CN109985049A - 5α-雄甾-3β,5,6β-三醇在制备治疗脑小血管病的药物中的应用 - Google Patents
5α-雄甾-3β,5,6β-三醇在制备治疗脑小血管病的药物中的应用 Download PDFInfo
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Abstract
本发明公开了5α‑雄甾‑3β,5,6β‑三醇、其氘代物或其药学上可接受的盐在制备治疗患者的脑小血管病的药物中的应用。所述脑小血管病优选是脑微出血。所述脑微出血为自发性脑微出血、药物相关性脑微出血或创伤性脑微出血。本发明证实5α‑雄甾‑3β,5,6β‑三醇显著增强血管外血红蛋白的清除,从而可用于治疗脑小血管病。
Description
技术领域
本发明涉及5α-雄甾-3β,5,6β-三醇(5α-androst-3β,5,6β-triol, “Triol”)的医药新用途,具体涉及5α-雄甾-3β,5,6β-三醇在脑小血管病治疗中的应用。
背景技术
脑小血管指脑的小的穿支动脉和小动脉(直径40 ~200μm)、毛细血管及小静脉,它们构成了脑组织血供的基本单位,对脑功能的维持起着重要作用(1)。脑大、小血管共同构成了脑血管树(vascular tree),它们在结构上有连续性,共同受到血流动力学影响,共同暴露于危险因素,因此脑大、小血管病变从理论上应具有严重程度的平行相关性。但在临床工作中常常会发现二者的不一致性,例如常常发现有严重脑小血管病变但并不合并脑大动脉狭窄的患者,反之亦然(2)。
脑小血管病(cerebral small vessel disease, CSVD) 泛指上述小血管的各种病变所导致的临床、认知、影像学及病理表现的综合征(3),习惯上多指小的穿支动脉和小动脉病变所导致的临床和影像学表现。CSVD 主要以卒中(深部小梗死、脑出血)、认知和情感障碍及总体功能下降为突出的临床表现,影像学上则突出表现为腔隙性梗死(lacunarinfarction,LI)、腔隙(lacune)、脑白质病变(white matter lesions, WML)、血管周围间隙扩大(enlarged perivascular space,EPVS)及脑微出血(cerebral microbleeds, CMB)等(1)。
CSVD的具体发病机制与血管内皮功能障碍、血脑屏障(blood-brain barrier,BBB)受损、炎性机制、遗传因素、缺血低灌注损伤有关,其中BBB受损是核心机制。BBB受损破坏导致通透性增加,血液成分外渗至血管周围组织和脑实质,继而造成相应的病理生理学改变,导致CSVD相关的影像学和病理学变化(4)。
脑微出血为脑小血管疾病表现的一种,是脑内微小血管病变所致的一种脑实质亚临床损害,以微量血液外漏为特征,红细胞溢出血管外可产生含铁血黄素影像,依病变的新旧,血管周围可见新鲜红细胞,或含铁血黄素颗粒沉积,或为吞噬含铁血黄素的巨噬细胞。
CMB表现在T2*加权序列(或对磁化率敏感的其他序列)上小区域信号缺失的病灶,病灶周边有晕染。病灶直径一般在2~5 mm,最大可至10 mm (5)。MR影像上的这些病灶称为“信号空洞(signal void)”、“敏感伪影(susceptibility artifact)”、“黑洞(blackhole)”、“小点(dot)”、“微出血(microbleed)”、“陈旧性微出血(old microbleed,OMB)”、“多灶性信号丧失损害(multifocal signal loss lesion)”或“微出血(microhemorrhage,MH)”。其通常分布在皮质与皮质下交界的区域、皮质深部的灰质核团、大脑半球白质、脑干及小脑。磁敏感加权成像序列(SWI)对CMBs的敏感率高于T2*W-GRE序列。
CMB多被认为是无症状性,缺乏急性临床表现。研究表明,脑微出血与年龄、心血管危险因素、脑白质变性、脑卒中、卒中后情感障碍有一定关系。此外,脑微出血也是急慢性高原病的脑损伤的重要病理原因(6),在高原病患者尸检或者高原脑水肿幸存者的MRI影像学检查中发现在脑组织(7)或者视网膜(8)存在微出血现象。应用MRI磁敏感加权成像(Susceptibilit1y weighted imaging,SWI)对慢性高原病患者(Chronic mountainsickness, CMS)脑微出血进行检查发现,经确诊的20例CMS患者共有11例检出脑微出血(55%),CMS组检出脑微出血灶的阳性率明显高于正常人群(9)。
溶栓药(如组织纤溶酶原激活物(Tissue plasminogen activator,t-PA)、链激酶(Streptokinase,SK))、抗凝药物(如华法林)、抗血小板药物(如阿司匹林)在抗栓治疗中的广泛使用导致药物相关性原发性脑出血(ICH)的发生率显著增加。研究显示,华法林相关性ICH患者与自发性ICH患者比较,CMB在前者中更为常见。目前的研究均认为,CMB与康宁药物相关出血风险增加有关。阿司匹林相关性ICH的风险随着CMB病灶数目增加而明显增加。一项荟萃分析显示,阿司匹林应用者与非应用者相比,CMB与ICH具有相关性(OR=1.7)。另有研究显示,应用大剂量他汀类药物(如阿托伐他汀)的脑卒中患者,ICH的发生率轻度增加。他汀类应用者中脑叶CMB的发生率约为非他汀类应用者的2倍,而其他部位的CMB两组见无显著差异,提示他汀类药物可能增加脑淀粉样血管病患者的出血风险。
然而,目前临床上仍缺乏用于脑微出血的治疗的有效药物。提供一种缓解或清除脑微出血的药物具有重要临床意义。
发明内容
本发明基于发明人对5α-雄甾-3β,5,6β-三醇(5α-androst-3β,5,6β-triol, 以下有时简称“Triol”)提高脑组织清除游离血红蛋白的能力的发现,提供了5α-雄甾-3β,5,6β-三醇在治疗脑小血管病方面的新用途。
因此,本发明一方面提供5α-雄甾-3β,5,6β-三醇、其氘代物或其药学上可接受的盐在制备治疗脑小血管病药物中的应用。在一些实施方式中,所述脑小血管病优选为脑微出血。在一些实施方式中,所述脑微出血为自发性脑微出血、药物相关性脑微出血或创伤性脑微出血。在一些实施方式中,所述自发性脑微出血为年龄相关性脑微出血、高血压性脑微出血、急性高原病伴随的脑微出血、慢性高原病伴随的脑微出血、缺血性脑卒中伴随的脑微出血或出血性脑卒中伴随的脑微出血。在一些实施方式中,所述药物相关性脑微出血是溶栓药相关性脑微出血、抗凝药相关性脑微出血、抗血小板凝集药相关性脑微出血或他汀类药物相关性脑微出血。
本发明另一方面提供一种治疗患者的脑微出血的方法,该方法包括向该患者施用有效量的5α-雄甾-3β,5,6β-三醇、其氘代物或其药学上可接受的盐、或包含5α-雄甾-3β,5,6β-三醇、其氘代物或其药学上可接受的盐的药物组合物。在一些实施方式中,所述患者的脑微出血通过MRI确定。在一些实施方式中,所述患者患有自发性脑微出血、药物相关性脑微出血或创伤性脑微出血。在一些实施方式中,所述自发性脑微出血为年龄相关性脑微出血、高血压性脑微出血、急性高原病伴随的脑微出血、慢性高原病伴随的脑微出血、缺血性脑卒中伴随的脑微出血或出血性脑卒中伴随的脑微出血。在一些实施方式中,所述药物相关性脑微出血是溶栓药相关性脑微出血、抗凝药相关性脑微出血、抗血小板凝集药相关性脑微出血或他汀类药物相关性脑微出血。
本发明再一方面提供5α-雄甾-3β,5,6β-三醇、其氘代物或其药学上可接受的盐用于患者的脑微出血的治疗。在一些实施方式中,所述患者的脑微出血通过MRI确定。在一些实施方式中,所述患者患有自发性脑微出血、药物相关性脑微出血或创伤性脑微出血。在一些实施方式中,所述自发性脑微出血为年龄相关性脑微出血、高血压性脑微出血、急性高原病伴随的脑微出血、慢性高原病伴随的脑微出血、缺血性脑卒中伴随的脑微出血或出血性脑卒中伴随的脑微出血。在一些实施方式中,所述药物相关性脑微出血是溶栓药相关性脑微出血抗凝药相关性脑微出血、抗血小板凝集药相关性脑微出血或他汀类药物相关性脑微出血。
本发明的又一方面提供一种增强患者的脑血管外游离血红蛋白的清除的方法,所述方法包括向所述患者施用有效量的5α-雄甾-3β,5,6β-三醇、其氘代物或其药学上可接受的盐、或包含5α-雄甾-3β,5,6β-三醇、其氘代物或其药学上可接受的盐的药物组合物。本发明的又一方面提供一种清除患者的脑血管外游离血红蛋白的方法,所述方法包括向所述患者施用有效量的5α-雄甾-3β,5,6β-三醇、其氘代物或其药学上可接受的盐、或包含5α-雄甾-3β,5,6β-三醇、其氘代物或其药学上可接受的盐的药物组合物。所述游离血红蛋白是由自发性脑微出血、药物相关性脑微出血或创伤性脑微出血引起的。在一些实施方式中,所述自发性脑微出血为年龄相关性脑微出血、高血压性脑微出血、急性高原病伴随的脑微出血、慢性高原病伴随的脑微出血、缺血性脑卒中伴随的脑微出血或出血性脑卒中伴随的脑微出血。在一些实施方式中,所述药物相关性脑微出血是溶栓药相关性脑微出血、抗凝药相关性脑微出血、抗血小板凝集药相关性脑微出血或他汀类药物相关性脑微出血。
附图说明
图1. 急性低压缺氧引起食蟹猴前额叶皮层脑组织游离血红蛋白的血管外分布增加。A. 食蟹猴脑组织免疫荧光成像,其中血管内皮细胞标志CD31显示红色信号,指示血管位置,虚线显示血管轮廓;游离血红蛋白显示为绿色;细胞核显示为蓝色。B. MFI(MeanFluorescence Intensity)相对荧光强度使用Nikon NIS-Element软件进行定量。食蟹猴脑组织血管外分布的游离血红蛋白相对荧光强度统计,使用单因素方差分析法和Dunnutt’st test两两比较法进行统计检验,**,p < 0.01,n.s.,无统计学差异,n = 4。NN:常压常氧组;HH:低压缺氧组;HH + Triol:低压缺氧Triol给药组;HH + PROG:低压缺氧对照药给药组。PROG是指对照药物孕酮(progesterone)。
图2.食蟹猴前额叶皮层脑组织中小胶质细胞的激活。 A. 食蟹猴前额叶皮层脑组织Iba-1免疫组织化学染色,Iba-1作为小胶质细胞激活的marker。黑色scale bar为25 μm,红色scale bar为200 μm。B. Iba-1相对光密度值的统计。使用image pro plus软件对各组免疫组化图片进行光密度扫描得到光密度值后,按照NN组进行标准化处理。NN:常压常氧组(n=4);HH:低压缺氧组(n=4);HH + Triol:低压缺氧Triol给药组(n=3);HH + PROG:低压缺氧对照药给药组(n=4)。使用单因素方差分析法和Dunnutt’s t test两两比较法进行统计检验,***,p < 0.01,n.s.,无统计学差异。
图3. Triol显著降低食蟹猴脑组织中炎症因子IL-6,IL-1β和TNF-α的表达量。A.食蟹猴前额叶脑组织中炎症因子IL-6,IL-1β和TNF-α的蛋白表达水平;B. 蛋白相对灰度扫描值的统计。NN:常压常氧组(N=3);HH:低压缺氧组(N=3);HH + Triol:低压缺氧Triol给药组(N=3);HH + PROG:低压缺氧对照药给药组(N=3)。灰度值使用Image Lab软件扫描获得,并经过对α-Tubulin的标准化得到相对值。使用单因素方差分析法和Dunnutt’s t test两两比较法进行统计检验,两两比较时各组均与HH组比较,*,p < 0.05;**,p < 0.01。
图4. Triol通过上调CD163和血红素加氧酶(Heme Oxygenase-1, HO-1)蛋白水平增强脑组织对游离血红蛋白的清除能力。A.食蟹猴前额叶脑组织中血红蛋白清道夫受体CD163和血红素加氧酶HO-1的蛋白表达水平;B. 蛋白相对灰度扫描值的统计。灰度值使用image lab软件扫描获得,并经过对α-Tubulin的标准化得到相对值。NN:常压常氧组(N=3);HH:低压缺氧组(N=3);HH + Triol:低压缺氧Triol给药组(N=3);HH + PROG:低压缺氧孕酮给药组(N=3)。使用单因素方差分析法和Dunnutt’s t test两两比较法进行统计检验,两两比较时各组均与HH组比较,*,p < 0.05;n.s.,无统计学差异。
图5. Triol恢复低压缺氧引起的CD163下调和小胶质细胞激活。A.食蟹猴脑组织CD163和Iba-1双染免疫荧光成像。B. CD163和Iba-1相对荧光强度统计。C. CD163和Iba-1相对荧光强度的相关性分析。NN:常压常氧组;HH:低压缺氧组;HH + Triol:低压缺氧Triol给药组;HH + PROG:低压缺氧孕酮给药组。使用单因素方差分析法和Dunnutt’s t test两两比较法进行统计检验,两两比较时各组均与HH组比较,***,p < 0.001。
图6. 缺氧加剧游离血红蛋白引起的小胶质细胞炎性激活。A. 游离血红蛋白刺激小胶质细胞BV2不同时间点后免疫荧光检测小胶质细胞激活标志CD11b。scale bar为25 μm. B. 图A中CD11b相对荧光强度的统计,使用单因素方差分析法和Dunnutt’s t test两两比较法进行统计检验,*,p < 0.05;**,p < 0.01。C. 游离血红蛋白刺激小胶质细胞BV2不同时间点后免疫荧光检测小胶质细胞激活标志Iba-1,鬼笔环肽染色显示小胶质细胞形态学变化。D. 图C中Iba-1相对荧光强度的统计,使用单因素方差分析法和Dunnutt’s t test两两比较法进行统计检验,*,p < 0.05;**,p < 0.01。E. 在游离血红蛋白刺激小胶质细胞BV2不同时间点western blot检测CD11b蛋白水平。F. 游离血红蛋白刺激小胶质细胞BV2 6小时后qPCR检测促炎细胞因子和趋化因子的mRNA表达水平。G. 缺氧加剧游离血红蛋白引起的小胶质细胞炎症因子TNF-α, IL-1β和IL-6的蛋白水平表达增加,而对抗炎因子IL-4无影响。
图7. 干扰CD163表达上调后,取消了Triol对缺氧和血红蛋白诱导的Iba-1和CD11b上调的抑制作用。按照厂商说明书,使用RNAiMAX分别转染CD163 01号以及乱码干扰片段NC到BV2细胞后,在BV2细胞培养基加入或不加入10 μM Triol 处理,以20 μM血红蛋白以及1%缺氧条件刺激BV2细胞6小时后收集蛋白样品,Western blot检测小胶质细胞激活标志Iba-1和CD11b的表达。
具体实施方式
如本文所用,术语“组合物”指适于给预期动物对象施用以达到治疗目的的制剂,其含有至少一种药物活性组分,例如化合物。任选地,所述组合物还含有至少一种药物学上可接受的载体或赋形剂。
术语“药学上可接受的”表示所述物质不具有这样的特性,即考虑到将被治疗的疾病或病症以及各自的施用途径,该特性将会使理性谨慎的医学从业者避免给患者服用该物质。例如,对于可注射物来说,通常要求这样的物质是基本无菌的。
在本文中,术语“治疗有效量”和“有效量”表示所述物质和物质的量对于预防、减轻或改善疾病或病症的一种或多种症状,和/或延长接受治疗的对象的存活是有效的。
术语“脑小血管病”或“CSVD”指脑的小的穿支动脉和小动脉(直径40 ~200μm)、毛细血管及小静脉的各种病变所导致的临床、认知、影像学及病理表现的综合征。在优选的实施方式中,“脑小血管病”表现为受损的血脑屏障,血脑屏障破坏导致通透性增加,血液成分外渗至血管周围组织和脑实质,继而造成相应的病理生理学改变,导致CSVD相关的影像学和病理学变化。在特定的实施方式中,所述“脑小血管病”不包括出血性脑卒中。
术语“脑微出血”是指脑内直径小于约1cm的区域内的出血。脑微出血可通过脑部MRI(包括T2*加权GRE MRI)检测,并且可为无症状的“无症状脑出血”,也可能与短暂性或永久性局灶运动或感觉障碍、共济失调、失语症、构音障碍等症状相关,即“症状性脑出血”(10)。在一些实施方式中,脑微出血表现为显著增多的血管外游离血红蛋白的分布。
术语“自发性脑微出血”在本文中是指在非外伤情况下各种原因引起的脑部血管(通常是静脉或毛细血管)自发性破裂引起的脑内出血。自发性脑出血是一种多因素疾病,受环境和遗传因素共同作用。例如,高龄与自发性脑微出血密切相关(年龄相关性脑微出血)。疾病引起的自发性脑微出血包括高血压(如长期高血压)、缺血性脑卒中和出血性脑卒中等,相应地在本文中称为“高血压性脑微出血”、“缺血性脑卒中伴脑微出血”和“出血性脑卒中伴脑微出血”。其他环境因素或疾病因素也可能导致脑微出血,本发明预期也可用于这些未具体列出的脑微出血的治疗。
术语“药物相关性脑微出血”在本文中是指由药物引起的脑内微出血。这些药物可包括,但不限于,溶栓药、抗凝药、抗血小板凝集药或他汀类药物。
随着溶栓治疗的广泛应用,溶栓药也由第一代发展到第三代。早期的第一代溶血栓药物为链激酶(Streptokinase,SK)、尿激酶(Urokinase,UK)、蚓激酶(Lumbrokinase)、尿激酶原(Pro-urokinase)、葡激酶(Staphylokinase)、甲氧苯甲酰纤溶酶原链激酶激活剂、蛇毒抗栓酶。第二代溶血栓药物alteplase(中文商品名为阿替普酶)是一种重组组织型纤溶酶原激活剂(t-PA),这是世界上第一个基因重组溶栓药,由美国Genetech公司开发上市。目前溶栓药已经发展到第三代。1996年德国宝灵曼(Boehringer Mannheim GmbH)公司研制的Reteplase(商品名Retavase,瑞替普酶)是其中的代表。瑞替普酶是一种蛋白质修饰药物,为重组人组织型纤维蛋白溶解酶原激活剂缺失变异体,具有半衰期长、溶栓作用强、副作用小等优点。正在研究开发的第三代溶栓药均为t-PA变异体,如TNKase(teneplase,TNK-t-PA)、Monteplase、La noteplase(nateplase,n-PA)等。第三代溶栓药的共同特点是能快速溶栓、开通堵塞的冠状动脉、恢复血液循环,治愈率达到73%~83%。
抗凝药也称抗凝血药,其用于防治血管内栓塞或血栓形成的疾病,预防中风或其它血栓性疾病。临床使用频率最高的抗凝血药包括:非肠道用药抗凝血剂(如肝素、依诺肝素、替他肝素、阿地肝素)、香豆素抗凝血剂类(如华法林、双香豆素、硝酸香豆素)、体外抗凝药(如枸橼酸钠)、凝血酶抑制剂(如水蛭素、阿加曲班)。
抗血小板凝集药根据药物的作用部位、途径,可分为4 类:(1)环氧化酶抑制剂(血栓素A2抑制剂、水杨酸类):常用的药物是阿司匹林片。(2)磷酸二酯酶抑制剂:如西洛他唑(培达)、双嘧达莫(潘生丁)等。西洛他唑(培达)抑制血小板及血管平滑肌磷酸二酯酶活性,增高血小板及平滑肌内cAMP 浓度,比阿司匹林、 噻氯匹啶(力抗栓) 更强力抑制血小板,并对血小板聚集块有解离作用,是周围血管病首选的药物。临床主要用于治疗慢性动脉闭塞性溃疡、疼痛及冷感等局部性疾病,用于无心功能不全的间歇性跛行患者,可以改善症状、提高行走距离。口服常规剂量双嘧达莫(潘生丁)能增加稳定性心绞痛患者运动诱导的心肌梗死发生率,因此目前局限于有卒中病史且无冠心病的患者使用,不推荐冠心病患者单独使用双嘧达莫。(3)ADP 受体拮抗剂(噻吩吡啶类):如氯吡格雷(波立维、泰嘉)、噻氯匹定(Ticlopidine)(抵克力得、力抗栓、齐洛)等。(4)血小板糖蛋白Ⅱb/Ⅲ拮抗剂(GP Ⅱb/Ⅲa 受体拮抗剂)如单克隆抗体阿昔单抗(abciximab ) ,中文别名“抗血小板凝聚单克隆抗体”,肽类抑制剂埃替非巴肽(eptifibatide )以及非肽类抑制剂替罗非班(tirofiban)等。
他汀类药物,也称3-羟基3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂,能显著降低胆固醇(TC)、低密度脂蛋白(LDL-C)和apoB(载脂蛋白),同时降低甘油三酯(TG)和轻度升高高密度脂蛋白(HDL-C)。适用于原发性高胆固醇血症及混合型高脂血症,是当前防治高胆固醇血症和动脉粥样硬化疾病非常重要的药物。目前已上市的药物第一代有洛伐他汀、辛伐他汀;第二代有普伐他汀、氟伐他汀;第三代有阿托伐他汀、瑞舒伐他汀以及匹伐他汀。
术语“创伤性脑微出血”或“外伤性脑微出血”在本文中是指由外伤引起的脑内微出血,如轻度颅脑损伤(TBI)或慢性颅脑创伤引起的脑内微出血。
α-雄甾-3β,5,6β-三醇、其氘代物及其药学上可接受的盐
5α-雄甾-3β,5,6β-三醇在本文也称为“Triol”或“本发明的化合物”,结构式如式(I)所示。业已证实,Triol是一种有效对抗急性缺血缺氧脑损伤的神经元保护剂。
(式I)
本发明的化合物可以被配制为药学上可接受盐的形式。预期的药学上可接受的盐形式包括,但不限于,单盐、双盐、三盐、四盐等。药学上可接受盐在它们被施用的量和浓度下是无毒的。在不阻止其发挥生理效应的情况下,通过改变化合物的物理特性,这样的盐的制备可以便于药理学应用。在物理性质上有用的改变包括降低熔点以便经粘膜给药,以及增加溶解度以便施用更高浓度的药物。
药学上可接受的盐包括酸加成盐,例如那些含硫酸盐、氯化物、氢氯化物、延胡索酸盐、马来酸盐、磷酸盐、氨基磺酸盐、乙酸盐、柠檬酸盐、乳酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、环己氨基磺酸盐和奎尼酸盐的盐。药学上可接受的盐可以从酸获得,所述酸例如盐酸、马来酸、硫酸、磷酸、氨基磺酸、乙酸、柠檬酸、乳酸、酒石酸、丙二酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环己氨基磺酸、延胡索酸和奎尼酸。
当酸性官能团例如羧酸或酚存在时,药学上可接受的盐也包括碱加成盐,例如那些含有苄星青霉素、氯普鲁卡因、胆碱、二乙醇胺、乙醇胺、叔丁胺、乙二胺、葡甲胺、普鲁卡因、铝、钙、锂、镁、钾、钠、铵、烷基胺和锌的盐。使用合适的相应的碱可以制备此类盐。
通过标准技术,可以制备药学上可接受的盐。例如,将游离碱形式的化合物溶解在合适的溶剂中,例如含有适宜酸的水性溶液或水-醇溶液中,然后蒸发溶液进行分离。在另一个实例中,通过使游离碱和酸在有机溶剂中反应来制备盐。
因此,例如,如果特定化合物是碱,则可以通过本领域可得的任何合适方法制备所需的药学上可接受的盐,例如,用无机酸或有机酸处理游离碱,所述无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸和类似酸,所述有机酸如乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸、吡喃糖苷酸(pyranosidyl acid) 如葡糖醛酸或半乳糖醛酸、α-羟基酸如柠檬酸或酒石酸、氨基酸如天冬氨酸或谷氨酸、芳香酸如苯甲酸或肉桂酸、磺酸如对甲苯磺酸或乙磺酸或类似物。
同样,如果特定化合物是酸,则可以通过任何合适方法制备所需的药学上可接受的盐,例如,用无机碱或有机碱处理游离酸,所述无机碱或有机碱例如胺(伯胺、仲胺或叔胺)、碱金属氢氧化物或碱土金属氢氧化物或类似物。合适的盐的示范性例子包括有机盐,其衍生自氨基酸(如L-甘氨酸、L-赖氨酸和L-精氨酸)、氨、伯胺、仲胺和叔胺,以及环胺(如羟乙基吡咯烷、哌啶、吗啉和哌嗪),以及无机盐,其衍生自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂。
化合物的药学上可接受的盐可以作为络合物存在。络合物的例子包括8-氯茶碱络合物(类似于,例如,茶苯海明:苯海拉明8-氯茶碱(1:1)络合物;晕海宁)和各种包含环糊精的络合物。
本发明还预期包括使用该化合物的药学上可接受的氘代化合物或其他非放射性取代化合物。氘代是将药物活性分子基团中的一个或多个或全部氢替换成同位素氘,因其无毒无放射性,又比碳氢键稳定约6~9倍,可以封闭代谢位点而延长药物的半衰期,从而降低治疗剂量,同时又不影响药物的药理活性,而被认为是一种优良的修饰方法。
8.药物组合物
在本发明中,“药物组合物”是指包含Triol化合物和药学上可接受的载体的组合物,其中化合物和药学上可接受的载体以混合形式存在于组合物中。所述组合物一般将被用于人类对象的治疗。然而,它们也可以被用于治疗在其它动物对象中的相似的或相同的病症。在本文中,术语“对象”、“动物对象” 和类似术语指人和非人类脊椎动物,例如哺乳动物,如非人类灵长类,竞技动物和商业动物,例如马、牛、猪、绵羊、啮齿类动物,和宠物(如狗和猫)。
合适的剂型,部分地取决于用途或给药的途径,例如经口、经皮、经粘膜、吸入或通过注射(肠胃外)。此类剂型应当使该化合物能够到达靶细胞。其它因素在本领域中是熟知的,包括需要考虑的事项,诸如毒性和延迟化合物或组合物发挥其效应的剂型。
载体或赋形剂可以被用于生产组合物。所述载体或赋形剂可以被选择为促进化合物的给药。载体的例子包括碳酸钙、磷酸钙、各种糖(例如乳糖、葡萄糖或蔗糖)、或淀粉类型、 纤维素衍生物、明胶、植物油、聚乙二醇和生理相容性溶剂。生理上相容性溶剂的例子包括注射用水(WFI)无菌溶液、盐溶液和葡萄糖。
可以通过不同的路径施用组合物或组合物的组分,包括静脉内、腹膜内、皮下、肌内、经口、经粘膜、 直肠、经皮或吸入。在一些实施方式中,优选注射剂或冻干粉针剂。对口服而言,例如,化合物可以被配制为常规口服剂型,例如胶囊、片剂,以及液体制剂,例如糖浆、酏剂和浓缩滴剂。
可以获得口服用途的药物制剂,例如通过将组合物或其组分与固体赋形剂组合,任选研磨所形成的混合物,以及在加入合适的辅剂之后(如需要)加工颗粒的混合物,从而获得片剂或糖衣丸。合适的赋形剂特别是,填料例如糖,包括乳糖、蔗糖、甘露糖醇或山梨醇;纤维素制剂,例如玉米淀粉、小麦淀粉、大米淀粉、马铃薯淀粉、明胶、黄蓍树胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠(CMC)和/或聚乙烯吡咯烷酮(PVP:聚维酮(povidone))。如果需要,可以加入崩解剂,例如交联的聚乙烯吡咯烷酮、琼脂或藻酸或它们的盐,例如藻酸钠。
作为选择,可以使用注射(肠胃外给药),例如肌内的、静脉内的、腹膜内的和/或皮下的。对于注射而言,本发明的组合物或其组分被配制为无菌液体溶液,优选在生理相容的缓冲液或溶液中,例如盐水溶液、Hank溶液或Ringer溶液。另外,组合物或其组分可以被配制为固体形式,并在使用之前一刻被再溶解或悬浮。也可以生产冻干粉形式。
给药也可以通过经粘膜、局部或经皮方式。对于经粘膜、局部或经皮给药,在配方中使用适合待穿透的屏障的穿透剂。这样的穿透剂在本领域中是普遍已知的,包括,例如,对于经粘膜给药,胆汁盐和梭链孢酸衍生物。另外,去垢剂可以用于促进穿透。经粘膜给药,例如,可以通过鼻喷雾或栓剂(经直肠或阴道)。
通过标准程序可以确定待施用的各种组分的有效量,考虑的因素例如所述化合物IC50、所述化合物的生物半衰期、对象的年龄、大小和体重以及与对象有关的病症。这些因素和其它因素的重要性对本领域普通技术人员而言是熟知的。一般而言,剂量将在被治疗的对象的大约0.01mg/kg至50mg/kg之间,优选在0. lmg/kg至20mg/kg之间。可以使用多次剂量。
本发明的组合物或其组分还可以与治疗相同疾病的其他治疗剂结合使用。这种结合使用包括在不同时间施用这些化合物以及一种或多种其他治疗剂,或同时使用这种化合物和一种或多种其他治疗剂。在一些实施方式中,可对本发明的一种或多种化合物或结合使用的其他治疗剂的剂量进行修改,例如,通过本领域技术人员已知的方法降低相对于单独使用的化合物或治疗剂的剂量。
要理解的是,结合使用或联用包括与其他疗法、药物、医学程序等一起使用,其中该其他疗法或程序可在不同于本发明的组合物或其组分的时间(例如,在短期内(如几个小时,如1、2、3、4-24小时)或在较长时间内(如1-2天、2-4天、4-7天、1-4周)或在与本发明的组合物或其组分相同的时间被施用。结合使用还包括与一次或不频繁施用的疗法或医学程序(如手术)一起使用,并伴随本发明的组合物或其组分在该其他疗法或程序之前或之后的短期或较长时间段内的施用。在一些实施方式中,本发明用于递送本发明的组合物或其组分和一种或多种其他药物治疗剂,它们通过相同或不同给药途径递送。
任何给药途径的结合施用包括通过相同给药途径将本发明的组合物或其组分和一种或多种其他药物治疗剂以任何制剂形式一起递送,包括两种化合物化学地相连且它们在施用时保持各自治疗活性的制剂。在一个方面,该其他药物疗法可与本发明的组合物或其组分共同施用。通过共同施用的结合使用包括施用共制剂(co-formulation)或化学上连接的化合物的制剂,或在短期内(例如,一个小时内、2小时内、3小时内、直至24小时内)施用两种或多种独立制剂形式的化合物,它们以相同或不同的途径给药。
独立制剂的共同施用包括经由一个装置的递送的共同施用,例如相同吸入装置、相同注射器等,或相对彼此短期内由不同装置施用。通过相同给药途径递送的本发明的化合物和一种或多种额外的药物疗法的共制剂包括将材料一起制备从而它们可通过一个装置被施用,包括不同化合物组合在一种制剂中,或化合物被修饰从而使得它们在化学上连接在一起但仍保持各自的生物学活性。这种化学上连接的化合物可包括将两个活性成分分开的连接体,该连接体在体内基本维持,或在体内可能降解。
实施例
实施例1. Triol显著减少游离血红蛋白激活小胶质细胞后导致的炎性细胞因子的表
达
方法
组织切片免疫荧光成像:石蜡切片切片厚度为5μm;对于新鲜的石蜡切片,37°C烘片过夜后55°C烘片30min,迅速将切片置于二甲苯中进行脱蜡,二甲苯10min*3次充分脱蜡后,依次使用无水乙醇-95%乙醇-90%乙醇-80%乙醇-70%乙醇-50%乙醇-ddH2O进行梯度复水。复水后将切片置于EDTA抗原修复液中进行微波高温修复。修复完成后自然降温到室温。一抗孵育:用吸水纸吸干组织周围水分,用免疫组化笔圈出样本,加入DAKO抗体稀释液稀释好的一抗,湿盒中避光4°C孵育过夜。室温平衡10分钟后PBST洗涤3次,每次5min。加入相应种属的荧光二抗,于湿盒中室温避光孵育1h。PBST洗涤3次,用DAKO稀释好的Hochest33342染液室温避光染色10min, PBST 洗涤3次,每次5min。水溶性封片,使用激光共聚焦显微镜进行成像。共聚焦拍摄方法与细胞免疫荧光相同。使用NIS-Elements Analysis软件进行共聚焦图像的荧光强度分析,并按照内设标尺对单位面积的组织荧光强度进行标准化。
食蟹候脑组织免疫组织化学染色:本实验按照常规免疫组织化学的操作规程进行操作,具体如下:食蟹猴前额皮层组织石蜡切片厚度为5 μm,新鲜的石蜡切片37°C烘片过夜;脱蜡:石蜡切片55°C烘片30min后迅速将切片置于二甲苯中进行脱蜡,二甲苯中10min*3次充分脱蜡;复水:依次使用无水乙醇-95%乙醇-90%乙醇-80%乙醇-70%乙醇-50%乙醇-ddH2O浸泡,每次3min,进行梯度复水;复水后将切片置于EDTA抗原修复液中进行微波高温修复30min。修复完成后自然降温到室温;一抗孵育:用吸水纸吸干组织周围水分,用免疫组化笔圈出样本,加入DAKO抗体稀释液稀释好的一抗,湿盒中避光4°C孵育过夜;室温平衡10分钟后PBST洗涤3次,每次5min。加入DAKO抗体稀释液稀释好的HRP二抗,于湿盒中室温孵育1h;PBST洗涤3次,滴加DAB进行底物显色,控制每张切片的显色时间相同;PBST洗涤1次,苏木素复染10s。使用流水轻轻冲洗切片,PBS洗片1次;脱水:依次使用ddH2O -50%乙醇-70%乙醇-80%乙醇-90%乙醇-95%乙醇-无水乙醇浸泡,每次3min,进行梯度复水;透化:使用二甲苯透化10min*3次;封片:使用二甲苯稀释的中性树脂封片,待2h后封片剂凝固,可用于拍照;拍照:使用Nikon ECLIPSE Ti-U倒置荧光显微镜对切片进行明场拍照,调节好适宜的曝光强度和背景白平衡,固定拍摄调节对各组切片进行多视野多倍数的拍照。
免疫印迹:1)蛋白质样品制备(参照M-PER蛋白裂解液说明书):细胞经过处理至指定时间点后,吸掉培养基,用4℃预冷的PBS(0.01M pH7.2~7.3)清洗3遍洗净培养基。加入混合蛋白酶抑制剂(PMSF 100 X)的M-PER蛋白裂解液150-200ul,冰上裂解10min,使细胞被充分裂解。收集裂解物后于4°C 12000rpm低温离心15min去除细胞碎片。2)BCA蛋白定量(参照BCA蛋白定量试剂盒说明书):根据定量试剂A液:B液:ddH2O:蛋白质 = 100:2:7.5:5的比例向96孔检测板中加入相应组分,并加入梯度浓度稀释的白蛋白标准品用于标准曲线的绘制。每个样品设置3个复孔。加样完毕后轻轻震荡,在37℃孵箱中孵育30min,使双缩脲反应进行完全。反应完后利用酶标仪检测各孔在562nm波长下的吸光度。利用标准品OD平均值制作蛋白浓度的标准曲线,相关系数r2 > 0.99视为线性良好。利用标准曲线计算各组样品蛋白浓度后,使用蛋白裂解液和5 X loading buffer调整各样品的浓度至同一浓度。100℃沸水中煮5min,使蛋白质变性为一级结构。12000g 离心5s,将管壁上的样品离到底部。3) 聚丙烯酰氨凝胶电泳:根据待测目标蛋白分子量大小配制适宜浓度的分离胶,待分离胶凝固后配制浓缩胶,并插好梳子,避免起泡产生。待浓缩胶凝固完全后,上样彩色预染marker和蛋白样品,使用Bio-Rad电泳系统进行恒压电泳。当marker指示的目标蛋白分离开后停止电泳。4) 转膜(湿转法):剪与胶适当大小的PVDF膜并在甲醇中预活化,将电泳的凝胶切下后,与PVDF膜和海绵夹成四层夹层,避免产生气泡。将夹层放入电转膜槽中倒入预冷的湿转buffer,使用100V恒压条件进行电转。根据目的蛋白分子量大小调整转膜时间。5) 封闭:转膜结束后将PVDF膜取出,于TBST洗膜液中洗3次,5min/次。用TBST配制5%脱脂奶粉,PVDF膜在5%脱脂奶粉中室温封闭1h。6)抗体孵育:封闭结束后,用5%TBST洗膜液洗膜3次,5min/次。根据目的蛋白分子量大小将膜剪成若干条带,分别放于隔层盒子中,加入对应一抗,4°C摇床孵育一抗过夜。一抗孵育完毕后,用5%TBST洗膜液洗膜3次,5min/次。加入抗对应一抗种属的二抗,置于低速摇床,室温孵育1h。7) 曝光显影:5%TBST洗膜液洗膜3次,5min/次。暗盒中按1:1的比例加入显影液A液和B液,混匀。将PVDF膜浸泡在显影液中1min后,使用Bio-Rad化学发光系统曝光显影,使用Image Lab软件对图像进行分析。
统计学处理:实验结果以均数±标准差表示,采用SigmaPlot软件进行统计分析。P< 0.05表示差异有统计学意义。其他特殊方法详见图注。
结果
应用高原低压舱模拟急进高原导致的急性低压缺氧,我们将食蟹猴从海拔320米处上升至7500米所用时间为190分钟,此后在7500米高度处理食蟹猴48小时,在实验条件下模拟了快速到达极高海拔。随着海拔上升,食蟹猴表现出显著的急性高原病症状,例如呕吐、共济失调、意识模糊等,表明非人灵长类食蟹猴急性高原病模型的复制成功。应用经典行为学、病理学和生物化学等检测,结果显示急性低压缺氧导致显著的食蟹猴骨骼肌协调性下降、脑组织结构空泡化改变、脑含水量上升、脑组织血管性水肿以及神经元变性损伤,表明急性低压缺氧引起显著的脑损伤。
为探讨血红蛋白在进行急性低压缺氧导致食蟹猴脑组织损伤的可能性,我们对食蟹猴的前额叶皮层脑组织进行免疫荧光染色。结果如图1所示,相比于常压常氧组,急性低压缺氧组存在显著增多的血管外游离血红蛋白的分布(图1A),而在Triol处理组其分布显著减少(图1B)。进一步在食蟹猴的前额叶皮层进行小胶质细胞激活标志物Iba-1(ionizedcalcium-binding adapter molecule 1)的免疫组化染色,结果显示急性低压缺氧引起小胶质细胞的丝状或板状伪足的增多,表现出激活样形态改变和Iba-1表达量的增加(图2A),而在Triol处理组激活样形态的细胞数量减少并且Iba-1的表达显著下降(图2B)。在食蟹猴前额皮层脑组织中,进一步应用免疫印迹分析急性低压缺氧对炎性细胞因子IL-6(Interleukin 6)、TNF-α(Tumor necrosis factor alpha)和IL-1β(Interleukin 1 beta)的前体和剪切成熟体形式的影响,结果显示,急性低压缺氧处理引起这些炎症因子表达显著增加,而Triol显著减少了这些炎性细胞因子的表达水平(图3A和3B)。
实施例2. Triol显著恢复脑组织的血红蛋白清除能力
CD163是具有抗炎活性的M2型巨噬细胞的分子标志之一,其功能是作为哺乳动物中唯一的血红蛋白清道夫受体参与血红蛋白分子的胞内清除。血红蛋白与触珠蛋白复合物在经过巨噬细胞/小胶质细胞上的CD163介导的吞噬过程后,通过内涵体转运到溶酶体中发生降解产生血红素,血红素进一步在HO-1的作用下降解产生Fe2+、CO和胆绿素,而Fe2+和胆绿素会进一步被氧化为Fe3+和胆红素。
为了分析低压缺氧对血红蛋白清除能力的影响,我们首先检测了食蟹猴前额叶皮层脑组织中CD163及其下游血红素降解关键限速酶HO-1的表达水平。我们发现急性低压缺氧引起了CD163的显著表达下调(图4A和4B),而这种CD163的表达下调可以被Triol显著恢复。与文献报道一致的是血红素加氧酶HO-1在低压缺氧后被应激性上调,而在本实验中Triol的处理进一步上调了HO-1的表达水平。
应用食蟹猴前额叶脑组织的免疫荧光染色,进一步分析了CD163表达变化与小胶质细胞激活标志Iba1的相关性。急性低压缺氧引起了CD163的显著表达下调(图5A和5B),并伴随着Iba1的表达上升;而当这种CD163的表达下调被Triol显著恢复上调表达时,伴随着Iba1的表达下调;而对照药孕酮没有取消缺氧导致的CD163表达抑制,此时Iba1的表达上升。
以上结果显示CD163与呈现与Iba1存在相反的表达模式,强烈提示游离血红蛋白是急性低压缺氧性脑损伤小胶质细胞的炎性诱发因素,CD163介导的血红蛋白清除受到缺氧的严重抑制。
实施例3. Triol通过增强血红蛋白的清除减少了小胶质细胞BV2的炎性激活
方法
细胞培养:小胶质细胞BV2复苏后培养于含10%FBS的DMEM培养基中,待细胞密度达到80%左右时进行传代种板,细胞接种密度约为4.0-5.0×105 /mL。
缺氧处理:缺氧工作站细胞程序开机后将气体条件设定为1%氧气和5%二氧化碳,紫外灭菌30min并且气体浓度稳定后可开始试验。细胞缺氧处理前先换成新鲜培养基,再将培养皿或共聚焦板放置于缺氧工作站中。处理指定的时间点后迅速将培养皿取出,并进行细胞固定或蛋白裂解等步骤。
血红蛋白处理:游离血红蛋白用无菌水配置成10mM母液,4°C保存,使用培养基稀释并加入培养皿中达到指定的终浓度。20μM血红蛋白和缺氧共刺激时,先将细胞用游离血红蛋白刺激,再立刻将培养皿置于缺氧工作站中进行缺氧处理。
细胞免疫荧光成像:将细胞接种于激光共聚焦专用皿,贴壁后换新鲜血清培养基,给予对应的血红蛋白刺激、缺氧处理或共同处理后将细胞固定。首先将培养基吸掉,0.3%PBST洗3遍,然后加入4%多聚甲醛固定细胞20min;0.3%PBST洗3遍,Triton X-100穿孔15min;0.3%PBST洗3遍,用DAKO抗体稀释液稀释好对应的一抗并混匀后,滴加到细胞上,置于闭暗的湿盒中,4度摇床孵育过夜;室温平衡后,0.3%PBST洗3次。用DAKO抗体稀释液稀释好特定浓度的荧光二抗后滴加到样品上,置于湿盒中避光室温孵育1h;0.3%PBST洗3次,用DAKO抗体稀释液稀释好Hochest33342核染液,混匀后滴加到样品上,置于湿盒中避光室温孵育15min;孵育完毕后,PBS洗1次,加入300ul PBS可进行拍照。使用尼康A1共聚焦显微镜进行拍照,程序开机后调试各通道激光强度与曝光时间后,固定拍照条件对各组样本进行拍照。使用NIS-Elements Analysis软件进行共聚焦图像的荧光强度分析,并按照细胞数量对单位细胞荧光强度进行标准化。
免疫印迹:同实施例1。
实时定量逆转录PCR扩增(qRT-PCR):1) 总RNA的抽提:按照Trizol抽提试剂说明书进行。细胞处理到指定时间点后,吸掉培养基,用PBS清洗2遍洗净培养基。加入1ml Triol充分吹打裂解细胞(以下试剂均按1ml Trizol计算)。加入200ul氯仿,剧烈手摇混匀后室温静置3min。4°C 12000g离心15min,取上层水相400ul到新管中,加入400ul异丙醇,手摇轻柔混匀,室温静置20min。4°C 12000g离心10min,弃上清。加入500ul预冷的75%乙醇,4°C7500g离心10min,小心弃上清。风干后加适量DEPC水溶解RNA沉淀。2) RNA定量:使用Nanodrop 2000核酸定量仪对RNA进行定量,并测定260/280nm波长下的OD比值,比值在1.8-2.0范围内视为质量较好。3)逆转录反应:每个反应体系RNA总量为2ug,oligo dT 1ul,使用DEPC水调整反应体系为13ul。离心混匀后置于65°C预变性5min。预变性后立刻放于冰上,加入RT Reaction Buffer 4ul,dNTP 2ul,Reverse Transcriptase 1ul。离心混匀后进行逆转录反应。逆转录反应条件为:42°C 60min – 70°C 10min – 4°C。4)qPCR扩增反应参数:qPCR扩增反应体系为:SYBR Green Mix 5ul,cDNA 1ul,primer 2ul,RNase free ddH2O2ul. 循环参数为:Holding stage:95°C 15min;Cycling stage(40 cycles): 95°C 10s -56°C 20s - 72°C 30s;Melt Curve stage:95°C 15s - 60°C 60s - 95°C 15s - 60°C60s. 5) 数据处理:使用Applied Biosystem 7500 fast real-time PCR softwarev2.0.5进行数据分析,相对基因表达量使用公式RQ =2 -ΔΔCt方法进行定量。
结果
为了探讨游离血红蛋白是否可以直接引起小胶质细胞的激活,首先应用血红蛋白刺激小胶质细胞观察其激活指标的变化。结果显示,在体外直接用游离血红蛋白刺激小胶质细胞BV2 不同时间,在24小时BV2呈现激活样形态,表现为胞体增大、丝状伪足的增加和延长(如图6A和图6C),同时小胶质细胞激活分子标志物Iba-1(如图6D)和CD11b(如图6B和6E)的表达量也被游离血红蛋白的刺激显著上调(如图6B和图6D),免疫印迹实验进一步验证了前述食蟹猴脑组织中免疫荧光的试验结果(图6E)。与这些观察相一致的是,游离血红蛋白刺激后引起小胶质细胞炎性细胞因子TNF-α、IL-1β和IL-6 mRNA水平的显著表达增加(如图6F),表明游离血红蛋白引起了小胶质细胞的炎性激活。
为了分析缺氧对游离血红蛋白介导的小胶质细胞激活的影响,对小胶质细胞给予游离血红蛋白直接刺激的同时,给予细胞1%氧气的缺氧处理,发现缺氧加剧了游离血红蛋白引起的小胶质细胞炎性细胞因子蛋白水平增加,这些炎症因子包括TNF-α、IL-1β和IL-6,但是对抗炎细胞因子IL-4无显著影响(如图6G)。这些结果显示缺氧可加剧游离血红蛋白引起的小胶质细胞激活。
在食蟹猴脑组织小胶质细胞中发现Triol上调表达血红蛋白清除受体CD163及其下游分子HO-1,在离体细胞模型上进一步应用CD163的RNA干扰,在缺氧和血红蛋白刺激激活小胶质细胞后,分析了CD163的干扰是否可取消Triol对小胶质细胞激活的抑制作用。如图7所示,在干扰CD163后,取消了Triol对缺氧和血红蛋白激活小胶质细胞的Iba-1和CD11b的表达上调的抑制作用,Iba-1和CD11b的表达恢复上调表达,表明Triol通过增强CD163 介导的细胞清除游离血红蛋白,阻止了小胶质细胞的炎性激活。
综上,游离血红蛋白引起小胶质细胞激活,Triol通过恢复小胶质细胞清道夫受体CD163表达水平,减轻游离血红蛋白引起的小胶质细胞激活。
10.参考文献
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Claims (10)
1.5α-雄甾-3β,5,6β-三醇、其氘代物或其药学上可接受的盐在制备治疗患者的脑小血管病的药物中的应用。
2.根据权利要求1所述的应用,其中所述脑小血管病是脑微出血。
3.根据权利要求1所述的应用,其中所述脑微出血为自发性脑微出血、药物相关性脑微出血或创伤性脑微出血。
4.根据权利要求3所述的应用,其中所述自发性脑微出血为年龄相关性脑微出血、高血压性脑微出血、急性高原病伴随的脑微出血、慢性高原病伴随的脑微出血、缺血性脑卒中伴随的脑微出血或出血性脑卒中伴随的脑微出血。
5.根据权利要求4所述的应用,其中所述药物相关性脑微出血是溶栓药相关性脑微出血、抗凝药相关性脑微出血、抗血小板凝集药相关性脑微出血或他汀类药物相关性脑微出血。
6.根据权利要求1至5的任一项所述的应用,其中所述脑小血管病是无症状的。
7.根据权利要求1至5的任一项所述的应用,其中所述脑小血管病是有症状的。
8.根据权利要求1至5的任一项所述的应用,其中所述患者是人。
9.根据权利要求1至5的任一项所述的应用,其中药物还包含另外的治疗剂。
10.根据权利要求1至5的任一项所述的应用,其中所述脑微出血表现为显著增多的脑血管外游离血红蛋白的分布。
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US16/958,600 US11911396B2 (en) | 2017-12-29 | 2018-12-28 | Use of compound in preparation of drug for treating cerebral small vessel disease |
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WO2021170073A1 (zh) * | 2020-02-28 | 2021-09-02 | 广州市赛普特医药科技股份有限公司 | 小分子化合物在治疗肺上皮细胞损伤和/或血管内皮细胞损伤介导的疾病中的用途 |
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BR112020013318A2 (pt) | 2020-12-01 |
IL275686B2 (en) | 2024-06-01 |
KR20200104361A (ko) | 2020-09-03 |
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IL275686B1 (en) | 2024-02-01 |
PT3733190T (pt) | 2023-07-27 |
EP3733190A4 (en) | 2021-09-29 |
ES2951306T3 (es) | 2023-10-19 |
JP2021507934A (ja) | 2021-02-25 |
EP3733190A1 (en) | 2020-11-04 |
TW201932115A (zh) | 2019-08-16 |
CA3087115C (en) | 2023-04-11 |
IL275686A (en) | 2020-08-31 |
RU2752089C1 (ru) | 2021-07-22 |
JP7097444B2 (ja) | 2022-07-07 |
AU2018396895A1 (en) | 2020-07-30 |
US11911396B2 (en) | 2024-02-27 |
TWI762754B (zh) | 2022-05-01 |
CN109985049B (zh) | 2022-02-22 |
AU2018396895B2 (en) | 2021-05-27 |
CA3087115A1 (en) | 2019-07-04 |
EP3733190B1 (en) | 2023-07-12 |
WO2019129179A1 (zh) | 2019-07-04 |
US20200330483A1 (en) | 2020-10-22 |
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