JP6999664B2 - 胆汁酸を含む虚血性再灌流損傷の予防または治療用薬学的組成物 - Google Patents
胆汁酸を含む虚血性再灌流損傷の予防または治療用薬学的組成物 Download PDFInfo
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Description
本発明は、胆汁酸(bile acid)またはその薬学的に許容可能な塩を含む虚血性再灌流損傷の予防または治療用薬学的組成物を提供する。
1.1 ベータ-カテニン(β-catenin)亢進薬物を発掘するためのスクリーニング
多様な種類の胆汁酸が核内のベータ-カテニン水準に及ぼす影響を分析して、ベータカテニン亢進効果がある薬物を発掘するための実験を実施した。Nuclear beta-catenin Luciferase assayを通じてウルソデオキシコール酸(ursodeoxycholic acid)、GlycochenDCA(glycochenodeoxycholic acid)、TauroDCA(Taurodeoxycholic acid)、グリココール酸(Glycocholic acid)、TauroCA(Taurocholic acid)、ChenoDCA(Chenodeoxycholic acid、ケノデオキシコール酸)、コール酸(Cholic acid)、デヒドロコール酸(Dehydrocholic acid)、リトコール酸(Lithocholic acid)及びデオキシコール酸(Deoxycholic acid、DCA)の処理が核内のベータ-カテニン水準の変化に及ぼす影響を観察した。
上記実施例1.1で確認したデオキシコール酸(DCA)によるβ-catenin核内移動関連機作を調べるために、western blotを行った。DCA 1μMを細胞に処理して30分、1、2、4、8時間後の細胞に対してwestern blotを行い、その結果を図2に示した。
上記実施例1でベータ-カテニンの水準を増加させる効果があることを確認したコール酸、リトコール酸、デオキシコール酸がミトコンドリアを保護する効果があるのかを確認するために、TMRM(Tetramethylrhodamine、Methyl Ester、Perchlorate)染色法を行った。TMRMは、正常なミトコンドリアに染色される蛍光マーカーである。
3.1 胆汁酸のin vitro細胞増殖効果の確認
胆汁酸の中でTauroCA、コール酸及びリトコール酸を1μM処理してHUVEC(human umbrical vein endothelial cell)で細胞増殖効果が表れるのかを確認するための実験を実施した。細胞counting方法及びCCK-8を利用した染色法としてTauroCA、コール酸及びリトコール酸を処理した24時間後の細胞の増殖効果を確認した。上記実験の結果を図4A及び4Bに示した。
胆汁酸の中でTauroCA、コール酸及びリトコール酸を1μM処理してHUVEC(human umbrical vein endothelial cell)で細胞移動効果が表れるのかを確認するためにBoyden chamberを利用して細胞の数を確認した。TauroCA、コール酸及びリトコール酸を処理した後の細胞の移動効果を確認し、上記実験の結果を図5A及び5Bに示した。
再灌流損傷マウスモデルを製造するために、ケタミンを利用してBalb/Cマウス(8週齢)を痲酔した。チューブを気道内に挿管して呼吸器に連結した後、マウスの左側横が上になるように補正して肌を切開した。3、4番の肋骨間を開いて心臓が表れるように固定し、左心室にデオキシコール酸またはスクリーニング及びin vitro assayで最も効果が優れたコール酸を血管注射方式で濃度別(2、10、50mg/kg)に注射した後、 左冠状動脈を縛ってから40分後解いて縫合した。24時間後に心臓を採取して-20℃に4時間氷らせた後、心臓を2mmの厚さで4等分して、それぞれの組織を2%TTC(PBS内)溶液に入れて40分間培養して染色した。以後、10%のホルマリン溶液に移して一日保管後に写真を撮り、その結果を図6Aに示した。また、組織写真で全体面積対比梗塞組織の面積を%に定量した結果を図6Bに示した。陽性対照群としては、mPTPの開放を抑制する物質であるCyp(cyclosporine A)を使用した。
上記再灌流損傷による心筋怪死の胆汁酸の中でデオキシコール酸による抑制効果を確認するために、Annexin-Vivo750蛍光染料を利用してマウス心筋怪死の確認実験を行った。上記実施例3で製造されたマウスモデルに24時間後にAnnexin-Vivo750蛍光染料を投入して、濃度別のデオキシコール酸(1、2、5mg/kg(mpk))の効果を観察し、その結果を図7A及び7Bに示した。Annexin染料は、細胞死滅が起こった所で結合して蛍光を表すと知られている。
1.1 カプセル剤の製造
胆汁酸:100ml
トウモロコシでん粉:100mg
乳糖:100mg
ステアリン酸マグネシウム:2mg
通常のカプセル剤の製造方法によって上記の成分を混合し、ゼラチンカプセルに充填して錠剤を製造する。
胆汁酸:100ml
注射用滅菌蒸留水:適量
pH調節剤:適量
通常の注射剤の製造方法によって1アンプル当り(2ml)上記の成分含量で製造する。
胆汁酸:100ml
砂糖:20g
異性化糖:20g
レモン香:適量
精製水を加えて全体1,000mlに合わせた。通常の液剤の製造方法によって上記成分を混合した後、茶色瓶に充填して滅菌させて液剤を製造する。
2.1 小麦粉食品の製造
本発明の食品組成物0.1~10.0重量部を小麦粉に添加し、この混合物を利用して通常の方法でパン、ケーキ、クッキー、クラッカー及び麺類を製造して健康増進用食品を製造した。
本発明の食品組成物0.1~1.0重量部を牛乳に添加し、前記牛乳を利用して通常の方法でバター及びアイスクリームのような多様な乳製品を製造した。
Claims (12)
- 胆汁酸(bile acid)またはその薬学的に許容可能な塩を含む心筋虚血性再灌流損傷の予防または治療用薬学的組成物であって、前記胆汁酸が、デオキシコール酸およびコール酸からなる群から選択される少なくとも1種である、前記薬学的組成物。
- 前記心筋虚血性再灌流損傷が外傷または再灌流手術により生じる、請求項1に記載の薬学的組成物。
- 前記再灌流手術が動脈硬化症または心血管疾患を治療するためのものである、請求項2に記載の薬学的組成物。
- 前記心血管疾患が心筋梗塞または狭心症である、請求項3に記載の薬学的組成物。
- 前記組成物は、再灌流手術の前処理用である、請求項1に記載の薬学的組成物。
- 前記胆汁酸またはその薬学的に許容可能な塩は、mPTP(mitochondrial permeability transition pore)の開放抑制剤である、請求項1に記載の薬学的組成物。
- 前記胆汁酸またはその薬学的に許容可能な塩は、ベータ-カテニン(β-catenin)のアゴニスト(agonist)である、請求項1に記載の薬学的組成物。
- 前記胆汁酸またはその薬学的に許容可能な塩は、ミトコンドリア保護用である、請求項1に記載の薬学的組成物。
- 前記胆汁酸またはその薬学的に許容可能な塩は、組織の梗塞を抑制するものである、請求項1に記載の薬学的組成物。
- 経口用製剤または注射用製剤の形態で剤形化されることを特徴とする、請求項1に記載の薬学的組成物。
- 胆汁酸(bile acid)またはその薬学的に許容可能な塩は、0.1~10mg/kg/日で投与されることを特徴とする、請求項1に記載の薬学的組成物。
- 胆汁酸またはその薬学的に許容可能な塩を含む心筋虚血性再灌流損傷の予防または改善用食品組成物であって、前記胆汁酸が、デオキシコール酸およびコール酸からなる群から選択される少なくとも1種である、前記食品組成物。
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---|
China Journal of Chinese Materia Medica,2005, Vol.30, No.12,pp.930-932 |
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JP2019537591A (ja) | 2019-12-26 |
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