JP2022058472A - 筋収縮を軽減するための組成物および方法 - Google Patents
筋収縮を軽減するための組成物および方法 Download PDFInfo
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- JP2022058472A JP2022058472A JP2021215484A JP2021215484A JP2022058472A JP 2022058472 A JP2022058472 A JP 2022058472A JP 2021215484 A JP2021215484 A JP 2021215484A JP 2021215484 A JP2021215484 A JP 2021215484A JP 2022058472 A JP2022058472 A JP 2022058472A
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Abstract
Description
本出願は、2017年2月2日に出願された米国特許出願第62/453,582号の優先権および利益を主張し、その内容は参照によりその全体があらゆる目的のために組み込まれる。
特に定義されない限り、本明細書で使用されるすべての技術用語および科学用語は、当業者によって一般に理解されるのと同じ意味を有する。矛盾する場合は、定義を含む本願が規制する。好ましい方法および材料を以下に記載するが、本明細書に記載のものと類似または同等の方法および材料を本発明の実施または試験に使用することが可能である。本明細書で言及されるすべての出版物、特許出願、特許および他の参考文献は、参照によりその全体が組み込まれる。本明細書で開示される材料、方法、および例は、例示のみであり、限定することを意図していない。
およびその薬学的に許容される塩。
当業者には明らかであるように、通常の熟練した臨床医または治療医は、適切な投与量およびレジメンの決定、ならびにその修正を容易に理解するだろう。
一態様では、キットが開示される。キットは、オキシムまたは薬学的に許容されるその塩および薬学的に許容される担体を含む組成物、および前記組成物をヒトに送達するための手段を含んでも良い。一態様では、オキシムは、1またはそれ以上の前記オキシムまたはその薬学的に許容される塩であっても良い。一態様では、オキシムはMMB4であっても良い。キットの組成物は、外科的目的のために個体への静脈内投与用に処方されても良い。
出願人は、モデル開発を調査し、神経筋(横隔膜および骨格)、肺、および心血管の変化を評価して、MMB4 DMSおよび臨床関連コンパレーター(オキシム)、塩化プラリドキシム(2-PAM)の両方の投与の効果を決定した。全体として、イソフルラン麻酔された機械的に換気された麻酔ウサギは、横隔膜および骨格筋機能の変化ならびに全身/左心室血行動態の変化を検出するために装備された。このin vivo/in situウサギ製剤は、安定性があり(最大8時間)、ベラパミルまたはシストラクリウムのいずれかによって引き起こされる独立した心血管/神経筋の変化に反応することが示されたため、この製剤を活用して効果を検出できたマイムの管理に続く。
エクスビボ実験では、MMB4 DMSを組織浴で投与すると、高濃度で横隔膜収縮性を直接抑制できることが示されました。出願人は以前にin vivo/in situ麻酔/換気ラット製剤を確立および検証し、横隔膜機能(うつ病)に対する2-PAMの効果を実証した。
動物は、フェンタニル(5pg/kg IVボーラス)およびケタミン(10mg/kg IVボーラス)で鎮静/麻酔された。気管内挿管に続いて、フェンタニル(45pg/kg/hr)とケタミン(9mg/kg/hr)を吸入イソフルランと併用して持続点滴静注することにより、心血管および神経筋機器に必要な麻酔の手術面に、(1.5~2.5%)陽圧小動物人工呼吸器を介して100%02で送達(呼気対呼気比1:2で30-35mL/呼吸で約30-35呼吸/分に設定)で到達した。このモデルでは、部分的な静脈麻酔/鎮痛(フェンタニル/ケタミン)と吸入剤(イソフルラン)の組み合わせが使用され、心血管/呼吸の安定性と、研究/モデルの目的に合わせて、自発呼吸ドライブが提供された。動物は、フェンタニル(5pg/kgIVボーラス)およびケタミン(10mg/kgIVボーラス)で鎮静/麻酔された。気管内挿管に続いて、フェンタニル(45pg/kg/hr)とケタミン(9mg/kg/hr)を吸入イソフルランと併用して持続点滴静注することにより、心血管および神経筋機器に必要な麻酔の手術面に、(1.5~2.5%)陽圧小動物人工呼吸器を介して100%02で送達(呼気対呼気比1:2で30-35mL/呼吸で約30-35呼吸/分に設定)で到達した。このモデルでは、部分的な静脈麻酔/鎮痛(フェンタニル/ケタミン)と吸入剤(イソフルラン)の組み合わせが使用され、心血管/呼吸の安定性と、研究/モデルの目的に合わせて、自発呼吸ドライブが提供された。
麻酔中に、中核体温(例えば、直腸温プローブを介して)、単一リードECG(リードII)、およびパルスオキシメトリーを監視した。左心室(LV)の圧力は、大動脈弁を越えて逆行性LVに進められた高忠実度のマイクロマノメーターカテーテルで記録されました。動脈圧は、大腿動脈に進められた液体充填カテーテルで記録されました。気管内ピーク圧(ITP)は、気管チューブに接続された圧力変換器を介して監視された。機械的に補助された(一回換気量)換気を考えると、そのような圧力は静的な肺硬直の代用として使用できる。
これらの実験では、以下の入力基準が満たされた場合、調製物は許容可能とみなされた;1)解釈に十分な品質の心血管、呼吸、および神経筋信号;2)ベースラインでの十分な横隔膜(発達力>g)および骨格筋(発達力>3g)の機能、および3)正常な心臓生理学(平均全身圧>50mmHg、dP/dtmax>1500mmHg/s、および心拍数>200bpm<350bpm)。
心血管および/または骨格線条体/横隔膜機能に対する独立した変化を評価する調製物の能力を実証するために、1)非脱分極筋弛緩薬(シストラクリウム)、または2)心臓チャンネルの毒性用量のいずれかに対する応答心血管虚脱を引き起こすブロッカー(ベラパミル)を評価した。予想通り、ベラパミル(3つの0.2mg/kg IVボーラス)は、誘発された顕著な心血管の変化を用量依存的に減少させ(表3および図4を参照)、体圧が低下、充満圧が上昇、および拡張期心機能(スロータウ)ばかりでなく、両方の収縮期の指数(例えば、dP/dtmax)が低下した。同様に、ベラパミルは横隔膜収縮を適度に抑制したが、骨格筋機能への影響は無視できた(表3および図4を参照)。これらの発見は、ベラパミルのCa2+チャネル遮断薬の特性と一致し、文献と一致する(例、Su、1988)。
出願人は、ラット横隔神経横隔膜調製物を開発し、収縮振幅および潜在的な神経筋接合部抑制に対するMMB4 DMSの効果を評価した。横隔神経横隔膜筋標本を使用して、横隔膜筋収縮を測定する機能評価を評価した。モデルの安定性を決定する時間制御は、最大3時間の連続刺激測定によって評価された。アセチルコリンエステラーゼ阻害薬(ネオスチグミン)およびニコチン性コリン作動性受容体アゴニスト(ニコチン)は、筋肉刺激のポジティブコントロールとして機能した。ニコチン性アセチルコリン受容体拮抗薬(d-ツボクラリンクロリド)は、筋肉抑制のポジティブコントロールとして機能した。ムスカリン、ムスカリン性コリン作動性受容体アゴニストは、筋肉刺激のネガティブコントロールとして機能した。別の設定;1)単独、2)刺激なしの単独、または3)d-ツボクラリンによる50%減少中でMMB4 DMS(10-7~10-2M)を使用して同じ手順を実行した。さらに、補助的な目的は、ネオスチグミンの追加により機能を調節できるかどうかを判断することだった。メタンスルホン酸ナトリウムの用量反応も、MMB4 DMSの同様の濃度で評価された。各製剤について、投与前の60分間ベースラインを収集した。垂直の横隔膜神経横隔膜の準備では、収縮力を最小限に抑え、強化、弱化、または変化させる試験品を検出できた。MMB4 DMSによる二相性効果の刺激部分は、おそらくAChEに対する直接的な阻害効果である。AChE阻害剤(ネオスチグミン)の追加は、収縮振幅が50%減少したときにMMB4 DMSを部分的に救助したため、高用量で観察された閉塞は、持続的な脱分極による脱感作の結果ではなく、おそらく受容体でのニコチン拮抗作用、または受容体にリンクされたイオンゲートチャネルレベルによるものであった。SMSは機能的効果を誘発しなかったため、MMB4の機能的効果は対イオンDMSによるものとは考えられていない。
試験物品:MMB4 DMS(メチレンビス{4-[(ヒドロキシイミノ)メチル]-ピリジニウム}ジメタンスルホネート);製剤:MMB4 DMSは蒸留水で調製し、調製後20日以内に使用した;濃度:1pMから10mMの目標濃度を得るために、試験品を3mMまたは1Mの濃度に調合した。保管条件:試験品は室温で保管された。ロット番号:1004
蒸留水:N/A
クレブスヘンゼルレイト緩衝液9.6g/L
NaHCO3 2.1g/L
CaCl2(99%)0.2g/L
保管条件:クレブスは製造業者の指示に従って保管された。未使用の際、処方されたクレブス液は、2~8℃の温度を維持するように設定された冷蔵庫に保存された。
投与経路:
すべての試薬は、ピペットを介して30mLのクレブスを含む器官浴に直接投与した。
横隔神経横隔膜筋標本を使用して、横隔膜筋収縮を測定する機能的評価を評価した。モデルの安定性を決定する時間制御は、最大3時間の連続刺激測定によって評価された。調査期間中、変数は15分ごとに評価された。これらの値は、時間制御として使用され、準備における収縮の時間依存の減少を補正した。実験セットアップの妥当性を確認するために、コントロールが研究された。アセチルコリンエステラーゼ阻害薬(ネオスチグミン)およびニコチン性コリン作動性受容体アゴニスト(ニコチン)は、筋肉刺激のポジティブコントロールとして機能した。ニコチン性アセチルコリン受容体拮抗薬(d-ツボクラリンクロリド)は、筋肉抑制のポジティブコントロールとして機能した。ムスカリン、ムスカリン性コリン作動性受容体アゴニストは、筋肉刺激のネガティブコントロールとして機能した。別の設定;1)単独、2)刺激なしの単独、または3)d-ツボクラリンによる50%減少中でMMB4 DMS(10-7~10-2M)を使用して同じ手順を実行した。さらに、補助的な目的は、ネオスチグミンの追加により機能を調節できるかどうかを判断することだった。メタンスルホン酸ナトリウムの用量反応も、MMB4 DMSの同様の濃度で評価された。各製剤について、投与前の60分間ベースラインを収集した。エスカレートする用量の試験試薬または物品は、累積的に15分ごとに臓器浴にピペットで入れられた。他の用量とは異なり、ネオスチグミンの用量の間にウォッシュアウトが必要であったことを注意するべきである。
ラットをケタミン/キシラジンの組み合わせ(-45/-5mg/kg IP;および必要に応じてイソフルラン[1~3%]、マスクを介して)で麻酔し、背部に剃毛し、気管内挿管した。気管切開、および換気(-90呼吸/分、2.5%換気量95%/5%[O2/CO2])、調整可能な小動物用人工呼吸器(ハーバード装置)。麻酔の手術面が確立されると(すなわち、つま先のピンチ反射がない)、胸腔が開かれ、横隔膜の下およびラットの脇腹の周りを横に切ることにより横隔膜が隔離された。左横隔神経は、アクセシビリティのためにこの準備でより一般的に使用されるため、左神経のみが除去された。神経横隔膜を胸部から取り出し、ジャケット付きの皿にすばやく置き、加温した修正クレブス溶液(-37°C)を含む水浴に引っ掛けた。
皿において、2つの3-0から4-0の絹縫合糸を横隔膜の中央結合組織に結び付け、電極ホルダーの2つの別個の穴を通して縫合した。別の3-0から4-0の絹縫合糸をinter間筋に貼り付けた。神経を電極の上に置いた。ホルダー/筋肉神経を皿から持ち上げて、オルガンバスに入れた。垂直に取り付けられた筋肉をピンと張って引っ張り、筋肉を電極ホルダーに接続した2本の縫合糸の間にしっかりと吊し、ひずみゲージに取り付けた間筋を通して縫合した。張力調整装置を使用して、受動的な力は1.5グラムに設定された。浴には、37℃で95%/5%[O2/CO2]でガス処理したクレブス液が含まれた。横隔神経は、0.2Hz、2Vで刺激された。
筋収縮に関するデータをデジタルで取得し(I0X;EMKA Technologies)、オフラインで分析した。すべてのデータ記録は、QTest Labsの標準操作手順に従って試験/動物番号とともに日付/ラベルが付けられ、別々のコンピューターに複製で保存された。全ての場合において、追加の計算(必要な場合)はスプレッドシート(Microsoft Excelなど)で実行された。データ(すべての時間/グループ)は、標準エラーを含む手段として提示する。
全体として、60個の左横隔神経横隔膜調製物が使用された。被験物質の評価の前に、製剤を開発し、製剤の収縮の時間依存性減少を決定するために、時間制御実験(薬理学的介入なし)を最初に行った(図8)。
続いて、正および負の対照の両方を使用して、横隔神経刺激を介して横隔膜収縮を正確かつ正確に測定する能力を実証した。分析では2つのエンドポイントパラメーターが使用されました。筋収縮の振幅とその最大上昇率。
筋肉抑制を検出する能力を調査するために、確立されたニコチン性コリン作動性受容体アンタゴニストであるd-ツボクラリンを評価した。表6および図9に示すように、d-ツボクラリンは用量依存的な効果をもたらし、筋肉収縮の0.6%および最大変化率の0.64pMの50%抑制濃度(IC50)で筋肉収縮および最大変化率を減少させた。
筋収縮に対する正の効果を検出する能力を調査するために、ニコチン、ニコチン性コリン作動性受容体アゴニスト、およびネオスチグミン、アセチルコリンエステラーゼ阻害剤の両方を評価した。全体として、低用量のニコチン(0.3および3pM)は、収縮および最大変化率にプラスの効果があるように見えた(表7および図10)。
収縮に対する効果の欠如を調査するために、ムスカリン性コリン作動性受容体アゴニストを評価した。表9および図12に示すように、ムスカリンは力の最小またはわずかな減少、および最大変化率を示した。
インビトロラット横隔神経横隔膜筋標本における神経筋接合部に対するMMB4 DMSの効果を決定するために、1pMから10mMの範囲の用量を評価した。表10および図13に示されるように、MMB4 DMSは用量依存効果をもたらした。
MMB4 DMS(メタンスルホン酸ナトリウム、SMS)のビヒクル対イオンが何らかの機能効果を有するかどうかを判定するために、MMB4 DMSと同様の濃度でSMSを試験した。表14と図23に示すように、SMSは機能に最小限の影響しか与えませんでした。
Naguib M and Lien CA."Pharmacology of Muscle Relaxants and Their Antagonists".Chapter 29, pp 859-911.Miller’s Anesthesiology (edited by Ronald D.Miller;consulting editors LI Eriksson,LA Fleisher,JP Wiener-Kronish, WL Young),7th edition,Published by Churchill,Livingstone,Elsevier;2010.
Foldes,FF,McNall PG,Borrego-Hinojosa JM:Succinylcholine,a new approach to muscular relaxation in anaesthesiology.N Engl J Med 247:596-600,1952.
Claims (10)
- それを必要とする個体において神経筋遮断を誘発するための薬剤であって、オキシムまたはその薬学的に許容される塩を含む、薬剤。
- 請求項1記載の薬剤において、前記オキシムは、
(メトキシムまたは「MMB4」)、
(トリメドキシムまたは「TMB-4」または1,3-ビス(5-ヒドロキシイミノメチルピリジニウム)-プロパンブロミド))、
(プラリドキシムまたは「2-PAM」または2-ヒドロキシイミノメチル-1-メチルピリジニウムクロリド)、
(オビドキシムまたは[1,3-ビス(4-ヒドロキシイミノ-メチルピリジニウム)-2-オキサプロパン)、
(「HI-6」または[1-(2-ヒドロキシイミノメチルピリジニウム)-3-(4-カルバモイルピリジニウム)-2-オキサプロパンクロリド]、
(「HLo-7」または(1-[2,4-ビス(ヒドロキシイミノメチルピリジニウム)]-3-(4-カルバモイルピリジニウム)-2-オキサプロパンクロリド)、
(「K027」または[1-(4-ヒドロキシイミノメチルピリジニウム)-3(4-カルバモイルピリジニウム)-プロパンブロミド]、
およびそれらの薬学的に許容される塩、好ましくはMMB4またはそれらの薬学的に許容される塩の1またはそれ以上から選択される、薬剤。 - 請求項1または2記載の薬剤において、前記それらの薬学的に許容される塩は、二塩化物またはジメタンスルホン酸塩から選択される、薬剤。
- 請求項1~3のいずれかに記載の薬剤であって、神経筋遮断薬、健忘薬、鎮痛薬、唾液分泌抑制薬、およびそれらの組み合わせから選択される薬剤をさらに含む、薬剤。
- 請求項1~4のいずれかに記載の薬剤において、前記薬剤は、静脈内、非経口、筋肉内、またはそれらの組み合わせから選択される経路を介した投与に適する、薬剤。
- 請求項1~5のいずれかに記載の薬剤において、前記オキシムは、薬学的に許容される担体において、約25~約500mg/mL、または約50~約250mg/mLまたは約100mg/mLのオキシムを含む組成物中に存在する、薬剤。
- キットであって、
a.オキシムおよび薬学的に許容される担体を含む組成物と、
b.前記組成物をヒトに送達する手段と、
を有する、キット。 - 請求項7記載のキットにおいて、前記オキシムは、MMB4、TMB-4、2-PAM、オビドキシム、プラリドキシム、HI6、HLo-7、およびそれらの薬学的に許容される塩、好ましくはMMB4から選択される、キット。
- 請求項7または8記載のキットにおいて、前記組成物は、外科目的のために個体への静脈内投与用に処方される、キット。
- 製造品であって、
a.ラベルを含む容器と、
b.オキシムを含む組成物であって、好ましくは、MMB4、TMB-4、2-PAM、オビドキシム、プラリドキシム、HI6、HLo-7、およびそれらの薬学的に許容される塩、より好ましくはMMB4から選択されるオキシムを含む組成物、および薬学的に許容される担体と、
を有し、前記ラベルが前記組成物は外科的処置の前および/または間に個人に投与されるべきであることを示す、製造品。
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