JPWO2013180240A1 - 全身麻酔薬と、水素とを組み合わせてなる、医薬 - Google Patents
全身麻酔薬と、水素とを組み合わせてなる、医薬 Download PDFInfo
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- JPWO2013180240A1 JPWO2013180240A1 JP2014518736A JP2014518736A JPWO2013180240A1 JP WO2013180240 A1 JPWO2013180240 A1 JP WO2013180240A1 JP 2014518736 A JP2014518736 A JP 2014518736A JP 2014518736 A JP2014518736 A JP 2014518736A JP WO2013180240 A1 JPWO2013180240 A1 JP WO2013180240A1
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Abstract
Description
[1]全身麻酔薬と、水素を組み合わせてなる、ヒト又はヒト以外の動物用医薬。
[2]全身麻酔薬と、水素とを併用で投与されることを特徴とする、ヒト又はヒト以外の動物の全身麻酔のための医薬。
[3]麻酔薬誘発性神経障害を予防及び/又は軽減するために使用される前記[1]又は[2]に記載の医薬。
[4]麻酔薬誘発性神経障害が、神経細胞アポトーシスに付随するものである前記[3]に記載の医薬。
[5]全身麻酔薬が、水素と併用されるように用いられることを特徴とする、全身麻酔薬を含有する麻酔薬誘発性神経障害の予防及び/又は軽減用医薬。
[6]全身麻酔薬が吸入麻酔薬又は液状の静脈麻酔薬であり、水素が水素ガスである前記[1]〜[5]のいずれか1項に記載の医薬。
[7]水素ガス濃度が、医薬中0.15〜7%(v/v)である前記[6]に記載の医薬。
[8]胎児、新生児、乳児、幼児、小児又は高齢者を対象とする前記[1]〜[7]のいずれか1項に記載の医薬。
[9]全身麻酔薬が、亜酸化窒素、イソフルラン、エンフルラン、メトキシフルラン、セボフルラン、デスフルラン、ジエチルエーテル、プロポフォール及びミダゾラムからなる群より選ばれた1種以上の麻酔薬である前記[1]〜[8]のいずれか1項に記載の医薬。
[10]麻酔薬誘発性神経障害が、神経運動障害、神経認知障害、精神認知障害又は自閉症である前記[3]、[5]〜[9]のいずれか1項に記載の医薬。
[11]麻酔薬誘発性神経障害を予防及び/又は軽減するために、全身麻酔薬と水素とを併用する医薬の調製方法。
[12]麻酔薬誘発性神経障害が、神経細胞アポトーシスに付随するものであることを特徴とする前記[11]に記載の調製方法。
[13]全身麻酔薬が吸入麻酔薬又は液状の静脈麻酔薬であり、水素が水素ガスである前記[11]又は[12]に記載の調製方法。
[14]水素ガス濃度が、医薬中0.15〜7%(v/v)である前記[13]に記載の調製方法。
[15]医薬が、胎児、新生児、乳児、幼児、小児又は高齢者を対象とする前記[11]〜[14]のいずれか1項に記載の調製方法。
[16]水素と組み合わせて用いられる全身麻酔剤製造のための全身麻酔薬の使用。
[17]全身麻酔薬と水素とを組み合わせてなる医薬の製造のための全身麻酔薬と水素の使用。
[18]麻酔薬誘発性神経障害を予防及び/又は軽減するための医薬の製造のための全身麻酔薬と水素の使用。
[19]麻酔薬誘発性神経障害が、神経細胞アポトーシスに付随するものである前記[18]に記載の使用。
[20]全身麻酔薬が吸入麻酔薬又は液状の静脈麻酔薬であり、水素が水素ガスである前記[16]〜[18]のいずれか1項に記載の使用。
[21]水素ガス濃度が、医薬中0.15〜7%(v/v)である前記[20]に記載の使用。
[22]胎児、新生児、乳児、幼児、小児又は高齢者を対象とする前記[16]〜[18]のいずれか1項に記載の使用。
[23]全身麻酔薬が、亜酸化窒素、イソフルラン、エンフルラン、メトキシフルラン、セボフルラン、デスフルラン、ジエチルエーテル、プロポフォール及びミダゾラムからなる群より選ばれた1種以上の麻酔薬である前記[16]〜[18]のいずれか1項に記載の使用。
[24]麻酔薬誘発性神経障害が、神経運動障害、神経認知障害、精神認知障害又は自閉症である前記[18]に記載の使用。
[25]全身麻酔薬と水素とを併用して対象に投与する工程を有する、麻酔薬誘発性神経障害を予防及び/又は軽減する方法。
[26]全身麻酔薬が吸入麻酔薬又は液状の静脈麻酔薬であり、水素が水素ガスである前記[25]に記載の方法。
[27]水素ガス濃度が、医薬中0.15〜7%(v/v)である前記[26]に記載の方法。
[28]投与対象が、胎児、新生児、乳児、幼児、小児又は高齢者である前記[25]に記載の方法。
[29]全身麻酔薬が、亜酸化窒素、イソフルラン、エンフルラン、メトキシフルラン、セボフルラン、デスフルラン、ジエチルエーテル、プロポフォール及びミダゾラムからなる群より選ばれた1種以上の麻酔薬である前記[25]に記載の方法。
[30]麻酔薬誘発性神経障害が、神経運動障害、神経認知障害、精神認知障害又は自閉症である前記[25]に記載の方法。
[31]麻酔薬誘発性神経障害が、神経細胞アポトーシスに付随するものである前記[25]に記載の方法。
上記具体例のうち、ハロタン、イソフルラン、エンフルラン、メトキシフルラン、セボフルラン、デスフルラン、エトミデート、チオペンタール、プロポフォール及びミダゾラム等の麻酔薬は、GABAA受容体作用薬である。さらに、前記麻酔薬のうちのいくつか(例えば、N2O、ケタミン及びイソフルラン等)はNMDA受容体アンタゴニストであるが、麻酔薬全てについてNMDA受容体拮抗作用が解明されているわけではない。
動物:この研究で使用したC57BL/6マウスは、12時間の明暗周期(照明の点灯時間は7時〜19時)と22±2℃の室温の条件下で管理した。マウスは自由摂餌及び自由摂水下で飼育した。この研究で使用した全てのマウスは、同齢の同腹仔であった。
空気、酸素(空気とは別に)、水素及びセボフルランを混合して、最終的に酸素が30%、水素が0.6%、セボフルラン(3%)となるように麻酔薬混合ガスを調製した以外は実施例1と同様に行った。
空気、酸素(空気とは別に)、水素及びセボフルランを混合して、最終的に酸素が30%、水素が0.3%、セボフルラン(3%)となるように麻酔薬混合ガスを調製した以外は実施例1と同様に行った。
空気、酸素(空気とは別に)、水素及びデスフルランを混合して、最終的に酸素が30%、水素が1.3%、デスフルラン(5.7%)となるように麻酔薬混合ガスを調製した以外は実施例1と同様に行った。
空気、酸素(空気とは別に)及び水素を混合して、酸素が30%、水素が1.3%の混合ガスを麻酔薬と同時吸入させながら、プロポフォール(100mg/kg ip)の腹腔内投与と同時に、併用して吸入投与した以外は実施例1と同様に行った。
空気、酸素(空気とは別に)、水素及びセボフルランを混合して、最終的に酸素が30%、水素が1.3%、セボフルラン(2%)となるように麻酔薬混合ガスを調製した以外は実施例1と同様に行った。
空気、酸素(空気とは別に)及びセボフルランを混合して、最終的に酸素が30%、セボフルラン(3%)となるように麻酔薬混合ガスを調製した以外は、実施例1と同様に行った。
空気、酸素(空気とは別に)及びデスフルランを混合して、最終的に酸素が30%、デスフルラン(5.7%)となるように麻酔薬混合ガスを調製した以外は、実施例1と同様に行った。
空気及び酸素(空気とは別に)を混合して、酸素が30%の混合ガスを麻酔薬と同時吸入させながら、プロポフォール(100mg/kg ip)の腹腔内投与と同時に、併用して吸入投与した以外は実施例1と同様に行った。
タンパク質抽出物の精製:タンパク質抽出物の調製は、Kodama M.et al., Anesthesiology,2011;115:979-991に記載したように、ウェスタンブロット法により実施した。以下に方法を簡単に記載する。マウスの前脳を速やかに取り出し、50mMのトリスHCl、pH7.4、150mMのNaCl、1%のNP-40、0.5%のデオキシコール酸ナトリウム、プロテアーゼ阻害薬混合物(Complete; Roche Diagnostics, ペンツベルク, ドイツ)及び脱リン酸化酵素阻害薬(20mMのグリセロリン酸、1mMのNa3VO4、2mMのNaF)を含んだ、4倍量のホモゲナイゼーションバッファ中で均質化した。続いて、ホモジネートを15,000g、30分間、4℃の条件で遠心分離した。上澄み溶液を分離し、使用時まで−80℃で保管した。各試料のタンパク質濃度は、ビシンコニン酸タンパク質定量キット(Pierce, Rockford, IL)を用いて測定した。
[試験例1−A]と同様にして、実施例4と比較例2について評価を行った。比較例2の分解PARPの定量値を100%としたとき、実施例4の分解PARPの相対的な定量値は、47.7%減少し、分解PARPの定量値は有位に減少した。このことから、本発明が、デスフルランの曝露によって引き起こされる神経細胞アポトーシスを45%以上も阻害することが示された。
[試験例1−A]と同様にして、実施例4と比較例3について評価を行った。比較例3の分解PARPの定量値を100%としたとき、実施例5の分解PARPの相対的な定量値は、55.1%減少し、分解PARPの定量値は有位に減少した。このことから、本発明が、プロポフォールの曝露によって引き起こされる神経細胞アポトーシスを50%以上も阻害することが示された。
病理組織学的な研究:免疫組織化学的染色は、Kodama M.et al., Anesthesiology,2011;115:979-991及びSatoh Y.et al., J Neurosci,2011;31:11953-11967に記載した方法で実施した。以下にその方法を簡単に記載する。4%のパラホルムアルデヒドを含有する0.1Mリン酸バッファーで、マウスを経心臓的に灌流した。頭蓋骨を開け、頭部を少なくとも2時間、同じバッファーに浸した。その後、脳を頭蓋骨から取り出し、パラフィン包埋した断片(5μm厚)を使って病理組織学的に分析した。断片は、確立された方法に従ってキシレン中でパラフィンを剥離し、グレードエタノールシリーズ(graded ethanol series)を使って水和させた。抗原賦活化処理は、抗原賦活化溶液(Antigen Unmasking Solution; Vector Laboratories, Burlingame, CA)を用い、オートクレーブで5分間加熱(121℃)することにより実施した。その後、バックグラウンドの染色を薄くするため、断片をブロッキング試薬(Protein Block, Serum-Free; Dako, Glostrup, デンマーク)で30分間処理した。続いて、断片を一次抗体と共に、多湿のチャンバーの中で、一晩4℃でインキュベートした。この研究で使用した一次抗体は、抗−活性カスパーゼ−3(ウサギポリクローナル;Cell Signaling Technology, Beverly, MA)及び抗−4−ヒドロキシ−2−ノネナール(anti-4-HNE)(マウスモノクローナル;日本老化制御研究所、静岡県、日本)抗体であった。
行動試験:行動研究に供したマウスは全て、実施例1及び比較例1と同じ条件で麻酔に暴露した同齢・同腹仔のオスであった。3週齢のマウスを母親から離し、3又は4匹のマウスがいるケージに収容した。所定の年齢で、それらに行動試験(麻酔薬の影響を評価するため、長期記憶障害評価のコントロールとしてのオープンフィールド試験、短期記憶障害の評価のためのY字型迷路における自発的交替行動試験、長期記憶障害の評価のための恐怖条件付け試験、社会性試験を行った。社会性試験については、社会的相互作用試験の他、そのコントロールとして新規性試験及び嗅覚試験を行った。)を受けさせた。それぞれのマウスの動きを観察し、コンピュータ作動ビデオ追跡システム(SMART; バルセロナ、スペイン)を用いて解析した。試験では、アームを持った装置を使用し、マウスの足がアームに4本全て入った数をカウントした。装置はトライアル毎に掃除した。この研究で用いた装置は全て、O’Hara & Co.,LTD(東京都,日本)製のものであった。同じマウスの集団を、全ての試験に供した。
これらの結果から、新生仔の全身麻酔薬曝露によって引き起こされる記憶障害の種類は長期記憶障害であり、かかる記憶障害を、水素が予防及び/又は軽減することが示された。
Claims (31)
- 全身麻酔薬と、水素を組み合わせてなる、ヒト又はヒト以外の動物用医薬。
- 全身麻酔薬と、水素とを併用で投与されることを特徴とする、ヒト又はヒト以外の動物の全身麻酔のための医薬。
- 麻酔薬誘発性神経障害を予防及び/又は軽減するために使用される請求項1又は2に記載の医薬。
- 麻酔薬誘発性神経障害が、神経細胞アポトーシスに付随するものである請求項3に記載の医薬。
- 全身麻酔薬が、水素と併用されるように用いられることを特徴とする、全身麻酔薬を含有する麻酔薬誘発性神経障害の予防及び/又は軽減用医薬。
- 全身麻酔薬が吸入麻酔薬又は液状の静脈麻酔薬であり、水素が水素ガスである請求項1〜5のいずれか1項に記載の医薬。
- 水素ガス濃度が、医薬中0.15〜7%(v/v)である請求項6に記載の医薬。
- 胎児、新生児、乳児、幼児、小児又は高齢者を対象とする請求項1〜7のいずれか1項に記載の医薬。
- 全身麻酔薬が、亜酸化窒素、イソフルラン、エンフルラン、メトキシフルラン、セボフルラン、デスフルラン、ジエチルエーテル、プロポフォール及びミダゾラムからなる群より選ばれた1種以上の麻酔薬である請求項1〜8のいずれか1項に記載の医薬。
- 麻酔薬誘発性神経障害が、神経運動障害、神経認知障害、精神認知障害又は自閉症である請求項3、5〜9のいずれか1項に記載の医薬。
- 麻酔薬誘発性神経障害を予防及び/又は軽減するために、全身麻酔薬と水素とを併用する医薬の調製方法。
- 麻酔薬誘発性神経障害が、神経細胞アポトーシスに付随するものであることを特徴とする請求項11に記載の調製方法。
- 全身麻酔薬が吸入麻酔薬又は液状の静脈麻酔薬であり、水素が水素ガスである請求項11又は12に記載の調製方法。
- 水素ガス濃度が、医薬中0.15〜7%(v/v)である請求項13に記載の調製方法。
- 医薬が、胎児、新生児、乳児、幼児、小児又は高齢者を対象とする請求項11〜14のいずれか1項に記載の調製方法。
- 水素と組み合わせて用いられる全身麻酔剤製造のための全身麻酔薬の使用。
- 全身麻酔薬と水素とを組み合わせてなる医薬の製造のための全身麻酔薬と水素の使用。
- 麻酔薬誘発性神経障害を予防及び/又は軽減するための医薬の製造のための全身麻酔薬と水素の使用。
- 麻酔薬誘発性神経障害が、神経細胞アポトーシスに付随するものである請求項18に記載の使用。
- 全身麻酔薬が吸入麻酔薬又は液状の静脈麻酔薬であり、水素が水素ガスである請求項16〜18のいずれか1項に記載の使用。
- 水素ガス濃度が、医薬中0.15〜7%(v/v)である請求項20に記載の使用。
- 胎児、新生児、乳児、幼児、小児又は高齢者を対象とする請求項16〜18のいずれか1項に記載の使用。
- 全身麻酔薬が、亜酸化窒素、イソフルラン、エンフルラン、メトキシフルラン、セボフルラン、デスフルラン、ジエチルエーテル、プロポフォール及びミダゾラムからなる群より選ばれた1種以上の麻酔薬である請求項16〜18のいずれか1項に記載の使用。
- 麻酔薬誘発性神経障害が、神経運動障害、神経認知障害、精神認知障害又は自閉症である請求項18に記載の使用。
- 全身麻酔薬と水素とを併用して対象に投与する工程を有する、麻酔薬誘発性神経障害を予防及び/又は軽減する方法。
- 全身麻酔薬が吸入麻酔薬又は液状の静脈麻酔薬であり、水素が水素ガスである請求項25に記載の方法。
- 水素ガス濃度が、医薬中0.15〜7%(v/v)である請求項26に記載の方法。
- 投与対象が、胎児、新生児、乳児、幼児、小児又は高齢者である請求項25に記載の方法。
- 全身麻酔薬が、亜酸化窒素、イソフルラン、エンフルラン、メトキシフルラン、セボフルラン、デスフルラン、ジエチルエーテル、プロポフォール及びミダゾラムからなる群より選ばれた1種以上の麻酔薬である請求項25に記載の方法。
- 麻酔薬誘発性神経障害が、神経運動障害、神経認知障害、精神認知障害又は自閉症である請求項25に記載の方法。
- 麻酔薬誘発性神経障害が、神経細胞アポトーシスに付随するものである請求項25に記載の方法。
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