JP2020059746A - ハロアルキルアミンを用いた神経細胞死の低減方法 - Google Patents
ハロアルキルアミンを用いた神経細胞死の低減方法 Download PDFInfo
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Abstract
Description
本出願は、U.S. Provisional Patent Application No. 61/874,865, 2013年9月6日出願に基づく優先権を主張し、その出願の開示内容を本明細書に援用する。
本出願は、外傷性脳損傷(TBI)および/または中枢神経系における一過性低酸素/虚血状態を伴なう被験体を処置するための、ハロアルキルアミン、たとえばフェノキシベンザミンを含む医薬組成物に関する。そのような状態は、神経細胞に酸化的損傷、アポトーシスまたはネクローシスを生じる可能性がある。開示する医薬組成物および方法は、これらの状態から生じる神経細胞の損傷または死の発生を低減する。
過性低酸素および/または虚血状態を処置する方法であって、その必要がある被験体に療法有効量のハロアルキルアミンを投与することを含む方法に関する。TBI事象には、たとえばむち打ち(whiplash)、爆風(blast wave)衝撃、および鈍器(blunt force)外傷が含
まれ、その際、それらの事象は神経細胞の損傷または死を引き起こすのに十分な力のものである。
キルアミン誘導体をアドレナリン作動性関連効果について試験した(Iversen L.L. et al., Inhibition of catecholamine uptake in the isolated heart by haloalkylamines related to phenoxybenzamine, Br. J. Pharmac, (1972) 46:647-657;たとえば pp. 650 - 651の表1および2を参照)。フェノキシベンザミンまたは他のハロアルキルアミンを溶液中に入れた際に自然に形成される化学的環化生成物も本発明の範囲に含まれる(たとえば、Adams and Kostenbauder, Phenoxybenzamine stability in aqueous ethanolic solutions. II. Solvent effects on kinetics, International J of Pharmaceutics, (1985) 25:313-327を参照)。上記2刊行物中の化合物およびそれらの構造式の開示を本明細書に援用する。
神経細胞の損傷または死の発生を阻止することにより神経保護効果を及ぼし、それには中枢神経系の神経細胞、たとえば神経脳細胞における酸化的損傷、アポトーシス、および/またはネクローシスの発生を低減することが含まれる。
キシカム(lomoxicam)、ロキソプロフェン(loxoprofen)、メクロフェナム酸(meclofenamic
acid)、メフェナム酸(mefenamic acid)、メロキシカム(meloxicam)、メサラミン(mesalamine)、メチアジン酸(metiazinic acid)、モフェゾラク(mofezolac)、モンテルカスト(montelukast)、ミコフェノール酸(mycophenolic acid)、ナブメトン(nabumetone)、ナプロキセン(naproxen)、ニフルム酸(niflumic acid)、ニメスリド(nimesulide)、オルサラジン(olsalazine)、オキサセプロル(oxaceprol)、オキサプロジン(oxaprozin)、オキシフェンブタゾン(oxyphenbutazone)、パラセタモール(paracetamol)、パルサルミド(parsalmide)、ペリソキサール(perisoxal)、アセチル−サリチル酸フェニル、フェニルブタゾン(phenylbutazone)、サリチル酸フェニル、ピラゾラク(pyrazolac)、ピロキシカム(piroxicam)、ピルプロフェン(pirprofen)、プラノプロフェン(pranoprofen)、プロチジン酸(protizinic acid)、レスベラトロール(resveratrol)、サラセタミド(salacetamide)、サリチルアミド、サリチルアミド−O−アセチル酸、サリチル硫酸(salicylsulphuric acid)、サリシン(salicin)、サリチルアミド、サルサレート(salsalate)、スリンダク(sulindac)、スプロフェン(suprofen)、スキシブタゾン(suxibutazone)、タモキシフェン(tamoxifen)、テノキシカム(tenoxicam)、テオフィリン(theophylline)、チアプロフェン酸(tiaprofenic acid)、チアラミド(tiaramide)、チクロプリジン(ticlopridine)、チノリジン(tinoridine)、トルフェナム酸(tolfenamic acid)、トルメチン(tolmetin)、トロペシン(tropesin)、キセンブシン(xenbucin)、キシモプロフェン(ximoprofen)、ザルトプロフェン(zaltoprofen)、ゾメピラク(zomepirac)、トモキシプロール(tomoxiprol)、ザフィルルカスト(zafirlukast)、ロフェコキシブ(rofecoxib)およびサイクロスポリン(cyclosporine)。さらに、The Merck Manual, 16th Edition, Merck Research Laboratories (1990) pp 1308-1309、およびThe Pharmacological Basis of Therapeutics, 9th edition, Macmillan Publishing Co., 1996, pp 617-655には周知のNSAIDの例が提示されている。
と共有(不可逆的)結合を形成し、それによって、処置した組織または臓器の脈管へのアドレナリン性伝達を持続的に遮断する。伝達は脈管において受容体が再合成されるまで遮断され、それは数日間、1週間、またはそれ以上かかると思われる。現在入手できる他のα アドレナリン受容体アンタゴニストはいずれもこの特性をもたない。それらは受容体との可逆的相互作用により作用する。その結果、それらの効果は薬物が全身循環により消失するのに伴なって漸減する(24時間の半減期)。ハロアルキルアミンの限定ではない例は、フェノキシベンザミンおよびジベナミンである。
Pharmaceutical)はα−1およびα−2両方のアドレナリン受容体を遮断するハロアルキルアミンであるが、α−1受容体に対して、より高い親和性をもつ。静脈内投与後、受容体拮抗は約1時間目にピーク効果に達する。フェノキシベンザミンは脳において約24時間の半減期をもつ持続的効果を及ぼす。先の研究で、フェノキシベンザミンの効果の反転は新たな受容体の合成に依存し、その薬物の半減期に依存するのではないことが示された。Hamiltonらは、フェノキシベンザミンの単回投与の8日後に50%のα−1受容体が回復したにすぎないことを証明した(J Cardiovasc Pharmacol (1983) 5(5):868-873)。有利なことに、フェノキシベンザミンの副作用はきわめて小さい:鼻詰まり、軽度の傾眠、かすみ目、および胃のむかつき。
される中枢神経系における一過性低酸素および/または虚血状態を処置する方法を提供する。そのような処置は、TBIを伴なう被験体において神経細胞の損傷または死の発生を低減できる。他の態様において、本発明はSCI事象により引き起こされる中枢神経系における一過性低酸素および/または虚血状態を処置する方法を提供する。そのような処置は、SCIを伴なう被験体において神経細胞の損傷または死の発生を低減できる。
一般に、完全脊髄損傷は、損傷部位より下の感覚および運動能力の完全喪失を生じる。
−セカール症候群(Brown-Sequard syndrome)、個々の神経細胞に対する損傷、および脊髄挫創。前脊髄症候群は、脊髄の前部における運動経路および感覚経路に対する損傷から生じる。影響には運動能力および感覚全般の喪失が含まれるが、なお無傷の経路を経由して伝わる若干の感覚は感じられる可能性がある。中心性脊髄症候群は、頚髄領域の中心に対する損傷から生じる。この損傷は、運動を制御するための脳と脊髄の間の信号伝達に関与する皮質脊髄路に影響を及ぼす。中心性脊髄症候群に罹患している患者は腕の脱力感または麻痺を経験し、若干の感覚受容喪失をも経験する。強度および感覚の喪失は腕より脚の方がはるかに少ない。中心性脊髄症候群を伴なう患者の多くは運動機能が自然に回復し、他は損傷後の最初の6週間でかなりの回復を経験する。ブラウン−セカール症候群は、脊髄の右側または左側に対する損傷から生じる。損傷が起きた側の身体では、損傷部位より下方で運動能力および感覚が喪失する。損傷の反対側では温度感覚および痛覚が喪失する;これらの経路は脊髄内で交差しているためである。個々の神経細胞に対する損傷は、損傷を受けた神経根が対応する身体領域の感覚機能および運動機能の喪失を生じる。したがって、これらの損傷からの症状は影響を受けた神経根の位置および機能に応じて変動する。脊髄挫創は最も一般的なタイプの脊髄損傷である。脊髄挫創では、脊髄が打撲傷を受けているけれども切断されてはいないので、一次結果は損傷部付近の炎症および血管からの出血である。脊髄挫創は一時的な(通常は1〜2日間)不完全または完全な衰弱(debilitation)を生じる可能性があり、あるいは脊髄の不完全衰弱または完全衰弱は脊髄の永続的な不完全衰弱または完全衰弱を含めてより長期間になる可能性がある。
、ある有効成分の分解が促進される可能性がある。
ース、α化デンプン、ヒドロキシプロピルメチルセルロース(たとえば、No.2208、2906、2910)、微結晶性セルロース、およびその混合物が含まれるが、これらに限定されない。
ニルピロリドン、ステアリン酸、コロイド状無水シリカ、およびゼラチンを含む。
非経口剤形は、皮下、静脈内、ボーラス注射、筋肉内、および動脈内を含めた(これらに限定されない)種々の経路により患者に投与できる。好ましくは、非経口剤形は静脈内送達に適切である。本発明の非経口剤形は好ましくは無菌であるか、あるいは患者に投与する前に殺菌することができる。非経口剤形の例には、注射できる状態の液剤、医薬的に許容できる注射用ビヒクルに溶解または懸濁できる状態の乾燥製剤、注射できる状態の懸濁液剤、および乳剤が含まれるが、これらに限定されない。
データセットについては、対応のない片側T検定(unpaired, one-tailed T-test)を用い
て適宜なパラメトリック解析を実施した(CI=95%)。2より多いグループを含むデータセットについての解析は、1元ANOVAをテューキーの事後検定(Tukey’s post-hoc)と共に用いてグループ間の統計学的有意性を決定した。p<0.05以下を有意とみなした。
海馬切片培養:
すべての実験動物操作は、米国国立衛生研究所、実験動物の管理と使用に関する指針(National Institutes of Health guide for the care and use of Laboratory animals) (NIH Publications No. 8023)に従ってモンタナ大学動物実験委員会(University of Montana Institutional Animal Care and Use Committee)により承認された。先の記載に従って7日齢Sprague−Dawley仔ラットの脳から海馬切片培養物を調製した(Selkirk et al., 2005, Eur J Neur 21:2291)。培養7日後に、切片を酸素−グルコース枯渇(OGD)曝露した。120mM NaCl、5mM KCl、1.25mM NaH2PO4、2mM MgSO4、2mM CaCl2、25mM NaHCO3、20mM HEPES、25mMスクロースからなる無グルコース緩衝塩類溶液(BSS);pH7.3に、5% CO2/95% N2を10L/時で1時間吹き込んだ。切片を脱酸素SBSS中で6回洗浄して残存グルコースを除去し、脱酸素SBSS中へ移し、0.1% O2、5% CO2、94.4%窒素のガスレベルを維持した37℃のフィードバックセンサー付きチャンバー(Pro−Ox)に60分間入れた。OGD後に、切片を直ちに正常酸素条件下の予熱したNeurobasal培地(B27を含有,抗酸化剤を含まない)へ戻した。用量応答試験においてフェノキシベンザミンで処理した切片は、OGD直後に、0.1μM〜1mMのフェノキシベンザミンを含有する予熱したNeurobasal培地中に置かれた。タイムコース試験については、OGD後2、4、8、または16時間目に100μMフェノキシベンザミンを添加した。神経損傷は、切片をヨウ化プロピジウム(PI;Molecular Probes,オレゴン州ユージーン)で染色し、ImagePro Plusソフトウェア(Media Cybernetics,メリーランド州シルバースプリングズ)を用いて相対蛍光強度(励起540/発光630)を定量することにより判定された。ヨウ化プロピジウム(PI)は、2μMの濃度で(Noraberg et al., 1999, Brain Research Protocols 3:278)、OGDの4時間前に培地に添加された。ベースライン蛍光を設定するためにOGD前に海馬切片のイメージを撮影した。OGD後に、2μMのPIを含有する普通培地中に切片を置き、OGD後24時間目にオリンパスIMT−2顕微鏡および浜松カメラによる蛍光光度法を用いて再びイメージ撮影した。ImagePro Plusソフトウェア(Media Cybernetics,メリーランド州シルバースプリングズ)を用いて各切片の総蛍光強度を決定し、すべての数値をOGD曝露した非処理切片からの変化率パーセントとして表わした。
ラット海馬切片培養(RHSC)−OGDモデルにおける本発明者らの試験は、フェノキシベンザミンを有効な神経保護薬候補化合物として同定した。本発明者らはさらにフェノキシベンザミンをRHSC−OGDモデルにおいて用量応答試験の実施により試験した。フェノキシベンザミンはCA1、CA3および歯状回内の一次神経細胞を保存し、広い用量範囲にわたって(0.1uM〜1mMの最終培地濃度)強い神経保護効果を生じた(図1)。神経保護化合物は臨床関連時点で投与した際に有効でなければならず、それは脳卒中または外傷性脳損傷の症例では損傷の多数時間後である可能性がある。したがって、本発明者らはフェノキシベンザミンの有効療法ウインドウをRHSC−OGDモデルにおいて調べた。中間用量(100μM)を選択し、OGD後2、4、8、または16時間目に培地に添加した。本発明者らは、OGD後2、4、および8時間目に送達した場合にフェノキシベンザミンが海馬の全領域でOGDから神経細胞死を阻止することを見出した。OGD後16時間目に送達した場合、フェノキシベンザミンは海馬のCA1領域においてのみ神経細胞死を阻止した(図2)。これらのデータは、フェノキシベンザミンが有効な神経保護薬として作用する可能性があることを強く示唆した。
神経学的重症度スコアリング:
神経学的重症度スコアリング(NSS)を先の記載に従って実施した(Rau et al., 2011, Neuropharmacology 61:677; Rau et al., 2012 J Trauma and Acute Care Surgery 73:S165)。査定は1、7、14、21、および30日目に盲検観察者により行なわれた。動物を0から16までスコアリングし、0は障害なしを示し、16は最大障害を示す。重篤なTBIについてのスコアリング基準は16〜10であり、中等度のTBIは9〜5であり、軽度のTBIは4〜1であった。1日目に9以下のNSSとスコアリングされた動物を中等度/軽度の損傷を伴なうと同定し、除外した。
フットフォールト査定を先の記載に従って実施した(Rau et al., 2011, Neuropharmacology 61:677; Rau et al., 2012 J Trauma and Acute Care Surgery 73:S165)。簡単に述べると、ラットを高い位置にあるグリッドに置いた。体重がかかる歩行毎にワイヤグリッドから足が落ちるかまたは滑り落ちる可能性がある。左前足(右脳半球に対する損傷の影響を受けている)をワイヤラックに置き損なう毎に、それをフットフォールトとして記録した。ラットがグリッドを渡るのに使った総歩数(各前足の移動)を計数し、かつ各前足についてのフットフォールトの総数を記録した。
フェノキシベンザミンの療法効力を試験するために、本発明者らはラット横方向流体パーカッション損傷(LFP)を重篤なTBIの in vivo モデルとして選択した。本発明者らは現在のFDA承認レベルに基づいてフェノキシベンザミンの試験用量を選択した。フェノキシベンザミンは通常は最大40mgで1日3回(合計120mg)投与される。一般的成人の体重を70kgと仮定すると、これは1.7mg/kg(体重)になる。したがって、本発明者らはこれよりわずかに低い1mg/kg(体重)の静脈内単回量を選択した。この用量を重篤なTBI後8時間目の臨床関連時点で投与した。行動転帰および認知転帰に基づいて療法有効性を判定した。
認知機能の査定:
モーリス水迷路(MWM)を用いて、フェノキシベンザミンがTBI後の認知機能(学習能力および記憶力)に及ぼす影響を査定した。この査定法は先に公表されたものに従って実施された(Rau et al., 2011, Neuropharmacology 61:677; Rau et al., 2012 J Trauma and Acute Care Surgery 73:S165)。予備順化(pre-acclimation)をTBI後24日目に開始した。トレーニング期を損傷後25日目に開始し、探査試験(probe trial)を損傷後30日目に開始した。
モーリス水迷路(MWM)を用い、損傷後25日目に開始して認知機能を査定した。TBIの8時間後のフェノキシベンザミン投与は、トレーニング期の2、3、4、および5日目に学習能力の有意の改善を生じた(図4A)。驚くべきことに、フェノキシベンザミン処理動物はいずれのトレーニング日においても非損傷偽対照動物と有意差がなかった。これらのデータは、重篤なTBI後にフェノキシベンザミンが学習能力を劇的に改善する
ことを示唆する。学習能力のほかに、探査試験を実施して空間記憶機能を査定した。探査試験に際して、フェノキシベンザミン処理動物は生理食塩水処理対照より有意に大きな空間記憶容量を示した(図4B)。10%の時間だけ目標の四分円内にいた生理食塩水処理対照と比較して、フェノキシベンザミン処理動物はそれらの探査時間の約28%を、取り除かれた脱出プラットフォームを求めて目標の四分円内で過ごした。トレーニング期のように、フェノキシベンザミン処理したTBI損傷動物は、同様にそれらの探索時間の約25%を目標の四分円内で過ごした非損傷偽対照と差がなかった(図4B)。
フェノキシベンザミン仲介による神経保護に関与する可能性のある神経保護機序を明らかにするために、本発明者らは損傷の32時間後の動物から採取した皮質組織の遺伝子アレイ解析を実施した(処理まで8時間の遅れ+処理後24時間)。二次損傷の発生に影響を及ぼすと思われる遺伝子変化を検出するためにこの時点を選択した。本発明者らは重篤なTBI後に炎症性シグナル伝達タンパク質の発現における有意の増大を検出した:CCL2(11倍,p=0.004)、IL1β(4.6倍,p=0.005)およびMyD88(3倍,p=0.0001)。対照的に、重篤なTBI後にフェノキシベンザミンで処理したラットはこれらのタンパク質の発現に有意の増大がなかった。これらのデータは、フェノキシベンザミンが神経炎症反応を調節することにより神経保護を仲介する可能性があることを示唆する。
漿エピネフリンおよびノルエピネフリンのレベルと、回復率との直接相関性を示唆する(Tran et al., 2008)。持続的昏睡状態にある患者はエピネフリンおよびノルエピネフリンの血漿レベルが対照より数倍高い。さらに、これらのカテコールアミンのレベルは昏睡状態の期間中、高いままである。逆に、初期カテコールアミンレベルの上昇が軽度であるTBI患者はTBI後1週目に11より大きなグラスゴー・コーマ・スケール(Glasgow Comma Scale)(GCS)値にまで一貫して改善することが見出された。多系統の外傷およびTBIを伴なう患者において損傷後48時間目の血漿ノルエピネフリンレベルは1週目のGCS、患者生存率、呼吸器装着日数、および入院期間を予測するが、TBIを伴なわない場合はこれらの関係は存在しなかった(Woolf 1987, Hamill 1987) (Woolf 1988)。
レイ解析から、生理食塩水処理動物はTBI後にIL−1βが有意に増加し、これに対しフェノキシベンザミン処理動物は有意の増加がないことを見出した。TBIに関して、IL−1βはミクログリアの主要アクチベーターであり、炎症の誘発に直接関与する。IL−1βはさらに、NMDA受容体および腫瘍壊死因子アルファ(TNF−アルファ)の感受性を増大させて脳の炎症および興奮毒性を増大させることにより、免疫興奮毒性に寄与する(Arand et al., 2001; Block et al., 2007; Brown and Neher, 2010)。
より外傷後炎症を低減できる。Myd88は、Toll様受容体および炎症性サイトカインシグナル伝達に関係する鍵アダプタータンパク質である(Li et al., 2011; Ling et al., 2013)。生理食塩水処理TBI動物において、Myd88は非損傷対照より有意にアップレギュレートされていた。しかし、TBI後にフェノキシベンザミン処理したラットでは、MyD88発現レベルは非損傷対照と同等であった。機序的に、Myd88はToll様受容体、サイトカイン、および核内因子カッパB(NF−κB)に対する鍵アダプタータンパク質である(Li et al., 2011; Janssens and Beyaert, 2002)。先の研究は、Toll様受容体の活性化は、結果的にMyd88の動員およびそれに続くNF−κB活性化を生じ、次いでそれが腫瘍壊死因子a(TNF−a)、IL−1β、インターロイキン−6(IL−6)、および細胞接着分子1(intracellular adhesion molecule-1)(ICAM−1)を含めた炎症性分子の急速な発現を誘発して炎症反応をもたらすことを示唆する(Janssens and Beyaert, 2002; Kenny and O’Neill, 2008)。
Arand M, Melzner H, Kinzl L, Bruckner UB, Gebhard F. Early inflammatory mediator
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Claims (39)
- 中枢神経系における一過性低酸素および/または虚血状態を伴なう被験体を処置する方法であって、被験体に療法有効量のハロアルキルアミンを投与することを含む前記方法。
- さらに、被験体が一過性低酸素および/または虚血状態を伴なったことがあり、その状態により引き起こされる神経細胞死のリスクをもつと判定することを含み、その状態が低血圧、失血、心臓発作、外傷性脳損傷(TBI)、脊髄損傷(SCI)、窒息、外科処置、脳卒中、脊髄梗塞、虚血性視神経障害、気道閉塞、または新生児の低酸素もしくは虚血により引き起こされる、請求項1に記載の方法。
- 外傷性脳損傷(TBI)事象を処置する方法であって、療法有効量のハロアルキルアミンを投与することを含む方法。
- さらに、被験体がTBI事象を伴なったことがあり、神経細胞死のリスクをもつと判定することを含み、TBI事象がむち打ち、爆風衝撃、および鈍器外傷からなる群から選択される、請求項3に記載の方法。
- ハロアルキルアミンが被験体における神経細胞死の発生を低減する、請求項1〜4のいずれか1項に記載の方法。
- ハロアルキルアミンが被験体の線条体、海馬、または皮質における神経脳細胞死の発生を低減する、請求項4に記載の方法。
- そのリスクをもつ被験体の中枢神経系における神経細胞死の発生を低減する方法であって、被験体の中枢神経系における神経細胞死を低減するのに十分な量のハロアルキルアミンを被験体に投与することを含む前記方法。
- さらに、被験体が一過性低酸素および/または虚血状態を伴なったことがあり、その状態により引き起こされる神経細胞死のリスクをもつと判定することを含む、請求項6に記載の方法。
- さらに、投与前に、被験体が外傷性脳損傷(TBI)事象を伴なったことがあると判定することを含む、請求項7および8に記載の方法。
- ハロアルキルアミンが約0.5mg/kg(体重)〜約20mg/kg(体重)の単位投与量である、請求項1〜9のいずれか1項に記載の方法。
- ハロアルキルアミンを医薬的に許容できるキャリヤーと共に投与する、請求項1〜10のいずれか1項に記載の方法。
- ハロアルキルアミンが持続放出配合物中にある、請求項1〜11のいずれか1項に記載の方法。
- ハロアルキルアミンを一過性低酸素および/または虚血状態の発生後24時間以内に投与する、請求項1〜12のいずれか1項に記載の方法。
- ハロアルキルアミンを一過性低酸素および/または虚血状態の発生後18時間以内に投与する、請求項1〜13のいずれか1項に記載の方法。
- ハロアルキルアミンを単回量で、低血圧、失血、心臓発作、TBI事象、SCI事象、窒息、外科処置、脳卒中、脊髄梗塞、虚血性視神経障害、気道閉塞、または新生児の低酸素もしくは虚血の発生後16時間以内に投与する、請求項1〜14のいずれか1項に記載の方法。
- 投与が静脈内注射による、請求項1〜15のいずれか1項に記載の方法。
- ハロアルキルアミンが、フェノキシベンザミンおよびジベナミンからなる群から選択される、請求項1〜16のいずれか1項に記載の方法。
- 中枢神経系における一過性低酸素および/または虚血状態を伴なう被験体を処置するための医薬組成物であって、ハロアルキルアミンを有効成分として含む前記医薬組成物。
- 一過性低酸素および/または虚血状態が、低血圧、失血、心臓発作、TBI、SCI、窒息、外科処置、脳卒中、脊髄梗塞、虚血性視神経障害、または気道閉塞により引き起こされる、請求項18に記載の医薬組成物。
- 中枢神経系における一過性低酸素および/または虚血状態が外傷性脳損傷(TBI)により引き起こされる、請求項18または19に記載の医薬組成物。
- 被験体における神経脳細胞死の発生を低減する、請求項19〜20のいずれか1項に記載の医薬組成物。
- ハロアルキルアミンが一過性低酸素および/または虚血状態の発生の24時間以内に被験体に投与される、請求項19に記載の医薬組成物。
- その必要がある被験体の中枢神経系における神経細胞死の発生を低減するための医薬組成物であって、ハロアルキルアミンを有効成分として含む前記医薬組成物。
- 神経細胞死の発生が一過性低酸素および/または虚血状態により引き起こされる、請求項23に記載の医薬組成物。
- 神経細胞死の発生が外傷性脳損傷(TBI)事象により引き起こされる、請求項23に記載の医薬組成物。
- TBI事象がむち打ち、爆風衝撃、および鈍器外傷からなる群から選択され、そのTBI事象が神経細胞の損傷または死を引き起こすのに十分な力のものである、請求項20または25に記載の医薬組成物。
- 被験体の海馬または皮質における神経脳細胞死の発生を低減する、請求項18〜26のいずれか1項に記載の医薬組成物。
- ハロアルキルアミンが約0.5mg/kg(体重)〜約20mg/kg(体重)の単位投与量である、請求項18〜27のいずれか1項に記載の医薬組成物。
- さらに医薬的に許容できるキャリヤーを含む、請求項18〜28のいずれか1項に記載の医薬組成物。
- 持続放出配合物である、請求項18〜19のいずれか1項に記載の医薬組成物。
- ハロアルキルアミンが、フェノキシベンザミンおよびジベナミンからなる群から選択される、請求項18〜30のいずれか1項に記載の医薬組成物。
- 単回量で投与される、請求項18〜31のいずれか1項に記載の医薬組成物。
- 一過性低酸素および/または虚血状態の発生後24時間以内に投与される、請求項18〜32のいずれか1項に記載の医薬組成物。
- 一過性低酸素および/または虚血状態の発生後16時間以内に投与される、請求項33に記載の医薬組成物。
- 被験体に単回量で、低血圧、失血、心臓発作、TBI事象、SCI事象、窒息、外科処置、脳卒中、脊髄梗塞、虚血性視神経障害、気道閉塞、または新生児の低酸素もしくは虚血により引き起こされた一過性低酸素および/または虚血状態の発生後16時間以内に投与される、請求項20〜32のいずれか1項に記載の医薬組成物。
- 単回量で、発生後8時間以内に投与される、請求項35に記載の医薬組成物。
- ハロアルキルアミン、NSAID、および医薬的に許容できるキャリヤーを含む医薬組成物。
- ハロアルキルアミンが、フェノキシベンザミンおよびジベナミンからなる群から選択される、請求項37に記載の医薬組成物。
- 非経口または経口経路により投与される、請求項18〜38のいずれか1項に記載の医薬組成物。
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