JP5908884B2 - 気道炎症及び粘液線毛輸送機能異常治療用のエアロゾル化したダプソン - Google Patents
気道炎症及び粘液線毛輸送機能異常治療用のエアロゾル化したダプソン Download PDFInfo
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- JP5908884B2 JP5908884B2 JP2013500079A JP2013500079A JP5908884B2 JP 5908884 B2 JP5908884 B2 JP 5908884B2 JP 2013500079 A JP2013500079 A JP 2013500079A JP 2013500079 A JP2013500079 A JP 2013500079A JP 5908884 B2 JP5908884 B2 JP 5908884B2
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/10—Sulfides; Sulfoxides; Sulfones
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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- A61K31/13—Amines
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
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Landscapes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
気道を、患者の体内環境を外部から隔てる上皮細胞で覆う。気道上皮は、外的刺激及び細菌に対する機械的バリアであるだけでなく、先天性且つ後天性免疫応答、及び、気道炎症に積極的に関与している。細菌が侵入すると、粘膜毛様体クリアランスが活性化され、炎症性メディエータ及びサイトカインが防衛として分泌されるが、これらもまた気道を損傷しうる。上皮由来の多面的サイトカインの中で、ステインXシステイン(CXC)ケモカインファミリーの1つであるIL−8は、最も強力な好中球走化性因子の1つとして作用する。好中球支配性炎症は、慢性閉塞性肺疾患(COPD)、びまん性汎細気管支炎(diffuse panbronchiolitis:DPB)及び嚢胞性線維症(cystic fibrosis:CF)の特性を示す。IL−8は、気道上皮細胞により作られる。痰及び気管支肺胞洗浄(bronchoalveolar lavage:BAL)液中の増量したIL−8は、DPB及びCFの重症度に関連するものであり、重症喘息及びCOPDを患う対象の気管支上皮内のIL−8遺伝子発現が増加する。
試薬
ダプソン(4,4’−ジアミノジフェニルスルホン)、LPS(大腸菌血清型0111:B4)及びその他の全ての試薬は、特に記載しない限り、Sigma - Aldrich社(ミズーリ州セントルイス)から購入した。MAPK/ERKキナーゼ(MEK、ERK1/2の上流のキナーゼ)阻害剤であるPD98059は、Calbiochem社(カリフォルニア州ラ・ホーラ)から入手した。リン酸化及び非リン酸化特異的ERK1/2、抗p38 MAPK、抗SAPK/JNK、リン酸化特異的NF-κB p65(Ser536)及び抗ウサギIgG-HRP抗体は、Cell Signaling Technology社(マサチューセッツ州ベバリー)から購入した。DMSO(ジメチルスルホキシド)をダプソンの溶媒として用い、最終的濃度が0.01%(v/v)を超えないようにした。体外での予備実験は、0.01%のDMSO媒体では、72時間までの細胞の生存率及びIL-8分泌に対し著しい作用がなかったことを示した(データ不掲載)。
NHBE細胞(Lonza Walkersville社、メリーランド州ウォーカービル)を、抗生物質を含まずSingleQuot(米国登録商標)キット(Lonza社)が補充された気管支上皮細胞増殖培地(bronchial epithelial cell growth medium:BEGM)で、1cm2あたり3500個の細胞を培養皿に播種し、37℃の5%CO2培養器内で培養した。全ての実験で、無エンドトキシン培地(0.005単位/ml未満のエンドトキシン)と第2継代細胞を使った。細胞を、密集するまで6日間増殖させた。その後、抗生物質を含まない培養液を、1型ラット尾コラーゲンでコーティングした6ウェルプレート又は35mm培養皿に移し、1cm2あたり3500個の細胞を播種した。24時間おきに培地を交換した。細胞シグナリングとIL-8分泌に対する増殖因子の影響を避けるため、刺激する前の24時間の間、補充物無しの気管支上皮細胞用基礎培地(bronchial epithelial cell basal medium:BEBM)内で細胞を培養した。細胞成熟が細胞シグナリングとサイトカイン分泌に影響を及ぼす可能性があり、密集の際に全ての細胞が同様の成長段階にあることから、細胞の相対数に標準化するのではなく、細胞密集時の細胞応答を評価した。
生存細胞数を判別するため、Cell Counting Kit−8(CCK−8、株式会社同仁堂、日本熊本)を用いて、ホルマザン色素の生成を測定した。CCK−8アッセイ溶液で処理した細胞を2時間培養し、マイクロプレートリーダーで450nmの吸光度を測定した。データは、ダプソンに暴露されなかった対照細胞に対する%として表わした。
培養上清を採取し、200×gで5分間遠心分離機にかけ、分析がされるまで−20℃で保管した。ELISA(Beckman Coulter社、カリフォルニア州ブレア)を用い、製造元の使用説明書に従ってIL−8を測定した。各サンプルの濃度を、標準曲線から補間して得た後、サンプル希釈の結果の平均として計算した。
刺激を行った後、播種した細胞を冷PBSで洗浄し、その後、改良放射線免疫沈降緩衝液(1%のノニデットP−40、1%のデオキシコール酸ナトリウム、150mMのNaCl、10mMのTris(pH7.5)、5mMのピロリン酸ナトリウム、1mMのNaVO4、5mMのNaF、1μg/mlのアプロチニン、1μg/mlのロイペプチン及び0.1mMのPMSF)中で15分間氷上で溶解させ、そして、培養皿からこすり取った。27ゲージ注射針に溶解物を通してDNAを剪断し、20,000gを4℃で15分間遠心分離することで不溶性物質を除去した。得られた上清のタンパク質濃度を、DCプロテインアッセイ(Bio-Rad社、カリフォルニア州ハーキュリーズ)により測量した。同量のタンパク質抽出物を、それぞれ12%のSDS‐PAGE用ミニゲルに載せ、ニトロセルロース膜(Bio-Rad社)に移した。膜は、5%の脱脂粉乳を含むブロッキング緩衝液(150mMのNaCl、20mMのTris及び0.1%のTween20(pH7.6))を用い、4℃で一晩ブロッキングした。その後、膜をすすぎ、以下の一次抗体で、室温で2時間培養した。リン酸化された(p)‐p44/42 MAPK(Thr202/Tyr204)(希釈1:2000)、p−p38 MAPK(Thrl80/Tyrl82)(希釈1:1000)、p−SAPK/JNK(Thr183/Tyr185)(希釈1:1000)又はリン酸化したNF‐κB p65ウサギポリクローナル免疫グロブリンG(IgG)(希釈1:1000)(Cell Signaling Technology社)。そして、膜を室温で1時間、抗ウサギIgG-HRP二次抗体(希釈1:2000)で培養した。その後、ブロット膜を、化学発光基質過酸化物LumiGLO(Cell Signaling Technology社)で成長させた。
IL-8mRNA発現の相対的定量化において、グリセルアルデヒド‐3‐リン酸デヒト゛ロゲナーゼ(GAPDH)の発現が、内在性コントロールの役割を果たした。DNAインターカレーター色素としてEvaGreen を用い、増幅したDNAの定量化を監視し、各サンプルの閾値サイクル(Ct)値を得るため、CFX Manager(商標)ソフトウェア(Bio-Rad社)によりリアルタイム定量的PCR曲線を分析した。定量化は、標準曲線に基づいて行った。適切なIL−8及びGAPDHのフォワード及びリバースプライマーを用いた。
成フェレットの雄(体重1.3〜2.0kg)20匹を、Marshall Farms(ニューヨーク州ローズ)から入手した。フェレットに40mg/kgのケタミンと5mg/kgのキシラジンで麻酔をかけ、300μlの水溶性K‐Yゼリー(Johnson & Johnson社、ニュージャージー州ニューブランズウィック)に混合された10mgのLPSでコーティングした3.0カフなし気管内チューブ(ETT)を挿管することにより、5日間毎日1日1回30分間エンドトキシンに暴露した(2009年Abanses et al.)。対照群として、2匹のフェレットには、LPSを含まないK‐Yゼリーを用いた。
結果を、平均値±SE又は必要に応じて±SDで表わしている。統計パッケージStatview 5(SAS Institute社、ノースカロライナ州ケアリー)でデータの統計分析を行った。2つのグループの比較は、2標本t検定により行った。多重比較については、FisherのPLSDテストを用いた一元配置分散分析により行い、0.05未満のP値を有意であるとした。
NHBE細胞の生存率に対するダプソンの作用
培養したNHBE細胞の総数がダプソン治療に影響されなかったことを確認するために、CCK−8(株式会社同仁堂)を用いて細胞の生存率を評価した。96ウェルプレート(1ウェルにつき3000細胞)上に播種したNHBE細胞を、37℃で72時間培養した(70%までの密集)。濃度0.3、1又は10μg/mlのダプソンを、24又は72時間の間添加した。結果は、ダプソンで治療した細胞では、生存細胞の総数が、72時間以上治療のなかった対照群と同様であったことを示した(図示せず)。
NHBE細胞からのIL-8分泌に対するダプソンの作用を評価するため、LPSと同時に添加されたダプソンの存在下又は非存在下において、LPSでの刺激から24時間後に細胞上清を採取した。細胞成熟が細胞シグナリングとサイトカイン分泌に影響を及ぼす可能性があり、密集の際に全ての細胞が同様の成長段階にあることから、細胞の相対数に標準化するのではなく、細胞密集時の細胞応答の評価を選んだ。LPSは、10μg/mlで、NHBE細胞からのIL-8分泌を大幅に増加させたが(P<0.001)、ダプソンは、0.3、1又は10μg/mlで、これを抑えた(それぞれP<0.01)(図1A)。1μg/mlのダプソンでは、48及び72時間での基礎IL-8分泌に影響はなかった(図1B)。1μg/mlのダプソンの存在下では、LPS誘導性のIL-8分泌が、最大72時間まで大幅且つ持続的に減少した(図1C)。
ダプソンのIL−8抑制効果が分化した細胞にも見られるかどうかを確認するため、14日間ALI調整下で培養したNHBE細胞を用いた。ALIの細胞については、サンプルを、フィルタ上で成長した細胞の頂端側チャンバ及び側底側チャンバの双方から採取した。頂端側チャンバから細胞を採取するため、150μlのハンクス平衡塩類溶液(HBSS、Lonza Walkersville社)を頂端側に添加した。頂端側のIL−8濃度は、側底側培地の体積600μlと等しくなるような4倍希釈値として表わした。
デキサメタゾン(DEX)の作用を調べた。DEXは、頂端側及び側底側の双方において、基礎IL-8レベルを抑止した(それぞれP<0.05)(図2C及び2D)。また、DEXは、AP‐LPS又はBL−LPS誘導性のIL-8の増加を大幅に抑制した(それぞれP<0.05)。
IL-8mRNAに対するダプソンの作用を調べるため、LPS、ダプソン、DEX又はその組み合わせでの刺激から4時間後に細胞からRNAを抽出し、リアルタイム定量PCR用に準備した。図3に示すように、1μg/mlのダプソンでは、基礎IL-8mRNAレベルに影響はなかったが、0.1μg/mlのDEXは、これを〜40%まで減少させている(P<0.05)。10μg/mlのLPSは、IL-8mRNAレベルを対照群の5倍を超えて増加させた(P<0.001)。1及び10μg/mlのダプソンは、LPS誘導性IL-8mRNAの過剰発現を大幅に抑制した(それぞれP<0.05)。また、DEXも0.1μg/mlでこれを抑制した(P<0.01)。
MAPKシグナリングは、IL-8合成において重要な経路である。NHBE細胞内におけるERK1/2、p38及びJNKのLPS誘導性リン酸化反応に対するダプソンの作用を評価した。10μg/mlのLPSは、1、4及び24時間の時点でERK1/2を大幅にリン酸化したが(それぞれP<0.05)、p38及びJNKはそうではなかった(図4)。1μg/mlのダプソンは、1時間の時点ではLPS誘導性のERK1/2リン酸化反応を抑制したが(P<0.05)、4時間後にはこの効果は消えた。そこで、選択的細胞透過性のMEK阻害剤であるPD98059(2'‐アミノ‐3'‐メトキシフラボン)の効果を評価した。図5Aに示すように、LPSは、用量依存的にERK1/2のリン酸化反応とIL-8分泌を増加させ、PD98059は20μMで10μg/mlのLPSで誘導されたERK1/2のリン酸化反応を消滅させた。しかし、この濃度のPD98059では、IL-8分泌は抑制されなかった(図5B)。
LPSはTLR4を刺激し、NF-κB経路を介してIL−8を誘導するので、NHBE細胞内におけるNF-κB p65のリン酸化反応に対するダプソンの作用を調べた。増殖因子は、LPS又はダプソンの暴露の24時間前に培地から引き上げた。NF-κB p65のトレオニンリン酸化を、ウェスタンブロッティング法により測定した。バンド強度は、NIH image Jソフトウェアで計算した。
フェレットをLPSで5日間刺激し、5日間のダプソン治療又は賦形剤のみの投与を行った(検査した各時点で、賦形剤はn=8、ダプソン群はn=9)。フェレットの活動又は食欲に対してダプソンの存在下又は非存在下におけるLPSの計測可能な作用はなく、これら2つのグループを比較した際、9日間にわたって体重の差もなかった(図示せず)。
ダプソンの生体内での効果を評価するにあたり、好中球を動員し、麻酔下にあり自発呼吸するフェレットの気管に炎症を起こさせるため、局所的にLPSをコーティングした気管内チューブ(ETT)を使用した(2009年Abanses et al.)。水溶性ゼリー(他のグループではLPSの賦形剤として使用)のみをコーティングしたETTを挿管した対照のフェレットは、3/150μm未満のわずかな上皮内好中球を示した。LSPで気管が炎症を起こし、噴霧化した賦形剤で治療された1匹のフェレットは、6日目に死亡したことから実験を終了できず、この動物については、更なる分析から除外した。LPS暴露で、フェレットの気管上皮に著しい好中球蓄積を誘発し、ダプソン治療で上皮内好中球数を減少させた(図示せず)。経口投与したダプソンは、好中球動員を抑制する傾向があり(p=0.3)(図6A)、噴霧化したダプソンは、好中球蓄積を大幅に抑制した(P<0.05)(図6B)。
粘液線毛輸送機能(又は「粘膜毛様体クリアランス(mucociliary clearance:MCC)」は、気道表面の健全性及び完全性の全般的尺度である。3mmの切片におけるMCTの時間を測った。LPSは、MCTを1〜3mm/分まで劇的に遅くした(通常、およそ7mm/分である)。経口のダプソンはMCTを増進させたが、その伸び率は著しいものではなかった(P=0.09)。しかし、エアロゾルのダプソンは、図7A及び7Bに示すように、ほぼ通常速度でMCTを持続させた(6mm/分、LPS対照との比較でP=0.007)。
ダプソンがLPSで刺激されたNHBE細胞からのIL-8分泌を抑制することを示してきた。ダプソンは、皮膚疾患、とりわけ好中球浸潤を伴ったものの治療に用いられる。ダプソンは、高い日和見感染リスクもなく炎症箇所の好中球走化性と機能を減じる、と仮定されてきた。これは、免疫調節とは一致するが、免疫抑制とは一致しない。
杯細胞は円柱状の上皮細胞であり、その唯一の機能が、水に溶解して粘液を形成するムチンの分泌である。杯細胞過形成は、喘息患者の気管支上皮細胞によって生じる病理学的分泌過多に関与するものであり、IL−13は、喘息の生体内及び生体外モデルのいずれにおいても、胚細胞過形成を調整する中心的役割を果たすことで知られる。杯細胞過形成を抑制するダプソンの能力は、生体外で実験した。杯細胞過形成の生体外モデルは、気液界面(ALI)条件下で培養した正常ヒト気管支上皮(NHBE)細胞を用いて発達させた。細胞分染及び顕微鏡法を用いて分析した対照実験は、ダプソン(3μg/ml)では、ALI調整したNHBE細胞の成長に対する計測可能な作用はなかったことを示した(図示せず)。しかし、IL−13を用いて杯細胞過形成を誘導した場合、ダプソン(10μg/ml)は、対照細胞培養よりも、杯細胞過形成の量と範囲を軽減した(図示せず)。このように、ダプソンは、IL−13で誘導された杯細胞過形成を抑制することによっても、炎症回復に有益な効果を発揮する可能性がある。
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Claims (10)
- エアロゾル投与装置内の気体媒質に浮遊し接触する薬学的有効量のエアロゾル化したダプソン粒子を含有することを特徴とする、
気道炎症の予防又は治療を必要とする患者の気道炎症を予防又は治療するための吸入投与用医薬組成物。 - 水溶液中に薬学的有効量のダプソンを含有することを特徴とする、
気道炎症の予防又は治療を必要とする患者の気道炎症を予防又は治療するための吸入投与用医薬組成物。 - 前記患者は、嚢胞性線維症、気管支拡張症、閉塞性細気管支炎、肺気腫、慢性気管支炎、慢性鼻副鼻腔炎、吸引毒性傷害、慢性閉塞性肺疾患、特発性肺線維症、喘息及び慢性気道炎症からなる群から選ばれる疾病又は疾患を患っている請求項1又は2に記載の医薬組成物。
- 前記水溶液は、前記水溶液のエアロゾルの噴霧化により投与される請求項2に記載の医薬組成物。
- 前記医薬組成物は、1日1回投与される請求項1〜4のいずれか1項に記載の医薬組成物。
- 前記医薬組成物は、均等な時限的投薬量で1日に2〜12回投与される請求項1〜4のいずれか1項に記載の医薬組成物。
- 前記医薬組成物の投与量は、1回の投与につき体重1kgあたり0.5mgから体重1kgあたり5.0mgである請求項1〜5のいずれか1項に記載の医薬組成物。
- 前記医薬組成物の投与量は、1回の投与につき体重1kgあたり1.0mgから体重1kgあたり4.0mgである請求項7に記載の医薬組成物。
- 前記医薬組成物の投与量は、1回の投与につき体重1kgあたり1.5mgから体重1kgあたり3.0mgである請求項8に記載の医薬組成物。
- 前記医薬組成物の投与量は、1回の投与につき体重1kgあたり2.0mgである請求項9に記載の医薬組成物。
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PCT/US2011/027494 WO2011115778A2 (en) | 2010-03-15 | 2011-03-08 | Aerosolized dapsone as a therapy for inflammation of the airway and abnormal mucociliary transport |
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JP2013522295A5 JP2013522295A5 (ja) | 2014-05-01 |
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EP2833885A4 (en) * | 2012-04-06 | 2015-12-16 | Uab Research Foundation | METHODS TO INCREASE CFTR ACTIVITY |
JP6944701B2 (ja) * | 2016-10-21 | 2021-10-06 | 国立大学法人山口大学 | CD11bアンタゴニストを含む劇症型急性肺炎治療用組成物 |
CA3126367A1 (en) * | 2020-03-30 | 2021-09-30 | Pulmonem Inc. | Dapsone formulations and methods of using same |
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ATE204743T1 (de) | 1991-12-18 | 2001-09-15 | Minnesota Mining & Mfg | Aerosolzusammensetzungen für arzneimittelsuspensionen |
MX9704550A (es) | 1994-12-22 | 1997-10-31 | Astra Ab | Formulaciones de medicamentos en aerosol. |
US20030082107A1 (en) * | 1997-10-01 | 2003-05-01 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating an infectious disease or cancer |
GB9820886D0 (en) | 1998-09-26 | 1998-11-18 | Glaxo Group Ltd | Inhalation device |
DZ2947A1 (fr) | 1998-11-25 | 2004-03-15 | Chiesi Farma Spa | Inhalateur à compteur de dose sous pression. |
CA2372443C (en) * | 1999-04-30 | 2010-07-13 | Apt Pharmaceuticals, L.L.C. | Local administration of anti-malarial agents for the treatment of inflammatory diseases |
AU5702201A (en) * | 2000-04-13 | 2001-10-30 | Mayo Foundation | Abeta<sub>42</sub> lowering agents |
GB2362101A (en) * | 2000-05-12 | 2001-11-14 | Astrazeneca Ab | Treatment of chronic obstructive pulmonary disease |
US7077130B2 (en) | 2000-12-22 | 2006-07-18 | Chrysalis Technologies Incorporated | Disposable inhaler system |
US20030072737A1 (en) * | 2000-12-29 | 2003-04-17 | Michael Brines | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs |
US7090830B2 (en) * | 2001-05-24 | 2006-08-15 | Alexza Pharmaceuticals, Inc. | Drug condensation aerosols and kits |
AUPS017702A0 (en) * | 2002-01-25 | 2002-02-14 | Atopic Pty Ltd | Methods and compositions for the treatment of asthma and related disorders |
WO2004022128A2 (en) | 2002-09-06 | 2004-03-18 | Chrysalis Technologies Incorporated | Liquid aerosol formulations and aerosol generating devices and methods for generating aerosols |
US7497214B2 (en) | 2002-09-16 | 2009-03-03 | 3M Innovative Properties Company | Aerosol dispensers and adaptors therefor |
ATE389034T1 (de) * | 2002-09-30 | 2008-03-15 | Novartis Pharma Gmbh | Verfahren zur voraussage der erhöhung von cholesterin während einer immunosuppresiven therapie |
US20040086469A1 (en) * | 2002-10-30 | 2004-05-06 | Osborne David W. | Protectant for UV-induced skin damage |
US7683029B2 (en) | 2003-05-07 | 2010-03-23 | Philip Morris Usa Inc. | Liquid aerosol formulations containing insulin and aerosol generating devices and methods for generating aerosolized insulin |
SG146624A1 (en) * | 2003-09-11 | 2008-10-30 | Kemia Inc | Cytokine inhibitors |
BRPI0415753A (pt) * | 2003-10-21 | 2006-12-19 | Pharmacia Corp | método para tratamento e prevenção da inflamação respiratória com um inibidor de ciclooxigenase-2 em associação com um inibidor de fosfodiesterase 4 e composições que os contêm |
WO2007059905A2 (en) * | 2005-11-25 | 2007-05-31 | Develogen Aktiengesellschaft | Thienopyrimidines treating inflammatory diseases |
US20080066739A1 (en) * | 2006-09-20 | 2008-03-20 | Lemahieu Edward | Methods and systems of delivering medication via inhalation |
EP2249765B1 (en) * | 2008-02-27 | 2019-11-13 | Allergan, Inc. | Dapsone to treat rosacea |
US20120093947A1 (en) * | 2009-02-27 | 2012-04-19 | United States Department Of Veterans Affairs | Method of treating reactive airway disease |
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BR112012023877A2 (pt) | 2016-08-02 |
AU2011227613B2 (en) | 2015-09-03 |
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AU2011227613A1 (en) | 2012-10-04 |
WO2011115778A9 (en) | 2012-01-12 |
CA2793170A1 (en) | 2011-09-22 |
US20130005822A1 (en) | 2013-01-03 |
JP2013522295A (ja) | 2013-06-13 |
US20150040894A1 (en) | 2015-02-12 |
EP2547335A2 (en) | 2013-01-23 |
US20180243213A1 (en) | 2018-08-30 |
CA2793170C (en) | 2018-04-17 |
KR101924162B1 (ko) | 2018-11-30 |
WO2011115778A2 (en) | 2011-09-22 |
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