Search

Aims/Background Hyperuricemia is a metabolic disorder characterized by elevated levels of uric acid in the blood. If left untreated, hyperuricemia can progress to gout, which manifests as acute arthritic attacks, and may also lead to uric acid nephrolithiasis and other renal conditions. This widespread condition poses significant risks to human health and quality of life. This study retrospectively evaluated the effectiveness and safety of using benzbromarone in combination with sodium bicarbonate tablets for the treatment of gout associated with hyperuricemia. Methods The study reviewed the electronic medical records (EMR) of 150 patients with gout and hyperuricemia who were admitted to our hospital between May 2018 and December 2023. These patients were divided into two groups: a control group and a research group. The control group received oral sodium bicarbonate tablets, while the research group was treated with oral benzbromarone tablets in addition to sodium bicarbonate tablets. The study compared the treatment outcomes and adverse reactions between the two groups, as well as assessed changes in blood-related indicators, the number of tophi, pain levels, and quality of life before and after treatment. Results The research group demonstrated a higher total effective rate compared to the control group (p < 0.05). Post-treatment, the research group exhibited significantly lower levels of serum uric acid (UA), serum creatinine (Scr), and urea (p < 0.05). Additionally, this group had fewer tophi and lower visual analog scale (VAS) scores compared to the control group (p < 0.05). Quality of life scores were also significantly higher in the research group (p < 0.05). No statistically significant difference was found in the incidence of adverse drug reactions between the two groups (p > 0.05). Conclusion The combination of benzbromarone and sodium bicarbonate tablets is highly effective in treating gout associated with hyperuricemia. This treatment not only reduces uric acid levels and the number of tophi but also enhances renal function, alleviates pain, and improves the overall quality of life for patients. [ABSTRACT FROM AUTHOR]

ObjectiveTo establish a rat model of hyperuricemia （HUA）， to study the effect of Liqing granules on lowering serum uric acid， and to evaluate its safety .MethodsMale SD rats were randomly divided into solvent control group and model group according to their body weight. For the model group， serum uric acid （SUA） was determined after 7 days of intra-gastric administration of potassium oxyazinate. The model group were randomly divided into model control group， positive control group， and low， medium， high dose group based on SUA level. Each group from the model group continued to receive potassium oxyazinate in the morning. The animals in the model groups received 0.5% CMC-Na， 10 mg·kg-1 benzbromarone （Doses by body weight） and Liqing granules 0.6， 1.2， 2.4 g·kg-1 （Doses by body weight）， respectively in the afternoon. 0.5% CMC-Na suspension with the same volume was given both in the morning and afternoon for the solvent control group. Levels of SUA， creatinine （CREA）， alanine aminotransferase （ALT） and aspartate transaminase （AST） were determined after 32 and 45 days administration of the test substance.ResultsSUA of the model group was （218±23） μmol·L-1 after 7 days of modeling， which was significantly higher than that of the solvent control group （P0.05）. CREA in the medium and high dose groups significantly decreased （P0.05）.ConclusionLiqing granules can assist in lowering blood serum uric acid in the rat HUA model， and no damage to liver and kidney function is found.

e two common drugs for the treatment of gout, but the clinical efficacy of these two drugs is controversial. This meta-analysis aimed to compare the efficacy of febuxostat and benzbromarone in the treatment of gout. MATERIALS AND METHODS: PubMed, Embase, and the Cochrane Library were searched for articles related to febuxostat and benzbromarone in the treatment of gout from inception to January 7, 2023. Titles and abstracts were reviewed in accordance with predesigned inclusion and exclusion criteria, and data were extracted independently. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the studies, and the continuous variables were expressed as the standard mean square error (SMD) by STATA 16 (Stata Corp., College Station, TX, USA). The sensitivity analysis was conducted by randomly removing a study, and the heterogeneity was analyzed by funnel plots and Egger’s test. RESULTS: According to the search strategy, a total of 1,043 publications were retrieved from the three aforementioned databases, of which 45 publications were excluded due to duplication. Fourteen studies remained after screening titles and abstracts, and a total of 7 studies met the inclusion criteria after a comprehensive evaluation of the 14 studies. Meta-analysis showed that the uric acid (UA)-reducing effect of febuxostat is better than that of benzbromarone, while febuxostat showed a better ability to improve the estimated glomerular filtration rate (eGFR) and reduce Cr and blood urea nitrogen (BUN). In terms of hepatotoxicity, benzbromarone was not as potent as febuxostat in increasing alanine transaminase (ALT) and aspartate transaminase (AST), suggesting that benzbromarone has less hepatotoxicity. Moreover, there was no significant difference in the effect on blood lipid levels between the two drugs. CONCLUSIONS: The beneficial effect of febuxostat on renal function-related indexes such as the eGFR, Cr and BUN is significant, while benzbromarone is more effective in reducing UA and has relatively less hepatotoxicity. The specific efficacy of the two drugs needs to be confirmed by further research. [ABSTRACT FROM AUTHOR]

The objective of the study was to compare the relative effects of benzbromarone and allopurinol on the risk of developing chronic kidney disease in persons with asymptomatic hyperuricemia. A retrospective cohort study was conducted to analyze a 2003–2015 national database including all claims data of 2 million beneficiaries in Taiwan. Asymptomatic hyperuricemia was defined as follows: persons using urate-lowering drugs who never developed gout flares. The benzbromarone group included persons ages 20–84 that had asymptomatic hyperuricemia and received benzbromarone alone. The allopurinol group included persons ages 20–84 that had asymptomatic hyperuricemia and received allopurinol alone. The maximum follow-up time was set as 5 years in this study. The main outcome was defined as follows: persons were newly diagnosed with chronic kidney disease. A Cox proportional hazards regression analysis was performed to test the association between variables and the risk of chronic kidney disease. After propensity score matching, 9107 persons in the benzbromarone group and 4554 persons in the allopurinol group were eligible for the study. Approximately 71% of the study subjects were males. The mean age was 56 years old. The incidence rate of chronic kidney disease was lower in the benzbromarone group than in the allopurinol group (1.18 versus 1.99/per 100 person-years, incidence ratio = 0.60, and 95% confidence interval = 0.52–0.68).The Cox proportional hazards regression analysis disclosed that after adjusting for co-variables, there was a decreased risk of developing chronic kidney disease in the benzbromarone group as compared with the allopurinol group (hazard ratio = 0.59, 95% confidence interval = 0.52–0.67 and P <0.001). The use of benzbromarone is associated with a lower hazard of developing chronic kidney disease as compared to allopurinol use among persons ages 20–84 with asymptomatic hyperuricemia. More studies are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Both hypertension and hyperuricemia are closely associated with the morbidity and mortality of heart failure with preserved ejection fraction (HFpEF). However, there is limited evidence on the effect of uric acid-lowering therapy on left ventricular (LV) diastolic function in this population. In this randomized study, we prescribed benzbromarone, a uric acid-lowering drug, to those with hypertension and asymptomatic hyperuricemia to investigate its clinical benefits by evaluating LV diastolic function, incidence of HFpEF and hospitalization for heart failure and cardiovascular death. 230 participants were randomly assigned into two groups: uric acid-lowering group (benzbromarone) and control groups (without uric acid-lowering drug). The primary endpoint was LV diastolic function evaluated by echocardiography. The secondary endpoint of composite endpoints is the combination of new-onset HFpEF, hospitalization for heart failure and cardiovascular death. After a median of 23.5 months' follow-up (16–30 months), the primary endpoint reflected by E/e' in benzbromarone group reached a significant improvement when compared to control group (p <.001). Composite endpoints occurred in 11 patients of the control group while only 3 patients occurred in the benzbromarone group (p =.027). We also presented the favorable trend of freedom from the composite endpoints or new-onset HFpEF using Kaplan–Meier curve by log-rank test in benzbromarone group (p =.037 and p =.054). Our study demonstrated the efficiency of benzbromarone in hypertensive patients with concomitant asymptomatic hyperuricemia, including the benefits on ameliorating LV diastolic dysfunction as well as improving composite endpoints. [ABSTRACT FROM AUTHOR]

As overproduction of reactive oxygen species (ROS) causes various diseases, antioxidants that scavenge ROS, or inhibitors that suppress excessive ROS generation, can be used as therapeutic agents. From a library of approved drugs, we screened compounds that reduced superoxide anions produced by pyocyanin-stimulated leukemia cells and identified benzbromarone. Further investigation of several of its analogues showed that benziodarone possessed the highest activity in reducing superoxide anions without causing cytotoxicity. In contrast, in a cell-free assay, benziodarone induced only a minimal decrease in superoxide anion levels generated by xanthine oxidase. These results suggest that benziodarone is an inhibitor of NADPH oxidases in the plasma membrane but is not a superoxide anion scavenger. We investigated the preventive effect of benziodarone on lipopolysaccharide (LPS)-induced murine lung injury as a model of acute respiratory distress syndrome (ARDS). Intratracheal administration of benziodarone attenuated tissue damage and inflammation via its ROS-reducing activity. These results indicate the potential application of benziodarone as a therapeutic agent against diseases caused by ROS overproduction. [ABSTRACT FROM AUTHOR]

Benzbromarone (BNR) is prescribed for the management of hyperuricemia, whereas glimepiride (GLM) for the treatment of Type 2 Diabetes Mellitus. Both drugs are certified to be mainly metabolized via cytochrome P450 (CYP) 2C9 in vivo and may have the potential drug-drug interactions. This study aims to investigate the possible influence of orally administered low- and high-dose glimepiride (GLM) on pharmacokinetic characteristics (PK) of benzbromarone (BNR) in rats. Fifteen rats were randomly assigned to group A, B and C (n=5) and administered 0.5% sodium carboxymethyl cellulose (CMC), 0.5mg/kg GLM (low-dose) and 1.0 mg/kg GLM (high-dose) once daily for 8 days, respectively, which were all followed with a single oral dose of BNR (9.0 mg/kg) on the day 8th. Blood samples were obtained from retroorbital plexus at the time points of 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24h and BNR in plasma was quantitated by HPLC-MS/MS assay. Resultantly a slight influence of GLM on PK of BNR could be found in rats. When compared with Group A, the half-life time (t1/2z) of BNR in Group B and C significantly decreased 52.39% and 73.49%, respectively, although other major PK parameters were negligibly changed by co-administration of GLM. On the whole, the combinational therapy of GLM at low or high dose would notably alter the elimination of BNR and the effect was dose-dependent. [ABSTRACT FROM AUTHOR]

Objective: To describe a patient with gout initiated after living kidney donation successfully treated with benzbromarone. Case Presentation: A 53 years old male with no previous history of prior illness who donated his left kidney to his father. Nine years after the surgical procedure, he had a podagra, and the arthritis progressed to other joints on evolution. He received allopurinol 300 mg/day plus colchicine 1 mg/day. He returned to our clinic 6 years later, referring to high alcoholic ingestion, especially beer on the weekend and using colchicine. His physical examination showed a podagra, but no tophi were noted. Laboratory tests revealed uric acid of 9.2 mg/dL (nr: < 7 mg/dL), 24 hours urinary uric acid (UUA) of 220 mg (nr: 25-750 mg/day), and C-reactive protein (CRP) was 8.3 mg/dL (nr: < 3 mg/dL). Benzbromarone colchicine, besides increased oral hydration to 3 liters/day, a hypocaloric diet, and stopping alcohol drinking were prescribed. After three months, he denied arthritis; his uric acid was reduced to 5.1 mg/dL, and UUA increased to 590 mg in 24 hours. After one year of treatment, he is asymptomatic, without alcoholic drinks, has normal inflammatory markers, hIs uric acid is 4.8 mg/dL, and uses only benzbromarone 100 mg/day. No side effect related to benzbromarone was observed in our patient. Conclusions: To the best of our knowledge, this is the first case illustrating a patient with gout after a living kidney transplant successfully treated with diet and benzbromarone.

The rise of antibiotic-resistant Gram-positive pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA), presents a significant challenge in clinical settings. There is a critical need for new antibacterial agents to combat these resistant strains. Our study reveals that the uricosuric drug Benzbromarone (Benz) exhibits potent antibacterial activity against Gram-positive pathogens, with minimum inhibitory concentrations (MICs) ranging from 8 to 32 μg/mL and minimum bactericidal concentrations (MBCs) ranging from 32 to 128 μg/mL against clinical isolates of S. aureus , S. epidermidis , Enterococcus faecalis , and Streptococcus agalactiae . Furthermore, Benz significantly inhibits biofilm formation at subinhibitory concentrations and eradicates mature biofilms at higher concentrations. Benz also suppresses the hemolytic activity of S. aureus , indicating its potential to reduce virulence. Proteomic and in vitro induced resistance analyses indicate that Benz inhibits protein synthesis and turnover. Additionally, Benz induces membrane depolarization and increases membrane permeability, likely by targeting the membrane phospholipid phosphatidylethanolamine (PE). In the mouse wound infection model, Benz promotes wound healing and significantly reduces bacterial load. These findings suggest that Benz is a promising candidate for developing new antibacterial therapies against Gram-positive bacterial infections.

Obesity and nonalcoholic fatty liver disease (NAFLD) are established risk factors for drug-induced liver injury (DILI). The previous study demonstrates that benzbromarone (BBR), a commonly prescribed pharmaceutical agent for managing gout and hyperuricemia, exacerbates hepatic steatosis and liver injury specifically in obese individuals. However, the precise mechanism underpinning this adverse effect remains incompletely elucidated. Given the significance of BBR and its analogs in anti-gout/hyperuricemia drug discovery, elucidating the mechanism by which BBR exacerbates obesity-specific DILI warrants further investigation. In this study, through a combined multi-omics, pharmacological, and pharmacokinetic approaches, it is found that BBR-induced obesity-specific DILI is primarily through the potentiation of peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathways. Further in vivo and in vitro pharmacokinetic analyses reveal that obese db/db mice exhibited a diminished capacity to metabolize BBR in their livers. This reduction leads to prolonged retention of BBR, subsequently resulting in chronic and sustained hepatic PPARγ agonism. This study demonstrates that a slow metabolism-driven amplification of hepatic PPARγ agonism mediates BBR-induced obesity-specific hepatic steatosis and subsequent DILI, which also emphasizes the importance of the reduced hepatic drug metabolism capacity in patients with obesity or pre-existing NAFLD in both clinical practice and drug discovery processes., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The efficacy of β-agonists in asthma is severely limited by β-adrenoceptor desensitization which results in poorly managed symptoms and refractory bronchoconstriction. Thus, there is a need to identify novel therapeutic pathways and to clarify the relationship between novel therapeutics and functional β-adrenoceptor responsiveness. We have previously demonstrated that acute antagonism of the calcium activated chloride channel, transmembrane member 16A (TMEM16A), relaxes airway smooth muscle (ASM). We sought to determine the efficacy and role of TMEM16A antagonism in the context of desensitization β - adrenoceptor responsiveness. For these studies, we exposed murine tracheal rings on wire myography and precision cut lung slices to contractile mediators in the presence or absence of TMEM16A antagonists and β-agonists with or without prior β-adrenoceptor desensitization. Contractile studies were also performed with human tracheal and bronchial ASM. Finally, the ability of TMEM16A antagonism to prevent desensitization of β 2 -adrenoceptor-induced cyclic AMP synthesis was measured in human ASM cells. From these studies we demonstrate that acute TMEM16A antagonism is effective in relaxing β-agonist desensitized ASM in central and peripheral murine ASM and human ASM. Furthermore, we demonstrate that chronic pretreatment with TMEM16A antagonists prevents functional desensitization of β-agonist responsiveness in mouse and human upper airways and prevents desensitization of β-agonist-mediated cyclic AMP production in human ASM cells. Taken together, the present study demonstrates a favorable therapeutic profile of TMEM16A antagonism for airway smooth muscle relaxation despite functional desensitization of β-agonist responsiveness which may be a novel therapeutic approach in the face of β-adrenoceptor tachyphylaxis.

Background: In previous studies, cardiovascular (CV) risk was increased in patients with gout. The effects of uric acid–lowering therapy on CV risk in gout patients have been investigated in numerous studies; however, allopurinol and benzbromarone have rarely been compared. Objectives: To compare CV risk based on allopurinol and benzbromarone treatment in Korean gout patients. Design: A nationwide population-based retrospective cohort study. Methods: We used South Korea database of the Health Insurance Review and Assessment (HIRA) service to identify gout patients ⩾18 years of age who newly started allopurinol or benzbromarone between 2009 and 2015. The primary outcome of the study was the occurrence of a composite CV endpoint, which included coronary revascularization, hospitalization due to myocardial infarction, ischemic stroke, and transient ischemic attack. Cox proportional hazard regression analysis and Kaplan–Meier curves were used for analysis. Results: The study included 257,097 allopurinol initiators and 7868 benzbromarone initiators. Compared with allopurinol initiators, the adjusted hazard ratio (aHR) of the composite CV endpoint of benzbromarone initiators was 1.01 [95% confidence interval (CI): 0.83−1.21], which was not significantly different. The results did not change even when 1:3 propensity score matching was performed for baseline characteristics. In subgroup analysis of high-risk patients with CV disease, significant difference was not observed between allopurinol and benzbromarone initiators. Conclusion: In this study, significant difference was not found in CV risk between allopurinol and benzbromarone initiators. In the high-CV-risk group, the incidence of CV events did not differ between allopurinol and benzbromarone initiators. [ABSTRACT FROM AUTHOR]

The effects of uricosuric agents have been evaluated in vitro with indices of uric acid uptake into human urate transporter 1 (URAT1)-overexpressed oocytes or cells. In the present study, we evaluated a method using primary human renal proximal tubule epithelial cells (RPTECs). Pretreatment of RPTECs with insulin significantly increased the uptake of uric acid into these cells. The uric acid uptake was inhibited in a concentration-dependent manner by the URAT1 inhibitors benzbromarone and dotinurad. Therefore, effects of uricosuric agents can be evaluated by the novel method, which is closer to the physiological system compared with previous methods. [ABSTRACT FROM AUTHOR]

Objectives: Benzbromarone and febuxostat use different mechanisms to reduce serum urate. However, the effectiveness of benzbromarone versus febuxostat in reducing serum urate in gouty patients classified with different types of hyperuricaemia remains unclear. Method: In this retrospective study from January 1, 2018, to September 30, 2020, subjects were identified if they were newly treated with benzbromarone 25 mg daily or febuxostat 20 mg daily. The subjects were classified into four types according to their 24-h urinary uric acid and fractional excretion of uric acid. The baseline data and follow-up information after 28 ± 3 days of treatment were collected. Results: Seventy-three subjects with gout were finally enrolled. Among them, 50 were treated with benzbromarone. The percent changes in serum urate from the baseline were − 33.71 ± 13.59% and − 29.45 ± 10.62% in the benzbromarone and febuxostat group, respectively, without a significant difference between the groups (P = 0.188). No differences were found between the groups in subjects classified as the renal underexcretion type, combined type, or "normal" type. In patients with eGFR ≥ 70 mL/min/1.73 m2, the rate of serum urate lowering was higher in those treated with benzbromarone than in those treated with febuxostat. Febuxostat treatment significantly lowered serum creatinine from the baseline (P = 0.001). Conclusions: Benzbromarone 25 mg daily and febuxostat 20 mg daily may have comparable effectiveness in lowering the serum urate among different types of hyperuricaemia. Benzbromarone was more effective than febuxostat in lowering serum urate in subjects with eGFR ≥ 70 mL/min/1.73 m2, while febuxostat had a renal protective effect. Key Points • Benzbromarone 25 mg daily and febuxostat 20 mg daily may have comparable effectiveness in lowering the serum urate in patients with different types of hyperuricaemia. • Benzbromarone 25 mg daily was more effective than febuxostat 20 mg daily in lowering serum urate in subjects with eGFR ≥ 70 mL/min/1.73 m2. • Febuxostat had a renal protective effect after about 1 month treatment. [ABSTRACT FROM AUTHOR]

Fungal infections in humans are responsible for mild to severe infections resulting in systemic effects that cause a large amount of mortality. Invasive fungal infections are having similar symptomatic effects to those of COVID-19. The COVID-19 patients are immunocompromised in nature and have a high probability of developing severe fungal infections, resulting in the development of further complications. The existing antifungal therapy has associated problems related to the development of drug resistance, being sub-potent in nature, and the presence of undesirable toxic effects. The fungal dihydrofolate reductase is an essential enzyme involved in the absorption of dietary folic acid and its conversion into tetrahydrofolate, which is a coenzyme required for the biosynthesis of the fungal nucleotides. Thus, in the current study, an attempt has been made to identify potential folate inhibitors of Candida albicans by a computational drug repurposing approach. Based upon the molecular docking simulation-based virtual screening followed by the molecular dynamic simulation of the macromolecular complex, benzbromarone has been identified as a potential anti-folate agent for the development of a novel therapy for the treatment of candidiasis. [ABSTRACT FROM AUTHOR]

Objectives. Whether uric acid-lowering agent use in asymptomatic hyperuricemia can reduce the development of the first gout flare remains unsettled. The goal of the present research was to test the efficacy of benzbromarone and allopurinol on primary prevention of the first gout flare in persons with asymptomatic hyperuricemia in Taiwan. Methods. One observational cohort study was constructed to examine the 2001–2015 dataset adapted from the National Health Insurance Program of Taiwan containing the claims data of 2 million beneficiaries. Asymptomatic hyperuricemia was considered as individuals on uric acid-lowering therapy who did not have gout flares. Individuals aged 20–84 without gout flares who had the use of benzbromarone alone were assigned into a benzbromarone group. Individuals ages 20–84 without gout flares who had the use of allopurinol alone were assigned into an allopurinol group. The final study included 6111 pairs of 1:1 propensity score-matched individuals from both benzbromarone and allopurinol groups. The end point was assigned as individuals who were newly diagnosed with their first gout flare. The incidence rate of the first gout flare was estimated between the benzbromarone and allopurinol groups. A Cox proportional hazards regression model was applied to explore the hazard ratio and 95% confidence interval of the first gout flare related to benzbromarone use and allopurinol use. Results. The incidence rate of the first gout flare was lower in the benzbromarone group compared with an allopurinol group (3.29 versus 5.46 per 1000 person-months, incidence rate ratio = 0.60 and 95% confidence interval = 0.56–0.64). After adjustment for co-variables, the adjusted hazard ratio of the first gout flare was 0.63 (95% confidence interval = 0.59–0.68, p < 0.001) for the benzbromarone group when compared with the allopurinol group. Conclusion. People with asymptomatic hyperuricemia taking benzbromarone have a lower hazard of developing their first gout flare when compared with those taking allopurinol. Based on the medication safety, the therapeutic effects and the low price, with oral administration once daily, we suggest that benzbromarone should be the first drug of choice if clinicians are treating asymptomatic hyperuricemia. [ABSTRACT FROM AUTHOR]

A 39-year-old male had a stomachache for 10 days before abnormal liver function tests were detected by a local doctor. Then, he was referred to us and admitted to our hospital for examination and treatment of elevated transaminases. He had taken benzbromarone to treat his hyperuricemia for seven months, and we diagnosed him with benzbromarone-induced liver injury. After the termination of benzbromarone, he finally recovered from his illness. There are several reports about benzbromarone-induced liver injury. In conclusion, as periodic liver function tests seem not to be completely performed, clinicians should regularly monitor liver function tests in patients taking benzbromarone. [ABSTRACT FROM AUTHOR]

Gout is an auto-inflammatory disease driven by urate deposits with a second co-stimulatory factor evoking an (peri)arthritic fulminant inflammation often with a debute at night; inflammatory signals are enhanced via a NLRP3 pathway. In gout patients, urate metabolism has had a positive balance for a time period of weeks to years before the arthritic syndrome or tophaecous disease becomes manifest. This may be due to katabolism or weight loss, enhanced dietary affluence, and overweight resulting in increased serum urate levels. Also, a decreased urate excretion results in proneness to hyperuricaemia and clinical gout. Pharmacotherapeutically, a negative urate balance should be the aim of clinicians and then the rational choice of treatment with uricosurics seems quite logical and promising, but has not had a thorough attention of pharma, researchers nor of clinicians, though most gout patients were and still are low excretors. Here, an overview on the 70-year-old journey mankind has made in a search for uricosurics resulting so far in only 1 registered uricosuric per continent. [ABSTRACT FROM AUTHOR]

Objectives: To compare the risk of urolithiasis in gout patients initiating allopurinol, a xanthine oxidase inhibitor, vs benzbromarone, a uricosuric., Methods: Using the 2011-20 Korea National Health Insurance Service database, we conducted a cohort study on gout patients initiating allopurinol vs benzbromarone as the first-line urate-lowering treatment. The primary outcome was a new onset urinary stone. The secondary outcome was a stone requiring intervention. We estimated hazard ratios (HRs) and 95% CIs using Cox proportional hazard models with a 5:1 ratio propensity-score matching on >80 variables. Subgroup analyses were done by age, sex, thiazide use and cardiovascular risk., Results: 61 300 allopurinol initiators PS-matched on 12 260 benzbromarone initiators were included (mean age 59 years, 79% male). During a mean follow-up of 322 days, 619 urolithiasis cases occurred with an incidence rate of 0.87 per 100 person-years in allopurinol and 1.39 in benzbromarone initiators, showing a HR of 0.64 (95% CI, 0.51-0.80). Approximately 44% of urinary stones required intervention with a HR of 0.61 (95% CI, 0.43-0.88). The lower risk associated with allopurinol compared with benzbromarone persisted across subgroups but was greater in the high than non-high cardiovascular risk subgroup (P for interaction = 0.02)., Conclusion: This population-based cohort study found that allopurinol compared with benzbromarone was associated with a substantially lower risk of urolithiasis particularly in the presence of the high cardiovascular risk. This finding provides important safety information for clinicians' decision-making on urate-lowering treatments of different mechanisms of action., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims  With the high prevalence of gout and associated cardiovascular (CV) diseases, information on the comparative CV safety of individual urate-lowering drugs becomes increasingly important. However, few studies examined the CV risk of uricosuric agents. We compared CV risk among patients with gout who initiated allopurinol vs. benzbromarone. Methods and results  Using the Korean National Health Insurance claims data (2002–17), we conducted a cohort study of 124 434 gout patients who initiated either allopurinol (n  = 103 695) or benzbromarone (n  = 20 739), matched on propensity score at a 5:1 ratio. The primary outcome was a composite CV endpoint of myocardial infarction, stroke/transient ischaemic attack, or coronary revascularization. To account for competing risk of death, we used cause-specific hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the outcomes comparing allopurinol initiators with benzbromarone. Over a mean follow-up of 1.16 years, 2258 patients developed a composite CV event. The incidence rate of the composite CV event was higher in allopurinol initiators (1.81 per 100 person-years) than benzbromarone (1.61 per 100 person-years) with a HR of 1.22 (95% CI 1.05–1.41). The HR for all-cause mortality was 1.66 (95% CI 1.43–1.93) among allopurinol initiators compared with benzbromarone. Conclusion  In this large population-based cohort of gout patients, allopurinol was associated with an increased risk of composite CV events and all-cause mortality compared to benzbromarone. Benzbromarone may reduce CV risk and mortality in patients with gout, although more studies are necessary to confirm our findings and to advance our understanding of the underlying mechanisms. [ABSTRACT FROM AUTHOR]

It has been widely reported that severe neurotoxicity can be induced by the application of propofol, which is closely related to the disruption of the blood-brain barrier (BBB) induced by inflammation and injury in the human brain microvascular endothelial cells (HBMVECs). Benzbromarone is a classic anti-gout agent that has been recently reported to exert anti-inflammatory and anti-oxidative stress effects. In the present study, we aim to investigate the protective property of Benzbromarone against propofol-induced injury on HBMVECs and the underlying mechanism. CCK8 assay was used to detect the cell viability of treated HBMVECs. Oxidative stress in HBMVECs was evaluated by measuring the levels of MDA and mitochondrial ROS. ELISA and qRT-PCR assay were used to determine the production of IL-1β, IL-8, MCP-1, ICAM-1, and VCAM-1 by treated HBMVECs. Calcein-AM staining was utilized to evaluate the attachment of U937 monocytes to HBMVECs. The expression level of Egr-1 was determined by qRT-PCR and Western blot assay. Firstly, the decreased cell viability of HBMVECs induced by propofol was significantly elevated by treatment with Benzbromarone. The increased levels of MDA and mitochondrial ROS induced by propofol were dramatically suppressed by Benzbromarone. Secondly, the excessive production of inflammatory factors (IL-1β, IL-8, and MCP-1) and adhesion molecules (ICAM-1 and VCAM-1) triggered by propofol was pronouncedly inhibited by Benzbromarone. Benzbromarone ameliorated propofol-induced attachment of U937 monocytes to HBMVECs. Lastly, Benzbromarone downregulated propofol-induced expression of the transcriptional factor Egr-1 in HBMVECs. Benzbromarone protected against propofol-induced inflammation and injury through suppressing Egr-1 in human brain vascular endothelial cells. [ABSTRACT FROM AUTHOR]

Objective: The study aimed to thoroughly address the influence of benzbromarone and allopurinol on the risk of the development of type 2 diabetes mellitus (T2DM) in people with asymptomatic hyperuricemia.Methods: We conducted a retrospective cohort study to examine the 2000–2015 national dataset containing all claims data of 23 million beneficiaries in Taiwan. Subjects who already had diabetes mellitus, gout-related diseases, and any cancer prior to the index date were excluded. Asymptomatic hyperuricemia was defined as subjects taking urate-lowering drugs who never had a gout flare. Subjects aged 20–84 with asymptomatic hyperuricemia who had benzbromarone prescriptions were selected as the benzbromarone group. Sex-matched and age-matched subjects with asymptomatic hyperuricemia who had allopurinol prescriptions were identified as the allopurinol group. The maximum follow-up duration was set as 5 years in our study. The outcome was set as subjects who had a new diagnosis of T2DM. The incidence density of T2DM was calculated in the benzbromarone and allopurinol groups. The hazard ratio (HR) and 95% confidence interval (CI) for T2DM was utilized to estimate the association between medications and the risk of T2DM.Results: The incidence of T2DM among benzbromarone users was significantly lower than that of allopurinol users (7.91 versus 8.48 per 100 person-years, incidence rate ratio = 0.93, and 95% CI = 0.87–0.99). After adjustment for co-variables, the adjusted HR of T2DM would be 0.91 (95% CI = 0.85–0.98 and p = 0.008) in benzbromarone users as compared to allopurinol users.Conclusion: There is a small but statistically significant risk reduction of developing T2DM in people with asymptomatic hyperuricemia taking benzbromarone as compared to those taking allopurinol during 5 years of follow-up. It indicates a future research direction for the use of individual urate-lowering drugs on the prevention of T2DM in the general population.

Abstract Simultaneous oral intake of herbal medicine with chemical drugs may result in beneficial pharmacodynamic efficacy, including additive and synergistic effects with reduced toxicity. Gnaphalium affine D. Don (GAD) is a traditional Chinese Medicine that has been used for the management of hyperuricemia and gout. Benzbromarone (BBR) is one of the first-line drugs used for urate-lowering therapy in China but is toxic to the liver. The present study aimed to determine the effects of GAD and BBR, both alone and in co-treatment (with dosing interval of 1 hour), on chronic hyperuricemic nephropathy (HN) and hepatotoxicity in rats. Our data indicated that GAD significantly inhibited the elevation of serum uric acid, blood urea nitrogen, and creatinine levels in chronic HN rats at doses of 450 and 900 mg/kg/day. The rise in serum alanine aminotransferase and aspartate aminotransferase in BBR (or vehicle)-treated HN rats was significantly reduced by pre- (or post)-administration of GAD (450 mg/kg/day). The q-value >1.15 (by Jin method) indicated synergistic effects of co-treatments of BBR (50 mg/kg) with GAD (450 mg/kg). The synergistic beneficial effects were validated by comparison of BBR alone at a dose of clinical usage (4.5 mg/kg/day, in two divided doses) and BBR + GAD at half dose plus half dose (2.25 + 225 mg/kg/day) or half dose plus full dose (2.25 + 450 mg/kg/day). In conclusion, co-treatment with GAD and BBR holds promise for the management of hyperuricemia and gout.

Background: Hyperuricemia is very common in patients with chronic kidney disease (CKD); the role of hyperuricemia in the occurrence and progression of kidney disease remains an interesting and unresolved issue for nephrologists, and whether urate-lowering therapy (ULT) is warranted in CKD patients is still in controversy. To summarize and compare the clinical outcomes and adverse events (AEs) of three common ULT drugs, we performed a systematic review and network meta-analysis of randomized clinical trials (RCTs).Method: PubMed, MEDLINE, Clinical Trials.gov, EMBASE, and the Cochrane Central Register of Controlled Trials electronic databases were searched. The network meta-analysis was performed using the “gemtc 0.8-7” and its dependent packages in R software. The primary outcome was the change of renal function and uric acid; creatinine, proteinuria, blood pressure, and adverse events were assessed as the secondary outcomes.Results: 16 RCTs involving 1,943 patients were included in the final network analysis. Febuxostat, allopurinol, and benzbromarone were not found to exert superior effects over placebo upon renoprotective effect. With respect to lowering urate, the three drugs showed to be statistically superior to placebo, while febuxostat could better lower urate than allopurinol (MD: −1.547; 95% CrI: −2.473 to −0.626). It is also indicated that febuxostat was superior to placebo at controlling blood pressure, while no differences were observed when allopurinol and benzbromarone were compared to placebo. These results are stable in subgroup analysis.Conclusion: There is insufficient evidence to support the renoprotective effects of the three urate-lowering agents in CKD patients with hyperuricemia; febuxostat shows a tendency to be superior to allopurinol on lowering the decline of eGFR and increment of proteinturia, but the difference does not reach a statistical significance. Regarding its urate-lowering effect, febuxostat appears to be a satisfactory alternative to allopurinol and benzbromarone, and can control blood pressure better.

Objective: The study aimed to thoroughly address the influence of benzbromarone and allopurinol on the risk of the development of type 2 diabetes mellitus (T2DM) in people with asymptomatic hyperuricemia. Methods: We conducted a retrospective cohort study to examine the 2000–2015 national dataset containing all claims data of 23 million beneficiaries in Taiwan. Subjects who already had diabetes mellitus, gout-related diseases, and any cancer prior to the index date were excluded. Asymptomatic hyperuricemia was defined as subjects taking urate-lowering drugs who never had a gout flare. Subjects aged 20–84 with asymptomatic hyperuricemia who had benzbromarone prescriptions were selected as the benzbromarone group. Sex-matched and age-matched subjects with asymptomatic hyperuricemia who had allopurinol prescriptions were identified as the allopurinol group. The maximum follow-up duration was set as 5 years in our study. The outcome was set as subjects who had a new diagnosis of T2DM. The incidence density of T2DM was calculated in the benzbromarone and allopurinol groups. The hazard ratio (HR) and 95% confidence interval (CI) for T2DM was utilized to estimate the association between medications and the risk of T2DM. Results: The incidence of T2DM among benzbromarone users was significantly lower than that of allopurinol users (7.91 versus 8.48 per 100 person-years, incidence rate ratio = 0.93, and 95% CI = 0.87–0.99). After adjustment for co-variables, the adjusted HR of T2DM would be 0.91 (95% CI = 0.85–0.98 and p = 0.008) in benzbromarone users as compared to allopurinol users. Conclusion: There is a small but statistically significant risk reduction of developing T2DM in people with asymptomatic hyperuricemia taking benzbromarone as compared to those taking allopurinol during 5 years of follow-up. It indicates a future research direction for the use of individual urate-lowering drugs on the prevention of T2DM in the general population. [ABSTRACT FROM AUTHOR]

Background: Hyperuricemia is very common in patients with chronic kidney disease (CKD); the role of hyperuricemia in the occurrence and progression of kidney disease remains an interesting and unresolved issue for nephrologists, and whether urate-lowering therapy (ULT) is warranted in CKD patients is still in controversy. To summarize and compare the clinical outcomes and adverse events (AEs) of three common ULT drugs, we performed a systematic review and network meta-analysis of randomized clinical trials (RCTs). Method: PubMed, MEDLINE, Clinical Trials.gov, EMBASE, and the Cochrane Central Register of Controlled Trials electronic databases were searched. The network meta-analysis was performed using the "gemtc 0.8-7" and its dependent packages in R software. The primary outcome was the change of renal function and uric acid; creatinine, proteinuria, blood pressure, and adverse events were assessed as the secondary outcomes. Results: 16 RCTs involving 1,943 patients were included in the final network analysis. Febuxostat, allopurinol, and benzbromarone were not found to exert superior effects over placebo upon renoprotective effect. With respect to lowering urate, the three drugs showed to be statistically superior to placebo, while febuxostat could better lower urate than allopurinol (MD: −1.547; 95% CrI: −2.473 to −0.626). It is also indicated that febuxostat was superior to placebo at controlling blood pressure, while no differences were observed when allopurinol and benzbromarone were compared to placebo. These results are stable in subgroup analysis. Conclusion: There is insufficient evidence to support the renoprotective effects of the three urate-lowering agents in CKD patients with hyperuricemia; febuxostat shows a tendency to be superior to allopurinol on lowering the decline of eGFR and increment of proteinturia, but the difference does not reach a statistical significance. Regarding its urate-lowering effect, febuxostat appears to be a satisfactory alternative to allopurinol and benzbromarone, and can control blood pressure better. [ABSTRACT FROM AUTHOR]

Gout is an immune-metabolic disease that frequently coexists with multiple comorbidities such as chronic kidney disease, cardiovascular disease and metabolic syndrome, therefore, it is often treated in combination with these complications. The present study aimed to evaluate the inhibitory effect of antigout drugs (allopurinol, febuxostat, topiroxostat, benzbromarone, lesinurad and probenecid) on the activity of the crucial phase I drug-metabolizing enzymes, carboxylesterases (CESs). 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) and fluorescein diacetate (FD) were utilized as the probe reactions to determine the activity of CES1 and CES2, respectively, through in vitro culturing with human liver microsomes. Benzbromarone and lesinurad exhibited strong inhibition towards CESs with Ki values of 2.16 and 5.15 μM for benzbromarone towards CES1 and CES2, respectively, and 2.94 μM for lesinurad towards CES2. In vitro-in vivo extrapolation (IVIVE) indicated that benzbromarone and lesinurad might disturb the metabolic hydrolysis of clinical drugs in vivo by inhibiting CESs. In silico docking showed that hydrogen bonds and hydrophobic interactions contributed to the intermolecular interactions of antigout drugs on CESs. Therefore, vigilant monitoring of potential drug-drug interactions (DDIs) is imperative when co-administering antigout drugs in clinical practice. [Display omitted] • CESs were strongly inhibited by benzbromarone and lesinurad. • Benzbromarone and lesinurad might induce drug-drug interactions by inhibiting CESs. • Intermolecular interactions contributed to the inhibition of antigout drugs on CESs. • Potential DDIs should be monitored when co-administering antigout drugs. [ABSTRACT FROM AUTHOR]

Abstract Background Low doses of febuxostat or benzbromarone are widely used in Asian countries, but lacking studies to compare the efficacy and safety of the two urate-lowering drugs. Methods To compare the efficacy and safety of low-dose febuxostat with low-dose benzbromarone in patients with primary gout, a randomized controlled, open-label trial was performed among male patients with primary gout for urate-lowering therapy (ULT) in a dedicated gout clinic in China. Randomization was carried out by a third-party institution according to random number table. Patients were randomly assigned 1:1 to febuxostat group (Feb group) (20 mg daily) or benzbromarone group (Ben group) (25 mg daily) and treated for 12 weeks. General information and biochemical data were collected at baseline and at every visit monthly. Clinical characteristics before and after the ULT were analyzed in the two groups by SPSS and EmpowerStats software. Results Two hundred forty patients were enrolled and randomized in the two groups, with 214 patients completing 12 weeks’ ULT (105 in the Feb group and 109 in the Ben group). After 12 weeks, substantial percentages of patients in both Feb and Ben group achieved the target serum uric acid (sUA) (

The growing interest in Green Analytical Chemistry (GAC) principles through the replacement of polluting analytical procedures with greener ones, has encouraged us to develop an eco-friendly stability-indicating HPLC with diode array detection method (HPLC-DAD) for simultaneous determination of allopurinol (ALP) and benzbromarone (BNZ). Effective separation was accomplished using Durashell C18 column (4.6 × 250 mm, 5 µm particle size) with gradient elution of the mobile phase composed of 0.02 M ammonium acetate (pH 5.0) and methanol. Quantification of ALP and BNZ was based on measuring their peak areas at 251 nm. ALP and BNZ peaks eluted at retention times 4.85 and 10.30 min respectively. The proposed HPLC procedure was carefully validated in terms of system suitability, linearity, ranges, precision, accuracy, specificity, robustness, detection, and quantification limits. The linearity range for both ALP and BNZ was 5–100 µg/mL with correlation coefficients >0.9999. Forced degradation conditions of neutral, acidic, and alkaline hydrolysis, oxidation, and thermal degradation were applied on both drugs. Good resolution of the drugs from their forced degradation products proved that the proposed method is stability-indicating. In addition, the resolution of both drugs from about 10 pharmacologically or chemically related pharmaceutical compounds of different medicinal categories showed the high specificity of the proposed method. The validated HPLC method was successfully applied to the simultaneous determination of both drugs in their tablet dosage forms. Furthermore, greenness assessment and comparison with previously published methods were carried out using two different GAC metrics, namely, the national environmental method index (NEMI) and the analytical Eco-Scale. [ABSTRACT FROM AUTHOR]

A combination of allopurinol and benzbromarone is a common gout treatment protocol. A suboptimal response to allopurinol in patients is very common due to its pharmacokinetics variability. Moreover, the safe doses of benzbromarone is very crucial in patients with hepatic diseases. This raised the inquisitiveness to develop and optimize a capillary zone electrophoresis method for the determination of allopurinol and benzbromarone in their coformulation and in the presence of oxypurinol, the active metabolite of allopurinol, in biological and pharmaceutical matrices. The method greenness profile was assessed using green metric tools the "National Environmental Method Index," the "Analytical Eco‐Scale," and the "Green Analytical Procedure Index" by which the method proved to be ecofriendly. The method was successfully applied for the analysis of the pharmaceutical preparation and urine samples spiked with both drugs and the active metabolite. The linearity range was 25.0‐250.0 μg/mL for benzbromarone, 50.0‐350.0 μg/mL for allopurinol, and 100.0‐500.0 μg/mL for oxypurinol. The recoveries were 99.60 ± 0.67, 99.89 ± 0.98, and 98.71 ± 1.18% for benzbromarone, allopurinol, and oxypurinol, respectively. The analysis results indicate potential usefulness of capillary zone electrophoresis as a competitive and greener method of analysis in biological and quality control labs. [ABSTRACT FROM AUTHOR]

Objectives: Gout is the most common form of inflammatory arthritis and was found to be independently associated with incident dementia in the elderly. However, the associations between anti-gout preparations and dementia were not well-studied.Methods: Data were collected from Taiwan's National Health Insurance Research Database (NHIRD). A 2005–2013 retrospective cohort study was conducted, and all investigated subjects were identified by International Statistical Classification of Diseases and Related Health Problems, 9th Revision, Clinical Modification. Conditional logistic regression was used to evaluate the odds ratio of dementia in relation to different gout preparations (benzbromarone, allopurinol, sulfinpyrazone, probenecid) and number of days of anti-gout preparation use, after adjustment for potential confounding variables.Results: A total of 3,242 gout patients with and without dementia were selected from the NHIRD and included in the final analysis after 1:1 matching for age, gender, and diagnosis year of gout. In the anti-gout preparations, only use of Benzbromarone decreased the risk of dementia (adjusted OR, 0.81; 95% CI, 0.68–0.97). The result of the subgroup analysis revealed a trend toward a lower risk of dementia with longer use of benzbromarone. Use of benzbromarone for ≥180 days showed a significantly lower risk of dementia (adjusted OR, 0.72; 95% CI, 0.58–0.89). Moreover, the protective effect was more pronounced in males compared with females.Conclusion: This cohort study reveals that gout patients taking benzbromarone are at a decreased risk of developing incident dementia, especially with longer use and in male. Further prospective trials are warranted to confirm our findings.

High levels of serum uric acid is closely associated with atrial fibrillation (AF); nonetheless, the detailed mechanisms remain unknown. Therefore, this work examined the intricate mechanisms of AF triggered by hyperuricemia and the impact of the uricosuric agent benzbromarone on atrial remodeling in hyperuricemic rats. After adjusting baseline serum uric acid levels, a total of 28 healthy male adult Sprague Dawley rats were randomly divided into 4 groups, namely, control (CTR), hyperuricemia (oxonic acid potassium salt, OXO) and benzbromarone (+ BBR), and OXO withdrawal groups. Primary rat cardiomyocytes were cultured with uric acid for 24 h to investigate the direct influence of uric acid on cardiomyocytes. Results revealed that AF vulnerability and AF duration were dramatically greater in hyperuricemic rats (OXO group), while the atrial effective refractory periods (AERPs) were significantly shorter. Meanwhile, BBR treatment and withdrawal of 2% OXO administration remarkably reduced AF inducibility and shortened AF duration. Moreover, abnormal morphology of atrial myocytes, atrial fibrosis, apoptosis, and substantial sympathetic nerve sprouting were observed in hyperuricemic rats. Apoptosis and fibrosis of atria were partly mediated by caspase-3, BAX, TGF-β1, and α-smooth muscle actin. Uric acid significantly induced primary rat cardiomyocyte apoptosis and fibrosis in vitro. Also, we found that sympathetic nerve sprouting was markedly upregulated in the atria of hyperuricemia rats, and was restored by BRB or absence of OXO administration. In summary, our study confirmed that AF induced by hyperuricemic rats occurred primarily via induction of atrial remodeling, thereby providing a novel potential treatment approach for hyperuricemia-related AF. [ABSTRACT FROM AUTHOR]

Objective Owing to lower mean uric acid excretion in women compared with men, uricosuric agents might be preferred in women over xanthine oxidase (XO) inhibitors. We therefore investigated the differences in response to two urate-lowering therapies (ULTs) with different modes of action within and between sexes. Methods This retrospective cohort study included patients with a clinical diagnosis of gout who started allopurinol and/or benzbromarone. The successful response to ULT, defined as reaching a serum uric acid (sUA) target of <0.36 mmol/l within 6 months after commencing ULT, was compared between allopurinol and benzbromarone in women and men. Effect modification by sex on differences in response was evaluated. Results Allopurinol was started in 255 women and 1045 men, and benzbromarone in 60 women and 205 men. After 6 months, the proportions of women reaching the sUA target were 58.4% and 66.7% for allopurinol and benzbromarone, respectively (difference, −8%; 95% CI: −22%, 5%). The respective proportions in men were 61.0% and 75.6%, respectively (difference, −15%; 95% CI: −21%, −8%). Corrected for confounding, the odds ratio (OR) of reaching the target on benzbromarone vs allopurinol within women was 0.91 (95% CI: 0.47, 1.75), and within men 1.55 (95% CI: 1.04, 2.32). Corrected for confounding, sex was not an effect modifier of the difference in allopurinol and benzbromarone response (OR, 0.59; 95% CI: 0.28, 1.24). Conclusion This study did not demonstrate between-sex differences regarding the response to either a uricosuric agent or an XO inhibitor, negating different treatment choices by sex. [ABSTRACT FROM AUTHOR]

Herein, an analytical method was developed for extraction and quantification of benzbromarone and tolfenamic acid in citrus and soil matrices using liquid-liquid extraction followed by liquid chromatography-triple quadrupole-tandem mass spectrometry analysis. The compounds were extracted using 0.1% formic acid in 6:4 ethyl acetate and n-hexane solution, and the analytes were separated using a mixture of 0.1% formic acid in ultrapure water and 0.1% formic acid in acetonitrile as mobile phase. A six-point in-matrix calibration curve was constructed providing good linearity with coefficients of determination R2 ≥ 0.98. The limits of detection and quantification for benzbromarone and tolfenamic acid were 3.0 and 10.0 μg/kg in roots, peel, juice, and soil, and 4.0 and 12.0 μg/kg for leaves samples, respectively. The method yielded excellent recoveries between 81.3 and 101.2%, with relative standard deviation ≤9.5% in the matrices. The developed technique provides a simple and sensitive method for the determination of the chemicals and can be applied to agricultural practices.

A 39-year-old male had a stomachache for 10 days before abnormal liver function tests were detected by a local doctor. Then, he was referred to us and admitted to our hospital for examination and treatment of elevated transaminases. He had taken benzbromarone to treat his hyperuricemia for seven months, and we diagnosed him with benzbromarone-induced liver injury. After the termination of benzbromarone, he finally recovered from his illness. There are several reports about benzbromarone-induced liver injury. In conclusion, as periodic liver function tests seem not to be completely performed, clinicians should regularly monitor liver function tests in patients taking benzbromarone.

The uricosuric benzbromarone is a mitochondrial toxicant associated with severe liver injury in patients treated with this drug. Since dysfunctional mitochondria can increase mitochondrial superoxide (O 2 •−) production, we investigated the consequences of benzbromarone-induced mitochondrial oxidative stress on the hepatic antioxidative defense system. We exposed HepG2 cells (a human hepatocellular carcinoma cell line) to increasing concentrations of benzbromarone (1-100 μM) for different durations (2-24 h), and investigated markers of antioxidative defense and oxidative damage. At high concentrations (≥50 μM), benzbromarone caused accumulation of mitochondrial superoxide (O 2 •−) and cellular reactive oxygen species (ROS). At concentrations >50 μM, benzbromarone increased the mitochondrial and cellular GSSG/GSH ratio and increased the oxidized portion of the mitochondrial thioredoxin 2. Benzbromarone stabilized the transcription factor NRF2 and caused its translocation into the nucleus. Consequently, the expression of the NRF2-regulated antioxidative proteins superoxide dismutase 1 (SOD1) and 2 (SOD2), glutathione peroxidase 1 (GPX1) and 4 (GPX4), as well as thioredoxin 1 (TRX1) and 2 (TRX2) increased. Finally, upregulation of NRF2 by siRNA-mediated knock-down of KEAP1 partially protected HepG2 cells from benzbromarone-induced membrane damage and ATP depletion. In conclusion, benzbromarone increased mitochondrial O 2 •− accumulation and activates the NRF2 signaling pathway in HepG2 cells, thereby strengthening the cytosolic and mitochondrial antioxidative defense. Impaired antioxidative defense may represent a risk factor for benzbromarone-induced hepatotoxicity. Image 1 • Benzbromarone increases primarily mitochondrial superoxide in HepG2 cells. • Benzbromarone provokes oxidation of mitochondrial GSH in HepG2 cells. • Benzbromarone activates the NRF2 signaling pathway in HepG2 cells. • Benzbromarone increases the expression of NRF2-regulated antioxidative proteins. • Upregulation of NRF2 protects cells from cell toxicity upon benzbromarone exposure. [ABSTRACT FROM AUTHOR]

Herein, an analytical method was developed for extraction and quantification of benzbromarone and tolfenamic acid in citrus and soil matrices using liquid-liquid extraction followed by liquid chromatography-triple quadrupole-tandem mass spectrometry analysis. The compounds were extracted using 0.1% formic acid in 6:4 ethyl acetate and n-hexane solution, and the analytes were separated using a mixture of 0.1% formic acid in ultrapure water and 0.1% formic acid in acetonitrile as mobile phase. A six-point in-matrix calibration curve was constructed providing good linearity with coefficients of determination R 2 ≥ 0.98. The limits of detection and quantification for benzbromarone and tolfenamic acid were 3.0 and 10.0 μg/kg in roots, peel, juice, and soil, and 4.0 and 12.0 μg/kg for leaves samples, respectively. The method yielded excellent recoveries between 81.3 and 101.2%, with relative standard deviation ≤9.5% in the matrices. The developed technique provides a simple and sensitive method for the determination of the chemicals and can be applied to agricultural practices. [ABSTRACT FROM AUTHOR]

Background: Dotinurad is a novel selective urate reabsorption inhibitor that reduces serum urate levels in hyperuricemic patients with or without gout by selectively inhibiting urate transporter 1. This study was conducted to compare the efficacy and safety of dotinurad with those of benzbromarone. Methods: In this 14-week, randomized, multicenter, double-blind, parallel-group, dose escalation, benzbromarone-controlled, phase 3 study, hyperuricemic patients with or without gout were randomized to two groups that received either dotinurad 2 mg or benzbromarone 50 mg. Dotinurad or benzbromarone was administered once a day for 14 weeks. The primary endpoint was the percent change in serum uric acid level from the baseline to the final visit. Results: A total of 201 Japanese hyperuricemic patients with or without gout (dotinurad: 102, benzbromarone: 99) received at least one dose of the study drug. The mean percent change in serum uric acid level from the baseline to the final visit in the dotinurad and benzbromarone groups was 45.9% and 43.8%, respectively. Non-inferiority of dotinurad 2 mg to benzbromarone 50 mg in lowering serum uric acid was verified by the predefined non-inferiority margin (95% CI − 1.27 to 5.37%). The incidence of adverse events and adverse drug reactions was comparable between the two groups. Conclusion: Dotinurad 2 mg was verified to have a non-inferior serum uric acid lowering effect compared with benzbromarone 50 mg, in Japanese hyperuricemic patients with or without gout. ClinicalTrials.gov Identifier: NCT03100318. [ABSTRACT FROM AUTHOR]

Allopurinol, an inhibitor of xanthine oxidase, reduces both plasma uric acid and oxidative stress and shows useful effects on some complications of diabetes. However, it is not defined which of the above mentioned properties are involved. Moreover, to the best of our knowledge no study has been done on the effects of allopurinol on diabetic retinopathy. In the present study, the effect of allopurinol on experimental diabetic retinopathy and its possible mechanism has been investigated. Thirty two rats were divided into four groups of eight rats each; (1) normal, (2) diabetic control, (3) diabetic + allopurinol (50 mg/kg.day), (4) diabetic + benzbromarone (10 mg/kg.day). Drugs were administered daily and orally from the day after diabetes induction for eight weeks. Thereafter retinal function and structure were evaluated by electroretinography and microscopic studies. Uric acid and oxidative stress biomarkers were measured biochemically. Diabetes significantly increased plasma uric acid and oxidative stress markers and reduced body weight and amplitude of electroretinogram (ERG) b-wave and oscillatory potentials. Treatment of diabetic rats with allopurinol caused a significant increase in the amplitude of ERG b-wave (87%) and decrease in blood sugar (20%), uric acid (49%), and 8-iso-prostaglandin F2a (56%), but had no effect on the number of retinal ganglionic cells and oscillatory potentials. Benzbromarone showed no significant effects on the considered parameters except the reduction of uric acid. Allopurinol improved the b-wave amplitude of diabetic rats. It seems that this beneficial effect is due to the reduction of oxidative stress rather than its effect on plasma uric acid.