Unique Binding Sites of Uricosuric Agent Dotinurad for Selective Inhibition of Renal Uric Acid Reabsorptive Transporter URAT1.

Dotinurad was developed as a uricosuric agent, inhibiting urate (UA) reabsorption through the UA transporter URAT1 in the kidneys. Due to its high selectivity for URAT1 among renal UA transporters, we investigated the mechanism underlying this selectivity by identifying dotinurad binding sites specific to URAT1. Dotinurad was docked to URAT1 using AutoDock4, utilizing the AlphaFold2-predicted structure. The inhibitory effects of dotinurad on wild-type and mutated URAT1 at the predicted binding sites were assessed through URAT1-mediated [14C]UA uptake in Xenopus oocytes. Nine amino acid residues in URAT1 were identified as dotinurad-binding sites. Sequence alignment with UA-transporting organic anion transporters (OATs) revealed that H142 and R487 were unique to URAT1 among renal UA-transporting OATs. For H142, IC50 values of dotinurad increased to 62, 55, and 76 nM for mutated URAT1 (H142A, H142E, and H142R, respectively) compared with 19 nM for the wild type, indicating that H142 contributes to URAT1-selective interaction with dotinurad. H142 was predicted to interact with the phenyl-hydroxyl group of dotinurad. The IC50 of the hydroxyl group methylated dotinurad (F13141) was 165 µM, 8420-fold higher than dotinurad, suggesting the interaction of H142 and the phenyl-hydroxyl group by forming a hydrogen bond. Regarding R487, URAT1-R487A exhibited a loss of activity. Interestingly, the URAT1-H142A/R487A double mutant restored UA transport activity, with the IC50 value of dotinurad for the mutant (388 nM) significantly higher than that for H142A (73.5 nM). These results demonstrate that H142 and R487 of URAT1 determine its selectivity for dotinurad, a uniqueness observed only in URAT1 among UA-transporting OATs. SIGNIFICANCE STATEMENT: Dotinurad selectively inhibits the urate reabsorption transporter URAT1 in renal urate-transporting organic ion transporters (OATs). This study demonstrates that dotinurad interacts with H142 and R487 of URAT1, located in the extracellular domain and unique among OATs when aligning amino acid sequences. Mutations in these residues reduce affinity of dotinurad for URAT1, confirming their role in conferring selective inhibition. Additionally, the interaction between dotinurad and URAT1 involving H142 is found to mediate hydrogen bonding.

The COMPARE head-to-head, randomized controlled trial of SEL-212 (pegadricase plus rapamycin-containing nanoparticle, ImmTOR™) versus pegloticase for refractory gout.

OBJECTIVES: Serum urate (SU) lowering with PEGylated uricases in gout can reduce flares and tophi. However, treatment-emergent anti-drug antibodies adversely affect safety and efficacy and the currently approved PEGylated uricase pegloticase requires twice-monthly infusions. Investigational SEL-212 therapy aims to promote uricase-specific tolerance via monthly sequential infusions of a proprietary rapamycin-containing nanoparticle (ImmTOR) and pegadricase. METHODS: COMPARE was a randomized, phase 2, open-label trial of SEL-212 vs pegloticase in adults with refractory gout. SEL-212 [ImmTOR (0.15 mg/kg) and pegadricase (0.2 mg/kg)] was infused monthly or pegloticase (8 mg) twice monthly for 6 months. The primary endpoint was the proportion of participants with SU <6 mg/dl for ≥80% of the time during 3 and 6 months. Secondary outcomes were mean SU, gout flares, number of tender and/or swollen joints and safety. RESULTS: During months 3 and 6 combined, numerically more participants achieved and maintained a SU <6 mg/dl for ≥80% of the time with SEL-212 vs pegloticase (53.0% vs 46.0%, P = 0.181). The percentage reductions in SU levels were statistically greater during months 3 and 6 with SEL-212 vs pegloticase (-73.79% and -47.96%, P = 0.0161). Reductions in gout flare incidence and number of tender and/or swollen joints were comparable between treatments. There were numerical differences between the most common treatment-related adverse events of interest with SEL-212 and pegloticase: gout flares (60.2% vs 50.6%), infections (25.3% vs 18.4%) and infusion-related reactions (15.7% vs 11.5%), respectively. Stomatitis (and related terms) was experienced by eight participants (9.6%) with SEL-212 and none with pegloticase. Stomatitis, a known event for rapamycin, was associated with ImmTOR only. CONCLUSIONS: SEL-212 efficacy and tolerability were comparable to pegloticase in refractory gout. This was associated with a substantial reduction in treatment burden with SEL-212 due to decreased infusion frequency vs pegloticase. CLINICAL TRIAL REGISTRATION: NCT03905512.

Dotinurad restores exacerbated kidney dysfunction in hyperuricemic patients with chronic kidney disease.

BACKGROUND: In this study, we aimed to clarify the beneficial effects of urate-lowering treatment with the novel agent dotinurad on renal function in patients with chronic kidney disease (CKD) and hyperuricemia (HUA). METHODS: Thirty-five patients with CKD (mean age 65.4 ± 14.8 years, 23 men) diagnosed with HUA were recruited. Changes in eGFR before and after dotinurad administration were assessed. Patients first underwent a 3-month observation period and then 3 months treatment with dotinurad. RESULTS: During the observation period, mean eGFR (mL/min/1.73 m2) declined significantly. The baseline eGFR was 31.8 ± 16.4 and the serum urate level (sUA, mg/dL) was 8.1 ± 1.7. During the treatment period, eGFR recovered to 36.5 ± 17.5 and sUA decreased to 6.7 ± 1.0. The increase in eGFR after dotinurad administration was correlated with a decrease in sUA (R = 0.375, p = 0.0263). CONCLUSION: Dotinurad administration to patients with CKD and HUA appears to be beneficial in restoring kidney function. Dotinurad may represent a potential medication for the prevention of kidney function decline caused by HUA.

The Development of Gout Treat-To-Target booklet.

INTRODUCTION: The treat-to-target serum uric acid approach is recommended in local and international guidelines on gout management. Instruction for initiation and dose escalation for urate lowering therapy may cause confusion to the patient. Our aim was to develop and validate Gout Treat-To- Target booklet to aid in patient education. MATERIALS AND METHODS: A content development team which consisted of three consultant rheumatologists developed the booklet. Content validation was performed by a panel of evaluators consisted of eleven physicians (four consultant rheumatologists, two clinical specialists, and five medical officers), who were involved in gout management. Face validation was performed by ten patients with gout. RESULTS: Item-Content Validity Index ranged from 0.9 to 1 with regards to relevancy, clarity, ambiguity and simplicity. Side effects of uricosuric agents were added to the draft based on an evaluator's comment. Item-Face Validity Index was 1, which indicated that all patients were in 100% agreement with all items. CONCLUSION: We developed and validated our Gout Treat-to- Target booklet. There was high agreement in I-FVI and I-CVI among physicians and patients.

A Novel Role of Uricosuric Agent Benzbromarone in BK Channel Activation and Reduction of Airway Smooth Muscle Contraction.

The uricosuric drug benzbromarone, widely used for treatment of gout, hyperpolarizes the membrane potential of airway smooth muscle cells, but how it works remains unknown. Here we show a novel role of benzbromarone in activation of large conductance calcium-activated K+ channels. Benzbromarone results in dose-dependent activation of macroscopic big potassium (BK) currents about 1.7- to 14.5-fold with an EC50 of 111 µM and shifts the voltage-dependent channel activation to a more hyperpolarizing direction about 10 to 54 mV in whole-cell patch clamp recordings. In single-channel recordings, benzbromarone decreases single BKα channel closed dwell time and increases the channel open probability. Coexpressing ß1 subunit also enhances BK activation by benzbromarone with an EC50 of 67 µM and a leftward shift of conductance-voltage (G-V) curve about 44 to 138 mV. Site-directed mutagenesis reveals that a motif of three amino acids 329RKK331 in the cytoplasmic linker between S6 and C-terminal regulator of potassium conductance (RCK) gating ring mediates the pharmacological activation of BK channels by benzbromarone. Further ex vivo assay shows that benzbromarone causes reduction of tracheal strip contraction. Taken together, our findings demonstrate that uricosuric benzbromarone activates BK channels through molecular mechanism of action involving the channel RKK motif of S6-RCK linker. Pharmacological activation of BK channel by benzbromarone causes reduction of tracheal strip contraction, holding a repurposing potential for asthma and pulmonary arterial hypertension or BK channelopathies. SIGNIFICANCE STATEMENT: We describe a novel role of uricosuric agent benzbromarone in big potassium (BK) channel activation and relaxation of airway smooth muscle contraction. In this study, we find that benzbromarone is an activator of the large-conductance Ca2+- and voltage-activated K+ channel (BK channel), which serves numerous cellular functions, including control of smooth muscle contraction. Pharmacological activation of BK channel by the FDA-approved drug benzbromarone may hold repurposing potential for treatment of asthma and pulmonary arterial hypertension or BK channelopathies.

Uricosuric Agents Affect Plasma and Kidney Concentration of Adefovir via Inhibition of Oat1 and Mrp2 in Rats.

Uricosuric agents lower serum uric acid levels by increasing urinary excretion via inhibition of urate transporter 1 (URAT1), urate reabsorption transporter in the renal proximal tubules. Probenecid and benzbromarone have been used as uricosurics, but these drugs inhibit organic anion transporters (OATs) in addition to URAT1. In this study, we investigated whether uricosuric agents interacted with adefovir, known as a substrate for OAT1, using Sprague-Dawley (SD) rats. Furthermore, involvement of other transporters, multi-drug resistance protein 2 (MRP2) in this interaction was examined using Mrp2-deficient rats. Probenecid and lesinurad increased plasma adefovir concentrations and decreased kidney-to-plasma partition coefficient (Kp) in these rats, presumably by inhibiting Oat1. Although benzbromarone had no effect on plasma adefovir concentration, it increased the Kp to 141% in SD rats. Since this effect was abolished in Mrp2-deficient rats, together with the MRP2 inhibition study, it is suggested that benzbromarone inhibits Mrp2-mediated adefovir excretion from the kidney. In contrast, dotinurad, a novel uricosuric agent that selectively inhibits URAT1, had no effect on the plasma and kidney concentrations of adefovir. Therefore, due to the lack of interaction with adefovir, dotinurad is expected to have low drug-drug interaction risk mediated by OAT1, and also by MRP2.

Pharmacokinetics, Mass Balance, and Metabolism of the Novel Urate Transporter 1 Inhibitor [14C]HR011303 in Humans: Metabolism Is Mediated Predominantly by UDP-Glucuronosyltransferase.

HR011303, a promising selective urate transporter 1 inhibitor, is currently being studied in a phase III clinical trial in China for the treatment of hyperuricemia and gout. In the current study, the pharmacokinetics, mass balance, and metabolism of HR011303 were examined in six healthy Chinese male subjects who received a single oral dose of 10 mg of [14C]HR011303 (80 µCi). The results showed that HR011303 was rapidly absorbed with a median time to reach C max of 1.50 hours postdose, and the arithmetic mean half-life of total radioactivity was approximately 24.2 hours in plasma. The mean blood-to-plasma radioactivity concentration ratio was 0.66, suggesting the preferential distribution of drug-related components in plasma. At 216 hours postdose, the mean cumulative excreted radioactivity was 91.75% of the dose, including 81.50% in urine and 10.26% in feces. Six metabolites were identified, and the parent drug HR011303 was the most abundant component in plasma and feces, but a minor component in urine. Glucuronidation of the carboxylic acid moiety of HR011303 was the primary metabolic pathway in humans, amounting to 69.63% of the dose (M5, 51.57% of the dose; M5/2, 18.06% of the dose) in the urine; however, it was not detected in plasma. UDP-glucuronosyltransferase (UGT) 2B7 was responsible for the formation of M5. Overall, after a single oral dose of 10 mg of [14C]HR011303 (80 µCi), HR011303 and its main metabolites were eliminated via renal excretion. The major metabolic pathway was carboxylic acid glucuronidation, which was catalyzed predominantly by UGT2B7. SIGNIFICANCE STATEMENT: This study determined the absorption and disposition of HR011303, a selective urate transporter (URAT) 1 inhibitor currently in development for the treatment of hyperuricemia and gout. This work helps to characterize the major metabolic pathways of new URAT inhibitors and identify the absorption and clearance mechanism.

Comparative efficacy and safety of dotinurad, febuxostat, and benzbromarone in hyperuricemic patients with or without gout: A network meta-analysis of randomized controlled trials.

OBJECTIVE: We aimed to assess the relative efficacy and safety of dotinurad (2 mg), benzbromarone (50 mg), and febuxostat (40 mg) in hyperuricemic patients with or without gout. MATERIALS AND METHODS: A Bayesian network meta-analysis was performed to combine direct and indirect evidence from randomized controlled trials (RCTs) to evaluate the efficacy and safety of dotinurad (2 mg), benzbromarone (50 mg), febuxostat (40 mg), and placebo in hyperuricemic patients with or without gout. RESULTS: Four RCTs, including 516 patients, fulfilled the inclusion criteria. The number of patients who achieved the target serum uric acid (sUA) level was significantly higher in the febuxostat 40-mg group than in the placebo group (OR 660.50, 95% credible interval (CrI) 75.47 - 19,584.80). The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that febuxostat 40 mg was more likely to achieve the best target sUA level (SUCRA = 0.849), followed by dotinurad 2 mg (SUCRA = 0.651), benzbromarone 50 mg (SUCRA = 0.501), and placebo (SUCRA < 0.001). The frequency of adverse drug reactions in the dotinurad 2-mg group, and in the benzbromarone 50-mg group tended to be lower than in the febuxostat 40-mg group. CONCLUSION: Febuxostat 40 mg and dotinurad 2 mg tended to be more effective than benzbromarone 50 mg, while dotinurad 2 mg and benzbromarone 50 mg tended to be safer than febuxostat 40 mg in hyperuricemic patients with or without gout.

Design, synthesis and biological evaluation of 4-amino-quinolines as antitumor agents.

Fifteen novel 4-amino-quinolines (I1-III3) as antitumor agent were synthesized by p-nitroaniline and ethoxymethylene malonic ester (EMME) via condensation, cyclization, hydrolysis, decarboxylation, chlorination, nucleophilic substitution, reduction and amidation. The antitumor activity of compounds I1-III3 was evaluated on SGC-7901, BEL-7402 and A549 cancer cell lines. In vitro bioassay indicated that some compounds showed different degree activity against all tested cancer cell lines. Compound I1, I4 and II2 exhibited high effects against A549 cell lines (IC50 = 1.34µM, 1.36µM and 3.00µM, respectively). In addition, the result of molecular docking showed that compound I1, I4 and II2 could dock into the pocket of EGFR.

Mechanism-Based Inactivation of Cytochrome P450 3A4 by Benzbromarone.

Benzbromarone (BBR), a potent uricosuric agent for the management of gout, is known to cause fatal fulminant hepatitis. Although the mechanism of BBR-induced idiosyncratic hepatotoxicity remains unelucidated, cytochrome P450 enzyme-mediated bioactivation of BBR to electrophilic reactive metabolites is commonly regarded as a key molecular initiating event. However, apart from causing aberrant toxicities, reactive metabolites may result in mechanism-based inactivation (MBI) of cytochrome P450. Here, we investigated and confirmed that BBR inactivated CYP3A4 in a time-, concentration-, and NADPH-dependent manner with K I, k inact, and partition ratio of 11.61 µM, 0.10 minutes-1, and 110, respectively. Coincubation with ketoconazole, a competitive inhibitor of CYP3A4, attenuated the MBI of CYP3A4 by BBR, whereas the presence of glutathione and catalase did not confer such protection. The lack of substantial recovery of enzyme activity postdialysis and after oxidation with potassium ferricyanide, combined with the absence of a Soret peak in spectral difference scans, implied that MBI of CYP3A4 by BBR did not occur through the formation of quasi-irreversible metabolite-intermediate complexes. Analysis of the reduced CO-difference spectrum revealed an ∼44% reduction in ferrous-CO binding and hinted that inactivation is mediated via irreversible covalent adduction to both the prosthetic heme moiety and the apoprotein. Finally, our in silico covalent docking analysis further suggested the modulation of substrate binding to CYP3A4 via the covalent adduction of epoxide-derived reactive intermediates of BBR to two key cysteine residues (Cys239 and Cys58) vicinal to the entrance of the orthosteric binding site. SIGNIFICANCE STATEMENT: Although the bioactivation of benzbromarone (BBR) to reactive metabolites has been well characterized, its potential to cause mechanism-based inactivation (MBI) of cytochrome P450 has not been fully investigated. This study reports the MBI of CYP3A4 by BBR via irreversible covalent adduction and develops a unique covalent docking methodology to predict the structural molecular determinants underpinning the inactivation for the first time. These findings lay the groundwork for future investigation of clinically relevant drug-drug interactions implicating BBR and mechanisms of BBR-induced idiosyncratic hepatotoxicity.

The efficacy and safety of citrate mixture vs sodium bicarbonate on urine alkalization in Chinese primary gout patients with benzbromarone: a prospective, randomized controlled study.

OBJECTIVES: To compare the efficacy and safety of citrate mixture and sodium bicarbonate on urine alkalization in gout patients under benzbromarone treatment. METHODS: A prospective, randomized, parallel controlled trial was conducted among 200 gout patients in the dedicated gout clinic of the Affiliated Hospital of Qingdao University. The participants were randomly divided into two groups (1:1), sodium bicarbonate group (3 g/day) and citrate mixture group (7 g/day). All patients were prescribed with 25 mg/day benzbromarone at initiation and maintained at a dose of 50 mg/day. Clinical and biochemical data were collected at each follow-up time point (baseline, weeks 2, 4, 8 and 12). RESULTS: A total of 182 patients completed the 12-week urine alkalization study. The urine pH value of both groups increased significantly from the baseline to the final follow-up time point (sodium bicarbonate group, 5.50-6.00, P < 0.05; citrate mixture group, 5.53-5.93, P < 0.05). While the comparisons regarding urine pH between treatment groups showed no significant differences for each time point. The estimated glomerular filtration rate (eGFR) dropped significantly after 12 weeks' trial in the sodium bicarbonate group (P < 0.01), while it was comparable between baseline and the last follow-up (P > 0.05) in the citrate mixture group. Results of urine analysis showed that the incident rate of occult blood in the sodium bicarbonate group was higher than that in the citrate mixture group (38 vs 24%, P < 0.05), accompanied by a similar occurrence of kidney stones. After 12-week follow-up, the frequency of twice gout flare in the citrate mixture group was significantly lower than that in sodium bicarbonate group (4 vs 12%, P = 0.037). No treatment-emergent adverse events occurred. CONCLUSION: The efficacy of citrate mixture on urine alkalization is comparable to sodium bicarbonate under benzbromarone treatment without significant adverse events. Citrate mixture is superior to sodium bicarbonate in lowering the incidence of urine occult blood and the frequency of gout attacks. TRIAL REGISTRATION: Registered with ChiCTR (http://www.chictr.org.cn), No. ChiCTR1800018518.

Soluble Uric Acid Promotes Atherosclerosis via AMPK (AMP-Activated Protein Kinase)-Mediated Inflammation.

OBJECTIVE: Uric acid is supposed but not yet determined to be associated with atherosclerosis. Uric acid is released from damaged cells to form urate crystal, which is recognized by the immune system to produce IL (interleukin)-1. Danger signals and IL-1 have been shown to play an important role in atherosclerosis. We determined whether the physiological level of soluble uric acid promotes inflammation and develops atherosclerosis. Approach and Results: The secretion of IL-1ß from human peripheral blood mononuclear cells mediated by NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome was promoted by physiological levels in serum uric acid. This augmentation of inflammation was mediated by the regulation of the AMPK (AMP-activated protein kinase)-mTOR (mammalian target of rapamycin) mitochondrial reactive oxygen species and HIF-1α (hypoxia-inducible factor-1α) pathway. In both of uricase transgenic and xanthine oxidase inhibitor-treated mice, decreased levels of uric acid resulted in the activation of AMPK and attenuation of the development of atherosclerotic plaques. Further, acute uric acid reduction by the administration of benzbromarone in healthy humans for 2 weeks significantly decreased plasma IL-18-an inflammasome-dependent cytokine. CONCLUSIONS: The data indicate that the development of atherosclerosis and inflammation is promoted by uric acid in vivo. Moreover, the lowering of uric acid levels attenuated inflammation via the activation of the AMPK pathway. This study provides mechanistic evidence of uric acid-lowering therapies for atherosclerosis.

Novel monocyclic amide-linked phenol derivatives without mitochondrial toxicity have potent uric acid-lowering activity.

Although benzbromarone (BBR) is a conventional, highly potent uricosuric drug, it is not a standard medicine because it causes rare but fatal fulminant hepatitis. We transformed the bis-aryl ketone structure of BBR to generate novel monocyclic amide-linked phenol derivatives that should possess uric acid excretion activity without adverse properties associated with BBR. The derivatives were synthesized and tested for uric acid uptake inhibition (UUI) in two assays using either urate transporter 1-expressing cells or primary human renal proximal tubule epithelial cells. We also evaluated their inhibitory activity against mitochondrial respiration as a critical mitochondrial toxicity parameter. Some derivatives with UUI activity had no mitochondrial toxicity, including compound 3f, which effectively lowered the plasma uric acid level in Cebus apella. Thus, 3f is a promising candidate for further development as a uricosuric agent.

Uric acid-induced pancreatic ß-cell dysfunction.

Hyperuricemia is associated with insulin resistance, pancreatic ß-cell dysfunction and consequently with development of type 2 diabetes. Although a direct relationship between high levels of uric acid (UA) and the development of diabetes is still a controversial issue, there is some evidence that strongly points to pancreatic ß-cells damage as a result of high serum UA levels. Here, the mechanisms underlying UA-induced ß-cell damage are discussed. Available literature indicates that UA can decrease glucose-stimulated insulin secretion and cause ß-cell death. The mechanisms underlying these effects are UA-induced oxidative stress and inflammation within the ß-cells. UA also stimulates inducible nitric oxide (NO) synthase (iNOS) gene expression leading to NO-induced ß-cell dysfunction. Thus hyperuricemia may potentially cause ß-cell dysfunction, leading to diabetes. It may be hypothesized that in hyperuricemic subjects, UA-lowering drugs may be beneficial in preventing diabetes.

Implementation Status of Liver Function Tests for Monitoring Benzbromarone-Induced Hepatotoxicity: An Epidemiological Survey Using the Japanese Claims Database.

A major adverse effect of benzbromarone is hepatotoxicity. Therefore, periodic liver function tests are required at least for the first 6 months of benzbromarone administration. However, it is not clear whether the relevant blood tests are implemented appropriately. Here, we performed a cross-sectional survey of the implementation status of liver function tests in patients who were newly prescribed benzbromarone, using the Japanese large claims database. Male patients who were newly prescribed benzbromarone from January 2010 to December 2016 were included. We targeted patients who continued benzbromarone during the observation period (up to 180 d from the start of administration). The primary endpoint was the proportion of patients in whom periodic liver function tests were implemented. A periodic liver function test was defined as one or more liver function tests performed during both 1-90 and 91-180 d of initial benzbromarone administration. We labeled the tests as a "periodic test" or "non-periodic test" based on whether periodic liver function tests were performed or not, respectively. Furthermore, factors influencing non-periodic test were analyzed. Periodic testing was implemented only in 28.7% of patients. Additionally, factors such as number of hospital beds ≤19 (compared to 100-199 beds) and duration of the first prescription of benzbromarone were associated with non-periodic testing. Our study revealed that periodic liver function tests are not performed sufficiently in Japan. Thus, clinicians prescribing benzbromarone should be educated about the test. Our blood-test-based approach should be applied to other drugs and countries in future research.

Comparative study of a novel selective urate reabsorption inhibitor "dotinurad" among patient groups with different stages of renal dysfunction.

BACKGROUND: Dotinurad is a selective urate reabsorption inhibitor (SURI), which selectively inhibits URAT1 to lower serum uric acid levels in patients with hyperuricemia. Herein, the effects of dotinurad were compared among patient groups with different stages of renal dysfunction. METHODS: Patient data from four clinical trials were pooled and divided into four groups according to the stage of renal dysfunction to compare the effects of dotinurad at different stages. The grouping (stages G1-G3b) was based on the estimated glomerular filtration rate (eGFR) of the patients. In addition, patient data from a long-term study (34 or 58 weeks) were evaluated in the same manner. RESULTS: In the pooled analysis, the percentage of patients achieving a serum uric acid level of ≤ 6.0 mg/dL was 64.7-100.0% at a dose of 2 or 4 mg. In the long-term analysis, the percentage of patients achieving a serum uric acid level of ≤ 6.0 mg/dL was 60.0-100.0% at a dose of 2 or 4 mg. Although the outcomes in stage G3b were worse due to higher baseline serum uric acid levels, satisfactory outcomes were observed in all stages. Even in stages G3a and G3b, when renal function declined, the eGFR remained constant throughout the dose period. CONCLUSION: The efficacy of dotinurad was confirmed in hyperuricemic patients with normal renal function (stage G1) and mild to moderate renal dysfunction (stage G2-G3b). Dotinurad was found to be effective in the treatment of hyperuricemia in patients with mild to moderate renal dysfunction.

Uric acid-lowering effect of dotinurad, a novel selective urate reabsorption inhibitor, in hypertensive patients with gout or asymptomatic hyperuricemia: a pooled analysis of individual participant data in phase II and III trials.

Background: Hyperuricemia is a risk factor for the development of hypertension and is comorbid in many hypertensive patients. According to Japanese hypertension management guidelines published in 2019, a target serum uric acid level of ≤6.0 mg/dL is recommended in hypertensive patients with gout or asymptomatic hyperuricemia. Dotinurad is a novel uric acid-lowering drug classified as a selective urate reabsorption inhibitor. A pooled analysis was performed on the uric acid-lowering effect of dotinurad in 222 hypertensive patients with gout or asymptomatic hyperuricemia in four clinical trials (NCT02344862, NCT02416167, NCT03100318, NCT03372200). Moreover, we analyzed the long-term uric acid-lowering effect of dotinurad in 154 hypertensive patients with gout or asymptomatic hyperuricemia (NCT03006445).Results: In the pooled analysis, the percent change in the decrease of serum uric acid with the use of dotinurad was 42.17 ± 12.42% at a dose of 2 mg and 60.42 ± 8.03% at a dose of 4 mg; the percentage of patients who achieved a serum uric acid level of ≤6.0 mg/dL was 82.8% and 100.0%. The long-term uric acid-lowering effect of dotinurad showed almost the same results. In this study, the concomitant use of diuretics or angiotensin II receptor blockers affected the uric acid-lowering effect of dotinurad at only a dose of 2 mg in the pooled analysis.Conclusions: In the pooled analysis, dotinurad lowered serum uric acid levels. Dotinurad has an achievement rate of over 80% for serum uric acid level of ≤6.0 mg/dL in both analyses, and will be clinically useful for the management of hyperuricemic states in hypertensive patients.

Therapeutic Strategies for the Treatment of Chronic Hyperuricemia: An Evidence-Based Update.

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

Pharmacotherapy for hyperuricaemia in hypertensive patients.

BACKGROUND: This is the second update of this systematic review. High blood pressure represents a major public health problem. Worldwide, approximately one-fourth of the adult population has hypertension. Epidemiological and experimental studies suggest a link between hyperuricaemia and hypertension. Hyperuricaemia affects 25% to 40% of those with untreated hypertension; a much lower prevalence has been reported in those with normotension or in the general population. However, whether lowering serum uric acid (UA) might lower blood pressure (BP), is an unanswered question. OBJECTIVES: To determine whether UA-lowering agents reduce BP in people with primary hypertension or prehypertension, compared with placebo. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to May 2020: the Cochrane Hypertension Specialised Register, CENTRAL 2018, Issue 12, MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also searched LILACS (1982 to May 2020), and contacted authors of relevant papers regarding further published and unpublished work. The searches had no language or date restrictions. SELECTION CRITERIA: To be included in this updated review, the studies had to meet the following criteria: 1) randomised or quasi-randomised, with a group assigned to receive a UA-lowering agent and another group assigned to receive placebo; 2) double-blind, single-blind, or open-label; 3) parallel or cross-over trial design; 4) cross-over trials had to have a washout period of at least two weeks; 5) minimum treatment duration of four weeks; 6) participants had to have a diagnosis of essential hypertension or prehypertension plus hyperuricaemia (serum UA greater than 6 mg/dL in women, 7 mg/dL in men, and 5.5 mg/dL in children or adolescents); 7) outcome measures included change in 24-hour ambulatory systolic or diastolic BP, or both; or clinic-measured systolic or diastolic BP, or both. DATA COLLECTION AND ANALYSIS: The two review authors independently collected the data using a data extraction form, and resolved any disagreements via discussion. We assessed risk of bias using the Cochrane 'Risk of bias' tool. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: In this review update, we screened 722 records, selected 26 full-text reports for evaluation. We identified no ongoing studies and did not add any new studies. We included three randomised controlled trials (RCTs), enrolling 211 people with hypertension or prehypertension, plus hyperuricaemia. Low-certainty evidence from three RCTs found inconclusive results between those who received UA-lowering drugs and placebo, in 24-hour ambulatory systolic (MD -6.2 mmHg, 95% CI -12.8 to 0.5) or diastolic BP (-3.9 mmHg, 95% CI -9.2 to 1.4). Low-certainty evidence from two RCTs found that UA-lowering drugs reduced clinic-measured systolic BP (-8.43 mmHg, 95% CI -15.24 to -1.62) but results for clinic-measured diastolic BP were inconclusive (-6.45 mmHg, 95% CI -13.60 to 0.70). High-certainty evidence from three RCTs found that serum UA levels were reduced by 3.1 mg/dL (95% CI 2.4 to 3.8) in the participants that received UA-lowering drugs. Low-certainty evidence from three RCTs found inconclusive results regarding the occurrence of adverse events between those who received UA-lowering drugs and placebo (RR 1.86, 95% CI 0.43 to 8.10). AUTHORS' CONCLUSIONS: In this updated Cochrane Review, the current RCT data are insufficient to know whether UA-lowering therapy lowers BP. More studies are needed.

Simultaneous separation and determination of 20 potential adulterant antigout and antiosteoporosis pharmaceutical compounds in herbal food products using LC with electrospray ionization MS/MS and LC with quadrupole-time-of-flight MS.

An analytical method for the simultaneous and reliable determination of 20 antigout and antiosteoporosis pharmaceutical compounds in adulterated health food products was developed using liquid chromatography with electrospray ionization tandem mass spectrometry and liquid chromatography with quadrupole-time-of-flight mass spectrometry. The method was validated through the determination of specificity, linearity, limit of detection, and limit of quantification, method detection limit, method quantitation limit, precision, accuracy, recovery, and stability. The matrix effect was also determined. The validation results of the developed method are as follows: for solid and liquid blank samples, limits of detection ranged from 0.05 to 5.00 ng/mL and limits of quantification ranged from 0.15 to 15.00 ng/mL. Linearity was acceptable, and the correlation coefficients (R2 ) were ≥0.99 for all target compounds. Both intra and interday precision were less than 9.16% RSD, and accuracies ranged from 95.31 to 116.68%. Mean recoveries for different types of dietary supplements classified as powders, liquids, tablets, and capsules were found to be 80.81 to 117.62% with less than 15.00% relative standard deviation. The stability of the standard mixture solution was less than 11.72% relative standard deviation after 48 h. By the proposed method, the presence of dexamethasone was determined in seized herbal food products at concentrations that ranged from 126 to 215 µg/g.