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Background: We investigate whether Intensive uric acid (UA)-lowering therapy (ULT) provides increased renal protection compared with standard therapy in chronic kidney disease (CKD) patients., Methods: This was a multicenter randomized controlled trial. Only CKD patients with hyperuricemia were included in this study. The participants were randomly assigned to either the Intensive therapy group (target serum UA level ≥ 4.0 mg/dL and < 5.0 mg/dL) or the standard therapy group (serum UA level ≥ 6.0 mg/dL and < 7.0 mg/dL). ULT was performed using topiroxostat, a non-purine-type selective xanthine oxidase inhibitor. The primary endpoint was change in the logarithmic value of urine albumin to the creatinine ratio (ACR) between baseline and week 52 of the treatment., Results: Three hundred fifty-two patients were included in the full analysis set. In the Standard therapy group, mean serum UA was 8.23 mg/dL at baseline and 6.13 mg/dL at 52 weeks. In the Intensive therapy group, mean serum UA was 8.15 mg/dL at baseline and 5.25 mg/dL at 52 weeks. There was no significant difference in changes in log ACR at 52 weeks between the Intensive therapy and the Standard therapy groups., Conclusion: This study did not reveal the benefit of Intensive ULT to improve albuminuria levels. (UMIN000026741 and jRCTs051180146)., (© 2024. The Author(s).)

Insulin resistance (IR) promotes atherosclerosis and increases the risk of diabetes and cardiovascular diseases. Our previous studies have demonstrated that high uric acid (HUA) increased oxidative stress, leading to IR in cardiomyocytes and pancreatic β cells. However, whether HUA can induce IR in monocytes/macrophages, which play critical roles in all stages of atherosclerosis, is unclear. Recent findings revealed that thioredoxin-interacting protein (TXNIP) negatively regulates insulin signaling; however, the roles and mechanisms of TXNIP in HUA-induced IR remain unclear. Therefore, in this study, we investigated the function of TXNIP in macrophages treated with UA. Transcriptomic profiling revealed TXNIP as one of the most upregulated genes, and subsequent RT-PCR and Western blot analyses confirmed that TXNIP was upregulated by HUA. HUA treatment significantly increased mitochondrial reactive oxygen species (MtROS) levels and decreased insulin-stimulated glucose uptake. Silencing TXNIP by RNA interference significantly diminished HUA-induced oxidative stress and IR. Mechanistically, silencing TXNIP reversed the inhibition of the phosphorylation of insulin receptor substrate 2 (IRS2)/protein kinase B (AKT) pathway induced by HUA. Additional study revealed that HUA induced the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway, but silencing TXNIP abolished it. Moreover, Nrf2 inhibitor (ML385) ameliorated HUA-induced IR independent of IRS2/AKT signaling. Probenecid, a well-known UA-lowering drug, significantly suppressed the activation of TXNIP and Nrf2/HO-1 signaling. Furthermore, RNA-seq revealed that activation of the TXNIP-related redox pathway may be a key regulator in patients with asymptomatic hyperuricemia. These data suggest that silencing TXNIP could ameliorate HUA-induced IR via the IRS2/AKT and Nrf2/HO-1 pathways in macrophages. Additionally, TXNIP might be a promising therapeutic target for preventing and treating oxidative stress and IR induced by HUA., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Uric acid is the end metabolite derived from the oxidation of purine compounds. Overwhelming evidence shows the vital interrelationship between hyperuricemia (HUA) and nonalcoholic fatty liver disease (NAFLD). However, the mechanisms for this association remain unclear. In this study, we established a urate oxidase-knockout (Uox-KO) mouse model by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 technology. To study the correlation between HUA and NAFLD, human HepG2 hepatoma cells were treated in culture medium with high level of uric acid. In vivo, the Uox-KO mice spontaneously developed hyperuricemia and aberrant lipid-metabolism, concomitant with abnormal hepatic fat accumulation. HUA activated c-Jun N-terminal kinase (JNK) in vivo and in vitro. Furthermore, inhibiting JNK activation by a JNK-specific inhibitor, SP600125, decreased fat accumulation and lipogenic gene expression induced by HUA. Overexpression of the lipogenic enzymes fatty acid synthase and acetyl-CoA carboxylase 1 was via activation of JNK, which was blocked by the JNK inhibitor SP600125. HUA activated AP-1 to upregulate lipogenic gene expression via JNK activation. In addition, HUA caused mitochondrial dysfunction and reactive oxygen species production. Pretreatment with the antioxidant N -acetyl-l-cysteine could ameliorate HUA-activated JNK and hepatic steatosis. These data suggest that ROS/JNK/AP-1 signaling plays an important role in HUA-mediated fat accumulation in liver. NEW & NOTEWORTHY Hyperuricemia and nonalcoholic fatty liver disease are global public health problems, which are strongly associated with metabolic syndrome. In this study, we demonstrate that uric acid induces hepatic fat accumulation via the ROS/JNK/AP-1 pathway. This study identifies a new mechanism of NAFLD pathogenesis and new potential therapeutic strategies for HUA-induced NAFLD.

Mounting evidence has implicated inflammation in ischemia-reperfusion injury following acute ischemic stroke (AIS). Microglia remain the primary initiator and participant of brain inflammation. Emerging evidence has indicated that uric acid has promise for the treatment of AIS, but its explicit mechanisms remain elusive. Here, we observed that uric acid reduced the severity of cerebral infarction and attenuated the activation of microglia in the cerebral cortex in a mouse middle cerebral-artery occlusion/reperfusion model. Thus, we speculated that uric acid may play a role by directly interfering with the inflammatory response of microglia. First, we investigated whether the HMGB1-TLR4-NF-κB signaling plays a role in oxygen glucose deprivation and reperfusion (OGD/R) injury of BV2 cells. Inhibition of the signaling significantly reduced the release of the proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin 1β (IL1β), and IL6 caused by OGD/R in BV2 cells. Second, uric acid weakened the decreased cell viability and lactate dehydrogenase release induced by OGD/R in BV2 cells. Finally, uric acid reduced the release of the proinflammatory cytokines TNF-α, IL1β, and IL6 caused by OGD/R in BV2 cells by dampening HMGB1-TLR4-NF-κB signaling, which was reversed by probenecid treatment, an inhibitor of the uric acid channel. Hence, uric acid halted the release of inflammatory factors and the decreased cell viability induced by ODG/R via inhibiting the microglia HMGB1-TLR4-NF-κB signaling, thereby alleviating the damage to microglia. This may be part of the molecular mechanisms by which uric acid protects mice against the brain damage of middle cerebral-artery occlusion/reperfusion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hyperuricaemia is a disorder of purine metabolism. Elevated serum uric acid is strongly associated with many diseases, including gout, abdominal obesity, insulin resistance, and cardiovascular and kidney disease. Our previous studies showed that high uric acid (HUA) induced insulin resistance in several peripheral organs, including the liver, myocardium and adipose tissue. However, whether HUA directly induces insulin resistance of pancreatic β cells, the only source of insulin in the body and also a sensitive insulin target, is unknown. In this study, pancreatic β cells pretreated with HUA showed impaired insulin expression/secretion, glucose uptake and the glycolytic pathway. RNA-seq revealed that HUA affected the biological processes of INS-1 cells broadly, including oxidoreduction coenzyme metabolic process, pyruvate metabolic process, and glycolytic process. In addition, HUA reduced mitochondrial membrane potential and increased the production of reactive oxygen species(ROS) in INS-1 cells. INS-1 cells pretreated with probenecid, an organic anion transporter inhibitor, protected INS-1 cells against HUA-induced insulin secretion decrease, Pretreatment with N-acetyl-L-cysteine(NAC), a globally used antioxidant, recovered HUA-decreased insulin secretion and glucose uptake by pancreatic β cells. Insulin-like growth factor 1 (IGF-1), the phosphatidylinositol 3-kinase (PI3K) activator, rescues HUA-decreased insulin secretion by re-activating AKT phosphorylation. Thus, HUA induce insulin resistance, impaired insulin secretion and glycolytic pathway of pancreatic ꞵ cell through IRS2/AKT pathway., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Inositol hexaphosphate (IP 6 ), a food constituent with various health benefits, has been shown to suppress postprandial elevations of serum uric acid (SUA) levels in healthy adults by inhibiting purine nucleoside and base absorption. Here, we investigated the effect of repeated intake of IP 6 on fasting SUA levels in hyperuricemic subjects. This randomized double-blind placebo-controlled crossover design study included 31 asymptomatic hyperuricemic subjects (fasting SUA level > 7.0 but <9.0 mg/dL). Subjects ingested placebo or IP 6 drinks (600 mg twice daily) during two 2-week intervention periods with a 2-week washout period. The primary outcome was fasting SUA level; the secondary outcome was the urinary uric acid to creatinine ratio. Fasting SUA levels in the IP 6 group were lower than those in the placebo group (p < 0.05). The urinary uric acid to creatinine ratio did not change between the placebo and IP 6 groups (p > 0.05). This study showed that a 2-weeks supplementation period of 600 mg IP 6 twice daily can improve fasting SUA levels in hyperuricemic subjects.

Hyperuricemia occurs together with abnormal glucose metabolism and insulin resistance. Skeletal muscle is an important organ of glucose uptake, disposal, and storage. Metformin activates adenosine monophosphate-activated protein kinase (AMPK) to regulate insulin signaling and promote the translocation of glucose transporter type 4 (GLUT4), thereby stimulating glucose uptake to maintain energy balance. Our previous study showed that high uric acid (HUA) induced insulin resistance in skeletal muscle tissue. However, the mechanism of metformin ameliorating UA-induced insulin resistance in muscle cells is unknown and we aimed to determine it. In this study, differentiated C2C12 cells were exposed to UA (15 mg/dl), then reactive oxygen species (ROS) was detected with DCFH-DA and glucose uptake with 2-NBDG. The levels of phospho-insulin receptor substrate 1 (IRS1; Ser307), phospho-AKT (Ser473) and membrane GLUT4 were examined by western blot analysis. The impact of metformin on UA-induced insulin resistance was monitored by adding Compound C, an AMPK inhibitor, and LY294002, a PI3K/AKT inhibitor. Our data indicate that UA can increase ROS production, inhibit IRS1-AKT signaling and insulin-stimulated glucose uptake, and induce insulin resistance in C2C12 cells. Metformin can reverse this process by increasing intracellular glucose uptake and ameliorating UA-induced insulin resistance., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Clinical studies have shown hyperuricemia strongly associated with insulin resistance as well as cardiovascular disease. Direct evidence of how high uric acid (HUA) affects insulin resistance in cardiomyocytes, but the pathological mechanism of HUA associated with cardiovascular disease remains to be clarified. We aimed to examine the effect of HUA on insulin sensitivity in cardiomyocytes and on insulin resistance in hyperuricemic mouse model. We exposed primary cardiomyocytes and a rat cardiomyocyte cell line, H9c2 cardiomyocytes, to HUA, then quantified glucose uptake with a fluorescent glucose analog, 2-NBDG, after insulin challenge and detected reactive oxygen species (ROS) production. Western blot analysis was used to examine the levels of insulin receptor (IR), phosphorylated insulin receptor substrate 1 (IRS1, Ser307) and phospho-Akt (Ser473). We monitored the impact of HUA on insulin resistance, insulin signaling and IR, phospho-IRS1 (Ser307) and phospho-Akt levels in myocardial tissue of an acute hyperuricemia mouse model established by potassium oxonate treatment. HUA inhibited insulin-induced glucose uptake in H9c2 and primary cardiomyocytes. It increased ROS production; pretreatment with N-acetyl-L-cysteine (NAC), a ROS scavenger, reversed HUA-inhibited glucose uptake induced by insulin. HUA exposure directly increased the phospho-IRS1 (Ser307) response to insulin and inhibited that of phospho-Akt in H9C2 cardiomyocytes, which was blocked by NAC. Furthermore, the acute hyperuricemic mice model showed impaired glucose tolerance and insulin tolerance accompanied by increased phospho-IRS1 (Ser307) and inhibited phospho-Akt response to insulin in myocardial tissues. HUA inhibited insulin signaling and induced insulin resistance in cardiomyocytes in vitro and in vivo, which is a novel potential mechanism of hyperuricemic-related cardiovascular disease.

Background/aims: Hyperuricemia is part of the metabolic-syndrome cluster of abdominal obesity, impaired glucose tolerance, insulin resistance, dyslipidemia, and hypertension. Monocytes/macrophages are critical in the development of metabolic syndrome, including gout, obesity and atherosclerosis. However, how high uric acid (HUA) exposure affects monocyte/macrophage function remains unclear. In this study, we investigated the molecular mechanism of HUA exposure in monocytes/macrophages and its impact on oxidized low-density lipoprotein (oxLDL)-induced foam-cell formation in a human monocytic cell line, THP-1., Methods: We primed THP-1 cells with phorbol-12-myristate-13-acetate (PMA) for differentiation, then exposed cells to HUA and detected the production of reactive oxygen species (ROS) and analyzed the level of phospho-AMPKα. THP-1 cells were pre-incubated with Compound C, an AMPK inhibitor, or N-acetyl-L-cysteine (NAC), a ROS scavenger, or HUA before PMA, to assess CD68 expression and phospho-AMPKα level. PMA-primed THP-1 cells were pre-treated with oxLDL before Compound C and HUA treatment. Western blot analysis was used to examine the levels of phospho-AMPKα, CD68, ABCG1, ABCA1, cyclooxygenase-2 (COX-2) and NF-κB (p65). Flow cytometry was used to assess ROS production and CD68 expression in live cells. Oil-red O staining was used to observe oxLDL uptake in cells., Results: HUA treatment increased ROS production in PMA-primed THP-1 cells; NAC blocked HUA-induced oxidative stress. HUA treatment time-dependently increased phospho-AMPKα level in PMA-primed THP-1 cells. The HUA-induced oxidative stress increased phospho-AMPKα levels, which was blocked by NAC. HUA treatment impaired CD68 expression during cell differentiation by activating the AMPK pathway, which was reversed by Compound C treatment. Finally, HUA treatment inhibited oxLDL uptake in the formation of foam cells in THP-1 cells, which was blocked by Compound C treatment. HUA treatment significantly increased the expression of ABCG1 and reversed the oxLDL-reduced ABCG1 expression but did not affect the expression of ABCA1, NF-κB (p65) or COX-2., Conclusions: HUA exposure activated the ROS-AMPK pathway, impaired CD68 expression, and inhibited oxLDL-induced foam-cell formation in a human monocytic cell line, THP-1., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

Objective: We assessed the efficacy and adverse effects of febuxostat in male hyperuricemia patients., Subjects and Methods: This was a 12-week, multicenter, open-label, uncontrolled study. The enrolled subjects were 89 hyperuricemic male patients (12 overexcretors, 56 normal excretors, and 21 underexcretors). The endpoint was percent change in serum urate level., Results: The concentration of urate in serum before and 12 weeks after beginning administration of febuxostat in the overexcretors was 9.34 ± 1.48 and 5.59 ± 1.17 mg/dl, respectively, while those were 8.59 ± 1.24 and 5.41 ± 1.35 mg/dl, respectively, in the normal excretors, and 8.29 ± 1.01and 5.11 ± 1.71 mg/dl, respectively, in the underexcretors. After 12 weeks, the rate of change in serum urate after beginning administration of febuxostat was - 0.384 ± 0.186 in the overexcretors, - 0.368 ± 0.128 in the normal excretors, and - 0.365 ± 0.217 in the underexcretors, with no significant differences among them. A common adverse event related to febuxostat was gout flare., Conclusion: Febuxostat effectively reduced the concentration of urate in serum in hyperuricemic patients regardless of the level of uric acid excreted in urine without severe adverse effects.

Background: 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., Methods: 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., Results: 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., Conclusion: Topiroxostat 160 mg effectively reduced the serum urate level in the hyperuricemic stage 3 chronic kidney disease patients with or without gout.

Background and Aim: Accumulating clinical evidence suggests that hyperuricemia is strongly associated with abnormal glucose metabolism and insulin resistance. However, how high uric acid (HUA) level causes insulin resistance remains unclear. We aimed to determine the direct role of HUA in insulin resistance in vitro and in vivo in mice., Methods: An acute hyperuricemia mouse model was created by potassium oxonate treatment, and the impact of HUA level on insulin resistance was investigated by glucose tolerance test, insulin tolerance test and insulin signalling, including phosphorylation of insulin receptor substrate 1 (IRS1) and Akt. HepG2 cells were exposed to HUA treatment and N-acetylcysteine (NAC), reactive oxygen species scavenger; IRS1 and Akt phosphorylation was detected by Western blot analysis after insulin treatment., Results: Hyperuricemic mice showed impaired glucose tolerance with insulin resistance. Hyperuricemia inhibited phospho-Akt (Ser473) response to insulin and increased phosphor-IRS1 (Ser307) in liver, muscle and fat tissues. HUA induced oxidative stress, and the antioxidant NAC blocked HUA-induced IRS1 activation and Akt inhibition in HepG2 cells., Conclusion: This study supplies the first evidence of HUA directly inducing insulin resistance in vivo and in vitro. Increased uric acid level may inhibit IRS1 and Akt insulin signalling and induce insulin resistance. The reactive oxygen species pathway plays a key role in HUA-induced insulin resistance., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Hyperuricaemia is a disorder of purine metabolism, and is strongly associated with insulin resistance and abnormal glucose metabolism. As the producer of insulin, pancreatic β cells might be affected by elevated serum uric acid levels and contribute to the disregulated glucose metabolism. In this study, we investigated the effect of high uric acid on rat pancreatic β cell function. Under high uric acid condition, proliferation of pancreatic β cells was inhibited, production of reactive oxygen species increased, and glucose stimulated insulin secretion was also compromised. Further examination on signal transduction pathways revealed that uric acid-induced ROS is involved in the activation of adenosine monophosphate-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK). Pharmacological inhibition of ERK activation rescued β cells from growth inhibition. More importantly, activation of ERK induced by uric acid is significantly diminished by AMPK inhibitor, indicating ERK as a downstream target of AMPK in response to high uric acid condition. We also investigated the transportation channel for uric acid into pancreatic β cells. While major urate transporter URAT1 is not expressed in β cells, organic anion transporter (OAT) inhibitor successfully blocked the activation of ERK by uric acid. Our data indicate that high uric acid levels induce oxidative damage and inhibit growth of rat pancreatic β cells by activating the AMPK and ERK signal pathways. Hyperuricemia may contribute to abnormal glucose metabolism by causing oxidative damage and function inhibition of pancreatic β cells., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Although hyperuricemia is suggested to increase allantoin production in both pro- and antioxidant manners, it remains undetermined whether it increases the serum concentration of allantoin. In addition, since uric acid has both pro- and antioxidant actions, a decrease in the serum concentration of uric acid may have an effect on the pro-oxidant-antioxidant balance., Methods: To examine whether serum allantoin is correlated with serum urate, we measured those levels as well as other parameters in 63 healthy subjects. In addition, to determine whether serum allantoin is correlated with reactive oxygen species (ROS) biomarkers, we measured 8-hydroxy deoxyguanosine and 15-F2t-isoprostane, markers of ROS, in urine samples from 30 gout patients before and 1 year after benzbromarone treatment (50 mg/d)., Results: The serum concentration of allantoin was correlated with that of urate in healthy subjects (R = 0.27, p < 0.05). Benzbromarone treatment in the patients decreased the concentrations of allantoin and urate in serum by 17% (p < 0.05) and 49% (p < 0.05), respectively, and the benzbromarone-induced change in serum allantoin was correlated with that in serum urate (R = 0.39, p < 0.05). However, benzbromarone treatment did not change the ratios of 8-hydroxydeoxyguanosine/creatinine or 15-F2t-isoprostane/creatinine in urine., Conclusions: Our findings suggest that hyperuricemia contributes to an increase in serum concentration of allantoin, though they do not indicate that hyperuricemia is a major factor for controlling oxidative stress in vivo.

Background: Allopurinol has been widely used for treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat is potentially a safe and efficacious alternative., Objectives: Febuxostat or allopurinol was administered to patients with hyperuricemia including gout for 8 weeks to compare the efficacy and safety of these drugs., Methods: Doses of febuxostat and allopurinol were 10 and 100 mg/d, respectively, during a 12-day introduction period and were increased to 40 and 200 mg/d for the subsequent treatment period of 44 days., Results: : The percent changes in serum uric acid levels after 8 weeks were -40.75% for the febuxostat group and -34.41% for the allopurinol group (P < 0.001, analysis of variance, closing testing procedure). The percentage of patients achieving serum uric acid levels 6.0 mg/dL or less after 8 weeks was 82.0% for the febuxostat group and 70.0% for the allopurinol group (P = 0.019, logistic regression analysis). Regarding safety, 213 adverse events were observed in the febuxostat group and 220 events in the allopurinol group. For 10 patients (8.2%) in the febuxostat group and 14 patients (11.6%) in the allopurinol group, association with the study drugs could not be ruled out. There were no severe adverse drug reactions in the febuxostat group other than a high frequency of gout attacks induced by the sudden reduction in blood uric acid levels during the early treatment period., Conclusions: Febuxostat at 40 mg/d demonstrated more potent hypouricemic effects than allopurinol at 200 mg/d, was efficacious regardless of medical history of gout, and is considered safe for treatment of hyperuricemia.

Background: Allopurinol has been widely used for the treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat has been identified as a potentially safe and efficacious alternative., Objectives: A multicenter study with randomized, placebo-controlled, double-blind, parallel, intergroup comparison was carried out to evaluate the dose-response relationship, efficacy, and safety of febuxostat in 202 patients with hyperuricemia (including patients with gout) in Japan., Methods: The subjects were treated with febuxostat at fixed maintenance doses (20-80 mg/d) or a placebo for 16 weeks. The percentage of patients achieving serum uric acid levels 6.0 mg/dL or less and the percent change in serum uric acid levels after 16 weeks of treatment were evaluated., Results: The percentage of patients achieving serum uric acid levels 6.0 mg/dL or less at 16 weeks was 87.8% in the 80-mg/d dose group, 83.3% in the 60-mg/d group, 82.9% in the 40-mg/d group, 46.5% in the 20-mg/d group, and 2.6% in the placebo group (P < 0.001, Mantel-Haenszel test). A statistically significant dose-response relationship was found. The percent change in serum uric acid levels after 16 weeks of treatment differed significantly between each febuxostat dose group and the placebo group and increased in a dose-dependent manner above 40 mg/d. No deaths, events posing a clinical problem, or serious adverse reactions attributable to febuxostat were noted. Similar results were obtained regardless of gout history., Conclusions: Febuxostat can safely reduce serum uric acid levels to 6.0 mg/dL or less in 80% or more of patients with hyperuricemia (including gout) at doses of 40 mg/d or higher.

Background: Allopurinol has been widely used for the treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat has been identified as a potentially safe and efficacious alternative., Objectives: Febuxostat was administered to patients with hyperuricemia including gout in Japan to compare its efficacy and safety with those of allopurinol., Methods: The starting dose of febuxostat and allopurinol was 10 and 100 mg/d, respectively, and was increased to the fixed maintenance dose of 40 or 60 mg/d for febuxostat and 300 mg/d for allopurinol for 16 weeks., Results: : The percent change in the serum uric acid level at 16 weeks compared with the baseline serum uric acid level was -42.96% ± 13.33% and -52.47% ± 9.79% for the febuxostat 40- and 60-mg/d groups, respectively, and -36.55% ± 18.59% for the allopurinol group, indicating that the hypouricemic effects of febuxostat increased in a dose-dependent manner and equaled to or surpassed those of allopurinol (P = 0.0239, 2-sample t test). The percentage of patients with serum uric acid levels of 6.0 mg/dL or less at 16 weeks was 88.9% and 100% for the febuxostat 40- and 60-mg/d groups, respectively, and 68.8% for the allopurinol group, showing higher achievements for the febuxostat groups compared with the allopurinol group. All adverse drug reactions were mild to moderate in severity, and there were no severe symptoms or reactions leading to drug discontinuation., Conclusions: These results suggest that febuxostat is safe at doses of 40 and 60 mg/d and has equal or greater efficacy than 300 mg/d allopurinol.

Background: : Allopurinol has been widely used for treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat has been identified as a potentially safe and efficacious alternative., Objectives: : A multicenter study with randomized, placebo-controlled, double-blind, parallel-group comparison was carried out to evaluate the efficacy and safety of febuxostat in 103 patients with hyperuricemia (including patients with gout) in Japan., Methods: : Subjects were treated with febuxostat (20 or 40 mg/d) or a placebo for 8 weeks. The variables evaluated were the percentage of patients achieving serum uric acid levels 6.0 mg/dL or less and the percent change in serum uric acid levels after 8 weeks., Results: : The percentage of patients achieving serum uric acid levels 6.0 mg/dL or less after 8 weeks was 91.2% in the febuxostat 40-mg/d group, 45.7% in the 20-mg/d group, and 0.0% in the placebo group. The percent changes in serum uric acid levels after 8 weeks were -44.9% in the febuxostat 40-mg/d group, -28.9% in the 20-mg/d group, and -0.6% to -0.5% in the placebo group. No severe or medically significant adverse reaction attributable to febuxostat was noted, and there was no event that could pose a clinical problem. The efficacy did not differ depending on the presence/absence of gout history., Conclusions: : These results suggest that febuxostat (20 or 40 mg/d) is useful as a new means of treating hyperuricemia and is capable of reducing serum uric acid levels to 6.0 mg/dL or less (goal of treatment) with high safety regardless of the presence/absence of gout history.

Background: In previous clinical studies of hyperuricemia including gout, although serum uric acid (sUA) levels reduced to 6.0 mg/dL or less in about 80% of patients treated with 40 mg/d febuxostat, a nonpurine selective xanthine oxidase inhibitor, a few patients did not show this result., Objective: The objective of the study was to evaluate the efficacy and safety of long-term febuxostat administration at up to 60 mg/d in patients with hyperuricemia and gout., Methods: In a 52-week, multicenter, open-label trial, febuxostat was initially administered at 10 mg/d; then, the dosage was increased in a stepwise fashion to 40 mg/d. For sUA levels greater than 6.0 mg/dL at week 10, the dosage was increased to 60 mg/d from week 14 onward (60-mg group), but it was maintained at 40 mg/d until the end of the study for patients with sUA levels 6.0 mg/dL or less at week 10 (40-mg group)., Results: The sUA levels in both groups decreased dose dependently. At 52 weeks, 84.5% and 85.0% of the 40- and 60-mg groups, respectively, achieved mean sUA levels 6.0 mg/dL or less. There was no marked difference between the 2 dosage groups in terms of the incidence of adverse events. Furthermore, there were no noteworthy adverse events or adverse drug reactions in the patients with renal dysfunction, and no differences in drug efficacy up to 60 mg/d were noted between the patients with moderate or mild renal dysfunction and those with normal renal function., Conclusions: Febuxostat seems to be a promising therapeutic drug for gout or hyperuricemia, even in patients with renal dysfunction.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Image duplication has been observed within Figure 3. The corresponding author has been asked to provide an acceptable explanation for this duplication but has not been able to do so, neither have the original source files been supplied.

There are many factors that contribute to hyperuricemia, including obesity, insulin resistance, alcohol consumption, diuretic use, hypertension, renal insufficiency, genetic makeup, etc. Of these, alcohol (ethanol) is the most important. Ethanol enhances adenine nucleotide degradation and increases lactic acid level in blood, leading to hyperuricemia. In beer, purines also contribute to an increase in plasma uric acid. Although rare, dehydration and ketoacidosis (due to ethanol ingestion) are associated with the ethanol-induced increase in serum uric acid levels. Ethanol also increases the plasma concentrations and urinary excretion of hypoxanthine and xanthine via the acceleration of adenine nucleotide degradation and a possible weak inhibition of xanthine dehydrogenase activity. Since many factors such as the ALDH2*1 gene and ADH2*2 gene, daily drinking habits, exercise, and dehydration enhance the increase in plasma concentration of uric acid induced by ethanol, it is important to pay attention to these factors, as well as ingested ethanol volume, type of alcoholic beverage, and the administration of anti-hyperuricemic agents, to prevent and treat ethanol-induced hyperuricemia.

Background: Uric acid is a strong scavenger of reactive oxygen species, which are known to contribute to the development of atherosclerosis, while the incidence of atherosclerotic diseases is rather high in patients with gout. Among the established risk factors for atherosclerosis, oxidized LDL is believed to play a major role in its development and progression. Allopurinol and its active metabolite, oxypurinol, have been suggested to possess an antioxidant ability to scavenge the hydroxyl radical. Therefore, allopurinol may be beneficial in the prevention of LDL oxidation, as well as in the treatment of hyperuricemia. The objective of this work was to determine the degree of LDL oxidation in gout and the effect of allopurinol on LDL oxidation., Methods: Age-matched male patients with primary intercritical gout and healthy male adults were included in the study. The serum concentrations of oxidized LDL autoantibodies and total antioxidant status were measured using an enzyme immunoassay., Results: Serum concentrations of oxidized LDL autoantibodies were significantly higher in patients with gout than the control subjects (p < 0.05) and were significantly decreased after allopurinol treatment (p < 0.05), but not by benzbromarone treatment, in spite of the similar concentrations of uric acid and total antioxidant status in serum following their separate administration., Conclusions: Although the exact mechanism remains unclear, increased serum concentrations of oxidized LDL may play a role in the high incidence of coronary artery disease in gout. In addition, allopurinol may be more preferable to benzbromarone for treatment of gout in light of its inhibitory action toward LDL oxidation.

Objective: The acute effects of the angiotensin II receptor antagonist losartan on uric acid and oxypurine metabolism were evaluated., Methods: Losartan (50 mg) was administered orally to 6 healthy males. Blood and urine samples for uric acid and oxypurine were collected before and up to 6 hours after losartan administration. The same examinations were performed later using enalapril (5 mg)., Results: Losartan decreased the serum uric acid concentration (from 5.9 +/- 0.9 to 5.2 +/- 1.0 mg/dl) and increased its fractional clearance, which reached a maximum after 2 hours, while enalapril did not. Losartan also induced an increase in the plasma concentration of hypoxanthine, peaking in the fourth hour, and a decrease in its urinary clearance, while the plasma xanthine concentration and its urinary clearance were unchanged. The extent of uric acid excretion was much greater than that of the oxypurines., Conclusions: Losartan, which has a high affinity for the urate/anion exchanger, has a transient uricosuric effect. Our data indicate that losartan induces a significant decrease in the urinary excretion of hypoxanthine without changes in xanthine.

Objective: To develop a simple means of selecting gout patients for treatment with uricosuric agents., Methods: In 124 gout patients, spot urine and blood were sampled before breakfast and after overnight fast (except water) on the day of 24 h urine collection. Spot urine uric acid/creatinine ratio (Ua/Cr mmol/mmol) and serum creatinine x Ua/Cr (Scr*Ua/Cr micromol/l) were calculated together with 24 h urinary uric acid excretion/body surface (24 Ua/S). The patients were then classified either below or above 2.84 mmol/m2/day for 24 Ua/S., Results: Classifications based on spot urine Ua/Cr (cut off value set at 0.34), spot urine Scr*Ua/Cr (cut off value set at 28.1), and a combination of spot urine Ua/Cr and Scr*Ua/Cr were found to be not significantly different in diagnostic accuracy for the detection of patients with 24 Ua/S below 2.84 mmol/m2 (77%, 81%, and 81%, respectively) and sensitivity (80%, 83%, and 76%, respectively). However, specificity by a combination of spot urine Ua/Cr, and spot urine Scr*Ua/Cr was higher than by spot urine Ua/Cr alone (91% vs 74%, P < 0.05), although the specificity was not significantly different between a combination and spot urine Scr*Ua/Cr alone (91% vs 78%) or between spot urine Ua/Cr and spot urine Scr*Ua/Cr (74% vs 78%)., Conclusion: A combination of spot urine Ua/Cr and spot urine Scr*Ua/Cr may be clinically useful in selecting gout patients with 24 Ua/S below 2.84 mmol/m2 for treatment with uricosuric agents without adverse effects.

To examine whether inosine increases the plasma concentration of uridine, 20 mg/kg body weight of inosine was orally administered to 5 healthy subjects. The plasma concentration of uridine was increased by 1.25-fold (P <.05), while that of hypoxanthine, xanthine, and uric acid was increased by 1.26-fold (P <.01), 1.26-fold (P <.01), and 1.2-fold (P <.05), respectively, 2.5 hours after the oral administration of inosine. In addition, the 1-hour urinary excretion of uridine was increased by 1.17-fold (P <.05) and that of hypoxanthine, xanthine, and uric acid by 1.38-fold (P <.05), 1.4-fold (P <.05), and 1.4-fold (P <.05) between 2 and 3 hours after the administration of inosine. We also conducted an in vitro study with Mahlavu cells and found that the addition of inosine (50 micromol/L) inhibited a decrease in the concentration of uridine in medium originally containing 50 micromol/L uridine. Further, we demonstrated that the apparent Km and Vmax values for Na-independent uridine transport were 67.0 +/- 4.3 micromol/L and 7.0 +/- 0.3 pmol/mg protein/s, respectively, and the Ki value of inosine for Na-independent uridine transport was 45.1 +/- 12.1 micromol/L. These results suggest that inosine inhibits uridine uptake via the nucleoside transport pathway, and administered inosine is converted to purine bases (uric acid, hypoxanthine, and xanthine) in the intestine and liver, before entering the systemic circulation via the hepatic vein., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Inositol hexaphosphate (IP6), a food constituent with various health benefits, has been shown to suppress postprandial elevations of serum uric acid (SUA) levels in healthy adults by inhibiting purine nucleoside and base absorption. Here, we investigated the effect of repeated intake of IP6 on fasting SUA levels in hyperuricemic subjects. This randomized double-blind placebo-controlled crossover design study included 31 asymptomatic hyperuricemic subjects (fasting SUA level > 7.0 but <9.0 mg/dL). Subjects ingested placebo or IP6 drinks (600 mg twice daily) during two 2-week intervention periods with a 2-week washout period. The primary outcome was fasting SUA level; the secondary outcome was the urinary uric acid to creatinine ratio. Fasting SUA levels in the IP6 group were lower than those in the placebo group (p < 0.05). The urinary uric acid to creatinine ratio did not change between the placebo and IP6 groups (p > 0.05). This study showed that a 2-weeks supplementation period of 600 mg IP6 twice daily can improve fasting SUA levels in hyperuricemic subjects. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether febuxostat with stepwise dose increase is as useful as colchicine prophylaxis in reducing gout flares during the initial introduction of urate-lowering therapy in patients with gout in comparison with febuxostat with no dose titration.Methods: In this prospective, multicentre, randomised open-label comparative study, patients were randomised to group A (stepwise dose increase of febuxostat from 10 to 40 mg/day), group B (fixed-dose febuxostat 40 mg/day plus colchicine 0.5 mg/day) or group C (fixed-dose febuxostat 40 mg/day) and observed for 12 weeks. Gout flare was defined as non-steroidal anti-inflammatory drug use for gout symptoms.Results: A total of 255 patients were randomised, and 241 patients were treated. Among the treated patients, gout flares were experienced by 20/96 (20.8%) in group A, 18/95 (18.9%) in group B and 18/50 (36.0%) in group C. The incidence of flare was significantly lower in groups A and B than that in group C (P=0.047 and P=0.024, respectively), although the differences were not significant after correction for multiple comparisons. No significant difference was noted between the incidence of gout flare in groups A and B.Conclusions: Our data suggested that stepwise dose increase of febuxostat and low-dose colchicine prophylaxis effectively reduced gout flares in comparison with fixed-dose febuxostat alone. Stepwise dose increase of febuxostat may be an effective alternative to low-dose colchicine prophylaxis during the introduction of urate-lowering therapy.Trial Registration Number: UMIN 000008414. [ABSTRACT FROM AUTHOR]

We reviewed lifestyle factors that influence serum uric acid levels and risk of gout flare, and how to improve their deleterious effects. Since obesity increases uric acid and weight gain increases gout risk, weight reduction by daily exercise and limiting intake of excess calories is recommended. However, strenuous exercise, which causes adenine nucleotide degradation; starvation, which decreases uric acid excretion; and dehydration may raise the level of uric acid in serum and trigger gout. Increased intake of purine-rich foods, such as meat and seafood, raise the level of uric acid in serum and is associated with increased risk of gout, whereas dairy products, especially low-fat types, are associated with a lower risk of gout. Also, heavy alcohol drinking raises the uric acid level and increases the risk of gout through adenine nucleotide degradation and lactate production. Sweet fruits and soft drinks containing fructose should be moderated, since fructose may raise uric acid and increase gout risk through uric acid production and/or decreased excretion. On the other hand, the Mediterranean diet is recommended for gout patients, since it may also help prevent hyperuricemia. Furthermore, coffee and vitamin C supplementation could be considered as preventive measures, as those can lower serum uric acid levels as well as the risk of gout. [ABSTRACT FROM AUTHOR]

Background and Aims The enzyme xanthine oxidoreductase (XOR) catalyzes the formation of uric acid (UA) from hypoxanthine and xanthine, which in turn are products of purine metabolism starting from ribose-5-phosphate. Besides the synthesis of UA, basic research has suggested that XOR is involved in the regulation of reactive oxygen species, adipogenesis, and peroxisome proliferator-activated receptor-γ (PPAR-γ). XOR activity has shown to be much lower in humans than in rodents, which makes its accurate measurement difficult. Recently, a novel human plasma XOR activity assay has been established using a combination of liquid chromatography (LC) and triple quadrupole mass spectrometry (TQMS) to detect [ 13 C 2 , 15 N 2 ]UA using [ 13 C 2 , 15 N 2 ]xanthine as a substrate. Using this novel assay, we for the first time determine plasma XOR activity in humans, and evaluate its association with insulin resistance, high-sensitivity C-reactive protein (hsCRP) levels, and other parameters. Methods Of the 29 volunteers who wished to participate in the study, 3 were excluded; of the remaining, 11 were female and 15 were male with a mean age of 25.9 ± 3.3 years. Blood samples were collected under fasting conditions in the early morning to measure XOR activity and other parameters. Results The natural logarithmic value of XOR activity (ln-XOR) in plasma was 3.4 ± 0.8 pmol/h/mL. Ln-XOR had a positive correlation with UA and body mass index (BMI) and a negative correlation with quantitative insulin sensitivity check index (QUICKI) and adiponectin. In addition, ln-XOR had a positive correlation with hsCRP levels, which serves as a marker of chronic inflammation. Conclusions The present study has shown that XOR activity is correlated with serum UA levels in humans. Furthermore, even in young subjects, XOR activity is correlated with insulin resistance, BMI, and subclinical inflammation. Thus, XOR activity may be potentially involved in adiposity and subclinical inflammation in humans. [ABSTRACT FROM AUTHOR]

Abstract: Epidemiological observations and laboratory studies have suggested that polyphenols possess anti-inflammatory, anti-microbial, anti-carcinogenic, and antioxidant properties. However, studies assessing the effects of polyphenols on uric acid metabolism in vivo are scarce. Herein, we investigated whether a phenolic substance, Oligonol®, has effects on uric acid metabolism. In six healthy male volunteers, Oligonol® significantly decreased 1-h uric acid excretion and fractional uric acid clearance, which was accompanied by a decreased serum concentration of uric acid. In addition, an in vitro experiment showed that Oligonol® inhibited buttermilk xanthine oxidase activity in a dose-dependent manner. Together, these results suggest that Oligonol® lowers serum uric acid through inhibition of xanthine oxidase, and may be effective for prevention and treatment of hyperuricemia and/or gout. [Copyright &y& Elsevier]