JP6005514B2 - 神経疾患の治療のためのモデル系及び治療計画 - Google Patents
神経疾患の治療のためのモデル系及び治療計画 Download PDFInfo
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Description
本出願は、仮出願ではなく、そして2009年6月10日に出願の米国仮出願番号第61/185,989号の利益を主張する。
「キメラペプチド」は、互いに自然状態では会合しない2つのコンポーネントのペプチドが、融合タンパク質として又は化学的連結により互いに連結されたペプチドを意味する。
<I. 一般>
本発明は、脳卒中及び他の神経疾患であって、特に興奮毒性によって少なくとも部分的にもたらされるものの治療又は効果的な予防に利用できる可能性がある薬剤を評価するための動物モデル及び臨床試験を提供する。本発明は、かかる薬剤の臨床応用に関する好ましい用量及び注入計画及び医薬組成物を提供する。
任意の薬剤(以前の脳卒中臨床試験では不成功であった薬剤を含む)は、後述する動物モデル又は臨床試験における有効性に関するスクリーニングを行なうことができるが、好ましい種類の薬剤はPSD-95と1又は複数のNMDARとの間の相互作用を阻害するものである。かかる薬剤は、脳卒中の損傷効果及び他の神経学的状態であってNMDAR興奮毒性によって少なくとも部分的にもたらされるものを低減させるのに有効である。かかる薬剤には、NMDA受容体のPLモチーフ又はPSD95のPDZドメインを有するペプチドかそれに基づくアミノ酸配列を有するペプチドが含まれる。かかるペプチドは、PSD-95とnNOS及び他のグルタミン酸受容体(例えば、カイニット受容体又はAMPA受容体) (例えばKV1-4及びGluR6 ) の間の相互作用を阻害することもできる。好ましいペプチドは、シナプス後肥厚-95タンパク質(PSD-95)(Stathakism, Genomics 44(1):71-82 (1997)により提供されるヒトアミノ酸配列)のPDZドメイン1及び2と、1又は複数のNMDA受容体2サブユニット(ニューロンN-メチル-D-アスパラギン酸受容体のNR2Bサブユニット(Mandich et al., Genomics 22, 216-8 (1994))を含む)のC末端PL配列との間の相互作用を阻害する。NMDAR2Bは、GenBank IDが4099612であり、C末端20アミノ酸FNGSSNGHVYEKLSSIESDV(配列番号:11)及びPLモチーフESDV(配列番号:12)を有する。好ましいペプチドは、ヒト型のPSD-95及びヒトNMDAR受容体を阻害する。しかしながら、阻害は、タンパク質の種変異体からも示すことができる。使用可能なNMDA及びグルタミン酸受容体のリストが、下に表示される:
各R7は、独立して、C1-6アルキル、C1-6アルコキシ、-C(O)R12、OH、COOH、-NO、N置換インドリン、及び細胞膜透過ペプチドからなる群より選択されたメンバーであり;
各R8及びR9は、独立して、H、OH、シクロヘキサン、シクロペンタン、フェニル、置換されたフェニル、及びシクロペンタジエンからなる群より選択され;
各R10及びR11は、独立して、H、シクロヘキサン、フェニル、及び細胞膜透過ペプチドからなる群より選択され;
R12は、C1-6アルキル及びアリールからなる群より選択され;
及び、u及びvのそれぞれは、独立して0から20であり;
式中、R2、R3、R4、R5及びR6の一つは-COOHで、式中R2、R3、R4、R5及びR6の残りは、それぞれ独立して、F、H、OCH3、及びCH3からなる群より選択される。)
背景節で述べたように、以前に行われた、脳卒中治療のための薬理学的薬剤に関するいくつかの臨床試験は、上記薬剤が脳卒中の下等動物(例えばラット)モデルにおいて有望な結果を示したにもかかわらず失敗に終わった。非ヒト霊長類を用いた類似のモデル実験を実施することは、ある薬剤がヒトにおいてどのように機能するかについてより良好な指標を提供し、不成功だった場合の臨床試験の労力と費用をおそらく抑えるだろう。しかしながら、ラットで実行される実験のタイプは、動物の屠殺を通常伴うため、ある薬剤を評価するのに必要な範囲で霊長類に対して実行することは非倫理的である、及び/又は極端に高価である。
大血管(例えば大動脈弓)を処置することを伴う手順(心肺バイパス)及びカテーテルを頸部頸動脈に導入する手順(例えば診断的及び治療的脳血管造影)は、一般的には、頻度及び重症度を変化させる虚血性脳卒中を引き起こす可能性がある塞栓物質を除去する(Bendszus, Lancet Neurol 2006 April;5(4):364-72 2006により報告)。例えば、選択的冠状動脈バイパス手術(CABG)を受けている35の継続被験体の代表研究においては、拡散強調磁気共鳴画像は、9(26%)の被験体に新しい虚血性病変を示す(Bendszus et al., Arch.Neurol. 59 (7):1090-1095, 2002)。文献によると、拡散強調MRI (DWI-MRI)による新しい病変についてのかかる評価は、CABG被験体群の45%にまで変動する (Knipp et al., Eur.J.Cardiothorac.Surg. 25 (5):791-80,0 2004)。そして心臓弁修復を受けている被験体群の47%にまで変動する(Knipp et al., Eur.J.Cardiothorac.Surg. 28 (1):88-96 2005)。大多数の被験体は、2以上の病変を示す(Knipp et al., 2004, supra)。この効果がオンポンプ又はオフポンプCABGのいずれかを受けている被験体に見られるのは、おそらく、これが有害な塞栓を除去するのに重要な大血管の処置だからである。
本発明の薬理学的薬剤には、様々な疾患、特に神経疾患及び特に興奮毒性(excitotoxity)によって部分的にもたらされる疾患を治療する際に有効である。かかる疾患及び状態は、脳卒中、てんかん、低酸素症、CNSに対する外傷であって脳卒中を伴わないもの(例えば外傷性脳損傷及び脊髄損傷)、他の脳虚血、アルツハイマー病及びパーキンソン病が含まれる。本発明の薬剤によって治療可能な他の神経疾患は、不安及び痛みを含む興奮毒性に関連していることは既知ではない。
内在化ペプチドに任意に連結された薬理学的薬剤は、効果的な量、頻度及び投与ルートで投与し、治療中の疾患を患っている患者における少なくとも一つの疾患の兆候又は症状の更なる治癒、低減又は、悪化を阻害する。特に明記しない限り、内在化ペプチドに連結された薬理学的薬剤を含むキメラ薬剤の用量は、キメラ薬剤に関する薬理学的薬剤の構成成分だけではなく、むしろ薬剤全体を指す。治療上有効量は、非常に十分な薬剤の量を意味し、薬剤で治療されない疾患又は状態を患っている患者(又は、動物モデル)のコントロール群の損傷と比較して、本発明の薬剤で治療される疾患を患っている患者(又は、動物モデル)群において、治療される疾患又は状態に関する少なくとも一つの兆候又は症状の更なる悪化を治癒、低減又は阻害する。本発明の方法で治療しない比較対象患者のコントロール群における平均予後よりも、個々の治療を受けた患者のほうがより好ましい予後を達成する場合、上記量は治療的に有効であるとも考えられる。治療的に有効な投与計画は、意図した目的を達成するのに必要な投与回数及び経路にて治療的に有効な用量を投与することに関する。
本発明のキメラ又は他の薬剤は、医薬組成物の形で投与できる。医薬組成物は、典型的にはGMP条件下で製造される。非経口投与のための医薬組成物は、特に滅菌処理(例えば、フィルターによるペプチドの滅菌)したものであり、そして発熱性物質が存在しないものである。医薬組成物は、単位用量型(すなわち、単回投与のための用量)として提供できる。医薬組成物は、一つ以上の生理的に許容可能な担体、希釈液、賦形剤又は助剤であって医薬的に使用可能な製剤へとキメラ薬剤を容易に処理できるものを使用する従来の方法を用いて調製することができる。適切な製剤は、選択される投与ルートに依存する。
以下の実施例は、10匹のマカクを5匹の被験体と5匹のコントロールに分けて実施した。各動物に対して、第一ラウンドでの試験動物を第二ラウンドではコントロールとする(その逆もしかり)、2回の手順を課した。
Tat-NR2B9cは、3分間又は60分間の注入時間で50mg/kgをラットに投与した。図4は、投与後の血圧変化を示す。3分間注入されたラットにおいては、回復する前の90分間に血圧が約50%低下した。1時間注入されたラットに関しては、わずかな血圧低下だけがあり、1時間にわたって回復した。
我々は、ヒトにおけるTat-NR2B9cの安全性、許容性及び薬物動態の研究を行った。被験体は、最小年齢が18歳である、通常で健常な、タバコを吸わない男性又は閉経後であるか外科的に不妊の女性被験体のいずれかであった。被験体は、Tat-NR2B9c ( Lot #: 124-134-001B )又は所定のプラセボ(リン酸緩衝生理食塩水) ( Lot #: 124-134-001A )のいずれかが、静脈内注入(10±1分)として投与された。4人の被験体は、コホート1〜3の各々において一回分投与され、10人の被験体はコホート4〜8の各々において一回分投与された。全62人の被験体に対する研究を完了した。
採血のタイムポイント:
試験期間中、薬物動体解析のため、11の血液サンプルを各被験体から以下のタイムポイントで回収した:投薬後0.00(投薬前)、0.08(5分)、0.17から0.25(各々の独立した薬物注入の終了から正確に10から15分)、0.33(20分)、0.50、0.75、1.00、2.00、6.00、12.00、及び24.00時間。それに加え、ヒスタミン分析のために、各被験体から以下のタイムポイントで8つの血液サンプルを回収した:投薬後0.00(投薬前)、0.08(5分)、0.17(10分)、0.25、0.50、1.00、2.00、及び24.00時間。
試験経過中少なくとも一回投薬を受けたすべての被験体において、安全性試験を行った。すべての有害事象(AE)の出来事を治療と被験体番号により集計した。バイタルサインの絶対値、心電図(ECG)パラメーター、実験パラメーター及び身体診察も文書化され、正常範囲外の値に印をつけた。ベースライン値からシフトしたものを集計した。AEは、研究者及び国際医薬用語集 (MedDRA)の用語を使って文書化した。
3.75mg/kg用量群での8被験体中7人は、NA1投与開始から10分後に10nmol/Lよりも高い(平均24.3nmol/L;最大39.8nmol/L)ヒスタミンレベルを有していた。上記被験体のうち3人は、NA1投与開始から15分後に10nmol/Lよりも高い(平均15.3nmol/L;最大20.3nmol/L)のヒスタミンレベルをまだ有していた。
有効性の主要な基準は、MRI検出可能なDWIの総容積及びFLAIR-シーケンス-陽性病変であって血管内介入後のものである。大きい体積脳卒中患者が多くいる場合、これらの異常値体積は、より通常の分布の体積を考慮するために最高10ccまでで切り捨てて、標準的なパラメーター統計によって検定する。主要な分析は、2つの治療グループ(薬剤対プラセボ)における平均値が等しい帰無仮説と、治療グループの平均病変総容積がプラセボ群より小さい対立仮説に関するt検定である。試験の最大サンプルサイズは400であり、治療群当たりは200である。
通常の(0.9%)生理食塩水中のTat-NR2B9c又はプラセボが入っている注射器のバイアルは、各臨床現場の薬局において-20℃で保存される。研究対象の登録において、1又は複数(必要とされる総量に依存)のTat-NR2B9c薬剤又はプラセボの注射器のバイアルは、薬:プラセボランダム化コードに基づいて薬局で選択され、使用の前に解凍される。個々の被験体に投薬するための注射器に被験体番号を付け、注射器のバイアルから吸い出す量を以下の通りに算出することによって調製する:(2.60 mg/kg×被験体重量(kg))/[mg/ml中の薬効]。これによって、注射器へ引き上げるミリリットル数を決定する。Tat-NR2B9c又はプラセボを含む注射器は、投与部位へ運ばれ、0.9%通常生理食塩水の100mL点滴バッグのIVポートに注入された。
Claims (10)
- 動脈瘤を治療する血管内手術、診断的血管造影又は頚動脈ステント術由来の虚血性障害を阻害するために使用される、PSD-95とNMDAR 2Bとの結合を阻害する薬剤を有効成分として含む医薬組成物であって、該薬剤がアミノ酸配列YGRKKRRQRRRKLSSIESDV(配列番号:6)を有するペプチドである、医薬組成物。
- 前記薬剤は、前記血管内手術の前に投与される、請求項1に記載の医薬組成物。
- 前記薬剤は、前記血管内手術が完了する1時間以内に投与される、請求項1に記載の医薬組成物。
- 前記血管内手術は、前記動脈瘤にコイルを挿入することか、前記動脈瘤にかかっている前記血管にステントを挿入することか、マイクロカテーテルを挿入することを含む、請求項1に記載の医薬組成物。
- 前記薬剤の用量は、2-3mg/kgである、請求項1に記載の医薬組成物。
- 前記薬剤の用量は、2.6mg/kgである、請求項1に記載の医薬組成物。
- 前記薬剤は、PSD-95とNMDAR 2Bとの結合及び/又 はPSD-95とnNOSとの結合を阻害し、前記薬剤は内在化ペプチドに連結され、前記薬剤は5-15分の期間にわたって静脈内注入によって投与される、請求項1に記載の医薬組成物。
- 前記内在化ペプチドに連結した前記薬剤は、アミノ酸配列YGRKKRRQRRRKLSSIESDV(配列番号:6)を有するペプチドであり、前記期間は5分である、請求項7に記載の医薬組成物。
- 前記薬剤は、内在化ペプチドを含むキメラ薬剤であって、
前記薬剤は、前記内在化ペプチドによってヒスタミン放出とその下流の効果を低減させる抗炎症剤と共に投与される、請求項1に記載の医薬組成物。 - 前記抗炎症剤は、マスト細胞脱顆粒阻害剤である、請求項9に記載の医薬組成物。
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CN114469084B (zh) * | 2022-04-02 | 2022-06-24 | 剑博微电子(深圳)有限公司 | 一种基于高精度adc的血氧监测*** |
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WO2004071531A1 (en) | 2003-02-13 | 2004-08-26 | Licentia Oy | Use of a mast cell activation or degranulation blocking agent in the manufacture of a medicament for the treatment of cerebral ischemia |
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DK2320927T3 (en) | 2008-07-09 | 2015-09-14 | Univ Copenhagen | Modified peptides as potent inhibitors of the PSD-95 / NMDA receptor interaction |
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US9241970B2 (en) | 2011-12-13 | 2016-01-26 | Nono Inc. | Therapy for subarachnoid hemorrhage and ischemia |
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PT2440230T (pt) | 2021-02-03 |
EP2440230A2 (en) | 2012-04-18 |
CA2765169C (en) | 2019-06-18 |
EP3808366A1 (en) | 2021-04-21 |
US20120269733A1 (en) | 2012-10-25 |
AU2010258664A1 (en) | 2012-01-12 |
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JP2016041731A (ja) | 2016-03-31 |
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US8940699B2 (en) | 2015-01-27 |
EP2440230A4 (en) | 2014-05-28 |
JP2012530057A (ja) | 2012-11-29 |
WO2010144721A3 (en) | 2011-04-21 |
HRP20210112T1 (hr) | 2021-04-16 |
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