JP7305560B2 - Nmdaアンタゴニスト及びd2/5ht2a又は選択的5ht2aアンタゴニストによるうつ病の治療 - Google Patents
Nmdaアンタゴニスト及びd2/5ht2a又は選択的5ht2aアンタゴニストによるうつ病の治療 Download PDFInfo
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- JP7305560B2 JP7305560B2 JP2019568331A JP2019568331A JP7305560B2 JP 7305560 B2 JP7305560 B2 JP 7305560B2 JP 2019568331 A JP2019568331 A JP 2019568331A JP 2019568331 A JP2019568331 A JP 2019568331A JP 7305560 B2 JP7305560 B2 JP 7305560B2
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Description
これは、2012年7月12日出願の米国仮特許出願第61/741,114号明細書及び米国仮特許出願第61/741,115号明細書に対して優先権を主張する2013年7月7日出願の米国特許出願公開第13/936,198号明細書の継続出願である、2017年7月16日出願の米国特許出願公開第15/650,912号明細書の一部継続出願である。2017年6月12日出願の米国仮特許出願第62/518,020号明細書に対する利益を更に主張する。前述の特許出願の内容は、その全体が参照により本明細書に組み込まれる。
別段の説明がない限り、本明細書で使用される全ての技術用語及び科学用語は、本開示が属する技術分野の当業者によって一般に理解されるのと同じ意味を有する。「a」、「an」、及び「the」という単数形の用語には、文脈が明確に示さない限り、複数の参照を含む。同様に、「又は」という言葉は、文脈が明確に示さない限り、「及び」を含むことを意図している。更に、核酸又はポリペプチドに与えられた全ての塩基サイズ又はアミノ酸サイズ、及び全ての分子量又は分子質量の値は、おおよそであり、説明のために提供されることが理解される。本明細書に記載のものと類似又は同等の方法及び材料を本開示の実施又は試験に使用することができるが、適切な方法及び材料を以下に記載する。「comprises」という用語は、「includes」を意味する。「consisting essentially of」は、リストされた特徴のみをアクティブ又は必須な要素として含む組成物、方法、又はプロセスを示すが、更に非アクティブ要素を含むことができる組成物、方法、又はプロセスを示す。略語「e.g.」は、ラテン語のexempli gratiaに由来し、非限定的な例を示すために本明細書中で使用される。したがって、略語「e.g.」は、「for example」などの用語と同義である。
矛盾する場合、用語の説明を含む本明細書が考慮される。更に、全ての材料、方法、及び例は例示的であり、限定することを意図したものではない。
本明細書に示されるように、選択的に、>25マイクログラム/mLの持続された血中(例えば、血清又は血漿)レベルをもたらす用量で、予想外に、NMDAR正味アンタゴニストが、抗うつ治療及び/又は抗精神病治療に関連するアカシジア及び不安を低減する用量で、D-サイクロセリンは、齧歯類における抗うつ病効果を誘発する。
実施例
薬物誘発アカシジアは、抗精神病医薬と抗うつ病医薬の両方の共通の副作用であり、新しい非定型抗精神病剤でも見られることがある(Iqbal et al.,CNS Spectrums,12:1-13,2007)。この症候群は、不安/イライラ(jitteriness)症候群とも記載され(Sinclair et al.,Br J Psychiatry,194:483-90,2009)、SSRIと三環系抗うつ剤の両方の後にも見られる。
医薬の行動効果を評価するために、全ての研究は、高架式十字迷路(EPM)装置を用いて、PsychoGenics,Inc.(765 Old Saw Mill River Road,Tarrytown,NYに本社がある)で行われた。
Jackson Laboratories(Bar Harbor、Maine)から雄のC57Bl/6Jマウスを本研究のために使用した。マウスは、6週齢で受領した。受領時に、特有の識別番号(尾に印を付ける)をマウスに割り当て、OPTIマウス換気ケージに4マウス/ケージでグループで収容した。研究の残りの間、全ての動物は、4頭のグループに収容されたままだった。全てのマウスは、試験前に少なくとも1週間コロニー室に馴化させ、その後平均7週齢で試験した。
高架式十字迷路試験は、不安を評価した。迷路(Kinder Scientific;Poway,CA)は、十字を形成する、2つのクローズドアーム(高さ14.5cm×幅5cm×長さ35cm)と、2つのオープンアーム(幅6cm×長さ35cm)とからなり、正方形の中心プラットフォーム(6cm×6cm)を有する。目に見える表面は、全て黒いアクリルからなる。迷路の各アームは、床から56cmで支柱の上に配された。帯電防止用の黒色ビニルカーテン(高さ7’)は、EPMを囲み、幅5’×長さ5’の囲いを作った。動物は、試験の少なくとも1時間前に実験室に馴化させた。マウスを、クローズドアームに面した高架式十字迷路の中心に置き、5分間走らせた。全ての動物を一度試験した。費やした時間、移動距離、各アームへの進入は、コンピューターによって自動的に記録された。各試験後に、EPMを徹底的に洗浄した。
医薬をIP注射によって投与した。全ての医薬を適切な溶媒に溶解した。用量は、キログラムあたりのミリグラム(mg/kg)で表される。表1に示される試験化合物を試験30分前に投与した。全ての場合において、2,5-ジメトキシ-4-ヨードアンフェタミン(DOI)2mg/kgを試験の10分前に投与した。
この研究の主要な依存指標は、オープンアーム内で費やされた時間の%からなり、これは抗不安効果の指標と見なされる。p<.05の両側有意性を用いたt検定又は事後のDunnett検定を用いて、条件間比較を実施した。
EPMの露出された部分対囲まれた部分への進入意欲を測定する、オープンアームでの%時間の測定値を用いて、不安/アカシジア関連症状におけるNMDARアンタゴニストの特異的効果を評価した。これは、オープンアームとクローズドアームの活動間の比率を表すので、全体的な活動レベルの変化に対して比較的非感受性である。全体の活動化の指標である移動した総距離を用いて、潜在的な非特異的効果を評価した。
MDL100,907、EMD281,014、及びケタンセリンを含む選択的5-HT2A受容体アンタゴニストは、オープンアームにおける移動距離及びオープンアームにおける%時間を有意に減少させ、不安及び/又はアカシジアにおける有意な増加を示唆することを過去に実証してきた(米国特許第9,846,453号明細書)。
これらの知見は、MDL100709、ケタンセリンなどの5-HT2Aアンタゴニスト又はルラシドンを含む非定型抗精神病剤によって誘導される、高架式十字迷路の費やされた%時間及びオープンアームにおける移動距離における減少を逆転させるという、高用量における(即ち、正味NMDARアンタゴニスト効果をもたらすとき)D-サイクロセリンの予想外の能力を実証する。プロ治療(pro-therapeutic)効果は、D-サイクロセリンだけでなく、D-CPPene、CGS19755、又はCP101606などの他のNMDARアンタゴニストにも見られた。対照的に、従来のチャネルブロッカーPCPは、DCSに対し、性能が悪化し、グルタメート又はグリシン結合部位で作用する剤、又はGlyX-13などの低親和性チャネルブロッカーは、PCP又はMK-801などの高親和非競合的アンタゴニストよりも優れていることができる。更に、5-HT2Aアンタゴニストは、ケタミン、MK-801、又はPCPなどのNMDAチャンネルブロッカーによって誘発される運動亢進を逆転させることが知られているが、%オープンアーム測定(オープンアーム対クローズドアームの移動距離を比較)は、活動レベルの全体的な変化を修正する。
この研究では、齧歯類の強制水泳試験を用いて、NMDARアンタゴニストの抗うつ病効果を評価した。NMDARアンタゴニストは、単独で及び特定の5-HT2A受容体アンタゴニストと組み合わせて研究された。
この研究では、齧歯類におけるD-サイクロセリンの薬物動態を評価した。この研究では、上記の実施例で示されたDCSの抗アカシジア及び抗うつ病効果が、>25マイクログラム/mLの持続された血中DCSレベルをもたらす処置レベルで特異的に観察されるという仮説を試験する。
中でも、Malspeis and Gold,J Pharmaceutical Sci,53:113-80,1964に記載されるように、D-サイクロセリンは、その化学的構造のために、胃で観察され得るような酸性(低pH)条件下において、水溶液中で加水分解を受けやすい。
この研究では、潜在的な抗うつ病効果を示唆する齧歯類のFST試験における不動時間を減少させる能力について、更なるNMDARアンタゴニスト化合物を試験し、ヒトにおける不安、アカシジア、及び自殺傾向を誘発する潜在的な易罹病性を示唆するEPMのオープンアームにおける費やされた時間の減少をもたらす能力について、更なる5-HT2ARアンタゴニストを試験した。
Claims (8)
- うつ病及び関連する自殺傾向の治療のための医薬組成物であって、前記医薬組成物が、
D-サイクロセリンのNMDAR-アンタゴニスト有効量と、
ルラシドン及びブレクスピプラゾールから選択される、組み合わされたドーパミンD2/5-HT2A受容体アンタゴニストである非定型抗精神病剤の有効量と、
を含み、
前記D-サイクロセリンのNMDAR-アンタゴニスト有効量が、25マイクログラム/mL超~125マイクログラム/mL未満の持続された血中血漿濃度をもたらすのに十分であることを特徴とする医薬組成物。 - 前記医薬組成物が、徐放用に配合される請求項1に記載の医薬組成物。
- 腸溶コーティングを更に含む請求項1から2のいずれかに記載の医薬組成物。
- 前記D-サイクロセリンのNMDAR-アンタゴニスト有効量が、プロドラッグとして提供される請求項1から3のいずれかに記載の医薬組成物。
- うつ病又は自殺傾向を罹患し、非定型抗精神病剤による治療を必要としているが、組み合わされたドーパミンD2/5-HT2A受容体アンタゴニストである前記非定型抗精神病剤の副作用を低減する必要がある対象の治療における使用のための請求項1から4のいずれかに記載の組成物。
- 前記副作用が少なくとも1つの不安を惹起する(anxiogenic)副作用である請求項5に記載の組成物。
- 前記少なくとも1つの不安を惹起する副作用が、アカシジア、激越、不安、及び自殺傾向からなる群から選択される請求項5に記載の組成物。
- 前記うつ病が、大うつ病又は双極性うつ病である請求項5に記載の組成物。
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CN110996948A (zh) | 2020-04-10 |
AU2018284335A1 (en) | 2020-01-30 |
ZA202000193B (en) | 2021-09-29 |
JP2023123720A (ja) | 2023-09-05 |
RU2020100230A (ru) | 2021-07-13 |
RU2020100230A3 (ja) | 2021-12-14 |
IL271371A (en) | 2020-01-30 |
KR20200027501A (ko) | 2020-03-12 |
CA3067162A1 (en) | 2018-12-20 |
EP3638234A1 (en) | 2020-04-22 |
KR102609676B1 (ko) | 2023-12-05 |
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