JP2017533276A - 認知低下を処置するための方法 - Google Patents
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Abstract
Description
本出願は、35 U.S.C. 119(e)の下で、2014年11月3日に出願された米国仮特許出願第62/074,134号の恩典を主張するものであり、その開示は参照により本明細書に組み入れられる。
本発明の態様は、認知低下を処置するための方法および認知低下を処置するための組成物に関する。
脳老化の過程は、複数の系、細胞型、および経路に影響を及ぼし、認知低下、およびアルツハイマー病 (AD) のリスク増加をもたらす場合が多い。加齢関連認知低下は、典型的に記憶障害と関連しているが、混乱、判断障害、人格変化、見当識障害、および言語技能の喪失を含むがこれらに限定されない症状を伴う場合がある。これらの老化過程は、自発的である場合が多く、他の病態または損傷には関係していない。
本発明の態様は、低用量のテトラヒドロカンナビノール (THC) をそれを必要とする患者に投与する段階を含む、加齢関連認知低下を処置および/または予防するための方法を提供する。低用量のTHCは、初老患者における加齢関連認知低下、例えば記憶障害の処置および予防において有効であり得る。好ましくは、低用量とは、患者が急性副作用を感知しない用量である。本発明の態様による方法を実施する場合に回避され得る急性副作用は、多幸感、鎮静、傾眠、意識混濁、運動協調性低下、および食欲増進からなる群より選択され得る。
約1〜約20ミリグラム/キログラム (mg/kg) という齧歯類における用量に相当する通常用量でのカンナビノイドの使用は、運動および精神活動の緩徐化を含む、カンナビノイドの通常の身体的効果および向精神効果を誘発する。THCを含むカンナビノイドのそのような通常用量が、齧歯類に慢性的に投与される場合、齧歯類は、脳の変性過程を伴う長期認知障害を誘発した。
各群につきマウス10匹を有する3群のICR雌マウスを、この検査に使用した。15月齢の被験マウス(老齢マウス)に、腹腔内経路を通じて、0.002 mg/kg THCを3週間にわたり週3回注射した。THC溶液は、エタノール中の100 mg/ml THCの貯蔵溶液を、1:1:18比のエタノール:クロモフォール:生理食塩水からなる媒体溶液中に溶解することにより調製した。THCは、適切な投薬量になるよう希釈し、10 gのマウス体重当たり0.1 mlの注射量で投与した。マウス2群を対照として使用した。一方の対照群は、THCなしの媒体で処置した8週齢の若齢マウス10匹を含んだ。もう一方の対照群は、THCなしの媒体で処置した老齢マウス10匹を含んだ。投与に際して、有害な急性作用は認められなかった。最終投与の3週間後に、マウスの認知能力を、新規物体を探索するマウスの自然な傾向に基づいて視覚的記憶を測定する行動アッセイである物体認識試験により検査した。実験の1日目に、マウスを実験活動領域内の2つの物体に馴化させた。マウスは2つの物体を区別することなく、それらの各々の探索に同様の時間を費やした。24時間後、マウスを、馴化させた物体の一方を新規物体に置き換えた同じ活動領域内に入れた。古い物体と比較して新しい物体の探索時間が統計的に有意により長いことによって表されるように、対照若齢マウス(若齢)は古い物体を覚えており、新規物体の探索を好んだ。未処置の老齢マウス(老齢)はこの能力を失い、古い物体よりも新しい物体を探索するのにより多くの時間を費やさず、これにより、これらのマウスが古い物体を覚えていられなかったことが示される。低用量THCで処置した老齢マウス(老齢+THC)は、若齢対照マウスと同様の行動を表し、古い物体と比較して新しい物体の探索に有意により多くの時間を費やし、これにより、これらのマウスが古い物体を覚えていたことが示される。各群の相対探索時間についての結果を図1に示す。相対探索時間は、所与の物体の探索時間を両物体の探索時間で除したものに等しい。
実施例1aに記載される方法を用いて製剤化され、適切な投薬量になるよう希釈された、通常用量のTHC(1、2、または10 mg/kg)または低用量のTHC(0.001、0.002、または0.01 mg/kg)の単回用量を、腹腔内経路を通じて各群6匹のICRマウスに投与した。次いで、注射の15分後に開始して、検査を行った。45℃に維持したホットプレート上の透明ガラスシリンダー内に動物を入れる「ホットプレート試験」を用いて、動物を、通常用量のTHCおよび低用量のTHCと関連した鎮痛について試験した。動物を観察して、足をなめるまたはジャンプすることによって示されるように、ホットプレートによって生じた疼痛に反応するまでの時間を決定した。直腸体温計を用いて、動物を、通常用量のTHCおよび低用量のTHCと関連した低体温について試験した。オープンフィールド試験を用いて、動物を、通常用量のTHCおよび低用量のTHCと関連した不動性について試験した。オープンフィールド試験では、動物を活動領域内に5分間入れ、動物の活動を測定した。加えて、5分間に行われた立ち上がりの回数を記録した。
それぞれ体重約30〜40グラムの約8〜12週齢の若齢ICRマウスおよび約15月齢の老齢ICRマウスを、食物および水を自由に利用できる状態で、標準条件において収容する。処置前に少なくとも4回、生理食塩水の腹腔内注射を毎日することにより、マウスを取扱いおよび注射に慣らす。
各群につきマウス10匹を有する3群のICR雌マウスを、この検査に使用した。15月齢の被験マウス(老齢マウス)に、腹腔内経路を通じて、0.002 mg/kg THCを、5 mg/kgのCBDと併用して、3週間にわたり週3回注射した。THC/CBD溶液は、エタノール中の100 mg/ml THCおよび100 mg/ml CBDの貯蔵溶液を、1:1:18比のエタノール:クロモフォール:生理食塩水からなる媒体溶液中に溶解することにより調製した。THCおよびCBDは、適切な投薬量になるよう希釈し、10 gのマウス体重当たり0.1 mlの注射量で投与した。マウス2群を対照として使用した。一方の対照群は、THC/CBDなしの媒体で処置した8週齢の若齢マウス10匹を含んだ。もう一方の対照群は、THC/CBDなしの媒体で処置した老齢マウス10匹を含んだ。
約100名のMCI患者が、治験に参加する。患者は、以下の基準に従って承認される:1. 年齢50歳から< 85歳。体重60〜90 kg。2. Petersen基準に従って、かつ約0.5という臨床的認知症尺度 (CDR) スコアにより裏付けられ、軽度認知障害、健忘型(単一または複数ドメイン)と診断される。3. ミニメンタルステート検査 (MMSE) スコアが、境界も含めて24〜30。4. すべての臨床的来院に参加することができ、2年間または試験期間の間、特定の来診時に被験者に同伴することができる情報提供者がいること。5. 認知および機能評価の全局面を行うために、適切な手先の器用さ、視覚能力、および聴覚能力があること。
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