CN104547289B - 一种具有治疗顺铂引起肾损伤作用的中药组合物 - Google Patents
一种具有治疗顺铂引起肾损伤作用的中药组合物 Download PDFInfo
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Abstract
本发明涉及到一种中药组合物在治疗顺铂引起的肾损伤中的应用及其制备方法。该组合物是由生地黄、白蜜、茯苓、人参组成,具体是由下述重量份配比的原料药制成:生地黄700份,白蜜400份,茯苓200份,人参100份。制备方法如下:准确称取生地黄700重量份,白蜜400重量份、茯苓200重量份、人参100重量份。将生地黄、茯苓、人参用八倍水浸泡30分钟,加热回流4小时,过滤,收集滤液。再加八倍水于滤渣中,加热回流3小时,过滤,收集滤液。将两次滤液合并,加入白蜜。加热浓缩至热密度为1.4kg/L(80℃),即得该中药组合物。经动物实验验证,表明本发明用于顺铂化疗引起的肾毒性疗效确切,且不影响顺铂的化疗效果。
Description
技术领域
本发明涉及中药技术领域,更具体地涉及到一种由生地黄、白蜜、茯苓、人参组成的中药组合物在治疗顺铂引起的肾损伤中的应用及其制备方法。
背景技术
顺铂是一种高效的抗肿瘤药物,广泛用于乳腺癌、头颈部癌、肺癌、卵巢癌等多种实体瘤的治疗。它具有抗癌谱广、作用强、与多种抗肿瘤药有协同作用、且无交叉耐药等特点,为当前联合化疗中最常用的药物之一,但是顺铂具有明显的肾毒性。在临床使用中,20%-30%的病人由于肾脏毒性被迫停止使用。顺铂经静脉注射后分布于肝、肾,大小肠等组织中,然后大量蓄积在肾组织中,经尿液排泄,但排泄缓慢。这种特殊的药代动力学特征提示了顺铂对肾脏的毒性作用。
在临床上,顺铂引起的肾毒性通常表现为病人血清肌酐和血清尿素氮的升高。病理检查表明顺铂首先损伤近端小管,尤其是髓质外侧近端小管的S3段,长期用药可使肾细胞囊肿形成和肾脏组织纤维化,具体表现为近曲小管上皮细胞坏死和变性,坏死的上皮脱落,充塞管腔。研究表明,顺铂主要通过肾小管上皮细胞表面的铜离子转运蛋白-1(Ctr1)和有机阳离子转运蛋白(OCT2)进入细胞,启动细胞凋亡程序,并刺激炎症因子的释放,加速细胞坏死。因此,寻找有效的方法减少肾毒性的发生,才能更加有利于肿瘤的治疗。
目前在临床上,对抗顺铂肾毒性的方法主要为水化疗法,即给予顺铂化疗的同时,静注大量的生理盐水或一定量的利尿剂,加速顺铂的排泄。但是有报道表明,这种方法可能会导致病人的水-电解质紊乱,进一步加重肾负担。针对顺铂引发顺损伤的机制,有人选用一些凋亡抑制剂、抗氧化剂等,但是顺铂引发肾损伤的通路往往也是顺铂治疗肿瘤的途径,因此封锁这些通路以期待降低药物的副作用实际上也降低了顺铂的抗癌作用。
发明内容
本发明提供了一种有效防治顺铂引起的顺毒性的中药组合物,并且该组合物不影响顺铂的化疗效果。该组合物是由生地黄、白蜜、茯苓、人参组成。
本发明组合物是由下述重量份配比的原料药制成:生地黄700份,白蜜400份,茯苓200 份,人参100份。
经动物实验验证,表明本发明用于顺铂化疗引起的肾毒性疗效确切,能有效降低血清肌酐和血清尿素氮,减少顺铂在肾组织的蓄积,降低肾细胞的凋亡,减少炎症因子的释放。
本发明的目的是提供一种中药组合物在制备防治顺铂化疗引起的顺毒性中的应用。
本发明中的中药组合物的制备方法如下:准确称取生地黄700重量份,白蜜400重量份、茯苓200重量份、人参100重量份。将生地黄、茯苓、人参用八倍水浸泡30分钟,加热回流 4小时,过滤,收集滤液。再加八倍水于滤渣中,加热回流3小时,过滤,收集滤液。将两次滤液合并,加入白蜜。加热浓缩至热密度为1.4kg/L(80℃),即得该中药组合物。
附图说明
图1各组小鼠尿液,从左到右依次为空白组、模型组、给药组
图2各组小鼠肾组织H&E染色(×200)
图3本中药组合物对小鼠肾组织中Pt+浓度的影响
图4 24小时内随尿液排出的Pt+总量
图5 TUNEL法检测各组小鼠肾组织凋亡情况(×200)
图6本中药组合物对荷瘤小鼠存活率的影响
具体实施例
一、采用动物水平实验验证该中药组合物对顺铂引起肾毒性的防治效果
(一)实验动物:C57BL/6小鼠21只,雄性,体重20-24g,6-8周龄。购自上海斯莱特实验动物中心。
(二)实验药物:本药物中的原料药和注射用顺铂及生理盐水均购自江苏省中西医结合医院,注射用顺铂由山东齐鲁制药有限公司生产(批号:山东齐鲁药业有限公司1WA2A130100413),生理盐水由四川科伦药业有限公司生产(批号:P13032102)。
(三)实验方法:将小鼠随机分为3组,①空白组,每日以生理盐水灌胃0.2ml,共10天,第7天时,以生理盐水腹腔注射0.2ml;②模型组,每日以生理盐水灌胃0.2ml,第7天时,以顺铂腹腔注射20mg/kg;③给药组,每日给予本发明中药组合物0.2ml(相当于中药组合物0.28g),第7天时,以顺铂腹腔注射20mg/kg。最后一次灌胃后,开始收集24小时尿液, 24小时后摘眼球取血(分离血清),再处死小鼠,摘取肾脏,准确称量肾脏重量后一部分置于多聚甲醛保存,另一部分-80℃保存。
(四)检测指标
1、小鼠的行为状况,包括精神状态,活动情况,毛发的光泽度,尿液性状。
2、体重变化。
3、根据试剂盒说明书提供的方法检测小鼠血清肌酐和尿素氮的值(南京建成生物技术有限公司)。计算肾脏指数,肾脏指数=双侧肾脏质量(g)*1000/体重(kg)。
4、病理学检测,采用H&E染色,观察各组小鼠肾脏损伤程度。
5、采用电感耦合等离子体质谱法检测肾组织消解液中Pt+含量,计算肾组织中Pt+浓度。
6、采用电感耦合等离子体质谱法检测尿液稀释液中Pt+含量,计算24内随尿液排出的 Pt+总量。
7、TUNEL法检测各组小鼠肾细胞凋亡情况。
8、RT-PCR的方法检测炎症因子TNF-α和IL-1βmRNA的相对表达量。
(五)实验结果
1、小鼠的行为状况:空白组小鼠精神良好,活动自如,毛发柔顺有光泽,尿液呈黄色澄明液体;模型组小鼠精神萎靡不振,活动缓慢,毛发凌乱无光泽,尿液呈无色带浑浊液体;给药组,精神状态良好,活动较缓慢,毛发有光泽,尿液呈淡黄色澄明液体。各组小鼠尿液性状见图1。
2、该中药组合物对小鼠的体重变化的影响,见表1。
表1该中药组合物对小鼠的体重变化的影响(mean±SD)
3、该中药组合物对小鼠血清肌酐、尿素氮以及肾脏指数的影响(mean±SD),见表2
表2该中药组合物对小鼠血清肌酐、尿素氮以及肾脏指数的影响(mean±SD)
注:与模型组相比,*p<0.05,**p<0.03
4、H&E检测该中药组合物对肾脏组织的影响,见图2。
5、该中药组合物对小鼠肾组织中Pt+浓度的影响,见图3。
6、该中药组合物对Pt+排泄量的影响,见图4。
7、TUNEL法检测各组小鼠肾细胞凋亡情况,见图5。
8、RT-PCR的方法检测炎症因子TNF-α和IL-1βmRNA的相对表达量,见表3。
表3 TNF-α和IL-1βmRNA的相对表达量(VS空白组)(mean±SD)
注:与模型组相比,*p<0.05,**p<0.03
以上数据表明,该中药组合物能有效降低顺铂引起的血肌酐和尿素氮水平,增加顺铂的排泄,减少肾小管上皮细胞的凋亡,减轻炎症反应,用于保护对顺铂引起肾损伤疗效确切。二、采用动物水平实验验证该中药组合物对顺铂化疗效果作用的影响。
(一)实验动物:C57BL/6小鼠50只,雄性,体重20-24g,6-8周龄。购自上海斯莱特实验动物中心。其中40只用于接种Lewis细胞,另外10只用于正常对照。
(二)实验药物:本药物中的原料药和注射用顺铂及生理盐水均购自江苏省中西医结合医院,注射用顺铂由山东齐鲁制药有限公司生产(批号:山东齐鲁药业有限公司1WA2A130100413),生理盐水由四川科伦药业有限公司生产(批号:P13032102)
(三)实验方法:将培养好的Lewis细胞用胰酶消化5min,PBS洗涤,离心,弃上清,再用PBS调成107/ml的细胞悬液,于小鼠右前肢腋下皮下注射,0.2ml/只,一周后将荷瘤小鼠随机分为4组并给药,每组10只。①模型组,每日以生理盐水灌胃;②顺铂组,腹腔注射顺铂2mg/kg,隔日一次,共3次;③中药组合物组,每日给予本发明中药组合物0.2ml(相当于中药组合物0.28g)灌胃;④顺铂+中药组,腹腔注射顺铂2mg/kg,隔日一次,共3次,并且每日以本中药组合物灌胃0.2ml(相当于中药组合物0.28g)。给药过程中,隔日测量肿瘤大小,每日记录小鼠死亡情况。
(四)检测指标
1、各组小鼠的肿瘤直径。
2、各组小鼠的存活率。
(五)实验结果
1、该中药组合物对肿瘤生长情况的影响,见表4。
表4该中药组合物对肿瘤生长情况的影响(mean±SD)
注:与模型组相比,*p<0.05,**p<0.03
2、该中药组合物对荷瘤小鼠存活率的影响,见图6。
以上数据表明,该中药组合物与顺铂联用,不影响顺铂的抑瘤作用,并且可有有效延长小鼠的生存时间。提示了该中药组合物用于顺铂的辅助用药可能改善病人的生活质量,延长生存时间。
通过实验,可以看出本发明能够有效防治顺铂引起的肾毒性,并且具有不影响顺铂的化疗效果的优点。
Claims (2)
1.一种具有治疗顺铂引起肾损伤作用的中药组合物,其特征在于由下述原料药组成:生地黄700重量份,白蜜400重量份、茯苓200重量份,人参100重量份。
2.如权利要求1所述的一种具有治疗顺铂引起肾损伤作用的中药组合物,其特征在于该组合物由以下制备方法制得:
a、按重量份准确称取生地黄700份,白蜜400份、茯苓200份、人参100份;
b、将生地黄、茯苓、人参用八倍水浸泡30分钟,加热回流4小时,过滤,收集滤液;
c、再加八倍水于滤渣中,加热回流3小时,过滤,收集滤液;
d、将两次滤液合并,加入白蜜;
e、加热浓缩至80℃时热密度为1.4kg/L,即得。
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琼玉膏对实验肺癌小鼠化疗导致骨髓抑制的影响;陈孝银等;《山东中医杂志》;20021231;第21卷(第12期);第736-738页,尤其是第736页摘要、第1.2节 * |
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