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Background Hereditary renal hypouricemia type-1 (RHUC1) is caused by URAT1/SLC22A12 dysfunction, resulting in urolithiasis and exercise-induced acute kidney injury (EIAKI). Because, however, there is no useful experimental RHUC1 animal model, the precise pathophysiological mechanisms underlying EIAKI have yet to be elucidated. We established a high HPRT activity Urat1-Uox double knockout (DKO) mouse as a novel RHUC1 animal model for investigating the cause of EIAKI as well as the potential therapeutic effect of xanthine oxidoreductase inhibitors (XOIs). Methods The novel Urat1-Uox DKO mice were used in a forced swimming test as loading exercise to explore the onset mechanism of EIAKI and evaluate related purine metabolism and renal injury parameters. Results Urat1-Uox DKO mice had uricosuric effects and elevated levels of plasma creatinine (Cr) and blood urea nitrogen (BUN) as renal injury markers, and decreased Cr clearance (CLCr) observed in a forced swimming test. In addition, Urat1-Uox DKO mice had increased NLRP3 inflammasome activity and downregulated levels of Na+-K+-ATPase (NKA) protein in the kidney, as Western blot analysis showed. Finally, we demonstrated that topiroxostat and allopurinol, XOIs, improved renal injury and functional parameters of EIAKI. Conclusions Urat1-Uox DKO mice are a useful experimental animal model for human RHUC1. The pathogenic mechanism of EIAKI was found to be due to increased levels of IL-1β via NLRP3 inflammasome signaling and NKA dysfunction associated with excessive urinary UA excretion. In addition, XOIs appear to be a promising therapeutic agent for the treatment of EIAKI.

Background. The treatment of some forms of arti­cular pathology with gout remains insufficiently effective, and often it’s impossible to achieve normal indicators of uricemia on the background of uric acid-normalizing medicines. The purpose of the study is to evaluate the effect of the initial parameters of purine metabolism and molecules of medium mass (MMM) of different fractions on the effectiveness of uricodepressive and uricosuric therapy of gouty arthritis. Materials and methods. One hundred five patients with primary gout were exa­mined: 92 % of men and 8 % of women aged 26 to 76 years. Before the beginning of the treatment, the content of purine metabolism factors (uric acid, oxypurinol, adenine, guanine, xanthine, hypoxanthine, xanthine oxidase, xanthine deaminase, adenosine deaminase, 5-nucleotidase, molybdenum, lead), as well as MMM of different fractions (aminopeptide (AF), peptide (PF), nucleotide (NF), chromatogra­phic (ChF)) and integral medium molecular index (MMI) were studied in the blood serum. A spectrophotometer SF46, Olympus-AU640 bioana­lyzer and an atomic absorption spectro­meter with SolAAr-Mk2-MOZe electrographitic atomi­zer were used. The efficacy of treatment was assessed after 3–5 weeks. Results. In 27 % of cases, a slight improvement was observed, in 68 % — an improvement, in 8 % — a significant improvement. Primary gout occurs with disturbances in the metabolism of uric acid, oxypurinol, purine bases, purine metabolism enzymes and purine-associated microelements. The integral changes of them depend on the type of the joint syndrome, the presence of peri­pheral and bone tophi, determine bone-destructive articular injuries, while the predictive factor for the severity of arthropathy is considered to be the high level of purine bases in the blood. In cases of gout, the concentration of AF, PF, NF, ChF increases, as well as MMI. Meanwhile, the AF content is closely related to the severity of the joint syndrome, it determines the degree of joint space narrowing and subchondral sclerosis, the development of bone erosions and meniscus changes, and the MMM of different fractions correlate with the parameters of purine metabolism. A significant improvement and improvement during the pathogenetic the­rapy is observed in 3/4 of patients that is closely related to the form of arthritis, the presence of tophi and intraarticular Hoffa’s bodies, as well as the type of hyperuricemia, depends on the use of febuxostat, statins and fibrates, the state of purine metabolism, levels of MMM, NF and ChF fractions. Conclusions. The studied metabolic factors are not only involved in the pathogenesis of gouty arthritis, but also have an impact on the efficacy of uric acid-normalizing drugs.

Urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are important targets for the development of uric acid-lowering drugs. We previously showed that the flexible linkers of URAT1 inhibitors could enhance their potency. In this study we designed and synthesized CDER167, a novel RDEA3710 analogue, by introducing a linker (methylene) between the naphthalene and pyridine rings to increase flexibility, and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo. We showed that CDER167 exerted dual-target inhibitory effects on both URAT1 and GLUT9: CDER167 concentration-dependently inhibited the uptake of [(14)C]-uric acid in URAT1-expressing HEK293 cells with an IC(50) value of 2.08 ± 0.31 μM, which was similar to that of RDEA3170 (its IC(50) value was 1.47 ± 0.23 μM). Using site-directed mutagenesis, we demonstrated that CDER167 might interact with URAT1 at S35 and F365. In GLUT9-expressing HEK293T cells, CDER167 concentration-dependently inhibited GLUT9 with an IC(50) value of 91.55 ± 15.28 μM, whereas RDEA3170 at 100 μM had no effect on GLUT9. In potassium oxonate-induced hyperuricemic mice, oral administration of CDER167 (10 mg·kg(−1) · d(−1)) for 7 days was more effective in lowering uric acid in blood and significantly promoted uric acid excretion in urine as compared with RDEA3170 (20 mg·kg(−1) · d(−1)) administered. The animal experiment proved the safety of CDER167. In addition, CDER167 displayed better bioavailability than RDEA3170, better metabolic stability and no hERG toxicity at 100 μM. These results suggest that CDER167 deserves further investigation as a candidate antihyperuricemic drug targeting URAT1 and GLUT9.

Xanthine oxidase (EC 1.17.3.2) (XO) is one of the main enzymatic sources that create reactive oxygen species (ROS) in the living system. It is a dehydrogenase enzyme that performs electron transfer to nicotinamide adenine dinucleotide (NAD+), while oxidizing hypoxanthin, which is an intermediate compound in purine catabolism, first to xanthine and then to uric acid. XO turns into an oxidant enzyme that oxidizes thiol groups under certain stress conditions in the tissue. The last metabolic step, in which hypoxanthin turns into uric acid, is catalyzed by XO. Uric acid, considered a waste product, can cause kidney stones and gouty-type arthritis as it is crystallized, when present in high concentrations. Thus, XO inhibitors are one of the drug classes used against gout, a purine metabolism disease that causes urate crystal storage in the joint and its surroundings caused by hyperuricemia. Urate-lowering therapy includes XO inhibitors that reduce uric acid production as well as uricosuric drugs that increase urea excretion. Current drugs that obstruct uric acid synthesis through XO inhibition are allopurinol, febuxostat, and uricase. However, since the side effects, safety and tolerability problems of some current gout medications still exist, intensive research is ongoing to look for new, effective, and safer XO inhibitors of natural or synthetic origins for the treatment of the disease. In the present review, we aimed to assess in detail XO inhibitory capacities of pure natural compounds along with the extracts from plants and other natural sources via screening Pubmed, Web of Science (WoS), Scopus, and Google Academic. The data pointed out to the fact that natural products, particularly phenolics such as flavonoids (quercetin, apigenin, and scutellarein), tannins (agrimoniin and ellagitannin), chalcones (melanoxethin), triterpenes (ginsenoside Rd and ursolic acid), stilbenes (resveratrol and piceatannol), alkaloids (berberin and palmatin) have a great potential for new XO inhibitors capable of use against gout disease. In addition, not only plants but other biological sources such as microfungi, macrofungi, lichens, insects (silk worms, ants, etc) seem to be the promising sources of novel XO inhibitors.

Introduction: Some previous studies and our recent study had shown low serum uric acid (UA) in Diabetic patients compared to Non diabetics and it was suggested that low serum UA levels in Diabetics are probably due to uricosuric effect of urinary Glucose. This study was conducted to have an insight regarding the pathophysiology of low serum UA levels in Diabetics. Materials And Methods:Fasting blood glucose(FBG) , Post lunch blood glucose(PLBG), serum UA and 24 hr urinary excretion were estimated in Type 2 Diabetics without nephropathy (Cases) and in Nondiabetic inpatients(Controls) who got admitted into various Departments of KIMS hospital. The comparison of serum UA and 24hr urinary excretion between cases and controls and correlation between 24 hr urinary excretion, FBG and serum UA in cases was tested using SPSS 19 version. Result: Serum UA Mean is low in Diabetics compared to Non diabetics and this difference is significant whereas 24 hr urinary excretion is significantly higher in Diabetics compared to Nondiabetics. Significant negative association between FBG and serum UA and positive association between 24hr urinary UA and FBG and negative association of 24 hr urinary excretion with serum UA in Diabetics which is nonsignificant. Summary and Conclusions:At high concentrations of FBG there is increase in 24 hr urinary excretion providing an objective evidence to hypothesis that low UA levels in diabetics are probably due to inhibition of UA reabsorption in the proximal convoluted tubule of kidney by glucose. Keywords: Type 2 Diabetics, Fasting blood glucose, serum UA, 24 hr urinary excretion.

Fur die bestmogliche Behandlung der Gicht ist eine umfangreiche Aufklarung des Patienten uber die Erkrankung und Therapieoptionen sowie systematisches Screening auf Komorbiditaten und eine Lebensstilmodifikation elementar. Beim Management des akuten Gichtanfalls sollte moglichst fruhzeitig mit der medikamentosen Therapie begonnen werden. Hier stehen Colchicin, nichtsteroidale Antirheumatika (NSAR) und Glukokortikoide oral oder intraartikular oder eine Kombinationstherapie zur Verfugung. Canakinumab ist Mittel der Wahl bei unzureichendem Ansprechen auf die Behandlung. Fur bis zu 6 Monate nach einem Anfall ist eine medikamentose Prophylaxe indiziert. Die harnsauresenkende Therapie (ULT) sollte zeitnah nach Indikationsstellung begonnen werden. Allopurinol ist Mittel der 1. Wahl. Liegen schwere Nierenfunktionseinschrankungen, Unvertraglichkeit oder unzureichendes Therapieansprechen vor, kommen alternativ Urikosurika, Febuxostat oder die Kombination aus einem Urikosurikum mit Febuxostat in Frage. Bei unzureichendem Therapieansprechen ist auch die Kombination von Allopurinol und einem Urikosurikum moglich. Zuletzt kann auch Pegloticase off-label eingesetzt werden. Die Therapieadharenz der ULT ist unzureichend. Comprehensive education about the disease and therapeutic options as well as lifestyle modification and screening for comorbidities are essential to treating gout optimally. Early onset of therapy is important in managing acute gout flares. Colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids applied either orally or intraarticularly and combination therapy are regarded first choice in gout flare therapy. In case of insufficient treatment response, Canakinumab is indicated. Gout flare prophylaxis should be implemented for up to six months after the flare. Urate-lowering therapy is recommended to be commenced as early as possible. Whilst allopurinol is the substance of first choice, patients with severe renal impairment, allopurinol intolerance or an insufficient treatment response should be treated with febuxostat, a uricosuric or a combination of both. An additional option for patients responding inadequately to allopurinol is combining allopurinol with a uricosuric. In the last resort Pegloticase can be used off-label. Treatment adherence in ULT is poor.

Clerodendranthus spicatus, popularly known as "kidney tea" in China, is consumed traditionally as a functional food for treatment of renal inflammation, dysuria, and gout. We evaluated the effects of C. spicatus on gout by assessing activities of antihyperuricemia, anti-gouty arthritis, and analgesia in vivo, and the results indicated that the ethyl acetate fraction shows potential activities. Subsequent phytochemical investigation of this fraction led to the isolation of 32 compounds, consisting of 20 diterpenoids (including the new orthosiphonones E and F), 2 triterpenoids, 6 flavonoids, 2 lignanoids, and 2 phenolic acid derivatives. Pharmacological investigation of the pure compounds in the cellular model of hyperuricemia indicated that 12 compounds could promote the excretion of uric acid at 10 μg/mL, and compounds 3, 4, 5, and 21 had better effects than that of benzbromarone, a famous uricosuric drug. Furthermore, compounds 4, 6, 7, 9, 14, 15, 23, 26, and 31 showed significant anti-gouty arthritis activity in monosodium urate (MSU)-induced joint swelling at the dose of 50 mg/kg, while compounds 4, 5, 7, 9, and 26 exhibited significant inhibition of pain induced by acetic acid. Our findings provided scientific justification to support the traditional application of "kidney tea" for treating gout and suggested its good application prospects in the future.

The incidence and prevalence of gout have increased, as have comorbid obesity, diabetes mellitus, hypertension, chronic kidney and cardiovascular disease. Gout is now the commonest type of inflammatory arthritis despite availability of safe, effective and potentially ‘curative’ urate-lowering drugs. Modern imaging studies show that gout is a chronic inflammatory crystal deposition disorder even at the first acute attack and they illuminate the need to eliminate urate crystals by continuing reduction of the serum urate below its solubility threshold. Clinical outcomes, adherence to therapy and quality of gout care in primary care and hospital practice can be greatly improved by better use of allopurinol and flare prophylaxis, greater patient engagement, education and follow-up, and by nurse-led models of care that employ a ‘treat-to-target’ principle (SUA< 360 or 300μmol/l). Advances in understanding the physiology and genetic control of urate transport in the kidney and gut have led to novel, more selective uricosuric drugs, and basic research on mediators of urate crystal-induced inflammation has pointed to alternative therapeutic targets for treating and preventing gout flares. Current guidelines for the management of gout and indications for the use of some more recently introduced drugs; febuxostat, lesinurad, pegloticase and interleukin-1 antagonists are also briefly reviewed.

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

Uric acid nephropathy (UAN) is caused by excessive uric acid, which results in the damage of renal tissue via urate crystals deposition in the kidneys. The roots and rhizomes of Salvia miltiorrhiza Bunge (S. miltiorrhiza) have been clinically used in many prescriptions to treat uric acid-induced renal damage. This study investigates the uricosuric and nephroprotective effects of the ethyl acetate extract of S. miltiorrhiza (EASM) and tanshinone IIA (a major component of S. miltiorrhiza, Tan-IIA) on UAN and explores the underlying molecular mechanism. Both EASM and Tan-IIA significantly decreased serum uric acid (SUA), serum creatinine (SCR), urine uric acid (UUA), and increased urine creatinine (UCR), and blood urea nitrogen (BUN) levels in experimental UAN mice. In adenine and potassium oxonate-induced mice, EASM and Tan-IIA treatment alleviated renal dysfunction and downregulated the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Moreover, EASM treatment significantly prevented excessive reactive oxygen species (ROS) production in uric acid-induced HK-2 cells and suppressed the expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). EASM also suppressed ROS-activated mitogen-activated protein kinases (MAPKs) in vivo and in vitro. These results suggest that both EASM and Tan-IIA demonstrated inhibitory effects on UAN through relieving NOX4-mediated oxidative stress and suppressing MAPK pathways activation.

This review aims to determine the metabolic effect of hyperuricemia in pregnant woman, especially those with gestational diabetes mellitus (GDM). In women, the serum uric acid level is lower compared to men of similar age. The value is related to higher estrogen concentration to increase uric acid clearance. Hyperuricemia already established as independent risk factors for metabolic syndrome and cardiovascular disease (CVD) as well as type 2 Diabetes Mellitus (DM). Asymptomatic hyperuricemia in non-pregnant adult women will increase insulin resistance due to oxidative stress, and production of inflammatory cytokine (tumor necrosis factor-a), which inevitably increases blood sugar level. Uric acid level and serum creatinine is lower in normal pregnancy due to increased renal clearance and the uricosuric effect of estrogen. Hyperuricemia is one of the contributing factors associated with insulin resistance among pregnancy instead direct effect of placental hormones. Earlier in the first trimester of pregnancy, the risk for GDM is increased. However, the causal effect of uric acid levels on DM still requires further study .

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 2) or moderate (eGFR, ≥ 30 to 2) 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.

Gout is more prevalent than ever and is associated with multiple chronic comorbidities, including Chronic Kidney Disease (CKD). While goals of treatment are the same as in those without renal impairment, co-morbid CKD poses a challenge in treatment selection and requires a solid understanding of potential drug-drug interaction and drug-related toxicity. In acute gout complicated by CKD, NSAIDs should be avoided, and colchicine used with caution. Systemic corticosteroids are effective but may be replaced by anakinra, in particular in inpatients with additional comorbidities that may make corticosteroids less desirable. Allopurinol remains the first line urate lowering therapy (ULT), starting at a low dose followed by careful goal driven up-titration. Febuxostat is a reasonable alternative, though second line in light of recent cardiovascular data. Uricosuric drugs are generally less effective, while pegloticase is reserved for refractory cases of polyarticular tophaceous disease. Gout treatment must be guided by renal function but in spite of renal disease can be successfully managed.

In clinical trials, few investigations have been conducted to determine the mechanism involved in teriflunomide-associated kidney stone formation. We report the first case of recurrent teriflunomide-induced uric acid urolithiasis. A 55-year-old man with relapsing-remitting multiple sclerosis experienced three occurrences of urolithiasis several months after the initiation of teriflunomide. While serum uric acid remained stable at 280 mmol/L, 24-hour urine uric acid was increased to 2195 mmol/24h. For the third episode, computed tomography showed three bladder stones and one stone in the right calyceal group. Endovesical lithotripsy was used to extract four orange-colored stones of more than 20 mm. Stone analysis exhibited morphology subtype IIIb with 100% of anhydrous uric acid. Given the disease control, teriflunomide was continued. After urinary alkalinisation by potassium citrate, the patient remained asymptomatic at 18 months follow-up. An inhibitory effect of dihydroorotate and/or teriflunomide on urate tubular reabsorption could explain teriflunomide-associated uric acid urolithiasis. This case in a patient without risk factors suggests that multiple sclerosis patients may be at greater risk of forming uric acid urinary stones when taking teriflunomide. Alkalinization of the urine may reduce the risk of recurrence, allowing further treatment with teriflunomide.

Background This study was designed to evaluate the impact of polymorphisms in the urate transporter 1 (URAT1) gene on the uricosuric action of losartan therapy in hypertensive patients suffering from hyperuricemia. Methods A MassARRAY approach was used to detect single nucleotide polymorphism (SNP) loci in the URAT1 and CYP2C9 genes (16 and 2 loci, respectively) in 111 patients with hypertension and hyperuricemia taking losartan and in 121 healthy controls. In addition, we compared serum urate (SUA) levels and other key clinical biochemistry indices between these two patient groups. Results We detected significant differences between the two patient groups with respect to age, SUA, urea, creatine, triglycerides, high‐density lipoprotein, low‐density lipoprotein, and fasting plasma glucose (all p, 121 healthy people and 111 patients with hypertension and hyperuric acid were screened out, 16 SNP loci of URAT.1 and 2 SNP loci of CYP2C9 were detected by MASS‐ARRAY technology. Through analysis, it was found that only rs3825016 was meaningful, We observed that patients with the heterozygous genotype (CT) exhibited a more pronounced decrease in uric acid levels.

Probenecid is a uricosuric drug, which inhibits the renal excretion of procaine penicillin via inhibition of the organic anion transporter (OAT-1) system in the proximal renal tubule producing higher plasma and cerebrospinal fluid (CSF) penicillin levels.1 2 Oral probenecid is recommended to be used with intramuscular procaine penicillin for the treatment of neurosyphilis. Rates of syphilis and neurosyphilis have increased significantly over the past 20 years particularly in men who have sex with men (MSM). There …

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

Dendropanax morbifera is a well-known traditional medicine used in China and Korea to treat intestinal disorders, urosis, diuresis, and chronic glomerulonephritis. Hyperuricemia is a metabolic disorder characterized by a high uric acid level in serum due to an imbalance between uric acid production and excretion and causes gout. Recently, the prevalence of hyperuricemia worldwide has been continuously increasing. Xanthine oxidase (XOD) inhibitors (allopurinol (ALP) and febuxostat) and uricosuric agents (benzbromarone and probenecid) are used to treat hyperuricemia clinically. However, because these drugs are poorly tolerated and cause side effects, such as kidney diseases, hepatotoxicity, gastrointestinal symptoms, and hypersensitivity syndrome, only a limited number of drugs are available. We investigated the antihyperuricemic effects of Dendropanax morbifera leaf ethanol extract (DMLE) and its underlying mechanisms of action through in vitro and in vivo studies. We evaluated uric acid levels in serum and urine, and xanthine oxidase (XOD) inhibition activity in the serum and liver tissue of a hyperuricemic rat model of potassium oxonate (PO)-induced hyperuricemic rats. In vitro study, XOD-inhibitory activity was the lowest among the test substances at the IC50 of ALP. However, the IC50 of DMLE-70 was significantly low compared with that of other DMLEs ( p < 0.05 ). In PO-induced hyperuricemic rats, uric acid (UA) levels in serum and urine were significantly reduced in all DMLE-70 and allopurinol-treated (ALT) groups than in the PC group ( p < 0.05 ). UA levels in urine were lower than those in serum in all DME groups. In PO-induced hyperuricemic rats, DMEE-200 reduced UA concentration in serum and increased UA excretion in the urine. These findings suggest that DMLE exerts antihyperuricemic and uricosuric effects on promoting UA excretion by enhanced secretion and inhibition of UA reabsorption in the kidneys. Thus, DMLE may be a potential treatment for hyperuricemia and gout.

Background Longer serum half-lives of perfluoroalkyl substances (PFAS) in humans compared to other species has been attributed to differences in the activity of organic anion transporters (OAT). Methods Among 56,175 adult participants in the community-based C8 Health Project, 23 subjects were taking the uricosuric OAT-inhibitor probenecid, and 36 subjects were taking the bile acid sequestrant cholestyramine. In regression models of log transformed serum PFAS, medication effects were estimated in terms of mean ratios, adjusting for age, gender, BMI, estimated glomerular filtration rate (eGFR) and water-district of residence. Results Probenecid was associated with modest, but not statistically significant increases in serum PFAS concentrations. In contrast, cholestyramine significantly lowered serum PFAS concentrations, notably for perfluorooctane sulfonic acid (PFOS). Conclusions The effectiveness of cholestyramine in a community setting supports the importance of gastrointestinal physiology for PFAS excretion kinetics, especially for PFOS. We did not find clear evidence that probenecid, an inhibitor of OAT, affects PFAS clearance.

Solidago virgaurea L. is a perennial plant used in European traditional medicine as a diuretic or a remedy for inflammatory conditions of the urinary tract but also for gout, especially in the Balkans. The present study was focused on a preclinical, in vivo evaluation of antihyperuricemic, anti-inflammatory, and antihypertensive effects of a dry extract from S. virgaurea L. (ESV). Colorimetric and HPLC–MS techniques were used to identify the main chemical constituents of ESV. Antihyperuricemic effect of ESV was assessed in a rat model of hyperuricemia induced by the administration of potassium oxonate. Antihypertensive effect of ESV was evaluated in hyperuricemic rats by monitoring systolic blood pressure with a non-invasive blood-pressure recording system. The anti-inflammatory effect of ESV was tested using a rat model of paw edema. The main chemical constituents of ESV were rutin and phenolic acids represented by chlorogenic and caffeic acid. ESV demonstrated significant antihyperuricemic effects in rats due to an uricosuric mechanism. Additionally, ESV reduced the progression of arterial hypertension in hyperuricemic rats and also showed anti-inflammatory properties slightly inferior to diclofenac. The results suggest that ESV could be a natural remedy for the treatment of gout and protection against endothelial dysfunction caused by hyperuricemia.

Background: Serum urate (SU) levels in primates are extraordinarily high among mammals. Urate is a Janus-faced molecule that acts physiologically as a protective antioxidant but provokes inflammation and gout when it precipitates at high concentrations. Transporters play crucial roles in urate disposition, and drugs that interact with urate transporters either by intention or by accident may modulate SU levels. We examined whether in vitro transporter interaction studies may clarify and predict such effects. Methods: Transporter interaction profiles of clinically proven urate-lowering (uricosuric) and hyperuricemic drugs were compiled from the literature, and the predictive value of in vitro-derived cut-offs like Cmax/IC50 on the in vivo outcome (clinically relevant decrease or increase of SU) was assessed. Results: Interaction with the major reabsorptive urate transporter URAT1 appears to be dominant over interactions with secretory transporters in determining the net effect of a drug on SU levels. In vitro inhibition interpreted using the recommended cut-offs is useful at predicting the clinical outcome. Conclusions: In vitro safety assessments regarding urate transport should be done early in drug development to identify candidates at risk of causing major imbalances. Attention should be paid both to the inhibition of secretory transporters and inhibition or trans-stimulation of reabsorptive transporters, especially URAT1.

Background Patients with gout have an increased risk of urolithiasis and usually need urate-lowering therapy (ULT) for the prevention of disease progression. However, there is a paucity of clinical data regarding the risk of future urolithiasis in ULT users. Methods This nested case-control study was performed using the Taiwan National Health Insurance Research Database. The aim of this study was to examine whether ULT (xanthine oxidase inhibitors [XOIs] or uricosuric agents) is associated with risk of future urolithiasis in patients with gout. Data were collected from January 2000 to December 2012. Results This study included 2307 case patients and 2307 matched controls. Case patients had gout that developed into urolithiasis, and control patients had gout but were not diagnosed with urolithiasis during the study period. Patients had a mean age of 56.3 years at diagnosis of gout, and 83.2% were male patients. No association was detected between use of XOIs or uricosuric agents and risk of future urolithiasis. Furthermore, there was no significant difference in the risk of future urolithiasis in patients exposed to various cumulative days of XOI or uricosuric prescriptions. Conclusion The present study provides evidence that neither XOIs nor uricosuric agents are associated with risk of future urolithiasis in patients with gout. Before the availability of more clinical evidence, ensuring high fluid intake and prospective monitoring of urolithiasis development are still important for uricosuric agent users.

Hyperuricaemia, which results from the overproduction and underexcretion of uric acid, has been linked with chronic renal dysfunction, cardiovascular diseases, diabetes and metabolic syndrome. However, available clinical drugs cannot simultaneously target the production and excretion of uric acid. Norathyriol, a natural xanthone, was expected to have the dual actions. We previously reported that norathyriol possessed potent anti-hyperuricaemic activity related to the inhibition of uric acid production. Here, we investigated the uricosuric actions in hyperuricaemic animals and explored the possible molecular mechanisms associated with renal urate transporters and xanthine oxidase (XO). The results showed that norathyriol (0.5–4.0 mg/kg) dose- and time-dependently decreased serum urate levels in uric acid-induced hyperuricaemic mice and markedly increased the fractional excretion of urate in oxonate-induced hyperuricaemic rats, demonstrating a promotion of urate excretion in the kidney. Further evidence showed that norathyriol markedly increased renal mRNA and protein expression of the secretory organic anion transporter 1 (OAT1) in hyperuricaemic mice and strengthened its transport function in vitro. Moreover, norathyriol also upregulated the mRNA expression of the secretory transporters OAT3, ATP-binding cassette transporter G2 and multidrug resistance protein 4, but not their protein expression. Changes in the expression of the reabsorptive transporters were not observed. This is the first report that norathyriol has uricosuric effects by targeting OAT1. Moreover, norathyriol significantly inhibited XO activity in an uncompetitive manner. Taken together, these findings suggest that norathyriol has the potential to be developed as a new anti-hyperuricaemic agent with dual actions that activate OAT1 and inhibit XO activity.

The aim of this review is to present current evidence about the efficacy and safety of lesinurad in combination with xanthine oxidase inhibitors (XOIs) in the treatment of hyperuricemia in patients with gout. Gout is the most common inflammatory form of arthritis. It is caused by an elevated concentration of serum uric acid (UA) that leads to the formation of monosodium urate crystals in joints and different tissues. The goal of therapy is to maintain serum UA levels at

Chronic kidney disease (CKD) has become a global public health issue and uric acid (UA) remains a major risk factor of CKD. As the main organ for the elimination of UA, kidney owned a group of urate transporters in tubular epithelium. Kidney disease hampered the UA excretion, and the accumulation of serum UA in return harmed the renal function. Commercially, there are three kinds of agents targeting at urate-lowering, xanthine oxidoreductase inhibitor which prevents the production of UA, uricosuric which increases the concentration of UA in urine thus decreasing serum UA level, and uricase which converts UA to allantoin resulting in the dramatic decrement of serum UA. Of note, in patients with CKD, administration of above-mentioned agents, alone or combined, needs special attention. New evidence is emerging for the efficacy of several urate-lowering drugs for the treatment of hyperuricemia in patients with CKD. Besides, loads of novel and promising drug candidates and phytochemicals are in the different phases of research and development. As of today, there is insufficient evidence to recommend the widespread use of UA-lowering therapy to prevent or slow down the progression of CKD. The review summarized the evidence and perspectives about the treatment of hyperuricemia with CKD for medicinal chemist and nephrologist.

Hyperuricemia is the main cause of gout, an inflammation induced by uric acid deposition in joints. Drugs available present side effects, so there is a need for new treatment alternatives. Lychnophora species are used in folk medicine to treat inflammation, rheumatism and muscle pain. Goyazensolide (10 mg/kg), eremantholide C (25 mg/kg) and lychnopholide (25 mg/kg), sesquiterpene lactones isolated from Lychnophora species were previously studied and showed anti-hyperuricemic effects in mice. However, the mechanisms of this effect were not elucidated. The methodology of this study consisted in treatment of hyperuricemic-induced rats, and comparison between control groups, clinically used anti-hyperuricemic drugs and sesquiterpene lactones. Urine and blood were collected for uric acid quantification. Xanthine oxidase inhibition was measured in liver homogenates. Results showed that all evaluated sesquiterpene lactones presented anti-hyperuricemic activity at the doses of 5 and 10 mg/kg and can act through one or both mechanisms, depending on the dose administrated. Goyazensolide and lychnopholide at dose of 5 mg/kg showed important uricosuric effect. Goyazensolide and lychnopholide at dose of 10 mg/kg, and eremantholide C (5 and 10 mg/kg) presented notable inhibition of hepatic xanthine oxidase activity and uricosuric effect. Thus, these sesquiterpene lactones are promising hypouricemic agent to treat hyperuricemia and gout. Keywords: Sesquiterpene lactones, Hyperuricemia, Xanthine oxidase, Uricosuric effect, Gout

Objective: Hyperuricemia is an excess of urate in blood. The kidneys play important parts in urate excretion, which involves handling reabsorption and secretion. A series of urate transporters is responsible for this process: urate transporter (URAT)1, glucose transporter (GLUT)9, organic anion transporter (OAT)1 and OAT3. Excessive fructose intake may result in increased serum urate levels. Chicory (Cichorium intybus L.) has been used as an edible vegetable and traditional Chinese medicine. Studies have shown that chicory is a promising anti-hyperuricemia agent and we explored the mechanism of its uricosuric effect via a renal pathway. Methods: Hyperuricemia was induced in rats by administration of 10% fructose. The uricosuric effect was evaluated by determining the serum urate level. Renal excretory function was detected by the clearance rate of creatinine, clearance rate of uric acid and histology. The location and expression of URAT1, GLUT9, OAT1 and OAT3 their mRNA expression in kidneys were analyzed. Results: Chicory decreased serum levels of urate and creatinine significantly, and promoted the clearance of creatinine and urate, as well as improving renal pathologic changes due to hyperuricemia. Chicory inhibited expression of URAT1 and GLUT9 markedly in a dose-dependent manner, but showed no influence on expression of OAT1 or OAT3. Conclusion: Chicory might be a promising anti-hyperuricemia agent. It can promote renal excretion of urate by inhibiting urate reabsorption, which may be related to down-regulation of mRNA and protein expression of URAT1 and GLUT9. Keywords: Chicory, Fructose, Hyperuricemia, Renal resorption, Urate transporters

The naturally available uricosuric agents are Tinospora cardifolia, Allium sepa, Cajanus Cajan, Piper nigrum etc., Natural medicinal plants having no side effects are more preferred when compared to synthetic medications. Uricosuric agents increase the urinary excretion of uric acid hence the natural uricosuric agent is preferred to prevent many diseases like gout, arthritis, kidney stones etc., without side effect. Uricosuric medications are the substances that increase the excretion of uric acid in urine, thus reducing the concentration of uric acid in blood plasma. Prolonged and untreated hyperuricemia results into gout, a severe inflammatory condition. Sustain hyperuricemia leads to impaired blood pressure control, renal impairment and nephropathy. The common factors for deposition of uric acid in blood are drinking alcohol and taking high purine diet. The various screening methods for the uricosuric activity are uricosuric activity in mice, Potassium oxonate induced activity, and Phenol red excretion methods are explained in this review.

This study was aimed at screening a potential anti-hyperuricemia agent with dual xanthine oxidase (XOD) inhibitory effect (XOI) and antioxidant activity from edible plants with health-promoting effects using non-targeted chemometric analysis (hierarchical cluster analysis and principal component analysis), evaluating its in vivo hypouricemic effect and mechanism, and identifying the key XOD inhibitor using ultrafiltration UPLC-MS/MS. Rhizoma Alpiniae Officinarum extract (GE), which has high contents of total phenolics and flavonoids, as well as dual XOI and antioxidant activity, showed significant hypouricemic and renal protective effects on hyperuricemic rats through inhibiting XOD activity, alleviating oxidative stress, down-regulating URAT1 and GLUT9 protein expression, and reducing urea nitrogen and creatinine levels. GE could be a dual-acting agent with XOI and uricosuric effect for preventing and treating hyperuricemia. Four flavonoids and eight diarylheptanoids were identified as potential XOD inhibitors from GE. Galangin, kaempferide and 3-methoxyl-galangin contributing to 70.1% of XOI were the key XOD inhibitors.

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.

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.

Gout is a rare phenomenon in reproductive age women due to the uricosuric effects of estrogen. Furthermore, gout in pregnancy has been reported in only a scant number of case reports. We present the case of a 21-year-old gravida-4 para-3 female at four-weeks gestation presenting with acute polyarticular gout, complicated by Haemophilus influenzae sepsis and hyperemesis gravidarum. The gout flare was likely precipitated by primary H. influenzae bacteremia, which was successfully treated with intravenous antibiotics. The treatment of gout in pregnancy is challenging because of the limited number of guidelines. We demonstrate successful management of an acute gout flare in pregnancy with colchicine and steroid injection of the affected joint. Unfortunately, the patient suffered a miscarriage, but the link between gout flare and spontaneous abortion is tenuous.

Transthyretin (TTR) is a homotetrameric protein involved in human amyloidosis, including familial amyloid polyneuropathy (FAP). Discovering small-molecule stabilizers of the TTR tetramer is a therapeutic strategy for these diseases. Tafamidis, the only approved drug for FAP treatment, is not effective for all patients. Herein, we discovered that benzbromarone (BBM), a uricosuric drug, is an effective TTR stabilizer and inhibitor against TTR amyloid fibril formation. BBM rendered TTR more resistant to urea denaturation, similarly to iododiflunisal (IDIF), a very potent TTR stabilizer. BBM competes with thyroxine for binding in the TTR central channel, with an IC50 similar to IDIF and tafamidis. Results obtained by isothermal titration calorimetry (ITC) demonstrated that BBM binds TTR with an affinity similar to IDIF, tolcapone and tafamidis, confirming BBM as a potent binder of TTR. The crystal structure of the BBM-TTR complex shows two molecules binding deeply in the thyroxine binding channel, forming strong intermonomer hydrogen bonds and increasing the stability of the TTR tetramer. Finally, kinetic analysis of the ability of BBM to inhibit TTR fibrillogenesis at acidic pH and comparison with other stabilizers revealed that benzbromarone is a potent inhibitor of TTR amyloidogenesis, adding a new interesting scaffold for drug design of TTR stabilizers, Funding I.C. works under the Investigator FCT Program which is financed by national funds through FCT and co-financed by ESF through HPOP, type 4.2, Promotion of Scientific Employment. I.C. acknowledges a grant from Fundação Millennium bcp. G.A. acknowledges a grant from Fundació Marató de TV3, Spain (project ref. 20140330-31-32-33-34) and from Spanish MINECO (grant CTQ2016-76840-R). Acknowledgments E.Y.C. acknowledges a contract funded by the project of Fundació Marató de TV3, Spain (project ref. 20140330-31-32-33-34) and a contract from Ford España—Fundación Apadrina la Ciencia. J.P. Leite acknowledges the FCT PhD fellowship SFRH/BD/129921/2017 (Portugal). G.A. acknowledges Rafel Prohens from Unitat de Polimorfisme i Calorimetria, Centres Científics i Tecnològics (University of Barcelona) for his supervision and assistance in ITC studies and acknowledges Antoni Planas (IQS-URL) for full support on the TTR production. We would also like to thank the SOLEIL (Essonne, France) beam line staff for the assistance during data collection, as well as the staff of the ESRF (France) and ALBA (Barcelona, Spain) synchrotrons for assistance in the collection of preliminary data.

Hyperuricemia is mainly the result of relative underexcretion of urate. Urate is mainly eliminated by kidney and several important transporters expressed on the membrane of renal tubular cells involved in urate excretion. Olsalazine sodium was screened from 3167 authorized small compounds/drugs, targeting xanthine oxidoreductase. In previous study, we reported that olsalazine sodium significantly reduced the serum urate levels, and the anti-hyperuricemic activity linked with inhibiting urate formation by reducing the activity of xanthine oxidoreductase. The current research aimed to assess olsalazine sodium renal urate excretion and likely molecular mechanism. The results showed that administration of olsalazine sodium 5.0 mg/kg decreased the levels of serum urate in hyperuricemic rats, and noticeably improved the fractional excretion of urate and urate clearance, exhibiting an uricosuric action. Moreover, olsalazine sodium (2.5, 5.0, 10.0 mg/kg) reduced the level of blood urea nitrogen in rats. Further study showed that olsalazine sodium reduced the mRNA expression of urate reabsorptive transporter glucose transporter 9 (GLUT9), increased the mRNA expression of urate secretory transporters, organic anion transporter 1 (OAT1), OAT3 and type 1 sodium-dependent phosphate transporter (NPT1) as well as the protein expression of OAT3 in the kidney in hyperuricemic mice. In conclusion, olsalazine sodium exhibited a promotion of urate excretion in kidney by increasing the expression of OAT3.

The most recent European Alliance of Associations for Rheumatology (EULAR) recommendations for gout advise against maintaining a serum urate (SU) level of3 mg/dl for prolonged periods of time. While several Asian cohort studies have shown higher rates of mortality in individuals with extremely low SU levels, data from non-Asian cohort studies are scarce, and the relationship between hypouricemia, cardiovascular risk, and mortality remains unclear.Using data collected from the 1988-1994 and 1999-2008 National Health and Nutrition Examination Survey (NHANES), we examined the relationship between SU level and overall and cause-specific mortality in 41,807 adults in the US. We calculated multivariable hazard ratios (HRs) that were compared to a referent SU level of 5-6 mg/dl for SU categories4, 4-5, 6-7, 7-8, and8 mg/dl in men and SU categories3, 3-4, 4-5, 6-7, and7 mg/dl in women.A higher mortality risk was not observed in women who had an SU level of3 mg/dl (HR 1.09 [95% confidence interval (95% CI) 0.92-1.28]). A 28% higher mortality risk was observed in men who had an SU level of4 mg/dl (HR 1.28 [95% CI 1.13-1.45]), with a nearly three-times higher mortality risk from diabetes mellitus also noted (HR 2.89 [95% CI 1.59-5.23]), but no increase in mortality from any other specific cause.We found no long-term excess mortality risk among American women with SU levels as low as3 mg/dl, a finding which is incompatible with the notion of a causal relationship between hypouricemia and premature mortality in women. We found excess all-cause mortality and diabetes mellitus-related mortality among hypouricemic American men, which may in part be attributable to the uricosuric effect of hyperglycemia in fatal uncontrolled diabetes mellitus (analogous to reverse causality).

The aim of this study was to examine the preventive action of grapefruit juice (GFJ) against potassium oxonate-induced hyperuricemic mice. The results showed that GFJ significantly (p < .05) inhibit the serum and hepatic xanthine oxidase enzyme, lower uric acid level, serum creatinine, uromodulin, and blood urea nitrogen levels to normal and lower inflammation related genes IL-1β, caspase-1, NLRP3, and ASC. Furthermore, histopathology analysis revealed that GFJ markedly improve the renal and intestinal morphology. The mRNA expression of urate transporter 1, glucose transporter 9 were downregulated, whereas ATP-binding cassette transporter (ABCG2) was upregulated in the GFJ-treated group. The results of immunohistochemistry revealed that the ABCG2 protein expression in the small and large intestine was significantly upregulated after the GFJ administration. These results suggested that GFJ can be used as a urate lowering agent and future mechanistic studies should be conducted. PRACTICAL APPLICATIONS: The results of current study indicated that utilization of GFJ as an anti-hyperuricemic agent for the treatment of hyperuricemia. This article will be very valuable for all those peoples which are directly or indirectly linked with this disease.

Background The 24-hour uric acid excretion measurement is important in assessing disease status and helping to select the appropriate uric acid-lowering agent for patients with gout, however, it is inconvenient. The authors investigated the efficacy of the random urine uric acid-to-creatinine (UA/CR) ratio to screen the patients who under-secreted 24-hour urine uric acid. Methods This was a retrospective cross-sectional study. Ninety patients with gout, without undergoing uric acid-lowering treatment were enrolled. Twenty-four-hour urine and random urine samples were obtained on the same day. Six hundred mg of uric acid in the 24-hour urine sample was used as a standard for distinguishing between over and under-excretion groups. Results The random urinary UA/CR ratio showed positive correlation with 24-hour urine uric acid excretion (γ = 0.398, P < 0.001). All the patients with the random UA/CR less than 0.2 excreted less than 600 mg uric acid in 24-hour urine collection. When the random urine UA/CR ratio < 0.2 was regarded as a positive result, the positive predictive value, negative predictive value, sensitivity, and specificity in the uric acid under-excretion were 100% (8 of 8), 64.6% (53 of 82), 21.6% (8 of 37), and 100% (53 of 53), respectively. Conclusion There is a moderate positive correlation between the random urinary UA/CR ratio and 24-hour urine uric acid excretion, so that UA/CR ratio may not be a good predictor of 24-hour urine uric acid excretion. However, the random urine UA/CR ratio 0.2 can be a useful predictor to screen the gouty patients who need to be treated with uricosuric drugs., Graphical Abstract

Recently, the US Food and Drug Administration (FDA) issued a public safety alert, responding to the results of the now-published Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities (CARES) trial. The CARES trial showed no significant difference between allopurinol and febuxostat in the primary composite end point of cardiovascular (CV) events in subjects with gout and established CV comorbidities at baseline. However, there was a significantly increased risk of CV and all-cause mortality with febuxostat. Urate-lowering therapy (ULT) is central to the long-term management of gout, and xanthine oxidoreductase inhibitor (XOI) therapy is the consensus first-line approach. Allopurinol is generally the first XOI used, but febuxostat is an effective XOI option, and is commonly used when allopurinol is not tolerated. These data are further relevant since CV comorbidities are common in gout. Here, we examine why the CARES trial was done, and discuss other, ongoing comparative studies of febuxostat and allopurinol whose results are awaited. We assess the strengths and limitations of the CARES trial, and appraise the robustness and biologic plausibility of the results. The CARES trial does not prove that febuxostat raises CV mortality risk, but suggests greater risk with febuxostat than allopurinol. The CARES trial results do not support first-line use of febuxostat ULT, and raise questions about febuxostat placement at various pharmacologic ULT decision tree branches. Alternatives to febuxostat that are frequently effective include allopurinol dose escalation and uricosuric therapy alone or combined with allopurinol. The FDA safety alert highlights the need for shared ULT medical decision-making with gout patients, including discussion of the CV safety of febuxostat.

Purpose of review SGLT2 inhibitors are a new class of antihyperglycemic drugs that protect kidneys and hearts of type 2 diabetic (T2DM) patients with preserved kidney function from failing. Here we discuss new insights on renal protection. Recent findings Also in T2DM patients with CKD, SGLT2 inhibition causes an immediate functional reduction in glomerular filtration rate (GFR) and reduces blood pressure and preserves kidney and heart function in the long-term, despite a lesser antihyperglycemic effect. According to modeling studies, the GFR reduction reduces the tubular transport work and metabolic demand, thereby improving renal cortical oxygenation. In humans, the latter is linked to protection from CKD. Urine metabolomics in T2DM patients suggested improved renal mitochondrial function in response to SGLT2 inhibition, and experimental studies indicated improved tubular autophagy. Modeling studies predicted that also in diabetic CKD, SGLT2 inhibition is natriuretic and potentially stimulates erythropoiesis by mimicking systemic hypoxia in the kidney. Meta-analyses indicated that SGLT2 inhibition also reduces risk and severity of acute kidney injury in T2DM patients. Studies in nondiabetic mice implied inhibition of the renal urate transporter URAT1 in the uricosuric effect of SGLT2 inhibition. Summary Renoprotection of SGLT2 inhibition involves blood glucose-dependent and independent effects and extends to CKD.

The purpose of this study was to create novel urate under-excretion animal models using pyrazinamide and to evaluate whether dihydropyridine calcium channel blockers (CCBs) have uricosuric effects in vivo.Adult male ICR mice were treated with pyrazinamide, vehicle (dimethyl sulfoxide: DMSO), or tap water. Thirty minutes later, pyrazinamide-treated mice were given benzbromarone, losartan, nilvadipine, nitrendipine, nifedipine or azelnidipine. Six hours after the second administration, urine (by urinary bladder puncture) and plasma were collected to measure uric acid and creatinine levels, and fractional excretion of uric acid (FEUA) and creatinine clearance (Ccr) were calculated and evaluated. There was no significant difference in the levels of plasma uric acid, plasma creatinine, Ccr, urinary N-acetyl-β-d-glucosaminidase (NAG) and urinary NAG-creatinine ratio between water, DMSO, and pyrazinamide-treated mice. But the FEUA of pyrazinamide-treated mice was significantly lower than water mice. The FEUA was significantly higher in mice taking the dihydropyridine CCBs (nilvadipine, nitrendipine, nifedipine, and high-dose azelnidipine) than in pyrazinamide-treated mice. There was no significant difference in Ccr.Thus, a novel animal model created with PZA administration was useful as a urate under-excretion animal model that was probably URAT1-mediated, and the uricosuric effects of dihydropyridine CCBs were confirmed in vivo. Keywords: Uric acid, Urate, Fractional excretion of uric acid, Urate under-excretion animal model, Calcium channel blocker

Jianbo Li,1 Yang Yang,1 Likang Lu,2 Qiujin Ma,2 Jinjie Zhang2 1Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, People’s Republic of China; 2School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, People’s Republic of China Background: Morin, one of the most widely distributed flavonoids in plants, has been identified as a potent antihyperuricemic agent. Its poor water solubility and fast in vivo clearance, however, have limited its application in the treatment of hyperuricemia. In this study, a novel amphiphilic polymer (hydroxyethyl starch-deoxycholic acid [HES-DOCA]) was synthesized to overcome these limitations.Methods: HES-DOCA conjugates with various substitution degrees were prepared by chemical grafting DOCA to HES through ester formation. The structures of the conjugates were confirmed by infrared spectroscopy and 1H-NMR. Physicochemical characterizations of HES-DOCA nanoparticles-loaded Morin (Morin/HES-DOCA-NPs) were studied using dynamic light scattering and transmission electron microscopy (TEM). In vitro release studies were performed to evaluate the release properties of Morin from the NPs. Subsequently, in vivo pharmacokinetic parameters of Morin/HES-DOCA-NPs were investigated in Wistar rats through intravenous administration (2 mg/kg, equivalent to Morin). Antihyperuricemic efficacy of the NPs was evaluated in a rat hyperuricemic model.Results: The optimized HES-based amphiphilic polymer contained approximately 10 DOCA groups per 100 anhydroglucose units of HES, which can spontaneously self-assemble to form spherical NPs as demonstrated by TEM images. Morin/HES-DOCA-NPs were monodispersed (polydispersity index = 0.05) with a mean diameter of 197 nm and exhibited a zeta potential of -14 mV. The use of DOCA as the polymer’s hydrophobic segment enabled high drug loading efficiency (15.6%). After systemic administration, Morin/HES-DOCA-NPs exhibited significantly longer half-life and higher systemic exposure (elimination half-life and area under the plasma concentration–time curve) compared with free drug Morin. In a rat hyperuricemic model, treatment with Morin/HES-DOCA-NPs demonstrated superior therapeutic efficacy over Morin in decreasing serum uric acid level, increasing the uricosuric action, as well as attenuating hyperuricemia-associated inflammation in kidney of rats.Conclusion: Collectively, these findings suggest that the novel HES-based NP formulation of Morin may have great potential for clinical treatment of hyperuricemia. Keywords: HES-DOCA, drug loading efficiency, antihyperuricemic activities, half-life&nbsp

Emodinol, 1β, 3β, 23-trihydroxyolean-12-en-28-acid, as the main active ingredient firstly extracted from the rhizomes of Elaeagus pungens by our Research Group, was identified with apparent uricosuric and nephroprotective effects in hyperuricemia mice in our previous study. This study aimed to investigate the renal protective effect of emodinol in urate nephropathy rats. Rats were orally administrated by combined adenine and ethambutol to induce urate nephropathy. Emodinol at various doses were administered intragastrically to urate nephropathy rats daily. Serum uric acid (Sur), serum creatinine (Scr) and blood urea nitrogen (BUN) levels, as well as Interleukin-1beta (IL-1β) and tumor necrosis factor- alpha (TNF-α) concentrations in serum and kidney were determined. Renal protein expressions of organic ion transporters, components of NLR pyrin domain containing 3 (NLRP3) inflammasome, as well as key factors involved in toll-like receptors (TLRs)/myeloid differentiation factor 88 (MyD88)/nuclear factor kappa B (NF-κB) signaling pathway were analyzed by western blot. Emodinol significantly decreased Sur, Scr and BUN levels in adenine and ethambutol - induced urate nephropathy rats. More importantly, emodinol reversed dys-expression of organic ion transporters, inhibited NLRP3 inflammsome activation and suppressed TLRs/MyD88/NF-κB signaling pathway in the kidneys of urate nephropathy rats. Consistently, dilated tubules and tubular UA crystal formation, as well as tubular interstitial inflammatory cells infiltration in kidneys of urate nephropathy rats were obviously attenuated by emodinol, accompanied by restored renal and serum inflammatory cytokines concentrations. Taken together, the date suggested that emodinol ameliorated urate nephropathy by regulating renal organic ion transporters and inhibiting immune inflammatory responses in rats.

Uric acid (UA) is synthesized mainly in the liver, intestines, and vascular endothelium as the end product of an exogenous purine from food and endogenously from damaged, dying, and dead cells. The kidney plays a dominant role in UA excretion, and the kidney excretes approximately 70% of daily produced UA; the remaining 30% of UA is excreted from the intestine. When UA production exceeds UA excretion, hyperuricemia occurs. Hyperuricemia is significantly associated with the development and severity of the metabolic syndrome. The increased urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) expression, and glycolytic disturbances due to insulin resistance may be associated with the development of hyperuricemia in metabolic syndrome. Hyperuricemia was previously thought to be simply the cause of gout and gouty arthritis. Further, the hyperuricemia observed in patients with renal diseases was considered to be caused by UA underexcretion due to renal failure, and was not considered as an aggressive treatment target. The evidences obtained by basic science suggests a pathogenic role of hyperuricemia in the development of chronic kidney disease (CKD) and cardiovascular diseases (CVD), by inducing inflammation, endothelial dysfunction, proliferation of vascular smooth muscle cells, and activation of the renin-angiotensin system. Further, clinical evidences suggest that hyperuricemia is associated with the development of CVD and CKD. Further, accumulated data suggested that the UA-lowering treatments slower the progression of such diseases.

Hyperuricemia is a metabolic disorder with characteristic elevated serum uric acid. Recently, several plant-based medicines are being used for the treatment of hyperuricemia. The study aimed to find the hypouricemic potential of Berberis vulgaris in in-vitro and in-vivo study models. In i n-vitro studies, xanthine oxidase inhibition assay was performed to evaluate IC50 value and capsule absorbance of the drug, respectively. For in-vivo experiment, the study comprised 15 groups of rats. In-vitro results revealed that significant xanthine oxidase inhibition was shown by Berberis vulgaris with an IC50 value of 272.73±.3 μg/mL. Similarly, oral administration of Berberis vulgaris with dosages of 250 and 500 mg/kg decreased serum and liver uric acid levels significantly in a dose- and time-dependent manner in oxonate-induced hyperuricemic rats. Furthermore, 3-day and 7-day administration of Berberis vulgaris showed more potential compared to 1-day administrations. The present study indicated marked hypouricemic effects of Berberis vulgaris in rats. Due to caveat of the small sample size, a firm assumption of the hypouricemic effect of Berberis vulgaris cannot be made. However, extensive study is needed to find out the exact molecular mechanism involved and to translate its effects into clinical trials for the further validation of the results.

Aims Dual-urate-lowering therapy (ULT) with xanthine oxidase inhibitor and uricosuric medications is a treatment option for severe gout. Uricosuric agents can cause hyperuricosuria, a risk factor for nephrolithiasis and acute uric acid nephropathy. The aims of the present study were to simulate the relationship between suboptimal drug adherence and efficacy, and to quantify the risk of hyperuricosuria in gout patients receiving mono- and dual-ULTs. Methods The impact of poor medication adherence was studied using two-compartment pharmacokinetic (PK) models based on published evidence, and a semi-mechanistic four-compartment pharmacodynamic (PD) model. The PKPD model was used to simulate mono and dual-ULT in gout patients with either under-excretion (lowered clearance) or overproduction of uric acid, with suboptimal adherence modelled as either a single drug holiday of increasing duration or doses taken at random. Results Simulation results showed a surge in urinary uric acid occurring when dosing is restarted following missed doses. For under-excreters taking a 20-day drug holiday, the addition of 200 mg (or 400 mg) lesinurad to 80 mg febuxostat increased the percentage of patients experiencing hyperuricosuria from 0% to 1.4% (or 3.1%). In overproducers, restarting ULTs following drug holidays of more than 5 days leads to over 60% of patients experiencing hyperuricosuria. Conclusions Suboptimal medication adherence may compromise the safety and efficacy of mono- and dual-ULTs, especially in patients with gout resulting from an overproduction of uric acid. Clinicians and pharmacists should consider counselling patients with respect to the risks associated with partial adherence, and offer interventions to improve adherence or tailor treatments, where appropriate.

Исследования последних 15 лет позволили выявить около 10 генов, кодирующих соответствующие уратные транспортеры, ассоциированные с сывороточным уровнем мочевой кислоты. Выяснено, что их мутации способны привести к развитию почечной гиперурикемии. Идентификация уратных транспортеров открывает перспективы создания новых урикозурических препаратов, которые являются потенциальными альтернативными средствами для лечения пациентов с рефрактерной подагрой, не чувствительных к ингибиторам ксантиноксидазы, таким как аллопуринол и фебуксостат.

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

Our goal was to establish a model for the evaluation of the effects of uricosuric agents and to clarify the underlying mechanism(s). The effects of a uricosuric agent co-treated with pyrazinamide, an anti-tubercular agent, on urate handling were examined in rats. Furthermore, the effects of uricosuric agents on urate uptake were evaluated using the vesicles of rat renal brush-border membrane. Treatment with probenecid, at a dose of 100 mg/kg, significantly increased the urinary urate to creatinine ratio (UUA/UCRE) in pyrazinamide-treated rats although the same treatment did not produce any uricosuric effects in intact rats. In this model, the urinary excretion of pyrazinecarboxylic acid (PZA), an active metabolite of pyrazinamide, was decreased by probenecid and indicated an inverse correlation between urinary excretion of urate and PZA. Furthermore, in the examination using FYU-981, a potent uricosuric agent, a more than 10-fold leftward shift of the dose–response relationship of the uricosuric effect was observed in pyrazinamide-treated rats when compared with intact rats. In the in vitro study, the treatment of the vesicles of rat renal brush-border membrane with PZA produced an increased urate uptake, which was inhibited by uricosuric agents. The pyrazinamide-treated model used in the present study seems to be valuable for the evaluation of uricosurics because of its higher sensitivity to these drugs when compared to intact rats, and this is probably due to the enhanced urate reabsorption accompanied with trans-stimulated PZA transport at the renal brush-border membrane.