JP2017506625A - 軽度脳損傷の治療方法 - Google Patents
軽度脳損傷の治療方法 Download PDFInfo
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Abstract
Description
本発明は、グレリン(ghrelin)を含む有効量の組成物を被験体に投与することによって、被験体における軽度脳障害及びそうした障害に起因する他の神経学的障害を治療する方法を提供する。
本明細書及び添付した請求項において使用する場合、単数形「a」、「an」及び「the」は、文脈が明らかに異なる記載をしていない限り、複数形の指示対象を含む。従って、例えば「化合物(a compound)」への言及は、複数の化合物を含む。
別に規定のない限り、本明細書において使用する全ての技術的及び科学的用語は、本開示が属する分野における通常の技術を有する者が一般的に理解するものと同じ意味を有する。本明細書において使用する場合、以下の用語は以下の意味を有する。
本明細書において使用する場合、数字表示、例えば温度、時間、量、濃度、及び同様の他の記載(範囲を含む)の前に使用する用語「約(about)」は、(+)又は(−)10%、5%又は1%まで変化し得る近似値(approximations)を示す。
本明細書において使用する場合、用語「親和性(affinity)」とは、受容体とそのリガンドとの間、例えば抗体とその抗原との間の結合の強度をいう。
本明細書において使用する場合、用語「個体」又は「被験体」は、ある状態、特にmBI又は脳震とうに罹患しやすい動物又はヒトである。一部の実施形態において、個体は哺乳動物であり、ヒト、及びイヌ、ネコ、ブタ、ウシ、ヒツジ、ヤギ、ウマ、ラット、及びマウス等の非ヒト哺乳動物を含む。
更に、mBIは、重度TBIと明確に異なっている。軽度脳損傷及び重度外傷性脳損傷は著しく異なる損傷である。軽度BI及び重度TBIは異なる特徴及び症状、異なる死亡率、異なる治療プロトコル等を有する。重度TBIは、損傷から数時間又は数日以内にヒトにおいて許容できないレベルの死亡及び永久的な障害となる損傷状態である。疾病管理センターによれば、このような損傷は米国における全ての損傷関連死の三分の一(30%)の要因である(米国人口動態統計(National Vital Statistics System, NVSS)、2006-2010を参照されたい)。重度TBIは、例えば交通事故及び頭部への戦闘での銃撃及び爆弾による負傷によって生じることが多い。重度TBIは、典型的には直接的かつ明白な脳出血、脳細胞の破壊、重度の脳浮腫及び重度の細胞アポトーシスを有し、全てが損傷を受けた患者の脳への解剖学的変化又は解剖学的損傷の特徴を有し、その全てが非侵襲的な解剖学的画像検査法によって検出することができる。こうした症状の重症性、及び死及び障害が差し迫っているために、外科的介入及び救命救急が最優先である。重量TBIは患者の脳に(肉眼解剖学レベルで観察可能な)不利な解剖学的変化をもたらし、死亡を回避できたとしても、脳機能の直接的かつ永久的な損失をもたらす。
本開示は、mBIにおけるグレリンの新規用途の同定に関する。脳震とうを含む軽度BIは、脳疾患に関連する他の外傷、及び虚血を生じるもの等の重度外傷性脳損傷(重度TBI)とは顕著に異なる病理を有する。軽度BIは、重度外傷性脳疾患で観察されるような大きな組織及び細胞の損傷を引き起こすものではない。むしろ、mBIは脳内にわずかな代謝的変化、特に酸化的ストレス及び活性酸素種(ROS)の過剰産生を生じさせ、これらが次いで神経の接続にダメージを与え、再発性の損傷を伴うニューロン損傷並びに脳障害及び心理的変化につながり得る。
対照的に、例えば、重度TBIは一般的に8以下のGCSスコアを有する。
本明細書に記載するグレリンは、医薬組成物として製剤化することができ、例えば保存及び/又は輸送のために急速冷凍又は凍結乾燥することができる。一部の実施形態において、化合物は、例えば無菌食塩水と共に組成物中に含めることができる。一部の実施形態において、グレリンは、そのような食塩水又は他の許容される希釈剤中に再構成することができる。一部の実施形態において、約10μgのグレリン粉末を、投与前に約100μLの生理食塩水溶液中に再構成する。更に、組成物は、単独で、又は担体、例えば薬学上許容される担体若しくは生体適合性を有する骨格(scaffold)と組み合わせて投与することができる。本発明の組成物は、非経口的に、注射によって、例えば静脈内、皮下、又は筋肉内に通常の方法で投与することができる。他の投与方法に適した更なる製剤としては経口製剤が挙げられる。経口製剤は、通常使用される賦形剤、例えば医薬グレードのマンニトール、ラクトース、デンプン、ステアリン酸マグネシウム、サッカリンナトリウム、セルロース、炭酸マグネシウム等を含む。これらの組成物は、溶液、懸濁液、錠剤、丸剤、カプセル剤、持続放出製剤又は粉末の形態をとり、約10%〜約95%、例えば約25%〜約70%の活性成分を含有する。
本開示は、グレリンを含有する有効量の化合物を被験体に投与し、それによってmBIの発症又は重症度を低減することを含む、被験体におけるmBIの発症又は重症度の低減方法を提供する。本開示はまた、有効量のグレリンを被験体に投与し、それによってmBIの発症又は重症度を低減することを含む、被験体におけるmBIの発症又は重症度の低減方法を提供する。本発明は更に、軽度脳損傷に罹患した患者に治療的有効量のグレリンを軽度脳損傷から特定の時間内(例えば72時間内)に投与することを含む、軽度脳損傷からの回復のために必要な時間を短縮する方法を提供する。
グレリン組成物は、単独で、又は製薬上許容される担体若しくは賦形剤と組み合わせて、単回用量又は複数回用量で投与することができる。製剤は、便宜的に当業者に公知の方法によって単位用量形態で提示することができる。化合物はキットで提供することができる。そのようなキットは、典型的には投与のための投与形態中に活性化合物を含む。キットは、投与レジメンに対応した用量単位の量を含む。一部の実施形態において、キットは、グレリン化合物又は薬学的に許容されるその塩、及び薬学的に許容される担体、ベヒクル及び/又は賦形剤を含む医薬組成物を含み、そのキットは複数の用量単位を有する。用量単位は、約0.3μg〜約600mgのグレリン、例えば約2.0μg〜約200mgのグレリン、例えば約5.0μg〜約100mgのグレリン、例えば約10μg〜約50mgのグレリン、例えば約10μg〜約5mgのグレリン、例えば約10μg〜約1.0mgのグレリンに等価な量のグレリン又はその塩を含む。
グレリンの投与によって、mBI後の炎症細胞における酸化的破壊(oxidative burst)が低減される。脳震とうについて広く受け入れられた動物モデルは存在しないため、mBIに非常に類似する(closely mimics)非常に小さな脳病変をmBIのモデルとして使用する。酸素(1.7L/分)中5%のイソフルランで麻酔したC57/B6マウスに、軽度脳損傷状態にさせる前に、鎮痛のために0.3mg/kgのブプレノルフィンを皮下投与する。麻酔はpaw pinch reflexによって評価する。麻酔は足の反射(paw pinch reflex)によって評価する。歯科用ドリルで硬膜(dura)を通る穿頭孔を開けた後、制御式皮質衝撃法(controlled cortical impactor、CCI)を使用した病変部を用いてブレグマ(bregma)の後方側面に1mmの損傷を作製する(1.0mmの深さに5.0mm/秒)。
GHS-Rに対するグレリンの結合能は、結合アッセイによって決定することができる。チャイニーズハムスター卵巣細胞株の細胞であるCHO-K1を、ヒト組換えGHS受容体を発現するように調製する。
グレリンの機能的活性を、GHS-R機能的活性アッセイを使用してin vitro及びin vivoで検討する。GSH受容体に対するグレリンの結合によって、in vitroにおける細胞内iCa2+の動員が改変され得る。グレリンはまた、成長ホルモン(GH)の放出をin vivoで刺激又は抑制する能力についても試験することができる。
Claims (41)
- 被験体における軽度脳損傷(mBI)を治療するのに十分な量でグレリンまたはその変異体若しくは誘導体を投与することによる該被験体におけるmBIの治療における使用のための、グレリン(ghrelin)又はその変異体若しくは誘導体。
- 被験体における軽度脳損傷(mBI)を治療するために被験体の内在グレリン血中濃度よりも少なくとも1.5倍高いグレリンの血中濃度を提供するのに十分な量でグレリンまたはその変異体若しくは誘導体を投与することによる、被験体におけるmBIの治療における使用のためのグレリン又はその変異体若しくは誘導体。
- 投与時に、グレリンが被験体に投与される唯一の活性剤である、請求項1又は2記載のグレリン。
- グレリンが、Gly-Ser-Ser-Phe-Leu-Ser-Pro-Glu-His-Gln-Arg-Val-Gln-Gln-Arg-Lys-Glu-Ser-Lys-Lys-Pro-Pro-Ala-Lys-Leu-Gln-Pro-Arg(配列番号1)の配列を有する、請求項1又は2のグレリン。
- mBIが脳震とうを含む、請求項1又は2記載のグレリン。
- 治療的有効量のグレリンを被験体に投与し、それによって軽度脳損傷(mBI)を治療することを含む、被験体におけるmBIの治療方法。
- グレリンが、Gly-Ser-Ser-Phe-Leu-Ser-Pro-Glu-His-Gln-Arg-Val-Gln-Gln-Arg-Lys-Glu-Ser-Lys-Lys-Pro-Pro-Ala-Lys-Leu-Gln-Pro-Arg(配列番号1)の配列を有する、請求項6記載の方法。
- グレリンが1種以上の脂肪酸で改変されている、請求項7記載の方法。
- 脂肪酸がオクタン酸である、請求項8記載の方法。
- グレリンが、配列番号1のアミノ酸位置2のセリン及び/又はアミノ酸位置3のセリンが改変されている、請求項7記載の方法。
- グレリンが、アミノ酸位置2のセリン及び/又はアミノ酸位置3のセリンがオクタン酸で改変されている、請求項10記載の方法。
- グレリンの改変が、アミノ酸位置2のセリン及び/又はアミノ酸位置3のセリンのオクタン酸によるアシル化である、請求項11記載の方法。
- 改変されたグレリンが、アミノ酸位置3のセリンのオクタン酸によるアシル化を有するオクタノイルグレリンである、請求項12記載の方法。
- mBIが脳震とうを含む、請求項6記載の方法。
- 被験体が哺乳動物である、請求項6記載の方法。
- mBIから約24時間以内にグレリンを投与する、請求項6記載の方法。
- mBIから約8時間以内にグレリンを投与する、請求項16記載の方法。
- グレリンが、被験体の内在グレリン血中濃度よりも少なくとも2倍高いグレリン血中濃度をもたらす量で投与される、請求項6記載の方法。
- グレリンが単回用量で投与される、請求項6記載の方法。
- グレリンが1日当たり10ng/kg〜10mg/kgの投与量で投与される、請求項6記載の方法。
- グレリンが1日当たり2μg/kgの投与量で投与される、請求項20記載の方法。
- 被験体の内在グレリン血中濃度よりも少なくとも1.5倍高いグレリンの血中濃度をもたらす量で治療的有効量のグレリンを被験体に投与し、それによって軽度脳損傷(mBI)を治療することを含む、被験体におけるmBIの治療方法。
- グレリンが、Gly-Ser-Ser-Phe-Leu-Ser-Pro-Glu-His-Gln-Arg-Val-Gln-Gln-Arg-Lys-Glu-Ser-Lys-Lys-Pro-Pro-Ala-Lys-Leu-Gln-Pro-Arg(配列番号1)の配列を有する、請求項22記載の方法。
- グレリンが1種以上の脂肪酸で改変されている、請求項22記載の方法。
- 脂肪酸がオクタン酸である、請求項24記載の方法。
- グレリンが、配列番号1のアミノ酸位置2のセリン及び/又はアミノ酸位置3のセリンが改変されている、請求項23記載の方法。
- グレリンが、アミノ酸位置2のセリン及び/又はアミノ酸位置3のセリンがオクタン酸で改変されている、請求項26記載の方法。
- グレリンの改変が、グレリンのアミノ酸位置2のセリン及び/又はアミノ酸位置3のセリンのオクタン酸によるアシル化である、請求項27記載の方法。
- 改変されたグレリンが、アミノ酸位置3のセリンのオクタン酸によるアシル化を有するオクタノイルグレリンである、請求項28記載の方法。
- mBIが脳震とうを含む、請求項22記載の方法。
- グレリンが単回用量で投与される、請求項22記載の方法。
- 投与される量が、被験者において内在的に見出される量よりも少なくとも1.5〜100倍高い血中濃度をもたらす、請求項22記載の方法。
- 投与される量が少なくとも55pg/mLの血中濃度をもたらす、請求項32記載の方法。
- グレリンが1日当たり10ng/kg〜10mg/kgの投与量で投与される、請求項32記載の方法。
- グレリンが1日当たり2μg/kgの投与量で投与される、請求項34記載の方法。
- グレリンが唯一の活性剤である、請求項6又は22記載の方法。
- 本質的に単離されたグレリンからなる医薬組成物の治療的有効量を被験体に投与することを含む、被験体における軽度脳損傷(mBI)の治療方法。
- 単離されたグレリンが、被験体の内在グレリン血中濃度よりも少なくとも1.5倍高いグレリンの血中濃度をもたらす量で被験体に投与され、それによってmBIを治療する、請求項37記載の方法。
- 単離されたグレリンが、被験体の内在グレリン血中濃度よりも少なくとも2.0倍高いグレリンの血中濃度をもたらす量で投与され、それによってmBIを治療する、請求項22又は37記載の方法。
- 被験体が、頭蓋内圧亢進、血液脳関門の血液透過性、脳組織の壊死、脳損傷と関連する重度の脳組織若しくは細胞障害、被験体の頭部における重度のニューロン炎症又は顕著な細胞若しくは血管原性浮腫、又は被験体の脳での損傷に関連した肉眼的な解剖学的変化を有さない、請求項6又は22記載の方法。
- mBIが、認知能力若しくは運動能力の喪失、代謝異常、慢性外傷性脳症(CTE)、神経接続(neuroconnectivity)障害、脳障害及び精神的(psychological)変化、又は意識消失と関連する、請求項6又は22記載の方法。
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BR112016017886A2 (pt) | 2017-10-10 |
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AU2015214028B2 (en) | 2020-08-27 |
BR112016017886A8 (pt) | 2018-04-17 |
MX2016010085A (es) | 2016-11-15 |
US9119832B2 (en) | 2015-09-01 |
IL293712B1 (en) | 2023-04-01 |
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NZ722600A (en) | 2023-06-30 |
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