JP2016190876A - 心不全の予防又は処置の方法 - Google Patents
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Images
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/07—Tetrapeptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0815—Tripeptides with the first amino acid being basic
- C07K5/0817—Tripeptides with the first amino acid being basic the first amino acid being Arg
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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- C07K5/1002—Tetrapeptides with the first amino acid being neutral
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1019—Tetrapeptides with the first amino acid being basic
Abstract
【解決手段】該方法は、芳香族カチオン性ペプチドを必要としている被検体にその有効量を投与することを含む。
【選択図】図8
Description
本願は、2009年10月5日に出願された米国仮出願第61/248,681号、及び2009年12月23日に出願された米国仮出願第61/289,483号の優先権を主張するもので、それらのすべての記載内容を援用する。
少なくとも1の正味正電荷;
最小4個のアミノ酸;
最大約20個のアミノ酸;
正味正電荷の最小の数(pm)とアミノ酸残基の総数(r)との間における、3pmがr+1以下の最大数である、との関係;及び、
芳香族基の最小の数(a)と正味正電荷の総数(pt)との間における、2aがpt+1以下の最大数である、との関係、ただし、aが1であり、ptも1である場合を除く。特定の実施態様では、哺乳動物被検体がヒトである。
(i)水素;
(ii)直鎖状又は分岐状の炭素数1〜6のアルキル;
(iii)
ここで、m=1〜3;
(iv)
(v)
R3とR4は、それぞれ独立して、以下から選ばれる
(i)水素;
(ii)直鎖状又は分岐状の炭素数1〜6のアルキル;
(iii)炭素数1〜6のアルコキシ;
(iv)アミノ;
(v)炭素数1〜4のアルキルアミノ;
(vi)炭素数1〜4のジアルキルアミノ;
(vii)ニトロ;
(viii)ヒドロキシル;
(ix)ハロゲン、ここで「ハロゲン」はクロロ、フロロ、ブロモ、及びヨードを含み;R5、R6、R7、R8、及びR9は、それぞれ独立して、以下から選択される
(i)水素;
(ii)直鎖状又は分岐状の炭素数1〜6のアルキル;
(iii)炭素数1〜6のアルコキシ;
(iv)アミノ;
(v)炭素数1〜4のアルキルアミノ;
(vi)炭素数1〜4のジアルキルアミノ;
(vii)ニトロ;
(viii)ヒドロキシル;
(ix)ハロゲン、ここで「ハロゲン」はクロロ、フロロ、ブロモ、及びヨードを含み、nは1〜5の整数である。
式中、R1とR2は、それぞれ独立して以下から選択される
(i)水素;
(ii)直鎖状又は分岐状の炭素数1〜6のアルキル;
(iii)
ここで、m=1〜3;
(iv)
(v)
R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12 は、それぞれ独立して以下から選択される
(i)水素;
(ii)直鎖状又は分岐状の炭素数1〜6のアルキル;
(iii)炭素数1〜6のアルコキシ;
(iv)アミノ;
(v)炭素数1〜4のアルキルアミノ;
(vi)炭素数1〜4のジアルキルアミノ;
(vii)ニトロ;
(viii)ヒドロキシル;
(ix)ハロゲン、ここで「ハロゲン」はクロロ、フロロ、ブロモ、及びヨードを含み、nは1〜5の整数である。
芳香族カチオン性ペプチド
Lys−D−Arg−Tyr−NH2
Phe−D−Arg−His
D−Tyr−Trp−Lys−NH2
Trp−D−Lys−Tyr−Arg−NH2
Tyr−His−D−Gly−Met
Phe−Arg−D−His−Asp
Tyr−D−Arg−Phe−Lys−Glu−NH2
Met−Tyr−D−Lys−Phe−Arg
D−His−Glu−Lys−Tyr−D−Phe−Arg
Lys−D−Gln−Tyr−Arg−D−Phe−Trp−NH2
Phe−D−Arg−Lys−Trp−Tyr−D−Arg−His
Gly−D−Phe−Lys−Tyr−His−D−Arg−Tyr−NH2
Val−D−Lys−His−Tyr−D−Phe−Ser−Tyr−Arg−NH2
Trp−Lys−Phe−D−Asp−Arg−Tyr−D−His−Lys
Lys−Trp−D−Tyr−Arg−Asn−Phe−Tyr−D−His−NH2
Thr−Gly−Tyr−Arg−D−His−Phe−Trp−D−His−Lys
Asp−D−Trp−Lys−Tyr−D−His−Phe−Arg−D−Gly−Lys−NH2
D−His−Lys−Tyr−D−Phe−Glu−D−Asp−D−His−D−Lys−Arg−Trp−NH2
Ala−D−Phe−D−Arg−Tyr−Lys−D−Trp−His−D−Tyr−Gly−Phe
Tyr−D−His−Phe−D−Arg−Asp−Lys−D−Arg−His−Trp−D−His−Phe
Phe−Phe−D−Tyr−Arg−Glu−Asp−D−Lys−Arg−D−Arg−His−Phe−NH2
Phe−Try−Lys−D−Arg−Trp−His−D−Lys−D−Lys−Glu−Arg−D−Tyr−Thr
Tyr−Asp−D−Lys−Tyr−Phe−D−Lys−D−Arg−Phe−Pro−D−Tyr−His−Lys
Glu−Arg−D−Lys−Tyr−D−Val−Phe−D−His−Trp−Arg−D−Gly−Tyr−Arg−D−Met−NH2
Arg−D−Leu−D−Tyr−Phe−Lys−Glu−D−Lys−Arg−D−Trp−Lys−D−Phe−Tyr−D−Arg−Gly
D−Glu−Asp−Lys−D−Arg−D−His−Phe−Phe−D−Val−Tyr−Arg−Tyr−D−Tyr−Arg−His−Phe−NH2
Asp−Arg−D−Phe−Cys−Phe−D−Arg−D−Lys−Tyr−Arg−D−Tyr−Trp−D−His−Tyr−D−Phe−Lys−Phe
His−Tyr−D−Arg−Trp−Lys−Phe−D−Asp−Ala−Arg−Cys−D−Tyr−His−Phe−D−Lys−Tyr−His−Ser−NH2
Gly−Ala−Lys−Phe−D−Lys−Glu−Arg−Tyr−His−D−Arg−D−Arg−Asp−Tyr−Trp−D−His−Trp−His−D−Lys−Asp
Thr−Tyr−Arg−D−Lys−Trp−Tyr−Glu−Asp−D−Lys−D−Arg−His−Phe−D−Tyr−Gly−Val−Ile−D−His−Arg−Tyr−Lys−NH2
(a)非極性アミノ酸:Ala(A) Ser(S) Thr(T) Pro(P) Gly(G) Cys(C);
(b)酸性アミノ酸:Asn(N) Asp(D) Glu(E) Gln(Q);
(c)塩基性アミノ酸:His(H) Arg(R) Lys(K);
(d)疎水性アミノ酸:Met(M) Leu(L) Ile(I) Val(V);及び
(e)芳香族アミノ酸:Phe(F) Tyr(Y) Trp(W) His(H)。
Dab=ジアミノ酪酸
Dap=ジアミノプロピオン酸
Dmt=ジメチルチロシン
Mmt=2’−メチルチロシン
Tmt=N,2’,6’−トリメチルチロシン
Hmt=2’−ヒドロキシ,6’−メチルチロシン
dnsDap=β−ダンシル−L−α、β−ジアミノプロピオン酸
atnDap=β−アントラニロイル−L−α、β−ジアミノプロピオン酸
Bio=ビオチン
芳香族カチオン性ペプチドの予防的及び治療的使用
投与の様式及び有効量
芳香族カチオン性ペプチドと他の治療薬による併用治療
本実施例では、高血圧性心筋症及び心不全におけるミトコンドリア標的抗酸化ペプチド(SS−31)によるミトコンドリア酸化ストレスの低減効果を調べた。ミトコンドリア標的抗酸化ペプチドSS−31を用いて、アンジオテンシンII(Ang II)誘発心筋症のほかに、心不全を患うGαq過剰発現マウスにおけるNADPHオキシダーゼ及びミトコンドリアの役割も特定した。
新生仔マウス心臓細胞の培養及びフローサイトメリー。
生後72時間齢より若い新生仔マウスから心室を切除し、細かく切り、Blendzyme 4(45 μg/mL、Roch)の酵素によって消化した。酵素消化後、ディファレンシャル・プレプレーティングを用いて2時間、心臓細胞をエンリッチし、その後、20%ウシ胎仔血清(Sigma)と25μMアラビノシルシトシン(Sigma)を含むDMEM(Gibco)中で24時間、フィブロネクチンを塗布した培養皿に播種して、培養した。心臓細胞を、0.5%インスリントランスフェリンセレン(Sigma)、2mMグルタミン、及び1mg/mLのBSAを含む無血清DMEMで3時間、アンジオテンシンII(1μM)によって刺激した。心臓細胞を以下のいずれかで同時に処理した:SS−31(1nM)、N−アセチルシステイン(NAC:0.5mM)、又はPBSコントロール。ミトコンドリアスーパーオキシド濃度を測定するために、Mitosox(5μM)を37℃で30分間培養し、心臓細胞に取り込ませ、続いてハンクス平衡塩溶液で2回洗浄した。フローサイトメリーによる488/625nmの励起/発光を用いて試料を分析した。流量データを、FCS Express(De Novo Software,Los Angels,CA)を用いて分析し、Mitosox蛍光強度のヒストグラム分布として示した。
すべての動物実験は、ワシントン大学動物実験委員会による承認を受けた。C57BL6マウスの飼育は、バリア指定病原体未感染施設(barrier specific pathoogen−free facility)でおこなった。6〜10匹のマウスを各々の実験群に含めた(生理食塩水、Ang II、Ang II+SS−31、WT、Gαq、Gαq+SS−31)。皮下Alzet 1004浸透ミニポンプを用いて、SS−31(3mg/kg/d)の追加が有る場合と無い場合の両方で、昇圧用量のAng II(1.1mg/kg/d)を4週間投与した。13MHzプローブを搭載したSiemens Acuson CV−70を用いて、ベースライン時と、ポンプ移植4週間後に心エコー検査をおこなった。攪拌を減らすために0.5%イソフルランの下で、標準のM−モード従来型組織ドップラー画像を取得し、米国心エコー検査学会の指針に従って関数計算をおこなった。等容収縮時間と弛緩時間の合計の左室駆出時間に対する比率として、MPIを計算した。MPIの増加は、心収縮の多くの割合が、等容相中の圧力変動に対処するために費やされることを示す兆候である。Ang II処理マウスにおけるSS−31ペプチドの効果の参考として、Rosa−26誘導型−mCATの遺伝マウスモデルを含め、そのモデルでAng II処理の2週間前にミトコンドリアカタラーゼが過剰発現した。
心室細胞を横断スライスに切断し、その後、パラフィンで包埋し、切片を作成し、マッソントリクローム染色をおこなった。心室の総断面積に対する青色染色線維症組織の割合を測定することで、線維症の定量分析をおこなった。
ミトコンドリアタンパク質抽出のために、ミトコンドリア分離緩衝液(1mM EGTA、10mM HEPES、250mMショ糖、10mMトリス塩酸、pH7.4)中で心室組織をホモゲナイズした。分解物を、4℃で800Gの回転数で7分間遠心した。次に上清を、4℃で4000Gの回転数で30分間遠心した。少量のミトコンドリア分離緩衝液中で粗製のミトコンドリアペレットを再懸濁し、氷冷しながら超音波をかけ、膜を破壊し、1%硫酸ストレプトマイシンで処理し、ミトコンドリア核酸を沈殿させた。OxiSelect(登録商標)タンパク質カルボニルELISAキット(Cell Biolabs)を使用して、1回のアッセイあたり1μgのタンパク質試料を分析した。取扱説明書に従って、わずかに変更してELISAをおこなった。簡単に述べると、タンパク質試料をジニトロフェニルヒドラジン(DNPH)と反応させ、抗DNPH抗体で、続いてHRP結合二次抗体でプローブした。抗DNPH抗体とHRP結合二次抗体の濃度はそれぞれ、1:2500と1:4000であった。
Taqman Gene Expression Assays on Demandを備えたApplied Biosystems 7900サーモサイクラーを用いて定量リアルタイムPCRによって遺伝子発現を定量した。サーモサイクラーの構成:PGCl−a(Mm00731216)、TFAM(Mm00447485)、NRF−1(Mm00447996)、NRF−2(Mm00487471)、Collagen Ia2(Mm00483937)、及びANP(Mm01255747)。発現分析を、18S RNAに正規化した。
他に記載された通りに、NADPHオキシダーゼ分析をおこなった。簡単に述べると、ジヒドロエチジウム(DHE、10μM)、精子DNA(1.25μg/mL)、及びNADPH(50μM)のPBS/DTPA(DTPAを100μM含む)溶液とともに、心室タンパク質抽出物を培養した。分析試料は37℃の暗所で30分間培養し、490/580nmの励起/発光を用いて蛍光を検出した。
氷冷しながらプロテアーゼ及びホスファターゼ阻害剤を含む分解緩衝液(1.5mM KCl、50mM トリス塩酸、0.125% デオキシコール酸ナトリウム、0.375% TritonX 100、0.15% NP40、3mM EDTA)中でホモゲナイズすることによって、心臓タンパク質抽出物を調製した。試料を超音波処理し、4℃で15分間、10,000gの回転数で遠心分離した。上澄みを収集し、BCA分析(Pierce Thermo Scientific, Rockford, IL)を用いて濃度を測定した。NuPAGE 4−12% ビス−トリスゲル(Invitrogen)で総タンパク質(25μg)を分離し、0.45μm PVDFメンブレン(Millipore)に移し、その後、1時間、0.1%Tween−20を用いて5%無脂肪粉ミルクのトリス緩衝溶液でブロックした。一次抗体を一晩培養し、二次抗体を1時間培養した。一次抗体としては、次のものが挙げられる:ウサギモノクローナル抗切断型カスパーゼ−3(Cell Signaling)、マウスモノクローナル抗−GAPDH(Millopore)、ウサギポリクローナルホスホ−p38 MAPキナーゼ(Cell Signaling)、及びマウスモノクローナル抗−p38(Santa Cruz Biotechnology)。検出には、増感化学発光法(Thermo Scientific)を使用した。Image Quantバージョン2.0を使用し、GAPDH(内部対照)に対する比率として相対的帯域密度を定量した。すべての試料を、同じ心臓タンパク質試料に対して正規化した。
すべてのデータを、平均値±SEMとして表す。スチューデントのt検定を用いて、2つの群の比較を行う。一元配置分散分析を使用して、複数の群の間の違いを比較し、続いて、有意性に関してチューキーポストホックテストをおこなった。P<0.05を有意であると見なした。
Ang−IIは新生仔心筋細胞のミトコンドリアROSを増加させた。これは、ミトコンドリア抗酸化ペプチドSS−31によって緩和された。
フローサイトメリー分析によって、アンジオテンシンIIが新生仔心筋細胞のMitosox蛍光(ミトコンドリアスーパーオキシドの指示薬)を約2倍増加させることを実証した。非標的抗酸化薬のN−アセチルシステイン(NAC)による処置は、Ang II投与後のミトコンドリアROSの濃度に対する効果を示さなかった。その一方、SS−31は、Ang II誘発mitosox蛍光を、生理食塩水で処理した心筋細胞と同様のレベルに低減させた(図1)。これらの結果からは、Ang IIが、ミトコンドリア標的抗酸化物質によって軽減できる心筋細胞のミトコンドリア酸化ストレスを誘発したことを示した。
高血圧性心筋症を再現するために、昇圧用量のAng II(1.1mg/kg/d)をAlzet 1004浸透ミニポンプによる皮下連続注入を通じて4週間投与した。図2A及び2Bに示したように、血管内遠隔測定によって、この用量のAng IIが収縮期及び拡張期血圧をベースライン時より25〜28mmHgと著しく増加させることが分かった(血圧:ベースライン時118.8±4.0/94.5±3.5mmHgに対して、Ang II後146.0±5.6/119.3±4.0mmHg、p<0.001)。SS−31(3mg/kg/d)の同時投与では、血圧に対して効果を示さなかった(図2)。
Ang IIが心筋細胞におけるミトコンドリアROSを誘発するという所見(図1)と一致して、Ang IIの4週間継続投与は、タンパク質の酸化的損傷の指標である心室ミトコンドリアタンパク質のカルボニル含有量を有意に増加させた(p=0.03、図5A)。 ミトコンドリア標的抗酸化物質SS−31は、心臓ミトコンドリアタンパク質のカルボニルを有意に低下させた(p=0.02、図5A)。
先の報告と一致して、Ang IIの4週間の投与が心臓NADPHオキシダーゼ活性を有意に高めた(p=0.03、図6A)、しかし、これは、SS−31を投与することでは変わらず(p=0.67、図6A)、SS−31の保護がNADPHオキシダーゼの下流に作動することを示している。
Gαqタンパク質は、高血圧性心臓血管疾患のメディエーターとして公知である、カテコールアミン及びAng IIの受容体に結合する。これらの観察を継続的なカテコールアミンとAng IIの刺激に拡げるため、Gαqの心臓特有過剰発現のある遺伝子マウスを使用した。このマウスは、生後14〜16週齢までに心不全を引き起こす。この研究のGαqマウスは、左室の肥大(図7B)とともにFSの有意な減少(図7A)によって示されるように、生後16週齢において、収縮機能の障害、Ea/Aaの減少によって示される拡張機能の障害(図7C)、及び心筋性能指数の悪化(MPI、図7D)を有していた。生後12〜16週齢に投与されたSS−31(3mg/kg/d)によって、収縮機能は著しく改善され(p<0.001、未処置Gαqに対して、図7A)、心筋性能が改善された(p=0.04、図7D)。左室肥大はわずかに軽減され(p=0.08、図7B)、Ea/Aaはきわどい有意性でSS−31によって良好に維持された(p=0.06、図7C)。生後16週齢において、Gαqマウスの正規化された心臓質量は33%増加し、一方でSS−31は心臓肥大を実質的に減少させた(p=0.001、図7E)。Gαqマウスの肺質量は22%と有意に増加し、肺うっ血を示し、これは、きわどい有意性でSS−31によってわずかに弱められた(p=0.09、図7E)。Gαqマウスでは心室線維症が約2倍に増加し、このことはSS−31処置マウスでも変わらず(図9A)、これは、プロコラーゲン1a2定量PCRで確認された(図9B)。ミトコンドリアタンパク質の酸化的損傷もGαq心臓で明らかであり(p=0.01、図9C)、SS−31処置マウスは心臓ミトコンドリアタンパク質のカルボニルの有意な減少を示した(p=0.05、図9C)。Gαqマウスの心臓における開裂カスパーゼ3増加のエビデンスはなかった(データは示さず)。
本研究は、H2O2がミトコンドリア発生の主要調節因子であるPGC−1αの転写を直接活性化するという以前の報告と一致して、4週間のAng IIの暴露が、心臓ミトコンドリアタンパク質の酸化的損傷を増加させ、ミトコンドリア発生のためのシグナル伝達を誘発する(図5)ことを示した。SS−31は、Angが誘発したミトコンドリア酸化ストレスを有意に弱め、それ故に、ミトコンドリア発生のアップレギュレーションを低下させるほか、ROS媒介シグナル伝達、例えばp38 MAPKのリン酸化も低下させた(図8)。さらに、ミトコンドリア酸化ストレスは、シトクロムc放出とプロカスパーゼ−9の活性化、続いて、カスパーゼ−3の活性化とアポトーシスの結果として、アポトーシスを引き起こす可能性がある。これらの結果は、SS−31によるミトコンドリアROSの減少が、Ang IIで誘発された心臓肥大、線維症、及び拡張機能障害の改善に付随して、活性化カスパーゼ−3で測定されるアポトーシスを防止したことを裏付けている。
Ang IIマウスモデル又はGαqマウスモデルで、心不全の処置又は予防における芳香族カチオン性ペプチドSS−20の効果を調べる。
本発明は、本願で述べられる特定の実施態様に関して限定されるものではなく、本発明の個別の観点の1つの説明となることを意図している。当業者には明白なように、本発明の精神及び範囲から逸脱することなく本発明の多くの変更及び変形を行うことができる。本願明細書に列挙される方法及び装置に加えて、本発明の範囲内の機能的に均等の方法及び装置は、前述の説明から当業者には明白である。このような変更及び変形は添付した特許請求の範囲含まれることを意図している。本発明は、添付された特許請求の範囲及びそれと共に権利付与された特許請求の範囲に均等なすべてのものによってのみ制限される。本発明が特定の方法、試薬、化合物、組成物、又は生物系に限定されるものではなく、当然のことながら、それらは変わる可能性があると理解されるべきである。また、本願明細書で使用される用語は、特定の実施態様のみを記載する目的で使用され、限定することを意図していないと理解されるべきである。
〔1〕哺乳動物被検体の心不全又は高血圧性心筋症を処置するための方法であって、
該疾患の処置を必要とする前記哺乳動物被検体に、治療上有効量のD−Arg−2’,6’−Dmt−Lys−Phe−NH2又はPhe−D−Arg−Phe−Lys−NH2のペプチドを投与することを含む、前記方法。
〔2〕前記ペプチドがD−Arg−2’6’−Dmt−Lys−Phe−NH2である、前記〔1〕記載の方法。
〔3〕前記ペプチドがPhe−D−Arg−Phe−Lys−NH2である、前記〔1〕記載の方法。
〔4〕前記被検体が心不全に罹患している、前記〔1〕記載の方法。
〔5〕前記〔4〕の方法であって、前記心不全が、高血圧;虚血性心疾患;心臓毒性化合物への暴露;心筋炎;甲状腺疾患;ウイルス感染症;歯肉炎;薬物乱用;アルコール乱用;心膜炎;アテローム性動脈硬化症;血管疾患;肥大型心筋症;急性心筋梗塞;左室機能障害;冠動脈バイパス手術;飢餓;摂食障害;又は遺伝子異常によって生じる、前記方法。
〔6〕前記被検体が高血圧性心筋症に罹患している、前記〔1〕記載の方法。
〔7〕前記ペプチドが投与された被検体の心筋収縮機能及び心拍出量が前記ペプチドを投与されていない対照被検体と比べて増加する、前記〔1〕記載の方法。
〔8〕前記被検体の心筋収縮機能及び心拍出量が前記ペプチドを投与されていない対照被検体と比べて少なくとも10%増加する、前記〔7〕記載の方法。
〔9〕前記被検体がヒトである、前記〔1〕記載の方法。
〔10〕前記ペプチドが経口投与、局所投与、全身投与、静脈内投与、皮下投与、腹腔内投与又は筋肉内投与される、前記〔1〕記載の方法。
〔11〕さらに、被検体に心血管作動薬を個別、順次、又は同時に投与することを含む、前記〔1〕記載の方法。
〔12〕前記心血管作動薬が抗不整脈薬、血管拡張薬、抗狭心症薬、コルチコステロイド、心臓グリコシド、利尿薬、鎮静剤、アンジオテンシン変換酵素(ACE)阻害薬、アンジオテンシンII拮抗薬、血栓溶解剤、カルシウムチャンネル遮断薬、トロンボキサン受容体拮抗剤、遊離基捕捉剤、抗血小板薬、β−アドレナリン受容体遮断薬、α−受容体遮断薬、交感神経抑制薬、ジギタリス製剤、変力物質、及び抗高脂血症薬からなる群から選択される、前記〔11〕記載の方法。
〔13〕心不全又は高血圧性心筋症に罹患している被検体の心筋収縮及び心拍出量を増加させる方法であって、治療上有効量のD−Arg−2’,6’−Dmt−Lys−Phe−NH2又はPhe−D−Arg−Phe−Lys−NH2のペプチドを該被検体に投与することを含む、前記方法。
本発明の更にまた別の態様は、以下のとおりであってもよい。
〔1'〕哺乳動物被検体の心不全又は高血圧性心筋症を処置するための医薬の調製のためのペプチドの使用であって、該ペプチドがD−Arg−2’,6’−Dmt−Lys−Phe−NH2である、使用。
〔2'〕前記被検体が心不全に罹患している、前記〔1'〕記載の使用。
〔3'〕前記心不全が、高血圧;虚血性心疾患;心臓毒性化合物への暴露;心筋炎;甲状腺疾患;ウイルス感染症;歯肉炎;薬物乱用;アルコール乱用;心膜炎;アテローム性動脈硬化症;血管疾患;肥大型心筋症;急性心筋梗塞;左室機能障害;冠動脈バイパス手術;飢餓;摂食障害;又は遺伝子異常によって生じる、前記〔2'〕記載の使用。
〔4'〕前記被検体が高血圧性心筋症に罹患している、前記〔1'〕記載の使用。
〔5'〕前記医薬が前記ペプチドを投与された被検体の心筋収縮機能及び心拍出量を増加させる、前記〔1'〕記載の使用。
〔6'〕前記医薬が前記被検体の心筋収縮機能及び心拍出量を少なくとも10%増加させる、前記〔5'〕記載の使用。
〔7'〕前記被検体がヒトである、前記〔1'〕記載の方法。
〔8'〕前記医薬が、経口投与、局所投与、全身投与、静脈内投与、皮下投与、腹腔内投与又は筋肉内投与されるために製剤化される、前記〔1'〕記載の使用。
〔9'〕さらに、前記医薬が心血管作動薬を含む、前記〔1'〕記載の使用。
〔10'〕前記心血管作動薬が抗不整脈薬、血管拡張薬、抗狭心症薬、コルチコステロイド、心臓グリコシド、利尿薬、鎮静剤、アンジオテンシン変換酵素(ACE)阻害薬、アンジオテンシンII拮抗薬、血栓溶解剤、カルシウムチャンネル遮断薬、トロンボキサン受容体拮抗剤、遊離基捕捉剤、抗血小板薬、β−アドレナリン受容体遮断薬、α−受容体遮断薬、交感神経抑制薬、ジギタリス製剤、変力物質、及び抗高脂血症薬からなる群から選択される、前記〔9'〕記載の使用。
〔11'〕心不全又は高血圧性心筋症に罹患している被検体の心筋収縮及び心拍出量を増加させるための医薬の調製のためのペプチドの使用であって、該ペプチドがD−Arg−2’,6’−Dmt−Lys−Phe−NH2である、使用。
他の実施態様は以下の請求項で示される。
Claims (15)
- アンジオテンシンII誘発心臓線維症の治療又は予防を必要とする哺乳動物被検体においてアンジオテンシンII誘発心臓線維症を治療又は予防するための医薬組成物であって、治療上有効量のペプチドD−Arg−2’,6’−Dmt−Lys−Phe−NH2又はPhe−D−Arg−Phe−Lys−NH2を含む、医薬組成物。
- 前記ペプチドがD−Arg−2’,6’−Dmt−Lys−Phe−NH2である、請求項1記載の組成物。
- 前記ペプチドがPhe−D−Arg−Phe−Lys−NH2である、請求項1記載の組成物。
- 前記被検体が心不全に罹患している、請求項1記載の組成物。
- 前記ペプチドを投与されていない対照被検体と比べて、前記ペプチドを投与された被検体の心筋収縮機能及び心拍出量を増加させる、請求項1記載の組成物。
- 前記ペプチドを投与されていない対照被検体と比べて、前記被検体の心筋収縮機能及び心拍出量を少なくとも10%増加させる、請求項5記載の組成物。
- 前記被検体がヒトである、請求項1記載の組成物。
- 経口投与、局所投与、全身投与、静脈内投与、皮下投与、腹腔内投与又は筋肉内投与されるために製剤化されている、請求項1記載の組成物。
- 心血管作動薬を更に含む、請求項1記載の組成物。
- 前記心血管作動薬が、抗不整脈薬、血管拡張薬、抗狭心症薬、コルチコステロイド、心臓グリコシド、利尿薬、鎮静剤、アンジオテンシン変換酵素(ACE)阻害薬、アンジオテンシンII拮抗薬、血栓溶解剤、カルシウムチャンネル遮断薬、トロンボキサン受容体拮抗剤、遊離基捕捉剤、抗血小板薬、β−アドレナリン受容体遮断薬、α−受容体遮断薬、交感神経抑制薬、ジギタリス製剤、変力物質、及び抗高脂血症薬からなる群から選択される、請求項9記載の組成物。
- アンジオテンシンII誘発心臓線維症に罹患している被検体の心筋収縮及び心拍出量を増加させるための医薬組成物であって、治療上有効量のペプチドD−Arg−2’,6’−Dmt−Lys−Phe−NH2又はPhe−D−Arg−Phe−Lys−NH2を含む、医薬組成物。
- 前記ペプチドがD−Arg−2’,6’−Dmt−Lys−Phe−NH2である、請求項11記載の組成物。
- 前記ペプチドがPhe−D−Arg−Phe−Lys−NH2である、請求項11記載の組成物。
- 心血管作動薬を更に含む、請求項11記載の組成物。
- 前記心血管作動薬が、抗不整脈薬、血管拡張薬、抗狭心症薬、コルチコステロイド、心臓グリコシド、利尿薬、鎮静剤、アンジオテンシン変換酵素(ACE)阻害薬、アンジオテンシンII拮抗薬、血栓溶解剤、カルシウムチャンネル遮断薬、トロンボキサン受容体拮抗剤、遊離基捕捉剤、抗血小板薬、β−アドレナリン受容体遮断薬、α−受容体遮断薬、交感神経抑制薬、ジギタリス製剤、変力物質、及び抗高脂血症薬からなる群から選択される、請求項14記載の組成物。
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