Febuxostat for the treatment of gout

Introduction: Gout is a rheumatologic condition associated with elevated serum uric acid levels and deposition of monosodium urate crystals in joints and soft tissues. The xanthine oxidase inhibitor, allopurinol, has historically been the principle agent utilized for reducing elevated uric acid levels and treating underlying cause of gout symptoms; the availability of febuxostat, a newer non-purine selective xanthine oxidase inhibitor, represents an alternative therapy for those patients with contraindications or intolerance to allopurinol.

Areas covered: This article reviews the published literature on the pharmacologic characteristics and clinical safety and efficacy data on the use of febuxostat in the treatment of gout. A literature search of MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations Databases (1996–November 2014) was conducted utilizing the key words ‘febuxostat’, ‘allopurinol’, and ‘gout’. All published articles regarding febuxostat were evaluated. References of selected articles, data from poster presentations, and abstract publications were additionally reviewed.

Expert opinion: Febuxostat has shown benefit with respect to symptomatic relief and uric acid level reduction. The safety profile of this agent makes it an ideal alternative in those patients with contraindications to or who are intolerant of allopurinol.     

顶空气相色谱法测定非布司他原料药中有机溶剂残留

目的建立了测定非布司他原料药中可能残留的7种有机溶剂(甲醇、乙醇、异丙醇、二氯甲烷、四氢呋喃、正庚烷、氯苯)的检测方法。方法采用顶空气相色谱法,色谱柱为DB-624毛细管柱(30.0 m×0.53 mm×3.00μm),载气为高纯氮气;顶空温度为80℃,顶空时间为30 min;柱温50℃,维持2 min,以10℃/min升至200℃,维持2 min;氢火焰离子化检测器(FID),温度为250℃。结果在考察的浓度范围内线性关系良好(r=0.998 0~0.999 8),7种残留溶剂均完全分离,精密度、重复性试验RSD值均小于5.0%,被测组分的平均回收率符合规定,供试品溶液稳定。结论该气相色谱法操作简便,准确,灵敏度高,可用于检测非布司他原料药中有机溶剂的残留物。     

非布索坦的合成

对羟基苄腈与硫代乙酰胺反应得到4-羟基硫代苯甲酰胺,与2-氯乙酰乙酸乙酯环合后与六亚甲基四胺进行Duff反应得到2-(3-甲酰基-4-羟基苯基)-4-甲基-5-噻唑甲酸乙酯,再相继与盐酸羟胺/甲醇钠反应、异丁基溴成醚后碱性水解,制得抗痛风药非布索坦,总收率为28%.     

HPLC法测定非布司他的含量及有关物质

目的建立测定非布司他原料药含量和有关物质的HPLC方法。方法采用Diamond ODS-C18色谱柱(200 mm×4.6 mm,5μm),流动相为甲醇-乙腈-质量分数为0.05%的磷酸溶液(体积比为24∶46∶30),流速为1.0 mL.min-1,UV检测波长为315 nm,柱温为35℃。结果非布司他在15.7~94.3 mg.L-1内线性关系良好(r=0.999 8),平均回收率为100.5%(RSD=1.0%)。非布司他和其有关物质得到良好分离,检测限为0.5 ng。结论 HPLC法可用于非布司他含量测定和有关物质检测。     

治疗痛风和高尿酸血症药物的研究进展

随着痛风和高尿酸血症发病率的逐年攀升,临床常用治疗药物（别嘌醇、苯溴马隆、非布司他等）市场销售额也逐年递增,但这些药物均存在明显的副作用,国内外药企已将研发重点放在更安全、更高效的新型降尿酸药物尿酸盐重吸收转运子1（URAT1）抑制剂领域,已上市的雷西那德在近几年备受关注,而在研新药SHR4640、SIM1909-13已处于临床试验阶段,同时用中医药治疗高尿酸血症和痛风也是未来的研究方向。对治疗痛风及高尿酸血症的药物研究进展进行综述,以期为临床用药和新药研发提供参考。     

Current and future therapies for gout

Introduction: Gout is a common disease responsible for recurrent flares triggered by the deposition of monosodium urate crystals secondary to longstanding hyperuricaemia. The management of gout implies both the treatment of flares and the treatment of hyperuricaemia itself. Recent improvement in the understanding of the disease led to the development of new drugs.

Areas covered: This review covers data related to ‘old’ treatments of flares and hyperuricaemia, evidence on the recently approved drugs and emerging therapies in development.

Expert opinion: Recent data provide a good grasp of the optimal use of colchicine, corticosteroids and NSAIDs for the treatment of flares. Interleukin-1 blocking therapies have an increasing role in the management of difficult-to-treat gout. Sub-optimal use of allopurinol is common and its potency to reduce serum uric acid (SUA) levels is underestimated. Febuxostat effectively reduces SUA levels. New uricosurics, notably lesinurad and arhalofenate, in combination with xanthine oxidase inhibitors, offer promising perspectives to help a greater number of patients achieve sufficient SUA reduction.     

Development of 2‐(Substituted Benzylamino)‐4‐Methyl‐1, 3‐Thiazole‐5‐Carboxylic Acid Derivatives as Xanthine Oxidase Inhibitors and Free Radical Scavengers

A series of 2‐(substituted benzylamino)‐4‐methylthiazole‐5‐carboxylic acid was designed and synthesized as structural analogue of febuxostat. A methylene amine spacer was incorporated between the phenyl ring and thiazole ring in contrast to febuxostat in which the phenyl ring was directly linked with the thiazole moiety. The purpose of incorporating methylene amine was to provide a heteroatom which is expected to favour hydrogen bonding within the active site residues of the enzyme xanthine oxidase. The structure of all the compounds was established by the combined use of FT‐IR, NMR and MS spectral data. All the compounds were screened in vitro for their ability to inhibit the enzyme xanthine oxidase as per the reported procedure along with DPPH free radical scavenging assay. Compounds 5j, 5k and 5l demonstrated satisfactory potent xanthine oxidase inhibitory activities with IC₅₀ values, 3.6, 8.1 and 9.9 μm , respectively, whereas compounds 5k , 5n and 5p demonstrated moderate antioxidant activities having IC₅₀ 15.3, 17.6 and 19.6 μm , respectively, along with xanthine oxidase inhibitory activity. Compound 5k showed moderate xanthine oxidase inhibitory activity as compared with febuxostat along with antioxidant activity. All the compounds were also studied for their binding affinity in active site of enzyme (PDB ID‐1N5X).