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Background & Aims Volixibat is an inhibitor of the apical sodium-dependent bile acid transporter (ASBT) that has been hypothesized to improve non-alcoholic steatohepatitis (NASH) by blocking bile acid reuptake and stimulating hepatic bile acid production. We studied the safety, tolerability and efficacy of volixibat in patients with NASH. Methods In this double-blind, phase II dose-finding study, adults with ≥5% steatosis and NASH without cirrhosis (N = 197) were randomized to receive volixibat (5, 10 or 20 mg) or placebo once daily for 48 weeks. The endpoints of a predefined interim analysis (n = 80), at week 24, were: ≥5% reduction in MRI-proton density fat fraction and ≥20% reduction in serum alanine aminotransferase levels. The primary endpoint was a ≥2-point reduction in non-alcoholic fatty liver disease activity score without worsening fibrosis at week 48. Results Volixibat did not meet either interim endpoint; the study was terminated owing to lack of efficacy. In participants receiving any volixibat dose, mean serum 7-alpha-hydroxy-4-cholesten-3-one (C4; a biomarker of bile acid synthesis) increased from baseline to week 24 (+38.5 ng/ml [SD 53.18]), with concomitant decreases in serum total cholesterol (−14.5 mg/dl [SD 28.32]) and low-density lipoprotein cholesterol (−16.1 mg/dl [SD 25.31]). These changes were generally dose-dependent. On histological analysis, a greater proportion of participants receiving placebo (38.5%, n = 5/13) than volixibat (30.0%, n = 9/30) met the primary endpoint. Treatment-emergent adverse events (TEAEs) were mainly mild or moderate. No serious TEAEs were related to volixibat. Diarrhoea was the most common TEAE overall and the most common TEAE leading to discontinuation. Conclusions Increased serum C4 and decreased serum cholesterol levels provide evidence of target engagement. However, inhibition of ASBT by volixibat did not elicit a liver-related therapeutic benefit in adults with NASH. Lay summary A medicine called volixibat has previously been shown to reduce cholesterol levels in the blood. This study investigated whether volixibat could reduce the amount of fat in the liver and reduce liver injury in adults with an advanced form of non-alcoholic fatty liver disease. Volixibat did not reduce the amount of fat in the liver, nor did it have any other beneficial effect on liver injury. Participants in the study generally tolerated the side effects of volixibat and, as in previous studies, the main side effect was diarrhoea. These results show that volixibat is not an effective treatment for people with fatty liver disease. Clinical trial identifier NCT02787304 .

In the presented synthetic work, a series of novel substituted 1, 4-Dihydropyridine derivatives (DHPs) have been prepared by the reaction of substituted aromatic aldehydes, ethyl acetoacetate, and ammonium acetate in the presence of a heterogeneous catalyst silica sulfuric acid at ambient temperature via expeditious, mild, inexpensive and one pot Hantszch multicomponent synthetic methodology. Various benefits of this approach are simple work-up; short reaction times at ambient reaction temperature, excellent yields, green solvent system, no by-products and purification of products without chromatographic separation. The catalyst was easily recovered by simple filtration and reused up to five times without washing with any solvent and without major loss in its activity. All the synthesized compounds were characterized by IR, 1H NMR, 13C NMR and LC-Mass spectroscopic techniques. Molecular modelling of the synthesized novel compounds with respect to Lipinski rule of five, drug likeness, toxicity profiles, drug score and other physico-chemical properties are described and compared with market available generic drugs. Theoretical screenings data suggested that the reported compounds possessed a broad range of lipophilic character, no toxicity risks and similar bioactivity scores as relative with standard drugs used for comparison.

Rifampicin, is an antibiotic used in the treatment of numerous types of bacterial infections, including tuberculosis, Mycobacterium avium complex, leprosy, and Legionnaires’ disease. To explicate the binding interactions of Rifampicin with bovine serum albumin (BSA) at molecular level, in the presence of cationic, anionic, and neutral surfactants, it is urgent to investigate their interactions to accomplish its pharmacokinetic and pharmacodynamics gaps vital for advance development and improvement as a therapeutic drug. Thus, we have investigated the binding interaction of Rifampicin with BSA at physiological pH 7.4 in the presence and absence of surfactants Sodium dodecyl sulfate, Cetyltrimethylammonium bromide, and Tween 80. The multispectroscopic studies of Rifampicin with BSA as investigated by UV–visible, fluorescence, and circular dichroism spectroscopy shown a significant stabilization of BSA in the presence of surfactants; that can help in designing more competent drug formulations from a pharmaceutical point of view.

BACKGROUND: A previous study of patients with unresectable hepatocellular carcinoma (HCC) was extended to further examine factors associated with overall survival (OS) after selective internal radiation therapy with yttrium-90 resin microspheres (Y90 SIRT). METHODS: Data from patients of any age diagnosed with unresectable HCC and treated with Y90 SIRT at our institution from 2004 through 2017 were retrospectively analyzed. Among other criteria, patients had to have Eastern Cooperative Oncology Group performance status 0 to 2, not have received Y90 SIRT previously, and not have extrahepatic disease. Primary outcome was OS; secondary outcomes included tumor response and adverse events (AEs). Kaplan-Meier survival analyses and multivariable Cox proportional hazards models were used to evaluate prognostic factors for OS. RESULTS: Of the 226 patients, 59% were White, 77% were male, and the mean age at first SIRT procedure was 65.1±9.4 years. More than half had received previous treatment for HCC. The most common etiology was hepatitis C (n=138/224 available, 62%), followed by alcohol use (n=45, 20%), and nonalcoholic steatohepatitis (n=27, 12%). The mean model for end-stage liver disease score at baseline was 8.8±2.2. Patients were followed-up for a median of 12.2 months (95% CI, 0.0–62.6). Median OS was 16.6 months (95% CI, 13.1 to not reached). Bilobar disease, higher albumin-bilirubin score at baseline, prior treatment with sorafenib, alcohol use etiology, and higher administered dose were associated with shorter survival, whereas subsequent liver transplant [in 26 patients (11.5%)] was associated with longer survival. Of the 186 patients with AEs data, 75 (40.3%) patients reported an event and, of these, 13 (17.3%) patients had grade 4 bilirubin values. CONCLUSIONS: In a large, diverse population treated at a single center over 13 years, Y90 SIRT produced a median OS of 16.6 months in patients with unresectable HCC and enabled subsequent transplantation in a subset of patients. Factors affecting the length of survival should be considered when making treatment decisions for unresectable HCC.

F-box motif encoding YDR131C is functionally uncharacterized gene which forms the complex with the SCF-E3 ligase. The F-box motif containing proteins are involved in substrate recruitment for the ubiquitination and subsequent degradation through 26S proteasome. Autophagy gene, ATG1 (ULK1in human) is a well conserved serine-threonine kinase, required for vesicle formation and cytoplasm to vacuole targeting pathway. Atg1p forms the complex with Atg13p and Atg17p during autophagy. The understanding of crosstalk between ubiquitin and autophagy pathways is crucial for synthetic lethality screen and drug targeting. Here we have conducted the study for genetic interaction between uncharacterized YDR131C and ATG1 gene representing both specific and non-specific protein degradation pathways. The single and double gene knockout strains of YDR131Cand ATG1 genes were constructed in the BY4741 genetic background and analysed for growth fitness. The strains were also evaluated for cellular growth response in presence of hydroxyurea (HU), methyl methane sulfonate (MMS), and hydrogen peroxide (H2O2) stress causing agents by spot assay. The ydr131cΔatg1Δ showed the synthetic growth defect phenotype with floc formation in rich medium which showed floc disruption in presence of EDTA. The ydr131cΔatg1Δ cells showed the sensitivity to stress agents HU, MMS, and H2O2 when compared with ydr131cΔ, atg1Δ, and WT cells.. Based on the observations, we report that YDR131C and ATG1 functions in parallel pathways for growth fitness and cellular growth response to stress agents. Interestingly this study also revealed the crosstalk between ubiquitination and autophagy pathways. The defects in both the pathways could lead to synthetic growth defects which may have implication for the precision medicine initiatives.

Background & Aims Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis. Methods This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points. Results There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (95% CI 0.59–1.77; p = 0.94) and 1.28 (95% CI 0.75–2.21; p = 0.37) for 5 mg and 25 mg of emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated. Conclusions Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis. Lay summary Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis are at high risk of additional decompensation events and death. Post hoc analyses in previous pilot studies suggested that emricasan might improve portal hypertension and liver function. In this larger randomized study, emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated cirrhosis related to non-alcoholic steatohepatitis. ClinicalTrials.gov Identifier NCT03205345 .

Biliary complications following liver transplant are common. Endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP) are the main techniques used to diagnose and treat biliary complications; however, these techniques have limits to the depth of visualization. In this report, we present five cases of orthotopic liver transplant patients with biliary complications that underwent ERCP- or MRCP-guided cholangioscopy with the SpyGlass™ DS Direct Visualization System (SDDVS). The SDDVS allowed for the visualization of the morphological characteristics of biliary strictures, and images collected using the SDDVS allowed for four of the cases to be treated endoscopically. Our findings suggest that cholangioscopy with the SDDVS is a promising method to guide the endoscopic treatment of biliary complications after liver transplantation.

Background & Aims Direct-acting antivirals (DAAs) are effective against hepatitis C virus and sustained virologic response is associated with reduced incidence of hepatocellular carcinoma (HCC). However, there is controversy over the use of DAAs in patients with active or treated HCC and uncertainty about optimal management of these patients. We aimed to characterize attitudes and practice patterns of hepatology practitioners in the United States regarding the use of DAAs in patients with HCC. Methods We conducted a survey of hepatology providers at 47 tertiary care centers in 25 states. Surveys were sent to 476 providers and we received 279 responses (58.6%). Results Provider beliefs about risk of HCC recurrence after DAA therapy varied: 48% responded that DAAs reduce risk, 36% responded that DAAs do not change risk, and 16% responded that DAAs increase risk of HCC recurrence. However, most providers believed DAAs to be beneficial to and reduce mortality of patients with complete response to HCC treatment. Accordingly, nearly all providers (94.9%) reported recommending DAA therapy to patients with early-stage HCC who received curative treatment. However, fewer providers recommended DAA therapy for patients with intermediate (72.9%) or advanced (57.5%) HCC undergoing palliative therapies. Timing of DAA initiation varied among providers based on HCC treatment modality: 49.1% of providers reported they would initiate DAA therapy within 3 months of surgical resection whereas 45.9% and 5.0% would delay DAA initiation for 3–12 months and >1 year post-surgery, respectively. For patients undergoing transarterial chemoembolization (TACE), 42.0% of providers would provide DAAs within 3 months of the procedure, 46.7% would delay DAAs until 3–12 months afterward, and 11.3% would delay DAAs more than 1 year after TACE. Conclusions Based on a survey sent to hepatology providers, there is variation in provider attitudes and practice patterns regarding use and timing of DAAs for patients with HCC. Further studies are needed to characterize the risks and benefits of DAA therapy in this patient population.

Inhibition of apoptosis signal-regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. We evaluated the safety and efficacy of selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1, alone or in combination with simtuzumab, in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of open-label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once-weekly injections of 125 mg of simtuzumab or simtuzumab alone. The effect of treatment was assessed by paired pretreatment and posttreatment liver biopsies, magnetic resonance elastography, magnetic resonance imaging-estimated proton density fat fraction, quantitative collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histology or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 weeks of treatment, the proportion of patients with a one or more stage reduction in fibrosis in the 18-mg selonsertib group was 13 of 30 (43%; 95% confidence interval, 26-63); in the 6-mg selonsertib group, 8 of 27 (30%; 95% confidence interval, 14-50); and in the simtuzumab-alone group, 2 of 10 (20%; 95% confidence interval, 3-56). Improvement in fibrosis was associated with reductions in liver stiffness on magnetic resonance elastography, collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups. Conclusion: These findings suggest that selonsertib may reduce liver fibrosis in patients with nonalcoholic steatohepatitis and stage 2-3 fibrosis. (Hepatology 2018;67:549-559).

Author(s): Tam, Edward; Luetkemeyer, Anne F; Mantry, Parvez S; Satapathy, Sanjaya K; Ghali, Peter; Kang, Minhee; Haubrich, Richard; Shen, Xianlin; Ni, Liyun; Camus, Gregory; Copans, Amanda; Rossaro, Lorenzo; Guyer, Bill; Brown, Robert S; RESCUE and ACTG A5348 study investigators | Abstract: Background a aimsWe report data from two similarly designed studies that evaluated the efficacy, safety, and optimal duration of ledipasvir/sofosbuvir (LDV/SOF)n±nribavirin (RBV) for retreatment of chronic hepatitis C virus (HCV) in individuals who failed to achieve sustained virological response (SVR) with prior SOF-based, non-NS5A inhibitor-containing regimens.MethodsThe RESCUE study enrolled HCV mono-infected adults with genotype (GT) 1 or 4. Non-cirrhotic participants were randomized to 12nweeks of LDV/SOF or LDV/SOFn+nRBV. Compensated cirrhotic participants were randomized to LDV/SOFn+nRBV (12nweeks) or LDV/SOF (24nweeks). The AIDS Clinical Trials Group A5348 study randomized genotype 1 adults with HCV/HIV co-infection to LDV/SOFn+nRBV (12nweeks) or LDV/SOF (24nweeks). Both studies used SVR at 12nweeks post-treatment (SVR12) as the primary endpoint.ResultsIn the RESCUE study, 82 participants were randomized and treated, and all completed treatment. Overall, SVR12 was 88% (72/82); 81-100% in non-cirrhotic participants treated with LDV/SOF or LDV/SOFn+nRBV for 12nweeks and 80-92% in cirrhotic participants treated with LDV/SOFn+nRBV for 12nweeks or LDV/SOF for 24nweeks. Adverse events (AEs), mostly mild-to-moderate in severity, were experienced by 78% of participants, with headache and fatigue most frequently reported. One serious AE, not related to treatment, was observed. No premature discontinuations of study drug, or deaths occurred. In the A5348 study, seven participants were randomized (cirrhotic nn=n1; GT1a nn=n5) and all attained SVR12, with no serious AEs or premature discontinuations.ConclusionsIn this SOF-experienced, NS5A inhibitor-naive population, which included participants with cirrhosis or HCV/HIV co-infection, high SVR12 rates were achieved.