CN107095870B - 一种具有抗淋巴瘤作用的复方药物组合物及其用途 - Google Patents
一种具有抗淋巴瘤作用的复方药物组合物及其用途 Download PDFInfo
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Abstract
本发明属于天然药物领域，公开了一种含荜茇酰胺和鱼腥草素的具有抗淋巴瘤作用的复方药物组合物及其用途。该复方药物组合物的活性成分是由摩尔比为1:1～1:20的荜茇酰胺和鱼腥草素组成。两者联合用药具有较强的协同治疗淋巴瘤的用途。
Description
技术领域
本发明属于天然药物领域，特别涉及一种含荜茇酰胺和鱼腥草素的具有抗淋巴瘤作用的复方药物组合物及其用途。
背景技术
癌症是严重危害人类健康的一大顽症，现已成为仅次于心血管病的第二大杀手。进入21世纪以来，由于现代工业化的快速进程，环境污染等诸多因素导致淋巴细胞***免疫被破坏而引起淋巴瘤发病率呈逐年上升的趋势，使我们意识到研发出一种能够用于防治淋巴瘤的药物***显得非常迫切。
荜茇酰胺(piperlongumine，PLM)又称荜茇明碱(piplOMAine)，属生物碱类化合物。最初分离自胡椒科植物荜茇Piper longum Linn.的根，在长柄胡椒P.sylvaticumRoxb.及瘤突胡椒P.tuberculatumJacq.等的根中也有分得。随着对荜茇酰胺研究的深入，发现荜茇酰胺具有多种药理学作用，其中对肿瘤细胞具有显著的细胞毒作用，可调节高脂血症大鼠的血脂代谢，并表现出抗血小板凝集、镇痛、抗真菌等诸多药理活性。最新研究表明它对多种肿瘤细胞具有特异性的细胞毒作用，而对正常细胞的毒性非常小(Nature.2011Jul 13；475(7355):231-4.；ACS Chem Biol.2013May 17；8(5):923-9.)，因此荜茇酰胺是一种极具潜力的能够选择性杀死肿瘤的中药单体。
鱼腥草为三白草科植物蕺菜Houttuynia cordata Thunb.的新鲜全草或干燥地上部分，始载于《名医别录》，其后历代本草文献都有记载“以清解肺热见长，为治肺雍之要药”。鱼腥草味辛，微寒，归肺经，具有清热解毒、消痈排脓、利尿通淋的功能，主要用于肺痈吐脓、痰热喘咳等。现代研究证明鱼腥草具有较好的抗炎活性，临床上用于治疗呼吸道感染，如结膜炎、角膜炎、急慢性鼻炎、鼻窦炎等炎症性疾病。作为传统的清热解毒中药，鱼腥草因其显著的抗炎、解热作用，在2003年***从上万种中药中推荐的8种抗SARS中药中，鱼腥草注射液排在第2位。鱼腥草素为鱼腥草挥发油中有效成分癸酰乙醛(decanoylacetaldehyde，DLH又名癸酰乙醛，其亚硫酸氢钠加成物称为合成鱼腥草素或鱼腥草素钠)，现代药理研究发现鱼腥草素有抗菌、抗炎的作用，而其抗癌的研究尚未见报道。在我们的前期研究发现，DLH具有良好的抗癌效应，尤其是组合PLM。这些为复合DLH和PLM给药治疗恶性肿瘤淋巴瘤提供了全新的机会。将鱼腥草素的优越抗癌疗效与具有良好抗癌活性的天然药物联合协同治疗淋巴瘤等恶性肿瘤，是一个值得关注而又很有潜力的抗肿瘤复合药物方向。组合鱼腥草素和天然药物荜茇酰胺用于恶性肿瘤淋巴瘤的预防和治疗作用尚未见相关文献报道几乎没有。
发明内容
为了克服现有技术中存在的缺点和不足，本发明的首要目的在于提供一种具有抗肿瘤作用的复方药物组合物；该复方药物组合物的活性成分是由荜茇酰胺和鱼腥草素组成。
本发明的另一目的在于提供一种上述具有抗肿瘤作用的复方药物组合物的用途；药理试验证明该复方药物组合物具有协同抗淋巴瘤作用。
本发明的目的通过下述技术方案实现：
一种具有抗淋巴瘤作用的复方药物组合物，该复方药物组合物的活性成分是由荜茇酰胺和鱼腥草素组成。
优选的，所述荜茇酰胺和鱼腥草素的摩尔比为1:1～1:20。
更加优选的，所述荜茇酰胺和鱼腥草素的摩尔比为1:1～1:10。
该复方药物组合物还含有药物上可接受的载体。
上述的一种具有抗淋巴瘤作用的复方药物组合物在制备抗淋巴瘤药物中的用途。
所述抗淋巴瘤药物可用于包括人在内的哺乳动物的淋巴瘤的治疗。
本发明与现有技术相比具有如下突出的优点及有益效果：
发明人在对荜茇酰胺(PLM)和鱼腥草素(DLH)配伍药理活性的研究中发现，将鱼腥草素和荜茇酰胺组合给药，特别是当两者摩尔比为1:1-1:20配伍时具有很好抗癌细胞的协同作用。发明人分别对Daudi，Raji和BC-3为模型进行体外DLHT筛选，发现其具有很强的抗增殖活性并呈良好的时效与量效关系，结合经典联合给药分析原理(Median-effectPrinciple)和统计分析，结果表明其具有协同作用，尤其是在fa＜0.5时可明显产生协同效应抑制三种癌细胞增殖，这说明荜茇酰胺(PLM)和鱼腥草素(DLH)组合物可在低剂量配伍时产生DLH或PLM单药高剂量的生物学效应，从而可以大大降低药物的毒副作用产生，具有良好的临床用药开发前景。同时，等效应剂量评价表明，复合药物对正常肝细胞L-O2的毒性尚未增加。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但本发明的实施方式不限于此。
实施例1：Daudi、Raji和BC-3细胞筛选优化荜茇酰胺(PLM)和鱼腥草素(DLH)复方药物组合物。
取对数生长期的细胞，分别接种3×104个细胞/孔于96孔板上，待生长6小时后，离心弃上清，然后按以下分组给药：肿瘤细胞设不加药组和加药组，其中加药组设DLH和PLM单药组、DLH和PLM联合用药不同摩尔比例组，每组设4-6个复孔，培养24小时，弃上清，加入100μl含5mg/ml的DLHT(四氮唑盐)无血清培养液培养4小时，加入100μl DMSO(二甲亚砜)，放置于微型振荡仪上振荡10min，再置于酶标仪上570nm处检测OD值。结果按照以下抑制率公式计算每种情况下肿瘤细胞生长的抑制率，具体结果见表1。
抑制率＝(1-加药组OD值/对照组OD值)
表1为DLH和PLM单独和联合给药作用细胞72小时后不同浓度的IC50抑制率。
当DLH和PLM按摩尔比1:1和1:20配伍组合时的抑制情况。从其中我们可以获得随着配伍浓度的增加，其抑制率呈浓度依赖性。其中我们发现随着配伍浓度的增加，其抑制率呈浓度依赖性。
表1 PLM和DLH单药作用72小时IC50(μg/mL)
实施例2：DLH和PLM联合给药效应分析
以Median-effect Principle(中效原理或Chou-Talalay联合指数法)为评价基础，应用CombiDrug统计软件绘制剂量-效应曲线及不同效应下的合用指数曲线(fa-C曲线)，从两药合用的效应与合用指数的关系定量评价两药之间是协同、拮抗或相加关系。具体步骤如下：
药物作用效应即抑制率(fa)＝1-(试验组平均OD570值/肿瘤细胞空白对照组平均OD570)根据中效方程式fa/fu＝(D/Dm)m，两边取对数logfa/fu＝mlogD–mlogDm，设a＝-mlogDm，b＝m，x＝logD，y＝logfa/fu,代入中效方程式得y＝bx–a；其中fa为药物作用效应，fu＝1–fa，D为药物浓度，m为斜率，Dm为中效浓度，即50％效应时的药物浓度。依上述公式，计算出两种抗癌药单用及合用时各自的中效浓度Dm(logDm＝-a/m)，再计算出单用及两药合用时在各种效应时所需药物浓度〔D＝Dm(fa/f u)1/m〕，可计算出两药合用时在各种效应时的合用指数〔CI＝D1/DX1+D2/DX2+α(D1D2)/(DX1DX2)，D1、D2为两药合用时产生X效应时两药各自所需浓度，DX1、DX2为两药单独使用时产生X效应时两药各自浓度〕。α＝0为两种相互排斥性药物，α＝1为两种相互非排斥性药物。因DLH与荜茇酰胺作用机制不同，故本实验中取α＝0。当CI<1，两药合用效应为协同；CI＝1，两药合用效应相加；CI>1，两药合用效应拮抗。
经过软件分析，本发明的复方药物组合物具有良好的协同作用，具体效应见表2，根据Median-effect Principle评价效应的原则，即CI指数<0.1时具有很强的协同作用(Very strong synergism)；CI指数为0.1–0.3时为强协同效应(Strong synergism)；CI指数为0.3–0.7具有协同效应(Synergism)；CI指数为0.7–0.85具有中度协同效应(Moderatesynergism)；CI指数为0.85–0.90区间时具有弱协同效应(Slight synergism)；CI指数为0.90–1.10区间时具有近叠加效应(Nearly additive)；CI指数>1.10及以上时具有拮抗效应。
表2可见，PLM和DLH配伍具有协同效应；尤其是当两者摩尔比为1-1:20配伍时具有良好的协同效应，当两者摩尔比为1:10时协同效应最强。
表2 PLM和DLH不同配伍组合作用72小时的联合指数CI比较
实施例3：荜茇酰胺(PLM)和鱼腥草素(DLH)复方药物组合物按照以下处方制成片剂：
处方如下：
制备工艺如下：
将药物和辅料分别过80目筛，将荜茇酰胺与48克微晶纤维素和12克羧甲基淀粉钠充分混合，10％淀粉浆制软材，18目筛制粒，60℃下干燥，得颗粒1。将鱼腥草素与24克微晶纤维素、15克淀粉和8克羧甲基淀粉钠充分混合，10％淀粉浆制软材，18目筛制粒，60℃下干燥，得颗粒2。按等量递增原则，将颗粒1和颗粒2充分混合，16目筛整粒，加入硬脂酸镁，混匀，压片，片重500mg。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (5)
1.一种具有抗淋巴瘤作用的复方药物组合物，其特征在于：该复方药物组合物的活性成分是由荜茇酰胺和鱼腥草素组成。
2.根据权利要求1所述的一种具有抗淋巴瘤作用的复方药物组合物，其特征在于：所述荜茇酰胺和鱼腥草素的摩尔比为1:1～1:20。
3.根据权利要求1所述的一种具有抗淋巴瘤作用的复方药物组合物，其特征在于：所述荜茇酰胺和鱼腥草素的摩尔比为1:1～1:10。
4.根据权利要求1所述的一种具有抗淋巴瘤作用的复方药物组合物，其特征在于：该复方药物组合物还含有药物上可接受的载体。
5.根据权利要求1～4任一项所述的一种具有抗淋巴瘤作用的复方药物组合物在制备抗淋巴瘤药物中的用途。
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