Delayed Treatment Effects of Xanthine Oxidase Inhibition on Systolic Overload-Induced Left Ventricular Hypertrophy and Dysfunction

The nonpurine selective xanthine oxidase (XO) inhibitor febuxostat attenuates development of left ventricular (LV) hypertrophy and dysfunction in mice when treatment is initiated within 1 hour of transverse aortic constriction (TAC). This study investigated whether a 7-day delay of treatment with the XO inhibitors febuxostat or allopurinol would reverse TAC-induced changes after onset of heart failure (HF). Neither treatment significantly affected TAC-induced LV hypertrophy; only febuxostat caused a modest improvement in LV function (～10% increase in LV ejection fraction). However, the purine analog allopurinol tended to increase mortality compared with vehicle or febuxostat in HF mice.     

非布司他对痛风合并高尿酸血症患者血清sICAM-1, ET-1 及尿酸水平的影响

目的:探讨非布司他对痛风合并高尿酸血症患者血清内皮素-1(ET-1)、细胞间粘附分子-1(ICAM-1)及尿酸水平的影响。方法:收集在我院就诊或住院治疗的80例痛风合并高尿酸血症患者,随机分为实验组和对照组,每组40例。对照组患者给予别嘌呤醇片治疗;实验组患者给予非布司他片治疗。观察并比较两组患者治疗前后血尿酸、s ICAM-1、ET-1水平及临床疗效。结果:与治疗前相比,两组患者治疗后的血尿酸、s ICAM-1、ET-1水平均显著降低(P0.05);与对照组相比,实验组患者的血尿酸、s ICAM-1、ET-1水平较低(P0.05),临床治疗总有效率较高(P0.05)。结论:非布司他能够降低痛风合并高尿酸血症的s ICAM-1、ET-1及尿酸水平,且临床疗效较好。     

PK/PD and Safety of a Single Dose of TMX‐67 (Febuxostat) in Subjects with Mild and Moderate Renal Impairment

A single oral dose of 20 mg febuxostat was administered to subjects with normal, mild or moderate impairment in renal function. There was less than a 2‐fold difference in AUC of plasma unchanged febuxostat among the renal function groups, and changes in plasma urate levels from pre‐dose levels were not significant. A total of five adverse events were reported with all mild in severity. The results indicate that renal impairment will have little clinical impact on the pharmacokinetics (PK), pharmacodynamics (PD) and safety of the study drug.     

Pharmacokinetics and Pharmacodynamics of Febuxostat (TMX‐67), a Non‐Purine Selective Inhibitor of Xanthine Oxidase/Xanthine Dehydrogenase (NPSIXO) in Patients with Gout and/or Hyperuricemia

The diurnal change of sUA and the effect of febuxostat on this change were investigated in 10 patients with gout and/or hyperuricemia. The diurnal sUA change after the last dose during the 4‐week treatment phase (20 mg, QD) was almost the same as the pre‐treatment value. Considering the dose, the AUC_obs and C _max of unchanged drug in patients with gout and/or hyperuricemia were estimated to be similar to those of healthy male adults. The results show that a 6‐week treatment with febuxostat is safe and well‐tolerated in the target patient population for this drug.     

Febuxostat (TMX‐67), a Novel,Non‐Purine,Selective Inhibitor of Xanthine Oxidase,Is Safe and Decreases Serum Urate in Healthy Volunteers

In order to evaluate the safety, pharmacological properties, and urate‐lowering efficacy of febuxostat, a non‐purine, selective inhibitor of xanthine oxidase, a Phase 1, 2‐week, multiple‐dose, placebo‐controlled, dose‐escalation study was conducted in 154 healthy adults of both sexes. Daily febuxostat doses in the range 10 mg to 120 mg resulted in proportional mean serum urate reductions ranging from 25% to 70% and in proportional increases in maximum febuxostat plasma concentrations and area under plasma concentration versus time curves. Accompanying the hypouricemic effect were increases in serum xanthine concentrations, decreases in urinary uric acid excretion, and increases in urinary xanthine and hypoxanthine excretion, confirming inhibition of xanthine oxidase activity by febuxostat. Hepatic conjugation and oxidative metabolism were the major pathways of elimination of febuxostat from the body, and renal elimination did not appear to play a significant role. Although not uncommon, adverse events were mild and self‐limited, and no deaths or serious adverse events were observed. Febuxostat is a safe and potent hypouricemic agent in healthy humans.     

Fluorimetric determination of febuxostat in dosage forms and in real human plasma via Förster resonance energy transfer

A rapid, simple, selective and precise fluorimetric method was developed and validated for determination of a selective xanthine oxidase inhibitor; febuxostat (FBX) in pharmaceutical formulations and in human plasma. The proposed method is based on quenching effect of FBX on the fluorescence intensity of terbium (Tb³⁺) through fluorescence resonance energy transfer (FRET) from Tb³⁺ to FBX. The formed complex was measured at λ_ex. 320 nm/λ_em. 490 nm against a reagent blank. Fluorescence intensity of Tb³⁺ was diminished when FBX was added. A linear relationship between the fluorescence quenching value of the formed complex and the concentration of FBX was investigated. The reaction conditions and the fluorescence spectral properties of the complex have been studied. The linearity range of the developed method was 1.0–16.0 μg/ml. The suggested method was applied successfully for the estimation of FBX in bulk powder, dosage forms and spiked plasma samples with excellent recoveries (96.79–98.89%). In addition, the developed method has been successfully applied for determination of FBX in real plasma samples collected from healthy volunteers with good recoveries (82.06–85.65%). All obtained results of the developed method were statistically analyzed and validated according to ICH (International Conference on Harmonization) guidelines.     

不同剂量百令胶囊联合非布司他对慢性肾功能不全伴高尿酸血症患者肾功能及血脂水平的影响

目的:探讨不同剂量百令胶囊联合非布司他对慢性肾功能不全(CRF)伴高尿酸血症(HU)肾功能及血脂水平的影响。方法:选取2017年7月至2018年8月三亚市人民医院收治的CRF伴HU患者167例为研究对象,按照数表法随机分为大剂量联合组(n=42)、中剂量联合组(n=42)、小剂量联合组(n=42)和非布司他单用组(n=41),所有研究对象均给予非布司他(40 mg/次,1次/日)治疗,大、中、小剂量联合组再分别给予百令胶囊3g/次、2g/次、1g/次,均3次/日。比较治疗后的临床疗效、治疗前后肾功能指标[血肌酐(Scr)、血尿素氮(BUN)、血尿酸(UA)、血β_2微球蛋白(血β_2-MG)、尿β_2-MG、24 h尿蛋白定量]、血脂指标[甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)]水平以及不良反应。结果:治疗后,大剂量联合组肾功能及高尿酸血症的临床总有效率最优(P0.05),其次为中剂量联合组,小剂量联合组和非布司他单用组比较差异无统计学意义(P0.05);各组患者治疗后BUN、Scr、UA、血β_2-MG、尿β_2-MG、24h尿蛋白定量水平均有不同程度的下降,其中大剂量联合组降低最显著(P0.05),小剂量联合组和非布司他单用组比较差异无统计学意义(P0.05);大、中、小剂量联合组患者治疗后TG、TC、LDL均有下降,HDL上升,其中大剂量联合组TG、TC、LDL降低最显著(P0.05),HDL升高最显著(P0.05);各组患者不良反应发生率比较无统计学差异(P0.05)。结论:大剂量百令胶囊联合非布司他治疗CRF伴HU能改善患者的肾功能和血脂指标,其不良反应发生率较低,但是稍高于其他剂量组,建议临床医师根据患者病情选择合适的剂量。     

非布司他对急性痛风性关节炎患者血清SUA水平及氧化应激的影响

目的:研究非布司他治疗急性痛风性关节炎(AGA)患者的临床疗效及对血清尿酸(SUA)水平及氧化应激的影响。方法:研究对象选取我院2014年6月到2016年10月收治的200例AGA患者,采用随机数字法将其分为对照组和观察组,每组各100例。对照组患者口服别嘌呤醇治疗,观察组患者口服非布司他治疗,均连续治疗24周。比较两组患者治疗前后各时间点的血清SUA、8-羟基脱氧鸟苷(8-OHdG)、3-硝基络氨酸修饰蛋白(3-NT)、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)水平的变化。结果:治疗后,观察组各时间点的血清SUA、8-OHdG和3-NT水平均明显低于对照组(P0.01)。治疗后,对照组患者的血清TG、TC、HDL、LDL水平较治疗前无明显变化(P0.05),观察组患者的血清TG水平明显低于治疗前(P0.01),血清HDL水平明显高于治疗前(P0.01),而血清TC和LDL水平比较无明显差异(P0.05)。结论:非布司他治疗AGA的疗效明显,能有效降低血清SUA水平,抑制氧化应激状态,并能改善血脂代谢。     

非布司他治疗老年高尿酸血症痛风患者的临床疗效及安全性分析

目的:探究非布司他治疗老年高尿酸血症痛风患者的临床疗效及安全性。方法:选取我院2017年3月-2018年3月收治的高尿酸血症并发痛风患者60例,将其分为对照组和观察组,每组各30例。对照组采取苯溴马隆治疗,观察组采取非布司他进行治疗,对比两组患者的疗效和不良反应的发生情况。结果:治疗后,观察组患者治疗的总有效率为96.7%,显著高于对照组患者(80%,P0.05);观察组患者的尿酸水平为(341.58±10.16)μmol/L,血沉水平变为(17.92±8.43) mm/h,均显著低于对照组患者[(341.58±10.16)μmol/L,(26.08±10.17) mm/h,P0.05];观察组患者生活质量(quality of life,QOL)评分明显优于对照组患者(P0.05);观察组患者只发生1例胃肠道反应,不良反应发生率为3.33%(1/30),显著低于对照组[23.33%(7/30),P0.05]。结论:与苯溴马隆相比,非布司他治疗老年高尿酸血症并痛风疗效更好,安全性更高。     

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.