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The cognitive neural mechanisms by which sleep deprivation affects cognitive flexibility are poorly understood. Therefore, the study investigated the neuroelectrophysiological basis of the effect of 24 h sleep deprivation on cognitive flexibility in adolescents. 72 participants (36 females, mean age ± SD=20.46 ± 2.385 years old) participated in the study and were randomly assigned to the sleep deprivation group and control group. They were instructed to complete a task switch paradigm, during which participants' behavioral and electroencephalographic data were recorded. Behaviorally, there were significant between-group differences in accuracy. The results of event-related potential showed that the P2, N2 and P3 components had significant group effects or interaction effects. At the time-frequency level, there were statistically significant differences between the delta and theta bands. These results suggested that 24 h sleep deprivation affected problem-solving effectiveness rather than efficiency, mainly because it systematically impaired cognitive processing associated with cognitive flexibility.
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The traditional shell technique is a practical method for augmenting horizontal and vertical alveolar bone defects. However, it has drawbacks, including increased morbidity in the donor site and imprecise harvesting of bone grafts. Instead of using a second surgical site, root areas at the defect site could be the in situ donor site. A digitally designed bone harvest guide was used for an in situ bone augmentation workflow, and the modified shell technique was planned and executed in the root area. This technique offered a controllable procedure which might enhance bone augmentation.
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Building occupancy information is significant for a variety of reasons, from allocation of resources in smart buildings to responding during emergency situations. As most people spend more than 90% of their time indoors, a comfortable indoor environment is crucial. To ensure comfort, traditional HVAC systems condition rooms assuming maximum occupancy, accounting for more than 50% of buildings' energy budgets in the US. Occupancy level is a key factor in ensuring energy efficiency, as occupancy-controlled HVAC systems can reduce energy waste by conditioning rooms based on actual usage. Numerous studies have focused on developing occupancy estimation models leveraging existing sensors, with camera-based methods gaining popularity due to their high precision and widespread availability. However, the main concern with using cameras for occupancy estimation is the potential violation of occupants' privacy. Unlike previous video-/image-based occupancy estimation methods, we addressed the issue of occupants' privacy in this work by proposing and investigating both motion-based and motion-independent occupancy counting methods on intentionally blurred video frames. Our proposed approach included the development of a motion-based technique that inherently preserves privacy, as well as motion-independent techniques such as detection-based and density-estimation-based methods. To improve the accuracy of the motion-independent approaches, we utilized deblurring methods: an iterative statistical technique and a deep-learning-based method. Furthermore, we conducted an analysis of the privacy implications of our motion-independent occupancy counting system by comparing the original, blurred, and deblurred frames using different image quality assessment metrics. This analysis provided insights into the trade-off between occupancy estimation accuracy and the preservation of occupants' visual privacy. The combination of iterative statistical deblurring and density estimation achieved a 16.29% counting error, outperforming our other proposed approaches while preserving occupants' visual privacy to a certain extent. Our multifaceted approach aims to contribute to the field of occupancy estimation by proposing a solution that seeks to balance the trade-off between accuracy and privacy. While further research is needed to fully address this complex issue, our work provides insights and a step towards a more privacy-aware occupancy estimation system.
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Lung immune cells such as lymphocytes and macrophages can induce an inflammatory response due to the activation of mineralocorticoid receptor (MR), which is manifested by the infiltration of inflammatory cells and the secretion of inflammatory cytokines and subsequent apoptosis, pyroptosis and necrosis of intrinsic lung cells and immune cells. Macrophages are immune cells that are abundant in the lung and act as the first line of defense against pathogens but are also aggravating factors of infection. The activation of the renin-angiotensin-aldosterone system (RAAS), especially aldosterone-stimulated MR activation, can induce macrophage and CD8+ T cell aggregation and the secretion of cytokines such as tumor necrosis factor-α (TNF-α) and interferon-gamma (IFN-γ). Increased IFN-γ secretion can induce macrophage pyroptosis and the release of interleukin 1-ß (IL-1ß), aggravating lung injury. In this study, lung injury in C57BL/6 mice was induced by subcutaneous micro-osmotic pump infusion of aldosterone. After 12 weeks of administration, the kidney, heart, blood vessels and lungs all showed obvious inflammatory injury, which manifested as rapid accumulation of macrophages. The overexpression of IFN-γ in the lungs of aldosterone-treated mice and the stimulation of MH-S and RAW264.7 alveolar macrophages (AMs) with aldosterone in vitro showed that IFN-γ induced pyroptosis of macrophages via the activation of the inflammasome, and the MR blocker esaxerenone effectively inhibited this effect and alleviated lung injury. In addition, IFN-γ secreted by CD8+ T cells is associated with macrophage pyroptosis. In conclusion, the inhibition of macrophage pyroptosis can effectively alleviate lung injury.
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This article investigates the finite-time stability of a class of fractional-order bidirectional associative memory neural networks (FOBAMNNs) with multiple proportional and distributed delays. Different from the existing Gronwall integral inequality with single proportional delay ( N = 1 ), we establish the Gronwall integral inequality with multiple proportional delays for the first time in the case of N ≥ 2 . Since the existing fractional-order single-constant delay Gronwall inequality with two different orders cannot be directly applied to the stability analysis of the aforementioned system, initially, we skillfully develop a novel one with generalized fractional multiproportional delays' Gronwall inequalities of different orders. Furthermore, combined with the newly constructed generalized inequality, the stability criteria of FOBAMNNs with fractional orders and under weaker conditions, i.e., at most linear growth and linear growth conditions rather than the global Lipschitz condition, are given respectively. Finally, numerical experiments verify the effectiveness of the proposed method.
ABSTRACT
Renal fibrosis is an inevitable process in the progression of chronic kidney disease (CKD). Angiogenesis plays an important role in this process. Vascular endothelial cells are involved in renal fibrosis by phenotypic transformation and secretion of extracellular matrix. Aldosterone stimulates mineralocorticoid receptor (MR) activation and induces inflammation, which is important for angiogenesis. Clinically, MR blockers (MRBs) have a protective effect on damaged kidneys, which may be associated with inhibition of angiogenesis. In this study, we used aldosterone-infused mice and found that aldosterone induced angiogenesis and that endothelial-mesenchymal transition (EndMT) in neovascular endothelial cells was involved in renal fibrosis. Notably, aldosterone induced inflammation and stimulated macrophages to secrete vascular endothelial growth factor (VEGF) A to regulate angiogenesis by activating MR, whereas EndMT occurred in response to transforming growth factor-ß1 (TGF-ß1) induction and participated in renal fibrosis. These effects were antagonized by the MRB esaxerenone. These findings suggest that reducing angiogenesis may be an effective strategy for treating renal fibrosis.
Subject(s)
Kidney Diseases , Transforming Growth Factor beta1 , Mice , Animals , Transforming Growth Factor beta1/metabolism , Aldosterone/pharmacology , Aldosterone/metabolism , Vascular Endothelial Growth Factor A/metabolism , Endothelial Cells/metabolism , Signal Transduction , Kidney/metabolism , Kidney Diseases/chemically induced , Kidney Diseases/drug therapy , Kidney Diseases/metabolism , Fibrosis , Inflammation/metabolism , Epithelial-Mesenchymal TransitionABSTRACT
Neuroinflammation plays a crucial role in the occurrence and development of cognitive impairment in type 2 diabetes mellitus (T2DM), but the specific injury mechanism is not fully understood. Astrocyte polarization has attracted new attention and has been shown to be directly and indirectly involved in neuroinflammation. Liraglutide has been shown to have beneficial effects on neurons and astrocytes. However, the specific protection mechanism still needs to be clarified. In this study, we assessed the levels of neuroinflammation and A1/A2-responsive astrocytes in the hippocampus of db/db mice and examined their relationships with iron overload and oxidative stress. First, in db/db mice, liraglutide alleviated the disturbance of glucose and lipid metabolism, increased the postsynaptic density, regulated the expression of NeuN and BDNF, and partially restored impaired cognitive function. Second, liraglutide upregulated the expression of S100A10 and downregulated the expression of GFAP and C3, and decreased the secretion of IL-1ß, IL-18, and TNF-α, which may confirm that it regulates the proliferation of reactive astrocytes and A1/A2 phenotypes polarize and attenuate neuroinflammation. In addition, liraglutide reduced iron deposition in the hippocampus by reducing the expression of TfR1 and DMT1 and increasing the expression of FPN1; at the same time, liraglutide by up-regulating the levels of SOD, GSH, and SOD2 expression, as well as downregulation of MDA levels and NOX2 and NOX4 expression to reduce oxidative stress and lipid peroxidation. The above may attenuate A1 astrocyte activation. This study preliminarily explored the effect of liraglutide on the activation of different astrocyte phenotypes and neuroinflammation in the hippocampus of a T2DM model and further revealed its intervention effect on cognitive impairment in diabetes. Focusing on the pathological consequences of astrocytes may have important implications for the treatment of diabetic cognitive impairment.
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BACKGROUND AND OBJECTIVE: Abiraterone acetate tablet is an inhibitor of androgen synthesis, primarily for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluated the bioequivalence and pharmacokinetics of the reference and test formulations of abiraterone acetate tablets in healthy Chinese volunteers. METHODS: A single-center, open, single-dose, randomized, three-period, three-sequence, semi-repeat (only repeated reference formulations), and reference formulation-corrected fasting reference-scaled average bioequivalence test was conducted in 36 healthy volunteers included in this study. Volunteers were randomly assigned to one of three groups in a 1:1:1 ratio. There was a minimum 7-day washout period between each dose. Blood samples were collected at prescribed time intervals, the plasma concentration of abiraterone acetate tablets was determined by liquid chromatography-tandem mass spectrometry, and adverse events were recorded. RESULTS: Under fasting conditions, the maximum plasma concentration (Cmax) was 27.02 ± 14.21 ng/mL, area under the concentration-time curve from time zero to time t (AUCt) was 125.30 ± 82.41 h·ng/mL, and AUC from time zero to infinity (AUC∞) was 133.70 ± 83.99 h·ng/mL. The 90% confidence intervals (CIs) of the geometric mean ratio (GMR) of AUCt and AUC∞ were in the range of 0.8000-1.2500, and the coefficient of variation (CVWR) of Cmax was more than 30%. The Critbound result was - 0.0522, and the GMR was between 0.8000 and 1.2500. CONCLUSION: Both test and reference formulations of abiraterone acetate tablets were bioequivalent in healthy Chinese subjects under fasting conditions. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04863105, registered 26 April 2021-retrospectively registered ( https://register. CLINICALTRIALS: gov/prs/app/action/SelectProtocol?sid=S000ARAA&selectaction=Edit&uid=U00050YQ&ts=2&cx=-vbtjri.
Subject(s)
Abiraterone Acetate , East Asian People , Male , Humans , Therapeutic Equivalency , Abiraterone Acetate/pharmacokinetics , Cross-Over Studies , Area Under Curve , Fasting , Tablets , Healthy VolunteersABSTRACT
BACKGROUND: Ezetimibe is a new class of antihyperlipidemic agent indicated for the prevention of atherosclerosis disease and for the treatment of hypercholesterolemia. Information on the pharmacokinetic profiles of ezetimibe tablet in healthy Chinese volunteers are lacking, and regulatory requirements necessitate a bioequivalence study of ezetimibe tablet versus Ezetrol® in China. METHODS: A single-dose randomized, open-label, two-group, two-period crossover study was conducted in 59 healthy Chinese volunteers under fasting or fed conditions to assess the bioequivalence between two preparations. Eligible participants were randomly divided into fasted and fed groups. Blood samples were collected at specified time intervals, and the plasma concentrations of ezetimibe and ezetimibe glucuronide were determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. PK and bioavailability parameters were estimated via non-compartmental methods. Adverse events were also recorded. RESULTS: Fifty-nine healthy volunteers were enrolled in the study. The main pharmacokinetic parameters of total ezetimibe in the plasma of the ezetimibe tablet (10 mg) and the Ezetrol® (10 mg) after a single fasting administration: Cmax were (65.73 ± 47.14), (71.32 ± 51.98) ng·mL- 1; Tmax were 1.75, 1.25 h; T½ were (17.09 ± 13.22), (17.35 ± 12.14) h; AUC0-t were (643.34 ± 400.77), (668.49 ± 439.57) h·ng·mL- 1; AUC0-∞ were (706.36 ± 410.92), (734.23 ± 468.26) h·ng·mL- 1. The main pharmacokinetic parameters of total ezetimibe in plasma of ezetimibe tablet (10 mg) and Ezetrol® (10 mg) after a fed administration: Cmax were (83.38 ± 38.95), (84.74 ± 34.62) ng·mL- 1; Tmax were 2.50, 2.50 h; T½ were (22.56 ± 12.68), (19.80 ± 15.59) h; AUC0-t were (494.21 ± 208.65), (536.69 ± 209.11) h·ng·mL- 1; AUC0-∞ were (573.74 ± 252.74), (604.75 ± 247.13) h·ng·mL- 1. The main pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞ of the two drugs were analyzed by variance analysis after logarithmic transformation. The total ezetimibe under fasting state with 90% confidence intervals (CIs) were 85.29 ~ 97.19, 90.41% ~ 104.38%, and 90.81 ~ 106.05%; total ezetimibe in fed state were 86.36% ~ 109.17, 84.96% ~ 96.40, and 85.32% ~ 101.0%. The 90% CIs of the ratio of geometric means (GMRs) of Cmax, AUC0-t, and AUC0-∞ of Ezetrol® and ezetimibe tablet both fasting and fed conditions fell within the conventional bioequivalence criteria of 0.80-1.25. Both Cmax and AUC met the predetermined criteria for assuming bioequivalence. No severe adverse events were observed. CONCLUSIONS: The test ezetimibe tablet and Ezetrol® were determined to be bioequivalent under both fasting and fed conditions in Chinese people. TRIAL REGISTRATION: Clinicaltrials, NCT05681247 (retrospectively registered in 11/01/ 2023).
Subject(s)
East Asian People , Tandem Mass Spectrometry , Humans , Therapeutic Equivalency , Cross-Over Studies , Chromatography, Liquid , Ezetimibe , Healthy Volunteers , Tandem Mass Spectrometry/methods , Area Under Curve , Fasting , TabletsABSTRACT
Resistance to ferroptosis, a form of programmed cell death, is associated with the development of some refractory cancers. In this issue, Yang et al. systematically illustrate the ferroptosis heterogeneity in triple-negative breast cancers (TNBCs) and reveal an innovative immunotherapy combination strategy for the luminal androgen receptor (LAR) subtype of TNBC.
Subject(s)
Ferroptosis , Triple Negative Breast Neoplasms , Humans , Immunotherapy , Triple Negative Breast Neoplasms/metabolism , HeelABSTRACT
Curcumin, from the rhizome of turmeric (Curcuma longa L.), has a wide variety of biological activities. Unfortunately, its poor water-solubility greatly limits its bioavailability. The purpose of this study was to evaluate CUMINUP60®, a novel preparation utilizing a solvent-free, co-grinding method designed to improve curcumin's bioavailability. We performed a single-center crossover experiment to compare the new product with standard 95% curcumin in the blood plasma of twelve healthy adults (10 males, 2 females). Total bioavailability of curcumin and its sulfate and glucuronide conjugates from the test product, measured by their areas under the curve over 12 h (AUC0-T), showed a combined increase of 178-fold over standard curcumin and its conjugates from the reference product. The new product represents a significant improvement for providing greater bioavailability of curcumin, as compared with several other branded preparations. It therefore has broad applications for preparing curcumin as a more effective health ingredient in functional foods, beverages, and nutraceuticals.
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Understanding the regulatory mechanisms of PD-L1 expression in tumors provides key clues for improving immune checkpoint blockade efficacy or developing novel oncoimmunotherapy. Here, we showed that the FDA-approved sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin dramatically suppressed PD-L1 expression and enhanced T cell-mediated cytotoxicity. Mechanistic study revealed that SGLT2 colocalized with PD-L1 at the plasma membrane and recycling endosomes and thereby prevented PD-L1 from proteasome-mediated degradation. Canagliflozin disturbed the physical interaction between SGLT2 and PD-L1 and subsequently allowed the recognition of PD-L1 by Cullin3SPOP E3 ligase, which triggered the ubiquitination and proteasome-mediated degradation of PD-L1. In mouse models and humanized immune-transformation models, either canagliflozin treatment or SGLT2 silencing significantly reduced PD-L1 expression and limited tumor progression - to a level equal to the PD-1 mAb - which was correlated with an increase in the activity of antitumor cytotoxic T cells. Notably, prolonged progression-free survival and overall survival curves were observed in the group of PD-1 mAb-treated patients with non-small cell lung cancer with high expression of SGLT2. Therefore, our study identifies a regulator of cell surface PD-L1, provides a ready-to-use small-molecule drug for PD-L1 degradation, and highlights a potential therapeutic target to overcome immune evasion by tumor cells.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Mice , Animals , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Canagliflozin/pharmacology , Sodium-Glucose Transporter 2 , Lung Neoplasms/pathology , Proteasome Endopeptidase Complex/metabolism , B7-H1 Antigen , Programmed Cell Death 1 Receptor , Cell Line, TumorABSTRACT
Aim: VDJ001 is a novel recombinant humanized monoclonal antibody against the anti-interleukin-6 receptor. As an analog of tocilizumab, it exhibited improved affinity and in vitro activity. Based on preclinical studies, a first-in-human clinical study was conducted to evaluate the safety, tolerability, and pharmacokinetics of VDJ001. Methods: This is a single-center, randomized, double-blinded, placebo-controlled phase I dose-escalation study conducted in healthy Chinese volunteers. Four cohorts were designed with dosages ranging from 1 to 8 mg/kg. There were equal numbers of female and male volunteers in each cohort. Enrolled subjects randomly received a single intravenous administration of VDJ001 or placebo (VDJ001: placebo = 4:1 in both female and male volunteers). Three sentinel volunteers in the 1 mg/kg cohort were first administered, and the treatment of the other seven volunteers was carried out after a safety assessment on D15. The following cohort was conducted only when the safety profile was evaluated as acceptable on D29 of the previous cohort. Samples for pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity were collected at specified time points and analyzed through validated methods. Adverse events and the results of the examination and laboratory were analyzed to assess the safety profile. Results: All cohorts were carried out according to the protocol. With the escalation of dosage, Cmax increased linearly, and AUC0-t and AUC0-∞ increased in a non-linear manner, while clearance decreased and t1/2 prolonged. Six volunteers who received VDJ001 tested ADA-positive, among whom one participant tested Nab-positive on D57. One volunteer in the placebo group tested ADA-positive but Nab-negative. CRP concentrations were not found to be correlated with the dosage. Both IL-6 and sIL-6R concentrations increased after the administration of VDJ001. All adverse events were mild to moderate in severity. No serious adverse events were reported in this study. No unexpected or clinically significant safety issues were found. Conclusion: The safety and tolerability of VDJ001 are acceptable with a single intravenous dosage of 1â¼8 mg/kg. Further clinical trials are warranted.
ABSTRACT
Cardiovascular complications are the leading causes of death in patients with chronic kidney disease (CKD), accounting for approximately 50% of deaths. Despite significant advances in the understanding of cardiac disease due to CKD, the underlying mechanisms involved in many pathological changes have not been fully elucidated. In our previous study, we observed severe fibrosis in the contralateral kidney of a 6-month-old rat UUO model. In the present experiment, we also observed severe fibrosis in the hearts of rats subjected to UUO and the macrophage-to-myofibroblast transition (MMT). These effects were inhibited by the mineralocorticoid receptor (MR) blocker eplerenone. Notably, in vitro, aldosterone-activated MR induced the MMT and subsequently promoted the secretion of CTGF, the target of MR, from macrophages; these changes were inhibited by eplerenone. The CTGF also induced the MMT and both the aldosterone and CTGF-induced MMT could be alleviated by the CTGF blocker. In conclusion, our results suggest that targeting the MR/CTGF pathway to inhibit the MMT may be an effective therapeutic strategy for the treatment of cardiac fibrosis.
Subject(s)
Cardio-Renal Syndrome , Heart Diseases , Renal Insufficiency, Chronic , Animals , Rats , Aldosterone , Cardio-Renal Syndrome/drug therapy , Eplerenone/pharmacology , Eplerenone/therapeutic use , Fibrosis , Macrophages , Myofibroblasts , Receptors, MineralocorticoidABSTRACT
Introduction: Cardiovascular disease constitutes the leading cause of mortality in patients with chronic kidney disease (CKD), which is termed cardiorenal syndrome type 4 (CRS-4). Here, we report the development of pathological cardiac remodeling and fibrosis in unilateral urinary obstruction (UUO) rats. Methods: Hematoxylin and eosin (H&E) staining was performed to observe the pathology of myocardial tissue. The degree of myocardial tissue fibrosis was observed by Masson and Sirius red staining. Immunohistochemical staining was applied to detect the expression of CD34 and CD105 in myocardial tissue, and immunofluorescent staining was performed to examine the expression of CD34, collagen I/collagen III, and alpha smooth muscle actin (α-SMA). The expression of the signal pathway-related proteins vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), nuclear factor κB (NF-κB), and interleukin (IL)-1ß was tested by western blotting. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the mRNA levels of serum and glucocorticoid-inducible kinase (SGK)-1, NF-κB, and interleukin-1ß (IL-1ß). Results: The results showed the development of pathological cardiac remodeling and cardiac dysfunction in UUO rats. Moreover, there was more angiogenesis and endothelial-mesenchymal transition (End-MT) in the UUO group, and these effects were inhibited by eplerenone. Conclusions: The results indicated that this cardiac fibrosis was associated with angiogenesis and that End-MT was related to aldosterone and mineralocorticoid receptor (MR) activation. Moreover, in association with the MR/IL-1ß/VEGFA signaling pathway, early treatment with the MR antagonist eplerenone in rats with UUO-induced CKD may significantly attenuate MR activation and cardiac fibrosis.
Subject(s)
Renal Insufficiency, Chronic , Ureteral Obstruction , Actins/metabolism , Aldosterone/metabolism , Animals , Collagen/metabolism , Eosine Yellowish-(YS)/metabolism , Eosine Yellowish-(YS)/pharmacology , Eplerenone/pharmacology , Fibrosis , Glucocorticoids/metabolism , Glucocorticoids/pharmacology , Hematoxylin/metabolism , Hematoxylin/pharmacology , Interleukin-1beta , Kidney/pathology , NF-kappa B/metabolism , NF-kappa B/pharmacology , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Mineralocorticoid/genetics , Receptors, Mineralocorticoid/metabolism , Renal Insufficiency, Chronic/complications , Ureteral Obstruction/complications , Ureteral Obstruction/drug therapy , Ureteral Obstruction/genetics , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , Vascular Endothelial Growth Factor Receptor-2/pharmacology , Ventricular RemodelingABSTRACT
Renal fibrosis is the inevitable pathway of the progression of chronic kidney disease to end-stage renal disease, which manifests as progressive glomerulosclerosis and renal interstitial fibrosis. In a previous study, we observed severe interstitial fibrosis in the contralateral kidneys of 6-month unilateral ureteral obstruction (UUO) rats, which was accompanied by increased macrophage infiltration and phenotypic transformation; after eplerenone administration, these effects were reduced. Therefore, we hypothesized that this effect was closely related to mineralocorticoid receptor (MR) activation induced by the increased aldosterone (ALD) level. In this study, we used uninephrectomy plus continuous aldosterone infusion in mice to observe whether aldosterone induced macrophage-to-myofibroblast transition (MMT) and renal fibrosis and investigated the signaling pathways. Notably, aldosterone induced predominantly M1 macrophage-to-myofibroblast transition by activating MR and upregulating TGF-ß1 expression, which promoted renal fibrosis. These effects were antagonized by the MR blocker esaxerenone. These findings suggest that targeting the MR/TGF-ß1 pathway may be an effective therapeutic strategy for renal fibrosis.
Subject(s)
Renal Insufficiency, Chronic , Transforming Growth Factor beta1 , Aldosterone/pharmacology , Animals , Eplerenone/pharmacology , Fibrosis , Macrophages/metabolism , Mice , Myofibroblasts/metabolism , Pyrroles , Rats , Receptors, Mineralocorticoid , Sulfones , Transforming Growth Factor beta1/metabolismABSTRACT
BACKGROUND: Famitinib is an oral, small-molecule, multi-targeted tyrosine kinase inhibitor under clinical investigation for the treatment of solid tumors. As famitinib is metabolized mainly by cytochrome P450 3A4 (CYP3A4), the study was conducted to investigate the effect of potent CYP3A4 inducer rifampin on the pharmacokinetics of famitinb. METHODS: This single-center, single-arm and fixed-sequence drug-drug interaction study enrolled 21healthy Chinese male subjects. Subjects received a single oral dose of famitinib 25 mg on days 1 and 16 and repeated administration of oral rifampin 600 mg once daily on days 10-23. Blood samples were collected and plasma concentrations of famitinib were measured by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic parameters were calculated using noncompartmental analysis and safety was assessed. RESULTS: In the presence of rifampin, the famitinib geometric mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) decreased by 48% and 69%, respectively, and the mean elimination half-life was shortened from 33.9 to 18.2 h. The geometric mean ratio (GMR) of famitinib Cmax and AUC0-∞ and their 90% CI were 0.52 (0.50, 0.54) and 0.31 (0.29, 0.33). Single dose of famitinib 25 mg was well tolerated and eight subjects (38.1%) reported treatment emergent adverse events, which were all grade 1-2 in severity. CONCLUSION: Co-administration of rifampin considerably reduces plasma concentration of famitinb due to CYP3A4 induction. Concomitant administration of famitinib and strong CYP3A4 inducers should be avoided, whereas when simultaneous use with inducers of CYP3A4, dose adjustment of famitinb is recommended. CLINICAL TRIAL REGISTRATION NUMBER: NCT04494659 (July 31, 2020).
Subject(s)
Indoles , Pyrroles , Rifampin , Chromatography, Liquid , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inducers/pharmacology , Drug Interactions , Healthy Volunteers , Humans , Indoles/pharmacokinetics , Male , Pyrroles/pharmacokinetics , Rifampin/pharmacology , Tandem Mass SpectrometryABSTRACT
Heat shock is a common environmental stress, although the response of the nucleus to it remains controversial in mammalian cells. Acute reaction and chronic adaptation to environmental stress may have distinct internal rewiring in the gene regulation networks. However, this difference remains largely unexplored. Here, we report that chromatin conformation and chromatin accessibility respond differently in short- and long-term heat shock in human K562 cells. We found that chromatin conformation in K562 cells was largely stable in response to short-term heat shock, whereas it showed clear and characteristic changes after long-term heat treatment with little alteration in chromatin accessibility during the whole process. We further show in silico and experimental evidence strongly suggesting that changes in chromatin conformation may largely stem from an accumulation of cells in the M stage of the cell cycle in response to heat shock. Our results represent a paradigm shift away from the controversial view of chromatin response to heat shock and emphasize the necessity of cell cycle analysis when interpreting bulk Hi-C data.
Subject(s)
Chromatin , Heat-Shock Response , Animals , Cell Cycle Checkpoints/genetics , Chromatin/genetics , Genomics , Heat-Shock Response/genetics , Humans , K562 Cells , Mammals/geneticsABSTRACT
In this bioequivalence study, we aimed to evaluate the bioequivalence of test (T) and reference (R) afatinib dimaleate tablets in healthy Chinese subjects under fasted conditions. This was a randomized, open-label, 2-period, single-dose, crossover study. A total of 60 healthy subjects were included in the study according to the screening criteria, and the subjects were randomly divided into the T/R and R/T groups. All subjects were administrated a single 40-mg oral dose of the test or reference formulation, separated by a 14-day washout period in the crossover manner. The pharmacokinetic parameters, including maximum concentration (Cmax ), area under the concentration-time curve (AUC) from time 0 to the last measurable concentration and AUC from time 0 to infinity were assessed for bioequivalence. The plasma concentrations of afatinib dimaleate were analyzed by liquid chromatography-tandem mass spectrometry. In addition, adverse events were monitored and recorded on the basis of patient interviews and physical examinations to assess the safety of the 2 formulations. There were 4 subjects who withdrew before the dosing of period 2. The 90%CIs of geometric mean ratios of Cmax , AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity were 95.9% to 104.1%, 98.8 % to 104.1%, and 98.9% to 104.0%, respectively, all of which were within the bioequivalence range of 80.0% to 125.0%. This randomized study demonstrated that the test formulation of afatinib was bioequivalent to the reference formulation in healthy Chinese subjects under fasted conditions. Both formulations were well tolerated, and no serious adverse events were observed during the study.
Subject(s)
Tandem Mass Spectrometry , Administration, Oral , Afatinib/adverse effects , Area Under Curve , Biological Availability , China , Chromatography, High Pressure Liquid/methods , Cross-Over Studies , Healthy Volunteers , Humans , Tablets , Tandem Mass Spectrometry/methodsABSTRACT
PURPOSE: The combination of lisinopril and amlodipine has a marked additional effect on blood pressure and fewer side effects than individual monotherapy. This study was conducted to compare the pharmacokinetic parameters and evaluate the bioequivalence between two Lisinopril/amlodipine tablets in healthy Chinese subjects. METHODS: A single center, randomized, open-label, single-dose, two-period crossover bioequivalence study was designed in healthy Chinese subjects under both fasting and fed conditions. Blood samples were collected before drug administration and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 24, 36, 48, 72, 96, 144, 168 h after administration. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to determine the plasma concentration of lisinopril and amlodipine. Maximum concentration (Cmax) and area under the concentration-time curve (AUC) were used to evaluate bioequivalence. Adverse events were recorded. RESULTS: Ninety-two healthy subjects were enrolled, and 75 completed the study. The 90% confidence intervals (CIs) of the ratio of geometric means (GMRs) of Cmax, AUC0-t, and AUC0-∞ of lisinopril and amlodipine under both fasting and fed conditions fell within the conventional bioequivalence criteria of 0.80-1.25. A high-fat meal appeared to decrease the Cmax and AUC of lisinopril. No severe adverse events were observed. CONCLUSION: The trial demonstrated that the test and the reference lisinopril/amlodipine tablets were bioequivalent and well tolerated in Chinese people under fasting and fed conditions. TRIAL REGISTRATION: Clinical Trails.gov identifier, NCT04885660 (retrospectively registered in 13/05/ 2021).