JP7174444B2 - 前立腺肥大症および尿路疾患におけるマルチキナーゼ阻害剤および使用 - Google Patents
前立腺肥大症および尿路疾患におけるマルチキナーゼ阻害剤および使用 Download PDFInfo
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- JP7174444B2 JP7174444B2 JP2020536605A JP2020536605A JP7174444B2 JP 7174444 B2 JP7174444 B2 JP 7174444B2 JP 2020536605 A JP2020536605 A JP 2020536605A JP 2020536605 A JP2020536605 A JP 2020536605A JP 7174444 B2 JP7174444 B2 JP 7174444B2
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Description
ヒトとげっ歯類の前立腺は形態的、解剖学的には異なるが、薬理学的、組織化学的には多くの類似性があり、ラットのBPHの研究は有用な研究アプローチである。ヒトでもラットでも前立腺は、腺要素を取り囲む細かいネットワークによって神経支配されている。これらの神経構造のほとんどはカテコールアミン作動性であり、異なるサブタイプのアドレナリン受容体を含んでいる。
形態学的には、BPHは、既存の管腔内に上皮が増殖することにより、新規の構造が形成されることで特徴付けられる。間質細胞が上皮細胞のホメオスタシスにおいて重要なパラクリン制御機能を果たしていることを考えると、間質-上皮相互作用の後期段階での変化は、BPHの進行についての見識を与え得る。第二の研究は、ラットにおけるテストステロンおよび/またはフェニレフリン誘導BPHを用いたプロトコールでの、誘導後の試験化合物および溶媒の治療効果を決定するために行われた。
(ラットにおける前立腺内注射後の前立腺でのソラフェニブ濃度)
この研究では、15日目と29日目に、前立腺内注射でソラフェニブが単回投与された。動物を42日目に安楽死させ、前立腺組織サンプルを解析のために得た。組織サンプルはBead Ruptorホモジナイザーを用いて調製し、その後、アセトニトリルで抽出し、高速遠心分離をした。ソラフェニブを測定するためにLC-MS/MS法を用いた。
線維形成は、一般的に、疾患、外傷、遺伝性疾患または感染症に関連する組織における後期の反応性および/または修復的な反応である。病態生理学的には、関与する臓器や組織にかかわらず、強固な重なりがある。前立腺以外の組織での所見は、前立腺肥大症やその関連する下部尿路症状など、前立腺の疾患または障害に関連する線維性疾患の進行および退行の我々の理解に貢献する可能性がある。
前立腺肥大症、高悪性度前立腺上皮内腫瘍、および前立腺癌において、VEGFおよびbFGFのような血管新生因子の発現の増加が、微小血管密度の増加とともに報告されている。このことは、BPHの調節におけるこれらの因子の阻害の役割を示唆している。本実施例では、ラットの血管新生モデルにおけるマルチキナーゼ阻害剤の局所投与の効果を調べた。新生血管の成長は成長因子受容体シグナル伝達経路によって制御されており、その機能は臓器および組織の間で幅広く重複している。本研究では、マルチキナーゼ阻害剤であるニンテダニブおよびレンバチニブの局所投与の効果を、レーザー誘導脈絡膜血管新生後のラットの眼に、硝子体内注射または局所投与して検討した。
(付記1)
上皮過形成および/または線維症に関連する前立腺疾患または障害の予防、治療および/または改善方法であって、前記方法は、それを必要とする対象に有効量のマルチキナーゼ阻害剤を投与することを含み、前記マルチキナーゼ阻害剤はある範囲のキナーゼ阻害活性を有する、方法。
前記マルチキナーゼ阻害剤が、スニチニブ、レゴラフェニブ、ポナチニブ、パゾパニブ、ニンテダニブおよび/またはレンバチニブである、付記1に記載の方法。
前記マルチキナーゼ阻害剤が、スニチニブ、レゴラフェニブ、ニンテダニブおよびレンバチニブである、付記1に記載の方法。
前記マルチキナーゼ阻害剤が、ニンテダニブおよびレンバチニブである、付記1に記載の方法。
前記マルチキナーゼ阻害剤がニンテダニブである、付記1に記載の方法。
前記マルチキナーゼ阻害剤がレンバチニブである、付記1に記載の方法。
前記前立腺疾患または障害が、動物およびヒトにおける、前立腺肥大症およびその関連する下部尿路症状、尿管および腎盂の線維症、前立腺腺腫、ならびに前立腺上皮内腫瘍からなる群から選択される、付記1に記載の方法。
前記前立腺疾患または障害が、前立腺肥大症(BPH)およびその関連する下部尿路症状である、付記1に記載の方法。
薬の投与が、非経口、筋肉内、皮内、皮下、局所、腹腔内、病変内、病変周囲、前立腺内、前立腺周囲、経直腸、および経尿道経路で行われる、付記1~8に記載の方法。
Claims (8)
- マルチキナーゼ阻害剤を含む、上皮過形成および/または線維症に関連する前立腺疾患または障害の予防、治療および/または改善のための薬剤であって、有効量の前記薬剤はそれを必要とする対象に投与され、前記マルチキナーゼ阻害剤はレンバチニブであり、前記前立腺疾患または障害は、前立腺肥大症(BPH)またはその関連する下部尿路症状である、薬剤。
- 前記対象は動物またはヒトである、請求項1に記載の薬剤。
- 前記マルチキナーゼ阻害剤が前立腺内注射により投与される、請求項1または2に記載の薬剤。
- 前記マルチキナーゼ阻害剤が前立腺周囲注射により投与される、請求項1または2に記載の薬剤。
- 前記マルチキナーゼ阻害剤が経直腸送達により投与される、請求項1または2に記載の薬剤。
- 前記マルチキナーゼ阻害剤が経尿道送達により投与される、請求項1または2に記載の薬剤。
- 前記マルチキナーゼ阻害剤が非経口送達により投与される、請求項1または2に記載の薬剤。
- 前記マルチキナーゼ阻害剤が、腹腔内、皮下、筋肉内、皮内、局所、病変内、または病変周囲への送達により投与される、請求項1または2に記載の薬剤。
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WO2017062694A1 (en) | 2015-10-07 | 2017-04-13 | Diane Tang-Liu | Compositions and methods of treating skin fibrotic disorders |
CN107019697A (zh) | 2016-02-02 | 2017-08-08 | 瑞阳(苏州)生物科技有限公司 | 预防或治疗纤维化疾病的药物组合物及其应用 |
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JP2011520971A (ja) | 2008-05-19 | 2011-07-21 | ブラッコ・イメージング・ソシエタ・ペル・アチオニ | ガストリン放出ペプチド化合物 |
WO2017062694A1 (en) | 2015-10-07 | 2017-04-13 | Diane Tang-Liu | Compositions and methods of treating skin fibrotic disorders |
CN107019697A (zh) | 2016-02-02 | 2017-08-08 | 瑞阳(苏州)生物科技有限公司 | 预防或治疗纤维化疾病的药物组合物及其应用 |
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AU2017445169B2 (en) | 2022-01-06 |
EP3731930A4 (en) | 2021-10-20 |
AU2017445169A1 (en) | 2020-07-02 |
US11376252B2 (en) | 2022-07-05 |
US20200352943A1 (en) | 2020-11-12 |
KR102542751B1 (ko) | 2023-06-12 |
JP2021509405A (ja) | 2021-03-25 |
CA3087477A1 (en) | 2019-07-04 |
CA3087477C (en) | 2022-11-15 |
EP3731930A1 (en) | 2020-11-04 |
CN111655339A (zh) | 2020-09-11 |
WO2019133022A1 (en) | 2019-07-04 |
CN111655339B (zh) | 2023-06-20 |
KR20200105874A (ko) | 2020-09-09 |
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