痛风性关节炎动物模型的研究现状与展望

痛风是由于机体嘌呤代谢紊乱,导致血内尿酸增高和/或肾脏排泄尿酸减少,从而引起尿酸盐在组织沉积的疾病,目前尚未见在实验动物中复制出类似人类的痛风性关节炎模型。通过对目前国内外高尿酸血症及痛风模型复制的方法、机制和应用的研究,分析各自的特点及不足之处,并提出复制更加符合临床的高尿酸血症及痛风性关节炎动物模型的展望与设想。     

高尿酸血症和痛风动物模型及其建立方法的研究进展

目前，全球范围内正面临着高尿酸血症和痛风患病率持续上升的趋势，且高尿酸血症与慢性肾病、高血压、肥胖、2型糖尿病和动脉粥样硬化性心脏病等疾病的发生发展密切相关。然而，至今为止，此类疾病及其并发症的发病机制尚未完全阐明，新药的研发也存在一定的局限性和迟滞性。其重要原因在于国内外现有的高尿酸血症和痛风模型制备方法众多，仍未形成统一的标准，且绝大多数模型在血尿酸水平的持续性、稳定性等方面存在一定不足。本文现从高尿酸血症和痛风性关节炎造模动物的选择、模型制备方法和主要内脏的组织病理学变化等方面展开讨论，以期为高尿酸血症和痛风的动物模型制备，以及发病机制研究提供更多参考。     

原发性痛风关节炎的诊断和药物治疗

探讨对原发性痛风关节炎的诊断和治疗。对症状不典型的疑似痛风病人,通过细心询问和观察,并作必要的实验室及X线检查,以尽量减少漏诊,误诊。在治疗时,宜按照痛风性关节炎急性发作期和慢性期的病情特点用药。慢性期痛风病人须作定期检查,高尿酸血症的健康者亦应进行必要的治疗。     

原发性痛风关节炎的诊断和药物治疗

探讨对原发性痛风关节炎的诊断和治疗。对症状不典型的疑似痛风病人,通过细心询问和观察,并作必要的实验室及X线检查,以尽量减少漏诊,误诊。在治疗时,宜按照痛风性关节炎急性发作期和慢性期的病情特点用药。慢性期痛风病人须作定期检查,高尿酸血症的健康亦应进行必要的治疗。     

高尿酸血症与高血压病相关性的研究进展

尿酸是人体内嘌呤代谢的最终产物,当尿酸生成增多和/或排出减少时,均可引起血中尿酸盐浓度增高。当血尿酸水平男性大于7.0 mg/dl,女性大于6.0 mg/dl称为高尿酸血症。作为嘌呤代谢紊乱所致疾病,高尿酸血症以往仅侧重于痛风性关节炎、痛风石沉积和肾尿酸结石形成等的诊断与治疗。目前新近研究表明:高尿酸血症可能是高血压病的独立危险因素之一且尿酸水平增高通常早于高血压的发生与进展,干预尿酸水平有望成为高血压治疗的新靶点,随着高血压研究的全球化深入,对于尿酸及尿酸水平增高的流行病学、基础学与临床方面的研究也日益备受关注。基于此,本文对尿酸的合成与代谢;高尿酸血症成因及其与高血压的流行病学研究;高尿酸血症通过引发一氧化氮合成水平减低、血管平滑肌细胞生物学行为改变、机体炎症与氧化应激反应及肾素-血管紧张素系统激活等方面所致高血压的发病机制;高尿酸血症干预治疗对于高血压病的转归进行简要综述。     

针药联合应用治疗痛风性关节炎30例

痛风性关节炎是长期嘌呤代谢障碍,血尿酸升高导致组织损伤的疾病.早期表现为高尿酸血症,急性关节炎反复发作,痛风石沉积,慢性关节炎和关节畸形,后期可出现肾脏损害.随着人类寿命的延长,饮食结构的改变,其发病率日益增高,发病年龄以中年为多见,40~50岁是发病的高峰,男性发病率约占95%,病情缠绵难愈[1].作者于2009年1月～2010年12月采用综合疗法治疗30例,取得较好疗效,现报告如下.     

禽类动物高尿酸血症的研究进展

高尿酸血症发病率逐年上升,与痛风、心脑血管疾病、代谢综合征等疾病均有相关关系。禽类动物尿酸代谢途径与人类相似,诱发及自发高尿酸血症较为常见,因而在高尿酸血症模型研究方面地位日益突出。本文对近30余年禽类高尿酸血症报道及实验研究进行综述,以期阐明禽类动物高尿酸血症模型发病特点与机制。     

痛风病临床诊治及菲牛蛭生物疗法的研究进展

<正>痛风性关节炎是目前最常见的、疼痛最明显的骨关节疾病之一,其已从古代的"王者之病"演变为近代的"疾病之王者"。根据中华医学会风湿病学分会编写的《原发性痛风诊治指南(草案)》提供的资料表明,痛风分为原发性和继发性两大类。痛风痛是由于嘌呤代谢紊乱及(或)尿酸排泄减少所引起的一种晶体性关节炎,临床表现为高尿酸血症和尿尿酸盐结晶沉积所致的特征性急(慢)性关节炎、痛风石形成、     

高尿酸血症和痛风的遗传学研究进展

痛风是由高尿酸血症引发的一种常见炎性关节炎,受遗传因素和环境因素共同作用。早期研究表明,PRPS1和HPRT1等单基因稀有突变会引起嘌呤合成代谢紊乱,从而引发高尿酸血症和痛风。近年来,全基因组关联分析(Genome-wide association studies,GWAS)已检出多个导致高尿酸血症和痛风的易感位点及相关候选基因。其中SLC2A9、SLC22A11和SLC22A12基因功能缺失性突变可引起遗传性低尿酸血症,而过表达则会加强尿酸的重吸收。ABCG2、SLC17A1和SLC17A3基因功能缺陷型变异会降低肾脏和肠道对尿酸的排泄量。因此,诱发尿酸排泄障碍(高重吸收和低排泄)的基因变异是影响高尿酸血症和痛风的主要遗传因素。另外,抑制-激活生长因子系统、转录因子、细胞骨架以及基因和环境的互作等因素也一定程度影响血液尿酸水平。在中国汉族人群中,两个新发现的易感基因RFX3和KCNQ1可能造成免疫应答受损和胰岛B细胞功能缺陷,从而直接或间接引起高尿酸酸血症和痛风。本文系统综述了高尿酸血症和痛风的遗传学研究,以促进人们对高尿酸血症和痛风发病机理的理解。     

抗痛风中药药效的研究进展

正痛风是一种慢性疾病,是由于人体内嘌呤代谢紊乱,导致血尿酸浓度超过正常上限,尿酸排泄减少,导致尿血结晶过多沉淀而引起[1]。其主要由高尿酸血症和尿酸盐沉积引起反复发作的急、慢性关节炎以及软组织损伤,痛风性肾病,关节畸形等[2]。在临床治疗上,西医常用的药物有秋水仙碱、非甾体类抗炎药、糖皮质激素和促肾上腺皮质激素和IL-1抑制剂等,由于这些药物的不良反应多,临床使用受到限     

高尿酸血症和痛风的流行病学及其危险因素的研究进展

高尿酸血症和痛风是由于长期嘌呤代谢紊乱所引起的一种代谢性疾病,随着各国经济的发展,其患病率在全球范围呈逐年升高的趋势,因此相关研究也日益增多.本文就近年来有关高尿酸血症与痛风的流行病学及其危险因素的研究作一综述,并着重阐述高尿酸血症与糖尿病关系的相关研究进展.     

Gout. Novel therapies for treatment of gout and hyperuricemia

In the past few decades, gout has increased not only in prevalence, but also in clinical complexity, the latter accentuated in part by a dearth of novel advances in treatments for hyperuricemia and gouty arthritis. Fortunately, recent research reviewed here, much of it founded on elegant translational studies of the past decade, highlights how gout can be better managed with cost-effective, well-established therapies. In addition, the advent of both new urate-lowering and anti-inflammatory drugs, also reviewed here, promises for improved management of refractory gout, including in subjects with co-morbidities such as chronic kidney disease. Effectively delivering improved management of hyperuricemia and gout will require a frame shift in practice patterns, including increased recognition of the implications of refractory disease and frequent noncompliance of patients with gout, and understanding the evidence basis for therapeutic targets in serum urate-lowering and gouty inflammation.     

Development of novel NLRP3-XOD dual inhibitors for the treatment of gout

Gout is a crystalline-related arthropathy caused by the deposition of monosodium urate (MSU). Acute gouty arthritis is the most common first symptom of gout. Studies have shown that NOD-like receptor protein 3 (NLRP3) inflammasome as pattern recognition receptors can be activated by uric acid crystallization, triggering immune inflammation and causing acute gouty arthritis symptoms. Currently, the treatment of gout mainly includes two basic methods: reducing uric acid and alleviating inflammation. In this paper, 22 novel benzoxazole and benzimidazole derivatives were synthesized from deoxybenzoin oxime derivatives. These compounds have good inhibitory effects on NLRP3 and XOD screened by our research group in the early stage. The inhibitory activities of XOD and NLRP3 and their derivatives were also screened. Notably, compound 9b is a multi-targeting inhibitor of NLRP3 and XOD with excellent potency in treating hyperuricemia and acute gouty arthritis.     

痛风性膝关节炎的关节镜诊疗价值分析

目的：探讨膝痛风性关节炎的关节镜治疗的临床疗效。方法：选取我院2006年至2009年共35例单膝痛风性关节炎患者,’喀随机分为2组：A组22例,给予药物治疗,同时行关节镜下检查及清理术;B组13例,仅给予药物治疗。观察比较两组患者膝关节Lysholm评分、疼痛VAS评分,关节活动度ROM改善情况。结果：关节镜治疗组22例病例中无关节镜手术并发症发生,关节镜治疗组在Lysholm、VAS评分和关节活动度ROM方面明显优于药物治疗组。结论：膝痛风性关节炎关节镜下有较显著的特点,膝关节镜下清理术治疗膝痛风性关节炎具有良好疗效,为药物治疗膝痛风性关节炎提供了良好的辅助治疗方法。     

Development of benzoxazole deoxybenzoin oxime and acyloxylamine derivatives targeting innate immune sensors and xanthine oxidase for treatment of gout

Both the inhibition of inflammatory flares and the treatment of hyperuricemia itself are included in the management of gout. Extending our efforts to development of gout therapy, two series of benzoxazole deoxybenzoin oxime derivatives as inhibitors of innate immune sensors and xanthine oxidase (XOD) were discovered in improving hyperuricemia and acute gouty arthritis. In vitro studies revealed that most compounds not only suppressed XOD activity, but blocked activations of NOD-like receptor (NLRP3) inflammasome and Toll-like receptor 4 (TLR4) signaling pathway. More importantly, (E)-1-(6-methoxybenzo[d]oxazol-2-yl)-2-(4-methoxyphenyl)ethanone oxime (5d) exhibited anti-hyperuricemic and anti-acute gouty arthritis activities through regulating XOD, NLRP3 and TLR4. Compound 5d may serve as a tool compound for further design of anti-gout drugs targeting both innate immune sensors and XOD.     

Current Concepts of Hyperuricemia and Gout

Recent studies have confirmed that gout is an inborn error of metabolism. It has now become evident that the hyperuricemia associated with gout might occur either due to overproduction of uric acid, underexcretion of uric acid or a combination of these processes. Furthermore, patients with excessive purine synthesis may have a specific enzyme defect resulting in altered feedback inhibition of purine synthesis. A neurological disease manifest by mental retardation, choreo-athetosis, aggressive behavior, lip-biting and self-mutilation and associated with decidedly increased purine biosynthesis serves as a prototype of this kind of disorder. Other defects in regulation of purine biosynthesis have been postulated but their existence not yet confirmed.It has been demonstrated that urate crystals which are deposited from hyperuricemic body fluids set up an acute inflammatory reaction by means of a variety of chemical mediators. Thus, acute gouty arthritis is now recognized as an example of “crystal induced” synovitis.The treatment of gout consists of (1) the control of acute gouty attacks, and (2) the maintenance of normal serum uric acid concentrations. This latter may be achieved either with uricosuric drugs or with xanthine oxidase inhibition. With these principles in mind, it is now possible to avoid many of the severe crippling effects of gout and to restore the vast majority of gouty patients to useful and productive lives.     

痛风性关节炎的中医治疗进展

痛风是嘌呤代谢紊乱造成尿酸盐结晶沉淀在皮下组织、关节周围、骨骼及尿路而引发的病变。发作时以足拇趾及踝关节红、肿、热、痛多见,呈间歇性反复发作。由于社会发展和人们生活方式的改变,痛风性关节炎患病率有明显上升和年轻化趋势,南方和沿海经济发达地区发病率尤高。痛风性关节炎作为一个常见病多发病,严重影响着患病者的生活质量,目前西医对痛风性关节炎的治疗并不能改变其病理性质,且毒副作用较大、效果不持续,临床多以排尿酸药、糖皮质激素及秋水仙碱等一些口服药物为主。近年来随着中医药对该病的研究,中医药治疗痛风性关节炎有了较大的进展,临床上取得令人乐观的成果。本文着重从中药内治及中医外治两个方面,综述了近年来痛风性关节炎中医药治疗的研究进展。     

Epidemiology,risk factors,and lifestyle modifications for gout

Gout affects more than 1% of adults in the USA, and it is the most common form of inflammatory arthritis among men. Accumulating data support an increase in the prevalence of gout that is potentially attributable to recent shifts in diet and lifestyle, improved medical care, and increased longevity. There are both nonmodifiable and modifiable risk factors for hyperuricemia and gout. Nonmodifiable risk factors include age and sex. Gout prevalence increases in direct association with age; the increased longevity of populations in industrialized nations may contribute to a higher prevalence of gout through the disorder's association with aging-related diseases such as metabolic syndrome and hypertension, and treatments for these diseases such as thiazide diuretics for hypertension. Although gout is considered to be primarily a male disease, there is a more equal sex distribution among elderly patients. Modifiable risk factors for gout include obesity, the use of certain medications, high purine intake, and consumption of purine-rich alcoholic beverages. The increasing prevalence of gout worldwide indicates that there is an urgent need for improved efforts to identify patients with hyperuricemia early in the disease process, before the clinical manifestations of gout become apparent.     

Ultrasonography in the diagnosis of asymptomatic hyperuricemia and gout

ABSTRACT

Sonography has detected urate deposits in 34%–42% of the patients with asymptomatic hyperuricemia. This may prompt reclassification of asymptomatic hyperuricemia into “asymptomatic gout” and consideration of urate lowering therapy (ULT) to resolve urate deposits. In patients with gout and no visible tophi, sonography has detected urate deposits in half of the patients. This may allow diagnosing “tophaceous gout” and influencing the serum urate target level, prophylaxis to avoid acute gout flares during ULT, and clinical follow-up. Current accessibility to sonography may better classify patients with hyperuricemia and gout and contribute to delineate therapeutic objectives and clinical guidance.     

Antihyperuricemia and antigouty arthritis effects of Persicaria capitata herba in mice

Background: Hyperuricemia (HUA) is an important risk factor for gout, renal dysfunction and cardiovascular diseases. The whole plant of Persicaria capitata (Buch.-Ham. ex D. Don) H. Gross, namely Persicaria capitata herba, is a well-known ethnic herb with potent therapeutic effects on urinary tract infections and urinary calculus, yet previous reports have only focused on its effect on urinary tract infections.Purpose: To evaluate the therapeutic potential of P. capitata herba against gout by investigating its antihyperuricemia and antigouty arthritis effects and possible mechanisms.Methods: The ethanol extract (EP) and water extract (WP) of P. capitata herba were prepared by extracting dried and ground whole plants of P. capitata with 75% ethanol and water, respectively, followed by removal of solvents and characterization by UHPLC-Q-TOF/MS. The antihyperuricemia and antigouty arthritis effects of the two extracts were evaluated in a potassium oxonate- and hypoxanthine-induced hyperuricemia mouse model and a monosodium urate crystal (MSUC)-induced acute gouty arthritis mouse model, respectively. The mechanisms were investigated by testing their effects on the expression of correlated proteins (by Western blot) and mRNAs (by RT–PCR).Results: UHPLC-HRMS fingerprinting and two chemical markers (i.e., quercetin and quercitrin) determination were used for the characterization of the WP and EP extracts. Both WP and EP extracts showed pronounced antihyperuricemia activities, with a remarkable decline in serum uric acid and a marked increase in urine uric acid in hyperuricemic mice. Unlike the clinical xanthine oxidase (XOD) inhibitor allopurinol, WP and EP did not show any distinct renal toxicities. The underlying antihyperuricemia mechanism involves the inhibition of the activity and expression of XOD and the downregulation of the mRNA and protein expression of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1). The extracts of P. capitata herba also demonstrated remarkable anti-inflammatory activity in MSUC-induced acute gouty arthritis mice. The mechanism might involve inhibitory effects on the expression of proinflammatory factors.Conclusions: The extracts of P. capitata herba possessed pronounced antihyperuricemia and antigouty arthritis effects and were, therefore, promising natural medicines for hyperuricemia-related disorders and gouty arthritis. The use of P. capitata herba for the treatment of urinary calculus may be, at least to some degree, related to its potential as an antihyperuricemia and antigouty arthritis drug.