JP6226962B2 - ノンレム睡眠促進剤、深睡眠促進剤、自然睡眠誘発剤、および睡眠初期デルタパワー向上剤 - Google Patents
ノンレム睡眠促進剤、深睡眠促進剤、自然睡眠誘発剤、および睡眠初期デルタパワー向上剤 Download PDFInfo
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- A61K31/7076—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 containing purines, e.g. adenosine, adenylic acid
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Description
〔1〕メチルチオアデノシンまたはその塩を含有する、ノンレム睡眠促進剤。
〔2〕メチルチオアデノシンまたはその塩を含有する、深睡眠促進剤。
〔3〕メチルチオアデノシンまたはその塩を含有する、自然睡眠誘発剤。
〔4〕上記〔1〕のノンレム睡眠促進剤、上記〔2〕の深睡眠促進剤または上記〔3〕の自然睡眠誘発剤を含有する、内服組成物。
本発明の深睡眠促進剤は、メチルチオアデノシンまたはその塩を有効成分として含有する。本明細書において、メチルチオアデノシンは、5’−デオキシ−5’−メチルチオアデノシンを意味する。5’−デオキシ−5’−メチルチオアデノシンは、アンチ(anti)型またはシン(syn)型のいずれの形態であってもよい。なお、以下本明細書においては、メチルチオアデノシンまたはその塩を、MTAと略称する場合がある。
マウスやモルモットの睡眠には、ヒトのIII層およびIV層の睡眠に対応した一般的な判定基準は現在ないため、マウスやモルモットの睡眠にはデルタパワー値そのものを用い、さらにデルタパワー値に時間を乗じた値を、深睡眠の大きさとし得る。
ノンレム睡眠はポリソムノグラフ解析(脳波、眼電図、筋電図)により判定できる。脳波としては、アルファ波の減少、およびデルタ波の増加によりノンレム睡眠を判定することができる。測定した脳波を、SleepSign(登録商標)などの自動解析ソフトを用いても判定することができる。
「深睡眠を促進する」とは、対比される状態(例えば、深睡眠促進剤投与前の状態)と比べて、1)深睡眠の状態がより長時間観察されること、2)深睡眠の深さがより深まること、または、3)深睡眠への移行がより円滑に進むこと、のいずれかの効果が観察されることをいう。マウスやモルモットを用いた実験系の場合には、上記のデルタパワー値に時間を乗じた値が大きくなることをいう。
(1)メチルチオアデノシンまたはその塩を投与する、深睡眠促進方法または自然睡眠誘発方法。
(2)メチルチオアデノシンまたはその塩を経口投与する、上記(1)の方法。
(3)メチルチオアデノシンまたはその塩の、深睡眠促進剤または自然睡眠誘発剤を製造するための使用。
日本SLCより購入した8週齢雄性C57BL/6マウスに、脳波および筋電用の電極を装着した。電極装着後、回復チャンバーにて10日間回復させた。その後、記録用チャンバーに移し、ケーブルを接続した。脳波解析ソフトであるSleepSign(登録商標)Ver 3.0(キッセイコムテック株式会社)にて脳波判別が可能であったマウスを、3日間馴化させた。さらに、脳波を24時間測定し、睡眠覚醒リズムが維持されているマウスに対して、投与群分けを実施した。投与群は、体重当たりのMTA投与量を、5mg/kg、10mg/kg、15mg/kg、または30mg/kgとする4つの群と、コントロール溶液を投与する群に分けた。各投与群のマウスは8匹とした(n=8)。MTAは、シグマ−アルドリッチ社から市販されている製品(商品名:5'−Deoxy−5'−(methylthio)adenosine)を用いた。コントロール溶液は、0.5質量%メチルセルロース水溶液を用いた。なお、メチルセルロースは、シグマ−アルドリッチ社市販品(商品名:Methyl cellulose、2%水溶液、20℃での、粘度が25cPのもの)を用いた。
MTA含有酵母培養物は、以下のようにして調製した。市販のS−アデノシルメチオニン含有酵母培養物粉末(メーカー名:三菱ガス化学株式会社、商品名:SAMe含有乾燥酵母)を120℃で20分加熱処理した。得られた酵母培養物中のメチルチオアデノシン含有量は320mg、酵母培養物(MTAを含む)の乾燥重量は5000mg、MTA以外の酵母培養物の乾燥重量は4680mgであった。すなわち、酵母培養物に対するメチルチオアデノシン含有量の質量比は6.4質量%であった。
脳波は、スリープウェル(株)に依頼して解析した。睡眠の深さは睡眠中脳波のデルタパワー値によって知ることができ、デルタパワー値が大きいほど睡眠の深さは深い。一般に、就寝直後にノンレム睡眠が出現し、その後レム睡眠が出現する。本実験では、就寝直後に出現したノンレム睡眠中のデルタパワー値(すなわち、就寝後一旦ノンレム睡眠に入ったその後にレム睡眠が出現するまでのデルタパワー値)を、睡眠初期のデルタパワー値とした。
式(1):
デルタパワー値の変化率(%)=
{(MTA含有酵母摂取後のデルタパワー値の平均値)
/(プラセボ摂取後のデルタパワー値の平均値)}×100
表3にデルタパワー値の変化率を示す。デルタパワー値の変化率は、被験者6人の平均値である。
Claims (8)
- メチルチオアデノシンまたはその塩を含有する、ノンレム睡眠促進剤。
- メチルチオアデノシンまたはその塩を含有する、深睡眠促進剤。
- メチルチオアデノシンまたはその塩を含有する、自然睡眠誘発剤。
- メチルチオアデノシンまたはその塩を含有する、睡眠初期デルタパワー向上剤。
- 1日あたりのメチルチオアデノシンまたはその塩の投与量が0.01〜1000mgである、請求項1〜4のいずれか1項に記載の剤。
- メチルチオアデノシンまたはその塩を含有する、ノンレム睡眠促進用、深睡眠促進用、自然睡眠誘発用、又は睡眠初期デルタパワー向上用内服組成物。
- メチルチオアデノシンまたはその塩を含有する、ノンレム睡眠促進用、深睡眠促進用、自然睡眠誘発用、又は睡眠初期デルタパワー向上用食品組成物。
- 1日あたりのメチルチオアデノシンまたはその塩の投与量が0.01〜1000mgである、請求項6又は7に記載の組成物。
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