JP2022051830A - 心筋症、収縮期心機能不全及びうっ血性心不全症状の治療のためのプロベネシド - Google Patents
心筋症、収縮期心機能不全及びうっ血性心不全症状の治療のためのプロベネシド Download PDFInfo
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Abstract
Description
本出願は、参照によりその全体が本明細書中に明示的に組み込まれている、先に出願された同時係属の米国出願第13/584,713号(2012年8月13日出願)の利益及び優先権を主張するものである。
動物 - 野生型(WT)マウス(B6129SF2/J F2及びC57BL6J、Jackson laboratories社)及びTRPV2-/-マウス[Dr. M. Caterina(John's Hopkins、Baltimore、MD)により提供されたブリーディングペア(breeding pair)]は、12~16週齢の雄であった。
心エコー評価。用量反応曲線を得るために、12~16週齢の雄C57 WT(n=39)マウスをイソフルランで麻酔すると同時に、既に記載されているようにして顕微鏡下で頸静脈の静脈内アクセス(IV)を得た。続いて、Mモード及びとBモードの両方での心エコー検査(echocardiographic study)は、後述するように傍胸骨長軸(PSLAX)で得た。生理食塩水又は種々の用量のプロベネシド(2mg/kgから200mg/kgまで増加させる)を、WTマウスにおいて初期収縮力の研究のために注射した(ボーラスIV)。
定量的RT-PCR - WT、TRPV2+/-及びTRPV2-/-マウスからRNA単離及びqRT-PCRのために得た心臓(LV)を、急速冷凍し、-80℃で保存した。TRPV2転写レベルを見積もるために、全RNAを単離し[RNeasyキット; Qiagen社(Valencia、CA)]、製造業者の指示に従って、198塩基対の産物を産生する、C末端に位置するプライマー5'-CTACTGCTCAACATGCTC-3'(センス)(配列番号1)及び5'-CTCATCAGGTATACCATCC-3'(アンチセンス)(配列番号2)を用いて、cDNAを合成した[high Capacity RNA-to-cDNAキット; Applied Biosystems社(Carlsbad、CA)]。全ての試料について、最低3つの独立した実験的複製を三重反復で行い、発現の差を、δ-δCt概算法を用いて18S mRNAを負荷対照として算出した。必要に応じて、プライマー効率のための補正を、Pfaffl法を用いて行った。
心室筋細胞の単離 - WTマウス(12週齢)からの心臓を、LangendorffシステムでNaCl 118mM、KCl 5.4mM、HEPES 10mM、NaH2PO4 0.33mM、MgCl2 2mM、グルコース10mM、タウリン30mM、ブタンジオンモノオキシム10mMから構成される修正Krebs-Henseleit緩衝液(KHB) (pH=7.4)を用いて灌流させた。次いで、酵素溶液(0.7mg/ml II型コラゲナーゼ、0.1%BSA及び25μM CaCl2を含有するKHB)を用いて、心臓を10分間消化した。最後に、心臓の心室を切除し、細かく切り刻み、濾過して、単離細胞を得た。十分に沈降させた後、上清を除去し、細胞を再懸濁させた。
プロベネシドは、WTではインビボでの収縮力を増加させるが、TRPV2-/-マウスでは増加させない。 - WTマウスへのプロベネシドの投与は、EFによって測定される収縮力を、生理食塩水を与えた対照マウスにおけるEFと比較して増加させた(図1A)。収縮力の増加は、75mg/kg以上の全ての用量においてボーラス注射後5分以内に認められた(75mg/kg、100mg/kg及び200mg/kgに関するピーク変化はそれぞれ、5.26±3.35、8.40±2.80、7.32±2.52)(図1B及び図1C、75及び100mg/kgに関してはデータは示さず)。5分間隔(合計30分間)で測定した収縮力変化により、収縮力の用量依存的な増加が明らかになり、推定EC50は49.33mg/kgであった(図1D)。EFは、より長い期間にわたって評価した対象(n=5、用量200mg/kg IV)では少なくとも1時間にわたって高い状態にどどまった(ベースラインと比べたEFの平均増加8.9±2.57、データは示さず)。
細胞生存率アッセイ - 細胞生存率は、ApoTox-Glo Triplex Assay[Promega社(Madison、WI)]を用いて製造業者の指示に従って見積もった。簡潔には、HL-1細胞を、96ウェルプレートに1×104細胞/ウェルの密度で播種し、10% FBS、100U/mlペニシリン/ストレプトマイシン及び2mM L-グルタミンが補充されたClaycomb培地中で一晩成長させた。細胞を、総容量100μlの補充成長培地中で指示用量のプロベネシド又はイソプロテレノールで処理し、一晩インキュベートした。次いで、GF-AFC(GF-AFC viability)を、ApoTox-Glo Assay Bufferに2.0mlのAssay Bufferに対してGF-AFC 10μlの比率で加え、この混合物20μlを各ウェルに加え、細胞を37℃で30分間インキュベートした。400nm(ex)/505nm(em)において蛍光を測定し、データを非処理の対照細胞に対して標準化した。
プロベネシドはインビトロで細胞死を誘発しない。 - これらの実験では、HL-1細胞を用いて、プロベネシドの効果をアッセイした。プロベネシド10-8の潅流前後におけるピーク細胞質蛍光の測定中央値に有意差は観察されなかった。他に、より高濃度のプロベネシドを潅流した後のピーク蛍光の中央値は、灌流前の値よりも有意に高かった(図8A)。
実施例1からのデータは、FDAに認可された薬物であるプロベネシドが、何十年も認識されずに済まされてきた変力性を有することを実証した。これらの実験は、プロベネシドが細胞質Ca2+レベルを増加させ、結果としてβ-アドレナリン作動性シグナル伝達とは独立した収縮力の増加をもたらすことを実証した。アドレナリン刺激は心筋代謝要求を増加させ、アポトーシスの経路を刺激し、筋細胞の肥大を引き起こすことは既に示されているので、β-AR経路の刺激の欠如が、本明細書中に示した研究を開始させた。これは、症状及び血行動態パラメーターが改善されるにもかかわらずこれらの薬物に曝露された患者の短期及び長期死亡率が増加することを見い出した、伝統的なβ1-アゴニスト(ドブタミン、ドーパミン)及びPDI(即ち、ミルリノン)を含む多くの臨床試験に反映されている。
Claims (20)
- 対象における心機能不全の心臓症状の治療方法であって、心機能不全の心臓症状を治療するのに有効な量のプロベネシドを投与する工程を含み、前記量のプロベネシドを、注射、経口投与又は経皮投与の少なくとも1つによって投与する、方法。
- 注射が静脈内注入である、請求項1に記載の方法。
- 注射が、ボーラス注射又は持続静脈内注入のうちの少なくとも1つである、請求項1に記載の方法。
- 前記量のプロベネシドが、長時間放出製剤で投与される、請求項1に記載の方法。
- プロベネシドの長期放出製剤が、プロベネシドの治療血漿濃度を約18時間/日から約24時間/日の間の範囲の持続時間にわたって維持する、請求項4に記載の方法。
- プロベネシドの量が、6分間歩行試験の標準化、ニューヨーク心臓協会(NYHA)分類の改善、利尿薬投与必要量の減少、血清BNPレベルの低下、血清ナトリウム濃度の正常化、及びその組合せに基づく、改善された性能をもたらすのに十分である、請求項1に記載の方法。
- プロベネシドの治療有効量が、約1mg/kg/日~約100g/kg/日の範囲の投与量を有する、請求項1に記載の方法。
- 前記治療有効量のプロベネシドが、約8時間/日~約24時間/日の期間にわたって投与される、請求項1に記載の方法。
- 対象が、治療有効量のプロベネシドで少なくとも1週間にわたって治療される、請求項1に記載の方法。
- 対象が、治療有効量のプロベネシドで少なくとも1ヶ月にわたって治療される、請求項1に記載の方法。
- 心機能不全がうっ血性心不全である、請求項1に記載の方法。
- うっ血性心不全が非代償性心不全である、請求項10に記載の方法。
- 対象における心機能不全の心臓症状の治療方法であって、プロベネシドの治療血漿濃度を約18時間/日から約24時間/日の間の持続時間にわたって維持する投与レジメンで対象にプロベネシドを投与する工程を含み、治療血漿濃度が、対象において心臓機能の心臓症状を治療するのに十分である、方法。
- 投与レジメンが、前記投与量のプロベネシドの静脈内投与を含む、請求項13に記載の方法。
- 投与レジメンが、前記用投与量のプロベネシドの経口投与を含む、請求項13に記載の方法。
- 投与レジメンが、前記投与量のプロベネシドの経皮投与を含む、請求項13に記載の方法。
- 投与レジメンが、プロベネシドの経口投与、静脈内注射及び経皮投与のうちの少なくとも2つの組合せを含む、請求項13に記載の方法。
- プロベネシドの量が、6分間歩行試験の標準化、ニューヨーク心臓協会(NYHA)分類の改善、利尿薬投与必要量の減少、血清BNPレベルの低下、血清ナトリウム濃度の正常化、及びそれらの組合せに基づく、改善された性能をもたらすのに十分である、請求項13に記載の方法。
- 対象が、治療有効量のプロベネシドで少なくとも1週間にわたって治療される、請求項13に記載の方法。
- 心機能不全がうっ血性心不全である、請求項13に記載の方法。
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US10806711B2 (en) | 2011-08-12 | 2020-10-20 | University Of Cincinnati | Method of treating acute decompensated heart failure with probenecid |
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KR20210150011A (ko) * | 2020-06-03 | 2021-12-10 | 주식회사 삼오파마켐 | 프로베네시드 및 아르기닌의 아미드 유도체, 이를 포함하는 약제학적 조성물 및 이의 제조 방법 |
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