JP2017521483A - 糖尿病を処置するためのカフェストール - Google Patents
糖尿病を処置するためのカフェストール Download PDFInfo
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- JP2017521483A JP2017521483A JP2017514786A JP2017514786A JP2017521483A JP 2017521483 A JP2017521483 A JP 2017521483A JP 2017514786 A JP2017514786 A JP 2017514786A JP 2017514786 A JP2017514786 A JP 2017514786A JP 2017521483 A JP2017521483 A JP 2017521483A
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- Prior art keywords
- diabetes
- derivative
- glucose
- type
- insulin
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Abstract
Description
本発明は、糖尿病および/または糖尿病関連の臨床状態の処置におけるカフェストール化合物の使用に関する。
コーヒーの摂取は、2型糖尿病のリスク低下に関連づけられている:Merlotti C, Morabito A, Pontiroli AE.: Prevention of type 2 diabetes; a systematic review and meta−analysis of different intervention strategies; Diabetes, obesity and metabolism. 2014 Jan 29; Ding M, Bhupathiraju SN, Chen M, van Dam RM, Hu FB.: Caffeinated and Decaffeinated Coffee Consumption and Risk of Type 2 Diabetes: A Systematic Review and a Dose−Response Meta−analysis; Diabetes Care. 2014 Feb;37(2):569−86. doi: 10.2337/dc13−1203; Higdon JV, Frei b.: Coffee and health: a review of recent human research; Crit Rev Food Sci Nutr. 2006;46(2):101−23を参照されたい。US2009/0175973号には、糖尿病を処置するためのコーヒーチェリーおよびその単離物の使用が提案されている。
本発明の主な目的は、カフェストールがインスリン産生細胞によるインスリン分泌に影響を及ぼし、インスリン感受性も上昇させることから、カフェストール化合物の使用により糖尿病および関連障害を処置する方法を提供することである。
用語および定義
以下の説明の理解を促すために、複数の定義を以下の段落に示す。
それは、本発明の範囲内では、糖尿病、特に2型糖尿病および/または2型糖尿病関連の臨床状態を処置、予防または改善するための方法、使用、化合物、組成物および成分キットを提供することである。
本明細書に提供された方法、使用、化合物、組成物および成分キットは一般に、糖尿病、特に2型糖尿病および/または糖尿病関連、特に2型糖尿病関連の臨床状態を処置、予防または改善することが意図される。
糖尿病は、高血糖(血糖値の上昇)を特徴とする代謝障害である。糖尿病は現在、1型糖尿病、2型糖尿病、他の特殊な型の糖尿病、および妊娠糖尿病に分類される(DIABETES CARE, VOLUME 36, SUPPLEMENT 1, JANUARY 2013)。糖尿病の共通する原因は、膵臓のβ細胞が高血糖を予防するのに十分なインスリンを産生できないことである。1型は通常、膵β細胞の自己免疫性破壊を原因とする。2型の顕著な特徴は、組織レベルのインスリン抵抗性である。最初、膵β細胞が、インスリン産生増加によりインスリン抵抗性を補填しようとする。その結果、インスリン産生活性を使い尽くすため、2型糖尿病は時に、β細胞機能の損失も進行させることがある。妊娠糖尿病は、インスリン抵抗性を含む点で2型糖尿病と類似している。妊娠糖尿病では、妊娠ホルモンが、この状態を発症する遺伝的素因のある妊婦のインスリン抵抗性を誘発する。
インスリン抵抗性および2型糖尿病は、複数の重篤な臨床状態と関連する。本明細書で用いられる用語「臨床状態」は、任意の障害、疾患または病的状態を含むことを意味する。
カフェストールには、グルコース依存性インスリン分泌を増加させる働きがある。その上カフェストールは、骨格筋細胞へのグルコース取り込みを増加させる。したがってカフェストールは、グルコースに応答してインスリン分泌を増加させる、そしてインスリン感受性を増強させる、という二重の機能を有する。それゆえカフェストールおよびその誘導体は、糖尿病を処置、予防または改善するための卓越した治療薬になる。したがってカフェストールおよびその誘導体は、本発明によれば、任意の型の糖尿病、即ち1型、2型糖尿病および妊娠糖尿病を処置、予防または改善するために用いられ得る。特にカフェストールおよびその誘導体は、本発明によれば、2型および妊娠糖尿病など、インスリン抵抗性に関連する糖尿病を処置、予防または改善するために用いられ得る。しかし、最も好ましい実施形態において、本発明の方法、使用、化合物、組成物および成分キットは、2型糖尿病および/または2型糖尿病関連の臨床状態もしくは障害を処置、予防または改善することに関する。
本明細書で提供された化合物、組成物または成分キットを、当該技術分野で利用可能な任意の適切な方法により投与することができる。主な投与経路は、以下に記載される通り、非経口注射、経口、および局所である。薬物を標的部位に送達するのに、または薬物を血流に導入するのに効果的な皮下注射などの他の薬物投与方法もまた、企図される。さらに、鼻内投与および肺吸入による投与が、用いられ得る簡便で効果的な投与方法である。
投薬要件は、用いられる個々の組成物、投与経路および処置される各個体に応じて変動する。理想的には、本発明の方法により処置される個体は、該化合物、組成物または成分キットの医薬的有効量を、一般には薬物耐性が発生する前に必要となる量以下の、最大耐容用量で受ける。
本発明は、カフェストールまたはその誘導体の有効量を必要とするヒトに投与することを含む、方法および使用を提供する。
一態様において、カフェストール化合物またはその誘導体は、2型糖尿病および/または糖尿病関連、特に2型糖尿病関連の臨床状態を処置、予防または改善する際の使用に提供される。しかしこの処置は、他の薬剤と組み合わせてもよく、したがって本発明の一態様は、糖尿病、特に2型糖尿病および/または糖尿病関連、特に2型糖尿病関連の臨床状態を処置、予防または改善する際に使用するための、カフェストール化合物またはその誘導体と、糖尿病および/または糖尿病関連の臨床状態を処置、予防または改善するのに適した少なくとも1種のさらなる薬剤と、に関する。
該方法、使用、化合物、組成物および成分キットは、糖尿病、特に2型糖尿病および関連の臨床状態を、カフェストールまたはその誘導体および少なくとも1種のさらなる薬剤の有効量で処置、予防または改善することを包含する。したがって該カフェストール化合物またはその誘導体は、有益には糖尿病、特に2型糖尿病および/または関連の臨床を処置、予防または改善するのに用いられる他の活性剤と組み合わせることもできる。
ビグアニド(メトホルミンは一般に2型糖尿病の処置での第一選択薬として許容されている)
スルホニルウレア
メグリチニド(グリニド)
アカルボース
胆汁酸捕捉剤
ドパミン−2−アゴニスト
アミリン模倣体
チアゾリジンジオン(グリタゾン)
グルカゴン様ペプチド1受容体アゴニスト
ジペプチジルペプチダーゼ4阻害剤(DPP4阻害剤)
ナトリウム−グルコースコトランスポーター2(SGLT2)阻害剤
GPR40アゴニスト
グルカゴンアンタゴニスト
ブロモクリプチンメシル酸塩
インスリン。
一態様における本発明は、カフェストール化合物またはその誘導体および少なくとも1種のさらなる薬剤を含む医薬組成物を提供する。該さらなる薬剤は、好ましくは糖尿病、例えば2型糖尿病および/または糖尿病関連、例えば2型糖尿病関連の臨床状態を処置、予防または改善するのに適した薬剤である。
インスリン分泌およびグルコース取り込みに及ぼすカフェストールの影響
インスリン分泌に及ぼすカフェストールの急性効果が、INS−1E細胞を形成する。
インスリン分泌に及ぼすカフェストールの慢性効果が、INS−1E細胞を形成する。
ヒト骨格筋細胞株におけるグルコース取り込みに及ぼすカフェストールの急性効果
ヒト骨格筋細胞を、増殖培地(Promocell、ドイツ、ハイデルベルグ所在)1mLを含有する24ウェル(0.3×106細胞/ウェル)を種播した。70〜90%コンフルエンスに達したら、増殖培地を分化培地(Promocell、ドイツ、ハイデルベルグ所在)1mLと交換した。多核合胞体が顕微鏡で可視になるまで、この培地を2日ごとに2週間交換した。細胞をPBSで2回洗浄した。選択的な(alternatively)改変クレブス・リンガー緩衝液(0.1mMグルコース、1.5μCiデオキシ−d−グルコース2−[1,2−3H(M)](Perkin Elmer、デンマーク、スコウルネ2740所在)と共に0.1%BSAを含有)300μLおよび100nMインスリンを、各ウェルに添加した。5種の溶液を調製した:カフェストールまたはロシグリタゾン(対照)のどちらかを含む1つ目、10−8Mカフェストールを含む2つ目、10−10Mカフェストールを含む3つ目、10−12Mカフェストールを含む4つ目、および10−8Mロシグリタゾンを含む5つ目。培地を添加しながら、細胞を氷上に保持した。37℃、5.0%CO2で15分間インキュベートした後、0.1%BSAおよび50mMグルコースを補充された改変クレブス・リンガー緩衝液で細胞を2回洗浄し、インキュベーションおよびグルコース取り込みを停止させた。その後、室温での30分間インキュベーションの間に、0.1M NaOH 0.2mLを各ウェルに添加した。0.1mLを各ウェルから24ウェルカウンティングプレート(Wallac Oy、フィンランド、トゥルク所在)に移し替えた。Hisafe IIシンチレータ(Perkin Elmer、デンマーク、スコウルネ2740所在)0.9mLを添加した後、プレートを12時間暗所に貯蔵し、その後Trilux Micro Beta Counter(Wallac Oy、フィンランド、トゥルク所在)を用いてカウントした。「カウント/分」は、グルコース取り込みの直接的な尺度である。
糖尿病KKAYマウスにおけるカフェストールの影響
カフェストールの影響を、2型糖尿病動物モデルにおける10週間食事介入試験で調査した。5週齢雄KKAyマウスを、3つの介入群(n=12/群)、即ち1)対照(カフェストール無添加)、2)マウス1kgあたり0.382mgカフェストール/日を補充、3)マウス1kgあたり1.146mgカフェストール/日を補充、のいずれかに無作為に割り付けた。カフェストールは、毎日のフードペレットに添加された。試験開始時(0週目)に、空腹時血糖値、インスリンおよび脂質(総コレステロール、LDL、HDLおよびトリグリセリド)を測定した。空腹時血糖値、体重および摂餌量を、隔週で測定した。介入の終了時(10週目)に空腹時血糖値、インスリン、グルカゴンおよび脂質(総コレステロール、LDL−コレステロール、HDL−コレステロール)を測定した。膵臓を取り出し、コラーゲナーゼで処理し、次にインスリン分泌能への影響を、単離されたランゲルハンス島で試験した。さらに、肝臓、脂肪および筋肉組織の重要な調節遺伝子の遺伝子発現レベルを、RT−PCRを利用して測定した。
上記実施例から、カフェストールが低用量および高用量の両方のカフェストールで空腹時血漿グルコースを有意に減少させ得ることが示される。カフェストールは、糖尿病誘発性ホルモンであるグルカゴンの血漿濃度を低下させるようである(グルカゴンは、糖尿病対象で増加することが多く血糖値の増加を誘導する)。
Claims (24)
- カフェストールまたはそのエステルおよび塩をはじめとする誘導体の有効量を、必要とするヒトに投与することを含む、2型糖尿病および/または2型糖尿病関連の臨床状態を処置、予防または改善する方法。
- 前記臨床状態が、インスリン抵抗性である、請求項1に記載の方法。
- 前記必要とするヒトが、経口耐糖能異常(IGT)および/または高血糖を有するヒトである、前記請求項のいずれかに記載の方法。
- 前記必要とするヒトが、空腹時血糖値が126mg/dL(7.0mmol/l)を超え、そして/もしくは75グラムグルコースの経口投与後2時間目の静脈内血漿グルコースレベルが200mg/dL(11.1mmol/l)以上のヒトであり、そして/または妊娠24〜28週目の前記必要とするヒトが、92mg/dl(5.1mmol/l)以上の空腹時血漿グルコースを有するか、75グラムグルコースの経口投与後1時間目に180mg/dl(10.0mmol/l)以上の血漿グルコースを有するか、もしくは75グラムグルコースの経口投与後2時間目に153mg/dl以上の血漿グルコースを有する、前記請求項のいずれかに記載の方法。
- 前記カフェストールまたはその誘導体が、1日あたり1〜500mgの量で投与される、前記請求項のいずれかに記載の方法。
- 前記カフェストールまたはその誘導体が、経口投与により投与される、前記請求項のいずれかに記載の方法。
- カフェストールの前記誘導体が、エステルおよび塩を含むカーウェオールである、前記請求項のいずれかに記載の方法。
- 前記誘導体が、カフェストールおよびカーウェオールのあらゆる安全で効果的な誘導体、類似体、または前駆体、特にそれらのエステルおよび塩から選択される、前記請求項のいずれかに記載の方法。
- 2型糖尿病および/または2型糖尿病関連の臨床状態を処置、予防または改善するのに適したさらなる薬剤が、前記必要とするヒトに投与される、前記請求項のいずれかに記載の方法。
- 前記さらなる薬剤が、ビグアニド(メトホルミン)、スルホニルウレア、メグリチニド(グリニド)、アカルボース、胆汁酸捕捉剤、ドパミン−2−アゴニスト、アミリン模倣体、チアゾリジンジオン(グリタゾン)、グルカゴン様ペプチド1受容体アゴニスト、ジペプチジルペプチダーゼ4阻害剤(DPP4阻害剤)、ナトリウム−グルコースコトランスポーター2(SGLT2)阻害剤、Gタンパク質共役受容体アゴニスト(例えば、GPR40アゴニスト)、グルカゴン受容体アンタゴニスト、ブロモクリプチンメシル酸塩およびインスリンからなる群の一員から選択される、請求項9に記載の方法。
- 前記関連の臨床状態が、アテローム性硬化症、動脈硬化症、細動脈硬化症、高血圧、心臓血管障害、2型糖尿病、網膜症、神経症、腎症、細血管症、大血管症、高血糖、高コレステロール血症、高インスリン血症、高脂血症、過体重、内臓肥満、脂質異常、インスリン抵抗性、経口耐糖能異常、空腹時血糖異常、メタボリックシンドローム、多嚢胞性卵巣症候群、脂肪肝(肝脂肪症)、虚血、虚血性心疾患、血栓性卒中、出血性卒中、四肢虚血および/または跛行からなる群から選択される、前記請求項のいずれかに記載の方法。
- 前記臨床状態が、2型糖尿病および/または2型糖尿病関連の臨床状態である、前記請求項のいずれかに記載の方法。
- 2型糖尿病および/または糖尿病関連、特に2型糖尿病関連の臨床状態を処置、予防または改善する際に使用するためのカフェストール化合物またはその誘導体。
- 前記誘導体が、カフェストールおよびカーウェオールのあらゆる安全で効果的な誘導体、類似体、または前駆体、特にそれらのエステルおよび塩から選択される、請求項13に記載のカフェストール化合物またはその誘導体。
- 2型糖尿病および/または2型糖尿病関連の臨床状態を処置、予防または改善するのに適した少なくとも1種のさらなる薬剤をさらに含む、請求項13および14のいずれか1項に記載のカフェストール化合物またはその誘導体。
- 前記さらなる薬剤が、メトホルミン、スルホニルウレア、メグリチニド(グリニド)、アカルボース、胆汁酸捕捉剤、ドパミン−2−アゴニスト、アミリン模倣体、チアゾリジンジオン(グリタゾン)、グルカゴン様ペプチド1受容体アゴニスト、ジペプチジルペプチダーゼ4阻害剤(DPP4阻害剤)、ナトリウム−グルコースコトランスポーター2(SGLT2)阻害剤、GPR40アゴニスト、グルカゴンアンタゴニスト、ブロモクリプチンメシル酸塩およびインスリンからなる群の一員から選択される、請求項15に記載のカフェストール化合物またはその誘導体。
- 前記カフェストールまたはその誘導体が、医薬組成物として配合される、請求項13および16のいずれか1項に記載のカフェストール化合物またはその誘導体。
- 前記カフェストールまたはその誘導体が、食物サプリメントとして配合される、請求項13および16のいずれか1項に記載のカフェストール化合物またはその誘導体。
- カフェストールまたはその誘導体と、2型糖尿病および/または2型糖尿病関連の臨床状態を処置、予防または改善するのに適した少なくとも1種のさらなる薬剤と、を含む組成物。
- 前記カフェストールもしくはその誘導体、さらなる薬剤および/または臨床状態が、前記請求項のいずれか定義された通りである、請求項19に記載の組成物。
- カフェストールまたはその誘導体の有効量を必要とするヒトに投与することを含む、インスリン分泌を増加させ、そして/またはインスリン依存性グルコース取り込みを増加させる方法。
- 前記カフェストールもしくはその誘導体および/または必要とするヒトが、前記請求項のいずれか定義された通りである、請求項21に記載の方法。
- 糖尿病および/または糖尿病関連の臨床状態を処置、予防または改善するための同時、分離、または連続投与のための、カフェストールまたはその誘導体と、糖尿病および/または糖尿病関連の臨床状態を処置、予防または改善するのに適したさらなる薬剤と、を含有する組み合わせ調製物を含む成分キット(kit−of−parts)。
- 前記さらなる薬剤が、メトホルミン、スルホニルウレア、メグリチニド(グリニド)、アカルボース、胆汁酸捕捉剤、ドパミン−2−アゴニスト、アミリン模倣体、チアゾリジンジオン(グリタゾン)、グルカゴン様ペプチド1受容体アゴニスト、ジペプチジルペプチダーゼ4阻害剤(DPP4阻害剤)、ナトリウム−グルコースコトランスポーター2(SGLT2)阻害剤、GPR40アゴニスト、グルカゴンアンタゴニスト、ブロモクリプチンメシル酸塩およびインスリンからなる群の一員から選択される、請求項23に記載の成分キット。
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PCT/DK2015/050139 WO2015180736A1 (en) | 2014-05-30 | 2015-06-01 | Cafestol for treating diabetes |
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EP (1) | EP3148525B1 (ja) |
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CN114028377A (zh) * | 2021-11-29 | 2022-02-11 | 中国农业大学 | 咖啡醇的医药新用途 |
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CA2950463A1 (en) | 2015-12-03 |
WO2015180736A1 (en) | 2015-12-03 |
US10328048B2 (en) | 2019-06-25 |
CN106573063A (zh) | 2017-04-19 |
AU2015266434A1 (en) | 2017-01-12 |
CA2950463C (en) | 2022-08-30 |
EP3148525B1 (en) | 2023-10-11 |
EP3148525A1 (en) | 2017-04-05 |
US20170231946A1 (en) | 2017-08-17 |
KR20170012480A (ko) | 2017-02-02 |
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