JP6661402B2 - 内因系血液凝固反応を特異的に阻害する抗血栓剤 - Google Patents
内因系血液凝固反応を特異的に阻害する抗血栓剤 Download PDFInfo
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- JP6661402B2 JP6661402B2 JP2016030915A JP2016030915A JP6661402B2 JP 6661402 B2 JP6661402 B2 JP 6661402B2 JP 2016030915 A JP2016030915 A JP 2016030915A JP 2016030915 A JP2016030915 A JP 2016030915A JP 6661402 B2 JP6661402 B2 JP 6661402B2
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Description
(1)サクランまたはサクラン含有素材を含有する、内因系血液凝固反応を阻害し、外因系血液凝固反応を阻害しない抗血栓剤、
(2)サクランまたはサクラン含有素材を含有する、内因系血液凝固反応を阻害し、外因系血液凝固反応を阻害しない抗血栓効果を有する飲食物、および
(3)サクランまたはサクラン含有素材を含む食品添加剤。
スイゼンジノリを凍結−融解処理し、純水にて洗浄して赤紫色素を除去した。洗浄したスイゼンジノリを大量のエタノールにて振盪洗浄した(120rpm、一晩x3回)。ガーゼを用いて濾過し、エタノール洗浄スイゼンジノリを得た。エタノール洗浄スイゼンジノリを0.1M NaOH水溶液に添加し、100℃で4時間激しく撹拌して透明溶液を得た。透明溶液をHClにて中和し、pH8.0〜9.0とし、濾過した。サクランを含む濾液を100%アセトン中にゆっくりと注いで、白色繊維状沈殿を得た。白色繊維状沈殿を熱水に再溶解し、再沈殿させた。再溶解および再沈殿を3回繰り返した。沈殿を純水に溶解して水溶液(pH約6.0〜7.0)とし、ゲル濾過クロマトグラフィー(Sephadex LH-20, GE Healthcare)にて精製し、サクランを含む透明溶液のフラクションを集め、凍結乾燥させものを以下の実験に使用した。
ヒト血漿を用いたin vitroでの血液凝固試験として希釈活性化部分トロンボプラスチン時間(diluted activated partial thromboplastin time:dAPTT)法と希釈プロトロンビン時間(diluted prothrombin time:dPT)法を行った(Takeya H., et al.:Anti-β2-Glycoprotein I (β2GPI) monoclonal antibodies with lupus anticoagulant-like activity enhance the β2GPI binding to phospholipids. J Clin Invest 99: 2260-2268 (1997))。血漿に、dAPTT法では陰性荷電物質のエラグ酸とリン脂質を活性化剤として用い、dPT法ではリン脂質で再構成したTFを活性化剤として用いた。両方法ともに、先ず活性化剤とサンプル(サクラン、ヘパリン、ヘパラン硫酸)を加えて室温5分間インキュベートし、次に50mM CaCl2を加えてトロンビン生成反応を5分間行った。その後、反応をEDTAで停止するとともに発色基質Z−Val−Pro−Arg−pNAあるいはH−D−Phe−Pip−Arg−pNA(S−2238)を加え、5分間インキュベートした。発色反応を20%酢酸で停止し、分光光度計(DU(登録商標)640 SPECTRO PHOTOMETER)を用い405nmにおける吸光度の測定を行った。
精製したアンチトロンビン(0〜1.6μg/mL)とサンプル(サクラン 10μg/mL、ヘパラン硫酸 10μg/mL、ヘパリン 0.2μg/mL)を加えて室温で5分間インキュベートした後、0.1μg/mL トロンビンを加え、5分間インキュベートし、EDTAと発色基質Z−Val−Pro−Arg−pNAあるいはH−D−Phe−Pip−Arg−pNA(S−2238)の混合溶液を加え、5分間インキュベートした。反応を20%酢酸で停止した後、分光光度計を用いて405nmにおける吸光度の測定を行った。また、アンチトロンビン濃度を0.5μg/mLに固定し、サクラン濃度を 〜40μg/mLまで変化させて測定した。
ヒト血漿を用いて、サクランが内因系凝固反応および外因系凝固反応に及ぼす影響を調べた。臨床検査用凝固時間測定試薬を用いて、ヒト血漿の凝固時間を測定し、サクランおよびヘパリンの影響を調べた。アクチンFSL(actin FSL reagents, Siemerns Healthcare Diagnostics)を用いて活性化部分トロンボプラスチン時間(activated partial thromboplastin time: APTT)を測定することにより内因系活性化凝固時間を得た。トロンボレルS(Thromborel S, Siemens Healthcare Diagnostics)を用いてプロトロンビン時間(prothrombin time: PT)を測定することにより外因系活性化時間を得た。アクチンFSLおよびトロンボレルSそれぞれの使用説明書に従って実験を行った。
硫酸化多糖サクランの外因系および内因系凝固反応に与える影響
ヘパリンやへパラン硫酸などの硫酸化多糖は、トロンビンやXa因子などの凝固セリンプロテアーゼとアンチトロンビンなどのセルピンとの複合体形成を間接的(触媒的)に促進することで血液凝固反応を阻害する。サクランにも同様の抗凝固作用が想定されたので、先ず、エラグ酸を陰性荷電物質として用いた内因系凝固反応に与えるサクランの影響を検討した。その結果、サクランはヘパリンよりは若干弱いが、ヘパラン硫酸と同程度の内因系凝固反応抑制作用が示された(図1)。そこで次に、TFを起点とする外因系凝固反応に与えるサクランの影響を検討したところ、サクランはヘパリンおよびヘパラン硫酸とは異なりトロンビン生成を全く抑制しないことが示された(図2)。また、アンチトロンビンによるトロンビン活性阻害作用はヘパリンおよびへパラン硫酸によって著しく増強されたのに対し、サクランは全く影響しなかった(図3)。高濃度のサクラン(40μg/mL)を用いて同様の実験を行ったが、高濃度のサクランはアンチトロンビン活性増強作用を示さなかった(図4)。さらに、サクランは、ヒト血漿において、内因系凝固反応を特異的に抑制するが、外因系凝固反応には影響しないことも確認された。これらの結果から、サクランは内因系凝固反応を特異的に抑制するが、外因系凝固反応には影響しないことが明らかとなった。したがって、サクランを用いれば出血の副作用のない抗血栓剤の開発が可能であると考えられた。
Claims (3)
- サクランまたはサクラン含有素材を含有する、内因系血液凝固反応を阻害し、外因系血液凝固反応を阻害しない抗血栓剤。
- サクランまたはサクラン含有素材を含有する、血栓症の治療または予防のための飲食物であって、内因系血液凝固反応を阻害し、外因系血液凝固反応を阻害しない抗血栓効果を有する飲食物。
- 請求項2記載の飲食物を製造するために用いられる、サクランまたはサクラン含有素材を含む食品添加剤。
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