JP6148618B2 - 呼吸器の病態又は疾患の治療のための化合物 - Google Patents
呼吸器の病態又は疾患の治療のための化合物 Download PDFInfo
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- JP6148618B2 JP6148618B2 JP2013504064A JP2013504064A JP6148618B2 JP 6148618 B2 JP6148618 B2 JP 6148618B2 JP 2013504064 A JP2013504064 A JP 2013504064A JP 2013504064 A JP2013504064 A JP 2013504064A JP 6148618 B2 JP6148618 B2 JP 6148618B2
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Description
ライノウイルスチャレンジ実験モデルにおける経口3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾールの予防効果を測定するための第2相二重盲検プラセボ比較試験
試験のデザインは、プラセボ比較二重盲検無作為化パラレルグループ臨床試験であった。試験の目的は、3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾール25mg、100mg又は400mgのいずれかを1日2回10日間投与して、効能、安全性及び薬物動態を測定することであった。具体的には、実験的HRV感染(ウイルスチャレンジデザイン)の予防について、3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾールの効果を評価した。
ヒト呼吸器の上皮組織のヒト細胞由来組織培養モデル(EpiAirway(商標)システム)
EpiAirway(商標)システム(MatTek Corporation、Ashland、MA)は、ヒト細胞由来の完全に分化した分泌性3次元組織培養モデルである。EpiAirway(商標)システムは、インビトロにおいて、微小孔性膜上で培養した非不死化ヒト由来気管/気管支上皮細胞から構成される。1次細胞は、ヒト呼吸器の上皮組織によく似た、偽重層化高度分化型組織培養モデルを形成する。培養された組織の組織学的横断面によって、正常なヒト気管支梢に類似した偽重層化粘液毛様体表現型であることが示される(Sheasgreen,J.K.M,et.al.,The Toxicologist(1999)48(1−S):Astract#594)。上皮は高度に分化しており、頂端面に機能的繊毛を有する。EpiAirway(商標)システムはまた、機能的な密着接合によってもたらされる経上皮電気抵抗の発生を含む、天然の気管/気管支上皮に類似したバリア特性を示す。
EpiAirway(商標)システムにおけるHRV血清型14に対する3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾール遊離塩基の抗ウイルス活性は、ウイルス力価の50%低下を生じる試験化合物の濃度(EC50)を測定するウイルス収量低下アッセイを使用して測定した。
HeLa Ohio細胞を96ウェルプレート(Corning;カタログ番号3595)中でウェル当たり1.0×104細胞の濃度でアッセイ培地200μLに接種し、5%CO2を含む湿潤な雰囲気中で37℃で一晩インキュベートした。このインキュベーション時間後、細胞は約50%コンフルエントであった。
症候性ヒトライノウイルス感染を有する喘息成人における3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾールの2用量レベルの第2相多施設無作為化二重盲検プラセボ対照パラレル試験
試験集団は、スクリーニングの少なくとも2年前に軽度から中程度の安定した喘息が既に診断されており、登録前90日以内に予備スクリーニングを行い、ヒトライノウイルス(HRV)と推定される症状を表している18〜70歳の男女229〜400人である。対象は、プラセボ又は3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾールの2用量のうち1つを投与するために無作為化する(1:1:1)。
Claims (23)
- ヒトライノウイルス(HRV)感染を有する対象における喘息の症状の治療又は緩和のための経口投与用医薬の調製における3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾール又は薬学的に許容されるその塩の使用。
- ヒトライノウイルス(HRV)感染を有する対象における慢性閉塞性肺疾患(COPD)の症状の治療又は緩和のための経口投与用医薬の調製における3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾール又は薬学的に許容されるその塩の使用。
- ヒトライノウイルス(HRV)感染を有する又はヒトライノウイルス(HRV)感染の危険性のある対象における喘息の症状の悪化の発生率を低下し、又は喘息の悪化を予防するための経口投与用医薬の調製における3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾール又は薬学的に許容されるその塩の使用。
- ヒトライノウイルス(HRV)感染を有する又はヒトライノウイルス(HRV)感染の危険性のある対象における慢性閉塞性肺疾患(COPD)の悪化の発生率を低下し、又は慢性閉塞性肺疾患(COPD)の悪化を予防するための経口投与用医薬の調製における3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾール又は薬学的に許容されるその塩の使用。
- 前記経口投与が経口経腸投与である、請求項1から4までのいずれか一項に記載の使用。
- 前記経口投与される3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾール又は薬学的に許容されるその塩が、固体形態又は液体形態である、請求項1から5までのいずれか一項に記載の使用。
- 前記固体形態が錠剤又はカプセルである、請求項6に記載の使用。
- 前記医薬が、少なくとも1種の喘息治療薬と組み合わせて、別々に、同時に、又は逐次的に投与するために製剤化されている、請求項1から7までのいずれか一項に記載の使用。
- 前記喘息の症状は、肺機能の低下、肺気量の低下、咳、喘鳴、息切れ及び気道壊死からなる群から選択される、請求項1、3、及び5〜8の何れか一項に記載の使用。
- 前記喘息の症状は、肺機能の低下である、請求項9に記載の使用。
- 前記肺機能の低下は、最大呼気流量(PEF)の最大平均低下率、1秒間の強制呼気容量(FEV1)、喘息管理質問票(ACQ−5)及び喘息QOL質問票(AQLQS)からなる群から選択される評価基準で計測される、請求項9又は10に記載の使用。
- 3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾール又は薬学的に許容されるその塩を含む、ヒトライノウイルス(HRV)感染を有する対象における喘息の症状の治療又は緩和のための経口投与用医薬組成物。
- 3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾール又は薬学的に許容されるその塩を含む、ヒトライノウイルス(HRV)感染を有する対象における慢性閉塞性肺疾患(COPD)の症状の治療又は緩和のための経口投与用医薬組成物。
- 3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾール又は薬学的に許容されるその塩を含む、ヒトライノウイルス(HRV)感染を有する又はヒトライノウイルス(HRV)感染の危険性のある対象における喘息の悪化の発生率を低下し、又は喘息の悪化を予防するための経口投与用医薬組成物。
- 3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾール又は薬学的に許容されるその塩を含む、ヒトライノウイルス(HRV)感染を有する又はヒトライノウイルス(HRV)感染の危険性のある対象における慢性閉塞性肺疾患(COPD)の悪化の発生率を低下し、又は慢性閉塞性肺疾患(COPD)の悪化を予防するための経口投与用医薬組成物。
- 経口経腸投与(oral enteral administration)のための、請求項12から15までのいずれか一項に記載の医薬組成物。
- 前記経口投与される3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾール又は薬学的に許容されるその塩が、固体形態又は液体形態である、請求項12から16までのいずれか一項に記載の医薬組成物。
- 前記固体形態が錠剤又はカプセルである、請求項17に記載の医薬組成物。
- 少なくとも1種の喘息治療薬と組み合わせて、別々に、同時に、又は逐次的に投与するための、請求項12から18までのいずれか一項に記載の医薬組成物。
- 前記喘息の症状は、肺機能の低下、肺気量の低下、咳、喘鳴、息切れ及び気道壊死からなる群から選択される、請求項12、14、及び16〜19の何れか一項に記載の医薬組成物。
- 前記喘息の症状は、肺機能の低下である、請求項20に記載の医薬組成物。
- 前記肺機能の低下は、最大呼気流量(PEF)の最大平均低下率、1秒間の強制呼気容量(FEV 1 )、喘息管理質問票(ACQ−5)及び喘息QOL質問票(AQLQS)からなる群から選択される評価基準で計測される、請求項20又は21に記載の医薬組成物。
- 3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾール又は薬学的に許容されるその塩と、少なくとも1種の喘息治療薬との組み合わせであって、
該組合せは、
HRV感染を有する対象における喘息の症状の治療又は緩和のため、
HRV感染を有する対象における慢性閉塞性肺疾患(COPD)の症状の治療又は緩和のための
ヒトライノウイルス(HRV)感染を有する又はヒトライノウイルス(HRV)感染の危険性のある対象における喘息の悪化の発生率を低下し、又は喘息の悪化を予防するため、又は
ヒトライノウイルス(HRV)感染を有する又はヒトライノウイルス(HRV)感染の危険性のある対象における慢性閉塞性肺疾患(COPD)の悪化の発生率を低下し、又は慢性閉塞性肺疾患(COPD)の悪化を予防するため
に使用され、
少なくとも、3−エトキシ−6−{2−[1−(6−メチル−ピリダジン−3−イル)−ピペリジン−4−イル]−エトキシ}−ベンゾ[d]イソオキサゾール又は薬学的に許容されるその塩は、経口投与される、組み合わせ。
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SG184430A1 (en) | 2012-11-29 |
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EA025224B1 (ru) | 2016-12-30 |
NZ603040A (en) | 2015-03-27 |
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ZA201207696B (en) | 2014-03-26 |
US20110257192A1 (en) | 2011-10-20 |
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EA201201416A1 (ru) | 2013-03-29 |
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