JP6323886B2 - うつ治療剤 - Google Patents
うつ治療剤 Download PDFInfo
- Publication number
- JP6323886B2 JP6323886B2 JP2016519322A JP2016519322A JP6323886B2 JP 6323886 B2 JP6323886 B2 JP 6323886B2 JP 2016519322 A JP2016519322 A JP 2016519322A JP 2016519322 A JP2016519322 A JP 2016519322A JP 6323886 B2 JP6323886 B2 JP 6323886B2
- Authority
- JP
- Japan
- Prior art keywords
- acetyl
- mannosamine
- depression
- administration
- represented
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- OHHDIOKRWWOXMT-UHFFFAOYSA-N trazodone hydrochloride Chemical compound [H+].[Cl-].ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 OHHDIOKRWWOXMT-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- 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
- A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
〔1〕 N−アセチル−D−マンノサミンを含有してなる、うつの治療剤。
〔2〕 N−アセチル−D−マンノサミンが下記式(I)、(IIa)、(IVa)、(IVb)および(IVc):
〔3〕 N−アセチル−D−マンノサミンが下記式(IVa):
〔4〕 経口剤、注射剤、点滴剤または外用剤である、〔1〕〜〔3〕のいずれかに記載の治療剤。
〔5〕 N−アセチル−D−マンノサミンの有効量および医薬として許容されうる担体を含有してなる、うつを治療するための医薬組成物。
〔6〕 N−アセチル−D−マンノサミンが下記式(I)、(IIa)、(IVa)、(IVb)および(IVc):
〔7〕 N−アセチル−D−マンノサミンが下記式(IVa):
〔8〕 静脈内、筋肉内、髄液内または経口投与用剤型である、〔5〕〜〔7〕のいずれかに記載の医薬組成物。
〔9〕 うつの治療用医薬を製造するためのN−アセチル−D−マンノサミンの使用。
〔10〕 N−アセチル−D−マンノサミンが下記式(I)、(IIa)、(IVa)、(IVb)および(IVc):
〔11〕 N−アセチル−D−マンノサミンが下記式(IVa):
〔12〕 N−アセチル−D−マンノサミンの有効量をそれを必要とする対象に投与する工程を含む、うつの治療方法。
〔13〕 N−アセチル−D−マンノサミンが下記式(I)、(IIa)、(IVa)、(IVb)および(IVc):
〔14〕 N−アセチル−D−マンノサミンが下記式(IVa):
「うつ」の診断は、DSM−5に規定されている。あるいは、ICD(International Statistical Classification of Diseases and Related Health Problems)−10にうつ病の診断基準が定められており、基本症状として、以下のうちの少なくとも2つがみられることが基準となっている。
1)抑うつ気分
2)興奮と喜びの喪失
3)活力の減退による易疲労感の増大、活動性の減少
N−アセチル−D−マンノサミンは、例えば、下記式(II)で示される化合物であってもよい。
R5は水素(H)、R6、−C(=O)OR6、−C(=O)NR6R7、−C(=O)−CH2−R8を示し、R6は置換基を有していてもよいC1−7の鎖状炭化水素または環状炭化水素を示し、R7は水素(H)、置換基を有していてもよいC1−7の鎖状炭化水素または環状炭化水素を示し、R8は置換基を有していてもよいC1−7の鎖状炭化水素または環状炭化水素、−(CH2)n−C(=O)R9(nは1〜6の整数であり、R9はC1−6アルキルである)、−NH−C(=O)R10(R10は置換基を有していてもよいC1−7の鎖状炭化水素である)、アジド、オキシカルボニル−C1−6アルキル、チオカルボニル−C1−6アルキルを示す。〕
置換基としてはハロゲン原子(フッ素、塩素、臭素、ヨウ素)を用いることができる。
SSRIとしては、フルボキサミン、シタロプラム、エスシタロプラム、フルオキセチン、パロキセチン、セルトラリンおよび医薬として許容されるそれらの塩などがあげられる。
ドーパミンおよびノルエピネフリン再取り込み阻害剤としては、ブプロピオンおよび医薬として許容されるその塩などがあげられる。
SNRIとしては、ミルナシプラン、ベンラファキシン、デスベンラファキシン、デュロキセチンおよび医薬として許容されるそれらの塩などがあげられる。
セロトニンモジュレータとしては、ネファゾドン、トラゾドンおよび医薬として許容されるそれらの塩などがあげられる。
ノルエピネフリン−セロトニンモジュレータとしては、ミルタザピンおよび医薬として許容されるその塩などがあげられる。
三環系抗うつ薬としては、アミトリプチリン、クロミプラミン、ドキセピン、イミプラミン、トリイミプラミン、アモキサピン、デシプラミン、マプロチリン、ノルトリプチリン、プロトリプチリンおよび医薬として許容されるそれらの塩などがあげられる。
四環系抗うつ薬としては、ミアンセリン、セチプチリンおよび医薬として許容されるそれらの塩などがあげられる。
トリアゾロピリジン系抗うつ薬としては、塩酸トラゾドンなどがあげられる。
MAOIとしては、フェネルジン、トラニルシプロミン、イソカルボキサジド、セレギリン、モクロベミドおよび医薬として許容されるそれらの塩などがあげられる。
あるいは、増補薬(抗不安薬、抗精神病薬、リチウム塩など)との組合せも可能である。
<ManNAc投与条件>
ManNAcを飲料水に溶解し、5mg/mlの濃度とした飲水を、若齢マウス(C57BL/6系統、オス)に対して自由飲水投与で10週齢時から14週齢時まで計4週間投与した(ManNAc投与群:16例)。週齢を合わせた対照群のマウスに対しては、飲料水を自由飲水させた(対照群:16例)。
同様に、5mg/mlのManNAc含有飲水を、老齢マウス(C57BL/6系統、オス)に対して自由飲水投与で56週齢時から59週齢時まで計4週間投与した(ManNAc投与群:14例)。週齢を合わせた対照群のマウスに対しては、飲料水を自由飲水させた(対照群:15例)。
<強制水泳試験>
S. C. Dulawa et al., Neuropsychopharmacology (2004) 29, 1321-1330に記載の方法に準じて、直径約28cm、高さ約18cmのプラスチック製バケットに深さ約12cmまで20-25℃の水を満たした水槽内に、マウスを1匹ずつ6分間放置し、マウスの行動をビデオテープに録画した。4つの評価基準:水泳、無動、よじ登り、およびその他に関して採点し、5秒毎に優勢な行動を記録した。1回6分間の実験を3日間繰り返した。結果を図1に示す。
マウスは、水プールに強制的に入れられると、泳いで岸にたどり着こうとする。しかし、一定の時間がくると、諦めて泳ぐことを止める(無動)。6分間の強制水泳試験は、水槽内の無動を定量することができ、該無動は、うつで観察される「行動的絶望」に類似していることが提案されている。無動時間が長いほどうつ行動が強いことを表し、無動時間が短いほどうつ行動が弱いことを表している。図1に示すように、若齢マウスの対照群では、約2分間の総無動時間が観察されたのに対し、ManNAc投与群では、約1分間の総無動時間が観察された。このことから、ManNAcは、経口投与による抗うつ効果に優れており、うつの著しい改善効果を有することが認められた。
また、図1に示すように、老齢マウスの対照群では、約2分30秒間の総無動時間が観察されたのに対し、ManNAc投与群では、約1分40秒〜2分間の総無動時間が観察された。このことから、ManNAcは、経口投与により、老齢マウスのうつ症状に対しても改善効果を有することが認められた。
S. C. Dulawa et al., Neuropsychopharmacology (2004) 29, 1321-1330において、本発明の実施例1と同様の強制水泳試験を実施して、SSRIであるfluoxetineの抗うつ作用を調べている(1325頁、Figure 2)。Figure 2に示されるように、用いたマウスの系統により無動時間は異なるが、BALB/cおよびC57BL/6系統では、薬物非投与群では約125-130秒(約2分間)の無動時間が観察されるのに対し、fluoxetine(10mg/kg/day)投与群では、BALB/c系統で約100秒、C57BL/6系統で約125秒と、無動時間はほとんど減少していない(1325頁、Figure 2 b)。S. C. Dulawa et al.の強制水泳試験で用いたマウスの週齢は明記されていないが、薬物非投与群の無動時間を考慮すると、本発明で若齢マウスを用いた強制水泳試験の結果との対比が可能であると考えられる。本発明の実験結果から、ManNAcは、既存の抗うつ薬と比較しても抗うつ効果に優れていることが認められる。
<ManNAc投与条件>
実施例1と同様の条件下で、ManNAcを若齢マウス(C57BL/6系統、オス)に自由飲水投与で10週齢時から14週齢時まで計4週間投与した(ManNAc投与群:14例)。週齢を合わせた対照群のマウスに対しては、飲料水を自由飲水させた(対照群:14例)。
<社会的敗北試験>
攻撃性の高いマウス(攻撃マウス)と一定期間(1時間)同居させたマウスは、その後攻撃マウスに近寄らなくなる。本試験方法は、脳の高次機能を反映し、社会的敗北試験として開発され、社会的不安を評価する系として広く利用されている(Nature (2008) 455,894-902)。ManNAc投与群および対照群を、攻撃マウスと1対1で1日1時間同居させ、敗北ストレスを5日間経験させた。その後、一辺45cmの正方形の区画内の特定の区画内に収容した攻撃マウスと、正方形区画内の特定区画外を自由に行動できるように収容した敗北ストレス経験マウスを5分間同居させた。5分間のうちの後半の3分間に、攻撃マウスが収容されている区画の周囲に設けられた接触ゾーンに敗北ストレス経験マウスが侵入した回数および敗北ストレス経験マウスの匂い嗅ぎ時間を計数した。敗北ストレスを経験しないマウス(非ストレス経験群)も同様に試験した。試験の概要および結果を図2に示す。
社会的敗北を経験したマウスは、社会(攻撃マウス)から回避する行動が誘発される。かかる回避行動は、うつで観察される「ひきこもり」に類似している。接触ゾーン侵入回数、接触ゾーン滞在時間および匂い嗅ぎ時間(覗き込み時間)が少ないほどうつ行動が強いことを表し、多いほどうつ行動が弱いことを表している。図2に示すように、接触ゾーン侵入回数では有意差は得られなかったが、非ストレス経験群(飲料水投与、非ストレス経験)は、約30秒間の匂い嗅ぎ行動が観察されるのに対し、敗北ストレス経験マウス(飲料水投与、水)では、約20秒間以下に減少していた。しかし、ManNAc投与群では、非ストレス経験群と同様に約30秒間の匂い嗅ぎ行動が観察された。このことから、ManNAcは、社会的敗北経験で誘発されるうつに対する改善効果にも優れていることが認められた。
<5S−ManNAcF、ManNAc投与条件>
脳室内にカテーテルを移植し、背部にオスミックポンプ(0.11μl/時間、Alzet社、No1004、100μlの容量が28日間で放出される)を連結した8−9週齢マウス(C57BL/6系統、オス)を用いて、生理食塩水に溶解した5S−ManNAcF(0.01、0.1mmol/L)またはManNAc(100mmol/L)を、脳室内に3週間投与した(投与群:各9−10例)。週齢を合わせた対照群のマウスに対しては、生理食塩水を投与した(対照群:各9−10例、SAL)。
<強制水泳試験>
投与3週間後に、実施例1と同様に強制水泳試験を実施した。結果を図3に示す。
0.1mmol/Lの5S−ManNAcF投与群では、対照群と比べて有意に総無動時間が減少した。このことから、5S−ManNAcFは、脳室内投与による抗うつ効果に優れており、うつの著しい改善効果を有することが認められた。
<5S−ManNAcF投与条件>
実施例3と同様に、5S−ManNAcF(0.01、0.1、1mmol/L投与群:各9−10例)を脳室内投与した。ただし、投与期間は1週間とした。週齢を合わせた対照群のマウスに対しては、生理食塩水を投与した(対照群:各9−10例、SAL)。
<強制水泳試験>
投与1週間後に、実施例1と同様に強制水泳試験を実施した。結果を図4に示す。
0.1mmol/Lの5S−ManNAcFの投与群では、1週間の投与でも、対照群と比べて総無動時間の減少傾向が認められた。また、5S−ManNAcFは、高用量の1mmol/Lの濃度よりも0.1mmol/Lの濃度における効果が高い傾向が認められた。
Claims (7)
- N−アセチル−D−マンノサミンを含有してなる、うつの治療剤であって、N−アセチル−D−マンノサミンが下記式(IIa)、(IVa)、(IVb)および(IVc):
- N−アセチル−D−マンノサミンが下記式(IVa):
- 経口剤、注射剤、点滴剤または外用剤である、請求項1または2に記載の治療剤。
- N−アセチル−D−マンノサミンの有効量および医薬として許容されうる担体を含有してなる、うつを治療するための医薬組成物であって、N−アセチル−D−マンノサミンが下記式(IIa)、(IVa)、(IVb)および(IVc):
- N−アセチル−D−マンノサミンが下記式(IVa):
- 静脈内、筋肉内、髄液内または経口投与用剤型である、請求項4または5に記載の医薬組成物。
- 下記式(IVa)、(IVb)および(IVc):
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