CN117599083A - 硝石矾石中药复方作为制备治疗肝癌术后复发药物的应用 - Google Patents
硝石矾石中药复方作为制备治疗肝癌术后复发药物的应用 Download PDFInfo
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Abstract
本发明涉及硝石矾石中药复方的新用途,尤其涉及硝石矾石中药复方作为制备治疗肝癌术后复发药物的应用。硝石矾石中药复方具有显著改善肝癌术后复发的作用,该复方可为肝癌术后复发提供一种疗效确切的中医药干预措施,该复方疗效确切,价廉易得,可缓解肝癌复发患者的经济负担。如将其开发为肝癌术后复发的中药产品具有明显的经济和社会价值。
Description
技术领域
本发明涉及硝石矾石中药复方的新用途,尤其涉及硝石矾石中药复方作为制备治疗肝癌术后复发药物的应用。
背景技术
手术切除是目前最主要的肝癌根治性治疗方式,也是最有效的治疗方法,但肝癌切除术后5年复发率高达70%,其中多数发生于手术后2年内(即早期复发),严重影响了肝癌患者的长期生存和生活质量。复发性肝癌现有治疗方式有再次肝切除、局部射频消融(RAF)、经皮肝动脉化疗栓塞(TACE)、补救性肝移植(SLT)、放射疗法、系统疗法等,但患者耐受性差,治疗效果有限。再次切除适用于肿瘤数目少、肝功能尚可,且无大血管侵犯,机体状况能耐受的患者。挽救性肝移植适用于肝功能良好、米兰标准以内的患者,但肝源短缺,费用高。射频消融适用于肿瘤数目少,体积小,且无血管癌栓形成、器官侵犯的患者,不适合手术的小肝癌。理论上TACE的疗效无法达到根治性效果。多靶点多激酶抑制剂索拉菲尼作为一线用药,主要用于无法再次手术的复发性肝癌患者,但易产生耐药性,临床效果有限。仑伐替尼、瑞戈非尼、卡博替尼、雷莫卢单抗等靶向治疗药物的Ⅲ期临床试验已得到阳性结果,但仍存在客观反应率低等不足。程序性死亡受体1(PD-1)类免疫治疗和药物联合治疗提高了治疗的客观缓解率,但易产生耐药性。
中医药临床上配合西医疗法,在抑制肝癌复发,改善肝癌患者的临床症状,提高机体免疫功能等方面具有独特的优势,且较于现有的治疗措施而言,中药副作用小、多分子多靶点作用,逐渐成为有效的补充替代疗法。肝癌复发转移患者常出现病程迁延、中焦痞满、舌苔薄腻、脉濡等表象,现代医家认为此乃肝阴不足,夹气滞血瘀,加之肝脾运化无权,致湿热之邪胶着,炼液为痰,日久痰浊蕴毒,形成癌毒反复发作和转移。痰浊血瘀是导致肝癌复发的基本原因,痰浊浸淫于肿瘤内环境,日久生变,酝酿成痰结,痰结凝聚变异,恶痰由生。“湿浊血瘀”在肝癌复发转移过程中即是致病因素又是病理产物,多数医家主张“从祛湿化瘀论治肝癌复发转移”,且取得了较好的临床疗效。
硝石矾石散出自《金匮要略·黄疸病脉证》,由硝石、矾石等分成散,大麦粥汁和服,日三服。主要用于瘀血、湿浊聚集于肾导致的女劳疸。本方硝石性重浊趋下,除瘀泻热;矾石性收敛,燥湿浊,适用于瘀血湿热证。本方现有的报道主要集中在黄疸、慢性肝炎、胆汁淤积性黄疸、胆结石等的治疗,但对肝癌术后复发尚未见相关研究。
发明内容
本发明的目的在于证明硝石矾石中药复方具有改善肝癌术后复发的作用,可在治疗肝癌术后复发的药物中应用,为肝癌术后复发提供一种新辅助药物。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了硝石矾石中药复方作为制备治疗肝癌术后复发药物的应用。
优选的,所述硝石矾石中药复方由包含如下质量份数的原料制备得到:硝石1份、矾石1份、大麦粥1份。
优选的,所述肝癌为H22肝癌、人肝癌HePg2细胞。
本发明通过不同浓度硝石矾石散含药血清作用于人肝癌HepG2细胞48h后,细胞活力逐渐降低,抑制率显著升高;细胞划痕愈合能力明显降低。动物实验证明,药物干预后,硝石矾石中药复方各剂量组小鼠的精神、食欲、活动量等改善;小鼠肝脏结节数量明显减少,小鼠的瘤重减轻;血清中AFP、γ-GT、ApoA1的含量降低;超声结果显示硝石矾石中药复方各剂量组病变部位边界较清晰、形态较规则、肿块内部回声较均匀;HE染色发现模型组细胞排列紊乱,条索状消失或不清,血流丰富,细胞间隙缩小,细胞异型核多见,大小不一,核膜边界不清,硝石矾石中药复方各剂量组出现不同程度的改善。
与现有技术相比,本发明具有如下有益效果:
硝石矾石中药复方具有显著改善肝癌术后复发的作用,该复方可为肝癌术后复发提供一种疗效确切的中医药干预措施,该复方疗效确切,价廉易得,可缓解肝癌复发患者的经济负担。如将其开发为肝癌术后复发的辅助中药产品具有明显的经济和社会价值。
附图说明
图1为不同浓度的硝石矾石散含药血清对HepG2细胞活力的影响图;
图2为硝石矾石散含药血清对HepG2细胞划痕愈合能力的影响图;
图3为硝石矾石散对肝原位癌术后复发模型小鼠表观指标的影响图;其中图3a为硝石矾石散对肝原位癌术后复发模型小鼠体重的影响图,图3b为硝石矾石散对肝原位癌术后复发模型小鼠肝脏结节数量的影响图,图3c为硝石矾石散对肝原位癌术后复发模型小鼠瘤重的影响图;
图4为各组小鼠肝脏及肿瘤组织超声影像图;
图5为各组小鼠肝脏及肿瘤组织HE染色图;
图6为硝石矾石散对肝原位癌术后复发模型小鼠血清中AFP、γ-GT、ApoA1含量的影响图。
具体实施方式
下面结合实施例对本发明提供的技术方案进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。
实施例1
制备硝石矾石散含药血清:SD大鼠分为空白组,硝石矾石散组,每组4只。适应性喂养3d后按照1.0g/kg,溶于2mL大麦粥中灌胃,1次/d,连续7d,末次灌完胃30min后,腹主动脉取血,离心取上清,保存备用。分别以不同浓度0、10、40、80、160μL硝石矾石散含药血清干预人肝癌HePg2细胞48h,观察细胞增殖情况;以8、16、32μL的含药血清作用HePg2细胞0、8、16、48h,观察细胞划痕愈合情况。
1.1硝石矾石散含药血清对HepG2细胞增殖的影响
分别以不同浓度10、20、40、80、160μL的硝石矾石散含药血清作用于人肝癌HepG2细胞48h后,随着药物浓度的增加,细胞活力逐渐降低,抑制率升高,结果见图1。
1.2硝石矾石散含药血清对HepG2细胞划痕愈合能力的影响
分别以不同浓度8、16、32μL的硝石矾石散含药血清作用于人肝癌HepG2细胞0、8、16和48h,结果发现随着药物浓度的增加,细胞划痕愈合率逐渐降低,结果见图2。
实施例2
采用H22肝癌细胞腹水悬液肝脏注射3d后手术切除,建立KM小鼠肝脏原位移植瘤术后复发模型,以硝石矾石中药复方高(1.5g/kg)、中(0.75g/kg)、低(0.375g/kg)剂量,连续给药10d,作为复方高剂量组、复方中剂量组、复方低剂量组;以未实行任何干预组为空白组,以注射癌细胞后手术切除为模型组,以单纯手术不接种癌细胞为假手术组,以替加氟为阳性组,观察小鼠肝脏结节数量,取瘤组织称重;采用酶联免疫吸附法(ELISA)测定血清中甲胎蛋白(AFP)、γ-谷氨酰转肽酶(γ-GT)、载脂蛋白A1(ApoA1)水平;小动物超声影像检查肿瘤生长情况;HE染色观察肝组织病理学变化。
1.1各组小鼠一般情况比较
空白对照组小鼠精神状态良好,食欲、活动正常,体重逐渐增加。造模后,小鼠精神萎靡,少动,食欲下降,饮水量减少,毛发凌乱无光泽,易激惹,并且个别有互相攻击的现象。实验过程中发现用硝石矾石中药复方或替加氟灌胃治疗约3天后,小鼠的状态开始有所好转,随着治疗时间的延长,小鼠的精神、食欲、活动量等接近空白对照组。阳性对照组在药物干预后期,有小鼠死亡,而硝石矾石中药复方高、中、低剂量组均未见明显的不良反应。
1.2硝石矾石中药复方对肝原位癌术后复发模型小鼠体重的影响
硝石矾石中药复方对肝原位癌术后复发模型小鼠体重的影响如图3a和表1所示,由图3a和表1可知,给药结束后,与模型组相比,阳性组以及硝石矾石中药复方高、中、低剂量组小鼠体重均降低。试验结果表明,硝石矾石中药复方可不同程度地减少肝原位癌术后复发模型小鼠体内腹水的量。
表1各组小鼠给药结束后体重情况(x±s)(n=12)
1.3硝石矾石中药复方对肝原位癌术后复发模型小鼠肝脏结节数量的影响
硝石矾石中药复方对肝原位癌术后复发模型小鼠肝脏结节数量的影响如表2、图3b所示,由表2和图3b可知,给药结束后,与模型组相比,阳性组以及硝石矾石中药复方高、中、低剂量组小鼠肝脏结节数量均明显减少(P<0.05)。试验结果表明,硝石矾石中药复方可不同程度地减少肝原位癌术后复发模型小鼠肝脏结节的数量,减轻或改善肝损伤,抑制肿瘤复发。
表2各组小鼠给药结束后肝脏结节数量(x±s)(n=12)
注a:与模型组相比:*P<0.05
1.4硝石矾石中药复方对肝原位癌术后复发模型小鼠瘤重的影响
硝石矾石中药复方对肝原位癌术后复发模型小鼠瘤重的影响如表3和图3c所示,由表3和图3c可知,给药结束后,与模型组相比,阳性组以及硝石矾石中药复方高、中、低剂量组小鼠的瘤重均明显降低(P<0.05)。实验结果表明,硝石矾石中药复方可明显降低肝原位癌术后复发模型小鼠肿瘤的重量,对肿瘤生长具有抑制作用。
表3各组小鼠给药结束后瘤重情况(x±s)(n=12)
注b:与模型组相比:*P<0.05
1.5小动物超声影像检查肿瘤生长情况
小动物超声影像检查肿瘤生长情况见图4,由图4可知,空白组和假手术组无明显回声;模型组病变部位边界不清晰、形态不规则、内部回声不均匀。与模型组相比,阳性组、硝石矾石中药复方各剂量组病变部位边界较清晰、形态较规则、肿块内部回声较均匀。
1.6HE染色观察肝组织病理改变
HE染色观察肝组织病理改变如图5所示,由图5可知,空白组与假手术组肝细胞排列整齐,呈条索状,细胞间隙正常,细胞核大小均匀,细胞核边缘清晰;模型组细胞排列紊乱,条索状消失或不清,血流丰富,细胞间隙缩小,细胞异型核多见,大小不一,核膜边界不清。与模型组相比,硝石矾石中药复方各剂量组出现不同程度的改善。
1.7硝石矾石中药复方对肝原位癌术后复发模型小鼠血清中AFP、γ-GT、ApoA1含量的影响
由图6a可知,阳性对照组、硝石矾石中药复方高剂量组、硝石矾石中药复方中剂量组模型小鼠血清中ApoA1含量显著降低(P<0.01),硝石矾石中药复方低剂量组模型小鼠血清中ApoA1含量明显降低(P<0.05);由图6b可知,给药结束后,与模型组相比,阳性对照组、硝石矾石中药复方高剂量组、硝石矾石中药复方中剂量组模型小鼠血清中AFP含量显著降低(P<0.01),硝石矾石中药复方低剂量组模型小鼠血清中AFP含量明显降低(P<0.05);由图6c可知,硝石矾石中药复方高剂量组模型小鼠血清中γ-GT含量显著降低(P<0.01),阳性对照组、硝石矾石中药复方中剂量组、硝石矾石中药复方低剂量组模型小鼠血清中γ-GT含量明显降低(P<0.05)。
由表4和图6可知,经药物干预后,硝石矾石中药复方各剂量组均可明显降低肝原位癌术后复发模型小鼠血清中AFP、γ-GT、ApoA1的含量(P<0.05),对肿瘤生长具有一定抑制作用,且硝石矾石中药复方高剂量组对肿瘤生长的抑制作用优于硝石矾石中药复方中、低剂量组。
表4各组小鼠治疗后血清中AFP、γ-GT、ApoA1的含量(x±s)(n=12)
注c:与模型组相比:**P<0.01,*P<0.05
由以上实施例可知,本发明提供了硝石矾石中药复方作为制备治疗肝癌术后复发药物的应用。硝石矾石散含药血清作用人肝癌HepG2细胞48h后,随着药物浓度的增加,细胞活力逐渐降低,抑制率升高,细胞划痕愈合率逐渐降低。硝石矾石中药复方干预后,硝石矾石中药复方各剂量组小鼠的精神、食欲、活动量等改善;小鼠肝脏结节数量明显减少,小鼠的瘤重减轻;血清中AFP、γ-GT、ApoA1的含量降低;超声结果显示硝石矾石中药复方各剂量组病变部位边界较清晰、形态较规则、肿块内部回声较均匀;HE染色发现模型组细胞排列紊乱,条索状消失或不清,血流丰富,细胞间隙缩小,细胞异型核多见,大小不一,核膜边界不清,硝石矾石中药复方各剂量组出现不同程度的改善。硝石矾石中药复方具有显著改善肝癌术后复发的作用,该复方可为肝癌术后复发提供一种疗效确切的中医药干预措施,该复方疗效确切,价廉易得,可缓解肝癌复发患者的经济负担。如将其开发为肝癌术后复发的中药产品具有明显的经济和社会价值。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (2)
1.硝石矾石中药复方作为制备治疗肝癌术后复发药物的应用。
2.根据权利要求1所述的应用,其特征在于,所述硝石矾石中药复方由包含如下质量份数的原料制备得到:硝石1份、矾石1份、大麦粥1份。
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