JP6811316B2 - ミドドリンまたはその薬学的に許容可能な塩を有効成分として含む糖尿病及び/または高脂血症の予防または治療用薬学的組成物 - Google Patents
ミドドリンまたはその薬学的に許容可能な塩を有効成分として含む糖尿病及び/または高脂血症の予防または治療用薬学的組成物 Download PDFInfo
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Description
本発明の他の目的は、有効成分であるミドドリンまたはその薬学的に許容可能な塩にインスリン(insulin)をさらに含む糖尿病の治療または予防のための薬学的組成物を提供することにある。
本発明のさらに他の目的は、ミドドリンを利用した糖尿病治療方法を提供することにある。
本発明のさらに他の目的は、ミドドリンまたはその薬学的に許容可能な塩を有効成分として含む高脂血症の治療または予防のための薬学的組成物を提供することにある。
本発明のさらに他の目的は、ミドドリンを利用した高脂血症治療方法を提供することにある。
AMPKは、生体内エネルギー状態を感知して、それを一定のレベルに保持させるエネルギーセンサー(energy sensor)の役割を行い、例えば、代謝性ストレスや運動によって細胞内のエネルギーが減少する場合、すなわち、ATPが枯渇してAMP/ATP比率が増加する場合に活性化されて、ATPを消費する過程(例えば、脂肪酸酸化と当該過程)を促進する。AMPKの活性化は、筋肉のような主要標的臓器に代謝的に重要な結果を誘導するが、特に、骨格筋で脂肪酸の酸化と糖吸収とを促進すると知られている。
PPAR−δは、AMPKを調節して細胞内異化的エネルギー代謝を促進し、抗炎症作用など生体代謝の均衡(恒常性)保持に必須的な役割を行うと知られている。
本発明において、運動類似効果とは、筋肉のインスリン鋭敏度増加及び酸化リン酸化機能増進、心臓機能改善(収縮力増加)、酸化リン酸化機能増進、コレステロール減少、脂肪蓄積及び体重減少など運動時に発揮される生理効果を意味し、特に制限はない。
その結果、ヒトの代謝症侯群に該当する自発性高血圧ラット(SHR)は、ミドドリンによってα1−ARを刺激時に、心臓、骨格筋、肝でAMPK、PPAR−δ、PGC−1αの活性化及び発現増加を引き起こすという事実を明らかにした。
したがって、α1−AR効能剤は、心臓収縮の直接的刺激に対する三重効果及びその運動効果を通じて、また、心臓、筋肉及び肝を含む多器官でのα1−AR刺激による運動類似AMPK−PPAR−δの活性化という間接的効果を通じて心臓機能を向上させることにより、インビボで運動耐性の向上に寄与すると判断される。
また、α1−AR刺激効果が、心臓機能/サイズ、アディポネクチン及び脂肪レベルなどに及ぼす効果を観察した。
1−1:細胞培養
ラット骨格筋細胞株(L6)、マウス心筋細胞株(HL1)及びマウス脂肪前駆細胞株(3T3−L1)は、37℃ CO2培養器内で6ウェルプレート(well plate)あるいは24ウェルプレートに各細胞を分注した。
自発性高血圧ラット(Spontaneously Hypertensive Rat;SHR)は、遺伝性高血圧が発現される実験動物であって、ヒトの原発性高血圧と最も類似した高血圧を発現させると知られている。SHRは、ほとんど4〜6週齢に血圧が上昇し始めて、8〜12週齢に本格的な高血圧が発現される。SHRは、心肥大、心不全及び腎障害のような高血圧性標的臓器の損傷をよく伴うために、原発性高血圧、特に、心臓病変を有した高血圧に対する動物モデルとして関連研究に幅広く使われている。
2−1:ATP測定のためのELISA方法
実施例1−2のラットから分離した肝組織0.02gを500μLのPBS中で均質化した。均質液を1500ug(または、5000rpm)で15分間遠心分離した以後に、上澄み液に対して測定を行った。基準物質またはサンプル100μLを抗体予めコーティングされたマイクロ適正プレート中の適当なウェルに注いだ後、残余溶液10μLをサンプルに添加した。50μLのコンジュゲートを各ウェルに添加し、混合した後、カバーを覆ったプレートを37℃で1時間培養した。それぞれ50μLの基質A及びBをそれぞれのウェルに添加し、37℃で15分間培養した。それぞれのウェルに停止液を添加した後、マイクロプレート判読器を使用して450nmで光学密度を測定した。
ウェル内PBS(phosphate buffer saline)溶液1ml当たりタンパク質分解酵素阻害剤カクテル10μLを添加して、ウェル当たり500μLになるように準備し、1Mリン酸緩衝溶液25μL×25=625μL、0.2Mコハク酸ナトリウム125μL×25=3125μL、NBT 25μL×25=625μL、D.W 235μL×25=5875μLを混ぜて作った培養溶液をウェル当たり410μLになるように準備して、反応20分前に37℃に温めておいた。実施例1−2のラットから分離した骨格筋肉組織0.02g当たり、前記であらかじめ準備したPBS 500μLを入れ、破砕機で磨くが、短い時間分けて磨いて、温度が上昇して酵素が破壊されないように準備した。13000rpm、4℃で5分間遠心分離後、上澄み液を収得して新たなチューブに移した。培養溶液410μLをあらかじめチューブに入れて置き、サンプル90μLを入れて酵素反応させた。さらに他のチューブに蒸留水(DW)410μLを入れ、サンプル90μLを添加した後、希釈液の吸光度を測定した。予め準備した酵素反応のチューブと他のチューブとをそれぞれ37℃水湯煎に入れ、30分間反応させ、氷にチューブを挿入して反応を終了させた後、96ウェルプレートに200μLずつ分注して、吸光度550nmで測定し、結果値を次のような式に適用して、コハク酸デヒドロゲナーゼ(SDH)の酵素活性度を計算した。
タンパク質は、細胞からPREPTMタンパク質抽出溶液(iNtRON Biotechnology、Seongnam−si,Gyeonggi−do,Korea)を用いて収得した後、タンパク質20〜30ugを10% SDS−PAGE(SDS−polyacrylamide gel electrophoresis)ゲル上にローディングして分離し、ニトロセルロースペーパー(GE Healthcare、イギリス)にトランスファー(transfer)した。メンブレンは、5%(w/v)スキムミルク、0.05%(v/v)tween−20を含むTBS(Tris−buffered saline)で4℃で一晩または室温で2時間ブロッキング(blocking)した後、AMPKα(全体形態のαサブユニット)、リン酸化されたAMPKα(Thr172でリン酸化)、PPAR−δ及びPGC−1αに対する1次抗体(Cell Signaling Technology,Inc.,Danvers,MA,USA)を投入し、室温で2時間または4℃で一晩培養した後、ワサビダイコン過酸化酵素(horseradish peroxidase)が結合された抗ウサギ2次抗体(Santa Cruz Biotechnology、Santa Cruz、CA,USA)で反応させた。検出試薬(detection reagent)としてClarity Western ECL Substrateキット(Bio−rad、Hercules、CA,USA)を利用した。映像は、Kodak GBX現像及び固定試薬(Kodak、Rochester、NY,USA)を使用して手動で収得した。X線フィルムは、Agfa(Mortsel,Belgium)から購入した。細胞由来の各タンパク質の含量は、ブラッドフォード法を使用して測定した。
実施例1−1の方法で培養したマウス骨格筋細胞(C2C12細胞)にインスリン100μM/L、ミドドリン30μM/L、ミドドリン30μM/L及びインスリン100μM/Lの混合物(1:2(w/w))をそれぞれ処理した後、2−デオキシブドウ糖(2−deoxy glucose)でブドウ糖吸収(uptake)レベルを測定した。
実施例1−2の8週齢ラットにゾレチル(zoletil)(8mg/kg)及びキシラジン(xylzine)(2mg/kg)を筋肉注射して麻酔させた後、ラットを左側に寝かせ、Mモードエコー映像を得た。あらゆる検査は、12MHzトランスデューサを備えたvivid 7(GE Medical Systems、Milwaukee,WI,USA)を使用して行った。乳頭筋レベルで左心室に対する最適2次元短縮映像を獲得した以後に、Mモードトレーシングを行う同時に心電図記録を行いながら、100mm/sの速度で記録した。Mモードトレーシングに対する少なくとも3回連続心臓サイクルからエコー心超音波検査を用いて(American Society for Echocardiography)測定方法を適用して、心臓壁の厚さ、左室駆出率(収縮機能)及び質量を測定した。
また、実施例1−2の4週齢ラットを対象にして1ヶ月にわたって心拍数を測定した。
実施例1−2のラット由来の血液から総コレステロール、HDL(high density lipoprotein)コレステロール、LDL(low density lipoprotein)コレステロール、及びトリグリセリドの濃度を測定するために、酵素発色法(Roche Diagnostics GmbH;Mannheim,Germany)を使用した。
実施例1−1の方法で培養したマウス由来の脂肪前駆細胞(3T3−L1)を脂肪細胞に分化させた後に、ミドドリン30μM/L、ミドドリン30μM/L及びGSK0660(PPAR(Peroxisome Proliferator−Activated Receptor)β/δ inverse agonist)50μM/Lの混合物(1:2(w/w))をそれぞれ処理した後、脂肪細胞内脂肪含有程度を顕微鏡(OLYMPUS IX71)を用いて肉眼で観察した。
連続的変数は、平均±標準偏差(SD)で記録した。4個群にわたった変数の全般的差値は、Kruskal−Wallisテストを使用して分析した。2つの群の間の差値は、Mann−Whitney U−テストを使用して評価した。0.05未満のp−数値は、統計的に有意なものと見なした。あらゆる統計的分析は、SPSS(ver.20.0;SPSS Inc.,Chicago,IL,USA)を使用して行った。
3−1:インビトロで骨格筋細胞または心筋細胞にミドドリン投与時に、AMPKのリン酸化に対する効果の検定
AMPK及びAMPKリン酸化(活性化)に対するα1−AR刺激効果をインビトロで確認するために、実施例1−1で培養したマウス骨格筋細胞株(C2C12)とマウス心筋細胞株(HL1)とにα1−AR効能剤であるミドドリン30μMを処理した後、実施例2−3の方法でウェスタンブロットを行った。
骨格筋でα1−ARの存在を確認するために、基底4週齢対照群ラット(I)、ミドドリン投与ラット(II)、アテノロール投与ラット(III)及び未投与8週齢対照群ラット(IV)の骨格筋でα1−ARのタンパク質発現状態を実施例2−3の方法でウェスタンブロッティングを行って確認した結果、図2Aに示すように、グループIVでα1−ARが最も高い発現を示した。
ミトコンドリア酸化過程(TCA回路)酵素であるSDH酵素活性度を骨格筋で実施例2−2の方法で測定した結果、図3Aに示すように、ミドドリン投与グループIIで最も高く増加するということが分かった。
このような結果から、ミドドリンが、代謝作用を増進させるということが分かった。
基底4週齢ラット(I)、ミドドリン投与したラット(II)、アテノロール投与ラット(III)及び未投与8週齢対照群ラット(IV)に対して、心臓、骨格筋及び肝でATPレベルをELISA方法を用いて実施例2−1の方法で測定して比較した。その結果、図4に示すように、ミドドリンまたはアテノロール投与グループの心臓組織では、ATPレベルが、心臓のさらに高い収縮活性にもかかわらず、対照群SHRsの数値よりも高く観察された。
マウス骨格筋細胞(C2C12細胞)でインスリンのブドウ糖吸収に及ぼすミドドリン効果を確認した結果、図5に示すように、インスリン単独よりもインスリンとミドドリンとの混合物を処理する場合、ブドウ糖吸収率が著しく増加するということを確認した。
このような結果から、ミドドリンが、糖尿病治療に有効であるということが分かった。
ミドドリン投与時に、インビボ心臓筋でも、AMPK、PPAR−δ及びPGC−1αが増加するならば、骨格筋で運動効果が既に証明されたAMPK−PPAR−δ−PGC−1αの同時発現カスケードが心筋収縮機能向上に影響を与えると見なすことができるので、実施例2−5の方法でインビボで心臓機能及び体重を確認した。
その結果、下記表1に示すように、8週齢ラットのエコー心拍動データから、ミドドリン投与ラットグループII及びアテノロール投与ラットグループIIIの左心室性能が、未投与対照グループIVの当該数値よりもさらに高いと表われた。
また、4週齢のラットからなる3個のグループ(青色:対照群、赤色:ミドドリン投与群、緑色:アテノロール投与群)で1ヶ月にわたって心拍数を測定した結果、実験の末尾にアテノロールグループで最も低かった(図6)。
ミドドリンの臓器投与が、アディポネクチン(adiponectin)発現及び脂肪プロファイルに及ぼす効果を実施例2−6の方法で確認した。
α1−AR刺激が如何にAMPKを活性化させるかを確認するために、AMPKの上流分子であるアディポネクチンレベルを測定した結果、下記表2に示すように、グループIIが、グループIVに比べて、内臓脂肪重量当たり著しく高い血清アディポネクチンレベルを示した。
脂肪前駆細胞(3T3−L1)にミドドリンを処理した結果、図8Aに示すように、脂肪細胞で脂肪含有量が減少し、GSK0660(PPAR β/δ inverse agonist)50μM/Lの混合物(1:2(w/w))を追加時に、ミドドリンの効果が減少した。また、ミドドリンを処理した脂肪細胞を実施例2−3の方法でウェスタンブロッティングした結果、図8Bに示すように、脂肪合成/蓄積を抑制するPPAR−δ、p−AMPK、PGC−1αのタンパク質発現が増加した。
Claims (6)
- ミドドリンまたはその薬学的に許容可能な塩を有効成分として含む糖尿病の治療または予防のための薬学的組成物。
- 前記ミドドリンまたはその薬学的に許容可能な塩は、AMPK活性化を誘導することを特徴とする請求項1に記載の糖尿病の治療または予防のための薬学的組成物。
- 前記ミドドリンまたはその薬学的に許容可能な塩は、PPAR−δまたはPGC−1αの発現を誘導することを特徴とする請求項1に記載の糖尿病の治療または予防のための薬学的組成物。
- 前記薬学的組成物は、インスリンをさらに含むことを特徴とする請求項1に記載の糖尿病の治療または予防のための薬学的組成物。
- 前記薬学的組成物は、薬学的組成物全体重量部に対して、ミドドリンまたはその薬学的に許容可能な塩20〜40重量部と、インスリン60〜80重量部と、を含むことを特徴とする請求項4に記載の糖尿病の治療または予防のための薬学的組成物。
- ミドドリンを含む血糖降下用健康補助食品。
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EP3361250B1 (en) * | 2015-09-25 | 2021-07-21 | Cellvertics Co., Ltd. | Midodrine for inducing exercise-like effects |
CN105920024A (zh) * | 2016-04-27 | 2016-09-07 | 荆燕 | 一种含有阿卡波糖治疗糖尿病合并高血压的复方制剂及其制备方法 |
KR101749588B1 (ko) * | 2016-10-21 | 2017-06-21 | 고려대학교 산학협력단 | 미도드린 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 고지혈증의 예방 또는 치료용 약학적 조성물 |
KR101692680B1 (ko) * | 2016-10-21 | 2017-01-17 | 고려대학교 산학협력단 | 미도드린 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 당뇨병의 예방 또는 치료용 약학적 조성물 |
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2017
- 2017-10-20 EP EP17862278.3A patent/EP3530269A4/en not_active Withdrawn
- 2017-10-20 WO PCT/KR2017/011636 patent/WO2018074879A1/ko unknown
- 2017-10-20 AU AU2017346267A patent/AU2017346267A1/en not_active Abandoned
- 2017-10-20 CN CN201780064858.6A patent/CN109937036A/zh not_active Withdrawn
- 2017-10-20 JP JP2019520949A patent/JP6811316B2/ja active Active
- 2017-10-20 US US16/343,464 patent/US20190240172A1/en not_active Abandoned
-
2020
- 2020-06-03 JP JP2020096849A patent/JP2020143154A/ja active Pending
- 2020-07-29 AU AU2020210225A patent/AU2020210225A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
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EP3530269A1 (en) | 2019-08-28 |
JP2020143154A (ja) | 2020-09-10 |
CN109937036A (zh) | 2019-06-25 |
AU2017346267A1 (en) | 2019-05-16 |
WO2018074879A1 (ko) | 2018-04-26 |
JP2019535663A (ja) | 2019-12-12 |
US20190240172A1 (en) | 2019-08-08 |
AU2020210225A1 (en) | 2020-08-20 |
EP3530269A4 (en) | 2020-05-27 |
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