Seasonal variations for newly prescribed urate-lowering drugs for asymptomatic hyperuricemia and gout in Japan.

Background: Urate-lowering drugs (ULDs) have been approved for treatment of asymptomatic hyperuricemia and gout in Japan. Although serum urate levels and rates of gout onset are known to have seasonal variations, no survey results regarding the seasonality of ULD prescriptions for asymptomatic hyperuricemia and gout have been reported. Methods: A large-scale database of medical claims in Japan filed between January 2019 and December 2022 was accessed. In addition to total size of the recorded population for each month examined, the numbers of patients every month with newly prescribed ULDs for asymptomatic hyperuricemia and gout were noted, based on the International Classification of Diseases, 10th Revision, codes E79.0 and M10. Results: The results identified 201,008 patients with newly prescribed ULDs (median age 49.0 years, male 95.6%). Of those, 64.0% were prescribed ULDs for asymptomatic hyperuricemia and 36.0% for gout. The proportion of new ULD prescriptions was seasonal, with that significantly (p < 0.001) higher in summer (June-August) [risk ratio (RR) 1.322, 95% CI 1.218 to 1.436] and autumn (September-November) (RR 1.227, 95% CI 1.129-1.335) than in winter (December-February), whereas the proportion in spring (March-May) was not significantly different from winter. There was no significant difference after stratification by drug type (uric acid production inhibitor/uricosuric agent) or size of the medical institution, nor subgrouping by age or sex (p for interaction = 0.739, 0.727, 0.886, and 0.978, respectively). On the other hand, the proportions of new ULD prescriptions for asymptomatic hyperuricemia were significantly lower and for gout significantly higher in spring than winter, while those were similar in summer and autumn for both groups (p for interaction<0.001). Conclusion: The present findings indicate that new prescriptions for ULDs to treat asymptomatic hyperuricemia or gout in Japan show seasonal differences, with higher rates noted in summer and autumn as compared to winter.

Association of plasma xanthine oxidoreductase activity with vascular endothelial function independent of serum uric acid level: MedCity21 health examination registry.

Background: Xanthine oxidoreductase (XOR) inhibitor administration, known to reduce uric acid and reactive oxygen species (ROS) production, also improves vascular endothelial function (VEF). This cross-sectional study examined our hypothesis that XOR contributes to impaired VEF through ROS but not uric acid production. Methods: In 395 subjects (196 males, 199 females) without urate-lowering agent administration who underwent a health examination, plasma XOR activity was determined using our highly sensitive assay based on [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. For VEF evaluation, flow-mediated dilatation (FMD) in the brachial artery was determined by ultrasound, with physical and laboratory measurements also obtained. Results: The median values for plasma XOR activity, serum uric acid, and FMD were 26.6 pmol/h/mL, 5.4 mg/dL, and 6.2%, respectively. Simple regression analysis showed weak correlations of both log plasma XOR activity and serum uric acid level with FMD (r = -0.213, p < 0.001 and r = -0.139, p = 0.006, respectively). However, multivariable linear regression analyses revealed that log plasma XOR activity but not serum uric acid level remained associated with FMD (ß = -0.116, p = 0.037 and ß = 0.041, p = 0.549, respectively) after adjustments for various clinical parameters, with no remarkable inconsistencies for the association observed in subgroups divided based on sex or uric acid level. Finally, a series of mediation analyses showed that serum uric acid level did not meet the criteria for mediator of the association of plasma XOR activity with FMD (p = 0.538). Conclusions: These findings suggest the possibility that XOR contributes to the pathophysiology of impaired VEF through ROS but not uric acid production.

The Effects of Topiroxostat, a Selective Xanthine Oxidoreductase Inhibitor, on Arterial Stiffness in Hyperuricemic Patients with Liver Dysfunction: A Sub-Analysis of the BEYOND-UA Study.

BACKGROUND: The effects of uric acid (UA)-lowering therapy with xanthine oxidoreductase (XOR) inhibitors on the development of cardiovascular diseases remain controversial. Based on recent findings that plasma XOR activity increased in liver disease conditions, we conducted a sub-analysis of the BEYOND-UA study to examine the differential effects of topiroxostat on arterial stiffness based on liver function in hyperuricemic individuals with hypertension. METHODS: Sixty-three subjects treated with topiroxostat were grouped according to baseline alanine aminotransferase (ALT) levels (above or below cut-off values of 22, 30, or 40 U/L). The primary endpoint was changes in the cardio-ankle vascular index (CAVI) from baseline to 24 weeks. RESULTS: Significant reductions in CAVI during topiroxostat therapy occurred in subjects with baseline ALT ≥30 U/L or ≥40 U/L, and significant between-group differences were detected. Brachial-ankle pulse wave velocity significantly decreased in the ALT-high groups at all cut-off values. Reductions in morning home blood pressure and serum UA were similar regardless of the baseline ALT level. For eleven subjects with available data, ALT-high groups showed high plasma XOR activity, which was significantly suppressed by topiroxostat. CONCLUSIONS: Topiroxostat improved arterial stiffness parameters in hyperuricemic patients with liver dysfunction, which might be related to its inhibitory effect on plasma XOR.

Associations of circulating xanthine oxidoreductase activity with cardiometabolic risk markers in overweight and obese Japanese men: a cross-sectional pilot study.

Circulating xanthine oxidoreductase (XOR) activity may contribute to the pathogenesis of obesity-related adverse cardiometabolic profiles. This pilot study aimed to examine the cross-sectional associations between plasma XOR activity and cardiometabolic risk (CMR) markers in overweight and obese men. In 64 overweight and obese Japanese men (aged 31-63 years), plasma XOR activity and several CMR markers, such as homeostasis model assessment of insulin resistance (HOMA-IR), and clustered CMR score were measured in each participant. Clustered CMR score was constructed based on waist circumference, triglyceride, blood pressure, fasting plasma glucose, and high-density lipoprotein cholesterol. Plasma XOR activity in overweight and obese men was positively associated with the body mass index, waist circumference, visceral fat area, body fat mass, hemoglobin A1c, serum 8-hydroxy-2'-deoxyguanosine, HOMA-IR, and clustered CMR score and was inversely associated with handgrip strength and high-density lipoprotein cholesterol. Multiple linear regression analysis further demonstrated that the associations of plasma XOR activity with HOMA-IR and the clustered CMR score remained significant after adjustment for covariates including uric acid. Our data demonstrate that circulating XOR activity was independently associated, albeit modestly, with HOMA-IR and the clustered CMR score. These preliminary findings suggest that circulating XOR activity can potentially be one of the preventive targets and biomarkers of cardiometabolic disorders in over-weight and obese men.

Systemic Endothelial Function, Plasma Xanthine Oxidoreductase Activity, and Blood Pressure Variability in Patients with Stable Coronary Artery Disease.

Background and Objectives: Although previous studies showed that an activity of xanthine oxidoreductase (XOR), a rate-limiting enzyme in purine metabolism, beyond the serum uric acid level, was associated with the development of coronary artery disease (CAD), the underlying mechanisms are unclear. Because endothelial dysfunction and a greater blood pressure (BP) variability may play a role, we investigated the relations among the endothelial function, XOR, and BP variability. Materials and Methods: This was a post-hoc study using pooled data of patients with a stable CAD from two prospective investigations, in which the systemic endothelial function was assessed with the reactive hyperemia index (RHI) and the XOR activity was measured. The BP variability was evaluated using BP measurements during the three- and four-day hospitalization. Results: A total of 106 patients with a stable CAD undergoing a percutaneous coronary intervention were included. Of the 106 patients, 46 (43.4%) had a systemic endothelial dysfunction (RHI < 1.67). The multivariable analysis identified a higher body mass index (BMI), female gender, and diabetes as factors associated with an endothelial dysfunction. A higher BMI was also related to an elevated XOR activity, in addition to current smoking. No significant correlation was observed between the RHI and XOR activity. Similarly, the in-hospital BP variability was associated with neither the endothelial function nor XOR. Conclusions: Among patients with a stable CAD, several factors were identified as being associated with a systemic endothelial dysfunction or an elevated XOR activity. However, no direct relations between the endothelial function, XOR, and BP variability were found.

The reality of treatment for hyperuricemia and gout in Japan: A historical cohort study using health insurance claims data.

Hyperuricemia causes gout and has also been associated with metabolic syndrome and cardiovascular disease. Uric acid-lowering drugs (ULDs) are used to reduce uric acid levels for the treatment of hyperuricemia and gout. However, there is a lack of robust and real-world data on the history and treatment of patients with newly diagnosed hyperuricemia or gout in Japan. This retrospective, longitudinal, historical cohort study determined the characteristics of patients with hyperuricemia and/or gout, and prescription of, and adherence to, ULDs using data from the JMDC Claims Database. The primary evaluation population included 64 677 patients with newly diagnosed hyperuricemia and/or gout. Of these, only 26 501 (41.0%) had a prescription for ULDs at diagnosis. Even when ULDs were prescribed, the persistence rate of prescriptions declined over time, with a 54.4% persistence rate for ULDs at 12 months after the index diagnosis. In subgroups of patients with or without hypertension and diabetes, the rate of ULD prescription continuation was significantly higher in those with comorbidities than in those without (76.8% vs. 42.6% in those with vs. without hypertension, and 78.7% vs. 52.2% in those with vs. without diabetes). These finding suggest that therapeutic interventions to lower serum uric acid levels are under-utilized for patients with newly diagnosed hyperuricemia and/or gout in Japan.

Possible role of insulin resistance in activation of plasma xanthine oxidoreductase in health check-up examinees.

We previously found an association of insulin resistance (IR) with plasma xanthine oxidoreductase (XOR) activity in a cross-sectional study. However, whether IR induces increased XOR activity has not been elucidated. This retrospective longitudinal observational study included 347 participants (173 males, 174 females) who underwent annual health examinations and were medication naïve. Homeostasis model assessment of IR (HOMA-IR) index, and physical and laboratory measurements were determined at the baseline. At baseline and 12-month follow-up examinations, plasma XOR activity was determined using our novel assay based on [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. Subjects with IR, defined as HOMA-IR index ≥ 1.7 (n = 92), exhibited significantly (p < 0.001) higher plasma XOR activity levels than those without IR (n = 255), with an increase in that activity seen in 180 (51.9%) after 12 months. Multivariable linear and logistic regression analyses showed that IR, but not BMI or waist circumference, at baseline was significantly associated with plasma XOR activity (ß = 0.094, p = 0.033) and increased plasma XOR activity over the 12-month period (odds ratio, 1.986; 95% confidence interval, 1.048-3.761; p = 0.035), after adjustments for various clinical parameters, including plasma XOR activity at baseline. These results suggest that IR induces increased plasma XOR activity in a manner independent of adiposity.

Xanthine oxidoreductase activity in marathon runners: potential implications for marathon-induced acute kidney injury.

Excess activation of circulating xanthine oxidoreductase (XOR) may contribute to the pathogenesis of widespread remote organ injury, including kidney injury. The purpose of this study was to determine the acute impact of marathon running on plasma XOR activity and to examine whether plasma XOR activity is associated with marathon-induced elevations in biomarkers of acute kidney injury (AKI). Twenty-three young men (aged 20-25 yr) who participated in the 38th Tsukuba Marathon were included. Blood and urine samples were collected before, immediately, 2 h (only blood sample), and 24 h after a full marathon run. Plasma XOR activity was evaluated using a highly sensitive assay utilizing a combination of [13C2,15N2] xanthine and liquid chromatography-triple quadrupole mass spectrometry. The levels of several AKI biomarkers, such as serum creatinine and urinary liver-type fatty acid-binding protein (L-FABP) were measured in each participant. Marathon running caused a transient elevation in plasma XOR activity and levels of purine degradation products (hypoxanthine, xanthine, and uric acid) as well as serum creatinine, urinary albumin, and urinary L-FABP levels. Immediately after the marathon, individual relative changes in plasma XOR activity were independently correlated with corresponding changes in serum creatinine and urinary L-FABP levels. In addition, the magnitude of marathon-induced elevation in plasma XOR activity and levels of purine degradation products were higher in individuals who developed AKI. These findings collectively suggest that marathon running substantially influences the purine metabolism pathway including XOR activity. Moreover, activated circulating XOR can be partly associated with elevated biomarkers of AKI after marathon running.NEW & NOTEWORTHY This study is the first to show marathon running transiently increases plasma XOR activity and levels of purine degradation products (hypoxanthine, xanthine, and uric acid), and further to demonstrate that activated plasma XOR may contribute to marathon-induced elevations in biomarkers of AKI. These findings significantly extend our prior knowledge of the purine metabolic pathway and several AKI biomarkers under strenuous exercise conditions.

Plasma xanthine oxidoreductase is associated with carotid atherosclerosis in stable kidney transplant recipients.

AIM: Xanthine oxidoreductase (XOR) is known as an enzyme related to purine metabolism, catalysing the oxidation of hypoxanthine to xanthine and of xanthine to uric acid. We investigated the relationship between plasma XOR activity in stable kidney transplantation (KT) recipients and carotid artery lesions. METHODS: A total of 42 KT patients visiting our outpatient clinic on regular basis were recruited. Associations between plasma XOR activity and the existence of plaque in the common carotid artery (CCA) or internal carotid artery (ICA) and maximum intima-medial thickness (IMT) of CCA (max-CIMT) > 0.9 mm were examined using univariate and multivariate analyses. RESULTS: At blood sampling, the mean and SD patient age was 52.7 ± 13.8 years old. Plasma XOR(pmol/h/ml) activity was significantly higher in patients with CCA/ICA plaque or max-CIMT >0.9 mm than those without. [23.9 (11.8, 38.3) vs. 8.29 (6.67, 17.5), p < .01, 23.9 (16.9, 71.2) vs. 9.16 (6.67, 28.2), p = .01] Univariate and multivariate logistic regression analyses revealed age and plasma XOR activity as independent predictors of CCA/ICA plaque or max-CIMT >0.9 mm. Receiver operator characteristic curve analyses revealed that the cutoff value of plasma XOR activity for the diagnosis of CCA/ICA plaque or CCA-IMT > 0.9 mm was 16.3 pmol/h/ml. CONCLUSION: Plasma XOR activity is associated independently with atherosclerotic changes in the carotid artery of stable post-KT patients.

Increased plasma XOR activity induced by NAFLD/NASH and its possible involvement in vascular neointimal proliferation.

Xanthine oxidoreductase (XOR) is an enzyme that catalyzes hypoxanthine to xanthine and xanthine to uric acid, respectively. However, the underlying mechanisms of increased plasma XOR and its pathological roles in systemic diseases, such as atherosclerosis, are not fully understood. In this study, we found that changes in plasma XOR activity after bariatric surgery closely associated with those in liver enzymes, but not with those in BMI. In a mouse model of nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), plasma XOR activity markedly increased. Besides, purine catabolism was accelerated in the plasma per se of NASH mice and human patients with high XOR activity. In our NASH mice, we observed an increased vascular neointima formation consisting of dedifferentiated vascular smooth muscle cells (SMCs), which was significantly attenuated by topiroxostat, a selective XOR inhibitor. In vitro, human liver S9-derived XOR promoted proliferation of SMCs with phenotypic modulation and induced ROS production by catabolizing hypoxanthine released from human endothelial cells. Collectively, the results from human and mouse models suggest that increased plasma XOR activity, mainly explained by excess hepatic leakage, was involved in the pathogenesis of vascular injury, especially in NAFLD/NASH conditions.

Association between plasma xanthine oxidoreductase activity and in-hospital outcomes in patients with stable coronary artery disease after percutaneous coronary intervention.

OBJECTIVES: Reactive oxygen species generated by xanthine oxidoreductase (XOR) are associated with the progression of atherosclerosis. However, changes in plasma XOR (pXOR) activity after percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD) remains unknown. METHODS: Herein, we compared the change in the pXOR activity in patients undergoing PCI with that in patients undergoing coronary angiography (CAG) and further evaluated the relation between changes in pXOR activity and in-hospital and long-term outcomes of patients undergoing PCI. The pXOR activity of 80 consecutive patients who underwent PCI and 25 patients who underwent CAG during the hospitalization was analyzed daily. The percentage changes from baseline regulated time interval was evaluated. RESULTS: We found that although pXOR activity decreased after PCI, and remained low until discharge, no significant changes were observed in patients undergoing CAG. Furthermore, among the patients undergoing PCI, those who experienced in-hospital adverse events, had a higher percentage of pXOR reduction 3 days after PCI. There was no association between these changes and long-term events. CONCLUSIONS: A significant change in pXOR activity was observed in patients undergoing PCI than in patients undergoing CAG, and there seems to be a correlation between the in-hospital outcomes and the percentage reduction from baseline in pXOR activity.

Independent association of plasma xanthine oxidoreductase activity with hypertension in nondiabetic subjects not using medication.

Xanthine oxidoreductase (XOR), a rate-limiting and catalyzing enzyme of uric acid formation in purine metabolism, is involved in reactive oxygen species generation. Plasma XOR activity has been shown to be a novel metabolic biomarker related to obesity, liver dysfunction, hyperuricemia, dyslipidemia, and insulin resistance. However, the association between plasma XOR activity and hypertension has not been fully elucidated. We investigated the association of hypertension with plasma XOR activity in 271 nondiabetic subjects (male/female: 119/152) who had not taken any medications in the Tanno-Sobetsu Study, a population-based cohort. Males had higher plasma XOR activity than females. Plasma XOR activity was positively correlated with mean arterial pressure (r = 0.128, P = 0.036). When the subjects were divided by the presence and absence of hypertension into an HT group (male/female: 34/40) and a non-HT group (male/female: 85/112), plasma XOR activity in the HT group was significantly higher than that in the non-HT group (median: 39 vs. 28 pmol/h/mL, P = 0.028). There was no significant difference in uric acid levels between the two groups. Multivariable logistic regression analysis showed that plasma XOR activity (odds ratio: 1.091 [95% confidence interval: 1.023-1.177] per 10 pmol/h/mL, P = 0.007) was an independent determinant of the risk for hypertension after adjustment for age, sex, current smoking and alcohol consumption, estimated glomerular filtration rate, brain natriuretic peptide, and insulin resistance index. The interaction of sex with plasma XOR activity was not significant for the risk of hypertension. In conclusion, plasma XOR activity is independently associated with hypertension in nondiabetic individuals who are not taking any medications.

Uric acid shown to contribute to increased oxidative stress level independent of xanthine oxidoreductase activity in MedCity21 health examination registry.

Uric acid has both antioxidant and pro-oxidant properties in vitro by scavenging and production of reactive oxygen species (ROS). This cross-sectional study examined whether uric acid possesses effects on oxidative stress under physiological conditions independent of xanthine oxidoreductase (XOR), which is involved in uric acid and ROS production. Serum uric acid level was measured, while plasma XOR activity was determined using our high-sensitive assay in 192 participants (91 males, 101 females) who underwent health examinations and were not taking an antihyperuricemic agent. For antioxidant potential and oxidative stress level, biological antioxidant potential (BAP) and derivative of reactive oxygen metabolites (d-ROMs) in serum, respectively, were measured. Median uric acid level and plasma XOR activity were 5.6 mg/dL and 26.1 pmol/h/mL, respectively, and BAP and d-ROMs levels were 2112.8 µmol/L and 305.5 Carr U, respectively. Multivariable regression analyses revealed no significant association of serum uric acid level with BAP level, whereas serum uric acid level showed a significant association with d-ROMs level independent of plasma XOR activity (p = 0.045), which was prominent in females (p = 0.036; p for interaction = 0.148). Uric acid might contribute to increased oxidative stress independent of XOR activity by increasing ROS production, without affecting ROS scavenging, especially in females.

Influence of xanthine oxidoreductase inhibitor, topiroxostat, on body weight of diabetic obese mice.

Plasma xanthine oxidoreductase (XOR) activity is high in metabolic disorders such as diabetic mellitus, obesity, or overweight. Thus, this study investigated whether the XOR inhibitor, topiroxostat, affected body weight. Male db/db mice were fed standard diets with or without topiroxostat for 4 weeks. Body weight and food intake were constantly monitored, along with monitoring plasma biochemical markers, including insulin and XOR activity. Additionally, hepatic hypoxanthine and XOR activity were also documented. Single regression analysis was performed to determine the mechanism. Topiroxostat treatment suppressed weight gain relative to the vehicle without any impact on food intake. However, the weight of fat pads and hepatic and muscle triglyceride content did not change. Topiroxostat decreased the plasma uric acid and increased hepatic hypoxanthine in response to the inhibition of XOR activity. Plasma ketone body and free fatty acid were also increased. Moreover, fat weight was weakly associated with plasma XOR activity in the diabetic state and was negatively associated with ketone body by topiroxostat. These results suggested that topiroxostat amplified the burning of lipids and the salvage pathway, resulting in predisposing the body toward catabolism. The inhibition of plasma XOR activity may contribute to weight loss.

Greater coronary lipid core plaque assessed by near-infrared spectroscopy intravascular ultrasound in patients with elevated xanthine oxidoreductase: a mechanistic insight.

Elevated serum uric acid level was reportedly associated with greater coronary lipid plaque. Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine metabolism and believed to play an important role in coronary atherosclerosis. However, the relation of XOR to coronary lipid plaque and its mechanism are unclear. Patients with stable coronary artery disease undergoing elective percutaneous coronary intervention under near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) guidance were prospectively enrolled. They were divided into three groups according to serum XOR activities: low, normal, and high. Coronary lipid core plaques in non-target vessels were evaluated by NIRS-IVUS with lipid core burden index (LCBI) and a maximum LCBI in 4 mm (maxLCBI4mm). Systemic endothelial function and inflammation were assessed with reactive hyperemia index (RHI) and high-sensitivity C-reactive protein, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio. Of 68 patients, 26, 31, and 11 were classified as low, normal, and high XOR activity groups. LCBI (474.4 ± 171.6 vs. 347.4 ± 181.6 vs. 294.0 ± 155.9, p = 0.04) and maxLCBI4mm (102.1 ± 56.5 vs. 65.6 ± 48.5 vs. 55.6 ± 37.8, p = 0.04) were significantly higher in high XOR group than in normal and low XOR groups. Although RHI was significantly correlated with body mass index, diabetes, current smoking, and high-density lipoprotein cholesterol, no relation was found between XOR activity and RHI. There were also no relations between XOR activity and C-reactive protein, neutrophil-to-lymphocyte ratio, or platelet-to-lymphocyte ratio. In conclusion, elevated XOR activity was associated with greater coronary lipid core plaque in patients with stable coronary artery disease, without significant relations to systemic endothelial function and inflammation.

Plasma xanthine oxidoreductase activity in Japanese patients with type 2 diabetes across hospitalized treatment.

AIMS/INTRODUCTION: Xanthine oxidoreductase (XOR) is an enzyme that catalyzes hypoxanthine and xanthine to xanthine and uric acid, respectively. Plasma XOR activity has recently been measured in humans. However, limited information is known about plasma XOR activity in patients with type 2 diabetes mellitus, and its changes after short-term glycemic control treatment. MATERIALS AND METHODS: We enrolled 28 Japanese patients (10 men/18 women) with type 2 diabetes mellitus who were hospitalized to undergo medical treatment for diabetes. Plasma XOR activity, quantified using triple quadrupole mass spectrometry and liquid chromatography, and other clinical parameters were examined at admission and 2 weeks after treatment during hospitalization. Changes in plasma XOR activity after treatment during hospitalization and associated clinical parameters were assessed. RESULTS: At the time of admission, the median plasma XOR activity was 83.1 pmol/h/mL, with a wide range of 14.4-1150 pmol/h/mL. Multiple regression analysis identified serum aspartate transaminase and alanine transaminase levels as significant and independent factors correlating with the baseline plasma XOR. Two weeks of treatment during hospitalization was associated with a significant decrease in plasma XOR activity. Changes in serum aspartate transaminase were also the only significant and independent factor correlating with changes in plasma XOR activity. CONCLUSIONS: A close relationship was observed between plasma XOR activity and liver transaminases in patients with type 2 diabetes mellitus, cross-sectionally, and also across treatment during hospitalization.