CN116392498A - 一种治疗白血病的药物组合物及其用途 - Google Patents
一种治疗白血病的药物组合物及其用途 Download PDFInfo
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Abstract
本发明属于医药技术领域，具体涉及一种治疗白血病的药物组合物，该药物组合物包含汉黄芩素、落新妇苷和丹参素，其中汉黄芩素、落新妇苷和丹参素的重量比为(1‑8):(1‑8):(0.5‑2)。本发明的药物组合物对于治疗白血病的疗效显著，这表明将汉黄芩素、落新妇苷和丹参素联用后，对于治疗白血病具有显著的协同增效作用，因而具有良好的临床用药开发前景。
Description
技术领域
本发明属于医药领域，具体涉及一种包含汉黄芩素、落新妇苷和丹参素的治疗白血病的药物组合物和药物制剂及其用途。
背景技术
白血病是常见的血液系统恶性肿瘤，又称血癌，也是一种常见的造血系统异常的恶性克隆性疾病，以增殖、克隆、低分化或异常分化的造血细胞浸润骨髓、血液以及其它组织为特征。病人的骨髓造血系统产生大量不成熟、无法正常工作的白细胞，造成正常的血小板、红细胞、白细胞减少。这些尚未发育完全的白细胞，被称为白血病细胞。根据白血病细胞的分化程度、自然病程的长短可分为急、慢性白血病。按照病变细胞系列分类，主要分为髓系和淋巴系。临床常见发病类型主要有四种，包括急性淋巴细胞白血病(ALL)，急性髓性白血病(AML)，慢性淋巴细胞白血病(CLL)和慢性髓性白血病(CML)。白细胞增生与浸润为白血病的特异性病理变化，变现为淋巴结、肝、脾肿大，胸骨压痛。亦可表现其他部位浸润，如出现胸腔积液、腹腔积液或心包积液，以及中枢神经系统浸润等。由于白血病导致中性粒细胞数量减少和功能缺陷，从而容易引发各种细菌感染，其中以口腔、肠、肺部等炎症最为常见。血小板减少，纤维蛋白溶解，弥散性血管内凝血及血浆蛋白结合多糖体增多，抑制凝血功能，患者多伴有出血现象，常见于皮肤黏膜、造血组织、脾、胃等。白血病产生的部正常分化细胞抑制正常造血细胞，破坏红细胞生长的骨髓环境，引致溶血现象，造成贫血。白细胞增多还可导致小血管阻塞及出血性栓塞，引起患者瘫痪、昏迷、甚至死亡。在我国，白血病的发病率约为每百万人3～4例，由于我国人口基数大，因此，白血病的发病人群仍非常庞大，严重危害病人的生命安全，为患者和社会带来极大的医疗负担。
由于白血病自身疾病性质所限制，手术切除的治疗策略并不适用，目前针对白血病的治疗策略主要以传统的化疗为主，还有放射治疗、造血干细胞移植、分子靶向治疗、免疫疗法等策略。化疗为目前主要治疗手段，但其副作用大，容易产生耐药性以及对某些病人不耐受，临床易复发，而且费用较高，一般人难以承受，给患者求医造成了很大的精神负担。而造血干细胞移植受到供体来源，以及耗费大、容易产生免疫排异反应等原因的限制，并不能很好的适用于所有白血病病人。因此迫切需要寻找更多、更有效的白血病治疗药物，为高效低毒白血病治疗药物的开发奠定基础。
汉黄芩素是唇形科(Labiatase)植物黄芩(Scutellariabaicalensis Georgi)及同属多种植物的根中所含的黄酮类化合物，又名5,7-二羟基-8-甲氧基-2-苯基-4H-1-苯并呋喃-4-酮，分子式为C16H12O5。研究表明，汉黄芩素具有多种药理作用，包括抗氧化作用，抗凝血作用，抗肿瘤作用，解痉作用，此外还有抗菌、抗病毒作用以及利尿作用等。CN100345537C公开了汉黄芩素在制备治疗白血病的药物中的应用，特别是在制备诱导白血病细胞向粒系定向分化的药物中的应用。汉黄芩素可以抑制肿瘤细胞增殖，但汉黄芩素的抗肿瘤活性较弱(CDK9:IC50＝198μM)并且其成药性较差。
落新妇苷是1950年由Kozo Hayashi和Kazuhiko Ouchi首次从植物落新妇中提取得到的类黄酮化合物，又名(2R,3R)-花旗松素-3-O-α-L-吡喃鼠李糖苷，分子式为C21H22O11。落新妇苷具有多种显著的生物学活性，包括抑制辅酶A还原酶，抑制醛糖还原酶，保护肝脏，镇痛，抗水肿等。近年又来有报道称落新妇苷有显著的选择性免疫抑制作用，且它的选择性作用与以往的免疫抑制剂相比具有明显优势，因此可以作为一种新的免疫抑制剂用于免疫相关疾病的治疗。CN107854476A公开了落新妇苷在制备治疗胃癌药物中的应用，落新妇苷可能是通过抑制血管内皮生长因子(VEGF)的表达、在肿瘤微环境中促进T淋巴细胞的活性等，从而在胃癌治疗方面发挥疗效。落新妇苷植物来源广泛，目前世界范围内共有12科15属26种植物中均可分离出落新妇苷，主要存在于藤黄科、金丝桃科、核桃科、百合科、桑寄生科、虎耳草科、葡萄科多种植物中。基于我国中药及植物资源分布及蕴藏情况，黄杞、土茯苓及葡萄可作为落新妇苷的主要来源。
丹参素为唇形科(Labiatase)植物丹参(Salvia miltiorrhiza Bunge)的干燥根及根茎提取而得的药效成分之一，化学名称为[D-(+)-β-(3,4-二羟基苯基)乳酸]，分子式为C9H10O5。研究表明，丹参素具有抗心肌缺血缺氧、抗心肌缺血再灌注损伤、舒张冠脉、抗心律失常和抗血栓等多种药理作用，对心脑血管系统具有广泛而显著的保护作用。还有研究表明，丹参素具有抗炎与增强免疫、抗肿瘤、保护神经细胞以及防治肝纤维化等作用。
目前汉黄芩素联合落新妇苷和丹参素对白血病的治疗并未有相关报道。
发明内容
为了解决现有技术存在的问题，本发明首次公开了汉黄芩素联合落新妇苷和丹参素治疗白血病的全新联合方案。具体的，本发明公开了一种包含汉黄芩素、落新妇苷和丹参素的治疗白血病的药物组合物和药物制剂及其用途。
本发明的上述目的是通过以下几个方面的技术方案来实现的。
在第一个方面中，本发明提供了一种治疗白血病的药物组合物，所述药物组合物包含汉黄芩素、落新妇苷和丹参素。
另外优选的，所述药物组合物由汉黄芩素、落新妇苷和丹参素组成。
优选的，上述药物组合物中汉黄芩素、落新妇苷和丹参素的重量比为(1-8):(1-8):(0.5-2)。
更优选的，上述药物组合物中汉黄芩素、落新妇苷和丹参素的重量比为(4-8):(1-4):(1-2)。
进一步优选的，上述药物组合物中汉黄芩素、落新妇苷和丹参素的重量比为4:(1-4):(1-2)。
最优选的，上述药物组合物中汉黄芩素、落新妇苷和丹参素的重量比为4:4:2，或者4:3:1，或者4:2:2。
在第二个方面中，本发明提供了一种药物制剂，所述药物制剂包含上述第一个方面所述的药物组合物，以及药学上可接受的载体。
优选的，在上述药物制剂中，所述药物制剂为口服剂型。
更优选的，在上述药物制剂中，所述口服剂型为片剂、胶囊剂、颗粒剂、口服液、丸剂。
优选的，在上述药物制剂中，所述药学上可接受的载体是指药物制剂领域常规的药物载体，选自填充剂、粘合剂、崩解剂、润滑剂、助悬剂、润湿剂、色素、矫味剂、溶剂、表面活性剂中的一种或几种。
在第三个方面中，本发明提供了上述第一个方面所述的药物组合物或者上述第二个方面所述的药物制剂在制备治疗白血病的药物中的用途。
优选的，所述白血病为慢性髓系白血病。
本发明还提供上述药物组合物或上述药物制剂在制备抑制K-562细胞增殖的药物中的应用。
本发明相对于现有技术，具有以下有益效果：
发明人在研究中发现，汉黄芩素、落新妇苷和丹参素的联用对于治疗白血病具有显著的效果，更令人意外的是，三种活性成分在适当重量范围内配比，对于治疗白血病产生了难以预期的优异效果。
具体实施方式
下面详细描述本发明的实施例，所举实施例是为了更好地对本发明的内容进行说明，仅用于解释本发明，而不能理解为对本发明的限制。
实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道购买得到的常规产品。
下面实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为市售产品。
实施例：本发明药物组合物对K-562细胞(人慢性髓系白血病细胞)增殖的抑制作用
(1)实验材料
K-562细胞购于American Type Culture Collection(ATCC，Rockville，MD，USA)。
8％胎牛血清、RPMI 1640培养基购自Thermo Fisher Scientific。
CCK-8试剂购自日本同仁。
(2)实验方法
K-562细胞采用含10％胎牛血清的1640培养液培养，取对数生长期细胞进行后续的药物干预实验。
取对数生长期细胞按照1×104个/孔接种于96孔板，实验时各实验组加入药物浓度分别为：汉黄芩素组、落新妇苷组和丹参素组的药物浓度设定均为6μmol/L，联合组1为2.4μmol/L汉黄芩素+2.4μmol/L落新妇苷+1.2μmol/L丹参素，联合组2为3μmol/L汉黄芩素+2.25μmol/L落新妇苷+0.75μmol/L丹参素，联合组3为3μmol/L汉黄芩素+1.5μmol/L落新妇苷+1.5μmol/L丹参素。另设阴性对照组(不加药)和空白对照组(不加药和细胞)。每一浓度设5个复孔，每孔总体积100ml。分别培养48h和72h后每孔加入10μl的CCK8，2h后酶标仪检测各孔570nm波长吸光度(A)值，实验重复3次。抑制率＝[(对照孔A值-加药孔A值)/(对照孔A值-空白孔A值)]×100％。
(3)实验结果
各实验组抑制K-562细胞增殖的试验结果见表1。
表1本发明药物组合物对抑制K-562细胞增殖的影响
表1实验结果显示，当汉黄芩素、落新妇苷和丹参素三者联用时，其对K-562细胞的增殖抑制作用显著增强，其中联合组1的抑制效果最佳。这表明将汉黄芩素、落新妇苷和丹参素联用后，对于治疗白血病具有显著的协同增效作用。
显然，上述实施例仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定。本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。
Claims (9)
1.一种治疗白血病的药物组合物，其特征在于，所述药物组合物包含汉黄芩素、落新妇苷和丹参素，其中汉黄芩素、落新妇苷和丹参素的重量比为(1-8):(1-8):(0.5-2)。
2.根据权利要求1所述的治疗白血病的药物组合物，其特征在于，所述药物组合物中汉黄芩素、落新妇苷和丹参素的重量比为(4-8):(1-4):(1-2)。
3.根据权利要求1或2所述的治疗白血病的药物组合物，其特征在于，所述药物组合物中汉黄芩素、落新妇苷和丹参素的重量比为4:(1-4):(1-2)。
4.根据权利要求1或2或3所述的治疗白血病的药物组合物，其特征在于，所述药物组合物中汉黄芩素、落新妇苷和丹参素的重量比为4:4:2，或者4:3:1，或者4:2:2。
5.根据权利要求1-4中任意一项所述的治疗白血病的药物组合物，其特征在于，所述白血病为慢性髓系白血病。
6.一种治疗白血病的药物制剂，其特征在于，所述药物制剂包含权利要求1-5中任意一项所述的药物组合物，以及药学上可接受的载体。
7.根据权利要求6所述的治疗白血病的药物制剂，其特征在于，所述药物制剂为口服剂型。
8.根据权利要求7所述的治疗白血病的药物制剂，其特征在于，所述口服剂型为片剂、胶囊剂、颗粒剂、口服液、丸剂。
9.权利要求1-5中任意一项所述的药物组合物或权利要求6-8中任意一项所述的药物制剂在制备治疗白血病的药物中的用途。
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