黄嘌呤氧化酶抑制剂的研究进展

黄嘌呤氧化还原酶（Xanthine oxidoreductase,XOD)是一种高度通用的黄素酶,在不同物种之间以及生物各种组织中普遍存在。痛风是由于体内尿酸代谢障碍,导致尿酸水平过高,影响机体的正常运行。抑制黄嘌呤氧化还原酶可以降低尿酸水平,发挥抗高尿酸的作用。现如今临床上用于治疗痛风、高尿酸血症最有效的药物还是黄嘌呤氧化还原酶抑制剂。本文归纳了黄嘌呤氧化还原酶抑制剂的药理作用和临床应用,并对近年来已经上市和处于开发阶段的黄嘌呤氧化还原酶抑制剂进行总结,综述了黄嘌呤氧化还原酶抑制剂的最新进展。     

黄嘌呤氧化酶抑制剂的研究进展

痛风症是一种因嘌呤代谢紊乱导致尿酸生成异常的常见病。以黄嘌呤氧化酶为靶点的药物是一类重要的抗痛风药物。有效抑制黄嘌呤氧化酶的活性可减少黄嘌呤向尿酸的转化,从而降低体内尿酸的水平,达到治疗痛风的目的。本文就近几年黄嘌呤氧化酶抑制剂的研究进展进行综述。     

治疗痛风新药——尿酸盐阴离子转运蛋白-1抑制剂来西雷特

来西雷特为一口服尿酸盐阴离子转运蛋白-1抑制剂,尿酸盐阴离子转运蛋白-1与尿酸在肾脏中的吸收密切相关,来西雷特通过抑制其作用,发挥降低血清尿酸的作用。来西雷特于2015年12月在美国获批,与黄嘌呤氧化酶抑制剂联合应用治疗单独应用黄嘌呤氧化酶抑制剂而没有使血清尿酸水平达标的痛风。来西雷特最常见的不良反应包括头痛、流感及胃食管返流等。     

痛风治疗药物及其研究进展

近年来,痛风的发病率呈上升的趋势,发病年龄也呈现低龄化的趋势,所以有关痛风的形成机制以及治疗药物的研发已成为人们关注的焦点。尿酸水平升高是痛风形成的生化基础,尿酸可介导血管炎症反应和氧化损伤、促进血管内皮细胞的增殖等,尿酸水平也是用来预测肾损伤的主要指标。本文对近些年来临床应用的治疗痛风的大部分药物,尤其是非嘌呤类黄嘌呤氧化酶抑制剂药物的研究进行综述。     

抗痛风药别嘌醇的用药注意

别嘌醇(Allopurinol)为1963年问世的抗痛风药(黄嘌呤氧化酶抑制剂),它的作用方式是抑制组织中黄嘌呤氧化酶,降低嘌呤体转化为尿酸,从而降低全身组织中尿     

以黄嘌呤氧化酶为靶点的新型非嘌呤类抗痛风及高尿酸血症药物研究进展

黄嘌呤氧化酶（XO）催化黄嘌呤生成尿酸及次黄嘌呤生成黄嘌呤的过程,是抗高尿酸血症或痛风药物研究的关键靶点。黄嘌呤氧化酶抑制剂由于作用机制明确、疗效显著而倍受关注,研发新型XO抑制剂具有广阔的应用前景。XO的结构生物学及分子模拟技术为新一代非嘌呤类XO抑制剂的合理药物设计奠定了基础。本文综述了以黄嘌呤氧化酶为靶标的新型非嘌呤类小分子杂环化合物及天然产物来源的活性分子在抗高尿酸血症或痛风药物研究领域中的进展。     

别嘌醇的合成工艺简介

别嘌醇(Allopurinolum)化学名4-羟基吡唑(3,4,d)嘧啶,为黄嘌呤氧化酶抑制剂,能阻止黄嘌呤氧化酶的作用而抑制黄嘌呤、次黄嘌呤氧化成尿酸。临床用于治疗原发性或继发性血清尿酸增多的各种疾病,如痛风、急性或慢性白血病、真性红细胞增多症、多发性骨髓瘤以及其他恶性肿瘤在化疗或放射治疗时的细胞大量坏死所导致的高尿酸血症,并可预防与治疗尿酸盐性肾病,疗效显著,副作用很小。本品已于1976年3月通过技术鉴定,上海第九制药厂将组织生产。     

痛风治疗药Lesinurad

痛风系因血液中尿酸水平异常升高所致的一种进行性疾病,可引起关节结缔组织内部、周围及肾脏内部出现针状尿酸晶体并沉积,导致炎症、关节损伤、间歇性疼痛及肾脏损害等。临床上常用的可降低血浆尿酸水平的药物包括黄嘌呤氧化酶抑制剂别嘌呤醇和非布索坦以及尿酸排泄促进剂丙磺舒、     

抗高尿酸血症药物研究进展

痛风是一种代谢性疾病,危害严重,近年来患病率呈上升趋势。尿酸排泄减少或生成增多所致的高尿酸血症是痛风的主要病因,而高尿酸又与多种疾病密切相关。降低血尿酸水平是治疗痛风,预防痛风复发的重要措施。目前,抗高尿酸血症药物主要有3类,分别是黄嘌呤氧化酶抑制剂、尿酸盐阴离子转运蛋白1(URAT1)抑制剂和尿酸氧化酶类似物。对现有抗高尿酸血症药物的现状以及研究进展进行总结,希望对其研发提供参考。     

别嘌醇与其它药物的相互作用

别嘌醇(Allopurinol)为黄嘌呤氧化酶抑制剂,能抑制尿酸的生成,降低血及尿中的尿酸浓度,是防止痛风急性发作疗效较为确切的药物。本文就其在临床应用中与一些药物的相互作用做一简单介绍,以供参考。1 与抗肿瘤药合用1.1 巯嘌呤或硫唑嘌呤:别嘌醇能抑制     

痛风和新型降尿酸药:非布索坦

非布索坦是一种新型非嘌呤类黄嘌呤氧化酶抑制药,对氧化型和还原型的黄嘌呤氧化酶均有抑制作用,其对黄嘌呤氧化酶的抑制具有特异性。与别嘌醇相比,非布索坦可快速降低血尿酸水平,尤其对于存在轻中度肾功能不全的患者无需调整剂量,且无明显不良反应。临床上,对于存在轻中度肾功能损害、别嘌醇不耐受、治疗不能使血尿酸降至目标值的患者应考虑选用非布索坦。在应用非布索坦的前6个月应合用秋水仙碱或非甾体消炎药以避免痛风的急性发作。     

Gout: an overview of available urate lowering therapies

The aim of urate-lowering therapy is to maintain urate concentration below the saturation point for monosodium urate. This therapy dissolves crystal deposits and cures gout while it is maintained. EULAR guidelines recommend that plasma urate should be maintained at a concentration less than 360μM, and the British Guidelines less than 300μM. Urate-lowering therapy is indicated for patients with recurrent gout attacks, chronic arthropathy, tophi, and gout with uric acid stones. Allopurinol lowers uricemia through inhibition of xanthine oxidase activity. The maximum allowed dose is reduced in case of renal failure, which is relatively frequent in gouty patients. Febuxostat has been approved for the treatment of chronic hyperuricemia in conditions where urate deposition has already occurred. Febuxostat is a novel non-purine, selective inhibitor of xanthine oxidase, metabolized and excreted by the liver, so no dose adjustment appears to be necessary in patients with mild-to-moderate renal impairment. Another powerful hypo-uricemic drug is the PEG-uricase (pegloticase). Pegloticase is a uric acid-specific PEGylated recombinant mammalian uricase recently approved by the FDA for treatment of patients with refractory chronic gout.     

Febuxostat: A Novel Agent for Management of Hyperuricemia in Gout

Gout is a metabolic disorder characterized by elevated uric acid levels in the body, associated with painful arthritis, tophi and nephropathy. The most frequently used pharmacologic urate lowering strategies involve reducing urate production with a xanthine oxidase inhibitor and enhancing urinary excretion of uric acid with a uricosuric agent. Urate lowering agents are limited in number, availability and effectiveness. The emergence of a new medication, febuxostat, to lower serum urate levels is welcome as no new drug have been approved since the introduction of allopurinol, in 1964, and the drugs that are available have limitations owing to inefficacy or toxicity. Febuxostat is a novel, nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia and gout.     

Lesinurad:一种选择性尿酸再吸收抑制剂

尿酸盐重吸收转运因子(URAT1)是一种阴离子转运体,它位于肾小管近端小管顶部细胞中,决定尿酸的重吸收,常作为治疗高尿酸血症及痛风药物的靶点。Lesinurad是一种URAT1选择性抑制剂,由阿斯利康制药公司研发,并于2015年底被FDA批准与黄嘌呤氧化酶抑制剂联合用于高尿酸血症及痛风症状的缓解治疗。主要介绍Lesinuard的药物概况、相关研发背景、合成路线、药理作用、药动学、临床试验等方面研究情况,为该药的推广应用以及同类新药研发提供依据。     

Management of acute and chronic gouty arthritis: present state-of-the-art

There are three stages in the management of gout: (i) treating the acute attack; (ii) lowering excess stores of uric acid to prevent flares of gouty arthritis and to prevent tissue deposition of urate; and (iii) providing prophylaxis to prevent acute flares. It is important to distinguish between therapy to reduce acute inflammation in acute gout and therapy to manage hyperuricaemia in patients with chronic gouty arthritis.During the acute gouty attack nonpharmacological treatments such as topical ice and rest of the inflamed joint are useful. NSAIDs are the preferred treatment in acute gout. The most important determinant of therapeutic success is not which NSAID is chosen, but rather how soon NSAID therapy is initiated. Other treatments include oral and intravenous colchicine, intra-articular and systemic corticosteroids, and intramuscular corticotropin.Optimal treatment of chronic gout requires long-standing reduction in serum uric acid. The urate-lowering drugs used to treat chronic gout are the uricosuric drugs, the uricostatic drugs, which are xanthine oxidase inhibitors, and the uricolytic drugs. Xanthine oxidase inhibitors such as allopurinol, oxipurinol and febuxastat should be used as first-line treatment in patients with renal calculi, renal insufficiency, concomitant diuretic therapy and ciclosporin (cyclosporine) therapy, and urate overproduction. Uricosuric drugs include probenecid, benzbromarone, micronised fenofibrate and losartan. They are the urate-lowering drugs of choice in allopurinol-allergic patients and underexcretors with normal renal function and no history of urolithiasis. The use of recombinant urate oxidase in patients with chronic gout is limited by the need for parenteral administration, the potential antigenicity and production of anti-urate oxidase antibodies, and declining efficacy.The effectiveness of colchicine prophylaxis as an isolated therapy is still to be confirmed by placebo-controlled trials. Another issue is prophylaxis with NSAIDs. There are no comparative studies with colchicine.     

Lesinurad for the treatment of hyperuricaemia in people with gout

Introduction: Gout is a common form of inflammatory arthritis caused by deposition of monosodium urate crystals. The central strategy for effective long-term management of gout is serum urate lowering. Current urate-lowering drugs include both xanthine oxidase inhibitors and uricosuric agents. Lesinurad is a URAT1 inhibitor that selectively inhibits urate rebsorption at the proximal renal tubule. Lesinurad 200mg daily in combination with a xanthine oxidase is approved for urate-lowering therapy in patients with gout.

Areas covered: The published literature was searched using Pubmed and additional information was obtained from publically available regulatory documents. Pre-clinical data and clinical trials of lesinurad are described. Serum urate-lowering efficacy and effects on other clinical endpoints are discussed. Adverse event data, focusing on renal safety are also presented.

Expert opinion: Lesinurad is an effective urate-lowering drug that has a generally acceptable safety profile when used at 200mg daily dosing in combination with a xanthine oxidase inhibitor. The recent approval of fixed dose combination pills of lesinurad with allopurinol is an important step in improving adherence and reducing risk of renal adverse events. It remains to be seen if this therapy will provide additional benefit for gout management above improved use of widely available generic therapies.     

Updates on the treatment of gout,including a review of updated treatment guidelines and use of small molecule therapies for difficult-to-treat gout and gout flares

Introduction: Gout is a rheumatologic condition associated with elevated serum uric acid levels and deposition of monosodium urate crystals in joints and soft tissues.

Areas covered: In this article, we describe the role of currently available drug therapies for managing acute gout flares and used in reducing serum urate levels. Further, we explore the role of novel small molecular therapies and biologic agents in the treatment of refractory or severe gout symptoms. A literature search of MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations Databases (1996-June 2017) was conducted utilizing the key words ‘gout’, ‘interleukin-1 inhibitors’, ‘acute gout’, ‘gout treatment’, ‘urate lowering therapies’, ‘hyperuricemia’, ‘colchicine’, ‘pegloticase’, ‘lesinurad’, ‘xanthine oxidase’, ‘xanthine oxidase inhibitors’, ‘allopurinol’, ‘febuxostat’, ‘uricosurics’, ‘probenecid’, and ‘benzbromarone’. All published articles regarding therapeutic management of gout and hyperuricemia were evaluated. References of selected articles, data from poster presentations, and abstract publications were additionally reviewed.

Expert opinion: Numerous therapies are currently available to managing acute gout flares and for lowering serum urate levels; advances in the understanding of the pathophysiology of this disorder has led to the emergence of targeted therapies and novel biologic preparations currently in development which may improve the clinical management of severe or refractory cases of disease that fail to respond to traditional therapies.     

2-苯基-5-吡啶基-1,3,4-噁二唑类化合物的合成及黄嘌呤氧化酶抑制活性

目的 设计合成2-苯基-5-吡啶基-1,3,4-噁二唑类化合物,并对其黄嘌呤氧化酶抑制活性进行初步评价。方法 以对羟基苯甲酸甲酯为原料,经烃化、肼解、环合等反应合成目标化合物。以非布司他为阳性对照药,采用牛源的黄嘌呤氧化酶对目标化合物的抑制活性进行评价。结果 共合成了15 个未见文献报道的目标化合物,结构经核磁共振氢谱、飞行时间质谱和红外光谱确证。目标化合物均表现出一定的黄嘌呤氧化酶抑制活性,其中化合物 4m（IC₅₀=1.04 µmol·L^-1）活性最好,但低于阳性对照药非布司他（IC₅₀=0.024 µmol·L^-1）。结论 2-苯基-5-吡啶基-1,3,4-噁二唑类化合物作为新型黄嘌呤氧化酶抑制剂,其构效关系值得进一步研究。