JP7097444B2 - 脳小血管病の治療用医薬の製造における化合物の使用 - Google Patents
脳小血管病の治療用医薬の製造における化合物の使用 Download PDFInfo
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Images
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
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Description
式I
式I
式I
式I
式I
式I
式I
本発明に係る方法又は用途に適用される化合物は、式Iの化合物、その重水素化物又は薬学的に許容されるその塩を含む。
式I
式II
本発明の別の態様では、有効量の式Iの化合物、その重水素化物又は薬学的に許容されるその塩と、薬学的に許容される担体とを含む医薬組成物が提供される。
本発明の別の態様では、脳小血管病の治療用医薬の製造における式Iの化合物、その重水素化物又は薬学的に許容されるその塩の使用が提供される。そして、本発明では、脳小血管病の治療のための、式Iの化合物、その重水素化物又は薬学的に許容されるその塩の使用が提供される。そして、本発明では、患者における脳小血管病の治療のために、有効量の式Iの化合物、その重水素化物もしくは薬学的に許容されるその塩、又は上記の医薬組成物を当該患者に投与することを含む方法が提供される。
方法:
組織切片の免疫蛍光イメージング:パラフィン切片の厚さは5μmとする。新鮮なパラフィン切片を、37℃で一晩乾燥後に55℃で30分間乾燥させて、直ちにキシレンに入れて脱パラフィンする。キシレンに10分間置き、これを3回繰り返して充分に脱パラフィンされた後、無水エタノール、95%エタノール、90%エタノール、80%エタノール、70%エタノール、50%エタノール、ddH2Oをこの順に使用して、勾配を利用して再水和させる。再水和後に、切片をEDTA抗原賦活化溶液に入れて、マイクロウェーブによる高温処理で賦活させる。賦活化が完了した後、室温に自然冷却させる。一次抗体インキュベーション:吸取紙で組織の周囲の水分を除き、免疫組織化学用パップペンでサンプルの周りに円を描き、DAKO抗体希釈液で希釈した一次抗体を加え、ウェットボックスで、4℃の暗所環境で一晩インキュベートする。室温で10分間平衡化させて、1回当たり5分間で、PBSTで3回洗浄する。対応の蛍光標識された二次抗体種を加え、ウェットボックスで、室温の暗所環境で1時間インキュベートする。PBSTで3回洗浄して、DAKO抗体希釈液で希釈したHochest33342染色液を用いて、室温の暗所環境で10分間染色し、1回当たり5分間で、PBSTで3回洗浄する。水溶性の封入剤で切片を封入し、共焦点レーザー顕微鏡を用いて画像を得る。共焦点撮影法は免疫蛍光染色と同じく、ソフトウェアNIS-Elements Analysisを用いて共焦点画像の蛍光強度を解析し、ソフトウェア内のスケールで単位面積の組織の蛍光強度を標準化する。
高原低圧キャビンを利用して、高原に入った初期の急性の低圧低酸素状態をシミュレートする。190分間でカニクイザルを標高320メートルから7500メートルに持ち上げ、次に7500メートルの高さにおいてカニクイザルを48時間保持することにより、非常に高い標高に迅速に到達することを実験的な条件でシミュレートする。標高が増加するにつれて、カニクイザルに顕著な急性高山病の症状、例えば、嘔吐、脊髄小脳失調症、意識障害等が出現することから、非ヒト霊長類であるカニクイザルの急性高山病モデルの複製に成功することが示される。古典的行動学的、病理学的、生化学的手法等によって検出した結果、急性の低圧低酸素のためカニクイザルに顕著な骨格筋の協調性低下、脳組織構造の空胞化改変、脳内の水分含量増加、脳組織の血管性浮腫及びニューロンの変性損傷が生じることから、急性の低圧低酸素が顕著な脳損傷を引き起こすことが示されている。
CD163は抗炎症活性を有するM2型マクロファージの分子マーカーの1つであり、その機能は哺乳動物における唯一のヘモグロビンスカベンジャー受容体としてヘモグロビン分子の細胞内除去に関与することである。ヘモグロビンとハプトグロビン複合体はマクロファージ/小膠細胞におけるCD163が仲介する貪食過程後に、エンドソームによってリソソームに輸送され、分解してヘムが生成される。さらにヘムはHO-1の作用で分解してFe2+、CO、ビリベルジンが生成され、Fe2+とビリベルジンが酸化されてFe3+、ビリルビンになる。
方法:
細胞培養:小膠細胞BV2を蘇生させた後、FBSを10%含むDMEM培地で培養し、細胞密度が約80%になるとプレートに接種して継代培養し、細胞の接種密度は約4.0~5.0×105/mLとする。
遊離ヘモグロビンが直接的に小膠細胞の活性化を引き起こせるかどうかを調べるために、ヘモグロビンで小膠細胞を刺激して、その活性化指標の変化を観察する。結果では、インビトロにおいて遊離ヘモグロビンを用いて異なる時間で、小膠細胞BV2を直接的に刺激したところ、24時間でBV2は活性化型の形態を示し、具体的には細胞体が拡大し、糸状の仮足が増加又は延長しており(図6のAとC)、且つ小膠細胞の活性化分子マーカーIba-1(図6のD)及びCD11b(図6のBとE)の発現量が遊離ヘモグロビンの刺激により顕著にアップレギュレーションされる(図6のBと6D)。ウェスタンブロッティング実験によって、カニクイザルの脳組織における免疫蛍光試験の結果がさらに確定している(図6のE)。これらの結果と一致するように、遊離ヘモグロビンの刺激が小膠細胞の炎症性サイトカインTNF-α、IL-1β、IL-6のmRNAレベルにおける顕著な発現増加を引き起こしていることから(図6のF)、遊離ヘモグロビンが小膠細胞の炎症性活性化を引き起こしていることが示される。
Claims (14)
- 前記R1はHである請求項1に記載の医薬。
- R1は、-CH(CH3) 2 及び-CH(CH3)(CH2)3CH(CH3)2からなる群から選ばれる請求項1に記載の医薬。
- 前記微小脳出血は自発性微小脳出血、薬物関連の微小脳出血、又は外傷性微小脳出血である請求項1~3のいずれか1項に記載の医薬。
- 前記自発性微小脳出血は加齢性の微小脳出血、高血圧性の微小脳出血、急性高山病に併発する微小脳出血、慢性高山病に併発する微小脳出血、虚血性脳卒中に併発する微小脳出血、又は出血性脳卒中に併発する微小脳出血である請求項4に記載の医薬。
- 前記薬物関連の微小脳出血は血栓溶解薬関連の微小脳出血、抗凝固薬関連の微小脳出血、血小板凝集抑制薬関連の微小脳出血、又はスタチン系薬物関連の微小脳出血である請求項4に記載の医薬。
- 前記外傷性微小脳出血は手術によって引き起こされる微小脳出血である請求項4に記載の医薬。
- 前記手術は中枢神経系に直接的な影響を与える手術である請求項7に記載の医薬。
- 前記手術は脳動脈瘤クリッピング術、脳動脈瘤塞栓術、又は脳腫瘍切除術である請求項7に記載の医薬。
- 前記脳小血管病は無症状である請求項1~3のいずれか1項に記載の医薬。
- 前記脳小血管病は症状がある請求項1~3のいずれか1項に記載の医薬。
- 前記患者はヒトである請求項1~3のいずれか1項に記載の医薬。
- 前記医薬はさらに他の治療薬を含む請求項1~3のいずれか1項に記載の医薬。
- 前記脳小血管病は、脳血管外の遊離ヘモグロビンの分布の顕著な増加として現れる請求項1~3のいずれか1項に記載の医薬。
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CN201711484028.7A CN109985049B (zh) | 2017-12-29 | 2017-12-29 | 5α-雄甾-3β,5,6β-三醇在制备治疗脑小血管病的药物中的应用 |
PCT/CN2018/124705 WO2019129179A1 (zh) | 2017-12-29 | 2018-12-28 | 化合物在制备治疗脑小血管病的药物中的应用 |
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CN101683348A (zh) | 2008-09-23 | 2010-03-31 | 中山大学 | 胆甾烷-3β,5α,6β-三醇在制备神经元保护药物中的应用 |
JP2013529657A (ja) | 2010-07-09 | 2013-07-22 | グァンツォウ セルプロテック ファーマシューティカル リミテッド | ニューロン保護薬の製造のための5α−アンドロスタン−3β,5,6β−トリオールの使用 |
JP2017513873A (ja) | 2014-04-25 | 2017-06-01 | グァンチョウ セルプロテック ファーマシューティカル カンパニー リミテッド | 神経保護剤及びその適応症 |
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WO2005123757A1 (en) * | 2004-06-10 | 2005-12-29 | Merck & Co., Inc. | Estrogen receptor modulators |
AU2005267210A1 (en) * | 2004-06-30 | 2006-02-02 | Merck & Co., Inc. | Estrogen receptor modulators |
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US20090258850A1 (en) * | 2007-08-21 | 2009-10-15 | Frincke James M | Stabilized therapeutic compositions and formulations |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101683348A (zh) | 2008-09-23 | 2010-03-31 | 中山大学 | 胆甾烷-3β,5α,6β-三醇在制备神经元保护药物中的应用 |
JP2013529657A (ja) | 2010-07-09 | 2013-07-22 | グァンツォウ セルプロテック ファーマシューティカル リミテッド | ニューロン保護薬の製造のための5α−アンドロスタン−3β,5,6β−トリオールの使用 |
JP2017513873A (ja) | 2014-04-25 | 2017-06-01 | グァンチョウ セルプロテック ファーマシューティカル カンパニー リミテッド | 神経保護剤及びその適応症 |
Non-Patent Citations (5)
Title |
---|
Biochemical and Biophysical Research Communications,2017年01月09日,Vol. 483,pp. 892-896 |
International Journal of Stroke,2015年,Vol. 10,pp. 469-478 |
Lancet Neurol,2013年,Vol. 12,pp. 483-497 |
Stroke and Vascular Neurology,2016年,Vol. 1,e000035, pp. 83-92 |
日薬理誌,2014年,Vol. 144,pp. 115-119 |
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JP2021507934A (ja) | 2021-02-25 |
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EP3733190A4 (en) | 2021-09-29 |
WO2019129179A1 (zh) | 2019-07-04 |
US20200330483A1 (en) | 2020-10-22 |
IL275686A (en) | 2020-08-31 |
AU2018396895A1 (en) | 2020-07-30 |
TWI762754B (zh) | 2022-05-01 |
IL275686B1 (en) | 2024-02-01 |
KR102466251B1 (ko) | 2022-11-10 |
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AU2018396895B2 (en) | 2021-05-27 |
CN109985049B (zh) | 2022-02-22 |
EP3733190A1 (en) | 2020-11-04 |
PT3733190T (pt) | 2023-07-27 |
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