CN111655339A - 多激酶抑制剂及其在前列腺增生和泌尿道疾病中的用途 - Google Patents
多激酶抑制剂及其在前列腺增生和泌尿道疾病中的用途 Download PDFInfo
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- CN111655339A CN111655339A CN201780098057.1A CN201780098057A CN111655339A CN 111655339 A CN111655339 A CN 111655339A CN 201780098057 A CN201780098057 A CN 201780098057A CN 111655339 A CN111655339 A CN 111655339A
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Abstract
一种用于预防、治疗和/或改善与上皮增生和/或纤维化相关的前列腺疾病或失调的方法，所述方法包括：向有此需要的受试者施用有效量的多激酶抑制剂，其中所述多激酶抑制剂具有一定范围的激酶抑制活性。所述多激酶抑制剂是舒尼替尼、瑞格非尼、普纳替尼、帕唑帕尼、尼达尼布和/或乐伐替尼。所述前列腺疾病或失调选自由以下项组成的组：动物和人类中的良性前列腺增生及其相关的下泌尿道症状，输尿管和肾盂的纤维化、前列腺腺瘤和前列腺上皮内瘤。
Description
技术领域
本发明涉及具有一定范围的多激酶抑制活性的化合物，所述化合物对泌尿道疾病中的特定生长因子和/或细胞因子信号转导途径和/或反应阶段起作用。
背景技术
良性前列腺增生(BPH)及其相关的下泌尿道症状(LUTS)在老年男性中是常见的。在组织病理学上，BPH的特征是前列腺的尿道周围部分中的上皮细胞和基质细胞的数量增加。这通过显微结节的出现体现，所述显微结节逐渐增殖并扩大以增加腺和基质前列腺组织的质量。
已提出睾酮参与BPH的进展。在前列腺中，核膜结合酶5α-还原酶将激素睾酮转换为二氢睾酮(DHT)。DHT在引起增生中很重要，这得到了临床观察的支持，即抑制5α-还原酶可以使前列腺中的DHT水平降低多达85％-90％，并进而减小前列腺体积并减少BPH症状。5种α-还原酶抑制剂，例如非那雄胺和度他雄胺，已在全球范围内用于治疗BPH。
BPH中基质细胞的增殖是该疾病进展的主要原因。有效的平滑肌紧张度由肾上腺素能神经系统调节。α1-肾上腺素能受体的刺激介导前列腺平滑肌的有效张力，并导致前列腺尿道阻力增加。α1-肾上腺素受体拮抗剂，例如坦索罗辛(tamsulosin)和阿夫唑嗪(alfuzosin)，可以缓解与BPH相关的尿道阻塞。
使用5种α-还原酶抑制剂是缓慢起效的，并且与性副作用相关。α1-肾上腺素受体拮抗剂更有效且快速起效，但是可产生血管扩张剂副作用。此外，这些药物疗法主要在疾病的轻度至中度阶段中有效。显然需要针对良性前列腺增生和下泌尿道症状的改进的药物疗法。
前列腺癌大部分是一种进展非常缓慢的疾病，并且在腺细胞中开始。前列腺癌开始于前列腺腺细胞的形状和大小的微小变化—前列腺上皮内瘤(PIN)。在所有50岁的男性中，将近50％具有PIN。任何在前列腺组织活检后被发现具有高等级PIN的患者都处于显著更大的在其前列腺中具有癌细胞的风险下。
BPH和/或PIN的进展中涉及许多生长因子和细胞因子。有人认为，FGF、IGF和TGF家族的成员尤其有助于BPH的进展。报道了人BPH组织中对VEGF、VEGFR-1、VEGFR-2和CD 105阳性微血管的染色。这表明了VEGF在BPH的病理过程中的有力作用。
这些数据表明，通过使用多激酶受体抑制剂调节生长因子和细胞因子信号转导途径将是用于预防和/或治疗前列腺和泌尿道的增殖性和纤维化失调及其相关症状的新策略。
发明概述
本发明的一些实施方式提供了具有一定范围(spectrum)的多激酶抑制剂活性并且可用于治疗与上皮增生和/或纤维化相关的前列腺疾病或失调的药剂，包括：向动物或人类施用有效量的多激酶抑制剂。本发明的一些实施方式还涉及此类化合物和组合物的治疗或预防用途，以及用于治疗与上皮增生和/或纤维化相关的前列腺疾病或失调的方法。
在一个方面中，本发明提供了具有一定范围的多激酶抑制剂活性并且相应地可用于治疗人类的与良性前列腺增生或下泌尿道症状相关的疾病状态和/或失调的方法中的药剂。更特别地，本发明还涉及此类化合物和组合物的治疗或预防用途，以及治疗与良性前列腺增生及其相关的下泌尿道症状、输尿管和肾盂的纤维化、前列腺腺瘤和前列腺上皮内瘤相关的疾病状态和/或失调的方法。
在一个方面中，本发明提供了一种通过向需要此类治疗或预防的人类受试者施用治疗有效量的多激酶抑制剂来治疗/预防良性前列腺增生及其相关的下泌尿道症状的方法，其中所述多激酶抑制剂可包括但不限于舒尼替尼(sunitinib)、瑞格非尼(regorafenib)、普纳替尼(ponatinib)、帕唑帕尼(pazopanib)、尼达尼布(nintedanib)和乐伐替尼(lenvatinib)。所述前列腺疾病或失调选自由以下项组成的组：动物和人类中的良性前列腺增生及其相关的下泌尿道症状，输尿管和肾盂的纤维化、前列腺腺瘤和前列腺上皮内瘤。
附图说明
图1示出了在100倍放大倍数下大鼠背外侧前列腺中腺体增生的显微镜图像。小图(A)是经载剂处理的样品，显示出正常的(评分＝0)腺体轮廓。小图(B)是经睾酮(TE)和去氧肾上腺素(PE)诱导且经载剂处理的样品，显示出显著的(评分＝4)上皮增生。小图(C)是经TE和PE诱导且经尼达尼布处理的样品，显示出中等的(评分＝3)上皮增生。小图(D)是经TE和PE诱导且经舒尼替尼处理的样品，显示出中等的(评分＝3)上皮增生。小图(E)是经TE和PE诱导且经乐伐替尼处理的样品，显示出轻微的(评分＝2)上皮增生。小图(F)是经TE和PE诱导且经多沙唑嗪(doxazosin)处理的样品，显示出中等的(评分＝3)上皮增生。
图2示出了在100倍放大倍数下来自腹侧前列腺的代表性图像。小图(A)是经载剂处理的样品，显示出正常的(评分＝0)腺体轮廓。小图(B)是经TE)和PE诱导且经载剂处理的样品，显示出显著的(评分＝4)上皮增生。小图(C)是经TE和PE诱导且经尼达尼布处理的样品，显示出中等的(评分＝3)上皮增生。小图(D)是经TE和PE诱导且经舒尼替尼处理的样品，显示出中等的(评分＝3)上皮增生。小图(E)是经TE和PE诱导且经乐伐替尼处理的样品，显示出轻微的(评分＝3)上皮增生。小图(F)是经TE和PE诱导且经多沙唑嗪处理的样品，显示出中等的(评分＝3)上皮增生。
图3示出了图1中描述的实验的背外侧前列腺的腺体增生平均评分。
图4示出了图2中描述的实验的腹侧前列腺的腺体增生平均评分。
图5示出了各个处理组的前列腺重量/100g体重。
图6示出了在100倍放大倍数下来自背外侧前列腺的代表性图像。小图(1)是组5(载剂)大鼠的图像，显示出正常的(评分＝0)腺体轮廓。小图(2)是组1(经TE+PE诱导并经载剂处理的)大鼠的图像，显示出轻微的(评分＝2)上皮增生。小图(3)是组3(经TE+PE诱导并经1％索拉非尼处理的)大鼠的图像，显示出轻微的(评分＝2)上皮增生。小图(4)是组4(经TE+PE诱导并经2.5％吡非尼酮(pirfenidone)处理的)大鼠的图像，显示出最小(评分＝1)上皮增生。小图(5)是组6(经TE诱导的)大鼠的图像，显示出轻微的(评分＝2)上皮增生。小图(6)是组7(经TE诱导并经1％利奥西呱(riociguat)处理的)大鼠，显示出最小的(评分＝1)上皮增生。
图7示出了图6中描述的实验在大鼠BPH模型中的上皮增生平均评分。
图8示出了在实施例4中所述的角膜缝合纤维化模型中的组织学发现。
图9示出了在实施例5中所述的大鼠脉络膜血管新生模型中新生血管病变的减少。
发明详述
本发明的一些实施方式涉及预防和/或治疗与动物和人类中的良性前列腺增生及其相关的下泌尿道症状，输尿管和肾盂的纤维化、前列腺腺瘤和前列腺上皮内瘤相关的疾病或失调。根据本发明的一些实施方式，用于治疗良性前列腺增生或其相关的下泌尿道症状的方法可涉及：向需要此类治疗的受试者给予包含多激酶抑制剂的组合物，所述多激酶抑制剂具有抑制选定激酶(例如VEGF和TGFβ)的选定范围的活性。
本发明的组合物可包含多激酶抑制剂或其药学上可接受的盐。如本文所用，术语“多激酶抑制剂”是指可抑制多种激酶的抑制剂。如本文所用，术语“药学上可接受的盐”是指所公开化合物的衍生物，其中母体化合物通过制备其酸式盐或碱式盐而被改性。
药学上可接受的盐的示例包括但不限于碱性残基(例如胺)的无机或有机酸盐；酸性残基(例如羧酸)的碱金属盐或有机盐；等等。药学上可接受的盐包括例如由无毒的无机酸或有机酸形成的母体化合物/分子的常规无毒盐或季铵盐。例如，此类常规的无毒盐可包括衍生自无机酸(例如盐酸)的那些盐。
根据一些实施方式，本发明还包括药物组合物，所述药物组合物含有本文的本发明化合物/分子中的一种或多种作为活性成分，以及至少一种药学上可接受的载体、稀释剂或赋形剂。
在一些实施方式中，本发明化合物/分子可以通过肠胃外、肌内、皮内、皮下、表面(topical)、腹膜内、病灶内、病灶周围、前列腺内、前列腺周围、经直肠和经尿道途径施用。
剂量将取决于施用途径、疾病的严重程度、患者的年龄和体重，以及主治医师在确定最适合特定患者的个体方案和剂量水平时通常考虑的其他因素。也就是说，治疗有效量将基于患者(年龄、体重等)、疾病状况、施用途径等。本领域技术人员将能够在无需创造性劳动的情况下确定治疗有效量。
根据本发明的一些实施方式，施用方案可以在(诱导)手术之前、在手术之后(创伤/急性炎症、增殖、重塑，至成熟时或之前)施用。
根据本发明的一些实施方式，为了由本发明的化合物/分子制备药物组合物，惰性的药学上可接受的载体可以是固体或液体。
术语组合物旨在包括活性成分或药学上可接受的盐以及药学上可接受的载体的制剂。例如，本发明可以通过本领域已知的手段配制成例如水性或油性溶液、悬浮液、乳液、乳膏剂(cream)、软膏剂(ointment)、凝胶剂的形式，以及用于肠胃外使用的无菌水性或油性溶液或悬浮液或无菌乳液。
液体形式的组合物包括溶液、悬浮液和乳液。可以提及活性化合物/分子的无菌水溶液或水-丙二醇溶液作为适于肠胃外施用的液体制备物的示例。液体组合物也可以在聚乙二醇水溶液中配制成溶液。可以通过以下方式来制备用于口服施用的水性溶液：将活性成分溶于水中，以及根据期望添加合适的着色剂、调味剂、稳定剂和增稠剂。可以通过以下方式来制备用于口服使用的水性悬浮液：将细碎的活性成分与粘性材料例如天然合成树胶、树脂、甲基纤维素、羧甲基纤维素钠，以及药物制剂领域中已知的其他悬浮剂一起分散在水中。
药物组合物可以是单位剂型。在此种形式中，将组合物分为含有适当量的活性成分的单位剂量。单位剂型可以是包装的制备物，所述包装含有分立量的制备物。
可以配制用于任何合适的施用途径和手段的组合物。药学上可接受的载体或稀释剂包括适用于直肠、表面或肠胃外施用的制剂中使用的那些。所述制剂可以方便地以单位剂型存在，并且可以通过药学领域中众所周知的方法中的任何方法制备。
对于固体组合物，可以使用常规的无毒固体载体包括，例如药用级的甘露醇、乳糖、纤维素、纤维素衍生物、淀粉、硬脂酸镁、糖精钠、滑石、葡萄糖、蔗糖、碳酸镁等等。液体的可药物施用的组合物可以例如通过以下方式来制备：将如上所定义的活性化合物/分子和任选的药物辅剂溶解、分散等在载体(例如水、盐水、葡萄糖水溶液、甘油、乙醇等等)中，从而形成溶液或悬浮液。如果期望的话，要施用的药物组合物还可含有少量的无毒辅助物质，例如润湿剂或乳化剂、pH缓冲剂等，例如乙酸钠、去水山梨糖醇单月桂酸酯、三乙醇胺乙酸钠、脱水山梨糖醇单月桂酸酯、三乙醇胺油酸酯等。制备此类剂型的实际方法对于本领域技术人员而言是已知的或将显而易见的。
将通过以下实施例说明本发明的实施方式。本领域技术人员应当理解，这些实施例仅用于说明，并且在不脱离本发明范围的情况下可以进行其他修改和变型。
实施例1
尽管人类和啮齿动物的前列腺之间存在形态学和解剖学差异，但在它们的药理学和组织化学方面存在许多相似之处，这使得在大鼠中研究BPH成为有用的研究方法。人类和大鼠中的前列腺都受到围绕腺体元件的精细网络的神经支配。这些神经结构中的大多数是儿茶酚胺能的并且含有不同亚型的肾上腺素能受体。
由于肾上腺素能神经支配对前列腺细胞生长的潜在效应，已经检查了去氧肾上腺素施用对大鼠前列腺的效应。在每天1mg/kg的剂量下，去氧肾上腺素诱导具有管腔内投影(intraluminal projection)的不规则管道。上皮变得更厚，甚至有细胞的局灶性“堆积”。基质继而表现出纤维细胞和平滑肌细胞的肥大和增生。这些变化对应于人类良性前列腺增生的存在。此外，去氧肾上腺素在PIN病变的进展中具有双重作用，影响大鼠前列腺的上皮和基质成分两者。
BPH是一种真正的增生过程。组织学研究证明细胞数量增加。因此，进行了研究以确定测试化合物和载剂对大鼠中睾酮(TE)和去氧肾上腺素(PE)诱导的良性前列腺增生的影响。在第5天至第32天，通过皮下注射每天施用睾酮(2mg/kg)加去氧肾上腺素(5mg/kg)来诱导雄性Wistar大鼠。在第1天和第18天，在背外侧叶和腹侧叶通过前列腺内注射(0.4ml)来施用载剂或测试化合物(均为1％w/w)尼达尼布、舒尼替尼、乐伐替尼和0.5％甲磺酸多沙唑嗪。在第32天对动物实施安乐死。测定体重并收获前列腺。实验设计列于表1中
表1：研究设计概要
*除组1外，所有动物均接受睾酮(TE)和去氧肾上腺素(PE)。
在尸检时，将前列腺的腹侧叶和背外侧叶分开，然后切成两半。将左半部分在10％中性缓冲福尔马林中固定，切片，并用苏木精和伊红(H&E)染色。对这些切片中的组织学变化进行评分。上皮增生被认为是正常出现的腺体轮廓内的上皮细胞增加，主要通过上皮细胞的分层以及上皮簇生和乳头状突起的存在增多来反映。将0(不存在)至5(严重)的严重等级分配给每个样品。代表性图像在图1和图2中呈现。平均评分(+/-SD)示出在图3和图4中。
图1示出了在100倍放大倍数下来自背外侧前列腺的代表性图像。小图(A)是经载剂处理的样品，显示出正常的(评分＝0)腺体轮廓。小图(B)是经睾酮(TE)和去氧肾上腺素(PE)诱导且经载剂处理的样品，显示出显著的(评分＝4)上皮增生。小图(C)是经睾酮(TE)和去氧肾上腺素(PE)诱导且经尼达尼布处理的样品，显示出中等的(评分＝3)上皮增生。小图(D)是经睾酮(TE)和去氧肾上腺素(PE)诱导且经舒尼替尼处理的样品，显示出中等的(评分＝3)上皮增生。小图(E)是经睾酮(TE)和去氧肾上腺素(PE)诱导且经乐伐替尼处理的样品，显示出轻微的(评分＝2)上皮增生。小图(F)是经睾酮(TE)和去氧肾上腺素(PE)诱导且经多沙唑嗪处理的样品，显示出中等的(评分＝3)上皮增生。
图2示出了在100倍放大倍数下来自腹侧前列腺的代表性图像。小图(A)是经载剂处理的样品，显示出正常的(评分＝0)腺体轮廓。小图(B)是经睾酮(TE)和去氧肾上腺素(PE)诱导且经载剂处理的样品，显示出显著的(评分＝4)上皮增生。小图(C)是经睾酮(TE)和去氧肾上腺素(PE)诱导且经尼达尼布处理的样品，显示出中等的(评分＝3)上皮增生。小图(D)是经睾酮(TE)和去氧肾上腺素(PE)诱导且经舒尼替尼处理的样品，显示出中等的(评分＝3)上皮增生。小图(E)是经睾酮(TE)和去氧肾上腺素(PE)诱导且经乐伐替尼处理的样品，显示出轻微的(评分＝3)上皮增生。小图(F)是经睾酮(TE)和去氧肾上腺素(PE)诱导且经多沙唑嗪处理的样品，显示出中等的(评分＝3)上皮增生。
研究结果表明了大鼠中TE和PE诱导后腺体增生的组织学变化，所述腺体增生的组织学变化在人的前列腺增生和腺瘤中观察到，即腺体增生朝向管腔形成乳头状结构。与未处理的TE/PE诱导的前列腺相比，测试化合物尼达尼布、舒尼替尼、乐伐替尼和多沙唑嗪显示为减少腺体增生(图1B和图2B)。尼达尼布、舒尼替尼、乐伐替尼和多沙唑嗪抑制该模型中的良性前列腺增生，表明这些化合物能够有效治疗良性前列腺增生(BPH)和泌尿生殖道的增殖性和纤维化失调。
实施例2
在形态上，BPH的特征是通过预先存在的导管中上皮的增殖形成新的架构。鉴于基质细胞在上皮细胞稳态中起着重要的旁分泌调节功能，基质-上皮相互作用中的后期变化可以提供对BPH进展的洞察。进行第二项研究以确定在大鼠中使用睾酮和/或去氧肾上腺素诱导的BPH的方案中，在诱导后测试化合物和载剂的治疗效应。
在第1天至第28天，通过皮下注射每天施用睾酮(2mg/kg)加去氧肾上腺素(5mg/kg)来诱导雄性Wistar大鼠。在第15天和第29天通过在背外侧叶中进行前列腺内注射(0.2ml)来施用载剂或测试化合物索拉非尼(1％w/w)、吡非尼酮(2.5％w/w)和利奥西呱(1％w/w)。在第42天对动物实施安乐死。确定体重。收获前列腺并称重。实验设计列于表2中。
表2：研究设计概要
确定每个治疗组的前列腺重量/100g体重。如图5所示，与载剂相比，索拉非尼和吡非尼酮没有显示出平均前列腺重量降低。在类似的测试(使用TE诱导)中，与载剂对照相比，利奥西呱处理降低了平均前列腺重量。
在尸检时，将前列腺的背外侧和腹侧叶分开并切成两半。将左半部分在10％中性缓冲福尔马林中固定，切片，并用苏木精和伊红(H&E)染色。上皮增生被认为是正常出现的腺体轮廓内的上皮细胞增加，如在上皮细胞的分层以及上皮簇生和乳头状突起的存在增多中所反映的。通过显微镜检查基质变化。这些变化包括炎症和组织纤维化。向每个切片给予范围是0(不存在)至5(严重)的严重性评分。
图6示出了在100倍放大倍数下来自背外侧前列腺的代表性图像。小图(1)是组5(载剂)大鼠的图像，显示出正常的(评分＝0)腺体轮廓。小图(2)是组1(经TE+PE诱导并经载剂处理的)大鼠的图像，显示出轻微的(评分＝2)上皮增生。小图(3)是组2(经TE+PE诱导并经1％索拉非尼处理的)大鼠的图像，显示出轻微的(评分＝2)上皮增生。小图(4)是组3(经TE+PE诱导并经2.5％吡非尼酮处理的)大鼠的图像，显示出最小(评分＝1)上皮增生。小图(5)是组5(经TE诱导的)大鼠的图像，显示出轻微的(评分＝2)上皮增生。小图(6)是组6(经TE诱导并经1％利奥西呱处理的)大鼠，显示出最小的(评分＝1)上皮增生。这些评分汇总在图7所示的条形图中。
该研究表明，随着时间的推移，大鼠模型中诱导的BPH的分解导致对测试化合物吡非尼酮和利奥西呱的响应降低。利奥西呱显示为对前列腺体积和上皮增生中的组织学变化有影响。还观察到具有抗VEGFR和抗PDGFR活性的多激酶抑制剂索拉非尼不是良性前列腺增生的有效抑制剂。因此，并非所有的多激酶抑制剂都将在前列腺增生和/或纤维化失调中提供预防或治疗益处。
实施例3
在大鼠中进行前列腺内注射后索拉非尼的前列腺浓度。
在这项研究中，在第15天和第29天进行索拉非尼的单次前列腺内注射。在第42天对动物实施安乐死，并获得前列腺组织样品用于分析。使用Bead Ruptor匀浆器制备组织样品，然后用乙腈萃取并进行高速离心。使用LC-MS/MS方法来测量索拉非尼。
在第42天，索拉非尼在前列腺中的平均浓度为892mg/gm。这些组织浓度高于抑制VEGFR和PDGFR活性所需的浓度。这项研究支持这样的想法：尽管在前列腺中有良好的索拉非尼暴露，但是索拉非尼在前列腺中未显示出任何治疗效应。
实施例4
通常，纤维增生是与疾病、创伤、遗传失调或感染相关的组织中的晚期反应性和/或修复性响应。无论涉及的器官或组织如何，在病理生理学中都存在强重复性。在前列腺以外的组织中进行的观察可有助于我们了解与前列腺疾病或失调(例如良性前列腺增生及其相关的下泌尿道症状)相关的纤维化疾病的进展和消退。
进行研究以确定在缝合诱导的兔子纤维化模型中表面施用测试化合物和载剂的潜在有益效应。在显微镜下基质内放置缝合线到兔子的角膜。在每只眼睛中，将一条9-0丝缝合线以竖直位置放置在角膜中心的颞侧，并将第二根缝合线放置在角膜中心的鼻侧。每根缝合线具有距角膜缘约2mm的两个基质入侵。在手术后将具有一定范围的多激酶抑制活性的测试化合物或载剂每天三次地表面滴注(35μL/眼)到眼中，持续10天。处理组包括载剂、尼达尼布(0.3％，w/w)、索拉非尼(0.3％，w/w)和乐伐替尼(0.3％，w/w)。每个处理组使用六只左眼。
在生前阶段(in-life phase)中，各组(包括载剂对照)的大体眼观察显示相似的非常轻微至中度结膜充血和肿胀。在第11天处死动物，并将眼睛摘出和解剖以用于组织病理学评估。结果示出在图8中。
结果显示，如组织学染色所证明的，尼达尼布和乐伐替尼显著减少了纤维增生和/或减小了胶原密度(参见图8)。相比之下，如通过用于将细胞与周围的结缔组织区分开的梅森三色测试所揭示的，索拉非尼对纤维增生或胶原形成，特别是在纤维化反应中的胶原形成几乎没有影响或没有影响。此外，如通过免疫组织化学分析所确定的，尼达尼布和乐伐替尼显著减少了αSMA染色，而索拉非尼相对于载剂处理对αSMA没有影响。αSMA是肌成纤维细胞的关键标志物，其在创伤愈合和细胞外基质形成中的功能与纤维化疾病相关。
实施例5
在良性前列腺增生、高等级前列腺上皮内瘤和前列腺癌中已经报告血管生成因子(例如VEGF和bFGF)的表达增加，并且微血管密度增大。这表明了在BPH调节中抑制这些因子的作用。在该实施例中，检查了在血管新生大鼠模型中局部施用多激酶抑制剂的效应。新血管的生长受生长因子受体信号转导途径的调节，所述生长因子受体信号转导途径的功能在器官和组织之间广泛地重复。在这项研究中，在激光诱导的脉络膜血管新生后，通过玻璃体内注射或表面施用于大鼠眼来检查局部施用多激酶抑制剂尼达尼布和乐伐替尼的效应。
进行22天的研究，以确定测试剂、阳性对照或载剂对新血管发生的影响。在第1天，使用520nm热激光对所有动物执行激光处理，以产生每只眼睛总共三个病变。在第2天至第21天，每天三次地执行载剂、1％尼达尼布或1％乐伐替尼的双侧表面施用。在第3天，在第二组动物中执行载剂、5μg/眼的大鼠抗VEGF抗体、50μg/眼的尼达尼布或50μg/眼的乐伐替尼的双侧玻璃体内注射。
在第22天，对所有动物执行荧光素血管造影，并使用图像分析软件(ImageJ)确定病变的大小/面积。如图9所示，当经由玻璃体内注射递送时，相对于经载剂处理的眼睛的病变大小，尼达尼布和乐伐替尼处理显著减小了病变大小。此外，相对于阳性对照大鼠抗VEGF的病变大小，乐伐替尼的玻璃体内注射也显著减小了病变大小。
除了玻璃体内注射外，本发明的化合物还可以用于表面应用。如图9所示，相对于载剂的表面滴眼剂施用的病变大小，尼达尼布或乐伐替尼的表面滴眼剂施用减小了病变大小。
这些数据表明，尼达尼布和乐伐替尼在局部施用(例如，注射或表面应用)之后有效减少激光诱导的病变引起的血管新生。
Claims (9)
1.一种用于预防、治疗和/或改善与上皮增生和/或纤维化相关的前列腺疾病或失调的方法，所述方法包括：向有此需要的受试者施用有效量的多激酶抑制剂，其中所述多激酶抑制剂具有一定范围的激酶抑制活性。
2.根据权利要求1所述的方法，其中所述多激酶抑制剂是舒尼替尼、瑞格非尼、普纳替尼、帕唑帕尼、尼达尼布和/或乐伐替尼。
3.根据权利要求1所述的方法，其中所述多激酶抑制剂是舒尼替尼、瑞格非尼、尼达尼布和乐伐替尼。
4.根据权利要求1所述的方法，其中所述多激酶抑制剂是尼达尼布和乐伐替尼。
5.根据权利要求1所述的方法，其中所述多激酶抑制剂是尼达尼布。
6.根据权利要求1所述的方法，其中所述多激酶抑制剂是乐伐替尼。
7.根据权利要求1所述的方法，其中所述前列腺疾病或失调选自由以下项组成的组：动物和人类中的良性前列腺增生及其相关的下泌尿道症状，输尿管和肾盂的纤维化、前列腺腺瘤和前列腺上皮内瘤。
8.根据权利要求1所述的方法，其中所述前列腺疾病或失调是良性前列腺增生(BPH)及其相关的下泌尿道症状。
9.根据权利要求1-8中任一项所述的方法，其中药物的施用通过肠胃外、肌内、皮内、皮下、表面、腹膜内、病灶内、病灶周围、前列腺内、前列腺周围、经直肠和经尿道途径进行。
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