Thromboembolic Events Associated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Pharmacovigilance Analysis of the US FDA Adverse Event Reporting System (FAERS) Database.

BACKGROUND AND OBJECTIVES: Although thromboembolic events (TEEs) have been reported with the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), their association remains largely unknown. In this study, we aimed to provide a comprehensive review of TEEs associated with EGFR-TKIs. METHODS: We collected EGFR-TKIs (gefitinib, erlotinib, afatinib, and osimertinib) adverse reaction reports from 2015 Q1 to 2023 Q1 from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Disproportionality analysis was conducted to identify thromboembolic adverse events associated with EGFR-TKIs by comparing them with the overall FAERS database according to the reporting odds ratio (ROR). Associated factors were explored using univariate logistic regression. RESULTS: We identified 1068 reports of TEEs associated with EGFR-TKIs (1.24% accounts for all TEEs). Affected patients were females (49.72%) and those older than 65 years (41.20%). The reported TEE case fatality was 30.24%. The median time to onset (TTO) of all cases was 39 days [interquartile range (IQR) 11-161], and the median TTO of fatalities [31 days (IQR 10-116)] was significantly shorter than that of non-fatal cases [46 days (IQR 12-186)]. CONCLUSION: This study yielded three key findings. Firstly, EGFR-TKIs seem to exhibit prothrombotic effects, elevating the risk of TEEs. Secondly, the clinical outcomes of TEEs associated with EGFR-TKIs were poor. Thirdly, most TEEs occurred within the initial 3 months, and fatal cases occurred earlier than non-fatal cases.

Novel Ag-modified vanadate nanosheets for determination of small organic molecules with laser desorption ionization mass spectrometry.

Laser desorption ionization mass spectrometry (LDI-MS) aroused intensive concerns for the merits of label-free and high-throughput analysis. Here, we designed a silver nanoparticles (AgNP)-modified indium vanadate nanosheets with doping samarium (AgNP@InVO4:Sm) nanosheets. The developed AgNP@InVO4:Sm nanosheets (AIVON) were synthesized based on the microemulsion-mediated solvothermal method and ultraviolet-assisted in situ formation of AgNP, then for the first time applied as a matrix in LDI-MS analysis. With the advantages including enhanced MS signal, little matrix-related background, high reproducibility, and good salt tolerance, AIVON exhibited much better prospect than non-modified indium vanadate nanosheets with doping samarium (IVON) and traditional organic matrix, thus allowing sensitive MS detection for a wide range of low-molecular-weight (LMW) molecules. Moreover, by coupling with headspace sampling thin-film microextraction (TFME), a kind of representative pollutant chlorophenols were identified and quantified via AIVON-assisted LDI-MS in environmental and biological samples. Volatile LMW pollutants could be preconcentrated after TFME, hence a sensitive and rapid assay with negligible sample matrix effect was realized by using AIVON-assisted LDI-MS. It is anticipated that this novel nano-matrix AIVON and the proposed TFME coupling detection strategy were of competitive merits for LDI-MS analysis in the fields of environment, biomedicine, and agriculture.

Temporally and spatially resolved molecular profiling in fingerprint analysis using indium vanadate nanosheets-assisted laser desorption ionization mass spectrometry.

This study presents the first-ever synthesis of samarium-doped indium vanadate nanosheets (IVONSs:Sm) via microemulsion-mediated solvothermal method. The nanosheets were subsequently utilized as a nano-matrix in laser desorption/ionization mass spectrometry (LDI-MS). It was discovered that the as-synthesized IVONSs:Sm possessed the following advantages: improved mass spectrometry signal, minimal matrix-related background, and exceptional stability in negative-ion mode. These qualities overcame the limitations of conventional matrices and enabled the sensitive detection of small biomolecules such as fatty acids. The negative-ion LDI mechanism of IVONSs:Sm was examined through the implementation of density functional theory simulation. Using IVONSs:Sm-assisted LDI-MS, fingerprint recognitions based on morphology and chemical profiles of endogenous/exogenous compounds were also achieved. Notably, crucial characteristics such as the age of an individual's fingerprints and their physical state could be assessed through the longitudinal monitoring of particular biomolecules (e.g., ascorbic acid, fatty acid) or the specific biomarker bilirubin glucuronide. Critical information pertinent to the identification of an individual would thus be facilitated by the analysis of the compounds underlying the fingerprint patterns.

Effects of single-nucleotide polymorphism on the pharmacokinetics and pharmacodynamics of metformin.

INTRODUCTION: Metformin has been recognized as the first-choice drug for type 2 diabetes mellitus (T2DM). The potency of metformin in the treatment of type 2 diabetes has always been in the spotlight and shown significant individual differences. Based on previous studies, the efficacy of metformin is related to the single-nucleotide polymorphisms of transporter genes carried by patients, amongst which a variety of gene polymorphisms of transporter and target protein genes affect the effectiveness and adverse repercussion of metformin. AREAS COVERED: Here, we reviewed the current knowledge about gene polymorphisms impacting metformin efficacy based on transporter and drug target proteins. EXPERT OPINION: The reason for the difference in clinical drug potency of metformin can be attributed to the gene polymorphism of drug transporters and drug target proteins in the human body. Substantial evidence shows that genetic polymorphisms in transporters such as organic cation transporter 1 (OCT1) and organic cation transporter 2 (OCT2) affect the glucose-lowering effectiveness of metformin. However, optimization of individualized dosing regimens of metformin is necessary to clarify the role of several polymorphisms.

Salidroside inhibits chronic myeloid leukemia cell proliferation and induces apoptosis by regulating the miR-140-5p/wnt5a/ß-catenin axis.

Salidroside, an active ingredient of Rhodiola rosea, exhibits antitumor effects in various types of cancer. However, the role of salidroside in chronic myeloid leukemia (CML) has not been elucidated. In the presents study, cell viability was assessed by CCK-8 assay, while apoptosis was detected by flow cytometry. Reverse transcription-quantitative PCR analysis was used to examine the expression levels of miR-140-5p in human CML cell lines. The expression levels of apoptosis and cell cycle-associated proteins and of the wnt5a/ß-catenin signaling pathway were determined by western blot analysis. Bioinformatic analysis and luciferase reporter assays were employed to investigate the association between miR-140-5p and wnt5a. The results revealed that exposure of CML cells to salidroside (80 µM) inhibited cell proliferation and promoted apoptosis. In addition, salidroside treatment led to the upregulation of miR-140-5p expression. Furthermore, the inhibition of wnt5a/ß-catenin signaling pathway and the pro-apoptotic effects induced by salidroside were attenuated by miR-140-5p silencing. Notably, wnt5a was revealed to be a direct target of miR-140-5p. The present findings indicated that salidroside exerted anti-CML effects through regulating miR-140-5p by suppressing the wnt5a/ß-catenin signaling pathway. The present study provided evidence of the therapeutic role of salidroside in CML.

Changes in serum inflammatory factor interleukin-6 levels and pathology of carotid vessel walls of rats with chronic periodontitis and diabetes mellitus after the periodontal intervention.

OBJECTIVE: The effects of the periodontal intervention on rats with type-II diabetes mellitus (T2DM) and chronic periodontitis (CP) were explored through observing the changes in carotid artery pathology and interleukin-6 (IL-6) levels. METHODS: The rats were randomly divided into 5 groups, i.e. group A (the normal control group), group B (the T2DM control group), group C (the CP control group), group D (the T2DM + CP group), and group E (the periodontal intervention T2DM + CP group). Blood samples of rats were collected from angular veins respectively at the following 5 time nodes: 1 week before the intervention (T1), 1 week after the intervention (T2), 3 weeks after the intervention (T3), 5 weeks after the intervention (T4), and 7 weeks after the intervention (T5); IL-6 concentrations before and after the intervention were determined by the enzyme-linked immunosorbent assay (ELISA), and the pathology of carotid arteries were observed by the Hematoxylin-Eosin (HE) stain. RESULTS: The pathological results of carotid arteries showed that the blood vessels of rats in group A were normal in morphology; most of the carotid artery vessel walls of rats in groups B, C, and D were significantly thickened and the fibers were disorderly arranged; the increased thickness of vessel walls of rats in group E was reduced, a small number of foam cells and inflammatory cells were observed, and the irregular arrangement of fibers was improved. In terms of the IL-6 concentrations, during the period of T1-T5, in groups B, C, and D, the IL-6 concentrations in rats were increased (P < 0.05); after the periodontal intervention, in group E, the IL-6 concentrations in rats were first increased then decreased (P < 0.05). CONCLUSION: In terms of the long-term effects, periodontal intervention may reduce the inflammations of patients with diabetes mellitus and periodontitis and improve the lesions of carotid arteries.

Molecularly imprinted layer-coated monodisperse spherical silica microparticles toward affinity-enrichment of isoflavonoid glycosides from Radix puerariae.

This paper reports the preparation of puerarin (PR) imprinted layer-coated silica microparticles toward selective recognition of PR and fast affinity-enrichment of the main isoflavonoid glycosides from the crude extract of Radix puerariae. Before the preparation, quantum mechanics (QM) method was applied to identify three kinds of common functional monomers capable of interaction with PR and then predicted optimal functional monomer (acrylamide, AA) and the relative molar ratio of template to functional monomer (PR/AA, 1:4). The obtained PR-imprinted silica microparticles were evaluated by transmission electron microscope (TEM) and rebinding experiments, exhibiting good morphology and high binding affinity to PR. Meanwhile, the rebinding amount of the imprinted microparticles to PR was nearly 2.1-folds that of non-imprinted microparticles. When the PR-imprinted microspheres were used as packing materials for solid-phase extraction, the recovery yields of PR, daidzin (DD) and genistin (GS) were simultaneously up to 90% by one-step extraction from the crude extract of Radix puerariae. Additionally, the PR-imprinted microparticles could be re-used for at least 5 times without losing any extraction efficiency. These results indicate that the PR-imprinted microparticles have highly selective adsorption capabilities to PR, DD and GS from the crude extract of Radix puerariae. The method of molecularly imprinted polymers (MIPs) coupled with solid-phase extraction (SPE) provides a good solution of the enrichment and separation of active extracts from complicated traditional Chinese medicine (TCM) with certain structures.

Isolation, identification and antioxidative capacity of water-soluble phenylpropanoid compounds from Rhodiola crenulata.

Six water-soluble phenylpropanoid compounds obtained from Rhodiola crenulata (R. crenulata) were fractionated by high-speed counter-current chromatography (HSCCC), and purified by semi-preparative high-performance liquid chromatography (Semi-prep HPLC). The purities of the six compounds were all above 98.0% and their structures were identified by spectroscopic methods. Among them, a new compound, 2-(4-hydroxyphenyl)-ethyl-O-ß-D-glucopyranosyl-6-O-ß-D-glucopyranoside (1), together with two known phenylpropanoids, p-hydroxyphenacyl-ß-D-glucopyranoside (3) and picein (4) were isolated from R. crenulata for the first time. Meanwhile, the contents of six isolated ingredients from the crude extract of R. crenulata had been simultaneously detected, with satisfactory results. Furthermore, the antioxidant activities of the six compounds were accessed by measuring the radical scavenging activity against 2,2-diphenyl-1-picrylhydrazy (DPPH), and four compounds exhibited potent antioxidative activity.