JP2019214558A - 腎障害の予防又は治療用の医薬組成物 - Google Patents
腎障害の予防又は治療用の医薬組成物 Download PDFInfo
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Abstract
Description
[1] D−アラニン、又はその誘導体を含む、腎臓病の予防又は治療用の医薬組成物。
[2] 前記予防又は治療用の医薬組成物が、腎臓の保護又は腎機能の回復に用いられる、項目1に記載の医薬組成物。
[3] 前記腎臓病が、急性腎障害、及び慢性腎臓病を含む、項目1又は2に記載の医薬組成物。
[4] 前記腎臓病が、虚血による腎障害である、項目1又は2に記載の医薬組成物。
[5] 局所投与、経腸投与又は非経口投与に用いられる、項目1〜4のいずれか一項に記載の医薬組成物。
[6] 前記誘導体が、投与後にD−アラニンに変化する化合物である、項目1〜5のいずれか一項に記載の医薬組成物。
[7] D−アラニン、又はその誘導体を含む、腎臓における炎症抑制剤。
[8] D−アラニン、又はその誘導体を含む、腎臓における炎症性細胞死抑制剤。
[9] D−アラニン、又はその誘導体を含む、腎臓病の予防用又は改善用食品。
[10] 前記誘導体が、投与後にD−アラニンに変化する化合物である、項目9に記載の腎臓病の予防用又は改善用食品。
[11] D−アラニン、又はその誘導体を投与することを含む、腎臓病の予防又は治療方法。
[12] 腎臓病の予防又は治療において使用するためのD−アラニン、又はその誘導体。
[13] 腎臓病の予防又は治療用の医薬組成物の製造のための、D−アラニン、又はその誘導体の使用。
[14] 腎臓の保護又は腎機能の回復に用いられる、項目11〜13のいずれか一項に記載の方法、D−アラニン又はその誘導体、或いは使用。
[15] 前記腎臓病が、急性腎障害、及び慢性腎臓病を含む、項目11〜14のいずれか一項に記載の方法、D−アラニン又はその誘導体、或いは使用。
[16] 前記腎臓病が、虚血誘導性又は炎症誘導性の腎障害である、項目11〜15のいずれか一項に記載の方法、D−アラニン又はその誘導体、或いは使用。
[17] 局所投与、経腸投与又は非経口投与に用いられる、項目11〜16のいずれか一項に記載の方法、D−アラニン又はその誘導体、或いは使用。
[18] 前記誘導体が、投与後にD−アラニンに変化する化合物である、項目11〜17のいずれか一項に記載の方法、D−アラニン又はその誘導体、或いは使用。
(1)尿検査、画像診断、血液検査、病理等で腎障害の存在が明らかであり、特に0.15g/gCr以上のタンパク尿(30mg/gCr以上のアルブミン尿)がある
(2)糸球体濾過量が、60mL/min/1.73m2未満である
のうちのいずれか、又は両方が、3ヶ月以上持続することにより、慢性腎臓病と診断される。糸球体濾過量は、血清クレアチニン値、年齢、性別から推算糸球体濾過量を算出することでも決定されうる。
1.材料及び方法
(1)研究倫理
全ての実験は施設のガイドラインに従い、該施設の動物実験委員会の承認を得て実施された。
アミノ酸のエナンチオマー及びHPLC級のアセトニトリルはナカライテスク(京都)から購入された。HPLC級のメタノール、トリフルオロ酢酸、ホウ酸等は和光純薬(大阪)から購入された。水はMilli−QグラジエントA10システムを用いて精製された。
動物はSPF環境、12時間ずつの明暗サイクルの条件下で、自由に水及び飼料を摂取できるようにして飼育された。C57BL/6Jマウスは日本クレア(大阪)から購入された。
12−16週齢のオスマウスを腎虚血再灌流(以下、「I/R」ともいう。)処理に供した。ペントバルビタール麻酔下で、Non-traumatic clip (Natsume Seisakusho. Tokyo)をもちい腎茎をクランプし、虚血を誘発した。40分後にクリップを開放した。処置中は対応を37℃に保持した。
虚血再かん流後、10日目で採取された腎臓を、10%中性緩衝ホルマリンで固定し、パラフィン包埋し、periodic acid-Schiff (PAS染色)(過ヨウ素酸シッフ染色)で染めた。染色した切片を明視野顕微鏡で撮影した(図1)。PASで染まったデブリス (皮髄境界部) 又はブラッシュボーダー (皮髄境界部と皮質領域) は、最低10か所異なる箇所で定量評価した。デブリ、尿細管拡張、ブラッシュボーダーの障害、尿細管壊死をATN scoreで評価した(0, none; 1, mild; 2, moderate; and 3, severe)。 サンプルの評価は、ブラインドで行った。結果を図2(A)〜(C)に示す。
マウス尿細管上皮細胞であるmProx24cellはSugaya (St. Marianna University School of Medicine, Tokyo)から提供された。この細胞を5%ウシ胎仔血清(FBS)及び1%ペニシリン及びストレプトマイシン添加DMEM培地で培養した。培養された細胞を、1%FBS添加DMEM培地を用いて1.0 × 106cell/ウェルで播種し、37℃、5%CO2及び20%O2加湿雰囲気下で24時間培養した。低酸素ストレス付加群では、24時間培養後に、5%FBS添加DMEM培地に5%CO2及び5%O2加湿雰囲気下でさらに20時間培養し、低酸素ストレス未付加群では、5%FBS添加DMEM培地に5%CO2及び20%O2加湿雰囲気下でさらに20時間培養した(図5(A))。これらのDMEM培地には、試験薬剤として1μM、10μM、及び100μMのD−アラニンを添加し、対照ではD−アラニンを含めなかった。
培養後細胞を回収し、the High Pure RNA Isolation Kit (Roche Diagnostics, Tokyo)を用いてTotal RNAを抽出した。SYBR Green fluorescence (Bio-Rad, Tokyo)を用いた定量的リアルタイムPCRは、Villa 7 Real-Time PCR System (Thermo Fisher Scientific, Tokyo)で行い、下記のプライマーを用いた。データはdelta-delta Ct 法で解析した(図5(B))。
KIM-1 Forward: 5’-aggaagacccacggctattt-3’ (配列番号1)
KIM-1 Reverse: 5’-tgtcacagtgccattccagt-3’ (配列番号2)
Claims (16)
- D−アラニン、又はその誘導体を含む、腎臓病の予防又は治療用の医薬組成物。
- 前記予防又は治療用の医薬組成物が、腎臓の保護又は腎機能の回復に用いられる、請求項1に記載の医薬組成物。
- 前記腎臓病が、急性腎障害又は慢性腎臓病を含む、請求項1又は2に記載の医薬組成物。
- 前記腎臓病が、虚血による腎障害である、請求項1又は2に記載の医薬組成物。
- 局所投与、経腸投与又は非経口投与に用いられる、請求項1〜4のいずれか一項に記載の医薬組成物。
- 前記誘導体が、投与後にD−アラニンに変化する化合物である、請求項1〜5のいずれか一項に記載の医薬組成物。
- D−アラニン、又はその誘導体を含む、腎臓における炎症抑制剤。
- D−アラニン、又はその誘導体を含む、腎臓における炎症性細胞死抑制剤。
- D−アラニン、又はその誘導体を含む、腎臓病の予防用又は改善用食品。
- 前記誘導体が、投与後にD−アラニンに変化する化合物である、請求項9に記載の腎臓病の予防用又は改善用食品。
- 腎臓病の予防又は治療用の医薬組成物の製造のための、D−アラニン、又はその誘導体の使用。
- 腎臓の保護又は腎機能の回復に用いられる、請求項11に記載の使用。
- 前記腎臓病が、急性腎障害、及び慢性腎臓病を含む、請求項11又は12に記載の使用。
- 前記腎臓病が、虚血誘導性又は炎症誘導性の腎障害である、請求項11〜13のいずれか一項に記載の使用。
- 局所投与、経腸投与又は非経口投与に用いられる、請求項11〜14のいずれか一項に記載の使用。
- 前記誘導体が、投与後にD−アラニンに変化する化合物である、請求項11〜15のいずれか一項に記載の使用。
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WO2022244846A1 (ja) * | 2021-05-19 | 2022-11-24 | Kagami株式会社 | 細胞増殖の調整のための組成物及び細胞増殖の調整方法 |
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