Table Info

Table 4.

Ratio of C_max/AUC_ss or C_max/C_min in steady-state pharmacokinetic profile for selected URAT1 inhibitors

Drug metabolite	URAT1 IC₅₀ (nM)	C_max/AUC_ss	C_max/C_min	Renal safety profile
Lesinurad [123]*	7,300	0.19	88	Serious renal issues, needed to combine with XOIs
Verinurad [124]*	< 50	0.52	33	Second generation of lesinurad by AstraZeneca; failed development; needed to combine with XOIs
Dotinurad [125]*	< 50	0.09	4.7	Approved by the Japanese Pharmaceuticals and Medical Devices Agency; no known renal-related safety events
Benzbromarone [126]*	196	0.14	18	Used in Asia; no known renal-related safety events
6-OH benzbromarone [126]*	NA	0.07	2.83	NA
Pozdeutinurad (AR882) [81, 127]*	67	0.08	2.7	In development; no renal safety signals identified in phase 2 trials

* Data have been derived from the cited publications. AUC_ss: area under the curve steady state; C_max: maximum concentration; C_min: minimum concentration; IC₅₀: half-maximal inhibitory concentration; NA: not available; URAT1: urate transporter-1; XOI: xanthine oxidase inhibitor

Declarations

Acknowledgments

The authors thank Nicola Beadle and Emily Atkinson of Alchemy Medical Writing Ltd. for providing medical writing assistance under the direction of the authors (sponsored by Arthrosi Therapeutics Inc.).

Author contributions

RTK: Conceptualization, Writing—original draft, Writing—review & editing. ZS, SY, and LTY: Writing—original draft. MHP: Writing—original draft, Writing—review & editing. All authors read and approved the submitted version.

Conflicts of interest

RTK, ZS, SY, and LTY are all employees of Arthrosi Therapeutics Inc. MHP has consulted for Sobi and Amgen. RTK who is the Editorial Board Member of Exploration of Musculoskeletal Diseases had no involvement in the journal review process of this manuscript.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Burke BT, Köttgen A, Law A, Windham BG, Segev D, Baer AN, et al. Physical Function, Hyperuricemia, and Gout in Older Adults. Arthritis Care Res (Hoboken). 2015;67:1730–8. [DOI] [PubMed] [PMC]

Dehlin M, Jacobsson L, Roddy E. Global epidemiology of gout: prevalence, incidence, treatment patterns and risk factors. Nat Rev Rheumatol. 2020;16:380–90. [DOI] [PubMed]

Chen-Xu M, Yokose C, Rai SK, Pillinger MH, Choi HK. Contemporary Prevalence of Gout and Hyperuricemia in the United States and Decadal Trends: The National Health and Nutrition Examination Survey, 2007-2016. Arthritis Rheumatol. 2019;71:991–9. [DOI] [PubMed] [PMC]

Towiwat P, Chhana A, Dalbeth N. The anatomical pathology of gout: a systematic literature review. BMC Musculoskelet Disord. 2019;20:140. [DOI] [PubMed] [PMC]

Salama A, Alweis R. Images in clinical medicine: Tophi. J Community Hosp Intern Med Perspect. 2017;7:136–7. [DOI] [PubMed] [PMC]

Jenkins C, Hwang JH, Kopp JB, Winkler CA, Cho SK. Review of Urate-Lowering Therapeutics: From the Past to the Future. Front Pharmacol. 2022;13:925219. [DOI] [PubMed] [PMC]

Ragab G, Elshahaly M, Bardin T. Gout: An old disease in new perspective - A review. J Adv Res. 2017;8:495–511. [DOI] [PubMed] [PMC]

Mandal AK, Mount DB. The molecular physiology of uric acid homeostasis. Annu Rev Physiol. 2015;77:323–45. [DOI] [PubMed]

Maiuolo J, Oppedisano F, Gratteri S, Muscoli C, Mollace V. Regulation of uric acid metabolism and excretion. Int J Cardiol. 2016;213:8–14. [DOI] [PubMed]

10.

Roch-Ramel F, Guisan B. Renal Transport of Urate in Humans. News Physiol Sci. 1999;14:80–4. [DOI] [PubMed]

11.

FitzGerald JD, Dalbeth N, Mikuls T, Brignardello-Petersen R, Guyatt G, Abeles AM, et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res (Hoboken). 2020;72:744–60. [DOI] [PubMed] [PMC]

12.

Richette P, Doherty M, Pascual E, Barskova V, Becce F, Castañeda-Sanabria J, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76:29–42. [DOI] [PubMed]

13.

Cicero AFG, Fogacci F, Cincione RI, Tocci G, Borghi C. Clinical Effects of Xanthine Oxidase Inhibitors in Hyperuricemic Patients. Med Princ Pract. 2021;30:122–30. [DOI] [PubMed] [PMC]

14.

Richette P, Latourte A, Bardin T. Cardiac and renal protective effects of urate-lowering therapy. Rheumatology (Oxford). 2018;57:i47–50. [DOI] [PubMed]

15.

Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12:R63. [DOI] [PubMed] [PMC]

16.

Yaseen W, Auguste B, Zipursky J. Allopurinol hypersensitivity syndrome. CMAJ. 2023;195:E483. [DOI] [PubMed] [PMC]

17.

Pillinger MH, Mandell BF. Therapeutic approaches in the treatment of gout. Semin Arthritis Rheum. 2020;50:S24–30. [DOI] [PubMed]

18.

Punzi L, Galozzi P, Luisetto R, Scanu A, Ramonda R, Oliviero F. Gout: one year in review 2023. Clin Exp Rheumatol. 2024;42:1–9. [DOI] [PubMed]

19.

Adomako EA, Moe OW. Uric acid transport, transporters, and their pharmacological targeting. Acta Physiol (Oxf). 2023;238:e13980. [DOI] [PubMed]

20.

Nigam SK, Bhatnagar V. The systems biology of uric acid transporters: the role of remote sensing and signaling. Curr Opin Nephrol Hypertens. 2018;27:305–13. [DOI] [PubMed] [PMC]

21.

Jansen TL, Tanja G, Matthijs J. A historical journey of searching for uricosuric drugs. Clin Rheumatol. 2022;41:297–305. [DOI] [PubMed]

22.

Gaffo AL, Saag KG. Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout. Core Evid. 2010;4:25–36. [DOI] [PubMed] [PMC]

23.

Neogi T, Choi HK. Editorial: Pursuit of a Dual-Benefit Antigout Drug: A First Look at Arhalofenate. Arthritis Rheumatol. 2016;68:1793–6. [DOI] [PubMed] [PMC]

24.

Pui K, Gow PJ, Dalbeth N. Efficacy and tolerability of probenecid as urate-lowering therapy in gout; clinical experience in high-prevalence population. J Rheumatol. 2013;40:872–6. [DOI] [PubMed]

25.

Rivera JV. Uricosuric effects of probenecid and zoxazolamine in gout. A comparative study. Arch Intern Med. 1961;108:512–8. [DOI] [PubMed]

26.

Chou H, Chiu H, Tsai C, Ting I, Yeh H, Huang H, et al.; CMUH Kidney Research Group. Comparative effectiveness of allopurinol, febuxostat and benzbromarone on renal function in chronic kidney disease patients with hyperuricemia: a 13-year inception cohort study. Nephrol Dial Transplant. 2018;33:1620–7. [DOI] [PubMed]

27.

Liu F, Liu X, Yang Q, Han S, Fan S. Enhanced Efficacy and Reduced Hepatotoxicity by Combination of Gnaphalium affine Extract and Benzbromarone in the Treatment of Rats with Hyperuricemic Nephropathy. Pharmaceutical Fronts. 2021;03:e129–37. [DOI]

28.

Leary WP, Reyes AJ. Angiotensin I converting enzyme inhibitors and the renal excretion of urate. Cardiovasc Drugs Ther. 1987;1:29–38. [DOI] [PubMed]

29.

Hamada T, Ichida K, Hosoyamada M, Mizuta E, Yanagihara K, Sonoyama K, et al. Uricosuric action of losartan via the inhibition of urate transporter 1 (URAT 1) in hypertensive patients. Am J Hypertens. 2008;21:1157–62. [DOI] [PubMed]

30.

Rubio-Guerra AF, Garro-Almendaro AK, Elizalde-Barrera CI, Suarez-Cuenca JA, Duran-Salgado MB. Effect of losartan combined with amlodipine or with a thiazide on uric acid levels in hypertensive patients. Ther Adv Cardiovasc Dis. 2017;11:57–62. [DOI] [PubMed] [PMC]

31.

Takahashi S, Moriwaki Y, Yamamoto T, Tsutsumi Z, Ka T, Fukuchi M. Effects of combination treatment using anti-hyperuricaemic agents with fenofibrate and/or losartan on uric acid metabolism. Ann Rheum Dis. 2003;62:572–5. [DOI] [PubMed] [PMC]

32.

Somagutta MKR, Luvsannyam E, Jain M, Cuddapah GV, Pelluru S, Mustafa N, et al. Sodium glucose co-transport 2 inhibitors for gout treatment. Discoveries (Craiova). 2022;10:e152. [DOI] [PubMed] [PMC]

33.

Nuki G, Simkin PA. A concise history of gout and hyperuricemia and their treatment. Arthritis Res Ther. 2006;8:S1. [DOI] [PubMed] [PMC]

34.

Drugs@FDA: FDA-Approved Drugs: Probalan (probenecid) [Internet]. FDA. [cited 2024 Oct 21]. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=080966

35.

Yu K, Chen D, Chen J, Chen S, Chen S, Cheng T, et al. Management of gout and hyperuricemia: Multidisciplinary consensus in Taiwan. Int J Rheum Dis. 2018;21:772–87. [DOI] [PubMed]

36.

Azevedo VF, Kos IA, Vargas-Santos AB, Pinheiro GdRC, Paiva EDS. Benzbromarone in the treatment of gout. Adv Rheumatol. 2019;59:37. [DOI] [PubMed]

37.

Lee MH, Graham GG, Williams KM, Day RO. A benefit-risk assessment of benzbromarone in the treatment of gout. Was its withdrawal from the market in the best interest of patients? Drug Saf. 2008;31:643–65. [DOI] [PubMed]

38.

ZURAMPIC^® (lesinurad) tablets, for oral use. Initial U.S. Approval: 2015 [Internet]. FDA. [cited 2024 Oct 21]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207988lbl.pdf

39.

Drugs@FDA: FDA-Approved Drugs: Anturane (sulfinpyrazone). FDA. [cited 2024 Oct 21]. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=011556.

40.

Hou X, Wang Y, Yang Y, Xiao Z. Discovery of Novel Biphenyl Carboxylic Acid Derivatives as Potent URAT1 Inhibitors. Molecules. 2023;28:7415. [DOI] [PubMed] [PMC]

41.

Robbins N, Koch SE, Tranter M, Rubinstein J. The history and future of probenecid. Cardiovasc Toxicol. 2012;12:1–9. [DOI] [PubMed]

42.

Wilson RC, Arkell P, Riezk A, Gilchrist M, Wheeler G, Hope W, et al. Addition of probenecid to oral β-lactam antibiotics: a systematic review and meta-analysis. J Antimicrob Chemother. 2022;77:2364–72. [DOI] [PubMed] [PMC]

43.

Tátrai P, Erdő F, Dörnyei G, Krajcsi P. Modulation of Urate Transport by Drugs. Pharmaceutics. 2021;13:899. [DOI] [PubMed] [PMC]

44.

Boelaert J, Schurgers M, Daneels R, Lijnen P, Amery A. Sulfinpyrazone: risk for renal insufficiency. Arch Intern Med. 1984;144:648–9. [PubMed]

45.

Prior C, Kirchmair H. Acute interstitial nephritis and kidney failure requiring dialysis after sulfinpyrazone therapy. Acta Med Austriaca. 1984;11:55–9. German. [PubMed]

46.

Walls M, Goral S, Stone W. Acute renal failure due to sulfinpyrazone. Am J Med Sci. 1998;315:319–21. [DOI] [PubMed]

47.

Durham DS, Ibels LS. Sulphinpyrazone-induced acute renal failure. Br Med J (Clin Res Ed). 1981;282:609. [DOI] [PubMed] [PMC]

48.

Lees P, Toutain P. Pharmacokinetics, pharmacodynamics, metabolism, toxicology and residues of phenylbutazone in humans and horses. Vet J. 2013;196:294–303. [DOI] [PubMed]

49.

Fung M, Thornton A, Mybeck K, Wu JHH, Hornbuckle K, Muniz E. Evaluation of the Characteristics of Safety Withdrawal of Prescription Drugs from Worldwide Pharmaceutical Markets-1960 to 1999. Ther Innov Regul Sci. 2001;35:293–317. [DOI]

50.

Hanvivadhanakul P, Akkasilpa S, Deesomchok U. Efficacy of benzbromarone compared to allopurinol in lowering serum uric acid level in hyperuricemic patients. J Med Assoc Thai. 2002;85:S40–7. [PubMed]

51.

Perez-Ruiz F, Calabozo M, Fernandez-Lopez MJ, Herrero-Beites A, Ruiz-Lucea E, Garcia-Erauskin G, et al. Treatment of chronic gout in patients with renal function impairment: an open, randomized, actively controlled study. J Clin Rheumatol. 1999;5:49–55. [DOI] [PubMed]

52.

Kaufmann P, Török M, Hänni A, Roberts P, Gasser R, Krähenbühl S. Mechanisms of benzarone and benzbromarone-induced hepatic toxicity. Hepatology. 2005;41:925–35. [DOI] [PubMed]

53.

McDonald MG, Rettie AE. Sequential metabolism and bioactivation of the hepatotoxin benzbromarone: formation of glutathione adducts from a catechol intermediate. Chem Res Toxicol. 2007;20:1833–42. [DOI] [PubMed]

54.

Wang H, Feng Y, Wang Q, Guo X, Huang W, Peng Y, et al. Cysteine-Based Protein Adduction by Epoxide-Derived Metabolite(s) of Benzbromarone. Chem Res Toxicol. 2016;29:2145–52. [DOI] [PubMed]

55.

Hoy SM. Lesinurad: First Global Approval. Drugs. 2016;76:509–16. [DOI] [PubMed]

56.

Deeks ED. Lesinurad: A Review in Hyperuricaemia of Gout. Drugs Aging. 2017;34:401–10. [DOI] [PubMed]

57.

Shen Z, Yeh L, Wallach K, Zhu N, Kerr B, Gillen M. In Vitro and In Vivo Interaction Studies Between Lesinurad, a Selective Urate Reabsorption Inhibitor, and Major Liver or Kidney Transporters. Clin Drug Investig. 2016;36:443–52. [DOI] [PubMed] [PMC]

58.

Lesinurad/Allopurinol (Duzallo) for Gout-Associated Hyperuricemia. JAMA. 2018;319:188–9. [DOI] [PubMed]

59.

Pérez-Ruiz F, Jansen T, Tausche A, Juárez-Campo M, Gurunath RK, Richette P. Efficacy and safety of lesinurad for the treatment of hyperuricemia in gout. Drugs Context. 2019;8:212581. [DOI] [PubMed] [PMC]

60.

Dalbeth N, Jones G, Terkeltaub R, Khanna D, Kopicko J, Bhakta N, 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. Arthritis Rheumatol. 2017;69:1903–13. [DOI] [PubMed] [PMC]

61.

Sanchez-Niño MD, Zheng-Lin B, Valiño-Rivas L, Sanz AB, Ramos AM, Luño J, et al. Lesinurad: what the nephrologist should know. Clin Kidney J. 2017;10:679–87. [DOI] [PubMed] [PMC]

62.

Grünenthal issues notice to the European Commission (EC) and the European Medicines Agency (EMA) to withdraw Zurampic® and Duzallo® 2020 [Internet]. Grünenthal; © 2024 [cited 2024 Oct 21]. Available from: https://www.grunenthal.com/en/press-room/statements/gruenenthal-issues-notice-to-the-ec-and-the-ema-to-withdraw-zurampic-and-duzallo

63.

Tausche A, Alten R, Dalbeth N, Kopicko J, Fung M, Adler S, et al. Lesinurad monotherapy in gout patients intolerant to a xanthine oxidase inhibitor: a 6 month phase 3 clinical trial and extension study. Rheumatology (Oxford). 2017;56:2170–8. [DOI] [PubMed]

64.

Tan PK, Liu S, Gunic E, Miner JN. Discovery and characterization of verinurad, a potent and specific inhibitor of URAT1 for the treatment of hyperuricemia and gout. Sci Rep. 2017;7:665. [DOI] [PubMed] [PMC]

65.

Fitz-Patrick D, Roberson K, Niwa K, Fujimura T, Mori K, Hall J, 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. Mod Rheumatol. 2019;29:1042–52. [DOI] [PubMed]

66.

Fleischmann R, Winkle P, Miner JN, Yan X, Hicks L, Valdez S, et al. Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study. RMD Open. 2018;4:e000584. [DOI] [PubMed] [PMC]

67.

Fleischmann R, Winkle P, Hall J, Valdez S, Liu S, Yan X, et al. Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with febuxostat in adults with gout: a phase IIa, open-label study. RMD Open. 2018;4:e000647. [DOI] [PubMed] [PMC]

68.

Taylor NP. AstraZeneca wields ax, scrapping midphase programs from $1B takeover, Heptares pact in latest quarterly cull [Internet]. Questex LLC; © 2024 [cited 2024 Oct 21]. Available from: https://www.fiercebiotech.com/biotech/astrazeneca-wields-ax-scrapping-midphase-programs-from-1b-takeover-heptares-pact-latest

69.

Hosoya T, Furuno K, Kanda S. A non-inferiority study of the novel selective urate reabsorption inhibitor dotinurad versus febuxostat in hyperuricemic patients with or without gout. Clin Exp Nephrol. 2020;24:71–9. [DOI] [PubMed] [PMC]

70.

Hosoya T, Sano T, Sasaki T, Fushimi M, Ohashi T. Dotinurad versus benzbromarone in Japanese hyperuricemic patient with or without gout: a randomized, double-blind, parallel-group, phase 3 study. Clin Exp Nephrol. 2020;24:62–70. [DOI] [PubMed] [PMC]

71.

Ishikawa T, Takahashi T, Taniguchi T, Hosoya T. Dotinurad: a novel selective urate reabsorption inhibitor for the treatment of hyperuricemia and gout. Expert Opin Pharmacother. 2021;22:1397–406. [DOI] [PubMed]

72.

Terkeltaub R. Emerging Urate-Lowering Drugs and Pharmacologic Treatment Strategies for Gout: A Narrative Review. Drugs. 2023;83:1501–21. [DOI] [PubMed]

73.

Lin Y, Chen X, Ding H, Ye P, Gu J, Wang X, et al. Efficacy and safety of a selective URAT1 inhibitor SHR4640 in Chinese subjects with hyperuricaemia: a randomized controlled phase II study. Rheumatology (Oxford). 2021;60:5089–97. [DOI] [PubMed]

74.

Tang H, Cui B, Chen Y, Chen L, Wang Z, Zhang N, et al. Safety and efficacy of SHR4640 combined with febuxostat for primary hyperuricemia: a multicenter, randomized, double-blind, phase II study. Ther Adv Musculoskelet Dis. 2022;14:1759720X211067304. [DOI] [PubMed] [PMC]

75.

Keenan R, Wei J, Morris S, Mundell P, Wei W, Shi K, et al. AR882, an Efficacious and Selective URAT1 Inhibitor for Patients with Chronic Gouty Arthritis and Subcutaneous Tophi: Results from a Global, Prospective, Proof-of-Concept Trial Using Dual Energy Computed Tomography. In: ACR Convergence 2023; 2023 November 10–15; San Diego, USA. Arthritis Rheumatol. 2023;75:L15.

76.

Shen Z, Polvent E, Hingorani V, Clouser Roche A, Colton C, Yan R, et al. Pharmacokinetics and serum urate lowering effects of AR882, a novel, potent and selective uricosuric agent, in patients with gout. Ann Rheum Dis. 2021;80:844. [DOI]

77.

Wei JCC, Fleischmann RM, Morris S, Polvent E, Shen Z, Clouser Roche A, et al. OP0295: A 12-week, randomized, double-blinded, placebo-controlled, Phase 2b study of safety, tolerability and efficacy of AR882 in gout patients. Annals of the Rheumatic Diseases. 2023;82:192.

78.

Shen Z, Polvent E, Hingorani V, Yan R, Yan S, Yeh L. AR882, a Potent and Selective Uricosuric Agent, Showed Effectiveness in Patients with Various Degrees of Renal Impairment. In: ACR Convergence 2021; 2021 November 5–9. Arthritis Rheumatol. 2021;73:1568.

79.

Jun J, Lee H, Suh C, Lee C, Kim D, Choe J, et al. A Series of Double-Blind, Placebo-Controlled, Randomized, Multicenter, Phase 2 Studies to Evaluate the Efficacy, Safety, and Dose-Response Relationship of Orally Administered URC102, a Novel URAT1 Inhibitor, in Korean Patients with Gout. In: 2017 ACR/ARHP Annual Meeting; 2017 November 3–8; San Diego, USA. Arthritis Rheumatol. 2017;69:2074.

80.

Ahn SO, Ohtomo S, Kiyokawa J, Nakagawa T, Yamane M, Lee KJ, 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 Pharmacol Exp Ther. 2016;357:157–66. [DOI] [PubMed]

81.

Yan R, Nanqun Z, Shen Z, Yan S, Yeh L. AR882, a Potent and Selective URAT1 Inhibitor with a Favorable Pharmacological, Pharmacokinetic and Toxicity Profile. In: 2019 ACR/ARP Annual Meeting; 2019 November 8–13; Atlanta (GA), USA. Arthritis Rheumatol. 2019;71:1224.

82.

Gurwith M, Smith D, Bird P, Leung J, Bloch M, Kim J, et al. A Double-Blind, Placebo-Controlled, Ascending Dose Phase 2a Study of ABP-671, a Novel, Potent and Selective URAT1 Inhibitor, in Patients with Gout or Hyperuricemia. In: ACR Convergence 2022; 2022 November 10–14; Philadelphia (PA), USA. Arthritis Rheumatol. 2022;74:1822.

83.

Qu Y, Yu Y, Pan J, Li H, Cui C, Liu D. Systematic review and model-based analysis to identify whether renal safety risks of URAT1 inhibitors are fully determined by uric acid-lowering efficacies. Semin Arthritis Rheum. 2023;63:152279. [DOI] [PubMed]

84.

Song K, He M, Kong X, Xian Y, Zhang Y, Xie X, et al. Benefits of uric acid-lowering medication after bariatric surgery in patients with gout. BMC Surg. 2024;24:186. [DOI] [PubMed] [PMC]

85.

Song K, Kong X, Yu Z, Xiao H, Ren Y. Research progress on bariatric surgery for hyperuricemia. BMC Surg. 2024;24:235. [DOI] [PubMed] [PMC]

86.

Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Eustace D, Palo WA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353:2450–61. [DOI] [PubMed]

87.

O’Dell JR, Brophy MT, Pillinger MH, Neogi T, Palevsky PM, Wu H, et al. Comparative Effectiveness of Allopurinol and Febuxostat in Gout Management. NEJM Evid. 2022;1:10.1056/evidoa2100028. [DOI] [PubMed] [PMC]

88.

White WB, Saag KG, Becker MA, Borer JS, Gorelick PB; CARES Investigators. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. N Engl J Med. 2018;378:1200–10. [DOI] [PubMed]

89.

Mackenzie IS, Ford I, Nuki G, Hallas J, Hawkey CJ, Webster J, et al.; FAST Study Group. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet. 2020;396:1745–57. [DOI] [PubMed]

90.

Scheepers LEJM, van Onna M, Stehouwer CDA, Singh JA, Arts ICW, Boonen A. Medication adherence among patients with gout: A systematic review and meta-analysis. Semin Arthritis Rheum. 2018;47:689–702. [DOI] [PubMed]

91.

Yin R, Li L, Zhang G, Cui Y, Zhang L, Zhang Q, et al. Rate of adherence to urate-lowering therapy among patients with gout: a systematic review and meta-analysis. BMJ Open. 2018;8:e017542. [DOI] [PubMed] [PMC]

92.

Spragg JCJ, Michael TJF, Aslani P, Coleshill MJ, Chan JS, Day RO, et al. Optimizing adherence to allopurinol for gout: patients’ perspectives. Br J Clin Pharmacol. 2023;89:1978–91. [DOI] [PubMed]

93.

Uloric® (febuxostat) tablets, for oral use. Initial U.S. Approval: 2015. FDA. [cited 2024 Oct 21]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021856s015lbl.pdf

94.

Abeles AM, Pillinger MH. Febuxostat and the Black Box Blues. ACR Open Rheumatol. 2019;1:343–4. [DOI] [PubMed] [PMC]

95.

Botson JK, Baraf HSB, Keenan RT, Albert J, Masri KR, Peterson J, et al. Expert Opinion on Pegloticase with Concomitant Immunomodulatory Therapy in the Treatment of Uncontrolled Gout to Improve Efficacy, Safety, and Durability of Response. Curr Rheumatol Rep. 2022;24:12–9. [DOI] [PubMed] [PMC]

96.

Botson JK, Saag K, Peterson J, Parikh N, Ong S, La D, et al. A Randomized, Placebo-Controlled Study of Methotrexate to Increase Response Rates in Patients with Uncontrolled Gout Receiving Pegloticase: Primary Efficacy and Safety Findings. Arthritis Rheumatol. 2023;75:293–304. [DOI] [PubMed] [PMC]

97.

Stack AG, Dronamraju N, Parkinson J, Johansson S, Johnsson E, Erlandsson F, et al. Effect of Intensive Urate Lowering With Combined Verinurad and Febuxostat on Albuminuria in Patients With Type 2 Diabetes: A Randomized Trial. Am J Kidney Dis. 2021;77:481–9. [DOI] [PubMed] [PMC]

98.

Prasad M, Matteson EL, Herrmann J, Gulati R, Rihal CS, Lerman LO, et al. Uric Acid Is Associated With Inflammation, Coronary Microvascular Dysfunction, and Adverse Outcomes in Postmenopausal Women. Hypertension. 2017;69:236–42. [DOI] [PubMed] [PMC]

99.

Kitzman Dalane W, Voors A, Mentz R, Lewis G, Perl S, Myte R, et al. Rationale and design for a phase 2 trial of verinurad plus allopurinol in patients with heart failure with preserved ejection fraction and hyperuricemia. Journal of the American College of Cardiology. 2021;77:597.

100.

A phase 2, multicentre, double-blind, placebo and active control efficacy and safety study to evaluate verinurad combined with allopurinol in heart failure with preserved ejection fraction (AMETHYST) [Internet]. [cited 2024 Oct 21]. Available from: https://frfr.www.astrazenecaclinicaltrials.com/study/D5496C00005/

101.

Taufiq F, Li P, Kuwabara M, Kurata Y, Hamada T, Takami A, et al. Novel inhibitory effects of dotinurad, a selective urate reabsorption inhibitor, on urate crystal-induced activation of NLRP3 inflammasomes in macrophages. Vascular Failure. 2020;3:59–67. [DOI]

102.

Yanai H, Adachi H, Hakoshima M, Iida S, Katsuyama H. A Possible Therapeutic Application of the Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease. Cells. 2024;13:450. [DOI] [PubMed] [PMC]

103.

Rusiecka OM, Tournier M, Molica F, Kwak BR. Pannexin1 channels-a potential therapeutic target in inflammation. Front Cell Dev Biol. 2022;10:1020826. [DOI] [PubMed] [PMC]

104.

Dahl G, Keane RW. Pannexin: from discovery to bedside in 11±4 years? Brain Res. 2012;1487:150–9. [DOI] [PubMed] [PMC]

105.

Wallis RB. Mechanisms of action of sulphinpyrazone. Thromb Res Suppl. 1983;4:31–8. [DOI] [PubMed]

106.

Yang M, Huang T, Lee Y, Lu F. Free radical scavenging properties of sulfinpyrazone. Free Radic Res. 2002;36:685–93. [DOI] [PubMed]

107.

Muraya N, Kadowaki D, Miyamura S, Kitamura K, Uchimura K, Narita Y, et al. Benzbromarone Attenuates Oxidative Stress in Angiotensin II- and Salt-Induced Hypertensive Model Rats. Oxid Med Cell Longev. 2018;2018:7635274. [DOI] [PubMed] [PMC]

108.

Huang Z, Huang B, Wei Q, Su X, Li X, Qin S, et al. The Protective Effects of Benzbromarone Against Propofol-Induced Inflammation and Injury in Human Brain Microvascular Endothelial Cells (HBMVECs). Neurotox Res. 2021;39:1449–58. [DOI] [PubMed]

109.

PROBENECID-probenecid tablet, film coated. Actavis Pharma, Inc. [Internet]. [cited: 2024 Oct 21]. Available from: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=ae126418-5474-4fbe-b83c-bde8b2b4ae6e&type=display

110.

Heel RC, Brogden RN, Speight TM, Avery GS. Benzbromarone: a review of its pharmacological properties and therapeutic use in gout and hyperuricaemia. Drugs. 1977;14:349–66. [DOI] [PubMed]

111.

112.

Worboys M, Toon E. Phenylbutazone (Bute, PBZ, EPZ): one drug across two species. Hist Philos Life Sci. 2018;40:27. [DOI] [PubMed] [PMC]

113.

Phenylbutazone [Internet]. [cited 2024 Oct 21]. Available from: https://go.drugbank.com/drugs/DB00812

114.

A Study of Evaluating the Efficacy and Safety of SHR4640 in Subjects With Gout (NCT04052932) [Internet]. Bethesda: National Library of Medicine (NLM); [cited 2024 Oct 21]. Available from: https://clinicaltrials.gov/study/NCT04052932

115.

A Therapeutic Confirmatory Study of Epaminurad Versus Febuxostat in Gout Patients (EPIC) (NCT05815901) [Internet]. Bethesda: National Library of Medicine (NLM); [cited 2024 Oct 21]. Available from: https://clinicaltrials.gov/study/NCT05815901

116.

Phase 2b/3 Study to Assess ABP-671 a Novel URAT1 Inhibitor in Participants With Gout (NCT05818085) [Internet]. Bethesda: National Library of Medicine (NLM); [cited 2024 Oct 21]. Available from: https://clinicaltrials.gov/study/NCT05818085

117.

118.

Xininurad [Internet]. Bethesda: National Library of Medicine (NLM); [cited 2024 Oct 21]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Xininurad

119.

Pozdeutinurad [Internet]. Bethesda: National Library of Medicine (NLM); [cited 2024 Oct 21]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Pozdeutinurad

120.

Verinurad [Internet]. Bethesda: National Library of Medicine (NLM); [cited 2024 Oct 21]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Verinurad

121.

Sulfinpyrazone [Internet]. Bethesda: National Library of Medicine (NLM); [cited 2024 Oct 21]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Sulfinpyrazone

122.

Ruzinurad [Internet]. Bethesda: National Library of Medicine (NLM); [cited 2024 Oct 21]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Ruzinurad

123.

Fleischmann R, Kerr B, Yeh L, Suster M, Shen Z, Polvent E, et al.; RDEA594-111 Study Group. Pharmacodynamic, pharmacokinetic and tolerability evaluation of concomitant administration of lesinurad and febuxostat in gout patients with hyperuricaemia. Rheumatology (Oxford). 2014;53:2167–74. [DOI] [PubMed]

124.

Shen Z, Gillen M, Miner JN, Bucci G, Wilson DM, Hall JW. Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects. Drug Des Devel Ther. 2017;11:2077–86. [DOI] [PubMed] [PMC]

125.

Taniguchi T, Ashizawa N, Matsumoto K, Saito R, Motoki K, Sakai M, et al. Pharmacological Evaluation of Dotinurad, a Selective Urate Reabsorption Inhibitor. J Pharmacol Exp Ther. 2019;371:162–70. doi: 10.1124/jpet.119.259341. [DOI] [PubMed]

126.

Uchida S, Shimada K, Misaka S, Imai H, Katoh Y, Inui N, et al. Benzbromarone pharmacokinetics and pharmacodynamics in different cytochrome P450 2C9 genotypes. Drug Metab Pharmacokinet. 2010;25:605–10. [DOI] [PubMed]

127.

Shen Z, Polvent E, Hingorani V, Clouser-Roche A, Mikelatis C, Yan R, et al.; Arthrosi Therapeutics Inc. ; Arthrosi Therapeutics Inc. AR882, a Potent and Selective Uricosuric Agent, Significantly Reduced Serum Urate Levels Following Multiple Ascending Once-Daily Doses in Healthy Subject Volunteers. In: ACR Convergence 2020; 2022 Nov 5–9; Philadelphia, USA. Arthritis Rheumatol; 2020.