Inhibition of Human UDP-Glucuronosyltransferases1A1-Mediated Bilirubin Glucuronidation by the Popular Flavonoids Baicalein, Baicalin, and Hyperoside Is Responsible for Herb (Shuang-Huang-Lian)-Induced Jaundice.

Bilirubin-related adverse drug reactions (ADRs) or malady (e.g., jaundice) induced by some herbs rich in certain flavonoids have been widely reported. However, the causes and mechanisms of the ADRs are not well understood. The aim of this paper was to explore the mechanism of Shuang-huang-lian (SHL) injections and its major constituents-induced jaundice via inhibiting human UDP-glucuronosyltransferases1A1 (hUGT1A1)-mediated bilirubin glucuronidation. The inhibitory effects of SHL and its major constituents in the herbal medicine, including baicalein (BAI), baicalin (BA), and hyperoside (HYP), on bilirubin glucuroBBREVInidation were investigated. This study indicated that the average formation rates of bilirubin glucuronides [i.e., mono-glucuronide 1 (BMG1), BMG2, and bilirubin diglucuronide] displayed significant differences (P < 0.05). Specifically, the formation of BMGs was favored regardless of whether an inhibitor was absent or present. SHL, BAI, BA, and HYP dose-dependently inhibit bilirubin glucuronidation, showing the IC50 values against total bilirubin glucuronidation were in the range of (7.69 ± 0.94)-(37.09 ± 2.03) µg/ml, (4.51 ± 0.27)-(20.84 ± 1.99) µM, (22.36 ± 5.74)-(41.35 ± 2.40) µM, and (15.16 ± 1.12)-(42.80 ± 2.63) µM for SHL, BAI, BA, and HYP, respectively. Both inhibition kinetics assays and molecular docking simulations suggested that SHL, BAI, BA, and HYP significantly inhibited hUGT1A1-mediated bilirubin glucuronidation via a mixed-type inhibition. Collectively, some naturally occurring flavonoids (BAI, BA, and HYP) in SHL have been identified as the inhibitors against hUGT1A1-mediated bilirubin glucuronidation, which well explains the bilirubin-related ADRs or malady triggered by SHL in clinical settings. SIGNIFICANCE STATEMENT: Herbal products and their components (e.g., flavonoids), which been widely used across the entire world, may cause liver injury. As a commonly used herbal products rich in flavonoids, SHL injections easily lead to symptoms of liver injury (e.g., jaundice) owing to significant inhibition of hUGT1A1-mediated bilirubin glucuronidation by its flavonoid components (i.e., baicalein, baicalin, and hyperoside). Herb-induced bilirubin-related ADRs and the associated clinical significance should be seriously considered.

Anlotinib and fruquintinib co-administrated with warfarin increases the risk of bleeding: Studied from pharmacokinetic and pharmacodynamic perspectives.

BACKGROUND: Recent studies have reported a higher risk of bleeding among patients that are co-administrated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) and anticoagulant, which raises our concern about the possible TKIs-warfarin pharmacokinetic and pharmacodynamic interaction that could be life-threatening to tumor patients who take warfarin for preventing deep vein thrombosis (DVT). METHODS: Influences of anlotinib and fruquintinib on the pharmacokinetic and dynamic behavior of warfarin were estimated. Influence on the activity of cytochrome P450 (CYP450) enzymes was detected in vitro through rat liver microsomes. Quantitative analysis of blood concentration in rats was finished by a validated UHPLC-MS/MS method. Furthermore, pharmacodynamic interactions were studied in rats by monitoring prothrombin time (PT) and activated partial thromboplastin time (APTT), while Inferior vena cava (IVC) stenosis-induced DVT model was built to further investigate the antithrombotic effect after co-administration. RESULTS: Anlotinib inhibited the activity of cyp2c6, cyp3a1/2 and cyp1a2 in rat liver microsomes in a dose-dependent manner, meanwhile enhanced the AUC0∼t and AUC0∼∞ of R-warfarin. However, fruquintinib showed no effects on pharmacokinetics of warfarin. Anlotinib and fruquintinib co-administrated with warfarin was found to exert more significant increase on PT and APTT values than that taking warfarin alone. In IVC stenosis-induced DVT model rats, the co-administration groups significantly reduced the length of thrombus compared with the single warfarin group. CONCLUSIONS: Anlotinib and fruquintinib enhanced the anticoagulated and antithrombotic effect of warfarin. The anlotinib-induced interaction may due to the inhibition of the metabolism of warfarin. The mechanism of the pharmacodynamic interaction between fruquintinib and warfarin should be further investigated.

Effect of Astragali radix extract on pharmacokinetic behavior of dapagliflozin in healthy and type 2 diabetic rats.

Objective: This study aimed to investigate effect of antidiabetic herb Astragali Radix (AR) on pharmacokinetic behavior of dapagliflozin (DAPA) in healthy rats and type 2 diabetes mellitus (T2DM) rats. Methods: The T2DM rats were induced by high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). Concentrations of DAPA in healthy and T2DM rat plasma were determined by UPLC-MS/MS method. Effect of AR extract (ARE) on pharmacokinetic behavior of DAPA in healthy and T2DM rats was evaluated, respectively. Results: The diabetes status and co-administrated with ARE significantly affected pharmacokinetic behaviors of DAPA in the rats. Compared to that in healthy rats, t max of DAPA significantly shortened, its C max significantly increased in T2DM rats, and its t 1/2, V, AUC, CL and MRT kept unchanged. When ARE was co-administrated with DAPA, C max of DAPA significantly increased, its t max and MRT significantly decreased, and its t 1/2, V, AUC and CL kept unchanged in healthy rats. t max and C max of DAPA significantly decreased, its t 1/2 and V significantly increased, and its AUC, CL and MRT were unchanged in T2DM rats when ARE was co-administrated with DAPA. Co-administration of DAPA and ARE promoted absorptive rate of DAPA, increased its extravascular tissue distribution, and prolonged its duration of action. ARE did not cause accumulation of DAPA in vivo. Conclusion: Both disease status of T2DM and co-administration of ARE affect pharmacokinetic behavior of DAPA in vivo. Potential pharmacokinetic interactions may occur in vivo when herbs and drugs are co-administrated, which may affect efficacy and safety of drugs.

Integration of pharmacodynamics, network pharmacology and metabolomics to elucidate effect and mechanism of Artemisia capillaris Thunb. in the treatment of jaundice.

ETHNOPHARMACOLOGICAL RELEVANCE: As one of the most commonly used herbs, Artemisia capillaris Thunb. (ACT) display favorable effect in the treatment of jaundice. However, mechanism of ACT in the treatment of jaundice remains unclear at present, which limits its development and application. AIM OF THE STUDY: To investigate effect and mechanism of Artemisia capillaris Thunb. (ACT) in the treatment of jaundice using pharmacodynamics, network pharmacology and metabolomics. METHODS: Effect of ACT in treating jaundice was evaluated by biochemical assays and pathological observation using the α-naphthyl isothiocyanate (ANIT)-induced mice. Jaundice-relieving mechanism of ACT was investigated by integration of network pharmacology and metabolomics. RESULTS: After the mice with jaundice were administrated ACT extract for 9 days, compared to that of the model group, serum D-BIL, T-BIL and ALP levels of the mice in the low, medium, high dose of ACT group decreased by 39.81%, 15.30% and 16.92%; 48.06%, 42.54% and 36.91%; 26.90%, 12.34% and 16.90%, respectively. The pathologic study indicated that ACT improved the symptoms of liver injury of the mice with jaundice. The network of herb (i.e., ACT)-components-targets-disease (i.e., jaundice) was established, which consisted of 17 components classified in flavonoids, chromones, organic acids, terpenoids, and 234 targets related to treatment of jaundice. Metabolomics analysis showed that, compared to that in the model group, level of 8 differential metabolites were upregulated and level of 29 differential metabolites were downregulated in the mice liver in the ACT group, respectively. The main metabolic pathways involved in treatment of jaundice by ACT were pantothenate and CoA biosynthesis, glutathione metabolism, biosynthesis of unsaturated fatty acids, primary bile acid biosynthesis in the liver, respectively. The integrated analysis of network pharmacology and metabolomics showed that 3α,7α,12α a-Trihydroxy-5ß-cholanate, glycocholate, taurocholate, pantetheine 4'-phosphate, and d-4'-phosphopantothenate were the potential biomarkers for treatment of jaundice, and AKR1C4, ALDH2 and HSD11B were the potential drug targets in the treatment of jaundice by ACT. CONCLUSION: The study based on metabolomics and network pharmacology indicated that ACT can display favorable jaundice-relieving effect by its multiple components regulating multiple biomarkers, multiple targets and multiple pathways, and may be a rational therapy for the treatment of jaundice.

Efficacy and safety of tirzepatide in patients with type 2 diabetes mellitus: A bayesian network meta-analysis.

Background: In light of clinical trials comparing different doses of tirzepatide with selective glucagon-like peptide-1 receptor agonist (GLP1-RA) or insulin analogue, a bayesian network meta-analysis was conducted to investigate the efficacy and safety of tirzepatide in patients with type 2 diabetes mellitus (T2DM). Methods: We systematically searched PubMed, Embase, Web of science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to 2 May 2022. Final included studies met the eligibility criteria and methodological quality recommendations. Data analysis was performed using Stata 15.1 software. Each outcome was presented as a mean difference or an odds ratio, and the surface under the cumulative ranking curve value (SCURA). Results: Ultimately, eight eligible RCTs involving 7245 patients were included. Generally speaking, compared with basal insulin (glargine or degludec); selective GLP1-RA (dulaglutide or semaglutide once weekly), 10 and 15 mg of tirzepatide exhibited better antidiabetic and weight-loss effect, especially, 15 mg of tirzepatide was dominant on reducing glycated hemoglobin (SCURA probability: 93.5%), body weight (99.7%), and fasting serum glucose (86.6%). As for safety, insulin caused less gastrointestinal events (93.5%), and there was no statistical difference between GLP1-RA and tirzepatide. Conclusion: Compare with insulin and GLP1-RA, tirzepatide display favorable efficacy and acceptable safety for T2DM patients. More well-designed RCTs are needed to evaluate its clinical performance with higher doses of GLP1-RA and determine its potential cardiovascular benefits.

Antidiabetic Effect of Rehmanniae Radix Based on Regulation of TRPV1 and SCD1.

Purpose: This study aimed to disclose the antidiabetic mechanisms of Rehmanniae Radix (RR). Methods: The antidiabetic effect of RR was studied in Streptozocin (STZ)-induced diabetes mellitus (DM) rats and HepG2 cells with insulin resistance (IR). Antidiabetic targets and signaling pathways of RR were confirmed by the network pharmacology and transcriptome analysis as well as HK2 cells induced by high glucose (HG). Results: After the DM rats were administrated RR extract (RRE) for 4 weeks, their body weight was 10.70 ± 2.00% higher than those in the model group, and the fasting blood glucose (FBG), AUC of the oral glucose tolerance test, and insulin sensitivity test values were 73.23 ± 3.33%, 12.31 ± 2.29%, and 13.61 ± 5.60% lower in the RRE group, respectively. When compared with the model group, an increase of 45.76 ± 3.03% in the glucose uptake of HepG2 cells with IR was seen in the RRE group. The drug (RR)-components-disease (DM)-targets network with 18 components and 58 targets was established. 331 differentially expressed genes (DEGs) were identified. TRPV1 and SCD1 were important DEGs by the intersectional analysis of network pharmacology and renal transcriptome. The TRPV1 overexpression significantly inhibited apoptosis and oxidative stress of the HK2 cells induced by HG, while SCD1 overexpression induced apoptosis and oxidative stress of the HK2 cells induced by low and high glucose. When compared to the HG group, the mRNA and protein expressions of TRPV1 in the presence of RRE (100 µg/ml) increased by 3.94 ± 0.08 and 2.83 ± 0.40 folds, respectively. Conclusion: In summary, RR displayed an inspiring antidiabetic effect by reducing FBG and IR, upregulating the mRNA and protein expressions of TRPV1, and downregulating mRNA expression of SCD1. Induction of TRPV1 and inhibition of SCD1 by RR was possibly one of its antidiabetic mechanisms.

Prevalence and Risk Factors of Self-Medication Among the Pediatric Population in China: A National Survey.

BACKGROUND: Self-medication of antibiotics is common in China, whereas the self-medication of other medicines is still unknown, especially for the younger children who are vulnerable to adverse drug events. The aim of this study was to estimate the prevalence of self-medication reported by parents among children under age 12 in China. METHODS: A national cross-sectional survey was conducted among parents of children under age 12 in China by using a self-administered online questionnaire. Parents were asked whether they have self-medicated their children in the past 12 months. Logistic regression analysis was performed to access the risk factors of self-medication. RESULTS: Eligible questionnaires were obtained from 4,608 parents. The majority of respondents were mothers aged between 30 and 39 years old who held a college degree. A total of 1,116 (or 24.21%) respondents reported self-medication in the previous year. In the logistic regression model, parents with graduate degrees were less likely to self-medicate their children [Adjusted OR (AOR) = 0.436; 95% CI = 0.296-0.641]. The odds of self-medication were associated with being a father, living in Northern China, having a child at age 6-11, even though these did not reach statistical significance. CONCLUSIONS: Our findings indicate that self-medication are common in children under age 12, highlighting the drug safety issue in China. It seems that the educational level is the risk factors of self-medication. More targeted intervention and educational program should be implemented to improve drug safety.