JP2020535198A - てんかんの治療における、5−ht2b受容体作動薬又はアンフェタミンと組合せたカンナビジオールの使用 - Google Patents
てんかんの治療における、5−ht2b受容体作動薬又はアンフェタミンと組合せたカンナビジオールの使用 Download PDFInfo
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Abstract
Description
本発明を説明するために使用された、いくつかの用語の定義を以下に説明する。
既知で一定の組成を有する高度に精製された(>98% w/w)カンナビジオール抽出物の生産が、以下の実施例に使用されたことを、以下に説明する。
ヒト5-HT2B受容体におけるCBD及び7-OH-CBDの活性の評価は、遺伝子導入されたCHO細胞で行われた。作動薬又は拮抗薬のいずれかとしてのそのような活性は、HTRF検出法を使用してIP1産生の効果を測定することによって、決定した。
拮抗薬の効果:
細胞を、10 mM Hepes/NaOH (pH 7.4)、4.2 mM KCl、146 mM NaCl、1 mM CaCl2、0.5 mM MgCl2、5.5 mM グルコース、及び50 mM LiClを含むバッファー内に懸濁し、次いで4.104 cells/wellの密度でマイクロプレートに分注し、バッファー(基礎となるコントロール)、テスト化合物、又は基準拮抗薬の存在下で室温で5分間プレインキュベーションした。
細胞を、10 mM Hepes/NaOH (pH 7.4)、4.2 mM KCl、146 mM NaCl、1 mM CaCl2、0.5 mM MgCl2、5.5 mM グルコース、及び50 mM LiClを含むバッファー内に懸濁し、次いで4.104 cells/wellの密度でマイクロプレートに分注し、バッファー(基礎となるコントロール)、テスト化合物、又は基準拮抗薬の存在下で37℃で30分間インキュベーションした。
図1は、拮抗薬及び作動薬アッセイの両方によって作られたデータを示している。
ヒトのてんかんの臨床試験では、約1μMのモル濃度と等しい最大330 ng/mLのCBDの濃度は血漿に到達した。CBDの臨床使用は、7-OH-CBDの産生をもたらし、CBDによって達成された濃度の約50%の濃度に到達する(すなわち、約0.5μM)。
以下の実施例は、発作のマウスモデルにおける、カンナビノイドCBDと、アンフェタミン誘導体のフェンフルラミンとの組合せからもたらされたデータを記載する。アイソボログラム解析を行って、そのような組合せが発作の相乗的な減少をもたらすかを決定した。
本研究は、二つの段階において実施された。第一に(実験A)、精製された植物由来CBD及びフェンフルラミン(FEN)単独の用量依存的抗痙攣効果を実証した。第二に(実験B)、CBD/FENの組合せにおける薬剤-薬剤相互作用(DDI)及び抗痙攣活性を実証した。
以下の薬がこの研究で使用された:GW Research Ltd.によって提供された精製された植物由来CBD、Sigma Merckから購入したフェンフルラミン塩酸塩(FEN)。使用されたコントロールビヒクルは1:1:18(5% エタノール、5% コリフォールEL、90% 生理的食塩水)である。CBD及びFENは、比較のために、同じコントロールビヒクルに溶解した。
電撃痙攣は、角膜電極を通して伝わる30 mA(0.2秒持続)の固定電流強度の使用によって生じさせた。これらのパラメーターは、100%のコントロール動物で強直後肢伸張発作が確実に生じると、以前に確認された。マウスを、電流使用後に強直後肢伸張発作があるか又はないかによって決定される発作の生成について、個別に評価した。
アイソボログラム解析は、DDIの解析のためのゴールドスタンダードであると考えられている:AEDsの等効果用量の決定、及び全臨床試験における相乗的(相加的を超えた(supra-additive))、相加的、又は拮抗的(相加的より低い(sub-additive))としてのDDIの分類。アイソボログラムは、DDIの所期作用及び副作用の両方について決定され、理想的には、所期作用にとって相乗的で、副作用にとって拮抗的な組合せを見つける。
全ての統計試験は、GraphPad Prism v7.0(GraphPad Software社、San Diego、CA、USA)を使用して実施した。個々の処置グループとビヒクル処置グループとの全ての違いは、両側フィッシャーの正確確率検定(p<0.05を有意とした)を使用して評価した。
実験A:
単剤AEDによる電撃痙攣のパーセント阻害
CBD及びFENは両方とも、ビヒクルと比べると、最大電気ショック発作の発生に対する用量依存的な抗痙攣効果を示した。パープロトコル解析は、統計学的に有意な(p<0.05)抗痙攣効果を、CBDで50-100 mg/kgから、FENで10 mg/kgから明らかにした(図3)。
CBD及びFENから導出されたEE50値にもとづいて、ロエベの相加方程式(CBD/FEN: 1.6/29.7、3.2/19.8、及び4.8/9.9 μM)を使用して、三つの固定比(1:3、1:1、及び3:1)を計算した。平均の脳曝露に対する用量のプロットを使用して、線形方程式を用いてアイソボログラム解析のためのCBD/FEN用量を計算した。当該CBD/FEN比用量は、20.9/2.5、13.6/3.9、及び28.3/1.2 mg/kgであった。
CBD/FENの組合せによる電撃痙攣の阻害パーセント
CBD又はFEN単独では、試験された用量のいずれにおいても、ビヒクルと比べて、最大電気ショック発作(MES)に対する有意な効果を与えず、先の研究(実験A)における低用量の効果に一致した。
CBD/FENの三つの固定比である1:3、1:1、及び3:1は、用量に調整した場合に、1:2.3(ED55+ADD)、1:1(ED50+ADD)、及び3:1(ED46+ADD)という比率を反映する相加的EE50に理論的には相当する。このように、用量と曝露比との間に十分な違いがあり、明確な効果を示す。
様々な比でのフェンフルラミンとCBDとの組合せは、発作の相乗的な減少をもたらすことを示し、そのため、ドラベ症候群又はレノックス・ガストー症候群のような治療の難しい小児期てんかん症候群において、有用な治療選択になり得る。
まとめると、CBDは5-HT2B受容体作動薬によってもたらされる弁膜症の副作用を防ぐことができることを示す、実施例1からのデータ、並びに、CBD、及び5-HT2B受容体作動薬でアンフェタミン誘導体であるフェンフルラミンの組合せは発作の相乗的な減少をもたらすことを実証する、実施例2のデータは、明らかにそのような組合せの高い治療価値を実証している。
細胞を、10 mM Hepes/NaOH (pH 7.4)、4.2 mM KCl、146 mM NaCl、1 mM CaCl2、0.5 mM MgCl2、5.5 mM グルコース、及び50 mM LiClを含むバッファー内に懸濁し、次いで4.104 cells/wellの密度でマイクロプレートに分注し、バッファー(基礎となるコントロール)、テスト化合物、又は基準作動薬の存在下で37℃で30分間インキュベーションした。
アイソボログラム解析は、DDIの解析のためのゴールドスタンダードであると考えられている:AEDsの等効果用量の決定、及び前臨床試験における相乗的(相加的を超えた(supra-additive))、相加的、又は拮抗的(相加的より低い(sub-additive))としてのDDIの分類。アイソボログラムは、DDIの所期作用及び副作用の両方について決定され、理想的には、所期作用にとって相乗的で、副作用にとって拮抗的な組合せを見つける。
Claims (19)
- てんかんの治療における使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたカンナビジオール(CBD)。
- 前記組合せが、5-HT2B受容体の受容体活性化作用に関連した副作用の防止又は減少における使用のためのものである、請求項1に記載の使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたCBD。
- 前記5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体が、グアンファシン、3,4-メチレンジオキシメタンフェタミン(MDMA)、メチレンジオキシアンフェタミン(MDA)、2,5-ジメトキシ-4-エトキシアンフェタミン(MEM)、ペルゴリド、カベルゴリン、ノルフェンフルラミン、フェンフルラミン、クロルフェンテルミン、アミノレックス、メタクロロフェニルピペラジン(mCPP)、ブロモドラゴンフライ、N,N-ジメチルトリプタミン(DMT)、5-メトキシ-N,N-ジメチルトリプタミン(5-MeO-DMT)、リゼルグ酸ジエチルアミド(LSD-25)、サイロシン、アンフェタミン、メタンフェタミン、エフェドリン、カチノン、フェンテルミン、メフェンテルミン、ブプロピオン、メトキシフェナミン、セレギリン、アンフェプラモン、n-フェンフルラミン、ピロバレロン、MDMA(エクスタシー)、及びDOM(STP)の一つ又は複数である、請求項1又は2に記載の使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたCBD。
- 前記5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体が、ノルフェンフルラミン又はフェンフルラミンである、請求項1から3のいずれか一項に記載の使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたCBD。
- 防止又は減少された前記副作用が心臓弁膜症である、請求項2に記載の使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたカンナビジオール(CBD)。
- 前記CBDが、少なくとも98%(w/w)のCBDを含む、高度に精製されたカンナビスの抽出物の形態である、請求項1から5のいずれか一項に記載の使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたカンナビジオール(CBD)。
- 前記CBDが合成化合物として存在する、請求項1から5のいずれか一項に記載の使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたカンナビジオール(CBD)。
- 前記てんかんが治療抵抗性てんかん(TRE)である、請求項1から7のいずれか一項に記載の使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたカンナビジオール(CBD)。
- 前記治療抵抗性てんかんが、ドラベ症候群、ミオクロニー欠神てんかん、レノックス・ガストー症候群、原因不明の全般てんかん、CDKL5変異、アイカルディ症候群、結節性硬化症、両側性多少脳回、Dup15q、SNAP25、及び熱性感染症関連てんかん症候群(FIRES)、良性ローランドてんかん、若年ミオクロニーてんかん、点頭てんかん(ウェスト症候群)、及びランドウ・クレフナー症候群の一つである、請求項8に記載の使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたカンナビジオール(CBD)。
- 前記高度に精製された抽出物が0.15%未満のTHCを含む、請求項6記載の使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたカンナビジオール(CBD)。
- 前記高度に精製された抽出物が最大1%のCBDVを含む、請求項6に記載の使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたカンナビジオール(CBD)。
- CBDと、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体との比が、20:1から1:20の間である、請求項1から11のいずれか一項に記載の使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたカンナビジオール(CBD)。
- CBDと、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体との比が、10:1から1:10の間である、請求項1から12のいずれか一項に記載の使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたカンナビジオール(CBD)。
- CBDと、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体との比が、3:1から1:3の間である、請求項1から13のいずれか一項に記載の使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたカンナビジオール(CBD)。
- CBDと、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体との比が、2:1から1:2の間である、請求項1から14のいずれか一項に記載の使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたカンナビジオール(CBD)。
- CBDと、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体との比が、およそ1:1である、請求項1から15のいずれか一項に記載の使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたカンナビジオール(CBD)。
- CBDの用量が5から50 mg/kg/dayである、請求項1から16のいずれか一項に記載の使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたカンナビジオール(CBD)。
- 5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体の用量が1 mg/kg/day、及び0.01 mg/kg/dayを下回る量である、請求項1から17のいずれか一項に記載の使用のための、5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せたカンナビジオール(CBD)。
- 5-HT2B受容体作動薬、アンフェタミン、又はアンフェタミン誘導体と組合せてカンナビジオール(CBD)を患者に投与することを含む、てんかん治療の方法。
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