CN1895671A - 治疗病毒型肝病的复方制剂 - Google Patents
治疗病毒型肝病的复方制剂 Download PDFInfo
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- CN1895671A CN1895671A CNA2005101309140A CN200510130914A CN1895671A CN 1895671 A CN1895671 A CN 1895671A CN A2005101309140 A CNA2005101309140 A CN A2005101309140A CN 200510130914 A CN200510130914 A CN 200510130914A CN 1895671 A CN1895671 A CN 1895671A
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Abstract
本发明公开了一种治疗病毒型肝病的复方制剂,有效成份包括抑止病毒复制再生的药物、增强人体免疫力的药物、保护与修复肝脏的药物和保护肾脏的药物。该复方制剂疗效显著、没有任何交叉作用、安全性高,具有更好的抗病毒能力,可增强患者的免疫力,还有防止乙肝感染和增强肝细胞再生的功能。
Description
发明领域:
本发明涉及一种治疗病毒型肝病的药物,更确切地说涉及一种治疗病毒型肝病的复方制剂。
发明背景:
病毒型肝病是具有潜在致死性的慢性疾病之一,主要是指乙肝和丙肝。中国是乙肝大国,每10个人中就有1个是乙肝病毒携带者。据权威统计,目前中国有慢性无症状乙肝病毒携带者约1.2亿,慢性乙肝病人约3000万。这些乙型肝炎病毒感染者中有50~60%发展成肝炎,而肝炎患者中又有约三分之一的人会发展成肝硬化与肝癌。中国人群流行病学调查结果显示,丙肝病毒的感染率约为3.0%,即约4000万感染了丙肝,两者相加约有7000万的病毒型肝炎患者,开发安全有效的治疗病毒型肝炎的特效药对中国极其重要。
现有的各种用药方式虽然均有一定的疗效,但是效果均不理想。比如干扰素是人体淋巴细胞在受到病毒刺激时分泌的一种细胞因子,有抑制病毒繁殖(复制)的作用。由于丙型肝炎的肝细胞损伤机制是由于丙型肝炎病毒直接作用的结果,因此,对丙型肝炎用干扰素治疗效果较好,一般有效率在50~70%左右。但干扰素只能干扰乙型肝炎病毒的复制,而不能阻断乙型肝炎病毒感染导致的免疫损伤。因此,对HBeAg(+),HBV DNA(+)者应用干扰素有效率只在30~40%左右。另外抗病毒药物干扰素容易受到剂量限制的毒副作用制约,如可引起发热、白细胞减低等症状(N.Engl.J.Med.,1996,334,1422-1427.;N.Engl.J.Med.,1997,336,347-356)。还有,最常使用的逆转录酶抑制剂乙肝药,短期(6个月-1年)使用无法清除细胞内的CCC DNA(共价闭合环状脱氧核糖核酸.J.Virol.,1994,68,1059-1065),停药后复发的常常是变异的病毒且具有抗药性,有很高的致命性。完全清除病毒需要很长的时间,如乙肝病毒一般需要1-5年的时间,而这么长时间的用药早已严重破坏人体的免疫系统,整体的健康状况严重下滑(Proc.Natl.Acad.Sci.USA,1996,93,4398-4402),并出现不少种类的并发症。所以治疗病毒型肝炎需要从两方面着手,既要确保清除肝病毒,还需要保持患者的各种功能系统如免疫系统功能不受太大损害,即预防并发症的发生。
慢性肝病患者一般还会出现低血钙,低血钙又可引起夜间“抽筋”的临床表现。(1)慢性肝病患者的门脉高压可影响肾功能,造成钙磷代谢异常,钙从尿中排泄增多;(2)肝病患者食欲差,造成钙进食减少;(3)服用某些药物,如利尿药,造成钙排泄增多。因此,肝病患者应注意加强钙的吸收和适当补钙。
丙肝病毒(HCV)是一种正链RNA病毒,RNA病毒的变异速度比DNA病毒快100万倍,而且体形经常改变。这就使得丙肝病毒的疫苗研制很难。乙肝病毒是病毒中的特例,其遗传信号物质虽然是双链DNA结构,但是乙肝病毒环型结构有约三分一的部分是单链(single stranded),由于该单链结构的存在,使得乙肝病毒同样易于变异,开发乙肝疫苗的速度很有可能赶不上乙肝病毒变异的速度。目前国际上还没有清楚认识到病毒肝病致病的关键机理,另外,病毒型肝病发展成为肝硬化的原因是肝细胞的不断坏死。肝细胞坏死后,正常的肝组织发生“塌陷”,机体的再生功能就会再生出一些纤维,来充填“塌陷”的部位。这是机体对坏死的组织的一种正常代偿功能,代表坏死部位的愈合,本应是有利的。但是,如果肝细胞不断地坏死,肝脏内不断地再生纤维,这些纤维取代了大部分的肝组织,而它们又没有正常肝细胞的功能,肝脏变得又硬又小,这就形成了肝硬化。因此,预防病毒型肝病患者发展成为肝硬化的关键在于阻断肝细胞的坏死。这就是说要保证肝功能的正常,理想境界为能同时增强肝的再生而恢复肝的正常功能,文献报道(J.Virol.1994,68,5469-5475)指出,没有成熟的病毒核心蛋白壳(viral nucleocapsids)在肝细胞分裂时被迅速的破坏掉,在抗病毒药物存在下增强肝的再生就意味着清理肝病毒的速度加快。
由于肝病毒变异快速和造成体内免疫系统的紊乱,因此,重建对肝病毒的有效免疫力,从而达到抑制病毒,改善肝脏炎症坏死,降低转氨酶,维持肝功能正常,增强肝的再生,可能是解决病毒性肝慢性感染的更根本和行之有效的策略。这样可以最有效的治疗病毒性肝病,并且还可以延缓及阻断慢性肝病向肝硬化及肝癌发展,延长患者寿命,提高患者的生存及生活质量。
最合理的的病毒性肝炎的治疗方法应当是对患者的全面保养与治疗,包括消灭肝炎病毒;调节机体免疫功能,保护肝细胞的完整,促进肝细胞的恢复再生;促进肝细胞的各种代谢,保证肝细胞的正常功能,促进转氨酶的下降;并治疗各种并发症等。我们参照中医的理论,使用已知的疗效显著安全性高的药物成份复方成耐受性良好而且没有抗药性的特效病毒性肝病新药。
发明内容
(一)发明目的
本发明的目的就是提供一种疗效显著、全面、没有任何交叉作用、安全性高、扶正祛邪、且耐受性良好、没有抗药性的特效病毒性肝病新药。避免病毒性肝病病人因病急乱用药而造成的对肝脏的进一步损害,为在本医疗领域的工作人员提供一个合理配方的复方用药,防止一部分人员随意的采用多种药物治疗而进一步损害病毒性肝病患者的身体健康造成难以解决的后果。
另外,本发明的复方病毒性肝病特效药还表现出没有预测到的疗效,如研究结果发现,本发明中的复方制剂有抗乙肝感染和增强肝再生的功能。
(二)复方制剂的有效成份
本发明中所描述的复方制剂有效成份包括以下三种:
(a)抑止病毒复制再生的药物;
(b)增强人体免疫力的药物;
(c)保护与修复肝脏的药物和保护肾脏的药物。
用于抑止病毒复制再生的有效成份包括甘草甜酸(glycyrrhizin),谷胱甘肽(Glutathione),硫辛酸(alpha-lipoic acid),DL-蛋氨酸(DL-2-hydroxy-4-methylthiobutanoic acid),阿德福韦酯(Adefovir dipivoxil),恩替卡韦(entecavir),拉米夫定(Lamivudine),泰诺福韦(Tenofovir),甲磺酸瑞莫夫韦(Remofovir,PMEA的药物前体),和其它用来对抗病毒的药物,如阿昔洛韦(Aciclovir),利巴韦林(三氮唑核苷,Ribavirin),和阿糖腺苷(Vidarabine)等。
用于增强人体免疫力的药物包括艾可尼西亚(Echinacea,中文又译为紫锥菊),维生素E,硒(Selenium),维生素C,辅酶Q10,和左旋咪唑(Levamisole)等。
用于保护与修复肝脏的药物,以及保护肾脏的药物包括水飞蓟素(Silymarin),L-肉碱(L-Carnitine),还有血管内皮细胞生长因子(VEGF),黄芪提取物(Astragalus Extract),维生素C,叶酸,葡萄糖醛酸内酯,肌苷(Inosine),谷胱甘肽等;以及必需的钙和协助钙吸收的维生素D。
甘草甜素 甘草甜素是甘草酸(glycyrrhizic acid)的钾、钙盐。甘草甜素在抑制病毒的增殖方面起者较好的作用。甘草甜素是一个研究得很多的化合物,早在1921年,Karrer,Chao从光果甘草中分离得到该化合物[Helv.Chim.Acta 4,100(1921)],其结构在1950年测定[J.Chem.Soc.1983,(1950)],1956年修正结构测定结果[Bio chem.J.63,9(1956)]。甘草甜素的药理作用涉及多个方面,主要有抗病毒、调节免疫功能、抗菌、抗炎、抗肿瘤、抗致突变、促皮质激素样作用等,还有保护肝脏,防治肝硬化的作用。甘草甜素是一种广谱抗病毒物质,文献报道有抗艾滋病病毒、白蛉热西西里病毒、流行性出血热病毒、非洲猪热病毒、顽固性人巨细胞病毒、马堡病毒、牛痘、单纯疱疹、带状疱疹、鸡病毒性肺炎、脑脊椎病、水疱性口炎病毒、流感病毒、甲乙丙肝等肝炎病毒等。甘草甜素是通过抑制病毒的增殖,阻断其复制达到其抗病毒的作用,直接灭活该病毒。甘草甜素抑制艾滋病毒增殖的作用。0.5mg/ml甘草甜素体外抑制艾滋病毒的增殖达98%以上,0.125mg/ml时能抑制50%空斑形成,提示甘草甜素不是抑制艾滋病毒的反转录酶活性,而是通过恢复辅助T淋巴细胞的功能起作用的。甘草甜素在体外可抑制带状疱疹病毒的增殖(ID50=0.71mmol/L),且可直接灭活该病毒。甘草甜素不仅仅抑制肝脏的激素代谢,而且也可能对肾脏、膜等局部的醛固酮(醛固酮是肾上腺分泌的激素,促进Na+吸收和K+分泌。醛固酮缺乏造成低血K+,过量造成高血K+。低血K+刺激尿酸化,高血钾减弱尿酸化。)有强化作用。甘草甜素对慢性乙型肝炎也有效[Antiviral Res.1996 May,30(2-3),171-7和J Hepatol.1994Oct,21(4),601-9.],其机制与增强NK细胞作用有关。甘草甜素的免疫作用表现为能非特异地增强Mφ的吞噬活性,并可清除抑制性Mφ的抑制活性。甘草甜素能抑制激活的大鼠腹腔Mφ产生前列腺素PGE2,抑制花生四烯酸的释放。甘草甜素对PGE2的抑制是由于抑制了PG合成的限速酶-磷酯酶A2的活性。甘草甜素体外处理小鼠腹腔Mφ可增加干扰素产生。甘草甜素可诱导M1细胞(由小鼠骨骼白血病细胞建立的Mφ株)产生白介素-1(IL-1),且与γ-干扰素(IFN-γ)有协同效应,还可增加脂多糖(LPS)刺激的Mφ瘤产生IL-1。给小鼠静脉注射20μg/kg甘草甜素2次,发现脾细胞IFN产生能力增强。给小鼠腹腔内注射330mg/kg甘草甜素,20h后IFN活性达高峰。体外实验表明,甘草甜素本身无诱发IFN能力,但用甘草甜素预处理人外周血淋巴细胞12h,增加刀豆球蛋白A(ConA)诱生IFN能力,但不能增强PHA诱导的人脾淋巴细胞产生IFN。甘草甜素可增强ConA诱导淋巴细胞分泌IL-2的能力。甘草甜素增强IFN-γ产生的机制,有人认为是通过抑制PG合成的限速酶-磷酯酶A2的活性来抑制PG的产生,并诱导IL-1产生,从而促进IFN-γ和IL-2的产生。给小鼠腹腔注射0.5mg/kg甘草甜素可增强肝脏中NK活性,但不增加NK细胞数量。慢性乙肝患者注射甘草甜素,也可增强其NK活性。体外实验表明甘草甜素本身无增强NK活性作用,但可促进IFN-γ和IL-2增强NK活性。临床试验研究成果显示甘草甜素和拉米夫定的治疗效果比单独使用拉米夫定的更好[Leuk Lymphoma.2001,41(1-2),191-5和Hepatol Res.2001,20(1),1-8],并且和使用其它合成的药物不同,使用甘草甜素没有任何毒副作用[Clin Ther. 1989,11(1),161-9]。
谷胱甘肽 谷胱甘肽(L-谷胱氨酸-L-半胱氨酸-甘氨酸),存在于所有动物细胞中,正常环境下以其硫醇还原型(GSH)存在,是细胞内主要的非蛋白质巯基化合物。在许多生命活动中起着直接或间接的作用,包括基因表达调控、酶活性和代谢调节、对细胞的保护、氨基酸转运、免疫功能调节等。氧化应激或亲电化合物攻击可使细胞内GSH含量下降,或使其转变为双硫氧化型(GSSG),后者又可通过以NADPH为辅酶的谷胱甘肽还原酶转变为GSH。谷胱甘肽在临床主要作为解毒、抗氧化作用的药物,防治肿瘤病人化疗和药物性肝损害,治疗慢性脂肪肝,辅助治疗病毒性肝炎和肝炎肝硬化,联合果糖二磷酸钠辅助治疗慢性重型肝炎。蒋兰英等[蒋兰英,叶坚虹,娄国强,等.谷胱甘肽辅助治疗病毒性肝炎的疗效,中国新药与临床杂志,1998,17(4),230]对乙型或乙戊重叠感染病毒性肝炎患者在综合治疗的基础上加用0.6~1.2g/日GSH静脉滴注,连续用30~60天,并与对照组进行比较。结果谷胱甘肽治疗组和对照组显效率分别为62%和43%,总有效率分别为80%和55%。谷胱甘肽组疗效明显优于对照组(P<0.05),且无毒副作用。蔡卫平等[蔡卫平,瘳履坦,谷胱甘肽治疗药物性急性肾损害,中国新药与临床杂志,2000,19(4),291]应用谷胱甘肽治疗各种药物性急性肾衰竭,并以传统用药复方氨基酸和金水宝胶囊为对照,结果谷胱甘肽组和对照组对急性肾功能衰竭总有效率分别为92%和64%(P<0.05),对血尿、蛋白尿总有效率分别为89%和85%,57%和50%(P<0.01和P<0.05),显示谷胱甘肽有助于肾功能恢复,肾功能恢复时间也可缩短,对无肾功能损害的血尿、蛋白尿也有明显疗效,用药过程中不良反应少而轻。
硫辛酸 硫辛酸是存在于人体内的天然抗氧化剂,由细胞的线粒体产生。它能使水溶性维生素C和脂溶性维生素E在细胞内外的浓度同时提高,而且通过硫辛酸的氧化还原特性,可使维生素C和维生素E再生。硫辛酸能在其他抗氧化剂短缺时成为“替身”。也就是说,如果体內缺乏维生素E或C时,硫辛酸将暂时接手它们的工作。硫辛酸抗氧化效果胜过维生素A、C、E,并能消除加速老化与致病的自由基,可能是目前人类所知的天然抗氧化剂中效果最强的一种。硫辛酸能够治疗肝坏死及乙肝、丙肝[Posit.Health News.1998,(No 17),19-21]。美国医师曾对3名食用毒蘑菇造成肝坏死的患者,采用硫辛酸治疗。结果3名患者的病情在短时间内得到控制,肝功能均恢复正常[Vet.Hum.Toxicol.1986,28(4),318-22,Ann Neurol.1978,3(2),177-9]。硫辛酸可结合并分解肝内毒素,减轻肝炎症状,恢复肝功能。艾滋病(HIV)和病毒性肝炎患者的抗氧化防御系统通常较薄弱,由于抗氧化剂缺乏,所以在氧化剂刺激病毒时无法防止病毒繁殖。硫辛酸可刺激患者血液中维生素C、总谷胱甘肽[Posit.Health News.1998,(No17),14-5]、总硫化物浓度增加,改善T4/T8淋巴细胞比例,从而降低自由基对患者的损伤[J.Appl.Toxicol.2004,24(1),21-6.]。
DL-蛋氨酸 DL-蛋氨酸是属于人体必须的氨基酸,具有强力解毒作用,能抑止病毒的复制再生。其分子中的甲基与体内的荷尔蒙作用而产生胆素,胆素再与脂肪酸,甘油,磷酸发生作用变成磷脂质后被体内吸收强化肝机能,如缺乏则会引起肝脏、肾脏障碍,对于保护肝功能尤其必要。
其它:如阿德福韦酯,恩替卡韦,拉米夫定,泰诺福韦,和甲磺酸瑞莫夫韦等均是人类化学合成的用于抗肝病毒的小分子化学药。
艾可尼西亚 在过去的二、三十年内,无数的临床试验从现代医学的角度证明了艾可尼西亚具有良好的治疗效果和用药安全性,包括对天生的免疫系统缺陷疾病的治疗效果[Pol.J.Vet.Sci.2003,6(3Suppl),3-5.和Z.Phytother.1989,10,67-70.以及Phytomed.1996,3,95-102]。艾可尼西亚在现代医学上的应用主要集中在它对免疫系统的强化作用上面,主要用于治疗病毒性感染[Exp Biol Med(Maywood).2003,228(9),1051-6],病菌性感染,原虫性疾病,和真菌性感染等(Alternative Medicine Review,2001,6,411-414),其中有六个临床试验和体外试验证明艾可尼西亚汁液能够刺激白细胞的产生并且提高白细胞的吞噬活性[Arzneimittelforschung.1985,35(9),1437-9.和J.Altern.Complement Med.1995,1,145-160]。在超过3900人的临床试验中证明,艾可尼西亚汁液能够很好地降低感冒和流感的发病率,减轻病患的症状等(Nutrition Science News,1999年九月号和1999年三月号等)。另外发现艾可尼西亚汁液能有效地抑制病毒的分裂,控制病毒的衍生复制(Planta Med.1978,33,89-102)。艾可尼西亚可刺激非特异性防御机制,攻击被病毒感染的细胞。还有一些临床试验显示,艾可尼西亚能够延长肝细胞癌症病人的生存期[Arch Geschwulstforsch.1990,60(5),379-83]。
维生素E 维生素E对动物的生殖、发育有明显的影响,缺乏时会使动物的生殖机能受损,而补充它则可恢复其生育机能。维生素E可以促进维生素A的吸收、利用和肝脏贮存。因为维生素E的结构特点和在人体内的分布特点,它具有抗自由基,抗衰老,保护肝脏和肝细胞的再生,增强免疫力,以及保护心血管与皮肤等一系列功能。自由基是广泛存在于各种化学反应中的活泼基团,对人体正常生理代谢具有重要的功能,倘若自由基过量,从而引起自由基链式反应,则将导致细胞膜不饱和脂肪酸的脂质过氧化,新产生的大量脂质过氧化物会损伤细胞膜及细胞内的大分子蛋白质与核酸,对机体造成损伤。当自由基进入脂相,发生链式反应时,维生素E起到捕捉自由基作用。维生素E对抗自由基脂质过氧化作用的效率很高。在研究中发现,维生素E的缺乏对人类或动物的免疫功能均有影响,不仅是体能免疫力降低,而且对细胞免疫也有很大影响。二十世纪80年代的研究阐明了维生素E是肝细胞生长的重要保护因子之一。研究发现,肝细胞死亡的最后途径之一是肝细胞中维生素E的耗竭[Free Radic Res.1996,25(6),461-6]。维生素E对多种急性肝损伤具有保护作用[Cancer Res.2003,63(20),6707-15],对乙肝有不错的疗效[Antiviral Res.2001,49(2),75-81和Ann InternMed.1998,128(2),156-7],并且明显的增强乙肝患者的免疫力[Lik Sprava.1992,(4),90-1和JAMA.1997,277(17),1380-6],对脂肪性肝炎有治疗作用且没有毒副作用[Aliment Pharmacol Ther.2001,15(10),1667-72],对慢性肝纤维化有延缓作用。临床试验结果还发现,复方使用干扰素和维生素E对急性乙肝的治疗效果好于单独使用干扰素[Pediatriia.1992,(1),60-4]。
硒 硒是人类近二十年來才发现的对人体的健康状况有重大影响的物质。动物实验发现,饮水中添加硒能使老鼠体内的天然杀手细胞活性增强,并经体外实验证实能造成肿瘤细胞凋亡[Ann Acad Med Singapore.1984,13(2),194-205]。硒不仅可以提高人体免疫力具有防癌的效果[Biol Trace Elem Res.1988,15,231-41和Cancer Res.2003,63(20),6707-15],而且能够保持人身体组织的年轻活力,减轻火伤、炎症、烫伤的痛苦,减少停经期的痛苦。根据CNN 98/8/22的报导,被医学界发现有抗癌抗氧化力的硒(Selenium)对于男性的摄护腺癌的发生可以減少1/2到2/3。美国每年有超过40,000名男性死于摄护腺癌(prostatecancer),成了头号男性杀手。这是由Natioanl Cancer Institute(国家癌症中心)比较高硒与低硒饮食的美国男性所作的研究所发现的。男性需要较多的硒,硒由精液中排出体外,造成消耗。如果人体内缺乏硒,男性的性能力会提早消失。硒对人体的肝脏有着极其重要的作用,跟踪乙肝病人血液检测发现,乙肝病人和从乙肝转化为肝癌的病人,他们血液中的硒和维生素E含量很低[J Trace ElemMed Biol.2002,16(4),227-30和Am J Epidemiol.1999,150(4),367-74];在1982年人类通过体外实验证实硒能刺激肝细胞的生长发育[Cancer Res.1982,42(9),3858-63];历时三年包含20,847人的临床试验中证实,硒能够预防乙肝的发生[Biol Trace Elem Res.1989,20(1-2),15-22]并预防肠肿瘤[中华预防医学杂志Zhonghua Yu Fang Yi Xue Za Zhi.1992,26(2),105-7]和减低肝癌的发病率[BiolTrace Elem Res.1991,29(3),289-94和中华预防医学杂志,1992,26(5),268-71];进一步的动物对比实验(四年)结果显示补充硒能降低乙肝的患病率77.2%和癌前病变75.8%。同时进行的历时八年使用加硒食盐,包括超过13万人口的预防实验显示,乙肝的患病率下降了35.1%,而使用硒的乙肝病人没有一个转化为肝癌,使用安慰剂的乙肝病人,其转化为肝癌几率是6%左右[Biol Trace Elem Res.1997,56(1),117-24]。硒对人体肝脏的保护作用最近又从基因组研究成果中得到了进一步的证明[Biol Trace Elem Res.1997,56(1),63-91和Nutr Cancer.2000,38(2),179-85]。鉴于硒对预防和治疗乙肝的重要性,一些新的含硒化合物被合成出来并验证它们对预防和治疗乙肝有作用[J Med Chem.2000,43(21),3906-12],所以对乙肝病人补充硒是一个重要治疗手段[Exp Mol Pathol.2004,77(2),121-32]。现代医药研究成果也在不断的证明中医复方理论,比如临床试验发现维生素E和硒是两种协同作用的物质,同时服用效力较強,分别服用效力相对较差[CancerRes.2003,63(20),6707-15]。
维生素C 维生素C是人体必需的维生素,一般认为在细胞呼吸的氧化还原作用上有重要的角色。细胞间基质及胶原蛋白的形成及维护、类固醇的合成、叶酸的转化及酪氨酸(tyrosine)的代谢都需要维生素C。维生素C是组织生长及修补健康牙龈必需的抗氧化剂,具有促进血液循环、消除疲老、改善白血球机能、增强免疫力、預防坏血病、骨折等多种功能,并能降低胆固醇及高血压、预防动脉硬化,保护肝脏和对肝中毒的解毒作用。动物试验结果显示,维生素C和水飞蓟素共用,对铅中毒的鼠肝的解毒作用比单独使用水飞蓟素的见效快,疗效彻底[Toxicology.2005,206(1),1-15]。许多研究成果表明维生素C对肝脏的保护作用和对肝病的预防与治疗作用是通过维生素C本身的抗氧化能力实现的[FreeRadic Biol Med.2003,34(1),1-10]。一般肝功能出现问题常常会增加肾脏的负担,有肾病变(nephropathy)的乙肝病人,其体内的维生素C浓度比正常人低,而其肾脏清除维生素C的速率(clearance rate)也比较快,这可能是因为肾病使维生素C容易由肾脏流失,因此体內浓度下降。研究人具大胆地推论,缺乏这种抗氧化维生素的保护,是导致肾病变肾病病人的心脏病机会增高的主要原因。还有,患乙肝的病人其血液中的维生素C浓度比正常人低[Liver Int.2005,25(3),518-26和Drug Alcohol Depend.1981,8(3),245-55],所以,我們在复方制剂中建议乙肝患者多服用维生素C,以补充其肾脏加速流失的损失,很好的预防和治疗乙肝病人可能的肾病变。维生素C对肝炎的治疗作用在分子水平的研究成果显示为完全恢复肝内重要代谢酶的活性,肝细胞发炎后产生过量的一氧化氮(NO),一氧化氮严重抑止肝内重要代谢酶如单氧酶(monooxygenases)和细胞色素P450s的活性,用维生素C可以使它们的活性完全恢复[Life Sci.2004,75(21),2559-72]。
辅酶Q10 人体的肝脏用蛋白质的酪氨酸(Tyrosine)及苯丙氨酸(Phenylalanine)及维生素E、B1、B6及叶酸等合成辅酶Q10,以供自身之需要。苏格兰爱丁堡大学米切尔博士(Peter D.Mitchell,Ph.D)发现人类的细胞在制造能量时,必须有辅酶Q10的参与,因而荣获1978年的诺贝尔化学奖。辅酶Q10主要存在于人体的心脏、肝脏、肾脏、和胰腺内。它的重要功能包括调节细胞的生长发育和细胞自身的维护,以及抗氧化作用。辅酶Q10的这种抗氧化作用可以通过降低自由基对这些器官内细胞的损害来保护心脏、肝脏、肾脏、和胰腺等重要器官。自由基对这些器官内细胞的损害包括对DNA的破坏性作用。所以,人体内如有充足的辅酶Q10,特别是乙肝病患者,其免疫功能得到提高,并消灭体内的病毒。对一些可怕的疾病如乙肝,癌症,慢性感染,念珠病菌,艾滋病等有预防作用。辅酶Q10能保护肝脏免于一些化学物的损害比如四氯化碳[Gastroenterol Jpn.1981,16(3),281-5],同时也有结果显示共同使用左旋肉碱和辅酶Q10的保护作用强于任何单一物质[Drugs Exp Clin Res.1993,19(2),65-8]。在一临床试验中,使用辅酶Q10的人在注射过疫苗后仅三十天后就产生了抗体,而使用安慰剂的人此时没有检测到任何抗体[Biofactors.1999,9(2-4),351-7],这几年市场上最热的他汀类药对肝脏有不小的损害作用,特别是对肝脏有问题的肝损伤更大,而使用辅酶Q10后可以使对肝脏的损害降低到检测不到的水平[ClinPharmacol Ther.2002,72(4),461-4]。
左旋咪唑 左旋咪唑是人工合成的化合物,用于治疗乙肝。临床试验研究发现,将左旋咪唑与拉米夫定联合使用,对慢性乙型肝炎病人的疗效优于单独用拉米夫定或左旋咪唑。左旋咪唑能够增强机体的免疫力,但是该药不能连续使用,否则会造成骨髓抑制。
水飞蓟素 水飞蓟素是从小飛雉的种子中提取的Milk Thistle(中文名乳荊)的主要有效成份。早于两千多年前,欧洲就发现乳荊有保肝、强肝的功能,在民间甚为盛行。1949年首次在德国临床试验中证实乳荊对被四氯化碳侵害的患者有保肝作用,以及具有治疗肝炎的功能。今年初南韩科学家通过动物试验发现,水飞蓟素对肝纤维化的预防作用是通过抑制纤维化过程中的炎症与低氧来实现的[World J Gastroenterol.2005,11(8),1141-8]。1968年,在德国从种子中提取出其主要有效成份水飞蓟素(Silymarin)。经过將近三十多年來的试管试验、动物试验、临床试验及研究,已经比较全面地证实了水飞蓟素确实具有保肝、强肝及解毒的功能。比如,2002年意大利科学家的临床试验发现水飞蓟素能强化熊去氧胆酸对肝病的治疗作用[Clin Ter.2002,153(5),305-7]。再比如关于急性肝炎的试验(Acute Viral Hepatitis):77人中42人用空白对比物(Placebo),35人用水飞蓟素。对照组平均复元期为43天,而用水飞蓟素的患者复元期仅29天[Drugs.2001,61(14),2035-63.以及其引用的文献]。迄今为止Milk Thistle已被证明确实具有如下重要的功能:防治酒精,药物,化学物(如四氯化碳等),殺虫剂,空气中的污染及放射性等對肝脏功能的破坏[Toxicology.2005,206(1),1-15;Toxicol Sci.2004,80(2),335-42];治疗及防止肝硬化,促进肝细胞之再生;防治各种不同的肝炎包括乙肝[Nephrol Dial Transplant.1989,4(4),297-301],降低肝酵素的指数;促进胆汁的流通性,进而防止胆结石;治疗及预防野生毒菇之中毒;其他如对于消炎,降低胆固醇,降低血压,血糖等亦有一些效果。
叶酸 叶酸天然存在于动物的肝、肾内。叶酸是由喋啶、对氨基苯甲酸和谷氨酸残基组成的一种水溶性B族维生素,为机体细胞生长和繁殖所必需的物质,是对红细胞发育成熟起辅助作用的水溶性维生素。叶酸制剂常与肝制剂同用,以治疗恶性贫血,是制造红血球不可缺少的物质。
L-肉碱 L-肉碱又叫左旋肉碱,是脂肪代谢过程中的一种必需的辅酶,能促进脂肪酸进入线粒体进行氧化分解。对有肝病的儿童血液检查中发现,他们的左旋肉碱明显低于健康人[Minerva Pediatr.1989,41(5),247-51]。肝脏是主要代谢使用和向全身运送左旋肉碱的器官,肝脏患病影响左旋肉碱的产生和使用造成全身损害,原发性胆汁性肝硬化的肝病患者其尿中排出的左旋肉碱量明显增多[Hepatology.1997,25(1),148-53],所以对肝病患者补充左旋肉碱非常重要[LifeSci.1996,59(19),1579-99和Ann Pharmacother.2000,34(5),630-8]。左旋肉碱除了有对肝脏的保护作用外,还能增加人体的免疫力[Treatmentupdate.1998,10(5),4-6],最新的研究成果显示左旋肉碱对肝病癌变的预防作用是痛国抑制线粒体功能反常来实现的并且疗效很好[Int J Cancer.2005,113(5),719-29]。
本发明中的实用配方包括所有以上有效成份,每个单独配方中可以仅含有每一种有效成份的一个,也可同时使用几个。本发明中的有效成份的选择同时建立在它们之间没有任何交叉毒副作用的基础上,所有的本发明中使用的这些有效成份均没有被报道过任何交叉毒副作用,可从网站http://www.drugdigest.org/DD/Interaction/上查到。
在本发明的单元剂型中:
甘草甜酸的含量一般介于500毫克到1500毫克之间,最合适剂量为1000毫克;
谷胱甘肽的含量一般介于50毫克到1500毫克之间;
DL-蛋氨酸的含量一般介于1.0毫克到800毫克之间;
阿德福韦酯的含量一般是10毫克;
恩替卡韦的含量一般介于0.25-0.5毫克;
拉米夫定的含量一般是100毫克;
泰诺福韦的含量一般介于100-400毫克;
甲磺酸瑞莫夫韦的含量一般介于400-600毫克;
艾可尼西亚原草或提取物浓缩液,用量为转化成酚醛树脂介于5-10毫克;
维生素E的含量一般介于50国际单位到3000国际单位之间,常用剂量介于100国际单位到1200国际单位之间,最合适剂量介于150国际单位到600国际单位之间;
硒的含量一般介于1.0微克到1000微克之间,常用剂量介于10微克到400微克之间,最合适剂量介于50微克到300微克之间;
左旋咪唑的含量一般是50毫克;
水飞蓟素的含量一般介于1毫克到800毫克之间,常用剂量介于50毫克到600毫克之间,最合适剂量介于200毫克到500毫克之间;
叶酸的含量一般介于50微克到2000微克之间,常用剂量介于100微克到1000微克之间,最合适剂量介于200微克到900微克之间;
L-肉碱的含量一般介于100毫克到1000毫克之间,常用剂量介于50毫克到800毫克之间,最合适剂量介于200毫克到500毫克之间;
黄芪提取物的含量一般介于1500毫克到3000毫克之间;(本发明使用的黄芪提取物为棕黄色粉末,为含黄芪多糖70%的标准化产品)。
维生素C的含量一般介于10毫克到2000毫克之间,常用剂量介于50毫克到800毫克之间,最合适剂量介于100毫克到700毫克之间;
葡萄糖醛酸内酯的含量一般介于50毫克到200毫克之间;
肌苷的含量一般介于200毫克到1500毫克之间;
硫辛酸的含量一般介于1.0毫克到3000毫克之间,常用剂量介于5.0毫克到1200毫克之间,最合适剂量介于40毫克到700毫克之间;或者说,有效硫辛酸的用量应当达到2.0毫克/千克体重到200毫克/千克体重的水平,最好是达到8.0毫克/千克体重到70毫克/千克体重的水平;
钙的含量一般介于400毫克到600毫克之间;
维生素D的含量一般是400国际单位;
辅酶Q10的含量一般介于1.0毫克到1000毫克之间,常用剂量介于5.0毫克到800毫克之间,最合适剂量介于40毫克到600毫克之间。
(三)药学上可接受的载体
本发明除了上述的有效成分外,还含有药学上可接受的载体。
基本上所有的复合维生素使用的赋型剂均可以用在本发明中作为赋型剂。比如以下这些赋型剂等:(Corn starch)玉米淀粉作为填充剂和崩解剂;(Cellulosegel and pregelatinized starch)纤维素胶和预胶化淀粉作为增塑剂和粘合剂;(Gelatin)明胶作为乳化剂,粘合剂和崩解剂;(Glycerin)甘油作为矫味剂;(Hydroxypropyl cellulose)羟丙纤维素作为水分散性材料;(Magnesium/Zincstearate,talc,silica)硬脂酸镁或锌,滑石粉,硅粉等作为润滑剂;微晶纤维素(microcellulose)作为粘合剂和崩解剂;(Croscarmellose sodium)交联羧甲纤维素钠作为粘合剂和崩解剂;(Lactose)乳糖作为填充剂和粘合剂;(Acacia)阿拉伯胶作为乳化剂和粘合剂;(Stearic acid)硬脂酸作为乳化剂和粘合剂;(Hydroxypropyl methylcellulose)甲基化羟丙纤维素作为粘合剂和崩解剂;(Sugar)蔗糖作为矫味剂;(Polyethylene glycol)聚乙二醇作为填充剂、乳化剂、和崩解剂;(Modified food starch)变性食用淀粉作为填充剂和崩解剂;以及(Soybean oil)豆油和(Lecithin)卵磷脂等作为脂溶性的辅助性物质;和(Titanium dioxide)二氧化钛用作着色剂等。
本发明中的复方制剂可以是片剂,药丸,胶囊,包衣片,气溶胶,和液体制剂。液体制剂可以是酒溶液或者水溶液,或者是悬浮液和乳胶液等。在选用液体制剂的情况下,所有的有效成份将尽可能的使用它们相应的盐。对于固体制剂,所有的有效成份可以在同一个成型剂内,也可以是不同有效成份在各个自己的成型剂内。
(四)给药方式:
片剂,药丸,胶囊,包衣片等制剂每日口服一次,治疗具体病症时的每次用量取决于多种因素,包括体重、年龄、性别、必然的医学症状、疾病轻重、给药途径等。
(五)制剂制备方法:
本发明中的固体制剂剂型生产可以采用现有的各种生产技术。如果所有的有效成份在同一个成型剂内,一般先将匹配的有效成份和一种或两种赋形剂采用湿法生产工艺,或干法生产工艺混合成混合物,再加入其它有效成份和赋形剂混合均匀。混合过程可以是制粒混合(granulating)、腾涌混合(slugging)、掺合混合(blend)等。混匀的混合物经压片或滚丸而成片剂或药丸。
当植物油作为脂类或脂溶性辅助性物质时,如棕榈油、椰籽油、棕榈果油、大豆油、红花油、坎劳勒(Canola)油、葡萄子油、棉籽油等等,采用软胶囊制剂。
本发明中的软胶囊生产采用现有的各种生产技术。一般先将匹配的有效成份、脂类或脂溶性辅助性物质、和一种或多种赋形剂混合成混合物,再加入其它有效成份和赋形剂混合均匀,混匀的混合物制成软胶囊。
(六)有益效果:
本发明中的复方制剂相比市场上现有的病毒性肝病用药不仅具有更好的抗病毒能力,和单独使用每个单一的抗病毒药相比,本发明中的复方制剂还能增强用药患者的免疫力,并且预防各种慢性并发症。另外,本发明中的复方制剂还有防止乙肝感染和增强肝细胞再生的功能。
附图说明:
图1是治疗乙肝复方制剂的抗感染细胞试验中测得的HBsAg分泌量的图;
图2是小鸭血清中病毒DNA的水平变化图;
图3是治疗前后肝脏内CCC DNA的变化情况图。
图1中,横坐标表示配方序号,纵坐标表示HBsAg分泌量;
图2中,横坐标表示监测天数,纵坐标表示DHBV DNA数值;◆表示使用配方1,■表示使用配方9,▲表示使用阿德福韦酯,x表示对照组;
图3中,横坐标的左边表示治疗前的数据,相对值为100%,横坐标的右边表示治疗后的数据;纵坐标表示CCC DNA的相对值。
具体实施方式
实施例1复方制剂的配方
本发明中的复方制剂可以是所有上述各种有效成份的组合。下面所给出的配方仅是为了更好地说明本发明,而不是指本发明中的复方制剂仅包括以下这些给出的有效成份的组合。
表一:治疗病毒性肝病复方制剂的配方
以下表格中的样品是各种配方。这些样品配方既可以用于片剂也可以用于软胶囊。
表格中的单位除非特别指出,均为毫克;I.U.是维生素D和维生素E的计量单位,国际单位。
固体剂型的一般生产方法如下所示:
1、配方的有效成份和赋形剂在一起混合均匀;
2、步骤1得到的均匀物进一步压紧成小颗粒;
3、把润滑剂如硬脂酸镁等和上述步骤2所得的小颗粒混合几分钟;
4、步骤3的混匀物压制成片剂或者其它固体剂型;
5、需要的话,将包衣液喷成雾状液滴覆盖在步骤4得到的片剂上。
若采用软胶囊制剂时,则把步骤1得到的均匀物直接进行软胶囊成型。
实施例2防止乙肝感染的功能——体外细胞试验
本发明中的复方制剂防止乙肝感染的功能用原发性人类肝细胞试验,细胞在有复方制剂和无复方制剂的条件下同时用50倍基因当量的乙肝病毒(HBV)感染14个小时。试验是在外加了3.5×10-6M氢化可的松琥珀酸酯(hydrocortisonehemisuccinate),2%DMSO,5%成年人血清,和5%胎牛血清(fetal calfserum)的H介质(H medium)中进行。感染完成后,用使用的介质洗去所有的复方制剂,然后每两天换一次介质,用定量ELISA仪测量感染后第十二天细胞所分泌的HBsAg的量。每一种配方有一个无复方制剂的对照样和八个平行样,HBsAg的量为八个样本的平均值。复方制剂的用量以配方中的硫辛酸计(用药中硫辛酸量是38μM)。
表二:治疗乙肝复方制剂的抗感染细胞试验中测得的乙肝表面抗原(HbsAg)分泌量
这项试验结果显示,本发明中的复方制剂具备很好的防止乙肝感染的功能,而所有的所使用的单一有效成份均没有被报道过有这种疗效。
实施例3复方制剂治疗乙肝的动物试验-对乙肝病毒的抑制作用
试验用小鸭保持正常光照,喂食标准食物,三天大的小鸭(Pekin Ducklings)用1.5×107基因当量的鸭乙肝病毒(DHBV)通过静脉注射感染(Antimicrob.AgentsChemother.1998,42,369-376)。感染三天后开始使用表一的复方制剂配方1,9,和阿德福韦酯治疗,每组三只小鸭包括对照组。监测小鸭血清中病毒DNA的水平变化,测量使用bDNA(branched chain DNA assay)方法,三只鸭DHBV DNA(pg/ml)的平均值列入表三。试验用药量为人用药量十倍(mg/Kg体重),给药共四个星期,监测乙肝病毒血症(Viremia)的发生情况。
表三.小鸭血清中病毒DNA的水平变化(pg/ml,单位为千)
结果显示,阿德福韦酯在复方制剂配方1中对乙肝病毒的抑制作用不受其它复方成份的影响,结果和阿德福韦酯一样;阿德福韦酯和复方制剂配方1均无法在四个星期内彻底清除乙肝病毒(停药后,又有乙肝病毒的大量出现,32-34天)。没有人工合成的乙肝病毒抑制剂的配方,如配方9,同样有不错的抑止和清理乙肝病毒的能力(图2中方块表示)。
实施例4复方制剂治疗乙肝的动物试验——增高肝细胞的更新率(hepatocyteturnover)
试验用鸭为天生(congenitally)感染乙肝的3到4个月大的鸭子,保持正常光照,喂食标准食物。分别使用复方制剂配方1、阿德福韦酯治疗五个星期,且分别在用药前和治疗后进行肝活组织检查(Lab.Anim.Sci.1991,41,474-475)。肝组织样品(0.07-0.1克)在0.01MTris-HCl(pH=7.5)-0.01M EDTA的介质中均质化后(J.Virol.1992,66,1377-1388),利用bDNA定量分析方法测定1.0×106肝细胞中的CCC DNA(covalently closed circular DNA)数。测量值以用药前作为100%,共三组鸭,每组六只包括对照组。正常化后的测量值(六只的平均值)列入表四。试验用药量为人用药量10倍(mg/Kg体重)。
表四:治疗前后肝脏内CCC DNA的变化情况
复方制剂配方1 | 阿德福韦酯 | 对照组 | |
治疗前 | 100% | 100% | 100% |
治疗后 | 9.3% | 51% | 104% |
这个结果显示,本发明中的复方制剂能够增高肝细胞的更新率,即新的复方制剂有提高肝细胞再生的能力,而合成的小分子抗乙肝药,如阿德福韦酯等,则没有报道过具有提高肝细胞再生能力的功能,且本试验再次证明它们确实没有这种功能。文献报道(J.Virol.1994,68,5469-5475)没有成熟的病毒核心蛋白壳(viral nucleocapsids)在肝细胞分裂时被迅速的破坏掉。使用相同的抑止病毒复制再生的药物时(两者的主要抑止病毒复制再生的有效成分相同),只有在肝细胞再生加快的条件下,清除肝脏内CCC DNA的速度才会加快。
Claims (8)
1、一种治疗病毒型肝病的复方制剂,其特征在于包含有:
(a)抑止病毒复制再生的药物;
(b)增强人体免疫力的药物;
(c)保护与修复肝脏的药物和保护肾脏的药物;
(d)药学上可接受的载体。
2、如权利要求1所述的治疗病毒型肝病的复方制剂,其特征在于:
所述的抑止病毒复制再生的药物选自:甘草甜酸、谷胱甘肽、硫辛酸、DL-蛋氨酸、阿德福韦酯、恩替卡韦、拉米夫定、泰诺福韦、甲磺酸瑞莫夫韦、阿昔洛韦、利巴韦林、阿糖腺苷、或其组合;
所述的增强人体免疫力的药物选自:艾可尼西亚、维生素E、硒、维生素C、辅酶Q10、左旋咪唑、或其组合;
所述的保护与修复肝脏的药物,以及保护肾脏的药物选自:水飞蓟素、L-肉碱、血管内皮细胞生长因子、黄芪提取物、维生素C、叶酸、葡萄糖醛酸内酯、肌苷、谷胱甘肽、钙、维生素D、或其组合。
3、如权利要求1或2所述的治疗病毒型肝病的复方制剂,其特征在于,在单元剂型中:
甘草甜酸的含量介于500毫克到1500毫克之间;谷胱甘肽的含量介于50毫克到1500毫克之间;DL-蛋氨酸的含量介于1.0毫克到800毫克之间;阿德福韦酯的含量是10毫克;恩替卡韦的含量介于0.25-0.5毫克;拉米夫定的含量是100毫克;泰诺福韦的含量介于100-400毫克;甲磺酸瑞莫夫韦的含量介于400-600毫克;
艾可尼西亚原草或提取物浓缩液,用量为转化成酚醛树脂介于5-10毫克;维生素E的含量介于50国际单位到3000国际单位之间;硒的含量介于1.0微克到1000微克之间;左旋咪唑的含量是50毫克;辅酶Q10的含量介于1.0毫克到1000毫克之间;
水飞蓟素的含量介于1毫克到800毫克之间;叶酸的含量介于50微克到2000微克之间;L-肉碱的含量介于100毫克到1000毫克之间;黄芪提取物的含量介于1500毫克到3000毫克之间;维生素C的含量介于10毫克到2000毫克之间;葡萄糖醛酸内酯的含量介于50毫克到200毫克之间;肌苷的含量介于200毫克到1500毫克之间;硫辛酸的含量介于1.0毫克到3000毫克之间;钙的含量介于400毫克到600毫克之间;维生素D的含量是400国际单位。
4、如权利要求1或2所述的治疗病毒型肝病的复方制剂,其特征在于,在单元剂型中:
甘草甜酸的含量为1000毫克;维生素E的含量介于100国际单位到1200国际单位之间;硒的含量介于10微克到400微克之间;水飞蓟素的含量介于50毫克到600毫克之间;叶酸的含量介于100微克到1000微克之间;L-肉碱的含量介于50毫克到800毫克之间;维生素C的含量介于50毫克到800毫克之间;硫辛酸的含量介于5.0毫克到1200毫克之间;辅酶Q10的含量介于5.0毫克到800毫克之间。
5、如权利要求1或2所述的治疗病毒型肝病的复方制剂,其特征在于,在单元剂型中:
维生素E的含量介于150国际单位到600国际单位之间;硒的含量介于50微克到300微克之间;水飞蓟素的含量介于200毫克到500毫克之间;叶酸的含量介于200微克到900微克之间;L-肉碱的含量介于200毫克到500毫克之间;维生素C的含量介于100毫克到700毫克之间;硫辛酸的含量介于40毫克到700毫克之间;辅酶Q10的含量介于40毫克到600毫克之间。
6、如权利要求1所述的治疗病毒型肝病的复方制剂,其特征在于是片剂,药丸,胶囊,包衣片,气溶胶,或液体制剂。
7、如权利要求1或2所述的治疗病毒型肝病的复方制剂在预防病毒型肝病上的应用。
8、如权利要求1或2所述的治疗病毒型肝病的复方制剂在增加肝细胞再生上的应用。
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CN1320925C (zh) * | 2005-03-30 | 2007-06-13 | 淮北市辉克药业有限公司 | 长期使用的治疗糖尿病的复方制剂 |
-
2005
- 2005-12-08 CN CN2005101309140A patent/CN1895671B/zh not_active Expired - Fee Related
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2006
- 2006-01-05 WO PCT/CN2006/000007 patent/WO2007065314A1/zh active Application Filing
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CN102245032A (zh) * | 2008-12-16 | 2011-11-16 | 希尔氏宠物营养品公司 | 用于增强陪伴动物抗病毒免疫力的含抗氧化剂的食品组合物 |
CN102245032B (zh) * | 2008-12-16 | 2014-12-10 | 希尔氏宠物营养品公司 | 用于增强陪伴动物抗病毒免疫力的含抗氧化剂的食品组合物 |
CN101961312A (zh) * | 2010-09-28 | 2011-02-02 | 北京世纪博康医药科技有限公司 | 一种注射用硫辛酸组合物 |
CN101961312B (zh) * | 2010-09-28 | 2012-10-03 | 北京世纪博康医药科技有限公司 | 一种注射用硫辛酸组合物 |
CN104431368A (zh) * | 2014-12-15 | 2015-03-25 | 中国水产科学研究院长江水产研究所 | 一种促进鱼类健康生长的复合饲料添加剂及制备方法 |
CN104998250A (zh) * | 2015-07-29 | 2015-10-28 | 福建广生堂药业股份有限公司 | 一种恩替卡韦与甘露聚糖肽药物组合物及其制备方法 |
CN104998250B (zh) * | 2015-07-29 | 2018-05-29 | 福建广生堂药业股份有限公司 | 一种恩替卡韦与甘露聚糖肽药物组合物及其制备方法 |
CN105727259A (zh) * | 2016-02-04 | 2016-07-06 | 单秀娟 | 一种用于治疗肝源性肾损害的复方护理剂及其制备方法 |
CN106511447A (zh) * | 2016-10-28 | 2017-03-22 | 肖远 | 一种细胞障碍修复营养补充方法及其药物配方 |
CN115120561A (zh) * | 2022-06-30 | 2022-09-30 | 中国药科大学 | 组合药物金属有机杂化纳米组装体及其应用 |
CN115120561B (zh) * | 2022-06-30 | 2023-12-19 | 中国药科大学 | 组合药物金属有机杂化纳米组装体及其应用 |
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