In vitro Assessment of the Effects of Silybin on CYP2B6-mediated Metabolism.

Silybin is a flavonol compound with a variety of physiological properties, such as hepatoprotective, anti-fibrogenic, and hypocholesterolemic effects. Although the in vivo and in vitro effects of silybin are frequently reported, studies on herb-drug interactions have yet to be performed. With the discovery of multiple important substrates of CYP2B6 recently, there is a growing body of evidence indicating that CYP2B6 plays a much larger role in human drug metabolism than previously thought.The purpose of this study is to determine how silybin affects the CYP2B6 enzyme's activity, as well as to clarify the molecular mechanisms for inhibition by silybin. The results showed that silybin inhibited CYP2B6 activity in liver microsomes in a non-competitive manner, with IC50 and Ki values of 13.9 µM and 38.4 µM, respectively. Further investigations revealed that silybin could down-regulate the expression of CYP2B6 protein in HepaRG cells. The hydrogen bond conformation of silybin in the active site of the CYP2B6 isoform was revealed by a molecular docking study. Collectively, our findings verify that silybin is an inhibitor of CYP2B6 and explain the molecular mechanism of inhibition. This can lead to a better understanding of the herb-drug interaction between silybin and the substrates of the CYP2B6 enzyme, as well as a more rational clinical use of silybin.

Assessment of Health-Related Quality of Life Using EuroQoL-5 Dimension in Populations With Prediabetes, Diabetes, and Normal Glycemic Levels in Southwest China.

Objectives: This study aimed to describe and compare health-related quality of life (HRQoL) among populations with normal glycemic levels, prediabetes, and diabetes in southwest China and to offer baseline data that can be easily compared to other regions in China or across countries. Methods: A quality of life survey based on the EuroQoL-5 Dimension-5 level (EQ-5D-5L) scale was conducted through face-to-face or telephone interviews. A total of 403 respondents with diabetes, 404 with prediabetes, and 398 with normal blood glucose were enrolled in the survey. Propensity score matching (PSM) was used to decrease the bias of three groups, conditioned on age and gender, body mass index (BMI), and household income. For the three groups, we matched two groups first and then matched the result with the third group. Differences among groups were compared by chi-square test one-way ANOVA after adjusting by PSM. Results: In general, the blood glucose of people with diabetes was generally well-controlled in southwest China, but they were often accompanied by the circulatory system and nutritional metabolic diseases. Ninety-nine individuals from each group were matched. The EuroQoL-5 Dimension index of the population with normal glycemic levels, prediabetes, and patients with diabetes was 0.901, 0.948, and 0.897. The EuroQol-visual analog scales (EQ-VAS) scores of each group above were 73.76, 77.45, and 68.34. HRQoL in males was higher than that of females in the three study groups. The results after PSM were consistent with that before matching. Conclusion: There was a general trend that patients were associated with a decline of HRQoL from the prediabetic population, population with normal glycemic levels to diabetic population. Pain/discomfort and anxiety/depression might not be specific for the population with or without diabetes.

Cost-Effectiveness Analysis of Triple Combination Preparations in the Treatment of Moderate-to-Severe Chronic Obstructive Pulmonary Disease.

Objectives: This study analyzed the long-term cost-effectiveness of fluticasone/umeclidinium/vilanterol triple combination (FF/UMEC/VI) vs. budesonide/formoterol double combination (BUD/FOR) in the treatment of moderate-to-severe chronic obstructive pulmonary disease (COPD) and provides evidence for COPD treatment decisions. Methods: From the perspective of the healthcare system, a Markov model was established that consists of four states-stable period, non-severely deteriorating period, severely deteriorating period, and death-according to real-world COPD progression. The model period comprises 6 months, with a cycle length of 14 years. The initial state, transition probabilities, costs, and utility data were collected from the FULFIL trial, published literature, hospital record surveys, and China Health Statistics Yearbook. The discount rate was 5%, and the threshold was set as the Chinese per capita GDP in 2020 (¥72,447). The cost, utility, transition probabilities, and discount rate were calculated through TreeagePro11 software. The results were analyzed via one-way factor analysis and probability sensitivity analysis. Results: The baseline study shows that the 14-year treatment for FF/UMEC/VI and BUD/FOR groups are ¥199,765.55 and ¥173,030.05 with effectiveness at 8.54 quality-adjusted life years (QALYs) and 7.73 QALYs, respectively. The incremental cost-effectiveness ratio is ¥33,006.80/QALY, which is below the threshold. A tornado diagram of a one-way sensitivity analysis shows that the top three factors that affected the results are the non-severe deterioration rates of FF/UMEC/VI, the cost of FF/UMEC/VI and the non-severe deterioration rates of BUD/FOR. Probabilistic sensitivity analysis shows that FF/UMEC/VI (compared to BUD/FOR) can be made cost-effective under the willingness-to-pay (WTP) threshold (¥38,000). Furthermore, the likelihood of cost-effectiveness increases with a higher WTP. Conclusions: Compared with the double combination (BUD/FOR), the triple combination (FF/UMEC/VI) is more cost-effective under the Chinese per capita GDP threshold.

In-vitro and in situ assessment of the efflux of five antidepressants by breast cancer resistance protein.

OBJECTIVES: Antidepressants need to penetrate the blood-brain barrier (BBB) to exert their functions in the central nervous system. Breast cancer resistance protein (BCRP), an efflux transporter abundantly expressed in the BBB, prevents the accumulation of many drugs in the brain. This study aimed to identify whether five commonly used antidepressants (sertraline, duloxetine, fluoxetine, amitriptyline and mirtazapine) are BCRP substrates. METHODS: A combination of bidirectional transport and intracellular accumulation experiments was conducted on BCRP-overexpressing MDCKII and wild-type (WT) cells, and in situ brain perfusion was conducted in rats. KEY FINDINGS: The bidirectional transport study revealed that the net efflux ratio (NER) of sertraline reached 2.08 but decreased to 1.06 when co-incubated with Ko143, a selective BCRP inhibitor. Conversely, the other four antidepressants did not appear to be BCRP substrates, due to their low NER values (<1.5). The accumulation of sertraline in MDCKII-BCRP cells was significantly lower than that in MDCKII-WT cells. The presence of Ko143 significantly increased the sertraline accumulation in MDCKII-BCRP cells but not in MDCKII-WT cells. Brain perfusion showed that the permeability of 1 and 5 µm sertraline was significantly higher in the presence of Ko143. CONCLUSIONS: Taken together, BCRP is involved in sertraline efflux.

Assessment and modulation of phillyrin absorption by P-gp using Caco-2 cells and MDR1-MDCKII cells.

The study was to investigate the absorption mechanism and transport modulation of phillyrin by P-gp in Caco-2 cells and MDR1-MDCKII cells. Three concentrations of phillyrin were tested in transport studies. The absorptive transports of phillyrin in the two cell models were not concentration-dependent which indicated passive diffusion as the dominating process in the test concentrations. The absorptive P (app) were 7.15, 6.39 and 10.03 × 10(-6) cm s(-1), respectively, for different concentrations (2.2, 4.8 and 8.4 µg ml(-1)) in Caco-2 cells. And the low absorptive P (app) was consistent with the low oral bioavailability of phillyrin observed in pharmacokinetic experiments. In transport inhibition experiment, the efflux inhibitors, verapamil and GF120918 can increase the absorption of phillyrin in Caco-2 cells which suggested the involvement of efflux transporters. In the further inhibition experiment in MDR1-MDCKII cells, the absorption was greatly increased and the efflux of phillyrin was competitively inhibited by verapamil and GF120918, which confirmed the involvement of P-gp in the efflux of phillyrin.

Rifaximin versus nonabsorbable disaccharides in the management of hepatic encephalopathy: a meta-analysis.

OBJECTIVE: To compare the positive and negative effects of rifaximin and nonabsorbable disaccharides in patients with hepatic encephalopathy. METHODS: We used the method recommended by The Cochrane Collaboration to perform a meta-analysis of comparative randomized trials of rifaximin and nonabsorbable disaccharides. RESULTS: Seven randomized controlled trials were identified, but only five trials involving 264 patients met all the inclusion criteria. There was no significant difference between rifaximin and nonabsorbable disaccharides on improvement in patients with hepatic encephalopathy [relative risk (RR) 1.08; 95% confidence interval (CI), 0.85-1.38; P=0.53]. RR was 0.98 (95% CI: 0.85-1.13; P=0.74) for acute hepatic encephalopathy in 157 patients and 0.87 (95% CI: 0.40-1.88; P=0.72) for chronic hepatic encephalopathy in 96 patients, respectively. There was no significant difference between rifaximin and nonabsorbable disaccharides on diarrhea (RR=0.90; 95% CI: 0.17-4.70; P=0.90). However, a significant difference in favor of rifaximin on abdominal pain (RR=0.28; 95% CI: 0.08-0.95; P=0.04) was identified. CONCLUSION: Rifaximin is not superior to nonabsorbable disaccharides for acute or chronic hepatic encephalopathy in the long-term or short-term treatment except that it may be better tolerated. Further studies on larger populations are required to provide more sufficient evidence for assessment of the use of rifaximin.