JP2011508765A - 抗精神病薬と組み合わせたカンナビノイドの使用 - Google Patents
抗精神病薬と組み合わせたカンナビノイドの使用 Download PDFInfo
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- JP2011508765A JP2011508765A JP2010541094A JP2010541094A JP2011508765A JP 2011508765 A JP2011508765 A JP 2011508765A JP 2010541094 A JP2010541094 A JP 2010541094A JP 2010541094 A JP2010541094 A JP 2010541094A JP 2011508765 A JP2011508765 A JP 2011508765A
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Abstract
【選択図】なし
Description
急性単回投与試験を行い、ここでは食餌誘導性肥満マウスに下記のいずれかを投与した:
純粋なTHCV(0.3mg/kg)+CBD BDS(0.3mg/kgでのCBD)又は
純粋なTHCV(3.0mg/kg)+CBD BDS(3.0mg/kgでのCBD)。
単回投与後の対照動物と比較して、THCV及びCBDの組合せを投与した研究動物の体重に対する単回投与後の効果の差は見られなかった(データは示さず)。
28日間の慢性投与試験を行い、ここでは食餌誘導性肥満マウスに強制経口投与により、毎日09:00に下記のいずれかを投与した:
純粋なTHCV(0.3mg/kg)+CBD BDS(0.3mg/kgでのCBD)又は
純粋なTHCV(3.0mg/kg)+CBD BDS(3.0mg/kgでのCBD)。
食品及び水の摂取量(毎日)、
体重(週に二度)、
24時間エネルギー消費量(3日目及び10日目)、
5時間絶食マウスにおける経口的ブドウ糖負荷試験(OGTT、グルコース負荷3g/kg)(7日目及び21日目)、
混合食餌に対する熱応答(17日目)、
麻酔をかけたマウスにおけるデキサスキャンによる身体組成(体脂肪%)(28日目)、
鼻−肛門長測定(28日目)、
グルコース、乳酸、インスリン、トリグリセリド、コレステロール、HDL−コレステロールの測定のための摂食マウスからの血液サンプル(28日目)、
グルコース、遊離脂肪酸、インスリン及びアディポネクチンの測定のための絶食マウスからの血液サンプル(30日目)、及び
投与の2〜3時間後の薬物レベル&エンドカンナビノイドレベル(30日目)。
純粋なTHCV+CBD BDSは、体脂肪パーセントを低減させる。
純粋なTHCV+CBD BDSは、エネルギー消費量を有意に増加させる(低用量及び高用量)。
純粋なTHCV+CBD BDSは、総コレステロールレベルを大きく低減させた(高用量)。
純粋なTHCV+CBD BDSは、HDLコレステロールレベルを大きく増加させた(低用量レベル及び高用量レベル)。
以下に記載する実施例では、カンナビノイド、カンナビジオール(CBD)及びテトラヒドロカンナビバリン(THCV)が、Δ9−テトラヒドロカンナビノールにより活性化されることが既知であるペルオキシソーム増殖剤活性化受容体ガンマ(PPARγ)を介して作用するかどうかを調査した。
大動脈におけるCBD及びTHCVの経時的効果
CBD(10μM)は、2時間にわたって全ての時点でビヒクル対照と比較して、ラット大動脈の有意な経時的弛緩を引き起こした(2時間、ビヒクル 19.7%±2.4% 比較 CBD 69.7%±4.0%弛緩、n=13、P<0.001)。2時間後、残留弛緩(CBDの血管弛緩効果−ビヒクルの血管弛緩効果及び時間)は、50.1%±3.3%弛緩であった。
動物をビヒクル又はCBDで2週間処理して、動脈機能を調査した。
CBDがPPARγを刺激するかどうかを判定するために、ルシフェラーゼレポーター遺伝子と組み合わせてPPARγ及びRXRαを一過的に過剰発現する同種細胞(3×PPRE TK luc)においてトランス活性化アッセイを実施した。
3T3L1細胞を集密になるまで培養した後、CBD又はロシグリタゾンのいずれかで8日間処理した。細胞を固定して、オイルレッドOで染色して、脂肪滴を同定し、その存在が、脂肪細胞への線維芽細胞の分化を示す。未処理細胞は、分化の幾らかの徴候を示したが、細胞の大部分が、オイルレッドOでほとんど染色されずにそれらの紡錘形状を保持した。ロシグリタゾンは、大量のオイルレッドO染色で明らかなように、脂肪細胞への3T3 L1細胞の分化を誘導し、細胞質内での脂肪滴蓄積を示した。CBDの存在下では、脂肪滴蓄積の徴候は、試験した全ての濃度において濃度依存的に明白であった。
これらのデータは、CBDがPPARγアゴニストであるという強力な証拠を提供し、CBDの効果がもたらされ得る新規手段を示唆する。PPARγリガンドが2型糖尿病、心血管系において、また潜在的に多種多様の他の障害(癌、胃炎症性障害及び多くの皮膚障害を含む)において有益な効果を有するという新たな証拠を鑑みて、これらのデータは、カンナビノイドが、とりわけ抗精神病薬物の使用に関連した代謝症状の予防において有用であり得るという証拠を提供する。
方法
それぞれ防音室中に置かれた2つの自動シャトル箱(幅46cm×奥行19.5cm×高さ20cm、BIO MEDICA, Ltd)を使用して、条件回避行動を評価した。各試行は、条件刺激(cs)としての10秒の警告音(105dBトーン)、続く非条件刺激(US)としての10秒のフットショック(1mA)及び15秒〜75秒(平均45秒)の試行間の間隔から構成された。USは、動物がある区画から他の区画へとハードルを越えて飛び跳ねたとき、又は10秒のカットオフ時間後に終結させた。ラットはそれぞれ、シャトル箱の区画の1つに入れて、第1の試行の前に1分間、シャトル箱を自由に探検させた。トレーニングセッション中に、3種類の応答が記録された:
CS単独に応答して飛び越えが起きた場合、CARが記録された。
USが付与される期間中に飛び越えが起きた場合、逃避応答が記録された。
ラットが反応しなかった場合、逃避失敗(EF)が記録された。
種/系統:ラット/ウィスター
供給業者:Japan SLC, Inc
性別:雄
年齢(トレーニングセッションの開始時):6週
実施例4
i)有効用量より低い無効用量レベル(単独で使用される場合)でのアリピプラゾールAPZ(7.5mg/kg po)及びTHCV(60mg/kg ip)の効果
結果は図3に示され、図3は、下記の効果を示す棒グラフである:
ビヒクル1及びビヒクル2、
APZ及びビヒクル2、
THCV及びビヒクル1、並びに
APZ及びTHCV。
ビヒクル1:5%アラビアゴム
ビヒクル2:EtOH:クレモホール:生理食塩水=1:1:18
結果は図4に示され、図4は、下記の効果を示す棒グラフである:
ビヒクル1及びビヒクル2、
APZ及びビヒクル2、
THCV及びビヒクル1、並びに
APZ濃度及びTHCV濃度。
両側ダネット検定による#p<0.05(ビヒクル1+2群に対して)
ビヒクル1:5%アラビアゴム、
ビヒクル2:EtOH:クレモホール:生理食塩水=1:1:18
カタレプシー(5a)及び眼瞼下垂(5b)に対するCBD及びTHCVの効果
方法
動物
種/系統:ラット/ウィスター
供給業者:Japan SLC, Inc
性別:雄
年齢(実験日にて):6週〜7週
ビヒクル2:EtOH:クレモホール:生理食塩水=1:1:18
1:軽度の下垂症(上眼瞼が目の1/4を覆っていた)
2:中等度の眼瞼下垂(上眼瞼が目の1/2を覆っていた)
3:重度の眼瞼下垂(上眼瞼が目の3/4を覆っていた)
4:完全な眼瞼下垂(上眼瞼が目全体を覆っていた)
実施例5a
種々の用量での結果は、図6a/図6b(APZ/CBD)及び図6a/図6c(APZ/THCV)に図示される。
ビヒクル1:5%アラビアゴム、ビヒクル2:EtOH:クレモホール:生理食塩水=1:1:18
ビヒクル1:5%アラビアゴム、ビヒクル2:EtOH:クレモホール:生理食塩水=1:1:18
結果は同様に図7(CBD)及び図8(THCV)に図示される。
ビヒクル1:5%アラビアゴム、
ビヒクル2:EtOH:クレモホール:生理食塩水=1:1:18
ビヒクル1:5%アラビアゴム、
ビヒクル2:EtOH:クレモホール:生理食塩水=1:1:18
Claims (17)
- 精神病若しくは精神病性障害の予防又は治療における使用のための薬学的配合物の製造における1つ又は複数の抗精神病薬との1つ又は複数のフィトカンナビノイドの使用であって、該1つ又は複数のフィトカンナビノイドは、該1つ又は複数の抗精神病薬に対して別個に、順次又は同時に投与される、使用。
- 前記1つ又は複数のフィトカンナビノイドは、群:カンナビジオール(CBD)、カンナビジオール酸(CBDA)、テトラヒドロカンナビバリン(THCV)、テトラヒドロカンナビバリン酸(THCVA)、カンナビクロメン(CBC)、カンナビクロメン酸(CBCA)、カンナビゲロール(CBG)及びカンナビゲロール酸(CBGA)から選ばれる、請求項1に記載の使用。
- 前記1つ又は複数のフィトカンナビノイドは、大麻植物抽出物の形態で存在し、該抽出物の組成に応じて、全ての若しくはある割合のTHC又はTHCAが選択的に除去され得る、請求項1又は2に記載の使用。
- 前記フィトカンナビノイドは、植物性薬品物質である、請求項1〜3のいずれか1項に記載の使用。
- 前記植物性薬品物質は、前記植物中の天然に存在するフィトカンナビノイド全てを含む、請求項1〜4のいずれか1項に記載の使用。
- 前記フィトカンナビノイドは、実質的に純粋な形態である、請求項1に記載の使用。
- 前記フィトカンナビノイドは、単離形態である、請求項1に記載の使用。
- 前記フィトカンナビノイドは、合成形態である、請求項1に記載の使用。
- 前記抗精神病薬と組み合わせた前記フィトカンナビノイドは、1つ又は複数の薬学的に許容可能なキャリア、賦形剤又は希釈剤を更に含む薬学的組成物として配合される、請求項1〜8のいずれか1項に記載の使用。
- 前記1つ又は複数の抗精神病薬は、非定型抗精神病薬である、請求項1〜9のいずれか1項に記載の使用。
- 前記非定型抗精神病薬は、群:アリピプラゾール、リスペリドン、パリペリドン、ジプラシドン、オランザピン、クエチアピン、クロザピン、スルピリド、アミスルプリド、イロペリドン、カリプラジン、アセナピンから選ばれる、請求項1〜10のいずれか1項に記載の使用。
- 前記非定型抗精神病薬はアリピプラゾールである、請求項11に記載の使用。
- 治療される精神病又は精神病性障害は、群:統合失調症、統合失調症様障害(急性統合失調性エピソード)、統合失調性感情障害、双極性障害I型(躁病、躁病性障害、躁鬱病)、双極性障害II型、精神病性特徴を伴う大鬱病性障害(精神病性鬱病)、妄想性障害(パラノイア)、共有精神病性障害(共有パラノイア障害)、短期精神病性障害(他の詳細不明の反応精神病)、不特定の精神病性障害(詳細不明の精神病)、妄想性人格障害、統合失調質人格障害及び統合失調症性人格障害から選ばれる、請求項1〜12のいずれか1項に記載の使用。
- 子供及び年少者における精神病若しくは精神病性障害の予防又は治療における使用のための薬学的配合物の製造における1つ又は複数の抗精神病薬との1つ又は複数のフィトカンナビノイドの使用であって、該1つ又は複数のフィトカンナビノイドは、該1つ又は複数の抗精神病薬に対して別個に、順次又は同時に投与される使用。
- 精神病若しくは精神病性障害を治療又は予防する方法であって、それを必要とする被験体へ、1つ又は複数の抗精神病薬とともに治療上有効な量の1つ又は複数のフィトカンナビノイドを投与することを含み、該1つ又は複数のカンナビノイドは、該1つ又は複数の抗精神病薬に対して別個に、順次又は同時に投与される、方法。
- 子供及び年少者における精神病若しくは精神病性障害を治療又は予防する方法であって、それを必要とする被験体へ、1つ又は複数の抗精神病薬と組み合わせて治療上有効な量の1つ又は複数のフィトカンナビノイドを投与することを含み、該1つ又は複数のフィトカンナビノイドは、該1つ又は複数の抗精神病薬に対して別個に、順次又は同時に投与される、方法。
- 精神病若しくは精神病性障害の予防又は治療における使用のための薬学的配合物であって、別個に、順次又は同時に投与するための1つ又は複数のフィトカンナビノイド及び1つ又は複数の抗精神病薬を含む、薬学的配合物。
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