CN115845003B - 一种中药组合物在制备治疗关节炎药物中的应用 - Google Patents
一种中药组合物在制备治疗关节炎药物中的应用 Download PDFInfo
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Abstract
本发明属于中药技术领域,具体公开了一种中药组合物在制备治疗关节炎药物中的应用,本发明所述中药组合物由黄芪、金银花、黄柏、苍术、薏苡仁、玄参、当归、白芍、甘草、水蛭、全蝎、蜈蚣12味药材制成。药效学试验数据表明,本发明中药组合物具有清热散结、化瘀止痛的功效,通过下调痛风性关节炎小鼠关节组织炎症因子IL‑1β、IL‑6、TNF‑α,降低小鼠踝关节肿胀度,从而改善小鼠异常步态,同时可提高小鼠的热痛阈值,减缓关节的疼痛。本发明具有作用全面,毒副作用低,治疗效果确切的特点,为临床治疗痛风性关节炎提供了新选择。
Description
技术领域
本发明属于中药技术领域,具体涉及脉络舒通颗粒的新用途,特别是脉络舒通颗粒在制备治疗关节炎药物中的应用。
背景技术
痛风性关节炎(Gouty Arthritis,GA)是由于嘌呤代谢紊乱、尿酸***减少所引起的疾病,临床表现为反复发作的关节疼痛,累及关节以第一跖趾关节最多见,一般下肢多于上肢,小关节多于大关节,严重者痛风石形成可出现关节致残、尿酸盐肾病、尿酸性泌尿系结石,甚至肾功能不全等。痛风性关节炎具有发作急骤,疼痛剧烈,病情反复特点,日久可导致关节畸形,影响功能活动。
目前痛风性关节炎的治疗方法主要是饮食控制、物理疗法、口服药物、外科手术等。临床针对现代医学治疗本病急性发作期,常常采用非甾体类抗炎药、秋水仙碱、糖皮质激素等,但上述药物均存在不同程度的副作用,包括胃肠道不适、溃疡、肝肾损害、神经毒性和免疫抑制等,亦或价格昂贵。因此,有必要寻找新的有效、安全的治疗痛风性关节炎的药物,以增加痛风性关节炎患者的用药选择。
痛风性关节炎在中医临床上属于“痹证”、“痛风”、“白虎历节风”范畴。关于痹证的病因病机早在《素问·痹论》就提出:“风、寒、湿三气杂至,合而为痹”。其病机主要是湿热、浊毒兼外感,加之平素过食膏粱厚味或嗜酒,导致湿热内蕴,郁而化为浊毒,流注于关节、肌肉、骨骼,气血不通,久则成淤,不通则痛,出现关节的红、肿、热、痛。痛风性关节炎以肝肾亏虚、脾运失调为本,风寒湿热、痰浊、瘀血痹阻经脉为标。现代中医学者大多认为肝、脾、肾功能失调,痰、湿、热、瘀、毒阻滞,气血不畅,经脉闭阻而发为本病。根据中医急则治标,缓则治本原则,痛风性关节炎发作期应以清热利湿、化瘀止痛为主。
本发明中药组合物颗粒是治疗血栓性静脉炎的Ⅰ类中药新药,商品名称为脉络疏通颗粒,其处方及制备方法已获得中国发明专利(授权公告号:CN1201787C),具有清热解毒、化瘀通络、祛湿消肿之功效,用于湿热瘀阻脉络所致的血栓性浅静脉炎,非急性期深静脉血栓形成所致的下肢肢体肿胀、疼痛、肤色暗红或伴有条索状物。处方由黄芪、金银花、黄柏、苍术、薏苡仁、玄参、当归、白芍、甘草、水蛭、蜈蚣、全蝎12味中药组成,融合了具有清热祛湿功能的四妙散,具有清热解毒、活血止痛功能的四妙勇安汤,具有解毒搜剔、止痉散结作用的止痉散,具有缓急解挛、和营止痛作用的芍药甘草汤以及具有益气生血功能的当归补血汤等治疗血栓性疾病的名方,其承袭了诸方之优点,弥补了原方之不足,相得益彰,左右兼顾。
发明内容
为了丰富临床治疗痛风性关节炎用药选择,本发明的目的在于提供一种中药组合物在制备治疗关节炎药物中的应用。
本发明的目的是通过如下的技术方案实现的。
一种中药组合物在制备治疗关节炎药物中的应用,所述中药组合物由如下的中药组分制成:黄芪、金银花、黄柏、苍术、薏苡仁、玄参、当归、白芍、甘草、水蛭、全蝎、蜈蚣。
优选地,所述关节炎是指非化脓性关节炎。
优选地,所述非化脓性关节炎是指非特异性炎症关节炎。
进一步地,所述的非特异性炎症关节炎是指痛风性关节炎。
优选地,所述的中药组合物为脉络疏通颗粒。
“脉络舒通颗粒(国药准字Z19991025)”是由鲁南厚普股份有限公司研发生产的用于血栓性静脉炎治疗的中成药,该药由黄芪、金银花、黄柏、苍术、薏苡仁、玄参、当归、白芍、甘草、水蛭、全蝎、蜈蚣12味原料药物制成。方中黄芪、薏苡仁、当归、白芍具有益气固表、健脾补血的功效,金银花、黄柏、玄参、苍术具有清热燥湿、泻火解毒、消炎退肿的功效,全蝎、蜈蚣具有熄风止痉、攻毒散结、通络止痛的功效,水蛭具有破血逐瘀、通经的功效。诸药配合,奏清热利湿,通络止痛,滋补肝肾之功效。
本发明在脉络舒通颗粒治疗静脉炎及静脉曲张的基础上,进行了大量深入的研究,意外发现脉络舒通颗粒对于关节炎有良好治疗效果,尤其是对痛风性关节炎具有显著的治疗作用,为临床治疗提供了一种新选择。
药效学研究表明,本发明中药组合物具有清热散结、化瘀止痛的功效,是治疗痛风性关节炎的有效处方,通过下调小鼠关节组织炎症因子IL-1β、IL-6、TNF-α,降低小鼠踝关节肿胀度,从而改善小鼠异常步态,同时可提高痛风性关节炎小鼠的热痛阈值,减缓受试关节的疼痛。
附图说明
图1为脉络舒通颗粒对痛风性关节炎小鼠踝关节肿胀度的影响(n=10)
与正常对照组比较:P<0.05用“#”表示;与模型对照组比较:P<0.05用“*”表示。
具体实施方式
为验证本发明脉络舒通颗粒治疗痛风性关节炎的功效,发明人开展了相应的药效学试验研究。需要说明的是,本发明药效学试验研究所选取的药品为本发明具有代表性的配方及其制备方法所得的药品。本发明所包含的其它配方及制备方法所得药品所涉及的试验及其结果,限于篇幅,在此不一一穷举。
试验例1脉络舒通颗粒对痛风性关节炎模型小鼠的治疗作用
1材料
1.1实验动物及饲料60只SPF级7~8周龄健康雄性C57BL/6小鼠,雌雄各半,体重(22±2)g,由鲁南制药集团股份有限公司提供,实验动物许可证号:SYXK(鲁)2018-0008。实验前在清洁级动物实验室适应性饲养1周,雌雄分开,室温20-25℃,相对湿度40%-60%,自然光照,自由摄食、饮水。
1.2试剂及药品脉络舒通颗粒(批准文号:国药准字Z20090031,鲁南厚普制药有限公司生产);秋水仙碱片(国药准字H53021389,昆明制药集团股份有限公司生产);白细胞介素-1β(IL-1β)、IL-6以及肿瘤坏死因子-α(TNF-α)的ELISA试剂盒均购自上海熹垣生物科技有限公司;尿酸钠购自上海源叶生物科技有限公司;
2方法
2.1分组与造模适应性培养一周后,应用随机数字表法将小鼠随机分为6组,分别为正常对照组、模型对照组、秋水仙碱阳性对照组(简称“阳性对照组”)、脉络舒通颗粒高剂量组(简称“试验高剂量组”)、脉络舒通颗粒中剂量组(简称“试验中剂量组”)和脉络舒通颗粒低剂量组(简称“试验低剂量组”),每组10只,雌雄各半。除正常对照组的其余各组小鼠吸入异氟烷约5s达到全身麻醉效果后,用灭菌胰岛素注射器吸取50mg·mL-1的尿酸钠混悬液25μL,向小鼠右踝关节内侧成30°方向注入到踝关节,关节腔对侧鼓起提示造模成功。此外,正常组小鼠按上述方法注射等体积的无菌生理盐水。
2.2给药造模成功后,根据《中药新药临床研究指导原则》中附录的不同动物的剂量折算系数进行剂量折算,其中阳性对照组给与药物剂量为秋水仙碱0.45mg/kg/d,试验高剂量组、试验中剂量组和试验低剂量组给予药物剂量分别为脉络舒通颗粒高、中、低剂量组(10g/kg/d、5g/kg/d、2.5g/kg/d),正常对照组、模型对照组则给予等体积生理盐水灌服,每日1次,连续给药4d,观察小鼠的相关症状及指标。
2.3检测指标及方法
(1)一般状态:观察小鼠的体质量、饮食、尿量、毛色及精神状态等。
(2)踝关节肿胀度变化:向小鼠右后踝关节注入尿酸钠混悬液或等体积的生理盐水后,用黑色记号笔在对侧鼓起的关节部位做标记,用于后续测量定位。用数显游标卡尺于造模前(0h),造模后第4、8、24、48、72h测量做好标记的关节的直径,重复测定3次取平均
值,并计算肿胀度变化。肿胀度=造模后某一时刻的关节直径–造模前的关节直径
(3)小鼠步态分析:给药完成后,按Coderre等方法对大鼠步态进行评分观察。评分标准:0级为正常行走,双足均匀着地;Ⅰ级为轻度跛行,受试下肢略有弯曲;II级为中度跛行,受试下肢刚触及地面;Ⅲ级为重度跛行,受试下肢离开地面,三足着地行走。
(4)热缩足反射潜伏期的测定:通过测定小鼠的热缩足反射潜伏期来测定模型大鼠的热痛阈。将玻璃箱置于玻璃板上,受试大鼠提前在箱中适应5min并安静后,用热刺激仪照射小鼠足底。落在足底的光圈照射大鼠左后爪足底,从照射开始至出现抬足回避时为热缩足反射潜伏期(PWL)。为防止组织损伤,将照射强度设置为30%,自动切断时间设置为30s。每只小鼠重复测定3次,每次最少间隔3min,取平均值为热刺激反应潜伏期并作为定量指标。
(5)关节组织炎症因子水平检测:实验结束后,使小鼠吸入过量异氟烷致死。以右踝关节为中心,剪取1cm关节组织,小心剔除皮毛和肌肉,置于含有1mL生理盐水的试管中,破碎关节,置于冰水中超声15min,3000r·min-1离心15min,上清液保存于-20℃冰箱中,用于后续检测。采用ELISA试剂盒检测关节组织中IL-1β、IL-6以及TNF-α的含量。
(6)测定小鼠脾脏和肾脏指数:处死小鼠后,迅速摘取小鼠脾脏和肾脏,电子天平精确称取小鼠脾脏和肾脏脏器质量,计算小鼠脾脏和肾脏的脏器指数。
脏器指数=脏器质量(mg)/小鼠体重(g)
2.4统计学处理采用SPSS 22.0统计学软件进行分析,实验数据以“均数±标准差”的形式表示。多组间比较采用单因素方差分析,以P<0.05表示差异具有统计学意义。
3结果
3.1各组小鼠一般状态观察
给药结束后,正常对照组小鼠全身毛色黝黑浓密且富有光泽,四肢行走情况正常,对外界感觉灵敏,饲养过程中进食量和体质量逐渐增加,未见腹泻、活动量下降等情况。与正常对照组相比,其余各组小鼠体质量增加缓慢,精神萎靡,毛色干枯发黄,小鼠出现关节红肿,局部皮肤温度增高、舔足现象,行动缓慢,摄食及饮水次数也明显减少,表明痛风关节炎小鼠造模成功,不同给药组小鼠精神状态有所差异。
3.2踝关节肿胀度变化
实验结束时,通过拍照记录各组的关节肿胀情况。注射尿酸钠混悬液后,痛风性关节炎模型小鼠踝关节明显红肿,给予秋水仙碱和脉络舒通颗粒灌胃后,小鼠红肿情况明显改善。从肿胀度数据结果看,与正常对照组相比,模型对照组小鼠踝关节肿胀度显著升高(P<0.05);与模型对照组相比,阳性对照组和试验高、中、低组小鼠关节肿胀度显著降低 (P<0.05),结果见图1。
3.3小鼠步态分析
通过观察发现,与正常对照组相比,模型对照组小鼠步长减小、步宽增大,活动明显减少,行动时出现不同程度的跛行,步态有显著差异(P<0.001);与模型对照组相比,阳性对照组、试验高、中、低剂量组小鼠步态明显得到改善(P<0.001),结果见表1。
表1对痛风性关节炎小鼠模型步态变化的影响(n=10)
3.4热缩足反射潜伏期的测定
与正常对照组相比,造模后模型对照组与各给药组小鼠的热痛阈与造模前比较明显降低(P<0.05)。随着造模时间的变化,模型对照组热痛阈值呈现先下降后上升的趋势,并在 24h达到峰值。与正常对照组比较,模型对照组在造模后的各时间点上热痛阈值显著下降 (P<0.05);与模型组比较,阳性对照组、试验高、中剂量组小鼠在造模后热痛阈值有显著性差异(P<0.05),结果见表2。试验结果说明脉络舒通颗粒能显著提高痛风性关节炎小鼠的热痛阈值,减缓受试关节的疼痛。
表2对痛风性关节炎小鼠模型热痛阈的影响(n=10)
注:与正常对照组比较:P<0.05用“△”表示;与模型对照组比较:P<0.05用“*”表示。
3.5关节组织炎症因子水平检测
小鼠注射尿酸钠后刺激巨噬细胞释放多种炎症介质,如IL-1β、IL-6和TNF-α等,从而诱发痛风性关节炎发作。与正常对照组相比,模型对照组小鼠关节组织中IL-1β、IL-6和TNF-α含量明显升高(P<0.05);与模型对照组比较,试验高、中、低剂量组和阳性对照组能显著降低关节组织中IL-1β、IL-6和TNF-α含量(P<0.05),结果见表3。
表3对痛风性关节炎小鼠关节组织炎症因子的影响(n=10)
注:与正常对照组比较:P<0.05用“△”表示;与模型对照组比较:P<0.05用“*”表示。
试验结果表明脉络舒通颗粒可以抑制炎性因子IL-1β、IL-6和TNF-α的释放,降低小鼠体内炎症反应。
3.6小鼠脾脏和肾脏指数的测定
既往研究发现痛风与脾、肾功能密切相关,痛风易引发肾小球萎缩、肾小管扩张及肾间质纤维化,导致湿浊内生,痰浊阻滞经络。与正常对照组相比,模型对照组小鼠脾脏指数明显升高,肾脏指数明显降低(P<0.05);与模型对照组比较,试验高、中、低剂量组和阳性对照组小鼠脾脏指数明显降低,肾脏指数明显升高(P<0.05),结果见表4。结果表明脉络舒通颗粒可以调节小鼠脾肾脏功能,具有健脾益肾的功效。
表4对痛风性关节炎小鼠脏器指数的影响(n=10)
注:与正常对照组比较:P<0.05用“△”表示;与模型对照组比较:P<0.05用“*”表示。
痛风性关节炎是一种长期性、难治性、反复发作性的非特异炎症性关节炎。目前西医对本病的治疗主要是控制关节肿痛的急性发作,但因其长期反复发作的特点,且秋水仙碱、非甾体抗炎药等药物均存在不同程度的副作用,包括胃肠道不适、溃疡、肝肾损害、神经毒性和免疫抑制等。实验结果表明脉络舒通颗粒具有清热散结、化瘀止痛的功效,有明显的抗炎作用和镇痛作用,对急性痛风性关节炎及痛风发作间期的各种病症有良好的治疗效果,且不易复发,无明显毒副作用和不良反应,为临床治疗痛风性关节炎提供了新选择。
Claims (1)
1.脉络疏通颗粒在制备治疗痛风性关节炎药物中的应用,所述脉络疏通颗粒由黄芪、金银花、黄柏、苍术、薏苡仁、玄参、当归、白芍、甘草、水蛭、全蝎、蜈蚣制成。
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