高尿酸血症药物治疗研究进展

doi:10.12092/j.issn.1009-2501.2019.05.017

摘要/Abstract

摘要：

高尿酸血症（hyperuricemia,HUA）是由于体内尿酸生成过多或尿酸排泄减少所致的代谢性疾病。慢性HUA和痛风与高血压、心血管疾病和慢性肾脏疾病（chronic kidney disease,CKD）等合并症密切相关。及时有效地进行降尿酸治疗（urate lowering therapy,ULT）是减少尿酸盐沉积、预防痛风发作、减轻对肾脏损害、减少其他伴随疾病发生的关键。根据药物作用靶点的不同将降尿酸药物主要分为抑制尿酸生成的药物、促进尿酸排泄的药物、促进尿酸溶解的药物以及最新发现的可同时抑制尿酸生成和促进排泄的药物四大类。近年来，新药的开发，药物的引进以及药物的联合应用已成为热点。本文就近年来降尿酸药物的研究进展进行综述。

关键词: 高尿酸血症, 药物治疗, 研究进展

Abstract:

Hyperuricemia (HUA) is a metabolic disease resulting from either the overproduction of uric acid or reduced uric acid excretion. Chronic hyperuricemia and gout are associated with comorbidities such as hypertension, cardiovascular disease and chronic kidney disease (CKD). Timely and effective urate lowering therapy (ULT) is the key to reducing urate deposition, preventing gout attacks, reducing kidney damage, and reducing the incidence of other accompanying diseases. According to the different targets of drugs, uric acid lowering drugs can be divided into four categories: drugs that inhibit the production of uric acid, drugs that promote the excretion of uric acid, drugs that promote the dissolution of uric acid, and newly discovered drugs that can simultaneously inhibit the production of uric acid and promote the excretion of uric acid. Recently the development of the promising drugs, the introduction of drugs and the combination therapy have become the research focus.This paper reviews the research progress of uric acid-lowering drugs in recent years.

Key words: hyperuricemia, drug therapy, research progress

中图分类号:

R969.3

孙珊珊，曲连悦，杜荣蓉，林建阳. 高尿酸血症药物治疗研究进展[J]. 中国临床药理学与治疗学, 2019, 24(5): 589-594.

SUN Shanshan, QU Lianyue, DU Rongrong, LIN Jianyang. Research progress on drug therapy of hyperuricemia[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(5): 589-594.

参考文献

［1］Bardin T, Richette P. Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options［J］. BMC Medicine, 2017, 15(1):123.
［2］Juraschek SP, Gelber AC. Body mass index, obesity, and prevalent gout in the United States in 1988-1994 and 2007-2010［J］. Arthritis Care Res (Hoboken), 2013, 65(1):127-132.
［3］Chen C, Lü JM, Yao Q. Hyperuricemia-related diseases and xanthine oxidoreductase (XOR) inhibitors: an overview［J］. Med Sci Monit, 2016, 22:2501-2512.
［4］Day RO, Graham GG, Hicks M, et al. Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol［J］. Clin Pharmacokinet, 2007, 46(8):623-644.
［5］Kao MP , Ang DS , Gandy SJ , et al. Allopurinol benefits left ventricular mass and endothelial dysfunction in chronic kidney disease［J］. J Am Soc Nephrol, 2011, 22(7):1382-1389.
［6］Dubreuil M, Zhu Y, Zhang Y, et al. Allopurinol initiation and all-cause mortality in the general population［J］. Ann Rheum Dis, 2015, 74(7):1368-1372.
［7］Grimaldi-Bensouda L, Alpérovitch, A, Aubrun E, et al. Impact of allopurinol on risk of myocardial infarction［J］. Ann Rheum Dis, 2015, 74(5):836-842.
［8］White WB, Chohan S, Dabholkar A, et al. Cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular comorbidities［J］. Am Heart J, 2012, 164(1):14-20.
［9］Schumacher HR, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: A 28-week, phase III, randomized, double-blind, parallel-group trial［J］. Arthritis Rheum, 2008, 59(11):1540-1548.
［10］Xu S, Liu X, Ming J, et al. A phase 3, multicenter, randomized, allopurinol-controlled study assessing the safety and efficacy of oral febuxostat in Chinese gout patients with hyperuricemia ［J］. Int J Rheum Dis, 2015, 18(6):669-678.
［11］Li S, Yang H, Guo Y, et al. Comparative efficacy and safety of urate-lowering therapy for the treatment of hyperuricemia: a systematic review and network meta-analysis［J］. Scientific reports, 2016, 6:33082.
［12］杨丹. 别嘌醇降尿酸治疗效益及药物经济学评价［D］. 北京协和医学院, 2016.
［13］Hosoya T, Ohno I, Nomura S, et al. Effects of topiroxostat on the serum urate levels and urinary albumin excretion in hyperuricemic stage 3 chronic kidney disease patients with or without gout［J］. Clin Exp Nephrol, 2014, 18(6):876-884.
［14］Hosoya T, Ogawa Y, Hashimoto H, et al. Comparison of topiroxostat and allopurinol in Japanese hyperuricemic patients with or without gout: a phase 3, multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group study［J］. J Clin Pharm Ther, 2016, 41(3):290-297.
［15］Hosoya T, Ishikawa T, Ogawa Y, et al. Multicenter, open-label study of long-term topiroxostat (FYX-051) administration in japanese hyperuricemic patients with or without gout［J］. Clin Drug Investig, 2018, 38(12):1135-1143.
［16］Wada T, Hosoya T, Honda D, et al. Uric acid-lowering and renoprotective effects of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia: a randomized, double-blind, placebo-controlled, parallel-group study (UPWARD study)［J］. Clin Exp Nephrol, 2018,22(4):860-870.
［17］Bantia S, Harman L, Hollister A, et al. FRI0401 BCX4208, a novel enzyme inhibitor for chronic management of GOUT, shows a low risk of potential drug-drug interactions［J］. Ann Rheum Dis, 2013, 71(Suppl 3):450.
［18］Hollister AS, Dobo S, Maetzel A, et al. FRI0380 long-term safety of BCX4208 added to allopurinol in the chronic management of GOUT: Results of a phase 2 24-week blinded safety extension and vaccine challenge study［J］. Ann Rheum Dis, 2013, 71(Suppl 3):442-443.
［19］Finch A, Kubler P. The management of gout［J］. Australian Prescriber, 2016, 39(4):119-122.
［20］Chou HW, Chiu HT, Tsai CW, et al. Comparative effectiveness of allopurinol, febuxostat and benzbromarone on renal function in chronic kidney disease patients with hyperuricemia: a 13-year inception cohort study［J］. Nephrol Dial Transplant, 2018, 33(9):1620-1627.
［21］曾小峰,陈耀龙. 2016中国痛风诊疗指南［J］. 浙江医学, 2017, 39(21):1823-1832.
［22］Miner JN, Tan PK, Hyndman D, et al. Lesinurad, a novel, oral compound for gout, acts to decrease serum uric acid through inhibition of urate transporters in the kidney［J］. Arthritis Res Ther, 2016,18(1):214.
［23］Gillen M, Valdez S, Zhou D, et al. Effects of renal function on pharmacokinetics and pharmacodynamics of lesinurad in adult volunteers［J］. Drug Des Devel Ther, 2016, 10:3555-3562.
［24］Tausche AK, Alten R, Dalbeth N, et al. Lesinurad monotherapy in gout patients intolerant to a xanthine oxidase inhibitor: a 6 month phase 3 clinical trial and extension study［J］. Rheumatol, 2017, 56(12):2170-2178.
［25］陈光亮, 周媛凤, 张颖. 治疗痛风和高尿酸血症药物研究进展［J］. 中国临床药理学与治疗学, 2017, 22(1):104-109.
［26］Fitz-Patrick D, Roberson K, Niwa K, et al. Safety and efficacy of verinurad, a selective URAT1 inhibitor, for the treatment of patients with gout and/or asymptomatic hyperuricemia in the United States and Japan: Findings from two Phase II trials［J］. Mod Rheumatol, 2018:1-27.
［27］Yu YK, Yu F, Ye C, et al. Combination therapies of diacerein and febuxostat inhibit IL-1β responses and improve clinical symptoms in patients with refractory gout［J］. Am J Ther, 2017,24(3):e290-e297.
［28］韩建勤, 李继东, 罗萍,等. 氯沙坦和缬沙坦治疗高血压合并高尿酸血症的临床效果对比［J］. 重庆医学, 2016, 45(26):3707-3708.
［29］Poiley J, Steinberg AS, Choi YJ, et al. A randomized, double-blind, active- and placebo-controlled efficacy and safety study of arhalofenate for reducing flare in patients with gout ［J］. Arthritis Rheumatol, 2016, 68(8):2027-2034.
［30］Ahn SO, Ohtomo S, Kiyokawa J, et al. Stronger uricosuric effects of the novel selective URAT1 inhibitor UR-1102 lowered plasma urate in tufted capuchin monkeys to a greater extent than benzbromarone［J］. J Pharmacol Exp Ther, 2016, 357(1):157-166.
［31］Taniguchi T, Ashizawa N, Matsumoto K, et al. Uricosuric agents decrease the plasma urate level in rats by concomitant treatment with topiroxostat, a novel xanthine oxidoreductase inhibitor［J］. J Pharm Pharmacol, 2016, 68(1):76-83.
［32］Mandal AK, Mercado A, Foster A, et al. Uricosuric targets of tranilast［J］. Pharmacol Res Perspect, 2017, 5(2):e00291.
［33］McWherter C, Choi Y, Serrano R L, et al. Arhalofenate acid inhibits monosodium urate crystal-induced inflammatory responses through activation of AMP-activated protein kinase (AMPK) signaling［J］. Arthritis Res Ther, 2018, 20(1):204.
［34］Cortes J, Moore JO, Maziarz RT, et al. Control of plasma uric acid in adults at risk for tumor Lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone--results of a multicenter phase III study［J］. J Clin Oncol, 2010, 28(27):4207-4213.
［35］Sundy JS, Baraf HS, Yood RA, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials［J］. JAMA, 2011,306(7):711-720.
［36］Yood RA, Ottery FD, Irish W, et al. Effect of pegloticase on renal function in patients with chronic kidney disease: a post hoc subgroup analysis of 2 randomized, placebo-controlled, phase 3 clinical trials ［J］. BMC Res Notes, 2014, 7(1):54.
［37］Phase II Exploratory Clinical Study of KUX-1151 U.S. Department of Health and Human Services: Clinicaltrials.gov;2015.
［38］Warrell RP, Klukovits A, Barnes K, et al. Profound hypouricemia induced in human subjects by novel bifunctional inhibitors of xanthine oxidase and URAT1 ［abstract］. Arthritis Rheum,2014,66 (Suppl 10):S1-S1402.
［39］Saag KG, Fitz-Patrick D, Kopicko J, et al. Lesinurad combined with allopurinol: a randomized, double-blind, placebo-controlled study in gout patients with an inadequate response to standard-of-care allopurinol (a US-based study)［J］. Arthritis Rheumatol, 2017, 69(1):203-212.
［40］Bardin T, Keenan RT, Khanna PP, et al. Lesinurad in combination with allopurinol: A randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study)［J］. Ann Rheum Dis, 2017,76(5):811-820.
［41］Dalbeth N, Jones G, Terkeltaub R, et al. Lesinurad, a selective uric acid reabsorption inhibitor, in combination with febuxostat in patients with tophaceous gout: findings of a phase III clinical trial［J］. Arthritis Rheumatol, 2017, 69(9):1903-1913.
［42］Fleischmann R, Winkle P, Miner JN, et al. Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study［J］. RMD Open, 2018, 4(1):e584.
［43］Shiramoto M, Liu S, Shen Z, et al. Verinurad combined with febuxostat in Japanese adults with gout or asymptomatic hyperuricaemia: A phase 2a, open-label study［J］. Rheumatology (United Kingdom), 2018,57(9):1602-1610.
［44］Perez-Ruiz F, Dalbeth N. Combination urate-lowering therapy in the treatment of gout: What is the evidence［J］? Semin Arthritis Rheum, 2019,48(4):658-668.

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