JP2023503413A - 脳卒中または脳卒中による後遺症治療のためのシルデナフィル及びrock阻害剤の用途 - Google Patents
脳卒中または脳卒中による後遺症治療のためのシルデナフィル及びrock阻害剤の用途 Download PDFInfo
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Abstract
Description
前記背景技術として説明された事項は、本発明の背景に対する理解増進のためのものであり、この技術分野で通常の知識を有する者に既に知られている従来技術に該当することを認めるものと受け止められてはならない。
ROCK阻害剤(Rho-associasted kinase inhibitor)を含む、虚血性脳血管疾患または虚血性脳血管疾患による後遺症の治療用薬学的組成物を提供することにある。
ROCK阻害剤(Rho-associasted kinase inhibitor)を含む、虚血性脳血管疾患の予後改善用薬学的組成物を提供することにある。
ROCK阻害剤(Rho-associasted kinase inhibitor)を含む認知機能増進用薬学的組成物を提供することにある。
ROCK阻害剤(Rho-associasted kinase inhibitor)を含む、虚血性脳血管疾患または虚血性脳血管疾患による後遺症の治療用薬学的組成物を提供する。
ROCK阻害剤(Rho-associasted kinase inhibitor)を含む、虚血性脳血管疾患の予後改善用薬学的組成物を提供する。
ROCK阻害剤(Rho-associasted kinase inhibitor)を含む、認知機能増進用薬学的組成物を提供する。
実施例1.実験材料及び実験方法
1-1.実験動物(Experimental animals)
雄ラット、Sprague-Dawley、8週齢及び260-280gの実験動物を使用し、前記実験動物は、順天郷大学校の実験動物センター(天安)から得た。すべての実験動物は、特定の温度、湿度及び照明条件下で市販の飼料及び水を任意に提供した(明暗周期12:12、22±2℃、55±5%)。すべての動物プロトコルは、順天郷大学の実験室動物管理に対する行政パネルによって承認された(許可番号SCH16-0024)。本発明に関連した実験を行うにおいて、前記実験動物の苦痛を避け、実験に使用される実験動物の数を最小限に抑えた。
ラットは、2%イソフルランで麻酔され(2%isoflurane in mixed gas of oxygen and nitrous oxide、0.3:0.7)、手術中に加熱パッドを使用して体温を37℃に維持した。
2)神経学的欠損後、梗塞が発生した側の反対方向に回る行動(circling toward contralateral to infarct)ができない。
本発明者らは、1)Sildenafil citrate、2)GSK429286A及び3)Sildenafil citrate及びGSK429286Aをそれぞれ実験動物に適用して軽微な虚血性脳卒中で発生した直接的な脳損傷または様々な表現型後遺症に対してホスホジエステラーゼタイプ5活性阻害剤(phosphodiesterase type 5 inhibitor)及び/又はROCK阻害剤(Rho-associasted kinase inhibitor)が及ぼす影響を評価した。
2)GSK429286A(10mg/kg/DMSO、Sigma、USA)
3)Sildenafil citrate(20mg/kg/saline)及びGSK429286A(10mg/kg/DMSO)
軽症虚血性脳卒中発症後の脳梗塞のサイズを測定するため、実験動物の頭部を切開し、脳を取り出して4℃で冷却して組織を硬化させた。
Open field testは、新しい環境において好奇心によって活動が多くなるげっ歯類の探索的行動に基づく実験であり、移動した総距離は、一般的な運動活動を評価するためのパラメータとして使用される。
Light-dark box test(45×27×27cm;長さ、幅、高さ)は2つの区画に分けられ、より具体的に、5分の3は明るい区画であり、5分の2は暗い区画である。各区画は、床に位置する9×9cmの入口で互いに連結されている。
Barnes mazeは、同じ距離の周りに20個の孔がある円形プラットフォーム(直径122cm)からなっており、床から105cm上昇している。実験動物を観察しやすい高さでプラットフォームを囲むそれぞれのクァドラントの壁に4つの異なる視覚的キューが配置され、クァドラント区域の1つの孔(脱出孔)は、プラットフォームの下に脱出チャンバーを含む。また、実験動物の安全のために脱出チャンバーにベディング(bedding)が追加された。脱出チャンバーを見つける動機付けのための不安を増幅させるため、メトロノームと明るい照明を使用した。より具体的には、メトロノームを使用して連続的に80Hzのノイズを生成し、プラットフォームの中心で測定された照度が300ラックス(lux)を維持するようにした。
fEPSP(Field potentials)は、海馬のCA1からわずかに修正された部位でレコーディングした。行動試験の後、ウレタン(1.5g/kg)を使用して動物を腹腔内麻酔させ、stereotaxic frameに入れた。温度調節器(Harvard Instruments、USA)を使用し、手術過程で直腸温度を37±0.3℃に維持した。
2)刺激電極(stimulating electrode、to the stratum radiatum of CA1):ブレグマから3.5後部、中心線から側面に2.0、海馬から3.5深さ。
急性期脳卒中(脳梗塞)モデルであるMCAo30を用いて、1)シルデナフィルまたはROCK阻害剤単独投与、2)シルデナフィル及びROCK阻害剤を併用投与した場合において、脳卒中発症による直接的な脳組織の損傷程度を確認する実験を行った。前記実験は、1~4に記載された方法に基づいて行った。
急性期脳卒中(脳梗塞)モデルであるMCAo30を使用し、1)シルデナフィルまたはROCK阻害剤単独投与、2)シルデナフィル及びROCK阻害剤を併用投与した場合において、脳卒中による後遺症の一つである運動機能の喪失の程度を確認するため、open field testを行い、運動機能は、正常対照群の運動機能を基準とした(運動機能の喪失なし、100%)。ここで、シルデナフィル及びROCK阻害剤の併用投与は、中大脳動脈閉塞後の再灌流後に行った。
急性期脳卒中(脳梗塞)モデルであるMCAo30を使用し、1)シルデナフィルまたはROCK阻害剤単独投与、2)シルデナフィル及びROCK阻害剤を併用投与した場合において、脳卒中による後遺症の一つである不安障害の程度を確認するため、Light-dark box testを行い、不安の程度は、正常対照群を基準とした(不安なし、100%)。ここで、シルデナフィル及びROCK阻害剤の併用投与は、中大脳動脈閉塞後の再灌流後に行った。
急性期脳卒中(脳梗塞)動物モデルであるMCAo30を使用し、1)シルデナフィルまたはROCK阻害剤単独投与、2)シルデナフィル及びROCK阻害剤を併用投与した場合において、脳卒中による後遺症の一つである認知機能の低下の程度を確認するため、Barnes maze testを行い、認知機能は正常対照群の脱出時間を基準とした。
急性期脳卒中(脳梗塞)動物モデルであるMCAo30を使用し、1)シルデナフィルを中大脳動脈閉塞後の再灌流前に単独投与、2)シルデナフィルを中大脳動脈閉塞後の再灌流後に単独投与した場合において神経可塑性の改善可否を確認する実験を行い、認知機能は、正常対照群と比較した。
Claims (6)
- ホスホジエステラーゼタイプ5活性阻害剤(phosphodiesterase type 5 inhibitor)と、
ROCK阻害剤(Rho-associasted kinase inhibitor)を含む、虚血性脳血管疾患または虚血性脳血管疾患による後遺症の治療用薬学的組成物。 - 前記虚血性脳血管疾患は、虚血性脳卒中(脳梗塞)、血栓症、塞栓症、一過性虚血発作、白質異常症及び小梗塞からなる群から選ばれるいずれかである、請求項1に記載の薬学的組成物。
- 前記虚血性脳血管疾患による後遺症は、運動機能の喪失、不安障害、認知機能の低下からなる群から選ばれるいずれか一つである、請求項1に記載の薬学的組成物
- 前記ホスホジエステラーゼタイプ5活性阻害剤は、ミロデナフィル(mirodenafil)、シルデナフィル(sildenafil)、バルデナフィル(vardenafil)、タダラフィル(tadalafil)、ユデナフィル(udenafil)、ダサンタフィル(dasantafil)、アバナフィル(avanafil)及びこれらの薬学的に許容される塩、溶媒和物及び水和物からなる群から選ばれるいずれか一つで
あることを特徴とする、請求項1~3のいずれか1項に記載の薬学的組成物。 - 前記ROCK阻害剤は、ファスジル(Fasudil)、リパスジル(Ripasudil)、RKI-1447、Y-27632、GSK429286A、Y-30141及びこれらの薬学的に許容される塩、溶媒和物及び水和物からなる群から選ばれるいずれか一つであることを特徴とする、請求項1~3のいずれか1項に記載の薬学的組成物。
- 前記薬学的組成物は、脳血管閉塞後の再灌流前、再灌流と同時または再灌流後に投与するためのものである、請求項1~3のいずれか1項に記載の薬学的組成物。
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KR1020190146223A KR102336700B1 (ko) | 2019-11-14 | 2019-11-14 | 실데나필 및 rock 저해제를 포함하는 뇌졸중으로 인한 불안 장애의 치료용 약학적 조성물 |
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