CN103877110B - 一种防治乙型病毒性肝炎的药物组合物及其应用 - Google Patents
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Abstract
本发明涉及一种防治乙型病毒性肝炎的药物组合物及其应用,该组合物由活性成分和辅料制备而成,其特征在于:所述的活性成分包括斯皮诺素或/和其衍生物。本发明具有较强的抗乙型病毒性肝炎病毒的生物活性,并且不会产生耐药性,为治疗乙肝提供了新的候选药物,具有非常重要的临床意义。
Description
技术领域
本发明属于天然药物技术领域,具体涉及一种防治乙型病毒性肝炎的药物组合物及其应用。
背景技术
乙型病毒性肝炎是由乙型病毒性肝炎病毒(HBV)引起的、以肝脏炎性病变为主并可引起多器官损害的一种病。本病广泛流行于世界各国,主要侵犯儿童及青壮年,少数患者可转化为肝硬化或肝癌。因此,它已成为严重威胁人类健康的世界性疾病,也是我国当前流行最为广泛、危害性最严重的一种病。乙型病毒性肝炎无一定的流行期,一年四季均可发病,但多属散发。近年来乙型病毒性肝炎发病率呈明显增高趋势。
慢性乙型病毒性肝炎治疗的目的是在肝脏发生明显损伤之前抑制HBV的复制。治疗的初期目标是抑制病毒复制,阻止肝脏损伤;治疗的远期目标是清除病毒,阻止疾病向肝硬化以及肝癌的发展,延长生存期。抗病毒治疗还用于防止肝移植后、化疗或免疫抑制治疗时乙型病毒性肝炎病毒的再复制。因为目前所有的抗病毒药物不能有效的清除HBVDNA,所以实现长期清除HBV的目标几乎不可能实现。慢性乙型病毒性肝炎的治疗有两种方式:免疫调节和抑制病毒。肝移植可用于对药物治疗无效的终末期肝病患者。
目前市场上治疗乙型病毒性肝炎的方法主要有注射干扰素类药物、服用阿德福韦酯,恩替卡韦等核苷类似物类药物以及注射乙型病毒性肝炎疫苗三种方式。但上述三种方式均存在比较大的缺点,长期服用干扰素会造成患者出现流感感样症状、并可能使患者出现消化道症状、脱发等不良反应。严重者还能抑制骨髓导致白细胞、血小板减少,这样就会导致患者的凝血功能下降。而服用阿德福韦酯,恩替卡韦等核苷类似物类则会导致乳酸性酸中毒和重度的脂肪性肝肿大,且很多患者服用半年左右就会耐药,而且还不能随时停药,否则可能会导致病情迅速恶化,甚至转化为肝硬化、肝癌。虽然乙型病毒性肝炎疫苗能够抑制HBV的复制,其安全性和耐受性都很好,但是还不足以打破乙型病毒性肝炎的免疫耐受状态进而清除HBV,仍需辅以抗乙型病毒性肝炎药物的治疗。
斯皮诺素(spinosin)是从酸枣仁中提取分离的黄酮类化合物,又名棘苷、酸枣素,为黄色粉末,分子式C28H32O15,分子量608.54,溶于甲醇。其化学结构如下:
通过检索国内外文献,尚没有发现斯皮诺素抗乙型病毒性肝炎病毒的文献报道。
发明内容
为了克服现有乙型病毒性肝炎治疗药物毒副作用大,治疗过程中易出现耐受性等不足,本发明通过对天然药物进行研究,提供一种植物源性的抗乙型病毒性肝炎病毒的药物。该治疗药物以斯皮诺素为活性成分,其用于乙型病毒性肝炎患者治疗时,疗效确切,毒剐作用小,且斯皮诺素的安全性和耐受性均较好,具有十分广泛的医疗应用前景。
本发明的目的是这样实现的:
一种防治乙型病毒性肝炎的药物组合物,由活性成分和辅料制备而成,所述的活性成分包括斯皮诺素或/和其衍生物。
优选地,如上所述防治乙型病毒性肝炎的药物组合物,其中所述的活性成分由斯皮诺素组成。
进一步优选地,如上所述防治乙型病毒性肝炎的药物组合物,其中所述的药物组合物为注射剂,所述的注射剂包括注射液、注射用冻干粉。
本发明通过体外试验研究证明,斯皮诺素在体外抗乙型病毒性肝炎病毒(HBV)的效果很显著。因此,本发明还提供一种制药用途,即:斯皮诺素或/和其衍生物在制备防治乙型病毒性肝炎的药物中的应用。优选的方案为:斯皮诺素作为唯一活性成分在制备防治乙型病毒性肝炎的药物中的应用。
与现有技术相比,本发明涉及的含有斯皮诺素的药物组合物具有如下突出的优势:
(1)有较强的抗乙型病毒性肝炎病毒的生物活性,并且不会产生耐药性;
(2)为治疗乙肝提供了新的候选药物,可以单独作为防治乙肝的药物使用,具有非常重要的临床意义。
具体实施方式
乙型肝炎病毒(HBV)是一种引起急性和慢性坏死炎症性肝病及肝细胞癌的DNA病毒。HBV具有特异嗜肝性、非细胞损伤与裂解、易发展为慢性等特征。HepG2.2.15细胞是能够表达HBV抗原和分泌完整HBV颗粒的肝胚瘤细胞系,也是目前用来研究HBV复制及筛选抗乙肝药物最为合适的细胞模型系统。本发明采用HepG2.2.15细胞的培养,MTT比色法检测药物对细胞的毒性,ELISA检测上清HBsAg及HBeAg,从而证实了斯皮诺素具有抗HBV的药效。具体试验过程如下:
实施例1斯皮诺素体外抗乙型病毒性肝炎病毒(HBV)的药效测定
(1)HepG2.2.15细胞培养
细胞培养液为MEN培养液,每100mL含胎牛血清10mL,3%(w/v)的谷氨酰胺溶液1mL,G418380μg/mL,庆大霉素50U/mL;细胞消化液为0.25%(w/v)的胰酶溶液,用Hanks液配制。
细胞培养方法:将HepG2.2.15细胞解冻后,接种入25cm2培养瓶,浓度为1×105个/mL,待细胞长满后,加0.25%(w/v)的胰酶溶液37℃消化3-5min。加培养液吹打,1∶3传代,每天收集上清,连续2周,冷藏待检。
(2)药物的细胞毒性试验
用MTT法测定药物的胞毒性,96孔板每孔加浓度为3×105个细胞/mL的HepG2.2.15细胞100μL,37℃5%CO2培养箱中培养。一天后,换用含药培养液,每个浓度4孔,将斯皮诺素用DMEM培养液稀释成(500μg/mL,250μg/mL,125μg/mL,62.5μg/mL),每3天换同浓度含药培养液,37℃5%CO2培养箱中继续培养8天。向每孔细胞中加入5μg/mLMTT10μL,每孔中存留有上清100μL,37℃5%CO2培养箱中培养4h后,酶标仪570/630nm波长测定OD值。细胞抑制百分率=[(细胞对照OD值-药物作用组OD值)/细胞对照OD值]×100%。按Reed-Muench法计算最大无毒浓度(TCO)。每个浓度斯皮诺素进行两批实验,每批进行3组平行实验,TCO为250μg/mL。表1显示斯皮诺素对HepG2.2.15细胞有低毒作用,它的最大无毒剂量是250μg/mL。
表1斯皮诺素对HepG2.2.15细胞的毒性作用
(3)斯皮诺素抗HBV药效测定
96孔板每孔加浓度为3×105个细胞/mL的HepG2.2.15细胞100μL,37℃5%CO2培养箱中培养。一天后,换用含药培养液,每个浓度4孔,将斯皮诺素用DMEM培养液稀释成(50μg/mL,25μg/mL,12.5μg/mL,6.25μg/mL),每3天换同浓度含药培养液,第9天收集培养液经高速离心后的上清液,ELISA检测上清HBsAg及HBeAg。每孔取上清5μL,原液不做稀释,按酶联免疫试剂盒说明进行检测。酶标仪在450nm波长读数,结果以P/N值表示,P/N值=标本A/阴性对照A值。抑制率=(未加药对照孔P/N值-实验孔P/N值)/(未加药对照孔P/N值-2.1)×100%。结果见表2。
表2斯皮诺素对HepG2.2.15细胞分泌HBsAg和HBeAg的影响
与未加药对照组比较,*P<0.05,**P<0.01;
本实验结果显示斯皮诺素对2.2.15细胞有较低的细胞毒性(最小无毒剂量为250g/mL)。在此剂量时对HBsAg和HBeAg的抑制率分别为45.5%和40.3%,有显著性作用(P<0.01)。HBsAg和HBeAg是乙型病毒性肝炎病人血清中主要的标记,提示斯皮诺素在体外有抗HBV作用。
Claims (5)
1.一种防治乙型病毒性肝炎的药物组合物,由活性成分和辅料制备而成,其特征在于:所述的活性成分包括斯皮诺素。
2.如权利要求1所述防治乙型病毒性肝炎的药物组合物,其特征在于:所述的活性成分由斯皮诺素组成。
3.如权利要求1或2所述防治乙型病毒性肝炎的药物组合物,其特征在于:所述的药物组合物为注射剂,所述的注射剂包括注射液、注射用冻干粉。
4.斯皮诺素在制备防治乙型病毒性肝炎的药物中的应用。
5.斯皮诺素作为唯一活性成分在制备防治乙型病毒性肝炎的药物中的应用。
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