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Aims: Dose escalation at the initiation of allopurinol therapy can be protracted and resource intensive. Tools to predict the allopurinol doses required to achieve target serum urate concentrations would facilitate the implementation of more efficient dose-escalation strategies. The aim of this research was to develop and externally evaluate allopurinol dosing tools, one for use when the pre-urate-lowering therapy serum urate is known (Easy-Allo1) and one for when it is not known (Easy-Allo2)., Methods: A revised population pharmacokinetic-pharmacodynamic model was developed using data from 653 people with gout. Maintenance doses to achieve the serum urate target of <0.36 mmol L -1 in >80% of individuals were simulated and evaluated against external data. The predicted and observed allopurinol doses were compared using the mean prediction error (MPE) and root mean square error (RMSE). The proportion of Easy-Allo predicted doses within 100 mg of the observed was quantified., Results: Allopurinol doses were predicted by total body weight, baseline urate, ethnicity and creatinine clearance. Easy-Allo1 produced unbiased and suitably precise dose predictions (MPE 2 mg day -1 95% confidence interval [CI] -13-17, RMSE 91%, 90% within 100 mg of the observed dose). Easy-Allo2 was positively biased by about 70 mg day -1 and slightly less precise (MPE 70 mg day -1 95% CI 52-88, RMSE 131%, 71% within 100 mg of the observed dose)., Conclusions: The Easy-Allo tools provide a guide to the allopurinol maintenance dose requirement to achieve the serum urate target of <0.36 mmol L -1 and will aid in the development of novel dose-escalation strategies for allopurinol therapy., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Gout affects 15%-30% of individuals with advanced kidney disease. Allopurinol which is rapidly and extensively metabolised to an active metabolite, oxypurinol, is the most commonly prescribed urate-lowering therapy. Oxypurinol is almost entirely eliminated by the kidneys (>95%) and has an elimination half-life of 18-30 h in those with normal kidney function. However, oxypurinol pharmacokinetics are poorly understood in individuals with kidney failure on peritoneal dialysis. This study characterised the elimination of oxypurinol and urate in people with gout receiving peritoneal dialysis. Oxypurinol steady-state oral clearance (CL/F), elimination half-life as well as kidney (CL k ) and peritoneal (CL pd ) clearances for oxypurinol and urate were calculated from the plasma, urine and dialysate concentration data for each individual. Our results demonstrate that oxypurinol and urate are removed by peritoneal dialysis, accounting for more than 50% of oxypurinol and urate clearances. An allopurinol dose about 50%-60% lower than the usual dose used for a patient with normal kidney function will provide adequate urate-lowering therapy., (© 2024 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

Aims: The aim of this study was to estimate adherence to urate-lowering therapy (ULT), predominately allopurinol, from Australia's Pharmaceutical Benefits Scheme (PBS) claims database in association with (1) patient-reported doses and (2) World Health Organization's (WHO) defined daily doses (DDD), namely, allopurinol (400 mg/day) or febuxostat (80 mg/day)., Methods: Proportion of days covered (PDC) was calculated in 108 Gout App (Gout APP) trial participants with at least two recorded ULT dispensings in an approximately 12-month period before provision of intervention or control apps. Adherence was defined as PDC ≥80%. We measured the correlation between the two methods of calculating PDC using a Wilcoxon signed rank test. Agreement between ULT-taking status (self-reports) and ULT-dispensed status (PBS records) was tested with Cohen's kappa (κ), and positive and negative percent agreement., Results: Allopurinol was prescribed in 93.5% of participants taking ULT. Their self-reported mean daily dose (SD) was 291 (167) mg/day. Mean PDC (SD) for allopurinol was 83% (21%) calculated using self-reported dose, and 63% (24%) using WHO's DDD. Sixty-three percent of allopurinol users were identified as adherent (PDC ≥80%) using self-reported dose. There was good agreement between self-reported ULT use and PBS dispensing claims (κ = 0.708, P < .001; positive percent agreement = 90%, negative percent agreement = 82%)., Conclusions: Participant-reported allopurinol daily doses, in addition to PBS dispensing claims, may enhance confidence in estimating PDC and adherence compared to using DDD. This approach improves adherence estimations from pharmaceutical claims datasets for medications where daily doses vary between individuals or where there is a wide therapeutic dose range., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Purpose of Review: To review the extent of treatment success or failure with the xanthine oxidoreductase inhibitors allopurinol and febuxostat and indicate how the dosage of urate-lowering therapy (ULT) may be modified to increase the response in the majority of patients with gout., Recent Findings: Gout flares are associated with serum concentrations of urate above 0.42 mmol/L (7 mg/dL). Achieving and maintaining serum urate below 0.36 mmol/L is considered an effective response to ULT. On an intention to treat basis, clinical trials indicate that allopurinol at daily doses of 100 to 300 mg decreases serum urate adequately in only about 40% of gout patients while febuxostat 80 mg daily reduces serum urate adequately in approximately 70% of gout patients. Higher doses of ULT may be required in patients receiving concomitant diuretics. The addition of a uricosuric agent to allopurinol and febuxostat therapy significantly increases the proportion of patients achieving adequate lowering of serum urate. Finally, carriers of a genetic variant of the transporter, ABCG2 (BCRP), have a decreased response to allopurinol. Careful examination of medication adherence, titration of doses, and the addition of uricosuric agents increase the percentage of patients responding to allopurinol and febuxostat.

Objective: To investigate the contributions towards hyperuricaemia of known risk factors, focusing on fractional (renal) clearance of urate (FCU) and variation in the ATP-binding cassette transporter, sub-family G 2 (ABCG2) gene., Methods: The contributions of age, sex, ancestry, Q141K genotype for ABCG2, FCU, sugar-sweetened beverage and alcohol consumption, metabolic syndrome disorders and measures of renal function to the risk of hyperuricaemia were evaluated by comparing hyperuricaemic (serum urate≥0.42 mmol/L, n=448) with normouricaemic (serum urate<0.42 mmol/L, n=344) participants using stepwise logistic regression. Model performance was evaluated using the area under the receiver operator characteristic curve (AUROC)., Results: ABCG2 genotype, FCU, male sex, body mass index, serum triglyceride concentrations, estimated glomerular filtration rate and consumption of alcohol were the best predictors of hyperuricaemia (AUROC 0.90, 81% accuracy). Homozygosity in the 141K variant for ABCG2 conferred an adjusted OR of 10.5 for hyperuricaemia (95% CI 2.4 to 46.2). For each 1% decrease of FCU, the adjusted OR increased by 51% (OR 1.51, 95% CI 1.37 to 1.66). There was no association between ABCG2 genotype and FCU (r=0.02, p=0.83)., Conclusions: The ABCG2 141K variant and the FCU contribute strongly but independently to hyperuricaemia. These findings provide further evidence for a significant contribution of ABCG2 to extra-renal (gut) clearance of urate., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Aims: The aim of the study was to identify and quantify factors that control the plasma concentrations of urate during allopurinol treatment and to predict optimal doses of allopurinol., Methods: Plasma concentrations of urate and creatinine (112 samples, 46 patients) before and during treatment with various doses of allopurinol (50-600 mg daily) were monitored. Non-linear and multiple linear regression equations were used to examine the relationships between allopurinol dose (D), creatinine clearance (CLcr) and plasma concentrations of urate before (UP) and during treatment with allopurinol (UT)., Results: Plasma concentrations of urate achieved during allopurinol therapy were dependent on the daily dose of allopurinol and the plasma concentration of urate pre-treatment. The non-linear equation: UT = (1 - D/(ID50 + D)) × (UP - UR) + UR , fitted the data well (r(2) = 0.74, P < 0.0001). The parameters and their best fit values were: daily dose of allopurinol reducing the inhibitable plasma urate by 50% (ID50 = 226 mg, 95% CI 167, 303 mg), apparent resistant plasma urate (UR = 0.20 mmol l(-1), 95 % CI 0.14, 0.25 mmol l(-1)). Incorporation of CLcr did not significantly improve the fit (P = 0.09)., Conclusions: A high baseline plasma urate concentration requires a high dose of allopurinol to reduce plasma urate below recommended concentrations. This dose is dependent on only the pre-treatment plasma urate concentration and is not influenced by CLcr ., (© 2013 The British Pharmacological Society.)

Introduction: Hyperuricemia is the greatest risk factor for gout and is caused by an overproduction and/or inefficient renal clearance of urate. The fractional renal clearance of urate (FCU, renal clearance of urate/renal clearance of creatinine) has been proposed as a tool to identify subjects who manifest inefficient clearance of urate. The aim of the present studies was to validate the measurement of FCU by using spot-urine samples as a reliable indicator of the efficiency of the kidney to remove urate and to explore its distribution in healthy subjects and gouty patients., Methods: Timed (spot, 2-hour, 4-hour, 6-hour, 12-hour, and 24-hour) urine collections were used to derive FCU in 12 healthy subjects. FCUs from spot-urine samples were then determined in 13 healthy subjects twice a day, repeated on 3 nonconsecutive days. The effect of allopurinol, probenecid, and the combination on FCU was explored in 11 healthy subjects. FCU was determined in 36 patients with gout being treated with allopurinol. The distribution of FCU was examined in 118 healthy subjects and compared with that from the 36 patients with gout., Results: No substantive or statistically significant differences were observed between the FCUs derived from spot and 24-hour urine collections. Coefficients of variation (CVs) were both 28%. No significant variation in the spot FCU was obtained either within or between days, with mean intrasubject CV of 16.4%. FCU increased with probenecid (P < 0.05), whereas allopurinol did not change the FCU in healthy or gouty subjects. FCUs of patients with gout were lower than the FCUs of healthy subjects (4.8% versus 6.9%; P < 0.0001)., Conclusions: The present studies indicate that the spot-FCU is a convenient, valid, and reliable indicator of the efficiency of the kidney in removing urate from the blood and thus from tissues. Spot-FCU determinations may provide useful correlates in studies investigating molecular mechanisms underpinning the observed range of efficiencies of the kidneys in clearing urate from the blood., Trial Registration: ACTRN12611000743965.

Aims: To determine whether low-dose aspirin and hydrochlorothiazide (HCTZ) affect the renal clearance of oxypurinol and/or urate., Methods: Healthy volunteers (n = 8) were treated with allopurinol (600 mg, control), and allopurinol (600 mg) co-administered with single doses of aspirin (100 mg) or HCTZ (25 mg) or a combination of the two., Results: Hydrochlorothiazide, low-dose aspirin or a combination of the two, when co-administered with allopurinol, did not significantly alter (P > 0.05) the renal clearance of oxypurinol or urate. In particular, aspirin and HCTZ, when taken together and with allopurinol, did not change (P > 0.05) oxypurinol fractional renal clearance (allopurinol alone: 0.217, 0.173-0.262; combined: 0.202, 0.155-0.250) or urate fractional renal clearance (allopurinol alone: 0.066, 0.032-0.099; combined: 0.058, 0.038-0.078)., Conclusions: A single, low-dose of aspirin or an anti-hypertensive dose of hydrochlorothiazide, when administered alone or together with allopurinol, are unlikely to alter the hypouricaemic effect of allopurinol. The effect of chronic aspirin and HCTZ dosing taken together upon the efficacy of chronic allopurinol therapy in patients with hyperuricaemia needs to be investigated.

Investigation of the genetic basis of hyperuricaemia is a subject of intense interest. However, clinical studies commonly include hyperuricaemic patients without distinguishing between 'over-producers' or 'under-excretors' of urate. The statistical power of studies of genetic polymorphisms of genes encoding renal urate transporters is diluted if 'over-producers' of uric acid are included. We propose that lower than normal fractional renal clearance of urate is a better inclusion criterion for these studies. We also propose that a single daytime spot urine sample for calculation of fractional renal clearance of urate should be preferred to calculation from 24-hour urine collections.

Gout is the most common inflammatory arthritis in adults. The prevalence of gout increases with age. Urate-lowering treatment (ULT) among older patients is often challenging in that patients frequently suffer insufficient effectiveness or adverse events due to comorbidities, concurrent medications, and altered pharmacokinetics. The large-scale randomized controlled trials (RCTs) directly investigating gout patients regarding cardiovascular (CV) safety have only recently been introduced; CARES and FAST compared the CV safety of the two xanthine oxidase inhibitors (XOis), febuxostat versus allopurinol, in patients with gout. Based on the CARES trial that showed CV concerns with febuxostat, the current international guidelines recommend allopurinol as first-line ULT in gout, while preserving other agents as a second-line treatment, despite a higher potency of febuxostat. XOis would be more suitable than uricosurics to treat older patients with gout due to the high prevalence of chronic kidney disease (CKD) in older patients. However, allopurinol alone might not achieve the target serum uric acid levels below 6 mg/dL and CKD might confer an increased risk of allopurinol induced cutaneous adverse reactions in older patients. Furthermore, as well as the later analysis of CARES participants who were lost to follow-up, data from the FAST trial and real-world studies suggest non-inferior CV safety for febuxostat compared to allopurinol even in the presence of CV diseases. Thus, febuxostat use in older patients with renal impairment may be more positively considered. The combination therapy of a novel uricosuric, verinurad, plus febuxostat reduced albuminuria in hyperuricemic patients with type 2 diabetes and CKD in a phase 2a trial, and further RCTs are awaited. Finally, the sodium-glucose cotransporter-2 inhibitor class of oral hypoglycemic agents, known to exert beneficial CV and renal effects independent of glycemic control, have shown a uricosuric effect and could be used as adjunctive therapy in older patients with cardiorenal comorbidities., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Gout is a metabolic disorder and one of the most common arthritic conditions. Hyperuricemia is the hallmark of developing gout and mostly caused by uric acid underexcretion. Gout disproportionately affects people of specific races and ethnicities. Filipinos are the second-largest Asian population in the USA and reported to have a higher prevalence of gout and hyperuricemia than non-Filipino counterparts and Filipinos residing in the Philippines. The genetic polymorphism rs2231142 G>T in the ABCG2 has been strongly associated with hyperuricemia and gout across multiple populations. However, the prevalence of this variant in Filipinos is unknown. Therefore, assessing the prevalence of this variant may provide insights on the high prevalence of hyperuricemia and gout in Filipinos. A total of 190 DNA samples from pregnant females who self-identified as a Filipino from the Hawaii Biorepository Bank were genotyped for rs2231142 G>T in the ABCG2. The prevalence of the gout risk allele (T) (46%) was significantly higher in Filipinos than in samples of Caucasians (12%, p < 0.001), Han Chinese (29%, p = 0.014), and African Americans (3%, p < 0.001). Similarly, the prevalence of the gout-risk genotype (TT) (21%) was significantly higher in Filipinos than in samples of Caucasians (1%, p < 0.001), Han Chinese (9%, p = 0.002), and African Americans (0.1%, p < 0.001). Though there were no gout cases in this cohort, these findings are suggestive of a genetic basis to the high prevalence of hyperuricemia and gout in Filipinos. This might also explain the reported reduced urinary uric acid excretion in Filipinos compared with Caucasians. Key Points • The Filipinos have the highest prevalence of the gout-associated risk allele (T) of the rs2231142 G>T in ABCG2. • The high prevalence of the risk allele (T) of the rs2231142 G>T in ABCG2 may partly explain the reduced urinary urate excretion and early-onset gout in Filipinos. • The high prevalence of the risk allele (T) of the rs2231142 G > T in ABCG2 may predispose Filipinos to hyperuricemia and gout when acculturated to high-purine diet.

Purpose of Review: Uric acid is produced after purine nucleotide degradation, upon xanthine oxidase catalytic action. In the evolutionary process, humans lost uricase, an enzyme that converts uric acid into allantoin, resulting in increased serum uric acid levels that may vary according to dietary ingestion, pathological conditions, and other factors. Despite the controversy over the inflammatory role of uric acid in its soluble form, crystals of uric acid are able to activate the NLRP3 inflammasome in different tissues. Uric acid, therefore, triggers hyperuricemic-related disease such as gout, metabolic syndrome, and kidney injuries. The present review provides an overview on the role of uric acid in the inflammasome-mediated kidney damage., Recent Findings: Hyperuricemia is present in 20-35% of patients with chronic kidney disease. However, whether this increased circulating uric acid is a risk factor or just a biomarker of renal and cardiovascular injuries has become a topic of intense discussion. Despite these conflicting views, several studies support the idea that hyperuricemia is indeed a cause of progression of kidney disease, with a putative role for soluble uric acid in activating renal NLRP3 inflammasome, in reprograming renal and immune cell metabolism and, therefore, in promoting kidney inflammation/injury., Summary: Therapies aiming to decrease uric acid levels prevent renal NLRP3 inflammasome activation and exert renoprotective effects in experimental kidney diseases. However, further clinical studies are needed to investigate whether reduced circulating uric acid can also inhibit the inflammasome and be beneficial in human conditions.

Objective: Hyperuricemia is a strong precursor of gout, which deteriorates patients' health and quality of life. Sustained adherence to urate-lowering therapies (ULTs) is crucial for efficacy and therapeutic cost-effectiveness. Recently, several new ULTs have been proposed. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to reassess the efficacy and safety of the current ULTs, focusing on adherence attrition-related adverse event reporting., Method: The Bayesian network meta-analysis was applied to compare ULTs. Drug efficacy and safety were measured by whether the target level of serum urate acid was achieved and whether any adverse events occurred. The results were summarized using the pooled estimates of effect sizes (odds ratios), their precisions (95% credible interval), and the ranking probabilities., Results and Conclusions: Thirty-nine RCTs were identified, accumulating 19,401 patients. Consistent with previous studies, febuxostat (≥ 40 mg/day) was superior to other monoagent ULTs. The new findings were as follows: (i) dual-agent ULTs were superior to febuxostat alone, and further surveillance on the adverse effects when lesinurad is uptitrated is needed, and (ii) terminalia bellerica 500 mg/day, a novel xanthine oxidase inhibitor (XOI) made of natural fruit extracts, and topiroxostat ≥ 80 mg/day, an XOI used mostly in Japan, could be new effective options for lowering the occurrence of adherence attrition events. Evidence from RCTs regarding second-line agents, such as probenecid and pegloticase, remains insufficient for clinical decision-making.Key Points• Dual-agent ULTs were superior to febuxostat alone, and further surveillance on the adverse-effects when lesinurad is uptitrated is needed.• Terminalia bellerica 500 mg/day, a novel xanthine oxidase inhibitor (XOI) made of natural fruit extracts, and topiroxostat 80 mg/day, an XOI used mostly in Japan, could be new effective options for lowering the occurrence of adherence attrition events.

Uric acid (UA) levels in blood serum have been associated with hypertension, indicating a potential causal relationship between high serum UA levels and the progression of hypertension. Therefore, the reduction of serum UA level is considered a potential strategy for lowering and mitigating blood pressure. If an individual is at risk of developing or already manifesting elevated blood pressure, this intervention could be an integral part of a comprehensive treatment plan. By addressing hyperuricaemia, practitioners may subsidize the optimization of blood pressure regulation, which illustrates the importance of addressing UA levels as a valuable strategy within the broader context of hypertension management. In this analysis, we outlined the operational principles of effective xanthine oxidase inhibitors for the treatment of hyperuricaemia and hypertension, along with an exploration of the contribution of nanotechnology to this field. [ABSTRACT FROM AUTHOR]

Background: Gout is a chronic disease caused by the accumulation of uric acid crystals in joints, resulting in sudden pain, stiffness, and swelling. Febuxostat (FBX), a xanthine oxidase inhibitor, is commonly used to treat gout but has poor solubility, which affects its bioavailability. Materials and Methods: To address this issue, a skin-permeating emulgel was developed using Cinnamon (CN) oil as an oil solvent, cremophor RH 40 (Cr. RH 40) as a co-surfactant/solubilizer, and Poloxamer 407 as an emulsifier. A solubility study was performed followed by optimization by 32 factorial designs. The formulation was further evaluated for viscosity, globule size, drug release, and stability studies. Results: Solubility of FBX was found 1 in 10 parts in selected oil. The optimized emulgel containing 10% Cremophor RH 40 and 20% Poloxamer 407 shown improved drug release compared to the pure drug. All other parameters were found satisfactory. Conclusion: The formulated emulgel designed to penetrate the skin shown a good potential for topical formulations enhancing the effectiveness of drug. Moreover, creating a skin-permeating emulsion-based gel in a cost-effective and industrially viable manner could enhance drug penetration and absorption through the skin thereby faster cure of gout compared to the conventional product. [ABSTRACT FROM AUTHOR]

Background: Hyperuricaemia is defined as an elevation of the uric acid level in the blood to more than 0.38 mmol/l. This increased uric acid gets deposited in the form of monosodium urate crystals in joint tissue to form a micro trophi complex. An increased uric acid level is associated with increased gouty risk. Antigout drugs such as allopurinol, Colchicine, probenecid, and Benzbromarone. The main action of these drugs is to decrease uric acid levels and symptoms of gouty arthritis. The main aim of our study is to detect a suitable mono-drug therapy for the treatment of gouty arthritis. Aim: To study the effect of allopurinol, probenecid, and Benzbromarone mono-drug therapy in gouty arthritis patients in tertiary care hospitals. Material and method: The present study was conducted on 150 gout patients. All the patients were equally divided into three groups; group -1, 50 patients were treated with allopurinol, group 2, 50 patients treated with probenecid, and group -3, 50 patients were treated with Benzbromarone. All these patients were monitored with symptoms and also tested with blood pressure, serum creatinine, blood urea, and blood uric acid. Results: In our study majority of the patients were male followed by female (p 0.342). With the age group of 61 - 65 years in all the groups (groups - 1, 2 & 3) respectively. On the basic characteristics of the gouty patients, 45.33% were alcoholic abuse, 35.33% were smokers, 52.66% were hypertensive, 80.66% were diabetic patients, 17.33% were Hypertriglyceridaemia, 45.33% were obesity, 21.33% positive family history and 58.66 % chronic tophaceous gout respectively. Based on the location of gouty arthritis and symptoms toes and swelling was observed in the majority of patients in all group - 1, 2 & 3. Based on biochemical parameters after 3 months of treatment, no significance was observed in serum creatinine in groups -1, 2 & 3 (p. >0.05) On blood urea no significance was observed in group -1(p>0.05), and significance was observed in blood urea in group 2 & 3 (p<0.05). Based on uric acid levels significance (p< 0.05) was observed in all three groups (group - 1, 2 & 3) respectively. Conclusion: Benzbromarone followed by is the better drug of choice in lower urea and uric acid levels compared with Probenecid and allopurinol group. [ABSTRACT FROM AUTHOR]

Background: TongFengTangSan (TFTS) is a commonly used Tibetan prescription for gout treatment. Previously, TFTS (CF) was confirmed to have a significant uric acid-lowering effect. However, the anti-hyperuricemia mechanisms and the main active fractions remain unclear. The current study aimed to investigate the anti-hyperuricemia mechanism using metabolomics and confirm the active CF fraction. Methods: The hyperuricemia model was established through intraperitoneal injection containing 100 mg/kg potassium oxonate and 150 mg/kg hypoxanthine by gavage. We used serum uric acid (sUA), creatinine (CRE), blood urea nitrogen (BUN), xanthine oxidase (XOD) activity, interleukin-6 (IL-6) and interleukin-1β (IL-1β) as indicators to evaluate the efficacy of CF and the four fractions (SX, CF30, CF60, and CF90). The anti-hyperuricemia mechanism of CF was considered through non-targeted metabolomics depending on the UPLC-Q-TOF–MS technology. Principle component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) helped explore the potential biomarkers in hyperuricemia. Moreover, the differential metabolites and metabolic pathways regulated by CF and four fractions were also assessed. Results: CF revealed a significant anti-hyperuricemia effect by down-regulating the level of sUA, sCRE, sIL-1β, and XOD. SX, CF30, CF60, and CF90 differed in the anti-hyperuricemia effect. Only CF60 significantly lowered the sUA level among the four fractions, and it could be the main efficacy fraction of TFTS. Forty-three differential metabolites were identified in hyperuricemia rats from plasma and kidney. Pathway analysis demonstrated that seven pathways were disrupted among hyperuricemia rats. CF reversed 19 metabolites in hyperuricemia rats and exerted an anti-hyperuricemia effect by regulating purine metabolism. CF60 was the main active fraction of TFTS and exerted a similar effect of CF by regulating purine metabolism. Conclusions: CF and CF60 could exert an anti-hyperuricemia effect by regulating the abnormal purine metabolism because of hyperuricemia while improving intestinal and renal function. CF60 could be the main active fraction of TFTS. [ABSTRACT FROM AUTHOR]

SHR4640 is a novel, selective urate reabsorption inhibitor. As the mode of action of SHR4640 differs from that of a xanthine oxidase inhibitor, such as febuxostat, coadministration of these drugs may be a treatment option for patients with primary hyperuricemia. We assessed the potential drug-drug interaction between SHR4640 and febuxostat. In this single-center, open-label, randomized, drug-drug interaction study, subjects received 80 mg febuxostat or 10 mg SHR4640 alone daily in the first week, whereas during the second week a combination of SHR4640 and febuxostat was administered daily to all subjects. Plasma concentrations of SHR4640 and febuxostat were analyzed. We compared their pharmacokinetic and pharmacodynamic parameters and assessed both safety and tolerability. Compared with febuxostat alone, the geometric mean ratios (90%CIs) of the maximum concentration (Cmax) and the area under the plasma concentration-time curve over the dosing interval t (AUC0-t) for febuxostat after coadministration were 1.284 (1.016 to 1.621) and 0.984 (0.876 to 1.106), respectively. The geometric mean ratios (90%CIs) of Cmax and AUC0-t for SHR4640 after coadministration compared with SHR4640 alone were 0.910 (0.839 to 0.988) and 0.929 (0.893 to 0.966), respectively. Febuxostat had no effect on SHR4640 pharmacokinetic parameters, as the 90%CIs of the geometric mean ratios were all within the range of 0.80 to 1.25. The coadministration of febuxostat and SHR4640 was well tolerated. The coadministration of SHR4640 with febuxostat was not associated with any clinically relevant pharmacokinetic drug interactions. SHR4640 combined with febuxostat had a synergistic effect on reducing uric acid in the pharmacodynamics, with the AUC decreasing from 7440 to 3170 h µmol/L compared with febuxostat alone and from 5730 to 2960 h µmol/L compared with SHR4640 alone. [ABSTRACT FROM AUTHOR]

Objectives: The current world witnesses a greatly increased prevalence and incidence of hyperuricemia and gout with unfortunately the comparative efficacy and safety of present available uricosuric agents remaining uncertain. We herein aimed to investigate the most appropriate uricosuric agent for gout or hyperuricemia patients. Method: PubMed, Embase, Cochrane Library databases, and ClinicalTrials.gov from inception to 2 July 2022 were searched to retrieve eligible studies assessing efficacy and safety of uricosuric drugs in hyperuricemia or gout patients. Network meta-analysis was carried out using the Stata 16.0 software. Results: Twelve randomized controlled trials comprising 1851 patients were eventually included. Network meta-analysis showed that dotinurad 4 mg once daily, verinurad, dotinurad 2 mg once daily, dotinurad 1 mg once daily, and benzbromarone were the top 5 effective treatments to achieve target serum uric acid. Furthermore, dotinurad 4 mg once daily was more effective at achieving urate-lowering targets (RR of dotinurad 4 mg once daily vs. probenecid: 1.68, 95% CI [1.13; 2.50]) and safer (RR of probenecid vs. dotinurad 4 mg once daily: 1.77, 95% CI [0.69; 4.56]) than probenecid. Conclusions: This network meta-analysis demonstrated an important absolute benefit of dotinurad 4 mg once daily to achieve target serum uric acid and low risk of adverse events for drug treatment of gout or hyperuricemia patients. Additionally, verinurad might be used as an alternative uricosuric therapeutic option to dotinurad. These findings provided further comprehensive insight into the treatment value of current uricosuric agents for gout or hyperuricemia. Key Points 1. This is the first systematic review and network meta-analysis examining the efficacy and safety of currently available uricosuric agents in gout or hyperuricemia patients. 2. Recommended doses of dotinurad 4mg once daily used for the treatment of gout or hyperuricemia patients can significantly decrease serum uric acid levels. 3. The present findings will provide further comprehensive insight into the treatment value of certain uricosuric agents for gout or hyperuricemia. [ABSTRACT FROM AUTHOR]

Hyperuricemia is described as a serum uric acid level more than 6.0 mg/dL. It is demonstrated by basic research and clinical studies, which the elevation of uric acid level may change the renal histology and function by developing acute and chronic kidney diseases (CKDs), diabetic nephropathy and end-stage renal disease (ESRD). There is no doubt about a significant relationship between uric acid and renal impairment. However, the details of this correlation, especially; between uric acid and renal failure, are discussable. Renal vasoconstriction, antiangiogenic properties, endothelial dysfunction, proinflammatory properties, renal fibrosis, pro-oxidative properties, and alteration of renal autoregulation are the most common mechanisms, which approve the association between uric acid and renal impairment. Allopurinol administration for CKD treatment in patients with gout is one of the most discussable challenges. It should be investigated whether allopurinol can diminish the deterioration of the glomerular filtration rate (GFR) in CKD patients who are at risk of ESRD. Some previous studies reported that allopurinol decreases the CKD incident risk, but others could not confirm this association. The benefit or risks of allopurinol in different stages of CKD, dialysis, and renal transplant are discussed in this study. [ABSTRACT FROM AUTHOR]

Recent studies suggest that Aster glehni extract (AGE) reduces hyperuricemia by preventing xanthine oxidase activity. However, its effect on renal urate transporters responsible for modulating urate excretion has not been examined. This study investigated whether AGE affects gene expressions of urate transporters using potassium oxonate (PO)-induced hyperuricemia rats. Furthermore, the underlying mechanisms of AGE were explored to ameliorate renal inflammation and injury by PO. AGE effectively restored PO-induced dysregulation of renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), ATP-binding cassette transporter subfamily G member 2 (ABCG2), organic anion transporter 1 (OAT1), and organic cation transporter 1 (OCT1), resulting in increasing urate excretion. Additionally, AGE suppressed toll-like receptor 4/myeloid differentiation factor 88 (TLR4/MyD88) signaling, phosphorylation of nuclear factor kappa B (NF-κB), and renal production of IFN-γ, IL-1β, TNF-α, and IL-6. These results suggest that AGE may ameliorate PO-induced hyperuricemia by modulating renal transporters, and further renal inflammation via inhibiting the TLR4/MyD88/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Background and Objective: Previously, we developed a pharmacokinetic-pharmacodynamic model of allopurinol, oxypurinol, and biomarkers, hypoxanthine, xanthine, and uric acid, in neonates with hypoxic-ischemic encephalopathy, in which high initial biomarker levels were observed suggesting an impact of hypoxia. However, the full pharmacodynamics could not be elucidated in our previous study. The current study included additional data from the ALBINO study (NCT03162653) placebo group, aiming to characterize the dynamics of hypoxanthine, xanthine, and uric acid in neonates with hypoxic-ischemic encephalopathy. Methods: Neonates from the ALBINO study who received allopurinol or placebo mannitol were included. An extended population pharmacokinetic-pharmacodynamic model was developed based on the mechanism of purine metabolism, where synthesis, salvage, and degradation via xanthine oxidoreductase pathways were described. The initial level of the biomarkers was a combination of endogenous turnover and high disease-related amounts. Model development was accomplished by nonlinear mixed-effects modeling (NONMEM®, version 7.5). Results: In total, 20 neonates treated with allopurinol and 17 neonates treated with mannitol were included in this analysis. Endogenous synthesis of the biomarkers reduced with 0.43% per hour because of precursor exhaustion. Hypoxanthine was readily salvaged or degraded to xanthine with rate constants of 0.5 1/h (95% confidence interval 0.33–0.77) and 0.2 1/h (95% confidence interval 0.09–0.31), respectively. A greater salvage was found in the allopurinol treatment group consistent with its mechanism of action. High hypoxia-induced initial levels of biomarkers were quantified, and were 1.2-fold to 2.9-fold higher in neonates with moderate-to-severe hypoxic-ischemic encephalopathy compared with those with mild hypoxic-ischemic encephalopathy. Half-maximal xanthine oxidoreductase inhibition was achieved with a combined allopurinol and oxypurinol concentration of 0.68 mg/L (95% confidence interval 0.48–0.92), suggesting full xanthine oxidoreductase inhibition during the period studied. Conclusions: This extended pharmacokinetic-pharmacodynamic model provided an adequate description of the complex hypoxanthine, xanthine, and uric acid metabolism in neonates with hypoxic-ischemic encephalopathy, suggesting a positive allopurinol effect on these biomarkers. The impact of hypoxia on their dynamics was characterized, underlining higher hypoxia-related initial exposure with a more severe hypoxic-ischemic encephalopathy status. [ABSTRACT FROM AUTHOR]

Background: Allopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE). Currently, a double-blind, placebo-controlled study (ALBINO, NCT03162653) is investigating the neuroprotective effect of allopurinol in HIE neonates. Objective: The aim of the current study was to establish the pharmacokinetics (PK) of allopurinol and oxypurinol, and the pharmacodynamics (PD) of both compounds on hypoxanthine, xanthine, and uric acid in HIE neonates. The dosage used and the effect of allopurinol in this population, either or not undergoing therapeutic hypothermia (TH), were evaluated. Methods: Forty-six neonates from the ALBINO study and two historical clinical studies were included. All doses were administered on the first day of life. In the ALBINO study (n = 20), neonates received a first dose of allopurinol 20 mg/kg, and, in the case of TH (n = 13), a second dose of allopurinol 10 mg/kg. In the historical cohorts (n = 26), neonates (all without TH) received two doses of allopurinol 20 mg/kg in total. Allopurinol and oxypurinol population PK, and their effects on inhibiting conversions of hypoxanthine and xanthine to uric acid, were assessed using nonlinear mixed-effects modelling. Results: Allopurinol and oxypurinol PK were described by two sequential one-compartment models with an autoinhibition effect on allopurinol metabolism by oxypurinol. For allopurinol, clearance (CL) was 0.83 L/h (95% confidence interval [CI] 0.62–1.09) and volume of distribution (Vd) was 2.43 L (95% CI 2.25–2.63). For metabolite oxypurinol, CL and Vd relative to a formation fraction (fm) were 0.26 L/h (95% CI 0.23–0.3) and 11 L (95% CI 9.9–12.2), respectively. No difference in allopurinol and oxypurinol CL was found between TH and non-TH patients. The effect of allopurinol and oxypurinol on XO inhibition was described by a turnover model of hypoxanthine with sequential metabolites xanthine and uric acid. The combined allopurinol and oxypurinol concentration at the half-maximal XO inhibition was 0.36 mg/L (95% CI 0.31–0.42). Conclusion: The PK and PD of allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid in neonates with HIE were described. The dosing regimen applied in the ALBINO trial leads to the targeted XO inhibition in neonates treated with or without TH. [ABSTRACT FROM AUTHOR]

Poria coco F.A.Wolf (Polyporaceae) dispels dampness and promotes diuresis implying hypouricaemic action. To examine hypouricaemic action of Poria coco. Ethanol extract (PCE) was prepared by extracting the sclerotium of P. cocos with ethanol, and the water extract (PCW) was produced by bathing the remains with water. PCE and PCW (50, 100 and 200 mg/kg, respectively) were orally administered to hyperuricemic Kunming mice (n = 8) to examine its hypouricaemic effect. Also, molecular docking was performed. P. cocos showed excellent hypouricaemic action, decreasing the serum uric acid of hyperuricaemia (HUA) control (526 ± 112 μmol/L) to 178 ± 53, 153 ± 57 and 151 ± 62 μmol/L (p < 0.01) by PCE and 69 ± 23, 63 ± 15 and 62 ± 20 μmol/L (p < 0.01) by PCW, respectively. According to SCrs, BUNs and H&E staining, PCE and PCW partially attenuated renal dysfunction caused by HUA. They presented no negative effects on ALT, AST and ALP activities. They elevated ABCG2 (ATP-binding cassette super-family G member 2) mRNA and protein expression in comparison to HUA control. In molecular docking, compound 267, 277, 13824, 15730 and 5759 were predicted as the top bioactives of P. cocos against HUA, which even presented better scores than the positive compound, oestrone 3-sulfate. This paper demonstrated the hypouricaemic and nephroprotective effects of P. cocos in hyperuricemic mice by up-regulating ABCG2. These results may be useful for the development of a hypouricaemic agent. [ABSTRACT FROM AUTHOR]

The missense variant, breast cancer resistance protein (BCRP) p.Q141K, which encodes a reduced function BCRP, has been linked to poor response to allopurinol. Using a multifaceted approach, we aimed to characterize the relationship(s) between BCRP p.Q141K, the pharmacokinetics (PK) and pharmacodynamics (PD) of oxypurinol (the active metabolite of allopurinol), and serum uric acid (SUA) levels. A prospective clinical study (NCT02956278) was conducted in which healthy volunteers were given a single oral dose of 300 mg allopurinol followed by intensive blood sampling. Data were analyzed using noncompartmental analysis and population PK/PD modeling. Additionally, electronic health records were analyzed to investigate whether clinical inhibitors of BCRP phenocopied the effects of the p.Q141K variant with respect to SUA. Subjects homozygous for p.Q141K had a longer half‐life (34.2 ± 12.2 h vs. 19.1 ± 1.42 h) of oxypurinol. The PK/PD model showed that women had a 24.8% lower volume of distribution. Baseline SUA was affected by p.Q141K genotype and renal function; that is, it changed by 48.8% for every 1 mg/dl difference in serum creatinine. Real‐world data analyses showed that patients prescribed clinical inhibitors of BCRP have higher SUA levels than those that have not been prescribed inhibitors of BCRP, consistent with the idea that BCRP inhibitors phenocopy the effects of p.Q141K on uric acid levels. This study identified important covariates of oxypurinol PK/PD that could affect its efficacy for the treatment of gout as well as a potential side effect of BCRP inhibitors on increasing uric acid levels, which has not been described previously. [ABSTRACT FROM AUTHOR]

Objectives: The study of sex differences in hyperuricemia can provide not only a theoretical basis for this clinical phenomenon but also new therapeutic targets for urate-lowering therapy. In the current study, we aimed to confirm that estradiol can promote intestinal ATP binding cassette subfamily G member 2 (ABCG2) expression to increase urate excretion through the PI3K/Akt pathway. Methods: The estradiol levels of hyperuricemia/gout patients and healthy controls were compared, and a hyperuricemia mouse model was used to observe the urate-lowering effect of estradiol and the changes in ABCG2 expression in the kidney and intestine. In vivo and in vitro intestinal urate transport models were established to verify the urate transport function regulated by estradiol. The molecular pathway by which estradiol regulates ABCG2 expression in intestinal cells was explored. Results: The estradiol level of hyperuricemia/gout patients was significantly lower than that of healthy controls. Administering estradiol benzoate (EB) to both male hyperuricemic mice and female mice after removing the ovaries confirmed the urate-lowering effect of estradiol, and hyperuricemia and estradiol upregulated the expression of intestinal ABCG2. Estradiol has been confirmed to promote urate transport by upregulating ABCG2 expression in intestinal urate excretion models in vivo and in vitro. Estradiol regulates the expression of intestinal ABCG2 through the PI3K/Akt pathway. Conclusion: Our study revealed that estradiol regulates intestinal ABCG2 through the PI3K/Akt pathway to promote urate excretion, thereby reducing serum urate levels. [ABSTRACT FROM AUTHOR]

This review aims to critically present the available clinical evidence supporting the treatment of chronic hyperuricemia with xanthine oxidase inhibitors. For this reason, the studies published on uric acid (UA)-lowering drugs in the English language from 2000 to August 2019 have been carefully reviewed. The terms "serum uric acid," "xanthine oxidase," "allopurinol," "febuxostat," and "topiroxostat" were incorporated into an electronic search strategy, alone and in combinations, in both MEDLINE (National Library of Medicine, Bethesda, MD) and the Cochrane Register of Controlled Trials (The Cochrane Collaboration, Oxford, UK). Even if new urate-lowering drugs seem of particular efficacy for acute treatment of refractory hyperuricemia, their use is supported by relatively small clinical evidence. On the contrary, large long-term clinical trials have demonstrated that xanthine oxidase inhibitors (XOIs, namely, allopurinol and febuxostat) are effective, safe, and relatively well-tolerated in most of the patients. They have mainly been tested in the elderly, in patients affected by chronic diseases such as heart failure and cancer, and in patients taking a large number of drugs, confirming their safety profile. Recent data also show that they could exert some positive effects on vascular health, renal function, and glucose metabolism. Their cost is also low. In conclusion, XOIs remain the first choice of UA-lowering drug for chronic treatment. [ABSTRACT FROM AUTHOR]

Lycium barbarum L. (Solanaceae) polysaccharides (LBPs) are important active constituents that have demonstrated kidney protection. This study investigated the effect of LBPs on hyperuricaemia and explored the underlying mechanism in mice. Thirty-six C57BL/6 mice were randomly divided into the control group, hyperuricaemia group, allopurinol group (5 mg/kg) and three LBP groups (n = 6). The LBP groups were treated orally with LBPs at 50, 100 and 200 mg/kg body weight for 7 days. We examined the levels of serum uric acid (SUA) and urinary uric acid (UUA), as well as xanthine oxidase (XOD) activities. mRNA and protein were quantified by quantitative real-time PCR and Western blotting, respectively. LBPs treatment (100 and 200 mg/kg) significantly reduced the SUA levels to 4.83 and 4.48 mg/dL, and markedly elevated the UUA levels to 4.68 and 5.18 mg/dL (p < 0.05), respectively, while significantly increased the mRNA and protein expression levels of renal organic anti-transporter 1 (OAT1) and organic anti-transporter 3 (OAT3), and markedly decreased the levels of glucose transporter 9 (GLUT9) (p < 0.05). Additionally, the serum XOD activities were reduced to 31.5 and 31.1 mU/mL, and the liver XOD activities were reduced to 80.6 and 75.6 mU/mL after treatment with 100 and 200 mg/kg LBPs (p < 0.01), respectively. This study demonstrated the potential role of LBPs in reducing the uric acid level in hyperuricemic mice. A border study population should be evaluated. These results are valuable for the development of new anti-hyperuricaemia agents from LBPs. [ABSTRACT FROM AUTHOR]

Objectives: To assess the improvement, safety and tolerability of Allopurinol 300mg/daily & Febuxostat 80mg/daily in hyperuricemic patients. Study Design: Clinical Interventional Study. Setting: Medical OPD, Dr. Ruth K M Pfau Civil Hospital Karachi. Period: September 2018 to March 2019. Material & Methods: The designed interventional study from the Department of Pharmacology Hamdard College of Medicine & Dentistry, approved by BASR & Ethical Review Board of Hamdard University Karachi. Initially 70 enrolled patients, 60-patients of sUA>6.8 mg/dl were registered, after fulfilled the inclusion and exclusion criteria and written consent, detail history on pro forma and biochemical assessments (sUA, S. Creatinine, Alkaline Phosphate, SGPT, Cholesterol, HDL, LDL and Blood sugar were measured at day 0), repeated at day 30, 60 and 90, keep in case record file, on follow up visits for final analysis. Group A, (Allopurinol) & B (Febuxostat) results data were compared of sUA, S. Creatinine and biochemical assessments, to estimate the improvement, safety and tolerability of the drugs. Results: Group-A baseline uric acid were, mean 8.79 ± 0.98 to mean 6.40 ± 0.86 with percentage change was 26%. Group-B treated sUA were changed mean 8.85±0.97 to 5.96±0.68 with percentage change was 33%. Overall improvement in mean was statistically highly significant. Mean difference ± SD for change of serum uric acid in Group-A is 2.39±1.15 with Group-B mean change is 2.90±0.87. Drug safety was determined by adverse effects and blood assay of follow up at day-90 from baseline. Conclusion: Improvement reported by mean of reduced uric acid & no serious adverse effects, results are highly significant. [ABSTRACT FROM AUTHOR]

Background: Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by selective inhibition of the urate transporter 1. We evaluated the efficacy and safety of dotinurad versus febuxostat, a widely used drug in Japan, in hyperuricemic Japanese patients with or without gout. Methods: This was a multicenter, randomized, double-blind, active-controlled, parallel-group, forced-titration study in hyperuricemic patients. Study treatment in the dotinurad and febuxostat groups was initiated at 0.5 and 10 mg/day, followed by dose titration to 2 and 40 mg/day, respectively, over 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 203 hyperuricemic patients with or without gout were enrolled in the study and randomized to receive dotinurad or febuxostat. The percent change in serum uric acid level from the baseline to the final visit was 41.82% in the dotinurad group and 44.00% in the febuxostat group. The mean difference was − 2.17% (two-sided 95% confidence interval − 5.26% to 0.92%). The lower limit of the interval was above the non-inferiority margin (− 10%), demonstrating the non-inferiority of dotinurad to febuxostat. The profiles of adverse events and adverse drug reactions raised no noteworthy safety concerns in either group. Conclusion: The non-inferiority of dotinurad to febuxostat in terms of serum uric acid lowering effect was confirmed. No noteworthy safety concerns arose. [ABSTRACT FROM AUTHOR]

Background: Dotinurad, a novel selective urate reabsorption inhibitor, exerts a serum uric acid-lowering effect by selectively inhibiting urate transporter 1 (URAT1) in patients with hyperuricemia. It is generally known that the progression of renal dysfunction is associated with a reduction in the serum uric acid-lowering effects of uricosuric drugs. We, therefore, investigated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of dotinurad in subjects with renal dysfunction. Methods: This was a parallel-group, open-label, single-dose clinical pharmacology study. Dotinurad (1 mg) was administered once, orally to subjects with mild (estimated glomerular filtration rate [eGFR], ≥ 60 to < 90 mL/min/1.73 m2) or moderate (eGFR, ≥ 30 to < 60 mL/min/1.73 m2) renal dysfunction or normal (eGFR, ≥ 90 mL/min/1.73 m2) renal function. Results: The time-course of mean plasma concentration of dotinurad had similar profiles across the groups. Regarding PK, there was no significant difference between the renal dysfunction groups and normal renal function group. Regarding PD, the maximum reduction rate in serum uric acid levels and the fractional uric acid excretion (FE) ratio (FE0–24/FE−24–0) were significantly lower in the moderate renal dysfunction group than in the normal renal function group. However, other PD parameters were not significantly different among the groups. No notable adverse events or adverse drug reactions were observed in this study. Conclusion: These results suggested that no dose adjustment might be necessary when administering dotinurad to patients with mild-to-moderate renal dysfunction. ClinicalTrials.gov Identifier: NCT02347046. [ABSTRACT FROM AUTHOR]

Background: Psyllium seeds, produced from Plantago ovata Forsk, are an herbal treatment generally used as a laxative. They also reportedly have lowering effects on some metabolic parameters such as blood glucose, lipids and uric acid. In this paper, we report the effect of this herbal medicine in reducing serum uric acid levels, without major adverse effects, in a hyperuricemic patient. Case report: A 51-year-old patient with a history of hyperuricemia (10.5 mg/dL in a recent measurement) gave consent to undergo a 40-day treatment using psyllium seeds with dosage of 83.3 mg/kg. Treatment was given in two 20-day courses: During the first course, the seeds were given daily and during the second course, the same dosage was given every other day. Serum uric acid levels decreased to 8.1 mg/dL and 6.8 mg/dL on the 20th and 40th days, respectively. No major adverse effects were observed, such as skin rashes, digestive disorders, muscular pain, allergic manifestations, abnormalities in liver and kidney function tests, and abnormalities in blood parameters. Conclusion: Psyllium seeds may be effective in reducing serum uric acid levels in hyperuricemia patients, and major adverse effects are not expected to occur. These data can be used for further research and designing clinical trials. [ABSTRACT FROM AUTHOR]

Objective: Evaluate efficacy/safety of verinurad monotherapy in patients with gout (Japan/US) or asymptomatic hyperuricemia (Japan). Methods: Two randomized, placebo-controlled, phase II studies were conducted (NCT01927198/NCT02078219). Patients were randomized to once-daily doses of placebo or escalating doses of verinurad (study 1: 5-12.5mg; study 2: 2.5-15mg). Primary endpoint was percentage change from baseline in serum urate (sUA) at week 12 (study 1)/week 16 (study 2). Safety was also assessed. Results: Most patients in study 1 (n=171) were white (74.9%); all patients were Japanese in study 2 (n=204). Least squares means (±SE) estimate of percentage change in sUA levels from baseline in study 1 was 1.2 ± 2.9 for placebo, and -17.5 ± 2.8, -29.1 ± 2.8, -34.4 ± 2.9 for verinurad 5, 10, 12.5mg, respectively. In study 2, results were -2.4 ± 2.5 and -31.7 ± 2.5, -51.7 ± 2.6,-55.8 ± 2.5, respectively. Difference from placebo was significant for each verinurad dose (p<.0001). The proportion of patients with treatment-emergent adverse events (TEAEs) was similar across all groups. Renal-related TEAEs were more common with verinurad than placebo. Conclusion: Verinurad monotherapy resulted in sustained reductions in sUA in Japanese/US patients but renal AEs occurred, so verinurad alone is not recommended for treatment of hyperuricemia or gout. The renal consequences of excessive uric acid excretion deserve study. [ABSTRACT FROM AUTHOR]

Background: To determine the possible correlation between raised serum uric acid and various components of metabolic syndrome (Waist circumference, serum triglyceride, plasma HDL-C). Study Design: Descriptive case control. Setting: Army Medical College laboratory, Military Hospital, Rawalpindi. Period: One year (November 2014 to October 2015). Material and Methods: Total of 100 subjects were enrolled in this study. WHO criteria were applied for identifying the patients of metabolic syndrome. Fasting plasma glucose, lipid profile and serum uric acid levels were measured by using colorimetric enzymatic method. The formula of Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) was applied to calculate Insulin resistance. Collected data was analyzed by using SPSS- Window version-17 for statistical analysis. Results: Serum uric acid levels were turned out to be high in metabolic syndrome patients (cases= 6.1±1.3mg/dL) when compared with controls (having no symptoms of MetS=3.6±1.2; p<0.001). Uric acid showed a statistically significant positive association with waist circumference (WC=r-value:0.250; p-value:0.000) and serum triglyceride (TG=r-value:0.341; p-value:0.000). Negative correlation had been found between plasma high-density lipoprotein-cholesterol (HDL-C=r-value: -0.173; p-value:<0.01) with uric acid levels. Conclusion: Serum uric acid levels show a significant association with components of metabolic syndrome making it a powerful biomarker of metabolic syndrome and its various cardiometabolic complications. [ABSTRACT FROM AUTHOR]

Objective URC102, a novel and potent inhibitor of human uric acid transporter 1 (hURAT1), is currently under clinical development to treat patients with gout. We performed a randomized, double-blind, placebo-controlled, phase I study to evaluate the safety, tolerability, pharmacodynamic, and pharmacokinetic profiles of URC102 after single and multiple oral administration in healthy male subjects. Methods Thirty-one Koreans and 23 Caucasians received a single dose of URC102 at 1–30 mg and 1–10 mg, respectively, while 44 Koreans received URC102 once-daily for 7 days at 1–20 mg. We evaluated safety and tolerability throughout the study, and serially determined serum uric acid, the fractional excretion of uric acid and URC102 concentrations. Results URC102 was well tolerated over the dose range of 1–10 mg after single and multiple administration. URC102 rapidly reduced serum uric acid, which was maintained over the entire treatment period. Furthermore, URC102 increased the area-under-the-effect curve over 168 h for fractional excretion of uric acid in a dose-dependent manner. The maximum plasma concentration and the area under the plasma concentration–time curve of URC102 increased dose-proportionally. The pharmacokinetic and pharmacodynamics characteristics of URC102 were similar in Koreans and Caucasians. Conclusion URC102 was safe and effectively lowered serum uric acid, which should be tested and confirmed in patients with hyperuricaemia and/or gout through further studies. Trial registration ClinicalTrials.gov, www.clinicaltrials.gov , NCT01953497 and NCT02524678. [ABSTRACT FROM AUTHOR]

The effects of hyperuricemia on the expression of kidney drug transporters and on the pharmacokinetics of several substrate drugs were examined. We first established a rat model of hyperuricemia without marked symptoms of chronic kidney failure by 10-day co-administration of oxonic acid (uricase inhibitor) and adenine (biosynthetic precursor of uric acid). These hyperuricemic rats showed plasma uric acid concentrations of up to 6 mg/dL, which is similar to the serum uric acid level in hyperuricemic humans, with little change of inulin clearance. The mRNA levels of multidrug and toxin extrusion 1 (Mate1, Slc47a1), organic anion transporter 1 (Oat1, Slc22a6), organic cation transporter 2 (Oct2, Slc22a2), urate transporter 1 (Urat1, Slc22a12) and peptide transporter 1 (Pept1, Slc15a1) were significantly decreased in kidney of hyperuricemic rats. Since Oct2, Mate1 and Oat1 are important for renal drug elimination, we next investigated whether the pharmacokinetics of their substrates, metformin, cephalexin and creatinine, were altered. The plasma concentration of metformin was not affected, while its kidney tissue accumulation was significantly increased. The plasma concentration and kidney tissue accumulation of cephalexin and the plasma concentration of creatinine were also increased. Furthermore, the protein expression of kidney Mate1 was decreased in hyperuricemic rats. Accordingly, although multiple factors may influence renal handling of these drugs, these observations can be accounted for, at least in part, by downregulation of Mate1-mediated apical efflux from tubular cells and Oct2-mediated basolateral uptake. Our results suggest that hyperuricemia could alter the disposition of drugs that are substrates of Mate1 and/or Oct2. [ABSTRACT FROM AUTHOR]

Aims: Plasma xanthine oxidoreductase (XOR) activity during the acute phase of acute heart failure (AHF) requires further elucidation. Methods and results: One hundred eighteen AHF patients and 231 control patients who attended a cardiovascular outpatient clinic were prospectively analysed. Blood samples were collected within 15 min of admission from AHF patients (AHF group) and control patients who visited a daily cardiovascular outpatient clinic (control group). Plasma XOR activity was compared between the two groups, and factors independently associated with extremely elevated XOR activity were identified using a multivariate logistic regression model. Plasma XOR activity in the AHF group (median, 104.0 pmol/h/mL; range, 25.9–423.5 pmol/h/mL) was significantly higher than that in the control group (median, 45.2 pmol/h/mL; range, 19.3–98.8 pmol/h/mL). The multivariate logistic regression model showed that serum uric acid (per 1.0 mg/dL increase, odds ratio: 1.280; 95% confidence interval: 1.066–1.536; P = 0.008) and lactate levels (per 1.0 mmol/L increase, odds ratio: 1.239; 95% confidence interval: 1.040–1.475; P = 0.016) were independently associated with high plasma XOR activity (>300 pg/h/mL) during the acute phase of AHF. Conclusions: Plasma XOR activity was extremely high in patients with severely decompensated AHF. This would be associated with a high lactate value and would eventually lead to hyperuricaemia in patients with AHF. [ABSTRACT FROM AUTHOR]

A fixed dose combination of lesinurad and allopurinol has been recently approved by USFDA and EMA for treatment of gout-associated hyperuricemia in patients who have not achieved target serum uric acid levels with allopurinol alone. In this study, an ultra-performance hydrophilic interaction liquid chromatography (UPHILIC) coupled with tandem mass spectrometry method was developed and validated for simultaneous determination of allopurinol, oxypurinol and lesinurad in rat plasma. Liquid liquid extraction using ethyl acetate as extracting agent was used for samples extraction procedure. Acquity UPLC HILIC column (100 mm x 2.1, 1.7μm) was used for separation of allopurinol, oxypurinol, lesinurad and internal standard (5-Florouracil). The mobile phase consisting of acetonitrile, water and formic acid (95:5:0.1, v/v/v), were eluted at 0.3 mL/min flow rate having total chromatographic run time of 3 min per sample. The analytes were detected on Acquity triple quadrupole mass spectrometer equipped with a Z-Spray electrospray ionization (ESI). The ESI source was operated in negative mode and multiple reaction monitoring was used for ion transition for all compounds. The precursor to product ion transition of m/z 134.94 > 64.07 for allopurinol, 150.89 > 41.91 for oxypurinol, 401.90 > 176.79 for lesinurad and 128.85 >41.92 for internal standard were used for identification and quantification. The calibration curves for all analytes were found to be linear with weighing factor of 1/x2 using regression analysis. The developed assay was successfully applied in an oral pharmacokinetic study of allopurinol, oxypurinol and lesinurad in rats. [ABSTRACT FROM AUTHOR]

Gout is an inflammatory musculoskeletal disorder with a prevalence of 1.6–6.8% in Australia. Gout is characterised by acute attacks of severe joint pain secondary to raised serum concentrations of uric acid and joint deposits of monosodium urate crystals. Recurrent attacks can affect quality of life and lead to irreversible joint damage. The prevalence of gout is increased in older people, and age‐related renal impairment, altered drug distribution and increased prevalence of comorbidities have significant consequences for safe and effective gout pharmacotherapy. For treatment of acute attacks in older people, dose reduction of colchicine may be needed due to renal impairment, and potential drug interactions require consideration. Use of non‐steroidal anti‐inflammatory drugs is limited by peptic ulceration, ischaemic heart disease, hypertension and renal impairment. Short courses of oral glucocorticoids may be preferable. For long‐term urate‐lowering therapy, allopurinol, probenecid and febuxostat are available in Australia. Lower starting doses of allopurinol are recommended in patients with renal impairment, but dose escalation to achieve target urate should follow. Concerns regarding increased cardiovascular risk with febuxostat are relevant to older patients. Despite the availability of effective therapy, gout remains undertreated, with maintenance of urate‐lowering therapy a major challenge. Education of patients and health professionals is essential to improve adherence to therapy. [ABSTRACT FROM AUTHOR]

This review article summarizes the relevant English literature on gout from 2010 through April 2017. It emphasizes that the current epidemiology of gout indicates a rising prevalence worldwide, not only in Western countries but also in Southeast Asia, in close relationship with the obesity and metabolic syndrome epidemics. New pathogenic mechanisms of chronic hyperuricaemia focus on the gut (microbiota, ABCG2 expression) after the kidney. Cardiovascular and renal comorbidities are the key points to consider in terms of management. New imaging tools are available, including US with key features and dual-energy CT rendering it able to reveal deposits of urate crystals. These deposits are now included in new diagnostic and classification criteria. Overall, half of the patients with gout are readily treated with allopurinol, the recommended xanthine oxidase inhibitor (XOI), with prophylaxis for flares with low-dose daily colchicine. The main management issues are related to patient adherence, because gout patients have the lowest rate of medication possession ratio at 1 year, but they also include clinical inertia by physicians, meaning XOI dosage is not titrated according to regular serum uric acid level measurements for targeting serum uric acid levels for uncomplicated (6.0 mg/dl) and complicated gout, or the British Society for Rheumatology recommended target (5.0 mg/dl). Difficult-to-treat gout encompasses polyarticular flares, and mostly patients with comorbidities, renal or heart failure, leading to contraindications or side effects of standard-of-care drugs (colchicine, NSAIDs, oral steroids) for flares; and tophaceous and/or destructive arthropathies, leading to switching between XOIs (febuxostat) or to combining XOI and uricosurics. [ABSTRACT FROM AUTHOR]

Objectives To determine factors that predict inadequate serum urate (SU) lowering response in a randomized controlled trial of allopurinol dose escalation (DE) in gout. Methods Participants undergoing allopurinol DE were classified as: complete response (CR)—reached target SU at month 9 and 12 of the DE phase or if still dose escalating at month 9 reached target SU by month 12; partial response (PR)—reached target at some stage but not fulfilling criteria for CR; or inadequate response (IR)—did not reach target SU at any time. Results IR was uncommon, occurring in 13/150 (8.7%), compared with 82 (54.7%) CR, and 55 (36.6%) PR. Mean (s. e. m.) SU was higher at the end of the 12-month DE in IR compared with both CR and PR groups; 7.6 (0.31) vs 5.01 (0.06) and 5.97 (0.17) mg/dl respectively (P < 0.001). In univariate analysis, compete responders tended to be older, be receiving less allopurinol, have longer gout duration and were more likely to be New Zealand (NZ) European ethnicity, compared with IR+PR. Using multi-variate logistic regression analysis, only longer duration of gout and NZ European ethnicity remained significant independent predictors of CR. Baseline SU ⩾ 8 mg/dl had a sensitivity of 69.2% and specificity of 85.1% in predicting IR. The odds ratio for an IR if baseline SU was ⩾8 mg/dl was 11.7 (95% CI 3.3, 41.2). Conclusion A minority of people with gout never reach target SU when allopurinol dose is increased in a treat-to-target manner. Approximately one-third of those with SU ⩾ 8mg/dl despite allopurinol ⩾300mg/d have an IR to DE. Trial registration Australian New Zealand Clinical Trails Registry, https://www.anzctr.org.au, ACTRN12611000845932. [ABSTRACT FROM AUTHOR]

Background Direct comparisons of the effectiveness of allopurinol with that of other urate-lowering agents in chronic kidney disease (CKD) populations, as well as guideline recommendations for clinical practice, are lacking. Methods We constructed a pharmacoepidemiology cohort study by including patients from Taiwan’s long-term integrated CKD care program to compare the effectiveness among allopurinol, febuxostat and benzbromarone in reducing the risk of progression to dialysis. A total of 874 patients with hyperuricemia who were newly treated with allopurinol, febuxostat or benzbromarone were included. The primary and secondary outcomes were incident end-stage renal disease (ESRD) and the serum uric acid (SUA) changes from baseline, respectively. The results were analyzed using multiple Cox proportional models adjusted for multinomial propensity scores. For subgroup analyses, we further stratified patients according to whether their latest SUA level reached the therapeutic target. Results Compared with allopurinol, benzbromarone therapy was associated with a reduced risk of progression to dialysis, the adjusted hazard ratio was 0.50 (95% confidence interval, 0.25–0.99). Patients who received allopurinol or febuxostat exhibited a comparable risk of ESRD [adjusted hazard ratio, 0.99 (0.40–2.44)]. Febuxostat was significantly more potent than allopurinol or benzbromarone in lowering SUA levels in the fully adjusted model. Among patients who reached the therapeutic target, those with febuxostat and benzbromarone initiation had a significantly lower risk of ESRD. Conclusions In conclusion, compared with conventional allopurinol, febuxostat and benzbromarone may be more effective in reducing the risk of progression to dialysis and in lowering SUA levels in CKD populations. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is an important social health problem characterized by a decrease in the kidney glomerular filtration rate (GFR). In this study, we analyzed genome-wide association studies for kidney disease-related traits using data from a Korean adult health screening cohort comprising 7,064 participants. Kidney disease-related traits analyzed include blood urea nitrogen (BUN), serum creatinine, estimated GFR, and uric acid levels. We detected two genetic loci (SLC14A2 and an intergenic region) and 8 single nucleotide polymorphisms (SNPs) associated with BUN, 3 genetic loci (BCAS3, C17orf82, ALDH2) and 6 SNPs associated with serum creatinine, 3 genetic loci (BCAS3, C17orf82/TBX2, LRP2) and 7 SNPs associated with GFR, and 14 genetic loci (3 in ABCG2/PKD2, 2 in SLC2A9, 3 in intergenic regions on chromosome 4; OTUB1, NRXN2/SLC22A12, CDC42BPG, RPS6KA4, SLC22A9, and MAP4K2 on chromosome 11) and 84 SNPs associated with uric acid levels. By comparing significant genetic loci associated with serum creatinine levels and GFR, rs9895661 in BCAS3 and rs757608 in C17orf82 were simultaneously associated with both traits. The SNPs rs11710227 in intergenic regions on chromosome 3 showing significant association with BUN is newly discovered. Genetic variations of multiple gene loci are associated with kidney disease-related traits, and differences in associations between kidney disease-related traits and genetic variation are dependent on the population. The meanings of the mutations identified in this study will need to be reaffirmed in other population groups in the future. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to develop a population pharmacodynamic (PPD) model to describe uric acid (UA)–lowering effects in patients treated with febuxostat based on electronic medical records in 2 independent hospitals (university and city hospitals). Interhospital differences in the PPD model were also evaluated. We conducted the following 2 approaches to build the PPD models. A PPD model was developed separately using individual hospital data, and structural models and covariates between the two hospitals were compared (approach A). Another PPD model was developed using all available data from both hospitals, and differences between the 2 hospitals were evaluated by performing a covariate analysis on all PPD parameters (approach B). PPD analyses were performed by NONMEM using data from 358 patients. In both approaches, one indirect response model was established. In approach A, 2 diuretics (loops and thiazides) and renal function tests (Scr or BUN) were selected as covariates for the UA baseline level (serum UA levels just before the febuxostat treatment), whereas 2 diuretics and BUN were selected in approach B. A covariate analysis indicated that loops and thiazides increased UA baseline levels by 7%–14% and 6%–11%, respectively. In approach B, “hospital” was identified as a significant covariate for the UA baseline level; the baseline level was 7% higher in the city hospital. A PPD analysis may provide a precise description of the time course of the UA‐lowering effects of febuxostat and quantitatively detect an interhospital difference in the UA baseline level. [ABSTRACT FROM AUTHOR]

Objective. According to recent guidelines, the mainstay of urate-lowering therapies remains xanthine oxidase inhibition. However, some patients with gout show failure to achieve the predefined target of 5-6 mg/dl with xanthine oxidase inhibitors alone, so alternative drugs are needed. The aim of this study was to review studies of novel drugs targeting uric acid transporter 1 (URAT1) and/or other urate transporters for the management of gout. Methods. MeSH terms were used to identify phase 2/3 trials assessing the efficacy of novel uricosurics. A narrative review of novel drugs targeting URAT1 and/or other urate transporters for the management of gout is provided. Results. Lesinurad is a recently approved uricosuric that inhibits URAT1 and the organic ion transporter organic anion transporter 4 (OAT4). Phase 3 trials showed that lesinurad, combined with allopurinol or febuxostat, is a potent urate-lowering therapeutic with an acceptable safety profile. Arhalofenate, another emerging uricosuric, also interacts with URAT1 and organic anion transporter 4. Phase 2 trials suggested that it can both lower serum UA levels and reduce the risk of flares. Conclusions. New drugs inhibiting URAT1 should cover the unmet need for patients with failure to respond or with contraindications to xanthine oxidase inhibitors. [ABSTRACT FROM AUTHOR]

Lesinurad is an oral inhibitor of the monocarboxylic/urate transporter URAT1 encoded by the SLC22A12 gene. Market authorization was granted in February 2016 in Europe and December 2015 in the USA. As a potentially nephrotoxic uricosuric drug acting on the kidney, nephrologists should become familiar with its indications and safety profile. The approved indication is treatment of gout in combination with a xanthine oxidase (XO) inhibitor in adult patients who have not achieved target serum uric acid levels with an XO inhibitor alone. It is not indicated for asymptomatic hyperuricaemia or for patients with estimated creatinine clearance <45 mL/min. The only authorized daily dose is 200mg and cannot be exceeded because of the nephrotoxicity risk. Nephrotoxicity is thought to be related to uricosuria. At the 200 mg/day dose, serum creatinine more than doubled in 1.8% of lesinurad patients (versus 0% in placebo) and in 11% of these it was not reversible. In addition, it is subject to a risk management plan given the potential association with cardiovascular events. In randomized clinical trials, the association of lesinurad with either allopurinol or febuxostat achieved a greater reduction in serum uric acid (~1 mg/dL lower) than the XO inhibitors alone, and this allowed the serum uric acid target to be met in a higher proportion of patients, which was the primary endpoint. However, no clinical differences were observed in gout flares or tophi, although these were not the primary endpoints. [ABSTRACT FROM AUTHOR]

Objective To investigate the efficacy and safety of lesinurad in combination with febuxostat in a 12-month phase III trial in patients with tophaceous gout. Methods Patients with serum urate (UA) ≥8.0 mg/dl (≥6.0 mg/dl with urate-lowering therapy) and ≥1 measurable target tophus were given febuxostat 80 mg/day for 3 weeks before randomization to receive lesinurad (200 or 400 mg daily) or placebo in addition to the febuxostat. The primary end point was the proportion of patients achieving a serum UA level of <5.0 mg/dl (month 6). The key secondary end point was the proportion of patients with complete resolution of ≥1 target tophus (month 12). Other end points included the percentage change in total target tophi area. Safety assessments included adverse events and laboratory data. Results Patients (n = 324) were predominantly male, with a mean age of 54.1 years. Significantly more patients achieved the serum UA target by month 6 with the addition of lesinurad 400 mg (76.1%; P < 0.0001), but not 200 mg (56.6%; P = 0.13), to the febuxostat therapy as compared with febuxostat alone (46.8%). At all other time points, significantly more patients in the lesinurad 200 mg group achieved the serum UA target. The number of patients with complete tophus resolution was not different between groups. Treatment with lesinurad (200 mg and 400 mg) plus febuxostat reduced the total target tophi area as compared with febuxostat alone (50.1% and 52.9% versus 28.3%, respectively; P < 0.05). Safety was generally comparable with that of febuxostat alone, except for higher rates of predominantly reversible elevations in the serum creatinine level, particularly with lesinurad 400 mg. Conclusion Treatment with lesinurad in combination with febuxostat demonstrated superior lowering of serum UA levels as compared with febuxostat alone, with clinically relevant added effects on tophi and an acceptable safety profile with lesinurad 200 mg in patients with tophaceous gout warranting additional therapy. [ABSTRACT FROM AUTHOR]