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1、百賽諾（雙環(huán)醇片）保肝抗炎作用研究進(jìn)展肝細(xì)胞損傷和肝臟炎癥壞死肝細(xì)胞損傷是各型肝病共同的病理基礎(chǔ)及共同表現(xiàn); 導(dǎo)致肝細(xì)胞變性、凋亡、壞死最終導(dǎo)致肝衰竭。肝臟炎癥壞死及其所致的肝纖維化是疾病進(jìn)展的主要病理學(xué)基礎(chǔ)。在對病因治療的基礎(chǔ)上有效控制肝組織炎癥，有可能減少肝細(xì)胞破壞和延緩肝纖維化的發(fā)展。 轉(zhuǎn)氨酶的功能及臨床意義n血清氨基轉(zhuǎn)移酶以肝臟含量最為豐富, ,臨床中用于血清學(xué)診斷主要為： 谷丙轉(zhuǎn)氨酶 (ALT):(ALT):肝 腎 心 肌肉 谷草轉(zhuǎn)氨酶 (AST):(AST):心 肝 肌肉 腎n在肝內(nèi)，ALTALT全部存在于肝細(xì)胞漿中；AST 80%AST 80%存在于線粒體內(nèi)，20%20%在胞漿內(nèi)
2、。 當(dāng)肝細(xì)胞發(fā)生炎癥、壞死、中毒等造成肝細(xì)胞受損時，轉(zhuǎn)氨酶會釋放入血液，血清轉(zhuǎn)氨酶升高。ALT水平可以比較敏感地監(jiān)測到肝臟是否受到損害。當(dāng)肝細(xì)胞嚴(yán)重?fù)p傷波及線粒體時AST也會進(jìn)入血中。肝損傷的基本治療策略病因治療： 消除各種致肝損害的原因?qū)ΠY治療： 降酶、退黃、消除其他癥狀保護(hù)肝功能：保護(hù)肝細(xì)胞、消除炎癥損害替代肝功能：促進(jìn)肝細(xì)胞生長、協(xié)助解毒功能 的藥物、人工肝替代療法綜合治療： 上述療法營養(yǎng)支持肝臟移植： 原位肝移植、活體肝移植病毒性肝炎酒精性肝病藥物性肝病 肝纖維化肝硬化u炎癥反應(yīng)肝癌肝功能衰竭u纖維組織增生，星狀細(xì)胞活化對因治療u肝細(xì)胞膜損傷非酒精性 脂肪肝u脂質(zhì)代謝紊亂u能量代謝紊亂
3、肝細(xì)胞壞死u自由基損傷肝病發(fā)展不同階段的治療重點保肝藥物作用環(huán)節(jié)對癥治療抗纖維化抗硬化抗癌治療肝移植抗病毒戒酒、停用導(dǎo)致肝損害的藥物、改變生活習(xí)慣、加強運動其他原因臨床常用的抗炎保肝藥物n雙環(huán)醇n甘草酸制劑n水飛薊素類n還原型谷胱苷肽n多烯磷脂酰膽堿n硫普羅寧等- -不是肝臟和血清ALTALT和ASTAST活性的抑制劑- -不是肝臟ALTALT酶蛋白合成的抑制劑百賽諾對轉(zhuǎn)氨酶的作用百賽諾不是肝臟和血清ALT和AST活性的抑制劑 大鼠肝臟、血清直接溫孵法，發(fā)現(xiàn)ALT活性不降低百賽諾不抑制小鼠肝臟和血清ALTALT、ASTAST活性Geng-Tao Liu, Yan Li, et al. Mech
4、anism of protective action of bicyclol against CCl4-induced liver injury in mice. Liver International, 2005, 25(4):872-879 .9小鼠肝臟ALT酶蛋白純化免疫家兔兔抗小鼠肝臟ALT抗體制備抗體+小鼠給藥后肝勻漿進(jìn)行免疫火箭電泳測定肝臟ALT蛋白水平1-4: 正常組 82.36.85-9: 雙環(huán)醇組 82.07.4 Protein: 170mg/each正常和給藥小鼠肝勻漿ALTALT免疫火箭電泳測定百賽諾不影響肝臟ALTALT酶蛋白含量Geng-Tao Liu, Yan Li
5、, et al. Mechanism of protective action of bicyclol against CCl4-induced liver injury in mice. Liver International, 2005, 25(4):872-879 .肝細(xì)胞保護(hù)劑對轉(zhuǎn)氨酶的作用（體內(nèi)）臨床耐受性試驗n志愿者：6.25-150mg, tidx4周n對志愿者血清ALT，AST活性無影響。（結(jié)果已發(fā)表在國內(nèi)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
6、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 microsomesBicyclol (200, 300 mg/kg) was given orally to mice three times before alcohol treatment. Mice were sacrificed at 12 h and 6 h af
7、ter 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
8、 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-intox
9、icated 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
10、acute alcohol-intoxicated miceZhao J, Chen H, Li Y. Eur J Pharmacol. 2008 ;586(1-3):322-331. 抗肝損傷- -對肝細(xì)胞/ /線粒體膜形態(tài)的保護(hù)作用藥物對肝線粒體膜的保護(hù)作用（體內(nèi)）A A，B-B-正常對照，C C，D-D-肝損傷，E E，F(xiàn)-F-給藥后藥物對肝細(xì)胞膜的保護(hù)作用（體外）Hui-Ping Wang, Yan Li. Protective effect of bicyclol on acute hepatic failure induced by lipopolysaccharide and D
11、-galactosamine in mice. European Journal of Pharmacology. 2006, 534(1-3):194-201.1趙冬梅，劉耕陶.雙環(huán)醇對對乙酰氨基酚致小鼠肝線粒體損傷的保護(hù)作用.中國新藥雜志，2002，7（11）：536-5402李燁，李燕，劉耕陶.雙環(huán)醇對實驗性肝纖維化的防護(hù)作用及分子機制.中華醫(yī)學(xué)雜志,2004,84(24):2096-21013李 燁，戴國煒，李 燕，劉耕陶.雙環(huán)醇對撲熱息痛弓l起小鼠肝臟能量代謝和線粒體功能障礙的影響.藥學(xué)學(xué)報.2001，36（10）：723-726抗肝損傷- -對線粒體功能的保護(hù)作用線粒體ATPATP
12、酶活性線粒體腫脹度線粒體膜流動性抗肝損傷- -對肝臟病理形態(tài)的保護(hù)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
13、,5,29-43.3莫成林, 李燁, 李燕. 雙環(huán)醇對小鼠慢性酒精性肝損傷的保護(hù)作用 J . 中華醫(yī)學(xué)雜志, 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 afte
14、r alcohol administration. 1: expression of TNF-; 2: expression of CD14. a: Control; b: Alcohol;c: Pretreatment with Bicyclol. Arrows: Positive cells. Original magnification100.抗肝損傷分子機制- -抑制炎癥因子表達(dá)Fig. 9. Effects of bicyclol on hepatic TNF- and IL-1mRNA expression in acute alcohol-intoxicated mice. Bi
15、cyclol (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 a
16、s 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李燁，李燕，劉耕陶.雙環(huán)醇對實驗性肝纖維化的防護(hù)作用及分子機制.中華醫(yī)學(xué)雜志,2004,84(24):2096-2101抗肝損傷分子機
17、制- -抑制炎癥導(dǎo)致的肝細(xì)胞凋亡趙冬梅、劉耕陶. 雙環(huán)醇對刀豆蛋白A所致小鼠肝細(xì)胞核DNA損傷的保護(hù)作用. 中華醫(yī)學(xué)雜志，2001, 81(14):844-848 .條帶標(biāo)準(zhǔn)品B C: 正常對照組D E F: ConA模型對照組G H I: 百賽諾150mg/kgWang 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 obt
18、ained 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
19、 LPS/D-galactosamine injection. Original magnification X100.小結(jié) 雙環(huán)醇體外對血清ALTALT、ASTAST的活性無直接抑制作用，體內(nèi)給藥對肝臟ALTALT蛋白水平無影響。臨床志愿者口服藥物對轉(zhuǎn)氨酶活性也無抑制作用。 保肝藥的降酶作用來自- - -肝細(xì)胞膜和線粒體膜形態(tài)和功能的改善- -抑制炎癥因子及相關(guān)受體的表達(dá)- -抑制炎癥導(dǎo)致的肝細(xì)胞凋亡雙環(huán)醇的臨床使用依據(jù)n慢性乙型肝炎防治指南(2010(2010年更新版) )n非酒精性脂肪性肝病診療指南(2010(2010年修訂版) )n酒精性肝病診療指南(2010(2010年修訂版) )n
20、河南省新農(nóng)合按病種付費臨床路徑“酒精性肝炎” （豫衛(wèi)醫(yī)改（20122012）4 4號文件）1.1.雙環(huán)醇治療酒精性肝病醫(yī)院：衛(wèi)生部中日友好醫(yī)院負(fù)責(zé)人：馬安林試驗組： 54 54例，給予百賽諾50mg50mg，tid. tid. 對照組： 49 49例，給予多烯磷脂酰膽堿456mg456mg，tid. tid. 2 2組均連續(xù)用藥3636周，試驗組2323例、對照組2121例患者完成治療前后2 2次肝穿刺活組織檢查馬安林, 郭新珍, 劉霞, 等.雙環(huán)醇與多烯磷脂酰膽堿治療酒精性肝病的療效比較. 中華肝臟病雜志. 2011, 19(6):471-472雙環(huán)醇與多烯磷脂酰膽堿治療酒精性肝病的療效比較
21、馬安林，郭新珍，劉霞.中華肝臟病雜志.2011.l9(6):471-472.雙環(huán)醇與多烯磷脂酰膽堿治療酒精性肝病的療效比較馬安林，郭新珍，劉霞.中華肝臟病雜志.2011.l9(6):471-472.雙環(huán)醇與多烯磷脂酰膽堿治療酒精性肝病的療效比較馬安林，郭新珍，劉霞.中華肝臟病雜志.2011.l9(6):471-472.雙環(huán)醇與多烯磷脂酰膽堿治療酒精性肝病的療效比較馬安林，郭新珍，劉霞.中華肝臟病雜志.2011.l9(6):471-472.研究結(jié)果及結(jié)論 百賽諾治療組ALTALT及ASTAST的下降速度和程度優(yōu)于多烯磷脂酰膽堿對照組。 百賽諾治療及對照組3636周后可使血清GSTPXGSTPX水
22、平顯著上升，MDAMDA水平顯著下降。 通過比較治療前后的超聲影像學(xué)表現(xiàn)，我們看到兩組治療前后均有一定程度的改善，而且百賽諾可在一定程度上改善肝內(nèi)脂肪沉積、炎癥死及纖維化，尤其對于炎癥的改善程度。2.2.百賽諾治療非酒精性脂肪肝注: 1、患者診斷標(biāo)準(zhǔn)符合2006年2月非酒精性脂肪性肝病診療指南 2、隨機分組采用 統(tǒng)計軟件 3、治療期間均未使用其他保肝藥物78例20歲64歲非酒精性脂肪性肝病患者，隨機分為兩組采用減輕體重(1200g/周)為前提的基礎(chǔ)治療聯(lián)合藥物治療，兩組療程均為24周治療組（40例）：基礎(chǔ)治療+百賽諾50mg，tid對照組（38例）：基礎(chǔ)治療+多烯磷脂酰膽堿456mg，tid治
23、療前后檢測：人體學(xué)指標(biāo)、B超、肝功能檢測、肝臟組織學(xué)檢查n蘇紅領(lǐng),韓英,樊代明,等.雙環(huán)醇與多烯磷脂酰膽堿治療非酒精性脂肪肝的療效比較. .中華肝臟病雜志.2011,19(7):552-553.1051711322320302515035%百賽諾組多烯磷脂酰膽堿組# 組間比，P 0.05 完全應(yīng)答率部分應(yīng)答率研究結(jié)果- -百賽諾組部分應(yīng)答率優(yōu)于對照組應(yīng)答標(biāo)準(zhǔn)：(1)完全應(yīng)答：ALT復(fù)常；超聲遠(yuǎn)場回聲衰減程度較治療前改善，且GST-PX和MDA至少l項較治療前改善；脂變、炎癥及壞死積分較治療前減少2分以上。(2)部分應(yīng)答：ALT復(fù)常；超聲檢查指標(biāo)改善不顯著；組織學(xué)改變不明顯。(3)無應(yīng)答：未達(dá)到
24、上述指標(biāo)者1.百賽諾顯著改善肝功能指標(biāo)研究結(jié)果百賽諾顯著改善肝功和血脂指標(biāo)ALP：堿性磷酸酶 GGT：谷氨酰轉(zhuǎn)肽酶2.百賽諾明顯改善血脂指標(biāo)3.百賽諾明顯改善B超積分研究結(jié)果百賽諾顯著改善B B超積分和炎癥近場回聲增高、灶性高回聲或肝光點增粗各計1分；遠(yuǎn)場回聲衰減、肝腫大、肝內(nèi)管道系統(tǒng)顯示不清或無法辨認(rèn)各計2分。4.百賽諾改善脂肪變性、炎癥、纖維化百賽諾治療后脂肪變、炎癥、纖維化不同程度減輕蘇木精一伊紅染色脂肪變性和炎癥壞死治療前治療后纖維化表現(xiàn)網(wǎng)狀纖維染色檢查項目：ALT、AST、TBiL3.3.百賽諾防治化療藥物所致肝損害周建鳳, 陳書長, 白春梅, 等. 雙環(huán)醇片防治化療藥物性肝損害的研
25、究. 肝臟, 2007, 12(4):286-287 .結(jié)果- -百賽諾對肝損害的治療作用結(jié)果- -百賽諾對肝損害的預(yù)防作用 本研究表明口服雙環(huán)醇片可有效治療化療藥物性肝 損害，中位治療1212天后肝功能即顯著恢復(fù)。 化療同時并用雙環(huán)醇片，患者肝功能損害的發(fā)生率 大為下降，程度也明顯減輕，保障了化療按時足量 進(jìn)行。研究結(jié)論Xie W, Shi G, Zhang H, et al. Hepatology International. 2012, 6(2):441-448 A randomized, multi-central, controlled study of patients with
26、hepatitis B e antigen-positive chronic hepatitis B treated by adefovir dipivoxil or adefovir dipivoxil plus bicyclolA randomized, multi-central, controlled study of patients with hepatitis B e antigen-positive chronic hepatitis B treated by adefovir dipivoxil or adefovir dipivoxil plus bicyclolXie W
27、, 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 bicyclolXie W, Shi G, Zhang H, et al. Hepatology Internatio
28、nal. 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 bicyclolFig. 6 Necroinflammati
29、on and fibrosis scores of patient No. 2were significantly improvedafter 48 weeks therapy (b) compared with baseline(a) using ADV plus bicyclolFig. 5 Necroinflammation and fibrosis scores of patient No. 1were significantly improved after 48 weeks therapy(b) compared with baseline(a) using ADV plus bi
30、cyclolA randomized, multi-central, controlled study of patients with hepatitis B e antigen-positive chronic hepatitis B treated by adefovir dipivoxil or adefovir dipivoxil plus bicyclolXie W, Shi G, Zhang H, et al. Hepatology International. 2012, 6(2):441-448 A randomized, multi-central, controlled
31、study of patients with hepatitis B e antigen-positive chronic hepatitis B treated by adefovir dipivoxil or adefovir dipivoxil plus bicyclolXie W, Shi G, Zhang H, et al. Hepatology International. 2012, 6(2):441-448 雙環(huán)醇（百賽諾）主要作用特點n保肝抗炎藥物：保護(hù)細(xì)胞膜、線粒體、細(xì)胞核，抑制自由基，抑制TNF- 、IL-1等炎性因子n適用于各種肝臟疾病的轉(zhuǎn)氨酶升高，安全性好n改善乙肝，酒精性肝病和非酒精性脂肪肝組織學(xué)n對腫瘤患者放療和化療引起肝損傷有預(yù)防及治療效果，而且不干擾化療藥物的作用謝 謝 ！
雙環(huán)醇保肝抗炎作用研究進(jìn)展
