JPWO2007037188A1 - 血管透過性亢進に起因する眼疾患の予防及び治療のための医薬 - Google Patents
血管透過性亢進に起因する眼疾患の予防及び治療のための医薬 Download PDFInfo
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Abstract
Description
「血液臓器関門と疾患」, 森道夫編著, 病気と細胞内小器官, 文光堂, pp.182-194, 2002 「"すきま"の細胞生物学」−細胞間接着装置タイト結合とヒト疾患−, 札幌医学雑誌, 72, pp.1-7, 2003 Med. Electron Microsc.,36, pp.147-156, 2003 Exp. Cell Res.,290, pp.275-288, 2003 Biochem. Biophys. Res. Commun.,261, pp.108-112, 1999 Am. J. Physiol. Cell Physiol., 279, C361-368, 2000 Cell Struct. Funct.,25, 237-241, 2000 Biochem. Biophys. Res. Commun., 330, 361-366, 2005 FASEB J.,10, pp.940-954, 1996 Exp. Cell Res.,263, pp.163-172, 2001. Exp. Cell Res.,222, pp.269-274, 1996.
上記の発明の好ましい態様によれば、血管透過性亢進に起因する眼疾患が糖尿病性網膜症又は加齢黄斑変性である上記の医薬が提供される。また、初期糖尿病又は中期糖尿病において糖尿病性網膜症の予防のために用いる上記の医薬;糖尿病性網膜症の前症状期において予防のために用いる上記の医薬が提供される。
また、本発明の別の好ましい態様によれば、該レチノイドがオールトランスレチノイン酸である上記の医薬;該レチノイドが非天然型のレチノイドである上記の医薬;該レチノイドが芳香環と芳香族カルボン酸又はトロポロンとが連結基を介して結合した基本骨格を有するレチノイドである上記の医薬が提供される。
特に好ましいレチノイドとして、Am80(4-[(5,6,7,8-テトラヒドロ-5,5,8,8-テトラメチル-2-ナフタレニル)カルバモイル]安息香酸)又はAm580(4-[(5,6,7,8-テトラヒドロ-5,5,8,8-テトラメチル-2-ナフタレニル)カルボキサミド]安息香酸)が挙げられる。
例1:GDNFのオールトランスレチノイン酸による調節制御
一般にアストロサイトのin vitroの研究系において、使用細胞の選択は重要な問題である。ヒトの脳から単離されたアストロサイトは、米国の細胞バンクあるいは研究会社経由で入手することは可能であるが、よく分化した形質を持つ神経系細胞の初代培養という性格上、細胞増殖は遅く、遺伝子発現等の解析には不適格である。そこで、本発明者らは、アストロサイトへの分化マーカーとして知られるGFAP(glial fibrillary acidic protein)が陽性であり、かつCell lineとして安定した性格を有するヒトグリオーマ細胞であるU373MG細胞を用いて実験を行った。U373MG細胞は、市場において容易に入手可能である。
1)94℃、30秒
2)94℃、15秒
3)52℃、15秒
4)72℃、30秒
5)2)から4)の反応を32回繰り返し
6)72℃、7分
この最終反応産物をサザンブロット法に使用した。結果を図2に示す。
例1において、atRAの濃度上昇に応じてGDNFの発現が上昇したが(濃度依存性)、この変化が生理的反応を有するか否かについて検討するために、血管内皮細胞との共培養を行った。図3に示されるように、トランスウェル(Transwell)を用いた2重チャンバー(double chamber)を構成した。図3から分かるように、外側チャンバー(outer chamber)にエフェクター細胞としてU373MG細胞(アストロサイト)を培養し、atRAで処理して24時間さらに培養した。別に用意した内側チャンバー(inner chamber)にはウシの脳より得られた血管内皮細胞を培養し、あらかじめ一層の密な細胞シートを形成するよう準備した。
例2において血管内皮細胞との共培養を行った結果から、atRAによって惹起されるGDNFの発現上昇が血管内皮細胞に対して機能的であることが判明した。予備実験の結果では、Am580がatRAと同様にGDNF mRNAの発現を濃度依存的かつ時間依存的に誘導することを確認した(以下の図6参照)。例2で用いた血管内皮細胞は、ウシの脳より得られた初代培養細胞株であり、より生体内に近い状況を試験管内で再現できるという利点を有する。しかし、初代培養細胞株は、いわゆるCell lineとは異なり、分裂回数に制限があり、分裂速度が遅く、繰り返し検証の必要な実験系には不向きであるという側面も有する。そこで、バリヤー機能の評価をするうえで最適であり、かつすでに広範な実験系で利用されている実績を持つイヌ由来腎尿細管細胞であるMDCK(Madin Darby Canine Kidney)細胞(市場で容易に入手可能である)を用いて、合成レチノイドの効果を例2と同様のパラメーターで評価した。その結果を図5に示す。図5における実験群は以下の通りである。
1. 非処理群
2. atRA(RARαアゴニスト)
3. Am80(RARαアゴニスト)
4. Am580(RARαアゴニスト)
例1及び2は、アストロサイトとしての形質を持つCell lineであるU373MG細胞を用い、実験の簡便化を図ったが、in vitroの実験系ではしばしばCell lineは元の形質を完全に保有していないことがあり、継代によっても形質が変化することが知られている。そこで、レチノイドによるGDNFの発現亢進が、ヒトアストロサイトを用いた系でも観察されるか否かを検討した。ここで使用したアストロサイトは、ヒト脳より分離された初代培養細胞で米国CAMBREX社より購入した。これにより、より生体に近い環境が観察できる利点がある。結果を以下の図6に示す。
1. 未処理群
2. atRA
3. Am580
オスの5〜6週齢のC57/BL6マウスにストレプトゾトシンを投与し、モデルマウスに化学的に糖尿病を誘導した。この糖尿病モデルマウスに対してレチノイドを投与して治療効果を評価した。参考のため、糖尿病を誘発していないマウスを使用してコントロールとした。
結果を図9に示す。実験群は以下の通りである。
実験群:
1. コントロール(糖尿病非誘発群)
2. 糖尿病群(非治療群)
3. 糖尿病群(atRA治療群)
4. 糖尿病群(Am580治療群)
5. 糖尿病群(Am80治療群)
生体パラメーターとして血糖値(BS)及び尿糖(US)を評価した。BS及びUSが糖尿病群で有意に高値(*p<0.05、**p<0.01)を示すことはヒト糖尿病で見られる変化とよく合致していた。atRA投与群では非投与群と比較して有意にUSの低値を認めた。
Claims (12)
- 血管透過性亢進に起因する眼疾患の予防及び/又は治療のための医薬であって、レチノイドを有効成分として含む医薬。
- 血管透過性亢進に起因する眼疾患が糖尿病性網膜症又は加齢黄斑変性である請求項1に記載の医薬。
- 初期糖尿病又は中期糖尿病において糖尿病性網膜症の予防のために用いる請求項2に記載の医薬。
- 糖尿病性網膜症の前症状期において予防のために用いる請求項2に記載の医薬。
- レチノイドがオールトランスレチノイン酸である請求項1ないし4のいずれか1項に記載の医薬。
- レチノイドが非天然型のレチノイドである請求項1ないし4のいずれか1項に記載の医薬。
- レチノイドが芳香環と芳香族カルボン酸又はトロポロンとが連結基を介して結合した基本骨格を有するレチノイドである請求項6に記載の医薬。
- レチノイドがレチノイン酸レセプター(RAR)・サブタイプα及びサブタイプβに結合するレチノイドである請求項1ないし4のいずれか1項に記載の医薬。
- レチノイドがレチノイドXレセプターX(RXR)に結合するレチノイドである請求項1ないし4のいずれか1項に記載の医薬。
- レチノイドがAm80(4-[(5,6,7,8-テトラヒドロ-5,5,8,8-テトラメチル-2-ナフタレニル)カルバモイル]安息香酸)又はAm580(4-[(5,6,7,8-テトラヒドロ-5,5,8,8-テトラメチル-2-ナフタレニル)カルボキサミド] 安息香酸である請求項1ないし4のいずれか1項に記載の医薬。
- 請求項1ないし4のいずれか1項に記載の医薬の製造のためのレチノイドの使用。
- 血管透過性亢進に起因する眼疾患の予防及び/又は治療方法であって、上記のレチノイドの有効量をヒトを含む哺乳類動物に投与する工程を含む方法。
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PT2187880E (pt) * | 2007-09-12 | 2014-03-25 | Univ Columbia | Composições e métodos para o tratamento da degenerescência macular |
CA2862746A1 (en) * | 2011-12-01 | 2013-06-06 | Bikam Pharmaceuticals, Inc. | Opsin-binding ligands, compositions and methods of use |
MX363111B (es) | 2012-11-08 | 2019-03-08 | Univ Yamaguchi | Agente terapeutico para trastornos de queratoconjuntivitis. |
CA2906800A1 (en) | 2013-03-15 | 2014-09-18 | Avisenna Cosmetics, Llc | Topical compositions for reducing the effects of aging |
CA2913005C (en) * | 2013-05-22 | 2021-08-10 | Yamaguchi University | Inhibitor for retinochoroidal disorders |
KR102486607B1 (ko) | 2016-06-08 | 2023-01-11 | 클레멘티아 파마슈티컬즈, 인크. | 이소성 골화를 치료하는 방법 |
SG10202105186XA (en) | 2016-11-16 | 2021-06-29 | Clementia Pharmaceuticals Inc | Methods for treating multiple osteochondroma (mo) |
US11931327B2 (en) | 2017-07-04 | 2024-03-19 | Daiichi Sankyo Company, Limited | Drug for retinal degenerative disease associated with photoreceptor degeneration |
TW202039421A (zh) * | 2018-12-25 | 2020-11-01 | 日商第一三共股份有限公司 | 具有稠環結構之對酞酸衍生物 |
EP3881840A1 (en) * | 2020-03-19 | 2021-09-22 | Insusense ApS | Sortilin antagonists for use inthe treatment of diabetic retinopathy |
CN112390731B (zh) * | 2020-11-16 | 2022-11-25 | 成都大学 | 一种具有多靶点的维甲酸类衍生物及其制备方法与应用 |
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JPH1087481A (ja) * | 1996-09-02 | 1998-04-07 | Cird Galderma | Vegf過剰発現疾病治療剤 |
JPH11171776A (ja) * | 1997-12-05 | 1999-06-29 | Iyaku Bunshi Sekkei Kenkyusho:Kk | 糖尿病の予防・治療剤 |
WO2000066595A1 (fr) * | 1999-04-28 | 2000-11-09 | Institute Of Medicinal Molecular Design. Inc. | Derives d'acides carboxyliques heterocycliques |
WO2002053523A1 (fr) * | 2000-12-26 | 2002-07-11 | Research Foundation Itsuu Laboratory | Derive de tropolone |
WO2004089916A1 (en) * | 2003-04-10 | 2004-10-21 | Novartis Ag | 11-phenyl-dibenzodiazepine derivatives as rxr-antagonists |
WO2005087713A1 (ja) * | 2004-03-12 | 2005-09-22 | Sakai Chemical Industry Co., Ltd. | アミド化合物、医薬組成物及びrxr機能調節剤 |
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FR2735367B1 (fr) * | 1995-06-19 | 1997-07-18 | Cird Galderma | Utilisation de ligands specifiques des recepteurs rxrs |
JP3865829B2 (ja) | 1995-09-21 | 2007-01-10 | 株式会社医薬分子設計研究所 | レチノイド作用増強性化合物 |
US6184256B1 (en) * | 1997-04-24 | 2001-02-06 | INSTITUT NATIONAL DE LA SANTé DE LA RECHERCHE MéDICALE | Methods and compositions for use in modulating expression of matrix metalloproteinase genes |
ITRM20010464A1 (it) * | 2001-07-31 | 2003-01-31 | Sigma Tau Ind Farmaceuti | Derivati retinoidi ad attivita' antiangiogenica, antitumorale e pro-apoptotica. |
PL371929A1 (en) * | 2001-11-09 | 2005-07-11 | Eyetech Pharmaceuticals | Methods for treating ocular neovascular diseases |
WO2005056010A1 (en) * | 2003-12-02 | 2005-06-23 | Allergan, Inc. | Prevention and/or reduction of photoreceptor degeneration with retinoids |
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2006
- 2006-09-25 WO PCT/JP2006/318919 patent/WO2007037188A1/ja active Application Filing
- 2006-09-25 US US12/088,154 patent/US20090281184A1/en not_active Abandoned
- 2006-09-25 CN CNA2006800443874A patent/CN101316584A/zh active Pending
- 2006-09-25 EP EP06810487A patent/EP1938815A1/en not_active Withdrawn
- 2006-09-25 JP JP2007537599A patent/JPWO2007037188A1/ja active Pending
Patent Citations (6)
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JPH1087481A (ja) * | 1996-09-02 | 1998-04-07 | Cird Galderma | Vegf過剰発現疾病治療剤 |
JPH11171776A (ja) * | 1997-12-05 | 1999-06-29 | Iyaku Bunshi Sekkei Kenkyusho:Kk | 糖尿病の予防・治療剤 |
WO2000066595A1 (fr) * | 1999-04-28 | 2000-11-09 | Institute Of Medicinal Molecular Design. Inc. | Derives d'acides carboxyliques heterocycliques |
WO2002053523A1 (fr) * | 2000-12-26 | 2002-07-11 | Research Foundation Itsuu Laboratory | Derive de tropolone |
WO2004089916A1 (en) * | 2003-04-10 | 2004-10-21 | Novartis Ag | 11-phenyl-dibenzodiazepine derivatives as rxr-antagonists |
WO2005087713A1 (ja) * | 2004-03-12 | 2005-09-22 | Sakai Chemical Industry Co., Ltd. | アミド化合物、医薬組成物及びrxr機能調節剤 |
Also Published As
Publication number | Publication date |
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CN101316584A (zh) | 2008-12-03 |
EP1938815A1 (en) | 2008-07-02 |
US20090281184A1 (en) | 2009-11-12 |
WO2007037188A1 (ja) | 2007-04-05 |
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