CN114569590A - 新鱼腥草素钠的医药用途 - Google Patents
新鱼腥草素钠的医药用途 Download PDFInfo
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Abstract
本发明涉及药学领域，特别是涉及一种新鱼腥草素钠的制药用途。所述新鱼腥草素钠可用于制备抑制具核梭杆菌的药物。
Description
技术领域
本发明属于医药领域，具体涉及新鱼腥草素钠的新应用。
背景技术
随着组学技术的发展，多种疾病的发生、发展的过程与具核梭杆菌的感染紧密联系在一起。具核梭杆菌(Fusobacterium nucleatum，Fn)是人类口腔中含量最高的梭杆菌，常引起多种机会性感染。临床研究显示具核梭杆菌除导致口腔疾病外，还在不良妊娠结局、肿瘤等疾病中发挥重要作用。在结肠癌、骨髓炎、心包炎、脑脓肿等多种疾病的临床标本中分离出大量具核梭杆菌。目前研究表明具核梭杆菌的黏附蛋白FadA和Fap2能诱导并促进炎症性肠病和结肠癌的发生和发展。主要表现有①高丰度的具核梭杆菌与患者的不良预后相关；②癌症的复发可能部分归因于具核梭杆菌能促进结肠癌组织对化疗产生耐药性。
结肠癌(Colorectal cancer,CRC)是全世界范围内与癌症相关死亡的第二大主要原因，尤其是在50岁以下的个体中其患病率正逐步攀升。CRC作为肠道上皮的异质性疾病，其特征在于突变的累积和免疫反应的失调。越来越多的证据表明，高达90％的疾病风险是由饮食等环境因素所致，这与近些年来提出CRC相关“致癌菌群”的文献报道相一致。然而，与众所周知的幽门螺杆菌在胃癌中的因果作用不同，目前尚未鉴定触发CRC的特定微生物。因此，破译驱动CRC的特定致病菌群或代谢产物并表征其潜在机制十分必要。
鱼腥草为三白草科植物蕺菜Houttuynia cordataThunb.的新鲜全草或干燥地上部分，始载于《名医别录》。鱼腥草素来源于鱼腥草挥发油，不稳定易降解。目前临床上常使用它的亚硫酸氢钠加成复合物新鱼腥草素钠。新鱼腥草素钠(Sodium New Houttuyfonate，SNH)抗菌效果明显，对金黄色葡萄球菌、大肠杆菌及孢子丝菌等均有明显抑制作用。临床上为抗菌消炎药。
发明内容
本发明旨在提供一种新鱼腥草素钠的新用途。
具体来说，本发明提供了一种新鱼腥草素钠在制备抑制具核梭杆菌的药物中的应用。
在一优选例中，所述新鱼腥草素钠是作为唯一的活性成分用于制备抑制具核梭杆菌的药物。
在另一优选例中，所述抑制具核梭杆菌的药物可用于治疗结肠癌。
本发明各个方面的细节将在随后的章节中详尽描述。通过下文以及权利要求的描述，本发明的特点、目的和优势将更为明显。
附图说明
图1：MIC法测定SNH对Fn的抑制作用。
图2a～图2c通过CCK-8法检测SNH对结肠癌和正常细胞生长的影响。
其中：图a，b，c分别为SNH对结肠癌HCT116，结肠癌HT29和结肠上皮细胞生长的影响。
图3a～图3d SNH对具核梭杆菌促结肠癌细胞增殖的抑制作用。
其中：图a为SNH对具核梭杆菌促结肠癌细胞增殖的总影响；图b，c，d分别为不同时间段24h， 48h和72h检测SNH对具核梭杆菌促结肠癌细胞增殖的抑制作用。
图4a～图4c SNH显著抑制感染Fn裸鼠结肠癌肿瘤的生长。
其中：图a为对照组和SNH给药组及阳性对照组裸鼠结肠癌肿瘤大小；图b为各组裸鼠结肠癌肿瘤重量；图c为各组裸鼠结肠癌肿瘤体积。
图5通过RT-PCR证实在该模型中Fn富集于裸鼠结肠癌肿瘤组织。
具体实施方式
本发明的新鱼腥草素钠(Sodium New Houttuyfonate，SNH)，化学名称：十二酰乙醛的亚硫酸氢钠加成物，分子式是C14H27NaO5S，相对分子量330.41，其结构式如下：
本发明的新鱼腥草素钠(SNH)可通过商业途径购买获得。其纯度均符合药用标准。新鱼腥草素钠(SNH)的纯度以>98％最佳。
以将本发明的新鱼腥草素钠(SNH)制成药物为例。本发明的新鱼腥草素钠(SNH)可以单独使用或以药物组合物的形式使用。药物组合物包括作为主要活性成分的本发明的新鱼腥草素钠(SNH)及可药用载体。通常，本发明的药物组合物应当含有0.1～99.9％重量百分比的本发明的活性天然成分新鱼腥草素钠(SNH)。“可药用载体”不会破坏本发明的新鱼腥草素钠(SNH)的药学活性；同时，其有效用量，即能发挥药物载体作用时的用量对人体无毒害作用。
所述可药用载体包括但不限于：软磷脂、硬脂酸铝、氧化铝、离子交换材料、自乳化药物传递系统、吐温或其他表面活化剂、血清蛋白、缓冲物质如磷酸盐、氨基乙酸、山梨酸、水、盐、电解质如硫酸盐精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅酸镁、饱和脂肪酸部分甘油酯混合物等。
其他常用的药物辅料如粘合剂(如微晶纤维素)、填充剂(如淀粉、葡萄糖、无水乳糖和乳糖珠粒)、崩解剂(如交联PVP、交联羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素)以及吸收促进剂、吸附载体、香味剂、甜味剂、赋形剂、稀释剂、润湿剂等。
本发明的新鱼腥草素钠(SNH)以及其药物组合物可按本领域常规方法制备并通过胃肠道途径给药。口服制剂包括胶囊剂、片剂、口服液、颗粒剂、丸剂等。因此，本发明的新鱼腥草素钠(SNH)以及其药物组合物的给药途径应选择口服递药途径。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本专利说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
实验一新鱼腥草素钠作用Fn后的抗菌活性检测
实验方法：根据微量二倍稀释法检测中药单体对具核梭杆菌的最小抑菌浓度。麦氏比浊法调整菌液浓度为108CFU/mL，试验组加入中药单体新鱼腥草素钠，空白对照组加入不含中药单体新鱼腥草素钠的液体培养基，溶剂组则加入0.1％DMSO作为空白对照，每组均设3 个重复孔，与配制好的具核梭杆菌菌液1:1体积充分混匀，置于37℃培养箱中培养。利用全波长酶标仪测定OD600值从而确定中药单体的MIC值。试验重复3次。
实验结果：最小杀菌浓度是杀死细菌所需的最低浓度。利用肉汤稀释最低抑制浓度试验，通过传代至不含药物的琼脂平板进行测定。37℃培养18-24h后观察细菌生长情况，无菌生长即为被测药的最小杀菌浓度。如图1所示，采用2倍系列稀释法测定新鱼腥草素钠的MIC。结果表明：新鱼腥草素钠对具有较强的抑菌活性，其MIC为200μM。
实验二新鱼腥草素钠对结肠癌细胞和结肠上皮细胞增殖毒性检测
实验方法：观察HCT-116、HT29和460细胞，待细胞密度到达90％时，用0.25％的胰酶消化细胞。对消化细胞进行细胞计数，接种到96孔板中每孔5000个HCT-116细胞。待细胞贴壁后加入不同浓度的新鱼腥草素钠的培养基到96孔板中，每组设置6个重复组。分别在24h、48h、72h时检测细胞活力，检测前去除培养基，每孔加入10μL CCK-8检测液。设置空白孔(只加检测液)，并在37℃孵育1-2h，利用酶标仪检测450nm的吸光度，实验重复3次。
实验结果：如图2a～图2c所示，CCK8实验表明SNH干预后，SNH在其具有抗菌活性的有效剂量下(200μM)对细胞活性影响很小，大部分结肠癌细胞和结肠上皮细胞可正常生长。
实验三新鱼腥草素钠对Fn感染的结肠癌细胞抑制作用检测
实验方法：为进行细胞增殖分析，将HCT-116细胞的再悬浮液以每孔1×104接种在24孔板中，并加入2mL完整培养基。将细胞与Fn感染倍数孵育，并给予不同浓度的中药，采用甲硝唑处理的细胞作为阳性对照。使用Counstar细胞计数仪在24小时、48小时和72小时进行细胞计数。每项试验重复3次。
实验结果：如图3a～图3d所示，细胞计数实验表明具核梭杆菌可显著促进结肠癌细胞增殖，使用新鱼腥草素钠干预后，细胞的增殖水平显著下降，并且时间越长，新鱼腥草素钠抑制作用越强。
实验四新鱼腥草素钠作用Fn感染的结肠癌模型小鼠后，肿瘤生长状况检测
实验方法：裸鼠购于上海斯莱克动物实验中心，正常适应性饲养1周后开始实验；复苏人结肠癌细胞HCT-116，传代培养至第三代，以胰蛋白酶消化细胞，离心收集，PBS洗涤两次，悬浮为单细胞悬液。以微量注射器接种于裸鼠皮下。接种第6天后形成肉眼可见的癌结节，应用游标卡尺测量肿瘤最大直径(a)与最小直径(b)，根据公式v＝0.5x(axb2)计算肿瘤体积。每3天测量一次肿瘤。接种第9天开始，每3天在层流超净工作台内，以无菌微量注射器于肿瘤周围多点注射0.9％NaC1和Fn，注射总体积100μL/个肿瘤；并以无菌微量注射器于腹腔注射0.9％NaCl，注射总体积100μL/只裸鼠。共注射6次，末次注射后第2天电子分析天平测量肿瘤重量，数码单镜头反光式取景照相机拍照。将肿瘤组织置于-80℃冰箱保存。
实验结果：如图4a～图4c和图5所示，具核梭杆菌可明显促进结肠癌小鼠肿瘤生长，当新鱼腥草素钠作用于Fn感染结肠癌模型小鼠后，小鼠体内肿瘤细胞生长被显著抑制，肿瘤取出后，较模型组肿瘤显著缩小，表明该肿瘤生长被抑制。
本发明所涉及的多个方面已做如上阐述。然而，应理解的是，在不偏离本发明精神之前提下，本领域专业人员可对其进行等同改变和修饰，所述改变和修饰同样落入本申请所附权利要求的覆盖范围。
Claims (3)
1.新鱼腥草素钠在制备抑制具核梭杆菌的药物中的应用。
2.权利要求1的应用，其特征在于，所述新鱼腥草素钠是作为唯一的活性成分用于制备抑制具核梭杆菌的药物。
3.权利要求1的应用，其特征在于，所述抑制具核梭杆菌的药物可用于治疗结肠癌。
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