JP5271272B2 - A型インフルエンザウィルス感染の治療のための薬剤としてのep2およびep4作動薬 - Google Patents
A型インフルエンザウィルス感染の治療のための薬剤としてのep2およびep4作動薬 Download PDFInfo
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- BHJHVDDOCMGCDD-UHFFFAOYSA-N piperazin-1-ium-1-sulfonate Chemical compound OS(=O)(=O)N1CCNCC1 BHJHVDDOCMGCDD-UHFFFAOYSA-N 0.000 description 1
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- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
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- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
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- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
- A61K31/5585—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5578—Eicosanoids, e.g. leukotrienes or prostaglandins having a pentalene ring system, e.g. carbacyclin, iloprost
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Emergency Medicine (AREA)
- Pulmonology (AREA)
- Communicable Diseases (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
プロスタグランジンの効果は、細胞表面上にあるGタンパク質共役受容体によって仲介される。プロスタグランジンE2(PGE2)は、機能的に異なる受容体サブタイプ、すなわちEP1、EP2、EP3およびEP4受容体であって、それらの全てはPGE2と反応するが、その作用が異なる受容体サブタイプ、と結合することを通じて、幅広い種類の細胞効果を有するため、特に興味深い。
本発明は、ウィルス性疾患に対する治療薬に有用である薬剤に関する。より具体的には、前記発明は、A型インフルエンザウィルスに関連する疾患の治療法に関するものであり、そしてとくに、A型インフルエンザH5N1亜型ウィルスに関する。前記方法は、EP2作動薬、EP4作動薬、混合型EP2/EP4作動薬、またはそれらの混合物(それらの全ては、本明細書において以下の用語「EP2およびEP4作動薬」、「EP2および/またはEP4作動薬」および「EP作動薬」に含まれる)の有効量を、それを必要とする患者に投与することを含む。
本発明において有用なEP2、EP4および混合型EP2/EP4作動薬は、A型インフルエンザウィルスによる、および好ましい実施形態としては、A型インフルエンザH5N1亜型ウィルスによる感染に対する応答である、サイトカインおよび/またはケモカインの放出を阻害する全てのものを含む。そのような阻害は、当業者によって、当技術分野で周知の手法または本明細書で教示されているような手法により、過度の実験を要することなく、決定され得る。
R1は、CH2OH、−COOR2、CONHR2または−CONHR3基であり、
R2は、水素、
直鎖または分岐鎖の、場合により一価から多価不飽和の、場合によりハロゲン、C1〜C4アルコキシ、置換C3〜C10アリール、場合により置換C3〜C10アロイル、場合により、置換ジ−C1〜C5アルキルアミノまたは場合により置換トリ−C1〜C5アルキルアミノによって一置換から多置換されたC1〜C10アルキル基、
場合によりC1〜C4アルキルで置換されたC3〜C10シクロアルキル、
3位および4位をフッ素、塩素、アルコキシ、またはトリフルオロメチル、あるいは4位をヒドロキシ、ハロゲン、フェニル、一もしくはそれ以上のC1〜C4アルキル基、クロロメチル、フルオロメチル、トリフルオロメチル、カルボキシ、ヒドロキシまたはC1〜C4アルコキシによって置換されていてもよい、フェニル、1−ナフチル、2−ナフチルで、場合により置換されたC3〜C10アリール、
または、C3〜C7ヘテロシクロアルキルであり、
R3は、C1〜C15カルボン酸またはC1〜C15スルホン酸であり、
Aは、シス−CH=CH−または−CH2−CH2−基であり、
Bがは、トランス−CH=CH−または−CH2−CH2−基であり、
Wは、C2〜C6アルキレンであり、
R4は、ヒドロキシ基、O−R6基またはO−R7基であり、ここでR6は、テトラヒドロピラニル、テトラヒドロフラニル、トリメチルシリル、tert−ブチルジメチルシリル、tert−ブチルジフェニルシリル、またはトリベンジルシリル基であり、R7は、C1〜C15カルボン酸であり、
R5は、水素、C1〜C10アルキル、またはC1〜C10アルケニル基であり、
nは、1〜4である。]
で表される、9−クロロ−15−デオキシプロスタグランジン誘導体、および生理学的に許容される塩基を用いたその塩、ならびにそのシクロデキストリン包接体から選択される。
R1が、CH2OH、−COOR2、−CONHR2、または−CONHR3基であり、
R2が、水素、
直鎖または分岐鎖の、場合により一価から多価不飽和の、場合により、フッ素、塩素、または臭素により、C1〜C4アルコキシ、置換C3〜C10アリール、または、場合により置換C3〜C10アロイル、置換ジ−C1〜C5アルキルアミノもしくは置換トリ−C1〜C5アルキルアミノにより一置換されたC1〜C10アルキル基、
場合により、C1〜C4アルキルで置換されたC5〜C6シクロアルキル、
3位または4位をフッ素、塩素、アルコキシ、またはトリフルオロメチルで、あるいは4位をヒドロキシで置換されていてもよい、フェニルで場合により置換された、C3〜C10アリール基、
窒素、酸素または硫黄により、1回またはそれ以上中断されていてもよい、C5〜C6ヘテロシクロアルキルであり、
R3が、C1〜C10カルボン酸またはC1〜C10スルホン酸であり、
Aが、シス−CH=CH−または−CH2−CH2−基であり、
Bが、トランス−CH=CH−または−CH2−CH2−基であり、
Wが、C2〜C6アルキレンであり、
R4が、ヒドロキシ基であり、
R5が、水素、C1〜C6アルキル、またはC1〜C10アルケニル基であり、そして、
nが、1〜4であり、好ましくは2〜3である、化合物である。
R1が、CH2OH、−COOR2、−CONHR2、または−CONHR3基であり、
R2が、水素、または場合によりフェニルで置換されているC1〜C4アルキル、
C5〜C6シクロアルキル、
場合によりフェニルで置換されているC3〜C6アリールであり、
R3が、C1〜C6カルボン酸またはC1〜C6スルホン酸であり、
Aが、シス−CH=CH−または−CH2−CH2−基であり、
Bが、トランス−CH=CH−または−CH2−CH2−基であり、
Wが、C2−アルキレンであり、
R4が、ヒドロキシ基であり、
R5が、水素、飽和C1〜C4アルキル、またはC1〜C5アルケニルであり、そして、
nが、1〜4であり、好ましくは2〜3であり、より好ましくは2である、化合物である。
のアルデヒドと、一般式III:
の化合物を反応させることからなる。
原理:
抗原提示細胞、およびT細胞受容体を介した抗原による、ヒトTリンパ球の活性化は、レクチン、コンカナバリンA(Concanavilin A)(ConA)による実験条件で模倣される。ConAは、T細胞受容体と結合し、そして細胞が種々のサイトカインを放出するように刺激することが知られている。EP受容体へのニレプロストの結合は、種々のサイトカインの放出を阻害する。Th−1細胞により放出されるサイトカインの一つが、IFN−γである。IFN−γの生化学的および生物学的活性は、広範囲にわたって文献に概説されている。
ヒトIFN−γは、143アミノ酸からなる、2量体の発現タンパク質である。IFN−γ特異的な抗体に基づく酵素結合免疫吸着検定法(ELISA)は、市販されている。スタンダードおよびサンプルを、マイクロプレートのウェルに、ピペットで入れた。ヒトIFN−γ特異的抗体を、前記ウェルに加えた。基質をウェルに加え、そして、IFN−γの結合量に比例して着色が生じた。色強度を測定した。
末梢血リンパ球を、ヒトドナーから、フィコール密度勾配遠心法を用いて単離し、残余の赤血球を選択的溶解により取り除いた。白血球を、10%ウシ胎児血清を加えたRPMI1640中で、約106細胞/mLで培養した。細胞培養を、上記で記述した2μg/mlのConAにより活性化した。ConAによる活性化の間、ニレプロストを種々の濃度に希釈して加えた。細胞を37℃で約18時間培養した。活性化の間に放出されたIFN−γを、ELISAを用いて測定した。
原理:
抗原提示細胞による、およびT細胞受容体を介した抗原による、ヒトTリンパ球の活性化は、レクチンである、コンカナバリンA(ConA)による実験条件で模倣される。ConAは、T細胞受容体と結合し、そして、細胞が種々のサイトカインを放出するように刺激することが知られている。EP受容体へのニレプロストの結合は、種々のサイトカインの放出を阻害する。阻害される炎症性サイトカインの一つが、TNFαである。TNFαの生化学的および生物学的活性は、広範囲にわたって文献に概説されている。
ヒトTNFαは、3量体の発現タンパク質である。TNFαに特異的な抗体に基づく、酵素結合免疫吸着検定法(ELISA)は、市販されている。スタンダードおよびサンプルを、マイクロプレートのウェルへ、ピペットで入れた。ヒトTNFαに特異的な抗体を、前記ウェルに加えた。基質をウェルに加え、そして、TNFαの結合量に比例して着色が生じた。色強度を測定した。
末梢血リンパ球を、ヒトドナーからフィコール密度勾配遠心法を用いて単離し、残余の赤血球を選択的溶解により取り除いた。白血球を、10%ウシ胎児血清を加えたRPMI1640中で、約106細胞/mLで培養した。細胞培養を、上記で記述した2μg/mlのConAにより活性化した。ConAによる活性化の間、ニレプロストを種々の濃度に希釈して加えた。細胞を37℃で約18時間培養した。活性化の間に放出されたTNFαを、ELISAを用いて測定した。
原理:
抗原提示細胞、およびT細胞受容体を介した抗原による、ヒトTリンパ球の活性化は、T細胞受容体のCD3サブユニットへの抗体の付加、およびCD28共刺激受容体への抗体の付加による実験条件で模倣される。Tリンパ球への抗CD−3、抗CD−28抗体の結合は、当該細胞が、種々のサイトカインの放出をするように刺激する。これらのサイトカインのいくつかは、IL−2、IFN−γおよびGM−CSFである。これらのサイトカインの生化学的および生物学的活性は、広範囲にわたって文献に概説されている。EPレセプターへのニレプロストの結合は、種々のCD8+サイトカインの放出を阻害する。
ヒトのサイトカインに特異的な抗体に基づいた、マルチ−サイトカイン免疫吸着法(Multi−cytokine immunosorbant assays)が、市販されている。スタンダードおよびサンプルを、サンプルチューブに、ピペットで入れた。サイトカイン特異的なモノクローナル抗体を、蛍光性のビーズセットへ共有結合により結合させ、それがサイトカインを補足する。相補的な、ビオチン化モノクローナルサイトカイン抗体により、免疫サンドイッチを完成させ、そして前記反応をストレプトアビジン−フィコエリスリンにより検出する。
ミルテニー社製のCD14ビーズにより、4人のドナーからCD14陰性の個体群を単離した。4つの個体群を、10%ウシ胎児血清を加えたRPMI1640中で一晩、別々のフラスコ中で、5×106/mLdで静置した。それまでの間、抗CD3抗体(OKT3、機能性抗体、イーバイオサイエンス(eBioscience))を、4℃で、炭酸ナトリウム結合バッファー中、5μg/mLで、10cmのプレートに結合した。次の日、細胞を混合し、そして、ミルテニー社製のCD8単離キット(ネガティブ セレクション)を用いた、CD8細胞の単離のために、1×109個の細胞を分取した。生じた3.9×108個のCD8細胞を、培地中で、4×106/mLで再懸濁させ、10cmの、CD3−結合プレートへ加えた。溶解性の抗CD28(2〜5μg/mL)および1μMのニレプロストまたはビヒクルのみを、CD8細胞に加えた。培養を一晩続け、そしてサイトカインを上記に従って検出した。結果を下記に示す。
原理:
樹状細胞(DC)は、最も強力な抗原提示細胞であり、免疫応答において中心的な役割を果たす。トル様受容体、TLRを介した刺激の後、DCは、炎症性のサイトカインおよびケモカインを発現し、ならびに放出し、そして、ナイーブT細胞の活性化および増殖を誘導することがある。EP受容体へのニレプロストの結合は、TLR4リガンド(LPS)により刺激されたIL−12の放出を阻害する。したがって、CD4T細胞のTh−2系統への分化を導く。
IL12は、2つの遺伝的に関連性のないサブユニットがジスルフィド結合により結合された、75kDaの糖タンパク質ヘテロ二量体(p70)である。IL−12p70に特異的な抗体に基づく酵素結合免疫吸着検定法は、市販されている。スタンダードおよびサンプルを、マイクロプレートのウェルへ、ピペットで入れた。ヒトIL12に特異的な抗体を、前記ウェルに加えた。基質をウェルに加え、そして、IL12の結合量に比例して着色が生じた。当該色強度を測定した。
ヒト単球由来の樹状細胞を、ヒトドナーからフィコール密度勾配遠心法を用いて単離し、残余の赤血球を選択的溶解により取り除いた。CD14マイクロビーズを、CD14抗原の発現に基づく、ヒト細胞の分離のために使用した。樹状細胞を、ウシ胎児血清、200ng/mLのGM−CSF(Leukine)および10ng/mLのIL−4を加えたRPMI1640中で、約1.5×106細胞/mLで培養した。細胞を3日間かけて成長させ、それから培地を換えた。10ng/mLのLPSを、細胞を活性化させるために加えた。LPSによる刺激の間、1μMのニレプロストおよび1μMのPGE2を加えた。細胞を、約18時間、37℃で培養した。活性化中に放出されたIL−12を、ELISAを用いて測定した。結果を以下に示す。
ヒトドナーの単球由来の樹状細胞を、10ng/mLのIL−4および200ng/mLのGM−CSF存在下、10%ウシ胎児血清を含むRPMI−1640中で6日間、培養した。当該細胞を、種々の活性化刺激剤(プロスタグランジンE2(PGE2)(1μM)、ビヒクルコントロール(DMSO)または検体(1μM)存在下で、18時間、10ng/mL LPS(シグマ),5μg/mL リコンビナントヒトCD−40リガンド(R&D システムズ)、あるいは5μM ヒトCpG−DNA(ハイカルト バイオテクノロジー(HyCult Biotechnology))を用いて活性化した。個々のドナーの、細胞培養上清中のTNFαのレベルを、市販のELISAキットで測定した。検体((5Z,13E)−(9R,11R)−9−クロロ−11−ヒドロキシ−17,17−テトラメチレン−20−ノル−5,13−プロスタジエン酸(検体1)および別のEP作動薬(検体2)を用いた結果を、以下の表に示す)は、以下の表に示すとおり、培養上清中において測定されたサイトカインレベルの阻害へと導いた。
検体(ニレプロスト)を、合成ウィルス性RNAにより活性化された、ヒト単球由来の樹状細胞からの、TNFαの放出を阻害するために使用した。細胞を、実施例4および実施例5で記載したとおりに、インビトロで培養した。細胞を、1マイクロモーラーの検体の存在下または非存在下において、2μg/mLのポリ(I:C)、すなわち二重鎖RNAの合成誘導体(A型インフルエンザウィルスの構成要素)を用いて活性化し、18時間培養した。細胞培養上清のTNFαのレベルを、市販のELISAキットにより測定した。検体(ニレプロスト)は、ポリ(I:C)により誘導されたTNFαの著しい減少を引き起こした。
実施例6の手順に従って、ヒト末梢血リンパ球を単離し、培養し、それらをポリ(I:C)を用いて活性化した後、さらに培養した。細胞培養上清中のTNFαのレベルを、ELISAキットにより測定した。検体(ベラプロスト)は、以下の表に示すとおり、ポリ(I:C)によって誘導されるTNFαの著しい減少を引き起こした。
試験A:耐性および薬物動態
14人のボランティアに、ニレプロストを2、4、8、16、32または65μg、単回経口投与した。以下のパラメーターを試験した:血圧、心拍、臨床化学、血小板凝集能、およびECG。
高用量における腸貯留以外の所見は認められず、このことは、ニレプロストが良好な耐性を有することを示している。
12人の志願者に、ニレプロストを50、75、112、255、または375μg、単回経口投与した。以下のパラメーターが、調査された:血圧、心拍、ECG、肺機能、臨床化学および血液学、血小板凝集能、ならびに糞便。
高用量(255μg、および375μg)における「無痛の下痢」以外の所見は認められず、このことは、ニレプロストの耐性を示している。
Claims (8)
- A型インフルエンザウィルスに関連する疾患の治療を必要とする患者における、当該疾患の治療のための医薬組成物であって、ベラプロスト、もしくは薬学的に許容されるその塩、またはそれらのシクロデキストリン包接体を含む、前記組成物。
- 前記A型インフルエンザウィルスが、H5N1型、またはその変異体である、請求項1に記載の組成物。
- 前記ベラプロストが、ヒト肺胞細胞及び気管支上皮細胞における、炎症性サイトカインおよび/またはケモカインの放出を阻害する、請求項1又は2に記載の組成物。
- 前記ベラプロストが、ヒト末梢血リンパ球における、炎症性サイトカインおよび/またはケモカインの放出を阻害する、請求項1〜3のいずれか1項に記載の組成物。
- A型インフルエンザウィルス感染の治療を必要とする患者における、当該治療のための医薬の製造における、ベラプロスト、もしくは薬学的に許容されるその塩、またはそれらのシクロデキストリン包接体の使用。
- 前記A型インフルエンザウィルスが、H5N1型、またはその変異体である、請求項5に記載の使用。
- 前記ベラプロストが、ヒト肺胞細胞及び気管支上皮細胞における、炎症性サイトカインおよび/またはケモカインの放出を阻害する、請求項5又は6に記載の使用。
- 前記ベラプロストが、ヒト末梢血リンパ球における、炎症性サイトカインおよび/またはケモカインの放出を阻害する、請求項5〜7のいずれか1項に記載の使用。
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JP2015000033A Active JP5869707B2 (ja) | 2006-11-16 | 2015-01-05 | A型インフルエンザウィルス感染の治療のための薬剤としてのep2およびep4作動薬 |
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EP (2) | EP2269611B1 (ja) |
JP (3) | JP5271272B2 (ja) |
CA (1) | CA2669763C (ja) |
WO (1) | WO2008058766A1 (ja) |
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JP5479092B2 (ja) * | 2007-05-08 | 2014-04-23 | 国立大学法人浜松医科大学 | Ep4アゴニストを含有してなる細胞傷害性t細胞の活性化剤 |
EP2488168A1 (en) * | 2009-10-14 | 2012-08-22 | Gemmus Pharma Inc. | Combination therapy treatment for viral infections |
WO2014151085A1 (en) * | 2013-03-15 | 2014-09-25 | Gemmus Pharma Inc. | Beraprost isomer as agent for the treatment of viral infection |
AU2014305843B2 (en) | 2013-08-09 | 2019-08-29 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
WO2015109112A1 (en) * | 2014-01-16 | 2015-07-23 | Gemmus Pharma Inc. | Combination treatment of antibiotic and gpcr agonist for viral/bacterial co-infections |
HU231080B1 (hu) * | 2016-04-05 | 2020-07-28 | CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. | Eljárás optikailag aktív Beraprost előállítására |
WO2019028387A1 (en) * | 2017-08-03 | 2019-02-07 | Rita Elena Serda | LIPOSOMAL COATED NANOPARTICLES FOR IMMUNOTHERAPY APPLICATIONS |
WO2020237096A1 (en) | 2019-05-21 | 2020-11-26 | Ardelyx, Inc. | Combination for lowering serum phosphate in a patient |
US12042503B2 (en) | 2020-02-12 | 2024-07-23 | Cytoagents, Inc. | Compositions and methods for treating coronavirus infections |
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2007
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- 2007-11-14 CA CA2669763A patent/CA2669763C/en not_active Expired - Fee Related
- 2007-11-14 JP JP2009536669A patent/JP5271272B2/ja active Active
- 2007-11-14 EP EP07846671A patent/EP2094273B1/en not_active Not-in-force
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CA2669763C (en) | 2015-02-17 |
US20090170931A1 (en) | 2009-07-02 |
US20120190739A1 (en) | 2012-07-26 |
EP2269611B1 (en) | 2016-03-23 |
EP2269611A2 (en) | 2011-01-05 |
WO2008058766A1 (en) | 2008-05-22 |
CA2669763A1 (en) | 2008-05-22 |
EP2094273B1 (en) | 2013-03-06 |
JP2013147518A (ja) | 2013-08-01 |
JP2010510183A (ja) | 2010-04-02 |
US8980944B2 (en) | 2015-03-17 |
JP2015061885A (ja) | 2015-04-02 |
US8183286B2 (en) | 2012-05-22 |
EP2269611A3 (en) | 2012-03-14 |
JP5869707B2 (ja) | 2016-02-24 |
US20150374715A1 (en) | 2015-12-31 |
EP2094273A1 (en) | 2009-09-02 |
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