JP6087836B2 - 併用療法 - Google Patents
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- JP6087836B2 JP6087836B2 JP2013547780A JP2013547780A JP6087836B2 JP 6087836 B2 JP6087836 B2 JP 6087836B2 JP 2013547780 A JP2013547780 A JP 2013547780A JP 2013547780 A JP2013547780 A JP 2013547780A JP 6087836 B2 JP6087836 B2 JP 6087836B2
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Description
a)少なくとも1種のアンジオテンシン受容体遮断薬または薬学的に許容されるその塩および
b)少なくとも1種のケモカイン受容体経路阻害薬または薬学的に許容されるその塩
を含む医薬組成物を提供する。
ACE アンジオテンシン変更酵素
ACEi アンジオテンシン変換酵素阻害薬
AIDS 後天性免疫不全症候群
AngI アンジオテンシンIペプチド
AngII アンジオテンシンIIペプチド
AngIII アンジオテンシンIIIペプチド
AT1R アンジオテンシン受容体1型
AT2R アンジオテンシン受容体2型
barr ベータ−アレスチン
BP 血圧
CCL2 ケモカイン(C−Cモティーフ)リガンド2
CCR CCケモカイン受容体
DOP デルタオピオイド
GFR 糸球体濾過率
GPCR Gタンパク質共役受容体
HIV ヒト免疫不全ウイルス
KOP カッパオピオイド
LPO 外側視錯野
MCP−1 単球走化性タンパク質−1(単球化学誘引物質タンパク質−1としても知られている)
NPY 神経ペプチドY
STNx 腎亜全摘出
総論
本明細書で引用される特許および特許出願を包含するすべての刊行物は、前出または後出にかかわらず、その全体が本明細書に援用される。しかしながら、本明細書で述べられる刊行物は、当該刊行物において報告され、本発明に関連して使用され得るプロトコル、試薬およびベクターを説明および開示する目的で引用されている。本明細書の一切の記載内容は、先行の発明のために本発明がこうした開示に先行しないことを容認するものとして解釈されてはならない。
Hilairet S.ら、2003(J.Biol.Chem.278:23731〜23737)によって、CB1アンタゴニストがCB1/OxR1のヘテロダイマーのペアによって作用することにより食欲を抑制することが最近になって示されている。
ソマトスタチンSSTR5受容体がドーパミンD2受容体とヘテロマー化することが示されている(Rocheville M.ら(2000)Science 288:154〜157)。
アンジオテンシンおよびCCR2シグナル伝達経路は以前に、相互作用することが示されている。例えば、血管病理に対するアンジオテンシンIIの作用は、CCR2受容体の不全によって緩和される(Daugherty A(2010)Clin Sci(Lond).118(11):681〜9;Ishibachi M(2004) Arteriosclerosis, Thrombosis, and Vascular Biology 24)。
発明者らは、アンジオテンシン受容体とケモカイン受容体ファミリーのメンバーとのヘテロマー化を示している(WO2010/108232号)。
好ましくは、併用療法は、ケモカイン受容体経路およびアンジオテンシン受容体を介して作用する。したがって本発明は、
a)少なくとも1種のアンジオテンシン受容体遮断薬または薬学的に許容されるその塩;および
b)少なくとも1種のケモカイン受容体経路阻害薬または薬学的に許容されるその塩を含む医薬組成物を提供する。
a)少なくとも1種のアンジオテンシン受容体遮断薬または薬学的に許容されるその塩;および
b)少なくとも1種の、ケモカイン受容体以外のケモカイン受容体経路の成分を阻害するケモカイン受容体経路阻害薬または薬学的に許容されるその塩
を含む医薬組成物を提供する。
(i)ケモカイン受容体のまたはケモカイン受容体以外のケモカイン受容体経路の成分のアンタゴニスト;
(ii)ケモカイン受容体またはケモカイン受容体以外のケモカイン受容体経路の成分のインバースアゴニスト;
(iii)ケモカイン受容体またはケモカイン受容体以外のケモカイン受容体経路の成分のネガティブアロステリック調節薬
からなる群から選択される。
a)少なくとも1種のアンジオテンシン受容体遮断薬または薬学的に許容されるその塩;および
b)プロパゲルマニウムまたは薬学的に許容されるその塩
を含む医薬組成物を提供する。
a)少なくとも1種のアンジオテンシン受容体遮断薬または薬学的に許容されるその塩;および
b)RS504393または薬学的に許容されるその塩を含む医薬組成物を提供する。
i)腎臓疾患および腎臓虚血再灌流障害(Yamada(2004)Critical Protection from Renal Ishemia Reperfusion Injury by CD55 and CD59、The Journal of Immunology 172:3869〜3875);
ii)糖尿病(その際、補体阻害因子の調節の欠陥およびCD55およびCD59のレベル低下は、糖尿病の一次作用およびこれらのGPIアンカー型補体阻害因子の選択的低下を伴う糖尿病血管における補体活性化に関する機構のうちの1つとみなすことができ、これらの分子の合成または加工に共通する調節ステップに対する糖尿病の作用を示唆している)。糖尿病においてCD59およびCD55のレベル低下をもたらす機構は細胞または組織特異的であり得ることが提案されている(Zhang(2002)Diabetes 51:3499〜3504);
iii)大血管性疾患(Ma(2009)Chinese medical journal、 1 22(18)21 23〜2128);
iv)黄斑変性(Bora(2007)The Journal of Immunology、178(3)1783〜1790;およびMa K(2010)Invest Ophthalmol Vis Sci.Dec;51(12):6776〜83.Epub 2010 Aug)。
a)アンジオテンシン受容体アンタゴニスト;
b)アンジオテンシン受容体インバースアゴニスト;または
c)アンジオテンシン受容体ネガティブアロステリック調節薬
からなる群から選択される。
a)オルメサルタンまたは薬学的に許容されるその塩;および
b)少なくとも1種の、ケモカイン受容体以外のケモカイン受容体経路の成分を阻害するケモカイン受容体経路阻害薬または薬学的に許容されるその塩
を含む医薬組成物を提供する。
a)少なくとも1種のアンジオテンシン受容体遮断薬または薬学的に許容されるその塩;および
b)プロパゲルマニウムまたは薬学的に許容されるその塩
を含む医薬組成物を提供する。
a)オルメサルタンまたは薬学的に許容されるその塩;および
b)プロパゲルマニウムまたは薬学的に許容されるその塩
を含む医薬組成物を提供する。
a)イルベサルタンまたは薬学的に許容されるその塩;および
b)少なくとも1種のケモカイン受容体経路阻害薬または薬学的に許容されるその塩
を含む医薬組成物を提供する。
a)イルベサルタンまたは薬学的に許容されるその塩;および
b)RS504393または薬学的に許容されるその塩。
を含む医薬組成物を提供する。
a)イルベサルタンまたは薬学的に許容されるその塩;および
b)少なくとも1種の、ケモカイン受容体以外のケモカイン受容体経路の成分を阻害するケモカイン受容体経路阻害薬または薬学的に許容されるその塩を含む医薬組成物を提供する。
本発明は、状態または疾患を治療、改善または予防する方法をさらに提供し、その方法は、前記対象に、治療有効量の(i)アンジオテンシン受容体遮断薬および(ii)ケモカイン受容体の阻害薬またはその下流経路の阻害薬(ケモカイン受容体経路阻害薬)の組合せを投与することを含む。
HIV感染およびAIDS発症、
虚血再潅流傷害、
アテローム発生、
慢性閉塞性肺疾患、
喘息およびアレルギー、
腎疾患、
関節リウマチ。
慢性心不全;
アテローム硬化症/虚血;
高血圧;
高カリウム血症;
子癇前症;
糖尿病;
糖尿病性網膜症;
サルコイドーシス;
アルツハイマー病。
本発明はまた、疾患を治療するための剤形を製造するための、少なくとも1種のアンジオテンシン受容体遮断薬または薬学的に許容されるその塩および少なくとも1種のケモカイン受容体経路阻害薬または薬学的に許容されるその塩を含む医薬組成物の使用を提供する。医薬組成物は場合によって、薬学的に許容される担体をさらに含んでよい。
本発明によって提供される剤形は、本発明の医薬組成物を含むバイアル、カートリッジ、容器、錠剤またはカプセル剤を、疾患を治療、改善または予防するために対象に剤形を投与するための投薬指示書と一緒にさらに含んでよい。
本発明の他の態様では、本発明の医薬組成物の効力を評価する方法を提供し、その際、その方法は、インビトロ生化学または細胞アッセイによって、MCP−1による単球のインビトロ走化性遊走を評価するステップ;イノシトールリン酸産生、細胞外調節キナーゼ(ERK)リン酸化またはcAMP産生を測定するステップ;インピーダンス、光屈折または電荷再分配などを使用する無標識技術を使用して組成物の効果を測定するステップ;近接レポーターシステムまたは他の手法を使用してGタンパク質カップリングを測定するステップ;β−アレスチン補充または媒介シグナル伝達を測定するステップ;転写因子をベースとするレポーターシステムを使用して組成物の効果を測定するステップ;蛍光標識を使用する顕微鏡可視化、抗体の使用(酵素結合免疫吸着検定法など)および蛍光活性化細胞選別などの、細胞位置限定を測定するためのインビトロ生化学または細胞技術を利用するステップ;自動分析器などによって、腎臓機能の指標として血漿クレアチニンおよび尿のインビボレベルを測定するステップ;ラジオイムノアッセイによってタンパク尿のレベルを測定するステップ、アルブミン尿のレベルを測定するステップ;GFR(シングルショット同位体技術)を測定するステップ;光学顕微鏡(LM)による腎臓および/または心臓および/または眼または他の組織構造を評価するステップ;糸球体および/または心臓肥大、糸球体硬化症および/または線維症の存在および/または規模を評価するステップ;マトリックス沈着の規模を評価するステップ、線維化促進性成長因子の変調およびその活性を評価するステップ;腎臓および/または心臓構造および/または眼構造および/または他の組織構造を評価するステップ;ならびに収縮期血圧、インスリン空腹時血漿グルコースの変調、ヘモグロビンA1cの変調を評価するステップを包含する群から選択されるステップを包含する。
実施例1 STNxモデルでのタンパク尿の低減(低用量のプロパゲルマニウム)
腎亜全摘出(STNx)外科手術
動物
6週齢の雄のSprague−Dawley(SD)ラット(体重200〜250g)は、Animal Resources Centre(Western Australia)から供給される。Animal Ethics Committee(St Vincent’s Hospitalおよびthe National Health and Medical Research Foundation of Australia)からの認可を受けて、動物研究を行う。全てのラットが通常のラット用固形飼料(Certified Rodent Diet #5002、LabDiet、USA)および飲料水を自由に摂取する。全ての動物を22±1℃に維持されている安定な環境中、午前6時に開始される12時間明暗サイクルで飼育する。STNx外科手術をSt Vincent’s Experimental Surgical Unitの手術シアター内で行う。全ての外科手術は、以前に記載された外科手術から変更されたものである(Gilbert,R.E.、L.L.Wuら(1999)。「Pathological expression of renin and angiotensin II in the renal tubule after subtotal nephrectomy. Implications for the pathogenesis of tubulointerstitial fibrosis」、Am J Pathol 155(2):429〜40;Kelly,D.J.、A.J.Edgleyら(2009)、「Protein kinase C−beta inhibition attenuates the progression of nephropathy in non−diabetic kidney disease」、Nephrol Dial Transplant 24(6):1782〜90.;Kelly,D.J.、C.Hepperら(2003)。「Vascular endothelial growth factor expression and glomerular endothelial cell loss in the remnant kidney model」 Nephrol Dial Transplant 18(7):1286〜92.;Wu,L、A.Coxら(1997)。「Transforming growth factor β1 and renal injury following subtotal nephrectomy in the rat:Role of the renin−angiotensin system」、Kidney Int 51:1553〜1567)。
外科手術の前の午後に、ラットの体重を計り、1用量の抗生物質(オキシテトラサイクリン、30mg/kg)を経口胃管により予防として与える。次いでラットを一晩絶食させる。
麻酔
Perspexプラスチックボックス中の酸素と混合されている2.5%イソフルランで、麻酔を誘発する。
ラットの腹部領域を胸骨から骨盤まで、クリッパを使用して剃毛する。剃毛領域を、アルコール70%中のクロルヘキシジンで、切開点(正中線)から開始して、外側へと清浄化する円形運動で3回清浄化する。
有窓ドレープを切開部位の上に置き、皮膚切開を、胸骨の下10mmから、生殖器の10mm上までNo.23メスブレードで行う。次いで、筋肉層を露出させ、組織鉗子で持ち上げて、白線(正中線に沿って筋肉層をつなぐ筋膜)に沿った切開を可能にする。筋肉層をこうして持ち上げることによって、小腸が偶発的に鋭利な機器によって損傷を受けることを防ぐ。
次いで、5.0溶解性縫合糸(PGA−ポリグリコール酸縫合糸)を使用して、連続する縫い目で筋肉層を縫う。次いで、皮膚を4.0シルクの連続する縫い目で縫う。次いで、領域をアルコール70%中のクロルヘキシジンで清浄化して、皮膚からの血液を全て除去する。次いで、麻酔マスクを外し、Op部位スプレー(組織スプレー)を切開部位に噴霧して、感染に対して保護するための特別なバリアを加える。ラットが麻酔から目覚め始めている間に、ブプレノルフィン(Temgesic)を0.03mg/kgの用量で皮下で与えた。
次いでラットを、37℃に維持されたヒートパッド上で回復させる。
術後に5%グルコース溶液を、水用ボトルと並べた飲料ボトル中で与えて、ラットが一方または他方を選んで飲めるようにする。食餌も、食べやすいようにボックスの床に置く。外科手術から12から24時間後に、ラットが食べないか、または飲まなければ、ブプレノルフィンを皮下投与する。外科手術から24から48時間後に、ラットが元気がないか、動きたがらないが、または丸まっているならば、これは腎不全の結果であり得る。この場合に、ラットを、過量のペントバルビトンナトリウム(120mg/kg、腹腔内)を使用してえりのける。
対照ラットで、上記のとおりの開腹術および両方の腎臓の処理からなるが、ただし、創傷閉鎖の前に腎臓動脈の切開は伴わないシャム手術を行う。
外科手術から14日後に、治療を開始する。
長期間(12週)
未処置群
群1、2 未処置:対照、糖尿病性
単一薬剤群
群3 STNx + イルベサルタン(ARB)(10mg/kg/日)
併用群
群4 STNx + イルベサルタン(10mg/kg/日)/プロパゲルマニウム(3mg/kg/日)
1群当たりn=16ラット
収縮期血圧(SBP)および臨床パラメーターの一連の測定を、動物研究のための標準的なプロトコルに従った間隔で行った(4週毎)(Kelly DJ、Wilkinson−Berka JL、T.J.Aら、A new model of progressive diabetic renal impairment in the transgenic (mRen−2)27 rat. Kidney Int. 54:343〜352、1998)。
動物研究のための標準的なプロトコル(Kellyら、1998)に従って血漿クレアチニンおよび尿(自動分析器)、アルブミン尿(ラジオイムノアッセイ、4週毎)およびGFR(シングルショット同位体技術、4および12週)の測定によって、腎臓機能の一連の測定を行った。
行うことができるであろうさらなる実験には、腎臓および心臓構造などの二次終点の評価が包含される。例えば、光学顕微鏡(LM)を使用して、糸球体および心臓肥大、糸球体硬化症および線維症を測定することができるであろう。免疫組織化学を使用して、マトリックス沈着の規模ならびに線維化促進性成長因子の変調およびその活性を測定することができるであろう。分子生物学も使用して、腎臓および心臓構造を評価することができるであろう。
ANOVAをFishers事後検定と共に使用して、動物群の間での比較を行った。動物使用の正当化は、1群当たりn=16ラットであると算出されている(組織診ではn=8、分子生物学ではn=8)。p<0.05の値を、統計的に有意とみなした。データおよび幾何平均×/÷許容係数を対数変換した後に、アルブミン尿を分析した。
実施例1に記載されているとおりであるが、次の処置を伴った:
研究設計および手順
外科手術から14日後に、治療を開始する。
長期間(12週)
未処置群
群1、2 未処置:対照、糖尿病性
単一薬剤群
群3 STNx + イルベサルタン(ARB)(10mg/kg/日)またはSTNx + プロパゲルマニウム(30mg/kg/日)
併用群
群4 STNx + イルベサルタン(10mg/kg/日)/プロパゲルマニウム(30mg/kg/日)
1群当たりn=16ラット
HEK293FT細胞の一過性トランスフェクションを介してのAT1RおよびCCR2の同時発現の際に、両方の受容体を合わせて阻害することは、いずれかの受容体単独の阻害よりも大規模にアレスチン補充を遮断する。
HEK293FT細胞の一過性トランスフェクションを介してのAT1RおよびCCR2の同時発現の際に、両方の受容体を合わせて阻害することは、いずれかの受容体単独の阻害よりも大規模にイノシトールリン酸シグナル伝達を遮断する。
標識受容体と未標識受容体の反対の配向を使用して、かつ2種の異なるAngllアンタゴニストのいずれかを使用して観察されるとおり、HEK293FT細胞の一過性トランスフェクションを介してAT1RおよびCCR2を同時発現させる際に、両方の受容体を合わせて阻害することは、いずれかの受容体単独の阻害よりも大規模にアレスチン補充を遮断する。
他のAngllアンタゴニスト、EXP3174、ロサルタンの活性代謝産物で実証されるとおり、HEK293FT細胞の一過性トランスフェクションを介してAT1RおよびCCR2を同時発現させる際に、両方の受容体を合わせて阻害することは、いずれかの受容体単独の阻害よりも大規模にイノシトールリン酸シグナル伝達を遮断する。
AT1Rの特異的活性化は、Gαi1へのMCP−1媒介カップリングを用量依存的に阻害し、このことは、AT1RがCCR2機能をモジュレートすることについてのインビトロ証拠を示し、かつAngllに加えてCCR2の阻害についてのさらなる合理性を示している。
Claims (13)
- a)少なくとも1種のアンジオテンシン受容体1型(AT1R)遮断薬または薬学的に許容されるその塩、および
b)少なくとも1種のケモカイン受容体2(CCR2)経路阻害薬または薬学的に許容されるその塩、
を含む、タンパク尿に関連する腎臓疾患の治療、改善または予防において使用するための医薬組成物であって、前記AT 1 R遮断薬がイルベサルタンであり、前記CCR2経路阻害薬がプロパゲルマニウムである、医薬組成物。 - 前記医薬組成物の全体効力が
a)他の成分を何ら投与することなくいずれかの成分を投与した場合の前記AT1R遮断薬または前記CCR2経路阻害薬の効力と比較して、より大きい、
b)他の成分を何ら投与することなくいずれかの成分を投与した場合の前記AT1R遮断薬および前記CCR2経路阻害薬の効力の合計と比較して、より大きい、または
c)他の成分を何ら投与することなくいずれかの成分を投与した場合の前記AT1R遮断薬および前記CCR2経路阻害薬の効力の合計に等しい、
請求項1に記載の医薬組成物。 - 前記医薬組成物の合わせた効力が、他の成分を何ら投与することなくいずれかの成分を投与した場合の前記AT1R遮断薬および前記CCR2経路阻害薬の効力の合計未満であり、前記治療が、単独で投与されるAT1R遮断薬または前記CCR2経路阻害薬の単独治療と比較してより大きな効力をもたらす、請求項1〜2のいずれか一項に記載の医薬組成物。
- 少なくとも1種のAT1R遮断薬または薬学的に許容されるその塩を含む、タンパク尿に関連する腎臓疾患の治療、改善または予防において使用するための医薬組成物であって、前記組成物は、少なくとも1種のCCR2経路阻害薬または薬学的に許容されるその塩と同時に、または順次に、対象に投与され、前記CCR2経路阻害薬はプロパゲルマニウムであり、前記AT 1 R遮断薬はイルベサルタンである、医薬組成物。
- 少なくとも1種のCCR2経路阻害薬または薬学的に許容されるその塩を含む、タンパク尿に関連する腎臓疾患の治療、改善または予防において使用するための医薬組成物であって、前記組成物は、少なくとも1種のAT1R遮断薬または薬学的に許容されるその塩と同時に、または順次に、対象に投与され、前記CCR2経路阻害薬はプロパゲルマニウムであり、前記AT 1 R遮断薬はイルベサルタンである、医薬組成物。
- 前記少なくとも1種のAT1R遮断薬または薬学的に許容されるその塩、および/または、前記少なくとも1種のCCR2経路阻害薬または薬学的に許容されるその塩が、剤形である、請求項1〜5のいずれか1項に記載の医薬組成物。
- 前記剤形が、約5mg〜1gのAT1R遮断薬または薬学的に許容されるその塩と、約5mg〜1gのCCR2経路阻害薬または薬学的に許容されるその塩と、を含む請求項6に記載の医薬組成物。
- 前記腎臓疾患が、腎臓における繊維性障害、糖尿病性腎障害が原因の慢性腎臓疾患、腎不全、腎不全状態、糖尿病性腎障害、糸球体腎炎、糸球体硬化症、一次腎疾患のタンパク尿を含む群から選択される、請求項1〜7のいずれか1項に記載の医薬組成物。
- 治療上有効な請求項1〜8のいずれか一項に記載の医薬組成物と放出遅延剤と、を含む経口徐放性医薬組成物または注射用徐放性医薬組成物。
- 請求項1〜8のいずれか一項に記載の医薬組成物を含む注射用懸濁剤。
- 請求項1〜8のいずれか一項に記載の医薬組成物を含む肺送達用または経鼻送達用の組成物。
- 請求項1〜8のいずれか1項に記載の医薬組成物の製造における、イルベサルタンまたは薬学的に許容されるその塩の使用。
- 請求項1〜8のいずれか1項に記載の医薬組成物の製造における、プロパゲルマニウムまたは薬学的に許容されるその塩の使用。
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