JP2020510651A - 併用療法のための医薬組成物 - Google Patents
併用療法のための医薬組成物 Download PDFInfo
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- JP2020510651A JP2020510651A JP2019546127A JP2019546127A JP2020510651A JP 2020510651 A JP2020510651 A JP 2020510651A JP 2019546127 A JP2019546127 A JP 2019546127A JP 2019546127 A JP2019546127 A JP 2019546127A JP 2020510651 A JP2020510651 A JP 2020510651A
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- fibrosis
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- liver
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Abstract
Description
本発明は、
(i)CVC又はこの類縁体、薬学的に許容される塩若しくは溶媒和物、及び
(ii)式(I)の少なくとも1つのPPARアゴニスト
Y1は、ハロゲン、Ra又はGa−Ra基を表し、
Aは、CH=CH又はCH2−CH2基を表し、
Y2は、Gb−Rb基を表し、
Ga及びGbは、同一であり又は異なり、酸素又は硫黄原子を表し、
Raは、水素原子、非置換(C1〜C6)アルキル基を表し、1個以上のハロゲン原子、(C1〜C6)アルコキシ若しくは(C1〜C6)アルキルチオ基で置換されている、(C6〜C14)アリール基若しくは(C1〜C6)アルキル基を表し、(C3〜C14)シクロアルキル基、(C3〜C14)シクロアルキルチオ基又は複素環基を表し、
Rbは、少なくとも1つの−COORc基(ここで、Rcは、水素原子を表す。)により置換されている(C1〜C6)アルキル基、又は1個以上のハロゲン原子で置換されている若しくは置換されていない(C1〜C6)アルキル基、又は(C3〜C14)シクロアルキル基、又は複素環基を表し、
Y4及びY5は、同一であり又は異なり、1個以上のハロゲン原子により置換されている若しくは置換されていない(C1〜C6)アルキル基、又は(C3〜C14)シクロアルキル基、又は複素環基を表す。)
を含む組合せ物に関する。
図中、表中及び本文中で使用される略語:
α−SMA:アルファ平滑筋アクチン
BMP:骨形成タンパク質
cDNA:相補的デオキシリボ核酸
COL1A1:コラーゲン、1型、アルファ1
CDAA:コリン欠乏L−アミノ酸
CSAA:コリン添加L−アミノ酸規定
CVC:セニクリビロク
DMSO:ジメチルスルホキシド
DNA:デスオキシリボ核酸
DTT:ジチオトレイトール
ELA:エラフィブラノール又はGFT505
ELISA:酵素結合免疫吸着アッセイ
EMT:上皮間葉転換
EOB:エクセス・オーバー・ブリス(Excess Over Bliss)
FBS:ウシ胎仔血清
FDA:食品医薬品局
FPP:ファルネシルピロリン酸
GDF:増殖分化因子
Hh:ヘッジホッグ
GGPP:ゲラニルゲラニルピロリン酸
HMG−CoA:3−ヒドロキシ−3−メチルグルタリル−補酵素A
hHSC:ヒト肝星状細胞
HSC:肝星状細胞
IC50:半最大阻害濃度
InMyoFib:腸筋線維芽細胞
LBD:リガンド結合ドメイン
MMP2:マトリックスメタロペプチダーゼ2
MMP9:マトリックスメタロペプチダーゼ9
μl:マイクロリットル
LDL:低密度リポタンパク質
NHLF:正常ヒト肺線維芽細胞
PBS:リン酸緩衝食塩水
PFOR:ピルビン酸フェレドキシンオキシドレダクターゼ
PPAR:ペルオキシソーム増殖因子活性化受容体
PPRE:PPAR応答エレメント
qPCR:定量的ポリメラーゼ連鎖反応
pMol:ピコモル
rhFGF:組換えヒト塩基性線維芽細胞増殖因子
RNA:リボ核酸
RT:逆転写酵素
SmBM:平滑筋細胞基本培地
SteCGS:星状細胞増殖サプリメント
STeCM:星状細胞培地
TGFβ1:腫瘍増殖因子ベータ1
TGFBRI:TGFβ I型受容体
TGFBRII:TGFβ II型受容体
THBS1:トロンボスポンジン1
TMB:テトラメチルベンジジン
Y1は、ハロゲン、Ra又はGa−Ra基を表し、
Aは、CH=CH又はCH2−CH2基を表し、
Y2は、Gb−Rb基を表し、
Ga及びGbは、同一であり又は異なり、酸素又は硫黄原子を表し、
Raは、水素原子、非置換(C1〜C6)アルキル基、(C6〜C14)アリール基若しくは(C1〜C6)アルキル基(ここで、該アリール基及びアルキル基は、1個以上のハロゲン原子、(C1〜C6)アルコキシ若しくは(C1〜C6)アルキルチオ基で置換されている。)、(C3〜C14)シクロアルキル基、(C3〜C14)シクロアルキルチオ基又は複素環基を表し、
Rbは、少なくとも1つの−COORc基により置換されている(C1〜C6)アルキル基を表し、ここで、Rcは、水素原子、又は1個以上のハロゲン原子で置換されている若しくは置換されていない(C1〜C6)アルキル基、(C3〜C14)シクロアルキル基又は複素環基を表し、
Y4及びY5は、同一であり又は異なり、1個以上のハロゲン原子により置換されている若しくは置換されていない(C1〜C6)アルキル基、(C3〜C14)シクロアルキル基又は複素環基を表す。)
を含む、組合せ物に関する。
Y1は、ハロゲン、Ra又はGa−Ra基を表し、
Aは、CH=CH基を表し、
Y2は、Gb−Rb基を表し、
Ga及びGbは、同一であり又は異なり、酸素又は硫黄原子を表し、
Raは、(C1〜C6)アルキル又は(C3〜C14)シクロアルキル基(特に、1個以上のハロゲン原子により置換されている又は置換されていない、(C1〜C7)アルキル又は(C3〜C14)シクロアルキル基)を表し、
Rbは、−COOR3基により置換されている(C1〜C6)アルキル基(ここでRcは、水素原子を表すか、又は1〜4個の炭素原子を有するアルキル基を表す。)を表し、
Y4及びY5は、独立して、(C1〜C4)アルキル基を表す。
Y1は、Ra又はGa−Ra基を表し、
Aは、CH2−CH2基を表し、
Y2は、Gb−Rb基を表し、
Gaは、酸素又は硫黄原子を表し、Gbは、酸素原子を表し、
Raは、(C1〜C6)アルキル又は(C3〜C7)シクロアルキル基を表し、
Rbは、少なくとも1つの−COORc基により置換されている(C1〜C6)アルキル基を表し、ここでRcは、水素原子又は(C1〜C4)アルキル基を表し、
Y4及びY5は、独立して、(C1〜C4)アルキル基を表す。
Y1は、ハロゲン原子又はRa若しくはGa−Ra基を表し、
Aは、CH2−CH2基を表し、
Y2は、Gb−Rb基を表し、
Gaは、酸素又は硫黄原子を表し、Gbは、酸素原子を表し、
Raは、1個以上のハロゲン原子により置換されている、(C1〜C6)アルキル又は(C3〜C14)シクロアルキル基を表し、
Rbは、1個以上のハロゲン原子で置換されている若しくは置換されていない、及び少なくとも1つの−COORc基により置換されている(C1〜C6)アルキル基を表し、ここでRcは、水素原子又は(C1〜C4)アルキル基を表し、
Y4及びY5は、(C1〜C4)アルキル基を表す。
(i)CVC又はこの誘導体又は類縁体又は薬学的に許容される塩若しくは溶媒和物、
(ii)PPARアゴニスト、特に、式(I)の化合物又はこの薬学的に許容される塩、特に、エラフィブラノール又はこの薬学的に許容される塩
を含む組合せ物に関する。
(i)CVC又はこの誘導体又は類縁体又は薬学的に許容される塩若しくは溶媒和物、
(ii)PPARアゴニスト、特に、式(I)の化合物又はこの薬学的に許容される塩、特に、エラフィブラノール又はこの薬学的に許容される塩、及び
(iii)薬学的に許容される担体
を含む組成物である。
(i)CVC又はこの誘導体又は類縁体又は薬学的に許容される塩若しくは溶媒和物、
(ii)PPARアゴニスト、特に、式(II)の化合物又はこの薬学的に許容される塩、特に、エラフィブラノール又はこの薬学的に許容される塩
を含むキットオブパーツであって、
特に、本明細書において言及する疾患のいずれかの治療における、逐次的使用、別々の使用又は同時使用のための、キットオブパーツである。
(i)CVC化合物又はこの誘導体、類縁体又は塩若しくは溶媒和物、
(ii)PPARアゴニスト、特に、式(I)の化合物又はこの薬学的に許容される塩、特に、エラフィブラノール又はこの薬学的に許容される塩
を含むキットオブパーツであって、
上述の疾患のいずれかの治療における逐次的使用、別々の使用又は同時使用のための、キットオブパーツである。
肝線維形成のインビトロモデル(in a vitro model)におけるエラフィブラノール、CVC及びこれらの組合せの評価
化合物をジメチルスルホキシド(DMSO、Fluka カタログ番号41640)に溶解した。CVCは、CLINISCIENCES(参照番号:A13643−10、バッチ番号:497223−25−3)から購入した。ベンザフィブラートは、Genfitにおいて合成した。
ヒト初代肝星状細胞(hHSC;Innoprot)を、2%ウシ胎仔血清(FBS、ScienCell カタログ番号0010)、1%ペニシリン/ストレプトマイシン(ScienCell カタログ番号0503)及び星状細胞増殖サプリメント(SteCGS;ScienCell カタログ番号5352)を補足したSTeCM培地(ScienCell カタログ番号5301)中で、培養した。細胞培養フラスコを、よりよい接着のために、ポリ−Lリシン(Sigma カタログ番号P4707)でコーティングした。
2成分組合せ行列(CVC/エラフィブラノール)
セニクリビロク(CVC)は、CLINISCIENCES(参照番号:A13643−10、CAS番号:497223−25−3)から購入した。ベンザフィブラート及びエラフィブラノール(GFT505)は、Genfitにおいて合成した。
ベンザフィブラートをジメチルスルホキシド(DMSO、Fluka カタログ番号41640)に溶解し、96ウェルプレートの行(ベンザフィブラート)において5点系列で及び列(CVC)おいて6点系列で系列希釈した。その後、全単剤濃度の1:1混合により、6×7組合せ行列を生成した。各化合物の試験濃度は、TGF−β1で刺激したHSCモデルにおけるα−SMA含量を測定することにより得た、単剤としての各化合物を測定することにより得た、単剤としての各化合物のそれぞれのIC50に基づいて、選択した。
ヒト初代肝星状細胞(hHSC;Innoprot)を、上文で説明したような標準条件下で培養した。その後、細胞を、ELISAによるα−SMAの測定のために96ウェルプレートに細胞2×104個/ウェルの密度で蒔いた。
サンドイッチELISAを使用して、α−SMAレベルを測定した。簡単に言うと、ELISAプレートのウェルを、先ず、捕捉抗体(マウスモノクローナル抗ACTA2、Abnova)で、4℃で終夜、コーティングした。PBS+0.2%Tween20で3回洗浄した後、PBS+0.2%BSAからなるブロッキング溶液を1時間にわたって添加し、続いて別の洗浄サイクルを行った。細胞溶解物を捕捉抗体との結合のために2時間にわたって室温でウェルに移入した。洗浄手順後、検出抗体(ビオチン標識マウスモノクローナル抗ACTA2、Abnova)を2時間にわたって室温で添加し、続いて3回洗浄した。検出のために、ストレプトアビジンHRPコンジュゲート(R&D Systems カタログ番号DY998)を、先ず、30分間、室温で適用した。洗浄後、HRP基質TMB(BD、カタログ番号555214)を添加し、7分間、室温で、暗所でインキュベートした。酸化し次第、TMBは、水溶性青色反応生成物を形成し、硫酸を添加(溶解停止)するとその反応生成物は黄色になり、これにより、分光光度計を使用する450nmでの強度の正確な測定が可能になる。発生する色は、溶解物中に存在するα−SMAの量と正比例する。
α−SMA ELISAアッセイにおいて得た値を、先ず、TGF−β1対照に対する阻害パーセンテージに変換した。20%より上の阻害を 生物学的に意義があるとみなした。次いで、これらの阻害パーセンテージを使用して、EOB(エクセス・オーバー・ブリス)を決定して、薬の組合せの相乗効果を定義した。期待ブリス相加作用スコア(E)を、先ず、方程式:
E=(A+B)−(A×B)
(式中、A及びBは、所与の用量でのエラフィブラノール(A)(又はベンザフィブラート)及びセニクリビロク(CVC)(B)の阻害パーセンテージである。)
により決定した。同じ用量での組み合わせたCVC/エラフィブラノール(又はベンザフィブラート)についてのブリス期待値と阻害実測値との差が、「エクセス・オーバー・ブリス」スコアである。
− エクセス・オーバー・ブリススコア=0は、併用治療が相加的(独立した経路の効果について期待通り)であることを示し、
− エクセス・オーバー・ブリススコア>0は、相加的より大きい活性(相乗作用)を示し、及び
− エクセス・オーバー・ブリススコア<0は、組合せが相加的未満(拮抗作用)であることを示す。
単独でのエラフィブラノール、単独でのCVC、及びこれらの組合せの予防効果を、CDAA+2%コレステロール+30%乳脂肪飼料、及び飲用水中の高フルクトースコーンシロップ55(42g/Lの最終濃度について55%フルクトース/45%グルコース)を摂取したマウスの線維性NASHモデル(Mellsら J Nutr Biochem 2015年)において、評価した。5〜6週齢雄C57Bl/6Jマウスに、対照(CSAA)飼料(n=4)、CDFF飼料(n=12)、又はエラフィブラノール 3mg/kg/日、CVC 10mg/kg/日若しくは組み合わせた薬物(CVC 10mg/kg/日と組み合わせたエラフィブラノール 3mg/kg/日)を補足したCDFF飼料(1群当たりn=8)を、8週間にわたって給餌した。
組織包埋及び切片作製
肝臓薄片を、ホルマリン4%溶液中で固定した。次いで、肝臓片を、30分間、PBSで洗浄し、エタノール溶液(70、80、95及び100%エタノールでの連続浴)において脱水した。肝臓片を、キシレン(Honeywell カタログ番号534056)の3つの異なる浴においてインキュベートし、続いて2つの浴の流動パラフィン(59℃)中でインキュベートした。次いで、肝臓片をラックに入れ、組織を完全に覆うようにラックにHistowax(登録商標)を穏やかに充填した。
肝臓切片を脱パラフィンし、再水和し、3分間、Mayerのヘマトキシリン(Microm、カタログ番号F/C0303)中でインキュベートした。次いで、肝臓切片を水ですすぎ、エオシンY 0.5%アルコール溶液(VWR、カタログ番号1.02439.0500)及びエリスロシン 0.5%溶液(VWR、カタログ番号1.15936.0010)中で1分インキュベートし、エタノールですすいだ。次いで、切片を2分間、サフラニン中でインキュベートし、最終的に脱水し、CV Mount媒体(Leica、カタログ番号046430011)を使用してマウントした。
各肝臓検体源について知らされていない技術者が、組織学的検査を行った。3D HistechからのPannoramic 250スキャナーを使用して、バーチャルスライドを生成した。動物ごとに、NASHの主要な組織学的病変を要約するスコアを、NASH Clinical Research Networkに従って帰属させた(Kleiner 2005年、Brunt 1999年)。簡単に言うと、脂肪化、小葉炎症及び肝細胞バルーニングを点数化した。NAFLD活動性スコア(NASスコア)を、各個体について、脂肪化(0〜3)、小葉炎症(0〜3)及びバルーン傷害(0〜2)等級付けの非重み付き合計として確立した。
血漿中のアラニンアミノトランスフェラーゼ(ALT)及びアスパラギン酸アミノトランスフェラーゼ(AST)濃度を、Daytonaオートメート用のRandoxキット(それぞれ、Randoxカタログ番号AL 3801及びAS 3804)を使用して測定した。アポトーシスの代替マーカーである血漿サイトケラチン18−M30は、Mouse Cytokeratin 18−M30 ELISA Kit(CUSABIO カタログ番号CSB−E14265m)を製造業者の推奨基準に従って使用して測定した。
RNeasy Mini Kit(Qiagen)を製造業者の説明書に従って使用して、全RNAをマウス肝臓から単離した。1×RT緩衝液(Invitrogen)、0.5mM DTT(Invitrogen)、0.18mM dNTPs(Promega)、200ng pdN6(Amersham)及び30UのRNase阻害剤(Promega)中の、M−MLV RT(モロニーマウス白血病ウイルス逆転写酵素)(Invitrogen カタログ番号28025)を使用して、全RNAをcDNAに逆転写した。
肝線維形成のインビトロモデル(in a vitro model)におけるエラフィブラノール、CVC及びこれらの組合せの評価
分化筋線維芽細胞の異常な存続は、多くの線維性疾患の特徴である。
西洋の生活様式は、非アルコール性脂肪性肝炎(NASH)(肝線維症及び硬変に進行することが多く、最終的に肝細胞癌に至ることもある、慢性肝疾患)高い発生率に、常に結び付けられる。現在、NASHのための認可されている治療法はない。複数の治療標的に同時に指向される薬の組合せには、薬物応答を劇的に向上させる可能性、及び最も幅広い患者集団に恩恵をもたらす可能性がある。薬の組合せは、高血圧、脂質異常症又は2型糖尿病のような、他の全身性疾患において以前に試験され、基礎疾患のより良好な制御を示し、罹患率及び死亡率を低下させた。最近の第2B相研究において、エラフィブラノール(PPARα/δアゴニスト)とCVCの両方が、NASH誘発性線維症に対する有効性を示した。本発明者らは、有意義なNASH病態アウトカムに対するそれらの作用を比較すること、および組合せの治療的恩恵を探すことを望んだ。
Claims (14)
- (i)CVC又はこの類縁体、薬学的に許容される塩若しくは溶媒和物、及び
(ii)式(I)の少なくとも1つのPPARアゴニスト
Y1は、ハロゲン、Ra又はGa−Ra基を表し、
Aは、CH=CH又はCH2−CH2基を表し、
Y2は、Gb−Rb基を表し、
Ga及びGbは、同一であり又は異なり、酸素又は硫黄原子を表し、
Raは、水素原子、非置換(C1〜C6)アルキル基、(C6〜C14)アリール基若しくは(C1〜C6)アルキル基(ここで、該アリール基及びアルキル基は、1個以上のハロゲン原子、(C1〜C6)アルコキシ若しくは(C1〜C6)アルキルチオ基で置換されている。)、(C3〜C14)シクロアルキル基、(C3〜C14)シクロアルキルチオ基又は複素環基を表し、
Rbは、少なくとも1つの−COORc基により置換されている(C1〜C6)アルキル基を表し、ここで、Rcは、水素原子、又は1個以上のハロゲン原子で置換されている若しくは置換されていない(C1〜C6)アルキル基、(C3〜C14)シクロアルキル基又は複素環基を表し、
Y4及びY5は、同一であり又は異なり、1個以上のハロゲン原子により置換されている若しくは置換されていない(C1〜C6)アルキル基、(C3〜C14)シクロアルキル基又は複素環基を表す。)
を含む、組合せ物。 - (i)CVC又はこの薬学的に許容される塩、及び
(ii)エラフィブラノール又はこれらの薬学的に許容される塩
を含む、請求項1に記載の組合せ物。 - 成分(i)及び(ii)及び薬学的に許容される担体を含む、組成物である、請求項1又は2に記載の組合せ物。
- 逐次的使用、別々の使用又は同時使用のための、成分(i)及び(ii)を含むキットオブパーツである、請求項1又は2に記載の組合せ物。
- 成分(i)及び(ii)が、注射用懸濁液、ゲル、油、ピル、錠剤、坐剤、粉末、カプセル、エアロゾル、軟膏、クリーム、パッチ、又は持続放出及び/若しくは徐放のためのガレヌス形態の手段に製剤化されている、請求項1〜4のいずれか一項に記載の組合せ物。
- 公知の抗線維化活性を有する少なくとも1つの治療活性剤をさらに含み、
前記治療活性剤が、ピルフェニドン若しくは受容体型チロシンキナーゼ阻害剤(RTKI)(例えば、ニンテダニブ、ソラフェニブ及び他のRTKI);又は、アンジオテンシンII(AT1)受容体遮断薬;又は、CTGF阻害剤;又は、潜在型TGFβ複合体の活性化因子(例えば、MMP2、MMP9、THBS1若しくは細胞表面インテグリン)、TGFβI型受容体(TGFBRI)若しくはII型受容体(TGFBRII)及びそれらのリガンド(例えば、TGFβ、アクチビン、インヒビン、ノダル、抗ミュラー管ホルモン、GDF若しくはBMP)、補助受容体(III型受容体としても公知)を含む、TGFβ及びBMP活性化経路に干渉しやすい抗線維化化合物;又は、調節性若しくは阻害性SMADタンパク質を含む、SMAD依存性古典的経路の成分;又は、MAPKシグナル伝達、TAK1、Rho様GTPaseシグナル伝達経路、ホスファチジルイノシトール−3キナーゼ/AKT経路、TGFβ誘導EMTプロセスの様々な分岐を含む、SMAD非依存性若しくは非古典的経路のメンバー;又は、Hhリガンド若しくは標的遺伝子を含む、古典的及び非古典的ヘッジホッグシグナル伝達経路のメンバー;又は、TGFβの影響を受けやすい、WNT若しくはNotch経路のメンバーから選択される、請求項1〜5のいずれか一項に記載の組合せ物。 - JAK/STAT阻害剤並びに他の抗炎症及び/又は免疫抑制剤から選択される、少なくとも1つの治療活性剤をさらに含む、請求項1〜6のいずれか一項に記載の組合せ物。
- 治療活性剤が、グルココルチコイド、NSAIDS、シクロホスファミド、ニトロソウレア、葉酸類縁体、プリン類縁体、ピリミジン類縁体、メトトレキサート、アザチオプリン、メルカプトプリン、シクロスポリン、ミリオシン、タクロリムス、シロリムス、ミコフェノール酸誘導体、フィンゴリモド及び他のスフィンゴシン−1−リン酸受容体モジュレーター;炎症性サイトカイン及び炎症性サイトカイン受容体、T細胞受容体並びにインテグリンのような標的に対する、モノクローナル及び/又はポリクローナル抗体から選択される、請求項7に記載の組合せ物。
- 医薬として使用するための、請求項1〜8のいずれか一項に記載組合せ物。
- 炎症性、代謝性、線維性及び胆汁うっ滞性疾患を治療するための方法における使用のための、請求項1〜9のいずれか一項に記載の組合せ物。
- 線維性障害が、肝臓、腎臓、皮膚、表皮、内皮、筋肉、腱、軟骨、心臓、膵臓、肺、子宮、神経系、精巣、卵巣、副腎、動脈、静脈、結腸、腸(例えば、小腸)、胆管、軟部組織(例えば、縦隔若しくは後腹膜)、骨髄、関節及び胃の線維症からなる群から選択される、請求項10に記載の使用のための組合せ物。
- 線維性障害が、肝臓、消化管、肺、心臓、腎臓、筋肉、皮膚、軟部組織、骨髄、腸及び関節の線維症からなる群から選択される、請求項10又は11に記載の使用のための組合せ物。
- 疾患が、代謝性肝疾患、非アルコール性脂肪肝疾患(NAFLD)、非アルコール性脂肪性肝炎(NASH)、薬物誘発性肝疾患、アルコール誘発性肝疾患、感染性因子誘発性肝疾患、炎症性肝疾患、免疫系機能障害媒介肝疾患、脂質異常症、心血管疾患、再狭窄、シンドロームX、メタボリックシンドローム、糖尿病、肥満、高血圧;原発性硬化性胆管炎(PSC)、原発性胆汁性胆管炎(PBC)のような、慢性胆管症;胆道閉塞症、家族性肝内胆汁うっ滞症3型(PFIC3)、炎症性腸疾患、クローン病、潰瘍性大腸炎、ケロイド、陳旧性心筋梗塞、強皮症/全身性強皮症、炎症性疾患、神経変性疾患、がん、肝がん、肝細胞癌、消化器がん、胃がん;神経線維腫症に関連する髄膜腫;膵神経内分泌腫瘍、膵外分泌腫瘍、白血病、骨髄増殖性/骨髄異形成(myelodisplastic)疾患、肥満細胞症、皮膚線維肉腫;乳、肺、甲状腺又は結腸直腸がんを含む、固形腫瘍;前立腺がん、任意の起源の肝線維症又は硬変、代謝性疾患誘発性肝線維症又は硬変、NAFLD誘発性線維症又は硬変、NASH誘発性線維症又は硬変、アルコール誘発性肝線維症又は硬変、薬物誘発性肝線維症又は硬変、感染性因子誘発性肝線維症又は硬変、寄生虫感染誘発性肝線維症又は硬変、細菌感染誘発性肝線維症又は硬変、ウイルス感染誘発性線維症又は硬変、HBV感染誘発性肝線維症又は硬変、HCV感染誘発性肝線維症又は硬変、HIV感染誘発性肝線維症又は硬変、二重HCV・HIV感染誘発性肝線維症又は硬変、放射線又は化学療法誘発性線維症又は硬変、胆管線維症;あらゆる慢性胆汁うっ滞性疾患に起因する肝線維症又は硬変;あらゆる原因の消化管線維症;クローン病誘発性線維症、潰瘍性大腸炎誘発性線維症、腸(例えば、小腸)線維症、結腸線維症、胃線維症、皮膚線維症、表皮線維症、内皮線維症;強皮症/全身性強皮症に起因する皮膚線維症;肺線維症;COPD、喘息、肺気腫、喫煙者肺、結核、肺線維症、特発性肺線維症(IPF)のような、慢性炎症性気道疾患に続いての、肺線維症;心線維症、腎線維症、腎性全身性線維症、筋線維症、軟部組織(例えば、縦隔又は後腹膜)線維症、骨髄線維症、関節線維症、腱線維症、軟骨線維症、膵線維症、子宮線維症、神経系線維症、精巣線維症、卵巣線維症、副腎線維症、動脈線維症、静脈線維症、眼線維症、心内膜心筋線維症、縦隔線維症、骨髄線維症、後腹膜線維症、進行性塊状線維症(炭鉱夫塵肺の合併症)、増殖性線維症、腫瘍性線維症、着床前後線維症、及び石綿肺、関節線維症、粘着性関節包炎からなる群から選択される、請求項10〜12のいずれか一項に記載の使用のための組合せ物。
- 疾患が、代謝性肝疾患、非アルコール性脂肪肝疾患(NAFLD)、非アルコール性脂肪性肝炎(NASH)、薬物誘発性肝疾患、アルコール誘発性肝疾患、感染性因子誘発性肝疾患、炎症性肝疾患、免疫系機能障害媒介肝疾患、脂質異常症、心血管疾患、再狭窄、シンドロームX、メタボリックシンドローム、糖尿病、肥満、高血圧;原発性硬化性胆管炎(PSC)、原発性胆汁性胆管炎(PBC)のような、慢性胆管症;胆道閉塞症、家族性肝内胆汁うっ滞症3型(PFIC3)、炎症性腸疾患、クローン病、潰瘍性大腸炎、肝がん、肝細胞癌、消化器がん、胃がん、結腸直腸がん、代謝性疾患誘発性肝線維症又は硬変、NAFLD誘発性線維症又は硬変、NASH誘発性線維症又は硬変、アルコール誘発性肝線維症又は硬変、薬物誘発性肝線維症又は硬変、感染性因子誘発性肝線維症又は硬変、寄生虫感染誘発性肝線維症又は硬変、細菌感染誘発性肝線維症又は硬変、ウイルス感染誘発性線維症又は硬変、HBV感染誘発性肝線維症又は硬変、HCV感染誘発性肝線維症又は硬変、HIV感染誘発性肝線維症又は硬変、二重HCV・HIV感染誘発性肝線維症又は硬変、放射線又は化学療法誘発性線維症又は硬変、胆管線維症;あらゆる慢性胆汁うっ滞性疾患に起因する肝線維症又は硬変;あらゆる原因の消化管線維症;クローン病誘発性線維症、潰瘍性大腸炎誘発性線維症、腸(例えば、小腸)線維症、結腸線維症、胃線維症、肺線維症;COPD、喘息、肺気腫、喫煙者肺、結核、肺線維症、特発性肺線維症(IPF)のような、慢性炎症性気道疾患に続いての、肺線維症からなる群から選択される、疾患が、代謝性肝疾患、非アルコール性脂肪肝疾患(NAFLD)、非アルコール性脂肪性肝炎(NASH)、薬物誘発性肝疾患、アルコール誘発性肝疾患、感染性因子誘発性肝疾患、炎症性肝疾患、免疫系機能障害媒介肝疾患、脂質異常症、心血管疾患、再狭窄、シンドロームX、メタボリックシンドローム、糖尿病、肥満、高血圧;原発性硬化性胆管炎(PSC)、原発性胆汁性胆管炎(PBC)のような、慢性胆管症;胆道閉塞症、家族性肝内胆汁うっ滞症3型(PFIC3)、炎症性腸疾患、クローン病、潰瘍性大腸炎、肝がん、肝細胞癌、消化器がん、胃がん、結腸直腸がん、代謝性疾患誘発性肝線維症又は硬変、NAFLD誘発性線維症又は硬変、NASH誘発性線維症又は硬変、アルコール誘発性肝線維症又は硬変、薬物誘発性肝線維症又は硬変、感染性因子誘発性肝線維症又は硬変、寄生虫感染誘発性肝線維症又は硬変、細菌感染誘発性肝線維症又は硬変、ウイルス感染誘発性線維症又は硬変、HBV感染誘発性肝線維症又は硬変、HCV感染誘発性肝線維症又は硬変、HIV感染誘発性肝線維症又は硬変、二重HCV・HIV感染誘発性肝線維症又は硬変、放射線又は化学療法誘発性線維症又は硬変、胆管線維症;あらゆる慢性胆汁うっ滞性疾患に起因する肝線維症又は硬変;あらゆる原因の消化管線維症;クローン病誘発性線維症、潰瘍性大腸炎誘発性線維症、腸(例えば、小腸)線維症、結腸線維症、胃線維症、肺線維症;COPD、喘息、肺気腫、喫煙者肺、結核、肺線維症、特発性肺線維症(IPF)のような、慢性炎症性気道疾患に続いての、肺線維症からなる群から選択される、請求項10〜12のいずれか一項に記載の使用のための組合せ物。
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