双环醇保肝抗炎作用研究进展课件

百赛诺（双环醇片）保肝抗炎作用研究进展,肝细胞损伤和肝脏炎症坏死,肝细胞损伤是各型肝病共同的病理基础及共同表现; 导致肝细胞变性、凋亡、坏死最终导致肝衰竭。肝脏炎症坏死及其所致的肝纤维化是疾病进展的主要病理学基础。在对病因治疗的基础上有效控制肝组织炎症，有可能减少肝细胞破坏和延缓肝纤维化的发展。,转氨酶的功能及临床意义,血清氨基转移酶以肝脏含量最为丰富,临床中用于血清学诊断主要为： 谷丙转氨酶 (ALT):肝肾心肌肉 谷草转氨酶 (AST):心肝肌肉肾在肝内，ALT全部存在于肝细胞浆中；AST 80%存在于线粒体内，20%在胞浆内。 当肝细胞发生炎症、坏死、中毒等造成肝细胞受损时，转氨酶会释放入血液，血清转氨酶升高。ALT水平可以比较敏感地监测到肝脏是否受到损害。当肝细胞严重损伤波及线粒体时AST也会进入血中。,肝损伤的基本治疗策略,病因治疗： 消除各种致肝损害的原因对症治疗： 降酶、退黄、消除其他症状保护肝功能：保护肝细胞、消除炎症损害替代肝功能：促进肝细胞生长、协助解毒功能 的药物、人工肝替代疗法综合治疗： 上述疗法营养支持肝脏移植： 原位肝移植、活体肝移植,病毒性肝炎,酒精性肝病,药物性肝病,肝纤维化,肝硬化,炎症反应,肝癌肝功能衰竭,纤维组织增生，星状细胞活化,对因治疗,肝细胞膜损伤,非酒精性 脂肪肝,脂质代谢紊乱,能量代谢紊乱,肝细胞坏死,自由基损伤,肝病发展不同阶段的治疗重点,保肝药物作用环节,对症治疗,抗纤维化抗硬化,抗癌治疗肝移植,抗病毒,戒酒、停用导致肝损害的药物、改变生活习惯、加强运动,其他原因,临床常用的抗炎保肝药物,双环醇甘草酸制剂水飞蓟素类还原型谷胱苷肽多烯磷脂酰胆碱硫普罗宁等,-不是肝脏和血清ALT和AST活性的抑制剂-不是肝脏ALT酶蛋白合成的抑制剂,7,百赛诺对转氨酶的作用,百赛诺不是肝脏和血清ALT和AST活性的抑制剂 大鼠肝脏、血清直接温孵法，发现ALT活性不降低,百赛诺不抑制小鼠肝脏和血清ALT、AST活性,Geng-Tao Liu, Yan Li, et al. Mechanism of protective action of bicyclol against CCl4-induced liver injury in mice. Liver International, 2005, 25(4):872-879 .,9,小鼠肝脏ALT酶蛋白纯化,免疫家兔,兔抗小鼠肝脏ALT抗体制备,抗体+小鼠给药后肝匀浆进行免疫火箭电泳测定肝脏ALT蛋白水平,1-4: 正常组 82.36.85-9: 双环醇组 82.07.4 Protein: 170mg/each,正常和给药小鼠肝匀浆ALT免疫火箭电泳测定,百赛诺不影响肝脏ALT酶蛋白含量,Geng-Tao Liu, Yan Li, et al. Mechanism of protective action of bicyclol against CCl4-induced liver injury in mice. Liver International, 2005, 25(4):872-879 .,肝细胞保护剂对转氨酶的作用（体内）,临床耐受性试验,志愿者：6.25-150mg, tidx4周对志愿者血清ALT，AST活性无影响。,（结果已发表在国内外核心刊物）,清除自由基、抗氧化,Liu GT, Li Y, Wei HL, et al. Mechanism of protective action of bicyclol against CCl4 induced liver injury in mice. Liver International. 2005, 25(4):872-879 .,Effect of bicyclol on the levels of CCl3 radical as detected by ESR in liver microsomes,Bicyclol (200, 300 mg/kg) was given orally to mice three times before alcohol treatment. Mice were sacrificed at 12 h and 6 h after alcohol administration for GSH content determination respectively. Data were expressed as meansSD (n=8).*, P0.05, *, P0.001 vs. control group; #, P0.05 vs. alcohol group.,Zhao J, Chen H, Li Y. Eur J Pharmacol. 2008 ;586(1-3):322-331.,Fig. 10. Time-course changes in plasma endotoxin level in acute alcohol intoxicated mice. Alcohol (6 g/kg) was administered to mice by gavage. The animals were sacrificed at 1.5, 3, 6, and 12 h after alcohol administration. Data were expressed as meansSD (n=6). , P0.01 vs. control group.,Fig.11. Effect of bicyclol on plasma endotoxin level in acute alcohol-intoxicated mice. Bicyclol (200, 300 mg/kg) was given orally to mice three times before alcohol treatment. Mice were sacrificed at 1.5 h after alcohol administration.Data were expressed as meansSD (n=6). , P0.01 vs. control group;#, P0.01 vs. alcohol group.,Effect of bicyclol on plasma endotoxin level in acute alcohol-intoxicated mice,Zhao J, Chen H, Li Y. Eur J Pharmacol. 2008 ;586(1-3):322-331.,抗肝损伤-对肝细胞/线粒体膜形态的保护作用,药物对肝线粒体膜的保护作用（体内）A，B-正常对照，C，D-肝损伤，E，F-给药后,药物对肝细胞膜的保护作用（体外）,Hui-Ping Wang, Yan Li. Protective effect of bicyclol on acute hepatic failure induced by lipopolysaccharide and D-galactosamine in mice. European Journal of Pharmacology. 2006, 534(1-3):194-201.,1赵冬梅，刘耕陶.双环醇对对乙酰氨基酚致小鼠肝线粒体损伤的保护作用.中国新药杂志，2002，7（11）：536-5402李烨，李燕，刘耕陶.双环醇对实验性肝纤维化的防护作用及分子机制.中华医学杂志,2004,84(24):2096-21013李 烨，戴国炜，李 燕，刘耕陶.双环醇对扑热息痛弓l起小鼠肝脏能量代谢和线粒体功能障碍的影响.药学学报.2001，36（10）：723-726,抗肝损伤-对线粒体功能的保护作用,线粒体ATP酶活性,线粒体肿胀度,线粒体膜流动性,抗肝损伤-对肝脏病理形态的保护作用,1Liu GT, Li Y, Wei HL, et al. Mechanism of protective action of bicyclol against CCl4 induced liver injury in mice. Liver International. 2005, 25(4):872-879 .2Geng Tao Liu. Bicyclol: A Novel Drug For Treating Chronic Viral Hepatitis B and C.Medicinal Chemistry,2009,5,29-43.3莫成林, 李烨, 李燕. 双环醇对小鼠慢性酒精性肝损伤的保护作用 J . 中华医学杂志, 2005, 85 (48) : 3409-3413.,Fig. 12. Localization of liver TNF- and CD14 expression in acute alcohol-intoxicated mice. Bicyclol (200, 300 mg/kg) was given orally to mice (n=5) three times before alcohol treatment. Mice were sacrificed at 12 h after alcohol administration. 1: expression of TNF-; 2: expression of CD14. a: Control; b: Alcohol;c: Pretreatment with Bicyclol. Arrows: Positive cells. Original magnification100.,抗肝损伤分子机制-抑制炎症因子表达,Fig. 9. Effects of bicyclol on hepatic TNF- and IL-1mRNA expression in acute alcohol-intoxicated mice. Bicyclol (200, 300 mg/kg) was given orally to mice three times before alcohol treatment. Mice were sacrificed at 12 h after alcohol administration. (A): lane 12, Control; lane 34, Alcohol; lane 56, By 200 mg/kg; lane 78, By 300 mg/kg. (B): Ratio of PCR products relative to GAPDH. Data were expressed as meansSD (n=4). *, Pb0.05 vs. control group; #, Pb0.05, #, Pb0.001 vs. alcohol group.,1Zhao J, Chen H, Li Y. Protective effect of bicyclol on acute alcohol- induced liver injury in mice J . Eur J Pharmacol, 2008, 586 (123) :322-331.2李烨，李燕，刘耕陶.双环醇对实验性肝纤维化的防护作用及分子机制.中华医学杂志,2004,84(24):2096-2101,抗肝损伤分子机制-抑制炎症导致的肝细胞凋亡,赵冬梅、刘耕陶. 双环醇对刀豆蛋白A所致小鼠肝细胞核DNA损伤的保护作用. 中华医学杂志，2001, 81(14):844-848 .,A: 100bp.DNA条带标准品B C: 正常对照组D E F: ConA模型对照组G H I: 百赛诺150mg/kg,Wang H, Li Y. Eur J Pharmacol. 2006 ;534(1-3):194-201.,Effect of bicyclol on liver injury induced by lipopolysaccharide/D-galactosamine in mice,Liver specimens were obtained at 6 h after LPS/Dgalactosamine injection. (A) Normal control; (B) (C) carboxymethyl cellulose vehicle administration 1 h before LPS/GalN injection; (D) bicyclol 300 mg/kg administration for 3 times 1 h before LPS/D-galactosamine injection; (E) bicyclol 300 mg/kg administration once 1 h before LPS/D-galactosamine injection. Original magnification X100.,小结,双环醇体外对血清ALT、AST的活性无直接抑制作用，体内给药对肝脏ALT蛋白水平无影响。临床志愿者口服药物对转氨酶活性也无抑制作用。 保肝药的降酶作用来自-肝细胞膜和线粒体膜形态和功能的改善-抑制炎症因子及相关受体的表达-抑制炎症导致的肝细胞凋亡,19,双环醇的临床使用依据,慢性乙型肝炎防治指南(2010年更新版)非酒精性脂肪性肝病诊疗指南(2010年修订版)酒精性肝病诊疗指南(2010年修订版)河南省新农合按病种付费临床路径“酒精性肝炎” （豫卫医改（2012）4号文件）,1.双环醇治疗酒精性肝病,医院：卫生部中日友好医院负责人：马安林试验组： 54例，给予百赛诺50mg，tid. 对照组： 49例，给予多烯磷脂酰胆碱456mg，tid. 2组均连续用药36周，试验组23例、对照组21例患者完成治疗前后2次肝穿刺活组织检查,马安林, 郭新珍, 刘霞, 等.双环醇与多烯磷脂酰胆碱治疗酒精性肝病的疗效比较. 中华肝脏病杂志. 2011, 19(6):471-472,双环醇与多烯磷脂酰胆碱治疗酒精性肝病的疗效比较,马安林，郭新珍，刘霞.中华肝脏病杂志.2011.l9(6):471-472.,双环醇与多烯磷脂酰胆碱治疗酒精性肝病的疗效比较,马安林，郭新珍，刘霞.中华肝脏病杂志.2011.l9(6):471-472.,双环醇与多烯磷脂酰胆碱治疗酒精性肝病的疗效比较,马安林，郭新珍，刘霞.中华肝脏病杂志.2011.l9(6):471-472.,双环醇与多烯磷脂酰胆碱治疗酒精性肝病的疗效比较,马安林，郭新珍，刘霞.中华肝脏病杂志.2011.l9(6):471-472.,研究结果及结论,百赛诺治疗组ALT及AST的下降速度和程度优于多烯磷脂酰胆碱对照组。 百赛诺治疗及对照组36周后可使血清GSTPX水平显著上升，MDA水平显著下降。 通过比较治疗前后的超声影像学表现，我们看到两组治疗前后均有一定程度的改善，而且百赛诺可在一定程度上改善肝内脂肪沉积、炎症死及纤维化，尤其对于炎症的改善程度。,2.百赛诺治疗非酒精性脂肪肝,注: 1、患者诊断标准符合2006年2月非酒精性脂肪性肝病诊疗指南 2、随机分组采用 SPSS15.0统计软件 3、治疗期间均未使用其他保肝药物,78例20岁64岁非酒精性脂肪性肝病患者，随机分为两组采用减轻体重(1200g/周)为前提的基础治疗联合药物治疗，两组疗程均为24周,治疗前后检测：人体学指标、B超、肝功能检测、肝脏组织学检查,苏红领,韩英,樊代明,等.双环醇与多烯磷脂酰胆碱治疗非酒精性脂肪肝的疗效比较.中华肝脏病杂志.2011,19(7):552-553.,10,5,17,11,32,23,20,30,25,15,0,35,%,研究结果-百赛诺组部分应答率优于对照组,应答标准：(1)完全应答：ALT复常；超声远场回声衰减程度较治疗前改善，且GST-PX和MDA至少l项较治疗前改善；脂变、炎症及坏死积分较治疗前减少2分以上。(2)部分应答：ALT复常；超声检查指标改善不显著；组织学改变不明显。(3)无应答：未达到上述指标者,1.百赛诺显著改善肝功能指标,研究结果百赛诺显著改善肝功和血脂指标,ALP：碱性磷酸酶 GGT：谷氨酰转肽酶,2.百赛诺明显改善血脂指标,3.百赛诺明显改善B超积分,研究结果百赛诺显著改善B超积分和炎症,近场回声增高、灶性高回声或肝光点增粗各计1分；远场回声衰减、肝肿大、肝内管道系统显示不清或无法辨认各计2分。,4.百赛诺改善脂肪变性、炎症、纤维化,*与对照组相比，P0.05,百赛诺治疗后脂肪变、炎症、纤维化不同程度减轻,苏木精一伊红染色,脂肪变性和炎症坏死,治疗前,治疗后,纤维化表现,网状纤维染色,检查项目：ALT、AST、TBiL,3.百赛诺防治化疗药物所致肝损害,周建凤, 陈书长, 白春梅, 等. 双环醇片防治化疗药物性肝损害的研究. 肝脏, 2007, 12(4):286-287 .,结果-百赛诺对肝损害的治疗作用,结果-百赛诺对肝损害的预防作用,本研究表明口服双环醇片可有效治疗化疗药物性肝 损害，中位治疗12天后肝功能即显著恢复。 化疗同时并用双环醇片，患者肝功能损害的发生率 大为下降，程度也明显减轻，保障了化疗按时足量 进行。,研究结论,Xie W, Shi G, Zhang H, et al. Hepatology International. 2012, 6(2):441-448,A randomized, multi-central, controlled study of patients with hepatitis B e antigen-positive chronic hepatitis B treated by adefovir dipivoxil or adefovir dipivoxil plus bicyclol,A randomized, multi-central, controlled study of patients with hepatitis B e antigen-positive chronic hepatitis B treated by adefovir dipivoxil or adefovir dipivoxil plus bicyclol,Xie W, Shi G, Zhang H, et al. Hepatology International. 2012, 6(2):441-448,A randomized, multi-central, controlled study of patients with hepatitis B e antigen-positive chronic hepatitis B treated by adefovir dipivoxil or adefovir dipivoxil plus bicyclol,Xie W, Shi G, Zhang H, et al. Hepatology International. 2012, 6(2):441-448,Xie W, Shi G, Zhang H, et al. Hepatology International. 2012, 6(2):441-448,A randomized, multi-central, controlled study of patients with hepatitis B e antigen-positive chronic hepatitis B treated by adefovir dipivoxil or adefovir dipivoxil plus bicyclol,Fig. 6 Necroinflammation and fibrosis scores of patient No. 2