JP2010168394A - エネルギーをインビボで増加させるための組成物 - Google Patents
エネルギーをインビボで増加させるための組成物 Download PDFInfo
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- JP2010168394A JP2010168394A JP2010089732A JP2010089732A JP2010168394A JP 2010168394 A JP2010168394 A JP 2010168394A JP 2010089732 A JP2010089732 A JP 2010089732A JP 2010089732 A JP2010089732 A JP 2010089732A JP 2010168394 A JP2010168394 A JP 2010168394A
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Abstract
【解決手段】ペントース糖を、個別に、あるいは固形食物又は溶液に混合して投与する。好ましいペントースはリボースであり、これを単独で、又はクレアチン、ピルビン酸、L-カルニチン及び/又は血管拡張剤と共に用いる。更にマグネシウム、電解質、脂肪酸及びヘキソース糖を用いることができる。本発明の組成物及び方法は、エネルギー利用度が低下した又はエネルギー要求性が高い哺乳動物に特に有益である。
【選択図】なし
Description
本発明は、エネルギー利用度が低下した又は高レベルのエネルギーを消費する哺乳動物に利用され得るエネルギーを増加させるための組成物又は方法に関する。前記哺乳動物には、細胞内アデノシン三リン酸(ATP)の減少を誘導する疾患を有する人間、運動又は労働などの激しい身体活動を行う人間、及びエネルギーレベルの増加を望む人間が含まれる。本発明では、その他の哺乳動物、例えばイヌ及びネコも含まれる。本発明の組成物の投与により、血液内及び細胞内ATPレベルが増加し、哺乳動物の活動の時間及び強度が拡大し、そして運動中の個体による酸素利用率が増加する。また運動してない哺乳動物、並びに身体障害、例えば外傷、火傷及び敗血症から回復する間に通常よりも多くのエネルギーを消費する哺乳動物にも、本発明の組成物の投与は有益である。
細胞のエネルギーの基本単位がアデノシン三リン酸であることが周知である。同化代謝において、栄養素の代謝から得られたエネルギーがATPの高エネルギーリン酸結合に転換される。前記結合エネルギーは、エネルギー消費相において消費される。ATPが急速に生成回転される重要且つ「多量」な消費が、筋収縮のために必要である。
Plimlは、ドイツ国特許No.4,228,215において、心機能不全及び血液量減少ショックを治療する際に、リボースの経口投与が有効であることを認めている。
本発明は、哺乳動物におけるエネルギーレベルを増加させる組成物及び方法を提供する。本発明の組成物及び方法は、細胞機能を支持するために、ATP利用度が最適未満である哺乳動物においてATP合成を刺激することによって作用する。特には、高レベルATPの要求前、要求中及び要求後に、哺乳動物のエネルギーを増強させるために有効な量で、ペントース、例えばD-リボースを経口投与する。リボースを供給された哺乳動物は、リボース非供給動物に比べてより長く運動すること、より強く運動すること、そして主観的により多くのエネルギーを有することができる。
本発明は、ペントースの経口投与によりATP合成を刺激する方法を提供し、そして高エネルギー要求性であり又は慢性的に低エネルギーレベルである哺乳動物に対して特に有益であるペントース含有組成物を提供する。
1.「ペントース」は単糖であり、限定でなくリボース、D-リボース、リブロース、キシリトール、キシルロース、及びリボースの任意の5炭素前駆体を含む。
2.「血管拡張剤」は血管を拡張する任意の物質であり、経皮又は経口投与されるアデニン、ヒドララジン、アルギニン及びニトログリセリンを含む。
3.「細胞内ATPレベル」は組織生検又は核磁気共鳴により直接的に、あるいは血中ATP濃度により間接的に決定されたATP濃度を指す。
4.「その他のエネルギー代謝産物及び補助因子」はクレアチン、補酵素、トリカルボン酸回路、ペントースリン回路、又は解糖系の中間体、ピリミジン及びプリンヌクレオチド、並びにミネラルを指す。
米国特許No.5,114,723には、電解質、ミネラル、炭水化物及びその他の成分を含有する経口投与用の低張飲用組成物が記載されている。この組成物は、100〜270 mOs/lの浸透圧を有する様に調整されている。
客観的に示されていないが、リボースが、PRPP合成を介して、ヌクレオチド再利用経路によるATP合成速度を増加させることが理論づけられている。しかし安静な筋肉における総アデニンヌクレオチド(ATN)又はリボースレベルに関して何も知られておらず、従って当合成酵素経路が既に飽和していて、リボースの投与が、正常な非虚血性の骨格筋においてATPレベルを増加させないことが有り得る。当経路に対するリボースの効果を証明するために、健康な成熟雄Sprague-Dawleyラットの足底複合筋を外科的に露出させ、そしてアミノ酸、mMグルコース及び100μU/mlのウシインスリンを含有する再構成した血液還流溶液により還流した。当筋肉を〜40ml/分の速度で再構成血液溶液により還流し、その結果約0.65ml/分の組織還流を得た。種々の濃度のD-リボースを還流液に加えて、その最終濃度を0.156mM, 0.5mM, 1.58mM, 5.0mM及び15.0mMに調整した。当筋肉を30分間還流した。用いた各リボース投与量での分析のために、最低2匹のラットを用いた。
骨格筋応答のリボース投与量依存性
──────────────────────────
mMリボース 観察値 ベースによる飽和キネティクス
──────────────────────────
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
──────────────────────────
24〜26歳の年齢範囲の4人の健康な適当な対象者を検査した。健康程度、性別及び平均年齢が均一であり、そして既知の代謝性、神経性、内分泌性及び心肺性の疾患が無い群を選択した。その全員が自転車運動をすることができ、又は自転車運動の経験があった。実験方法は下記の4相から成った:(1)運動を行わない開始ベースライン相;(2)1日3回のD-リボース又はプラセボ(グルコース)の投与を3日間行う添加相;(3)1日に2回(午前と午後)、スプリント間に50秒間の休憩を伴って、体重の7%の抵抗負荷に対する短時間(10秒)の高強度の自転車スプリントを連続的(N=6)に行う運動を3日間行う訓練相;及び、(4)最終訓練後48時間の回復相。図1は、自転車スプリント運動1回毎のグラフである。
生検試料において下記の分析物の濃度を決定した:ATP, ADP, AMP, IMP(イノシン一リン酸), TAN(総アデニンヌクレオチド), クレアチンリン酸及びクレアチン。
平均仕事率/Kg (ワット)
──────────────────────────
対象者 1 2 3 4 5 6 平均
──────────────────────────
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
プラセボ 6.8 7.4 7.5 8.0 7.6 7.5 7.5 100.0%
リボース 7.8 8.4 8.5 8.3 8.2 7.8 8.2 109.0%
──────────────────────────
ピーク仕事率/Kg (ワット)
──────────────────────────
対象者 1 2 3 4 5 6 平均
──────────────────────────
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
プラセボ 7.7 8.6 8.7 9.4 8.8 9.0 8.7 100.0%
リボース 8.9 9.7 10.0 9.9 9.8 9.3 9.6 109.9%
──────────────────────────
総仕事量/Kg
──────────────────────────
対象者 1 2 3 4 5 6 平均
──────────────────────────
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
プラセボ 66.8 73.6 74.8 80.4 76.3 75.3 74.5 100.0%
リボース 79.3 83.3 84.2 82.8 81.8 77.9 81.6 109.5%
──────────────────────────
運動性の向上は、筋生検におけるATPレベルに反映される。表Vに示される通り、3日間リボースを予め添加した対象者は、訓練相の前により高レベルのATPを示したが、スプリント運動後、このATPは、プラセボ群に比べて有意に減少し、これは、ATPがより効率的に利用されたことを意味する。48時間後のリボース群の回復値は、最初のレベルの82%であり、これに対してプラセボ群では78%であった。
平均ATP値(mmol/kg dw)
────────────────────────────────────
群 事前 事後 回復 事前値の回復率 変化 変化
% 事前−事後 事後−回復
────────────────────────────────────
プラセボ 23.60 20.05 18.30 78% -3.55 -1.75
リボース 25.33 13.90 20.80 82% -11.43 6.90
────────────────────────────────────
運動直前及び運動中に投与したD-リボースは、以前に訓練を受けていない対象者に対しても有効であり得る。4人の正常な男性被験者に対して、実施例2の通りに自転車運動におけるスプリントの仕事率出力を検査する。各被験者は、自分自身をコントロールとして検査する。スプリント運動の間に、被験者はゆっくりと自転車運動を持続する。検査の総時間は1時間であり、その間4回スプリント運動がある。
冠状動脈疾患の履歴、ポストトリプル状態冠状動脈バイパスを有する68歳の男性老患者は、運動誘発性狭心症の経験があった。当人の現在の適用薬物は、エナプリル(アンジオテンシン変換酵素阻害剤)、カルベジルオール(βブロッカー)、ニトログリセリンパッチ及び、必要な場合ニトログリセリン舌下錠である。最近の冠状動脈血管造影から、バイパスグラフトの1本の完全な閉塞を伴う冠状動脈疾患の進行が判明した。当患者は、2回の負荷検査をほとんど行えなかった。当人の運動態様は毎日の散歩であった。
安定冠状動脈疾患を有する60歳の男性老患者は、1本超の心外膜冠状動脈の50%超の閉塞及び安定狭心症を有することが観察された。当患者のトレッドミル運動性を検査した。Bruce法に従って、2回のベースライントレッドミル検査の後、当人は3日間D-リボース(1日40gを3回に分けて投与)を摂取し、そして3回目のトレッドミル検査を実行した。各回、a)ECG追跡記録において当患者が1mm以上のSTセグメントの抑制を示した場合、b)当患者が狭心症を訴えた場合、又はc)呼吸困難又は疲労のために当患者が止めた場合、当検査を中止することにした。各検査において、この患者は、呼吸が短くなったために検査を終えたが、狭心症を起こさなかった。
拍数/分と収縮期血圧mmHgの積としての心拍数・血圧の積
───────────────────────────────────
時間 ベースライン1 ベースライン2 平均 検査 変化%
───────────────────────────────────
0(安静) 11,088 9,272 10,180 9,177 -9.55%
3分 17,574 13,468 15,521 15,272 -1.60%
6分 26,500 22,344 24,422 20,592 -15.68%
9分 33,396 29,526 31,461 25,356 -9.87%
───────────────────────────────────
許容時間
秒 483.00 545.00 514.00 540.00 5.06%
───────────────────────────────────
Bruce法では、トレッドミル速度を、3分後に時速2.74から9.66kmに増加し、一方傾斜を10から20%に増加する。
エネルギーレベルの低下を特徴とする慢性疾患、例えば限定でなく、冠状動脈疾患、AIDS、間欠性跛行、結核及び慢性疲労症候群に罹った患者にとって、更に明白な疾患を有さないが、加齢、外傷、火傷、及び病気又は手術からの回復のためにエネルギーが低下した対象者にとっても、継続的な治療介入を行うことなく当人のエネルギーレベルを増加できることは有益である。比較的に安定な疾患を有する多くの個人は、医薬補給に伴って、生活様式の変化に合わせて毎日生きている。しばしば、この様な者は、不愉快な作用、例えば狭心症、息切れ、筋肉痛、筋肉痙攣又は消耗感を起こす恐れから、中度の身体活動を行うことが抑制されている。この様な回避は、当人の生活の質を下げ、そして永続する背景的な不安を生む。更に当人は、消化促進、睡眠、より安心且つ積極的な心理状態などの適度な運動による利益を得られない。更に、疾患が無く且つ健康であると思われる者でも、主観的なエネルギーレベル感及び満足感を満たさないことがある。
実施例6に示した通り、低エネルギーレベルを有する者に、ペントースの自己投与が有益であることが予想される。またこの様な者に、経口投与できる血管拡張剤、例えばL-アルギニンが更に有益であることも予想される。更にまた、ミトコンドリア内へ脂肪酸を輸送させるためのL-カルニチンの摂取が更に有益であることも予想される。更にまた、その他のエネルギー代謝産物及び補助因子の追加が更に有益であることも予想される。
これらの被験者は、実施例2で示した通り、心拍数・圧の積値の10%減少及び許容時間の5%増加を更に超える向上を示すことが予想される。
Claims (16)
- 哺乳動物のエネルギーレベルを増加させるための方法であって、前記哺乳動物に有効量のペントースを経口投与することを含んで成る前記方法。
- 前記ペントースがリボースである、請求項1に記載の方法。
- 前記哺乳動物のATP利用度が低下している、請求項1に記載の方法。
- 前記哺乳動物のエネルギー要求性が増加している、請求項1に記載の方法。
- 前記哺乳動物が冠状動脈疾患を有する、請求項3に記載の方法。
- 前記哺乳動物が、感染、外傷又は火傷から回復中である、請求項4に記載の方法。
- 前記哺乳動物が激しく運動している、請求項4に記載の方法。
- 前記哺乳動物が虚血性障害を受けていない、請求項4に記載の方法。
- 哺乳動物のエネルギーレベルを増加させるために投与される組成物であって、有効量のペントースを含有する前記組成物。
- 前記ペントースがリボースである、請求項9に記載の組成物。
- 更にマグネシウム及びクレアチンを含有する、請求項9に記載の組成物。
- 約0.1〜50gのペントースを、医薬上容認される担体と共に含有する、経口摂取に適する単位投与剤。
- 前記ペントースがリボースである、請求項12に記載の単位投与剤。
- 前記担体が液体である、請求項12に記載の単位投与剤。
- 前記液体が水性液体である、請求項14に記載の単位投与剤。
- 前記担体が、固体又は半固体の食べられる担体である、請求項12に記載の単位投与剤。
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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 |
CN1306431A (zh) | 2001-08-01 |
ES2374260T3 (es) | 2012-02-15 |
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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