A Retrospective Cohort Study: Safety and Effectiveness of Elbasvir/Grazoprevir ± Ribavirin Compared With Ombitasvir/Paritaprevir/Ritonavir/Dasabuvir ± Ribavirin in Patients With Chronic Hepatitis C Genotype 1 Infection.

Background: The direct-acting antiviral (DAA) agents are widely used to treat hepatitis C virus (HCV) genotype (GT) 1 infection, while it may cause severe liver damage. The objectives of the study were to evaluate the incidence of drug-induced liver injury (DILI), sustained virologic response at post-treatment week 12 (SVR12), and recurrence rates in HCV GT 1 infection. Methods: This was a retrospective cohort study that included patients diagnosed with HCV GT 1 infection, who had received intervention and treatment with elbasvir/grazoprevir (EBR/GZR) ± ribavirin (RBV) versus ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) + dasabuvir ± RBV (as control group) for 12 or 24 weeks at a regional hospital in southern Taiwan between April 2016 and August 2018. The primary outcome of the study was to compare the incidence rate ratio (IRR) of DILI via Poisson regression, and the secondary outcome was to evaluate the effectiveness of two treatment regimens expressed as a percentage. Results: The study included 149 patients in the control group and 105 patients in the intervention group of which 99.33 and 98.1% patients, respectively, achieved SVR12. In the control group, one patient experienced relapse, whereas in the intervention group, two patients relapsed. Furthermore, in the control group, a total of nine patients developed DILI as determined during follow-up care. Of these patients, three were 55-84 years old. In the intervention group, six patients developed DILI. The IRR of DILI caused by EBR/GZR treatment was 2.84 times higher than that caused by the OBV/PTV/r treatment regimen. Conclusion: There was no significant difference between the studied DAA regimens regarding the incidence of DILI and effectiveness during the treatment. DILI occurrence during therapy did not affect the cure rate of medication. The present study results can provide reference data for drug selection among patients with HCV. Trial registration: The study was approved by DMF-CYCH (CYCH IRB No: 2018067).

Drug Safety of Benzodiazepines in Asian Patients With Chronic Obstructive Pulmonary Disease.

Purpose: Many comorbidities, including depression, anxiety, and insomnia, occur in patients with chronic obstructive pulmonary disease (COPD). These patients may be prescribed benzodiazepines (BZDs). However, there are some concerns that benzodiazepines increase the risk of drug overdose, hypercapnic respiratory failure, acute exacerbation and increased mortality. The aim of our study was to evaluate the drug safety of BZDs in patients with COPD. Methods: We used the National Health Insurance Research database in Taiwan from 2002 to 2016 to perform a retrospective cohort study. We enrolled patients who were exposed to the first prescription of BZDs, non-BZDs or a combination (mix user) after COPD diagnosis. We performed 1:1:1 propensity score matching in three groups. The outcomes were COPD with acute exacerbation and all-cause mortality. Poisson regression analysis was performed to evaluate the incidence rate ratios for the outcomes in the groups. Results: After propensity score matching, there were 2,856 patients in each group. After adjusting for confounding factors, we found that compared to BZD users, non-BZD and mix users had nonsignificant differences in outpatient management of acute exacerbations, hospitalization management of acute exacerbations, emergency department management of acute exacerbations and all-cause mortality. BZD and mix groups showed significantly increased admission for acute exacerbation of COPD compared with that of the nonuser group, with IRRs of 2.52 (95% CI, 1.52-4.18; p = 0.0004) and 2.63 (95% CI, 1.57-4.40; p = 0.0002), respectively. Conclusion: BZD, non-BZD, and mix users showed increased COPD-related respiratory events compared to nonusers in Asian subjects.

HMG-CoA reductase inhibitors activate caspase-1 in human monocytes depending on ATP release and P2X7 activation.

Recent studies have demonstrated the stimulatory effects of HMG-CoA reductase inhibitors, statins, on IL-1ß secretion in monocytes and suggest a crucial role for isoprenoids in the inhibition of caspase-1 activity. In this study, we further elucidated the molecular mechanisms underlying the stimulatory effects of statins on caspase-1. Three commonly recognized mechanistic models for NLRP3 inflammasome activation (i.e., ATP/P2X7/K(+) efflux, ROS production, and lysosomal rupture) were investigated in statin-stimulated human THP-1 monocytes. We found that fluvastatin and lovastatin can synergize with LPS to trigger inflammasome activation. Moreover, statin-induced caspase-1 activation and IL-1ß production in LPS-primed THP-1 cells are dependent on GGPP deficiency and P2X7 activation. In particular, increased ATP release accounts for the action of statins in P2X7 activation. We also provide evidence that statin-induced moderate ROS elevation is involved in this event. Moreover, the cathepsin B inhibitor was shown to reduce statin-induced IL-1ß secretion. Consistently statins can induce cathepsin B activation and lysosomal rupture, as evidenced by LysoTracker staining. Statins also increase intracellular ATP secretion and IL-1ß release in primary human monocytes and murine macrophages. Notably, exogenous ATP-elicited P2X7 activation and consequent IL-1ß release, an index of direct NLRP3 inflammasome activation, were not altered by statins. Taken together, statin-induced enhancement of inflammasome activation in monocytes and macrophages covers multiple mechanisms, including increases in ATP release, ROS production, and lysosomal rupture. These data not only shed new insight into isoprenylation-dependent regulation of caspase-1 but also unmask mechanisms for statin-elicited inflammasome activation.

Anti-atherosclerotic action of Ger-Gen-Chyn-Lian-Tang and AMPK-dependent lipid lowering effect in hepatocytes.

ETHNOPHARMACOLOGICAL RELEVANCE: The Ger-Gen-Chyn-Lian-Tang (GGCLT), an officially standardized mixture of Chinese herbal medicines, consists of Puerariae Radix, Scutellariae Radix, Coptidis Rhizoma and Glycyrrhizae Radix in a ratio of 8:3:3:2. In this study, we evaluated the benefits of GGCLT in atherosclerotic progression. METHODS: The major constituents of GGCLT were analyzed by HPLC. ApoE-/- mice taken 0.15% cholesterol diet were orally given vehicle or GGCLT (2 g/kg/day) for 12 weeks. Serum levels of lipid and glucose were analyzed, and atherosclerosis was examined by histological analyses. Cultures of vascular smooth muscle cells, hepatocytes and bone marrow-derived macrophages were used to investigate the action mechanisms of GGCLT. RESULTS: Our quantitation results indicated that GGCLT contains puerarin, daidzin, daidzein, baicalin, baicalein, wogonin, palmatine, coptisine, berberine and glycyrrhizin. GGCLT decreased serum levels of total cholesterol and LDL, but not TG and HDL in ApoE-/- mice. In parallel, GGCLT treatment reduced atherosclerotic lesions and collagen expression in atheroma plaques. In vascular smooth muscle cells, GGCLT could reduce cell migration, but failed to affect cell viability and proliferation. In hepatocytes, GGCLT can reduce lipid accumulation, and this action was accompanied by the activation of AMPK, upregulation of PPARs, and downregulation of FAS. Pharmacological approach indicated that the latter two events contributing to the anti-lipogenesis is resulting from AMPK pathway, and the lipid lowering effect of GGCLT in hepatocytes is mediated by AMPK and PPARα pathways. Meanwhile, two of the major components of GGCLT, berberine and puerarin, also activated AMPK and decreased lipid accumulation in hepatocytes with berberine of higher efficacy. Besides in hepatocytes, AMPK signaling was also activated by GGCLT in vascular smooth muscle cells and macrophages. CONCLUSIONS: These results demonstrate the anti-atherosclerotic action of Chinese medicine mixture GGCLT in ApoE-/- atherosclerotic mouse model. Mechanistic study suggests that activation of AMPK and PPARα in hepatocytes leading to a decrease of lipid formation contributes to the beneficial action of GGCLT in atherosclerosis treatment.