CN1365279A - 用于降低身体运动期间耗氧量的制剂 - Google Patents
用于降低身体运动期间耗氧量的制剂 Download PDFInfo
- Publication number
- CN1365279A CN1365279A CN00810920A CN00810920A CN1365279A CN 1365279 A CN1365279 A CN 1365279A CN 00810920 A CN00810920 A CN 00810920A CN 00810920 A CN00810920 A CN 00810920A CN 1365279 A CN1365279 A CN 1365279A
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- Prior art keywords
- component
- product
- pharmaceutically acceptable
- thiamine
- salt
- Prior art date
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Abstract
本发明涉及选自咪达唑仑和氮杂环的环上氮原子被甲基取代的化合物的药学活性物质。这些物质用于减少身体运动期间的耗氧量。它们能够与有效量的D-葡萄糖、D-麦芽糖、乙醇、能生成葡萄糖的胺、能生成葡萄糖的氨基酸或可被乙醛酸盐代谢的氨基酸或者这样一种氨基酸的二肽或药学上可接受的盐、和有效量的硫胺、药学上可接受的硫胺盐或叶酸与氰钴胺的组合一起给药,其条件是若该第二组分是D-葡萄糖、D-麦芽糖、能生成葡萄糖的胺、不可被乙醛酸盐代谢的能生成葡萄糖的氨基酸或这种氨基酸的二肽或药学上可接受的盐,则该第三组分是硫胺或药学上可接受的硫胺盐。
Description
本发明涉及某些化合物、特别是活性药物成分在制备在身体运动期间具有氧节省作用的产品中的应用,本发明还涉及具有这种作用的新制剂。
已知肌糖原依赖于饮食,仅有某些饮食组分才适合于它的合成,并且有效的程度也不同。作为其功效的先决条件,必要的是在它们的代谢转化期间能生成葡萄糖或能生成葡萄糖的代谢产物。功效事实上受到碳水化合物和蛋白质的限制,因此进一步必要的先决条件是它们迅速分解为它们的元素级组分,在此期间,释放葡萄糖和能生成葡萄糖的氨基酸,能够对肌糖原的合成具有有益效果。
除了糖原以外,脂肪也可为肌肉所利用,并且能够单独或者与糖原一起被利用。不过,糖原和脂肪的不同之处在于,糖原与脂肪形成对比的是它不要求氧参与能量产生,因为从糖原生成葡萄糖是一种厌氧的代谢程序,在此期间从脂肪中释放的脂肪酸经历需氧的利用。
在身体运动期间的运动能力、尤其是持续运动受到个体摄氧能力和最大个体心率的限制。不过,仅有一部分摄氧量被用于机械运动,而大部分起到产热的作用。机械运动的效率可以在宽泛的限度内变化,不过平均仅为约20%。
减少相同机械活动对氧的需求的活性成分增加运动能力。在这种意义上,贮存在肌肉中的糖原的分解有可能以天然方式增加运动能力。分解发生之后,在静止期间重新生成糖原,只要消耗适合的营养物即可,例如易消化的碳水化合物或幼小动物和鱼的肉。另一方面,在身体运动期间或之前不久所给予的营养物对耗氧量没有作用或者具有相反作用,因为它们增加相同运动对氧的需求。这些相互作用可归因于由消化、吸收和代谢所导致的额外的需氧量。
除了这些已知的关联以外,还已惊人地发现,由机械运动所诱导的耗氧量也受到大气压变化的影响。在这一点上已经发现,压力平均下降1毫巴,需氧量增加约4%,这意味着在低压地区的影响下,运动能力可能明显减少。已知关于这种作用尚无解释。不过,假定血液中二氧化碳含量的变化可能引起需氧量的变化,因为已知当大气压下降时,肺泡二氧化碳浓度上升。
表1a显示在1999年2月13日至3月6日期间,在标准条件下利用身体条件良好的男性受验者所得到的结果。要求受验者每天早晨在空腹状态下连续(不间断)进行100W、125W和150W的机械功率输出,每项持续10分钟(每次试验总的持续时间为30分钟)。试验使用Ergo Fit(Pirmasens,Germany)的自行车测力计,借助涡流闸,在每种情况下将所需运动控制在每分钟踏板转60圈(受Seiko,Japan的节拍器控制)。心率的连续测量使用Polar Electro(Kempele,Finland)的心率计算机;用Altitude Instrumentation(Paris,France)的电子气压记录器测量大气压,分辨率为0.1毫巴;用电子温度湿度计测量温度和相对湿度。从心率变化计算由机械活动所诱导的产热量。另一种可能性是在由出汗(试验是在封闭的房间内进行的)或体重减少(1g水=2.26kJ)所导致的湿度增加的基础上测定之。在试验的三周持续时间内,受验者接受高碳水化合物饮食,主要由糊状物以及幼小动物(小牛、小鸡、鱼)的肉组成,目的是确保蛋白质的充分供应。表1a关于“平均心率”的数值在每种情况下都是试验的30分钟持续时间内的平均值;关于耗氧量的相对值是以已知方式确定在心率的基础上的,表1a所示相对值是基于第一天(=100%)的耗氧量的;表1a中“产热量”一栏所列数值给出产热量的偏差百分比,这是确定在出汗的基础上、从全部试验的平均值得到的。
大气压变化对由身体运动诱导的耗氧量的作用
*来自全部实验平均值的偏差
日期1999 | 大气压(毫巴) | 平均心率(每分钟) | 相对耗氧量 | 开始 | 相对湿度结束 | 增加 | 产热量*(%) |
2/132/142/152/162/172/182/192/202/212/222/232/242/252/262/272/283/13/23/33/43/53/6 | 1028.11029.41026.11014.91012.91015.61021.71016.81014.81003.31011.61010.31019.31021.41016.11024.31024.61019.51004.6995.2995.41002.3 | 78.483.8116.8109.6114.8116.8109.0122.4123.5115.1102.1116.879.382.7123.575.6115.6113.5114.8116.5118.0113.3 | 100%108%178%164%174%178%162%188%192%174%148%178%102%110%190%96%176%172%174%178%180%170% | 34%33%32%33%34%35%35%36%41%40%35%34%36%34%33%36%36%38%39%40%38%35% | 36%35%46%43%48%48%46%52%58%54%45%48%38%38%48%39%49%55%55%55%44%48% | 2%3%14%10%14%13%11%16%17%14%10%14%2%4%15%3%13%17%16%15%16%14% | -61-31+20+5+16+20+4+32+34+16-11+20-59-52+34-67+17+13+16+19+22+12 |
已知通过测量心率,作为机械运动的函数,可以测定摄氧量。这种测力方法是基于通过心脏的搏动确定氧转运体积的。由于心搏量本质上是恒定的,与机械运动的强度无关,由运动增加所导致的需氧量增加进而导致心率增加,通过测定由运动所导致的额外脉搏,可以确定氧的转运量。在世界各地的生理学研究学会和健身俱乐部中都使用世界卫生组织(WHO)推荐的3-级测力计。
运动中的肌肉利用糖原和脂肪酸一起获得能量。肌糖原被厌氧分解。脂肪酸的分解取决于分子氧。如果糖原储备被耗尽,并且仅剩脂肪可用,那么需氧量增加,因而心率也增加。在恒定的运动下,如果存在肌糖原,那么在机械运动开始后心率仅略微增加,并且保持在低水平下,只要糖原是可利用的即可。被耗尽后,重新增加至较高水平,这归因于脂肪的排他性利用。心脏搏动的氧转运体积因此可以这样测定,如果为供应能量而对肌糖原的利用在试验期间由于肌糖原在参与机械运动的肌肉的身体运动测定方法之前直接完全分解或者由于它的节省氧的反应被有效剂量抗糖尿病活性剂给药阻滞而被切断了,这有利于脂肪的排他性利用,那么通过机械运动(例如各自至少5分钟)确定两种不同身体运动下的脉搏次数,不过二者各自是保持恒定的。试验人员发现每次心脏搏动的氧转运体积基于标准压力为36ml氧。然后可以从机械运动差异和相应的脉搏次数差异计算氧转运体积,出于本发明的目的,在假定摄氧量的五分之一用于机械运动、其余用于产热的基础上,效率为20%。利用1千卡的代谢需氧量为200ml。
从表1a可明显看出,当压力下降时,耗氧量明显上升,并且随着低压的持续而保持在高水平上。在耗氧量与涉及天气的相对湿度之间发现没有相互关系。另一方面,由产热所导致的出汗(相应的封闭房间湿度增加可以发现这一点)显示变化基本上与耗氧量平行,也就是说当压力下降时它同样上升。可以想象,大气压对产热量的作用是由温度调节系统所导致的,因为压力下降在正常情况下伴随温度下降。血液二氧化碳的突然上升可以通过等长收缩增加肌肉张力,这种反应也发生在体温下降时。
由机械运动所诱导的、基本上平行的脉搏次数、产热量和需氧量变化也得到汇集在表1b中的结果的证明,这些结果是利用相似试验获得的,受验者相同(静止脉搏率为50min-1),封闭房间约20m3,试验周期为41分钟,每种情况下的机械运动恒定。计算是基于下列关系的:1g水=2.26kJ,20kJ=1l氧(大气压)。
表1b
心脏功能、需氧量和产热量之间的关系
身体功率输出(W) | 125 | 150 | 175 | 200 | 增加* |
平均心率(min-1) | 71.8 | 85.8 | 99.8 | 125.8 | |
由身体运动诱导的脉搏次数 | 893 | 1468 | 2042 | 3108 | 3.5 |
相对湿度的增加(%) | +5 | +9 | +15 | +20 | 4.0 |
出汗损失的水分(l) | 0.2 | 0.3 | 0.5 | 0.7 | 3.5 |
产热能量(kJ) | 438 | 661 | 1041 | 1522 | 3.5 |
产热的需氧量(l) | 21 | 31 | 50 | 72 | 3.5 |
*200W和125W功率输出下的数值比例
已经公开了大量这样的产品,它们首先含有能量供应组分,其次含有其代谢所必需的维生素,并且试图确保最佳能量摄取、维持合成代谢或者对抗维生素缺乏。另外,还已知各种这样的药物产品,除了活性药物成分以外,还可以含有维生素与碳水化合物、蛋白质或乙醇。不过,以前公开的产品通常既没有针对于、也没有成功地减少耗氧量。
例如,US-A 5,292,538描述了一种果糖/葡萄糖/蛋白质混合物,除了葡萄糖聚合物、果糖、部分水解的蛋白质和酌情的脂质来源以外,还含有镁配合物和维生素,例如维生素A、B1、B2、B5、B6、B12、C、D、E、叶酸、烟酰铵和生物素,该混合物试图提高耐久性和合成代谢。
WO-A 90/02489公开了一种供应能量的饮食产品,通过结合快糖和慢糖,使立即的与持续的能量分布成为可能,并且包覆有含有维生素B1和/或B2的巧克力涂层。
FR-A 2,704,392公开了一种用于提高体力与脑力运动能力的可吸收的补充食品,含有镁和维生素C与B1以及一种载体,该载体优选地可以由纤维素、葡萄糖、硬脂酸镁和胡萝卜粉组成。这种情况的试图是利用这样一个事实,维生素C增加肌肉的运动能力,另一方面,镁和维生素B1是糖与脂肪的酶分解所需的。另外,据说镁的存在能减少耗氧量。
EP-A 0,087,068公开了一种营养添加剂,含有硒、半胱氨酸、L-色氨酸、L-酪氨酸和酌情的其他成分,例如果糖、维生素B1、维生素C和钙盐,据说适合于代替因过度酒精消耗而耗尽的必需营养成分。
US-A 5,039,668描述了一种用于治疗维生素缺乏并且作为咳嗽抑制剂的组合物,除了液体蜂蜜、组氨酸、赖氨酸、色氨酸和钙或铁盐以外,还含有维生素,例如维生素B12与叶酸或维生素B1、B6和B12,和烟酸。
EP-A 0,482,715提出了一种基于不含蛋白质的碳水化合物和植物脂肪以及必需氨基酸的组合物,试图提供营养物的平衡供应,具有免疫刺激作用,而且——由于必需氨基酸的特定比例——试图使NNU(净氮利用)值更高成为可能。所提出的组合物——除了氨基酸异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、苏氨酸、色氨酸和缬氨酸以外——含有碳水化合物,选自蔗糖、麦芽糖和山梨糖醇;极不饱和植物脂肪,选自红花油、向日葵油和玉米油;和维生素A、B1、B2、B6、B12、C、D、K、生物素、叶酸、α-生育酚、烟酰胺和泛酸。
JP-A 07/330583公开了一种液体制剂,适合作为外科手术或灼伤患者的肠内营养物,除了氨基酸以外,还可以优选地含有无机盐、糊精、大豆油和维生素A、B1、B2、B6、B12、C、D、E、K、叶酸和生物素。
JP-A 05/124974提供了一种基于灵芝的制剂,试图促进贮存在肝内的糖原的分解。它例如可以制成饮料的形式,除了真菌提取物以外,还可以含有麦芽糖、寡糖、叶酸、维生素C、维生素B12和铁。
JP-A 02/078624公开了竹芽纤维提取物用于治疗风湿病的用途,描述了一种制剂,除了该提取物以外,还含有乙醇、维生素B1和维生素L
JP-A 02/078625描述了轮叶沙参(Adenophora triphylla)提取物以及维生素B1用于治疗花粉病的用途,公开了乙醇制剂。
JP-A 52/143255提供了一种用于掩蔽药物物质味道的药物饮料,除了药物物质以外,例如大蒜、人参、老鹳草、维生素A、B1、B2等,还含有通过表层发酵所得到的啤酒,酒精含量为0.2至3重量%。
此外,WO-A 98/08521公开了这样的产物,含有(a)有效量的D-葡萄糖、D-麦芽糖、乙醇、能生成葡萄糖的胺、能生成葡萄糖或能够经由乙醛酸盐被代谢的氨基酸或者这种氨基酸的二肽或药学上可接受的盐作为第一组分,和(b)有效量的硫胺、药学上可接受的硫胺盐或叶酸与氰钴胺的组合作为第二组分,其条件是如果D-葡萄糖、D-麦芽糖、能生成葡萄糖的胺、不能经由乙醛酸盐代谢的能生成葡萄糖的氨基酸或这样一种氨基酸的二肽或药学上可接受的盐用做第一组分,那么该第二组分是硫胺或药学上可接受的硫胺盐。所公开的产品减少身体运动期间的需氧量,它们的作用是基于它们对由糖原储备分解所导致的耗氧量增加的对抗作用的。
现已惊人地发现,具有含氮杂环、并且环中至少一个氮原子具有甲基取代基的药物以及咪达唑仑能减少由机械运动所导致的耗氧量,而且它们能够对抗特别是由低大气压或压力下降所导致的耗氧量增加。它们因此适合于明显提高机械运动的效率,由此能够显著减少相同机械运动的需氧量。由于需氧量增加导致心率增加和出汗增加(这是由产热量增加所导致的),因此所述药物还能够同时降低心率和出汗或产热量。
已知人的大多数摄氧量用于产热,目的是维持体温。假定静止期的产热量根据环境温度变化而变化,系数一般大约为4,而在恒定的环境温度下经过身体剧烈运动,结果系数可以上升至大约10。
按照本发明所发现的作用原因是未知的。不过,似乎至少在部分程度上可归因于这样的事实,产热所消耗的氧越少,一方面可供身体运动所利用的氧比例越高,另一方面,另外减少了出汗。因此可以假定,该化合物可能减少或防止二氧化碳对产热量的作用。
本发明因此涉及选自咪达唑仑和含氮杂环的环上氮原子被甲基取代的化合物的药学活性成分在制备用于减少身体运动期间的耗氧量的产品中的应用。由于心率、需氧量与产热量(或出汗)之间的所述联系,这些活性成分和产品不仅适合于减少由身体运动所诱导的需氧量增加,而且适合于减少由身体运动所诱导的心率增加和减少由身体运动所诱导的产热量(或出汗)增加。
按照本发明可以使用的产品的给药适合于需氧量限制身体运动能力的所有情况,尤其是摄氧能力因下列因素而减少的情况:心血管系统与肺的病理改变、老年人、食物摄取后与高原身体活动、由需氧量受天气影响而增加所导致的疲劳、和用于防止药物对需氧量的不良副作用,特别是安定药、安眠药、抗抑郁药和神经安定药。它们适合于预防性或治疗性用途,根据给药剂型应当优选地在所需作用发生之前至少约半小时服用。
适合本发明的活性药物成分例如可以是生物碱或生物碱类似物。不过,化合物是否具有生物碱样结构,物质是否是合成的或天然存在的,或者它们是否已知用于另一种医疗适应症,原则上对根据本发明所发现的作用都没有实质性影响。相反,关键是除了咪达唑仑以外,它们具有惊人地相同有效性,而且另一方面,它们都具有N杂环,并且在环氮原子上具有至少一个甲基。
而且,根据本发明所发现的作用与已知治疗作用无关,并且不限于具有特定医疗适应症的化合物。这是因为已经发现,镇咳药、例如双氢可待因、诺司卡品、可待因和右美沙芬,止痛药、例如吗啡和双氢可待因,麻醉药、例如可卡因,安眠药、例如咪达唑仑和氟硝西泮,抗组胺药、例如赛庚啶、氯马斯汀和甲亢平,安定药、例如地西泮,抗抑郁药、例如二苯西平和氯噻平,神经安定药、例如硫利达嗪,镇静药、例如佐匹克隆等,都是适合的。而且,适合于本发明的化合物通常在非常少的用量下是有效的;例如,在已知活性药物成分的情况下,足够的剂量经常低于以前已知的医疗适应症100倍。
另一方面,已经发现,如果不具有甲基取代的环氮原子,那么具有同一已知医疗适应症和/或相似结构的活性成分显示没有节省氧的作用或者甚至具有拮抗活性。例如,多西拉敏、奥沙西泮、甲氨二氮、溴西泮、硝西泮、米帕明、曲米帕明、阿米替林、奥匹哌醇、氯米帕明、氯普噻吨、劳拉西泮或氟哌噻吨给药后的需氧量没有减少,甚至偶尔增加。特别是在安定药、抗抑郁药和神经安定药中已经观察到后者现象,并且已经发现,由它们给药所导致的需氧量增加可以通过适合于本发明的化合物的额外给药加以防止。
适合于本发明的药学活性成分可以使用其本身或它们的药学上可接受的盐。它们可以是单环化合物,或者优选地具有多环结构,带有桥连环和/或稠合环。适合的活性成分特别可以在环中具有N-甲基取代的胺或酰胺基。带有N-甲基的N杂环可以是饱和、部分不饱和或芳族环,具有饱和或部分不饱和的、非芳族N-甲基取代的N杂环的活性成分通常是优选的。
适合于本发明的活性成分特别可以提到的是:
-具有N-甲基取代的哌啶环的化合物,该环可以是饱和的或部分不饱和的(例如N-甲基哌啶衍生物赛庚啶、硫利达嗪和佐匹克隆)和/或可以是2-甲基-2-氮杂双环并[3.3.1]壬烷结构的一部分(尤其是N-甲基吗啡喃衍生物,例如双氢可待因、可待因、吗啡、蒂巴因和右美沙芬)或2-甲基-1,2,3,4-四氢异喹啉结构的一部分(例如诺司卡品);
-具有N-甲基取代的二氮杂环的化合物,特别是N-甲基苯并二氮杂,例如地西泮、氟硝西泮、二苯西平和氯巴占;
-具有N-甲基取代的哌嗪环的化合物,例如氯噻平;
-具有N-甲基取代的吡咯烷环的化合物,例如氯马斯汀;
-具有N-甲基取代的咪唑环的化合物,例如甲亢平,和N-甲基嘌呤衍生物,例如咖啡因;
-具有N-甲基取代的嘧啶环的化合物,例如咖啡因。
按照本发明特别优选使用的活性成分是:右美沙芬、赛庚啶、氯噻平、地西泮、咪达唑仑、氟硝西泮、氯马斯汀、二苯西平、硫利达嗪、佐匹克隆、甲亢平、可待因和咖啡因。
利用常规的赋形剂,药物产品可以按照已知或本质上已知的方法制备。所有常规的给药模式和方式原则上都是适合的,但是应当注意,商业上可得到的产品多数对本发明的用途来说剂量过高。
如果需要的话,药学活性成分或它们的药学上可接受的盐可以以水溶液或悬液的形式给药。不过,优选的产品含有胶凝剂,适合的胶凝剂是可胶凝的聚合碳水化合物,例如琼脂或果胶或可胶凝的蛋白质,特别是明胶。这是因为已经发现,经常可能的是使用诸如明胶等胶凝剂来减少剂量,并且活性成分的活性更少受到其亲水性或亲脂性的影响,然而一般可能地和优选地是在没有胶凝剂的存在下使用亲脂性活性成分。
含有胶凝剂的产品可以按照本身已知的方法加以制备,例如通过将活性成分或其盐的水溶液或混悬液与胶凝剂混合,使其胶凝,或者加工活性成分或其盐的溶液或混悬液,其中含有胶凝剂,喷雾得到微球(beadlet),优选为明胶珠粒。适合于制备微球的方法是本领域技术人员已知的,例如参照维生素A明胶微球的制备。如果需要的话,可以将微球本身给药,或者按照本身已知的方法进一步加工得到适合的给药剂型。
除了药学活性成分和可选的胶凝剂以外,产品还可以优选地含有WO-A 98/08521所公开的组分组合,它们对抗由糖原储备分解所导致的耗氧量增加。以这种方式有可能在每种情况下都实现最佳的节省氧的作用,而与耗氧量增加是否是由糖原储备分解、低大气压或药物所导致的无关。
本发明因此同样涉及用于减少身体运动期间耗氧量的产品,包含(a)有效量的选自咪达唑仑和含氮杂环的环上氮原子被甲基取代的化合物的药学活性成分作为第一组分,(b)有效量的D-葡萄糖、D-麦芽糖、乙醇、能生成葡萄糖的胺(glucogenic amine)、能生成葡萄糖或能够经由乙醛酸盐被代谢的氨基酸或者这种氨基酸的二肽或药学上可接受的盐作为第二组分,和(c)有效量的硫胺、药学上可接受的硫胺盐或叶酸与氰钴胺的组合作为第三组分,其条件是若该第二组分是D-葡萄糖、D-麦芽糖、能生成葡萄糖的胺、不能经由乙醛酸盐代谢的能生成葡萄糖的氨基酸或这种氨基酸的二肽或药学上可接受的盐,则该第三组分是硫胺或药学上可接受的硫胺盐。
术语“二肽”出于本发明的目的包含能生成葡萄糖的或者能够经由乙醛酸盐被代谢的氨基酸的二肽,特别是两个同一氨基酸的二肽,例如H-Gly-Gly-OH、H-Ser-Ser-OH和H-Glu-Glu-OH。术语“能够经由乙醛酸盐被代谢的氨基酸”出于本发明的目的特别是适于核酸合成的氨基酸。
按照优选的方面,产品可以含有D-葡萄糖、D-麦芽糖、能生成葡萄糖的胺、能生成葡萄糖或能够经由乙醛酸盐被代谢的氨基酸或者这种氨基酸的二肽或药学上可接受的盐作为第二组分,并且可以是用胶凝剂胶凝的。如果第二组分是D-葡萄糖或D-麦芽糖,那么优选使用的胶凝剂是可胶凝的聚合碳水化合物,特别是琼脂或果胶,如果第二组分是能生成葡萄糖或能够经由乙醛酸盐被代谢的氨基酸或者这种氨基酸的二肽或药学上可接受的盐,那么优选使用的胶凝剂是可胶凝的蛋白质,特别是明胶。含有明胶的产品是特别优选的。
产品还可以优选地含有吡哆辛(维生素B6)或药学上可接受的吡哆辛盐(例如盐酸吡哆辛),抗坏血酸(维生素C)或药学上可接受的抗坏血酸盐、例如抗坏血酸钠,和/或生物素(维生素H)。
按照第一种实施方式,组合产品可以优选地含有D-葡萄糖、D-麦芽糖、能生成葡萄糖的胺、能生成葡萄糖或能够经由乙醛酸盐被代谢的氨基酸或者这种氨基酸的二肽或药学上可接受的盐作为第二组分,含有硫胺或药学上可接受的硫胺盐作为第三组分,如果需要的话,进一步含有胶凝剂、维生素C和/或维生素B12作为其他组分。还有可能采用水果或水果产品代替纯的D-葡萄糖。其他可以用作第二组分的物质实例是能生成葡萄糖的氨基酸例如有L-丙氨酸、L-丝氨酸、L-半胱氨酸、L-胱氨酸、L-谷氨酸、L-天冬氨酸、L-精氨酸、L-鸟氨酸、L-苏氨酸、L-缬氨酸、L-异亮氨酸、L-脯氨酸、L-羟脯氨酸、L-色氨酸、L-酪氨酸、L-苯丙氨酸、L-甲硫氨酸和L-组氨酸,能够转化为乙醛酸盐的有氨基酸例如有甘氨酸、L-丝氨酸和L-谷氨酸,能生成葡萄糖或能够转化为乙醛酸盐的氨基酸的二肽例如有H-Gly-Gly-OH、H-Ser-Ser-OH和H-Tyr-Tyr-OH,能生成葡萄糖或能够被转化为乙醛酸盐的氨基酸的药学上可接受的有盐例如有L-谷氨酸一钠和L-天冬氨酸一钠,和能生成葡萄糖的胺例如有L-谷氨酰胺和L-天冬酰胺。若使用L-天冬氨酸、L-天冬氨酸盐、L-苯丙氨酸、L-酪氨酸和/或L-色氨酸作为第二组分,使用硫胺作为第三组分,则产物可以优选地另外含有维生素C、维生素B12,如果需要的话,还进一步含有明胶和/或维生素B6(吡哆辛)。通常优选的是使用甘氨酸、L-丝氨酸、L-谷氨酸(或L-谷氨酸盐)和/或其二肽,它们可以优选地与叶酸、维生素B12和/或明胶一起使用。
按照另一种实施方式,本发明的组合产品可以含有乙醇作为第二组分,含有硫胺或药学上可接受的硫胺盐作为第三组分,含有生物素作为其他组分,或者按照另一种可选实施方式,含有乙醇作为第二组分,或者含有叶酸与氰钴胺的组合作为第三组分。在这两种情况下,可能的和优选的是该产物是以水溶液的形式。
按照特别优选的实施方式,本发明的组合产品可以含有选自咪达唑仑和含氮杂环的环上氮原子被甲基取代的化合物的药学活性成分,例如咖啡因,含有选自H-Gly-Gly-OH、H-Ser-Ser-OH、H-Glu-Glu-OH、甘氨酸、丝氨酸和谷氨酸(或谷氨酸盐)的化合物,另外含有叶酸、氰钴胺和明胶。这样的组合产品也适合于对抗由蔗糖、具有抗糖尿病活性的磺酰脲衍生物、胰岛素、糖皮质激素等给药所导致的需氧量增加,这明显可归因于厌氧肌肉ATP合成的刺激作用。
关于该组合产品的适量第二、第三和任意其他组分进一步与维生素的组合,可以参照WO-A 98/08521。
按照本发明可以使用的N-甲基N杂环通常在低至约1-5mg或以下的剂量下是有效的,即使它们不与胶凝剂结合也是如此,而在咖啡因的情况下,优选给药的剂量为约10-100mg,特别是约25-57mg。不过,如果N-甲基N杂环是与胶凝剂结合给药的,例如明胶,那么在咖啡因的情况下剂量可以减少至约1-5mg,在其他N-甲基N杂环的情况下剂量通常减少至约0.1-1.0mg或以下。
正如上文已经提到的,根据本发明所得产品可以按照本身已知的方法制成常规的液体、固体或半固体剂型,例如水溶液或悬液(例如可饮用的溶液)、泡腾粉剂、颗粒剂或片剂、微粒剂等,如果需要的话,含有常规的药学上可接受的载体、稀释剂或赋形剂,例如碳酸氢钠、柠檬酸、甘露糖醇、滑石、玉米淀粉、甘油单硬脂酸酯、食用色素、较味剂等。如果需要的话,药学活性成分、维生素和能量供应物质还可以单独给药,因为各组分是分开还是与组合产品一起服用对节省氧和增强运动的作用来说不是关键。
由于WO-A 98/08521所公开的药学活性成分和组合都是迅速起效的,按照本发明可以使用的产品可以在身体运动之前或期间服用,目的是实现需氧量的减少和生力效果。本发明因此提供用于减少身体运动期间耗氧量的方法,通过将根据本发明所得产品在身体运动之前和/或期间给药,在大量活性组分给药的情况下,后者有可能作为组合产品给药或者单独而同时给药。
下列实施例进一步阐述发明。实施例所述相对耗氧量值是用关于表1所述方法测量的。
实施例1
在标准化的条件下,身体条件良好的男性受验者进行下述一系列试验。除非另有指定,试验均在早晨空腹状态下进行,在一个或多个10分钟试验阶段均要求受验者的机械功率输出为100W、125W或150W。试验使用Ergo Fit(Kaiserslautern,Germany)的自行车测力计,借助涡流闸,在每种情况下将所需运动控制在每分钟踏板转60圈(受Seiko,Japan的节拍器控制)。心率的连续测量使用Polar Electro(Kempele,Finland)的心率计算机;用Altitude Instrumentation(Paris,France)的电子气压记录器测量大气压,分辨率为0.1毫巴;用电子温度湿度计测量温度和相对湿度。表中所示“平均心率”在每种情况下是特定试验阶段的平均值。在一系列试验期间,受验者接受高碳水化合物饮食,主要由糊剂和幼小动物(小牛、小鸡、鱼)的肉组成,目的是确保蛋白质的充分供应。每天仅进行一项试验。
a)在第一系列试验中,研究了各种N杂环的活性,在每种情况下测定10分钟试验期间在恒定的125W功率输出下的平均心率、耗氧量和产热量。在每种情况下首先进行5分钟准备运动后,记录10分钟对照试验期间125W功率输出下的脉搏,然后将药学活性成分的稀水溶液(20ml水)给药,之后立即进行实际的试验。所用活性成分与剂量及其对心率、需氧量和产热量的作用(以全部试验的平均产热量的偏差表示)汇集在表2中,产热量是在封闭试验房间内的湿度变化的基础上计算而来的。结果显示,咪达唑仑和具有N-甲基取代的N杂环的化合物即使在低剂量下也引起心率、耗氧量和产热量的显著减少,而其他在环氮原子上没有甲基的药学活性成分没有导致显著作用,或者甚至引起产热量增加。
b)在另一系列试验中,研究了活性与非活性物质之间的拮抗作用,在每种情况下测定两个10分钟试验期间在恒定的100W功率输出下的平均心率、耗氧量和产热量。在每种情况下首先进行5分钟准备运动后,记录10分钟对照试验期间100W功率输出下的脉搏,然后将第1剂量非活性物质(20ml水溶液)给药,之后立即测定10分钟试验期间对心率、耗氧量和产热量的作用;暂停5分钟后,将第2剂量活性物质(20ml水溶液)给药,之后再次立即测定第二个10分钟试验期间的作用。所用物质与剂量及其对心率和需氧量的作用汇集在表3中,其中第2次给药后的耗氧量变化在每种情况下都涉及第1次给药后所测量的耗氧量变化。结果显示,第一次给药在每种情况下都引起心率和耗氧量的显著增加,第二次给药引起显著减少,第二次给药后的数值在每种情况下事实上都低于第一次给药前的对照值。关于产热量也测量到相应的结果,其中第1次给药引起产热量增加13-55%,第2次给药引起产热量减少26-45%。按照本发明可以使用的活性成分因而适合于防止由药物所导致的需氧量、心率和产热量增加。
表2
药学活性成分在身体运动期间对需氧量和产热量的作用
活性成分 | 平均心率(每分钟) | 需氧量变化 | 产热量* | |
给药前 | 给药后 | |||
没有活性成分 | 106.1 | 109.1 | 0% | +6% |
具有减少氧作用的:0.2mg可待因0.2mg右美沙芬0.2mg赛庚啶1mg氯马斯汀5mg甲亢平1mg地西泮1mg咪达唑仑1mg氟硝西泮1mg二苯西平1mg氯噻平1mg硫利达嗪1mg氯巴占25mg咖啡因1mg佐匹克隆没有减少氧作用的:4mg多西拉敏1mg奥沙西泮1mg甲氨二氮1mg溴西泮1mg硝西泮1mg米帕明1mg阿米替林1mg奥匹哌醇1mg氯米帕明1mg氯普噻吨1mg曲米帕明 | 113.1117.5107.6120.6120.3102.3104.5109.8100.3112.0120.3106.1110.8116.8109.5112.6104.0114.8116.1109.5106.0111.4112.8106.1108.6 | 98.889.281.6102.2104.981.083.490.183.686.4104.980.897.197.8109.5116.5110.2118.2119.8110.9112.0112.0117.5112.0109.8 | -29%-57%-52%-37%-30%-44%-42%-39%-33%-51%-31%-51%-26%-6%0%0%0%0%-2%0%-5%0%0% | -27%-49%-55%-30%-26%-50%-40%-41%-49%-26%-49%-44%0%+7%+14%+6%+7%+3%+13%+1%+9%+13%+2% |
*来自全部试验平均值的偏差
表3
具有与没有减少需氧量作用的活性成分之间的拮抗作用
第1次给药 | 第2次给药 | 平均心率(每分钟) | 耗氧量变化 | |||
给药前 | 第1次给药后 | 第2次给药后 | 第1次给药后 | 第2次给药后 | ||
没有活性成分(对照)7mg奥沙西泮1mg劳拉西泮10mg氯普噻吨0.5mg氟哌噻吨6mg阿米替林+2.5mg甲氨二氮6mg阿米替林+2.5mg甲氨二氮5mg甲氨二氮10mg阿米替林7mg奥沙西泮3mg溴西泮10mg硝西泮50mg奥匹哌醇25mg氯米帕明50mg奥匹哌醇10mg米帕明 | 0.5mg可待因0.5mg可待因0.5mg可待因0.5mg可待因0.5mg可待因0.2mg右美沙芬0.2mg赛庚啶0.2mg赛庚啶1mg地西泮1mg地西泮1mg地西泮1mg二苯西平1mg氯噻平1mg氯噻平1mg硫利达嗪 | 106.1121.3104.4101.7102.697.0107.2111.983.6109.5118.0121.0111.5113.7103.198.1 | 109.1137.6121.5124.6118.4112.7125.4126.4119.3125.3129.3131.4118.0134.8121.4109.5 | 108.1104.191.890.089.786.584.888.587.689.497.0102.188.3100.088.981.5 | +33%+34%+46%+32%+31%+36%+29%+71%+32%+23%+21%+14%+42%+37%+23% | -67%-59%-69%-57%-52%-81%-76%-63%-72%-65%-59%-59%-70%-65%-56% |
c)在另一系列试验中,研究了另外给药的蔗糖和WO-A 98/08521所公开的氨基酸/维生素产品的作用,在每种情况下测定连续10分钟时间期间在恒定的100W功率输出下的平均心率和耗氧量。在每种情况下首先进行5分钟准备运动后,记录10分钟对照试验期间100W功率输出下的脉搏,然后将活性成分(稀水溶液,第1次给药)、2.5g蔗糖(第2次给药)、其他活性成分(稀水溶液,第3次给药)和含有100mg谷氨酸钠、0.3mg叶酸、5μg氰钴胺和10mg明胶的氨基酸/维生素产品给药(第4次给药),4次给药各自间隔10分钟,在每次给药之后立即测定10分钟试验期间对心率和耗氧量的作用。所用活性成分与剂量和四次给药对心率和需氧量的作用汇集在表4中,其中耗氧量变化在每种情况下都涉及前次给药后所测量的耗氧量变化。结果显示,按照本发明可以使用的药学活性成分独自不适合于代偿由蔗糖给药所导致的心率和耗氧量增加;减少作用仅发生在WO-A98/08521所公开的产品给药之后。
表4
药学活性成分与氨基酸/维生素产品之间的协同作用
第二次给药剂量:2.5g蔗糖第四次给药剂量:在10mg明胶中的100mg谷氨酸钠,0.3mg叶酸和5μg氰钴胺
第1次给药剂量 | 第3次给药剂量 | 平均心率(每分钟) | 耗氧量变化 | |||||
第1次 | 第2次 | 第3次 | 第4次 | 第2次 | 第3次 | 第4次 | ||
0.2mg可待因0.2mg右美沙芬0.2mg赛庚啶1mg地西泮1mg咪达唑仑1mg二苯西平1mg氯噻平1mg硫利达嗪 | 0.2mg可待因0.2mg右美沙芬0.2mg赛庚啶1mg地西泮1mg咪达唑仑1mg二苯西平1mg氯噻平1mg硫利达嗪 | 73.075.874.774.875.977.273.276.3 | 107.3110.4109.1111.9110.9111.5112.4111.0 | 108111106.4113.1112.1115113.9111.2 | 82.987.883.986.383.286.482.286.5 | +69%+69%+69%+74%+70%+69%+78%+69% | +2%+1%-5%+2%+2%0%+3%0% | -50%-46%-45%-54%-58%-57%-63%-49% |
实施例2
在类似于实施例1的试验条件下的另一系列试验中,在恒定的125W机械功率输出下研究了心率对大气压的依赖性和地西泮的作用。每天仅进行一项试验。汇集在表5中的结果证实,心率和耗氧量在低压环境下增加,地西泮给药能够代偿大气压的这种作用。
表5
地西泮预先给药或不给药的心率,为大气压的函数
活性成分 | 大气压(毫巴) | 平均心率(每分钟) |
没有活性成分没有活性成分没有活性成分没有活性成分没有活性成分没有活性成分没有活性成分没有活性成分没有活性成分没有活性成分 | 1010.51013.71014.81014.81016.11023.11023.91025.51026.31028.4 | 1241241241231238787747584 |
2mg地西泮2mg地西泮1mg地西泮1mg地西泮0.1mg地西泮+4mg明胶0.02mg地西泮+1mg明胶1mg地西泮1mg地西泮1mg地西泮1mg地西泮1mg地西泮1mg地西泮 | 1005.91007.81010.01010.81011.01014.81015.21015.91017.41017.51021.71026.3 | 767980717782777274727675 |
实施例3
将200重量份Gly-Gly、3重量份叶酸、0.05重量份氰钴胺、1重量份地西泮和200重量份明胶加热溶于10000重量份水。将溶液喷雾制得明胶微粒,可以进一步加工成药物剂型。
实施例4
将100重量份酪氨酸、50重量份硫胺、50重量份吡哆辛、100重量份抗坏血酸、0.05重量份氰钴胺、1重量份右美沙芬和200重量份明胶加热溶于10000重量份水。将溶液喷雾制得明胶微粒,可以进一步加工成药物剂型。
实施例5
将150mg谷氨酸一钠、0.3mg叶酸、5μg氰钴胺、0.1mg可待因和5mg明胶加热溶于1ml水,与9ml的4%乙醇水溶液混合。10ml溶液相当于单一剂量。
实施例6
类似于实施例1,在30分钟试验中,在恒定的125W机械功率输出下研究抗坏血酸、蔗糖、格列本脲和H-Arg-Asp-OH在独自给药后或者在与咖啡因/氨基酸/维生素组合产品(含有5mg H-Gly-Gly-OH、250μg叶酸、5μg氰钴胺、1mg咖啡因和1mg明胶,类似于实施例3制备)一起给药后对需氧量和产热量的作用。结果汇集在表6中,耗氧量是在预先测定的心脏每次收缩耗氧29ml(在标准压力下)的基础上从心率计算而来的,产热量是在每g水的汽化热为2.26kJ的基础上从水分因出汗损失(根据封闭试验房间内的湿度变化测定)计算而来的。结果显示,该组合产品适合于补偿由试验物质所导致的耗氧量和产热量增加。
表6
身体运动期间与食物或药物有关的需氧量与产热量增加的防止
试验物质 | 对需氧量(l)的作用* | 对产热量(kJ)的作用* |
500mg抗坏血酸500mg抗坏血酸+产品A5g蔗糖5g蔗糖+产品A2.5mg格列本脲2.5mg格列本脲+产品A100mg H-Arg-Asp-OH100mg H-Arg-Asp-OH+产品A | +19-16+19-11+20-10+13-7 | +380-320+380-220+400-200+260-100 |
*与没有试验物质的对照试验相比的变化
产品A:5mg H-Gly-Gly-OH、250μg叶酸、5μg氰钴胺、1mg咖啡因和1mg明胶
表7
活性因与明胶结合而增加
第1次给药 | 第2次给药 | 平均心率(每分钟) | ||
给药前 | 第1次给药后 | 第2次给药后 | ||
0.1mg地西泮+5mg明胶7mg奥沙西泮+0.1mg地西泮+5mg明胶25mg米帕明+0.1mg二苯西平+5mg明胶25mg氯米帕明+0.1mg氯噻平+5mg明胶12.5mg曲米帕明+0.1mg氯巴占+5mg明胶12.5mg曲米帕明+0.1mg佐匹克隆+5mg明胶12.5mg曲米帕明+0.02mg赛庚啶+5mg明胶12.5mg曲米帕明12.5mg曲米帕明10mg米帕明 | 0.1mg氯巴占+5mg明胶0.1mg佐匹克隆+5mg明胶0.1mg二苯西平+5mg明胶 | 89.481.973.0100.574.086.878.979.881.787.7 | 66.666.664.079.163.071.357.0101.797.0100.2 | 74.272.180.2 |
实施例7
在类似于实施例1的试验中,利用类似于实施例3-5制备的明胶产品进行表7所示试验。在每种情况下首先进行5分钟准备运动后,记录10分钟对照试验期间在100W机械功率输出下的脉搏,然后进行第1次给药,之后立即测量10分钟试验期间在100W功率输出下的心率。在第2次给药的情况下,在第一试验阶段之后立即进行该次给药和第二个10分钟试验阶段。表7结果显示,如果与明胶结合给药,那么按照本发明可使用的活性成分的剂量通常可以明显减少至1mg以下。另外,结果还显示,如此低剂量的活性成分能够代偿其他药物对耗氧量和心率的增加作用,而与后者是与按照本发明可使用的活性成分一起给药还是单独给药无关。
Claims (21)
1、选自咪达唑仑和含氮杂环的环上氮原子被甲基取代的化合物的药物活性成分在制备用于减少身体运动期间的耗氧量的产品中的应用。
2、选自咪达唑仑和含氮杂环的环上氮原子被甲基取代的化合物的药物活性成分在制备用于减少由身体运动所诱发的心率增加的产品中的应用。
3、选自咪达唑仑和含氮杂环的环上氮原子被甲基取代的化合物的药物活性成分在制备用于减少由身体运动所诱发的产热量增加的产品中的应用。
4、如权利要求1至3中任何一个要求保护的应用,其特征在于所述药学活性成分是具有桥连和/或稠合环的多环化合物。
5、如权利要求1至4中任何一个要求保护的应用,其特征在于所述药学活性成分具有N-甲基取代的哌啶、二氮杂、哌嗪、吡咯烷、咪唑或嘧啶环或者2-甲基-2-氮杂双环并[3.3.1]壬烷或2-甲基-1,2,3,4-四氢异喹啉环的结构或者是咪达唑仑。
6、如权利要求1至5中任何一个要求保护的应用,其特征在于所述药学活性成分是右美沙芬、赛庚啶、氯噻平、地西泮、咪达唑仑、氟硝西泮、氯马斯汀、二苯西平、硫利达嗪、甲亢平、可待因、咖啡因、双氢可待因、吗啡、蒂巴因、诺司卡品、氯巴占、佐匹克隆或其药学上可接受的盐。
7、如权利要求1至6中任何一个要求保护的应用,其用于制备水溶液或混悬液或者含有胶凝剂的产品,优选明胶珠粒。
8、如权利要求1至7中任何一个要求保护的用于制备一种产品的应用,其中所述产品还另外含有有效量的D-葡萄糖、D-麦芽糖、乙醇、能生成葡萄糖的胺、能生成葡萄糖或能够经由乙醛酸盐被代谢的氨基酸或者这种氨基酸的二肽或药学上可接受的盐作为第二组分,和有效量的硫胺、药学上可接受的硫胺盐或叶酸与氰钴胺的组合作为第三组分,其条件是若所述第二组分是D-葡萄糖、D-麦芽糖、能生成葡萄糖的胺、不能经由乙醛酸盐代谢的能生成葡萄糖的氨基酸或这种氨基酸的二肽或药学上可接受的盐,则所述第三组分是硫胺或药学上可接受的硫胺盐。
9、如权利要求8要求保护的用于制备一种产品的应用,其中所述产品还另外含有吡哆辛或药学上可接受的吡哆辛盐、抗坏血酸或药学上可接受的抗坏血酸盐和/或生物素。
10、如权利要求1至9中任何一个要求保护的用于制备一种产品的应用,其中所述产品还另外含有D-葡萄糖、D-麦芽糖、能生成葡萄糖的胺、能生成葡萄糖或能够经由乙醛酸盐被代谢的氨基酸或者这种氨基酸的二肽或药学上可接受的盐作为第二组分,含有硫胺或药学上可接受的硫胺盐作为第三组分,如果需要的话,进一步含有胶凝剂、维生素C和/或维生素B12作为其他组分。
11、如权利要求10要求保护的用于制备一种产品的应用,其中所述产品含有甘氨酸、L-丝氨酸、L-谷氨酸和/或其二肽或药学上可接受的盐作为第二组分,如果需要的话,进一步含有叶酸、维生素B12和/或明胶作为其他组分。
12、如任意权利要求1至8所要求保护的用途,用于制备产品,该产品另外包含乙醇作为第二组分,包含硫胺或药学上可接受的硫胺盐作为第三组分,包含生物素作为其他组分。
13、如权利要求1至8中任何一个要求保护的用于制备一种产品的应用,其中所述产品还另外含有乙醇作为第二组分,包含叶酸与氰钴胺的组合作为第三组分。
14、一种用于减少身体运动期间耗氧量的产品,其包含(a)有效量的选自咪达唑仑和含氮杂环的环上氮原子被甲基取代的化合物的药学活性成分作为第一组分,(b)有效量的D-葡萄糖、D-麦芽糖、乙醇、能生成葡萄糖的胺、能生成葡萄糖或能够经由乙醛酸盐被代谢的氨基酸或者这种氨基酸的二肽或药学上可接受的盐作为第二组分,和(c)有效量的硫胺、药学上可接受的硫胺盐或叶酸与氰钴胺的组合作为第三组分,其条件是若所述第二组分是D-葡萄糖、D-麦芽糖、能生成葡萄糖的胺、不能经由乙醛酸盐代谢的能生成葡萄糖的氨基酸或这样一种氨基酸的二肽或药学上可接受的盐,则该第三组分是硫胺或药学上可接受的硫胺盐。
15、如权利要求14要求保护的产品,其特征在于该药学活性成分是右美沙芬、赛庚啶、氯噻平、地西泮、咪达唑仑、氟硝西泮、氯马斯汀、二苯西平、硫利达嗪、甲亢平、可待因、咖啡因、双氢可待因、吗啡、蒂巴因、诺司卡品、氯巴占或其药学上可接受的盐。
16、如权利要求14或15要求保护的产品,它是水溶液或混悬液的形式,或者是含有胶凝剂的产品,优选为明胶珠粒的形式。
17、如权利要求14至16中任何一个要求保护的产品,其特征在于它另外包含吡哆辛或药学上可接受的吡哆辛盐、抗坏血酸或药学上可接受的抗坏血酸盐和/或生物素。
18、如权利要求14至17中任何一个要求保护的产品,其特征在于它包含D-葡萄糖、D-麦芽糖、能生成葡萄糖的胺、能生成葡萄糖或能够经由乙醛酸盐被代谢的氨基酸或者这种氨基酸的二肽或药学上可接受的盐作为第二组分,包含硫胺或药学上可接受的硫胺盐作为第三组分,如果需要的话,进一步包含胶凝剂、维生素C和/或维生素B12作为其他组分。
19、如权利要求18要求保护的产品,其特征在于它包含甘氨酸、L-丝氨酸、L-谷氨酸和/或其二肽或药学上可接受的盐作为第二组分,如果需要的话,进一步包含叶酸、维生素B12和/或明胶作为其他组分。
20、如权利要求14至16中任何一个要求保护的产品,其特征在于它包含乙醇作为第二组分,包含硫胺或药学上可接受的硫胺盐作为第三组分,进一步包含生物素作为其他组分。
21、如权利要求14至16中任何一个要求保护的产品,其特征在于它包含乙醇作为第二组分,包含叶酸与氰钴胺的组合作为第三组分。
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JP3005091B2 (ja) | 1991-10-29 | 2000-01-31 | 東洋製薬株式会社 | 糖質代謝改善飲食品 |
US5292538A (en) | 1992-07-22 | 1994-03-08 | Metagenics, Inc. | Improved sustained energy and anabolic composition and method of making |
FR2704392B1 (fr) | 1993-04-30 | 1995-06-02 | Boiron | Complément nutritionnel absorbable pour améliorer et optimiser les niveaux d'activité physique et cérébrale des individus. |
JPH07330583A (ja) | 1994-06-03 | 1995-12-19 | Terumo Corp | 遊離型グルタミン酸を含有する液状製剤 |
JP2000516937A (ja) | 1996-08-26 | 2000-12-19 | ヴィス,オスヴァルト | 運動時の酸素消費を低下するビタミン製剤 |
-
2000
- 2000-07-21 WO PCT/CH2000/000400 patent/WO2001008680A1/de not_active Application Discontinuation
- 2000-07-21 JP JP2001513410A patent/JP2003505505A/ja active Pending
- 2000-07-21 EP EP00943512A patent/EP1200082A1/de not_active Withdrawn
- 2000-07-21 US US10/030,708 patent/US6703371B1/en not_active Expired - Fee Related
- 2000-07-21 AU AU58004/00A patent/AU5800400A/en not_active Abandoned
- 2000-07-21 CN CN00810920A patent/CN1365279A/zh active Pending
Also Published As
Publication number | Publication date |
---|---|
EP1200082A1 (de) | 2002-05-02 |
JP2003505505A (ja) | 2003-02-12 |
US6703371B1 (en) | 2004-03-09 |
AU5800400A (en) | 2001-02-19 |
WO2001008680A1 (de) | 2001-02-08 |
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