JP2005515186A - ClC−2チャンネルオープナーを含む医薬組成物 - Google Patents
ClC−2チャンネルオープナーを含む医薬組成物 Download PDFInfo
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Abstract
Description
本発明者は、ClC−2チャンネルをオープンする能力を有する化合物を用いて鋭意検討の結果、ClC−2チャンネルオープナーが種々の疾患の処置に有効であることを見出した。
ClC−2チャンネルオープナーである被験物質1:13,14−ジヒドロ−15−ケト−16,16−ジフルオロ−プロスタグランジンE1を用いた。少なくとも16時間絶食させたWistar系雄性ラット(6週齢、体重180〜210g)に、被験物質1の10あるいは100μg/kgを媒体中5ml/kgの容量で経口投与した。対照群には、媒体(0.5%エタノール・0.01%ポリソルベート80含有蒸留水)を同容量投与した。投与30分後に動物をエーテル麻酔下で開腹した。十二指腸起始部と回腸末端部をそれぞれ結紮後、腸管を摘出した。各動物の腸液を摘出した腸管から集め容量を測定した。腸液を10,000xg、5分間遠心した後、上清を分取した。腸液上清中のクロライドイオン濃度をクロライドカウンター(CL−7、平沼産業(株))を用い測定した。対照群と被験物質1各用量投与群間の比較にDunnett検定法を用いた。危険率5%未満を統計的有意差ありと判定した。
雄性白色家兎に、被験物質1の0.001%点眼液を、30μl/眼の容量で点眼した。対照群には同容量の点眼液媒体を点眼した。点眼2時間後に、無麻酔下で、シルメル試験紙(昭和薬品化工K.K.、ロット番号9011N)を耳側1/3の下眼瞼に掛けるように結膜嚢内に先端を1分間挟み、濾紙上の目盛りから濾紙の濡れの長さを読み取り涙液量を測定した。また、キャピラリーピペットを用い、下眼瞼の結膜嚢内から涙液5μlを採取し、これを蒸留水で5倍に希釈した後、涙液中クロライドイオン濃度をクロライドカウンター(CL−7、平沼産業(株))を用いて測定した。対照群と被験物質1投与群間の比較にStudentのt検定法およびWilcoxon検定法を用いた。危険率5%未満を統計的有意差ありと判定した。
ClC−2チャンネルオープナーである被験物質2(13,14−ジヒドロ−15−ケト−16,16−ジフルオロ−18(S)−メチル−プロスタグランジンE1)を用いた。Wistar系雄性ラット(6週齢、体重:180〜210g)に、被験物質2の100μg/kgを1日3回7日間経口投与した。対照群には、同容量の媒体(0.01%ポリソルベート80、0.5%エタノール含有蒸留水)を投与した。投与最終日の翌朝(最終投与の約17時間後)、エーテル麻酔下でラットの総胆管内にポリエチレンカテーテル(PE10、Becton Dickinson and Company)を挿入した。ラットをボールマンケージに収容後1時間放置し麻酔から覚醒させた。カテーテル挿入1〜2時間後の1時間に排出された胆汁を採取後、胆汁量を測定した。また、クロライドイオン濃度をクロライドカウンター(CL−7、平沼産業(株))を用い測定した。対照群と被験物質2投与群間の比較にStudentのt検定法を用いた。危険率5%未満を統計的有意差ありと判定した。
Wistar系雄性ラットを用いた。被験群、対照群ともにペントバルビタールナトリウム麻酔下で胆汁採取用として総胆管内にカテーテルを挿入した。門脈にカテーテルを挿入固定後、95%O2と5%CO2で飽和させたタウロコール酸ナトリウム(30μmol/l)を含むKrebs−Ringer液(pH7.4,37℃)を、ペリスタポンプを用い4.0ml/分/g肝の一定速度で注入し、灌流しながら肝臓を摘出した。被験群にはKrebs−Ringer液中に被験物質2を添加した。被験群、対照群ともに灌流開始30分後の胆汁量を測定した。また、胆汁中のクロライドイオン濃度を測定した。被験物質2あるいは媒体投与直前の胆汁量に対する被験物質2あるいは媒体投与30分後の胆汁量を相対値(%)で表した。
Wistar系雄性ラット(体重約280g)をペントバルビタールナトリウム(50mg/kg)の腹腔内注射で麻酔し、腹部正中切開を行い肝門部を露出した。総胆管にカニューレを挿入した後、門脈本幹に三方活栓を装着した19ゲージのサーフロ(登録商標)針を挿入すると同時に酸素化したKrebs−Ringer緩衝液を4.0ml/分/g肝で肝臓を灌流し、下大静脈を切開して脱血した。肝臓周囲の組織から切離して肝臓を体外に出し、分離灌流状態にした。肝臓に15分の前灌流を行い酸素消費を定常状態にした後、4℃の臓器保存液(University of Wisconsin solution;U-W solution)による灌流に切り替えることにより肝臓内の灌流液を置換し、ただちに灌流回路から三方活栓を装着した状態で肝臓を外し、注入口をクランプした後、同じ温度にした保存液(U-W solution)内に保存した。保存時間は16時間とした。再灌流はKrebs−Ringer緩衝液を用いて行い、再灌流開始30分後の胆汁流量を測定した。
上記の灌流プロトコールで被験物質2を10μM濃度に保存液(U-W solution)内に添加した。
(2)再灌流時の灌流液内に添加した被験物質2の効果
上記の灌流プロトコールで被験物質2を、保存液内には添加せず、再灌流時の灌流液(Krebs−Ringer緩衝液)内に10μM濃度に添加した。
ddY系雄性マウス(5週令、体重27〜30g)に0.3mg/kgの被験物質1を媒体中10ml/kgにて皮下投与した。対照群には媒体を投与した。投与30分後にギロチンによって断頭し、断頭後に発現するガスピング(gasping)の持続時間を測定した。
Wistar系雄性ラット(7週令、体重200〜250g)に媒体中5ml/kgにて被験物質1を0.1または0.01mg/kgの投与容量で皮下投与した。対照群には同容量の媒体(生理食塩液)を投与した。投与30分後に硫酸アンモニウム600mg/mlを腹腔内投与した。硫酸アンモニウム投与30分後における生存率を求めた。また、硫酸アンモニウム投与30分後まで生存した動物は、クロロホルム下で致死させ、肺を摘出し重量を測定した。硫酸アンモニウム投与30分後までに死亡した動物は死亡後速やかに肺を摘出し重量を測定した。各群の肺重量を硫酸アンモニウム投与をされていない正常群の肺重量と比較した。測定した肺重量の結果から、対照群の肺重量増加に対比して、被験物質1投与群による肺重量増加抑制率を求めた。
急性潰瘍に対する作用を水浸拘束ストレス誘導潰瘍モデルおよびインドメタシン誘導潰瘍モデルによって調べた。
Wistar系雄性ラット(体重245〜290g)に塩化第2水銀(HgCl2)4mg/kgを筋肉内投与し、大腸潰瘍を誘発した。HgCl2投与の30分前、2時間後および6時間後に被験物質2を皮下投与した。対照群には媒体を投与した。HgCl2投与24時間後に動物をエーテル麻酔下で放血致死させた。開腹して回盲口上部および肛門上部を結紮後、盲腸から直腸までの大腸部分を摘出した。摘出した大腸を1%ホルマリンで固定後に切開し、実体顕微鏡下でノギスを用い潰瘍の長径および短径を測定した。長径と短径の積を潰瘍面積とした。また、各個体毎に潰瘍面積の和を求め、潰瘍総面積とした。
Wistar系雄性ラット(体重240〜270g)を一夜絶食後、ペントバルビタールナトリウム麻酔下で開腹後、10%タウロコール酸3mlと0.3%トリプシン液0.3mlの混合液を、胆管十二指腸開口部から逆行性に注入することにより、膵炎を誘発した。タウロコール酸・トリプシン混合液注入の30分前、2時間後および4時間後に被験物質2を皮下投与した。対照群には媒体を投与した。タウロコール酸・トリプシン混合液注入の6時間後に採血し、血清アミラーゼ活性を測定した。
ビーグル犬(体重8.8〜10.3kg)を用い、チオペンタールナトリウムおよびα−クロラロースによる麻酔下で、心拍出量を、大動脈弓部に装着したFJ型プローブから矩形波電磁血流計(MFV−3100、日本光電)を介して血流表示ユニットに誘導し、レコーダに記録した。心不全モデルを次の方法により作成した。すなわち、左大腿静脈に挿入したカテーテルよりDL−プロプラノロール(0.06mg/ml)を溶解した乳酸リンゲル液の持続注入(5ml/体/分)により容量負荷を開始し、30分後に左前下行枝(LAD)を結紮した。LAD結紮30分後にメトキサミン溶液を右大腿静脈より持続注入(5μg/kg/分)し、心拍出量が容量負荷前より20%以上低下するまで、メトキサミン溶液の注入を5μg/kg/分ずつ増量し、最大20μg/kg/分まで増加した。心拍出量が容量負荷前より20%以上低下した時点で、メトミサミンの投与量を5μg/kg/分に、また乳酸リンゲル液の注入量を3ml/kg/分に減じ、実験終了までこの用量を持続した。心拍出量が20%以上低下し、他の血行動態パラメータが安定した60〜90分後に、被験物質2を十二指腸内に留置したカニューレを介し投与した。対照群には媒体を投与した。被験物質2あるいは媒体投与直前の心拍出量に対する被験物質2投与30分後の心拍出量の比を相対値(%)で表した。
Claims (48)
- ClC−2チャンネルの開口に応答性の状態または疾患(嚢胞性線維症を除く)の予防的あるいは治療的処置を必要とする対象に対して、有効量のClC−2チャンネルオープナーを投与する工程を含む、該状態または疾患の処置方法。
- 該疾患が脳機能障害である請求項1記載の方法。
- 該疾患が心循環器系障害である請求項1記載の方法。
- 該疾患が呼吸器系障害である請求項1記載の方法。
- 該疾患が消化器系障害である請求項1記載の方法。
- 該疾患が膵疾患である請求項1記載の方法。
- 該疾患が液分泌の異常に関連する請求項1記載の方法。
- 該疾患が外分泌障害である請求項7記載の方法。
- 外分泌障害がドライアイである請求項8記載の方法。
- 該疾患が肝疾患である請求項7記載の方法。
- 該疾患が便秘である請求項7記載の方法。
- 組織または臓器をClC−2チャンネルオープナーを有効成分として含む医薬組成物と接触させる工程を含む、移植の際移植される組織または臓器の処置方法。
- 血液再灌流の前に該組成物で組織または臓器をリンスする請求項12に記載の方法。
- 組織または臓器を該組成物で灌流する請求項12に記載の方法。
- 組織または臓器を該組成物中で保存する請求項12に記載の方法。
- 肝移植の処置に使用することを特徴とする請求項12記載の方法。
- ClC−2チャンネルオープナーを有効成分として含むClC−2チャンネルの開口に応答性の状態または疾患(嚢胞性線維症を除く)の予防的あるいは治療的処置のための医薬組成物。
- 該疾患が脳機能障害である請求項17記載の組成物。
- 該疾患が心循環器系障害である請求項17記載の組成物。
- 該疾患が呼吸器系障害である請求項17記載の組成物。
- 該疾患が消化器系障害である請求項17記載の組成物。
- 該疾患が膵疾患である請求項17記載の組成物。
- 該疾患が液分泌の異常に関連する請求項17記載の組成物。
- 該疾患が外分泌障害である請求項23記載の組成物。
- 外分泌障害がドライアイである請求項24記載の組成物。
- 該疾患が肝疾患である請求項23記載の組成物。
- 該疾患が便秘である請求項23記載の組成物。
- ClC−2チャンネルオープナーを有効成分として含む、移植の際移植される組織または臓器の処置用組成物。
- 血液再灌流の前に組織または臓器をリンスするために使用する請求項28に記載の組成物。
- 組織または臓器を灌流するために使用する請求項28に記載の組成物。
- 組織または臓器を保存するために使用する請求項28に記載の組成物。
- 肝移植の処置に使用することを特徴とする請求項28に記載の組成物。
- ClC−2チャンネルの開口に応答性の状態または疾患(嚢胞性線維症を除く)の予防的あるいは治療的処置のための医薬組成物を製造するためのClC−2チャンネルオープナーの使用。
- 該疾患が脳機能障害である請求項33に記載の使用。
- 該疾患が心循環器系障害である請求項33に記載の使用。
- 該疾患が呼吸器系障害である請求項33に記載の使用。
- 該疾患が消化器系障害である請求項33に記載の使用。
- 該疾患が膵疾患である請求項33に記載の使用。
- 該疾患が液分泌の異常に関連する請求項33に記載の使用。
- 該疾患が外分泌障害である請求項39に記載の使用。
- 外分泌障害がドライアイである請求項40に記載の使用。
- 該疾患が肝疾患である請求項39に記載の使用。
- 該疾患が便秘である請求項39に記載の使用。
- 移植の際移植される組織または臓器の処置用の医薬組成物の製造のためのClC−2チャンネルオープナーの使用。
- 該組成物を血液再灌流の前に組織または臓器をリンスするために使用する請求項44に記載の使用。
- 該組成物を組織または臓器を灌流するために使用する請求項44に記載の使用。
- 該組成物を組織または臓器を保存するために使用する請求項44に記載の使用。
- 該組成物を肝移植の処置に使用する請求項44に記載の使用。
Applications Claiming Priority (2)
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US33154201P | 2001-11-19 | 2001-11-19 | |
PCT/JP2002/012037 WO2003043639A2 (en) | 2001-11-19 | 2002-11-19 | PHARMACEUTICAL COMPOSITION COMPRISING A ClC-2 CHANNEL OPENER |
Publications (3)
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JP2005515186A true JP2005515186A (ja) | 2005-05-26 |
JP2005515186A5 JP2005515186A5 (ja) | 2006-01-12 |
JP4377692B2 JP4377692B2 (ja) | 2009-12-02 |
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US (2) | US7732487B2 (ja) |
EP (2) | EP2364708A3 (ja) |
JP (1) | JP4377692B2 (ja) |
AR (1) | AR037556A1 (ja) |
AT (1) | ATE498402T1 (ja) |
AU (1) | AU2002348670A1 (ja) |
CA (1) | CA2466906C (ja) |
DE (1) | DE60239220D1 (ja) |
DK (1) | DK1455794T3 (ja) |
ES (1) | ES2359804T3 (ja) |
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WO (1) | WO2003043639A2 (ja) |
Cited By (2)
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WO2017043612A1 (ja) * | 2015-09-10 | 2017-03-16 | 株式会社Lttバイオファーマ | ドライアイ改善剤 |
JP2017085943A (ja) * | 2015-11-06 | 2017-05-25 | 江崎グリコ株式会社 | 唾液分泌促進剤及び口腔用組成物 |
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TWI331920B (en) | 2001-11-14 | 2010-10-21 | Sucampo Ag | Unit dosage form for relieving or treating constipation in human patients |
ATE539756T1 (de) * | 2002-10-23 | 2012-01-15 | Sucampo Ag | Prostaglandinsubstanzen für die behandlung von fettsucht |
CN1753680B (zh) * | 2002-12-27 | 2010-12-08 | 苏坎波公司 | 用于治疗腹部不适的前列腺素衍生物 |
US8337891B2 (en) | 2003-07-03 | 2012-12-25 | Sucampo Ag | Enteric coated composition comprising prostaglandin analogs as chloride channel opener |
TWI387454B (zh) | 2004-09-02 | 2013-03-01 | Sucampo Ag | 治療胃腸道疾病之方法及組成物 |
MX2007010833A (es) | 2005-03-07 | 2009-02-17 | Univ Chicago | Uso de antagonistas opioides para atenuar proliferacion y migracion de células endoteliales. |
US9662325B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US8518962B2 (en) | 2005-03-07 | 2013-08-27 | The University Of Chicago | Use of opioid antagonists |
US20060281818A1 (en) | 2005-03-21 | 2006-12-14 | Sucampo Ag, North Carolina State University | Method for treating mucosal disorders |
CA2602812C (en) * | 2005-04-12 | 2014-11-18 | Sucampo Ag | Combined use of prostaglandin compound and proton pump inhibitor for the treatment of gastrointestinal disorders |
PT1884234E (pt) * | 2005-05-17 | 2012-07-26 | Santen Pharmaceutical Co Ltd | Agente profiláctico ou terapêutico para distúrbio corneano e conjuntival |
US20080207759A1 (en) * | 2007-02-27 | 2008-08-28 | Sucampo Ag | Method for protecting mitochondria |
JP5314931B2 (ja) * | 2007-05-25 | 2013-10-16 | 参天製薬株式会社 | 加齢黄斑変性の予防又は治療剤 |
US20090030072A1 (en) | 2007-07-03 | 2009-01-29 | Sucampo Ag | Pharmaceutical combination of opioid and prostaglandin compound |
US20090012165A1 (en) | 2007-07-03 | 2009-01-08 | Sucampo Ag | Pharmaceutical combination of nsaid and prostaglandin compound |
WO2014159679A1 (en) | 2013-03-12 | 2014-10-02 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Methods for using lubiprostone to absorb fluid from the subretinal space |
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US5225439A (en) | 1987-01-28 | 1993-07-06 | K.K. Ueno Seiyaku Oyo Kenkyujo | Prostaglandins E and anti ulcers containing same |
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US5380709A (en) | 1987-01-28 | 1995-01-10 | K.K. Ueno Seiyaku Oyo Kenkyujo | Prostaglandins E and anti ulcers containing same |
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TWI225398B (en) | 1999-07-14 | 2004-12-21 | R Tech Ueno Ltd | Composition for treatment of external secretion disorders |
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- 2002-11-18 TW TW91133604A patent/TWI263505B/zh not_active IP Right Cessation
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- 2002-11-19 EP EP10010108A patent/EP2364708A3/en not_active Withdrawn
- 2002-11-19 AR ARP020104435 patent/AR037556A1/es not_active Application Discontinuation
- 2002-11-19 DK DK02781814T patent/DK1455794T3/da active
- 2002-11-19 EP EP20020781814 patent/EP1455794B1/en not_active Expired - Lifetime
- 2002-11-19 JP JP2003545320A patent/JP4377692B2/ja not_active Expired - Fee Related
- 2002-11-19 WO PCT/JP2002/012037 patent/WO2003043639A2/en active Application Filing
- 2002-11-19 ES ES02781814T patent/ES2359804T3/es not_active Expired - Lifetime
- 2002-11-19 AU AU2002348670A patent/AU2002348670A1/en not_active Abandoned
- 2002-11-19 AT AT02781814T patent/ATE498402T1/de active
- 2002-11-19 DE DE60239220T patent/DE60239220D1/de not_active Expired - Lifetime
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017043612A1 (ja) * | 2015-09-10 | 2017-03-16 | 株式会社Lttバイオファーマ | ドライアイ改善剤 |
JP2017085943A (ja) * | 2015-11-06 | 2017-05-25 | 江崎グリコ株式会社 | 唾液分泌促進剤及び口腔用組成物 |
Also Published As
Publication number | Publication date |
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WO2003043639A3 (en) | 2004-02-19 |
US7732487B2 (en) | 2010-06-08 |
DK1455794T3 (da) | 2011-03-14 |
US20100204332A1 (en) | 2010-08-12 |
ATE498402T1 (de) | 2011-03-15 |
AR037556A1 (es) | 2004-11-17 |
US20030166632A1 (en) | 2003-09-04 |
ES2359804T3 (es) | 2011-05-27 |
EP2364708A3 (en) | 2011-12-28 |
JP4377692B2 (ja) | 2009-12-02 |
TW200304829A (en) | 2003-10-16 |
EP1455794A2 (en) | 2004-09-15 |
WO2003043639A2 (en) | 2003-05-30 |
EP1455794B1 (en) | 2011-02-16 |
CA2466906A1 (en) | 2003-05-30 |
TWI263505B (en) | 2006-10-11 |
DE60239220D1 (de) | 2011-03-31 |
AU2002348670A1 (en) | 2003-06-10 |
EP2364708A2 (en) | 2011-09-14 |
CA2466906C (en) | 2011-10-18 |
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