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OBJECTIVE：To analyze the mass spectrometry fragmentation regularity of bicyclol ，bifendate and schisandrin C ， and to identify the impurities of bicyclol raw material. METHODS ：UHPLC-ESI-Q-TOF-MS method was adopted. Using electrospray ionization source ，in positive ion mode ，the excimer ion and characteristic fragments of bicyclol ，bifendate and schisandrin C were analyzed by means of TOF-MS. According to the mass change of fragments ，the possible fragmentation pathways were speculated ，and the fragmentation regularity were analyzed and summarized. Bicyclol raw material sample was first separated by liquid chromatography to find the impurity peaks in it ，and then the impurity peaks were analyzed by mass spectrometer；the impurity identification was conducted by combining with the fragmentation regularity. RESULTS ：The 3 compounds all produced [M+H] + excimer ion in the positive ion mode. After collision-induced dissociation ，the C-O bond ，the simple rupture of the C-C bond and the ring-opening cleavage of the oxygen ring occurred ；with the loss of neutral fragments ， mainly CH 2O，supplemented by CO 2，CO and CHO ，the dissociation was concentrated in the middle and high quality regions. C-C and C-O bonds of 3 compounds were simply broken only in the branched chain structure and/or oxygen ring structure ，but the structure of the biphenyl parent nucleus remained unchanged. Among them ，the bicyclol contained a benzyl alcohol structure ，so under acidic mobile phase conditions ，it would exist stably in the form of [M+H －H2O]+. Because schisandrin C contained 8-membered ring structure，ring opening first occurred under collision voltage ，and then neutral fragment loss occurred. The secondary mass spectra of impurity in bicyclol raw material were consistent with the mass spectra fragmentation of secondary fragments of bifendate. CONCLUSIONS：The study summarized mass spectrometry fragmentation regularity of 3 schisandrin derivatives. The impurity in bicyclol raw material may be bifendate.
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Objective@#To investigate the interventional effect of bicyclol on isoniazid-induced liver injury in rats and the expression of endoplasmic reticulum stress (ERS) protein, glucose regulatory protein 78 (GRP78), and growth arrest and DNA-damage-inducible gene 153(CHOP).@*Methods@#Eighty Wistar rats were randomly divided into control group (8 rats) and model group (72 rats). After 10 days of intragastric administration of isoniazid, the model group rats were randomly divided into treatment group (A), natural recovery group (B), etiological persistence group (C) and etiological persistence plus treatment group (D). Sixteen rats from each group were sacrificed after 1 and 2 weeks of intervention with different methods. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected. Liver pathological morphology was observed. Apoptotic cells were detected by TUNEL assay. ERS protein expression was detected by Western blot. A t-test or randomized block analysis of variance, K-S test and Levene’s test were used to analyze the normality and homogeneity of variance. Kruskal-Wallis rank sum test was used for data that did not suit the conditions of t-test and variance analysis.@*Results@#ALT and AST were elevated in the model group, and liver pathological examination showed liver tissue damage. Apoptotic index was higher than control group (7.13% ± 1.55% vs. 0.75% ± 0.71%, Z = -3.411, P < 0.01), and the expression value of ERS protein in model group was significantly higher than control group (GRP78: 1.16 ± 0.30 vs. 0.23 ± 0.05, t = -6.008, P < 0.01; CHOP: 0.98±0.23 vs. 0.20 ± 0.10, t = -6.378, P < 0.01). Serum enzymes, apoptotic index and ERS protein expressions of rats were decreased after treatment with bicyclol, and the pathological damage was eased. Rats in natural recovery group recovered less than the treatment group.@*Conclusion@#Isoniazid-induced liver injury is associated to ERS-related excessive apoptosis and the therapeutic effect of bicyclol on drug-induced liver injury may minimize ERS-induced apoptosis.
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To investigate the effects of small molecule compound bicyclol on type 2 diabetes mellitus (T2DM) and its mechanism of action, KKAy mice were treated with various doses of bicyclol (100, 200, and 400 mg·kg-1·d-1) with metformin (200 mg·kg-1·d-1) as a positive control, respectively. Age-matched C57BL/6J mice were used as the non-diabetic control (Con). The effect on hyperglycemia was evaluated by the levels of no-fasting blood glucose, fasting blood glucose (FPG), and glucose tolerance. Whole body insulin sensitivity was evaluated by fasting plasma insulin (FPI) and homeostasis model assessment-insulin resistance (HOMA-IR). The hepatic response to insulin was evaluated by insulin-induced activation of insulin signaling pathway. Western blot was performed to detect hepatic protein expressions. All animal experimental procedures were approved by the Animal Ethics Committee of Chinese Academy of Medical Sciences. KKAy mice showed T2DM characteristics such as hyperglycemia and insulin resistance, including attenuated response to insulin in the liver. A 28-day treatment of bicyclol suppressed both FPG and no-fasting blood glucose, in a dose- and time-dependent manner. Moreover, FPI and HOMA-IR values were both significantly decreased, and hepatic insulin-induced-phosphorylation of IRβ and Akt were up-regulated in KKAy mice after bicyclol treatment. Phosphorylation of FoxO1, the key transcription factor for regulating gluconeogenesis, was also significantly elevated by bicyclol treatment. These results suggested that bicyclol has some therapeutic effects on hyperglycemia in a time- and dose-dependent manner in KKAy mice. Its mechanism might be attributed to improving insulin resistance, enhancing hepatic insulin signaling pathway, and inhibiting gluconeogenesis. No significant interference on the hypoglycemic effect of metformin by bicyclol was observed in this study.
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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 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.
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OBJECTIVE@#To assess the genotoxicity and embryotoxicity of bicyclol methyl ether (BME), the main impurity in bicyclol.@*METHODS@#Five concentrations of BME (0.5, 5, 50, 500 and 5000 μg/plate) were used in the Ames test to detect gene mutation. In the chromosome aberration test, Chinese hamster lung cells were used to detect chromosomal aberration of BME (15, 30, 60, 120 μg/mL) with or without S9 mixture. Embryotoxicity test was also conducted to determine any embryotoxicity of BME (7.5, 22.5, 67.5 μg/L) using zebrafish embryos.@*RESULTS@#No significant differences were observed in the Ames test and the chromosome aberration test in the BME groups compared with the vehicle control group. The zebrafish embryos toxicity test also showed no embryo development toxicity of BME, including hatching rate, body length, pericardial area and yolk sac area.@*CONCLUSIONS@#Bicyclol methyl ether has no genotoxicity in vitro and embryotoxicity in zebrafish embryos, and the impurity in bicyclol is qualified.
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OBJECTIVE:To explore the effectiveness and safety of bicyclol combined with ganciclovir in the treatment of infan-tile cytomegaloirus hepatitis. METHODS:One hundred and twenty children with cytomegaloirus hepatitis in department of pediatrics of our hospital during May 2012-Aug. 2015 were selected and divided into observation group and control group according to random number table,with 60 cases in each group. Both groups received conventional treatment such as protecting liver,vitamin C,vitamin K and Compound glycyrrhizin injection 20 mL,ivgtt,qd. Control group additionally received Ganciclovir injection(induction period:5 mg/kg,q12 h,dripping time >1 h,for 7 d;maintenance period:5 mg/kg,q24 h,for 7 d);observation group was additionally giv-en Bicyclol tablet 0.5 mg/kg,bid,on the basis of control group. Clinical efficacies of 2 groups were observed as well as liver enzyme level,jaundice level before and after treatment. The rate of negative CMV and the occurrence of ADR were compared. RESULTS:Clinical total response rate of observation group was 93.3%,which was significantly higher than 80.0% of control group,with statisti-cal significance(P0.05). After treatment,liver enzyme level and jaundice level of 2 groups were decreased significantly,and observation group was significantly lower than control group,with statistical significance(P0.05). CONCLUSIONS:Bicyclol combined with ganci-clovir shows significant therapeutic efficacy for infantile cytomegaloirus hepatitis,and can effectively reduce the levels of liver en-zymes,eliminate jaundice,protect liver function,promote virus clearance with good safety.
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Objective To study the real world of bicyclol tablets in the treatment of viral hepatitis and its influence on platelets.Methods The hospital information system (HIS) was selected from 18 Triple-A hospitals in China on patients with bicyclol tablets information as exposed group (2 690 cases),patients with unused bicyclol tablet (2 690 cases) as an exposed group,an exception occurs of platelet as an index of the ending.Results The incidence of abnormal platelet difference in two groups before the treatment were not statistically significant.The incidence of abnormal platelet reduce between two groups have statistical significance,can be thought of exposure of abnormal lower rate (11.75%)lower than that of non exposed group(15.17%) (P<0.01).Conclusion Bicyclol piece have signficantly curative effect on the treatment of viral hepatitis.It shows more safety,and less impact on platelets.It is worth to be used in clinical practice.
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Objective To investigate the effect of bicyclol on liver tissue proliferation in mice with tetracycline-induced fatty liver. Methods Fifty ICR mice were randomly assigned into 5 groups (10 each): normal group (control), tetracycline 6h group, bicyclol 6h group, tetracycline 24h group and bicyclol 24h group. Mice in the two bicyclol groups received bicyclol (300mg/ kg) by gavage for 3 times in 12h interval, meanwhile, those in the other groups received the equal amount of forming agents. Tetracycline (200mg/kg) was then injected intraperitoneally to the mice in bicyclol groups and tetracycline groups 1h after the last dose of bicyclol, and mice in control group received equal amount and pH of saline. The liver issues and blood samples from eyes were collected 6h and 24h after tetracycline injection for detection of the corresponding indicators. RT-PCR was performed to detect the gene expression of proliferation index (PCNA, cyclin D1 and c-myc), Western blotting was performed to detect the expression of Cyclin D1 in liver tissue, and immunohistochemistry was employed to detect the expression of PCNA and c-myc proteins. Results The expression level of PCNA gene 6h after tetracycline injection in mice of tetracycline group was 43% of that in control group, meanwhile the expression of protein also reduced obviously. Bicyclol remarkably inhibited the decrease of PCNA gene and protein expressions at early time (6h) of fatty liver. In addition, the expression of cyclin D1 gene in tetracycline 24h group was 59%, and the expression of c-myc was 5.7 folds of that in control group. Bicyclol remarkably up-regulated the gene expressions of cyclin D1 and c-myc 6h after tetracycline injection, and up-regulated the protein expression of cyclin D1 24h after tetracycline injection. Conclusion Bicyclol can enhance hepatocyte proliferation of mice with tetracycline-induced fatty liver by up-regulation of PCNA, cyclin D1 and c-myc expression.
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Objective To evaluate the efficacy and safety of bicyclol tablet on hepatic lesions caused by Epstein-Barr virus( EBV) infection in children.Methods A single-center controlled retrospective study was conducted in 121 children with hepatic lesions caused by EBV infection for evaluating safety,tolerability, and efficacy of treatment with bicyclol tablets or Glycyrrhizin capsules.Childer n in bicyclol group ( n=63 ) were treatedw ith bicyclol at blets and cotn rol group ( n =58 ) were treated with Glycyrrhizin capsules.The course of the treatment were both 8 weeeks for two groups.The level of the EBV load pretreatment and plas-ma aminotransferase,blood routine,urine routine pretreatment and 1 week,4 weeks and 8 weeks after treat-mentw ere analyzed er trospectively.Rse ults (1) The pal smaA LT level sigin ficantly decreased in theb icy-clol group compared with that in the contro l group(P<0.01), se pecai lly the levle after 8 weeks treatm ent. (2) Bicycol l was more effce tive in the bicyclol group than Glycyrrhizin capslu se in the control group( P<0.01).(3) Both grousp had no significantlya dvesr e events.Conclusion Bicyclol tablet can derc ease plas-ma aminotransferase level,espce ially ALT,inc hildren caused by EBV infection with better efficiency and safety.
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To observe the clinical efficacy and safety of bicyclol and polyene phosphatidylcholine in the treatment of liver injury induced by hyperthyroidism. Methods: Totally 112 cases of hyperthyroidism patients were randomly divided into two groups, and both groups were treated with antithyroid drug methimazole. The 56 patients in the treatment group were orally treated with bicyclol, and the other 56 patients in the control group received polyene phosphatidylcholine capsules orally. The changes of liver func-tion were compared before and after the 4-week treatment, including the level of alanine aminotransferase (ALT), aspartate amin-otransferase ( AST) , total bilirubin ( TBIL) and alkaline phosphatase ( ALP) . The efficacy and adverse reactions were also observed. Results:There was no difference in the levels of ALT, AST, TBIL and ALP in both groups before the treatment (P>0. 05), while the levels were all decreased significantly in both groups after the treatment (P0. 05). No drug-related adverse events were shown during the treatment. Conclusion:Bicyclol is effective and reliable in the treatment of liver injury induced by hyperthyroidism, and the clinical efficacy is remarkable when compared with that of polyene phosphatidylcholine.
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Objective To investigate the protective effect of bicyclol tablets on drug-induced hepatic injury in patients with severe psoriasis.Methods One hundred and six patients with severe psoriasis and drug-induced hepatic injury were enrolled in this study,and randomly divided into 2 groups:bicyclol group (53 cases) treated with oral bicyclol tablets (25 mg thrice a day) for 8 weeks,diammonium glycyrrhizinate group (53 cases) treated with diammonium glycyrrhizinate capsules (150 mg thrice a day) for 8 weeks.Serum biochemical indices of hepatic function were measured before and after treatment,therapeutic efficacy was evaluated,and adverse reactions were observed and recorded after treatment.Intergroup and intragroup differences in these parameters were assessed.Results During the treatment,3 patients were lost to follow up.After treatment,serum biochemical indices of hepatic function markedly improved in both the bicyclol group (52 cases) and diammonium glycyrrhizinate group (51 cases) (both P ＜ 0.01),and the bicyclol group showed a better treatment response than the diammonium glycyrrhizinate group (P ＜ 0.01).The marked response rate was 71.15％ and 47.06％ (P ＜ 0.05),and the response rate was 84.62％ and 66.67％ (P ＜ 0.05),respectively,in the bicyclol group and diammonium glycyrrhizinate group.No adverse reactions related to tested drugs were observed in either of the two groups.Conclusion Bicyclol can attenuate antipsoriatic drug-induced hepatic injury with good safety.
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Objective To investigate the effects of different liver protective drugs on preventing liver injury induced by anti-tuberculosis drugs. Methods Retrospective analysis was made on 355 patients with primary pulmonary tuberculosis during intensified time. The patients received silibinon and bicyclol to prevent liver injury. 82 patients with TB were treated as control group during the same time. Results The number of patients with liver injury in silibinon group and bicyclol group were 16 cases (14.7%) and 55 cases (22.4%) respectively. The number of control group with liver injury was 9 cases (11.0%) (χ2 = 3.627,P > 0.05). The liver injuries within 4 weeks were mainly counted in. There is no difference between intervention and control groups(χ2 = 0.414,P > 0.05). There is no difference between three groups in liver injury degree (U = 0.288,P> 0.05). Conclusion Without high risk factors, anti-inflammatory and enzyme reduction drugs have no significant protective effects on liver injury caused by anti-tuberculosis drugs.
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Objective To observe the clinical effect of bicyclol combined with polyene phosphatidyl choline in elderly non-alcoholic fatty liver disease (NAFLD).Methods One hundred and twenty elderly patients with NAFLD were divided into 3 groups by block randomization method,40 cases in each group.Therapeutic group was treated by bicyclol combined with polyene phosphatidyl choline; bicyclol group was only treated by bicyclol; and polyene phosphatidyl choline group was only treated by polyene phosphatidyl choline.The blood biochemical indexes,liver ultrasound score and clinical curative effect of 3 groups were compared after treated for 24 weeks.Results The total cholesterol (TC),triglyceride (TG),alanine aminotransferase (ALT),aspartate aminotransferase (AST) and gamma glutamine transferase (GGT) in 3 groups after treatment were lower than those before treatment,and the difference was statistically significant (P ＜ 0.05) ; TC,TG and ALT levels in therapeutic group after treatment were significantly lower than those in bicyclol group and polyene phosphatidyl choline group [(1.36 ± 0.84) mmol/L vs.(2.77 ± 1.27),(2.84 ±1.35) mmol/L; (1.32 ±0.71) mmol/L vs.(1.89 ±0.87),(1.92 ±0.90) mmol/L; (38.26 ± 12.75) U/L vs.(57.83 ± 16.67),(62.07 ± 18.16) U/L],and the difference was statistically significant (P ＜ 0.05).The liver ultrasound score in 3 groups after treatment was significantly decreased compared with that before treatment,and the difference was statistically significant (P ＜ 0.05).Liver ultrasound scores in therapeutic group after treatment were significantly lower than those in bicyclol group and polyene phosphatidyl choline group [(2.08 ± 0.93) scores vs.(3.17 ± 1.14),(3.34 ± 1.07) scores],and the difference was statistically significant (P ＜ 0.05).The total effective rate in therapeutic group was significantly higher than that in bicyclol group and polyene phosphatidyl choline group [85.0％ (34/40) vs.67.5％ (27/40),65.0％ (26/40)],and the difference was statistically significant (P ＜0.05).Conclusions Bicyclol combined with polyene phosphatidyl choline has better clinical effect in elderly patients with NAFLD.It is better than single bicyclol and polyene phosphatidyl choline and worth clinical promotion.
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Objective To observe the effect of bicyclol tablets in preventing liver damage caused by anti -tu-berculosis drugs .Methods According to the different treatment method ,100 tuberculosis patients were divided into the treatment group and the control group ,each group 50 cases.Both groups were given standardized anti-TB treat-ment,while the treatment group were added to bicyclol tablets throughout the treatment ,and add the control group were added to silibinin capsule throughout the treatment .The liver damage of the two groups were compared .Results There were 6 cases who had liver damage in treatment group (6.0%),and 20 cases who had liver damage in the con-trol group(20.0%),and there was significant difference between the two groups (χ2 =8.66,P<0.01).Conclusion Bicyclol tablets is more effective in preventing liver damage caused by anti-tuberculosis drugs than silibinin cap-sules.
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Objective This study investigates the protective effect of bicyclol on liver function in patients after liver resection.Methods One hundred and twenty patients undergoing liver resection with Pringle's maneuver were randomly divided into groups A,B,and C,and given bicyclol (50 mg),diammonium glycyrrhizinate (150 mg),and silybum marianum (77 mg),respectively.The medication was orally given preoperatively for 5 days and postoperatively for days 3 to 7.The fasting serum ALT,AST,TB,ALP,and PAB levels were determined before operation and on days 1,3,5,and 7 after operation.Results ALT levels in the A group were significantly lower than those in the B and C group on post operative days 1,3,5,and 7 (P＜0.01).On postoperative day 7,the ratio of serum ALT returned to normal was significantly higher than the B and C group ratios (P＜0.05).Conclusion Therefore,oral bicyclol given before and after liver resection can significantly inhibit the rapid increase and promote the normalization of serum ALT levels.
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Objective To evaluate the clinical efficacy and safety of bicyelol tablets in treatment of hepatitis B patients infected with YMDD mutation of HBV. Methods Sixty-eight chronic hepatitis patients infected with HBV YMDD mutants and 100 patients with non-mutants HBV were enrolled in the study. All patients received bicyclol tablets orally 150 mg/d, t. i. d, for 24 weeks. Clinical symptoms, signs and adverse effects were observed, and the blood routine, liver function tests, serum HBV markers and HBV DNA loads were examined at 12th and 24th week of the study, Results After treatment for 24 weeks, the normalization rates of ALT and AST in mutant group were 79.4% ( 54/68 ) and 70. 6% (48/68) ; 11 ( 16. 2% ) patients were markedly effective and 14 (20. 6% ) were effective. Clearance rates of HBeAg and HBV DNA were 27.9% ( 17/61 ) and 17.6% ( 12/68 ), while the seroconversion rate of HBeAg was 14. 7% (9/61). The differences of the above indexes were not statistically significant between mutant group and non-mutant group. Conclusion Bicyciol can both protect liver functions and inhibit virus replication in patients infected with HBV YMDD mutants.
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Objective To stndy the clinical efficacy of bicyclol treatment for chronic hepatitis B.Methods 70 cases of chronic hepatitis B patients were randomly divided into 2 groups;35 cases in test group,with bicyclol 75mg daily,and 35 cases control group,in with SNMC 150mg daily patients in the 2 groups got continuous medication for 12 weeks.levels of serum aminotransferase changes before and after treatment were observed.Results Serum aminotransferase decreased more significantly in test group(P
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Objective To investigate the curative effect of bicyclol in treatment of chronic type B hepatitis.Methods 60 cases of chronic type B hepatitis were treated with bicyclol and the changes of hepatic function,HBV-DNA and antigen-antibody of HBV were investigated between pretherapy and post-treatment.Results The ALT and AST decreased obviously after treatment of bicyclol for 3 months,there was significant difference compared with pretherapy(49.30?28.30) vs (139.05?37.31),P
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OBJECTIVE To survey the therapeutic effect of lamivudine alone or in combination with bicyclol on chronical viral hepatitis B.METHODS Ninety patients with chronic viral hepatitis B were divided into 3 groups: A,B and C.Patients of group A(n=30) were given each 100mg lamivudine po qd,and 25 mg(bicyclol) po,tid,and the course of treatment lasted 72 weeks.Patients of group B(n=30) were subjected to(lamivudine) treatment alone at the same dosage as that of patients in group A.Patients of group C(n=30) were treated with(conventional) hepatinica and symptomatic therapeutic measures,serving as controls.Changes in serum HBV DNA and liver functions and YMDD mutant were dynamically monitored.RESULTS At the end of the 24,48 and 72 weeks of treatment,the rates of sera to turn negative for HBV DNA were 90.0%,(86.7%,) and(83.3%),(respectively),in patients of group A,and 86.7%,83.3%,and 76.7%,respectively,in patients of group B.The rates of sera to turn negative for HBV DNA,in patients of groups A and B were significantly higher than those in patients of group C(P0.05);at the end of 72 weeks,the rates of YMDD mutant were 16.7% in group A and 36.7% in group B,the rates in group A were significantly higher than in group B((P
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0.05) between in 2 groups.CONCLUSION: Used in combination with rifampin,bicyclol showed insignificant effect on the pharmacokinetics of rifampin in rats.