JP3872290B2 - 迷走神経誘発不全収縮における薬理学的薬物併用 - Google Patents
迷走神経誘発不全収縮における薬理学的薬物併用 Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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Description
背景技術
胸骨切開術およびその代替切開術による、最小侵襲性直接冠状動脈バイパス(MIDCAB)手術は、拍動中の心臓にバイパス手術を施すことを可能にするため、外科手術における実質的に画期的な進展である。しかしながら、拍動中の心臓の手術は、心肺バイパスおよび心停止法を用いた通常の冠状動脈バイパス法よりも、好ましからぬ高比率で初期の移植不全を示す。拍動中の心臓に対して冠状動脈吻合を縫合することの技術的困難さは、この二つの技術間の成果の差異においては恐らく重要な因子であろう。吻合部縫合に必要とされる短い間隔の調節間欠不全収縮(CIA)は、拍動中の心臓に対して施される大動脈吻合の精度の改良に適したものであり、移植不全を減少させると共に手術の容易さを増すものである。
【0002】
心肺バイパス(CPB)および心停止溶液を用いた化学物質による停止は、最適な手術条件、すなわち血流動態の制御および心臓の静止を伝統的に外科医に提供してきた。この最適な場は、ますます複雑化する心臓外科手術における技術的成功に貢献してきた。しかしながら、最近では完全な心肺バイパスも心停止法も用いずに冠状動脈バイパス手術を行なうことに興味が持たれるようになった。心停止法による停止および心肺バイパスによらない冠状動脈バイパス移植(CABG)法を観察および実行している心臓外科医の間では、遠位の吻合の質が一番の関心事である。冠状動脈バイパス移植の失敗率は、最小侵襲性直接冠状動脈バイパス術を用いた場合3.8〜8.9%の範囲であると報告されており、一方CPBに基づく慣例的なCABGでは吻合の失敗率は0.12%と報告されている。このことはMIDCABと、CPBによるCABGとの間の吻合の精度の差異を反映しているのかもしれない。拍動中の心臓を処す場合、体外循環と全体的な心停止とを避ける利点は重要ではあるが、それらは最適な冠状動脈吻合の実施にまさることはない。
【0003】
通常のCABGと拍動中の心臓のCABGとの間の吻合結果における重要な差異は、遠位吻合の実施時の選択的な不全収縮の達成に関係する。心臓の動きは、薬理学的徐脈(アデノシン、β遮断薬)および種々の装置を用いた機械的安定化により、MIDCAB手術中最小化することができる。これらの技術は手術条件を改良はするが、CPBおよび心停止法を用いて行なわれる選択的不全収縮の利点に近づくにすぎない。
【0004】
出願人らは調節間欠不全収縮(CIA)の状態がCPB以外から作り出され、それにより、CPBに基づく心停止法により得られる重要な利点が得られることを示す。とくに、CIAは電気機械的逸脱活動の薬理学的抑制と組合せた片側(または両側)の迷走神経刺激を用いて行なわれる。
【0005】
出願人らは、選択的な調節間欠不全収縮が、アセチルコリンエステラーゼ阻害剤、アドレナリンβ受容体遮断薬もしくはカルシウムチャンネル遮断薬またはそれらの組合わせを用いて処理した後の迷走神経刺激により引き起こされることを証明する。
【0006】
略語および定義
CABG 冠状動脈バイパス移植
CIA 調節間欠不全収縮(controlled intermittent asystole)
CPB 心肺バイパス
MIDCAB 最小侵襲性直接冠状動脈バイパス(minimally invasive direct coronary artery bypass);全体的な心停止を使用しない全てのCABGを含む;切開に拘わらず、拍動中の心臓の外科手術と同義
【0007】
発明の実施の形態
迷走神経刺激時の、アセチルコリンエステラーゼの阻害による亢進されたアセチルコリン活性と、アドレナリンβ受容体およびカルシウムチャンネルの遮断による電気機械的な逸脱収縮の防止は、迷走神経により誘発される不全収縮の著しい増強作用と、CIAを達成するための手段とを生じる。迷走神経により誘発される不全収縮の薬理学的増強によって達成されるCIAは、MIDCAB手術を容易にするために適した技術である。とくに、吻合および他の複雑な縫合は、かかる調節不全収縮事象の間は容易化され、拍動する心臓に対する最小侵襲性直接冠状動脈バイバス手術を含む外科手術において容易に認識される利益である。CIAは部分的または全体的に内視鏡によるCABGにおいて、また経皮的または外科的な心筋層を横切るレーザーによる血管再生において、特に有利であろう。
【0008】
本発明は、アセチルコリンエステラーゼ阻害剤と、アドレナリンβ遮断薬およびカルシウムチャンネル遮断薬を含む医薬組成物であって、拍動する心臓の外科手術を行なうために有用である組成物を提供する。本発明はまた前記組成物が、最小侵襲性直接冠状動脈バイバス手術における調節間欠不全収縮に有用な組成物であるものを提供する。本発明はさらに前記組成物が、迷走神経刺激と組合せて投与することができるものを提供する。迷走神経刺激は直接または間接的な電気刺激により行なうことができる。
【0009】
好ましい個々の態様においては、アセチルコリンエステラーゼ阻害剤は臭化ピリドスチグミンでよく、アドレナリンβ受容体遮断薬は塩酸プロパノロールでよく、またカルシウムチャンネル遮断薬は臭化ベラパミルでよい。
【0010】
本発明はまたアセチルコリンエステラーゼ阻害剤とアドレナリンβ受容体遮断薬とを含む医薬組成物であって、拍動する心臓の外科手術を行なうために有用である組成物を提供する。好ましい態様においては、アセチルコリンエステラーゼ阻害剤は臭化ピリドスチグミン、アドレナリンβ受容体遮断薬は塩酸プロパノロール、またカルシウムチャンネル遮断薬は臭化ベラパミルでよい。本発明はまた、前記組成物が最小侵襲性直接冠状動脈バイパス手術における調節間欠不全収縮に有用な組成物であるものを提供する。本発明はさらに、前記組成物が迷走神経刺激と組合わせて投与することができるものを提供する。迷走神経刺激は直接または間接的な電気刺激により行なうことができる。
【0011】
本発明はまた、アセチルコリンエステラーゼ阻害剤とカルシウムチャンネル遮断薬とを含む医薬組成物であって、拍動する心臓の外科手術を行なうために有用である組成物を提供する。好ましい態様においては、アセチルコリンエステラーゼ阻害剤は臭化ピリドスチグミン、アドレナリンβ受容体遮断薬は塩酸プロパノロール、またカルシウムチャンネル遮断薬は臭化ベラパミルでよい。本発明はまた、前記組成物が最小侵襲性直接冠状動脈バイパス手術における調節間欠不全収縮に有用な組成物であるものを提供する。本発明はさらに、前記組成物が迷走神経刺激と組合わせて投与することができるものを提供する。迷走神経刺激は直接または間接的な電気刺激により行なうことができる。
【0012】
拍動する心臓のCABG手術の主要な問題は、CPBと心停止法による停止を用いた通常のCABG時に提供される静止した手術野という有利な手術条件を再現することにある。種々の薬理学的処置および機械的安定化技術がポンプ無しのCABGの実行を補佐する。今日までのこのような介入は、心臓の動きを最小にするが消失させることはない。CPBにより補佐されない場合の調節間欠不全収縮の状態が遠位の冠状動脈バイパスの形成条件を改善するという概念が、出願人により証明された。CIAは、手術者によって開始かつ調節される機械的な心臓停止の間隔として定義される。このような間隔は、吻合部における縫合の設置に一致するべく時間を定めることができ、その後に正常な心臓のリズムおよび血流動態が回復すると共に、次のひと針の準備がなされるようにする。出願人により報告された実験は、迷走神経刺激により生じることが周知である小さい徐脈が、アセチルコリンエステラーゼの薬理学的阻害とアドレナリンβ受容体およびカルシウムチャンネルの薬理学的遮断とにより、電気機械的な「オンオフスイッチ」として機能するべく劇的に増大することを示している。調節間欠不全収縮は、全体的な心停止を用いないCPBに支援された心臓手術に対しても同様に有用であることが証明されよう。
【0013】
迷走神経刺激の周期変更作用はよく説明されており、典型的には初期の停止と、それに続く「迷走神経逸脱」拍動と、迷走神経の連続最適刺激の間持続する徐脈を生じる。付加的な処置なしで迷走神経を60秒間刺激した場合の心臓は、心拍数の19%の減少を伴う迷走神経による逸脱拍動で終結する平均1.6秒間の停止という反応を示した。迷走神経刺激のみでは、CIAに所望される制御された不全収縮期間を生ずることはなかった。対照的に、たとえば、ピリドスチグミン、プロプラノロールおよびベラパミルの3種からなる薬理学的処置方式は、迷走神経による逸脱拍動を阻害し、かつ60秒間まで持続する不全収縮の持続期間と、15秒間ずつの続発性の不全収縮とを可能にした。分節性の不全収縮には何ら有意な血流動態上の影響がなかった。
【0014】
迷走神経刺激の間の電気機械的逸脱拍動の抑制が、遠位のCABG吻合部の形成に縫合のひと針を確実に設置するのに十分な不全収縮の間隔を生じるために必要であることは明白である。迷走神経刺激の周期変更の負の作用は、アセチルコリン放出により生じる。アセチルコリン活性は、ピリドスチグミンなどの薬物によるアセチルコリンエステラーゼ活性の阻害により亢進されてもよい。さらに、たとえばベラパミルによるカルシウムチャンネルの遮断が、迷走神経刺激の周期変更の負の効果を強化することが知られている。電気機械的逸脱拍動におけるもう一つの成分は、交感神経系における、低血圧が引き金となって亢進されるカテコールアミン活性に関係しているかもしれない。カテコールアミンは、拡張期脱分極の速度を亢進し、閾値電位を低下させる。たとえばプロプラノールなどによるアドレナリンβ受容体遮断は、カテコールアミン活性の効果を減じ、かつ電気機械的逸脱拍動の抑制を容易にする。
【0015】
このような組み合わせ処置を施すことで、左心室拡張終期圧の増加と共に、心拍数および最大心室内圧の有意な減少を生じたが、平均動脈圧は変わらなかった。刺激を繰り返した後でも、この薬理学的作用による明らかな疲労はみられなかった。予備実験に用いた動物は、アシドーシスなどの有害な血流動態上の副作用なしにこの薬理学的処置方式に耐えるようであった。
【0016】
単回の長い刺激が短時間の血流動態上に及ぼす作用は、実質的に有意ではないことがわかった。同様に、pHおよび塩基欠乏の変化により検出される代謝への影響も有意ではなかった。
【0017】
本発明に用いた薬理学的処置方式は、迷走神経により誘発される不全収縮の期間を約60分間にわたって持続した。この間隔により、遠位のCABG吻合形成に十二分な時間が得られる。薬物の投与後2時間を経た動物は、迷走神経刺激に対して非薬物処理の状態の動物と同様の反応を示し、薬物作用の可逆性が確証された。
【0018】
臨床応用の前に検討を要する薬理学的処置方式の有害作用は、迷走神経により誘導される分泌である。すべての動物が迷走神経刺激開始の後に有意な唾液分泌過多を示した。しかしながら、これらの実験では気管・気管支分泌による酸素付加および換気については問題がなかった。迷走神経により誘導される口と咽頭との、また気管・気管支の分泌は、この臨床上の環境にあっては適切である。さらに、再発性の喉頭神経機能に対する影響は検討を要する。
【0019】
迷走神経に対するこの処置方式の長期間の影響が有害ではないことは、証拠が示唆している。慢性の迷走神経刺激は難治性の発作障害のための療法として、明らかな神経損傷または欠陥機能なしに利用されてきた。出願人らは、実験プロトコルの完了の2時間後の、迷走神経を介する変時性の調節が非薬物処理の状態と同様であることを示した。
【0020】
要約すれば、調節間欠不全収縮を、電気機械的逸脱拍動抑制用のたとえばプロパノロールおよびベラパミルと、アセチルコリンエステラーゼ阻害用のたとえばピリドスチグミンとの薬理学的組合わせによる、迷走神経により誘発される不全収縮の増強により達成することが可能である。この技術を用いれば長い間隔用に、またより短い一連の多くの間隔用に、不全収縮を再現性をもって達成することができる。
【0021】
神経刺激
出願人らは、一貫した不全収縮を達成するためには、本発明の薬理学的組合せによる処理の前または後の、右側迷走神経の神経刺激が好ましいことを発見した。
【0022】
電気刺激は、右側迷走神経上の、好ましくは頚部の位置におこなわれる。迷走神経刺激用に適した他の位置は、右または左迷走神経、あるいはその両方の単極または双極性の電気刺激、胸骨切開後の胸部における迷走神経刺激、内頚静脈、食道もしくは気管またはそれらの組み合わせにおける経皮カテーテルまたは電極プローブを用いた刺激を含むが、これらに制限されない。神経の刺激装置は、典型的には単一の接点を有するグラス(Grass)ワイヤーであるが、他の適当な刺激装置には、双極性前駆刺激を可能にするように約1cm離して設置された一対のペーシングワイヤーまたは電極が含まれる。単回の連続したインパルスを、約5秒間から約90秒間までの間、好ましくは約5秒間から約15秒間までの間適用して外科手術の間の単一のステッチができるようにする。インパルスパラメータは容易に変えることができ、たとえば周波数は約1Hz〜約500Hz、好ましくは約20Hz〜約80Hzの範囲であり、さらに好ましくは約40Hzであり、振幅は約1〜約40ボルトの間である。
【0023】
薬理学的増強作用
アセチルコリンエステラーゼ阻害剤は、コリンエステラーゼ阻害剤としても知られている。適当なアセチルコリンエステラーゼ阻害剤は、塩酸タクリン、臭化ピリドスチグミン、メチル硫酸ネオスチグミンおよび塩化エドロフォニウムを含むがこれらに制限されない。好ましいアセチルコリンエステラーゼ阻害剤は臭化ピリドスチグミンである。アセチルコリンエステラーゼ阻害剤は、約0.01mg/kg〜約100mg/kgであり、好ましくは約0.1mg/kg〜約2.0mg/kgの用量範囲内で、さらに好ましくは約0.5mg/kgで投与される。
【0024】
アドレナリンβ受容体遮断薬は、またアドレナリンβ遮断薬としても知られている。適当なアドレナリンβ受容体遮断薬は、塩酸ソタロール、マレイン酸チモロール、塩酸エスモロール、塩酸カルテロール、塩酸プロプラノロール、塩酸ベタキソロール、硫酸ペンブトロール、酒石酸メトプロロール、塩酸アセブトロール(acetbutolol hydrochloride)、アテノロールとクロルタリドンとの組み合わせ、コハク酸メトプロロール、ピンドロールおよびフマル酸ビソプロロール(bisoprolol fumarate)を含むがこれらに制限されない。好ましいアドレナリンβ受容体遮断薬は、塩酸プロプラノロールである。アドレナリンβ受容体遮断薬は、約0.01mg/kg〜約100mg/kg、好ましくは約0.1mg/kg〜約2.0mg/kgの用量範囲内で、さらに好ましくは約80μg/kgで投与される。
【0025】
適当なカルシウムチャンネル遮断薬は、ニフェジピン、塩酸ニカルジピン、塩酸ジルチアゼム、イスラジピン、塩酸ベラパミル、ニモジピン、ベシル酸アムロジピン、フェロジピン、塩酸ベプリジルおよびニソルジピンを含むがこれらに制限されない。好ましいカルシウムチャンネル遮断薬は、塩酸ベラパミルである。カルシウムチャンネル遮断薬は、約1mg/kg〜約1000mg/kg、好ましくは約10mg/kg〜約200mg/kgの用量範囲内で、さらに好ましくは約50μg/kgで投与される。
【0026】
他の投与量の組み合わせが有効であり得ることが理解されよう。適切な用量は、患者の年齢、体重、性別、健康状態によって決定され、通常の臨床診療による他の種々の因子により変わり得る。
【0027】
実施例1
実験準備
本発明の実施例におけるヒツジは、国立医学研究学会(National Society for Medical Research)によりまとめられた「実験動物管理基準 (Principles of Laboratory Animal Care)」ならびに国立科学アカデミー(National Academy of Science)により作成され国立予防衛生研究所により発表された「実験動物の管理および使用に関する指針(Guide for Care and Use of Laboratory Animals)」(NIH出版 No. 80-23、1985年改訂)に従って保護管理を受けた。実験のプロトコールは、エモリ(Emory)大学の実験動物管理使用委員会(Institutional Animal Care and Use Committee)により承認された。
【0028】
体重44〜45kgのヒツジ7匹に、チオペンタール(2.2mg/kg)およびリドカイン(2.2mg/kg)の静脈内投与による麻酔の導入の30分前に、キシラジン(0.1mg/kg)およびアトロピン(0.2mg/km)の前投薬を行なった。この動物に気管内挿管し、麻酔の維持のためのイソフルランを用い従量式ベンチレータ(volume ventilator)を装着した。四肢誘導ならびに胸部誘導をエレクトロカルジオグラフィーによるモニタリング用に設置した。右大腿動脈にカニューレ挿入して、動脈圧ならびに動脈血ガスのモニタリング用とした。一回換気量は10cc/kgで毎分12回の呼吸速度に調整し、pHは7.35〜7.45に、pO2は100mmHgより高く、またpCO2は35〜45mmHgに維持するべく調整した。
【0029】
右頚部切開を行ない、迷走神経を注意深く分離し、さらにこの神経の上に神経刺激プローブ(Harvard Apparatus、サウスナテック、マサチューセッツ州)を設置した。胸骨正中切開を施して心臓を露出させた。高性能固体マイクロマノメーター(Miller Inc.、ヒューストン、テキサス州)を上大動脈に取付けて大動脈血圧のモニタリング用とした。左心室圧のモニタリング用には、付加的なマイクロマノメーターを尖を通して左心室に導入した。
【0030】
実施例2
実験プロトコール
各々の動物は、薬物投与の前後に迷走神経刺激を受けた。薬理学的処置方式は、アセチルコリンエステラーゼ阻害用のピリドスチグミン(0.5mg/kg)、アドレナリンβ受容体遮断用のプロプラノロール(80μg/kg)、および、カルシウムチャンネル遮断用のベラパミル(50μg/kg)からなっていた。迷走神経刺激は、神経刺激装置(Grass Instrument Co.、クインシー、マサチューセッツ州)において、単極モードで周波数40Hz、インパルス持続時間0.4ミリ秒、振幅2〜6ボルトにて行なった。迷走神経刺激は二つの治療用処置方式、すなわち1)連続した60秒間のインパルス、および2)続発性(sequential)の15秒間のインパルス、で与えられた。連続した60秒間の刺激は、迷走神経により誘発される不全収縮の寿命と迷走神経により誘発される延長された低血圧の生理学的影響とを測定するべく設定された。続発性の15秒間の迷走神経刺激は、移植片の吻合に必要な縫合のための間隔をシミュレートするべく、またこのような実際的条件下において心臓の疲労、電気機械的逸脱拍動および生理学的影響が生じるかどうかを決定するべく行なわれた。
【0031】
実施例3
データ収集および分析
エレクトロカルジオグラフィーおよび血流動態についてのデータをアナログ−ディジタル変換ボード(Data Translation Inc.、マールボロ、マサチューセッツ州)により集め、さらにマイクロプロセッサーパーソナル486コンピュータ(Compaq Computer Corp.、ヒューストン、テキサス州)により、対話式の専売ソフトウェア(SpectrumTM, Triton Technology、サンジエゴ、カリフォルニア州)を用いて処理、記録および分析した。このシステムは、周波数50Hz(徐波の波形および平均内圧のデータには十分)における4チャンネルの生理学的データを、60秒間の刺激または続発性の15秒間の刺激の連続を包含する200秒間より長い期間収集すべく構成された。このソフトウェアは、血流動態のデータのその後のビデオグラフによる表示および分析を可能にした。
【0032】
実施例4
結果
薬物投与の前では、60秒間の迷走神経刺激は、電気機械的活動度に短い休止期(1.6±0.9秒)とそれに続く迷走神経の逸脱拍動、および、刺激前の心拍数に比較して19.4±11.9%までの心拍数の減少を伴う洞律動の再開を生じた。同様に、CABGの吻合に必要な縫合用休止期を刺激するべく行なわれた続発性の15秒間の迷走神経刺激は、短い休止期(1.1±0.4秒)とそれに続く迷走神経の逸脱拍動、および、37±6%の心拍数の減少を伴う洞律動を生じた。
【0033】
薬理学的処置方式(プロプラノロール、ベラパミル、ピリドスチグミン)は、表1に示したように、心拍数を減少させ、左心室拡張終期圧を増加させたが、平均動脈圧または最大dP/dtには何ら影響しなかった。
【0034】
【表1】
薬物投与後では、60秒間の迷走神経刺激は平均52±5.6秒間の不全収縮を生じた。薬物投与前後の動物の個々の反応を第1図に示す。6匹の動物で調節不全収縮が得られた。これらの6匹のうち5匹は、50秒間より長い間調節された不全収縮が得られた。反応性の動物における薬物処理前後の60秒間の迷走神経刺激の効果を、代表的な左心室圧および大動脈圧の追跡によって対比させたものを、代表的な実験として第2図に示す。薬物処置の前では、迷走神経刺激は心臓リズムまたは血流動態に何ら明らかな変化を生じなかった。対照的に、三つの薬物による処置方式は、刺激が止められるまでの一貫した不全収縮および循環停止を容易にし、その後の血流動態は速やかに刺激前の値に回復した。延長された不全収縮および循環停止は、薬物に補佐された60秒間の迷走神経刺激の前後に測定された血流動態パラメーターに何ら有意の差異を生じなかった(表2)。
【0035】
【表2】
同様に、60秒間の刺激の1および5分後の動脈血ガスによって測定されたパラメーターは、刺激前の値と比較して差異がなかった(表3)。
【0036】
【表3】
薬物処理状態における続発性の5ないし6回の15秒間の迷走神経刺激は、一貫した安定な不全収縮を生じた(第3図)。6匹の動物のうち3匹には、15秒刺激のうちの一つの間に単一の逸脱拍動収縮があった。他の3匹は、各々の15秒刺激の間完全な不全収縮を示した。持続性の心リズムは、15秒インパルス終了後平均5.3±1.8秒で開始し、その間隔の間には、刺激の停止直後に単一の拍動がしばしば観察された。
【0037】
前述の明細書は、説明のために提供した実施例を用いて本発明の原理を教示するものであるが、すべての通常の変更、適用および修正が特許請求の範囲及びその均等の範囲内に入るものとして本発明の実施に含まれることが理解されよう。
【図面の簡単な説明】
【図1】 第1図。60秒間の迷走神経刺激の間に達成された不全収縮の持続時間である。直線は、非薬物処理および薬物処理状態で観察された不全収縮の期間を個々の動物ごとに結んだものである。薬物投与は不全収縮の期間を有意に延長した。
【図2】 第2図A。非薬物処理状態における60秒間の迷走神経刺激時の左心室圧および大動脈圧の追跡を示す。黒い矢印および白い矢印は、各々迷走神経刺激の開始および終了を示す。薬物処理の前では、60秒間の刺激の間に短い停止とその後逸脱収縮と徐脈が観察された。lvp−左心室圧;aop−大動脈圧。
【図3】 第2図B。薬物処理状態における60秒間の迷走神経刺激時の左心室圧および大動脈圧の追跡を示す。黒い矢印および白い矢印は、各々迷走神経刺激の開始および終了を示す。薬物処理後では、60秒間の刺激の間に延長された不全収縮が起き、終了後に機械的な機能が回復した。lvp−左心室圧;aop−大動脈圧。
【図4】 第3図A。非薬物処理状態における、迷走神経を15秒間続発的に刺激した場合の左心室圧および大動脈圧の追跡を示す。黒の矢印および白の矢印は、各々迷走神経刺激の開始および終了を示す。薬物処理前では、各15秒間の刺激は短い停止とそれに続く徐脈を引き起こした。lvp−左心室圧;aop−大動脈圧。
【図5】 第3図B。薬物処理状態における、迷走神経を15秒間続発的に刺激した場合の左心室圧および大動脈圧の追跡を示す。黒の矢印および白の矢印は、各々迷走神経刺激の開始および終了を示す。薬剤処理後では、各15秒間の刺激の間不全収縮が持続した。lvp−左心室圧;aop−大動脈圧。
Claims (16)
- アセチルコリンエステラーゼ阻害剤、アドレナリンβ受容体遮断薬、および、カルシウムチャンネル遮断薬を含む、心臓外科手術における迷走神経刺激による調節不全収縮を得るための医薬組成物。
- 最小侵襲性直接冠状動脈バイパス手術における迷走神経刺激による調節間欠不全収縮を得るための請求項1記載の組成物。
- 迷走神経刺激が、一方もしくは両方の迷走神経に対する少なくとも一つの単極もしくは双極の電極の直接適用を伴うか、または気管、食道、内頚静脈もしくはそれらのある組合せにおける少なくとも一つの単極もしくは双極の電極の設置を伴うことを特徴とする、請求項1記載の組成物。
- アセチルコリンエステラーゼ阻害剤が臭化ピリドスチグミンである請求項1記載の組成物。
- アセチルコリンエステラーゼ阻害剤が約0.01mg/kg〜約100.0mg/kgの用量範囲内にある請求項4記載の組成物。
- アセチルコリンエステラーゼ阻害剤が約0.1mg/kg〜約2.0mg/kgの用量範囲内にある請求項5記載の組成物。
- アドレナリンβ受容体遮断薬が塩酸プロプラノロールである請求項1記載の組成物。
- アドレナリンβ受容体遮断薬が約0.01mg/kg〜約100.0mg/kgの用量範囲内にある請求項7記載の組成物。
- アドレナリンβ受容体遮断薬が約0.1mg/kg〜約2.0mg/kgの用量範囲内にある請求項8記載の組成物。
- カルシウムチャンネル遮断薬が臭化ベラパミルである請求項1記載の組成物。
- カルシウムチャンネル遮断薬が約1mg/kg〜約1000mg/kgの用量範囲内にある請求項10記載の組成物。
- カルシウムチャンネル遮断薬が約10mg/kg〜約200mg/kgの用量範囲内にある請求項11記載の組成物。
- アセチルコリンエステラーゼ阻害剤である臭化ピリドスチグミン、アドレナリンβ受容体遮断薬である塩酸プロプラノロール、および、カルシウムチャンネル遮断薬である臭化ベラパミルを含む医薬組成物であって、最小侵襲性直接冠状動脈バイパス手術における迷走神経刺激による調節間欠不全収縮を得るための組成物。
- 迷走神経刺激が、一方もしくは両方の迷走神経に対する少なくとも一つの単極もしくは双極の電極の直接適用を伴うか、または、気管、食道、内頚静脈もしくはそれらのある組合せにおける少なくとも一つの単極もしくは双極の電極の設置を伴うことを特徴とする、請求項13記載の組成物。
- アセチルコリンエステラーゼ阻害剤が約0.01mg/kg〜約100.0mg/kgの用量範囲内にあり、アドレナリンβ受容体遮断薬が約0.01mg/kg〜約100.0mg/kgの用量範囲内にあり、かつカルシウムチャンネル遮断薬が約1mg/kg〜約1000mg/kgの用量範囲内にある請求項13記載の組成物。
- アセチルコリンエステラーゼ阻害剤が約0.1mg/kg〜約2.0mg/kgの用量範囲内にあり、アドレナリンβ受容体遮断薬が約0.1mg/kg〜約2.0mg/kgの用量範囲内にあり、かつカルシウムチャンネル遮断薬が約10mg/kg〜約200mg/kgの用量範囲内にある請求項15記載の組成物。
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US6778854B2 (en) | 2004-08-17 |
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AU9035698A (en) | 1999-03-16 |
JP2001526176A (ja) | 2001-12-18 |
ATE295161T1 (de) | 2005-05-15 |
US6429217B1 (en) | 2002-08-06 |
DE69830178T2 (de) | 2006-01-26 |
CA2301183C (en) | 2007-09-25 |
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US20020198571A1 (en) | 2002-12-26 |
US7310552B2 (en) | 2007-12-18 |
WO1999009973A1 (en) | 1999-03-04 |
MXPA00002043A (es) | 2004-03-10 |
DE69830178D1 (de) | 2005-06-16 |
EP1005337B1 (en) | 2005-05-11 |
CA2301183A1 (en) | 1999-03-04 |
US20020183237A1 (en) | 2002-12-05 |
US20050143412A1 (en) | 2005-06-30 |
US6479523B1 (en) | 2002-11-12 |
EP1005337A4 (en) | 2002-06-12 |
US20040059383A1 (en) | 2004-03-25 |
EP1005337A1 (en) | 2000-06-07 |
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