JP2007529562A - 心不全に罹患した哺乳類の心サイズ低下のためのpdeiiiインヒビターの使用 - Google Patents
心不全に罹患した哺乳類の心サイズ低下のためのpdeiiiインヒビターの使用 Download PDFInfo
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- JP2007529562A JP2007529562A JP2007504329A JP2007504329A JP2007529562A JP 2007529562 A JP2007529562 A JP 2007529562A JP 2007504329 A JP2007504329 A JP 2007504329A JP 2007504329 A JP2007504329 A JP 2007504329A JP 2007529562 A JP2007529562 A JP 2007529562A
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- pde iii
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Abstract
【選択図】 なし
Description
1. 技術分野
本発明は、心不全(heart failure)に罹患した患者の心サイズを低下するための医薬品を調製するための、III型ホスホジエステラーゼ(PDE III)インヒビター又は「Ca2+-増感剤(Ca2+-sensitizing agent)」又はそれらの医薬として許容できる誘導体の使用に関する。
静脈内投与の陽性変力性薬は、急性心不全の管理において極めて重大な役割を果たしており、かつ拡張型心筋症(DCM)のイヌにおいて短期間の改善を生じることが多い。DCMイヌの多くは、非常に慎重を要する予後(guarded prognosis)を有し(Monnetら、1995)、ドーベルマンは特に概してわずかに短い生存期間を経験する(Calvertら、1982;Calvert ら、1997)。DCMイヌの生存への治療の影響を試験する研究はほとんどないが、LIVE試験におけるDCMイヌのサブ解析は、エナラプリルを受け取ったそのようなイヌにおける不全を治療する時間が、プラセボと比較し改善することを示した(各々、142.8、対、56.5日)(Ettingerら、1998)。総合的には、経口投与の陽性変力性薬について、多くの臨床試験が短期の血流力学的恩恵にもかかわらず、生存に対する有害作用を明らかにしてから以降、近年ヒト患者の慢性心不全の治療においてこれは好ましくなくなっている(Packerら、1991;Cowley and Skene, 1994)。最近、カルシウム増感剤は、ドブタミン、アムリノン及びミルリノンなどのより従来の陽性変力作用に関連した何らかの有害作用(カルシウム過負荷を含む)を生じることなく、陽性変力作用を生じることが示唆されている。
本発明の基礎となる問題点は、医薬品を提供することであり、これは冠動脈疾患の患者の死亡リスクを低下するための、心臓のサイズのリモデリングを可能にする。特に本発明の基礎となる問題点は、医薬品を提供することであり、これは心不全に罹患した患者の死亡リスクを低下するために、心臓のサイズを低下することを可能にする。
驚くべきことに、III型ホスホジエステラーゼ(PDE III)インヒビター及び/又はCa2+-増感剤又はそれらの医薬として許容できる誘導体は、心不全に罹患した患者の心サイズ低下のための医薬品の調製に使用することができることがわかっている。
更に本発明は、心不全に罹患した患者の心サイズ低下の方法に関し、この方法は、該患者への有効量のPDE IIIインヒビター又はそれらの医薬として許容できる誘導体の投与を含む。
本発明は、心不全に罹患した患者の心サイズの低下のための医薬品を調製するための、III型ホスホジエステラーゼ(PDE III)インヒビター、好ましくはPDE IIIインヒビター、Ca2+-増感剤、又は追加的にカルシウム増感作用を示すPDE IIIインヒビター(Ca2+-増感剤)、又はそれらの医薬として許容できる誘導体の使用に関する。
PDE IIIインヒビターの作用は、概して、陽性変力及び血管拡張であり、これは心不全が快方へ向かう患者の後負荷を減少する。
好ましいPDE IIIインヒビター又はCa2+-増感剤は、シロスタゾール、ピモベンダン、ミルリノン、レボシメンダン、アムリノン、エノキシモン及びピロキシモンTZC-5665、又はそれらの医薬として許容できる塩、誘導体、代謝産物もしくはプロドラッグである。最も好ましいのは、ピモベンダン及びレボシメンダン、又はそれらの医薬として許容できる塩、誘導体、代謝産物又はプロドラッグである。更により好ましいのは、ピモベンダン及びレボシメンダンである。なおより好ましいのは、ピモベンダン、その医薬として許容できる塩、誘導体、代謝産物又はプロドラッグである。
霊長類に加えて、様々な他の哺乳類を、本発明の方法に従い治療することができる。例えば、ウシ、ヒツジ、ヤギ、ウマ、イヌ、ネコ、モルモット、ラット、又は他のウシ科、ヒツジ科、ウマ科、イヌ科、ネコ科、齧歯類もしくはマウス種を含むが、これらに限定されるものではない哺乳類を治療することができる。しかし本方法は、トリ種のような、他の種において実践することもできる。
好ましいのは、ヒト患者、イヌ、ネコ及びウマである。ヒト患者は、心不全に罹患した女性又は男性である。概してそのようなヒトは、年齢が6〜80歳、好ましくは30〜65歳の範囲の、小児、青年、成人又は高齢者である。
圧倒的にこれらの患者は心不全に罹患し、これは慢性うっ血性心不全、心筋梗塞に起因した心不全、又は心停止に起因した心筋虚血である。
本願明細書において使用される用語「有効量」は、該PDE IIIインヒビター又はCa2+-増感剤が単回投与剤形で投与される場合に、心サイズの低下を実現するのに十分な量を意味する。
・カルシウムチャネルブロッカー、インヒビターは、ジルチアゼム、ベラパミル及びフェロジピン、もしくはそれらの医薬として許容できる誘導体からなる群より選択され;及び/又は
・ACE阻害薬は、オマパトリラット、MDL100240、アラセプリル、ベナゼプリル、カプトプリル、シラザプリル、デラプリル、エナラプリル、エナラプリラット、フォシノプリル、フォシノプリラット、イミダプリル、リシノプリル、ペリンドプリル、キナプリル、ラミプリル、ラミプリラット、酢酸サララシン、テモカプリル、トランドラプリル、トランドラプリラット、セラナプリル、モエキシプリル、キナプリラット及びスピラプリル、もしくはそれらの医薬として許容できる誘導体からなる群より選択され;及び/又は
・β遮断薬は、ビソプロロール、カルベジロール、メトプロロール、プロプラノロール及びチモロール、もしくはそれらの医薬として許容できる誘導体からなる群より選択され;並びに/又は
・アンギオテンシンIIアンタゴニストは、酢酸サララシン、カンデサルタンシレキセチル、バルサルタン、カンデサルタン、ロサルタンカリウム、エプロサルタン、イルベサルタン、タソサルタン、ポミサルタン及びテルミサルタンもしくはそれらの医薬として許容できる誘導体からなる群より選択され;並びに/又は
・アルドステロンアンタゴニストは、スピロノラクトン、エプレレノン、カンレノン、カンレノンカリウム、もしくはそれらの医薬として許容できる誘導体からなる群より選択され;及び/又は
・抗不整脈薬は、アミオダロン、ベトリリウム(betrylium)、ジソピラミド、ドフェチリド、フレカイニド、イブチリド、メキシレチン、トカイニド、プロカインアミド、プロパフェノン、キニジン、ソタロール、もしくはそれらの医薬として許容できる誘導体からなる群より選択され;及び/又は
・利尿薬は、フロセミド、トラセミド、ブメタニド、エタクリン酸、アゾセミド、ムゾリミン、ピレタニド、トリパミド、ベンドロフルメタジド、クロロチアジド、ヒドロクロロチアジド、ヒドロフルメチアジド、メチルクロロチアジド(methchlothiazide)、ポリチアジド、トリクロロメチアジド、クロルチアリドン、インダパミド、メトラゾン、キネタゾン、エトゾリン、トリアムテレン、アミロリド、もしくはそれらの医薬として許容できる誘導体からなる群より選択され;及び/又は
・ジギタリス配糖体は、ジゴキシン、ジギトキシン、g-ストロファンチン、β-メチルジゴキシン、β-アセチルジゴキシン、もしくはそれらの医薬として許容できる誘導体からなる群より選択される。
本発明の化合物は、錠剤、カプセル剤(各々持続放出又は時限放出製剤を含む)、丸剤、散剤、顆粒剤、エリキシル剤、チンキ剤、懸濁剤、シロップ剤、及び乳剤のような経口剤形で投与することができる。これらは、静脈内(ボーラス又は点滴)、腹腔内、皮下、又は筋肉内の形で投与されてもよく、これらは全て医薬分野の業者に周知の剤形を使用する。これらは、単独で投与することができるが、一般には、選択された投与経路及び標準の医薬実践を基に選択される、医薬担体と共に投与されるであろう。
最も好ましくは、ピモベンダン約0.1mg/kg〜1.5mg/kgが、1日に投与される。
PDE IIIインヒビター及び/又はCa2+-増感剤は、単回一日量で投与するか、又は合計の一日量を、1日に2、3、又は4回に分割して投与することができる。
PDE IIIインヒビター及び/又はCa2+-増感剤は典型的には、投与の意図された形、すなわち経口錠剤、カプセル剤、エリキシル剤、シロップ剤などに応じ、並びに通常の医薬実践に相反せぬよう、適宜選択された、適当な医薬希釈剤、賦形剤又は担体(集合的に医薬担体と称される)と混合して投与される。
PDE IIIインヒビター及び/又はCa2+-増感剤は、標的化可能な薬物担体として、可溶性ポリマーと組合せることもできる。このようなポリマーは、ポリビニルピロリドン、ピランコポリマー、ポリヒドロキシプロピルメタクリルアミド-フェノール、ポリヒドロキシエチルアスパルトアミドフェノール、又はパルミトイル残基で置換されたポリエチレンオキシドポリリシンがある。
更にPDE IIIインヒビター及び/又はCa2+-増感剤は、薬物の放出制御を実現するのに有用な、生分解性ポリマーのクラス、例えばポリ乳酸、ポリグリコール酸、ポリ乳酸とポリグリコール酸のコポリマー、ポリイプシロンカプロラクトン、ポリヒドロキシ酪酸、ポリオルトエステル、ポリアセタール、ポリジヒドロピラン、ポリシアノアクリレート、及びヒドロゲルの架橋した又は両親媒性のブロックコポリマーなどと組合せることができる。
これらの医薬組成物において、活性成分は、通常組成物の総質量を基に約0.5〜95質量%の量で存在するであろう。
一般に、水、適当な油、生理食塩水、水性デキストロース(グルコース)、及び関連糖溶液、並びにプロピレングリコール又はポリエチレングリコールなどのグリコールが、非経口液剤の担体に適している。非経口投与のための溶液は好ましくは、活性成分の水溶性塩、安定剤、及び必要ならば緩衝剤を含む。亜硫酸水素ナトリウム、亜硫酸ナトリウム、又はアスコルビン酸などの酸化防止剤は、単独又は組合せのいずれかで、適当な安定剤である。同じくクエン酸及びその塩並びにEDTAナトリウムも使用される。加えて非経口液剤は、塩化ベンザルコニウム、メチル-又はプロピル-パラベン、及びクロロブタノールなどの保存剤を含有することができる。
適当な医薬担体は、この分野の標準の参考図書である、「Remington's Pharmaceutical Sciences」、Mack Publishing Companyに記されている。
更に持続-放出される成分は、追加的に腸溶性コーティングされ、その結果この成分の放出は小腸でのみ生じる。更に別の方法は、活性成分を更に分離するために、ひとつの成分が持続性及び/又は腸溶性放出ポリマーでコーティングされ、及び他方の成分は、低粘度のヒドロキシプロピルメチルセルロース(HPMC)又は当該技術分野において公知の他の適当な物質などのポリマーでコーティングされる、組合せ製品の製剤に関連している。ポリマーコーティングは、他の成分との相互作用に対する追加の障壁を形成するために役立つ。
ピモベンダンに対する長期効能及び忍容性、並びにDCMのコッカスパニエル及びドーベルマンの長期生存に対するその作用を評価するために、二重盲検試験を実施した。
両品種において、標準の治療様式へのピモベンダンの追加は、患者のニューヨーク心臓協会(NYHA)-分類状態の有意な改善に関連している。従ってピモベンダン療法の利点は、フロセミド、エナラプリル及びジゴキシンの有益な作用に追加され、並びにこれは、多くのDCMイヌと比べ、従来の療法により好ましい臨床経過と見なされるものを有することが、コッカスパニエルにおいてさえも認められる(Monnetら、1995)。
生存期間の顕著な差異は、ピモベンダンで処置したドーベルマン・ピンシャーにおいても認められた。この品種はうっ血性徴候の顕在化後予後不良であるが、ピモベンダン-処置した動物について、生存期間の有意な延長が認められた。
一日量0.4〜0.6mg/kgのピモベンダン治療の臨床効能を、一日量約0.25〜0.5mg/kg体重のベナゼプリル塩酸塩を伴うアンギオテンシン転換酵素(ACE)阻害薬治療と比べて評価するために、二重-盲検ランダム化陽性比較多施設現地調査(field)試験を行った。両方の治療は、適宜フロセミド(最大8mg/kg/日)又は抗不整脈薬と組合せることができる。本試験は、「医薬品臨床試験の実施基準」(GCP)規定に従い、経験を積んだ獣医心臓学者により、ヨーロッパの11施設で行った。強制的な最低治療期間は、各患者について56日間であった。イヌは、初回治療前0日目、並びに治療開始後7日目及び56日目に試験した。長期生存データを得るために、治験担当医は、治療を56日目以降も継続する選択肢を有した。適切なピモベンダン対照群を維持するために、ピモベンダンをベナゼプリル群に添加することをできなくするように、任意の試験期間において、動物の治療コードは外して実行された(decode)。他の許可を受けた併用薬は全てが可能であった。生存分析に関して、脱落した動物又は療法の失敗のために治療を変更した動物も、死亡例として分類した。しかしこれらの症例は、打ち切りデータとして統計学的には評価した。
ピモベンダン群41匹及びベナゼプリル群35匹の全体で76匹のイヌが、含まれた。全てのイヌは、弁の機能不全のために、心不全の臨床的に明白な症状を示した。組入れ(inclusion)前の症状の平均期間は、ピモベンダン群4.05ヶ月及びベナゼプリル群2.77ヶ月であった。調査したパラメータのいずれにおいても、治療開始前には、これらの群間に臨床に関連のある差異はなかった。
側方X線写真において、心臓の長軸(L)は、左主気管支幹(気管分岐部門(hilus)、気管竜骨)の腹側面から、左心室心尖の最も遠位まで伸びるキャリパーにより測定した。このキャリパーは、第4胸椎の頭側端に始まる脊椎に沿って位置づけられる。心臓の長さは、その点の椎骨尾部の数として記録し、椎骨を最も近い0.1と概算した。最大垂直短軸(S)は、同じ様式で、第4胸椎から始まり測定した。
次に長軸及び短軸の椎骨の長さ(v)を加算し、脊椎心サイズ和(VHS)を得、これはイヌのサイズに比例した心サイズを表している単独の数値を提供した。健常なイヌのVHSの正常な範囲は、8.5v〜10.5v(平均9.7v)であった。
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Claims (14)
- 心不全に罹患した患者の心サイズ低下のための医薬品調製のための、III型ホスホジエステラーゼ(PDE III)インヒビター又はCa-2+-増感剤又はそれらの医薬として許容できる誘導体の使用。
- PDE IIIインヒビターが、追加のカルシウム増感作用を示す、請求項1記載の使用。
- PDE IIIインヒビター又はCa2+-増感剤が、ピモベンダン、ミルリノン、レボシメンダン、アムリノン、エノキシモン、及びピロキシモン又はそれらの医薬として許容できる誘導体からなる群より選択される、請求項1又は2記載の使用。
- PDE IIIインヒビター又はCa2+-増感剤が、経口又は非経口の形で利用される、請求項1〜3のいずれか1項記載の使用。
- PDE IIIインヒビター又はCa2+-増感剤が、10μg/kg〜10mg/kgの一日量で投与される、請求項1〜4のいずれか1項記載の使用。
- PDE IIIインヒビター又はCa2+-増感剤が、カルシウムチャネルブロッカー、ACE阻害薬、利尿薬、アスピリン、β遮断薬及びアンギオテンシンIIアンタゴニストからなる群より選択される医薬品と共に投与される、請求項1〜5のいずれか1項記載の使用。
- ACE阻害薬が、オマパトリラット、MDL100240、アラセプリル、ベナゼプリル、カプトプリル、シラザプリル、デラプリル、エナラプリル、エナラプリラット、フォシノプリル、フォシノプリラット、イミダプリル、リシノプリル、ペリンドプリル、キナプリル、ラミプリル、ラミプリラット、酢酸サララシン、テモカプリル、トランドラプリル、トランドラプリラット、セラナプリル、モエキシプリル、キナプリラット及びスピラプリル、又はそれらの医薬として許容できる誘導体からなる群より選択される、請求項1〜6いずれか1項記載の使用。
- アンギオテンシンIIアンタゴニストが、酢酸サララシン、カンデサルタンシレキセチル、バルサルタン、カンデサルタン、ロサルタンカリウム、エプロサルタン、イルベサルタン、タソサルタン及びテルミサルタン又はそれらの医薬として許容できる誘導体からなる群より選択される、請求項1〜7のいずれか1項記載の使用。
- PDE IIIインヒビター又はCa2+-増感剤が、1種又は複数のACE阻害薬、1種又は複数の利尿薬及び1種又は複数のジギタリス配糖体からなる群より選択される1種又は複数の医薬品と共に投与される、請求項1〜8のいずれか1項記載の使用。
- 前記患者の脊椎心サイズ和(VHS)の相対平均が、PDE IIIインヒビター又はCa2+-増感剤による治療の10〜100日以内に0.05〜0.25低下する、請求項1〜9のいずれか1項記載の使用。
- 心不全が、慢性うっ血性心不全、心筋梗塞に起因した心不全、又は狭心症の増悪もしくは心停止に起因した心筋虚血である、請求項1〜10のいずれか1項記載の使用。
- 前記患者が、ヒトを含む霊長類、イヌ、ネコ及びウマからなる群より選択される哺乳類である、請求項1〜11のいずれか1項記載の使用。
- 心不全に罹患した患者の心サイズを低下する方法であり、この方法が、該患者へ有効量のPDE IIIインヒビター又はCa2+-増感剤又はそれらの医薬として許容できる誘導体を投与することを含む、方法。
- その中に心不全に罹患した患者の心サイズを低下するのに有効な組成物を含んでいる包装材料を含む製品であり、並びにこの包装材料が、組成物は心不全に罹患した患者の心サイズ低下のために使用することができることを示すラベルを含み、ここで該組成物は、少なくとも1種のIII型ホスホジエステラーゼ(PDE III)インヒビター又はCa2+-増感剤又はそれらの医薬として許容できる誘導体を含有する、製品。
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EP04007179A EP1579862A1 (en) | 2004-03-25 | 2004-03-25 | Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure |
PCT/EP2005/002957 WO2005092343A1 (en) | 2004-03-25 | 2005-03-19 | Use of pde iii inhibitors for the reduction of heart size in mammals suffering from heart failure |
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JP2017061512A (ja) * | 2012-05-18 | 2017-03-30 | ルオダ ファーマ ピーティーワイ リミテッド | 液体配合剤 |
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