Urate lowering therapy in patients starting hemodialysis limit gout flares occurrence: ten years retrospective study.

BACKGROUND: Uncontrolled gout can cause articular impairment but is also associated with a global and cardiovascular excess mortality, especially in dialysis population. Data documented within existing research is not conclusive regarding gout flares evolution during hemodialysis and their control by urate lowering therapy (ULT). Without clear guidelines concerning hemodialysis patients management with chronic gout, this study proposes to investigate whether gout flare incidence reduction could be observed on this population treated by urate lowering therapy versus patients without treatment. METHODS: We performed a retrospective cohort study in two hemodialysis centers in France. Were selected patients over 18 years old with a gout history who started hemodialysis between January 2005 and September 2015. Demographics and clinicals data were recorded at hemodialysis start and throughout 5 years of follow up. Gout flare was defined as presence of uric acid crystal in joint punction or clinically diagnosed as such with a colchicine prescription. All statistical analysis were performed in SAS® version 9.4 (SAS Institute Inc., Cary, NC). RESULTS: One hundred eighty-one patients have been included, mean age at dialysis initiation was 68.6 years (± 12.4) with 72% of men, 54% were treated by ULT: 89.7% by allopurinol and 9.3% by febuxostat. One patient received both treatments successively. After hemodialysis initiation, 35.36% patients had experienced at least one gout flare. The appearance of at least one gout flare concerned 50% of patients in no ULT group and 22.68% patients in ULT group (p = 0.0002). Dialysis efficiency was measured at regular interval during follow-up and was similar in both groups. To study the association strength between clinical factors and gout flares occurrences, a Cox model was performed; ULT is a protector factor of gout flare (HR:0,42, CI 95: 0,25-0,71). The proportion of serum urate values within the target (median 53% vs 29.3%, p < 0.0001) was significantly higher in ULT group versus no ULT group (median 53% vs 29.3%, p < 0.0001). CONCLUSION: Urate lowering therapy limit new gout flares occurrence in hemodialysis patients with gout historyCollaboration between rheumatologists and nephrologists may help to update guidelines for urate-lowering therapies in patients on dialysis.

Discovery of a Potent and Orally Bioavailable Xanthine Oxidase/Urate Transporter 1 Dual Inhibitor as a Potential Treatment for Hyperuricemia and Gout.

The main uric acid-lowering agents in clinical use for hyperuricemia and gout are xanthine oxidase (XO) inhibitors or urate transporter 1 (URAT1) inhibitors. While these therapies can partially control the disease, they have various limitations. The development of XO/URAT1 dual inhibitors offers the potential to enhance therapeutic potency and reduce toxicity compared with single-target inhibitors. Through scaffold hopping from the XO inhibitor febuxostat (2) and the URAT1 inhibitor probenecid (3), followed by structure-activity relationship (SAR) studies, we identified compound 27 as a potent dual inhibitor of XO and URAT1. Compound 27 demonstrated significant dual inhibition in vitro (XO IC50 = 35 nM; URAT1 IC50 = 31 nM) and exhibited favorable pharmacology and pharmacokinetic (PK) profiles in multiple species including monkeys. Furthermore, toxicity studies in rats and monkeys revealed general safety profiles, supporting that compound 27 emerges as a promising novel drug candidate with potent XO/URAT1 dual inhibition for the treatment of gout.

Effects of Xanthine Oxidase Inhibition by Febuxostat on Lipid Profiles of Patients with Hyperuricemia: Insights from Randomized PRIZE Study.

Although patients with hyperuricemia and gout often have dyslipidemia, the effects of febuxostat, a xanthine oxidase inhibitor, on their lipid profiles are unclear. Thus, we performed a sub-analysis of the randomized PRIZE study in which the effects of febuxostat on carotid atherosclerosis were investigated in patients with hyperuricemia. The participants were randomized to the febuxostat or control group. The primary endpoint of this sub-analysis was changes in the patients' non-high-density lipoprotein cholesterol (HDL-C) levels from baseline to 6-month follow-up. Correlations between the changes in lipid profiles and cardiometabolic parameters were also evaluated. In total, 456 patients were included. From baseline to 6 months, non-HDL-C levels were significantly reduced in the febuxostat group (-5.9 mg/dL, 95% confidence interval [CI]: -9.1 to -2.8 mg/dL, p < 0.001), but not in the control group (-1.3 mg/dL, 95% CI: -4.4 to 1.8, p = 0.348). The reduction in non-HDL-C levels was more pronounced in women and correlated with changes in serum uric acid and estimated glomerular filtration rate levels only in the febuxostat group. In patients with hyperuricemia, febuxostat treatment was associated with reduced non-HDL-C levels from baseline to the 6-month follow-up compared to the control treatment, suggesting that the lipid-lowering effect of febuxostat should be considered when targeting dyslipidemia.

Rapid Screening of Emergent Febuxostat Adulteration in Functional Foods Based on a Simulation-Inspired High-Quality Antibody.

Due to the potential health risks of adulterated febuxostat in uric-acid-lowering foods, it is urgent to develop rapid detection methods. However, there are no fast analytical techniques for febuxostat yet. Herein, an efficient hapten simulation strategy was proposed to successfully produce a highly sensitive and selective monoclonal antibody toward febuxostat. Based on such a robust recognition element, easy colorimetric and ultrasensitive fluorescent lateral flow immunochromatographic immunoassays were first established, which can detect febuxostat as low as 60 µg/kg by the naked eye or 1.01 µg/kg by a commercial test strip reader with acceptable stability. Furthermore, in the recovery test and blind sample analysis, consistent results between our methods and the authorized liquid chromatography-tandem mass spectrometry method suggested the high accuracy and practicality of this work. The present work not only proposes a rational hapten design idea but also provides favorable tools for the rapid screening of febuxostat in functional foods.

Effects of allopurinol and febuxostat on uric acid transport and transporter expression in human umbilical vein endothelial cells.

Uric acid induces radical oxygen species formation, endothelial inflammation, and endothelial dysfunction which contributes to the progression of atherosclerosis. Febuxostat inhibits BCRP- and allopurinol stimulates MRP4-mediated uric acid efflux in human embryonic kidney cells. We hypothesized that endothelial cells express uric acid transporters that regulate intracellular uric acid concentration and that modulation of these transporters by febuxostat and allopurinol contributes to their different impact on cardiovascular mortality. The aim of this study was to explore a potential difference between the effect of febuxostat and allopurinol on uric acid uptake by human umbilical vein endothelial cells. Febuxostat increased intracellular uric acid concentrations compared with control. In contrast, allopurinol did not affect intracellular uric acid concentration. In line with this observation, febuxostat increased mRNA expression of GLUT9 and reduced MRP4 expression, while allopurinol did not affect mRNA expression of these uric acid transporters. These findings provide a possible pathophysiological pathway which could explain the higher cardiovascular mortality for febuxostat compared to allopurinol but should be explored further.

Comparative Cardiovascular Risks of Febuxostat and Allopurinol in Patients with Diabetes Mellitus and Chronic Kidney Disease.

BACKGROUND Hyperuricemia, which is common in chronic kidney disease and diabetes mellitus patients, raises health concerns. Febuxostat, a first-line urate-lowering agent, prompts cardiovascular risk questions, especially in high-risk patients. This study compared the effects of febuxostat and allopurinol on cardiovascular risk in diabetes mellitus and chronic kidney disease patients. MATERIAL AND METHODS This retrospective observational cohort study, conducted using Taiwan's National Health Insurance Research Database, focused on patients diagnosed with chronic kidney disease and diabetes between January 2012 and December 2017. The study population was divided into 2 groups: allopurinol users (n=12 901) and febuxostat users (n=2997). We performed 1: 1 propensity score matching, resulting in subgroups of 2997 patients each. The primary outcomes were assessed using a competing risk model, estimating hazard ratios (HR) for long-term outcomes, including the risks of all-cause hospitalization, hospitalization for heart failure, and hospitalization for cardiovascular interventions. RESULTS Febuxostat users, compared to allopurinol users, had higher all-cause hospitalization (HR: 1.33; 95% confidence interval [CI]: 1.25 to 1.42; P<.001), hospitalization for heart failure (HR: 1.62; 95% CI: 1.43 to 1.83; P<.001), and hospitalization for cardiovascular interventions (HR: 1.51; 95% CI: 1.32 to 1.74; P<.001). Moreover, the adverse effects of febuxostat on cardiac health were consistent across most subgroups. CONCLUSIONS Use of febuxostat in patients with diabetes mellitus and chronic kidney disease is associated with higher cardiovascular risks compared to allopurinol. Prudent evaluation is essential when recommending febuxostat for this at-risk group.

Reno-protective effect of fenofibrate and febuxostat against vancomycin-induced acute renal injury in rats: Targeting PPARγ/NF-κB/COX-II and AMPK/Nrf2/HO-1 signaling pathways.

BACKGROUND: Vancomycin (VCM) is used clinically to treat serious infections caused by multi-resistant Gram-positive bacteria, although its use is severely constrained by nephrotoxicity. This study investigated the possible nephroprotective effect of febuxostat (FX) and/or fenofibrate (FENO) and their possible underlying mechanisms against VCM-induced nephrotoxicity in a rat model. METHODS: Male Wistar rats were randomly allocated into five groups; Control, VCM, FX, FENO, and combination groups. Nephrotoxicity was evaluated histopathologically and biochemically. The oxidative stress biomarkers (SOD, MDA, GSH, total nitrite, GPx, MPO), the apoptotic marker, renal Bcl-2 associated X protein (Bax), and inflammatory and kidney injury markers (IL-1ß, IL-6, TNF-α, Nrf2, OH-1, kappa-light-chain-enhancer of activated B cells (NF-κB), NADPH oxidase, Kim-1, COX-II, NGAL, Cys-C were also evaluated. RESULTS: VCM resulted in significant elevation in markers of kidney damage, oxidative stress, apoptosis, and inflammatory markers. Co-administration of VCM with either/or FX and FENO significantly mitigated nephrotoxicity and associated oxidative stress, inflammatory and apoptotic markers. In comparison to either treatment alone, a more notable improvement was observed with the FX and FENO combination regimen. CONCLUSION: Our findings show that FX, FENO, and their combination regimen have a nephroprotective impact on VCM-induced kidney injury by suppressing oxidative stress, apoptosis, and the inflammatory response. Renal recovery from VCM-induced injury was accomplished by activation of Nrf2/HO-1 signaling and inhibition of NF-κB expression. This study highlights the importance of FX and FENO as effective therapies for reducing nephrotoxicity in VCM-treated patients.

Influence of xanthine oxidase inhibitors on all-cause mortality in adults: a systematic review and meta-analysis.

Xanthine oxidase inhibitors, including allopurinol and febuxostat, are the first-line treatment of hyperuricemia. This meta-analysis investigated the association between urate-lowering therapy and all-cause mortality in different chronic diseases to match its users and non-users in a real-world setting. Overall, 11 studies were included, which reported adjusted hazard ratios for all-cause mortality over at least 12 months. Meta-analysis of all included studies showed no effect of the therapy on all-cause mortality. However, subgroup analyses showed its beneficial effect in patients with chronic kidney disease (14% risk reduction) and hyperuricemia (14% risk reduction), but not in patients with heart failure (28% risk increase). Urate-lowering therapy reduces all-cause mortality among patients with hyperuricemia and chronic kidney disease, but it seems to increase mortality in patients with heart failure and should be avoided in this subgroup.

Febuxostat provides renoprotection in patients with hyperuricemia or gout: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: It is unknown whether febuxostat can delay the progression of kidney dysfunction and reduce kidney endpoint events. The aim was to evaluate the renoprotective effect of febuxostat in patients with hyperuricemia or gout by performing a meta-analysis of randomized controlled trials (RCTs). METHODS: MEDLINE, Web of science, EMBASE, ClinicalTrials.gov, and the Cochrane Central Register for Randomized Controlled Trials were searched. The main outcomes included kidney events (serum creatinine doubling or progression to end-stage kidney disease or dialysis). The secondary outcomes were the rate of change in the estimated glomerular filtration rate (eGFR) and changes in the urine protein or urine albumin to creatinine ratio from baseline to the end of follow-up. We used random-effects models to calculate the pooled risk estimates and 95% CIs. RESULTS: A total of 16 RCTs were included in the meta-analysis. In comparison with the control group, the patients who received febuxostat showed a reduced risk of kidney events (RR = 0.56, 95% CI 0.37-0.84, p = 0.006) and a slower decline in eGFR (WMD = 0.90 mL/min/1.73 m2, 95% CI 0.31-1.48, p = 0.003). The pooled results also revealed that febuxostat use reduced the urine albumin to creatinine ratio (SMD = -0.21, 95% CI -0.41 to -0.01, p = 0.042). CONCLUSION: Febuxostat use is associated with a reduced risk of kidney events and a slow decline in eGFR. In addition, the urine albumin to creatinine ratio decreased in febuxostat users. Accordingly, it is an effective drug for delaying the progression of kidney function deterioration in patients with gout.Systematic review registration: PROSPERO CRD42021272591.

Predicting gastric emptying of drug substances taken under postprandial conditions by combination of biorelevant dissolution and mechanistic in silico modeling.

Physiologically based pharmacokinetic (PBPK) models can help to understand the effects of gastric emptying on pharmacokinetics and in particular also provide a platform for understanding mechanisms of food effects, as well as extrapolation between different postprandial conditions, whether standardized clinical or patient-oriented, non-clinical conditions. By integrating biorelevant dissolution data from the GastroDuo dissolution model into a previously described mechanistic model of fed-state gastric emptying, we simulated the effects of a high-calorie high-fat meal on the pharmacokinetics of sildenafil, febuxostat, acetylsalicylic acid, theobromine and caffeine. The model was able to simulate the variability in Cmax and tmax caused by the presence of the stomach road. The main influences investigated to affect the gastric emptying process were drug solubility (theobromine and caffeine), tablet dissolution rate (acetylsalicylic acid) and sensitivity to gastric motility (sildenafil and febuxostat). Finally, we showed how PBPK models can be used to extrapolate pharmacokinetics between different prandial states using theobromine as an example with results from a clinical study being presented.

Comparison of the therapeutic effects of febuxostat combined with a low-purine diet and allopurinol combined with a low-purine diet on the improvement of gout patients.

OBJECTIVE: To compare the clinical efficacy of febuxostat combined with a low-purine diet versus allopurinol combined with a low-purine diet in the treatment of gout. METHODS: In this prospective controlled trial, 98 gout patients admitted to our hospital from February 2021 to December 2022 were enrolled as study subjects. Patients were randomly assigned to the study group (febuxostat combined with a low-purine diet) and the control group (allopurinol combined with a low-purine diet), with 49 patients in each group. The therapeutic effect was evaluated based on joint function and serum uric acid levels after treatment, and classified into three levels: markedly effective, effective, and ineffective. The levels of inflammatory factors, including tumor necrosis factor-a (TNF-a), cytokine interleukin-1beta (IL-1ß), and interleukin (IL)-18 (IL-18), were collected. The Numeric Rating Scale (NRS) was used to assess the degree of pain in patients. Clinical indicators before and 6 months after treatment were compared between the two groups. RESULTS: There was no statistically significant difference in age and gender between the two groups. After 6 months of treatment, the effective rate in the study group (48 cases, 97.96%) was higher than that in the control group (42 cases, 85.71%), with a statistically significant difference (p = .027). At the same time, the study group had significantly lower levels of serum uric acid (162.39 µmol/L ± 17.23 µmol/L vs. S198.32 µmol/L ± 18.34 µmol/L, p < .001), creatinine (87.39 mmol/L ± 9.76 mmol/L vs. 92.18 mmol/L ± 9.27 mmol/L, p = .014), total cholesterol (3.65 mmol/L ± 0.65 mmol/L vs. 4.76 mmol/L ± 0.73 mmol/L, p < .001), and triglycerides (1.76 mmol/L ± 0.32 mmol/L vs. 2.28 mmol/L ± 0.41 mmol/L, p < .001) compared to the control group, with statistically significant differences (p < .05). After treatment, the levels of inflammatory factors and degree of pain in the study group were significantly lower than those in the control group (all p < .05). During the treatment process, the incidence of adverse reactions in the study group (2 cases, 4.08%) was lower than that in the control group (9 cases, 18.37%), with a statistically significant difference (p = .025). CONCLUSION: Febuxostat combined with a low-purine diet can reduce inflammatory factors and alleviate the degree of pain in gout patients, significantly improving their clinical symptoms.

Xanthine oxidoreductase inhibition ameliorates high glucose-induced glomerular endothelial injury by activating AMPK through the purine salvage pathway.

Xanthine oxidoreductase (XOR) contributes to reactive oxygen species production. We investigated the cytoprotective mechanisms of XOR inhibition against high glucose (HG)-induced glomerular endothelial injury, which involves activation of the AMP-activated protein kinase (AMPK). Human glomerular endothelial cells (GECs) exposed to HG were subjected to febuxostat treatment for 48 h and the expressions of AMPK and its associated signaling pathways were evaluated. HG-treated GECs were increased xanthine oxidase/xanthine dehydrogenase levels and decreased intracellular AMP/ATP ratio, and these effects were reversed by febuxostat treatment. Febuxostat enhanced the phosphorylation of AMPK, the activation of peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC)-1α and PPAR-α and suppressed the phosphorylation of forkhead box O (FoxO)3a in HG-treated GECs. Febuxostat also decreased nicotinamide adenine dinucleotide phosphate oxidase (Nox)1, Nox2, and Nox4 expressions; enhanced superoxide dismutase activity; and decreased malondialdehyde levels in HG-treated GECs. The knockdown of AMPK inhibited PGC-1α-FoxO3a signaling and negated the antioxidant effects of febuxostat in HG-treated GECs. Despite febuxostat administration, the knockdown of hypoxanthine phosphoribosyl transferase 1 (HPRT1) also inhibited AMPK-PGC-1α-FoxO3a in HG-treated GECs. XOR inhibition alleviates oxidative stress by activating AMPK-PGC-1α-FoxO3a signaling through the HPRT1-dependent purine salvage pathway in GECs exposed to HG conditions.

The contradictory role of febuxostat in ABCG2 expression and potentiating hypericin-mediated photodynamic therapy in colorectal cancers.

Photodynamic Therapy (PDT) is an emerging method to treat colorectal cancers (CRC). Hypericin (HYP) is an effective mediator of PDT and the ABCG2 inhibitor, Febuxostat (FBX) could augment PDT. HT29 and HEK293 cells showed light dependant cytotoxic response to PDT in both 2D and 3D cell models. FBX co-treatment was not found to improve PDT cytotoxicity. Next, ABCG2 protein expression was observed in HT29 but not in HEK293 cells. However, ABCG2 gene expression analysis did not support protein expression results as ABCG2 gene expression results were found to be higher in HEK293 cells. Although HYP treatment was found to significantly reduce ABCG2 gene expression levels in both cell lines, FBX treatment partially restored ABCG2 gene expression. Our findings indicate that FBX co-treatment may not be suitable for augmenting HYP-mediated PDT in CRC but could potentially be useful for other applications.

Estimation of the spatial pattern of gout prevalence across China by wastewater-based epidemiology.

Gout is a metabolic arthritis caused by hyperuricemia. In recent years, the prevalence of gout has been increased significantly in China due to the improvement of the living standards, and gout has become another common metabolic disease following diabetes mellitus. Gout severely affects the health status and life quality of human. In order to monitor the near real-time prevalence of gout, a wastewater-based epidemiology (WBE) approach was carried out in 257 Chinese cities using febuxostat as the biomarker. Febuxostat in wastewater was measured by a LC-MS/MS method with satisfactory results of method validation. The average concentration of febuxostat in wastewater was 53.05 ± 31.76 ng/L, with the estimated per capita consumption of 124.40 ± 73.37 mg/day/1000 inhabitant. The calculated prevalence of febuxostat was 0.41 % ± 0.24 %, and the prevalence of gout was finally estimated to be 1.30 % ± 0.77 % (0.60 % to 2.11 %), which was nearly consistent with value of 1.10 % obtained from the Guideline for the diagnosis and management of hyperuricemia and gout in China (2019). The results indicated that the febuxostat-based WBE approach might be reasonable to assess the near real-time gout prevalence in China.

Comparison of the efficacy and safety of benzbromarone and febuxostat in gout and hyperuricemia: a systematic review and meta-analysis.

OBJECTIVE: Urate-lowering therapy (ULT) is widely recognized as the primary treatment for hyperuricemia and gout. Xanthine oxidase inhibitors (XOI), particularly febuxostat, have gained popularity as a frontline approach. However, the divergent efficacy and safety between febuxostat and the traditional ULT drug, benzbromarone, remain poorly understood. This knowledge gap necessitates a comprehensive analysis and evidence update to guide drug selection for physicians and patients. METHOD: We conducted a systematic analysis by extracting relevant clinical studies from four medical literature databases. Forest plots, funnel plots, sensitivity analysis, Egger's test, and subgroup analysis were utilized to compare relevant indicators. RESULTS: The advantages and disadvantages of the two drugs were evaluated based on various indicators such as serum uric acid (SUA), triglyceride (TG), urinary uric acid (UUA), white blood cell count (WBC), total cholesterol (TC), blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), estimated glomerular filtration rate (eGFR), and serum creatinine (SC). Benzbromarone demonstrated better efficacy in rapidly reducing SUA levels and inhibiting inflammation for hyperuricemia and gout patients. Febuxostat was slightly less effective in lowering SUA, but there was no significant difference in its impact on liver and kidney function after long-term use. CONCLUSION: This study highlights the superiority of benzbromarone in rapidly reducing SUA and inhibiting inflammation. Febuxostat shows comparable effects on liver and kidney function after long-term use. These findings provide valuable insights for clinicians and patients in drug selection. Key Points • Benzbromarone stands out as a highly effective treatment for hyperuricemia and gout, offering rapid reduction of serum uric acid levels and potent anti-inflammatory effects. • When it comes to long-term use, febuxostat demonstrates comparable effects on liver and kidney function. This provides reassurance for patients who require extended treatment duration. • Moreover, our study goes beyond previous research by presenting a more comprehensive and detailed analysis.

Urate-lowering agents do not have clinically relevant negative effects on sperm quality and reproductive hormones in men with gout: a prospective open-label cohort study.

OBJECTIVE: The objective of this study was to analyze and compare the effects of different urate-lowering agents on testicular functions in men with gout in a clinical setting. METHODS: In this prospective cohort study (Clinical Trial Registration Number: NCT04213534), a total of 49 male patients aged 18-45 years with gout were enrolled. They were divided into three groups and received treatment with either allopurinol, febuxostat or benzbromarone for a duration of 3 months. Semen parameters, reproductive hormones and biochemical assessments were evaluated at baseline, month 1, and month 3. RESULTS: Overall, 40 individuals (81.6%) completed the follow-up visits. In allopurinol group, there were no significant differences in semen parameters from baseline to month 3. Most of sperm parameters in febuxostat group did not show notable changes, except for a decrease in sperm motility at month 3(33.6%, [22.9-54.3] vs 48.4%, [27.4-67.6], p = 0.033). However, the total motile sperm count did not differ significantly after febuxostat treatment. Surprisingly, administration of benzbromarone resulted in improved sperm concentration (37.19 M/mL, [29.6-69.92] vs 58.5 M/mL, [49.8-116.6], p = 0.001). There were no significant changes observed in sperm DNA integrity and reproductive hormones in the three groups from baseline to month 3. The incidence of adverse events did not differ significantly among the three groups as well. CONCLUSION: This study is the first to demonstrate that urate-lowering agents, allopurinol and febuxostat, do not have clinically relevant negative effects on sperm quality and reproductive hormones in men with gout, and benzbromarone presents improving sperm concentration. Results provide important preliminary guidance for the development of reproductive health management guidelines for patients RCID with gout.

Cardiovascular safety of febuxostat versus allopurinol among the Asian patients with or without gout: A systematic review and meta-analysis.

The cardiovascular (CV) safety of febuxostat compared to allopurinol for the treatment of hyperuricemia among Asian patients is uncertain. In this study, we conducted a systematic review and meta-analysis to compare the CV safety profiles of febuxostat with allopurinol in Asian patients with hyperuricemia. A total of 13 studies were included. On the basis of the pooled results of cohort studies, febuxostat users were at a significantly higher risk for acute coronary syndrome (ACS; hazard ratio [HR]: 1.06, 95% confidence interval [CI]: 1.03-1.09, p < 0.01), atrial fibrillation (HR: 1.19, 95% CI: 1.05-1.35, p < 0.01) than allopurinol users, whereas no significant difference between febuxostat and allopurinol existed for urgent coronary revascularization (HR: 1.07, 95% CI: 0.98-1.16, p = 0.13), and stroke (HR: 0.96, 95% CI: 0.91-1.01, p = 0.13). Nevertheless, that difference in results of acute decompensated heart failure (ADHF; HR: 0.73, 95% CI: 0.35-1.53, p = 0.40) and all-cause death (HR = 0.86, 95% CI: 0.49-1.51, p = 0.60) was not significant based on randomized controlled trials. In the Chinese subgroup, febuxostat could increase the risk of ADHF (HR: 1.22, 95% CI: 1.01-1.48, p < 0.05), CV death (HR: 1.25, 95% CI: 1.03-1.50, p < 0.05), and all-cause mortality (HR: 1.07, 95% CI: 1.01-1.14, p < 0.05) compared to allopurinol. In conclusion, the use of febuxostat, compared with allopurinol among Asian patients, was associated with a significantly increased risk of adverse CV events.

Estimation of adherence to urate-lowering therapy in people living with gout using Australia's Pharmaceutical Benefits Scheme and patient-reported dosing.

AIMS: The aim of this study was to estimate adherence to urate-lowering therapy (ULT), predominately allopurinol, from Australia's Pharmaceutical Benefits Scheme (PBS) claims database in association with (1) patient-reported doses and (2) World Health Organization's (WHO) defined daily doses (DDD), namely, allopurinol (400 mg/day) or febuxostat (80 mg/day). METHODS: Proportion of days covered (PDC) was calculated in 108 Gout App (Gout APP) trial participants with at least two recorded ULT dispensings in an approximately 12-month period before provision of intervention or control apps. Adherence was defined as PDC ≥80%. We measured the correlation between the two methods of calculating PDC using a Wilcoxon signed rank test. Agreement between ULT-taking status (self-reports) and ULT-dispensed status (PBS records) was tested with Cohen's kappa (κ), and positive and negative percent agreement. RESULTS: Allopurinol was prescribed in 93.5% of participants taking ULT. Their self-reported mean daily dose (SD) was 291 (167) mg/day. Mean PDC (SD) for allopurinol was 83% (21%) calculated using self-reported dose, and 63% (24%) using WHO's DDD. Sixty-three percent of allopurinol users were identified as adherent (PDC ≥80%) using self-reported dose. There was good agreement between self-reported ULT use and PBS dispensing claims (κ = 0.708, P < .001; positive percent agreement = 90%, negative percent agreement = 82%). CONCLUSIONS: Participant-reported allopurinol daily doses, in addition to PBS dispensing claims, may enhance confidence in estimating PDC and adherence compared to using DDD. This approach improves adherence estimations from pharmaceutical claims datasets for medications where daily doses vary between individuals or where there is a wide therapeutic dose range.

Optimization and validation of a UPLC-MS/MS assay for simultaneous quantification of 2,8-dihydroxyadenine, adenine, allopurinol, oxypurinol and febuxostat in human plasma.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare , hereditary disorder characterized by renal excretion of 2,8-dihydroxyadenine (DHA), leading to kidney stone formation and chronic kidney disease (CKD). Treatment with a xanthine oxidoreductase inhibitor, allopurinol or febuxostat, reduces urinary DHA excretion and slows the progression of CKD. The method currently used for therapeutic monitoring of APRT deficiency lacks specificity and thus, a more reliable measurement technique is needed. In this study, an ultra-performance liquid chromatography-tandem mass spectrometry method for simultaneous quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in human plasma was optimized and validated. Plasma samples were prepared with protein precipitation using acetonitrile followed by evaporation. The chemometric approach design of experiments was implemented to optimize gradient steepness, amount of organic solvent, flow rate, column temperature, cone voltage, desolvation temperature and desolvation flow rate. Experimental screening was conducted using fractional factorial design with addition of complementary experiments at the axial points for optimization of peak area, peak resolution and peak width. The assay was validated according to the US Food and Drug Administration guidelines for bioanalytical method validation over the concentration range of 50 to 5000 ng/mL for DHA, allopurinol and febuxostat, 100 to 5000 ng/mL for adenine and 50 to 12,000 ng/mL for oxypurinol, with r2 ≥ 0.99. The analytical assay achieved acceptable performance of accuracy (-10.8 to 8.3 %) and precision (CV < 15 %). DHA, adenine, allopurinol, oxypurinol and febuxostat were stable in plasma samples after five freeze-thaw cycles at -80 °C and after storage at -80 °C for 12 months. The assay was evaluated for quantification of the five analytes in clinical plasma samples from six APRT deficiency patients and proved to be both efficient and accurate. The proposed assay will be valuable for guiding pharmacotherapy and thereby contribute to improved and more personalized care for patients with APRT deficiency.

The Association between High-Dose Allopurinol and Erythropoietin Hyporesponsiveness in Advanced Chronic Kidney Disease: JOINT-KD Study.

INTRODUCTION: The aim of the study was to explore the association between urate-lowering agents and reduced response to erythropoietin-stimulating agents in patients suffering from chronic kidney disease G5. METHODS: We conducted a cross-sectional, multicenter study in Japan between April and June 2013, enrolling patients aged 20 years or older with an estimated glomerular filtration rate of ≤15 mL/min/1.73 m2. Exclusion criteria encompassed patients with a history of hemodialysis, peritoneal dialysis, or organ transplantation. The patients were categorized into four groups based on the use of urate-lowering drugs: high-dose allopurinol (>50 mg/day), low-dose allopurinol (≤50 mg/day), febuxostat, and no-treatment groups. We used a multivariable logistic regression model, adjusted for covariates, to determine the odds ratio (OR) for erythropoietin hyporesponsiveness, defined by an erythropoietin resistance index (ERI) of ≥10, associated with urate-lowering drugs. RESULTS: A total of 542 patients were included in the analysis, with 105, 36, 165, and 236 patients in the high-dose allopurinol, low-dose allopurinol, febuxostat, and no-treatment groups, respectively. The median and quartiles of ERIs were 6.3 (0, 12.2), 3.8 (0, 11.2), 3.4 (0, 9.8), and 4.8 (0, 11.2) in the high-dose allopurinol, low-dose allopurinol, febuxostat, and no-treatment groups, respectively. The multivariate regression model showed a statistically significant association between the high-dose allopurinol group and erythropoietin hyporesponsiveness, compared to the no-treatment group (OR = 1.98, 95% confidence interval: 1.10-3.57). CONCLUSIONS: Our study suggests that the use of high-dose allopurinol exceeding the optimal dose may lead to hyporesponsiveness to erythropoiesis-stimulating agents.