JP4976412B2 - エンドセリン、エンドセリンアゴニスト及びアドレノメジュリンアンタゴニストによる危篤患者の診断及び治療のための方法 - Google Patents
エンドセリン、エンドセリンアゴニスト及びアドレノメジュリンアンタゴニストによる危篤患者の診断及び治療のための方法 Download PDFInfo
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Description
本発明の一態様において、本発明は、LES及び/または前記の疾患を含む関連疾患の診断に関する。本発明はさらに、END-r及びADM-rの濃度、より具体的には、プロEND及びプロADM及び/またはそれらの断片の濃度の同時判定に関する。この組み合わせ測定によって、診断、予測、重症度の経過の予後、及びLES及び/または前記の疾患の死亡危険性に関する比率及び/またはアルゴリズムの算出並びにそのような誘導された比率及び/またはアルゴリズムの使用が可能になる(図1及び2)。
1. AMD-r濃度(>8nmol/l)に従う
2. ADM-r/END-rの比率に従う(図4)。
当該技術分野の現状とは対照的に、本発明は、エンドセリン(特に、END-rとして判定される場合)の濃度上昇は、例えば、敗血症及び前記の関連疾患のような重篤な病態における患者に典型的に見られるようなADM-rの高い濃度上昇を有する患者にとって有益であるという驚くべき発見を開示している。言い換えると、高濃度のEND-rは、敗血症のような病態に典型的であるが、別な場合には致命的な高濃度のADM-rを患者が許容することを可能にし、その結果、死を防ぐことができる。すなわち、十分に高い生理的END濃度は、高濃度のADMより明らかに優勢となり得る。
ヒトプロADM及びプロENDの合成ペプチドに、N末端システイン残基を付加した。質量分析を用いてそれらを精製し、逆相HPLCを用いて品質管理し、当業者に知られた標準的操作に従い、アリコートで凍結乾燥した(Jerini AG、ベルリン、ドイツ国)。
PIERCE、ロックフォード、イリノイ州、米国による「NHS-エステル-マレイミド架橋剤」に関するプロトコルに従い、MBS(マレイミド-ベンゾイル-N-ヒドロキシスクシンイミドエステル)により、配列番号1〜4のペプチドを、担体タンパク質KLH(キーホールリンペットヘモシアニン)に結合させた。100μgの結合体(該結合体のペプチド含量によるμg)を投与してヒツジを免疫化した。免疫化から4ヵ月後に開始して、4週ごとに各ヒツジから700mlの血液を採取し、遠心分離により抗血清を獲得した。結合、免疫化及び抗血清の作製は、Micropharm、カーマーセンシャー、英国により行った。
リガンド特異的アフィニティー精製を用いて、ヒツジからのポリクローナル抗体を精製した。このステップのために、Cys(0)-ペプチドを、Pierce(ボストン、米国)から供給されたSulfoLink-Gelに結合させた。Pierceのプロトコルに従って結合が生じた。5mlのゲル当たり、5mgのペプチドを加えた。
配列番号1〜4のペプチドに対して作製したアフィニティー精製抗体の500μlを、100mMのリン酸カリウム緩衝液(pH8.0)1ml中に再緩衝化し、NAP-5ゲルろ過カラム(Pharmacia)により、Pharmaciaのプロトコルに従って再緩衝化した。
サンドイッチアッセイのために、配列番号1〜4のペプチドに対する精製抗体を、照射済みポリスチロール管(Greiner、ドイツ国)上に固定化した。その操作のために、抗体溶液を、50mMのTris、100mMのNaCl、pH7.8によって、6.7μg/mlのタンパク質濃度に希釈した。1つの管当たり、300μlの希釈タンパク質溶液をピペットで移した。これらを室温で20時間インキュベートし、該溶液を取り出した。次いで、10mMのリン酸ナトリウム、2%のKarion FP、0.3%のウシ血清アルブミン、pH6.5の溶液4.2mlを、各管に加えた。20時間後、該溶液を取り出し、該管を真空乾燥器内で乾燥させた。該操作は、当業者に既知の操作に従い、逆サンドイッチアッセイとして行うこともできる。
以下のアッセイ緩衝液を用いた:100mMのリン酸ナトリウム、150mMのNaCl、5%のウシ血清アルブミン、0.1%の非特異的ヒツジIgG、0.1%のアジ化ナトリウム、pH7.4。
健康な個体及び疾患状態の個体におけるADM-r及びEND-rの濃度
種々の理由で集中治療室に滞在し、集中治療室に滞在中に敗血症を発症した149人の患者を該試験に含めた(基準:www.talessin.de/scripte/medizin/sepsis1.html)。集中治療室に滞在中(3〜29日)、毎日、患者のEDTA-血漿を採集し、さらなる使用まで、-20℃で保存した。
疾患/障害の重症度に関するADM-r及び予後
ADM-rの濃度を用いて、生存の予後を判定した(表1及び図1)。表1の欄2(特異性)に、17nmol/l血漿未満の濃度のADM-rを有する生存患者数を示す。すなわち、126人中117人の患者は17nmol/l未満の濃度を有し、102人の患者は8nmol/l未満の濃度を有した。従って、ADM-rは、生存に関して、17nmol/lでは切捨てで93%の特異性、8nmol/lでは切捨てで81%の特異性を示す。死亡率の感度は、以下の方法で判定した:23人の患者がICU滞在中に死亡した。17nmol/lのADM-r切捨て値で、6人の患者(26%=死亡率の感度)が死亡2日前に、12人の患者(52%)が死亡1日前に、13人の患者(57%)が死亡日に、17nmol/l以上の濃度を示した。8nmol/lの切捨て値で、23人の患者のうち19人(83%)が死亡2日前に、21人の患者(91%)が死亡1日前に、19人の患者(83%)が死亡日に、8nmol/l以上のADM-r濃度を示した(表1)。
ADM-r/END-rの比率
ADM-r/END-rの比率を、表1及び図3に示す。個々の健常者におけるADM-r/END-rの比率は、約50(中央値20)の最高値を有する。ICUにおける生存患者の中央値は、56に増加する。さらに有意な増加が、死亡2日前(中央値135)、死亡1日前(中央値129)に、驚くべき劇的な増加が中央値336で死亡日に見ることができる。76%の特異性における予後(表1、すなわち、含まれる患者で、43nmol/l未満のADM-r濃度を有する者は、死亡2日前に91%、死亡1日前に96%、死亡日に87%である(表1及び図3)。93%のより高い特異性、すなわち、含まれる患者で、18nmol/l未満のADM-r濃度を有する者は、61%の感度を有する死亡日にのみ予後が可能である(表1)。
8nmol/l以上のADM-r濃度を有する患者を含むADM-r/END-rの比率
従って、患者を、ADM濃度(>8nmol/l)により、また、ADM-r/END-rの比率により、さらに選択した(図4)。
Claims (10)
- 危篤患者において致死的なエンドセリン欠乏(「低エンドセリン症候群」または「LES」)の発現可能性または存在の指標とするためのインビトロ方法であって、
−患者の体液由来のサンプルにおいてプロアドレノメジュリン(プロADM)分子及び/または生理的に生じた1種または複数のその断片の濃度をインビトロで測定する工程と、
−同時に、患者の前記体液由来のサンプルにおいてプロエンドセリン(プロEND)分子及び/または生理的に生じた1種または複数のその断片の濃度をインビトロで測定する工程と、
−前記測定された濃度を使用してプロADM/プロENDの比率を算出する工程と、
−前記算出された比率を、プロADM単独の測定濃度と場合によって組み合わせて使用して、LESの発現もしくは存在、LESの重症度、並びに/またはLESの経過及び/もしくは経過の予後を評価する工程と
を含み、
ここで、危篤患者における前記プロADM/プロENDの比率は健常者のそれよりも有意に高く、より高い比率が致死的なエンドセリン欠乏の重篤な発現または存在を示し得る、方法。 - 前記比率が死亡危険性の評価の過程で使用される、請求項1に記載の方法。
- 前記体液が血漿、血清、血液、羊水または尿である、請求項1または2に記載の方法。
- 前記患者が、敗血症、SIRS、敗血症ショック、多臓器不全、全身または局所感染症、細菌感染症、心疾患、腹膜炎、膵炎、局所及び/または全身炎症、髄膜炎、外傷、大動脈瘤破裂、中毒、内毒血症、無尿症、腎機能不全、動脈性高血圧、肺高血圧、アテローム性動脈硬化症、癌、うっ血性心不全、循環器疾患、冠動脈疾患、虚血、抗不整脈作用、腎不全及び/または心不全、臓器損傷のうちの1つまたは複数の診断で集中治療室(ICU)に入ることが認められたICU患者である、請求項1から3のいずれか一項に記載の方法。
- 前記プロADM分子及び/またはプロEND分子が、血管作用性の成熟ADM及びENDをそれぞれ含まない生理的に生じた断片を認識する選択的免疫診断アッセイを使用して測定される、請求項1から4のいずれか一項に記載の方法。
- プロADM及びプロENDを測定するアッセイにおいて、選択的抗体の組み合わせが用いられ、生理的に生じる断片に特異的に結合する抗体の少なくとも1種が固相に固定化され、同一断片の他の部分に特異的に結合する少なくとも1種の第2の抗体が、前記固相に付着した前記断片の検出に用いられる、請求項5に記載の方法。
- 検出に用いられる前記第2の抗体に発光性マーカーがタグ付けされている、請求項6に記載の方法。
- 測定されるプロADM断片が、配列番号2または3によるアミノ酸配列を有するペプチドであり、測定されるプロEND断片が、配列番号6または7によるアミノ酸配列を有するペプチドである、請求項1から7のいずれか一項に記載の方法。
- 前記プロアドレノメジュリンまたは生理的に生じるその断片の測定が、免疫クロマトグラフィーPOC測定装置を使用した半定量的測定として行われる、請求項1から8のいずれか一項に記載の方法。
- 前記比率の算出、診断及び予後を目的とした前記比率の使用、並びにスコア群への患者の分類のために、アルゴリズム及び好適なコンピュータプログラムがそれぞれ使用される、請求項1から9のいずれか一項に記載の方法。
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