JP2018534362A - 外傷性脳損傷を処置するための方法および組成物 - Google Patents
外傷性脳損傷を処置するための方法および組成物 Download PDFInfo
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Abstract
Description
外傷性脳損傷(TBI)は、外部からの機械的な力が脳機能不全を引き起こすときに生じる。
外傷性脳損傷は、通常、頭または体への激しい打撃または衝撃によってもたらされる。頭蓋骨を貫通する物体、例えば弾丸などまたは頭蓋骨の破砕片もまた、外傷性脳損傷を引き起こし得る。
脳震とうのための可能な処置としてのカンナビノイドはまた、Shohami et al.(Journal of Neurotrauma 2009, 10(2): 109-119. doi: 10.1089/neu.1993.10.109)、Fernandez-Ruiz et al.(Handb Exp Pharmacol. 2015;231:233-59)およびPryce et al.(Handb Exp Pharmacol. 2015;231:213-31)によっても開示されている。
本発明は、対象において外傷性脳損傷を処置するための方法および組成物に関する。
本発明の一側面は、対象において外傷性脳損傷を処置するための方法であって、N−メチル−D−アスパラギン酸(NMDA)受容体アンタゴニストを含む第1の組成物、および、血液脳関門を越えることを可能とする抗炎症剤を含む第2の組成物を、対象へ投与することを含む、前記方法に関する。
一つの非限定的な態様において、第2の組成物は、非カンナビノイドCB2アゴニストを含む。
別の非限定的な態様において、第2の組成物は、NMDA受容体にも結合するカンナビノイドCB2アゴニストを含む。
別の非限定的な態様において、第2の組成物は、2−AGのレベルを減少させる剤を含む。
一つの非限定的な態様において、処置される外傷性脳損傷は、脳震とうである。
本発明は、対象において外傷性脳損傷を処置するための方法を提供する。一つの非限定的な態様において、処置される外傷性脳損傷は、脳震とうである。
一つの非限定的な態様において、第1の組成物は、外傷性脳損傷から12時間以内に、またはこれに代えて、外傷性脳損傷から6時間以内に、またはこれに代えて、外傷性脳損傷から3時間以内に、投与される。これらの態様において、第1の組成物は、単回用量または複数回用量として投与されてもよい。
一つの非限定的な態様において、第1の組成物は、外傷性脳損傷の症状が緩和されるまで、毎日または2日毎に投与される。
第2の組成物は、第1の組成物の投与前、同時、または後に投与され得る。
一つの非限定的な態様において、第1および第2の組成物は、一緒に、両方の治療剤を含む単一組成物へと製剤化される。
一つの非限定的な態様において、第2の組成物は、外傷性脳損傷から12時間以内に、またはこれに代えて、外傷性脳損傷から6時間以内に、またはこれに代えて、外傷性脳損傷から3時間以内に、投与される。これらの態様において、第2の組成物は、単回用量または複数回用量として投与されてもよい。
一つの非限定的な態様において、第2の組成物は、外傷性脳損傷の症状が緩和されるまで、毎日または1日おきに投与される。
以下の非限定例は、本発明をさらに例証するために提供される。
例1:げっ歯類での研究
選択されたNMDAアンタゴニストのデキサナビノール(HU 211としてもまた知られる)およびCB2アゴニストのカンナビジオール(CBD)を含む併用療法(本明細書において「SP処置された」と称される併用療法)の、プラセボ(無処置)と比較したときの、爆風に誘発されたmTBIまたは脳震とう性のmTBIの感覚神経の後遺症を低減させる能力を、小げっ歯類モデルにおいて確認する。
げっ歯類の爆風波管曝露(Rodent Blast Wave Tube Exposures):衝撃波生成システムは、単一の12フィートの長さで8インチの内径の凝縮管と並ぶことにより圧力密封状態の嵌合を形成する3フィートの圧縮管から構成される。圧縮管は、産業用圧縮機によって圧力装填(charged)される。油圧作動デバイスが、プラスチックのフィルムの上から凝縮管の摺動部を圧縮管に対して押圧して、圧縮管を密封する。システムを、圧縮チャンバーの選択された圧力までの管理、新たなフィルムを適所に移動させること、非破裂のフィルムの上からの気密な封を形成するための凝縮管の圧縮管への閉鎖、選択された圧力でフィルムを破裂させるための内部のアーマチュアの活性化、ならびに新たな非破裂のフィルムを次の爆風事象のために適所に移動させることのために遠隔操作する。管の出力は、超音速のFriedlanderタイプの過圧/負圧波を生じさせ、これは爆薬爆発からの衝撃圧力波をシミュレートする。2ポンド/平方インチ(psi)または14.5キロパスカル(kPa)〜>50psi(0.35メガパスカル)の過圧強度が生成され得る。単一の爆風過圧(BOP)についての曝露の研究は、10〜20psiの間の範囲とする(動物の苦痛軽減(refinement animals)上決定した初期反応に依存する)。
ラットに、以前にFodaおよびMarmarou(J Neurosurg. 1994 80(2):301-13)によって記載された方法により、軽度TBI(mTBI)を経験させる。具体的には、雄のSprague-Dawleyラットを、ガラス鐘中において、3%イソフルラン、70% N2Oおよび30% O2で、ポーピンチまたはテールピンチ(paw or tail pinch)への応答がなくなるまで麻酔する。初めの麻酔後、ノーズコーンを通じて動物を1〜2.5%の維持投薬量で維持する。外科手術中に眼が乾かないように、滅菌した眼用潤滑剤を使用する。動物の頭部を剃毛し、クロロヘキサジンで拭き落とす。頭蓋骨を露出させるために切開を行う。スチール製の円板(直径10mmおよび厚さ3mm)を、ブレグマおよびラムダ縫合線の間に、頭蓋骨の歯科用アクリルを使用して取り付ける。
Sprague-Dawleyラットを、特注の麻酔チャンバー中にて、麻酔の誘発のために3%イソフルランで麻酔する。動物が適切に麻酔されていることを確めるために、トウピンチ(toe pinch)を行う。動物の呼吸数を、視覚的に評価する。次に、イソフルラン麻酔をノーズコーンを通じて維持し、および、以下のとおり、露出した硬膜上に損傷キャップ(injury cap)を設置する:ラットの頭部を剃毛し、クロロヘキサジン溶液で拭き取る;次にラットを定位フレーム中に置き、頭皮を外科手術的に切開する;トレフィンを使用した傍矢状開頭(4.8mm)を、ブレグマの3.8mm後方で正中線の2.5mm側方にて行う;滅菌されたプラスチックの損傷チューブ(injury tube)(長さ1cmにカットされて開頭を完全に充填するように整えられた滅菌された針のプラスチックのコネクタ)を次に露出した硬膜の上から設置し、およびシアノアクリル系接着剤(crynoacrylic adhesive)によって頭蓋骨へ固着させ;次に完全な密封を得るために歯科用アクリルを損傷チューブの周りに注ぎ入れ;アクリルが硬化した後、損傷チューブを、滅菌されたゲルフォームスポンジで、またはLuer-Lokアダプタで塞ぎ、頭皮をステープル留め/縫合して元のとおりにし;動物を麻酔から取り出してそれらのホームケージへ戻す。
全ての動物を、曝露前後、および曝露後の回復期間全体の間、STARR Life Sciences, Corp.製品およびパルスオキシメーターを使用して、呼吸数、心拍数および血液酸素飽和度についてモニターする。動物が、極度の痛みの様相を、またはそれらが爆風曝露後に回復しないかもしれないことの様相を示す場合、獣医師が動物を検査する。動物を、痛みの様相について発声、食欲不振、攻撃、防御、および極度の興奮を包含するようにして、入念に観察する。動物は、獣医師の助言に基づいて、安楽死させることも、させないこともある。潜在的な疼痛反応の可能性を回避するために、爆風曝露の直後にケトプロフェンを与える。
曝露2時間後に、SPに腹腔内(IP)注射を通じて有効用量の10mg/kgのCBDおよび1mg/KgのHU 211を投与する。この投薬を、追加の7日間、毎日繰り返す。
感覚運動試験:
自発的な前肢の使用:このSchallertおよびLindner(Can J Psychol. 1990 44(2):276-92)によって記載されている試験は、動物が後肢立ちしているかまたは立っている間にその前肢を内転させる傾向を評価することにより、自由意思による自発的な活動の間における前肢の使用を評価する。動物を透明なプラスチックのシリンダー中で5分間ビデオテープ録画する。
対側/(同側+対側)
として算出する。
認知機能の分析は、水迷路を使用した空間的ナビゲーションの評価を伴う。TBIに続いて数多くの時点での動物の活動を評価すること(TBIが招く結果を少なくさせるようにデザインされた治療的な処置法の有効性を評価する場合など)に主に向けられた実験は、各試験セッションの間において動物が新たなプラットフォームの場所を学習することを必要とする簡素な位置タスクおよび作業記憶タスクを伴う「取得」の枠組みを主に頼りにする。このプロトコルは、外科手術前の水迷路における事前訓練または試験を伴わない。
聴性脳幹応答(ABR):
聴覚閾値を、頭頂(参照)、右乳様突起(負)および左後肢に設置した皮下の白金針電極を通じて聴性脳幹応答によって決定する。デジタル的に生成された刺激は、全体的な期間が5msの台形包絡線を有する3〜30kHzの間の1024の特定周波数のバースト音から構成される。台形は、3msのプラトーおよび1msの立ち上がりおよび立ち下がりで現れる。刺激は、コンピュータ制御された減衰器を通って挿入形イヤホン(Etymotic Research ER-2)へと送られる。挿入形イヤホンの音声送達管は、鼓膜から約5mmに位置させる。挿入形イヤホンの出力は、鼓膜から4〜5mm離れた位置の音圧レベルを測定することにより校正する。
平衡機能を試験するための前庭筋電位(cVEMP)を、外傷の前に、および外傷後の複数の時点で第30日まで測定する。測定は、プリアンプに取り付けられた皮下の針電極およびデータ取得システム(Intelligent Hearing Systems)を用いて行う。球形嚢を刺激する音刺激に応答して、首の筋肉に設置された皮下電極によって前庭誘発筋電位(VEMP)を測定する。
組織採取:
行動試験後、動物を安楽死させ、組織を以下のやり方で収集する:
組織学のために、ケタミン(150mg/kg)およびキシラジン(10mg/kg)の過剰投与下またはイソフルラン麻酔下、ラットを経心的に生理食塩水で、続いて4%パラホルムアルデヒドで灌流する。頭部、肝臓および腎臓を取り出し、同じ固定剤中で後固定する。脱灰した頭部または抽出した脳のいずれかを、組織病理学的分析のために使用する。
適切な生存時間の後、偽処置ラットおよび外傷を受けることに曝されたラットをペントバルビタールナトリウム(100mg/kg、i.p.)で麻酔し、経心的に0.1M PBSで、続いて過ヨウ素酸−リシン−パラホルムアルデヒド固定剤で灌流する。無傷の頭部を、4%パラホルムアルデヒド中で24時間、室温で後固定し、10%ギ酸中で化学的l試験基準(chemical l testing criterion)まで脱灰し、および終夜5%硫酸ナトリウム中で中和する。パラフィン中に埋設した後、切片を水平面中において8〜10mでカットする。25枚目毎の切片を、標準的な組織病理学的分析のためにヘマトキシリンおよびエオシンで染色する。
動物を、損傷後第1、3または7日に安楽死させる。ケタミン/キシラジン(100mg/kg;10mg/kg)麻酔下、各ラットの胸を開き、頭部を、上行大動脈中に設置されたカテーテルを通じて50〜100mlのリン酸緩衝生理食塩水で室温で灌流し、血液を頭部から上大動脈中の開口を通じて流し出させる。灌流液からほとんど血液が取り除かれたら、頭蓋骨を注意深く開き、脳を解剖する。髄膜を取り出した後、各脳を、固体CO2中でのビーカーの浸漬により予冷された約30mlの冷イソペンタンを含んだ小さなビーカー中で速やかに冷凍し、次に取り出し、個別にアルミニウム箔で包み、切片化するまで−80℃で保管する。脳を、前頭面において18ミクロンの厚さで、クリオスタット(Leica Microsystems CM3050S, Bannockburn, IL)を使用して切片化する。
Claims (25)
- 外傷性脳損傷をそれを患っている対象において処置するための方法であって、N−メチル−D−アスパラギン酸(NMDA)受容体アンタゴニストを含む第1の組成物、および、CB2アゴニスト、内因性CB2アゴニストを効果的に増加させる剤および/またはアナンダミド(AEA)もしくは2−アラキドノイルグリセロール(2−AG)のレベルを変化させる剤を含む第2の組成物を、対象へ投与することを含む、前記方法。
- 第1の組成物が、非競合性NMDA受容体アンタゴニストを含む、請求項1に記載の方法。
- 第1の組成物が、7−ヒドロキシ−デルタ−6−テトラヒドロカンナビノール−1,1−ジメチルヘプチルを含む、請求項1に記載の方法。
- 第1の組成物および/または第2の組成物が、外傷性脳損傷から12時間以内に投与される、請求項1に記載の方法。
- 第1の組成物および/または第2の組成物が、外傷性脳損傷から6時間以内に投与される、請求項1に記載の方法。
- 第1の組成物および/または第2の組成物が、外傷性脳損傷から3時間以内に投与される、請求項1に記載の方法。
- 第1の組成物が、静脈内に、鼻腔内に、経口で、局所的に、経皮的にまたは吸入経由で、投与される、請求項1に記載の方法。
- 第1の組成物が、単回用量として投与される、請求項1に記載の方法。
- 第1の組成物が、複数回用量として投与される、請求項1に記載の方法。
- 複数回用量が、外傷性脳損傷に続いて72時間の期間にわたって投与される、請求項9に記載の方法。
- 第2の組成物が、非カンナビノイドCB2アゴニストを含む、請求項1に記載の方法。
- 第2の組成物が、NMDA受容体にも結合するカンナビノイドCB2アゴニストを含む、請求項1に記載の方法。
- 第2の組成物が、AEAのレベルを増加させる剤を含む、請求項1に記載の方法。
- 第2の組成物が、2−AGのレベルを減少させる剤を含む、請求項1に記載の方法。
- 第2の組成物が、脂肪酸アミド加水分解酵素の阻害剤を含む、請求項1に記載の方法。
- 第2の組成物が、外傷性脳損傷の12〜72時間後に投与される、請求項1に記載の方法。
- 第2の組成物が、外傷性脳損傷に続いて第7日まで、毎日投与される、請求項1に記載の方法。
- 第1の組成物および/または第2の組成物が、外傷性脳損傷の症状が緩和されるまで、毎日または1日おきに投与される、請求項1に記載の方法。
- 外傷性脳損傷をそれを患っている対象において処置するための方法であって、N−メチル−D−アスパラギン酸(NMDA)受容体アンタゴニストを含む第1の組成物、および、血液脳関門を越えることを可能とする抗炎症剤を含む第2の組成物を、対象へ投与することを含む、前記方法。
- 第2の組成物が、第1の組成物の投与前、同時、または後に投与される、請求項1に記載の方法。
- 第2の組成物が、第1の組成物の投与前、同時、または後に投与される、請求項19に記載の方法。
- 処置される外傷性脳損傷が、脳震とうを含む、請求項1に記載の方法。
- 処置される外傷性脳損傷が、脳震とうを含む、請求項19に記載の方法。
- 外傷性脳損傷の処置のための医薬組成物であって、
N−メチル−D−アスパラギン酸(NMDA)受容体アンタゴニスト、
CB2アゴニスト、内因性CB2アゴニストを効果的に増加させる剤またはアナンダミド(AEA)もしくは2−アラキドノイルグリセロール(2−AG)のレベルを変化させる剤;および
薬学的に許容し得るビヒクル
を含む、前記組成物。 - 外傷性脳損傷の処置のための医薬組成物であって、
N−メチル−D−アスパラギン酸(NMDA)受容体アンタゴニスト;
血液脳関門を越えることを可能とする抗炎症剤;および
薬学的に許容し得るビヒクル
を含む、前記組成物。
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PCT/US2016/057304 WO2017066744A1 (en) | 2015-10-16 | 2016-10-17 | Methods and compositions for treating traumatic brain injury |
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