JP2020532417A - 体液からの終末糖化産物の削減 - Google Patents
体液からの終末糖化産物の削減 Download PDFInfo
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- JP2020532417A JP2020532417A JP2020512515A JP2020512515A JP2020532417A JP 2020532417 A JP2020532417 A JP 2020532417A JP 2020512515 A JP2020512515 A JP 2020512515A JP 2020512515 A JP2020512515 A JP 2020512515A JP 2020532417 A JP2020532417 A JP 2020532417A
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Abstract
Description
[0004]病態生理学的に重要な翻訳後修飾である終末糖化産物(AGEs)は、タンパク質と反応性炭水化物の非酵素的反応によってインビボで形成され、老化の過程で蓄積する。それらは、変性疾患の原因であることが議論されている。糖化は、タンパク質の構造や機能を修飾し、架橋によって組織の硬化を誘導する。可溶性のAGEsは、終末糖化産物受容体(RAGE)のような受容体と結合できる。RAGEへの結合は、一方ではRAGE自体の発現を、他方では長期間持続する炎症反応につながる炎症性サイトカインの発現を誘導する。老化は大部分が炎症に関連しているので(炎症老化(Inflammaging))、これは老化に影響を及ぼしうる。RAGEノックアウトマウスは、敗血症モデルで保護される(生存の増加)。心臓血管系において、AGEsは心機能及び血管機能障害の主因である。
[0007]一定の態様において、本発明は、体液から終末糖化産物を除去することによる変性疾患の治療に関し、該治療は体液を収着剤と接触させることを含む。
[0015]本明細書中で使用されている用語“生理液”は、身体を起源とする液体で、これらに限定されないが、鼻咽頭、口腔、食道、胃、膵臓、肝臓、胸膜、心膜、腹膜、腸、前立腺からの分泌物、精液、膣分泌物のほか、涙、唾液、肺又は気管支分泌物、粘液、胆汁、リンパ液、血漿、血清、滑液、脳脊髄液、尿、ならびに間質液、細胞内液、及び細胞外液、例えば火傷又は創傷から滲出する液体などでありうる。
[0020]一部の態様において、収着剤は、少なくとも一つの架橋剤と少なくとも一つのモノマーとを含む。他の態様において、収着剤は、少なくとも一つの架橋剤、少なくとも一つのモノマー、少なくとも一つの分散剤及び少なくとも一つのポロゲンを含む。
[0024]一部の好適なポリマーはセルロース系ポリマーを含む。適切なポリマーは、SephadexTMのような架橋デキストランゲルなどである。
[0027]本発明の実施に有用な一部のポリマーは、アミン、ヒドロキシル、スルホネート、及びカルボキシル基などの親水性官能基を含有する乾燥粉末として投与できる親水性自己湿潤性ポリマーである。
[0037]変性疾患も老化も、主として、分子、細胞及び組織内での分子損傷の生涯にわたる蓄積に起因すると考えられている。損傷構造の重要な例は終末糖化産物(AGEs)である。AGEsは多くの変性疾患に関連しうると考えられている。例示的な変性疾患は、アルツハイマー病、黄斑変性、骨関節炎、アテローム性動脈硬化症、心疾患及び腎不全である。本発明の方法及び収着剤は該疾患の治療に有用でありうる。又は予防的に使用できる。
実施例1
[0043]血漿サンプルを、アスピリン/グルコース又はその両方で処理して翻訳後修飾を誘導した。サンプルを、直接(−)又はCytoSorbents社製収着体に通した後(+)使用し、ゲル電気泳動によって分離し、ブロッティング及びアセチルリシン又はカルボキシメチルリシン(CML、終末糖化産物、AGE)に対する抗体で染色した。図1aは、CytoSorbents社製収着体がアセチルリシンと効率的に結合しないことを示している(比較は対のレーン(−/))。図1bは、CytoSorbents社製収着体がAGEs(CML)と効率的に結合することを示している(比較は対のレーン(−/+))。
[0044]本実施例では、一つのタンパク質(25kD)を利用し、CMLを緑に、アセチルリシンを赤に染色する(Odysseeシステム)。図2から、収着体の通過後、緑(GFP)修飾タンパク質は消失したが、赤(アセチルリシン)修飾タンパク質はなお検出可能であることが明らかに分かる(比較は対のレーン(−/+))。
[0045]80又は100又は120kDa又はそれを超える分子量を有するAGE分子の吸収は、体液を本発明の収着剤と接触させることによって達成できることが観察された。
Claims (19)
- 体液から終末糖化産物を除去する方法であって、前記体液を収着剤と接触させることを含む方法。
- 収着剤が、50Å〜40,000Åの範囲の複数の細孔を含み、細孔容積が0.5cc/g〜5.0cc/g、サイズが0.05mm〜2cmである、請求項1に記載の方法。
- 収着剤が生体適合性である、請求項1又は請求項2に記載の方法。
- 体液が、唾液、鼻咽頭液、血液、血漿、血清、唾液、胃腸液、胆汁、脳脊髄液、心膜液、膣液、精液、前立腺液、腹水、胸膜液、尿、滑液、間質液、細胞内液、細胞外液、リンパ液、粘液、又は硝子体液を含む、請求項1〜3のいずれか1項に記載の方法。
- 収着剤が、50Å〜40,000Åの範囲の細孔径の全細孔容積が0.5cc/g〜5.0cc/g乾燥収着剤より大きく、収着剤の50Å〜40,000Å(細孔径)の細孔容積対1,000Å〜10,000Å(細孔径)の細孔容積の比率が2:1より小さいような細孔構造を有する、請求項1〜4のいずれか1項に記載の方法。
- 収着剤が少なくとも一つの架橋剤と少なくとも一つのモノマーとを含む、請求項1〜5のいずれか1項に記載の方法。
- 収着剤が、少なくとも一つの架橋剤、少なくとも一つのモノマー、少なくとも一つの分散剤及び少なくとも一つのポロゲンを含む、請求項1〜5のいずれか1項に記載の方法。
- 分散剤が、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ポリ(ヒドロキシエチルメタクリレート)、ポリ(ヒドロキシエチルアクリレート)、ポリ(ヒドロキシプロピルメタクリレート)、ポリ(ヒドロキシプロピルアクリレート)、ポリ(ジメチルアミノエチルメタクリレート)、ポリ(ジメチルアミノエチルアクリレート)、ポリ(ジエチルアミノエチルメタクリレート)、ポリ(ジエチルアミノエチルアクリレート)、ポリ(ビニルアルコール)、ポリ(N−ビニルピロリジノン)、ポリ(メタクリル酸)の塩、又はポリ(アクリル酸)の塩の一つ又は複数である、請求項7に記載の方法。
- 架橋剤が、ジビニルベンゼン、トリビニルベンゼン、ジビニルナフタレン、トリビニルシクロヘキサン、ジビニルスルホン、トリメチロールプロパントリメタクリレート、トリメチロールプロパンジメタクリレート、トリメチロールプロパントリアクリレート、トリメチロールプロパンジアクリレート、ペンタエリトリトールジメタクリレート類、ペンタエリトリトールトリメタクリレート類、ペンタエリトリトール、テトラメタクリレート類、ペンタエリトリトールジアクリレート類、ペンタエリトリトールトリアクリレート類、ペンタエリトリトールテトラアクリレート類、ジペンタエリトリトールジメタクリレート類、ジペンタエリトリトールトリメタクリレート類、ジペンタエリトリトールテトラメタクリレート類、ジペンタエリトリトールジアクリレート類、ジペンタエリトリトールトリアクリレート類、ジペンタエリトリトールテトラアクリレート類、又はジビニルホルムアミドの一つ又は複数である、請求項6又は7に記載の方法。
- モノマーが、ジビニルベンゼン及びエチルビニルベンゼン、スチレン、エチルスチレン、アクリロニトリル、ブチルメタクリレート、オクチルメタクリレート、ブチルアクリレート、オクチルアクリレート、セチルメタクリレート、セチルアクリレート、エチルメタクリレート、エチルアクリレート、ビニルトルエン、ビニルナフタレン、ビニルベンジルアルコール、ビニルホルムアミド、メチルメタクリレート、メチルアクリレート、トリビニルベンゼン、ジビニルナフタレン、トリビニルシクロヘキサン、ジビニルスルホン、トリメチロールプロパントリメタクリレート、トリメチロールプロパンジメタクリレート、トリメチロールプロパントリアクリレート、トリメチロールプロパンジアクリレート、ペンタエリトリトールジメタクリレート、ペンタエリトリトールトリメタクリレート、ペンタエリトリトールテトラメタクリレート、ペンタエリトリトールジアクリレート、ペンタエリトリトールトリアクリレート、ペンタエリトリトールテトラアクリレート、ジペンタエリトリトールジメタクリレート、ジペンタエリトリトールトリメタクリレート、ジペンタエリトリトールテトラメタクリレート、ジペンタエリトリトールジアクリレート、ジペンタエリトリトールトリアクリレート、ジペンタエリトリトールテトラアクリレート、ジビニルホルムアミド及びそれらの混合物の一つ又は複数である、請求項6又は7に記載の方法。
- ポロゲンが、ベンジルアルコール、シクロヘキサン、シクロヘキサノール、シクロヘキサノール/トルエン混合物、シクロヘキサノン、デカン、デカン/トルエン混合物、ジ−2−エチルヘキシルリン酸、ジ−2−エチルヘキシルフタレート、2−エチル−1−ヘキサン酸、2−エチル−1−ヘキサノール、2−エチル−1−ヘキサノール/n−ヘプタン混合物、2−エチル−1−ヘキサノール/トルエン混合物、イソアミルアルコール、n−ヘプタン、n−ヘプタン/エチルアセテート、n−ヘプタン/イソアミルアセテート、n−ヘプタン/テトラリン混合物、n−ヘプタン/トルエン混合物、n−ヘキサン/トルエン混合物、ペンタノール、ポリ(スチレン−コ−メチルメタクリレート)/ジブチルフタレート、ポリスチレン/2−エチル−1−ヘキサノール混合物、ポリスチレン/ジブチルフタレート、ポリスチレン/n−ヘキサン混合物、ポリスチレン/トルエン混合物、トルエン、トリ−n−ブチルホスフェート、1,2,3−トリクロロプロパン/2−エチル−1−ヘキサノール混合物、2,2,4−トリメチルペンタン(イソオクタン)、トリメチルペンタン/トルエン混合物、ポリ(プロピレングリコール)/トルエン混合物、ポリ(プロピレングリコール)/シクロヘキサノール混合物、及びポリ(プロピレングリコール)/2−エチル−1−ヘキサノール混合物の一つ又は複数である、請求項7に記載の方法。
- 接触がエクスビボで行われる、請求項1〜11のいずれか1項に記載の方法。
- 接触がインビボで行われる、請求項1〜11のいずれか1項に記載の方法。
- 請求項1〜13のいずれか1項に記載の方法を含む変性疾患の治療。
- 変性疾患がアルツハイマー病である、請求項14に記載の治療。
- 変性疾患が黄斑変性である、請求項14に記載の治療。
- 変性疾患が骨関節炎である、請求項14に記載の治療。
- 変性疾患がアテローム性動脈硬化症である、請求項14に記載の治療。
- 変性疾患が心疾患又は腎不全である、請求項14に記載の治療。
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US20230310493A1 (en) | 2023-10-05 |
BR112020003638A2 (pt) | 2020-09-01 |
WO2019046506A1 (en) | 2019-03-07 |
EP3675737A4 (en) | 2021-02-17 |
IL272542A (en) | 2020-03-31 |
CA3072349A1 (en) | 2019-03-07 |
RU2020111589A3 (ja) | 2022-02-21 |
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CN111405870A (zh) | 2020-07-10 |
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