抗痛风药物febuxostat的合成

目的合成新型抗痛风药物febuxostat(1)。方法以羟基苯腈为原料,经硫代甲酰化得到对羟基硫代苯甲酰胺(3),3经环合得到2-(4-羟基苯基)-4-甲基-噻唑-5-羧酸乙酯(4),4与乌洛托品反应,得到中间体2-(3-甲酰基-4-羟基苯基)-4-甲基-噻唑-5-羧酸乙酯(5),之后再经醚化、氰化、水解得到目标产物(1)。结果与结论中间体及目标化合物的结构经1H-NMR和FAB-MS确证。该合成路线中使用的原料和试剂价廉易得,反应条件温和易控,操作简便。

Febuxostat对痛风伴高尿酸血症患者的血液流变学和血小板活化功能的影响

目的探讨febuxostat(非布司他)对痛风伴高尿酸血症患者血液流变学及血小板活化功能的影响。方法选取滨海县人民医院2015年4月至2017年3月收治的痛风伴高尿酸血症患者68例,随机分为对照组(35例)(给予别嘌醇治疗)和观察组(33例)(给予febuxostat治疗)。比较两组患者的临床疗效、血液流变学变化以及血小板活化功能的变化。结果治疗总有效率,观察组患者高于对照组患者(P<0. 05),与对照组相比,观察组患者在治疗后的血液流变学指标改善和血小板活化功能改善方面均更为明显(P<0. 05)。结论 Febuxostat治疗能有效地降低痛风伴高尿酸血症患者的高尿酸状态,改善患者的血液流变学与血小板活化功能,疗效优于别嘌醇。

Effects of febuxostat on atrial remodeling in a rabbit model of atrial fibrillation induced by rapid atrial pacing

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.

Perturbation of Quorum Sensing in <i>Pseudomonas aeruginosa</i>by Febuxostat

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.

Preparation, optimization and in vitro–in vivo investigation for capsules of the choline salt of febuxostat

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.

Febuxostat治疗妇女痛风的效果优于AUopurinol

据美国WebMD医学新闻网（2011-12-15）报道，根据已发表期刊的资料中，回顾性分析参与第3期比较实验222名高尿酸妇女的数据显示，每天80 mg febuxostat降低血清尿酸值低于6．0mg／dL之效果优于每天100、200或300mg的allopurinol。芝加哥大学Pritzker医学院和武田全球研发小组的Saima Chohan医生等人，比较了痛风患者使用febuxostat、allopurinol和安慰荆的随机控制实验数据进行了事后分析，这些数据共包括了4101名患者，其中226名女性，有4名女性在开始时的血清尿酸值低于8．0mg／dL，所以仅纳入其他222名患者。

Green UHPLC Method for Simultaneous Determination of Febuxostat and Diclofenac in Pharmaceutical Dosage Form and Human Plasma

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 v/v) utilizing phenomenex Kinetex C18 column (4.6 × 100 mm 2.6 μm), flow rate 1 ml/min and UV detection at 280 nm 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 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.

其它：04073 Febuxostat在美国申请治疗痛风

武田／Abbott公司的合资企业TAP医药产品公司已经为选择性的黄嘌呤氧化酶抑制剂febuxostat(Ⅰ)在美国提出新药申请，该药用于治疗慢性痛风患者的高尿酸血症(高尿酸水平)。

EMEA开始审查febuxostat

Ipsen公司已递交febuxostat（Ⅰ）用于治疗症状性高尿酸血症的集中欧盟审批申请。如果获得批准，（Ⅰ）将成为40年来首个治疗高尿酸血症的新药，高尿酸血症与痛风有关。（Ⅰ）是一种口服黄嘌呤氧化酶抑制剂，可降低血中的尿酸水平，并阻止痛风病人关节处尿酸晶体的沉积。（Ⅰ）比现有治疗药物别嘌呤（auopurin01）特异性更强，别瞟呤是通过抑制尿酸通路中的一系列酶发挥作用的。

Febuxostat治疗痛风与别嘌醇疗效相仿

据美国风湿病学会72届科学年会与美国风湿病科医务人员协会43届年会（ACR／ARHP）上宣读的一项Ⅲ期研究，febuxostat（1）40mg在痛风患者中降低尿酸盐的疗效与别嘌醇（Ⅱ）300rag的相仿。

The preparation and characteristics of febuxostat SiO2 solid dispersions

In the present research, we selected Sylysia as a porous material and febuxostat（FBT） as model drug to prepare the FBT SiO2 solid dispersions using a solvent evaporation method. We firstly established an HPLC method for determining FBT in our prepared FBT SiO2 solid dispersions. And then, the characteristics of FBT SiO2 solid dispersions were investigated, including differential scanning calorimetry（DSC）, powder X-ray diffraction（PXRD）, scanning electron microscope（SEM）, particle size and distribution. The solubility and dissolution of FBT SiO2 solid dispersion were also evaluated. The results of DSC and PXRD showed that the FBT existed in an amorphous state in FBT SiO2 solid dispersions. The SEM and particle size results indicated that the shape and average particle size of FBT SiO2 solid dispersions was similar to the Sylysia. The solubility and dissolution of FBT in FBT SiO2 solid dispersions were significantly enhanced compared with the pure FBT. In conclusion, we successfully prepared FBT SiO2 solid dispersions to increase the solubility and dissolution rate of the poorly water-soluble FBT.

Characteristic dysbiosis in gout and the impact of a uric acid-lowering treatment,febuxostat on the gut microbiota

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.

Febuxostat, a nonpurine selective inhibitor of xanthine oxidase： a promising medical therapy for chronic heart failure？

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.

非布司他联合阿托伐他汀钙治疗高脂血症合并高尿酸血症患者的效果

目的:观察非布司他联合阿托伐他汀钙治疗高脂血症合并高尿酸血症患者的效果。方法:选取2020年2月至2023年3月该院收治的120例高脂血症合并高尿酸血症患者进行前瞻性研究,按照随机数字表法将其分为对照组和观察组各60例。对照组予以阿托伐他汀钙治疗,观察组在对照组基础上联合非布司他治疗。比较两组临床疗效、治疗前后血脂指标[总胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)]水平、血尿酸水平、血管内皮功能指标[可溶性细胞间黏附分子-1(sICAM-1)、内皮素-1(ET-1)]水平和不良反应发生率。结果:观察组治疗总有效率为93.33%(56/60),高于对照组的80.00%(48/60),差异有统计学意义(P<0.05);治疗后,观察组TG、TC、LDL-C、血尿酸水平均低于对照组,HDL-C水平高于对照组,差异有统计学意义(P<0.05);观察组sICAM-1、ET-1水平均低于对照组,差异有统计学意义(P<0.05);两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论:非布司他联合阿托伐他汀钙治疗高脂血症合并高尿酸血症患者可提高治疗总有效率,改善血脂指标水平,降低血尿酸和血管内皮功能指标水平,效果优于单纯阿托伐他汀钙治疗。

血清胱抑素C、内皮素-1、转化生长因子-β1预测高尿酸血症患者非布司他治疗后疗效的价值

目的研究血清胱抑素C、内皮素-1、转化生长因子-β1(TGF-β1)预测高尿酸血症(HUA)非布司他治疗后疗效的价值。方法回顾性分析2021年1月至2023年1月在武警山西总队医院收治的160例HUA患者的临床资料,所有患者均口服非布司他进行治疗,根据患者使用非布司他治疗3个月后的疗效情况分为有效组(n=118)和无效组(n=42)。观察两组基础资料信息[性别、年龄、体重指数、病程、疾病类型、合并高血压、合并糖尿病、血肌酐、肾小球过滤率(GFR)、血尿酸、胱抑素C、内皮素-1、TGF-β1水平]差异。采用多因素Logistic回归分析影响HUA患者非布司他治疗效果的危险因素。绘制受试者操作特征(ROC)曲线评估血清胱抑素C、内皮素-1、TGF-β1预测HUA患者非布司他治疗效果的效能。结果两组性别构成比、年龄、体重指数、病程、疾病类型、合并高血压、合并糖尿病、血肌酐、eGFR比较,差异均无统计学意义(P>0.05);无效组的血尿酸、胱抑素C、内皮素-1、TGF-β1水平分别为(435.89±33.05)μmol/L、(10.84±1.65)mg/L、(32.81±5.55)ng/L、(25.74±4.85)ng/mL,均显著高于有效组[(351.85±24.76)μmol/L、(8.15±1.43)mg/L、(24.56±4.12)ng/L、(19.28±3.62)ng/mL],差异均有统计学意义(P<0.05)。经多因素Logistic回归分析证实,血清血尿酸、胱抑素C、内皮素-1、TGF-β1高水平均是影响HUA患者非布司他治疗无效的危险因素(P<0.05)。经ROC分析证实,血清胱抑素C、内皮素-1、TGF-β1可用于HUA患者非布司他治疗效果的预测,曲线下面积分别为0.917、0.853、0.825,预测价值较好(P<0.05)。结论血清血尿酸、胱抑素C、内皮素-1、TGF-β1高水平均是影响HUA患者非布司他治疗效果的危险因素,可将以上指标作为评估HUA患者非布司他治疗效果的标志物,为临床降低HUA治疗无效风险提供参考。

非布司他联合吲哚美辛对痛风性关节炎患者血尿酸、疼痛程度及氧化应激水平的影响

目的探究非布司他联合吲哚美辛对痛风性关节炎患者血尿酸、疼痛程度及氧化应激水平的影响。方法选取2022年1月—2023年5月新疆维吾尔自治区人民医院内分泌与代谢病科收治的痛风性关节炎患者86例,按随机数字表法分为对照组(n=43)和观察组(n=43)。对照组患者接受非布司他片口服,观察组患者在此基础上联合吲哚美辛片口服,2组均持续治疗1个月。评价2组患者的临床疗效,通过视觉模拟评分法(VAS)评估患者治疗前、治疗2周及1个月时关节疼痛程度;比较2组患者治疗前后肾功能指标[血清肌酐(SCr)、血尿酸(UA)、尿素氮(BUN)]、血清炎性指标[白介素1β(IL-1β)、核苷酸寡聚化结构域样受体蛋白3(NALP3)、肿瘤坏死因子α(TNF-α)]、氧化应激指标[血清谷胱甘肽过氧化物酶(GSH-Px)、超氧化物歧化酶(SOD)及丙二醛(MDA)]及不良事件发生率。结果观察组治疗总有效率高于对照组(88.37%vs.69.77%,χ^(2)/P=4.497/0.034);治疗2周后,2组患者VAS评分均低于治疗前,且观察组低于对照组(t/P=5.324/<0.001);治疗1个月后2组患者血清UA及SCr水平较治疗前降低,且观察组低于对照组(t/P=3.081/0.003、2.692/0.009);2组血清IL-1β及NALP3水平较治疗前降低,且观察组低于对照组(t/P=5.587/<0.001、2.465/0.016);2组血清GSH-Px及SOD水平较治疗前升高,血清MDA降低,且观察组高于/低于对照组患者(t/P=3.709/<0.001、3.655/<0.001、3.653/<0.001);观察组疼痛消失时间短于对照组(t/P=4.025/<0.001);观察组药物相关不良事件总发生率低于对照组,但差异无统计学意义(11.63%vs.18.60%,χ^(2)/P=0.816/0.366)。结论非布司他联合吲哚美辛对痛风性关节炎患者的肾功能改善具有更显著的效果,同时可有效降低患者炎性反应及氧化应激水平,有利于提高患者临床疗效且具有较好的临床安全性。

基于FDA不良事件报告系统数据库的别嘌醇和非布司他不良事件信号挖掘研究

目的基于FDA不良事件报告系统数据库对非布司他、别嘌醇进行不良事件信号挖掘,探索其潜在的用药风险,促进临床合理安全用药。方法提取FDA不良事件报告系统数据库2017年第一季度至2022年第二季度共22个季度有关非布司他、别嘌醇的不良事件报告数据,利用ROR法及PRR法对非布司他、别嘌醇不良事件(AE)进行信号挖掘。结果别嘌醇AE报告5060份,集中于≥60岁患者,累及系统器官分类项目(SOC)共计25项,主要累及在皮肤及皮下组织类疾病(40.01%),发现说明书中未累及系统12项,非布司他AE报告905份,累及SOC共计17项,主要累及在心脏器官疾病(40.17%),发现说明书中未累及系统2项。别嘌醇、非布司他累及感染及侵染类疾病(5.51%、0.49%),肝胆系统疾病(5.35%、0.87%),但别嘌醇说明书中均未收录。别嘌醇累及生殖系统及乳腺疾病(0.55%),妊娠期、产褥期及围产期状况(0.03%),但非布司他未发现累及以上SOC。结论别嘌醇较非布司他,说明书收录不良反应较不充分,新发现的累及SOC及AE为完善别嘌醇说明书不良反应可提供参考。研究发现别嘌醇和非布司他累及SOC差异,可为临床个体化治疗提供参考。

别嘌醇及非布司他对家兔快速心房起搏房颤模型心房结构重构的影响

目的探讨黄嘌呤氧化酶(XO)抑制剂(别嘌醇及非布司他)对家兔快速心房起搏(RAP)房颤模型心房结构重构的影响。方法24只健康雄性新西兰白兔,随机分为4组:假手术组(S组)、快速心房起搏组(P组)、快速心房起搏-别嘌醇干预组(ALL组)及快速心房起搏-非布司他干预组(FP组)。4周的RAP后行经胸超声心动图检查,同时对左心房心肌组织进行HE染色、Masson染色,并进行透射电子显微镜观察。qRT-PCR及Western blot检测TGF-β1、Smad7、Collagen I及α-SMA的mRNA和蛋白表达。结果P组的LAD、LAVmax及LAVmin均显著高于S组(P<0.01),LAEF显著低于S组(P<0.01);FP组的LAD显著低于ALL组(P<0.01),而两组LAVmax、LAVmin、LAEF之间的比较不具有统计学差异(P>0.05)。RAP导致左心房心肌组织出现严重的病理性损伤,并导致心房肌细胞超微结构发生改变,应用XO抑制剂干预(尤其是非布司他)可以减轻这些异常的病理改变,同时减轻左心房组织超微结构的损伤。P组左心房纤维组织面积的比例明显高于S组(P<0.01);应用XO抑制剂干预后纤维组织面积的比例与P组相比均明显降低(P<0.01),且FP组明显低于ALL组(P<0.05)。RAP导致TGF-β1 mRNA和蛋白表达显著增加,Smad7 mRNA和蛋白表达显著降低,同时上调Collagen I和α-SMA mRNA和蛋白表达水平;应用XO抑制剂干预可使TGF-β1、Collagen I和α-SMA mRNA和蛋白表达水平在一定程度上降低,同时上调Smad7 mRNA和蛋白表达,在FP组尤为明显。结论与别嘌醇相比,非布司他的干预显著改善了RAP诱导的心房结构重构,减轻了心房纤维化。

非布司他联合塞来昔布治疗痛风性关节炎的效果分析

目的:分析非布司他联合塞来昔布治疗痛风性关节炎的效果。方法:选取2023年1—12月南通大学附属江阴市人民医院收治的痛风性关节炎患者80例作为研究对象,随机分为传统组和联合组,各40例。传统组给予塞来昔布治疗,联合组在传统组基础上给予非布司他治疗。对比两组治疗效果、血清尿酸水平、炎性因子水平、生活质量。结果:联合组治疗有效率高于传统组(P=0.023)。治疗前,两组血清尿酸水平对比,差异无统计学意义(P>0.05);治疗后,两组血清尿酸水平低于治疗前,且联合组低于传统组(P<0.001)。治疗前,两组炎性因子水平比较,差异无统计学意义(P>0.05);治疗后,两组髓过氧化物酶、肿瘤坏死因素-α、白细胞介素-1β、C反应蛋白水平低于治疗前,且联合组低于传统组(P<0.05)。治疗前,两组生活质量评分比较,差异无统计学意义(P>0.05);治疗后,两组疼痛程度、活动能力、睡眠质量、满意度评分高于治疗前,且联合组高于传统组(P<0.05)。结论:非布司他联合塞来昔布治疗痛风性关节炎的效果显著,可降低患者血清尿酸水平,减轻炎性反应,改善其生活质量。

非布司他治疗慢性肾脏病伴高尿酸血症的有效性及安全性评价

目的 评价非布司他治疗慢性肾脏病(chronic kidney disease,CKD)伴高尿酸血症(hyperuricemia,HUA)的有效性及安全性。方法 目的选取2022年1月—2023年12月涟水县人民医院收治的62例CKD伴HUA患者,按治疗方法不同分为对照组(别嘌醇治疗,31例)与干预组(非布司他治疗,31例),比较两组的疗效、尿酸水平、不良反应发生率。结果 干预组的总有效率96.77%(30/31)高于对照组的74.19%(23/30),差异有统计学意义(χ^(2)=4.679,P<0.05);治疗1个月、3个月,干预组尿酸水平优于对照组,差异有统计学意义(P均<0.05);干预组的总不良反应率低于对照组,差异有统计学意义(P<0.05)。结论 非布司他应用于CKD伴HUA患者治疗中的效果较好,安全性高,不良反应发生率低。