Objective: The introduction of Bruton’s tyrosine kinase (BTK) inhibitors was a milestone in the treatment of B-cell malignancies in recent years owing to its desired efficacy against chronic lymphocytic leukaemia and small cell lymphocytic lymphoma. However, safety issues have hindered its application in clinical practice. The current study aimed to explore the safety warning signals of BTK inhibitors in a real-world setting using the FDA Adverse Event Reporting System (FAERS) to provide reference for clinical rational drug use.Methods: Owing to the short marketing time of other drugs (zanbrutinib and orelabrutinib), we only analysed ibrutinib and acalabrutinib in this study. All data were obtained from the FAERS database from January 2004 to December 2021. Disproportionality analysis and Bayesian analysis were utilised to detect and assess the adverse event (AE) signals of BTK inhibitors.Results: In total, 43,429 reports of ibrutinib were extracted and 1527 AEs were identified, whereas 1742 reports of acalabrutinib were extracted and 220 AEs were identified by disproportionality analysis and Bayesian analysis. Among reports, males were more prone to develop AEs (58.2% for males vs. 35.6% for females treated with ibrutinib, and 55.9% vs. 31.9%, respectively, for acalabrutinib), and more than 30% of patients that suffered from AEs were over 65 years of age. Subsequently, we investigated the top 20 preferred terms (PTs) associated with the signal strength of ibrutinib and acalabrutinib, and our results identified 25 (13 vs. 12, respectively) novel risk signals. Among the top 20 PTs related to death reports, the terms infectious, pneumonia, pleural effusion, fall, asthenia, diarrhoea, and fatigue were all ranked high for these two BTK inhibitors. Further, cardiac disorders were also an important cause of death with ibrutinib.Conclusion: Patients treated with ibrutinib were more prone to develop AEs than those treated with acalabrutinib. Importantly, infection-related adverse reactions, such as pneumonia and pleural effusion, were the most common risk signals related to high mortality associated with both BTK inhibitors, especially in elderly patients. Moreover, cardiovascular-related adverse reactions, such as atrial fibrillation and cardiac failure, were fatal AEs associated with ibrutinib. Our results provide a rationale for physicians to choose suitable BTK inhibitors for different patients and provide appropriate monitoring to achieve safer therapy and longer survival.

Emodin (EMO) has the effect of anti-cholestasis induced by alpha-naphthylisothiocyanate (ANIT). But its mechanism is still unclear. The farnesoid X receptor (Fxr) is the master bile acid nuclear receptor. Recent studies have reported that Sirtuin 1 (Sirt1) can regulate the activities of Fxr. The purpose of the current study was to investigate the mechanism of EMO against ANIT-induced liver injury based on Sirt1/Fxr signaling pathway. The ANIT-induced cholestatic rats were used with or without EMO treatment. Serum biochemical indicators, as well as liver histopathological changes were examined. The genes expressions of Sirt1, Fxr, Shp, Bsep and Mrp2 were detected. The expressions of Sirt1, Fxr and their downstream related genes were investigated in vitro. The results showed that EMO significantly alleviated ANIT-induced liver injury in rats, and increased Sirt1, Fxr, Shp, Bsep and Mrp2 gene expression in liver, while decreased the expression of Cyp7a1. EMO significantly activated Fxr, while Sirt1 inhibitor and Sirt1 gene silencing significantly reduced Fxr activity in vitro. Collectively, EMO in the right dose has a protective effect on liver injury induced by ANIT, and the mechanism may be through activation of Fxr by Sirt1, thus regulating bile acid metabolism, and reducing bile acid load in hepatocytes.

Shengmai Formula (SMF) is one of the traditional Chinese medicine representative formulas and is widely used for the treatment of cardio- and cerebrovascular disease. Previous studies demonstrated that the major effective ingredients in SMF can interact with each other based on some uptake transporters. However, the role of the efflux transporter breast cancer resistance protein (BCRP) in these interactions involving SMF remains unclear. The purpose of this study was to investigate the interactions of the major active components of SMF with BCRP and the compatibility mechanism of these complex components in SMF based on BCRP. We selected 4 main fractions, including ginseng total saponins (GTS), ophiopogon total saponins (OTS), ophiopogon total flavonoids (OTF), and fructus schisandrae total lignans (STL), and 12 bioactive components, including ginsenosides Re, Rd, Rb1, and Rg1, ophiopogonins D and D', methylophiopogonanones A and B, schizandrins A and B, and schizandrols A and B to explore the interactions of SMF with BCRP in LLC-PK1 and LLC-PK1/BCRP cells and BCRP membrane vesicles. The results showed that ginsenosides Re and Rg1, methylophiopogonanone B, and schizandrin A can be transported by BCRP into LLC-PK1/BCRP cells. Schisandrol B exhibited a markedly inhibitory effect on the transport function of BCRP and can significantly inhibit the uptake of methylophiopogonanone B and schizandrin A into LLC-PK1/BCRP cells. In "Inside-Out" BCRP membrane vesicles, BCRP mediated the transport of ginsenosides Re and Rg1, methylophiopogonanone B, and schizandrin A, with K_m values of 111.9 ± 31.26 μM, 82.01 ± 16.72 μM, 57.06 ± 8.789 μM, and 37.19 ± 6.512 μM, respectively. GTS, STL, ginsenosides Rd and Rb1, and schisandrol B were potent inhibitors of BCRP and showed different degrees of inhibition on the transport of ginsenosides Re and Rg1, methylophiopogonanone B, and schizandrin A via BCRP. In conclusion, GTS, STL, ginsenosides Rd and Rb1, and schizandrol B are potential inhibitors of BCRP. Ginsenosides Re and Rg1, methylophiopogonanone B, and schizandrin A are potential substrates of BCRP, and their transport, which is mediated by BCRP, may be inhibited by potential inhibitors in SMF. There are potential interactions of these main effective components of SMF at the cellular and vesicular levels that are mediated by BCRP. The interplay of these bioactive components based on BCRP may be an important compatibility mechanism in SMF.