Background Febuxostat,a novel nonpurine selective inhibitor of xanthine oxidase(XO),may be used in the prevention and management of atrial fibrillation(AF).The purpose of this study was to evaluate the effects of febu...Background Febuxostat,a novel nonpurine selective inhibitor of xanthine oxidase(XO),may be used in the prevention and management of atrial fibrillation(AF).The purpose of this study was to evaluate the effects of febuxostat on atrial remodeling in a rabbit model of AF induced by rapid atrial pacing(RAP)and the mechanisms by which it acts.Methods Twenty-four rabbits were randomly divided into four groups:sham-operated group(Group S),RAP group(Group P),RAP with 5 mg/kg per day febuxostat group(Group LFP),and RAP with 10 mg/kg per day febuxostat group(Group HFP).All rabbits except those in Group S were subjected to RAP at 600 beats/min for four weeks.The effects of febuxostat on atrial electrical and structural remodeling,markers of inflammation and oxidative stress,and signaling pathways involved in the left atrium were examined.Results Shortened atrial effective refractory period(AERP),increased AF inducibility,decreased mRNA levels of Cav1.2 and Kv4.3,and left atrial enlargement and dysfunction were observed in Group P,and these changes were suppressed in the groups treated with febuxostat.Prominent atrial fibrosis was observed in Group P,as were increased levels of TGF-β1,Collagen I,andα-SMA and decreased levels of Smad7 and eNOS.Treatment with febuxostat attenuated these differences.Changes in inflammatory and oxidative stress markers induced by RAP were consistent with the protective effects of febuxostat.Conclusions This study is the first to find that febuxostat can inhibit atrial electrical and structural remodeling of AF by suppressing XO and inhibiting the TGF-β1/Smad signaling pathway.展开更多
Quorum sensing is a signal-based communication system in bacteria. It is an attractive target because it regulates the production of virulence factors in Pseudomonas aeruginosa. As a result, interference with quorum s...Quorum sensing is a signal-based communication system in bacteria. It is an attractive target because it regulates the production of virulence factors in Pseudomonas aeruginosa. As a result, interference with quorum sensing could result in inhibition of virulence of Pseudomonas aeruginosa with the merit of lack of selective pressure on growth that leads to development of resistance. This study investigated the anti-quorum sensing and anti-virulence activities of febuxostat in Pseudomonas aeruginosa PAO1 strain. At 1/8 MIC of febuxostat, the production of the quorum-sensing regulated violacein pigment of Chromobacterium violaceum CV026 was significantly reduced. Moreover, it markedly reduced pyocyanin, hemolysin, protease and elastase production. Significant inhibitory activities were also found against biofilm, swimming, twitching and swarming motilities. Molecular docking showed the ability of febuxostat to inhibit quorum sensing by competing with the autoinducers to bind with LasR and RhlR receptors. Febuxostat could bind to both receptors by hydrogen bonding and hydrophobic interaction. From the Molecular docking scores, febuxostat is a very promising quorum sensing inhibitor. Febuxostat could also significantly decrease the level of expression of all QS genes LasI, LasR, RhlI, RhlR, PqsA and PqsR that regulate the production of virulene factors as confirmed by qRT-PCR.展开更多
The objective of the present study was to exhibit the enhanced water-solubility and in vivo oral absorption when febuxostat(FXT) became the salt formation of choline. The formation of the choline salt of febuxostat wa...The objective of the present study was to exhibit the enhanced water-solubility and in vivo oral absorption when febuxostat(FXT) became the salt formation of choline. The formation of the choline salt of febuxostat was confirmed by X-ray powder diffraction, infrared spectroscopy analysis and differential scanning calorimetry. The direct filling method was used to develop a capsule formulation. Cellactose 80 was used as the filler due to its good fluidity, while cross-linked polyvinylpyrrolidone(PVPP) and magnesium stearate(MS) were used as the disintegrant and lubricant, respectively. Then the in vitro release of the formulation was carried out in five different dissolution media including HCl solution(pH 1.2),acetate buffer(pH 4.5), phosphate buffer(pH 6.8 and pH 7.2) and water. Evident improvement of release for choline febuxostat(CXT) was presented in water while the dissolution degree was decreased for CXT in the medium of phosphate buffer(pH 6.8) in comparison with FXT. Furthermore, the pharmacokinetics of CXT was studied in rats using UPLC-MS/MS compared with FXT. The data acquired illustrated that AUC0-24 h of CXT and FXT were22,245.96 ± 7342.92 μg·h/l and 12,249.70 ± 2024.04 μg·h/l, respectively. The relative bioavailability of CXT to FXT was about 181.6% and the P value of AUC0-24 h was less than 0.05. It showed significant difference between the two drugs after oral administration. In conclusion, the water-solubility and oral bioavailability were both improved remarkably for the choline salt of febuxostat and choline salinization was proved an effective way to increase the in vivo absorption for FXT.展开更多
Eco-friendly Ultra-high-performance liquid chromatography (UHPLC) with green aqueous-organic mobile phase was applied for the simultaneous determination of febuxostat (FEB) and diclofenac (DIC) with the composition of...Eco-friendly Ultra-high-performance liquid chromatography (UHPLC) with green aqueous-organic mobile phase was applied for the simultaneous determination of febuxostat (FEB) and diclofenac (DIC) with the composition of water:ethanol (85:15<span> </span>v/v) utilizing phenomenex Kinetex C<sub>18</sub> column (4.6 × 100 mm 2.6 μm), flow rate 1 ml/min and<b><span> </span></b>UV detection at 280 nm<b><span> </span></b>with linear ranges of 0.4 - 4.0 μg/mL and 0.5 - 5.0 μg/mL for FEB and DIC, respectively. The proposed method was also successfully applied to analyze the two drugs in pharmaceutical dosage form and human plasma. The results obtained were validated and statistically analyzed and found to be in accordance with those given by reported methods. Moreover, the greenness of the developed method is assessed using suitable analytical Eco-Scale and GAPI tools<b><span> </span></b>and comparison with the previously published methods have been carried out to indicate the priority of the proposed method. UHPLC is considered eco-friendly method regarding uses of safe solvents, simple, accurate and short time of analysis.展开更多
Gut dysbiosis is suggested to play a critical role in the pathogenesis of gout.The aim of our study was to identify the characteristic dysbiosis of the gut microbiota in gout patients and the impact of a commonly used...Gut dysbiosis is suggested to play a critical role in the pathogenesis of gout.The aim of our study was to identify the characteristic dysbiosis of the gut microbiota in gout patients and the impact of a commonly used uric acid-lowering treatment,febuxostat on gut microbiota in gout.16S ribosomal RNA sequencing and metagenomic shotgun sequencing was performed on fecal DNA isolated from 38 untreated gout patients,38 gout patients treated with febuxostat,and 26 healthy controls.A restriction of gut microbiota biodiversity was detected in the untreated gout patients,and the alteration was partly restored by febuxostat.Biochemical metabolic indexes involved in liver and kidney metabolism were significantly associated with the gut microbiota composition in gout patients.Functional analysis revealed that the gut microbiome of gout patients had an enriched function on carbohydrate metabolism but a lower potential for purine metabolism,which was comparatively enhanced in the febuxostat treated gout patients.A classification microbial model obtained a high mean area under the curve up to 0.973.Therefore,gut dysbiosis characterizings gout could potentially serve as a noninvasive diagnostic tool for gout and may be a promising target of future preventive interventions.展开更多
Heart failure is currently one of the most common and most cost-intensive of the chronic diseases The main cause of chronic heart failure （CHF） is the abnormalities of both cardiac contractile performance and myocar...Heart failure is currently one of the most common and most cost-intensive of the chronic diseases The main cause of chronic heart failure （CHF） is the abnormalities of both cardiac contractile performance and myocardial energy metabolism. Elevated levels of reactive oxygen species （ROS） have been proposed to contribute to both of them. Xanthine oxidoreductase （XO） is a major source of ROS in the cardiovascular system. XO inhibitors （XOIs） have been the cornerstone of the clinical management of gout and conditions associated with hyperuricemia for several decades.展开更多
基金supported by the Beijing Natural Science Foundation(Z141100002114050)
文摘Background Febuxostat,a novel nonpurine selective inhibitor of xanthine oxidase(XO),may be used in the prevention and management of atrial fibrillation(AF).The purpose of this study was to evaluate the effects of febuxostat on atrial remodeling in a rabbit model of AF induced by rapid atrial pacing(RAP)and the mechanisms by which it acts.Methods Twenty-four rabbits were randomly divided into four groups:sham-operated group(Group S),RAP group(Group P),RAP with 5 mg/kg per day febuxostat group(Group LFP),and RAP with 10 mg/kg per day febuxostat group(Group HFP).All rabbits except those in Group S were subjected to RAP at 600 beats/min for four weeks.The effects of febuxostat on atrial electrical and structural remodeling,markers of inflammation and oxidative stress,and signaling pathways involved in the left atrium were examined.Results Shortened atrial effective refractory period(AERP),increased AF inducibility,decreased mRNA levels of Cav1.2 and Kv4.3,and left atrial enlargement and dysfunction were observed in Group P,and these changes were suppressed in the groups treated with febuxostat.Prominent atrial fibrosis was observed in Group P,as were increased levels of TGF-β1,Collagen I,andα-SMA and decreased levels of Smad7 and eNOS.Treatment with febuxostat attenuated these differences.Changes in inflammatory and oxidative stress markers induced by RAP were consistent with the protective effects of febuxostat.Conclusions This study is the first to find that febuxostat can inhibit atrial electrical and structural remodeling of AF by suppressing XO and inhibiting the TGF-β1/Smad signaling pathway.
文摘Quorum sensing is a signal-based communication system in bacteria. It is an attractive target because it regulates the production of virulence factors in Pseudomonas aeruginosa. As a result, interference with quorum sensing could result in inhibition of virulence of Pseudomonas aeruginosa with the merit of lack of selective pressure on growth that leads to development of resistance. This study investigated the anti-quorum sensing and anti-virulence activities of febuxostat in Pseudomonas aeruginosa PAO1 strain. At 1/8 MIC of febuxostat, the production of the quorum-sensing regulated violacein pigment of Chromobacterium violaceum CV026 was significantly reduced. Moreover, it markedly reduced pyocyanin, hemolysin, protease and elastase production. Significant inhibitory activities were also found against biofilm, swimming, twitching and swarming motilities. Molecular docking showed the ability of febuxostat to inhibit quorum sensing by competing with the autoinducers to bind with LasR and RhlR receptors. Febuxostat could bind to both receptors by hydrogen bonding and hydrophobic interaction. From the Molecular docking scores, febuxostat is a very promising quorum sensing inhibitor. Febuxostat could also significantly decrease the level of expression of all QS genes LasI, LasR, RhlI, RhlR, PqsA and PqsR that regulate the production of virulene factors as confirmed by qRT-PCR.
文摘The objective of the present study was to exhibit the enhanced water-solubility and in vivo oral absorption when febuxostat(FXT) became the salt formation of choline. The formation of the choline salt of febuxostat was confirmed by X-ray powder diffraction, infrared spectroscopy analysis and differential scanning calorimetry. The direct filling method was used to develop a capsule formulation. Cellactose 80 was used as the filler due to its good fluidity, while cross-linked polyvinylpyrrolidone(PVPP) and magnesium stearate(MS) were used as the disintegrant and lubricant, respectively. Then the in vitro release of the formulation was carried out in five different dissolution media including HCl solution(pH 1.2),acetate buffer(pH 4.5), phosphate buffer(pH 6.8 and pH 7.2) and water. Evident improvement of release for choline febuxostat(CXT) was presented in water while the dissolution degree was decreased for CXT in the medium of phosphate buffer(pH 6.8) in comparison with FXT. Furthermore, the pharmacokinetics of CXT was studied in rats using UPLC-MS/MS compared with FXT. The data acquired illustrated that AUC0-24 h of CXT and FXT were22,245.96 ± 7342.92 μg·h/l and 12,249.70 ± 2024.04 μg·h/l, respectively. The relative bioavailability of CXT to FXT was about 181.6% and the P value of AUC0-24 h was less than 0.05. It showed significant difference between the two drugs after oral administration. In conclusion, the water-solubility and oral bioavailability were both improved remarkably for the choline salt of febuxostat and choline salinization was proved an effective way to increase the in vivo absorption for FXT.
文摘Eco-friendly Ultra-high-performance liquid chromatography (UHPLC) with green aqueous-organic mobile phase was applied for the simultaneous determination of febuxostat (FEB) and diclofenac (DIC) with the composition of water:ethanol (85:15<span> </span>v/v) utilizing phenomenex Kinetex C<sub>18</sub> column (4.6 × 100 mm 2.6 μm), flow rate 1 ml/min and<b><span> </span></b>UV detection at 280 nm<b><span> </span></b>with linear ranges of 0.4 - 4.0 μg/mL and 0.5 - 5.0 μg/mL for FEB and DIC, respectively. The proposed method was also successfully applied to analyze the two drugs in pharmaceutical dosage form and human plasma. The results obtained were validated and statistically analyzed and found to be in accordance with those given by reported methods. Moreover, the greenness of the developed method is assessed using suitable analytical Eco-Scale and GAPI tools<b><span> </span></b>and comparison with the previously published methods have been carried out to indicate the priority of the proposed method. UHPLC is considered eco-friendly method regarding uses of safe solvents, simple, accurate and short time of analysis.
基金the Project of Zhejiang Provincial Department of Education,China(Y202045471)the Project of Wenzhou Science and Technology,China(NO.Y2020205)。
文摘Gut dysbiosis is suggested to play a critical role in the pathogenesis of gout.The aim of our study was to identify the characteristic dysbiosis of the gut microbiota in gout patients and the impact of a commonly used uric acid-lowering treatment,febuxostat on gut microbiota in gout.16S ribosomal RNA sequencing and metagenomic shotgun sequencing was performed on fecal DNA isolated from 38 untreated gout patients,38 gout patients treated with febuxostat,and 26 healthy controls.A restriction of gut microbiota biodiversity was detected in the untreated gout patients,and the alteration was partly restored by febuxostat.Biochemical metabolic indexes involved in liver and kidney metabolism were significantly associated with the gut microbiota composition in gout patients.Functional analysis revealed that the gut microbiome of gout patients had an enriched function on carbohydrate metabolism but a lower potential for purine metabolism,which was comparatively enhanced in the febuxostat treated gout patients.A classification microbial model obtained a high mean area under the curve up to 0.973.Therefore,gut dysbiosis characterizings gout could potentially serve as a noninvasive diagnostic tool for gout and may be a promising target of future preventive interventions.
文摘Heart failure is currently one of the most common and most cost-intensive of the chronic diseases The main cause of chronic heart failure （CHF） is the abnormalities of both cardiac contractile performance and myocardial energy metabolism. Elevated levels of reactive oxygen species （ROS） have been proposed to contribute to both of them. Xanthine oxidoreductase （XO） is a major source of ROS in the cardiovascular system. XO inhibitors （XOIs） have been the cornerstone of the clinical management of gout and conditions associated with hyperuricemia for several decades.
