CN113509457B - 山椒素在制备治疗湿疹的药物中的用途 - Google Patents
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Abstract
本发明提供了一种山椒素在制备治疗湿疹的药物中的用途。山椒素可以有效改善湿疹皮肤皮损导致浸润性肥厚进而引发的皮层增厚，降低肥大细胞和IgE含量。以山椒素为活性成分，加上药学上可接受的辅料或者辅助性成分制备而成的药物可以治疗湿疹，毒副作用小，为临床提供了一种新的选择。
Description
技术领域
本发明属于生物医药领域，具体涉及山椒素在制备治疗湿疹的药物中的用途。
背景技术
湿疹是临床常见的过敏性炎性反应性皮肤病,病因复杂,一般认为与变态反应有关,临床上皮肤损害以丘疹、水疱、渗出、糜烂、瘙痒为主,，具有剧烈瘙痒、多形损害、反复发作而缠绵难愈等特点；患者皮损部位会出现浸润性肥厚的症状，且体内肥大细胞数量大大增加。目前临床主要采用H1受体拮抗剂、糖皮质激素、免疫调节剂、抗菌药等进行治疗，例如一些临床研究测试了一种涉及阻断过敏原特异性免疫球蛋白E(IgE)的策略，IgE是免疫系统在应对过敏原时所产生的，在花粉、尘螨等环境过敏源的刺激下，过敏患者会产生IgE，随后IgE会与皮肤常驻细胞肥大细胞上的高亲和力受体结合，迅速诱发肥大细胞脱颗粒，释放组胺等瘙痒介质，进而激活感觉神经元，引发神经炎症和瘙痒。目前甚至有研究认为，肥大细胞是引起湿疹的罪魁祸首(Tomoaki Ando,Toshiaki Kawakami.et al.Critical Rolefor Mast Cell Stat5Activity in Skin Inflammation[J].Cell Reports,2014,6(2):)。然而，现有的临床药物虽短期疗效显著,但可能出现痤疮样皮疹、皮肤萎缩、毛细血管扩张、色素沉着、激素依赖性皮炎及嗜睡、口干、乏力、头晕、恶心等不良反应，且停药后易反复发作，甚至造成进一步恶化。因此，探索治疗湿疹的有效方法具有重要意义。
花椒为芸香科(Rutaceae)花椒属植物(Zanthoxylum)的果皮，《中药大辞典》记录其功效:温中散寒，除湿，止痛，杀虫，治积食停饮，心腹冷痛，齿痛，阴痒，疮疥。酰胺类物质是花椒中最具特征的一类生物碱，是花椒麻味来源，目前已分离鉴定超过50种，以山椒素为代表。近年来研究发现，山椒素具有广泛的生物学效应，包括促胃动力、麻醉镇痛、驱虫、抗肿瘤、抗血小板聚集等多种作用。不过，山椒素对湿疹的治疗作用目前还未见报道。
发明内容
本发明的目的在于提供一种山椒素的新用途。
本发明提供了山椒素在制备治疗湿疹的药物中的用途。
进一步地，上述山椒素为羟基-α-山椒素、羟基-β-山椒素、羟基-γ-山椒素、羟基-δ-山椒素、羟基-ε-山椒素、α-山椒素、β-山椒素、γ-山椒素、δ-山椒素、ε-山椒素中的一种或多种。
更进一步地，上述山椒素为羟基-α-山椒素，优选地，所述羟基-α-山椒素的纯度不低于96％。
进一步地，上述药物为治疗皮肤多形性皮损的药物。
更进一步地，上述药物为改善皮层增厚的药物。
更进一步地，上述药物为改善皮肤浸润性肥厚的药物。
进一步地，上述药物为降低肥大细胞数量的药物。
进一步地，上述药物为降低过敏原特异性免疫球蛋白E的药物。
本发明还提供了一种治疗湿疹的药物，它是以山椒素为活性成分，加上药学上可接受的辅料或者辅助性成分制备而成的制剂。
进一步地，上述制剂中山椒素的含量为1％～5％；优选地，所述山椒素为羟基-α-山椒素、羟基-β-山椒素、羟基-γ-山椒素、羟基-δ-山椒素、羟基-ε-山椒素、α-山椒素、β-山椒素、γ-山椒素、δ-山椒素、ε-山椒素中的一种或多种；更优选地，所述山椒素为羟基-α-山椒素，纯度不低于96％。
本发明提供了山椒素在制备治疗湿疹的药物中的新用途，证实了山椒素可以有效改善湿疹皮肤皮损导致浸润性肥厚进而引发的皮层增厚，降低肥大细胞和IgE含量。以山椒素为活性成分，加上药学上可接受的辅料或者辅助性成分制备而成的药物可以治疗湿疹，毒副作用小，为临床提供了一种新的选择。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1是本发明小鼠建模和给药流程示意图。
图2是各组小鼠血清IgE含量结果。
图3是各组小鼠表皮厚度测试结果。
图4是各组小鼠肥大细胞计数结果。
具体实施方式
本发明的山椒素是羟基-α-山椒素，购自成都麦德生科技有限公司，纯度96％。
除另有说明外，本发明所用原料均为已知产品，通过购买市售产品所得。
实施例1、治疗湿疹的药物的配制
以山椒素为活性成分，加上辅料凡士林混匀配置成质量分数1％的药物，并将配置好的药物保存在1ml针管中便于给药，4℃避光保存。
实施例2、治疗湿疹的药物的配制
以山椒素为活性成分，加上辅料凡士林混匀配置成质量分数5％的药物，并将配置好的药物保存在1ml针管中便于给药，4℃避光保存。
实验例1、山椒素治疗湿疹的效果验证
1、实验方法：
1.1、动物造模流程：
使用2，4-二硝基氯苯(DNCB)造模，模型周期共28天。造模前一天用脱毛膏对小鼠背部皮肤脱毛，第1、4天使用高浓度2％DNCB刺激小鼠背部，第7-27天每周三次使用低浓度0.5％DNCB刺激小鼠背部维持皮损，从第14天起连续14天按不同分组予对应治疗，给药方式为0.1ml/只小鼠/天，每只小鼠按摩1分钟便于药物均匀分布于皮损处并促进吸收。第28天处死小鼠(造模和给药流程如图1所示)。
分组如下：(1)山椒素高浓度治疗组(SH-H，造模小鼠采用实施例2制备的含5％山椒素的药物给药)；(2)山椒素低浓度治疗组(SH-L，造模小鼠采用实施例1制备的含1％山椒素的药物给药)(3)糖皮质激素组(Dex，造模小鼠采用凡士林为辅料配制含量为0.1％地塞米松药物进行给药)；(4)模型组(Model，造模小鼠涂抹等量凡士林)；(5)正常小鼠组(Normal，正常小鼠涂抹等量凡士林)
1.2、ELISA：第28天麻醉小鼠后心脏采小鼠全血，静置30分钟以上待血液凝固，后1000g离心15min，分装血清并保存于-80℃至使用时。使用赛默飞IgE Mouse UncoatedELISAKit(Catalog#88-50460-88)进行检测。
1.3、病理切片：第28天处死小鼠后取小鼠背部皮损处皮肤组织在10％甲醛溶液中固定过夜，冲洗后梯度乙醇脱水，二甲苯透明，浸蜡包埋；使用切片机切取4μm厚度切片，将切片贴于载玻片上，染色前置于60℃烘箱预热，染色前二甲苯脱蜡处理。
HE染色：苏木素染色5分钟，水洗2-3次，盐酸酒精分化5-7秒，水洗2-3次，氨水返蓝1分钟，水洗2-3次，75％乙醇短暂浸泡，伊红染色45秒，水洗2-3次。镜下检查染色情况，无水乙醇脱水1分钟，自然干燥后封片。
甲苯胺蓝染色：甲苯胺蓝染色10分钟，水洗2-3次镜下检查染色情况，无水乙醇脱水1分钟，自然干燥后封片。
采图、统计：HE染色切片每张随机选取三个视野测量表皮厚度，结果用平均值表示；甲苯胺蓝染色切片每张随机选取3个400X视野，并分别计数肥大细胞，结果用平均值表示。
2、实验结果：
小鼠血清进行100倍稀释后检测IgE的ELISA结果(图2)显示，与模型组相比山椒素治疗的实验组小鼠血清IgE水平均有下降趋势，且下降程度与山椒素浓度成正比。
HE染色病理切片中对小鼠表皮厚度进行测量后的统计结果(图3)，显示，与模型组相比山椒素组表皮厚度均有下降趋势，且下降程度与山椒素浓度成正比。
肥大细胞计数的统计结果(图4)显示，与模型组相比，山椒素组表皮中肥大细胞数量均有下降趋势，且下降程度与山椒素浓度成正比。
上述结果说明，山椒素具有优异的改善湿疹所引起的肥大细胞数量上升、IgE水平升高的作用，并且能够改善湿疹皮肤皮损导致浸润性肥厚而引发的皮层增厚。
在整个给药过程中，山椒素组的小鼠没有出现明显的不良反应，说明山椒素不会引起明显的毒副作用。
综上，本发明提供了一种本发明提供了一种山椒素在制备治疗湿疹的药物中的用途。山椒素可以有效改善湿疹皮肤皮损导致浸润性肥厚而引发的皮层增厚，并且降低肥大细胞和IgE含量。以山椒素为活性成分，加上药学上可接受的辅料或者辅助性成分制备而成的药物可以治疗湿疹，毒副作用小，为临床提供了一种新的选择。
Claims (7)
1.羟基-α-山椒素作为唯一活性成分在制备治疗湿疹的药物中的用途。
2.如权利要求1所述的用途，其特征在于，所述羟基-α-山椒素的纯度不低于96%。
3.如权利要求1所述的用途，其特征在于，所述药物用于治疗皮肤多形性皮损。
4.如权利要求3所述的用途，其特征在于，所述药物用于改善皮层增厚。
5.如权利要求4所述的用途，其特征在于，所述药物用于改善皮肤浸润性肥厚。
6.如权利要求1-5任一项所述的用途，其特征在于，所述药物用于降低肥大细胞数量。
7.如权利要求1-5任一项所述的用途，其特征在于，所述药物用于降低过敏原特异性免疫球蛋白E。
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