CN1306431A - 用于增加体内能量的组合物 - Google Patents
用于增加体内能量的组合物 Download PDFInfo
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- CN1306431A CN1306431A CN99807560A CN99807560A CN1306431A CN 1306431 A CN1306431 A CN 1306431A CN 99807560 A CN99807560 A CN 99807560A CN 99807560 A CN99807560 A CN 99807560A CN 1306431 A CN1306431 A CN 1306431A
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- ribose
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Abstract
本发明公开了三磷酸腺苷的前体作为食品强化剂经口服给药用来提高细胞内ATP的浓度或用于治疗因耗体力活动、疾病或创伤所致能量有效性降低。戊糖单独施用,或混合在干燥食品或溶液内给药。优选的戊糖是D-核糖,单独施用或与肌酸、丙酮酸盐、L-肉碱和/或血管舒张药结合施用。另外,可以应用镁、电解质、脂肪酸和己糖。本发明的组合物和方法特别有利于能量有效性低下或高能需求的哺乳动物。
Description
发明领域
本发明涉及有效增加能量有效性低或能量消耗水平高的哺乳动物的能量的组合物和方法。所述哺乳动物包括患有因细胞内三磷酸腺苷(ATP)减少所致疾病的人体,从事重体力活动的人群如运动员或体力劳动者,和希望提高其能量水平的人体。其它哺乳动物如狗和猫也包括在本发明方法内。给予本发明的组合物可提高血液和细胞内的ATP水平,延长哺乳动物活动的时间和强度,并且提高运动试验者对氧的利用率。无运动哺乳动物和那些在身体损伤(如创伤、烧伤和脓毒病)复原期间消耗高于正常水平的能量的哺乳动物也受益于本发明组合物的给药。
发明背景
已知细胞的能量制造者是三磷酸腺苷(ATP)。在合成代谢过程中,来源于营养物代谢的能量转移至ATP的高能磷酸键。这些键内的能量在能量耗费阶段中被消耗。肌肉收缩需要重要和“高成本”的消耗,其中ATP快速循环。
能量积累步骤发生在肌肉细胞内两个基础过程期间。氧化磷酸化作用通过分解循环脂肪酸、葡萄糖和肌内糖原和甘油三酯重新补足ATP。无氧磷酸化作用由磷酸肌酸、循环葡萄糖和肌内糖原经过激酶反应如肌激酶反应提供ATP。
美国专利号5714515描述了施用含有丙酮酸盐,一种葡萄糖的中间分解产物的组合物可以增强手术或意外创伤、休克、长期体力消耗所致疲劳和其它适应症的复原。美国专利号5709971公开了与烟碱腺嘌呤二核苷酸、辅酶A和乙酰基辅酶A联合给药的其它葡萄糖代谢产物,也就是甘油醛-3-磷酸、磷酸烯醇丙酮酸和3-磷酸甘油酸。
一种现已被用来增加生产ATP的有效底物的不同途径是给予氨基酸L-肉碱,该物质被认为能够增强脂肪酸运送和吸收到线粒体中,线粒体是氧化磷酸化部位。美国专利号4968719描述了L-肉碱治疗外周血管疾病的用途。
无论ATP的高能磷酸键是在有氧或是在无氧下生成,并且无论其生成所用底物如何,如果没有ATP分子的前体就无法合成ATP。ATP分子的再合成可以通过从头或补救途径进行。
在经核苷酸补救途径合成ATP中,可存在于组织内的核苷酸前体被转化为AMP且进一步磷酸化为ATP。腺嘌呤直接磷酸化为AMP,而黄嘌呤和肌苷首先被5-磷酸核糖基-1-焦磷酸(PRPP)核糖基化且进而转化为AMP。发现核糖在普通饮食中含量很低,在机体内通过戊糖磷酸途径合成。在从头合成途径中,核糖磷酸化为PRPP,并且与腺嘌呤缩合成为中间体一磷酸腺苷(AMP)。AMP进一步经高能磷酸键磷酸化成为二磷酸腺苷(ADP)和ATP。
通过从头途径合成缓慢。通常,AMP合成主要通过补救途径进行,然而,缺氧或局部缺血后,从头途径的活性增高。
在能量耗费过程中,ATP失去一个高能键成为ADP,ADP可以水解成为AMP。肌肉细胞内的AMP及其代谢产物腺嘌呤、次黄嘌呤和肌苷可以随意扩散,但不能通过补救途径用于ATP的再合成。
在美国专利号4719201中,它公开称当ATP在心肌内在局部缺血期间水解为AMP时,AMP进一步代谢为腺嘌呤、肌苷和次黄嘌呤,细胞在再灌注时失去它们。当AMP不存在时,无法发生再磷酸化得到ADP和ATP。由于上述前体被冲洗出细胞,核苷酸补救途径无法有效重新补充ATP的水平。该专利公开了当核糖经静脉内输液给药至心脏内用于局部缺血复原时,ATP水平的恢复增高。
Pliml在德国专利号4228215中发现口服核糖可在人体中有效治疗心肌机能不全和血容量减少性休克。
Zolner等人(Klinische Wochenshritt 64:1281-1290,1986)提出了给予戊糖如核糖或木糖醇用于在患有常染色体隐性遗传病肌腺苷酸脱氨酶(MAD)缺陷的患者中预防骨骼肌疼痛和强直的优越性。这种疾病的特征是永久性肌张力减退、过度肌肉虚弱、疲劳、痛苦、灼痛、强直和痛性痉挛。这些症状被认为是ATP循环间断的后果。蓄积的AMP抑制了ATP的脱磷酸化,导致缺少影响肌肉收缩和松弛的可利用能量。然而,尽管缺乏MAD患者的症状通过核糖给药可以缓解,但细胞内腺嘌呤核苷酸的水平仍然维持在异常高水平,正常志愿者无法由核糖给药获益。(Gross,Reiter & Zollher,KlinischeWochenshritt,67:1205-1213,1989)。
Tullson等人(《美国生理学杂志》(Am.J.Physiol.),261(细胞生理学30)C343-347,1991)引用参考文献提出,高强度运动增加了离体肌肉内AMP的降解和继发损失。他们进一步公开了向灌注液内添加核糖可在大鼠后腿标本中增加静坐肌肉内AMP的从头合成,但无法消除收缩肌肉中从头合成减退。
Carniglia等人在美国专利号4871718中公开了当含有氨基酸、代谢产物、电解质和核糖或核糖前体的复合混合物作为食品强化剂口服给予赛马时,可以提高肌肉内ATP水平和机体行为表现效果。行为表现的评估是轶事的,然而基于该试验者的行为表现史。
因此,始终需要能够在正常哺乳动物即不是因局部缺血时应用该方法的哺乳动物中,在进行体力活动之前或期间提高骨骼肌行为表现的简便方法。还需要一种提高哺乳动物能量水平以提供舒适感的方法。
发明概述
本发明提供提高哺乳动物中能量水平的组合物和方法。本发明的组合物和方法通过在ATP供应不足的哺乳动物中促进ATP的合成而起作用以便支持细胞功能。具体而言,在高ATP需求的一段时期之前、期间和之后以能够有效提高哺乳动物能量的有效量口服给予戊糖如D-核糖。核糖给药的哺乳动物比未给予核糖的哺乳动物能够活动更长时间,获得更高强度,具有更多的能量。
据称细胞PRPP的浓度在通过从头合成或核苷酸补救途径的ATP水平恢复或增高中是限制因子,并且给予的核糖可以促进ATP合成,为能量消耗提供更大的ATP储备。ATP需求不足的哺乳动物包括高能需求的正常、健康试验者,如运动员和进行重体力劳动的工作者。还推测,正常试验者甚至在休息状态也将在给予有效量核糖后感受到积极的高舒适感。
PRPP的有效性可能控制补救途径和从头途径的活性,和腺嘌呤向ATP的直接转化。由葡萄糖生产PRPP似乎受到葡糖-6-磷酸脱氢酶(G6PDH)限制。葡糖在酶如G6PDH的作用下转化为核糖-5-磷酸并且进一步磷酸化为PRPP,其增强从头途径和补救途径,以及腺嘌呤的利用。加入核糖绕过这个限速酶促步骤。
本发明方法所受益试验者中还包括具有因衰老、创伤、脓毒症所致慢性低能量水平,或如充血性心衰的病症或其他慢性病的哺乳动物。
还提供了增强戊糖效益的组合物。此类组合物适宜含有镁、肌酸、丙酮酸盐、L-肉碱、戊糖、其他能量代谢产物的至少一种和任选的至少一种血管舒张物质。其中,核糖优选和肌酸和镁合用。经受高能需求和损失体液的哺乳动物也可从进一步含有电解质和附加能源如碳水化合物的组合物获益。
附图简述
图1表示核糖给药的正常成年大鼠中腺嘌呤补救途径的剂量反应。
图2表示在核糖或安慰剂给药后,基于放能循环(exercycle)测量,正常成人每次全速冲刺期间的平均功率输出。
图3表示在核糖或安慰剂给药后,基于放能循环测量,正常成人每次全速冲刺期间的功率输出峰。
发明详述
本发明提供一种通过口服给予戊糖促进ATP合成的方法,并且提供特别有益于经受高能需求或患有慢性低能量水平的哺乳动物的含戊糖组合物。
为了说明本发明,以下术语具有如下含义:
1.“戊糖”是指单糖,包括但不限于核糖、D-核糖、核酮糖、木糖醇,木酮糖和任何核糖的5-碳前体。
2.“血管舒张药”包括任何可经皮或口服给药引起血管扩张的物质,包括腺嘌呤、肼苯哒嗪、精氨酸和硝酸甘油。
3.“细胞内ATP水平”是指通过组织活检或核磁共振直接测量或通过血液ATP浓度间接测量的ATP浓度。
4.“其他能量代谢产物和辅因子”是指肌酸,辅酶类,三羧酸、戊糖磷酸或糖酵解酶途径的中间体,嘧啶和嘌呤核苷酸和无机物。
所述组合物优选含有溶解或分散在水载体如水中的能量提高量的戊糖,该组合物可以含有少而有效量的添加剂,如多元醇、防腐剂、矫味剂、着色剂等。适于口服给药的含戊糖组合物还包括固体剂型,如片剂、锭剂、胶囊等。戊糖还可以混合在固体营养物中,例如方条状食品、湿的或干燥的狗食,粉末或混合饮料。核糖的有效总剂量在下文中公开,可由此推及其他戊糖。
由于戊糖是具有宜人味道的天然糖并且实际上无毒,可以鼓励试验者自己施用片剂、锭剂、散剂、混悬液、溶液形式或与固体食物混合的戊糖。当试验者是犬科或猫科时,戊糖易于被加入“高级食品”或“心脏病饮食”并且不一定分开给药。当该试验者是人体时,戊糖可以含在饮料、方条状食品、鸡尾酒或快餐中。优选的戊糖是核糖或木糖醇。剂量适宜是0.1至100gm戊糖/天,优选1至20gm戊糖/天。发现成人平均4至8gm戊糖/天足以提供本发明的有益作用。上限剂量仅受到试验者味觉偏爱的限制,尽管剂量很高,试验者可能发生腹泻。可以以单位剂型每天给药1次,但优选全天给药2或3次,最常见在进餐期间或之后给药。
在费劲的活动中,个体可能大量流汗,需要补充体液和电解质。不出汗的试验者如狗经肺失去大量水分并且也需要补充液体。除了戊糖单独提供的优越性以外,对于肉碱和或血管舒张药,一般补充液中含有其他组分,以便在运动过程中和之后饮用。再水化溶液如Gatorade、Thirst Quencher,和Max饮料为运动员所喜爱。
这些持久能量和合成代谢配方一般是由以下物质组成:不同的碳水化合物,包括玉米糖浆、蔗糖、果糖和麦芽糖糊精;蛋白质类,包括酪蛋白和得自牛奶和大豆的其他蛋白质;和脂质类,包括玉米、大豆、红花和白桂皮(canola)油和中链甘油三酯。为改进此类“行为饮料”的努力仍在继续。
美国专利号5292538描述了能量维持组合物,该组合物含有果糖、葡萄糖、水解蛋白和与氨基酸螯合物配合的镁。特别有益的其他组分包括钾、磷、锰、锌、硼、铜、钼、铬、钒、维生素B1,2,5,6,和12、维生素C、E和肉碱。
美国专利号5114723描述了用于口服给予的低渗饮料组合物,包括电解质、无机物、碳水化合物和其他组分。该组合物调至100至70mOs/l重量摩尔渗透压浓度。
这些再水化饮料可以分别通过加入约1至20%戊糖,首选10%戊糖(重量/体积)来改进。戊糖的加入量应取决于组合物的其他组分,以使重量摩尔渗透压浓度维持在优选限度内。通过加入其他能量代谢产物和辅因子可以进一步改进这些饮料。
本发明将通过以下实施例进一步说明。
实施例1 D-核糖在静止大鼠肌肉中对核苷酸补救的影响
理论上但不是客观上显示,核糖通过PRPP合成提高了经核苷酸补救途径的ATP合成速率。然而,对于静止肌肉中总的腺嘌呤核苷酸(TAN)或核糖水平无任何了解。因此可能该合成酶途径已经被饱和,核糖的给予无法提高正常、无局部缺血骨骼肌的ATP水平。为了证明核糖对该途径的影响,将健康成年雄性Sprague-Dawley大鼠跖肌复合肌手术暴露并用重构血液输注介质灌注,该介质内含有氨基酸、mM葡萄糖和100μU的牛胰岛素/ml。肌肉用重构血液介质以约40ml/分钟灌注,提供约0.65ml/分钟的组织灌注。将不同浓度的D-核糖加入到灌注液中以使其浓度达到0.156mM,0.5mM,1.58mM,5.0mM和15.0mM。灌注肌肉30分钟。对于每个核糖试验剂量最少分析2只大鼠。
灌注后,迅速由肢体切取肌肉切片并且在液氮中用铝钳冻夹。将肌肉切片冷冻干燥且在蒸馏水中重构用于通过反相高压液相色谱分离腺嘌呤核苷酸。结果以每克肌肉湿重每小时补救的腺嘌呤(即,ATP的形成)的毫微摩尔数(nM/gm/hr)来表示。
表Ⅰ核糖骨骼肌剂量-反应动力学
核糖 | 观察值 | 用基质的饱和动力学 |
0.000 | 48.6 | |
0.158 | 113.0 | 85.82 |
0.500 | 110.0 | 118.68 |
1.000 | 154.12 | |
1.580 | 188.5 | 183.51 |
2.000 | 199.74 | |
2.500 | 215.29 | |
3.000 | 227.85 | |
5.000 | 250.0 | 260.68 |
15.000 | 315.5 | 310.37 |
如图1和表Ⅰ所示,0毫摩尔(mM)核糖时腺嘌呤补救低于50nM/gm/hr。当给予0.158mM核糖时加倍。在5mM核糖时,ATP合成速率达到250nM/gm/hr。这些结果表明正常、健康肌肉具有低核糖基线水平和核苷酸补救能力,这些可以通过给予核糖提高。实施例2在正常试验者中提高运动能力
试验4名年龄在24-26岁之间的健康合适试验者。选择的该组人员的健康水平、性别和平均年龄一致,并且没有已知的代谢、神经元、内分泌或心肺疾病。他们全部能够或有过骑车的经验。研究方案包括四个阶段:(1)由无运动期组成的起始基线阶段;(2)负荷阶段,每天给予3次D-核糖或安慰剂(葡萄糖)共3天;(3)3天采用以下运动期的训练阶段,其特征在于以7%体重的阻力连续回合(N=6)的短时间(10秒)高强度循环全速跑,全速跑之间休息50秒,每天两次(清晨和下午),和(4)自末次训练期后48小时的恢复阶段。图1是一个循环全速跑回合的图示。
对腿部的股外侧肌(vastis lateralis musele)进行肌肉活检(MB)以便在每只腿均匀分布且使活组织取样和可能的肌肉疼痛最小。在研究开始建立基线时在静止下进行首次MB并且在第0天或第1阶段的首次训练期后立刻进行MB。在负荷阶段,不进行MB。在末次训练后和恢复48小时后进行肌肉活检。
安慰剂或核糖组中包括随机选择的两个试验者。在训练(负荷阶段)之前3天和训练(训练阶段)期间的3天内,核糖或葡萄糖以250ml含有10g核糖或安慰剂的等渗溶液每天口服给药3次。活动后立刻给予0.5L等渗电解质溶液并且在30分钟后再次给予以避免脱水。
测定MB样品中的下列分析物的浓度:ATP,ADP,AMP,IMP(肌苷一磷酸),TAN(总的腺嘌呤核苷酸),肌酸磷酸和肌酸。
表Ⅱ
运动员核糖研究
平均功率/千克(瓦特)
试验者 | 1 | 2 | 3 | 4 | 5 | 6 | 平均值 | 100.0%109.0% |
1P | 6.0 | 6.7 | 7.3 | 7.4 | 7.3 | 7.5 | 7.0 | |
2R | 6.9 | 7.5 | 7.8 | 7.6 | 7.9 | 7.4 | 7.5 | |
3R | 8.7 | 9.2 | 9.1 | 9.0 | 8.5 | 8.2 | 8.8 | |
4P | 7.5 | 8.0 | 7.7 | 8.7 | 8.0 | 7.6 | 7.9 | |
安慰剂 | 6.8 | 7.4 | 7.5 | 8.0 | 7.6 | 7.5 | 7.5 | |
核糖 | 7.8 | 8.4 | 8.5 | 8.3 | 8.2 | 7.8 | 8.2 |
表Ⅲ
运动员核糖研究
功率峰/千克(瓦特)
试验者 | 1 | 2 | 3 | 4 | 5 | 6 | 平均值 | 100.0%109.9% |
1P | 6.8 | 7.9 | 8.6 | 8.6 | 8.3 | 9.0 | 8.2 | |
2R | 7.9 | 8.8 | 9.2 | 9.0 | 9.4 | 8.7 | 8.8 | |
3R | 9.8 | 10.6 | 10.7 | 10.7 | 10.1 | 9.9 | 10.3 | |
4P | 7.7 | 8.6 | 8.7 | 9.4 | 8.8 | 9.0 | 8.7 | |
安慰剂 | 7.7 | 8.6 | 8.7 | 9.4 | 8.8 | 9.0 | 8.7 | |
核糖 | 8.9 | 9.7 | 10.0 | 9.9 | 9.8 | 9.3 | 9.6 |
表Ⅳ
运动员核糖研究
总功率/千克
试验者 | 1 | 2 | 3 | 4 | 5 | 6 | 平均值 | 100.0%109.5% |
1P | 59.1 | 67.0 | 72.7 | 73.3 | 72.5 | 74.2 | 69.8 | |
2R | 71.9 | 74.7 | 77.1 | 75.6 | 78.1 | 73.4 | 75.1 | |
3R | 86.8 | 91.9 | 91.3 | 90.0 | 85.4 | 82.5 | 88.0 | |
4P | 74.5 | 80.3 | 76.8 | 87.4 | 80.0 | 76.4 | 79.2 | |
安慰剂 | 66.8 | 73.6 | 74.8 | 80.4 | 76.3 | 75.3 | 74.5 | |
核糖 | 79.3 | 83.3 | 84.2 | 82.8 | 81.8 | 77.9 | 81.6 |
如表Ⅱ至Ⅳ和图2和3所示,核糖的给予令行为表现提高9%。
行为表现的提高在肌肉活检中反映在ATP水平中。如表Ⅴ所示,在训练阶段开始3天用核糖预负荷试验者具有较高的ATP水平,在全速跑回合后较安慰剂组的ATP水平降低更为明显,这表明ATP利用更有效。与安慰剂组的78%比较,核糖组在48小时后恢复到起始水平的82%。
表Ⅴ
平均ATP值(mmol/kg dw)
实施例3在正常、无训练试验者中精力和舒适感的增强
组 | 之前 | 之后 | 恢复率 | 之前给药的恢复率% | 前后变化 | 给药后-恢复的变化 |
安慰剂 | 23.60 | 20.05 | 18.30 | 78% | -3.55 | -1.75 |
核糖 | 25.33 | 13.90 | 20.80 | 82% | -11.43 | 6.90 |
在活动之前和期间立刻给药D-核糖可以为那些未曾锻练过的试验者提高有益作用。如上述实施例2所述,试验4名健康、正常男性志愿者在放能循环中的全速跑输出功率。各个试验者充当其自身的对照。在全速跑回合之间,试验者应慢速和连续环行。总试验时间是1小时,在该试验期间共4个全速跑回合。在起始基线测定后和在每个全速跑回合之后,给该试验者施用存在于200m1中的5gD-核糖或类似味道的安慰剂(葡萄糖)。在摄取试验溶液后15分钟时测定全速跑输出功率。各试验者以随机顺序经历两个时期,一个时期给予核糖并且一个时期给予安慰剂,其间间隔一周。安慰剂用葡萄糖加甜以便无法区分于核糖溶液。所述试验者在持续缓和运动后给予核糖表现出比用安慰剂给药后高的输出功率。可以进一步认为这些试验者主观上具有更强的舒适感。实施例4对运动引起的心绞痛的缓解
患有慢性动脉疾病病史、处于三次冠状动脉搭桥术后状态的68岁男性患者经历运动引起的心绞痛。其当前用药是:依那普利(一种血管紧张素转化酶抑制剂)、卡维地洛(β阻断剂)、硝酸甘油贴剂和必要时使用的硝酸甘油舌下片。最新的冠状血管造影片表明他的冠状动脉疾病发展到一个旁路移植已完全闭合。该患者在两个应激试验中表现不良。其运动仅限于每天步行。
因绞痛恶化,该患者每天只能步行少于1英里,到达地点后必须舌下摄取硝酸甘油。经口服给予该患者溶于约250cc水中的D-核糖。在6个月内,该患者每天接受间断剂量的5-10g D-核糖。核糖给药后,该患者能够提高其每天运动耐力达到2英里,而且不需要任何补充的口服硝酸给药。当中断核糖时,其再次出现核糖给药之前的运动诱发性心绞痛,必须使用补充的口服硝酸甘油。重新口服核糖使该患者能够每天步行2英里,不发生心绞痛或需要硝酸甘油。其对核糖治疗的主观评价是“很弱的心绞痛,我感觉较好,更有精力并且可以进行更多活动而无痛苦或药物(硝酸甘油)”。实施例5对踏车试验行为的改善
由1名患有持久冠状动脉疾病的60岁男性患者观察到其不止一个心外膜冠状动脉的闭塞超过百分之五十并且持续绞痛。测试该患者的踏车行为。在两个基线踏车试验后,按照Bruce方案,他接受D-核糖给药(40gm,每天分3次给药)三天并且完成第3次踏车试验。每次,当患者出现以下情况时停止试验a)当患者在心电图(ECG)示踪中ST段衰退1mm或更多时;b)当患者抱怨心绞痛时或c)当患者因呼吸困难或疲劳停止时。在各个试验中,该患者在因呼吸短促但无心绞痛时结束试验。
由表Ⅵ可以看出,通过测量试验各阶段,包括静止(0时刻)时的速率-压力结果,在末次踏车试验之前3天给予D-核糖可以提高能量和心功能。一般可接受的是,心搏率和全身压力的结果是心肌功能和能量水平的量度,数值越低表示心肌功能越好。核糖给药的结果,对踏车的平均耐受时间延长。除了客观测定效能,患者主观上提出在核糖给药期间感觉更有精力。
表Ⅵ
每分钟心跳次数乘以收缩血压mmHg的速率-压力结果
在Bruce方案中,踏车速度在3分钟内由1.7英里/小时提高至6.0英里/小时,同时斜率由10%增加至22%。实施例6核糖的自行给药
时间0(静止)3分钟6分钟9分钟 | 基线111,08817,57426,50033,396 | 基线29,27213,46822,34429,526 | 平均10,18015,52124,42231,461 | 试验9,17715,27220,59225,356 | %变化-9.55%-1.60%-15.68%-9.87% |
耐受时间(秒) | 483.00 | 545.00 | 514.00 | 540.00 | 5.06% |
患有慢性病(包括但不限于冠状动脉疾病、AIDS、间歇性跛行、结核和慢性疲劳综合征)而其特征是能量水平低的患者,以及那些没有明显疾病但因衰老、创伤、烧伤和由患病或手术复原所致的能量水平低下的试验者可以在无需持续医疗干预的同时通过提高其能量水平而受益。许多具有相对稳定疾病的个体通过遵照一种改变了的生活方式,结合药物的补充日复一日地生存着。通常,这些试验者因担心引起不适感如心绞痛、喘不过气、肌肉疼痛、痛性痉挛或疲惫感而被阻止从属适度体力活动。这种逃避降低了这些试验者的生活质量并且产生始终存在的本底焦虑。此外,这些试验者被剥夺了有益或适度的运动,包括增强消化、睡眠以及更松弛和正面的精神状态。甚至无疾病但担心健康的试验者可能在主观上对其能量水平和舒适感不满意。
没有明显疾病但得益于核糖自行给药的试验者的实例是一个55岁老年男子。他在其生活大部分时间内每周坚持严格的运动方案直至持续系统细菌感染,需要住在加强护理室中1个月并且又康复1个月。其心血管和肺系统主要在其患病期间和之后被感染并且1年后功能无法恢复到原先水平,或令他感到满意。
康复期后,他试图恢复运动方案,包括每周在踏车上跑步4天并且每周2天内举重。但跑步限制在短时间内。每天运动后,他持续感到疲劳达到虚脱点并且需要时常小睡。患者开始自行口服D-核糖,每天给予2个剂量,每个剂量4-5g。在7天内,他声称其“活力”和运动耐受性有所增强。自他患病后首次能够在踏车上奔跑达30分钟。他仍然感到一定程度的疲劳,但能够在运动后停止小睡。他持续每天口服核糖给药,同时坚持有计划的运动,并且在核糖给药4周后感到其能量水平继续提高。核糖对他无副作用。实施例7核糖和精氨酸和/或内碱对患有慢性病症试验者的影响
如实施例6所述,可以预言经历低能量水平的试验者可受益于戊糖的自行给药。可以进一步推断摄取口服可接受的血管舒张药如L-精氨酸将对此类试验者具有附加有利效果。仍然可进一步预言摄取L-肉碱以运送脂肪酸进入线粒体将为这些试验者提供另外的有益作用。还可以预计加入其他能量代谢产物和辅因子将为此类试验者提供附加有益效果。
已知精氨酸是内皮松弛因子一氧化氮的前体。体外分析已经证明在正常情况下,内皮细胞可以获得过量的L-精氨酸。然而,体外研究还显示,当L-精氨酸的储存被耗尽或如果L-谷酰胺,一种L-精氨酸的拮抗剂存在时,内皮依赖型血管舒张可以通过加入L-精氨酸得以提高。在本发明之前未知的是,口服精氨酸是否可以增强心灌注并且由此使核糖分配在肌肉组织内。所选试验组应是因心脏病能量水平低下的患人,其是可利用和充分研究的群体。预期结果可以同等地应用于具有低能量水平的其他试验者(例如患有虚弱疾病的试验者和老年人和犬)。
将患有已知稳定冠状动脉疾病但无静止局部缺血的30名成年(45-70岁)试验者随机分成3个独立的组。每个试验者应接受连续的踏车试验以首先确认有资格加入这个方案。在给予L-精氨酸、D-核糖、L-肉碱或含L-精氨酸、D-核糖和L-肉碱的组合物3天后进行末次踏车试验。该研究的终点是调查在踏车运动期间心绞痛的进展和/或心电图的变化。
预期这些试验者的改善比实施例2中所述的速率-压力降低10%和耐受时间增加5%更大。
在此引用的所有文献和专利全文引入作为参考。本发明已描述了多个具体和优选的实施方案。然而,应理解,在本发明的实质和范围内可以进行多种变化或改进。
Claims (16)
1.一种提高哺乳动物的能量水平的方法,其中包括向所述试验者口服给予有效量的戊糖。
2.按照权利要求1所述的方法,其中所述戊糖是核糖。
3.按照权利要求1所述的方法,其中所述哺乳动物具有低ATP有效性。
4.按照权利要求1所述的方法,其中所述哺乳动物具有高能量需求。
5.按照权利要求3所述的方法,其中所述哺乳动物患有冠状动脉疾病。
6.按照权利要求4所述的方法,其中所述哺乳动物在由感染、创伤或烧伤复原。
7.按照权利要求4所述的方法,其中所述哺乳动物剧烈运动。
8.按照权利要求4所述的方法,其中所述哺乳动物未经局部缺血损伤。
9.一种在哺乳动物中施用的用于提高能量水平的组合物,其中含有有效量的戊糖。
10.按照权利要求9所述的组合物,其中所述戊糖是核糖。
11.按照权利要求9所述的组合物,其中进一步含有镁和肌酸。
12.一种适于口服摄取的单位剂型,其中含有与可药用赋形剂结合的约0.1至50gm戊糖。
13.权利要求12的单位剂型,其中所述戊糖是核糖。
14.权利要求12的单位剂型,其中赋形剂是液体。
15.权利要求14的单位剂型,其中所述液体是含水液体。
16.权利要求12的单位剂型,其中所述赋形剂是固体或半固体的可食用赋形剂。
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JPS6049764A (ja) * | 1983-08-29 | 1985-03-19 | Ajinomoto Co Inc | 食品組成物 |
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IT1247125B (it) * | 1991-03-01 | 1994-12-12 | Depha Team Srl | Composizioni dietetiche o farmaceutiche per il ripristino del contenuto cellulare degli adenin nucleotidi nel muscolo scheletrico e cardiaco. |
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DE4228215A1 (de) * | 1992-08-25 | 1994-03-03 | Pliml Wolfgang | Verwendung von Ribose zur Herstellung eines Arzneimittels zur Behandlung von Leistungsschwächen des Körpers, insbesondere von Organinsuffizienzen |
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1999
- 1999-04-12 US US09/290,789 patent/US6159942A/en not_active Expired - Lifetime
- 1999-06-17 ES ES99928759T patent/ES2374260T3/es not_active Expired - Lifetime
- 1999-06-17 AU AU45752/99A patent/AU4575299A/en not_active Abandoned
- 1999-06-17 CA CA002334415A patent/CA2334415C/en not_active Expired - Lifetime
- 1999-06-17 WO PCT/US1999/013720 patent/WO1999065476A2/en active Application Filing
- 1999-06-17 AT AT99928759T patent/ATE534393T1/de active
- 1999-06-17 NZ NZ508478A patent/NZ508478A/en unknown
- 1999-06-17 JP JP2000554356A patent/JP2002518321A/ja active Pending
- 1999-06-17 CN CN99807560A patent/CN1306431A/zh active Pending
- 1999-06-17 EP EP99928759A patent/EP1087779B1/en not_active Expired - Lifetime
-
2010
- 2010-04-08 JP JP2010089732A patent/JP2010168394A/ja active Pending
-
2013
- 2013-08-05 JP JP2013162441A patent/JP2013237697A/ja active Pending
- 2013-11-05 JP JP2013229436A patent/JP2014043453A/ja active Pending
-
2016
- 2016-04-27 JP JP2016089312A patent/JP2016153421A/ja active Pending
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101356971B (zh) * | 2007-07-30 | 2012-11-07 | 石药集团中奇制药技术(石家庄)有限公司 | 一种用于抗疲劳耐缺氧的保健食品组合物 |
CN105232564A (zh) * | 2008-08-20 | 2016-01-13 | 生物能生命科学公司 | D-核糖用于改善心肺功能的用途 |
US8825735B2 (en) | 2009-09-14 | 2014-09-02 | International Business Machines Corporation | Public BOT management in private networks |
CN102058045A (zh) * | 2010-10-26 | 2011-05-18 | 开平牵牛生化制药有限公司 | 一种用于补充人体能量和恢复疲劳的饮品及其制备方法与应用 |
CN102058045B (zh) * | 2010-10-26 | 2012-09-19 | 开平牵牛生化制药有限公司 | 一种用于补充人体能量和恢复疲劳的饮品 |
Also Published As
Publication number | Publication date |
---|---|
WO1999065476A3 (en) | 2000-04-06 |
CA2334415C (en) | 2004-08-24 |
JP2002518321A (ja) | 2002-06-25 |
CA2334415A1 (en) | 1999-12-23 |
WO1999065476A2 (en) | 1999-12-23 |
EP1087779B1 (en) | 2011-11-23 |
US6159942A (en) | 2000-12-12 |
ES2374260T3 (es) | 2012-02-15 |
JP2010168394A (ja) | 2010-08-05 |
JP2013237697A (ja) | 2013-11-28 |
EP1087779A2 (en) | 2001-04-04 |
ATE534393T1 (de) | 2011-12-15 |
NZ508478A (en) | 2003-10-31 |
AU4575299A (en) | 2000-01-05 |
JP2014043453A (ja) | 2014-03-13 |
JP2016153421A (ja) | 2016-08-25 |
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