JP2011509917A - 糖尿病性合併症治療用薬学的組成物 - Google Patents
糖尿病性合併症治療用薬学的組成物 Download PDFInfo
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- JP2011509917A JP2011509917A JP2009546863A JP2009546863A JP2011509917A JP 2011509917 A JP2011509917 A JP 2011509917A JP 2009546863 A JP2009546863 A JP 2009546863A JP 2009546863 A JP2009546863 A JP 2009546863A JP 2011509917 A JP2011509917 A JP 2011509917A
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Abstract
Description
本発明は、βアドレナリンアンタゴニストまたはβ遮断薬を投与することによる、糖尿病から生じる糖尿病性合併症の治療の方法および組成物を提供することを目的とする。
この詳細な描写にしたがって、次の省略形および定義を適用する。本願書で用いられる場合、文脈によって明確にそうでないことが示されない限り、単数形は、複数の対象も含む。したがって、例えば、「濃度」への言及は、1以上の濃度および当業者に既知の濃度相当物への言及を含む。
本発明の一つの側面は、糖尿病性合併症を含め、任意の形態の糖尿病から生じる状態の治療における、βアドレナリン遮断薬、そのプロドラッグ、またはその薬学的に許容可能な塩の使用を意図するものである。
酵素阻害実験のために、(大腸菌に発現させ)精製したヒト組み換えアルドース還元酵素を、グリセルアルデヒドを基質として用いた、βアドレナリンアンタゴニストのアルドース還元酵素(AR)の分光光度分析法による阻害活性試験に用いた。
DL−グリセルアルデヒド、グルコース、硫酸リチウム、2−メルカプトエタノール、NADPH、ジメチルスルホキシド、TC−199培地(M−3769)、ソルビトール、ソルビトール脱水素酵素、NAD、グルタチオン還元酵素は、シグマ化学薬品会社(セントルイス、MO)から購入した。実験で用いた、チモロール、エスモロール、ソタロール、ネビボロール、カルベジロール、メトプロロールおよびラベタロールを含むβアドレナリンアンタゴニストは、地方の商業的供給業者から、精製医薬原体(APIs)として得た。実験で用いたβアンタゴニスト塩は、マレイン酸チモロール、塩酸ソタロール、塩酸ラベタロール、酒石酸メトプロロール、塩酸ネビボロール、塩酸エスモロールおよび塩酸プロプラノロールである。
未精製アルドース還元酵素(AR)は、ラット水晶体から調製した。眼球は、インド、ハイデラーバードの国立栄養研究所の国立実験動物サービスセンターから得た、9週齢のWNIN雄ラットから摘出した。動物の世話およびプロトコールは、研究所動物倫理委員会に従い、かつ、認可を得た。水晶体は、後方進入術式により切り取り、10倍量の100mmol/L リン酸カリウム緩衝液(pH6.2)中でホモゲナイズした。前記ホモジネートは、15,000×g、30分間、4℃で遠心し、結果生じる上清をAR源として用いた。
ヒト組み換えアルドース還元酵素は、細菌培養液から精製した。発現培養液中の酵素は、最終精製工程としてAfTiGeI Blue(Bio−Rad社製)によるアフィニティクロマトグラフィーを用いた以外には、以前に記述したように抽出し、精製した(J Biol Chem 1992;267:24833-40)。
AR活性は、HaymanおよびKinoshitaによって記述された方法(J Biol Chem 1965;240:877-82)に従ってアッセイした。1mLの前記アッセイ混合液は、50μmol/L リン酸カリウム緩衝液(pH6.2)、0.4mmol/L 硫酸リチウム、5μmol/L 2−メルカプトエタノール、10μmol/L DL−グリセルアルデヒド、0.1μmol/L NADPHおよび酵素調製物(ラット水晶体または組み換え酵素)である。補正のために適正なブランクを用いた。前記アッセイ混合物を、37℃でインキュベートし、37℃でNADPHを添加することによりアッセイを開始した。NADPH酸化による340nmでの吸光度変化は、Cary Bio100分光光度計で測定した。
阻害実験のために、βアドレナリンアンタゴニストであるチモロール、エスモロール、ソタロール、ネビボロール、カルベジロール、メトプロロールおよびラベタロールの高濃度ストックを、水で調製した。試験化合物として、種々の濃度のβアドレナリンアンタゴニストをアッセイ混合物に添加し、前述したようなNADPHによる反応を開始する前に5〜10分間インキュベートした。試験化合物による阻害パーセントは、阻害剤非存在下でのAR活性を100%と考えて算出した。そして、50%阻害を起こす各試験サンプルの濃度(IC50)を評価した。
アルドース還元酵素の効果的阻害を示す化合物(エスモロール、チモロール、プロプラノロール)の、赤血球(RBC)中のソルビトール形成を阻害する能力を試験した。前記細胞は、30mmol/Lグルコースとin vitroでインキュベートした。ソルビトールは、Maloneら(Diabetes;1980;29:861-864)によって報告された方法で評価した。
ウィスター系ラットを、不断給餌(Harland Teklad社(Harlan Teklad社)の照射済みネズミ餌)およびオートクレーブ済みの水を有する、標準的なオートクレーブ済みネズミ用ケージ中で維持した。前記ラットは、華氏72℃、湿度60%および12時間光周期で、静的マイクロアイソレータ中の小紙片(Harlan Teklad社製)上で飼った。前記動物は、環境に慣れさせるため、納入業者から到着後10日間施設で維持した。5日間連続で50mg/体重kgのストレプトゾシンを腹腔内注射することによって糖尿病を誘導した。ラットに傷をつけるのには、前記動物の背面の皮膚に、ゆがんだひっかき器(制御可能なひっかき器)を用いて、深さ0.57〜0.62mmで長さ2mmの切り込みを入れた。前記領域は、前記ひっかき器を用いる前に、剃毛し、通常のルゴールヨード液で消毒した。
薬剤を直接創傷上に塗布することによって、塩酸エスモロール(10%)を毎日3回投与するか、標準的な治療コントロールをおこなった。用いたポジティブコントロールは、市販されている血小板由来成長因子であった。前記治療は、治療を受けたマウスの創傷が完全に治癒するまで続けた。
大まかに言えば、図1から、溶媒で処置したラットにおいて、元々の創傷の大部分には創傷後のかさぶた(27日)がまだあったように見える。一方、治療した動物の皮膚は完全に治癒したように見える(図1B参照)。組織学的レベルでは、治療したラットの皮膚には、溶媒で処置したラットにおいて見られるよりも、はるかに濃い仮マトリックスがあったように見える。治療した皮膚にはより多くの紡錘細胞が存在した。図1Cおよび1Dにおける組織は、ヘマトキシリン−エオシンで染色した(330倍)。
新鮮な組織(約0.2g)を、1mLの冷たいホモゲナイジング緩衝液(20mmol/L HEPES−KOH,pH7.9;25%グリセロール;420mmol/L NaCI;1.5mmol/L MgCI2;0.2mmol/L EDTA;0.5mmol/L ジチオスレイトール;0.2mmol/L フッ化フェニルメチルスルホニル)に添加した。前記緩衝化した組織は、最大のスピードで5秒間ホモゲナイズし、氷水で30秒間冷やした。組織の破壊を確実に完全にするために、この工程は5回繰り返した。
2倍量の冷たい100%エタノールを、前記ホモゲナイズしたサンプルに添加した;これらはボルテックスにかけ、氷上で30分間インキュベートした。前記ホモジネートは、4℃、12,000×gで5分間遠心し、NO測定のために、前記上清を氷上の新しいチューブに移した。
高速化学発光分析器を用いて、全気層のNO(亜硝酸塩/硝酸塩)を測定した。NOガスは、オゾンと反応し、光の形でエネルギーを産生し、前記光は存在するNO量と比例関係にあります。前記発光は、NO濃度を決定するために、照度計を用いて測定した。
他のタンパク質についてと同様に、19の既知のコラーゲンの合成が、細胞中で起こる。コラーゲン分子は、Gly−X−Yという繰り返し配列で特徴付けられる。Xは、プロリンであることが多く、Yは、ヒドロキシプロリンであることが多い。ヒドロキシプロリンは、コラーゲン分解の最終産物である。この理由により、組織のヒドロキシプロリン量は、組織コラーゲン生成の間接的かつ客観的な変数である。多くの実験的研究において、ヒドロキシプロリンは、組織のコラーゲン生成を見積もるために用いられる。
溶媒で処置したラットにおいて、元々の創傷は、治癒せず、創傷後のかさぶた(27日)がまだあることが観察された。一方、治療した動物の皮膚において創傷は、完全に治癒し、創傷の閉鎖も観察された。
Claims (24)
- 哺乳類の糖尿病性合併症の治療方法であって、そのような治療が必要な患者に治療効果量のβアドレナリン遮断薬、そのプロドラッグ、またはその薬学的に許容可能な塩を投与する事を特徴とする方法。
- 前記治療効果量のβアドレナリン遮断薬、そのプロドラッグ、またはその薬学的に許容可能な塩が、薬学的に許容可能なキャリア、賦形剤、またはその希釈剤によって供給される請求項1に記載の方法。
- 前記糖尿病性合併症が、糖尿病性神経障害、糖尿病性ネフロパシー、糖尿病性心筋症、糖尿病性網膜症、糖尿病性白内障、糖尿病性膀胱機能障害、糖尿病性角膜症、糖尿病性皮膚障害、糖尿病性細小血管症、心筋梗塞、黄斑浮腫、神経伝導障害および糖尿病性創傷からなる群から選択される少なくとも一つである請求項1に記載の方法。
- 前記βアドレナリン遮断薬、そのプロドラッグ、またはその薬学的に許容可能な塩が、徐放剤の形式で投与される請求項1に記載の方法。
- 前記哺乳類が、霊長類、イヌ、ネコ、ウシ、羊、豚、ラクダ、ヤギ、ネズミ、またはウマである請求項1に記載の方法。
- 前記霊長類がヒトである請求項5に記載の方法。
- 前記糖尿病性合併症が、治療効果量のβアドレナリン遮断薬を投与する事によって治療され、前記βアドレナリン遮断薬が、アセブトロール、アルプレノロール、アモスラロール、アロチノロール、アテノロール、ベフノロール、ベタキソロール、ベバントロール、ビソプロロール、ボピンドロール、ブレチロール、ブクモロール、ブフェトロール、ブフラロール、ブニトロロール、ブプランドロール、ブプラノロール、ブトフィロロール、カラゾロール、カルテオロール、カルベジロール、セリプロロール、セタモロール、シナモロール、クロラノロール、ジレバトール、エントブトロール、エパノロール、エスモロール、フモロール、インデノロール、イスタロール、ラベタロール、レボベタキソロール、レボブノロール、メピンドロール、メチプラノロール、メチプロプラノロール、メトプロロール、モプロロール、ナドロール、ナドキソロール、ネビボロール、ニプラジロール、オプティプラノロール、オクスプレノロール、ペンブトロール、ペルブトロール、ピンドロール、プラクトロール、プロネタロール、プロプラノロール、プロトキロール、ソタロール、スルフィナロール、タリンドール、テルタトロール、チリソロール(tillisolol)、チモロール、トリプロロール、トラジロール、キシベノロール、および薬学的に許容可能な塩からなる群から選択される少なくとも一つまたはその溶媒和組成物である請求項1に記載の方法。
- 前記投与が、毎時間、1日に1〜6回、毎週、または毎月行われる請求項1に記載の方法。
- 前記βアドレナリン遮断薬が、口腔、静脈内、腹腔内、眼、非経口、局所、皮下、硬膜下、静脈内、筋肉内、髄腔内、腹腔内、大脳内、動脈内、病巣内、限局または肺経由で投与される請求項1に記載の方法。
- 前記βアドレナリン遮断薬が、哺乳類に口腔経由で約1mg〜1000mg投与される請求項1に記載の方法。
- 前記βアドレナリン遮断薬が、哺乳類に眼経由で約0.001%〜10.0%の濃度で投与される請求項2に記載の方法。
- 前記βアドレナリン遮断薬が、哺乳類に局所経由で約0.001%〜50.0%の濃度で投与される請求項2に記載の方法。
- 糖尿病性創傷の治癒を必要とする患者の糖尿病性創傷を治療する薬学的局所用組成物であって、治療効果量のβアドレナリン遮断薬、そのプロドラッグ、またはその薬学的に許容可能な塩、および薬学的に許容可能な局所用キャリア、賦形剤、またはその希釈剤を含み、前記組成物はクリーム、軟膏、局所用スワブ、エマルション、スプレー、またはローションの形状である組成物。
- 糖尿病性創傷の治癒を必要とする患者の糖尿病性創傷を治療する薬学的局所用組成物であって、治療効果量のβアドレナリン遮断薬エスモロール、そのプロドラッグ、またはその薬学的に許容可能な塩、および薬学的に許容可能な局所用キャリア、賦形剤、またはその希釈剤を含み、前記組成物はクリーム、ゲル、局所用溶液、パッチ、軟膏、局所用スワブ、エマルション、スプレー、またはローションの形状である組成物。
- 糖尿病性創傷等の糖尿病性合併症の治療で使用される前記エスモロールが、酸化窒素生成の誘導、前記糖尿病性創傷におけるコラーゲン濃度の上昇、前記糖尿病性創傷における新血管形成の強化による酸素供給の増加、糖尿病患者のアルドース還元酵素活性増加の阻害、糖尿病性創傷における神経成長因子、上皮成長因子、血管内皮成長因子、血小板由来成長因子等の成長因子の増進、およびこれらの組み合わせからなる機構を有する請求項14に記載の方法。
- 前記βアドレナリン遮断薬が、クリーム、軟膏、局所用スワブ、エマルション、スプレー、またはローションの形状で局所的に適用される請求項13に記載の方法。
- 前記エスモロールが、クリーム、ゲル、局所用溶液、パッチ、軟膏、局所用スワブ、エマルション、スプレー、またはローションの形状で局所的に適用される請求項14に記載の方法。
- 前記哺乳類が、霊長類、イヌ、ネコ、ウシ、羊、豚、ラクダ、ヤギ、ネズミ、またはウマである請求項13に記載の方法。
- 前記霊長類がヒトである請求項18に記載の方法。
- アルドース還元酵素による哺乳類の糖尿病性合併症の治療方法であって、そのような治療が必要な患者にアルドース還元酵素活性を有する治療効果量のβアドレナリン遮断薬、そのプロドラッグ、またはその薬学的に許容可能な塩を投与する事を特徴とする方法。
- 前記βアドレナリン遮断薬が、エスモール、チモロール、またはプロプラノロール(propanolol)である請求項20に記載の方法。
- 前記治療効果量のβアドレナリン遮断薬、そのプロドラッグ、またはその薬学的に許容可能な塩が、薬学的に許容可能なキャリア、賦形剤、またはその希釈剤によって供給される請求項20に記載の方法。
- 前記アルドース還元酵素による糖尿病性合併症が、糖尿病性神経障害、糖尿病性ネフロパシー、糖尿病性心筋症、糖尿病性網膜症、糖尿病性白内障、糖尿病性膀胱機能障害、糖尿病性角膜症、糖尿病性皮膚障害、糖尿病性細小血管症、心筋梗塞、黄斑浮腫、神経伝導障害および糖尿病性創傷からなる群から選択される少なくとも一つである請求項20に記載の方法。
- 前記βアドレナリン遮断薬が、口腔、静脈、腹腔、眼、非経口、局所、皮下、硬膜下、静脈、筋肉内、髄腔内、腹腔内、大脳内、動脈内、病巣内、限局または肺経由で投与される請求項20に記載の方法。
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CN114053419B (zh) * | 2021-12-09 | 2023-02-24 | 山东第一医科大学附属青岛眼科医院(山东省眼科研究所、青岛眼科医院) | 去甲肾上腺素或β-肾上腺素能受体抑制剂在制备治疗糖尿病神经修复的药物中的应用 |
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WO2020026471A1 (ja) * | 2018-07-31 | 2020-02-06 | 株式会社親広産業 | グルコース消費促進剤および解糖系促進剤 |
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CA2680843C (en) | 2016-05-31 |
HK1204932A1 (en) | 2015-12-11 |
US20110021526A1 (en) | 2011-01-27 |
ES2400004T3 (es) | 2013-04-04 |
EP2114386B9 (en) | 2013-09-18 |
CA2680843A1 (en) | 2008-08-07 |
CN101616662B (zh) | 2015-07-29 |
DK2114386T3 (da) | 2013-03-18 |
HK1137149A1 (en) | 2010-07-23 |
EP2444077A1 (en) | 2012-04-25 |
CN104189906A (zh) | 2014-12-10 |
CY1113784T1 (el) | 2016-07-27 |
CN101616662A (zh) | 2009-12-30 |
EP2114386A1 (en) | 2009-11-11 |
US8686051B2 (en) | 2014-04-01 |
WO2008093356A1 (en) | 2008-08-07 |
ZA200905970B (en) | 2012-08-29 |
EP2114386B1 (en) | 2012-12-26 |
JP5240586B2 (ja) | 2013-07-17 |
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