CN116687896A - 氟西汀在制备治疗皮肤屏障受损的局部制剂中的用途 - Google Patents
氟西汀在制备治疗皮肤屏障受损的局部制剂中的用途 Download PDFInfo
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Abstract
本发明涉及生物医药领域,具体涉及氟西汀或其药学上可接受的盐在制备治疗由皮肤屏障受损引起的皮肤病症的局部制剂中的用途。本发明向皮肤屏障受损处局部应用一定剂量的氟西汀,其能够在较短时间内、以较低的剂量通过局部发挥药物效应,不仅能够调节免疫失衡、缓解瘙痒、改善局部和全身炎症,而且还能快速地促进皮肤屏障的改善,从多方面减轻、改善和/或缓解由皮肤屏障受损引起的皮肤病症的外观和主观症状,进而提高患者的身心健康和生活质量。
Description
技术领域
本发明涉及生物医药领域,具体涉及氟西汀或其药学上可接受的盐在制备治疗由皮肤屏障受损引起的皮肤病症的局部制剂中的用途。
背景技术
皮肤由表皮、真皮、皮下组织三层组成,其最重要的功能是在生物体的内部和外部环境之间提供有效屏障,以向生物体提供保护和支持。表皮屏障有三个主要功能,包括限制被动水分流失、限制环境化学物质吸收和防止微生物感染。表皮屏障通过形成终末分化的角质细胞来保护皮肤免受机械损害、化学物质和微生物的危害(这一过程被称为角化)。
研究显示,皮肤屏障受损是对皮肤产生负面作用的条件的基础,且皮肤屏障受损是变应原致敏的必不可少的事件。皮肤屏障受损不仅会使更多的水分从皮肤中流失,还会使环境触发因素(例如变应原、刺激物和毒素)侵入,甚至导致各种类型的皮肤病症(特别是皮肤炎症性疾病)的发生。皮肤屏障受损造成对外部环境的屏障功能降低、对内部环境的保护作用下降,而变应原则通过表皮进入体内并诱发炎症和变应性免疫应答,使得过敏状态持续存在。然而,现有技术中常用的用于控制炎症的药物(例如类固醇)的使用(特别是长期使用)与不可逆的副作用相关联(例如皮肤萎缩),反而会导致皮肤屏障的进一步受损。此外,现有技术中的这些常用药物无法直接缓解瘙痒,而瘙痒引起的抓挠行为会导致“瘙痒-抓挠-瘙痒”的恶性循环的形成和皮肤屏障的进一步受损。
发明内容
本发明提供了氟西汀或其药学上可接受的盐在制备治疗由皮肤屏障受损引起的皮肤病症的局部制剂中的用途,其特征在于,所述局部制剂用于皮肤外用。
在一些实施例中,所述局部制剂用于降低所述皮肤屏障受损处的经皮水分流失;和/或提高所述皮肤屏障受损处的水合作用。
在一些实施例中,所述局部制剂用于降低炎症反应,所述炎症反应包括所述皮肤屏障受损处和/或全身性的所述炎症反应。
在一些实施例中,所述由皮肤屏障受损引起的皮肤病症包括特应性皮炎、接触性皮炎、湿疹、牛皮癣、脂溢性皮炎、手足皮炎、慢性荨麻疹、痤疮、皮肤干燥症和鱼鳞病中的一种或多种。
在一些实施例中,所述局部制剂用于缓解所述由皮肤屏障受损引起的皮肤病症的相关症状,所述相关症状包括以下中的一种或多种:皮肤敏感、发红、干燥、瘙痒、红斑、肿胀、水肿、糜烂、灼热、渗出物、鳞屑、色素沉着过度和易感染。
在一些实施例中,所述相关症状还包括以下中的一种或多种的增加:Th2相关的细胞因子、血清IgE、血清TARC。
在一些实施例中,所述Th2相关的细胞因子包括IL-5、IL-13和IL-31中的一种或多种。
在一些实施例中,所述由皮肤屏障受损引起的皮肤病症由变应原致敏导致。
在一些实施例中,所述局部制剂的形式包括喷雾剂、溶液剂、洗剂、凝胶剂、乳膏剂、软膏剂、糊剂和乳剂中的一种或多种。
在一些实施例中,所述局部制剂包含0.375-1.5mg/mL的所述氟西汀或其药学上可接受的盐。
在一些实施例中,所述局部制剂包含0.4mg/mL、0.5mg/mL、0.6mg/mL、0.7mg/mL、0.8mg/mL、0.9mg/mL、1.0mg/mL、1.1mg/mL、1.2mg/mL、1.3mg/mL、1.4mg/mL或1.5mg/mL的所述氟西汀或其药学上可接受的盐。
在一些实施例中,所述氟西汀或其药学上可接受的盐为氟西汀盐酸盐。
如本文所使用,“皮肤屏障受损”是指皮肤的屏障功能(例如,限制个体的被动水分流失、保护个体免受外部危害(包括微生物、化学物质和/或机械损害)受到损害。个体的皮肤屏障受损会引起各种类型的皮肤病症的发生。在一些实施例中,由皮肤屏障受损引起的皮肤病症包括皮肤炎症性疾病,例如特应性皮炎、接触性皮炎、湿疹、牛皮癣、脂溢性皮炎、手足皮炎、慢性荨麻疹和痤疮。在一些实施例中,由皮肤屏障受损引起的皮肤病症包括皮肤干燥症和鱼鳞病。在一些实施例中,由皮肤屏障受损引起的皮肤病症的相关症状包括皮肤敏感、发红、干燥、瘙痒、粗糙,甚至红斑、肿胀、水肿、糜烂、灼热、渗出物、鳞屑、色素沉着过度、易感染等。
如本文所使用,“局部制剂”是指用于局部递送本发明涉及的指定化合物的药学上可接受的任何制剂。本发明中,用于局部给药的示例性的制剂形式包括喷雾剂、溶液剂、洗剂、凝胶剂、乳膏剂、软膏剂、糊剂和乳剂。
如本文所使用,局部制剂的“应用”、“施用”和“给药”是指将局部制剂应用至个体的皮肤(例如皮肤屏障受损处,和/或受由皮肤屏障受损引起的皮肤病症或其相关症状影响的皮肤区域)的任何方式。在一些实施例中,所述方式包括将局部制剂递送至(例如通过向个体皮肤涂、擦、抹、喷洒局部制剂)个体的皮肤表面。
如本文所使用,“治疗”是指对由皮肤屏障受损引起的皮肤病症或其相关症状产生积极作用,包括减轻、改善和/或缓解所述皮肤病症的至少一种症状、减轻、改善和/或缓解所述皮肤病症的严重程度、以及延迟、预防或抑制所述皮肤病症的进展。换句话说,本发明的“治疗”并非意指完全治愈所述皮肤病症。本发明中,用于治疗由皮肤屏障受损引起的皮肤病症的局部制剂仅需实现以下中的一种或多种:降低所述皮肤病症的严重程度、降低所述皮肤病症的相关症状的严重程度、改善患者生活质量、以及延迟、预防或抑制一种或多种皮肤病症的发作。在一些实施例中,所述症状包括身体上的症状(例如上述皮肤敏感、发红、干燥、瘙痒、红斑、肿胀、水肿、糜烂、灼热、渗出物、鳞屑、色素沉着过度、易感染等症状),和可测量的生理参数(例如TEWL和/或皮肤水分水平)。
如本文所使用,“个体”、“受试者”和“患者”可互换地使用,是指将应用或已应用本发明涉及的局部制剂的任何哺乳动物。在一些实施例中,所述哺乳动物为人类。在一些实施例中,所述哺乳动物包括牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴。
如本文所使用,“药学上可接受的盐”是指向指定化合物的盐,所述盐在向个体局部应用时,是安全、有效且具有所需生物学活性的。药学上可接受的盐包括指定化合物中存在的酸性或碱性基团的盐。药学上可接受的酸加成盐包括例如,盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、醋酸盐、乳酸盐、水杨酸盐、柠檬酸盐、酒石酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡萄糖醛酸盐、蔗糖盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐。药学上可接受的碱盐包括例如,铝、钙、锂、镁、钾、钠、锌和二乙醇胺盐。
如本文所使用,“皮损”是指与周围皮肤具有不同特征的任何皮肤区域,包括颜色、形状、大小和肤质等的异常变化。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。显而易见地,下面描述中的附图是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动性的前提下,还可以根据这些附图获得其它的附图。
图1示出了本发明实施例一的部分实验设计的流程图;
图2A示出了局部应用氟西汀对各实验组的皮肤TEWL水平的影响(***p<0.001);
图2B示出了局部应用氟西汀对各实验组的皮肤水分水平的影响(**p<0.01);
图3A示出了局部应用氟西汀对各实验组的皮损的组织学特征(苏木精和伊红(H&E)染色以及甲苯胺蓝染色,放大倍数均为200倍)的影响;
图3B示出了局部应用氟西汀对各实验组的真皮层中肥大细胞数量(由五位病理学家随机选择切片,从每个切片中随机筛选出五个镜下区域进行肥大细胞计数)的影响(*p<0.05,**p<0.01,ns:非统计学显著);
图4A示出了局部应用氟西汀对各实验组背部皮肤的IL-5mRNA表达水平的影响(***p<0.001);
图4B示出了局部应用氟西汀对各实验组背部皮肤的IL-13mRNA表达水平的影响(**p<0.01,***p<0.001);
图4C示出了局部应用氟西汀对各实验组背部皮肤的IL-31mRNA表达水平的影响(*p<0.05);
图5A示出了局部应用氟西汀对各实验组血清IgE浓度的影响(*p<0.05,ns:非统计学显著);
图5B示出了局部应用氟西汀对各实验组血清TARC浓度的影响(**p<0.01,***p<0.001);
图6示出了在实验第29天时,局部应用氟西汀对各实验组的临床特征的影响的照片;
图7A示出了对各实验组一分钟内抓挠行为的计数(*p<0.05,**p<0.01,ns:非统计学显著);
图7B示出了使用游标卡尺测量各实验组背部皮肤厚度的结果(*p<0.05,**p<0.01)。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述。显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
本文中“和/或”包括任何和所有一个或多个列出的相关项的组合。
本文中“多个”意指两个或两个以上,即其包含两个、三个、四个、五个等。
需要说明的是,在本文中,术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含,从而使得包括一系列要素的过程、方法、物品或者装置不仅包括那些要素,而且还包括没有明确列出的其他要素,或者是还包括为这种过程、方法、物品或者装置所固有的要素。在没有更多限制的情况下,由语句“包括一个……”限定的要素,并不排除在包括该要素的过程、方法、物品或者装置中还存在另外的相同要素。
如在本说明书中使用的,术语“大约”,典型地表示为所述值的+/-5%,更典型的是所述值的+/-4%,更典型的是所述值的+/-3%,更典型的是所述值的+/-2%,甚至更典型的是所述值的+/-1%,甚至更典型的是所述值的+/-0.5%。
在本说明书中,某些实施方式可能以一种处于某个范围的格式公开。应该理解,这种“处于某个范围”的描述仅仅是为了方便和简洁,且不应该被解释为对所公开范围的僵化限制。因此,范围的描述应该被认为是已经具体地公开了所有可能的子范围以及在此范围内的独立数字值。例如,范围1~6的描述应该被看作已经具体地公开了子范围如从1到3,从1到4,从1到5,从2到4,从2到6,从3到6等,以及此范围内的单独数字,例如1,2,3,4,5和6。无论该范围的广度如何,均适用以上规则。
实施例一
皮肤屏障受损小鼠模型的建立和氟西汀的局部应用:6周龄BALB/c小鼠(n=30)由沈阳实验动物公司提供,在受控的湿度(40%)、温度(23℃)和12-h/12-h光暗循环条件下,饲养在无特定病原体(SPF)的独立塑料笼中。用标准的实验室食物和水喂养小鼠一周。图1显示了皮肤屏障受损小鼠模型的构建和药物干预过程。30只小鼠被随机分为5组,每组6只。第1组为假手术(sham)组,第2组为DNCB模型组(Flu-0),而第3、4和5组分别为高氟西汀浓度组(1.5mg/mL,Flu-1.5)、中氟西汀浓度组(0.75mg/mL,Flu-0.75)和低氟西汀浓度组(0.375mg/mL,Flu-0.375)。本发明中使用的氟西汀和DNCB购自Sigma-Aldrich公司(St.Louis,MO,USA)。DNCB溶液(例如1%DNCB和0.5%DNCB)通过将DNCB溶解在丙酮-橄榄油(4:1,v/v)中制得并充分混合。氟西汀溶液通过将氟西汀(例如盐酸氟西汀)粉末溶解在灭菌超纯水中并充分混合制得。例如,为了制备1.5mg/mL的氟西汀溶液,将18mg氟西汀粉末加入12mL灭菌超纯水中并充分混合。为避免其他因素的干扰(例如凝胶剂中常用的成分甘油能够起到改善皮肤屏障受损的作用),本发明实施例以水作为溶剂,测试了局部应用以溶液剂形式的氟西汀对皮肤屏障受损的效果。本领域技术人员应当理解,氟西汀还可以以其他合适的局部制剂(例如喷雾剂、洗剂、凝胶剂、乳膏剂、软膏剂、糊剂和乳剂)的形式或者在其他合适的溶剂中、以合适的剂量应用至皮肤表面。此外,药物应用和实验测试是以双盲方式进行的。所有的实验和程序都得到了批准。
实验过程如图1所示。在实验的第0天,将小鼠背部脱毛。在实验的第1周和第2周,用1%的DNCB刺激第2、3、4和5组的BALB/c小鼠的背部皮肤,每周两次,以建立DNCB诱导的皮肤屏障受损小鼠模型。从第3周到实验结束,用0.5%DNCB来维持刺激,每周两次。DNCB(2,4-二硝基氯苯)是一种半抗原(变应原),其容易穿透皮肤,进入生物体内后,可与上皮蛋白的可溶部分进行共价结合并形成完全抗原。完全抗原使生物体产生致敏淋巴细胞。当DNCB再次进入体内时,致敏的淋巴细胞与其接触后会产生过敏反应。如图6中的Flu-0组显示,小鼠产生皮肤屏障受损、皮损(或皮肤病变,包括红斑、水肿、糜烂、渗出物、鳞屑、干燥等)和抓挠行为(瘙痒)等表现,表明皮肤屏障受损小鼠模型建立成功。在假手术组,整个实验期间没有观察到皮损。
为了研究氟西汀改善皮肤屏障受损中的作用,从第3周到实验结束,将不同浓度的氟西汀溶液(0.375mg/mL、0.75mg/mL、1.5mg/mL)外用在受影响的皮肤区域,每天两次。
局部应用氟西汀改善皮肤屏障受损
皮肤屏障的破坏导致经皮水分流失(TWEL)增加、皮肤水化下降、抗原提呈细胞(例如朗格汉斯细胞)增加,进而引发炎症。根据“由外而内”假说(“outside-in”hypothesis),表皮屏障功能障碍(也可以理解为皮肤屏障受损)是一个关键的前兆,它可以增加表皮的渗透性并导致免疫失衡(例如,Th2应答的增加和大量Th2相关的细胞因子释放,例如IL-13、IL-5、IL-8、IL-10、IL-31、IL-22等),进而导致皮肤炎症性疾病(例如特应性皮炎、慢性荨麻疹、银屑病(牛皮癣)、痤疮等)的发展。除此之外,皮肤屏障受损还可能增加发展哮喘、花粉症以及对食物过敏原的经皮致敏的风险。
为了检测皮肤屏障,在药物干预结束后,检测了DNCB诱导的皮肤屏障受损小鼠模型的TWEL和水分含量。TEWL的测量可用于直接测定皮肤渗透屏障的完整性。
皮肤水分和TWEL检测:药物干预终止后,用多参数皮肤检测仪(CallegariSoftPlus)测量皮肤水分,用MPA10皮肤检测仪(CK Company,Germany)在室温(20~25℃)和受控的湿度(50%~60%)下完成小鼠背部TWEL检测。检测前,每只小鼠都被放置在检测环境中,进行一小时的安静适应。每组的每只小鼠在不同的位置测量三次,取其平均值。
结果如图2A所示,与假手术组(sham:n=6,49.08±4.90)相比,使用DNCB致敏后,小鼠背部皮肤TWEL明显增加(DNCB+Flu-0:n=6,118.52±14.66,p<0.0001vs.sham),而水分水平明显下降(DNCB+Flu-0:n=6,14.98±3.07,p<0.0001vs.sham),这表明小鼠背部皮肤屏障受损的发生。
如图2A所示,局部应用不同浓度的氟西汀后,TWEL随氟西汀浓度的增加,而显著降低(DNCB+Flu-0:n=6,118.52±14.66,p<0.0001vs.sham;DNCB+Flu-0.375:n=6,94.75±12.78,p<0.0001vs.sham,p<0.0001vs.DNCB+Flu-0;DNCB+Flu-0.75:n=6,84.01±8.88,p<0.0001vs.sham,p=0.91vs.DNCB+Flu-0.375;DNCB+Flu-1.5:n=6,71.94±3.71,p<0.0001vs.sham,p=0.48vs.DNCB+Flu-0.75)。此外,随着氟西汀浓度的增加,氟西汀处理组的小鼠的水分含量逐渐增加(图2B)。这些结果表明,局部应用氟西汀可以提高皮肤水合作用,修复受损的皮肤屏障并保护皮肤屏障功能,而健康的皮肤屏障会进一步抑制炎症反应。上述实验结果还反映,局部应用氟西汀可以减少局部细菌(特别是金黄色葡萄球菌)定植,并阻断皮肤变应原的进入。
事实上,发明人还测试了更高浓度的氟西汀溶液对皮肤屏障受损的影响。然而,结果表明,更高浓度的氟西汀溶液(例如2mg/mL、2.5mg/mL、3mg/mL)并不能以浓度依赖性地改善皮肤屏障受损,甚至会刺激和加重皮肤屏障受损。
实施例二
局部应用氟西汀溶液减少小鼠皮肤屏障受损模型的肥大细胞的浸润
据报道,真皮层中肥大细胞的数量与皮肤肿胀和瘙痒呈正相关。因此,本实施例根据病理切片,比较了不同处理组的炎症细胞和肥大细胞在真皮层的浸润情况。
组织学检查:小鼠背部皮肤组织用4%多聚甲醛固定24小时、包埋、包裹、切成5μm薄片、用多聚甲醛脱蜡、然后用梯度浓度的无水乙醇(80%、90%、95%)脱水、以及用苏木精和伊红(H&E)染色。之后,在显微镜下观察皮损的病理变化。接下来,使用由0.5g甲苯胺蓝和100mL蒸馏水组成的甲苯胺蓝染色液对肥大细胞的数量进行计数。冰醋酸分化液包含0.5mL冰醋酸和100mL蒸馏水。然后,将4μm的石蜡组织切片脱蜡至水,用甲苯胺蓝溶液染色10分钟,用蒸馏水洗两次。之后,用冰醋酸分化液进一步处理组织切片约30秒,直到颗粒清晰(由显微镜控制)。用蒸馏水洗两次后,用无水乙醇快速脱水,用纸过滤,用二甲苯使其透明,用中性胶密封。用冰醋酸溶液分化后,肥大细胞颗粒呈紫红色,细胞核呈蓝色。
与假手术组小鼠相比,DNCB处理组的炎症细胞数量明显增加(图3A)。与假手术组小鼠相比,DNCB处理组(DNCB+Flu-0:n=6,84.67±32.52,p<0.0001vs.sham)的炎症细胞和肥大细胞数量显著增加。氟西汀局部应用后,各氟西汀处理组(DNCB+Flu-0.375:n=6,44.67±9.61,p=0.016vs.sham,p=0.014vs.DNCB+Flu-0;DNCB+Flu-0.75:n=6,27.33±7.10,p=0.139vs.sham,p=0.002vs.DNCB+Flu-0;DNCB+Flu-1.5:n=6,22.00±12.29,p=0.253vs.sham,p=0.001vs.DNCB+Flu-0)的肥大细胞数量明显减少,特别是中氟西汀浓度组和高氟西汀浓度组(图3B)。
局部应用氟西汀抑制Th2细胞因子的释放
为了进一步评估氟西汀在抑制炎症反应中的作用,本实施例测量了不同处理组的小鼠皮肤中Th2相关细胞因子的mRNA表达。
测量皮损中IL-5、IL-13和IL-31水平的QT-PCR测定:在实验的最后一天(第29天)收集背部皮肤,并将其放入无RNA的EP管。按照制造商的实验流程,使用Trizol试剂(Invitrogen1,5596018,USA)从组织样本中提取总RNA,然后进行异丙醇沉淀和乙醇洗涤。之后,按照制造商的说明,使用cDNA合成试剂盒(Thermo Fisher Scientific,K1612,USA)和1μg总RNA作为模板进行反转录。使用SYBR Green PCR试剂盒和实时PCR机进行实时定量PCR。引物使用Primer Express软件设计(表1),GAPDH被用作内部对照。采用2^-ΔΔCt方法分析数据。
表1RT-PCR中使用的引物序列
反复局部应用DNCB后,Th2相关细胞因子包括IL-5(DNCB+Flu-0:n=6,3.44±0.18,p<0.0001vs.sham)、IL-13(DNCB+Flu-0:n=6,892.00±123.39,p=0.004vs.sham)和IL-31(DNCB+Flu-0:n=6,102.47±12.87,p=0.013vs.sham)的mRNA表达水平升高,表现出典型的Th2细胞因子极化模式。辅助性T细胞(Th)为免疫系统的其他细胞(例如抗原提呈细胞,如巨噬细胞、树突状细胞和B细胞)提供辅助功能,并对这些细胞的活化和成熟起到重要的作用。CD4+Th细胞有不同的亚群(例如Th1、Th2、Th9、Th17、Th22、Tfh和Treg细胞),每个亚群都由一组特定的细胞因子和转录因子活化,分泌细胞因子并发挥效应功能。Th2细胞通过生成各种细胞因子,来介导针对微生物、变应原(过敏原)和毒素的体液或抗体介导的免疫反应的活化和维持,以及扩大炎症的过程。Th2细胞能够影响抗体生成和过敏反应,还能够调控B细胞IgE类别转换。Th2细胞也被认为是导致过敏性炎症疾病恶化的原因。
与DNCB处理组相比,不同浓度氟西汀治疗后,小鼠皮损中IL-5的mRNA表达水平(DNCB+Flu-0.375:n=6,2.03±0.59,p=0.002vs.sham,p<0.0001vs.DNCB+Flu-0;DNCB+Flu-0.75:n=6,1.84±0.47,p=0.002vs.sham,p<0.0001vs.DNCB+Flu-0;DNCB+Flu-1.5:n=6,1.45±0.41,p=0.002vs.sham,p<0.0001vs.DNCB+Flu-0)均明显降低(图4A)。而IL-13(DNCB+Flu-1.5:n=6,1072.98±119.54,p=0.002vs.sham,p=0.004vs.DNCB+Flu-0)(图4B)和IL-31(DNCB+Flu-1.5:n=6,17.91±2.55,p=0.002vs.sham,p<0.01vs.DNCB+Flu-0)的mRNA表达仅在高氟西汀浓度组显著降低(图4C)。上述结果表明,局部皮肤外用氟西汀可以使得Th2相关的细胞因子(例如IL-5、IL-13和IL-31)在皮损中明显下调并抑制Th2型免疫反应(特别是在高氟西汀浓度组)。
综上所述,氟西汀的局部应用减少了组织中炎症细胞的浸润和肥大细胞的数量,能够改善局部炎症。
局部应用氟西汀抑制血清IgE和TARC水平的升高
为了评估疾病的严重程度,在评估的第29天,用ELISA检测血清中的IgE和TARC(胸腺活化调节趋化因子)水平。
ELISA法测定血清IgE和TARC水平:在室温下以8000g离心5分钟,从全血样本中分离出血清。此后,按照制造商的说明,用IgE(E-EL-M3034)和TARC(E-EL-M0012c)ELISA试剂盒测量血清中的总IgE和TARC浓度。实验进行了两次。
结果显示(图5A),DNCB处理组血清IgE浓度(DNCB+Flu-0:n=6,118.52±14.66,p<0.0001vs.sham)高于假手术组。低氟西汀浓度组(DNCB+Flu-0.375:n=6,8600.00±1252.99,p=0.003vs.sham,p=0.052vs.DNCB+Flu-0)的小鼠的血清IgE浓度出现暂时性升高,但差异非统计学显著。中氟西汀浓度组(DNCB+Flu-0.75:n=6,6869.00±1209.15,p=0.179vs.sham,p=0.215vs.DNCB+Flu-0)和高氟西汀浓度组(DNCB+Flu-1.5:n=6,5622.00±707.11,p=0.612vs.sham,p=0.059vs.DNCB+Flu-0)的血清IgE浓度有下降趋势,与DNCB处理组比较,差异非统计学显著。
与假手术组相比,DNCB处理组(DNCB+Flu-0:n=6,1360.67±79.69,p<0.0001vs.sham)血清TARC浓度显著升高(图5B)。相对于DNCB处理组,不同浓度氟西汀治疗后,小鼠血清TARC水平显著降低(DNCB+Flu-0.375:n=6,958.71±87.48,p=0.150vs.sham,p=0.001vs.DNCB+Flu-0;DNCB+Flu-0.75:n=6,958.00±32.32,p=0.152vs.sham,p=0.001vs.DNCB+Flu-0;DNCB+Flu-1.5:n=6,259.57±46.67,p<0.0001vs.sham,p<0.0001vs.DNCB+Flu-0)。此外,即使是低氟西汀浓度组(DNCB+Flu-0.375:n=6,958.71±87.48,p=0.150vs.sham,p=0.001vs.DNCB+Flu-0),小鼠的血清TARC水平也显著下降,几乎恢复至假手术组水平。据报道,TARC水平与湿疹面积和严重程度指数得分呈正相关,且它还能选择性地控制Th2向炎症损伤处迁移。本实施例发现,与IgE相比,TARC水平以浓度依赖的方式呈现明显的下降趋势,一个可能的解释是,TARC比IgE更敏感。这样的结果与临床症状和病理变化相一致,上述实验结果证明,局部应用氟西汀可以修复皮肤屏障和抑制皮损处的炎症反应,进而抑制全身性的过敏状态和全身性的炎症。
实施例三
本实施例进一步观察了局部应用氟西汀能否减轻皮损,并测量了不同处理组的皮肤厚度和瘙痒感。
皮肤厚度和瘙痒测量:在小鼠被处死前,用游标卡尺测量每只小鼠的皮肤厚度。测量时选择不同的部位,从五个测量值中计算出平均值。在第2周或第4周结束时,在一分钟内计算瘙痒,转动头部,抓挠腹部,洗脸,然后在每个抓痕处进行平面垫材料计数。然后,计算抓痕总数除以小鼠数量,以确定每组的抓痕数量。
从照片上观察,局部应用氟西汀溶液(特别是高氟西汀浓度组)在第29天减轻了皮损(包括红斑、水肿、鳞屑和糜烂等)的严重程度(图6)。
与假手术组(sham:n=6,0.13±0.35)相比,DNCB处理组(DNCB+Flu-0:n=6,4±0.27,p<0.0001vs.sham)显著加重了抓挠行为。而高氟西汀浓度组(DNCB+Flu-1.5:n=6,1.43±1.13,p=0.098vs.sham,p=0.002vs.DNCB+Flu-0)和中氟西汀浓度组(DNCB+Flu-0.75:n=6,2.33±1.86,p=0.58vs.sham,p=0.04vs.DNCB+Flu-0)(而非低氟西汀浓度组(DNCB+Flu-0.375:n=6,3.43±1.40,p<0.0001vs.sham,p=0.46vs.DNCB+Flu-0))显著抑制了DNCB诱导的抓挠行为(即瘙痒感)。低氟西汀浓度组的抓痕数量下降,但差异非统计学显著(图7A)。
此外,DNCB处理组(DNCB+Flu-0:n=6,1.94±0.25,p<0.0001vs.sham)的皮肤厚度相对于假手术组(sham:n=6,0.91±0.14)增加,这表明相对于假手术组,DNCB处理组的表皮增生明显。另一方面,即使在0.375mg/mL的低氟西汀浓度组(DNCB+Flu-0.375:n=6,1.51±0.18,p<0.0001vs.sham,p=0.001vs.DNCB+Flu-0),局部应用氟西汀也可以显著降低皮肤厚度。在高氟西汀浓度组(DNCB+Flu-1.5:n=6,1.27±1.11,p=0.002vs.sham,p<0.0001vs.DNCB+Flu-0)也观察到类似的结果(图7B)。基于上述发现,局部使应用氟西汀能够缓解皮损症状,还能够降低皮肤厚度和瘙痒感。
上述所有实验数据均以平均值±SEM表示。多组平均值的比较采用单因素方差分析和LSD事后检验。显著性水平被设定为P<0.05。
综上所述,出乎意料地,本发明发现局部应用氟西汀能够通过提高皮肤水化程度、缓解皮损症状和瘙痒感、降低局部炎症反应(例如抑制皮损处的Th2炎症反应)、甚至抑制全身性的过敏状态,改善受损的皮肤屏障和皮肤外观。换句话说,氟西汀可以作为一种皮肤外用的局部制剂,应用至由皮肤屏障受损引起的皮肤病症,特别是皮肤炎症性疾病,例如特应性皮炎(AD)、慢性荨麻疹和银屑病等。
特应性皮炎(AD)是一种有代表性的继发于皮肤屏障受损的免疫驱动疾病,其全球累及患者高达2.3亿人,已成为疾病负担最高的皮肤病。皮肤屏障受损造成特应性皮炎患者的对外屏障功能降低、对内保护作用下降,变应原通过表皮进入体内诱发炎症和变应性免疫应答,使得过敏状态持续存在。现有技术主要通过抑制患者的炎症反应,来治疗皮肤炎症性疾病(例如皮质类固醇(TCS)、钙神经元抑制剂(TCI)和PDE-4抑制剂)。然而,越来越多的研究显示,上述药物在长期应用后反而会导致皮肤屏障受损。
氟西汀(商品名为“百忧解”)是一种选择性5-羟色胺再摄取抑制剂(SSRIs),其可以选择性抑制5-羟色胺的消除,缓解患者的心理压力和调节患者情绪,进而实现治疗抑郁症、焦虑症和强迫症等精神疾病。而本发明发现,向皮肤屏障受损处(和/或受由皮肤屏障受损引起的皮肤病症或其相关症状影响的皮肤区域)针对性地局部应用一定剂量的氟西汀,其能够在较短时间内、以较低的剂量通过局部发挥药物效应,不仅能够调节免疫失衡、缓解瘙痒、改善局部和全身炎症,而且还能快速地促进皮肤屏障的改善,从多方面减轻、改善和/或缓解由皮肤屏障受损引起的皮肤病症的外观和主观症状,进而提高患者的身心健康和生活质量。
上面结合附图对本发明的实施例进行了描述,但是本发明并不局限于上述的具体实施方式,上述的具体实施方式仅仅是示意性的,而不是限制性的,本领域的普通技术人员在本发明的启示下,在不脱离本发明宗旨和权利要求所保护的范围情况下,还可做出很多形式,这些均属于本发明的保护之内。
Claims (10)
1.氟西汀或其药学上可接受的盐在制备治疗由皮肤屏障受损引起的皮肤病症的局部制剂中的用途,其特征在于,所述局部制剂用于皮肤外用。
2.如权利要求1所述的用途,其特征在于,所述局部制剂用于降低所述皮肤屏障受损处的经皮水分流失;和/或提高所述皮肤屏障受损处的水合作用。
3.如权利要求1所述的用途,其特征在于,所述局部制剂用于降低炎症反应,所述炎症反应包括所述皮肤屏障受损处和/或全身性的所述炎症反应。
4.如权利要求1所述的用途,其特征在于,所述由皮肤屏障受损引起的皮肤病症包括特应性皮炎、接触性皮炎、湿疹、牛皮癣、脂溢性皮炎、手足皮炎、慢性荨麻疹、痤疮、皮肤干燥症和鱼鳞病中的一种或多种。
5.如权利要求1所述的用途,其特征在于,所述局部制剂用于缓解所述由皮肤屏障受损引起的皮肤病症的相关症状,所述相关症状包括以下中的一种或多种:皮肤敏感、发红、干燥、瘙痒、皮肤粗糙、红斑、肿胀、水肿、糜烂、灼热、渗出物、鳞屑、色素沉着过度和易感染。
6.如权利要求1所述的用途,其特征在于,所述由皮肤屏障受损引起的皮肤病症由变应原致敏导致。
7.如权利要求1所述的用途,其特征在于,所述局部制剂的形式包括喷雾剂、溶液剂、洗剂、凝胶剂、乳膏剂、软膏剂、糊剂和乳剂中的一种或多种。
8.如权利要求1所述的用途,其特征在于,所述局部制剂包含0.375-1.5mg/mL的所述氟西汀或其药学上可接受的盐。
9.如权利要求1所述的用途,其特征在于,所述局部制剂包含0.4mg/mL、0.5mg/mL、0.6mg/mL、0.7mg/mL、0.8mg/mL、0.9mg/mL、1.0mg/mL、1.1mg/mL、1.2mg/mL、1.3mg/mL、1.4mg/mL或1.5mg/mL的所述氟西汀或其药学上可接受的盐。
10.如权利要求1所述的用途,其特征在于,所述氟西汀或其药学上可接受的盐为氟西汀盐酸盐。
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