JP2020510616A - 心不全および心臓虚血再灌流障害の治療 - Google Patents
心不全および心臓虚血再灌流障害の治療 Download PDFInfo
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Abstract
Description
(a)心不全の治療もしくは予防、または
(b)心臓虚血再灌流障害の治療
における使用のための、DPP−4阻害剤、または該阻害剤を含有する医薬組成物を提供し、該被験者は、体外心臓衝撃波療法を受けており、該阻害剤または組成物は、該衝撃波療法を行う前、行うのと同時、および/または行った後に投与される。したがって、本発明は、心不全を患う被験者、または心不全の恐れがある被験者の予後を改善するのに用いられる、DPP−4阻害剤、または該阻害剤を含有する医薬組成物を提供し、該被験者は、体外心臓衝撃波療法を受けており、該阻害剤または組成物は、該衝撃波療法を行う前、行うのと同時、および/または行った後に投与される。
(a)心不全の治療もしくは予防、または
(b)心臓虚血再灌流障害の治療
のための医薬品の製造における、DPP−4阻害剤、または該阻害剤を含有する医薬組成物の使用を提供し、該被験者は、体外心臓衝撃波療法を受けており、該医薬品は、該衝撃波療法を行う前、行うのと同時、および/または行った後に投与される。したがって、本発明は、心不全を患う被験者、または心不全の恐れがある被験者の予後を改善するための医薬品の製造における、DPP−4阻害剤、または該阻害剤を含有する医薬組成物の使用を提供し、該被験者は、体外心臓衝撃波療法を受けており、該阻害剤または組成物は、該衝撃波療法を行う前、行うのと同時、および/または行った後に投与される。
(i)DPP−4阻害剤、または該阻害剤および少なくとも1つの薬学的に許容される担体、希釈剤、もしくは賦形剤を含む医薬組成物と、
(ii)副甲状腺ホルモンまたはその断片などの、幹細胞を動員する薬理的作用薬、または該薬理的作用薬および少なくとも1つの薬学的に許容される担体、希釈剤、もしくは賦形剤を含む医薬組成物と、場合によっては、
(iii)心不全の治療用の薬剤もしくはグルコースなどの追加的な薬剤、または該追加的な薬剤および少なくとも1つの薬学的に許容される担体、希釈剤、もしくは賦形剤を含む医薬組成物と、
を含むキットまたは製品を提供するものとみなされてもよい。
(a)心不全の治療もしくは予防、または
(b)心臓虚血再灌流障害の治療
に、同時に、順次的に、または個別に用いられる複合製剤として提供され、該被験者は、体外心臓衝撃波療法を受けており、該(i)および(ii)、ならびに場合によっては(iii)は、該衝撃波療法を行う前、行うのと同時、および/または行った後に投与される。
実施例1:低酸素状態によって誘導されたラット心筋細胞のアポトーシスにおよぼす衝撃波による処理の効果
初代ラット心筋細胞を、ランゲンドルフ法によって単離した。この方法では、摘出した心臓を、逆行的に、大動脈を通して、酸素飽和低カルシウム溶液およびコラゲナーゼ溶液で潅流した。その後、心臓をさいころ状に切り、コラゲナーゼ溶液中で攪拌して細胞を遊離させた。細胞を洗浄し、その後、低速遠心分離およびラミニンコート培養プレート(ペトリディッシュ)への付着によって、心筋細胞のポジティブ選択を行った。
摘出したヒト心臓の心室組織を小片に切り分け、24ウェルプレート内のM199培地中で個別に培養した。1.5mLエッペンドルフチューブ内のM199培地に組織片を一時的に入れることによって、種々の衝撃波条件への曝露を行った。超音波ゲルを用いて、実施例1に記載の衝撃波付与装置をチューブに直接連結した。その後、インキュベータ(37℃、5% CO2)内の培地に組織片をそれぞれ戻し、4時間後に、RNA−レイター(Later)中、−80℃で保存した。各バッチにおいて、電動ホモジナイザーを用いて、トリゾール中で試料を完全に均質化した。クロロホルムおよび市販のスピンカラムを用いて、RNAを精製した。ナノドロップ分光光度計を用いて、RNAの質を検査し、逆転写反応を行った。アプライド・バイオシステムズ(商標)7900HTファスト・リアルタイムPCRシステムにおいて、タックマン遺伝子発現マスターミックスのタックマン・プローブを用いて、SDF1(間質細胞由来因子1)、VEGFA(血管内皮増殖因子A)、MCP1(単球走化性タンパク質1)、ANGP1(アンジオポエチン)、TAC1(タヒキニン前駆体1)、およびNOS3(一酸化窒素合成酵素3)の遺伝子発現を、GAPDHで標準化して評価した。ΔΔCT法によって、倍率変化を計算した。結果を図2〜4に示す。これらの結果は、測定したすべての遺伝子で、未処理のコントロールと、4時間後のものとの間に、統計的有意差があることを示している。
コラゲナーゼを用いて、ヒト心臓の心室組織を解離させ、10%FCSを添加したDMEM中で、単一細胞の懸濁液を洗浄し、播種し、培養した。ヒトの臍帯からHUVECを採取し、EGM2中で培養した。継代数が3〜5の細胞を実験に用いた。
実施例3で説明した方法にしたがってヒト心臓線維芽細胞を取得し、これを、実施例1で説明したように、衝撃波による処理に供した。衝撃波による処理を行った後、実施例2で説明した方法にしたがって、様々な時点においてVEGFAおよびMCP1の遺伝子発現を測定した。結果を図6に示す。これらの結果は、VEGFAおよびMCP1の遺伝子発現が、SDF1とは対照的に、3時間の時点までに急速に上昇し、24時間の時点までにベースラインレベルまで戻るということを示している。このデータは、線維芽細胞におけるSDF1発現は、内皮細胞におけるSDF1発現よりも24時間遅れており、血管内組織から心臓組織へと、時間的および空間的な勾配を生じるということを示している。
ラット心筋細胞を標準的な条件で培養し、衝撃波による処理(1バールで1000パルス)、外因性SDFによる処理、またはPI3キナーゼ阻害剤(LY294002)による処理に供した。様々な時点において、ウェスタンブロットを用いてAKTリン酸化を測定し、コントロールとしてロードした汎AKTおよびCOX IVを用いて標準化した。
実施例1の方法にしたがって、ラット心筋細胞を培養し、衝撃波による処理(1バールまたは2バールで1000パルス)に供した。実施例2で説明したように、処理の4時間後に、SDF1およびVEGFAの遺伝子発現を測定した。結果を図8に示す。これらの結果は、SDF1およびVEGFAの遺伝子発現で、未処理のコントロールと衝撃波条件との間に統計的有意差はないということを示している。このことは、心筋細胞に対する衝撃波の抗アポトーシス効果は、SDF1およびVEGFAなどの抗アポトーシス因子とは無関係であることを示している。
オスのルイスラット(250〜275g)を4日間、以下の処理に供した:(1)処理しない、(2)4日のうちの2日目に体外心臓衝撃波処理を行い、毎日水を強制経口投与する、(3)4日のうちの2日目に体外心臓衝撃波処理を行い、毎日DPP4iを強制経口投与する、(4)毎日DPP4iを強制経口投与する。
Claims (50)
- 被験者の
(a)心不全の治療もしくは予防、または
(b)心臓虚血再灌流障害の治療
における使用のための、ジペプチジルペプチダーゼ−4(DPP−4)阻害剤、または前記阻害剤を含有する医薬組成物であって、前記被験者は、体外心臓衝撃波療法を受けており、前記阻害剤または組成物は、前記衝撃波療法を行う前、行うのと同時、および/または行った後に投与される、DPP−4阻害剤、または前記阻害剤を含有する医薬組成物。 - 前記阻害剤または組成物は、個別的、同時的、または順次的な使用または投与のために、幹細胞を動員するのに適した薬理的作用薬との複合製剤として提供される、請求項1に記載の使用のためのDPP−4阻害剤または組成物。
- 前記幹細胞を動員するのに適した薬理的作用薬は、副甲状腺ホルモンまたはその断片である、請求項2に記載の使用のためのDPP−4阻害剤または組成物。
- 前記副甲状腺ホルモンの断片は、テリパラチドを含む、請求項3に記載の使用のためのDPP−4阻害剤または組成物。
- 前記阻害剤または組成物は、前記衝撃波療法を行う前に投与され、投与は、前記衝撃波療法が終わるまで継続される、請求項1〜4のいずれか1項に記載の使用のためのDPP−4阻害剤または組成物。
- 前記幹細胞を動員するのに適した薬理的作用薬は、前記衝撃波療法を行う少なくとも8時間前に投与される、請求項2〜5のいずれか1項に記載の使用のためのDPP−4阻害剤または組成物。
- 前記阻害剤は、個別的、同時的、または順次的な使用または投与のために、幹細胞との複合製剤として提供される、請求項1に記載の使用のためのDPP−4阻害剤または組成物。
- 前記幹細胞は、骨髄由来の単核細胞に由来するものである、または骨髄由来の単核細胞を含むものである、請求項7に記載の使用のためのDPP−4阻害剤または組成物。
- 前記幹細胞は、前記衝撃波療法を行う少なくとも8時間前に投与される、請求項6または7に記載の使用のためのDPP−4阻害剤または組成物。
- 前記DPP−4阻害剤は、シタグリプチン、リナグリプチン、ビルダグリプチン、ゲミグリプチン、アナグリプチン、テネリグリプチン、トレラグリプチン、デュトグリプチン、オマリグリプチン、ルペオール、またはこれらの組み合わせである、請求項1〜9のいずれか1項に記載の使用のためのDPP−4阻害剤または組成物。
- 前記心不全は、慢性心不全または梗塞後心不全である、請求項1〜10のいずれか1項に記載の使用のためのDPP−4阻害剤または組成物。
- 前記衝撃波療法は、約0.05〜0.25mJ/mm2のエネルギーを有する衝撃波のパルスを加えることを含む、請求項1〜10のいずれか1項に記載の使用のためのDPP−4阻害剤または組成物。
- 前記衝撃波療法は、衝撃波を少なくとも約500パルス、好ましくは衝撃波を少なくとも約1000パルス加えることを含む、請求項1〜12のいずれか1項に記載の使用のためのDPP−4阻害剤または組成物。
- 前記衝撃波療法は、1回分として、衝撃波を約500〜2000パルス加えることを含む、請求項1〜13のいずれか1項に記載の使用のためのDPP−4阻害剤または組成物。
- 前記衝撃波療法は、心臓周期の等容性収縮期中および/または等容性弛緩期中に、衝撃波のパルスを加えることを含む、請求項1〜14のいずれか1項に記載の使用のためのDPP−4阻害剤または組成物。
- 前記衝撃波のパルスの焦点は、心臓の特定の領域を標的としている、請求項1〜15のいずれか1項に記載の使用のためのDPP−4阻害剤または組成物。
- 前記標的とされる心臓の領域は、心エコー検査(エコー)による可視化および/または心電図(ECG)によるパターン認識によって決定される、請求項16に記載の使用のためのDPP−4阻害剤または組成物。
- 前記標的とされる心臓の領域は、磁気共鳴映像法によって決定される、請求項16に記載の使用のためのDPP−4阻害剤または組成物。
- 標的とされる心臓の特定の領域は、瘢痕組織を含む、請求項16〜18のいずれか1項に記載の使用のためのDPP−4阻害剤または組成物。
- 前記1回分の衝撃波のパルスは、2回以上に分けて加えられる、請求項1〜19のいずれか1項に記載の使用のためのDPP−4阻害剤または組成物。
- 心不全を治療または予防する、または心臓虚血再灌流障害を治療する、方法であって、前記方法は、必要とする被験者に対して体外心臓衝撃波療法を行うことと、DPP−4阻害剤または前記阻害剤を含む医薬組成物を投与することとを含み、前記阻害剤または組成物は、前記衝撃波療法を行う前、行うのと同時、および/または行った後に投与される、方法。
- 前記被験者に、幹細胞を動員するのに適した薬理的作用薬を投与することをさらに含み、前記作用薬は、前記阻害剤または組成物とは別途、または前記阻害剤または組成物と同時に、または前記阻害剤または組成物と順次、投与される、請求項21に記載の方法。
- 前記幹細胞を動員するのに適した薬理的作用薬は、副甲状腺ホルモンまたはその断片である、請求項22に記載の方法。
- 前記副甲状腺ホルモンの断片は、テリパラチドを含む、請求項23に記載の方法。
- 前記阻害剤または組成物は、前記衝撃波療法を行う前に投与され、かつ前記衝撃波療法が終わるまで継続的に投与される、請求項21〜24のいずれか1項に記載の方法。
- 前記幹細胞を動員するのに適した薬理的作用薬は、前記衝撃波療法を行う少なくとも8時間前に投与される、請求項21〜25のいずれか1項に記載の方法。
- 前記被験者に幹細胞を投与することをさらに含み、前記幹細胞は、前記阻害剤または組成物とは別途、または前記阻害剤または組成物と同時に、または前記阻害剤または組成物と順次、投与される、請求項21に記載の方法。
- 前記幹細胞は、前記衝撃波療法を行う少なくとも8時間前に投与される、請求項27に記載の方法。
- 前記前駆細胞は、骨髄由来の単核細胞に由来するものである、または骨髄由来の単核細胞を含むものである、請求項27または28に記載の方法。
- 前記DPP−4阻害剤は、シタグリプチン、リナグリプチン、ビルダグリプチン、ゲミグリプチン、アナグリプチン、テネリグリプチン、トレラグリプチン、デュトグリプチン、オマリグリプチン、ルペオール、またはこれらの組み合わせである、請求項21〜29のいずれか1項に記載の方法。
- 前記心不全は、慢性心不全または梗塞後心不全である、請求項21〜30のいずれか1項に記載の方法。
- 前記衝撃波療法は、約0.05〜0.25mJ/mm2のエネルギーを有する衝撃波のパルスを加えることを含む、請求項21〜31のいずれか1項に記載の方法。
- 前記衝撃波療法は、衝撃波を少なくとも約500パルス、好ましくは衝撃波を少なくとも約1000パルス加えることを含む、請求項21〜32のいずれか1項に記載の方法。
- 前記衝撃波療法は、1回分として、衝撃波を約500〜2000パルス加えることを含む、請求項21〜33のいずれか1項に記載の方法。
- 前記衝撃波療法は、心臓周期の等容性収縮期中および/または等容性弛緩期中に、衝撃波のパルスを加えることを含む、請求項21〜34のいずれか1項に記載の方法。
- 前記衝撃波の焦点の標的を、心臓の特定の領域とすることを含む、請求項21〜35のいずれか1項に記載の方法。
- 前記標的とされる心臓の領域を、心エコー検査(エコー)による可視化および/または心電図(ECG)によるパターン認識によって決定することをさらに含む、請求項36に記載の方法。
- 前記標的とされる心臓の領域を、磁気共鳴映像法によって決定することをさらに含む、請求項36に記載の方法。
- 標的とされる心臓の特定の領域は、瘢痕組織を含む、請求項36〜38のいずれか1項に記載の方法。
- 前記1回分の衝撃波のパルスを、2回以上に分けて加えることを含む、請求項21〜39のいずれか1項に記載の方法。
- 必要とする被験者に対して体外心臓衝撃波療法を行うことを含む、心臓虚血再灌流障害を治療する方法。
- 前記衝撃波療法は、約0.05〜0.25mJ/mm2のエネルギーを有する衝撃波のパルスを加えることを含む、請求項41に記載の方法。
- 前記衝撃波療法は、衝撃波を少なくとも約500パルス、好ましくは衝撃波を少なくとも約1000パルス加えることを含む、請求項41または42に記載の方法。
- 心臓周期の等容性収縮期中または等容性弛緩期中に、衝撃波のパルスを加えることを含む、請求項41〜43のいずれか1項に記載の方法。
- 前記衝撃波の焦点の標的を、心臓の特定の領域とすることを含む、請求項41〜44のいずれか1項に記載の方法。
- 前記標的とされる心臓の領域を、心エコー検査(エコー)による可視化および/または心電図(ECG)によるパターン認識によって決定することをさらに含む、請求項45に記載の方法。
- 前記1回分の衝撃波のパルスを、2回以上に分けて加えることを含む、請求項41〜46のいずれか1項に記載の方法。
- キットまたは製品であって、
(i)DPP−4阻害剤または前記阻害剤を含む組成物と、
(ii)副甲状腺ホルモンまたはその断片などの、幹細胞を動員する薬理的作用薬、または前記薬理的作用薬および少なくとも1つの薬学的に許容される担体、希釈剤、もしくは賦形剤を含む医薬組成物と、場合によっては
(iii)心不全の治療用の薬剤もしくはグルコースなどの追加的な薬剤、または前記追加的な薬剤および少なくとも1つの薬学的に許容される担体、希釈剤、もしくは賦形剤を含む医薬組成物と
を含むキットまたは製品。 - (i)および(ii)、ならびに場合によっては(iii)は、被験者の
(a)心不全の治療もしくは予防、または
(b)心臓虚血再灌流障害の治療
に、同時に、順次的に、または個別に用いられる複合製剤として提供され、前記被験者は、体外心臓衝撃波療法を受けており、前記阻害剤および/またはホルモンは、前記衝撃波療法を行う前、行うのと同時、および/または行った後に投与される、請求項48に記載のキットまたは製品。 - 前記DPP−4阻害剤、幹細胞を動員する薬理的作用薬、および/または衝撃波療法は、先行する請求項のいずれかにおいて定義されたものである、請求項49に記載のキットまたは製品。
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