JP2013516457A - Vb−201を用いた併用治療法 - Google Patents
Vb−201を用いた併用治療法 Download PDFInfo
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Abstract
Description
a)治療的有効量のスタチンを対象に投与する工程;
b)治療的有効量のスタチンに対する対象の応答性を決定する工程であって、それによって、対象が治療的有効量に対して十分に応答しないかどうか決定する、工程;および
c)対象が治療的有効量に対して十分に応答しないと決定されたら、治療的有効量のVB-201を対象に投与する工程を含み、それによって、心血管疾患を治療する。
a)ある投与量のVB-201を対象に投与する工程;
b)前記投与量のVB-201に対する対象の応答性を決定する工程であって、それによって、対象が前記投与量のVB-201に十分に応答しないかどうか決定する、工程;ならびに
c)対象が十分に応答するまで、および/または最大投与量に達するまで、対象に投与されるVB-201の投与量を段階的に増大させる工程を含み、それによって、対象において投与するためのVB-201の治療的有効量を決定する。
a)治療的有効量のさらなる治療上活性のある薬剤を用いて治療されている対象に、異なる投与量のVB-201を投与する工程であって、対象は、治療的有効量の治療上活性のある薬剤に十分に応答しないと決定されており、対象の一部にはVB-201の代わりにプラセボが投与される工程;
b)治療的有効量の治療上活性のある薬剤と組み合わせた前記投与量のVB-201またはプラセボに対する対象の応答性をモニタリングする工程;および
c)治療的有効量の治療上活性のある薬剤と組み合わせて投与された前記投与量のVB-201に対象が応答するようになる、少なくとも1つのVB-201投与量を特定する工程を含み、それによって、さらなる治療上活性のある薬剤と組み合わせて投与するためのVB-201の治療的有効量を決定する。
本発明は、その一部の態様において薬理学の分野に関し、具体的には、酸化型リン脂質VB-201の新規の投与量、治療レジメン、および治療的使用に関するが、これに限定されない。
[LDLコレステロール]=[総コレステロール]-[HDLコレステロール]-(0.2x[トリグリセリド])
によって見積もることができる。
a)最高耐性投与量(本明細書において説明される);および/または
b)それに対する対象の応答性が、さらに高い投与量に対する対象の応答性と少なくとも同程度である投与量(本明細書において説明される)
であり、いずれか少ない方である。
材料:
アトルバスタチンはPfizerから入手した。
屠殺時に大動脈を収集した。Image-Pro Plusソフトウェア(Media Cybernetics)を用いて、病変組織に付着しているSudan IV染色液の強度をスキャンすることによって病変面積を求めた。大動脈(大動脈弓、胸大動脈、および腹大動脈)の3つの異なる切片において病変面積を計算した。総大動脈病変面積(3つ全ての切片にある病変面積の合計)を3つ全ての切片面積の合計に対するパーセントとして計算した。
血漿コレステロールレベルは、Bert W. Strassburger Lipid Center(Sheba Medical Center, Israel)において、Cobas Mira分析器(Roche)およびコレステロール試薬(Roche/Hitach)を用いて決定した。
血液化学的性質は、Pathological Chemistry Institute Laboratory (Sheba Medical Center, Israel)によってAU2700(登録商標)分光光度計(Olympus)および適切なOlympus試薬を用いてアッセイした。評価したパラメータは、尿素、クレアチニン、グルコース、カリウム、ナトリウム、塩素イオン、総カルシウム、リン(phopshorus)、尿酸、ビリルビン、SGOT、SGPT、LDH、総CPK、CPK-MB、CK-MB%、総タンパク質、アルブミン、グロブリン、アルカリホスファターゼ、および重量オスモル濃度レベルであった。
VB-201レジメンの安全性および耐容性は、以下の測定値における異常知見の発生率を評価することによって判断した:
生命徴候:収縮期血圧および拡張期血圧、脈拍数、呼吸数、体温;
理学的検査;
12誘導心電図;
以下についての血液試料臨床検査:ヘモグロビン、ヘマトクリット、平均赤血球容積、平均赤血球ヘモグロビン濃度、赤血球数、白血球数、白血球百分率、血小板数、好中球数、LDL-コレステロールおよびHDL-コレステロール、総コレステロール、トリグリセリド、グルコース、尿素、ナトリウム、カリウム、クレアチニン、カルシウム、塩素イオン、無機リン酸、クレアチニンホスホキナーゼ、アスパラギン酸トランスアミナーゼ、アラニントランスアミナーゼ、γ-グルタミルトランスフェラーゼ、アルカリホスファターゼ、総タンパク質、アルブミン、総ビリルビンおよび間接型ビリルビン;
日常的な尿検査;ならびに
全ての有害事象が、Good Clinical Practiceの基準に従って、重篤とみなされるかどうか、治験薬との関連性があるかどうか。
アテローム性動脈硬化症に対するアトルバスタチンおよびVB-201の併用治療
雄のニュージーランドホワイトウサギ(hsdIF:NZ, Harlan)に高コレステロール飼料(0.5%w/wコレステロール)を14週間与えることによって、アテローム性動脈硬化症を誘導した。ウサギを、4つの治療群(1群当たり7匹または8匹の動物):a)アトルバスタチン治療;b)VB-201治療;c)アトルバスタチン+VB-201併用治療;およびd)0.5%エタノールを含むPBS(対照群)に割り当てた。
デキストラン硫酸ナトリウム(DSS)誘導性大腸炎モデルにおける酢酸グラチラマーおよびVB-201による併用治療
炎症障害モデルとして役立つように、マウスにおいてデキストラン硫酸ナトリウム(DSS)を用いて大腸炎を誘導した。実験の0〜4日目、19〜23日目、および32〜36日目に、2%DSS溶液をマウス飲料水に入れて投与した。
高感度C反応性タンパク質(hs-CRP)レベルの高い患者におけるVB-201とスタチンの効力
実施例1に示したように、VB-201とスタチンの組み合わせを用いた治療はアテローム性動脈硬化症に対して特に有効である。さらに、VB-201は、健常ヒトにおいて、炎症マーカーであるC反応性タンパク質(CRP)レベルの低減において有効であることが以前に示された。従って、スタチンを用いて治療された患者においてVB-201が炎症を低減する効力を調べる。
Claims (64)
- 心血管疾患を治療する必要のある対象において心血管疾患を治療する方法であって:
a)治療的有効量のスタチンを対象に投与する工程;
b)該治療的有効量のスタチンに対する対象の応答性を決定する工程であって、それによって、対象が該治療的有効量に対して十分に応答しないかどうか決定する、工程;および
c)対象が該治療的有効量に対して十分に応答しないと決定されたら、治療的有効量のVB-201を対象に投与する工程を含み、
それによって、心血管疾患を治療する、方法。 - 治療的有効量より多い投与量のスタチンの有害作用に対して対象が脆弱であるかどうか決定する工程、および治療的有効量のVB-201を、該治療的有効量のスタチンに十分に応答しない該対象に投与する工程であって、該対象が、該治療的有効量より多い投与量のスタチンの該有害作用に対して脆弱である、工程をさらに含む、請求項1記載の方法。
- 治療的有効量より多い投与量のスタチンの有害作用に対して対象が脆弱であるかどうか決定する工程が、該治療的有効量より多い投与量の該スタチンを該対象に投与し、該対象における該有害作用を特定することによって行われ、該対象に投与される該スタチンの投与量を該治療的有効量まで低減する工程をさらに含む、請求項2記載の方法。
- 治療的有効量より多い投与量のスタチンの有害作用に対して対象が脆弱であるかどうか決定する工程が、該スタチンの最大許容投与量の50%〜100%の範囲にある治療的有効量の該スタチンを投与することによって行われる、請求項2記載の方法。
- 最大許容投与量が、FDA最大推奨投与量および欧州医薬品庁最大推奨投与量からなる群より選択される、請求項4記載の方法。
- スタチンが、アトルバスタチン、フルバスタチン、ロバスタチン、プラバスタチン、ロスバスタチン、およびシンバスタチンからなる群より選択される、請求項4記載の方法。
- 有害作用が、高い肝臓酵素レベル、筋肉痛、筋痙攣、多発ニューロパチー、筋炎、ミオパチー、横紋筋融解症、および急性腎不全からなる群より選択される、請求項2〜6のいずれか一項記載の方法。
- 治療的有効量のスタチンに十分に応答しない対象が、該治療的有効量の該スタチンの投与後、1.1mg/L以上のhs-CRPレベルにより特徴付けられる、請求項1〜7のいずれか一項記載の方法。
- 治療的有効量のスタチンに十分に応答しない対象が、該治療的有効量の該スタチンの投与後、予め決められたカットオフレベルを上回る低密度リポタンパク質(LDL)レベルにより特徴付けられ、該カットオフレベルは70〜190mg/dLの範囲にある、かつ/または該治療的有効量の該スタチンの投与前の該対象における低密度リポタンパク質(LDL)レベルの50%〜65%の範囲にある、請求項1〜8のいずれか一項記載の方法。
- 予め決められたカットオフレベルが、高い心血管事象リスクにより特徴付けられる対象では70mg/dLである、請求項9記載の方法。
- 対象が糖尿病により特徴付けられ、かつ予め決められたカットオフレベルが70〜80mg/dLの範囲にある、かつ/または前記治療的有効量のスタチンの投与前の該対象における低密度リポタンパク質(LDL)レベルの65%である、請求項9記載の方法。
- 予め決められたカットオフレベルが、血管事象の既往および/または証明された心血管疾患により特徴付けられる対象では100mg/dLである、請求項9記載の方法。
- 予め決められたカットオフレベルが、少なくとも2つの心血管疾患リスク因子により特徴付けられる対象では100〜130mg/dLの範囲にある、請求項9記載の方法。
- 予め決められたカットオフレベルが、2つより少ない心血管疾患リスク因子により特徴付けられる対象では130〜190mg/dLの範囲にある、請求項9記載の方法。
- カットオフレベルが、治療的有効量のスタチン投与前の対象における低密度リポタンパク質(LDL)レベルの50%である、請求項9〜14のいずれか一項記載の方法。
- 治療的有効量のスタチンに十分に応答しない対象が、該治療的有効量の該スタチンの投与後、少なくとも200mg/dLのLp-PLA2レベルにより特徴付けられる、請求項1〜15のいずれか一項記載の方法。
- 治療的有効量のスタチンに十分に応答しない対象が、該治療的有効量の該スタチンの投与後、少なくとも125mg/dLのアポリポタンパク質B100レベルにより特徴付けられる、請求項1〜16のいずれか一項記載の方法。
- 治療的有効量のスタチンに十分に応答しない対象が、該治療的有効量の該スタチンの投与後、100mg/dL未満のアポリポタンパク質Aレベルにより特徴付けられる、請求項1〜17のいずれか一項記載の方法。
- 治療的有効量のスタチンに十分に応答しない対象が、該治療的有効量の該スタチンの投与後、少なくとも150mg/dLの血中トリグリセリドレベルにより特徴付けられる、請求項1〜18のいずれか一項記載の方法。
- 治療的有効量のスタチンに十分に応答しない対象が、該治療的有効量の該スタチンの投与後、少なくとも30mg/dLのリポタンパク質(a)レベルにより特徴付けられる、請求項1〜19のいずれか一項記載の方法。
- 治療的有効量のスタチンに十分に応答しない対象が、該治療的有効量の該スタチンの投与後、男性対象の場合は45mg/dL未満の高密度リポタンパク質(HDL)レベル、または女性対象の場合は55mg/dL未満の高密度リポタンパク質(HDL)レベルにより特徴付けられる、請求項1〜20のいずれか一項記載の方法。
- 治療的有効量のスタチンに十分に応答しない対象が、該治療的有効量の該スタチンの投与後、心血管疾患の進行により特徴付けられる、請求項1〜21のいずれか一項記載の方法。
- 対象において投与するためのVB-201の治療的有効量を決定する方法であって:
a)ある投与量のVB-201を対象に投与する工程;
b)該投与量のVB-201に対する対象の応答性を決定する工程であって、それによって、対象が該投与量のVB-201に十分に応答しないかどうか決定する工程;ならびに
c)該対象が十分に応答するまで、および/または最大投与量に達するまで、該対象に投与されるVB-201の該投与量を段階的に増大させる工程を含み、
それによって、対象において投与するためのVB-201の治療的有効量を決定する、方法。 - ある投与量のVB-201が投与された対象において起こる有害作用をモニタリングする工程であって、最大投与量が該対象の最高耐性投与量である、工程をさらに含む、請求項23記載の方法。
- 最大投与量は、それに対する対象の応答性が、さらに高い投与量に対する該対象の応答性と少なくとも同程度である投与量である、請求項23記載の方法。
- ある投与量のVB-201が投与された対象において起こる有害作用をモニタリングする工程であって、最大投与量が該対象の最高耐性投与量である、かつ/または、それに対する該対象の応答性が、さらに高い投与量に対する該対象の応答性と少なくとも同程度である投与量である、工程をさらに含む、請求項23記載の方法。
- ある投与量に対する対象の応答性を決定する工程が、炎症バイオマーカーの存在および/またはレベルを決定する工程を含む、請求項23〜26のいずれか一項記載の方法。
- 炎症バイオマーカーが高いhs-CRPレベルである、請求項27記載の方法。
- 高いhs-CRPレベルが1.1mg/L以上である、請求項28記載の方法。
- 投与量を段階的に増大させる工程が、該投与量を25%〜300%増加させる工程を含む、請求項23〜29のいずれか一項記載の方法。
- 対象において投与するためのVB-201の治療的有効量が、炎症性疾患または炎症性障害を治療するための治療的有効量であり、かつ前記応答性は該疾患または障害の症状を緩和することを含む、請求項23〜30のいずれか一項記載の方法。
- 対象において投与するためのVB-201の治療的有効量が、心血管疾患または心血管障害を治療するための治療的有効量であり、かつ前記応答性は該疾患または障害の症状を緩和することを含む、請求項23〜30のいずれか一項記載の方法。
- ある投与量のVB-201が、さらなる治療上活性のある薬剤と組み合わせて投与され、かつ対象において投与するためのVB-201の治療的有効量は、該さらなる治療上活性のある薬剤と組み合わせて投与するための治療的有効量である、請求項23〜31のいずれか一項記載の方法。
- さらなる治療上活性のある薬剤と組み合わせて投与するためのVB-201の治療的有効量を決定する方法であって:
a)治療的有効量の該さらなる治療上活性のある薬剤を用いて治療されている対象に、異なる投与量のVB-201を投与する工程であって、該対象は、該治療的有効量の該治療上活性のある薬剤に十分に応答しないと決定されており、該対象の一部にはVB-201の代わりにプラセボが投与される、工程;
b)該治療的有効量の該治療上活性のある薬剤と組み合わせた該投与量のVB-201または該プラセボに対する該対象の応答性をモニタリングする工程;および
c)該治療的有効量の該治療上活性のある薬剤と組み合わせて投与された該投与量のVB-201に該対象が応答性になる、少なくとも1つのVB-201投与量を特定する工程を含み、
それによって、さらなる治療上活性のある薬剤と組み合わせて投与するためのVB-201の治療的有効量を決定する、方法。 - 治療的有効量の治療上活性のある薬剤と共に、ある投与量のVB-201が投与された対象において起こる有害作用をモニタリングする工程であって、該治療的有効量の該治療上活性のある薬剤と組み合わせて投与された該投与量のVB-201が該対象において有害作用を増加しないように、該対象が応答性になる少なくとも1つのVB-201投与量が選択される、工程をさらに含む、請求項34記載の方法。
- 治療上活性のある薬剤の治療的有効量が、該治療上活性のある薬剤の最大許容投与量の少なくとも25%である、請求項34〜35のいずれか一項記載の方法。
- 最大許容投与量が、FDA最大推奨投与量および欧州医薬品庁最大推奨投与量からなる群より選択される、請求項36載の方法。
- さらなる治療上活性のある薬剤が、心血管疾患を治療するための薬剤である、請求項34〜37のいずれか一項記載の方法。
- さらなる治療上活性のある薬剤がスタチンである、請求項34〜38のいずれか一項記載の方法。
- スタチンが、アトルバスタチン、フルバスタチン、ロバスタチン、プラバスタチン、ロスバスタチン、およびシンバスタチンからなる群より選択される、請求項39記載の方法。
- スタチンが、アトルバスタチン、ロスバスタチン、およびシンバスタチンからなる群より選択される、請求項39記載の方法。
- 治療的有効量の治療上活性のある薬剤に対する対象の応答性およびある投与量のVB-201と該治療的有効量の該治療上活性のある薬剤の組み合わせに対する対象の応答性が、心血管疾患の進行が無いことによって特徴付けられる、請求項38〜41のいずれか一項記載の方法。
- 治療的有効量の治療上活性のある薬剤に対する対象の応答性およびある投与量のVB-201と該治療的有効量の該治療上活性のある薬剤の組み合わせに対する対象の応答性が、炎症バイオマーカーレベルの低減によって特徴付けられる、請求項34〜42のいずれか一項記載の方法。
- 応答性が、1.1mg/L未満のhs-CRPレベルによって特徴付けられる、請求項43記載の方法。
- VB-201の投与量が1μg/日〜1グラム/日の範囲にある、請求項34〜44のいずれか一項記載の方法。
- 炎症性疾患または炎症性障害を治療する方法であって、治療的有効量のVB-201および治療的有効量の酢酸グラチラマーを同時投与する工程を含み、それによって、炎症性疾患または炎症性障害を治療する、方法。
- VB-201の治療的有効量が1μg/日〜1グラム/日の範囲にある、請求項46記載の方法。
- 酢酸グラチラマーの治療的有効量が2〜200mg/日の範囲にある、請求項46〜47のいずれか一項記載の方法。
- 炎症性疾患または炎症性障害の治療のための、酢酸グラチラマーとの併用用の、VB-201を含む薬学的組成物であって、包装材料の中に入れられ、かつ該包装材料の中または上で特定されている、薬学的組成物。
- 100mgを超えるVB-201および薬学的に許容される担体を含み、経口投与用に製剤化された、薬学的組成物単位剤形。
- 炎症性疾患または炎症性障害を治療または予防するための医用薬剤の単位剤形であって、100mgを超えるVB-201を含み、かつ経口投与用に製剤化された、単位剤形の製造におけるVB-201の使用。
- 単位剤形が101mg〜1グラムのVB-201を含む、請求項50〜51のいずれか一項記載の薬学的組成物単位剤形または使用。
- 単位剤形が約120mgのVB-201を含む、請求項52記載の薬学的組成物単位剤形または使用。
- 単位剤形が約240mgのVB-201を含む、請求項52記載の薬学的組成物単位剤形または使用。
- 炎症性疾患または炎症性障害の治療または予防における使用のための、包装材料の中に入れられ、かつ該包装材料の中または上で印刷により特定されている、請求項50および52のいずれか一項記載の薬学的組成物単位剤形。
- 炎症性疾患または炎症性障害を治療または予防する方法であって、炎症性疾患または炎症性障害を治療または予防する必要のある対象に、治療的有効量のVB-201を経口投与する工程であって、該治療的有効量が100mg/日を超える、工程を含む、方法。
- 治療的有効量が101mg〜1グラム/日の範囲である、請求項56記載の方法。
- 治療的有効量が約120mg/日である、請求項57記載の方法。
- 治療的有効量が約160mg/日である、請求項57記載の方法。
- 治療的有効量が約240mg/日である、請求項57記載の方法。
- 投与する工程が1日に少なくとも2回行われる、請求項56〜60のいずれか一項記載の方法。
- 請求項50および52〜55のいずれか一項記載の薬学的組成物単位剤形の単位を投与する工程を含む、請求項56〜61のいずれか一項記載の方法。
- 炎症性疾患または炎症性障害が内因性酸化脂質と関連している、請求項51および55〜62のいずれか一項記載の薬学的組成物単位剤形、使用、または方法。
- 炎症性疾患または炎症性障害が、特発性炎症性疾患または特発性炎症性障害、慢性炎症性疾患または慢性炎症性障害、急性炎症性疾患または急性炎症性障害、自己免疫疾患または自己免疫障害、感染性疾患または感染性障害、炎症性悪性疾患または炎症性悪性障害、炎症性移植関連疾患または炎症性移植関連障害、炎症性変性疾患または炎症性変性障害、過敏症に関連した疾患または障害、炎症性心血管疾患または炎症性心血管障害、炎症性脳血管疾患または炎症性脳血管障害、末梢血管疾患または末梢血管障害、炎症性腺疾患または炎症性腺障害、炎症性胃腸疾患または炎症性胃腸障害、炎症性皮膚疾患または炎症性皮膚障害、炎症性肝臓疾患または炎症性肝臓障害、炎症性神経学的疾患または炎症性神経学的障害、炎症性筋肉-骨疾患または炎症性筋肉-骨障害、炎症性腎臓疾患または炎症性腎臓障害、炎症性生殖疾患または炎症性生殖障害、炎症性全身疾患または炎症性全身障害、炎症性結合組織疾患または炎症性結合組織障害、炎症性腫瘍、壊死、炎症性移植片関連疾患または炎症性移植片関連障害、炎症性加齢プロセス、免疫不全疾患または免疫不全障害、増殖性疾患または増殖性障害、ならびに炎症性肺疾患または炎症性肺障害からなる群より選択される、請求項51および55〜62のいずれか一項記載の薬学的組成物単位剤形、使用、または方法。
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JP2012547586A Pending JP2013516455A (ja) | 2010-01-05 | 2011-01-05 | Vb−201を用いた治療 |
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EP (2) | EP2521454A4 (ja) |
JP (2) | JP2013516455A (ja) |
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CN (1) | CN102834011B (ja) |
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NZ (1) | NZ601224A (ja) |
WO (3) | WO2011083469A1 (ja) |
ZA (1) | ZA201205425B (ja) |
Families Citing this family (13)
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US6838452B2 (en) | 2000-11-24 | 2005-01-04 | Vascular Biogenics Ltd. | Methods employing and compositions containing defined oxidized phospholipids for prevention and treatment of atherosclerosis |
US7807847B2 (en) | 2004-07-09 | 2010-10-05 | Vascular Biogenics Ltd. | Process for the preparation of oxidized phospholipids |
US8569529B2 (en) | 2007-01-09 | 2013-10-29 | Vascular Biogenics Ltd. | High-purity phospholipids |
US9006217B2 (en) | 2007-01-09 | 2015-04-14 | Vascular Biogenics Ltd. | High-purity phospholipids |
US8999960B2 (en) * | 2008-10-08 | 2015-04-07 | Vascular Biogenics Ltd. | Oxidized thiophospholipid compounds and uses thereof |
CA2740726A1 (en) * | 2008-11-06 | 2010-05-14 | Vascular Biogenics Ltd. | Oxidized lipid compounds and uses thereof |
AU2012301602B2 (en) * | 2011-09-01 | 2015-09-03 | Vascular Biogenics Ltd. | Formulations and dosage forms of oxidized phospholipids |
US20150320773A1 (en) * | 2011-12-12 | 2015-11-12 | Vascular Biogenics Ltd. | Treatment of inflammation |
WO2013121300A2 (en) * | 2012-02-16 | 2013-08-22 | Vascular Biogenics Ltd. | Methods for treating psoriasis and vascular inflammation |
US9763992B2 (en) | 2014-02-13 | 2017-09-19 | Father Flanagan's Boys' Home | Treatment of noise induced hearing loss |
WO2016084023A1 (en) | 2014-11-26 | 2016-06-02 | Vascular Biogenics Ltd. | Oxidized lipids and treatment or prevention of fibrosis |
US9771385B2 (en) | 2014-11-26 | 2017-09-26 | Vascular Biogenics Ltd. | Oxidized lipids |
US20190145953A1 (en) * | 2016-03-31 | 2019-05-16 | Mayo Foundation For Medical Education And Research | Methods and materials for assessing intestinal permeability |
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JP2007531706A (ja) * | 2003-05-27 | 2007-11-08 | ヴァスキュラー バイオジェニックス リミテッド | 酸化脂質、ならびに炎症性の疾患および障害の治療におけるその使用 |
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CA2429817C (en) * | 2000-11-24 | 2013-02-12 | Vascular Biogenics Ltd. | Methods employing and compositions containing defined oxidized phospholipids for prevention and treatment of atherosclerosis |
PL1773352T3 (pl) * | 2004-07-09 | 2014-04-30 | Vascular Biogenics Ltd | Ulepszony sposób wytwarzania utlenionych fosfolipidów |
US8084209B2 (en) * | 2005-07-22 | 2011-12-27 | Children's Hospital & Research Center Oakland | HMGCR isoforms in prediction of efficacy and identification of cholesterol-modulating compounds |
US20090074720A1 (en) * | 2005-10-28 | 2009-03-19 | Sabbadini Roger A | Methods for decreasing immune response and treating immune conditions |
US8137977B2 (en) * | 2006-04-24 | 2012-03-20 | Children's Hospital & Research Center At Oakland | Lipidomic approaches to determining drug response phenotypes in cardiovascular disease |
US20090149541A1 (en) * | 2007-11-28 | 2009-06-11 | Yafit Stark | Method of delaying the onset of clinically definite multiple sclerosis |
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AU2011204406B2 (en) | 2015-05-07 |
AU2011204406A1 (en) | 2012-08-02 |
ZA201205425B (en) | 2015-07-29 |
US20120329758A1 (en) | 2012-12-27 |
MX2012007807A (es) | 2012-10-03 |
WO2011083467A1 (en) | 2011-07-14 |
KR20120133375A (ko) | 2012-12-10 |
US20130225525A1 (en) | 2013-08-29 |
US20160008381A1 (en) | 2016-01-14 |
EP2521569A4 (en) | 2013-05-22 |
CA2786060A1 (en) | 2011-07-14 |
BR112012016543A2 (pt) | 2015-09-01 |
NZ601224A (en) | 2015-03-27 |
CN102834011B (zh) | 2016-01-13 |
EP2521569B1 (en) | 2017-11-01 |
ES2654944T3 (es) | 2018-02-15 |
WO2011083465A1 (en) | 2011-07-14 |
EP2521454A1 (en) | 2012-11-14 |
WO2011083469A1 (en) | 2011-07-14 |
US20130172294A1 (en) | 2013-07-04 |
CN102834011A (zh) | 2012-12-19 |
EP2521454A4 (en) | 2013-06-26 |
EP2521569A1 (en) | 2012-11-14 |
JP2013516455A (ja) | 2013-05-13 |
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