CN113648421A - 磺酰脲类药物在制备治疗葡萄膜炎的药物中的应用 - Google Patents
磺酰脲类药物在制备治疗葡萄膜炎的药物中的应用 Download PDFInfo
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Abstract
本发明公开了磺酰脲类药物在制备治疗葡萄膜炎的药物中的应用。所述磺酰脲类药物优选格列本脲，该药物能够安全有效治疗葡萄膜炎尤其是自身免疫性葡萄膜炎，避免了现有葡萄膜炎糖皮质激素联合免疫抑制剂治疗的副作用。本发明证实在经过格列本脲治疗后，葡萄膜炎的发病率降低或发病后根据眼底成像系统评价的临床评分下降，视网膜全层炎症浸润减少或无炎症浸润，病理评分下降，视网膜损伤减少或无视网膜损伤。
Description
技术领域
本发明涉及磺酰脲类药物的医药新用途，具体涉及磺酰脲类药物在葡萄膜炎治疗中的应用。
背景技术
磺酰脲类药物（sulfonylureas，SU）是应用最早、品种最多、临床应用也最广泛的口服降糖药，SU类药物有第一代和第二代之分，近年研制的格列美脲则以其用药剂量小、具有一定的改善胰岛素抵抗作用、减少胰岛素用量而被称为第三代SU类药物。磺酰脲类药物的作用机制大致分为两种，一种是对胰岛β细胞的作用，已知SU在发挥对胰岛β细胞的作用时，必须先与β细胞表面的SU受体相结合，然后与β细胞表面的ATP敏感钾通道偶联，使此通道关闭，细胞膜去极化，从而释放胰岛素。因此，SU能刺激β细胞释放胰岛素，从而降低血糖；另一种是胰外作用，SU可以促进肝糖原合成，减少肝糖的产生，并能减缓肝脏葡萄糖向血液中的释放速率。同时，SU可使周围组织对葡萄糖的摄取、利用增加，并可增加细胞膜上胰岛素受体的数量，从而使机体的胰岛素敏感性增加。同时，磺酰脲类药物往往会与位于心脏组织和内皮细胞上的 SUR2 受体结合。在最初的胰岛素分泌后，磺酰脲类药物还可以降低肝脏中胰岛素的清除率，进而导致血浆中胰岛素水平的增加。
格列本脲（Glibenclamide, GLB），是美国食品和药物管理局 (FDA) 批准用于治疗 2 型糖尿病的第二代磺脲类药物，分子式为C23H28ClN3O5S。格列本脲和其他磺脲类药物一样，其作用机制也是基于增加胰腺β细胞的胰岛素分泌。由于其作用机制的重叠，最近的研究甚至开始强调低剂量的格列本脲可能是降低颅内压和脑水肿的药物。
葡萄膜炎是世界范围内常见的严重不可逆致盲眼病，多由免疫稳态失衡导致，并且多数伴发全身性症状。该病主要多发于中青年，且病程长易反复发作，致盲率极高。目前葡萄膜炎临床主要治疗方法为使用糖皮质激素联合免疫抑制剂以拮抗炎症反应，但长期使用激素和免疫抑制剂易诱发高血压，动脉硬化，骨质疏松等疾病。葡萄膜炎发病的确切机制尚不完全明确，安全有效的葡萄膜炎靶向治疗药物研发迫在眉睫。
然而，目前临床上仍缺乏用于葡萄膜炎治疗的安全有效的药物。提供一种治疗葡萄膜炎的安全有效药物具有重要临床意义。
发明内容
为了克服现有葡萄膜炎治疗药物毒副作用多的不足，本发明提供了将磺酰脲类药物用于制备治疗葡萄膜炎的药物，该药物可以减少毒副作用的产生，并且安全有效。
为实现上述目的，本发明采取如下技术方案：将磺酰脲类药物用于制备治疗葡萄膜炎的药物。
优选地，所述磺酰脲类药物选自格列本脲、格列波脲、氯磺丙脲、甲苯磺丁脲、妥拉磺脲、格列吡嗪、格列齐特、格列喹酮、格列吡脲、格列美脲、格列派特，以及它们的任何组合。
更优选地，其中所述磺酰脲类药物选自格列本脲。
格列本脲是第二代磺脲类药物，其结构式如下：
其通常作为降血糖的药物，其作用机理和其他磺酰脲类药物类似，格列本脲是与140KDa受体蛋白结合，能刺激β细胞释放胰岛素，从而降低血糖。本发明人意外发现，磺酰脲类药物尤其是格列本脲可减轻实验性葡萄膜炎模型小鼠的眼底炎症病灶，减轻眼底毛细血管渗漏，抑制小胶质细胞炎症反应，并抑制视网膜组织炎症细胞浸润，从而可以作为葡萄膜炎治疗的药物。格列本脲可以减轻炎症反应，而且免受激素和免疫抑制剂造成的高血压和骨质增生等疾病的困扰。
优选地，所述葡萄膜炎选自虹膜睫状体炎、脉络膜炎、脉络膜视网膜炎、视网膜炎、视网膜血管炎中的一种或多种。或者所述葡萄膜炎选自白塞氏病、伏格特-小柳-原田综合征、Fuchs综合症、前葡萄膜炎、中间葡萄膜炎、后葡萄膜炎、全葡萄膜炎、感染性葡萄膜炎、自身免疫性葡萄膜炎、外伤性葡萄膜炎、特发性葡萄膜炎中的一种或多种。
更优选地，所述葡萄膜炎为自身免疫性葡萄膜炎。
进一步优选地，所述葡萄膜炎为视网膜炎。
本发明所述的用于治疗葡萄膜炎的药物除了磺酰脲类药物活性成分之外，还可以包括药用辅料例如各种赋形剂和附加剂等，具体的可以为溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂等。所述药物可以为各种剂型，例如片剂、胶囊剂、丸剂、口服液体制剂、颗粒剂、散剂或注射液中的一种或几种。
葡萄膜炎发病的确切机制尚不完全明确，目前一般认为多数内因性葡萄膜炎的发生与机体免疫功能失调有关：前葡萄膜炎多由体液免疫介导, 很可能通过免疫复合物诱发炎症, 而后葡萄膜炎多由细胞免疫介导。大部分葡萄膜炎是自身免疫性疾病，视网膜和脉络膜中有多种致葡萄膜炎的自身抗原，如视网膜S抗原、光感受器间维生素A类结合蛋白、视紫红质、视蛋白、黑素相关抗原等，这些抗原被抗原提呈细胞加工后提呈给自身反应性辅助性T细胞（Th细胞），如这些细胞被激活，即通过一系列反应引起免疫反应和炎症。
葡萄膜炎是累及葡萄膜、视网膜、视网膜血管及玻璃体的一组炎症性疾病，也称为眼内炎症。由于炎症的初始部位及累及的组织不同，临床上有多种类型，如虹膜睫状体炎、脉络膜炎、脉络膜视网膜炎、视网膜炎及视网膜血管炎等；按病因可分为感染性、自身免疫性、外伤性及特发性葡萄膜炎等多种类型；根据炎症发生的部位将葡萄膜炎分为前、中间、后及全葡萄膜炎4类；根据葡萄膜炎的临床特点及与全身性疾病的关联性，又将其分为白塞氏病、伏格特-小柳-原田综合征（VKH综合症）及Fuchs综合征等类型。这些众多的名称不仅是分类学上的术语，更重要的是对判断病情发展趋势、预后及指导临床用药有重要价值。葡萄膜炎病因复杂，种类繁多，在治疗上有很大不同，如Fuchs综合征，一般不需糖皮质激素、细胞毒性制剂及其他免疫抑制剂治疗；初发性VKH综合征，主要应用大剂量糖皮质激素治疗；白塞氏病则不宜长期、大剂量使用糖皮质激素，而需要细胞毒性制剂和其他免疫抑制剂治疗。而本发明人意外发现，降糖药磺酰脲类药物尤其是格列本脲能够治疗葡萄膜炎，在经过格列本脲治疗后，葡萄膜炎的发病率降低或发病后根据眼底成像系统评价的临床评分下降，视网膜全层炎症浸润减少或无炎症浸润，病理评分下降，视网膜损伤减少或无视网膜损伤。
本发明的有益效果在于：本发明提供了磺酰脲类药物的医药新用途，即用于治疗葡萄膜炎，为葡萄膜炎的治疗提供了一种安全有效的方法，该方法副作用小。
附图说明
图1. 模型小鼠的眼底炎症病灶成像。NC：正常对照组；EAU：经过葡萄膜炎造模后的组（实验性自身免疫性葡萄膜炎）；EAU+GLB：经过葡萄膜炎造模后，采用格列本脲GLB给药治疗的组。可以证明格列本脲减少葡萄膜炎模型小鼠的眼底炎症病灶。 “→”表示发病病灶。
图2. 模型小鼠的视网膜组织损伤成像。NC：正常对照组；EAU：经过葡萄膜炎造模后的组（实验性自身免疫性葡萄膜炎）；EAU+GLB：经过葡萄膜炎造模后，采用格列本脲GLB给药治疗的组。可以证明格列本脲减少葡萄膜炎模型小鼠的视网膜组织损伤。“→”表示视网膜皱褶。
具体实施方式
实施例1. 格列本脲减少葡萄膜炎模型小鼠的眼底炎症病灶
C57小鼠（18-20 g）一共15只随机分为三组，每组5只：（1）正常C57小鼠为对照组；（2）葡萄膜炎组；（3）葡萄膜炎小鼠格列本脲治疗组。
本实施例采用的葡萄膜炎小鼠动物模型，造模方式为：将用光感受器间视黄醇结合蛋白IRBP 1-20与完全弗氏佐剂以体积比1:1混合乳化，并通过尾根部和双腿皮下注射，每只小鼠注射150 μg IRBP 1-20，随后腹腔注射1 μg百日咳毒素。
对于格列本脲GLB给药治疗的组，治疗方式为：在造模之后一天开始隔天腹腔注射格列本脲溶液，连续给药21天（即一共10次），每次每只给药量为5mg/kg。
在每组小鼠中选取两只具有代表性的小鼠，于免疫后第7天开始每2~3天观察一次眼底并评分，图中显示同一时间测试的不同组中两只代表性小鼠的情况（如图1），发现未经格列本脲治疗组（EAU组）的眼底可以看到大面积的线状炎症病灶和大型的融合病灶以及严重的血管炎症，临床评分2分，而经格列本脲治疗组（EAU+GLB组）仅有轻度血管炎症，无视乳头水肿，无炎症灶以及网脱等，临床评分0.5分。即采用本发明的格列本脲治疗后临床评分明显下降，眼炎症浸润及视网膜病变明显减少。
实施例2. 格列本脲减少葡萄膜炎模型小鼠的视网膜组织损伤与炎性细胞浸润
本实施例采用的小鼠，其造模过程，以及治疗过程均同实施例1。在每组小鼠中选取三只具有代表性的小鼠，于免疫后第21天，处死小鼠取眼球组织，行石蜡切片，HE染色，观察视网膜全层的炎症浸润情况和视网膜脱离，肉芽肿，出血，新生血管等病理表现，图中显示同一时间测试的不同组中三只代表性小鼠的情况（图2），结果发现，未经格列本脲治疗组（EAU组）出现严重的网脱和视网膜皱褶，病理切片评分3分，而经格列本脲治疗组（EAU+GLB组），视网膜皱褶减少且程度大幅减轻，病理切片评分0.5分。可见本发明治疗组的视网膜病理切片的病理评分与未治疗葡萄膜小鼠组相比明显下降。
因此，格列本脲可以显著抑制葡萄膜炎尤其是实验性自身免疫性葡萄膜炎的炎症损伤，降低临床评分。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。
Claims (9)
1.磺酰脲类药物在制备治疗葡萄膜炎的药物中的应用。
2.根据权利要求1所述的应用，其中所述磺酰脲类药物选自格列本脲、格列波脲、氯磺丙脲、甲苯磺丁脲、妥拉磺脲、格列吡嗪、格列齐特、格列喹酮、格列吡脲、格列美脲、格列派特，以及它们的任何组合。
3.根据权利要求1所述的应用，其中所述磺酰脲类药物选自格列本脲。
4.根据权利要求1至3任一项所述的应用，其中所述葡萄膜炎选自虹膜睫状体炎、脉络膜炎、脉络膜视网膜炎、视网膜炎、视网膜血管炎中的一种或多种。
5.根据权利要求1至3任一项所述的应用，其中所述葡萄膜炎选自白塞氏病、伏格特-小柳-原田综合征、Fuchs综合症、前葡萄膜炎、中间葡萄膜炎、后葡萄膜炎、全葡萄膜炎、感染性葡萄膜炎、自身免疫性葡萄膜炎、外伤性葡萄膜炎、特发性葡萄膜炎中的一种或多种。
6.根据权利要求1至3任一项所述的应用，其中所述葡萄膜炎为自身免疫性葡萄膜炎。
7.根据权利要求1至3任一项所述的应用，其中所述葡萄膜炎为视网膜炎。
8.根据权利要求1至3任一项所述的应用，其中所述药物还含有药用辅料。
9.根据权利要求1至3任一项所述的应用，其中所述药物为选自片剂、胶囊剂、丸剂、口服液体制剂、颗粒剂、散剂或注射液中的一种或几种的剂型。
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