JP2015506981A - 下痢を処置するための材料および方法 - Google Patents
下痢を処置するための材料および方法 Download PDFInfo
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- JP2015506981A JP2015506981A JP2014556712A JP2014556712A JP2015506981A JP 2015506981 A JP2015506981 A JP 2015506981A JP 2014556712 A JP2014556712 A JP 2014556712A JP 2014556712 A JP2014556712 A JP 2014556712A JP 2015506981 A JP2015506981 A JP 2015506981A
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Abstract
Description
本願は、参照によってその全体が本明細書に組み入れられる、2012年2月8日に出願された米国仮出願第61/596,480号の恩典を主張する。
ロタウイルス感染は、世界中の乳児および幼児の重度の下痢性疾患および脱水症の主因である。ロタウイルス感染の症状には、水様下痢、重度脱水症、発熱、および嘔吐が含まれる。ロタウイルス感染は、接種後3日目に最大の傷害が起こる空腸損傷をもたらすこともあり、いくつかの場合、正常値の30%〜50%への絨毛表面積の低下を引き起こす(Rhoads et al.(1996)J.Diarrhoeal Dis.Res.14(3):175-181(非特許文献1))。
本発明は、下痢のような胃腸の疾患および状態の処置、補液の提供、電解質および体液の不均衡の修正、ならびに/または小腸機能の改善のための治療用組成物および方法を提供する。
本発明は、下痢のような胃腸の疾患および状態の処置、補液の提供、電解質および体液の不均衡の修正、ならびに/または小腸機能の改善のための治療用組成物および方法を提供する。
本発明に従って、管腔側グルコースが小腸における正味のイオン分泌を誘導することが見出された。具体的には、グルコースは、細胞内のcAMPおよびCa2+のレベルの増加によって媒介される能動性の塩素イオン分泌を誘導する。また、小腸における正味のNa+輸送は、高いグルコース濃度では吸収性である。さらに、グルコースは、小腸における炭酸水素分泌をもたらす。
一つの局面において、本発明は、下痢のような胃腸の疾患および状態の処置、補液の提供、電解質および体液の不均衡の修正、ならびに/または小腸機能の改善のための治療用組成物を提供する。
本発明のもう一つの局面は、胃腸の疾患および状態の処置の方法を提供する。ある種の態様において、本発明は、下痢を処置するため、補液を提供するため、電解質および体液の不均衡を修正するため、かつ/または小腸機能を改善するため、使用され得る。好ましい態様において、本発明は、ロタウイルスによって誘導された下痢の処置を提供する。もう一つの好ましい態様において、本発明は、NSP4によって誘導された下痢の処置を提供する。
本発明は、治療的に有効な量の本発明の組成物を含み、任意で、薬学的に許容される担体を含む治療用組成物または薬学的組成物を提供する。そのような薬学的担体は、水のような無菌の液体であり得る。治療用組成物は、補液の提供、電解質および体液の不均衡の修正、ならびに/または小腸機能の改善のための、胃腸の疾患および状態の処置(一つの態様において、下痢の処置)に影響しない賦形剤、香味剤、着色剤、および保存剤等も含んでいてよい。
動物の準備
普通食を与えられた8週齢雄NIHスイスマウスを、CO2吸入後の頚部脱臼によって屠殺する。小腸を静かに摘出し、セグメントを氷冷リンゲル液で洗浄し、洗い流す。次いで、以前に記載されたようにして(Zhang el al.(2007)J Physiol 581(3):1221-1233)、粘膜下面での剥離によって、漿膜および筋肉層から粘膜を分離する。瀉血後、盲腸に近い10cmのセグメントから、回腸粘膜を入手する。全ての実験が、University of Florida Institutional Animal Care and Use Committeeによって承認される。
イオン輸送研究を回腸シートに対して実施する。次いで、組織を、開口部面積0.3cm2のUssing型Luciteチャンバー(P2304、Physiologic Instruments,San Diego,CA,USA)の半室間に設置する。95%O2:5%CO2を通気した普通のリンゲル液(115mM NaCl、25mM NaHCO3、4.8mM K2HPO4、2.4mM KH2PO4、1.2mM MgCl2、および1.2mM CaCl2)を、組織のための槽溶液として両側で使用し、温度を37℃に一定に維持する。浸透圧的および静水学的な力を排除するため、チャンバーを平衡化する。液体による抵抗も補償する。組織を安定させる。基底短絡電流(Isc)および対応するコンダクタンス(G)を、コンピューターによってコントロールされた電圧/電流クランプ装置(VCC MC-8、Physiologic Instruments)を使用して記録する。
基本条件下およびその後のグルコース添加条件下で、ナトリウムの同位体22Naを使用して、粘膜を越えるNa流動を研究する。コンダクタンスによって対にされた組織を、分泌機能を表す漿膜粘膜流動(Jsm)および吸収機能を表す粘膜漿膜流動(Jms)を研究するために指定する。組織の指定された側へ22Naを添加し、15分毎に反対側から500μlの試料を収集する。組織の別のセットにおいて、36Clを漿膜側または粘膜側のいずれかに添加する。完全刺激のため8mM濃度のグルコースをチャンバーへ添加し、Iscおよびコンダクタンスの対応する変化を記録する。コンダクタンスをオームの法則に基づき記録する。
類似したコンダクタンスおよび電流によって対にした組織を、不可逆性プロテインキナーゼA(PKA)阻害剤である100μM H-89(Santa Cruz Biotechnology,Inc,Santa Cruz,CA)によって処理するかまたは未処理とする。組織をH-89と共に30分間インキュベートする。増加する濃度のグルコース(0.015〜8mM)を5分毎に添加し、ピーク電流に注目する。処理された組織および未処理の組織についての対応するKmおよびVmaxについて、飽和動力学定数を計算する。
Caco-2細胞は、コンフルエンス後、胎児回腸上皮の機能的特徴を有する細胞へ分化する。Caco-2細胞は、微絨毛を産生し、SGLT1を含む小腸特異的な輸送タンパク質の増加した発現を有し、従って、腸細胞機能を研究するためのモデル系として広く使用されている。
25mmの丸型カバーガラスにおいて増殖したCaco2細胞を、シリーズ20ステージアダプター(Warner Instruments,CT USA)に付着したバスチャンバーRC-21BRに設置する。シングルチャネルテーブルトップヒーターコントローラー(TC-324B、Warner Instruments,CT USA)を使用して、細胞を37℃で維持する。細胞に、室温で、0.5μM濃度の蛍光性カルシウム指示薬Fluo-8 AM色素(カタログ番号0203、TEFLab,Inc.,Austin,TX USA)を負荷し、45分間インキュベートする。共焦点レーザー走査顕微鏡法を、倒立Fluoview 1000 IX81顕微鏡(Olympus,Tokyo,Japan)およびU Plan S-Apo 20×対物レンズを使用して実施する。488nmにおける励起および515nmにおける放出で、アルゴンレーザーによって蛍光を記録する。蛍光画像を走査共焦点顕微鏡によって収集する。VC-8バルブコントローラー(Warner instruments,Hamden CT,USA)を使用してコントロールされたマルチバルブ灌流系(VC-8,Warner instruments,Hamden CT,USA)を使用して、リンゲル液、グルコース含有リンゲル液、またはBAPTA-AM含有グルコース-リンゲル液のいずれかをバスに添加する。様々な細胞について変化を記録し、蛍光を測定する。細胞をリンゲル液によって洗浄し、3-O-メチルグルコースおよびカルバコール(陽性対照)を使用して、実験を繰り返す。
回腸上皮細胞の新鮮に単離された粘膜擦過標本を、37℃で1.2mM Ca2+を含有するリンゲル液で3回洗浄する。次いで、洗浄された細胞を2つの群へ分割し、生理食塩水または6mMグルコースのいずれかによって処理し、45分間インキュベートする。内在性ホスホジエステラーゼ活性を止めるため、0.1M HClによって細胞を処理する。次いで、cAMP直接イムノアッセイキット(Calbiochem,USA)を使用したcAMPアッセイのため、溶解物を使用する。
本実施例は、グルコースがマウス回腸におけるIscの増加を刺激することを示す。具体的には、管腔側へのグルコース(8mM)の添加は、基底レベルと比較した時、Iscの有意な増加をもたらす(3.4±0.2対1.1±0.1μEq.h-1.cm-2)。標準的なUssingチャンバー研究を使用して入手されたIscは、上皮を越える正味のイオン移動の総計である(Isc=JnetNa+ + JnetCl- + JnetHCO3 - - JnetK+)。
本実施例は、実施例1において観察されたグルコース飽和動力学が、上皮細胞におけるグルコース代謝によるものではなく、SGLT1によって媒介される輸送によるものであるか否かかを調査する。具体的には、Na+共役グルコース輸送の飽和動力学を研究するため、グルコースの低代謝型である3-O-メチルグルコース(3-OMG)を管腔側に添加する。
現在公知の輸送機序に基づき、グルコースによって刺激されるIscの増加は、起電性陰イオン分泌または起電性Na+吸収に起因する可能性がある。
* グルコースおよび3-OMGによって刺激される電流の一部は、PKAの存在下で消失する。結果はn=8の組織からである。
グルコース輸送の阻害によってPKA感受性電流が消失するか否かを調査するため、SGLT1の可逆性競合的阻害剤であるフロリジン(Santa Cruz Biotechnology,Inc,Santa Cruz,CA,USA)を使用して実験を実施する。具体的には、Ussingチャンバーに設置された回腸組織を、管腔側で100μMフロリジンによって処理し、グルコース飽和動力学研究を実施する。
粘膜から漿膜への移行Jmsまたは漿膜から粘膜への移行Jsmの定常状態速度において、22Naを使用して、Na+の同位体流動測定を実施する。Na+の正味の流動は、Jnet=Jms - Jsmという式を使用して計算される。正のJnetは正味の吸収を示し;負のJnetは正味の分泌を示す。
0.6mMグルコースにおけるIscの変化は、1.1μEq.h-1.cm-2(2.2±0.3 - 1.1±0.1μEq.h-1.cm-2)と計算され、6mMグルコースにおけるIscの変化は、2.2μEq.h-1.cm-2(3.4±0.2 - 1.1±0.1μEq.h-1.cm-2)と計算される。増加するグルコース濃度によるIscの増加は、(0.6mMおよび6mMグルコースにおける値に基づく)JnetNa+値に基づき、完全には説明され得ない。
経上皮電気測定および流動研究は、回腸組織へのグルコースの添加が、有意なCl-分泌を誘導することを示す。0.6mMおよび6mMグルコースにおけるJnetCl-は、有意な陰イオン分泌を示すが、これは、特に、6mMグルコースと0.6mMグルコースとの間の6μEq.h-1.cm-2(7.5±0.4 - 1.5±0.1μEq.h-1.cm-2)というIsc値の有意な差を考慮すると、Iscの変化の全ての原因ではない。
管腔側Cl-依存性のHCO3 -分泌に対するグルコースの効果を決定するため、pHスタット実験を実施する。管腔Cl-の存在下で、管腔側へのグルコースの添加は、有意なHCO3 -分泌をもたらす(7.6±μEq.h-1.cm-2)。
グルコースによって刺激されるHCO3 -分泌が、小腸組織におけるグルコース代謝によるものであるか否かを査定するため、小腸組織を、管腔側HCO3 -およびバスHCO3 -の非存在下で、グルコースの低代謝型である3-OMGと共にインキュベートする。HCO3 -分泌(0.1±0.03μEq.h-1.cm-2)は、3-OMG(6mM)の存在下、管腔側HCO3 -およびバスHCO3 -の非存在下で観察される。
グルコースの非存在下で、絨毛細胞からの細胞溶解物は、腺窩細胞のものと比較した時、より高い細胞内cAMPレベルを示す。フォルスコリンとのインキュベーションは、絨毛細胞および腺窩細胞における[cAMP]iレベルの有意な増加をもたらす(図3A)。フォルスコリンによって処理された細胞を、陽性対照として使用する。
PKA阻害剤(H-89)は、cAMPによって刺激される陰イオン分泌およびSGLT1によって媒介されるグルコース輸送の両方を阻害する。H-89非感受性Iscの存在(図1AおよびB)は、PKA非依存性の機序も、グルコースによって誘導される分泌に寄与することを示す。cAMPと同様に、細胞内Ca2+も、陰イオン分泌に関与する主要な細胞内セカンドメッセンジャーのうちの一つである。
ある種の態様において、本実施例は、ロタウイルスによって誘導された下痢のような下痢を処置するための製剤を提供する。一つの態様において、製剤は、グルコース、グルコース類似体、グルコーストランスポーターの基質、または糖分子を含まない。
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