JP2011001380A - 脈絡膜血管新生の抑制方法 - Google Patents
脈絡膜血管新生の抑制方法 Download PDFInfo
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- JP2011001380A JP2011001380A JP2010223994A JP2010223994A JP2011001380A JP 2011001380 A JP2011001380 A JP 2011001380A JP 2010223994 A JP2010223994 A JP 2010223994A JP 2010223994 A JP2010223994 A JP 2010223994A JP 2011001380 A JP2011001380 A JP 2011001380A
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Abstract
本発明は、望ましくない血管新生、特に眼の組織の血管新生を抑制するための組成物および方法を課題とする。
【解決手段】
抗血管新生および抗CNV剤として潜在的な作用物質のスクリーニングを可能にするCNVのための動物モデルおよび画像形成技法とともに、脈絡膜血管新生(CNV)の治療、抑制および/または予防法が提供される。
【選択図】 なし
Description
本発明は、米国国立衛生研究所からの補助金Y12727により一部支援された。政府は本発明においてある種の権利を有する。
3年を越えて、そして>60%が5年で)(非特許文献4)。さらにCNVはレーザー治療には大きすぎるため、あるいは位置が確定され得ず、したがって医者が正確にレーザーを向けることができないため、CNVを発症する多数の患者は、レーザー療法のための良好な候補でない。したがって本発明までは、脈絡膜血管新生を防止するかまたは有意に抑制する方法の必要性があると長い間思われていた。
本発明は、血管新生および新生血管形成を含む障害、例えば眼障害、特に網膜障害、例えば黄斑変性、脈絡膜血管新生等、および上記のような網膜における、あるいは網膜とその下にある脈絡膜組織との間における、または脈絡膜組織を含む網膜における障害の治療のための方法を提供する。本方法は、大環状ラクトンシロリムス(ラパムン(登録商標)(Wyeth-Ayerst)として市販)としても既知である免疫抑制剤のラパマイシンに関する新規の使用を含む(非特許文献5 参照)。メルクインデックス(Merck Index), 第12版(非特許文献6)によれば、ラパムンは、RAPA、RPM、シロリムス、AY22989およびNSC−226080としても既知である。
マトリゲル(商標)ベースの動物モデル
本出願内では、別記しない限り、利用される技法はいくつかの既知の参考文献、例えば以下の参考文献のいずれかに見出すことができる(非特許文献12、非特許文献13、非特許文献14)。
CNVの抑制
モデルの初期の特性化に際して、新生血管形成の生成におけるマトリゲル(商標)に対する炎症反応の潜在的な関与が存在する、と推測した。その結果、2つの既知の免疫抑制剤、シクロスポリンおよびラパマイシンを試験した。
血管ペインティング
CO2過剰投与により屠殺した正常3か月齢スプラーグ−ドーリーラットからの網膜を血管ペイント(DiI、0.1mg/ml)により灌流し、その後4%パラホルムアルデヒドを用いて灌流した。網膜を切り出して、同一固定剤液中で1時間、固定して、リン酸緩衝生理食塩水(PBS)中ですすぎ、スライドガラス上に平らに封入する(flat-mounted)。ニコンE800顕微鏡で顕微鏡写真を撮った。
マトリゲル(商標)注入領域におけるCNV
マトリゲル(商標)は、ネズミEHS(Engelbreth-Holm-Swarm)腫瘍からの細胞外マトリックス(ECM)タンパク質の抽出物であり、細胞培養実験において再構築基底膜として広範に用いられる。それは、in vivo検定であるマトリゲル(商標)プラグ検定において血管新生または抗血管新生性作用物質を評価するためにも用いられる(非特許文献17)。病理学的試験は、網膜色素上皮(RPE)とブルック膜との間の位置におけるCNVと細胞外マトリックス(ECM)の異常沈着物との間の会合を示す。AMDにおいて起こる異常沈着物を模倣するために、ラットの網膜下間隙にマトリゲル(商標)を注入した。マトリゲル(商標)注入直後に、新血管がマトリゲル(商標)沈着物を侵襲する。
ラパマイシンによるCNVの抑制
マトリゲル(商標)モデルを用いた潜在的な抗血管新生作用物質の初期スクリーンにおいて、ラパマイシンは、新血管形成を抑制する顕著な能力を実証した。免疫抑制剤として臨床的に用いられるラパマイシン(カハン BD(Kahan BD) (2001) シロリムス:包括的レビュー(非特許文献18)は、FKBP(FK506結合タンパク質)と結合して、FKBP−ラパマイシン複合体を形成し、これが次に、細胞増殖の中心制御物質であるmTOR(ラパマイシンの哺乳類標的)の機能を抑制する(非特許文献19)。ラパマイシンは内皮細胞増殖を(非特許文献20)、そしてVEGF(非特許文献21)ならびにbFGF(塩基性線維芽細胞増殖因子)およびPDGF(血小板由来増殖因子)に対する応答を抑制する。ツァオ等(Cao et al.)(1995) 増殖因子に刺激された血管平滑筋細胞のDNA合成におけるラパマイシンの影響。塩基性線維芽細胞増殖因子および血小板由来増殖因子活性の抑制とFK506によるラパマイシンの拮抗作用(Effects of rapamycin on growth factor-stimulated vascular smooth muscle cell DNA synthesis. Inhibition of basic fibroblast growth factor and platelet-derived growth factor action and antagonism of rapamycin by FK506). Transplantation 59 (3): 390-5(非特許文献22)、およびルイグロク等(Ruygrok et al.)(2003) ラパマイシンと循環器系内科(Rapamycin and cardiovascular medicine). Intern. Med. J. 33(3): 103-9(非特許文献23)を参照。腫瘍血管新生を遮断することも示されている(非特許文献24)。
FK506タクロリムス処理眼におけるCNV指数
水溶性でないFK506を、10μg/μlでマトリゲル(商標)(懸濁液として)と混合し、1.2μlを上記のように網膜下間隙に注射した。注射後10日目に眼を回収し、血管を血管ペイントで染色した。眼を5%アガロース中に包埋し、ビブラトームで連続切片を切断した(100μm厚)。蛍光顕微鏡によりCNVを検査し、各眼のCNV指数を算定した。結果を以下に示す。
Claims (6)
- 脈絡膜血管新生を抑制または予防するための、目または目の組織に投与するのに適した医薬組成物であって、前記医薬組成物が、治療に有効な量のラパマイシン、タクロリムス、エベロリムス、ピメクロリムス、CCI−779、ABT−578、またはAP23841、並びに薬学的に許容可能な担体を含む、医薬組成物。
- 前記脈絡膜血管新生は、加齢性黄斑変性、推定眼ヒストプラスマ症候群、近視性変性、色素線条、または眼性外傷の網膜または網膜下の障害において起こる、請求項1に記載の医薬組成物。
- 投与方法が、眼内注入、網膜下注入、強膜下注入、脈絡膜内注入、結膜下注入、硝子体内注入からなる群から選択される、請求項1又は2に記載の医薬組成物。
- 血管形成又は新生血管形成の治療のための他の作用物質を含む、請求項1〜3の何れか1項に記載の医薬組成物。
- 前記作用物質は、ピロリジン、ジチオカルバメート(NFκB阻害剤);スクアラミン;TPN470類似体およびフマギリン;PKC(プロテインキナーゼC)阻害剤;Tie−1およびTie−2キナーゼ阻害剤;VEGF受容体キナーゼの阻害剤;プロテオソーム阻害剤、例えばベルケード(商標)(ボルテゾミブ、注射用);ラニブズマブ(ルセンチス(商標))および同一標的に対するその他の抗体;ペガプタニブ(マキュゲン(商標));ビトロネクチン受容体アンタゴニスト、例えばビトロネクチン受容体型インテグリンの環状ペプチドアンタゴニスト;α−v/β−3インテグリンアンタゴニスト;α−v/β−1インテグリンアンタゴニスト;チアゾリジンジオン、例えばロシグリタゾンまたはトログリタゾン;インターフェロン、例えばγ−インターフェロン、あるいはデキストランの使用および金属配位によりCNVに対して標的化されるインターフェロン;色素上皮由来因子(PEDF);エンドスタチン;アンギオスタチン;酢酸アネコルタブ;アセトニド;トリアムシノロン;テトラチオモリブデート;アキュタン(商標)(13−シスレチン酸);ACE阻害剤、例えばキノプリルまたはペリンドズリル;mTOR(ラパマイシンの哺乳類標的)の阻害剤;3−アミノサリドマイド;ペントキシフィリン;2−メトキシエストラジオール;コルヒチン;AMG−1470;シクロオキシゲナーゼ阻害剤、例えばネパフェナク、ロフェコキシブおよびジクロフェナク;t−RNAシンターゼモジュレーター;メタロプロテアーゼ13阻害剤;アセチルコリンエステラーゼ阻害剤;カリウムチャンネル遮断剤;エンドレペリン;6−チオグアニンのプリン類似体;環状ペルオキシドANO−2;(組換え)アルギニンデイミナーゼ;エピガロカテキン−3−ガレート;セリバスタチン;スラミンの類似体;ならびにビスダイン(商標)およびその他の光線感作物質から選択される、請求項4に記載の医薬組成物。
- 脈絡膜血管新生を抑制または予防するための、目または目の組織に投与するのに適した医薬組成物であって、前記医薬組成物が治療に有効な量のラパマイシンおよび薬学的に許容可能な担体を含み、前記脈絡膜血管新生が加齢性黄斑変性において起こり、投与方法が結膜下注入又は硝子体内注入である、医薬組成物。
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JP2016094441A (ja) * | 2012-02-06 | 2016-05-26 | プリジェン,ウィリアム,エル. | ファムシクロビルとセレコキシブとの組合せを含む、機能性身体症候群のための抗ウイルス化合物とcox−2インヒビターとの組合せ療法 |
US10034846B2 (en) | 2012-02-06 | 2018-07-31 | Innovative Med Concepts, LLC | Famciclovir and celecoxib combination therapy for functional somatic syndromes |
US10251853B2 (en) | 2012-02-06 | 2019-04-09 | Innovative Med Concepts, LLC | Synergistic famciclovir and celecoxib combination therapy for functional somatic syndromes |
WO2020080275A1 (ja) * | 2018-10-15 | 2020-04-23 | 国立大学法人大阪大学 | 網膜および/または光受容に関連する症状の改善または予防用医薬ならびに網膜および/または光受容に関連する症状を改善または予防する物質のスクリーニング方法 |
JP7431451B2 (ja) | 2018-10-15 | 2024-02-15 | 国立大学法人大阪大学 | 網膜および/または光受容に関連する症状の改善または予防用医薬ならびに網膜および/または光受容に関連する症状を改善または予防する物質のスクリーニング方法 |
Also Published As
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JP5395024B2 (ja) | 2014-01-22 |
EP2514420A2 (en) | 2012-10-24 |
PT1539157E (pt) | 2013-10-04 |
ES2494791T3 (es) | 2014-09-16 |
US20090036479A1 (en) | 2009-02-05 |
EP2514420B1 (en) | 2014-08-13 |
CA2498191C (en) | 2012-04-10 |
WO2004027027A2 (en) | 2004-04-01 |
EP2514420A3 (en) | 2012-11-28 |
AU2003272471A1 (en) | 2004-04-08 |
US8618088B2 (en) | 2013-12-31 |
AU2010221791A1 (en) | 2010-11-18 |
EP1539157B1 (en) | 2013-08-21 |
CA2498191A1 (en) | 2004-04-01 |
AU2003272471B2 (en) | 2010-10-07 |
EP1539157A2 (en) | 2005-06-15 |
EP1539157A4 (en) | 2008-09-03 |
US20050187241A1 (en) | 2005-08-25 |
JP2006511475A (ja) | 2006-04-06 |
DK1539157T3 (da) | 2013-10-07 |
ES2428354T3 (es) | 2013-11-07 |
US8163726B2 (en) | 2012-04-24 |
SI1539157T1 (sl) | 2013-11-29 |
WO2004027027A3 (en) | 2004-05-21 |
US20120190705A1 (en) | 2012-07-26 |
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