JP6166786B2 - 脳機能低下の予防または改善剤 - Google Patents
脳機能低下の予防または改善剤 Download PDFInfo
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- JP6166786B2 JP6166786B2 JP2015538829A JP2015538829A JP6166786B2 JP 6166786 B2 JP6166786 B2 JP 6166786B2 JP 2015538829 A JP2015538829 A JP 2015538829A JP 2015538829 A JP2015538829 A JP 2015538829A JP 6166786 B2 JP6166786 B2 JP 6166786B2
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- citrulline
- citicoline
- brain function
- decline
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
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- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Vascular Medicine (AREA)
- Cardiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
(1)シトルリンまたはその塩、およびシチコリンまたはその塩を有効成分として含有する脳神経細胞保護剤。
(2)シトルリンまたはその塩、およびシチコリンまたはその塩を有効成分として含有する脳機能低下の予防または改善剤。
(3)脳機能低下が、知覚能力低下、記憶学習能力低下、思考能力低下、集中力低下、注意力低下、判断能力低下、うつ症状、およびこれらに起因する運動パフォーマンス低下からなる群から選ばれる1以上の脳機能低下である(2)記載の脳機能低下の予防または改善剤。
(4)シトルリンまたはその塩、およびシチコリンまたはその塩を有効成分として経口的に摂取させることを特徴とする、脳機能低下の予防または改善方法。
(5)シトルリンまたはその塩、およびシチコリンまたはその塩を有効成分として含有する経口剤を摂取させることを特徴とする、脳機能低下の予防または改善方法。
(6)シトルリンまたはその塩、およびシチコリンまたはその塩を有効成分として経口的に摂取させることを特徴とする、脳機能低下の予防または改善方法、ただし該予防または改善方法は医師によるヒトに対する手術方法、治療方法または診断方法を含まない。
(7)シトルリンまたはその塩、およびシチコリンまたはその塩を有効成分として含有する経口剤を摂取させることを特徴とする、脳機能低下の予防または改善方法、ただし該予防または改善方法は医師によるヒトに対する手術方法、治療方法または診断方法を含まない。
(8)脳神経細胞保護に使用するためのシトルリンまたはその塩、およびシチコリンまたはその塩。
(9)脳機能低下の予防または改善に使用するためのシトルリンまたはその塩、およびシチコリンまたはその塩。
(10)脳機能低下が、知覚能力低下、記憶学習能力低下、思考能力低下、集中力低下、注意力低下、判断能力低下、うつ症状、及びこれらに起因する運動パフォーマンス低下からなる群から選ばれる1以上の脳機能低下である(9)に記載のシトルリンまたはその塩、およびシチコリンまたはその塩。
(11)脳神経細胞保護剤の製造のためのシトルリンまたはその塩、およびシチコリンまたはその塩の使用。
(12)脳機能低下の予防または改善剤の製造のためのシトルリンまたはその塩、およびシチコリンまたはその塩の使用。
(13)脳機能低下が、知覚能力低下、記憶学習能力低下、思考能力低下、集中力低下、注意力低下、判断能力低下、うつ症状、及びこれらに起因する運動パフォーマンス低下からなる群から選ばれる1以上の脳機能低下である(12)に記載の使用。
アンモニウム塩としては、アンモニウム、テトラメチルアンモニウム等の塩があげられる。
10週齢雄性C57BL/6Jマウス(日本クレア株式会社、一匹当たり平均体重約25g程度)を1週間の予備飼育した後、実験に供した。L−シトルリンおよびシチコリンは協和発酵バイオ株式会社製を用いた。
Y字迷路試験には3本のアーム(50×16×32cm)で接続されたY字型迷路装置を用いた。マウスをY字迷路のいずれかのアームの先端に置き、8分間、迷路内を自由に探索させ、マウスが移動したアームを順に記録した。マウスが測定時間内に各アームに移動した回数を計数し、これを総進入数とした。この内、連続して異なる三つのアームを選択した組み合わせを調べ、この数を自発的交替行動数とした。自発的交替行動数を総進入数から2を引いた数で割り、それに100を掛けて求めた値を自発的交替行動変化率(Alternation)とし、これを自発的交替行動の指標とした。
受動的回避試験は暗室(25×25×25cm)と明室(14×10×25cm)で構成され、暗室の床に電気刺激装置を設置した箱を用いて実施した。訓練施行では、マウスが明室から暗室に移動した際、扉を閉め、電気刺激(0.3mA、2秒間)を与えた。訓練施行から24時間後、マウスを再び明室に入れ、明室に留まった時間(Latencytime)を計測した。明室に留まる時間の測定は最大300秒とした。
新規物体認識試験はオープンフィールド装置(35×25×35cm)にマウスを個別
に2日間馴化させた後、実施した。訓練施行では、二つの同一物体を対称に置いた装置内で、マウスを10分間自由に探索させた。1時間後に片一方の物体を新規物体に置き換え、再び5分間自由に探索させた。探索行動は、マウスが物体の上に立つこと、鼻が物体に触れること、もしくは物体から1cm以内で臭いを嗅ぐことと定義した。総探索回数に対する既存物体と新規物体の探索回数の割合を算出し、視覚的認知記憶の指標とした。
両総頚動脈閉塞処置から12日後、マウスをペントバルビタールナトリウムにより麻酔をかけ、体内の血液がなくなるまで氷冷のリン酸緩衝液(PBS,pH7.4)で灌流した。その後、直ちに4%パラホルムアルデヒドを含んだ固定液で灌流した。脳組織を4℃で24時間固定し、50μmの厚さで冠状切片を作製した。海馬領域を含む連続切片をPBSに溶解したヨウ化プロピジウム(PI,5μmol/L)を用いて染色し、蛍光顕微鏡を用いて観察を行った。海馬CA1領域の錐状体細胞層の生存神経細胞と非生存神経細胞をブレグマの後方1.4〜1.8mmの区分から計数し、PIにより核が染色され、通常の形態特性を持った細胞を生存神経細胞と定義した。細胞生存率は第1群の生存神経細胞の平均数の割合から算出した。
シトルリンおよびシチコリンを含有する錠剤の製造
L−シトルリン120kg、シチコリン120kg、環状オリゴ糖19kg、セルロース57kgおよびプルラン1kgを流動層造粒乾燥機で造粒した。得られた造粒物とステアリン酸カルシウム3kgとをコニカルブレンダーで混合した後、ロータリー圧縮成形機で圧縮成形して錠剤を製造する。
シトルリンおよびシチコリンを含有する腸溶錠剤の製造
実施例1で製造する錠剤の表面をシェラック溶液でコーティングして腸溶錠剤を製造する。
シトルリンおよびシチコリンを含有する腸溶カプセルの製造
L−シトルリン120kg、シチコリン120kg、環状オリゴ糖19kg、セルロース57kg、ステアリン酸カルシウム3kgおよびプルラン1kgを、コニカルブレンダーで混合する。得られる混合物20kgと0.2kgの二酸化ケイ素とを混合攪拌して得られた混合物をカプセル充填機に投入、ハードカプセルに充填してハードカプセルを得る。得られるハードカプセルの表面をツェイン溶液でコーティングして腸溶カプセルを製造する。
シトルリンおよびシチコリンを含有する飲料の製造(1)
L−シトルリン1.28kg、シチコリン1.28kg、エリスリトール3kg、クエン酸0.05kg、人工甘味料3g、香料0.06kgを液温70℃で水50Lに攪拌溶解し、クエン酸でpHを3.3に調整後、プレート殺菌を用いて滅菌して瓶に充填後、パストライザー殺菌し、飲料を製造する。
シトルリンおよびシチコリンを含有する飲料の製造(2)
L−シトルリン20mg、シチコリン20mg、L−アルギニン20mgと適当量の果糖ぶどう糖液糖、食塩、クエン酸、香料、クエン酸Na、乳酸Ca、ピロリン酸鉄、グルコン酸Ca、塩化K、塩化Mg、甘味料とを配合し555mlの飲料を製造する。
シトルリンおよびシチコリンを含有する飲料の製造(3)
L−シトルリン100mg、シチコリン100mg、L−アルギニン100mg、L−アラニン2.5mg、L−グリシン 2.5mg、L−ロイシン2.5mg、L−イソロイシン 1.3mg、L−バリン 1.3mgと適当量の香料、甘味料を配合し300mlの飲料を製造する。
Claims (3)
- シトルリンまたはその塩、およびシチコリンまたはその塩を有効成分として含有する脳神経細胞保護剤。
- シトルリンまたはその塩、およびシチコリンまたはその塩を有効成分として含有する脳機能低下の予防または改善剤。
- 脳機能低下が、知覚能力低下、記憶学習能力低下、思考能力低下、集中力低下、注意力低下、判断能力低下、うつ症状、及びこれらに起因する運動パフォーマンス低下からなる群から選ばれる1以上の脳機能低下である請求項2に記載の脳機能低下の予防または改善剤。
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