双环醇保肝抗炎作用研究进展

Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Title (no leads) (30 Pt.) Times bold,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Title (no leads) (30 Pt.) Times bold,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Title (no leads) (30 Pt.) Times bold,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Title (no leads) (30 Pt.) Times bold,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Title (no leads) (30 Pt.) Times bold,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Title (no leads) (30 Pt.) Times bold,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Title (no leads) (30 Pt.) Times bold,*,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Title (no leads) (30 Pt.) Times bold,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Title (no leads) (30 Pt.) Times bold,*,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Title (no leads) (30 Pt.) Times bold,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Title (no leads) (30 Pt.) Times bold,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Title (no leads) (30 Pt.) Times bold,*,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Text: 24 pt. with 24 pt. square bullet,Subpoint,Subpoint,Subpoint,Title (no leads) (30 Pt.) Times bold,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,双环醇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,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 .,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 .,9,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 CCl,4,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 means,SD (,n,=8).*,P,0.05, *,P,0.001 vs. control group; #,P,0.05 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 means,SD (,n,=6). ,P,0.01 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 means,SD (,n,=6). ,P,0.01 vs. control group;#,P,0.01 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,）：,536-540,2,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):2096-2101,3,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 CCl,4,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 .,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,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 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,治疗组（,40,例）：基础治疗,+,百赛诺,50mg,，,tid,对照组（,38,例）：基础治疗,+,多烯磷脂酰胆碱,456mg,，,tid,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,%,百赛诺组,多烯磷脂酰胆碱组,#,组间比，,P, 0.05,完全应答率,部分应答率,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-P,X,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,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. 2were significantly improved,after 48 weeks therapy (b) compared with baseline(a) using ADV plus bicyclol,Fig. 5 Necroinflammation and fibrosis scores,of patient No. 1were significantly improved after 48 weeks therapy(b) compared with baseline(a) using ADV 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,双环醇（百赛诺）主要作用特点,保肝抗炎药物：保护细胞膜、线粒体、细胞核，抑制自由基，抑制,TNF-,、,IL-1,等炎性因子,适用于各种肝脏疾病的转氨酶升高，安全性好,改善乙肝，酒精性肝病和非酒精性脂肪肝组织学,对肿瘤患者放疗和化疗引起肝损伤有预防及治疗效果，而且不干扰化疗药物的作用,谢 谢 ！,谢谢观赏,