CN105496996A - 绿原酸在制备治疗银屑病的药物中的用途 - Google Patents
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Abstract
本发明提供了绿原酸在制备治疗银屑病的药物中的用途。绿原酸是小分子化合物，为生物反应调节剂，着重于整体调节，对于重建免疫功能自稳状态有良好作用，且对肝肾无损害作用，可长期使用，对机体不产生毒副作用，安全有效，复发率低，提高患者的生活质量，对银屑病有显著的疗效，对寻常型银屑病、脓疱型银屑病作用尤为明显，故绿原酸治疗银屑病有广阔的应用前景。
Description
技术领域
本发明涉及绿原酸在制备治疗银屑病的药物中的用途。
背景技术
银屑病俗称“牛皮癣”，是一种常见的并易复发的慢性炎症性皮肤病，以云母状鳞屑、红膜症、点状出血为临床特征，在我国的发病率约为0.123％。近年来,银屑病发病呈上升趋势，其初期有明显的季节性，呈冬重夏轻，无论男女老幼皆可发病，目前病因未明，尚缺乏有效的治疗方法。
银屑病目前分为4型，寻常型银屑病、关节病型银屑病、红皮病型银屑病和脓疱型银屑病，其中寻常型银屑病占99％以上。寻常型银屑病为普通型银屑病，而其他三型称为特殊型银屑病。根据历代中医名家经验总结,寻常型银屑病一般分为4型：即血热型(血热风燥型)，血虚型(血虚风燥型)，血燥型，血瘀型(瘀滞肌肤型)；特殊型银屑病中，脓疱型一般辨证为脓毒型(湿热蕴毒型)，红皮病型为毒热型(血热毒盛型)，关节型为寒湿型或风湿痹阻型。
寻常型银屑病的主要临床表现为：白色麟屑、发亮薄膜和点状出血。主要病理表现为：角化不全，在角层内或角层下，可见由中性粒细胞构成的小脓肿(Munro小脓肿)，颗粒层变薄或消失。棘层增厚，表皮突延长。真皮乳头部血管扭曲扩张，管壁轻度增厚。真皮上部轻度到中度炎症细胞浸润。寻常型银屑病较为常见，大约占90％以上。
脓疱型银屑病是银屑病中病情较为严重的一种类型,分泛发性银屑病及局限性银屑病。临床上以周身泛发红斑基础上粟粒大小的无菌性脓疱为特征，常伴有高热及白细胞升高和低蛋白血症，甚至可以危及生命。本型在临床上较少见，约占银屑病人的0.77％。
银屑病组织病理为表皮角质细胞不能完全成熟，细胞束之间充满空气，并折射光线成为临床上所见的银白色云母状鳞屑；真皮内的乳头水肿胀大突入表皮接近角质层，临床上搔刮鳞屑可损伤乳头血管而出现点状出血。西医认为，银屑病的发生主要与自身免疫、代谢及内分泌功能紊乱有关，而气候变化、情绪波动、感染、外伤等为诱发因素。
银屑病发病机制复杂，目前尚未完全得以阐明，其发病机制大致可以概括为：在一定遗传背景的基础上，多种致病因子刺激机体免疫系统引起以T细胞为主的免疫系统功能紊乱，炎症细胞移行到表皮并在局部浸润，造成局部炎症和角质形成细胞异常增生，最终导致银屑病病理改变的发生。
银屑病是一种常见的以角质形成细胞过度增生、炎症细胞浸润和新生血管形成为主要病理改变的慢性炎症性皮肤病，为皮肤科常见病、多发病。本病病因不明，治疗困难，尚无法完全根除，目前西药多使用维A酸及免疫抑制剂治疗该病，其在控制银屑病活动方面具有优势，但存在不良反应多、停药后复发率高等问题。
发明内容
本发明的技术方案是提供了绿原酸的新用途。
本发明绿原酸在制备治疗银屑病的药物中的用途。
其中，所述的药物是以有效量的绿原酸为活性成分，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。所述的药物是治疗寻常型银屑病、脓疱型银屑病的药物。
其中，所述的药物制剂中每制剂单位含有绿原酸1～3000mg。
其中，所述的药物制剂中绿原酸的使用剂量为10～40mg/kg。
其中，所述的药剂是口服制剂、外用制剂或者注射剂。
银屑病是一种由多基因遗传决定的、多环境因素刺激诱导的免疫异常性慢性炎症性增生性皮肤病，在世界范围内自然人群患病率为0.1％-3％，我国患病率为0.123％，年发病率为0.1％。尽管该病不危及人的生命，但其病程长且顽固难治，严重者可发生致残性银屑病性关节炎、红皮病型银肩病，甚至累及眼、肝脏、肾脏、心血管、肺等器官，从而严重影响患者的生活质量。有些患者可出现心理障碍如羞愧、紧张、焦虑、忧郁等，不愿参加社交活动，影响日常生活，给患者身体和心理带来极大的痛苦。由于该病反复发作，常需反复治疗，因而给患者及其家庭带来沉重的经济负担。目前银屑病无法治愈，传统的治疗除中药外多为免疫抑制剂及维A酸类药物，长期应用这些药物易产生依赖性及肝肾损害等严重的副作用。
绿原酸是小分子化合物，为生物反应调节剂，着重于整体调节，对于重建免疫功能自稳状态有良好作用，且对肝肾无损害作用，可长期使用，对机体不产生毒副作用，安全有效，提高患者的生活质量，对银屑病有显著的疗效，尤其对寻常型银屑病和脓疱型银屑病作用尤为明显，故绿原酸治疗银屑病有广阔的应用前景。
附图说明
图1空白组
图2模型组
图3阳性组
图4绿原酸低剂量组
图5绿原酸高剂量组
图6各组豚鼠耳部银屑病样病理变化Baker评分(注：与空白组比较，**P<0.01；与模型组比较，##P<0.01。)
具体实施方式
试验例1本发明绿原酸治疗银屑病的药效试验(寻常型银屑病模型)
实验研究：
1.材料
1)动物
雄性豚鼠，体质量350-400g，四川大学试验动物中心提供。动物级别：一级，许可证号：第10号。
2)药品与试剂
阿维A胶囊，购自重庆华邦制药股份有限公司，批号：2013010
绿原酸，四川九章生物科技有限公司提供，批号：130601
5％心得安原料100g，湖北康宝泰精细化工有限公司，批号20130525
乳剂基质由四川大学华西药学院制剂室提供
2.实验方法
1)模型制备及分组
豚鼠60只，适应性饲养1周后开始实验，将豚鼠双耳去毛，随机分为空白组和实验组。空白组12只，实验组48只。实验组用5％心得安乳剂均匀涂于豚鼠双侧耳背，空白组涂抹空白基质，每次涂抹厚度约1.0mm，4次/d，共14天，使其产生寻常型银屑病样病理改变。14天后，空白组取2只、实验组取4只用于病理检测，结果显示豚鼠耳组织出现角化不全及角化过度，颗粒层变薄，炎细胞浸润，真皮浅层血管扩张，乳突突出，提示造模成功。将所剩实验组44只豚鼠根据体质量和造模情况用随机数字表法分为4个组，分别是模型组、阳性组、绿原酸低剂量组、绿原酸高剂量组，每组11只。
2)给药
空白组和模型组给予0.9％氯化钠溶液；阳性药对照组给予阿维A胶囊混悬剂2.25mg/kg，灌胃量均为每次1mL/100g，2次/d；绿原酸低剂量组肌肉注射给予20mg/kg，绿原酸高剂量组肌肉注射给予40mg/kg，容量为0.2ml/10g，1次/d。
3)取材及处理
给药14d后取材，腹腔注射12％水合氯醛，0.35mL/100g，麻醉后，腹主动脉取血处死，剪取豚鼠双耳组织，固定于10％甲醛溶液中。取豚鼠耳组织，石蜡包埋，切片，常规HE染色，中性树胶封片。光学显微镜下观察耳部病理变化，在10×20视野下观察并拍照。参照Baker法进行组织病理积分评估：角质层有Munro小脓肿计2.0分；过度角化0.5分；角化不全1.0分；颗粒层变薄或消失计1.0分；棘层肥厚计1.0分；皮突延长、基底层迂曲起伏，根据轻、中、重程度分别计0.5、1.0、1.5分；真皮层单一核及多形核细胞浸润，根据轻、中、重程度分别计0.5、1.0、2.0分；乳突突出明显计0.5分；真皮浅层毛细血管扩张计0.5分。
4)对肝功肾功能的影响
处死豚鼠前，经腹腔静脉抽血，采用酶法检测尿素氮和肌酐，采用速率法检测谷丙转氨酶和谷草转氨酶。
3.统计学方法
所有数据均用SPSS13.0统计软件处理，实验结果计量资料用x±s表示，以P<0.05为差异具有统计学意义。多样本均数比较采用方差分析。
4.结果
1)光镜观察结果显示，空白组角质层薄，呈网状交织，几乎无颗粒层清晰，约1-2层；棘层细胞3-5层；基底层为单层柱状细胞，表皮突平坦；真皮层未见浅层毛细管扩张，少量分布淋巴细胞。模型组可见角化过度，角化不全，颗粒层变薄或消失，棘层肥厚，真皮毛细血管扩张等现象，还可见真皮层有轻中度炎细胞浸润。给药后，阳性组和绿原酸组，其皮损组织病理有明显改善。豚鼠耳部的病理切片见图1-图5，各组豚鼠耳部银屑病病理变化Baker评分见图6。
统计结果显示，空白组、各个给药组与模型组相比，Baker评分数具有显著性差异(P<0.01)，提示造模成功，各个给药组对改善豚鼠银屑病样病变有效。阳性组与绿原酸高、低剂量组评分无显著性差异。绿原酸低剂量组评分优于高剂量组，量效关系不呈剂量依赖型。各个给药组光镜下观察可见过度角化和角化不全现象减轻，颗粒层增加，棘层变薄，炎性细胞浸润程度降低，提示绿原酸能够治疗银屑病。
2)对肝功肾功能的影响
单因素方差分析显示，阳性对照组尿素氮、血肌酐、谷丙转氨酶(ALT)、谷草转氨酶(AST)明显高于其他各组(P<0.05)，见表1。提示绿原酸对肝肾功能具有保护作用，安全性好。
表1绿原酸对豚鼠肝肾功的影响
注：与空白组比较，*P<0.05。
试验例2本发明绿原酸治疗银屑病的药效试验(脓疱型银屑病)
实验研究：
1.材料
1)动物
昆明种小鼠，体质量18-22g，四川大学试验动物中心提供。动物级别：一级，许可证号：第10号。
2)药物
绿原酸，四川九章生物科技有限公司提供，批号：130601
2.实验方法
1)动物分组
昆明种小鼠随机均分为3组。空白对照组：根据体重每天用0.5ml左右的花生油灌胃；绿原酸高剂量组(20mg·kg-1)，各鼠腹腔注射0.4ml/20g；绿原酸低剂量组(10mg·kg-1)、各鼠腹腔注射0.4ml/20g。观察时相点：未给药时(0天)，给药后第1、2、4、6天。
2)实验方法
将一块1cm2的无菌明胶海绵在0.75％酵母聚糖A中浸泡30min后，手术置入小鼠的腹膜腔中，并给予正常喂饲。术后24小时，断颈处死同一时相点的5只小鼠，取出明胶海绵，分别置于0.5ml的细胞洗脱液中37℃孵育30min，以0.01mol/LPBS0.5ml分别漂洗明胶海绵3次，收集洗脱液，过40μm尼龙筛网后离心定容至0.5ml，以全自动血细胞仪对上述洗脱液进行细胞分类计数，读取多形核白细胞(PMN)的数量。
3.结果
绿原酸不同剂量组在不同时相点的PMN迁移数量的比较见表2。绿原酸不同剂量组间PMN迁移数量有显著性差异(P<0.01)，同组内各时间点PMN迁移数量也有显著性差异(P<0.01)。
表2绿原酸不同剂量组在不同时相点的PMN迁移数量(×109/L)
4.结论
PMN在脓疱型银屑病的发病中具有十分重要的作用。脓疱型银屑病患者的脓疱消退的同时伴有PMN趋化活性的显著减低，如果药物能够抑制正常PMN的趋化活性，说明药物可通过抑制PMN趋化活性从而具有治疗脓疱型银屑病的作用。
上述实验结果表明，绿原酸可以显著抑制正常小鼠PMN的趋化活性，绿原酸高剂量组对小鼠PMN趋化活性的抑制作用较低剂量组更强。绿原酸可抑制脓疱型银屑病患者PMN表面黏附分子的表达，从而绿原酸在治疗脓疱型银屑病方面具有良好功效。
Claims (6)
1.绿原酸在制备治疗银屑病的药物中的用途。
2.根据权利要求1所述的用途，其特征在于：所述的药物是治疗寻常型银屑病、脓疱型银屑病的药物。
3.根据权利要求1或2所述的用途，其特征在于：所述的药物是以有效量的绿原酸为活性成分，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。
4.根据权利要求3所述的用途，其特征在于：所述的药物制剂中每制剂单位含有绿原酸1～3000mg。
5.根据权利要求4所述的用途，其特征在于：所述的药物制剂中绿原酸的使用剂量为10～40mg/kg。
6.根据权利要求3-5任意一项所述的用途，其特征在于：所述的药剂是口服制剂、外用制剂或者注射剂。
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