JP6851652B2 - Idhpの冠状動脈アテローム性硬化症の予防及び治療のための薬物又は健康補助食品の調製における応用 - Google Patents
Idhpの冠状動脈アテローム性硬化症の予防及び治療のための薬物又は健康補助食品の調製における応用 Download PDFInfo
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- JP6851652B2 JP6851652B2 JP2019518211A JP2019518211A JP6851652B2 JP 6851652 B2 JP6851652 B2 JP 6851652B2 JP 2019518211 A JP2019518211 A JP 2019518211A JP 2019518211 A JP2019518211 A JP 2019518211A JP 6851652 B2 JP6851652 B2 JP 6851652B2
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- dihydroxyphenyl
- hydroxypropionate
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Description
1.1 IDHPによるヒト臍帯静脈内皮細胞(HUVEC)増殖促進−CCK−8法
ヒト臍帯静脈内皮細胞は、密度が約2,500個/ウェルで96ウェルプレートに播種された。播種24h後、100μl/ウェルで新鮮な薬物含有培地に交換し、48h培養を続け、薬物処理終了前の2時間で、暗所の条件下で、1ウェル当たり10μlで培養液にCCK−8試薬を加えた。2h培養を続けた後、マイクロプレートリーダーで450nmにおける吸光度を測定し、細胞増殖率を算出した。図1の結果により、ブランク対照群よりも、IDHPが10−9〜10−7Mで血管内皮細胞増殖(P<0.01)を有意に促進したことが示された。
内皮細胞を24ウェルプレート内のゼラチンでプレコートされたカバーガラスに播種して移動させ、播種密度が約105個/ウェルであり、細胞がカバーガラスの壁に付着させて融合させた後、4h血清飢餓させ、実験室で特に作製されたマルチチャンネルの傷つけ手段にて引っ掻き傷を作成し、カバーガラスをPBSで2回洗浄し、600μl/ウェルで薬物含有培地を加え、0時間で対照群において直ちに冷メタノールで固定し、残った群で細胞を16h培養し続けた後、冷メタノールで固定し、顕微鏡で観察して写真撮影し、統計を行った。結果により(図2)、IDHPが10−10〜10−7Mでヒト臍帯静脈内皮細胞(HUVEC)の遊走を用量依存的に促進することができることが示された。
ピペットチップ及び96ウェルプレートを−20℃で予冷却し、マトリゲルを氷上にセットして融解させ、マトリゲル(60μL/ウェル)を採取し、気泡を形成させないように、予冷却された96ウェルプレートに加え、氷上に5min放置し、マトリゲルの液面を水平にした後、細胞培養インキュベーターに30min放置して凝固させ、内皮細胞(細胞数5×104/ウェル)を採取してマトリゲル含有ウェルに加え、さらに、異なる濃度の薬物を含む新鮮な培地を加え、37℃で8h培養し、顕微鏡で観察し、1ウェル当たり0、3、6、9時及び正中の合計5つの視野を選択し、管数及び管状構造の完全性を観察して写真撮影し、統計を行った。結果により、Ctrl対照群よりも、IDHPが、初代ヒト臍静脈内皮細胞(HUVEC)の管腔形成を有意に促進できることが示され、IDHPがin vitroで血管新生の促進活性を持つことが明らかになる。
遺伝子組み換えTg(VEGFR2:GFP)ゼブラフィッシュを明期14h/暗期10h、28℃標準条件下で飼育し、卵を使用する時に、健康で性的に成熟したゼブラフィッシュを取り出し、性比(雌雄)が1/1又は1/2の割合で繁殖用タンク内に入れ、翌日9〜10時で受精卵を取得した。受精卵を消毒して洗浄した後、ゼブラフィッシュ胚の培養液中に移し、28℃で培養した。
相対発生率(%)=(投与群の血管全長−PTK787対照群の血管全長)÷正常対照群の血管全長×100
志願者から全血を採取して抗凝固剤入り採血管に加え、800gで室温で5min遠心し、淡黄色の上澄みを取り多血小板血漿(PRP)とし、残りの液を4000gで室温下で10min遠心し、上澄みを取り乏血小板血漿(PPP)とした。
4.1 マウスへの迅速投与による急性毒性試験
マウス60匹を選択し、雌雄各半分、無作為に6群に分けた。β−(3,4−ジヒドロキシフェニル)−α−ヒドロキシプロピオン酸イソプロピルを生理食塩水で3.145%、2.68%、2.4%、2%、1.875%及び1.6%の6種の濃度である溶液を調製した。各濃度間の間隔は、1:0.9である。動物を12h絶食させた後、各群にそれぞれ静脈内投与(iv)し、容積が20mL/kgであり、各動物への投与を5秒以内に完了した。6群の用量は、それぞれ629mg/kg、530mg/kg、480mg/kg、400mg/kg、375mg/kg及び320mg/kgである。静脈内投与(iv)後、動物は、息切れし、心拍が速く、跳躍し、痙攣し、動きが遅くなって、横になった。中毒現象は投与量の増加とともに増加し、死亡した動物は基本的に投与後1min以内に死亡し、死んでいない動物は10分後に正常に戻った。死亡したマウスを剖検して肉眼で観察し、心臓、肝臓、脾臓、肺、腎臓、脳、胃、腸など重要な臓器にいずれも異常がなった。Blissのプロビツト法により測定し、LD50が424±58mg/kgであり、95%信頼区間が370〜486mg/kgであり、結果は表2に示された。
異質性検定:Chi2=6.90 Chi2.05=9.64 Sb=2.7993 異質性なし
回帰式:Y(Probit)=9.8687+13.0795×log(D) r=0.8716
LD50=424.4±39.7(mg/kg)
Feiller異質性補正:Sx=0.0229 Sb=3.6778
LD50=424.4±57.9(mg/kg)
95%信頼区間:370.4〜486.2mg/kg
試験用マウスは、実験室で1日飼育した後、体重合格者を選択し、無作為に体重及び性別に応じて群分けし、1群当たり10匹であり、雌雄各半分、予測結果により、全死亡用量が2.4g/kgであった。マウスに尾静脈内投与し、体重に応じて投与量を算出し、投与量が順に2.4g/kg、2.2g/kg、2.0g/kg、1.8g/kgであり、投与速度を算出し、10分間以内に投与を完成し、投与後にマウスの状態を観察し、マウスの死亡率を14日以内に記録した。
ウサギの動脈から採血し、フィブリンを除去し、赤血球を生理食塩水で洗浄した後、2%の赤血球含有生理食塩水溶液を調製した。表4に従って1群当たり試験管4本を並行的に使用して操作した。
試験結果により示されるように、赤血球の形態が無傷であり、明らかな溶血現象がなく、β−(3,4−ジヒドロキシフェニル)−α−ヒドロキシプロピオン酸イソプロピルが溶血作用を持たないことが示唆された。
リパーゼの触媒によりダンシェンスとイソプロパノールからβ−(3,4−ジヒドロキシフェニル)−α−ヒドロキシプロピオン酸イソプロピルを合成する。
ダンシェンス(5.0mg、0.025mmol)、イソプロパノール(0.3mg、0.005mmol)、水(1.5ml)、リパーゼ(5mg)を37℃で密閉したシェーカー(220回転/分間)で24時間インキュベートし、反応液100μlを採取し、酢酸エチル100μlを加え、20秒振動させ、有機相を採取して液体クロマトグラフィー及び質量分析を行った。質量分析結果([M−1]=239.0965)は図7に示され、液体クロマトグラフィーの結果は、図8に示された。
乳剤処方は、β−(3,4−ジヒドロキシフェニル)−α−ヒドロキシプロピオン酸イソプロピル:10.0g、ビタミンE:3.0g、精製大豆:200.0g、オレイン酸:15.0g、精製卵黄レシチン:25.0g、注射用水:約900ml、グリセリン:2.0gである。
β−(3,4−ジヒドロキシフェニル)−α−ヒドロキシプロピオン酸イソプロピル:10.4g、澱粉:6.3g、カルボキシメチルスターチナトリウム:1.8g、ポリエチレングリコール(分子量6000):26.5gであり、調製時に、処方量のβ−(3,4−ジヒドロキシフェニル)−α−ヒドロキシプロピオン酸イソプロピルとポリエチレングリコール6000とを採取して80℃まで加熱して融解させ、澱粉及びカルボキシメチルスターチナトリウムを加え、均一に混合し、流動パラフィンの冷媒中(1〜5℃)に滴下し、1粒重量が45mgの滴丸を1000粒作製し、表面の油痕を除去して得られた。
Claims (6)
- β−(3,4−ジヒドロキシフェニル)−α−ヒドロキシプロピオン酸イソプロピルを含有する、抗血小板凝集用薬物。
- β−(3,4−ジヒドロキシフェニル)−α−ヒドロキシプロピオン酸イソプロピルを含有する、抗血小板凝集用健康補助食品。
- β−(3,4−ジヒドロキシフェニル)−α−ヒドロキシプロピオン酸イソプロピルを含有する、血管新生促進用薬物。
- β−(3,4−ジヒドロキシフェニル)−α−ヒドロキシプロピオン酸イソプロピルを含有する、血管新生促進用健康補助食品。
- β−(3,4−ジヒドロキシフェニル)−α−ヒドロキシプロピオン酸イソプロピルを含有する、老人性血管性認知症を予防又は治療するための薬物。
- β−(3,4−ジヒドロキシフェニル)−α−ヒドロキシプロピオン酸イソプロピルを含有する、老人性血管性認知症を予防するための健康補助食品。
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CN201610876752.3 | 2016-10-08 | ||
PCT/CN2017/104278 WO2018064953A1 (zh) | 2016-10-08 | 2017-09-29 | Idhp在制备预防和治疗冠状动脉粥样硬化疾病药物或保健品中的应用 |
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