Atorvastatin and rosuvastatin do not prevent thioacetamide induced liver cirrhosis in rats

AIM:To examine whether the administration of atorvastatin and rosuvastatin would prevent experimentallyinduced hepatic cirrhosis in rats.METHODS:Liver cirrhosis was induced by injections of thioacetamide(TAA).Rats were treated concurrently with TAA alone or TAA and either atorvastatin(1,10 and 20 mg/kg) or rosuvastatin(1,2.5,5,10 and 20 mg/kg) given daily by nasogastric gavage.RESULTS:Liver fibrosis and hepatic hydroxyproline content,in the TAA-treated group was significantly higher than those of the controls [11.5 ± 3.2 vs 2.6 ± 0.6 mg/g protein(P = 0.02)].There were no differences in serum aminotransferase levels in the TAA controls compared to all the groups treated concomitantly by statins.Both statins used in our study did not prevent liver fibrosis or reduce portal hypertension,and had no effect on hepatic oxidative stress.Accordingly,the hepatic level of malondialdehyde was not lower in those groups treated by TAA + statins compared to TAA only.In vitro studies,using the BrdU method have shown that atorvastatin had no effect of hepatic stellate cells proliferation.Nevertheless,statin treatment was not associated with worsening of liver damage,portal hypertension or survival rate.CONCLUSION:Atorvastatin or rosuvastatin did not inhibit TAA-induced liver cirrhosis or oxidative stress in rats.Whether statins may have therapeutic applications in hepatic fibrosis due to other etiologies deserve further investigation.

Daclatasvir vs telaprevir plus peginterferon alfa/ribavirin for hepatitis C virus genotype 1

AIM: To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin(peg IFN/RBV), in treatment-naive hepatitis C virus(HCV) genotype(GT) 1-infected patients.METHODS: In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned(2:1) to daclatasvir vs telaprevir, stratified by IL28 B rs12979860 host genotype(CC vs non-CC), cirrhosis status(compensated cirrhosis vs no cirrhosis), and HCV GT1 subtype(GT1a vs GT1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus peg IFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus peg IFN/RBV; those without an extended rapid virologic response(e RVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of peg IFN/RBV. Telaprevir-treated patients received 12 wk of telaprevir plus peg IFN/RBV followed by 12(with e RVR) or 36(no e RVR) wk of peg IFN/RBV. The primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12(SVR12) in GT1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia(hemoglobin < 10 g/d L) and rashrelated events, through week 12, were lower with daclatasvir + peg IFN/RBV than with telaprevir + peg IFN/RBV among GT1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5 A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA ≥ 1000 IU/m L, to investigate any link between NS5 A polymorphisms associated with daclatasvir resistance and virologic outcome. RESULTS: Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups(6.0% and 8.2% in the GT1 b and GT1 a groups, respectively) than in the telaprevir groups(2.2% and 3.0%). Among GT1 binfected patients, daclatasvir plus peg IFN/RBV was noninferior to telaprevir plus peg IFN/RBV for SVR12 [85%(228/268) vs 81%(109/134); difference, 4.3%(95%CI:-3.3% to 11.9%)]. Anemia(hemoglobin < 10 g/d L) was significantly less frequent with daclatasvir than with telaprevir [difference,-29.1%(95%CI:-38.8% to-19.4%)]. Rash-related events were also less common with daclatasvir than with telaprevir, but the difference was not statistically significant. In GT1 ainfected patients, SVR12 was 64.9% with daclatasvir and 69.7% with telaprevir. Among both daclatasvir and telaprevir treatment groups, across GT1b- or GT1a-infected patients, lower response rates were observed in patients with IL28 B non-CC and cirrhosis- factors known to affect response to peg IFN/RBV. Consistent with these observations, a multivariate logistic regression analysis in GT1b-infected patients d e m o n s t ra t e d t h a t S V R 1 2 wa s a s s o c i a t e d w i t h IL28 B host genotype(CC vs non-CC, P = 0.011) and cirrhosis status(absent vs present, P = 0.031). NS5 A polymorphisms associated with daclatasvir resistance(at L28, R30, L31, or Y93) were observed in 17.3% of GT1b-infected patients at baseline; such variants did not appear to be absolute predictors of failure since 72.1% of these patients achieved SVR12 compared with 86.9% without these polymorphisms. Among GT1b-infected patients, treatment was completed by 85.4%(229/268) in the daclatasvir group, and by 85.1%(114/134) in the telaprevir group, and among GT1a-infected patients, by 67.2%(90/134) and 69.7%(46/66), respectively. Discontinuations(of all 3 agents) due to an AE were more frequent with telaprevir than with daclatasvir, whereas discontinuations due to lack of efficacy were more frequent with daclatasvir, due, in part, to differences in futility criteria. CONCLUSION: Daclatasvir plus peg IFN/RBV demonstrated noninferiority to telaprevir plus peg IFN/RBV for SVR12 and was well-tolerated in treatment-naive GT1 binfected patients, supporting the use of daclatasvir with other direct-acting antivirals.

Effect of hepatic iron concentration reduction on hepatic fibrosis and damage in rats with cholestatic liver disease

瞄准：在肝的纤维变性的前进上与“正常”的肝的铁集中(HIC ) 在老鼠在静脉切开放血术以后估计铁减小的效果，由于胆汁管结扎(BDL ) 。方法：老鼠在假冒的操作或 BDL 前后经历了静脉切开放血术。经历的动物仅仅 BDL 或假冒的操作用作控制。在外科以后的二个星期，肝的损坏和纤维变性的索引被评估。结果：静脉切开放血术降低了 HIC。在 BDL 以后的静脉切开放血术与体重增加，更低的肝的重量，更少的门静脉高血压，更少的仙子门坏死，更少的门发炎，更低的肝的活动索引分数和更高的白朊层次被联系。在另一方面，在 BDL 前的静脉切开放血术与体重减少和肝的活动索引 20 增加被联系。在假冒的操作以后的静脉切开放血术没与任何肝或全身的不利效果被联系。结论：在肝损坏的正式就职以后的 HIC 的减小可以在 BDL 老鼠有有益的效果。然而，铁缺乏能导致肝功能的缺陷并且可以使肝更易受影响到象 BDL 一样的侮辱。