Excellent uricosuric efficacy of benzbromarone in cyclosporin-A-treated renal transplant patients: a prospective study

Patients on cyclosporin A (CsA) often develop hyperuricaemiaand gout. In transplant patients the use of uricosuric drugsfor treating hyperuricaemia may be preferable to allopurinolbecause of the known interaction of the latter with azathioprine.We therefore prospectively studied the uricosuric efficacy of100 mg benzbromarone (Bbr;Desuric®) daily in 25 CsA-treatedrenal transplant patients with stable graft function and hyperuricaemia(>359 µmol/l for females, >491 µmol/l formales). Benzbromarone decreased plasma uric acid from 579±18µmol/l to 313±24 µmol/l (mean±SEM;P<0.001) and thereby normalized plasma uric acid in 21 of25 patients. The remaining four patients had creatininc clearancesbetween 21 and 25 ml/min, the lowest of the entire study group.Mean fractional clearance of uric acid increased from 5.4±0.4%to 17.2±1.0% (P<0.001). The relative decrease of plasmauric acid closely correlated with baseline creatinine clearance(r=0.67; P<0.001). CsA trough values were not influenced.None of the patients experienced any significant side-effects.As an unexpected find-ing, urinary uric acid excretion increasedfrom 2082 ± 175 µmol7sol;24 h to 3233 ±232µmol/24 h after 4 weeks' treatment with benzbromarone. In conclusion, benzbromarone normalized plasma uric acid inall CsA-treated renal transplant recipients with a creatinineclearance >25 ml/min. Due to its excellent efficacy and lackof significant side-effects, benzbromarone appears to be preferableto allopurinol in CsA-treated renal transplant recipients witha creati nine clearance over 25 ml/min.     

老年高尿酸血症患者立加利仙应用的探讨

目的评价小剂量立加利仙治疗老年高尿酸血症患者的有效性和安全性。方法选择30例老年肾脏尿酸排泄减少的原发高尿酸患者作为研究对象,10例血尿酸正常的老年人作为基线对照。每日给予25 mg立加利仙,疗程一周。计算肌酐清除率(Ccr)、24 h尿尿酸(24h Uur)、尿酸清除率(Cur)、尿酸清除分数(FRUAC)、单位肾小球滤过率尿酸排出(EurGFCur)、尿尿酸与尿肌酐比值(Uur/Ucr)。结果治疗一周后,高尿酸患者平均Sur从8.48±1.52 mg/dl降低至4.98±1.53 mg/dl,24h Uur、Cur、FRUAC、EurGFCur、Uur/Ucr均显著增加(P<0.01),同时Ccr无明显变化,肾脏尿酸负荷(Flur)明显减少(P<0.001)。不同Ccr水平患者24h Uur增加百分数和Sur降低百分数无显著差异(P>0.05)。无不良反应发生。结论对轻度肾功能减退老年患者,立加利仙可促进尿酸排泄,显著降低血尿酸水平。短时间应用未见不良反应。     

苯溴马隆对高尿酸血症模型大鼠脂质代谢的影响

目的 基于脂质组学方法研究苯溴马隆治疗高尿酸血症（hyperuricemia,HUA）大鼠的作用机制,并揭示尿酸水平增高与脂质代谢异常的内在相关性。方法 利用超高效液相色谱-四极杆飞行时间质谱（UPLC-Q-TOF/MS）技术,结合主成分分析（PCA）和偏最小二乘法判别分析（OPLS-DA）研究正常组、模型组和苯溴马隆组的大鼠血清中内源性脂质代谢物的变化,寻找潜在生物标记物,分析相关代谢通路,绘制代谢网络机制图。结果 脂质组学分析发现,苯溴马隆可使HUA大鼠体内水平异常的20个差异代谢物回调到正常水平;相关代谢通路分析发现,苯溴马隆影响果糖诱导HUA大鼠血清中的脂质水平,主要与甘油磷脂代谢通路相关。结论 苯溴马隆对HUA的治疗可能与改善体内甘油磷脂代谢通路异常密切相关。     

国产苯溴马隆治疗2型糖尿病合并高尿酸血症的疗效与安全性

目的:评价国产苯溴马隆治疗2型糖尿病合并高尿酸血症的疗效与安全性。方法:2型糖尿病合并高尿酸血症96例,在控制血糖、血压后,分成2组;试验组64例,在进行低嘌呤饮食的基础上,给予国产苯溴马隆50 mg·d~(-1),qd;对照组32例,仅给予低嘌呤饮食。疗程4周。测定第2,4周血尿酸含量和24 h尿尿酸排泄量。结果:治疗后第2,4周试验组血尿酸值均明显下降(P＜0．05),24 h尿尿酸排泄量均明显升高(P＜0．05);对照组变化无统计学意义。试验组无明显不良反应发生。结论:国产苯溴马隆对2型糖尿病合并高尿酸血症降尿酸安全有效。     

Novel urate transporter 1 (URAT1) inhibitors: a review of recent patent literature (2016–2019)

ABSTRACT

Introduction: Human urate transporter 1 (URAT1), which is an influx transporter protein, is located at the apical surface of renal tubular cells and presumed to be the major transporter responsible for the reabsorption of urate from blood. About 90% of patients develop hyperuricemia due to insuf?cient urate excretion; thus, it is important to develop URAT1 inhibitors that could enhance renal urate excretion by blocking the reabsorption of urate anion.

Areas covered: In this review, the authors addressed the patent applications (2016–2019) about URAT1 inhibitors and some medicinal chemistry strategies employed in these patents.

Expert opinion: Substituent decorating, bioisosterism, and scaffold hopping are three common medicinal chemistry strategies used in the discovery of URAT1 inhibitors. Meanwhile, the introduction of sulfonyl group into small molecules has become one of the important strategies for structural optimization of URAT1 inhibitors. Furthermore, developing drug candidates targeting both URAT1 and xanthine oxidase (XOD) has attracted lots of interest and attention.     

Identification of CYP isozymes involved in benzbromarone metabolism in human liver microsomes

Benzbromarone (BBR) is metabolized to 1′‐hydroxy BBR and 6‐hydroxy BBR in the liver. 6‐Hydroxy BBR is further metabolized to 5,6‐dihydroxy BBR. The aim of this study was to identify the CYP isozymes involved in the metabolism of BBR to 1′‐hydroxy BBR and 6‐hydroxy BBR and in the metabolism of 6‐hydroxy BBR to 5,6‐dihydroxy BBR in human liver microsomes. Among 11 recombinant P450 isozymes examined, CYP3A4 showed the highest formation rate of 1′‐hydroxy BBR. The formation rate of 1′‐hydroxy BBR significantly correlated with testosterone 6β‐hydroxylation activity in a panel of 12 human liver microsomes. The formation of 1′‐hydroxy BBR was completely inhibited by ketoconazole in pooled human liver microsomes. On the other hand, the highest formation rate of 6‐hydroxy BBR was found in recombinant CYP2C9. The highest correlation was observed between the formation rate of 6‐hydroxy BBR and diclofenac 4′‐hydroxylation activity in 12 human liver microsomes. The formation of 6‐hydroxy BBR was inhibited by tienilic acid in pooled human liver microsomes. The formation of 5,6‐dihydroxy BBR from 6‐hydroxy BBR was catalysed by recombinant CYP2C9 and CYP1A2. The formation rate of 5,6‐dihydroxy BBR was significantly correlated with diclofenac 4′‐hydroxylation activity and phenacetin O‐deethylation activity in 12 human liver microsomes. The formation of 5,6‐dihydroxy BBR was inhibited with either tienilic acid or α‐naphthoflavone in human liver microsomes. These results suggest that (i) the formation of 1′‐hydroxy BBR and 6‐hydroxy BBR is mainly catalysed by CYP3A4 and CYP2C9, respectively, and (ii) the formation of 5,6‐dihydroxy BBR is catalysed by CYP2C9 and CYP1A2 in human liver microsomes. Copyright © 2012 John Wiley & Sons, Ltd.     

非诺贝特和苯溴马隆治疗高尿酸血症的效果

目的 比较非诺贝特和苯溴马隆联合治疗高尿酸血症的效果及其安全性.方法 将45例B超检查泌尿系统无尿酸结石、伴或不伴有高三酰甘油血症的高尿酸血症病人,按不平衡指数最小的原则随机分为甲、乙、丙3组（各15例）,甲组给予非诺贝特200 mg,乙组给予苯溴马隆50 mg,丙组为两种药物联合,均每日1次,治疗10 d.各组均同时加用碳酸氢钠1.0 g,每日3次碱化体液,均要求低脂低嘌呤饮食.治疗前后检测血尿酸（UA）、三酰甘油、24 h尿UA及肝肾功能,治疗结束后行泌尿系统B超检查.结果 3组治疗后血UA水平均较治疗前下降,差异有显著性（t=1.86～2.75,P＜0.05）;治疗后乙组血UA水平低于甲组,丙组低于甲、乙两组,差异均有显著性（F=3.42,q=5.85～6.98,P＜0.01）.3组治疗后24 h尿尿酸定量高于治疗前,差异有显著性（t=1.96～2.89,P＜0.05）;治疗后3组间24 h尿尿酸定量比较,差异有显著性（F=3.14,q=5.97～7.16,P＜0.05）.3组均未出现肝肾功能异常,未出现关节炎及尿酸结石.结论 非诺贝特降尿酸效果略低于苯溴马隆,二者联用降尿酸效果明显高于各药单用.     

苯溴马隆的合成

以水杨醛为原料,经缩合、还原、酰化、脱甲基、溴化反应制得苯溴巴隆,总收率４０．６％。     

Kinetics of allopurinol and oxipurinol after chronic oral administration. Interaction with benzbromarone

Summary Previous studies have described a pharmacokinetic interaction between probenecid, a uricosuric drug, and oxipurinol, the major metabolite of allopurinol. In single dose studies, no interaction was found to occur between benzbromarone, another uricosuric agent, and oxipurinol.A cross over study was conducted in 12 volunteers to compare the kinetics of allopurinol and oxipurinol following treatment for 7 days with allopurinol alone or combined with benzbromarone 20 or 100 mg.The pharmacokinetic parameters of allopurinol were not modified by the uricosuric therapy, but those of oxipurinol were markedly altered by concurrent administration even of the lower dose of benzbromarone; the average plasma level fell by 30% and the renal elimination rate was increased by 50%.A parallel increase in the renal elimination rate of uric acid was observed (significant only with the higher dose of benzbromarone) and a positive linear correlation between the fractional excretion of uric acid and that of oxipurinol was established.