补充品,其特征在于,该营养补充品进一步包含至少一选自于由醣类、矿物质、维他命、多酚、L-肉碱、辅酶Q10、烟碱及β-羟基-β-甲基丁酸(β-hydroxy-β-methylbutyrate)所组成的群组。
7.如权利要求6所述的营养补充品,其特征在于,该醣类来自于毛木耳(Auricularia polytricha)及海带的β-葡聚醣样多醣体。
8.如权利要求6所述的营养补充品,其特征在于,该醣类为一寡糖,且该寡糖为果寡糖(fructo-oligosaccharide)。
9.如权利要求6所述的营养补充品,其特征在于,该多酚为白藜芦醇(resveratrol)。
10.如权利要求6所述的营养补充品,其特征在于,该矿物质选自于由钙、镁、锌、铜及硒所组成的群组。
11.如权利要求6所述的营养补充品,其特征在于,该维他命是选自于由维他命A、维他命B6、维他命B12、维他命C、维他命D、维他命E、硫胺素、核黄素及叶酸所组成的群组。
12.如权利要求3所述的营养补充品,其特征在于,该营养补充品不含中链三酸甘油脂(medium-chain triglycerides)、酪胺酸(tyrosine)、亚精胺(spermidine)、精胺(spermine)或苯丙胺酸(phenylalanine)。
13.如权利要求3所述的营养补充品,其特征在于,该营养补充品选自于粉末、液体及即可使用(ready-to-use)的型式所组成的群组。
14.一种如权利要求1所述的营养组合物在制备改善心脏衰竭患者症状的营养补充品的用途。
15.如权利要求14所述的用途,其特征在于,该营养补充品为每日口服给予。
16.如权利要求14所述的用途,其特征在于,该心脏衰竭患者为患有急性或慢性心脏衰竭的患者。
17.如权利要求14所述的用途,其特征在于,该营养补充品能有效提增该心脏衰竭患者骨骼肌肉质量、左心室射血分数、血红蛋白及6-分钟步行距离。
18.如权利要求14所述的用途,其特征在于,该营养补充品每日的单位剂量为33.0%-65.0%(w/w)的营养组合物、6.8%-12.0%(w/w)的异白胺酸及12.5%-23.0%(w/w)的缬胺酸。
19.如权利要求14所述的用途,其特征在于,该营养补充品进一步包含至少一选自于由醣类、矿物质、维他命、多酚、L-肉碱、辅酶Q10、烟碱所组成的群组及β-羟基-β-甲基丁酸(β-hydroxy-β-methylbutyrate)。
20.如权利要求14所述的用途,其特征在于,该营养补充品不含中链三酸甘油脂、酪胺酸、亚精胺、精胺或苯丙胺酸。
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CN108813624A (zh) * | 2018-05-31 | 2018-11-16 | 量子高科(中国)生物股份有限公司 | 一种具有提升皮肤弹性及水分含量的组合物及其制备方法和应用 |
CN112885455B (zh) * | 2021-01-18 | 2024-02-27 | 复旦大学附属中山医院 | 一种心力衰竭分型模型及试剂盒 |
CN115501132A (zh) * | 2022-06-28 | 2022-12-23 | 广州大学 | 一种毛木耳多糖-锌复合物的制备方法 |
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WO2002002103A2 (en) * | 2000-07-04 | 2002-01-10 | Professional Dietetics S.R.L. | Compositions based on aminoacids, suitable for the treatment of heart failure |
CN1812776A (zh) * | 2003-05-21 | 2006-08-02 | 得克萨斯州大学系统董事会 | 抑制蛋白激酶c-mu(pkd)用作心脏肥大和心力衰竭的疗法 |
CN1925876A (zh) * | 2004-03-04 | 2007-03-07 | 通用电气医疗集团股份有限公司 | 用于诊断和治疗的血管紧张素肽类似物和螯合剂的缀合物 |
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WO2002002103A2 (en) * | 2000-07-04 | 2002-01-10 | Professional Dietetics S.R.L. | Compositions based on aminoacids, suitable for the treatment of heart failure |
CN1812776A (zh) * | 2003-05-21 | 2006-08-02 | 得克萨斯州大学系统董事会 | 抑制蛋白激酶c-mu(pkd)用作心脏肥大和心力衰竭的疗法 |
CN1925876A (zh) * | 2004-03-04 | 2007-03-07 | 通用电气医疗集团股份有限公司 | 用于诊断和治疗的血管紧张素肽类似物和螯合剂的缀合物 |
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WO2020227512A1 (en) * | 2019-05-08 | 2020-11-12 | Gamot Global Pte. Ltd. | Use of isothiocyanate in smokeless tobacco products |
US11730187B2 (en) | 2019-05-08 | 2023-08-22 | Gamot Global Pte. Ltd. | Use of isothiocyanate in smokeless tobacco products |
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US20150238464A1 (en) | 2015-08-27 |
CN104872685B (zh) | 2017-12-19 |
TW201532527A (zh) | 2015-09-01 |
TWI587793B (zh) | 2017-06-21 |
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