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BACKGROUND: Lenvatinib (LEN) is approved as first-line therapy for advanced hepatocellular carcinoma (HCC). Schisantherin A (STA) can exert hepatoprotective and anti-tumor effects. The clinical combination of LEN and STA is very common, especially for patients with advanced HCC, but the effect of STA on the pharmacokinetics of LEN is unclear. This study aimed to investigate the effects of STA on the pharmacokinetics of LEN in rats and explore its potential mechanism. METHODS: Male Sprague-Dawley (SD) rats were orally administered different doses of STA or vehicle control for 7 consecutive days, and 1.2 mg/kg of LEN was given on day 7. The messenger RNA (mRNA) and protein expression levels in the intestines and liver were investigated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. RESULTS: It was revealed that STA increased the oral bioavailability of LEN. The area under the curve from time 0 to infinity (AUC(0–∞)) and maximum plasma concentration (C(max)) of LEN after co-administration with STA (20 mg/kg) increased by 54.3% (3,396.73±989.35 vs. 5,240.03±815.49 µg/L/h) and 54.8% (490.64±124.20 vs. 759.66±152.75 µg/L), respectively. The clearance decreased from 0.38±0.12 to 0.23±0.04 L/h/kg, and the apparent volume of distribution (Vz) decreased from 10.83±3.19 to 6.35±1.38 L/kg in the presence of 20 mg/kg STA. In addition, the expression of P-glycoprotein (P-gp) mRNA and protein in the intestines was markedly decreased. CONCLUSIONS: This study showed that STA increased the bioavailability of LEN, probably due to inhibition of P-gp in the intestine, thereby increasing systemic absorption of LEN. Thus, there is an interaction between the two drugs, and careful monitoring must be conducted when they are used in combination.

Almonertinib was included in the first-line treatment of non-small cell lung cancer with EGFR T790M mutations by the Chinese Society of Clinical Oncology in 2021. Considering that immunocompromised lung cancer patients are prone to opportunistic fungal infections, and most triazole antifungal drugs are moderate or strong inhibitors of CYP3A4, this study was conducted to develop and validate an accurate and rapid ultra-performance liquid chromatography tandem mass spectrometry method for quantifying almonertinib in plasma and for investigating the pharmacokinetic changes of almonertinib caused by voriconazole and fluconazole in rats. After liquid-liquid extraction with tert-butyl methyl ether, an XSelect HSS T3 column (2.1 × 100 mm, 2.5 μm, Waters) was used for the chromatographic separation of almonertinib and sorafenib-D

Previous studies have suggested benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors including improving glycemic control, lower body weight, uric acid-lowering effect and decreasing blood pressure. The aim of this study was to evaluate the effects of SGLT2 inhibitors on hematocrit (Hct) levels in patients with type 2 diabetes mellitus.Embase, CENTRAL, PubMed and other databases were searched from the establishment of the database through to July 2020. Randomized controlled trials (RCTs) involving patients with type 2 diabetes mellitus who were treated with SGLT2 inhibitors were analyzed using the random effects model. Stata 12.0 statistical software was used to estimate the weighted mean difference (WMD) and the 95% confidence intervals (CIs).A total of 40 RCTs were included, comprising 21,050 patients. SGLT2 inhibitors resulted in a significant increase in Hct levels compared to patients treated with a placebo (WMD 2.67%, 95% CI, 2.53 to 2.82; P0.001). Treatment with 2.5, 5, and 10 mg of dapagliflozin significantly increased Hct levels (WMD 1.96%, 2.27%, and 2.47%, respectively; P0.001). Administration of 100 and 300 mg of canagliflozin also resulted in a significant increase in Hct (WMD 2.91% and 2.94%, respectively; P0.001). Similarly, empagliflozin, at concentrations of 10 and 25 mg, caused a significant increase in Hct (WMD 3.39% and 3.44%, respectively; P0.001). However, treatment with ipragliflozin (12.5 and 50 mg) and ertugliflozin (5 and 15 mg) only resulted in a slight increase in patient Hct levels (WMD 1.26% and 1.98%, respectively for ipragliflozin, P0.05; WMD 2.24% and 2.64%, respectively for ertugliflozin; P0.05).SGLT2 inhibitors, as a class of drugs, increased Hct levels in patients with type 2 diabetes, and this increase was slightly more pronounced at higher doses compared to lower doses.The protocol of this study has been submitted to the PROSPERO platform (https://www.crd.york.ac.uk/PROSPERO/), and the registration number is CRD42020200699.

Background Abnormal DNA methylation of tumor suppressor gene promoter has been found in breast cancer. Therefore, the current study set out to explore how DNA methyltransferase 1 (DNMT1) affects breast cancer through mediating miR-497/GPRC5A axis. Methods After loss and gain-of-function approaches were conducted in MCF-7/ADR and MCF-7 cells, cell viability, IC50 value, invasion, migration and apoptosis were measured, respectively. In addition, drug resistance, metastasis and apoptosis-related protein expression were examined using immunoblotting. ChIP and dual-luciferase reporter gene assays were carried out to validate relationship among DNMT1, miR-497, and GPRC5RA. Subcutaneous xenograft tumor model in nude mice was established to detect effects of DNMT1 on growth and metastasis of breast cancer in vivo. Results It was found that DNMT1 was notably increased, while miR-497 was poorly-expressed in breast cancer. Highly-expressed DNMT1 could promote chemotherapy resistance and metastasis of breast cancer. Meanwhile, DNMT1 modified methylation of CpG island in miR-497 promoter region, thereby repressing miR-497 level. In addition, miR-497 targeted GPRC5A expression to curb chemotherapy resistance and metastasis of breast cancer cells. Lastly, in vivo experiments showed that knockdown of DNMT1 could suppress breast cancer growth and metastasis. Conclusions Collectively, our findings indicated that DNMT1 may inhibit miR-497 and boost the expression of GPRC5A through methylation, thus augmenting breast cancer chemotherapy resistance and metastasis, which provides novel mechanistic insight into the unrecognized roles of DNMT1 in breast cancer.

Biochanin A is a dietary isoflavone with multiple biological functions. Owing to a lack of comprehensive studies of biochanin A metabolism, this study was designed to further clarify the processes involved in biochanin A metabolism. In this study, ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) was utilized to characterize the metabolism of biochanin A in vivo and in vitro. As a result, 43 metabolites in rats, 22 metabolites in liver microsomes, and 18 metabolites in intestinal flora were elucidated, and 5 metabolites were identified by comparison with standards. Oxidation, demethylation, hydrogenation, internal hydrolysis, conjugation (e.g., glucuronidation, sulfonation, glucose conjugation, methylation, and acetylation), and their composite reactions were determined to be major processes involved in biochanin A biotransformation. The results contribute to a better understanding of the pharmacological mechanism of biochanin A and provide a basis for comprehension of the safety and toxicity of biochanin A.

Although farrerol, a characteristically bioactive constituent of Rhododendron dauricum L., exhibits extensive biological and pharmacological activities (e.g., anti-oxidant, anti-immunogenic, and anti-angiogenic) as well as a high drug development potential, its metabolism remains underexplored. Herein, we employed ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry coupled with multiple data post-processing techniques to rapidly identify farrerol metabolites produced in vivo (in rat blood, bile, urine and feces) and in vitro (in rat liver microsomes). As a result, 42 in vivo metabolites and 15 in vitro metabolites were detected, and farrerol shown to mainly undergo oxidation, reduction, (de)methylation, glucose conjugation, glucuronide conjugation, sulfate conjugation, N-acetylation and N-acetylcysteine conjugation. Thus, this work elaborates the metabolic pathways of farrerol and reveals the potential pharmacodynamics forms of farrerol.

Acacetin, a dietary component, is abundant in acacia honey and has superior anticancer activities. To date, no research on the metabolism of acacetin has been reported. In the current research, an online detection strategy of ultra-high-performance liquid chromatography connected to a quadrupole time-of-flight mass spectrometer (UHPLC-Q-TOF-MS/MS) was utilized for metabolite identification in vivo (rat plasma, bile, urine, and feces) and in vitro (rat liver microsomes). A total of 31 metabolites were structurally characterized in rats, and 25 metabolites were detected in rat liver microsomes, among which, 4 metabolites were compared with standards. Oxidation, the loss of CH2, reduction, hydrolysis, glucuronide conjugation, sulfate conjugation, methylation, and N-acetylation were the main metabolic pathways of acacetin. This study is the first to characterize acacetin metabolites in vivo and in vitro, and the results of this study offer novel and valuable evidence for a comprehensive understanding of the safety and efficacy of acacetin.

Galangin is a marker compound of honey and Alpinia officinarum Hance that exhibits great potential for anti-microbial, anti-diabetic, anti-obesity, anti-tumour and anti-inflammatory applications. Galangin is frequently consumed in combination with common clinical drugs. Here, we evaluated the effects of galangin on cytochrome P450 (CYP)-mediated metabolism, using two different approaches, to predict drug&ndash, drug interactions. Male Sprague Dawley rats were administered galangin daily for 8 weeks. A &ldquo, cocktail-probes&rdquo, approach was employed to evaluate the activities of different CYP450 enzymes. Blood samples of seven probe drugs were analysed using liquid chromatography-tandem mass spectrometry in positive and negative electrospray-ionisation modes. Pharmacokinetic parameters were calculated to identify statistical differences. CYP mRNA-expression levels were investigated in real-time quantitative polymerase chain reaction experiments. The galangin-treated group showed significantly decreased AUC0&ndash, &infin, and Cmax values for CYP1A2, and CYP2B3. The galangin-treated group showed significantly increased AUC0&ndash, and Cmax values for CYP2C13 and CYP3A1. No significant influences were observed in the pharmacokinetic profiles of CYP2C11, CYP2D4 and CYP2E1. The mRNA-expression results were consistent with the pharmacokinetic results. Thus, CYP450 enzyme activities may be altered by long-term galangin administration, suggesting galangin to be a promising candidate molecule for enhancing oral drug bioavailability and chemoprevention and reversing multidrug resistance.

Oroxin B, a flavonoid, is a major bioactive component form Oroxylum indicum (L.) Vent. with enormous anti-hepatoma effects. To data, the oroxin B metabolism studies remain underexplored. This study was designed to characterize oroxin B metabolism in vivo and in vitro by ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS). Consequently, 30 metabolites in rats, 8 metabolites in liver microsomes and 18 metabolites in intestinal bacteria were identified, and 9 metabolites were recognized by comparison with standards. The biotransformation processes involved ketone, acetylation, loss of C12H20O10, and loss of C6H10O5. And baicalein and oroxin A were generated after loss of C12H20O10, and loss of C6H10O5, respectively, and further went through some other reactions, such as oxidation, methylation, internal hydrolysis, hydrogenation, loss of O, ketone, glycine conjugation, glucuronide conjugation and their composite reactions. The results provide valuable evidence for elucidation the potential mechanism of oroxin B pharmacological action, and offer reasonable guidelines for further investigations of oroxin B safety and efficacy.

Tuberculosis of cervical lymph nodes is called scrofula in Traditional Chinese Medicine (TCM). Clinical manifestation is that unilateral or bilateral neck can have multiple enlarged lymph nodes of different sizes. Current therapeutic drugs include Lysionotus pauciflorus Maxim. tablets and compound of Lysionotus pauciflorus Maxim., which have a significant effect on tuberculosis of cervical lymph nodes. This compound is composed of three herbs, Lysionotus pauciflorus Maxim., Prunella vulgaris L. and Artemisia argyi Levl.et Vant. A selective and sensitive LC–MS/MS method was established and validated in rat plasma for the first time. Chromatographic separation was achieved on a Wonda Cract ODS-2 C18 Column (150 mm × 4.6 mm, 5 μm). The mobile phase contained 0.1% formic acid aqueous solution and acetonitrile with a flow rate of 0.8 mL/min. The detection was performed in negative electrospray ionization mode and the precursor/product ion transitions of six components and internal standard (IS) sulfamethoxazole were quantified in multiple reaction monitoring (MRM) using QTRAP-3200 MS/MS. The method fulfilled US Food and Drug Administration guidelines for selectivity, sensitivity, accuracy, precision, matrix effect, extraction recovery, dilution integrity, and stability. This proposed method was then successfully applied to a pharmacokinetic study after oral administration of 10 mL/kg compound extracts in rats. The pharmacokinetic parameters and plasma concentration-time profiles would prove valuable in pre-clinical and clinical investigations on the disposition of compound medicine.

Voriconazole is a second-generation triazole antifungal drug, which exhibits characteristics of wide antibacterial spectru, high biological utilization and passing through plasma brain barrier. The most common adverse reactions of voriconazole include neurological dysfunction, visual disturbance, abnormal liver function and renal dysfunction, here, this is the report to show that voriconazole can induce allergic purpura. The present report mainly describes one patient with rare adverse reactions, namely mixed type allergic purpura induced by high concentration of plasma drug caused by slow metabolism of voriconazole. Aafter using voriconazole, the patient was diagnosed as mixed type allergic purpura, methylprednisolone sodium succinate was given for treatment. After treatment, abdominal pain and abdominal distension of the patient was significantly alleviated, and the color of rash faded. Edemas of both lower extremities were significantly improved, and the color of stool turned into yellow. The measured concentration of plasma drug of voriconazole was 15 μg/ml on admission of the patient. Genetic testing result demonstrated that the patient belonged to heterozygous mutation of CYP2C19*1*2, and the metabolism of voriconazole of the patient was relatively slow. The report prompted the clinicians that there were significant metabolic differences of voriconazole in different populations. Therefore, monitoring of drug concentration should be conducted timely in the clinical application to reduce the risk of medication and achieve individualized administration.

A novel simple non-gel capillary electrophoresis (NGCE) method was developed for the qualitative and quantitative determination of oligonucleotides (ODNs). ODNs were synthesized in a DNA synthesizer and separated by NGCE under optimized conditions as follows: 25 mmol L−1 Tris–boric–EDTA buffer (pH 8.0) with 7 mmol L−1 urea in the presence of 20% (w/v) polyethylene glycol (PEG) 35000 at 30 °C and −20 kV. Single-base differences, in which there are differences in the base quantity and the single-base structure with the same base quantity, can be identified by the proposed method, and the quantitative determination was carried out. The obtained regression equation revealed a good linear relationship between the peak area ratio and the ODNs concentration. The correlation coefficient was 0.9986 and the relative standard deviation (RSD) of the precision was

In this paper, we propose a novel salient line detection algorithm for 3-dimensional (3D) mesh models based on ant colony optimization algorithm. In proposed method, the heuristic function in ACO transition function is improved based on tensor feature and the relationship between mean curvature information via vertex geometric feature. In addition, the proposed method establishes a similarity measurement criterion of feature points by combining the normal tensor voting with discrete mean curvature. Moreover, a direction control function is utilized to conduct the detection process to a expect direction, which can achieve an interaction between operator and computer. The experimental results show that the proposed method can extract the salient line effectively and precisely.