双环醇抗病毒与保护肝细胞作用的动态观察和分析

目的：探讨双环醇抗病毒机制，为进一步研究和开发双环醇打下理论基础。方法：通过2．2．15细胞与双环醇混合培养，观察血清丙氨酸氨基转移酶(ALT)、血清门冬氨酸氨基转移酶(AST)用药后与HBsAg，HBeAg，乙型肝炎病毒中DNA(HBV—DNA)之间的动态变化，定量逆转录PCR(RT—PCR)观察CTAT—1变化；临床实验中，患口服双环醇，每2周观察血清HBV—DNA与ALT，AST动态变化。结果：细胞模型实验中，随着双环醇与2．2．15细胞混合培养时间延长，HBsAg，HBV—DNA滴度逐渐降低，而培养上清ALT，AST无明显变化，细胞内稳定高水平表达STAT—1的mRNA；临床实验发现，以干扰素α为对照，患血清ALT，AST可以随着HBV—DNA水平降低而下降，但未发现患血清ALT，AST有一过性升高。结论：双环醇在发挥肝细胞保护作用的同时．还可能通过非细胞溶解性机制清除乙型肝炎病毒。     

双环醇治疗慢性乙型病毒性肝炎50例疗效观察

目的观察双环醇治疗慢性乙型病毒性肝炎的临床效果及不良反应。方法100例慢性乙型病毒性肝炎患者分为2组,治疗组50例,口服双环醇片25 mg,每日3次;对照组50例,口服健肝灵胶囊3粒,每日3次,疗程均为24周,观察两组治疗前后肝功能指标(ALT、AST)及病毒标志物情况(HBV-DNA、HBeAg)和停药后反跳的发生情况。结果两组在治疗12周及24周时,ALT及AST均较治疗前下降,治疗12周时双环醇治疗组ALT及AST下降幅度较健肝灵治疗组好,差异有统计学意义(P<0.05);停药12周后双环醇治疗组未见明显ALT及AST反跳,而健肝灵治疗组在停药12周后ALT及AST均有所升高,差异有统计学意义(P<0.05)。结论双环醇片与健肝灵一样,具有较好的保肝、显著降低血清转氨酶、改善肝功能的疗效,双环醇对ALT、AST的早期下降作用优于健肝灵,可以在临床推广使用。     

多烯磷脂酰胆碱联合双环醇治疗胃癌化疗导致的药物性肝损伤患者疗效及其对血清细胞因子和氧化应激指标水平的影响

目的 探讨应用多烯磷脂酰胆碱联合双环醇治疗胃癌化疗所致的药物性肝损伤(DILI)患者疗效及其对血清细胞因子和氧化应激指标的影响。方法 2017年5月～2019年5月我院收治的胃癌根治术后患者78例,给予奥沙利铂、多西他赛和氟尿嘧啶化疗。在化疗过程中出现DILI患者40例,被随机分为对照组(n=19)和观察组(n=21),给予对照组患者多烯磷脂酰胆碱治疗,给予观察组多烯磷脂酰胆碱联合双环醇片治疗,两组均观察4周。采用ELISA法检测血清肿瘤坏死因子-α(TNF-α)和白细胞介素-6(IL-6),采用硫代巴比妥酸法检测血清丙二醛(MDA),采用黄嘌呤氧化法检测血清超氧化物歧化酶(SOD)。采用卡氏功能状态(KPS)量表评估患者生存质量。结果 在治疗4周末,观察组血清丙氨酸氨基转移酶(ALT)水平为(33.5±7.9)U/L,显著低于对照组【(42.4±8.8)U/L,P<0.05】,血清天冬氨酸氨基转移酶(AST)水平为(34.4±5.7)U/L,显著低于对照组【(39.4±6.2)U/L,P<0.05】,血清碱性磷酸酶(ALP)水平为(60.6±14.2)U/L,显著低于对照组【(75.3±16.6)U/L,P<0.05】,而KPS评分为(64.1±17.2)分,显著高于对照组【(48.3±14.5)分,P<0.05】;联合组肝功能复常率为81.0%,显著高于对照组的63.2%(P<0.05);观察组血清TNF-α水平为(15.2±2.1)mg/L,显著低于对照组【(21.4±3.6)mg/L,P<0.05】,血清IL-6水平为(28.1±4.5)pg/mL,显著低于对照组【(46.2±5.9)pg/mL,P<0.05】;血清MDA水平为(5.1±0.8)nmol/mL,显著低于对照组【(5.9±0.7)nmol/mL,P<0.05】,而血清SOD水平为(2.3±0.5)U/mL,显著高于对照组【(1.8±0.4)U/mL,P<0.05】。结论 联合应用多烯磷脂酰胆碱和双环醇片治疗化疗药导致的DILI患者能改善肝功能,可能与抑制了氧化应激反应,降低了血清细胞因子水平有关,值得进一步研究。     

Up-regulation of glycolipid transfer protein by bicyclol causes spontaneous restriction of hepatitis C virus replication

Bicyclol is a synthetic drug for hepatoprotection in clinic since 2004. Preliminary clinical observations suggest that bicyclol might be active against hepatitis C virus (HCV) with unknown mechanism. Here, we showed that bicyclol significantly inhibited HCV replication in vitro and in hepatitis C patients. Using bicyclol as a probe, we identified glycolipid transfer protein (GLTP) to be a novel restrictive factor for HCV replication. The GLTP preferentially bound host vesicle-associated membrane protein-associated protein-A (VAP-A) in competition with the HCV NS5A, causing an interruption of the complex formation between VAP-A and HCV NS5A. As the formation of VAP-A/NS5A complex is essential for viral RNA replication, up-regulation of GLTP by bicyclol reduced the level of VAP-A/NS5A complex and thus inhibited HCV replication. Bicyclol also exhibited an inhibition on HCV variants resistant to direct-acting antiviral agents (DAAs) with an efficacy identical to that on wild type HCV. In combination with bicyclol, DAAs inhibited HCV replication in a synergistic fashion. GLTP appears to be a newly discovered host restrictive factor for HCV replication, Up-regulation of GLTP causes spontaneous restriction of HCV replication.     

双环醇治疗慢性乙型病毒性肝炎肝纤维化的临床研究

目的研究双环醇对慢性乙型病毒性肝炎(乙肝)肝纤维化的治疗作用。方法以双环醇治疗慢性乙肝患者20例,疗程6个月。分别于治疗前后检测患者血清丙氨酸氨基转移酶(ALT)、γ谷氨酰转肽酶(GGT)及血清纤维化指标层粘连蛋白(LN)、Ⅳ型胶原(CⅣ)、Ⅲ型前胶原肽(PⅢP)和透明质酸(HA)水平。同时经皮肝活检观察治疗前后肝脏组织病理学变化。结果双环醇可以显著降低慢性乙肝患者血清ALT和GGT水平,复常率分别达95%和70%,同时可以明显降低慢性乙肝患者血清LN、CⅣ和PⅢP水平,尤其PⅢP和CⅣ水平与肝组织纤维化程度呈明显正相关(相关系数分别为0.653和0.530,P<0.01)。结论双环醇可以减轻慢性乙肝患者肝脏炎症反应,保护肝细胞和抑制肝纤维化。     

百赛诺治疗非酒精性脂肪肝50例疗效观察

目的观察百赛诺治疗非酒精性脂肪肝的临床疗效。方法将100例非酒精性脂肪肝患者随机分为2组。治疗组50例给予百赛诺50 mg,每日3次口服;对照组50例给予甘利欣150 mg,每日3次口服。2组均24周为1个疗程,1个疗程后统计临床疗效及治疗前后血清学变化。结果2组治疗后丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、γ-谷氨酰转肽酶（GGT）、总胆固醇（TC）及甘油三酯（TG）与本组治疗前比较差异均有统计学意义（P〈0.01）;2组治疗后TC、TG比较差异均有统计学意义（P〈0.05）。治疗组总有效率90.0%,对照组总有效率70.0%,2组比较差异有统计学意义（P〈0.05）。结论百赛诺治疗非酒精性脂肪肝疗效确切,副作用小。     

肾移植术后早期肝损害的预防和治疗效果分析

目的探讨肾移植术后早期肝损害的预防措施和治疗效果。方法将504例肾移植术后患者按照随机原则分为两组,常规预防组251例,于肾移植术后在应用常规药物同张顺财时即开始采用还原型谷胱甘肽2400mg,静脉滴注;未预防组253例,除肾移植后药物外未采用任何保肝预防药物。如果预防治疗后仍出现肝损害,依照治疗方案不同将患者随机分为两组,A组34例,连续8周口服双环醇片75mg/d（每次25mg,每日3次）。B组34例,连续8周口服硫普罗宁片600mg/d（每次200mg,每日3次）。结果常规预防组的肝损害发生率明显小于未预防组（P〈0.01）;常规预防后仍出现肝损害的患者联用双环醇后,在肝功能与综合疗效改善方面明显优于硫普罗宁组（P〈0.05,P〈0.01）;未发现与研究药物明显相关的不良事件。结论还原型谷胱甘肽可预防肾移植后早期肝损害的发生,联用双环醇片可有效治疗常规预防后仍出现的肝损害。     

罗格列酮联合双环醇治疗非酒精性脂肪肝的疗效观察

目的观察罗格列酮联合双环醇治疗非酒精性脂肪肝的临床疗效。方法将65例非酒精性脂肪肝患者随机分为治疗组33例和对照组32例,对照组仅给予常规治疗方法;治疗组在对照组基础上给予罗格列酮和双环醇联合治疗,疗程均为24周。治疗结束后比较两组临床疗效及血清学各指标变化。结果治疗组总有效率84．8％明显优于对照组总有效率71．9％（P〈0．05）;治疗结束后治疗组ALT、AST、TG、TC和LDL-C为（46．46士11．26）U／L,（50．55士14．62）U／L,（1．92士0．32）mmol／L,（4．37±0．38）mmol／L和（2．27±0．41）mmoI／L,较对照组显著降低（P〈0．05）,HDL-C为（1．68士0．30）mmol／L,较对照组显著升高（P〈0．05）;治疗期间两组均未见明显不良反应。结论罗格列酮联合双环醇治疗非酒精性脂肪肝疗效显著,可明显改善肝功能和血脂情况,且治疗中无明显副作用,值得在临床推广应用。     

Bicyclol attenuates oxidative stress and neuronal damage following transient forebrain ischemia in mouse cortex and hippocampus

To assess its potential neuroprotective effect against ischemia/reperfusion (IR) injury in mice, bicyclol was administered intragastrically once a day for 3 days. After 6 h of bicyclol pretreatment on the third day, forebrain ischemia was induced for 1 h by bilateral occlusion of the carotid arteries. After different times of reperfusion, the histopathological changes and the levels of mitochondria-generated reactive oxygen species (ROS), malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) in the cortex and hippocampus were measured. We found that extensive neuronal death occurred in the cortex and the CA1 area of the hippocampus at day 7 after IR and that bicyclol significantly attenuated IR-induced neuronal death in a dose-dependent manner. We also found that pretreatment with bicyclol dose dependently decreased the generation of ROS and the MDA content and reduced the compensatory increase in SOD activity in the cortex and hippocampus at 4 h of reperfusion. These results suggest that bicyclol protects the mouse brain against cerebral IR injury by attenuating oxidative stress and lipid peroxidation.     

Protective effect of bicyclol on tetracycline-induced fatty liver in mice

Peroxisome proliferators-activated receptor α (PPARα) and oxidative stress are two important pathological factors in non-alcoholic fatty liver disease (NAFLD). Tetracycline-induced fatty liver was partly due to the disturbance of mitochondrial fatty acids β-oxidation regulated by PPARα. Bicyclol was found to protect against high fat diet-induced fatty liver through modulating PPARα and clearing reactive oxygen species (ROS). The present study was performed to further investigate the effect of bicyclol on tetracycline-induced fatty liver and related mechanism in mice. Bicyclol (75, 150, 300 mg/kg) was given orally three times in two consecutive days. Tetracycline (200 mg/kg) was injected intraperitoneally 1 h after the last administration of bicyclol. Oxidative stress, mitochondrial function, PPARα and its target genes were evaluated by biochemical and RT-PCR analysis. The activity of CYP4A was assessed by liquid chromatography/mass spectrometry (LC/MS) method. Bicyclol significantly protected against tetracycline-induced fatty liver by reducing the accumulation of hepatic lipids and elevation of serum aminotransferase. In addition, bicyclol remarkably alleviated the over-production of thiobarbituric acid-reactive substance. The reduced activity of mitochondrial respiratory chain (MRC) complexes I and IV and mitochondrial permeability transition (MPT) were also improved by bicyclol. Furthermore, bicyclol inhibited the decrease of PPARα expression and its target genes, including long-chain acyl CoA dehydrogenase (LCAD), acetyl CoA oxidase (AOX) and CYP4A at mRNA and enzyme activity level. Bicyclol protected against tetracycline-induced fatty liver mainly through modulating the disturbance of PPARα pathway and ameliorating mitochondrial function.