CN115475165A - 马来酸茚达特罗在出血性脑损伤相关疾病中的应用 - Google Patents
马来酸茚达特罗在出血性脑损伤相关疾病中的应用 Download PDFInfo
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- CN115475165A CN115475165A CN202110603757.XA CN202110603757A CN115475165A CN 115475165 A CN115475165 A CN 115475165A CN 202110603757 A CN202110603757 A CN 202110603757A CN 115475165 A CN115475165 A CN 115475165A
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Abstract
本发明涉及医药技术领域，涉及马来酸茚达特罗(Indacaterol)在出血性脑损伤相关疾病治疗、改善和/或预防中的应用。具体地，本发明公开了马来酸茚达特罗(式(I)所示化合物)对抗血红素(Hemin)所致神经元损伤的药理作用，有望进一步开发成治疗出血性脑损伤相关疾病的先导化合物或药物。
Description
技术领域
本发明涉及医药技术领域，具体地涉及马来酸茚达特罗在治疗、改善和/或预防出血性脑损伤相关疾病中的应用。
背景技术
脑出血(Intracerebral hemorrhage,ICH)或称出血性脑卒中，是指非外伤性脑内血管破裂导致自发溢出的血液进入大脑实质，伴或不伴有血液渗入蛛网膜下腔或脑室的疾病。脑出血占所有卒中病例的10％-15％，并以高致死率，高致残率为主要特点。
脑出血可分为原发性损伤与继发性损伤两类，其病理机制复杂，造成继发性脑损伤的关键因素包括以下几个方面：凝血酶持续释放导致的细胞毒性；红细胞裂解释放的血红蛋白及其相关代谢产物引发的细胞凋亡和炎症反应；胞外谷氨酸浓度升高带来的兴奋性毒性以及自由基增加所致的氧化应激等。
目前，临床上对于脑出血的治疗策略包括内科治疗和外科治疗，大多数患者均以内科治疗为主。若病情危重或有其他继发原因，则进行外科治疗。内科治疗主要包括血压血糖管理，一般治疗(持续心肺监护，持续生命体征监测，神经系统评估等)，病因治疗，并发症治疗和药物治疗。药物治疗中主要应用药物有两类：止血药如重组VII因子，氨甲环酸；中药制剂和神经保护剂如依达拉奉，铁螯合剂等。但事实上，药物治疗的安全性与药物疗效均有限，仍待进一步试验证实。外科治疗以手术为主，在脑实质出血方面，微创手术相较开颅手术更为安全有效，后者治疗的有效性尚未确定；在脑室出血方面，脑室外引流联合重组组织型纤溶酶原激活剂(rt-PA)可有效降低重症死亡率，但对神经功能的改善仍待研究。上述两类干预策略均存在一定临床疗效，但也十分局限。
因此，本领域亟待研发高效的脑出血治疗手段或药物来应对此公共健康问题。
发明内容
本发明的主要目的在于提供一种新型的治疗出血性脑损伤相关疾病的药物。具体地，本发明提供了马来酸茚达特罗在制备治疗、缓解和/或预防出血性脑损伤相关疾病的药物中的用途。
在本发明的第一方面，提供了一种式(I)所示化合物或其药学上可接受的盐的用途，用于制备治疗和/或改善和/或预防出血性脑损伤相关疾病的药物。
在另一优选例中，出血性脑损伤相关疾病选自下组：出血性脑卒中、脑外伤、颅内动脉瘤、脑血管畸形、颅内恶性肿瘤、梗死后出血、抗凝或溶栓治疗、瘤卒中、或其组合。
在另一优选例中，所述药物的剂型选自下组：注射剂、片剂、胶囊剂、丸剂、悬浮剂、乳剂、或其组合。
在另一优选例中，所述注射剂的剂型为静脉或肌肉注射剂型。
在另一优选例中，所述药物的给药途径选自下组：经皮、口服、静脉注射、肌肉注射、或其组合。
在另一优选例中，所述式(I)所示化合物或其药学上可接受的盐用于制备以下一种或多种效果的药物：
(x1)改善神经元细胞损伤；
(x2)抑制神经元细胞内ROS的过量生成。
在另一优选例中，所述神经元细胞损伤由血红素缺失引起。
本发明的第二方面，提供了一种药物组合物，包含：
(A1)式I所示的化合物或其药学上可接受的盐；和/或
(A2)选自下组的其他药物：抗氧化剂、抗炎剂或神经保护剂；和/或
(B)药学上可接受的载体和/或赋形剂和/或辅料。
在另一优选例中，所述抗氧化剂选自下组：褪黑素、维生素E、维生素C、艾地苯醌、丹参酚酸，或其组合。
在另一优选例中，所述抗炎剂选自下组：阿司匹林、吲哚美辛、布洛芬、罗格列酮，或其组合。
在另一优选例中，所述神经保护剂选自下组：尼莫地平、姜黄素、美金刚、胞磷胆碱，或其组合。
本发明的第三方面，提供了一种本发明第二方面所述的药物组合物的用途，用于制备治疗和/或改善和/或预防出血性脑损伤相关疾病的药物。
本发明的第四方面，提供了一种体外的改善神经元细胞损伤的方法，给所述细胞施用医学有效量的式I所示的化合物或其药学上可接受的盐和/或本发明第二方面所述的药物组合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1.马来酸茚达特罗对血红素诱发SH-SY5Y细胞损伤的改善作用。其中，(A)SH-SY5Y细胞经血红素损伤处理24小时后，不同处理组的细胞形态代表图，标尺为100μm。代表图中马来酸茚达特罗组指血红素损伤+马来酸茚达特罗给药组；其中(B)不同组SH-SY5Y细胞活力统计图。数据显示为平均值±标准误，##p<0.01与正常对照组相比，*p<0.05，**p<0.01与血红素损伤组相比，n＝4。
图2为实施例2所得马来酸茚达特罗抑制血红素(Hemin)所致SH-SY5Y神经细胞内ROS过量生成的测试结果。数据显示为平均值±标准误，###p<0.001与正常对照组相比，*p<0.05，**p<0.01与血红素损伤组相比，n＝3。
具体实施方式
本发明人经过广泛而深入的研究,意外地发现马来酸茚达特罗能有效治疗出血性脑损伤相关疾病，在此基础上，完成了本发明。
具体地，本发明提供了马来酸茚达特罗及其药学上可接受的盐不仅能够治疗出血性脑损伤，还能够同时改善神经细胞损伤。
术语
如本文所用，术语“本发明化合物”指式(I)所示的化合物。该术语还包括及式(I)化合物的及其各种药学上可接受的盐。
如本文所用，术语“药学上可接受的盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过已知的成盐方法由式I的化合物制备。
马来酸茚达特罗
马来酸茚达特罗(Indacaterol)作为一种新型长效β2受体激动剂，适用于中重度慢性阻塞性肺疾病(COPD)的长期维持治疗，且治疗效果优于其他长效β2的受体激动剂。
马来酸茚达特罗(Indacaterol)的结构式如下所示：
2009年12月在德国首次上市，2011年7月由FDA批准上市。该药与β2受体亲和力强[11]，通过引起支气管平滑肌松弛，舒张支气管，快速起效。使用后，可显著改善患者肺功能，缓解呼吸困难等临床症状，提高患者生命质量，减少慢阻肺急性加重。近年来研究显示，将马来酸茚达特罗与长效毒蕈碱拮抗剂如格隆溴铵联合使用，疗效更好，且可改善慢阻肺(COPD)的预后。迄今尚无马来酸茚达特罗在抗出血性脑卒中方面的研究报道。
药物组合物和给药(施用)方法
由于本发明化合物具有显著改善脑出血相关神经细胞损伤，因此，本发明化合物及其药学上可接受的无机或有机盐，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由脑出血损伤介导的神经系统疾病。根据现有技术，本发明化合物可用于治疗和/或缓解出血性脑中风，脑外伤等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药学上可接受的盐及药学上可以接受的赋形剂或载体或辅料。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-100mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～100mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。本发明实施例中所用原料或仪器，若非特别说明，均市售可得。
本发明的主要优点包括：
(a)本发明首次提出了马来酸茚达特罗在治疗出血性脑损伤相关疾病中的用途。
(b)本发明的有效疾病在治疗出血性脑损伤相关疾病的同时能够缓解神经细胞的损伤。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，例如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring HarborLaboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
实施例1马来酸茚达特罗抗血红素(Hemin)所致SH-SY5Y神经细胞损伤
本实施例采用MTT法评价马来酸茚达特罗对脑出血相关神经细胞损伤的改善作用。
1.1具体方法和步骤：
受试化合物溶液的配制：受试化合物为马来酸茚达特罗(上海陶素生化科技有限公司)。精密称取1.0mg化合物，用196.6μL的二甲亚砜充分溶解，配制成10mM的化合物母液，分装后-20℃保存。使用时，用新鲜细胞培养基进行稀释。
细胞系及细胞培养条件：神经母细胞瘤SH-SY5Y细胞系来源于ATCC，细胞在含10％胎牛血清(FBS)，0.05mg/ml青霉素，0.06mg/ml链霉素的MEM/F12培养基中，置于含5％二氧化碳的37℃的恒温培养箱中培养。
应用血红素(Hemin，购自Sigma公司)作为脑出血相关神经细胞损伤诱导剂。取对数生长期的SH-SY5Y细胞，用含10％FBS(胎牛血清)的新鲜MEM/F12培养基配制成密度为每毫升2×105个细胞的细胞悬液，并按每孔100μL接种于96孔板中。培养44-48小时后，更换为含1％FBS的新鲜MEM/F12培养基，并加入损伤剂血红素(终浓度50μM)和不同浓度受试化合物(终浓度1—30μM)(10μL/孔)，对每个浓度均设两个复孔，另设空白对照、正常对照和模型对照组。
细胞在37℃、5％二氧化碳条件下培养24小时后，以溴化3-(4,5-二甲基噻唑)-2,5-二苯基四氮唑(MTT)活细胞染色方法评价受试化合物对血红素诱发SH-SY5Y细胞活力下降的改善作用。上述细胞每孔加入MTT溶液10μL(5mg/mL)，继续培养3-4h后，弃上清，加入二甲亚砜(100μL/孔)，然后用酶联免疫检测仪于490nm处测定吸光度值。按下列公式计算细胞存活率：
细胞存活率％＝(受试化合物组吸光度值-空白组吸光度值)/(正常对照组吸光度值-空白组吸光度值)×100％
1.2测试结果
测试结果如图1所示。SH-SY5Y细胞经血红素处理损伤24小时后，显微镜下观察结果发现，损伤组细胞皱缩，聚团，突触消失，而马来酸茚达特罗(10μM和30μM)给药可改善SH-SY5Y的细胞形态(图1A)。
应用MTT评价细胞活力的结果表明，马来酸茚达特罗可以浓度依赖地保护细胞免受血红素损伤，受试化合物终浓度为10μM时开始起效(p<0.05相比于血红素损伤组)，30μM浓度下可将SH-SY5Y细胞活力提升回94.59％(p<0.01相比于血红素损伤组)(图1B)。
实施例2马来酸茚达特罗抑制血红素(Hemin)所致SH-SY5Y神经细胞内ROS过量生成
本实施例采用DCFH-DA荧光染色法评价马来酸茚达特罗对脑出血相关神经细胞内ROS生成的抑制作用。
2.1具体方法和步骤：
受试化合物溶液的配制：受试化合物为马来酸茚达特罗(上海陶素生化科技有限公司)。精密称取1.0mg化合物，用196.6μL的二甲亚砜充分溶解，配制成10mM的化合物母液，分装后-20℃保存。使用时，用新鲜细胞培养基进行稀释。
DCFH-DA荧光染料的配制：精密称取1.5mg DCFH-DA，用307.8μL二甲亚砜充分溶解，配制成10mM的化合物母液，分装后-20℃保存。使用时，用37℃预热的Na+缓冲液稀释至终浓度为10μM。
Na+缓冲液的配制：精密称取1.544g氯化钠、0.06g氯化钾、0.022g氯化钙、0.056g七水合氯化镁、0.0376g二水合磷酸二氢钠、0.236g无水葡萄糖、0.476g 4-羟乙基哌嗪乙磺酸，充分溶解于200mL去离子水中，调整pH至7.4。保存在4℃冰箱中备用。
1％SDS溶液配制：精密称取5g SDS粉末，394mg Tris-HCl，用去离子水充分溶解，调整pH至7.4，定容至500mL。
细胞系及细胞培养条件：神经母细胞瘤SH-SY5Y细胞系来源于ATCC，细胞在含10％胎牛血清(FBS)，0.05mg/ml青霉素，0.06mg/ml链霉素的MEM/F12培养基中，置于含5％二氧化碳的37℃的恒温培养箱中培养。
应用血红素(Hemin，购自Sigma公司)作为脑出血相关神经细胞损伤诱导剂。取对数生长期的SH-SY5Y细胞，用含10％FBS(胎牛血清)的新鲜MEM/F12培养基配制成密度为每毫升2×105个细胞的细胞悬液，并按每孔100μL接种于96孔透底黑板中。培养44-48小时后，更换为含1％FBS的新鲜MEM/F12培养基，并加入损伤剂血红素(终浓度为30μM)和不同浓度受试化合物(终浓度3—30μM)(10μL/孔)，对每个浓度均设3个复孔，另设空白对照、正常对照和模型对照组。
细胞损伤处理30分钟后，吸去细胞上清，加入终浓度为10μM的Na+缓冲液(100μL/孔)，于37℃恒温培养箱中孵育45分钟。吸走染料，用Na+缓冲液温和地将96孔透底黑板中的细胞清洗三遍(100μL/孔)。吸走Na+缓冲液，加入1％SDS溶液(100μL/孔)。使用SpectraMaxM5多功能酶标仪在Ex485 nm/Em520 nm处检测荧光强度。ROS水平％＝(受试化合物组荧光强度-空白组荧光强度)/(模型组荧光强度-空白组吸光度值)×100％
2.2测试结果
测试结果如图2所示。SH-SY5Y细胞经血红素处理损伤30分钟后，DCF荧光强度测定结果表明，模型组DCF荧光强度显著高于正常对照组(p<0.001相比于血红素损伤组)受试化合物终浓度为3μM(p<0.01相比于血红素损伤组)、10μM(p<0.01相比于血红素损伤组)、30μM(p<0.05相比于血红素损伤组)均可显著降低SH-SY5Y神经细胞内ROS水平(图2)。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种式(I)所示化合物或其药学上可接受的盐的用途，其特征在于，
用于制备治疗和/或改善和/或预防出血性脑损伤相关疾病的药物。
2.如权利要求1所述的用途，其特征在于，出血性脑损伤相关疾病选自下组：出血性脑卒中、脑外伤、颅内动脉瘤、脑血管畸形、颅内恶性肿瘤、梗死后出血、抗凝或溶栓治疗、瘤卒中、或其组合。
3.如权利要求1所述的用途，其特征在于，所述药物的剂型选自下组：注射剂、片剂、胶囊剂、丸剂、悬浮剂、乳剂、或其组合。
4.如权利要求3所述的用途，其特征在于，所述注射剂的剂型为静脉或肌肉注射剂型。
5.如权利要求1所述的用途，其特征在于，所述药物的给药途径选自下组：经皮、口服、静脉注射、肌肉注射、或其组合。
6.如权利要求1所述的用途，其特征在于，所述式(I)所示化合物或其药学上可接受的盐用于制备以下一种或多种效果的药物：
(x1)改善神经元细胞损伤；
(x2)抑制神经元细胞内ROS的过量生成。
7.如权利要求6所述的用途，其特征在于，所述神经元细胞损伤由血红素缺失引起。
8.一种药物组合物，其特征在于，包含：
(A1)式I所示的化合物或其药学上可接受的盐；和/或
(A2)选自下组的其他药物：抗氧化剂、抗炎剂或神经保护剂；和/或
(B)药学上可接受的载体和/或赋形剂和/或辅料。
9.一种权利要求8所述的药物组合物的用途，其特征在于，用于制备治疗和/或改善和/或预防出血性脑损伤相关疾病的药物。
10.一种体外的改善神经元细胞损伤的方法，其特征在于，给所述细胞施用医学有效量的式I所示的化合物或其药学上可接受的盐和/或权利要求8所述的药物组合物。
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| US20110201553A1 (en) * | 2007-10-02 | 2011-08-18 | Hemostatis Holding ApS | Systemic Pro-hemostatic Effect of Sympathicomimetics with Agonistic Effects on Alfa-Adrenergic and/or Beta-Adrenergic Receptors of the Sympathetic Nervous System, Related to Improved Clot Strength |
| US20160184241A1 (en) * | 2014-06-10 | 2016-06-30 | The Board Of Trustees Of The Leland Stanford Junior University | INTRANASAL DELIVERY OF Beta2-ADRENERGIC RECEPTOR AGONISTS FOR IMPROVING COGNITION IN HUMANS WITH DOWN SYNDROME AND COMPOSITIONS THEREFOR |
| WO2020217116A2 (en) * | 2019-03-28 | 2020-10-29 | Orbicular Pharmaceutical Technologies Pvt Ltd | Long acting inhalation compositions of indacaterol |
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| US20110201553A1 (en) * | 2007-10-02 | 2011-08-18 | Hemostatis Holding ApS | Systemic Pro-hemostatic Effect of Sympathicomimetics with Agonistic Effects on Alfa-Adrenergic and/or Beta-Adrenergic Receptors of the Sympathetic Nervous System, Related to Improved Clot Strength |
| US20160184241A1 (en) * | 2014-06-10 | 2016-06-30 | The Board Of Trustees Of The Leland Stanford Junior University | INTRANASAL DELIVERY OF Beta2-ADRENERGIC RECEPTOR AGONISTS FOR IMPROVING COGNITION IN HUMANS WITH DOWN SYNDROME AND COMPOSITIONS THEREFOR |
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