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Atenolol, a cardioselective ß1-blocker, exhibits efficacy in treating cardiovascular diseases. We conducted a single-center, randomized, open, single-dose, 2-preparation, 2-cycle, 2-sequence, double-crossover trial with a 7-day washout period to investigate the pharmacokinetics, bioequivalence (BE), and safety of test and reference atenolol tablets (25 mg) in healthy Chinese volunteers. Forty-eight healthy participants were randomized into the fasting and fed arms. After administering a single oral dose of the test or reference formulation (25 mg), plasma atenolol concentrations were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were obtained from concentration-time profiles. In total, 23 and 24 individuals were included in the fasting and fed arms, respectively. The mean concentration-time profiles for both formulations were similar, and Cmax, AUC0-t, and AUC0-∞ were within the BE range of 80%-125%. Thirteen adverse events (AEs) were observed in 7 participants in the fasting arm; 1 withdrew from the trial early owing to an AE. In the fed arm, 20 AEs were observed in 8 participants, and none withdrew from the trial. All adverse reactions were grade I, with no serious AEs or deaths. Therefore, the 2 tablets are bioequivalent in healthy Chinese individuals under fasting and fed conditions, supporting their further clinical development.
Assuntos
Área Sob a Curva , Atenolol , Estudos Cross-Over , Jejum , Voluntários Saudáveis , Comprimidos , Equivalência Terapêutica , Humanos , Atenolol/farmacocinética , Atenolol/administração & dosagem , Atenolol/efeitos adversos , Masculino , Adulto , Feminino , Adulto Jovem , Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/efeitos adversos , Povo Asiático , Administração Oral , Interações Alimento-Droga , China , População do Leste AsiáticoRESUMO
Lung adenocarcinoma (LUAD) is a malignant tumor of the respiratory system that has a poor 5-year survival rate. Anoikis, a type of programmed cell death, contributes to tumor development and metastasis. The aim of this study was to develop an anoikis-based stratified model, and a multivariable-based nomogram for guiding clinical therapy for LUAD. Through differentially expressed analysis, univariate Cox, LASSO Cox regression, and random forest algorithm analysis, we established a 4 anoikis-related genes-based stratified model, and a multivariable-based nomogram, which could accurately predict the prognosis of LUAD patients in the TCGA and GEO databases, respectively. The low and high-risk score LUAD patients stratified by the model showed different tumor mutation burden, tumor microenvironment, gemcitabine sensitivity and immune checkpoint expressions. Through immunohistochemical analysis of clinical LUAD samples, we found that the 4 anoikis-related genes (PLK1, SLC2A1, ANGPTL4, CDKN3) were highly expressed in the tumor samples from clinical LUAD patients, and knockdown of these genes in LUAD cells by transfection with small interfering RNAs significantly inhibited LUAD cell proliferation and migration, and promoted anoikis. In conclusion, we developed an anoikis-based stratified model and a multivariable-based nomogram of LUAD, which could predict the survival of LUAD patients and guide clinical treatment.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Anoikis/genética , Adenocarcinoma de Pulmão/genética , Biomarcadores , Biologia Computacional , Neoplasias Pulmonares/genética , Prognóstico , Microambiente Tumoral/genéticaRESUMO
Cytokine storms characterized by excessive secretion of circulating cytokines and immune-cell hyperactivation are life-threatening systemic inflammatory syndromes. The new strategy is in great demand to inhibit the cytokine storm. Here, we designed a type of magnetically controlled nanorobots (MAGICIAN) by fusing neutrophil membranes onto Fe3O4 nanoparticles (Fe3O4NPs). In our study, the receptors of neutrophil membranes were successfully coated to the surface of Fe3O4NPs. The associated membrane functions of neutrophils were highly preserved. MAGICIAN could in vitro neutralize the inflammatory cytokines including interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). Interestingly, MAGICIAN could be navigated to the liver sites under magnetic control and accelerated the cytokine clearance by the liver. Administration of MAGICIAN could efficiently relieve the inflammation in the acute lung injury mouse model. In addition, MAGICIAN displayed good biosafety in systemic administration. The present study provides a safe and convenient approach for the clearance of cytokine storms, indicating the potential for clinical application in acute lung injury therapy.
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Lesão Pulmonar Aguda , Síndrome da Liberação de Citocina , Camundongos , Animais , Citocinas , Fator de Necrose Tumoral alfa , Lesão Pulmonar Aguda/tratamento farmacológico , Interferon gamaRESUMO
In this study, we compared the pharmacokinetics and safety of a new generic product and a branded reference product of amisulpride tablets. Additionally, we assessed the bioequivalence of the 2 products in healthy Chinese volunteers to acquire sufficient evidence for the marketing approval of the generic drug. Thirty volunteers under fasting and fed conditions were randomly administered a single dose of the test or reference drug orally, followed by a 7-day washout period. The pharmacokinetic parameters were obtained by the concentration-time profiles, including the area under the plasma concentration-time curve (AUC) over the dosing interval, AUC from time zero to infinity, maximum plasma concentration, time to achieve maximum plasma concentration, and elimination half-life. AUC from time zero to infinity of amisulpride in the postprandial group was reduced by approximately 25%, suggesting that a high-fat diet can affect this parameter. In the aspect of safety, no serious adverse events occurred. This study demonstrated that generic and reference products of amisulpride tablets were bioequivalent in healthy Chinese volunteers under fasting and fed conditions.
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Jejum , Voluntários , Humanos , Amissulprida/efeitos adversos , China , Comprimidos , Equivalência TerapêuticaRESUMO
Background: High-level low-density lipoprotein cholesterol (LDL-C) plays a vital role in the development of atherosclerotic cardiovascular disease. Low-density lipoprotein receptors (LDLRs) are scavengers that bind to LDL-C in the liver. LDLR proteins are regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9), which mediates the degradation of LDLR and adjusts the level of the plasma LDL-C. The low expression of PCSK9 leads to the up-regulation of liver LDLRs and the reduction of plasma LDL-C. Hepatocytes are attractive targets for small interfering RNA (siRNA) delivery to silence Pcsk9 gene, due to their significant role in LDL-C regulation. Methods: Here, a type of liver-specific ionizable lipid nanoparticles is developed for efficient siRNA delivery. This type of nanoparticles shows high stability, enabling efficient cargo delivery specifically to hepatocytes, and a membrane-active polymer that reversibly masks activity until an acidic environment is reached. Results: Significantly, the siPcsk9 (siRNA targeting to Pcsk9)-loaded nanoparticles (GLP) could silence 90% of the Pcsk9 mRNA in vitro. In vivo study showed that the improved accumulation of GLP in the liver increased LDLR level by 3.35-fold and decreased plasma LDL-C by 35%. Conclusion: GLP has shown a powerful effect on reducing LDL-C, thus providing a potential therapy for atherosclerotic cardiovascular disease.
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Aterosclerose , Doenças Cardiovasculares , Nanopartículas , Humanos , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , LDL-Colesterol/genética , LDL-Colesterol/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Pró-Proteína Convertases/genética , Pró-Proteína Convertases/metabolismo , Interferência de RNA , Doenças Cardiovasculares/metabolismo , Fígado/metabolismo , Colesterol , Receptores de LDL/genética , Receptores de LDL/metabolismo , Aterosclerose/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismoRESUMO
This study aimed to assess the bioequivalence of 2 cefprozil dispersible tablet formulations (250 mg) in healthy Chinese volunteers under fasting and fed conditions and to determine the pharmacokinetics of cefprozil. A randomized, single-dose, open-label, 2-formulation, 2-period study was conducted. The elimination period for this study was 7 days. Forty-eight healthy volunteers received 250-mg cefprozil dispersible tablets in each study period under both test and reference conditions. The test and the reference cefprozil were bioequivalent in healthy Chinese volunteers, and there was no significant food effect in individuals receiving either formulation. No serious adverse event was recorded, and no volunteers withdrew from the study.
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População do Leste Asiático , Humanos , Voluntários Saudáveis , Comprimidos , Equivalência Terapêutica , CefprozilRESUMO
This study compared the safety, bioequivalence, and pharmacokinetic properties of 2 formulations of 10-mg rivaroxaban tablets in healthy Chinese participants in fasting and fed arms. The trial was an open, randomized, 4-period, replicated crossover scheme, and 36 volunteers were recruited separately for the fasting and fed arms. Volunteers were randomly administered a single dose of the test or reference formulation (10 mg) orally, followed by a 5-day washout period. Rivaroxaban concentrations in the plasma were determined using liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were obtained from the concentration-time profiles. The mean values of the test and the reference product for the area under the plasma concentration-time curve from time 0 to the last measurable concentration, area under the plasma concentration-time curve from time 0 to infinity, and maximum plasma concentration were 996 and 1014 ng ⢠h/mL, 1024 and 1055 ng ⢠h/mL, and 150 and 152 ng/mL in the fasting arm, respectively; the values were 1155 and 1167 ng ⢠h/mL, 1160 and 1172 ng ⢠h/mL, and 202 and 193 ng/mL in the fed arm, respectively. All the parameters were within acceptable limits in terms of bioequivalence. No serious adverse events were observed. This study demonstrated that the 2 rivaroxaban tablets were bioequivalent in healthy Chinese participants under fasting and fed conditions.
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Ibuprofen is a nonsteroidal anti-inflammatory agent. In this study, we compared the pharmacokinetic properties, bioequivalence, and safety of a newly developed generic formulation (test) and a branded formulation (reference) of 0.2 g ibuprofen granules in healthy Chinese participants in fasting and fed arms. The randomized, single-dose, open-label, two-preparation, two-sequence, two-period crossover study had a washout period of 7 days between each period. It was conducted in 72 participants, 24 in the fasting arm and 48 in the fed arm. The concentration of ibuprofen in the plasma was determined using high-performance liquid chromatography-tandem mass spectroscopy. The primary pharmacokinetic parameters were calculated using a noncompartmental model. Safety assessments were performed throughout the study. The mean values of Cmax , AUC0-t , and AUC0-∞ for the test and reference preparations of ibuprofen were 19 295 and 21 101 ng/mL, 70 795 and 70 558 ng * h/mL, and 72 023 and 71 647 ng * h/mL, respectively, in the fasting arm and 11 299 and 11 605 ng/mL, 70 983 and 69 157 ng * h/mL, and 73 279 and 71 267 ng * h/mL, respectively, in the fed arm. For all parameters, bioequivalence was within acceptable limits. No serious adverse reactions were reported in this study. This study demonstrated that the 2 formulations of ibuprofen granules were bioequivalent in healthy Chinese volunteers under fasting and fed conditions.
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Ibuprofeno , Humanos , Equivalência Terapêutica , Ibuprofeno/efeitos adversos , Estudos Cross-Over , Área Sob a Curva , Disponibilidade BiológicaRESUMO
Nucleic acids have emerged as promising therapeutic agents for many diseases because of their potential in modulating gene expression. However, the delivery of nucleic acids remains a significant challenge in gene therapy. Although viral vectors have shown high transfection efficiency, concerns regarding teratogenicity or carcinogenicity have been raised. Non-viral vehicles, including cationic polymers, liposomes, and inorganic materials possess advantages in terms of safety, ease of preparation, and low cost. Nevertheless, they also face limitations related to immunogenicity, quick clearance in vivo, and lack of targeting specificity. On the other hand, bioinspired strategies have shown increasing potential in the field of drug delivery, yet there is a lack of comprehensive reviews summarizing the rapid development of bioinspired nanoparticles based on the cell membrane camouflage to construct the nucleic acids vehicles. Herein, we enumerated the current difficulties in nucleic acid delivery with various non-viral vehicles and provided an overview of bioinspired strategies for nucleic acid delivery.
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Nanopartículas , Ácidos Nucleicos , Transfecção , Lipossomos , Membrana CelularRESUMO
Objectives: This study examined the dose-effect relationship of chitosan and danshen combined injections on the long-term prevention of fallopian tube re-obstructions, with increased pregnancy rates in infertile women. Methods: High-performance liquid chromatography was used to determine the content changes of combined chitosan and danshen injection. Two hundred and eighty patients with fallopian tube obstructions were randomly assigned to four groups. Group A (control group, saline), Group B (2 ml chitosan, 4 ml danshen), Group C (2 ml chitosan, 10 ml danshen), and Group D (1 ml chitosan, 10 ml danshen). Injections were administered after tubal recanalization. Results: The effective constituent of chitosan and danshen injection was stable. Tubal patency rate was 94.2% and 87.3% in Group C after 1 and 3 years, respectively, which was significantly higher than Groups A (38.6%, 31.5%), B (73.5%, 64.1%), and D (68.5%, 50.7%). Intrauterine pregnancy rates were 61.8% and 79.4% in Group C after 1 and 3 years, respectively, and were significantly higher than Groups A (31.8%, 34.8%), B (40.1%, 62.5%), and D (38.5%, 58.5%) (p < 0.05). Conclusion: Combined Chitosan and danshen injections prevented tubal obstruction and increased pregnancy rates for long periods using an optimal ratio of 1 part chitosan and 5 parts danshen.
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Objective: To illustrate the functions of protein tyrosine phosphatase nonreceptor type 18 (PTPN18) in the progression of ovarian cancer and the potential molecular mechanism. Methods: Differential PTPN18 expression in ovarian cancer samples was determined. Following PTPN18 knockdown, changes in proliferation and migration in ovarian cancer cells were detected. Nude mice with ovarian cancer were used to uncover the effects of PTPN18 on ovarian cancer growth in vivo. Results: PTPN18 was significantly upregulated in ovarian cancer samples and linked to pathological staging and metastasis rate. PTPN18 displayed prognostic and diagnostic potentials in ovarian cancer. Knockdown of PTPN18 and treatment of the PI3K inhibitor could inhibit proliferative and migratory abilities in ovarian cancer cells. Moreover, PTPN18 was capable of inactivating PI3K/AKT signaling. In vivo knockdown of PTPN18 suppressed ovarian cancer growth in nude mice. Conclusions: PTPN18 is upregulated in ovarian cancer, which stimulates the malignant development by activating PI3K/AKT signaling. The PTPN18 level is also associated with pathological staging and metastasis in ovarian cancer patients, which may be utilized as a hallmark predicting the malignant level.
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Introduction: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with low 5-year survival rate. Cellular senescence, characterized by permanent and irreversible cell proliferation arrest, plays an important role in tumorigenesis and development. This study aims to develop a cellular senescence-based stratified model, and a multivariable-based nomogram for guiding clinical therapy for HCC. Materials and methods: The mRNAs expression data of HCC patients and cellular senescence-related genes were obtained from TCGA and CellAge database, respectively. Through multiple analysis, a four cellular senescence-related genes-based prognostic stratified model was constructed and its predictive performance was validated through various methods. Then, a nomogram based on the model was constructed and HCC patients stratified by the model were analyzed for tumor mutation burden, tumor microenvironment, immune infiltration, drug sensitivity and immune checkpoint. Functional enrichment analysis was performed to explore potential biological pathways. Finally, we verified this model by siRNA transfection, scratch assay and Transwell Assay. Results: We established an cellular senescence-related genes-based stratified model, and a multivariable-based nomogram, which could accurately predict the prognosis of HCC patients in the ICGC database. The low and high risk score HCC patients stratified by the model showed different tumor mutation burden, tumor microenvironment, immune infiltration, drug sensitivity and immune checkpoint expressions. Functional enrichment analysis suggested several biological pathways related to the process and prognosis of HCC. Scratch assay and transwell assay indicated the promotion effects of the four cellular senescence-related genes (EZH2, G6PD, CBX8, and NDRG1) on the migraiton and invasion of HCC. Conclusion: We established a cellular senescence-based stratified model, and a multivariable-based nomogram, which could predict the survival of HCC patients and guide clinical treatment.
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The objective of this study was to prepare silk fibroin SF microspheres containing the enhanced green fluorescent protein (EGFP) by using a novel ultra-fine particle processing system (UPPS) and to evaluate the microspheres as possible carriers for long-term delivery of sensitive biologicals. The drug content, encapsulation efficiency, and in vitro release were evaluated by Microplate Absorbance Reader. The particle size distribution and morphology of the microspheres were analyzed by Malvern Master Sizer 2000 and scanning electron microscopy. The distribution of EGFP and the interactions between SF and EGFP were investigated by Confocal Laser Scanning Microscopy, FTIP, Raman and NMR spectroscopy. The results showed that spherical microspheres with narrow size distribution, glossy and dense surface were successfully manufactured by using UPPS technology and over 95% of EGFP encapsulation efficiency and uniform drug distribution in the microspheres were achieved. Furthermore, a burst free and sustained release of encapsulated EGFP for a period of 50 days in deionized water was obtained. In conclusion, the novel UPPS technology could be used to manufacture SF matrix microspheres as a potential long-term protein delivery system to improve patient compliance and convenience.