JP2011500617A - 血栓溶解についての新規な患者亜群 - Google Patents
血栓溶解についての新規な患者亜群 Download PDFInfo
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Abstract
Description
血栓溶解治療の標的組織は、いわゆるリスクのある組織である。この裏側にある病態生理学的原理は、以下のとおりである。
現在の血栓溶解治療とは対照的に、本発明は、一方では、脳卒中発生後の時間経過に拘わらず、上記患者のリスクのある組織(半影(penumbra))の個々の評価(診断)に基づく。他方では、本発明は、脳血管内の閉塞に起因する脳卒中を被っている脳卒中患者の選択(診断)に基づく。一実施形態において、上記閉塞は、画像化ツールによって検出可能である。よって、上記脳卒中処置のための患者は、彼らのリスクのある組織に鑑みて、および/もしくは動脈閉塞について選択される。
グレード3:正常な血流
グレード2:全体的に還流しているが、血流は遅れている動脈
グレード1:造影剤が通るが、遠位灌流がない動脈
グレード0:血管の完全な閉塞。
上記で概説されるように、本発明の一局面において、個々の画像化は、上記血栓溶解(再疎通および/もしくは再灌流)治療についての候補を診断もしくは同定(選択)するために使用される。任意の適切な画像化ツールが使用され得る。例えば、MRIは、適用され得る画像化ツールであり、これは、拡散強調シーケンス(diffusion−weighted sequence)(DWI)で行われ得る。DWIでの強力な過度の強度は、治療的再灌流あってもなくても、梗塞することが運命付けられたコア病変を示す。それは、通常、PWI(灌流強調画像化)で測定される低灌流領域によって囲まれている。
・MCAの約1/3超、またはACAおよび/もしくはPCA領域の実質的に全体が関わる急性梗塞
・ICH、SAH、AV奇形、脳動脈瘤もしくは脳新生物の徴候
これら患者は、都合のよいことには、脳卒中発生後の3時間より遅く、4.5時間より遅く、もしくは6時間より遅く処置される。最も好ましくは、彼らは、脳卒中症状の発生後3〜9時間以内に処置される。
i.90日目に少なくとも8点のNIHSS改善もしくは0〜1の最終NIHSSスコア(例えば、24から16へ、もしくは0〜1へのNIHSSスコアの改善(上記患者が、ベースラインにおいて、9以下のNIHSSスコアを有した場合))。
ii.0〜2の改変Rankinスケール(mRS)におけるスコア。
iii.約75〜約100の間のバーセルインデックス。
背景:急性虚血性脳卒中−2(DIAS−2)においてデスモテプラーゼは、無作為化したプラセボ制御した二重盲検研究であった。この研究は、症状の発生後3〜9時間以内に、急性脳卒中におけるデスモテプラーゼ、DSPA(90μg/kgおよび125μm/kg)の安全性および効力を調査した。上記陰性の処置目的(intent−to−treat)分析結果および異常に高いプラセボ応答率(46%)によって、臨床データおよび画像化データのより詳細な分析が促進された。
背景:上記を参照のこと。
(応答者速度 対 TIMIグレード)
上記DIAS/DEDASデータは、38名の患者(42.75%)が、ベースラインにおいてTIMI 2〜3を有し、51名の患者(57.3%)はTIMI 0〜1を有することを示した。このことは、患者の70.4%がベースラインでTIMI 2〜3を有する場合の上記DIAS−2データとは異なった。ベースラインTIMI 2〜3の最高のパーセンテージは、90μg/kg(74.1%)において見いだされ、125μg/kg群(64.5%)において最低が見いだされた(表1を参照のこと)。
上記で既に言及されたように、DIAS−2における上記絶対的ミスマッチ容積は、上記プラセボ応答速度に反比例し、その結果、より小さなミスマッチ容積(すなわち、50cc以下)を有する患者は、より高いプラセボ応答速度を示した。よって、上記DIAS/DEDAS/DIAS−2のMRI分析した患者を含む亜群分析は、プラセボを超えるデスモテプラーゼの用量依存性応答が、50cc〜100ccの間の絶対的ミスマッチ容積を有する患者について、および100ccより大きなミスマッチ容積を有する患者について観察されうるのに対して、デスモテプラーゼが、50ccより小さい絶対的ミスマッチ容積を有する亜群においてプラセボより顕著に良好ではなかったことを示す(図5)。
上記DIAS−2研究において、TIMI 0〜1を有する上記患者亜群は、ベースラインで13.0のNIHSSを示したのに対して、TIMI 2〜3を有する患者がベースラインで9.0のNIHSSを示した(表3)。この相関は、より重篤な閉塞を有する患者が、より重篤な梗塞を有する可能性が高いという事実に基づく。よって、上記TIMIグレードはまた、上記絶対的ミスマッチ容積に対して相関を示す。なぜなら、TIMI 0〜1を有する患者は、167.7ccのミスマッチ容積を示し、TIMI 2〜3を有する患者は、53.5ccのミスマッチ容積を示す(表3)。
上記部位マップの分析は、上記DIAS−2研究において、23名の患者がミスマッチ/明らかな半影(penumbra)を示さないことを明らかにした。半影(penumbra)なしの患者で、23名の患者のうちの11名が、応答者であった。
表1.上記DIAS−2研究についてのベースラインの特徴。
表2a.上記DIAS研究およびDEDAS研究のプールした患者集団と比較した場合の、上記DIAS−2研究におけるTIMI群についての応答者速度。
表2b.上記DIAS−2研究におけるTIMI群についての応答者速度。
表2c.上記DIAS研究およびDEDAS研究のプールした患者集団と比較した場合の、上記DIAS−2研究におけるTIMI群(M1よみとりのみ)についての応答者速度。
表3.上記DIAS−2研究における、TIMIグレード 対 NIHSSおよびミスマッチ容積。
表4.全体像DIAS/DEDASおよびDIAS−2は、DIAS−2が、より小さなミスマッチ容積および血管閉塞の非存在を有するより軽度な脳卒中を含むということを示す。
Claims (18)
- 患者における脳卒中を処置するための医薬の製造のためのプラスミノゲン活性化因子の使用であって、ここで該患者は、処置の前に、ベースラインにおいて、以下の基準のうちの1つ以上を示すことについて選択される、使用:
a.リスクのある脳組織
b.大脳動脈閉塞
c.少なくとも4のNIHSSスコア
d.高グレード狭窄
e.少なくとも50ccの絶対的ミスマッチ容積。 - 前記大脳動脈閉塞もしくは前記高グレード狭窄は、MCA、ACAもしくはPCAまたはこれらの枝脈に位置している、請求項1に記載のプラスミノゲン活性化因子の使用。
- 前記動脈閉塞もしくは前記高グレード狭窄は、前記MCA、ACAもしくはPCAの枝脈M1もしくはM2に存在する、請求項2に記載のプラスミノゲン活性化因子の使用。
- 前記動脈閉塞は、0もしくは1のTIMIのものである、請求項1〜3のいずれか1項に記載のプラスミノゲン活性化因子の使用。
- 前記リスクのある組織は、MCA、ACAもしくはPCAの領域に位置している、請求項1〜4のいずれか1項に記載のプラスミノゲン活性化因子の使用。
- 前記患者は、少なくとも8、好ましくは、8〜24(両端を含む)の間のNIHSSスコアの脳卒中を示す、請求項1〜5のいずれか1項に記載のプラスミノゲン活性化因子の使用。
- 前記動脈閉塞および/もしくは前記リスクのある組織は、個々の画像化によって処置前に評価される、請求項1〜6のいずれか1項に記載のプラスミノゲン活性化因子の使用。
- 前記リスクのある組織は、コア梗塞より少なくとも約20%大きい、請求項1〜7のいずれか1項に記載のプラスミノゲン活性化因子の使用。
- 前記絶対的ミスマッチ容積は、75cc以上である、請求項1〜8のいずれか1項に記載のプラスミノゲン活性化因子の使用。
- 前記患者は、ベースラインにおいて以下の特性:
a.急性梗塞は、MCAの約1/3より多く、もしくは実質的にACAもしくはPCA領域全体に関わらない、ならびに/または
b.ICH、SAH、AV形成異常の非存在、脳動脈瘤もしくは脳新生物の非存在、
のうちの1つ以上によってさらに特徴付けられる、請求項1〜9のいずれか1項に記載のプラスミノゲン活性化因子の使用。 - 前記プラスミノゲン活性化因子は、約90〜約125μg/kg 体重、特に、約90もしくは約125μg/kg 体重の投与量において前記患者に投与される、請求項1〜10のいずれか1項に記載のプラスミノゲン活性化因子の使用。
- 前記プラスミノゲン活性化因子は、フィブリンなしの活性と比較して、フィブリンの存在下で少なくとも約550倍より高く増大した活性を有する、請求項1〜11のいずれか1項に記載のプラスミノゲン活性化因子の使用。
- 前記プラスミノゲン活性化因子は、
i.β−アミロイドおよび/もしくはプリオンタンパク質によって本質的に活性化できない、ならびに/または
ii.実質的に神経毒性でない、そして/あるいは
iii.少なくとも2.5分間より長い半減期を有する、
請求項1〜12のいずれか1項に記載のプラスミノゲン活性化因子の使用。 - 前記プラスミノゲン活性化因子は、フィブリンなしの活性と比較して、フィブリンの存在下で少なくとも約550倍より高く増大した活性を有し、少なくとも約50分間より長い半減期を有する、請求項1〜13のいずれか1項に記載のプラスミノゲン活性化因子の使用。
- 前記プラスミノゲン活性化因子は、デスモテプラーゼである、請求項1〜14のいずれか1項に記載のプラスミノゲン活性化因子の使用。
- 前記プラスミノゲン活性化因子は、
i.図3に従うアミノ酸配列もしくはその微小不均一形態を有するか、または
ii.図3のアミノ酸配列に対して、少なくとも80%同一、より好ましくは、95%同一、さらにより好ましくは、98%同一である、
請求項1〜15のいずれか1項に記載のプラスミノゲン活性化因子の使用。 - 脳卒中発生後3時間より長い、請求項1〜17のいずれか1項に記載のプラスミノゲン活性化因子の使用。
- 脳卒中症状の発生後3〜9時間以内である、請求項1〜17のいずれか1項に記載のプラスミノゲン活性化因子の使用。
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