JP6502350B2 - 臓器保護のための液体麻酔薬と組み合わせた非麻酔性保護ガス - Google Patents
臓器保護のための液体麻酔薬と組み合わせた非麻酔性保護ガス Download PDFInfo
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- JP6502350B2 JP6502350B2 JP2016535280A JP2016535280A JP6502350B2 JP 6502350 B2 JP6502350 B2 JP 6502350B2 JP 2016535280 A JP2016535280 A JP 2016535280A JP 2016535280 A JP2016535280 A JP 2016535280A JP 6502350 B2 JP6502350 B2 JP 6502350B2
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Description
本出願は、2013年8月19日に出願した米国仮出願第61/867,367号の優先権を主張するものである。
B6.Cg-Tg(Thy1-YFP)16Jrs/Jマウス
Thy1-YFPマウスを、麻酔導入チャンバ中で、蒸気麻酔薬(イソフルラン又はセボフルラン)に曝した。動物の体温を調査し、角膜損傷を防止するために滅菌した眼用潤滑剤を適用した。眼窩縁付近に切り目を形成した。左の眼窩を露出させ、涙腺をゆっくり切除し、生理食塩水に浸したガーゼで覆った。ついで、上外眼筋を使用して、眼を回転させ、視神経を露出させた。マイクロシザーズを使用して、硬膜を切除し、視神経を眼球の後面から約0.5mm切開した。血液供給の維持を、散瞳により焦点合わせされた解剖顕微鏡及びカバーガラスにより評価した。皮膚を縫合クリップで閉じ、鎮痛剤(生理食塩水におけるブプレノルフィン)を投与し、マウスを、アルゴン(70%)/酸素(30%)かん流空気チャンバに、保温マット上に移した。マウスをモニターし、傷害後24又は72時間通気ラックに収容した。対照マウスは、傷害後に常圧条件に曝した(図1を参照のこと)。内部手術対照は、反対側の眼の未傷害網膜とした。
マウスをイソフルランで軽く麻酔し、頸椎脱臼で屠殺した。直ちに眼を取り出し、氷冷したハンクス平衡塩類溶液(HBSS)に入れた。結膜に1つの孔を開け、角膜を顕微解剖により除去した。ついで、毛様体上皮及びレンズを切除した。吸引及び顕微解剖による除去を助けるために、トリアムシノロンアセトニド液を使用して、硝子体液を可視化した。ついで、浮動性の網膜を、氷上の新鮮なHBSSに移し、ついで、トリプシン(MACS-Miltenyi Biotec社)を含む1mlの酵素溶液に移した。周期的に振動させながら、37℃での15分のインキュベート後、網膜を、火仕上げピペットで分離させ、遠心分離した。ペレットを、アネキシンV結合バッファーで洗浄し、遠心分離した。ペレットを、DNase含有結合バッファー中で再度分離させ、アネキシンV-PeCy7プローブで染色した。細胞を洗浄し、細胞を引っ張り(40um)、BD FacsAria IIIフローサイトメトリを使用して分析した。
未染色、YFPのみ、アネキシンVのみ及び二重標識の細胞サンプルを使用して、補償及びゲーティングを確立した。ヨウ化プロピジウム及び7-AAD DNAインターカレート染料を使用して、死細胞アッセイ(図示せず)も行った。前方及び側方の散乱ゲーティングを使用して、残渣を除外した。YFP陽性細胞をゲートし、参照集団として使用した。象限分析を使用して、群間のYFP発現細胞内のアネキシンV標識を特定及び定量した。同じ動物からの傷害網膜と未傷害網膜を比較することにより、対象内比較を行った。右眼におけるアネキシンVバックグラウンド標識を正規化するために、差分スコア(未傷害-傷害アネキシンV細胞数)を生成した。全てのデータを、平均の+/-1.0平均標準誤差として表現した。
眼を取り出し、角膜及びレンズを除去し、氷冷した4%のパラホルムアルデヒドに25分間浸漬した。30%のスクロース凍結保護後、眼を、OCT媒体に導入し、包埋し、クライオスタットにおいて、14ミクロンに切断し、スライドに載せた。Topro-3ヨウ化物及びDRAQ5核標識を使用して、網膜の構造及び完全性を評価した。YFP及び開裂したカスパーゼ-3の免疫標識を使用して、Thy-1レポータ動物の神経節細胞層におけるアポトーシスの初期誘導を評価した。全ての画像化を、Zeiss LSM 710共焦点顕微鏡で行った。
傷害網膜神経節細胞における初期アポトーシスのアネキシンV-PeCy7評価により、アルゴンの傷害後処置についての神経保護の役割が明らかにされる。
これらのデータは、液体麻酔薬と組み合わせて投与された場合、アルゴンが、中枢神経系内での神経保護作用を提供することを示す。この作用は、アルゴンが液体麻酔薬と同時、液体麻酔薬の前、及び/又は、液体麻酔薬に続けて投与された場合に、生じるであろうと期待される。
(参考文献)
Claims (18)
- 麻酔と臓器保護とを、それを必要とする対象に提供するためのキットであって、
常圧条件において、臓器保護を提供するのに有効な量のアルゴンである非麻酔性保護ガスと、麻酔を提供するのに有効な量の液体麻酔薬とを含む、キット。 - アルゴンが、1%から79%の間の濃度で投与される、請求項1に記載のキット。
- 液体麻酔薬が、液体の形態で投与される、請求項1または2に記載のキット。
- 液体麻酔薬が、チオペンタール、プロポフォール、ケタミン、ヒプノミデート、バルビツレート、ブプレノルフィン又はデクスメデトミジンである、請求項3に記載のキット。
- 液体麻酔薬が、静脈内に投与される、請求項3または4に記載のキット。
- 液体麻酔薬が、蒸気の状態で投与される、請求項1または2に記載のキット。
- 液体麻酔薬が、セボフルラン、イソフルラン又はデスフルランである、請求項6に記載のキット。
- 液体麻酔薬が、セボフルランである、請求項7に記載のキット。
- 非麻酔性保護ガス及び液体麻酔薬が、膜型装置によって対象に投与される、請求項6から8のいずれか一項に記載のキット。
- 非麻酔性保護ガス及び液体麻酔薬が、人工呼吸器によって対象に投与される、請求項6から8のいずれか一項に記載のキット。
- 人工呼吸器が、対象により吐き出された空気から非麻酔性保護ガスを選択的に保持、隔離又は排気する1つ又は複数のガス分離膜を備え、場合により、i)非麻酔性保護ガスが保持される場合には、非麻酔性保護ガスは、患者における更なる使用に利用可能であり、ii)非麻酔性保護ガスが隔離又は排気される場合には、非麻酔性保護ガスは、後の使用のためにその後に再捕捉される、請求項10に記載のキット。
- 液体麻酔薬と組み合わせた非麻酔性保護ガスの投与が、脳、脊髄、腎臓、肝臓及び/又は心臓に対する損傷を減少させる、請求項1から11のいずれか一項に記載のキット。
- 液体麻酔薬と組み合わせた非麻酔性保護ガスの投与が、低血糖症、低酸素血症、低酸素症、虚血、脳浮腫又は軸索切断により生じる損傷を減少させる、請求項1から12のいずれか一項に記載のキット。
- 非麻酔性保護ガス及び液体麻酔薬が、同時又は連続的に投与される、請求項1から13のいずれか一項に記載のキット。
- 液体麻酔薬及び非麻酔性保護ガスが、脳卒中のために挿管及び人工呼吸を施されている患者、心臓手術、神経系手術、場合により、全身手術又は外傷手術、場合により、衝撃性外傷、例えば、外傷性CNS傷害(脳傷害又は脊髄傷害)若しくは胴体の臓器に対する外傷性傷害を処置する外傷手術を含む手術を受けている患者に投与される、請求項1から14のいずれか一項に記載のキット。
- 非麻酔性保護ガス及び液体麻酔薬が、キセノンが存在しない状態で投与される、請求項1から15のいずれか一項に記載のキット。
- 非麻酔性保護ガス及び液体麻酔薬が、亜酸化窒素が存在しない状態で投与される、請求項1から15のいずれか一項に記載のキット。
- 非麻酔性保護ガス及び液体麻酔薬が、正常体温条件下において投与される、請求項1から17のいずれか一項に記載のキット。
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US201361867367P | 2013-08-19 | 2013-08-19 | |
US61/867,367 | 2013-08-19 | ||
PCT/CA2014/000630 WO2015024100A1 (en) | 2013-08-19 | 2014-08-19 | Non-anesthetic protective gases in combination with liquid anesthetic agents for organ protection |
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DE19833014A1 (de) * | 1998-07-23 | 2000-01-27 | Messer Griesheim Gmbh | Edelgashaltige Injektionsanästhesiemittel |
TW523409B (en) * | 2000-09-15 | 2003-03-11 | Baxter Int | Container for inhalation anesthetic |
DE10161252A1 (de) * | 2001-12-13 | 2003-06-26 | Messer Griesheim Gmbh | Injektionsanästhesiemittel in Kombination mit Xenon |
GB0418540D0 (en) * | 2004-08-19 | 2004-09-22 | Protexeon Ltd | Use |
DE102005032977B3 (de) | 2005-07-14 | 2006-12-21 | Schmidt, Klaus, Prof. Dr. | Vorrichtung und Verfahren zur Aufbereitung von Gasgemischen |
DE102006034601B3 (de) * | 2006-07-26 | 2008-02-07 | Schmidt, Klaus, Prof. Dr. | Rückhaltung von Edelgasen im Atemgas bei beatmeten Patienten mit Hilfe von Membranseparation |
US8618056B2 (en) * | 2007-12-22 | 2013-12-31 | Cuthbert O. Simpkins | Methods and compositions for treating conditions related to lack of blood supply, shock and neuronal injuries |
EP2268304A2 (en) * | 2008-03-26 | 2011-01-05 | Orthologic Corp. | Methods for treating acute myocardial infarction |
WO2010035074A1 (en) * | 2008-09-25 | 2010-04-01 | Nnoxe Pharmaceutiques Inc | Use of nitrous oxide, argon, xenon, helium, or neon, for the manufacture of a pharmaceutical composition for treating ischemic insults in patients who cannot be treated with thrombolytic agents |
FR2956323B1 (fr) | 2010-02-15 | 2013-12-20 | Air Liquide | Medicament gazeux inhalable a base d'argon contre les deficiences ou defaillances d'organes peripheriques |
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