JP2012526828A5 - - Google Patents
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- JP2012526828A5 JP2012526828A5 JP2012510958A JP2012510958A JP2012526828A5 JP 2012526828 A5 JP2012526828 A5 JP 2012526828A5 JP 2012510958 A JP2012510958 A JP 2012510958A JP 2012510958 A JP2012510958 A JP 2012510958A JP 2012526828 A5 JP2012526828 A5 JP 2012526828A5
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Claims (44)
- 哺乳動物の代謝性障害の治療、代謝性障害の症状の緩和、代謝性障害の進行の阻害、または代謝性障害の予防のための医薬組成物であって、治療的有効量の少なくとも1つの環境影響因子(env影響因子)を含み、ここで環境影響因子が哺乳動物の疾患細胞において、正常化されたミトコンドリア酸化的リン酸化への細胞代謝エネルギーシフトを選択的に誘発する、医薬組成物。
- 環境影響因子が哺乳動物の正常細胞において、ミトコンドリア酸化的リン酸化への細胞代謝エネルギーシフトを実質的に誘発しない、請求項1に記載の医薬組成物。
- 哺乳動物がヒト(または非ヒト哺乳動物)である、請求項1または2に記載の医薬組成物。
- 代謝性障害がコエンザイムQ10またはその代謝産物もしくはその類似体による治療に応答性または感受性である、請求項1〜3のいずれか1項に記載の医薬組成物。
- 代謝性障害が、代謝性疾患の一因となるか、または原因となって代謝性疾患を引き起こす改変された遺伝子調節および/またはタンパク質−タンパク質相互作用を引き起こすミトコンドリア酸化的リン酸化機能の調節不全によって特徴付けられる、請求項1〜4のいずれか1項に記載の医薬組成物。
- 環境影響因子が:
(a)ベンゾキノンまたはベンゾキノン環の生合成を容易にする少なくとも1つの分子、ならびに
(b)イソプレノイドユニットの合成および/またはイソプレノイドユニットのベンゾキノン環への結合を容易にする少なくとも1つの分子
を含む、請求項1〜5のいずれか1項に記載の医薬組成物。 - ベンゾキノン環の生合成を容易にする前記少なくとも1つの分子が:L−フェニルアラニン、DL−フェニルアラニン、D−フェニルアラニン、L−チロシン、DL−チロシン、D−チロシン、4−ヒドロキシ−フェニルピルベート、3−メトキシ−4−ヒドロキシマンデレート(バニリルマンデレートまたはVMA)、バニリン酸、ピリドキシン、またはパンテノールを含む、請求項6に記載の医薬組成物。
- イソプレノイドユニットの合成および/またはイソプレノイドユニットのベンゾキノン環への結合を容易にする前記少なくとも1つの分子が:フェニルアセテート、4−ヒドロキシベンゾエート、メバロン酸、アセチルグリシン、アセチルCoA、またはファルネシルを含む、請求項6または7に記載の医薬組成物。
- 環境影響因子が:
(a)L−フェニルアラニン、L−チロシン、および4−ヒドロキシフェニルピルベートの1つ以上;ならびに
(b)4−ヒドロキシベンゾエート、フェニルアセテート、およびベンゾキノンの1つ以上;
を含む、請求項1〜8のいずれか1項に記載の医薬組成物。 - 環境影響因子が:
(a)Bcl−2発現を阻害するおよび/もしくはカスパーゼ−3発現を増進する;ならびに/または
(b)細胞増殖を阻害する、
請求項1〜9のいずれか1項に記載の医薬組成物。 - 環境影響因子が多次元細胞内分子(MIM)である、請求項1〜10のいずれか1項に記載の医薬組成物。
- MIMが:アルファケトグルタレート/アルファケトグルタル酸、マレート/リンゴ酸、スクシネート/コハク酸、グルコサミン、アデノシン、アデノシン二リン酸、グルクロニド/グルクロン酸、ニコチン酸、ニコチン酸ジヌクレオチド、アラニン/フェニルアラニン、ピリドキシン、チアミン、またはフラビンアデニンジヌクレオチドから選択される、請求項11に記載の医薬組成物。
- 環境影響因子がエピメタボリックシフター(エピシフター)である、請求項1〜12のいずれか1項に記載の医薬組成物。
- エピメタボリックシフターが:トランスアルドラーゼ、トランスケトラーゼ、スクシニルCoAシンターゼ、ピルビン酸カルボキシラーゼ、またはリボフラビンから選択される、請求項13に記載の医薬組成物。
- エピメタボリックシフターがコエンザイムQ10である、請求項13に記載の医薬組成物。
- 治療されているヒトの組織における環境影響因子の濃度が、健常または正常状態を表すヒト組織の対照標準の環境影響因子の濃度とは異なる、請求項1〜15のいずれか1項に記載の医薬組成物。
- ヒトに投与された環境影響因子の形態がヒトにおける全身循環中で見出される優勢形態とは異なる、請求項1〜16のいずれか1項に記載の医薬組成物。
- ヒトの代謝性障害を治療するのに十分な量の環境影響因子が、ミトコンドリア酸化的リン酸化を上方調節または下方調節する、請求項1〜17のいずれか1項に記載の医薬組成物。
- ヒトの代謝性障害を治療するのに十分な量の環境影響因子が、グルコースの嫌気的使用および/またはラクテート生合成を調節する、請求項18に記載の医薬組成物。
- 治療がenv影響因子とHNF4アルファとの相互作用を介してなされる、請求項1〜19のいずれか1項に記載の医薬組成物。
- 治療がenv影響因子とトランスアルドラーゼとの相互作用を介してなされる、請求項1〜19のいずれか1項に記載の医薬組成物。
- 代謝性障害が糖尿病、肥満、前糖尿病、メタボリックシンドロームおよび代謝性障害のいずれかの主要な要素からなる群より選択される、請求項1〜21のいずれか1項に記載の医薬組成物。
- 代謝性障害が糖尿病であり、env影響因子がベータ細胞機能、インスリン代謝、および/またはグルカゴン沈着に影響を及ぼす、請求項22に記載の医薬組成物。
- 代謝性障害が肥満であり、env影響因子がミトコンドリアにおけるベータ細胞酸化、脂肪細胞サイズの低下、および/またはコルチゾールレベルの制御に影響を及ぼす、請求項22に記載の医薬組成物。
- 代謝性障害が心血管疾患であり、env影響因子が中膜における平滑筋細胞増殖の低下、脂質過酸化、トロンボキサン−ax2合成、TNFa、IL−1B、血小板凝集、一酸化窒素(NO)産生の低下、プラーク沈着および/または正常化した血糖制御に影響を及ぼす、請求項22に記載の医薬組成物。
- 前記代謝性障害の主要な要素が空腹時血糖異常、耐糖能異常、腹囲増加、内臓脂肪量増加、空腹時血漿グルコースの増加、空腹時血漿トリグリセリドの増加、空腹時高密度リポタンパク質レベルの低下、血圧の上昇、インスリン抵抗性、高インスリン血症、心血管疾患、動脈硬化症、冠動脈疾患、末梢血管疾患、脳血管疾患、うっ血性心不全、血漿ノルエピネフリンの上昇、心血管関連炎症因子の上昇、血管内皮機能障害を増強する血漿因子の上昇、高リポタンパク血症、動脈硬化症またはアテローム性動脈硬化症、過食症、高血糖症、高脂血症、および高血圧症(hypertension)または高血圧症(high blood pressure)、食後血漿トリグリセリドレベルまたは遊離脂肪酸レベルの上昇、細胞酸化ストレスまたはその血漿指標の上昇、循環過凝固状態の増加、肝臓脂肪症、肝臓脂肪症(hetaptic steatosis)、腎不全および腎機能不全を含む腎疾患からなる群より選択される、請求項22に記載の医薬組成物。
- 医薬組成物が追加の治療剤とともに投与される、請求項1〜26のいずれか1項に記載の医薬組成物。
- 追加の治療剤が真性糖尿病治療剤、糖尿病合併症治療剤、抗高脂血剤、降圧剤または抗高血圧剤、抗肥満剤、利尿薬、化学治療剤、免疫治療剤および免疫抑制剤からなる群より選択される、請求項27に記載の医薬組成物。
- 治療的有効量の少なくとも1つのenv影響因子を含む、代謝性障害の治療を必要する哺乳動物の疾患細胞においてミトコンドリア酸化的リン酸化を選択的に増強するための医薬組成物であって、該env影響因子は哺乳動物の前記疾患細胞にてミトコンドリア酸化的リン酸化を選択的に増強する、医薬組成物。
- 前記env影響因子はさらに、正の倍率変化を有する表2〜4および表6〜28および表63〜68に挙げられた分子からなる群より選択される1つ以上の遺伝子の発現を上方調節し;ならびに/または負の倍率変化を有する表2〜4および表6〜28および表63〜68に挙げられた分子からなる群より選択される1つ以上の遺伝子の発現を下方調節する、請求項29に記載の医薬組成物。
- 前記env影響因子はさらに、HNF4−アルファ、Bcl−xl、Bcl−xS、BNIP−2、Bcl−2、Birc6、Bcl−2−L11、XIAP、20 BRAF、Bax、c−Jun、Bmf、PUMA、cMyc、トランスアルドラーゼ1、COQ1、COQ3、COQ6、プレニルトランスフェラーゼ、4−ヒドロベンゾエート、好中球サイトゾル因子2、一酸化窒素シンターゼ2A、スーパーオキシドディスムターゼ2、VDAC、Baxチャネル、ANT、シトクロムc、複合体I、複合体II、複合体III、複合体IV、Foxo3a、DJ−1、IDH−1、Cpt1CおよびカムキナーゼIIからなる群より選択される1つ以上の遺伝子の発現を調節する、請求項29に記載の医薬組成物。
- 代謝性障害が糖尿病、肥満、前糖尿病、メタボリックシンドロームおよび代謝性障害のいずれかの主要な要素からなる群より選択される、請求項29〜31のいずれか1項に記載の医薬組成物。
- 前記代謝性障害の主要な要素が空腹時血糖異常、耐糖能異常、腹囲増加、内臓脂肪量増加、空腹時血漿グルコースの増加、空腹時血漿トリグリセリドの増加、空腹時高密度リポタンパク質レベルの低下、血圧の上昇、インスリン抵抗性、高インスリン血症、心血管疾患、動脈硬化症、冠動脈疾患、末梢血管疾患、脳血管疾患、うっ血性心不全、血漿ノルエピネフリンの上昇、心血管関連炎症因子の上昇、血管内皮機能障害を増強する血漿因子の上昇、高リポタンパク血症、動脈硬化症またはアテローム性動脈硬化症、過食症、高血糖症、高脂血症、および高血圧症または高血圧症、食後血漿トリグリセリドレベルまたは遊離脂肪酸レベルの上昇、細胞酸化ストレスまたはその血漿指標の上昇、循環過凝固状態の増加、肝臓脂肪症、肝臓脂肪症、腎不全および腎機能不全を含む腎疾患からなる群より選択される、請求項29〜31のいずれか1項に記載の医薬組成物。
- 医薬組成物が、追加の治療剤とともに投与される、請求項29〜33のいずれか1項に記載の医薬組成物。
- 追加の治療剤が真性糖尿病治療剤、糖尿病合併症治療剤、抗高脂血剤、降圧剤または抗高血圧剤、抗肥満剤、利尿薬、化学治療剤、免疫治療剤および免疫抑制剤からなる群より選択される、請求項34に記載の医薬組成物。
- 代謝性障害を治療するのに有効である薬剤を同定する方法であって:
(1)環境影響因子を選択することと;
(2)細胞の代謝状態をシフトさせることができる環境影響因子を同定することと;
(3)環境影響因子が代謝性障害を治療するのに有効か否かを判定して;
これにより代謝性障害を治療するのに有効である薬剤を同定することとを含む、方法。 - 環境影響因子がmRNA発現、タンパク質発現、脂質または代謝産物濃度、生体エネルギー分子のレベル、細胞エネルギー特性、ミトコンドリア機能およびミトコンドリア数のいずれか1つ以上の変化を測定することによって、細胞の代謝状態をシフトさせることができるとして同定される、請求項36に記載の方法。
- 代謝性障害の治療に有効な環境影響因子が患者のグルコースレベルまたは脂質レベルを低下させることができる、請求項36または37に記載の方法。
- 請求項36〜38のいずれか1項に記載の方法によって同定された薬剤を含む組成物。
- 請求項39に記載の組成物を含むキット。
- 請求項39に記載の組成物の有効量を含む、患者のグルコースレベルを低下させるための医薬組成物。
- 請求項39に記載の組成物の有効量を含む、患者の脂質レベルを低下させるための医薬組成物。
- 哺乳動物のコエンザイムQ10応答性障害の治療、コエンザイムQ10応答性障害の症状の緩和、コエンザイムQ10応答性障害の進行の阻害、またはコエンザイムQ10応答性障害の予防のための医薬組成物であって、治療的有効量の少なくとも1つの環境影響因子(env影響因子)を含み、環境影響因子が哺乳動物の疾患細胞において、正常な生理学的条件下にて哺乳動物の正常細胞中で観察された解糖およびミトコンドリア酸化的リン酸化のレベルへの細胞代謝エネルギーシフトを選択的に誘発する、医薬組成物。
- コエンザイムQ10応答性障害が代謝性障害である、請求項43に記載の医薬組成物。
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