Uricosuric drugs

Bach, Mary; Simkin, Peter A.

doi:10.1097/bor.0000000000000035

Cited by 47 publications

(20 citation statements)

References 31 publications

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“…Other therapies that inhibit URAT1 have been associated with the development of kidney stones 18, 26. Few kidney stone TEAEs were reported during the study.…”

Section: Discussionmentioning

confidence: 86%

Lesinurad, a Selective Uric Acid Reabsorption Inhibitor, in Combination With Febuxostat in Patients With Tophaceous Gout: Findings of a Phase III Clinical Trial

Dalbeth

Jones

Terkeltaub

et al. 2017

Arthritis & Rheumatology

131

137

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ObjectiveTo investigate the efficacy and safety of lesinurad in combination with febuxostat in a 12‐month phase III trial in patients with tophaceous gout.MethodsPatients with serum urate (UA) ≥8.0 mg/dl (≥6.0 mg/dl with urate‐lowering therapy) and ≥1 measurable target tophus were given febuxostat 80 mg/day for 3 weeks before randomization to receive lesinurad (200 or 400 mg daily) or placebo in addition to the febuxostat. The primary end point was the proportion of patients achieving a serum UA level of <5.0 mg/dl (month 6). The key secondary end point was the proportion of patients with complete resolution of ≥1 target tophus (month 12). Other end points included the percentage change in total target tophi area. Safety assessments included adverse events and laboratory data.ResultsPatients (n = 324) were predominantly male, with a mean age of 54.1 years. Significantly more patients achieved the serum UA target by month 6 with the addition of lesinurad 400 mg (76.1%; P < 0.0001), but not 200 mg (56.6%; P = 0.13), to the febuxostat therapy as compared with febuxostat alone (46.8%). At all other time points, significantly more patients in the lesinurad 200 mg group achieved the serum UA target. The number of patients with complete tophus resolution was not different between groups. Treatment with lesinurad (200 mg and 400 mg) plus febuxostat reduced the total target tophi area as compared with febuxostat alone (50.1% and 52.9% versus 28.3%, respectively; P < 0.05). Safety was generally comparable with that of febuxostat alone, except for higher rates of predominantly reversible elevations in the serum creatinine level, particularly with lesinurad 400 mg.ConclusionTreatment with lesinurad in combination with febuxostat demonstrated superior lowering of serum UA levels as compared with febuxostat alone, with clinically relevant added effects on tophi and an acceptable safety profile with lesinurad 200 mg in patients with tophaceous gout warranting additional therapy.

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“…Other therapies that inhibit URAT1 have been associated with the development of kidney stones 18, 26. Few kidney stone TEAEs were reported during the study.…”

Section: Discussionmentioning

confidence: 86%

Lesinurad, a Selective Uric Acid Reabsorption Inhibitor, in Combination With Febuxostat in Patients With Tophaceous Gout: Findings of a Phase III Clinical Trial

Dalbeth

Jones

Terkeltaub

et al. 2017

Arthritis & Rheumatology

131

137

View full text Add to dashboard Cite

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“…However, the first three are not widely used due to various safety and availability issues 9 . Lesinurad was recently approved for the treatment of hyperuricemia associated with gout, in combination with a xanthine oxidase inhibitor 10–14 .…”

Section: Introductionmentioning

confidence: 99%

Discovery and characterization of verinurad, a potent and specific inhibitor of URAT1 for the treatment of hyperuricemia and gout

Tan

Gunić

et al. 2017

Sci Rep

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Gout is caused by elevated serum urate levels, which can be treated using inhibitors of the uric acid transporter, URAT1. Here, we characterize verinurad (RDEA3170), which is currently under evaluation for gout therapy. Verinurad specifically inhibits URAT1 with a potency of 25 nM. High affinity inhibition of uric acid transport requires URAT1 residues Cys-32, Ser-35, Phe-365 and Ile-481. Unlike other available uricosuric agents, the requirement for Cys-32 is unique to verinurad. Two of these residues, Ser-35 and Phe-365, are also important for urate transport kinetics. A URAT1 binding assay using radiolabeled verinurad revealed that distinct URAT1 inhibitors benzbromarone, sulfinpyrazone and probenecid all inhibit verinurad binding via a competitive mechanism. However, mutations made within the predicted transporter substrate channel differentially altered the potency for individual URAT1 inhibitors. Overall, our results suggest that URAT1 inhibitors bind to a common site in the core of the transporter and sterically hinder the transit of uric acid through the substrate channel, albeit with vastly different potencies and with differential interactions with specific URAT1 amino acids.

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“…The serum level of UA is influenced by multiple factors, including exogenous ingestion (particularly with an animal protein-rich diet), endogenous production by the liver, and renal excretion. [1] Over the decades, the pathological consequences of excess UA have been found to be associated with its tendency to form crystals, as manifested in gouty arthritis or UA stones. This accumulation triggers complex proinflammatory cascades, leading to increased neutrophil phagocytosis, and activation of macrophages, fibroblasts, inflammatory mediators, and complement.…”

Section: Introductionmentioning

confidence: 99%

Asymptomatic hyperuricemia is independently associated with coronary artery calcification in the absence of overt coronary artery disease

Kim

Choi

et al. 2017

Medicine

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Recently, the pathogenic role of uric acid (UA) in both systemic metabolic and atherosclerotic diseases has been investigated. We sought to determine the independent correlation between serum UA levels and coronary artery calcification, as a marker of subclinical atherosclerosis. A total of 4188 individuals without prior coronary artery disease or urate-deposition disease were included. All of the participants underwent multidetector computed tomography (MDCT) for the evaluation of coronary artery calcification (CAC) during their health check-ups. The subjects were divided into thre groups according to CAC scores (group 1: 0; group 2: 1-299; group 3: ≥300). After controlling for other confounders, serum UA levels were found to be positively associated with increasing CAC scores (P = 0.001). Adjusted mean serum UA levels in each CAC group were estimated to be 5.2 ± 0.1 mg/dL, 5.3 ± 0.1 mg/dL, and 5.6 ± 0.2 mg/dL from groups 1, 2, and 3, respectively. Subsequent subgroup analyses revealed that this positive association was only significant in participants who were male, relatively older, less overweight, and did not have diabetes mellitus (DM), hypertension, smoking history, or renal dysfunction. In conclusion, serum uric acid levels were independently associated with CAC score severity and this finding is particularly relevant to the subjects who were male, relatively older, less overweight (body mass index < 25 kg/m 2 ), and without a history of DM, hypertension, smoking, or renal dysfunction.Abbreviations: BMI = body mass index, BUN = blood urea nitrogen, CAC = coronary artery calcification, CHD = coronary heart disease, CRP = C-reactive protein, CSF-1 = colony-stimulating factor 1, DM = diabetes mellitus, eGFR = estimated glomerular filtration rate, HDL = high-density lipoprotein, LDL = low-density lipoprotein, MDCT = multidetector computed tomography, MDRD = the Modification of Diet in Renal Disease, RANKL = receptor activator of NF-kB ligand, TNF-a = tumor necrosis factor-a, UA = uric acid.

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Uricosuric drugs

Abstract: Conceptually, modest inhibition of renal tubular reabsorption should provide effective relief for the millions of individuals who are now hyperuricemic and who suffer from its principal consequence, gout.

Cited by 47 publications

References 31 publications

Lesinurad, a Selective Uric Acid Reabsorption Inhibitor, in Combination With Febuxostat in Patients With Tophaceous Gout: Findings of a Phase III Clinical Trial

Lesinurad, a Selective Uric Acid Reabsorption Inhibitor, in Combination With Febuxostat in Patients With Tophaceous Gout: Findings of a Phase III Clinical Trial

Discovery and characterization of verinurad, a potent and specific inhibitor of URAT1 for the treatment of hyperuricemia and gout

Asymptomatic hyperuricemia is independently associated with coronary artery calcification in the absence of overt coronary artery disease

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