JP6263540B2 - 脳機能向上用組成物 - Google Patents
脳機能向上用組成物 Download PDFInfo
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- JP6263540B2 JP6263540B2 JP2015533015A JP2015533015A JP6263540B2 JP 6263540 B2 JP6263540 B2 JP 6263540B2 JP 2015533015 A JP2015533015 A JP 2015533015A JP 2015533015 A JP2015533015 A JP 2015533015A JP 6263540 B2 JP6263540 B2 JP 6263540B2
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Description
本願において、別途の記載がない限り、略語AKGはα−ケトグルタル酸(式Iを参照)、
式I
及びその薬学的に許容可能な塩を意味する。本発明において、前記塩は有機塩又は無機塩である。好ましい塩の例としては、α−ケトグルタル酸のナトリウム塩及びカルシウム塩が挙げられる(それぞれ、Na−AKG及びCa−AKGと表記する)。他の好ましい塩には、カリウム−AKGとマグネシウム−AKG、また反対イオンがタンパク質(アルギニン、ロイシン、イソロイシン等)、ピリドキシン、キトサン、クレアチン又はオルチニンから自然的に発生するアミノ酸であるα−ケトグルタル酸の有機塩が含まれる。
本発明において、<パンクレリパーゼ>は、当該技術分野で定義する一般的な意味のパンクレリパーゼは勿論、パンクレアチンのような類似調合剤及び動物から採取した類似調合剤をいずれも包括する。
発明者は、AKG、またリパーゼ、プロテアーゼ、及びアミラーゼを含む組成物が神経発生と認知に影響を及ぼすという事実を明らかにした。AKGと上述の酵素を組み合わせた結果、神経発生と認知向上に相乗的効果をもたらした。当該組み合わせはシナプス形態にも相乗的効果を及ぼした。
第1様態において、本発明はα−ケトグルタル酸又はその薬学的に許容される塩(AKG)と、リパーゼ、プロテアーゼ、及びアミラーゼからなる群より選択される1種以上の酵素を含み、各成分は相乗的有効相対量で存在する新規相乗作用組成物を開示する。
第1様態の組成物はリパーゼを含んでいてもよく、必要に応じて後述のプロテアーゼ、後述のアミラーゼ、又は両方と組み合わせて含んでいてもよい。リパーゼは、哺乳類リパーゼ、微生物リパーゼ、細菌性リパーゼ、パンクレリパーゼリパーゼ(パンクレリパーゼに含まれているリパーゼ)、リプロタマーゼリパーゼ(リプロタマーゼに含まれているリパーゼ)、シュードモナスリパーゼ、ヒト又は他の哺乳類の胆汁酸塩刺激性リパーゼ(BSSL)、あるいは胆汁酸塩依存性リパーゼ(BSDL)、リゾプスオリーゼリパーゼ、クロモバクテリウムビスコスムリパーゼ、リゾプスデレマーリパーゼ、バークホルデリアリパーゼ、より好ましいバークホルデリアセパシアリパーゼ、最も好ましい架橋リパーゼ結晶であるバークホルデリアセパシアリパーゼから選択してもよい。
第1様態の組成物はプロテアーゼを含んでいてもよく、必要に応じて上述のリパーゼ、後述のアミラーゼ、又は両方と組み合わせて含んでいてもよい。プロテアーゼは、哺乳類プロテアーゼ、微生物プロテアーゼ、真菌性プロテアーゼ、パンクレリパーゼプロテアーゼ(パンクレリパーゼに含まれているプロテアーゼ)、リプロタマーゼプロテアーゼ(リプロタマーゼに含まれているプロテアーゼ)、アスペルギルスプロテアーゼ、最も好ましいアスペルギルスメレウスプロテアーゼから選択してもよい。
第1様態の組成物はアミラーゼを含んでいてもよく、必要に応じて上述のリパーゼ、上述のプロテアーゼ、又は両方と組み合わせて含んでいてもよい。アミラーゼは、哺乳類アミラーゼ、微生物アミラーゼ、真菌性アミラーゼ、パンクレリパーゼアミラーゼ(パンクレリパーゼに含まれているアミラーゼ)、リプロタマーゼアミラーゼ(リプロタマーゼに含まれているアミラーゼ)、アスペルギルスアミラーゼ、最も好ましいアスペルギルスオリーゼアミラーゼから選択してもよい。
第1様態の組成物は、AKG1g当たり300〜3,000,000USP単位のバークホルデリアセパシアリパーゼ(好ましくは架橋リパーゼ結晶)、AKG1g当たり200〜2,000,000USP単位のアスペルギルスメレウスプロテアーゼ、及びAKG1g当たり30.0〜3,000,000USP単位のアスペルギルスオリーゼアミラーゼを含んでいてもよい。
プロテアーゼ含有量:5000〜5000×5USP単位s/mmol AKG。すなわち、5,000〜25,000USP単位/mmol AKG
アミラーゼ含有量:2000/25〜2000×25USP単位/mmol AKG。すなわち、8〜50,000USP単位/mmol AKG
上述の第1様態の組成物(表Xに記載の実施形態を含む)に含有されたAKG成分は、α−ケトグルタル酸ナトリウム、α−ケトグルタル酸カルシウム、又はこれらの組み合わせ(同一量で組み合わせることが好ましい)で構成されるか、又はこれらを含んでいてもよい。AKG成分は、さらに、α−ケトグルタル酸マグネシウム又はα−ケトグルタル酸カリウムのようなAKGの他の薬学的に許容可能な無機塩、又は、オルチニン−AKG、アルギニン−AKG、キトサン−AKG、ピロドキシン−AKG、ロイシン−AKG、イソロイシン−AKG又はクレアチン−AKG、あるいはこれらの組み合わせのようなAKGの薬学的に許容可能な有機塩で構成されるか、又はこれらを含んでいてもよい。
第2様態において本発明は、薬剤として用いられる第1様態による組成物を提供する。
第9様態において、本発明は鬱病又は慢性疲労症候群の治療又は予防に用いられるα−ケトグルタル酸又はその薬学的に許容される塩を提供する。
第10様態において、本発明は、さらに神経変性疾患、神経幹細胞疾患、神経前駆細胞疾患、虚血性疾患、神経性外傷、情動障害、神経精神疾患、網膜変性疾患、網膜損傷/外傷、認知・学習・記憶障害、アルツハイマー病、軽度認知障害(MCI)、パーキンソン病及びパーキンソン症候群、ハンチントン病、筋萎縮性側索硬化症、脊髄虚血、虚血性脳卒中、外傷性脳損傷、外傷性脊髓損傷、がん関連脳/脊髓損傷、統合失調症及び他の精神疾患、脳回欠損、鬱病、双極性鬱病/障害、慢性疲労症候群、不安症候群/障害、恐怖症、ストレス症候群及び連関症候群、認知機能障害、攻撃性、薬物及びアルコール濫用、強迫性行動症候群、季節性情動障害、境界性人格障害、脳性麻痺、生活改善薬物濫用、多発虚血性脳卒中性認知症、レビー小体認知症、加齢に伴う老人性認知症、てんかん及びてんかん関連損傷、側頭葉てんかん、脊髓損傷、脳損傷、脳手術、脳震盪関連脳損傷、反復性の脳震盪又は頭部外傷による脳損傷、及び爆発の衝撃波による脳損傷を含む外傷関連脳/脊髓損傷、坑がん治療関連脳/脊髓組織損傷、感染及び炎症関連脳/脊髓損傷、環境毒素関連脳/脊髓損傷、多発性硬化症、自閉症、アスペルガー症候群、注意欠陥障害、嗜眠症、睡眠障害、認知能力又は記憶力関連障害、好酸球増加症連関障害、喘息、アトピー性皮膚炎、好酸球性食道炎及び鼻炎結膜炎;原発性胆汁性硬化、侵襲繊維状リーデル甲状腺炎、皮膚筋炎、全身性紅斑性狼瘡及びシェーグレン症候群を含む自己免疫疾患;蠕虫感染誘発性好酸球増加症を含む寄生虫感染誘発性好酸球増加症;移植片対宿主病;薬物誘発性好酸球増加症;原発性好酸球増加症、原発性皮膚T細胞リンパ腫関連好酸球増加症を含む新生物性疾患誘発性好酸球増加症、セザリー症候群、ホジキン病、ランゲルハンス細胞組織球増加症、甲状腺がん、胃がん、肝がん及び膀胱がんを治療又は予防する方法として用いられるα−ケトグルタル酸又はその薬学的に許容される塩を提供する。当該方法は、被験体にα−ケトグルタル酸又はその薬学的に許容される塩と、リパーゼ、プロテアーゼ、及びアミラーゼの中1種以上を投与することを含む。
実施例1:海馬神経発生の誘導
「構成物質及び方法」で指定された治療過程を経た後、実験動物を解剖して脳を組織学的に分析して海馬の神経発生を定量化した。
治療過程において、「構成物質及び方法」で指定されたようにT型迷路試験を通じて実験動物の認知機能及び/又は記憶力を測定した。
「構成物質及び方法」に詳しく記述されたように、血液標本を分析して血液パラメーターにおける効果を判定した。
序論
研究者は、ヒト及び他の脊椎動物の頭脳で重要な構成要素に該当する海馬を研究対象として選定した。海馬は、大脳辺縁系の一部であり、また短期記憶から長期記憶への情報の統合、空間記憶及び空間知覚、感情及び行動の形成、認知機能において重要な役割を担当する。海馬は多様な侵害刺激に非常に脆弱である。酸素欠乏(低酸素症)、脳炎、側頭葉てんかん、加齢関連疾患(アルツハイマー病)等によって海馬は損傷することがある。海馬は、脳で最初に損傷する領域の中の1つであり、初期症状としては記憶喪失及び方向感覚の喪失が含まれる。
高齢体の錐体ニューロンがさらに小さく、樹状突起の枝と棘の数も少ないという事実が明らかになった。シナプス後膜の長さ単位に対するシナプス前末端の密度も低い。
研究で分析したCA1放射状層の中央部分において、シナプス入力のほとんど大部分は興奮性であり、樹状突起軸で選択的に断絶される。この点を考慮して、研究者は興奮性CA1棘シナプスのプールに分析の焦点を合わせた。
高齢体アレチネズミの海馬シナプスで小胞から活性帯までの距離及び直近の小胞までの距離増加を含む、シナプス小胞の空間分布の変化が発生した。
実施例1ラインの高齢のスナネズミを用いて実験を繰り返して行い、但し、酵素成分を「構成物質及び方法」に指定されたことによって改良した。
実施例1において、表1に記載の試験化合物を動物に補ったLabofeed B標準飼料(Labofeed company;Andrzej Morawski Feed Production Plant,Kcynianear.Bydgoszcz,Poland)を供給した。
動物及び動物飼育方法(実施例1〜4)
長期間(6ヶ月)飼育した雄スナネズミ75匹を任意に選択して実験に用いた。選択したネズミは実験開始時点で約1.5歳であり、平均体重は88.0±6gであり、実験終了時点では2歳であった。また、ちょうど成体になった「幼年体」の雄スナネズミ6匹(6月齢)を追加し、<年齢適合対照群>として用いた(グラフでは「Control(young)」、「Young」又は「Y」で示す)。
上述の実施例1〜4と同一の方法で実験動物を飼育し、実験対象は2つの群に限定し、表3〜4によって治療した。
形態学的標本の製造
実験終了時点で、スナネズミをケタミン(100mg/kg体重i/m)で麻酔し、固定して0.1Mリン酸緩衝液内の4%ホルムアルデヒド及び0.25%グルタルアルデヒドで経心腔的灌流を行った。灌流後に脳を摘出して両半球に分離した。
兔疫細胞化学用標本(各動物の半球1つ)を+4℃で同一固定剤でひと晩の間後置した。翌日、標本をvibratome Vibroslice 752M(Campden Instruments社、イギリス)を用いて50μm厚さの前頭骨切片に切り出した。脳切片を0.1Mリン酸緩衝液(pH7.4)で洗浄し、1%正常ヤギ血清と0.3%Triton X−100を含有する遮断溶液で処理した。ヤギの単クロン性抗ネスチン抗体(1:500)(Santa Cruz biotechnology社、USA)を神経特異性中間フィラメントネスチンを見つける増殖型幼若神経細胞を検出するに用いた。切片を+4℃で16時間1次抗体で培養した。洗浄後に切片をAlexa Fluor 647(1:1000)(Molecular probes、USA)と接合した抗ヤギ2次抗体で1.5時間室温で培養した。その後、切片を洗浄し、組織スライド上に蛍光染色用マウンティングメディウム(Dako、デンマーク)と共に載置した。海馬組織の画像を共焦点型FV1000−BX61WI顕微鏡(Olympus、日本)で撮影した。CA1海馬領域のネスチン陽性細胞分布図の定性的分析を各実験群に対して行った。
統計データはいずれもSTATISTICA ver.7.0(StatSoft、USA)で評価した。2標本コルモゴルフ−スミルノフ検定を用いて標本間の差異を評価した(p<0.05は統計的有意性を現す)。SE(標準誤差)をエラーバーとして用いた。
電子顕微鏡検査
スナネズミを致死量未満のケタミン(100mg/kg体重i/m)で麻酔し、固定して0.1Mリン酸緩衝液内の4%ホルムアルデヒド、及び0.25%グルタルアルデヒドで経心腔的灌流を行った。灌流後に脳を摘出して両半球に分離した。
2群(リパーゼ+プロテアーゼ+アミラーゼ)
3群(AKG+リパーゼ+プロテアーゼ+アミラーゼ)
4群(高齢対照群)
群(幼年体)
調査領域のシナプス末端はシナプス末端形状(単純、穿孔、複数の神経繊維末端)の比率変化を含んで高い水準の構造可塑性を現した。穿孔シナプスは不連続PSDを有するシナプスで定義した。同一のシナプス前末端と接触する棘が1つ以上であるシナプスを、複数棘神経繊維末端(MSB)に分類した。
単一写真を用いて、計数フレーム(36mkm2検定領域)に限定される顕微鏡写真面上の非対称棘シナプス(シナプス前末端の活性帯において***PSDとドッキングされているシナプス小胞(SV)とを有する棘の存在の有無により判定する)を全部計数し、単位表面積当たりのシナプス数を算出してシナプス密度を推定した。
T型迷路自発的交替行動
T型迷路自発的交替行動は、動物、特にCNS障害げっ歯類モデルの探査行動を測定する行動試験である。この試験は、新しい環境を探険しようとするげっ歯類の意欲、すなわち迷路の慣れた通路よりも新しい通路を選好する傾向に基づいている。脳の多くの部分(海馬、中隔、前脳基底部、前頭葉皮質)がこのような課題に関与する。
研究終了時点で、血液分析機ABX Micros 60 OT(フランス)を用いて標準方法によって血液パラメーターを研究した。
Claims (31)
- α−ケトグルタル酸(AKG)又はその薬学的に許容される塩、リパーゼ、プロテアーゼおよびアミラーゼを含む組成物であって、神経変性疾患、神経幹細胞疾患、神経前駆細胞疾患、虚血性疾患、神経性外傷、情動障害、神経精神疾患、網膜変性疾患、網膜損傷/外傷、認知・学習・記憶障害、アルツハイマー病、軽度認知障害(MCI)、パーキンソン病及びパーキンソン症候群、ハンチントン病、筋萎縮性側索硬化症、虚血性脳卒中、外傷性脳損傷、鬱病、双極性鬱病/障害、慢性疲労症候群、不安症候群/障害、自閉症、アスペルガー症候群、注意欠陥障害又は認知能力又は記憶力関連障害の治療又は予防のための、組成物。
- AKG1mmol当たり200ないし20,000USP単位のリパーゼ、AKG1mmol当たり500ないし50,000USP単位のプロテアーゼおよびAKG1mmol当たり200ないし20,000USP単位のアミラーゼを含む、請求項1に記載の組成物。
- リパーゼ、プロテアーゼ、及び/又はアミラーゼを、表Y及び表Zを参照として表Xに示した実施形態に基づく量で含む、請求項1に記載の組成物。
- 哺乳類リパーゼ、微生物リパーゼ、細菌性リパーゼ、パンクレリパーゼリパーゼ、リプロタマーゼリパーゼ、シュードモナスリパーゼ、ヒト又は他の哺乳類の胆汁酸塩刺激性リパーゼ(BSSL)、ヒト又は他の哺乳類の胆汁酸塩依存性リパーゼ(BSDL)、リゾプスオリーゼリパーゼ、クロモバクテリウムビスコスムリパーゼ、リゾプスデレマーリパーゼ、バークホルデリアリパーゼ、バークホルデリアセパシアリパーゼおよび架橋リパーゼ結晶であるバークホルデリアセパシアリパーゼからなる群より選択されるリパーゼを含む、請求項1ないし3のいずれか一項に記載の組成物。
- 哺乳類プロテアーゼ、微生物プロテアーゼ、真菌性プロテアーゼ、パンクレリパーゼプロテアーゼ、リプロタマーゼプロテアーゼ、アスペルギルスプロテアーゼおよびアスペルギルスメレウスプロテアーゼからなる群より選択されるプロテアーゼを含む、請求項1ないし4のいずれか一項に記載の組成物。
- 哺乳類アミラーゼ、微生物アミラーゼ、真菌性アミラーゼ、パンクレリパーゼアミラーゼ、リプロタマーゼアミラーゼ、アスペルギルスアミラーゼおよびアスペルギルスオリーゼアミラーゼからなる群より選択されるアミラーゼを含む、請求項1ないし5のいずれか一項に記載の組成物。
- 架橋リパーゼ結晶であるAKG1g当たり3,000〜300,000USP単位のバークホルデリアセパシアリパーゼ、AKG1g当たり2,000〜200,000USP単位のアスペルギルスメレウスプロテアーゼ、及びAKG1g当たり300〜30,000USP単位のアスペルギルスオリーゼアミラーゼを含む請求項1に記載の組成物。
- AKG1g当たり300〜300,000USPリパーゼ単位のリプロタマーゼに相当する量のリプロタマーゼを含む、請求項1に記載の組成物。
- AKG1g当たり300〜300,000USPリパーゼ単位のパンクレリパーゼに相当する量のパンクレリパーゼを含む、請求項1に記載の組成物。
- 前記組成物はα−ケトグルタル酸ナトリウムまたはα−ケトグルタル酸カルシウムを含む請求項1ないし請求項9のいずれか一項に記載の組成物。
- 患者に1日当たりAKG0.1〜30gの量を投与するために製剤される、請求項1ないし請求項10のいずれか一項に記載の組成物。
- 患者にAKG0.5〜240mmolの量を投与するために製剤される、請求項1ないし請求項11のいずれか一項に記載の組成物。
- 投与される量がAKG0.5〜24mmolである、請求項12に記載の組成物。
- 投与される量がAKG1〜12mmolである、請求項13に記載の組成物。
- α−ケトグルタル酸(AKG)又はその薬学的に許容される塩、リパーゼ、プロテアーゼおよびアミラーゼを含む、神経変性疾患、神経幹細胞疾患、神経前駆細胞疾患、虚血性疾患、神経性外傷、情動障害、神経精神疾患、網膜変性疾患、網膜損傷/外傷、認知・学習・記憶障害、アルツハイマー病、軽度認知障害(MCI)、パーキンソン病及びパーキンソン症候群、ハンチントン病、筋萎縮性側索硬化症、虚血性脳卒中、外傷性脳損傷、鬱病、双極性鬱病/障害、慢性疲労症候群、不安症候群/障害、自閉症、アスペルガー症候群、注意欠陥障害、又は認知能力又は記憶力関連障害の治療又は予防のための組み合わせ剤であって、前記AKG、リパーゼ、プロテアーゼおよびアミラーゼを同時に、別途に又は連続して投与できるものである、組み合わせ剤。
- リパーゼ、プロテアーゼ、及び/又はアミラーゼを、表Y及び表Zを参照として表Xに示した実施形態に基づきAKGの量に対応する量で投与することを含む、請求項15に記載の組み合わせ剤。
- 前記リパーゼは哺乳類リパーゼ、微生物リパーゼ、細菌性リパーゼ、パンクレリパーゼリパーゼ、リプロタマーゼリパーゼ、シュードモナスリパーゼ、ヒト又は他の哺乳類の胆汁酸塩刺激性リパーゼ(BSSL)、ヒト又は他の哺乳類の胆汁酸塩依存性リパーゼ(BSDL)、リゾプスオリーゼリパーゼ、クロモバクテリウムビスコスムリパーゼ、リゾプスデレマーリパーゼ、バークホルデリアリパーゼ、バークホルデリアセパシアリパーゼおよび架橋リパーゼ結晶であるバークホルデリアセパシアリパーゼからなる群より選択される、請求項15または16に記載の組み合わせ剤。
- 前記プロテアーゼは哺乳類プロテアーゼ、微生物プロテアーゼ、真菌性プロテアーゼ、パンクレリパーゼプロテアーゼ、リプロタマーゼプロテアーゼ、アスペルギルスプロテアーゼおよびプロテアーゼはアスペルギルスメレウスプロテアーゼからなる群より選択される、請求項15ないし17のいずれか一項に記載の組み合わせ剤。
- 前記アミラーゼは哺乳類アミラーゼ、微生物アミラーゼ、真菌性アミラーゼ、パンクレリパーゼアミラーゼ、リプロタマーゼアミラーゼ、アスペルギルスアミラーゼおよびアスペルギルスオリーゼアミラーゼからなる群より選択される、請求項15ないし18のいずれか一項に記載の組み合わせ剤。
- リパーゼの量はAKG1mmol当たり200〜20,000USP単位のリパーゼである、請求項15ないし請求項19のいずれか一項に記載の組み合わせ剤。
- プロテアーゼの量はAKG1mmol当たり500〜5,000USP単位のプロテアーゼである、請求項15ないし請求項20のいずれか一項に記載の組み合わせ剤。
- アミラーゼの量はAKG1mmol当たり200〜20,000USP単位のアミラーゼである、請求項15ないし請求項21のいずれか一項に記載の組み合わせ剤。
- 各酵素の量が架橋リパーゼ結晶としてAKG1g当たり3,000〜300,000USP単位のバークホルデリアセパシアリパーゼ、AKG1g当たり2,000〜200,000USP単位のアスペルギルスメレウスプロテアーゼ、及びAKG1g当たり300〜30,000USP単位のアスペルギルスオリーゼアミラーゼである、請求項15に記載の組み合わせ剤。
- AKG1g当たり300〜300,000USPリパーゼ単位のリプロタマーゼに相当する量のリプロタマーゼを含む、請求項15に記載の組み合わせ剤。
- AKG1g当たり300〜300,000USPリパーゼ単位のパンクレリパーゼに相当する量のパンクレリパーゼを含む、請求項15に記載の組み合わせ剤。
- α−ケトグルタル酸ナトリウムまたはα−ケトグルタル酸カルシウムを含む、請求項15ないし請求項25のいずれか一項に記載の組み合わせ剤。
- 被験者に1日当たりAKG0.03〜100gを投与するために製剤される、請求項15ないし請求項26のいずれか一項に記載の組み合わせ剤。
- 被験者に1日当たりAKG0.5〜240mmolを投与するために製剤される、請求項15ないし請求項27のいずれか一項に記載の組み合わせ剤。
- 被験者に1日当たりAKG0.5〜24mmolを投与するために製剤される、請求項28に記載の組み合わせ剤。
- 被験者に1日当たりAKG1〜12mmolを投与するために製剤される、請求項29に記載の組み合わせ剤。
- 被験者に1日当たりAKG3〜9mmolを投与するために製剤される、請求項30に記載の組み合わせ剤。
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