CN106727541A - 一种治疗耳肿胀的药物组合物 - Google Patents
一种治疗耳肿胀的药物组合物 Download PDFInfo
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Abstract
本发明涉及一种治疗耳肿胀的药物组合物,所述药物组合物包含下式的化合物或其药学上可接受的盐、和药学上可以接受的载体:其中R1独立地选自:H或烷基。本发明药物疗效确切,毒副作用小,能显著缓解耳肿胀炎症,有望研制成为临床上的新药。
Description
技术领域
本发明涉及医药领域,具体的说,本发明涉及一种治疗耳肿胀的药物组合物。
背景技术
炎症是损伤和抗损伤的统一过程。尽管炎性反应过程中,通过实质和间质细胞的再生使受损的组织得以修复和愈合,但损伤因子直接或间接造成组织和细胞的破坏,也会给机体带来损伤。目前的抗炎药物仍存在许多问题,如选择性较差,会引起肠胃道不适,肾衰竭和心功能衰竭等副作用。因此寻找安全有效的抗炎药物,以及选择合适的动物模型评价抗炎药物的药效和机制仍是目前关注的问题。
发明内容
本发明的目的在于提供一种治疗耳肿胀的药物组合物。
为了实现本发明的目的,本发明提供一种治疗耳肿胀的药物组合物,所述药物组合物包含下式的化合物或其药学上可接受的盐、和药学上可以接受的载体:
其中
R1独立地选自:H或烷基;
优选地,R1为CH3。
更优选地,所述药学上可接受的载体为稀释剂、崩解剂、粘合剂、润滑剂、稳定剂或矫正剂。
更优选地,所述药物组合物可以制成散剂、颗粒剂、胶囊剂或片剂。
本发明还提供化合物在制备治疗耳肿胀的药物中的用途,所述化合物具有下列结构:
其中
R1独立地选自:H或烷基;
优选地,R1为CH3。
本发明药物疗效确切,毒副作用小,能显著缓解耳肿胀炎症,有望研制成为临床上的新药。
附图说明
图1是本发明药物对AA致小鼠蛋白渗出量的影响。
图2是本发明药物对LTB4生成量的影响。
图3是组织病理学检查结果。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
实验例1本发明药物的表征
1HNMR(400MHz,DMSO-d6)δppm1.63-1.78(m,4H)1.91(br.s.,4H)2.99(br.s.,2H)3.09-3.21(m,2H)3.46(br.s.,2H)3.58-3.68(m,2H)3.73(s,3H)3.88(s,3H)3.96(s,2H)6.55-6.64(m,2H)6.78(m,J=8.20,1.60Hz,1H)6.89-6.98(m,2H)7.21(t,J=7.83Hz,1H)7.79(dd,J=8.20,1.37Hz,1H)8.01(d,J=1.40Hz,1H)8.34(d,J=8.22Hz,1H)11.62(s,1H);HRMSm/z487.2701(M+H)+。
实验例2本发明药物对于耳肿胀的治疗效果
选取雄性ICR小鼠,根据文献(Young JM,SpiresDA,BedordCJ,etal.The mouseear in flammatory response to topical arachidonicacid[J].Journal ofInvestigative Dermatology,1984,82(4):367-371.)的方法,用磷酸缓冲盐溶液(PBS)配制体积分数为0.5%的依文斯蓝溶液,用0.20μm滤膜过滤除菌。雄性ICR小鼠随机分为4组,分别为模型组,本发明药物高、中、低剂量组。造模前,为了测定蛋白渗出量,先将所有的实验小鼠尾静脉注射0.20mL依文斯蓝溶液。依据分组,将所有实验小鼠右耳耳廓正反两面涂抹20.0μL质量浓度分别为62.50、125.00和250.00mg/mL的本发明药物,即实验小鼠分组I为模型组,II为本发明药物低剂量组(1.25mg/耳),Ⅲ为本发明药物中剂量组(2.50mg/耳),IV为本发明药物高剂量组(5.00mg/耳)。30min后,将所有小鼠右耳耳廓正反面涂20.00μL花生四烯酸(100mg花生四烯酸1mL溶于丙酮)造模,1h后,擦除实验小鼠耳朵残留物,检测小鼠的耳肿胀各项指标。
耳肿胀度的测量
花生四烯酸刺激1h后,小鼠颈椎脱臼处死,剪下双侧耳朵,用直径6mm打孔器双侧同样位置打孔,立即用电子天平称量耳片质量,并用游标卡尺测量耳片厚度。小鼠耳肿胀程度用每只小鼠同位置同面积耳片的质量差(mR-mL)和厚度差(dR-dL)来评价。其中,mR和dR为发炎右耳片的质量及厚度;mL和dL为未发炎左耳片的质量及厚度。
蛋白渗出量的检测
花生四烯酸刺激1h后,小鼠颈椎脱臼处死,剪下双侧耳朵,用直径6mm打孔器双侧同样位置打孔,耳片放在对应的EP管中,加入1mL酰胺,置于55℃水浴中充分震荡24h后,在酶标仪610nm波长处测量光密度值(OD),记作D(610)。耳组织染料渗出液的变化为D(610)R-D(610)L。
本发明药物对小鼠肿胀耳片中LTB4含量测定
LTB4是目前发现的最强效的炎症趋化介质之一,也是一种炎症性疼痛的介质。所以LTA4H(花生四烯酸代谢产物)可以作为很重要的抗炎靶点。药物对LTA4H的影响可以通过对其产物LTB4的测定来判断药物对纯化酶的抑制作用强弱。
将耳片放在EP管中,液氮研碎,加入500μL乙醇震荡混匀后12000r/min离心取上清,用LTB4ELISA试剂盒检测LTB4的含量。
组织病理学分析
先将小鼠耳片完整剪下,用体积分数为10%的福尔马林溶液固定。耳片脱水后石蜡包埋,切片机接近耳根部位切片,进行H&E染色。50×光学显微镜下拍片,观察小鼠耳肿胀程度和炎症细胞浸润聚集情况。
本发明药物对5-LOX(花生四烯酸代谢通路中的关键酶)活性的影响
通过ELISA方法和脂氧化酶抑制剂筛选试剂盒,测定本发明药物对5-LOX的酶活性的抑制作用强弱。在96孔板内,空白对照组加入50.00μL反应缓冲液,100%纯酶活性组加入49.50μL5-LOX纯酶稀释液和0.50μL二甲基亚飒(DMSO),给药组加入49.50μL5-LOX纯酶稀释液和0.50μL溶于DMSO的本发明药物的溶液;然后,每孔加入5μL底物亚麻酸,25℃震荡孵育5min后,加入显色剂色原酮50.00μL/孔,25℃震荡孵育5min后终止反应,在酶标仪上检测D(490)值,计算抑制率为
采用SPSS19.0软件,实验数据用表示,两组比较用t-检验,多组比较用方差分析。P<0.05时表示差异显著。半抑制浓度(IC50)值由半数效应图计得。
本发明药物对花生四烯酸致小鼠耳肿胀度的影响
以耳朵局部涂抹给药方式来评价本发明药物对小鼠耳肿胀的作用,结果见下表。
表1本发明药物对花生四烯酸致小鼠耳质量差的影响
1)表示与模型组比较P<0.05;2)表示与模型组比较P<0.01。
表2本发明药物对花生四烯酸致小鼠耳厚度差的影响
1)表示与模型组比较P<0.05;2)表示与模型组比较P<0.01
从表中看出,局部涂花生四烯酸能引起耳朵发红、肿胀。与模型组相比,本发明药物可以明显减少小鼠耳质量差(表1)及厚度差(表2),并呈一定量效关系,说明本发明药物对耳肿胀程度有明显抑制作用。
本发明药物对花生四烯酸致小鼠蛋白渗出量的影响
蛋白渗出量以伊文思蓝染料渗出量表示。实验结果表明,本发明药物能显著抑制小鼠肿胀耳朵的染料渗出,低、中、高剂量组的抑制率分别为22.13%、41.50%和60.66%,结果见图1。
本发明药物对耳肿胀小鼠耳中LTB4生成量影响
实验结果表明,局部涂花生四烯酸能引起LTB4成量显著升高。本发明药物能显著抑制LTB4生成量,低、中、高剂量组的抑制率分别为65.63%、81.25%和87.50%,见图2。
组织病理学检查结果
在50×光学显微镜下观察,耳组织病理切片结果如图3。由图3可见,模型组花生四烯酸刺激的耳朵出现水肿现象,胶原纤维间隙增大,但是炎性细胞浸润现象不明显。本发明药物处理组耳朵厚度较对照组明显有所减小,水肿程度降低。
本发明药物对5-LOX的影响
为研究本发明药物对5-LOX的作用机制,本实验就本发明药物对花生四烯酸通路中关键酶5-LOX以及COX-2的活性影响进行了检测。结果显示,本发明药物对5-LOX的酶活性有明显的抑制作用,且呈现剂量依赖性,其半数抑制浓度IC50值为12.16μmol/L,结果见下表。本发明药物对COX-2无明显抑制作用。
Claims (6)
1.一种治疗耳肿胀的药物组合物,其特征在于,所述药物组合物包含下式的化合物或其药学上可接受的盐、和药学上可以接受的载体:
其中
R1独立地选自:H或烷基。
2.根据权利要求1所述的治疗耳肿胀的药物组合物,其特征在于,R1为CH3。
3.根据权利要求2所述的治疗耳肿胀的药物组合物,其特征在于,所述药学上可接受的载体为稀释剂、崩解剂、粘合剂、润滑剂、稳定剂或矫正剂。
4.根据权利要求3所述的治疗抑郁症的药物组合物,其特征在于,所述药物组合物可以制成散剂、颗粒剂、胶囊剂或片剂。
5.化合物在制备治疗耳肿胀的药物中的用途,其特征在于,所述化合物具有下列结构:
其中
R1独立地选自:H或烷基。
6.根据权利要求5所述的用途,其特征在于,R1为CH3。
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2011159857A1 (en) * | 2010-06-16 | 2011-12-22 | Bristol-Myers Squibb Company | Carboline carboxamide compounds useful as kinase inhibitors |
CN106414445A (zh) * | 2014-04-22 | 2017-02-15 | 蒙特利尔大学 | 化合物及其在扩增造血干细胞和/或造血祖细胞中的应用 |
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WO2011159857A1 (en) * | 2010-06-16 | 2011-12-22 | Bristol-Myers Squibb Company | Carboline carboxamide compounds useful as kinase inhibitors |
CN106414445A (zh) * | 2014-04-22 | 2017-02-15 | 蒙特利尔大学 | 化合物及其在扩增造血干细胞和/或造血祖细胞中的应用 |
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