CN116919957A - 用于预防或治疗免疫炎性皮肤病的方法和药物组合物 - Google Patents
用于预防或治疗免疫炎性皮肤病的方法和药物组合物 Download PDFInfo
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- CN116919957A CN116919957A CN202310291594.5A CN202310291594A CN116919957A CN 116919957 A CN116919957 A CN 116919957A CN 202310291594 A CN202310291594 A CN 202310291594A CN 116919957 A CN116919957 A CN 116919957A
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- Prior art keywords
- berberine
- skin disorder
- diacerein
- dermatitis
- igg
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Abstract
提供一种预防或治疗免疫炎性皮肤病的方法。还提供用于预防或治疗免疫炎性皮肤病的药物组合物。
Description
本案是申请日为2018年1月19日、题为《用于预防或治疗免疫炎性皮肤病的方法和药物组合物》的中国发明专利申请201880007670.2的分案申请。
技术领域
本发明涉及用于预防或治疗免疫炎性皮肤病的方法和药物组合物。
背景技术
免疫炎性皮肤病包括多种病症，包括自身免疫性皮肤病、增殖性皮肤病和炎性皮肤病。免疫炎性皮肤病通过炎症过程、免疫系统的失调和细胞的不希望的增殖导致健康组织的破坏。
大疱性类天疱疮(BP)是最常见的自身免疫性水疱性皮肤病，并且通常在老年人中发展，其发作通常在70岁后期，并且在80岁以上的人中发病率显著增加。
据表明，BP的发病机制包括补体激活、肥大细胞脱粒、中性粒细胞和嗜酸性粒细胞的募集和活化以及从这些效应细胞释放基底膜区(BMZ)-降解蛋白酶。
尽管这些事件的确切顺序在很大程度上是未知的，但已提出在BP中导致水疱形成的第一步骤之一包括靶向半桥粒跨膜蛋白BP180的自身抗体(autoAb)(也称为胶原XVII(COL17))，其为被认为是真皮-表皮交界处的主要自身抗原(autoAg)。在结合NC16A(BP180的细胞外结构域)后，autoAb启动Fc受体非依赖性事件，导致白细胞介素(IL)-6和IL-8以基于剂量和时间的方式从基底角质形成细胞释放。此外，据报道autoAb和BP180的结合诱导BP180内化，这在BP疾病发病机制的起始中起关键作用(Bullous Pemphigoid IgG InducesBP180 Internalization via a Macropinocytic Pathway,Hiroyasu等,The AmericanJournal of Pathology,第182卷,第3期,2013年3月,第828–840页)。
本申请的发明人发现双醋瑞因和/或小檗碱能够抑制与免疫炎性皮肤病症以及BP180内化有关的促炎细胞因子的产生，因此具有免疫炎性皮肤病、特别是BP的治疗潜力。
发明内容
在一个实施方案中，本发明提供预防或治疗免疫炎性皮肤病的方法，包括向有需要的受试者施用药物组合物，所述药物组合物包含治疗有效量的小檗碱或小檗碱的生物学等效类似物或其药学上可接受的盐。
在另一个实施方案中，本发明提供预防或治疗免疫炎性皮肤病的方法，包括向有需要的受试者施用药物组合物，所述药物组合物包含治疗有效量的选自双醋瑞因、大黄酸、单乙酰基蛋白和其盐或酯或前药的化合物。
本发明还提供预防或治疗免疫炎性皮肤病的药物组合物，所述药物组合物包含治疗有效量的小檗碱或小檗碱的生物学等效类似物或其药学上可接受的盐。
本发明还提供预防或治疗免疫炎性皮肤病的药物组合物，所述药物组合物包含治疗有效量的选自双醋瑞因、大黄酸、单乙酰基蛋白和其盐或酯或前药中的化合物。
附图说明
图1a是显示丙酸氯倍他索对IL-6产生的抑制作用的统计条形图；
图1b是显示丙酸氯倍他索对IL-8产生的抑制作用的统计条形图；
图2a是显示双醋瑞因对IL-6产生的抑制作用的统计条形图；
图2b是显示双醋瑞因对IL-8产生的抑制作用的统计条形图；
图3a是显示小檗碱对IL-6产生的抑制作用的统计条形图；
图3b是显示小檗碱对IL-8产生的抑制作用的统计条形图；
图4a是显示丙酸氯倍他索对IL-6和IL-8的mRNA产生的抑制作用的统计条形图；
图4b是显示双醋瑞因对IL-6和IL-8的mRNA产生的抑制作用的统计条形图；
图4c是显示小檗碱对IL-6和IL-8的mRNA产生的抑制作用的统计条形图；
图5a显示用荧光颜色染色并用IgG(右图)和对照(左图；未用IgG处理)处理的角质形成细胞的共聚焦显微镜照片(细胞核：深蓝色；BP180：亮绿色)；
图5b显示用荧光颜色染色并用IgG处理的角质形成细胞的共聚焦显微镜照片；
图5c显示用荧光颜色染色并用IgG和不同浓度的小檗碱处理的角质形成细胞的共聚焦显微镜照片；
图6a显示用荧光颜色染色并用IgG(右图)和对照(左图；未用IgG处理)处理的角质形成细胞的共聚焦显微镜照片；
图6b显示用荧光颜色染色并用IgG处理的角质形成细胞的共聚焦显微镜照片；和
图6c显示用荧光颜色染色并用IgG和不同浓度的双醋瑞因处理的角质形成细胞的共聚焦显微镜照片。
具体实施方式
本文所用的术语“治疗有效量”是指减轻或减轻至少一个或多个患者的疾病的一种或多种症状的量。
本文所用的术语“双醋瑞因或其类似物”是指双醋瑞因、大黄酸、单乙酰基蛋白、或其药学上可接受的盐或酯或前药。
本文所用的术语“前药”是指可以代谢成其母体化合物并以母体化合物的形式在体内发挥其生理功能的任何化合物。
除非本文另有说明，否则本说明书中使用的术语“一种”、“所述”等(特别是在下文的权利要求书中)应理解为包括单数形式和复数形式。
化学上，大黄酸是具有式(I)结构的9,10-二氢-4,5-二羟基-9,10-二氧代-2-蒽羧酸，并且其前药之一双醋瑞因是具有式(II)的结构的4,5-双(乙酰氧基)9,10-二氢-4,5-二羟基-9,10-二氧代-2-蒽羧酸。双醋瑞因在到达体循环之前完全转化为大黄酸，并在体内以大黄酸的形式发挥其生理功能。
式(I)
式(II)
双醋瑞因是广泛用于治疗骨关节炎的抗炎剂，已证明其可抑制白细胞介素-1(IL-1)信号传导。目前，双醋瑞因胶囊的强度为50毫克，并在不同国家以不同的商品名销售，包括Art等。
小檗碱(天然黄18，5,6-二氢-9,10-二甲氧基苯并(g)-1,3-苯并二氧杂环庚烷(5,6-a)喹喔啉)是草药植物如黄连(Coptidis rhizome)、黄柏、黄芩、冬青叶十大功劳和小檗中存在的异喹啉生物碱。已发现小檗碱及其衍生物具有抗微生物和抗疟疾活性。它可以对抗各种病原体，如真菌、酵母菌、寄生虫、细菌和病毒。
本申请的发明人发现双醋瑞因和小檗碱能够抑制与免疫炎性皮肤病症以及BP180内化有关的促炎细胞因子的产生，因此可用于治疗这些疾病。因此，本发明提供预防或治疗免疫炎性皮肤病的方法，包括向有需要的受试者施用药物组合物，所述药物组合物包含治疗有效量的小檗碱或小檗碱的生物学等效类似物或其药学上可接受的盐。
本方法中小檗碱的生物学等效类似物包括但不限于例如药根碱、巴马汀、黄连碱、9-去甲基小檗碱、9-去甲基帕马汀、13-羟基小檗碱、小檗红碱、巴马亭红碱、9-O-乙基小檗碱、9-O-乙基-13-乙基小檗碱、13-甲基二氢小檗碱N-甲基盐、四氢原小檗碱及其N-甲基盐、和9-月桂酰小檗碱氯化物。
优选地，药学上可接受的盐是小檗碱氯化物。
在一个实施方案中，在本发明的方法中小檗碱或小檗碱的生物学等效类似物或其药学上可接受的盐是主要的药物活性成分。
在另一实施方案中，在本发明的方法中小檗碱或小檗碱的生物学等效类似物或其药学上可接受的盐是唯一的药物活性成分。
本发明还提供预防或治疗免疫炎性皮肤病的方法，包括向有需要的受试者施用药物组合物，所述药物组合物包含治疗有效量的选自双醋瑞因、大黄酸、单乙酰基蛋白和其盐或酯或前药的化合物(即双醋瑞因及其类似物)。
在一个实施方案中，所述化合物是双醋瑞因。
在一个实施方案中，双醋瑞因及其类似物是本发明方法中的主要药物活性成分。
在另一个实施方案中，双醋瑞因及其类似物是本发明方法中唯一的药物活性成分。
在一个实施方案中，所述化合物的治疗有效量相当于每天10至200mg双醋瑞因碱。
优选地，本发明的受试者是人。
在一个实施方案中，所述免疫炎性皮肤病选自急性发热性中性粒细胞性皮肤病、皮肌炎、剥脱性皮炎、汗疱疹、中性粒细胞性汗腺炎、无菌性脓疱病、瘙痒性荨麻疹性丘疹和妊娠斑、大疱性类天疱疮、寻常型天疱疮、皮炎疱疹、妊娠性类天疱疮、肠相关性皮肤病-关节炎综合征、类风湿性中性粒细胞性皮肤病、背部中性粒细胞性皮肤病、龟头炎、脉络膜炎、白塞病、离心红斑、多形性红斑、多形性红斑、环状肉芽肿、手部皮炎、扁平苔藓、扁平苔癣、硬化性苔藓、单纯性扁平苔藓、脊髓性苔藓、皮肤炎、坏疽性脓皮病、结节病、角膜下脓疱性皮肤病、荨麻疹、掌跖脓疱病、药疹、急性全身性发疹性脓疱病、接触性皮炎和短暂的棘层松解性皮肤病。
优选地，免疫炎性皮肤病是大疱性类天疱疮。
在下文中，将参考以下实施例进一步说明本发明。然而，这些实施例仅用于说明目的，而不是限制本发明的范围。
实施例
[实施例1]细胞因子产生抑制研究
研究了双醋瑞因或小檗碱降低抗BP180免疫球蛋白G(IgG)刺激从人成体皮肤角质形成细胞HaCaT细胞产生BP相关促炎细胞因子IL-6或IL-8的作用。丙酸氯倍他索(一种常用的用于治疗血压以及各种其他皮肤病的皮质类固醇)被用作阳性对照。
从正常或BP患者血液中纯化IgG。因此，来自健康供体或BP患者的血液收集参与该研究。纯化的IgG用于刺激来自HaCaT细胞的促炎细胞因子如IL-6和IL-8的产生。
血液收集
在台湾大学医院皮肤科接受治疗的患者必须根据典型的临床表现以及通过酶联免疫吸附测定(ELISA)(MBL Co Ltd，名古屋，日本)，通过直接免疫荧光(DIF)显微术或针对BP180 NC16A的循环IgG自身抗体在真皮-表皮连接处检测IgG和/或C3的线性沉积物的记录确诊BP。
从BP患者和健康志愿者收集两次血液。来自健康供体或BP患者的血液总量为40mL，每次受试者一次就诊时的最大血液量为20mL。
记录包括年龄、性别的人口统计学、包括BP和诊断信息的病史以及循环正常IgG、抗BP180或抗BP230 IgG自身抗体水平。
血液样本的收集由台湾大学医院的研究伦理委员会(REC)批准，并且根据赫尔辛基宣言获得了知情同意。
BP180-NC16A蛋白的表达
BP180-NC16A表达质粒由Hiroshi Shimizu教授和Wataru Nishie教授(Department of Dermatology,Hokkaido University Graduate School of Medicine,Sapporo,Japan)友情提供。将编码NC16A结构域的构建体(77个氨基酸)插入pGEX-6P1载体的MCS内。将质粒转化到DH5α感受态细胞中，然后提取DNA，其确认为人BP180 NC16A的序列。为了获得大量的NC16A蛋白，通过导入质粒转化BL21，然后根据制造商的说明使用Overnight Express Autoinduction系统(Novagen)表达NC16A结构域蛋白。
IgG的纯化
使用Hitrap Protein A HP柱(GE Healthcare Life Sciences)分离来自健康献血者(Healthy-IgG)和诊断为BP(BP-IgG)的患者的总血清IgG。用0.1M NaPi pH8.0(平衡)、0.1M柠檬酸钠pH6.0(洗涤)和0.1M柠檬酸钠pH3.0(洗脱)洗脱免疫球蛋白。然后通过与BP180-NC16A蛋白偶联的CNBr活化的Sepharose柱(GE Healthcare Life Sciences)进一步洗脱浓缩的免疫球蛋白，并且可以分离与NC16A反应的浓缩的特异性IgG(蛋白A Elu-NC16A-Elu)。通过抗BP180-NC16A ELISA(MBL Co Ltd，名古屋，日本)证实亲和纯化的BPIgG制剂的免疫反应性。
细胞培养
将HaCaT细胞(CLS Cell Lines Service，德国)在补充有4.5g/L葡萄糖、2mM L-谷氨酰胺和10％胎牛血清的Dulbecco改良的eagle培养基(DMEM)培养基中培养。将细胞接种在24孔或12孔板上并生长至80％汇合用于以下测定。
细胞活力或细胞毒性评估
将#3-6代的指数生长细胞(3000个细胞/孔，100μl培养基)在96孔板中铺板过夜，使细胞附着(80％汇合)，然后在37℃下暴露于不同浓度的双醋瑞因(0.1、1、10μM)或小檗碱(0.1、1、10μM)或丙酸氯倍他索(0.1、1、10μM)，以及2mg/mL的健康IgG、BP-IgG或特异性IgG48小时。
药物处理后，轻轻除去细胞培养基。然后用温热的培养基轻轻洗涤细胞三次以除去任何脱落和死亡的细胞。将细胞与MTT试剂以1.0mg/mL的终浓度一起在细胞培养基中孵育2小时。通过使用ELISA板读数器记录570nm处的吸光度变化来测量甲臜的量(可能与活细胞数量成正比)。
促炎细胞因子测量
基于先前的研究进行细胞因子测量。简而言之，将细胞与单独的培养基或与2mg/mL纯化的BP-IgG或特异性IgG一起孵育，并在不存在或存在双醋瑞因或小檗碱或丙酸氯倍他索(0.1、1和10μM)的情况下培养，孵育48小时后收集培养上清液，储存在-20℃下用于分析。根据制造商的说明，通过ELISA(BD Biosciences)在细胞培养物上清液中分析IL-6和IL-8水平。
定量实时聚合酶链反应定量检测IL-6和IL-8 mRNA的表达
如先前报道的，使用定量实时聚合酶链反应(qPCR)定量IL-6和IL-8信使RNA(mRNA)水平。将BP IgG处理的HaCaT细胞与或不与双醋瑞因或小檗碱或丙酸氯倍他索一起培养48小时。根据制造商的说明，使用TRIzol试剂(LifeTechnologies)从培养的HaCaT细胞中分离总RNA。通过按照制造商的说明将1μgRNA与RevertAid First Strand cDNASynthesis Kit(Thermo Scientific)一起孵育，从分离的RNA逆转录互补DNA(cDNA)。使用SelectMaster Mix(Life Technologies)在Mastercycler(Eppendorf)中进行定量RT-PCR。PCR混合物含有0.5μM的每种正向和反向引物。每种反应混合物在50℃下进行2分钟，在95℃下进行2分钟，然后进行40个循环的在95℃下15秒、在60℃下1分钟。将数据针对持家基因甘油醛-3-磷酸脱氢酶(GAPDH)标准化。RT-PCR中使用的引物如下：IL-8信使RNA(mRNA),正向,5’-ACC GGA AGG AAC CAT CTC AC-3’,和反向,5’-AAA CTG CAC CTT CACACA GAG-3’和IL-6信使RNA(mRNA),正向,5’-GGT ACA TCC TCG ACG GCA TCT-3’,和反向,5’-GTG CCT CTT TGC TGC TTT CAC-3’和GAPDH,正向,5’-ACA ACT TTG GTA TCG TGG AAGG-3’,和反向,5’-GCC ATC ACG CCA CAG TTT-3’。
统计分析
使用Student's t检验或单因素方差分析(ANOVA)分析数据。p值<0.05被认为表示统计学上的显著差异。
[结果]
在研究期间共招募了13名受试者。其中6个是正常对照，而其他7个受试者最初被诊断为患有大疱性类天疱疮(BP)。由于DIF/IIF阴性结果，7名BP患者中有一名(病例编号12)是筛查失败。案例编号1、2、3、4和13具有通过ELISA检测到的升高的针对BP180 NC16A的循环IgG自身抗体。
通过使用GST-Bulk试剂盒和B-PER蛋白质提取试剂(Thermo)获得大量人NC16A蛋白，然后通过使用PreScission蛋白酶系统进行GST-标签的切割。
为了从健康献血者(健康IgG)和诊断为BP(BP-IgG)的患者中分离血清IgG，使用Hitrap Protein A HP柱，并通过CNBr激活的Sepharose柱与BP180-NC16A蛋白偶联进一步洗脱浓缩的免疫球蛋白。通过从初始步骤分离的IgG(蛋白AElu)和与NC16A反应的浓缩特异性IgG(蛋白AElu-NC16A-Elu，即特异性IgG)的相对倍数变化证明了分离的效率，其具有最高的纯化倍数，高达23.46和6821IU/mg的特异性IgG。
通过MTT试验评估不同浓度的双醋瑞因、小檗碱或丙酸氯倍他索的角质细胞细胞毒性。0.1-10μM的双醋瑞因处理对HaCaT细胞具有显著的细胞毒性，活力降低至50％。用健康对照(健康IgG)、BP-IgG或BP特异性IgG的血清样品处理增强HaCaT活力高达250％，但10μM双醋瑞因处理仍显著降低HaCaT活力。相比之下，0.1-10μM的小檗碱和丙酸氯倍他索治疗对HaCaT细胞没有显著的细胞毒性。
HaCaT细胞与单独培养基或2mg/mL纯化BP-IgG或与不同浓度(0、0.1、1和10μM)双醋瑞因、小檗碱或丙酸氯倍他索的特异性IgG孵育后检测IL-6和IL-8的变化，孵育48小时后收集培养上清液。阳性对照处理、丙酸氯倍他索，以剂量依赖性方式减少IL-6(图1a)和IL-8分泌(图1b)。双醋瑞因显著减少用特异性抗BP180 IgG处理的HaCaT细胞中IL-6的分泌(图2a)。相反，0.1μM的双醋瑞因不会减少用特异性抗BP180 IgG处理的HaCaT细胞中IL-8的分泌。仅在浓度为1或10μM时才注意到双醋瑞因对IL-8分泌的抑制作用(图2b)。
小檗碱不会减少用特异性抗BP180 IgG处理的HaCaT细胞中IL-6的分泌(图3a)。小檗碱剂量依赖性地减少用BP特异性IgG处理的HaCaT细胞中IL-8的分泌。在用BP特异性IgG处理的那些细胞中抑制作用显著更好(图3b)。
用不同浓度(0、0.1、1、10μM)的双醋瑞因、小檗碱或丙酸氯倍他索培养BP IgG处理的HaCaT细胞48小时。从培养的HaCaT细胞中分离总RNA，并进行定量RT-PCR(RT-qPCR)分析。结果显示丙酸氯倍他索显著降低IL-6和IL-8mRNA表达水平(图4a)，而双醋瑞因对IL-6mRNA表达水平具有剂量依赖性抑制作用，但对IL-8mRNA仅在10μM具有抑制作用(图4b)。相反，小檗碱对IL-6和IL-8mRNA表达均具有剂量依赖性抑制作用(图4c)。
上述研究表明，双醋瑞因和小檗碱对与免疫炎性皮肤病有关的促炎细胞因子的产生具有抑制作用，因此可能具有免疫炎性皮肤病的治疗潜力。
[实施例2]BP180内化研究
BP180是半桥粒的重要组成部分，可使角质形成细胞附着在皮肤的基底膜上。BP180损伤可能导致角质形成细胞附着不良，并与皮肤病或水疱疾病有关。BP180内化被认为是大疱性类天疱疮发病机制中的关键因素，因此可用于评估该疾病。进行以下研究以评估小檗碱、双醋瑞因或大黄酸对用BP-IgG处理的角质形成细胞中autoAb(BP-IgG)诱导的BP180内化和半桥粒破坏的影响。
方法：BP180内化的免疫荧光研究
对于该BP180内化研究，根据实施例1中描述的程序进行BP患者的IgG纯化和用不同IgG和药物(双醋瑞因或小檗碱)处理的细胞培养物。
将在玻璃盖玻片上生长的角质形成细胞固定在4％多聚甲醛中，在PBS中彻底洗涤，并在PBS中的0.1％(v/v)Triton X-100中透化10分钟。将一抗覆盖在细胞上，并将制备物在室温下孵育1小时。用PBS洗涤盖玻片上的细胞，并在室温下施加荧光缀合的二抗1小时。用PBS洗涤后，将盖玻片固定在载玻片上。细胞核的荧光颜色为深蓝色，BP180为亮绿色。通过共聚焦显微镜检查所有制备物。
[结果]
小檗碱处理
在对照角质形成细胞(即未经IgG处理)和用健康受试者的IgG处理的角质形成细胞中，BP180(亮绿色)的免疫荧光分析显示出显著的细胞质和膜定位(图5(a))。相反，用BP-IgG处理的细胞中BP180的膜定位显著降低并且在细胞质中看起来更加弥散，表明BP-IgG处理诱导BP180内化和半桥粒破坏的发生(图5(b))。随着小檗碱浓度增加(0.1至10μM)，BP180的膜定位恢复，表明在小檗碱处理后抑制BP180内化和维持半桥粒完整性(图5(c))。
双醋瑞因处理
与对照角质形成细胞(即未经IgG处理)和用健康IgG处理的角质形成细胞(图6(a))相比，细胞膜中BP180分布在BP-IgG处理的角质形成细胞的细胞质中减少并且更加弥散，表明发生由BP-IgG处理诱导的BP180内化(图6(b))。随着双醋瑞因浓度增加(0.1至10μM)，BP180的膜定位恢复，表明在双醋瑞因处理后抑制BP180内化和维持半桥粒完整性(图6(c))。
结果表明，双醋瑞因和小檗碱能够抑制BP180内化，因此可能具有治疗BP的潜力。
以上公开内容涉及其详细技术内容和发明特征。本领域技术人员可以基于所描述的本发明的公开和建议进行各种修改和替换而不脱离其特征。
Claims (16)
1.一种预防或治疗免疫炎性皮肤病的方法，包括向有需要的受试者施用药物组合物，所述药物组合物包含治疗有效量的小檗碱或小檗碱的生物学等效类似物或其药学上可接受的盐。
2.根据权利要求1所述的方法，其中所述免疫炎性皮肤病选自急性发热性中性粒细胞性皮肤病、皮肌炎、剥脱性皮炎、汗疱疹、中性粒细胞性汗腺炎、无菌性脓疱病、瘙痒性荨麻疹性丘疹和妊娠斑、大疱性类天疱疮、寻常型天疱疮、皮炎疱疹、妊娠性类天疱疮、肠相关性皮肤病-关节炎综合征、类风湿性中性粒细胞性皮肤病、背部中性粒细胞性皮肤病、龟头炎、脉络膜炎、白塞病、离心红斑、多形性红斑、多形性红斑、环状肉芽肿、手部皮炎、扁平苔藓、扁平苔癣、硬化性苔藓、单纯性扁平苔藓、脊髓性苔藓、皮肤炎、坏疽性脓皮病、结节病、角膜下脓疱性皮肤病、荨麻疹、掌跖脓疱病、药疹、急性全身性发疹性脓疱病、接触性皮炎和短暂的棘层松解性皮肤病。
3.根据权利要求1所述的方法，其中所述免疫炎性皮肤病是大疱性类天疱疮。
4.根据权利要求1所述的方法，其中小檗碱的生物学上等同的类似物选自药根碱、巴马汀、黄连碱、9-去甲基小檗碱、9-去甲基帕马汀、13-羟基小檗碱、小檗红碱、巴马亭红碱、9-O-乙基小檗碱、9-O-乙基-13-乙基小檗碱、13-甲基二氢小檗碱N-甲基盐、四氢原小檗碱及其N-甲基盐和9-月桂酰小檗碱氯化物。
5.根据权利要求1所述的方法，其中所述药学上可接受的盐是小檗碱氯化物。
6.根据权利要求1所述的方法，其中小檗碱或小檗碱的生物学等效类似物或其药学上可接受的盐是主要的药物活性成分。
7.根据权利要求1所述的方法，其中小檗碱或小檗碱的生物学等效类似物或其药学上可接受的盐是唯一的药物活性成分。
8.根据权利要求1所述的方法，其中所述受试者是人。
9.一种预防或治疗免疫炎性皮肤病的方法，包括向有需要的受试者施用药物组合物，所述药物组合物包含治疗有效量的选自双醋瑞因、大黄酸、单乙酰基蛋白和其盐或酯或前药中的化合物。
10.根据权利要求9所述的方法，其中所述免疫炎性皮肤病选自急性发热性中性粒细胞性皮肤病、皮肌炎、剥脱性皮炎、汗疱疹、中性粒细胞性汗腺炎、无菌性脓疱病、瘙痒性荨麻疹性丘疹和妊娠斑、大疱性类天疱疮、寻常型天疱疮、皮炎疱疹、妊娠性类天疱疮、肠相关性皮肤病-关节炎综合征、类风湿性中性粒细胞性皮肤病、背部中性粒细胞性皮肤病、龟头炎、脉络膜炎、白塞病、离心红斑、多形性红斑、多形性红斑、环状肉芽肿、手部皮炎、扁平苔藓、扁平苔癣、硬化性苔藓、单纯性扁平苔藓、脊髓性苔藓、皮肤炎、坏疽性脓皮病、结节病、角膜下脓疱性皮肤病、荨麻疹、掌跖脓疱病、药疹、急性全身性发疹性脓疱病、接触性皮炎和短暂的棘层松解性皮肤病。
11.根据权利要求9所述的方法，其中所述免疫炎性皮肤病是大疱性类天疱疮。
12.根据权利要求9所述的方法，其中所述化合物是双醋瑞因。
13.根据权利要求9所述的方法，其中所述化合物是主要的药物活性成分。
14.根据权利要求9所述的方法，其中所述化合物是唯一的药物活性成分。
15.根据权利要求9所述的方法，其中所述受试者是人。
16.根据权利要求9所述的方法，其中所述化合物的治疗有效量相当于每天10至200mg双醋瑞因碱。
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- 2018-01-19 WO PCT/US2018/014366 patent/WO2018136706A1/en unknown
- 2018-01-19 CA CA3049450A patent/CA3049450A1/en active Pending
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| US10675260B2 (en) | 2020-06-09 |
| WO2018136706A1 (en) | 2018-07-26 |
| EP3570835B1 (en) | 2023-08-09 |
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| TW201831474A (zh) | 2018-09-01 |
| EP3570835A4 (en) | 2021-03-03 |
| TWI794200B (zh) | 2023-03-01 |
| CN110191710B (zh) | 2023-04-18 |
| KR102563841B1 (ko) | 2023-08-03 |
| JP7381629B2 (ja) | 2023-11-15 |
| JP2022078204A (ja) | 2022-05-24 |
| CN110191710A (zh) | 2019-08-30 |
| EP3570835A1 (en) | 2019-11-27 |
| SG11201907443PA (en) | 2019-09-27 |
| US20180200235A1 (en) | 2018-07-19 |
| KR20190105070A (ko) | 2019-09-11 |
| CA3049450A1 (en) | 2018-07-26 |
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