topiroxostat and Hyperuricemia

This review aims to critically present the available clinical evidence supporting the treatment of chronic hyperuricemia with xanthine oxidase inhibitors. For this reason, the studies published on uric acid (UA)-lowering drugs in the English language from 2000 to August 2019 have been carefully reviewed. The terms "serum uric acid," "xanthine oxidase," "allopurinol," "febuxostat," and "topiroxostat" were incorporated into an electronic search strategy, alone and in combinations, in both MEDLINE (National Library of Medicine, Bethesda, MD) and the Cochrane Register of Controlled Trials (The Cochrane Collaboration, Oxford, UK). Even if new urate-lowering drugs seem of particular efficacy for acute treatment of refractory hyperuricemia, their use is supported by relatively small clinical evidence. On the contrary, large long-term clinical trials have demonstrated that xanthine oxidase inhibitors (XOIs, namely, allopurinol and febuxostat) are effective, safe, and relatively well-tolerated in most of the patients. They have mainly been tested in the elderly, in patients affected by chronic diseases such as heart failure and cancer, and in patients taking a large number of drugs, confirming their safety profile. Recent data also show that they could exert some positive effects on vascular health, renal function, and glucose metabolism. Their cost is also low. In conclusion, XOIs remain the first choice of UA-lowering drug for chronic treatment.

Topics: Allopurinol; Benzaldehydes; Chronic Disease; Comorbidity; Febuxostat; Gout Suppressants; Humans; Hyperuricemia; Nitriles; Pyridines; Randomized Controlled Trials as Topic; Xanthine Oxidase

This article aims to critically review the evidence on the available therapeutic strategies for the treatment of hyperuricemia. For this reason, several papers were reviewed. Xanthine oxidase inhibitors are the safest and most effective uric acid lowering drugs for the management of chronic hyperuricemia, while the efficacy of uricosuric agents is strongly modulated by pharmacogenetics. Emergent drugs (lesinurad, peglotidase) were found to be more effective for the acute management of refractory hyperuricemia, but their use is supported by a relatively small number of clinical trials so that further well-designed clinical research is needed to deepen their efficacy and safety profile.

Topics: Acetamides; Allopurinol; Benzbromarone; Chronic Disease; Evidence-Based Medicine; Febuxostat; Gout Suppressants; Humans; Hyperuricemia; Naphthalenes; Nitriles; Phenylacetates; Polyethylene Glycols; Probenecid; Propionates; Pyridines; Thioglycolates; Triazoles; Urate Oxidase; Uricosuric Agents; Xanthine Oxidase

Uric acid (UA) remains a risk factor for the progression of chronic kidney disease (CKD). Most observational studies showed a slight elevation in the serum UA level and this independently predicts the incidence and development of CKD. The recent meta-analysis, however, did not reach the conclusion that urate-lowering therapy with allopurinol retards the progression of CKD. The target level of serum UA if treated is another issue of debate. Our recent analysis by propensity score analysis has shown that the serum UA should be targeted below 6.0 mg/dL to inhibit the progression towards end-stage renal disease. Underlying mechanisms whereby an increase in serum UA induces kidney injury have been elucidated in animal models. Hyperuricemic models can lead to systemic hypertension, arteriolosclerosis including afferent arteriolopathy as well as albuminuria probably due to the activation of oxidative stress. Discoveries of urate transporters have elucidated the novel mechanism of UA transport in the kidney and intestine. The intestinal ABCG2 may play a compensatory role in light of decreased renal clearance of UA in CKD model rats, the trigger of which is not a uremic toxin but serum UA itself. Insulin directly upregulates URAT1 and downregulates ABCG2 in the kidney tubules, suggesting a possible link between UA and metabolic syndrome. This review summarizes the recent knowledge on the causal effect of serum UA on the kidney injury.

Topics: Allopurinol; Animals; Anion Transport Proteins; ATP Binding Cassette Transporter, Subfamily G, Member 2; Disease Progression; Enzyme Inhibitors; Febuxostat; Glucosides; Gout Suppressants; Humans; Hyperuricemia; Monosaccharide Transport Proteins; Nitriles; Oxidative Stress; Pyridines; Renal Insufficiency, Chronic; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes; Uric Acid; Xanthine Oxidase

Inhibitors of xanthine oxidoreductase decrease production of uric acid, thus they act as hypouricemic drugs. Allopurinol, a prototypical xanthine oxidoreductase inhibitor, has been widely prescribed for treatment of gout and hyperuricemia. However, severe side effects of allopurinol may occur in patients with renal insufficiency. Recently, novel nonpurine selective inhibitors of xanthine oxidoreductase have been developed as potential alternatives to allopurinol. They have different inhibition mechanisms, utilizing the enzyme structure and the reaction mechanism. Such variation of the inhibition mechanism affects/in vivo/hypouricemic effects of the inhibitors.

Topics: Allopurinol; Drug Design; Enzyme Inhibitors; Febuxostat; Gout; Gout Suppressants; Humans; Hyperuricemia; Nitriles; Pyrazoles; Pyridines; Thiazoles; Xanthine Dehydrogenase

Elevated serum uric acid is a cardiovascular risk factor in patients with hypertension, even when blood pressure (BP) is well controlled. Xanthine oxidoreductase inhibitors (XORi) reduce serum uric acid levels and have several other potential effects. This multicenter, randomized, open-label study compared the effects of two XORi, topiroxostat and febuxostat, on arterial stiffness, uric acid levels, and BP in hypertensive patients with hyperuricemia. Patients received topiroxostat 40-160 mg/day or febuxostat 10-60 mg/day, titrated to maintain serum uric acid <6 mg/dl, for 24 weeks. The primary endpoint was change in the cardio-ankle vascular index (CAVI) from baseline to 24 weeks. There were no significant changes in CAVI from baseline to 24 weeks (from 9.13 to 9.16 [feboxustat] and 8.98 to 9.01 [topiroxostat]). Compared with baseline, there were significant reductions in serum uric acid (-2.9 and -2.5 mg/dl; both p < 0.001) and morning home systolic BP (-3.6 and -5.1 mm Hg; both p < 0.01) after 24 weeks' treatment with febuxostat and topiroxostat. BP decreased to the greatest extent in the subgroup of patients with uncontrolled blood pressure at baseline. Topiroxostat, but not febuxostat, significantly decreased plasma xanthine oxidoreductase activity versus baseline. The urinary albumin-creatinine ratio (UACR) decreased significantly from baseline to 24 weeks with topiroxostat (-20.8%; p = 0.021), but not febuxostat (-8.8%; p = 0.362). In conclusion, neither topiroxostat nor febuxostat had any significant effects on arterial stiffness over 24 weeks' treatment.

Topics: Febuxostat; Gout Suppressants; Humans; Hypertension; Hyperuricemia; Nitriles; Pyridines; Treatment Outcome; Uric Acid

Dotinurad, a novel selective urate reabsorption inhibitor (SURI), increases urinary uric acid excretion. The aim of this study is to examine the pharmacokinetics, pharmacodynamics, and safety of dotinurad according to the type of hyperuricemia, with or without concomitant use of xanthine oxidase inhibitor, in uric acid "overproduction type" patients.. This open-label clinical pharmacology study was conducted in a hospital. Dotinurad 1 mg was administered for 7 days to hyperuricemic patients with uric acid "overproduction type" (overproduction group, n = 6; and combination group, n = 6) and uric acid "underexcretion type" (underexcretion group, n = 6). In the combination group, topiroxostat 80 mg was used concomitantly.. No significant differences were observed in pharmacokinetics and safety between overproduction group and underexcretion group, and the percent change in serum uric acid level and the amount of urinary uric acid excretion after administration were comparable. In "overproduction type" patients of combination group, the percent change in serum uric acid level significantly increased and the amount of urinary uric acid excretion significantly decreased compared to those of overproduction group. No clinically meaningful differences were observed in safety between the overproduction group and the combination group.. In inpatients, differences in hyperuricemic type did not significantly influence the pharmacokinetics, pharmacodynamics, and safety of dotinurad. Moreover, in "overproduction type", the coadministration of dotinurad and topiroxostat had an add-on serum uric acid lowering effect and suppressed urinary uric acid excretion.. ClinicalTrials.gov Identifier: NCT02837198.

Topics: Adult; Aged; Benzothiazoles; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Hyperuricemia; Inpatients; Middle Aged; Nitriles; Pyridines; Uric Acid; Uricosuric Agents; Xanthine Oxidase

The TROFEO trial demonstrated that febuxostat causes greater and more rapid reduction of serum uric acid (s-UA) than topiroxostat. We compared these drugs in patients with chronic kidney disease (CKD) by sub-analysis of the TROFEO trial.. There was no significant difference of s-UA between the two groups either before or after treatment. However, s-UA did not exceed 6.0 mg/dL in febuxostat group during the study period, but it exceeded this level in seven patients from topiroxostat group, with the number being significantly higher in topiroxostat group. Serum creatinine (s-Cr) and eGFR were significantly better after 6 months of febuxostat treatment compared with topiroxostat Cystatin-C was significantly lower after 6 months of febuxostat treatment compared with topiroxostat. The Ox-LDL was significantly lower after 3 and 6 months of febuxostat treatment compared with topiroxostat.. Febuxostat had stronger renoprotective and antioxidant effects than topiroxostat in patients with hyperuricemia and CKD.

Topics: Aged; Antioxidants; Biomarkers; Cross-Over Studies; Down-Regulation; Enzyme Inhibitors; Febuxostat; Female; Glomerular Filtration Rate; Gout Suppressants; Humans; Hyperuricemia; Kidney; Male; Middle Aged; Nitriles; Pyridines; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome; Uric Acid; Xanthine Oxidase

We aimed to evaluate the anti-albuminuric effects of topiroxostat in Japanese hyperuricaemic patients with diabetic nephropathy.. A total of 80 patients underwent randomization. The changes in UACR after 24 weeks of treatment (or at the final time point if patients failed to reach 24 weeks) relative to the baseline were -122 mg/gCr (95% CI: -5.1 to -240.1, P = 0.041) in patients treated with high dose, while treatment with low dose topiroxostat could not show significant reduction (P = 0.067). In the linear mixed model including baseline albuminuria, eGFR, age, and sex as covariates, the decreases in UACR were still significant from baseline to 12 weeks by 228.7 ± 83.2 mg/gCr (P = 0.0075) in the high dose group. The adverse-event profile during this study was not different between the groups.. Topiroxostat 160 mg daily reduced albuminuria in patients with diabetic nephropathy. (Funded by Sanwa Kagaku Kenkyusho; Trial registration, UMIN000015403).

Topics: Aged; Aged, 80 and over; Albuminuria; Blood Pressure; Creatinine; Diabetic Nephropathies; Fatty Acid-Binding Proteins; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Hyperuricemia; Kidney; Male; Middle Aged; Nitriles; Prospective Studies; Pyridines

Hyperuricemia is supposed to be an independent risk factor for kidney dysfunction in diabetic patients. We attempted to examine the uric acid-lowering effect and the renoprotective effect of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia in this pilot study.. The study design was randomized, double-blind, placebo-controlled, parallel-group study. A total of 65 patients with hyperuricemia and diabetic nephropathy with microalbuminuria were enrolled and assigned to either the topiroxostat group or the placebo group. Topiroxostat (stepwise dosing from 40 to 160 mg/day) or matching placebo was administered BID for 28 weeks. The primary endpoint was a change in the urinary albumin-to-creatinine ratio in the first-morning-void urine sample. Secondary endpoints were changes in the estimated glomerular filtration rate and the serum uric acid level.. These findings support that diabetic nephropathy combined with hyperuricemia may be associated with kidney dysfunctions. Topiroxostat provides strict control of the serum uric acid level preventing decline of eGFR in these patients.

Topics: Aged; Diabetic Nephropathies; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Hyperuricemia; Male; Middle Aged; Nitriles; Pilot Projects; Pyridines; Treatment Outcome; Uric Acid; Xanthine Dehydrogenase

Hyperuricemia has a close relationship with cardiovascular diseases including heart failure. However, it is controversial whether xanthine oxidase inhibition has benefits for patients with chronic heart failure. We designed the Effect of Xanthine Oxidase Inhibitor in Chronic Heart Failure Patients Complicated with Hyperuricemia study (Excited-UA study) to compare the beneficial effects between a novel xanthine oxidoreductase inhibitor, topiroxostat, and a conventional agent, allopurinol, in patients with chronic heart failure and hyperuricemia. We focus on serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level, echocardiography-based cardiac function, vascular endothelial function, renal function, inflammation, and oxidative stress.. The excited-UA is a prospective, randomized, open-label, blinded-endpoint clinical trial designed to prove our hypothesis that topiroxostat is more effective than allopurinol in patients with chronic heart failure and hyperuricemia. A total of 140 patients with chronic heart failure and hyperuricemia (plasma brain natriuretic peptide level ≥ 40 pg/mL and serum uric acid level ≥ 7.0 mg/dL) are randomly assigned (ratio 1:1) into either the topiroxostat group (40-160 mg/day) or allopurinol group (100-300 mg/day), to achieve the target uric acid level of 6.0 mg/dL. According to the protocol, all patients are followed up annually for 24 weeks. The primary endpoint is percent change in serum NT-proBNP level at 24 weeks from baseline.. The Excited-UA study would provide novel evidence for the clinical relevancy of xanthine oxidoreductase inhibitor treatment in patients with chronic heart failure and hyperuricemia.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Chronic Disease; Echocardiography; Enzyme Inhibitors; Heart Failure; Humans; Hyperuricemia; Middle Aged; Natriuretic Peptide, Brain; Nitriles; Peptide Fragments; Pyridines; Randomized Controlled Trials as Topic; Research Design; Xanthine Oxidase; Young Adult

Topiroxostat-a novel selective xanthine oxidoreductase inhibitor-has been reported to reduce serum urate levels. The purpose of this study was to assess the efficacy and safety of long-term topiroxostat administration in Japanese hyperuricemic patients with or without gout.. This multicenter, open-label study evaluated the efficacy and safety of long-term twice-daily oral topiroxostat administration in patients with or  without gout. The initial topiroxostat dosage was 40-80 mg/day, and the maintenance dosage was 120 mg/day, which was increased to 240 mg/day at 40 mg increments if the serum urate level exceeded 6.0 mg/dL.. Serum urate level, which was the primary endpoint, decreased stably over time and showed significant reduction on the final visit (38.44% ± 13.34%) compared with that at the baseline. Both urinary albumin/creatinine ratio and mean blood pressure significantly improved. The overall incidence rate of adverse drug reactions to topiroxostat was 67.8%; on the final visit, the rate of adverse drug reactions was 66.7% with 120 mg/day, 72.2% with 160 mg/day, 53.8% with ≥ 200 mg/day, and 100% with the other dosages. On the final visit, the incidence of gouty arthritis, for which a causal relationship with topiroxostat could not be ruled out, was 4.1% overall, 4.8% with 120 mg/day, 0% with 160 mg/day, and 7.7% with ≥ 200 mg/day.. We verified the efficacy and safety of 58-week oral topiroxostat administration at stepwise increments to up to 240 mg/day.. JAPIC CTI-101068.

Topics: Administration, Oral; Adult; Aged; Drug Administration Schedule; Enzyme Inhibitors; Female; Gout; Gout Suppressants; Humans; Hyperuricemia; Japan; Male; Middle Aged; Nitriles; Pyridines; Treatment Outcome; Uric Acid

We previously reported that febuxostat was more effective for hyperuricemia than allopurinol. The efficacy, however, of topiroxostat (a novel xanthine oxidase reductase inhibitor similar to febuxostat), for hyperuricemia is unknown.Methods and Results:Patients with cardiovascular disease and hyperuricemia, in whom serum uric acid (s-UA) was controlled at ≤6 mg/dL, were eligible for enrollment. Fifty-five patients were randomized to receive either febuxostat or topiroxostat for 6 months and were switched to the other drug for the following 6 months. The primary endpoint was s-UA. Secondary endpoints included serum creatinine, estimated glomerular filtration rate, urinary albumin, cystatin-C, oxidized low-density lipoprotein, eicosapentaenoic acid/arachidonic acid ratio, lipid biomarkers, high-sensitivity C-reactive protein and B-type natriuretic protein. Although s-UA level was similar for both drugs, significantly more patients required dose escalation during treatment with topiroxostat. There were no differences in renal function, inflammatory and lipid markers between the 2 drugs. A biomarker of oxidative stress was significantly lower after 3 months of febuxostat compared with topiroxostat.. Febuxostat causes more marked and more rapid reduction of s-UA than topiroxostat. With regard to the antioxidant effect, febuxostat was superior to topiroxostat after 3 months. The renal protective and anti-inflammatory effects of both drugs were also similar after 6 months of treatment. Thus, both of these agents were similarly effective for hyperuricemia in patients with cardiovascular disease.

Topics: Adult; Aged; Anti-Inflammatory Agents; Antioxidants; Cardiovascular Diseases; Cross-Over Studies; Febuxostat; Female; Humans; Hyperuricemia; Male; Middle Aged; Nitriles; Pyridines; Treatment Outcome; Uric Acid

Topiroxostat, a selective xanthine oxidoreductase inhibitor, is used in Japan for the treatment of hyperuricemic patients with or without gout. In terms of the effectiveness of topiroxostat in lowering serum urate levels, the dose-response relationship has been evaluated; however, it remains to be verified. A randomized, multi-center, double-blinded study of topiroxostat was performed for Japanese hyperuricemic patients with or without gout. During the 16-week study, 157 Japanese hyperuricemic patients with or without gout were randomly assigned to receive a placebo, topiroxostat at 120 or 160 mg/day, or allopurinol at 200 mg/day. The primary endpoint of this study was to determine the lowering rate of serum uric acid levels compared to those of baseline at the end of administration. A dose-response relationship (regarding decreases in the serum urate levels) was confirmed for the placebo and topiroxostat at 120 and at 160 mg/day. Moreover, at the end of administration, the lowering rate of serum urate levels was determined to be -44.8% in the topiroxostat 160-mg/day group. No significant difference in the incidence of adverse events was observed among all groups, including the allopurinol group. The serum urate-lowering effect of topiroxostat was found to have a dose-response relationship in Japanese hyperuricemic patients with or without gout.

Topics: Adult; Allopurinol; Double-Blind Method; Female; Gout; Gout Suppressants; Humans; Hyperuricemia; Japan; Male; Middle Aged; Nitriles; Pyridines; Treatment Outcome; Uric Acid; Young Adult

In Japan, although topiroxostat, a selective xanthine oxidoreductase inhibitor, has been used for the treatment of patients with hyperuricemia including gout, no published randomized controlled studies evaluating the dose-dependent relationship with respect to the serum urate-lowering efficacy have been reported. The aim of this study was to evaluate the dose-dependent relationship with serum urate-lowering efficacy and safety of topiroxostat in Japanese hyperuricemic patients including gout.. We conducted an exploratory, phase 2a, multicentre, randomized, double-blind, 8-week, placebo-controlled study in Japanese hyperuricemic patients with or without gout. The study arms were placebo and topiroxostat 40, 60, 80 or 120 mg/day. The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit.. One hundred and eighty-seven eligible patients were randomized and 186 received at least one dose of the study drug. The study results demonstrated a dose-dependent serum urate reduction effect ranging from 40 to 120 mg/day (P < 0·001, Jonckheere-Terpstra test). The mean per cent change in serum urate level from baseline at the final visit was -30·8% in the 120-mg group and 1·6% with placebo, with a between-group difference of -32·4% ([95% confidence interval, -38·9% to -25·9%]; P < 0·001). Incidences of overall adverse events (AEs) in the topiroxostat groups were comparable to those in the placebo group; however, the incidence of AEs in the 120-mg group was statistically lower than that in the placebo group. The incidences of gouty arthritis were not statistically but numerically higher in the topiroxostat 80- and 120-mg groups.. A dose-dependent serum urate-lowering efficacy of topiroxostat was observed in Japanese hyperuricemic male patients with or without gout. Further clinical studies aimed at evaluating the long-term safety and clinical efficacy are warranted.

Topics: Adult; Dose-Response Relationship, Drug; Double-Blind Method; Follow-Up Studies; Gout; Gout Suppressants; Humans; Hyperuricemia; Japan; Male; Middle Aged; Nitriles; Pyridines; Treatment Outcome; Uric Acid; Xanthine Oxidase

There are no clinical reports that have compared topiroxostat, a selective xanthine oxidase inhibitor, with allopurinol in serum urate-lowering efficacy. The aim of this study was to compare the efficacy and safety 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 conducted in Japan. Patients who had inadequate serum urate levels (a gout patient: serum urate level ≥416·4 μmol/L; an asymptomatic hyperuricemic patient with specific complications (urinary lithiasis, hypertension, hyperlipidemia and/or diabetes): serum urate level ≥475·8 μmol/L; and an asymptomatic hyperuricemic patient with no specific complications: serum urate level ≥535·3 μmol/L) were randomized to topiroxostat 120 mg/day or allopurinol 200 mg/day, with an equal allocation ratio, for 16 weeks. To prevent the onset of gouty arthritis by rapid serum urate reduction, these doses were increased in a stepwise manner. The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit.. Overall, 206 patients were randomly assigned to topiroxostat and allopurinol. Two hundred and three patients (allopurinol: n = 105, topiroxostat: n = 98) received at least one dose of the study drug and had their serum urate level assessed at least once. The baseline characteristics were comparable between groups. The mean age of patients was 53·0 ± 11·4 years and 99% of patients were male. The primary efficacy endpoint was -34·3 ± 11·1% in the allopurinol group (n = 105) and -36·3 ± 12·7% in the topiroxostat group (n = 98). Non-inferiority of the serum urate-lowering efficacy of topiroxostat to allopurinol was proved by the predefined non-inferiority margin (95% confidence interval, -5·3 to 1·3%). The overall incidences of adverse events and adverse drug reactions were similar between both groups.. Topiroxostat 120 mg/day provides non-inferior serum urate reduction compared with allopurinol 200 mg/day and is well tolerated in Japanese hyperuricemic patients with or without gout.

Topics: Adult; Aged; Allopurinol; Double-Blind Method; Female; Follow-Up Studies; Gout; Gout Suppressants; Humans; Hyperuricemia; Japan; Male; Middle Aged; Nitriles; Pyridines; Treatment Outcome; Uric Acid; Xanthine Oxidase

Proteinuria is an established risk factor for diabetic nephropathy. Recent studies indicate that some xanthine oxidase inhibitors have a renoprotective effect. The aim of this study was to assess whether topiroxostat reduces albuminuria in hyperuricemic patients with diabetic nephropathy and overt proteinuria. The ETUDE study is an ongoing 24-week, multicenter, open-label, randomized (1:1), parallel group study involving hyperuricemic patients with diabetic nephropathy (estimated glomerular filtration rate [eGFR] ≥ 20 mL/min/1.73 m(2)) and overt proteinuria (0.3 ≤ urine protein to creatinine ratio (UPCR) < 3.5 g/g Cr). Patients are randomly assigned to high dose (topiroxostat 160 mg daily) or low dose (topiroxostat 40 mg daily) on top of standard of care. The primary endpoint is the change in albuminuria indicated by urine albumin-to-creatinine ratio after 24 treated weeks relative to the baseline values. This trial was registered at the Japanese University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR: UMIN 000015403). The background, rationale, and study design of this trial are presented here. Seventy-six patients from four registered facilities have already been enrolled and received at least one dose of topiroxostat. This trial will end in 2017. The ETUDE trial is the first randomized controlled study of topiroxostat in hyperuricemic patients with diabetic nephropathy and overt proteinuria. We will clarify the pleiotropic function of topiroxostat including an anti-albumiuric effect as well as its effects on safely decreasing serum uric acid levels.

Topics: Diabetic Nephropathies; Glomerular Filtration Rate; Humans; Hyperuricemia; Nitriles; Pyridines; Treatment Outcome; Uric Acid

Topiroxostat, a selective xanthine oxidase inhibitor, shows effective reduction in the serum urate level in hyperuricemic patients with or without gout. The objective of this study was to evaluate the efficacy and safety of topiroxostat in hyperuricemic stage 3 chronic kidney disease patients with or without gout.. The study design was a 22-week, randomized, multicenter, double-blind study. The enrolled patients were randomly assigned to treatment with topiroxostat 160 mg/day (n = 62) or to the placebo (n = 61). The endpoints were the percent change in the serum urate level, change in the estimated glomerular filtration rate, the urinary albumin-to-creatinine ratio, the proportion of patients with serum urate levels of 356.88 μmol/L or less, blood pressure, and serum adiponectin.. After 22 weeks, although the changes in the estimated glomerular filtration rate and blood pressure were not significant, the percent change in the serum urate level (-45.38 vs. -0.08 %, P < 0.0001) and the percent change in urinary albumin-to-creatinine ratio (-33.0 vs. -6.0 %, P = 0.0092) were found to have decreased in the topiroxostat as compared with the placebo. Although the incidence of 'alanine aminotransferase increased' was higher in the topiroxostat, serious adverse event rates were similar in the two groups.. Topiroxostat 160 mg effectively reduced the serum urate level in the hyperuricemic stage 3 chronic kidney disease patients with or without gout.

Topics: Adiponectin; Aged; Albuminuria; Blood Pressure; Comorbidity; Creatinine; Double-Blind Method; Enzyme Inhibitors; Female; Glomerular Filtration Rate; Gout; Humans; Hyperuricemia; Male; Middle Aged; Nitriles; Prevalence; Pyridines; Renal Insufficiency, Chronic; Treatment Outcome; Uric Acid; Xanthine Oxidase

Topics: Animals; Enzyme Inhibitors; Febuxostat; Gout; Hyperuricemia; Mice; Triazoles; Xanthine Dehydrogenase; Xanthine Oxidase

Various optimal medical therapies have been established to treat heart failure (HF) with reduced ejection fraction (HFrEF). Both HFrEF and HF with preserved ejection fraction (HFpEF) are associated with poor outcomes. We investigated the effect of topiroxostat, an oral xanthine oxidoreductase inhibitor, for HFpEF patients with hyperuricemia or gout.. In this nonrandomized, open-label, single-arm trial, we administered topiroxostat 40-160 mg/day to HFpEF patients with hyperuricemia or gout to achieve a target uric acid level of 6.0 mg/dL. The primary outcome was rate of change in log-transformed brain natriuretic peptide (BNP) level from baseline to 24 weeks after topiroxostat treatment. The secondary outcomes included amount of change in BNP level, uric acid evaluation values, and oxidative stress marker levels after 24 weeks of topiroxostat treatment. Thirty-six patients were enrolled; three were excluded before study initiation.. Change in log-transformed BNP level was -3.4 ± 8.9% (p = 0.043) after 24 weeks of topiroxostat treatment. The rate of change for the decrease in BNP level was -18.0 (-57.7, 4.0 pg/mL; p = 0.041). Levels of uric acid and 8-hydroxy-2'-deoxyguanosine/creatinine, an oxidative stress marker, also significantly decreased (-2.8 ± 1.6 mg/dL, p < 0.001, and -2.3 ± 3.7 ng/mgCr, p = 0.009, respectively).. BNP level was significantly lower in HFpEF patients with hyperuricemia or gout after topiroxostat administration; however, the rate of decrease was low. Further trials are needed to confirm our findings.

Topics: Aged; Aged, 80 and over; Biomarkers; Gout; Heart Failure; Humans; Hyperuricemia; Middle Aged; Natriuretic Peptide, Brain; Nitriles; Pilot Projects; Pyridines; Stroke Volume; Treatment Outcome; Uric Acid

Topiroxostat, a selective xanthine oxidoreductase inhibitor, is used for the management of hyperuricemic patients with or without gout in Japan. Accumulating evidence has demonstrated the efficacy of topiroxostat for the treatment of hyperuricemia with or without gout. However, the safety and efficacy of topiroxostat in the clinical setting remain unclear, and there is little large-scale clinical evidence. We conducted a post-marketing observational study over 54 weeks.. Patients were centrally enrolled, and case report forms of 4491 patients were collected between April 2014 and March 2019 from 825 medical sites.. Overall, 4329 patients were assessed for safety and 4253 patients for effectiveness. The overall incidence of adverse drug reactions was 6.95%, and the incidence rates of adverse drug reactions of gouty arthritis, hepatic dysfunction, and skin disorders, which are of special interest in this study, were 0.79%, 1.73%, and 0.95%, respectively. No case of serious gouty arthritis was observed. Serum urate levels decreased stably over time and showed a significant reduction rate at 54 weeks (21.19% ± 22.07%) and on the final visit (19.91% ± 23.35%) compared to the baseline. The rates for subjects who achieved serum uric acid levels ≤ 6.0 mg/dL at 18 and 54 weeks after administration were 43.80% and 48.28%, respectively.. This study suggests that there is no particular concern about adverse drug reactions or the efficacy of topiroxostat for hyperuricemic patients with or without gout in a post-marketing setting in Japan.

Topics: Adult; Enzyme Inhibitors; Female; Gout; Gout Suppressants; Humans; Hyperuricemia; Incidence; Japan; Male; Middle Aged; Nitriles; Product Surveillance, Postmarketing; Pyridines; Treatment Outcome; Uric Acid; Xanthine Dehydrogenase

Hyperuricemia is an independent risk factor for renal dysfunction, cardiovascular events, and gouty arthritis. Xanthine oxidoreductase (XOR) inhibitors inhibit uric acid (UA) production and may be treatment options for hyperuricemia patients. I aimed to evaluate the effects of topiroxostat on circulating lipid concentrations in patients with hyperuricemia.. 83 hyperuricemic patients taking topiroxostat were enrolled into this retrospective study.. Serum UA significantly decreased, total cholesterol (TC) decreased, and low-density lipoprotein cholesterol (LDL-c) decreased between baseline and 24 weeks.. Topiroxostat may have the potential to lower serum UA, TC, and LDL-c concentrations in hyperuricemic patients.

Topics: Cholesterol; Cholesterol, LDL; Humans; Hyperuricemia; Lipids; Nitriles; Pyridines; Retrospective Studies; Treatment Outcome; Uric Acid

Topics: Cardiovascular Diseases; Humans; Hypertension; Hyperuricemia; Nitriles; Pyridines; Risk Factors; Uric Acid; Xanthine Oxidase

Xanthine oxidoreductase (XOR) inhibitors, such as allopurinol and febuxostat, inhibit the catalysis of serum uric acid (SUA) synthesis. In doing so, they are thought to improve vascular endothelial function in patients with hyperuricemia and cardiovascular risk by reducing increases in SUA and reactive oxygen species levels. We performed a retrospective cohort study to evaluate the effects of topiroxostat, a novel XOR inhibitor, on vascular function measured by flow-mediated dilation (FMD) on ultrasonography. In total, 23 patients with hyperuricemia were enrolled. After approximately 8 weeks, topiroxostat was associated with a significant increase in the peak percentage change in diameter (∆FMD) from 4.53% ± 2.09% to 5.54% ± 3.08% (P = .045). It also significantly reduced the SUA levels from 7.31 ± 1.43 to 5.44 ± 1.11 mg/dL (P < .001). Although further studies are needed to validate these results, it appears that topiroxostat improves vascular endothelial function in patients with hyperuricemia.

Topics: Biological Availability; Blood Flow Velocity; Enzyme Inhibitors; Female; Humans; Hyperuricemia; Male; Middle Aged; Nitriles; Pyridines; Reproducibility of Results; Retrospective Studies; Ultrasonography, Doppler; Uric Acid; Vasodilation; Xanthine Dehydrogenase

Hyperuricemia is associated with chronic kidney disease (CKD). Although topiroxostat, a novel, non-purine, selective xanthine oxidase inhibitor, has a strong effect against hyperuricemia, limited data are available on its renoprotective effect against CKD.. This study was conducted between October 2014 and May 2016. Thirty patients (20 male, 10 female) were administered 40 mg/day of topiroxostat twice daily. All patients were followed for a year. To elucidate the effects of topiroxostat, we evaluated the clinically documented primary indication of progression, viz. laboratory evidence of kidney function decline (reference indicator), uric acid, and hypertension in different patient groups, separated according to their baseline uProt levels and baseline eGFR.. Topiroxostat treatment resulted in significant reduction in SUA (-1.53 mg/dL), systolic blood pressure (-8.9 mmHg), diastolic blood pressure (-5.0 mmHg), and urinary protein excretion (-795.5 mg/gCr) compared with baseline values. However, serum creatinine and urinary NAG levels, and estimated glomerular filtration rate did not change significantly.. Topiroxostat reduced SUA levels effectively and may exhibit renoprotective effect in hyperuricemic patients with CKD. Further studies are required to clarify whether topiroxostat prevents the progression of renal disease and improves the prognosis of CKD patients.

Topics: Aged; Biomarkers; Blood Pressure; Enzyme Inhibitors; Female; Humans; Hypertension; Hyperuricemia; Incidence; Japan; Kidney; Male; Middle Aged; Nitriles; Proteinuria; Pyridines; Renal Insufficiency, Chronic; Retrospective Studies; Time Factors; Treatment Outcome; Uric Acid; Xanthine Dehydrogenase; Xanthine Oxidase

Topiroxostat, a recently developed xanthine oxidase inhibitor, is expected to have fewer adverse effects than allopurinol because it has different mechanism of action from alloprinol. However, its dosage, usage and safety have not been established in patients with impaired renal function or those undergoing dialysis at the development since no studies was conducted in these patients.. Cross over clinical trial using 3 months of allopurinol and topiroxostat on 27 maintain Japanese HD patients were carried out. The effects on oxidative stress status of both drugs were also evaluated by measuring oxidation reduction potential.. Twenty-five of twenty-seven patients completed study. The mean serum uric acid levels in the topiroxostat-treated arm was significantly lower than it in the allopurinol-treated arm time-dependently (P < 0.0001). Corrected oxidative stress ratio defined as biological antioxidant potential/diacron reactive oxygen metabolites was significantly increased in topiroxostat-arm (*P = 0.0035), but not in allopurinol-arm (P = 0.1429). No significant difference was seen in diacron reactive oxygen metabolites, biological antioxidant potential, static oxidation-reduction potential, and capacity oxidation-reduction potential between pre and post treatment of both drugs.. It is suggested that a low dose of topiroxostat decreased serum uric acid sufficiently to maintain it below 7.0 mg/dL in patients receiving hemodialysis.

Topics: Aged; Enzyme Inhibitors; Female; Humans; Hyperuricemia; Male; Middle Aged; Nitriles; Pyridines; Renal Dialysis; Treatment Outcome; Uric Acid

Topics: Diabetic Nephropathies; Gout; Humans; Hyperuricemia; Nitriles; Pyridines

A diverse library of 1-phenyl-pyrazole-4-carboxylic acid derivatives were synthesized and evaluated for their inhibitory potency against xanthine oxidoreductase (XOR) in vitro and vivo, and the structure-activity relationship (SAR) analyses were also presented. Approximately half of the target compounds exhibited the inhibitory potency for XOR at the nanomolar level. Compounds 16c, 16d, and 16f emerged as the most potent xanthine oxidoreductase inhibitors with IC

Topics: Animals; Carboxylic Acids; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hyperuricemia; Mice; Mice, Inbred ICR; Models, Molecular; Molecular Structure; Oxonic Acid; Pyrazoles; Structure-Activity Relationship; Xanthine Dehydrogenase

To determine the response of hemodialysis (HD) patients to topiroxostat after a switch from febuxostat, we evaluated the efficacy, tolerability, and serum concentration of topiroxostat in HD patients after the switch. In this 16-month prospective observational study, we assessed the serum uric acid (UA) levels, other laboratory data, and serum topiroxostat concentrations of 10 HD patients who had been receiving febuxostat at a dose of 10 mg/d for over 1 year. No statistical difference was observed between the tolerability index at baseline and 16 months after the switch to topiroxostat. Serum UA after the switch in all patients (attained serum UA levels of ≤6 mg/dL) was 5.6±1.7 mg/dL (60%) at baseline, 4.9±0.5 mg/dL (100%) at 6 months and 5.7±0.4 mg/dL (50%) at 16 months (p=0.25), respectively. In patients with baseline serum UA levels >6 mg/dL, serum UA was significantly reduced at 6 and 16 months compared with baseline. Minimum serum concentrations of serum topiroxostat were lower than the limit of quantification (<25 ng/mL). Our results indicate that a switch from febuxostat 10 mg/d to topiroxostat 40 mg/d might reduce serum UA levels, with no change in other clinical laboratory data over the long term. These effects were more frequent in patients with high serum UA levels. Furthermore, topiroxostat therapy was more cost effective than febuxostat therapy. Thus, topiroxostat therapy could be a better treatment option for HD patients who develop high serum UA levels after febuxostat 10 mg/d administration.

Topics: Adult; Aged; Febuxostat; Female; Follow-Up Studies; Humans; Hyperuricemia; Male; Middle Aged; Nitriles; Prospective Studies; Pyridines; Renal Dialysis; Uric Acid; Uricosuric Agents

Hyperuricemia is associated with the progression of chronic kidney disease (CKD) and cardiovascular diseases. Topiroxostat, a selective xanthine oxidase inhibitor, effectively reduces serum uric acid (UA) levels and urinary albumin excretion (UAE) in CKD patients. A 50-year-old Japanese man was referred to our hospital due to albuminuria and hyperuricemia, and renal biopsy showed a typical hyperuricemic arteriolopathy. Treatment with topiroxostat decreased serum UA levels (9.2 mg/dL at baseline to 6.4 mg/dL after 6 months), UAE (388 to 88 mg/g.cr), and urinary level of liver-type fatty acid-binding protein (28.8 to 19.8 µg/g.cr). Interestingly, topiroxostat treatment was associated with a trend towards improved flow-mediated dilation (5.4 to 5.8%). These results suggested that topiroxostat in CKD patients with hyperuricemia is potentially effective, not only for ameliorating renal damages but also for improving endothelial function beyond its UA-lowering action.

Topics: Humans; Hyperuricemia; Male; Middle Aged; Nitriles; Pyridines; Renal Insufficiency, Chronic

Topics: Aged; Aged, 80 and over; Drug Substitution; Enzyme Inhibitors; Febuxostat; Female; Gout Suppressants; Humans; Hyperuricemia; Kidney; Male; Middle Aged; Nitriles; Proteinuria; Pyridines; Renal Insufficiency, Chronic; Treatment Outcome; Xanthine Dehydrogenase; Xanthine Oxidase

Inhibition of xanthine oxidase (XO) has obviously been a central concept for controlling hyperuricemia, which causes serious and painful inflammatory arthritis disease such as gout. We discovered a series of novel 2-(indol-2-yl)thiazole derivatives as XO inhibitors at the level of nanomolar activity. Structure-guided design using molecular modeling program (Accelrys Software program) provided an excellent basis for optimization of 2-(indol-2-yl)thiazole compounds. Structure-activity relationship indicated that hydrophobic alkoxy group (isopropoxy, cyclopentoxy) at 5-position and hydrogen binding acceptor (NO2, CN) at 7-position of indole ring appear as critical functional groups. Among the compounds, 2-(7-nitro-5-isopropoxy-indol-2-yl)-4-methylthiazole-5-carboxylic acid (9m) exhibits the most potent XO inhibitory activity (IC50 value: 5.1 nM) and the excellent uric acid lowering activity in potassium oxonate induced hyperuricemic rat model.

Topics: Administration, Oral; Animals; Binding Sites; Cattle; Drug Design; Enzyme Inhibitors; Half-Life; Hyperuricemia; Microsomes, Liver; Molecular Docking Simulation; Protein Structure, Tertiary; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thiazoles; Uric Acid; Xanthine Oxidase

Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder caused by mutations in UMOD that encodes uromodulin. Topiroxostat, a novel non-purine analog, selectively inhibits xanthine oxidase and reduces the serum uric acid levels and the urinary albuminuria.. Genomic DNA of a patient was extracted from peripheral white blood. Exons and flanking sequences of UMOD were amplified by PCR with primers. Mutation analysis was performed by direct sequencing of the PCR products. The wild-type and mutant uromodulin were expressed in HEK293 cells and analyzed by western blotting, immunoprecipitation, immunofluorescence, and flow cytometry.. We identified an FJHN patient who carried a novel UMOD mutation G335A (C112Y). The levels of both cytosolic and secreted C112Y protein were significantly decreased compared with the wild-type, whereas the level of ubiquitination was higher in C112Y than that in the wild type. The half-life of C112Y was shortened and it was restored by a proteasome inhibitor MG132. Immunofluorescence revealed decreased levels of C112Y in the Golgi apparatus and on the plasma membrane. Expression of C112Y induced cellular apoptosis as revealed by flow cytometry. Apoptosis induced by C112Y was suppressed by topiroxostat.. C112Y causes its protein instability resulting cellular apoptosis which could be suppressed with topiroxostat.

Topics: Adult; Apoptosis; Gout; HEK293 Cells; Humans; Hyperuricemia; Kidney Diseases; Male; Mutation; Nitriles; Proteasome Endopeptidase Complex; Pyridines; Uromodulin

Topics: Enzyme Inhibitors; Febuxostat; Humans; Hyperuricemia; Nitriles; Pyridines; Renal Insufficiency, Chronic; Thiazoles; Treatment Outcome; Uric Acid; Xanthine Oxidase

Our previous study identified 2-[2-(2-methoxyethoxy)ethoxy]-5-[5-(2-methyl-4-pyridyl)-1H-[1,2,4] triazol-3-yl]benzonitrile (2)[corrected]as a safe and potent xanthine oxidoreductase (XOR) inhibitor for the treatment of hyperuricemia. Here, we synthesized a series of 3,5-dipyridyl-1,2,4-triazole derivatives and, in particular, examined their in vivo activity in lowering the serum uric acid levels in rats. As a result, we identified 3-(2-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole (FYX-051, compound 39) [corrected] to be one of the most potent XOR inhibitors; it exhibited an extremely potent in vivo activity, weak CYP3A4-inhibitory activity and a better pharmacokinetic profile than compound 2. Compound 39 is currently being evaluated in a phase 2 clinical trial.

Topics: Administration, Oral; Animals; Binding Sites; Crystallography, X-Ray; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Design; Enzyme Inhibitors; Humans; Hyperuricemia; Nitriles; Pyridines; Rats; Structure-Activity Relationship; Xanthine Dehydrogenase