CN109620820B - 对羟基苯甲酸在制备治疗炎症性肠病药物中的应用 - Google Patents
对羟基苯甲酸在制备治疗炎症性肠病药物中的应用 Download PDFInfo
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Abstract
本发明公开了对羟基苯甲酸在制备治疗炎症性肠病药物中的应用。在剂量明显低于美沙拉嗪的情况下,对羟基苯甲酸可明显抑制葡聚糖硫酸钠诱导的肠炎模型小鼠疾病活动指数评分的升高,改善结肠炎模型小鼠结肠长度缩短,降低小鼠结肠MPO活力,减轻结肠炎模型结肠组织炎性细胞浸润。可知,对羟基苯甲酸可以减轻DSS诱导的炎症性肠病模型小鼠炎症反应,改善炎症性肠病疾病严重程度,可用于制备治疗炎症性肠病的药物。
Description
技术领域
本发明涉及对羟基苯甲酸的应用,具体涉及对羟基苯甲酸在制备治疗炎症性肠病药物中的应用。
背景技术
炎症性肠病(inflammatory bowel disease,IBD)是一种主要累及回肠、直肠、结肠的特发性肠道炎症性疾病,临床表现为腹泻、腹痛,甚至可有血便。炎症性肠病包括溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(crohn’s disease,CD)。溃疡性结肠炎是结肠黏膜层和黏膜下层连续性炎症,疾病通常先累及直肠,逐渐向全结肠蔓延;克罗恩病为非连续性全层炎症,可累及全消化道,最常累及部位为末端回肠、结肠和肛周。UC作为一种典型的炎症性肠病,好发于30-40岁青壮年,且无性别差异,表现为腹泻、腹痛、黏液脓血便等临床症状,多并发肠穿孔、息肉、溃疡等,病程漫长且癌变率高,严重影响患者生活质量和生存。流行病学研究表明,欧洲地区的UC发病率高达505/100000,加拿大地区的发病率为248/100000,美国的发病率为214/100000。随着生活方式、饮食规律的改变,亚洲和中东等地区的UC发病率呈逐年增高的趋势。
目前,药物治疗和手术切除是控制UC的主要方法,常用治疗药物有以下5类:(1)、氨基水杨酸类,如柳氮磺胺吡啶和美沙拉嗪;(2)、糖皮质激素类,如***和二丙酸倍氯米松;(3)、免疫抑制剂,如6-巯基嘌呤和环孢素;(4)、生物制剂,如TNF-α抑制剂英夫利昔单抗;(5)、抗感染药物,如抗菌素甲硝唑和环丙沙星。这些药物主要通过抑制异常的免疫应答,减轻结肠局部炎症,阻止病情进展,但存在疗效不稳定、不良反应多、耐受性差和不适合长期用药或价格昂贵等不足。因此,寻找疗效确切、不良反应少,且质量可控的抗UC药物具有重要的价值。
发明内容
本发明的目的在于提供对羟基苯甲酸在制备治疗炎症性肠病药物中的应用。
申请人通过大量实验发现,在剂量明显低于美沙拉嗪的情况下,对羟基苯甲酸可明显抑制葡聚糖硫酸钠诱导的肠炎模型小鼠疾病活动指数(disease activity index,DAI)评分的升高,改善结肠炎模型小鼠结肠长度缩短,降低小鼠结肠MPO活力,减轻结肠炎模型结肠组织炎性细胞浸润。可知,对羟基苯甲酸可以减轻DSS诱导的炎症性肠病模型小鼠炎症反应,改善炎症性肠病疾病严重程度,可用于制备治疗炎症性肠病的药物。
本发明的目的是通过以下技术方案实现的:
对羟基苯甲酸在制备治疗或预防炎症性肠病药物中的应用。
本发明还提供了一种治疗或预防炎症性肠病的药物,以对羟基苯甲酸为有效成分,含有治疗上有效剂量的对羟基苯甲酸。所述的药物的剂型可以是药学上可接受的剂型,所述的剂型为胶囊剂、片剂、颗粒剂、栓剂、缓释剂等剂型。
优选的,所述的炎症性肠病为溃疡性结肠炎。
优选的,所述的炎症性肠病为DSS诱导结肠炎。
附图说明
图1为对羟基苯甲酸对DSS诱导的UC小鼠DAI评分的影响曲线;其中,normal表示正常组,DSS表示模型组,HHA(20mg/kg)表示对羟基苯甲酸组,Mesalazine(200mg/kg)表示美沙拉嗪组;与正常组比较,##表示p<0.01;与模型组比较,*表示p<0.05,**表示p<0.01。
图2为对羟基苯甲酸对DSS诱导的UC小鼠结肠长度的影响;与正常组比较,##表示p<0.01;与模型组比较,*表示p<0.05,**表示p<0.01。
图3为对羟基苯甲酸对DSS诱导的UC小鼠MPO活力的影响;其中,与正常组比较,##表示p<0.01;与模型组比较,*表示p<0.05,**表示p<0.01。
图4为对羟基苯甲酸对DSS诱导的UC小鼠病理形态学的影响;其中,normal表示正常组,DSS表示模型组,HHA(20mg/kg)表示对羟基苯甲酸组,Mesalazine(200mg/kg)表示美沙拉嗪组。
具体实施方式
下面结合具体实施方式对本发明的技术方案作进一步说明。
动物实验采用2.5%葡聚糖硫酸钠(dextran sulfate sodium,DSS)溶液诱导C57BL/6小鼠构建UC模型,灌胃给予模型小鼠对羟基苯甲酸和阳性药美沙拉嗪,分析对羟基苯甲酸对UC的改善作用。
1.材料
1.1实验动物
SPF级C57BL/6小鼠,雌性,6~8周龄,体重20±2g,购于湖南斯莱克景达实验动物有限公司,许可证号:SCXK(湘)2016-0002,合格证号:SYXK(桂)2013-0001。于温度25±2℃、相对湿度55±10%环境中饲养,自由摄食和饮水。适应饲养一周后使用。
1.2实验试剂
对羟基苯甲酸;美沙拉嗪,上海爱的发制药有限公司,货号:151007;葡聚糖硫酸钠,美国MP Biomedicals公司,货号:160110;髓过氧化物酶(myeloperoxidase,MPO)试剂盒,南京建成生物工程研究所,批号:20170717;TRIzol试剂,美国Invitrogen公司,货号:152104;其它试剂均为市售分析纯,国药集团化学试剂有限公司。
1.3实验仪器
2.实验方法
2.1小鼠结肠炎模型的建立
为考察对羟基苯甲酸对DSS诱导小鼠结肠炎的抑制作用,将小鼠随机分成5组:正常组(normal),模型组(DSS),对羟基苯甲酸(HHA)组(20mg/kg)、美沙拉嗪(Mesalazine)组(100mg/kg),每组8只。正常组自由饮用双蒸水;除正常组外,其余组均自由饮用2.5%DSS 7天,随后自来水饮用3天。
开始造模当日记为d1,记录此时小鼠体重作为初始体重。造模当天开始灌胃给药(0.1mL/10g),每天一次,连续10天。葡聚糖硫酸钠、对羟基苯甲酸、美沙拉嗪均采用双蒸水溶解给药。
2.2疾病活动指数评价
每天观察小鼠精神状态、毛色、大便性状,活动状态和便血等情况,记录小鼠体重、腹泻指数和粪便隐血情况,计算疾病活动指数(DAI),DAI=(体重降低+腹泻指数+粪便隐血)/3。DAI评分标准详见表1。
表1:DAI评分标准
隐血检测:采用邻甲苯胺法,用棉签挑取少许粪便,先滴加邻甲苯胺冰乙酸溶液0.3mL,然后迅速滴加3%过氧化氢溶液0.3mL,2min内显蓝褐色为阳性。
2.3结肠MPO活力测定
称取结肠组织40mg,加入磷酸盐缓冲液(PBS)制备成10%组织匀浆,按照MPO试剂盒说明书,于460nm处测定吸光度(OD),根据公式计算得到MPO含量。计算公式如下:
MPO活力单位/g组织=(测定管OD值-对照管OD值)×2/22.6×取样量(g)。
2.4标本采集
末次给药后1h,自眼底静脉丛采血,4℃静置2h,离心(3500rpm,4℃)15min,吸取上层血清并分装,-80℃冻存备用。于距离***1cm处取出结肠,直尺测量结肠长度并拍照,PBS清洗结肠2次,从靠近直肠端量取结肠0.4cm,置于4%多聚甲醛溶液中固定,剩余结肠-80℃冻存。
2.4结肠组织病理学检查
取固定于4%多聚甲醛溶液(不少于24h)的结肠组织,以5%硫酸钠溶液中和36h,流水冲洗过夜,无水乙醇脱水,石蜡包埋切片,常规脱蜡,经苏木素伊红(H&E)染色,中性树脂封片后于光学显微镜观察肠壁病理组织学变化,具体评分细则如下:(1)肠壁炎症的严重程度,记为1、2和3分,分别代表轻度、中度和重度炎症;(2)病变严重程度,记为1、2和3分,即病变位于黏膜层、黏膜和黏膜下层及透壁性损伤;(3)隐窝损害程度,记为1、2、3和4分,即1/3隐窝损害、2/3隐窝损害、隐窝缺失但表面上皮完整和隐窝表面上皮都缺失。
2.5数据分析
所有数据均以means±S.E.M.表示,组间统计学差异采用SPSS软件中one-wayANONA和Dunnett’s检验。p值小于0.05被认为有显著性差异。
3.实验结果
3.1对羟基苯甲酸对DSS诱导的UC小鼠DAI评分的影响
图1为对羟基苯甲酸对DSS诱导UC小鼠DAI评分的影响,表明:DSS诱导的结肠炎小鼠疾病炎症活动指数DAI逐渐升高,主要表现为体重降低、腹泻和便血。与正常组相比,模型组小鼠DAI评分明显升高(p<0.01);与模型组相比,对羟基苯甲酸组和美沙拉嗪组的DAI明显降低,且对羟基苯甲酸组(p<0.01)对DSS诱导结肠炎的抑制作用强于阳性药(p<0.05)。
3.2对羟基苯甲酸对DSS诱导的UC小鼠结肠长度的影响
图2为对羟基苯甲酸对DSS诱导的UC小鼠结肠长度的影响,表明:与正常组相比,DSS诱导的结肠炎小鼠结肠长度明显缩短(p<0.01)。与模型组相比,灌胃给予对羟基苯甲酸能保护模型小鼠结肠缩短(p<0.01),其抑制结肠缩短的能力强于阳性药(p<0.05)。
3.3对羟基苯甲酸对DSS诱导的UC小鼠MPO活力的影响
图3为对羟基苯甲酸对DSS诱导的UC小鼠MPO活力的影响,表明:与正常组相比,DSS诱导的结肠炎小鼠MPO活力明显增强(p<0.01)。与模型组相比,灌胃给予对羟基苯甲酸明显降低模型小鼠结肠MPO活力(p<0.01),其降低MPO活力的能力强于阳性药(p<0.05)。
3.4对羟基苯甲酸对DSS诱导的UC小鼠病理形态学的影响
由图4可知,正常组小鼠结肠组织无明显病理改变;模型组小鼠结肠组织病变主要累及粘膜层和粘膜下层,炎细胞类型主要为单核巨噬细胞和中性粒细胞,炎症严重区域局部粘膜层全层坏死,形成溃疡。与正常组相比,模型组小鼠结肠组织炎性细胞浸润、隐窝损伤(p<0.01)。与模型组相比,灌胃给予对羟基苯甲酸(p<0.01)明显减轻上述组织病理学改变,其对降低组织病变的作用强于阳性药(200mg/kg,p<0.05)。
4.结论与讨论
在剂量明显低于美沙拉嗪的情况下,对羟基苯甲酸明显改善DSS诱导的UC模型小鼠体重降低,抑制DAI升高,减轻DSS所致小鼠结肠长度缩短,降低模型小鼠结肠MPO活力,同时减少炎性细胞浸润和组织损伤。
Claims (6)
1.对羟基苯甲酸在制备治疗或预防炎症性肠病药物中的应用。
2.根据权利要求1所述的应用,其特征在于所述的炎症性肠病为溃疡性结肠炎。
3.根据权利要求1所述的应用,其特征在于所述的炎症性肠病为DSS诱导的结肠炎。
4.根据权利要求1所述的应用,其特征在于所述的药物的剂型为药学上可接受的剂型。
5.根据权利要求4所述的应用,其特征在于所述的剂型为胶囊剂、片剂、颗粒剂、栓剂。
6.根据权利要求4所述的应用,其特征在于所述的剂型为缓释剂。
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