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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.

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.

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.

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.

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.

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.

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

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.

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.

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.

The purpose of this meta-analysis was to determine if uric acid-lowering therapy is associated with a decrease in blood pressure (BP) and serum creatinine levels.Medline, Cochrane, EMBASE, and Google Scholar databases were searched until 29 June 2016, with keywords: uric-acid-lowering therapy, allopurinol, febuxostat, uricosuric, and BP. Only randomized controlled trials were included. The primary outcomes were reduction in systolic BP (SBP) and diastolic BP (DBP), and secondary was reduction in serum creatinine level.Patients treated with allopurinol had greater reduction in SBP (standardized difference in means [SDM] = 0.321, 95% confidence interval [CI]: 0.145-0.497, p 0.001), DBP (SDM = 0.260, 95% CI: 0.102 to 0.417, p = 0.001), and creatinine level (SDM = 0.312, 95% CI: 0.008 to 0.615, p = 0.044) than control patients. Subgroup analysis showed that allopurinol significantly decreased SBP whether or not antihypertensive drugs were being administered; a decrease in DBP was only seen in patients receiving antihypertensive drugs. Low-dose allopurinol (≤300 mg/day) was more effective at reducing SBP than high-dose (300 mg/day) in patients receiving antihypertensive drugs.These results support that allopurinol decreases BP and creatinine levels in patients with hyperuricemia. KEY MESSAGES Allopurinol decreases SBP and DPB, and creatinine levels in patients with hyperuricemia. Allopurinol resulted in a significant decrease in SBP in patients with or without treatment of antihypertensive drugs. A dose of allopurinol of ≤300 mg per day might be more effective than a higher dose.

Background Benzbromarone is a uricosuric drug that has been used in the treatment of gout over the last 30 years. Due to its potent inhibition of the dominant apical (luminal) urate exchanger in the human proximal tubule URAT1, it reduces the urate reabsorption, diminishing serum urate levels and therefore preventing gout flares. Main body of the abstract Through several clinical trials, Benzbromarone has been proved effective and safe, inclusive in patients with chronic kidney disease and as combination therapy with allopurinol. Due to hepatotoxicity reports, it was withdrawn from the European market by the manufacturer, however many authors have questioned the product’s withdrawal due to a lack of clinical evidence in order to support its hepatotoxicity. Benzbromarone is still available in several European countries, New Zealand, Brazil and several other countries. Despite the product’s marketing over more than 20 years after the first hepatotoxicity reports, we have found only five reports in our literature search, and no prospective or retrospective study correlating hepatotoxicity with benzbromarone use. Short conclusion Benzbromarone is a safe and effective molecule for the treatment of gout. However, due to in vitro and in vivo data related to hepatotoxicity, it is prudent to prescribe it with some caution, especially for patients with an already known liver condition.

The effect of dotinurad [(3,5-dichloro-4-hydroxyphenyl)(1,1-dioxo-1,2-dihydro-3H-1λ6-1,3-benzothiazol-3-yl)methanone] was compared with that of commercially available uricosuric agents—namely, benzbromarone, lesinurad, and probenecid. Its effect on urate secretion transporters was evaluated using probe substrates for respective transporters. Dotinurad, benzbromarone, lesinurad, and probenecid inhibited urate transporter 1 (URAT1) with IC50 values of 0.0372, 0.190, 30.0, and 165 μM, respectively. Dotinurad weakly inhibited ATP-binding cassette subfamily G member 2 (ABCG2), organic anion transporter 1 (OAT1), and OAT3, with IC50 values of 4.16, 4.08, and 1.32 μM, respectively, indicating higher selectivity for URAT1. The hypouricemic effects of dotinurad and benzbromarone were evaluated in Cebus monkeys. Dotinurad, at doses of 1–30 mg/kg, concomitantly decreased plasma urate levels and increased fractional excretion of urate (FEUA) in a dose-dependent manner. On the contrary, benzbromarone, at a dose of 30 mg/kg, showed a modest effect on plasma urate levels. The inhibitory effect of dotinurad on urate secretion transporters was evaluated in Sprague-Dawley rats, with sulfasalazine and adefovir as probe substrates of ABCG2 and OAT1, respectively. Drugs, including febuxostat as a reference ABCG2 inhibitor, were administered orally before sulfasalazine or adefovir administration. Dotinurad had no effect on urate secretion transporters in vivo, whereas benzbromarone, lesinurad, probenecid, and febuxostat increased the plasma concentrations of probe substrates. These results suggested dotinurad is characterized as a selective urate reabsorption inhibitor (SURI), which is defined as a potent URAT1 inhibitor with minimal effect on urate secretion transporters, including ABCG2 and OAT1/3, because of its high efficacy in decreasing plasma urate levels compared with that of other uricosuric agents. SIGNIFICANCE STATEMENT Our study on the inhibitory effects on urate transport showed that dotinurad had higher selectivity for urate transporter 1 (URAT1) versus ATP-binding cassette subfamily G member 2 (ABCG2) and organic anion transporter (OAT) 1/3 compared to other uricosuric agents. In Cebus monkeys, dotinurad decreased plasma urate levels and increased fractional excretion of urate in a dose-dependent manner. To determine the inhibitory effect of dotinurad on urate secretion transporters, we studied the movement of substrates of ABCG2 and OAT1 in rats. Dotinurad had no effect on these transporters, whereas the other uricosuric agents increased the plasma concentrations of the substrates. These results suggested dotinurad as a potent and selective urate reabsorption inhibitor is characterized by increased efficacy with decreasing plasma urate levels.

Uric acid (UA) has been associated with hypertension, renal disease and cardiovascular disease. The aim of the present study was to compare the UA-lowering effects of a standard dose of the UA synthesis inhibitor febuxostat to a standard dose of the uricosuric agent benzbromarone, and to investigate the effects of a low-dose combination of both agents in hypertensive patients with hyperuricemia. Twenty hypertensive patients with inadequate UA control were administered febuxostat 40 mg (Feb), benzbromarone 50 mg (Ben) and febuxostat 20 mg and benzbromarone 25 mg (feb/ben) for 3 months each in a randomized modified crossover manner. UA metabolism, blood pressure (BP) and the indices of organ damage were assessed at baseline and the end of each treatment period. No significant changes were observed in BP or estimated glomerular filtration rate (eGFR) after the treatment with each UA-lowering regimen. The change in UA was significantly greater with feb/ben than with Feb. The excretion of UA and clearance of UA were higher with Ben than with Feb and feb/ben. Urinary 8-hydroxydeoxyguanosine and liver-type fatty-acid-binding protein levels were slightly lower with Ben, whereas flow-mediated dilation was slightly higher with feb/ben and Ben. The UA-lowering effects of the low-dose combination of the UA synthesis inhibitor and uricosuric agent were greater than those of the standard dose of each agent alone. The uricosuric agent may be more effective at improving vascular function than the UA synthesis inhibitor. Thus, the appropriate management of hyperuricemia with uricosuric drugs appears to be useful for hypertensive patients with hyperuricemia.

Background Benzbromarone is a potent uricosuric, but is not widely available due to concerns about hepatotoxicity. In Aotearoa New Zealand benzbromarone has been available since April 2013, subject to funding restrictions, for patients with inadequate urate-lowering response or intolerance to allopurinol and probenecid. Aim The aim of this study was to assess the safety and efficacy of benzbromarone in a real-life setting. Methods All patients who received funding for benzbromarone from 1/4/2013 to 30/9/2014 were identified. Prescribers were sent a questionnaire for each individual. Information on demographics, efficacy of previous urate-lowering drugs and reasons for discontinuation were collected. Specific information about the dose, effect on serum urate, adverse effects and liver function tests after commencing benzbromarone was recorded. Results Completed questionnaires were returned for 123/164 (75%) patients. Mean (SD) serum urate prior to benzbromarone was 0.57 (0.12) mmol/l and estimated glomerular filtration rate (eGFR) 50.3 (22.8) ml/min/1.73 m2. The median dose of benzbromarone was 100 mg/day (25-200 mg/day). Six months after commencing benzbromarone, mean (SD) serum urate was 0.35 (0.12) mmol/l. Benzbromarone related adverse events included rash (n = 4), diarrhoea (n = 9), nausea (n = 6), and urate stones (n = 3). Liver function tests abnormalities were uncommon and tended to be mild. There were 14 patient deaths; none were considered related to benzbromarone. Allopurinol had been prescribed prior to benzbromarone in 117/123 patients; median maximum allopurinol dose was 200 mg/day (range 25-600 mg/day), and 19% patients received allopurinol >300 mg/day. Conclusions Benzbromarone provides useful urate-lowering efficacy and does not appear unsafe in patients with gout. Urate-lowering therapy prescribing requires further optimisation.

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, has been demonstrated to exhibit uricosuric activity by our previous study. The aim of this study was to evaluate the uricosuric and nephroprotective effects of emodinol and explore its possible mechanisms in potassium oxonate-induced hyperuricemic mice with renal dysfunction. Mice were orally administrated 250 mg/kg of potassium oxonate once daily for 7 consecutive days to induce hyperuricemia with renal dysfunction. Emodinol was given at doses of 25, 50, and 100 mg/kg on the same day 1 h after oxonate treatment, and allopurinol (10 mg/kg) was given as a positive control. After 1 week, serum uric acid, serum creatinine, urine uric acid, urine creatinine, blood urea nitrogen, and hepatic xanthine oxidase activity were determined. The mRNA and protein levels of urate transporter 1, glucose transporter 9, ATP-binding cassette subfamily G member 2, organic anion transporter 1, oncoprotein-induced transcript 3, and organic cation/carnitine transporters in the kidney were detected by real-time polymerase chain reaction and Western blot analysis. In addition, urinary and renal Tamm-Horsfall glycoprotein concentrations were examined by ELISA assays. Emodinol significantly reduced serum urate levels, increased urinary urate levels and fractional excretion of uric acid, and inhibited hepatic xanthine oxidase activity in hyperuricemic mice. Moreover, potassium oxonate administration led to dys expressions of renal urate transporter 1, glucose transporter 9, ATP-binding cassette subfamily G member 2, organic anion transporter 1, and oncoprotein-induced transcript 3 as well as alternations of uromodulin concentrations, which could be reversed by emodinol. On the other hand, treatment of emodinol caused upregulated expressions of organic cation/carnitine transporters, resulting in an improvement of renal function characterized by decreased serum creatinine and blood urea nitrogen levels. Emodinol exhibited hypouricemic and nephroprotective actions by inhibiting xanthine oxidase activity and regulating renal ion transporters and oncoprotein-induced transcript 3, which may be a potential therapeutic agent in hyperuricemia and renal dysfunction.

Rationale Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder presenting with uric acid overproduction, neurocognitive disability, and behavioral disturbances. Inhalational anesthesia has been frequently used in LNS patients undergoing surgery. Characteristic compulsive self-injurious behavior and high risk of emesis may hinder inhalational induction. Propofol may be beneficial for these patients because of its easy and rapid titration for anesthetic depth during induction, early recovery from anesthesia, and antiemetic effect as well as uricosuric effect. Patient concerns A 16-year-old male adolescent was scheduled for percutaneous nephrolithotomy. He exhibited poorly controlled muscle, self-injurious behaviors and intellectual disability. Diagnosis The patient presented with neurodevelopmental delay in the first year of life, and was diagnosed with LNS, with a substitution of phenylalanine to leucine in hypoxanthine-guanine phosphoribosyltransferase (HPRT) 1 gene on the X-chromosome at 3 years of age. Interventions Total intravenous anesthesia was used for induction and maintenance of anesthesia with propofol and remifentanil using target-controlled infusion. Outcomes Time to recovery of consciousness was prolonged after uneventful surgery. Serum uric acid levels gradually increased during postoperative period. Lessons Propofol anesthesia using target-controlled infusion does not provide significant clinical advantages in rapid emergence from anesthesia and management of hyperuricemia in LNS patients undergoing urological surgery.

Objective The present study is to determine the potential treatment effects of ethyl acetate fraction of Tephrosia purpurea Linn. leaves (EATP) against gout. Methods Gout in experimental rats was induced with potassium oxonate at the dose of 250 mg/kg (intraperitoneal injection) for 7 consecutive days; EATP was administered 1 h after administration of the potassium oxonate on each day of experiment. Potassium oxonate was discontinued on the 8th day; thereafter allopurinol (10 mg/kg, p.o.) and EATP (200 and 400 mg/kg, p.o.) were continued until day 14. The uric acid level was measured from serum and urine during the experiment. Other biochemical parameters were assessed, including blood and urine creatinine, erythrocyte sedimentation rate, and total protein. Blood urea nitrogen, serum aspartate aminotransferase serum alanine aminotransferase and alkaline phosphatase were also measured. The blood was analyzed for levels of malondialdehyde and the antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase. Histopathological and radiological changes in the ankle of rats were observed after completion of the experiment. Results EATP was able to decrease serum uric acid and creatinine level; it also reduced inflammation, oxidative stress and lysosomal enzyme level, which has a role in acute inflammation. EATP increased uric acid excretion through urine due to its uricosuric effect. Conclusion EATP lowered the serum uric acid level and increased the urine uric acid level through excretion, which is useful in the treatment of gout. Hence the EATP was found to be helpful in the treatment of gout.

Objective To compare outcomes of 2 gout clinics that implemented different treatment strategies. Methods Patients newly diagnosed with gout and a follow-up of 9-15 months were included. Co-primary outcomes were the proportion of patients reaching a serum uric acid (UA) ≤0.36 mmoles/liter and free of flares. Secondary outcomes were the proportion of patients requiring treatment intensification and experiencing adverse events. One clinic adopted a strict serum UA (≤0.30 mmoles/liter target) strategy, with early addition of a uricosuric to allopurinol, and the other clinic adopted a patient-centered (PC) strategy emphasizing a shared decision based on serum UA and patient satisfaction with gout control. Independent t-tests or chi-square tests were used to test differences in outcomes, and logistic regressions were used to adjust the effect of the treatment center on outcomes for confounders. Results In total, 126 and 86 patients had a follow-up mean ± SD of 11.3 ± 1.8 versus 11.1 ± 1.9 months. In the UA strategy, 105 of 126 patients (83%) compared to 63 of 86 (74%) in the PC strategy (P = 0.10) reached the threshold of ≤0.36 mmoles/liter; and 58 of 126 (46%) versus 31 of 86 (36%) were free of flares (P = 0.15). In the UA strategy, 76 of 126 patients (60%) were on allopurinol monotherapy compared to 63 of 86 (73%) in the PC strategy (P = 0.05), yet the number of adverse events was not different (n = 25 [20%] versus n = 20 [23%]; P = 0.55). Adjusting for confounders did not substantially change these associations. Conclusion A strict UA strategy resulted in a nonsignificantly higher proportion of patients reaching a serum UA ≤0.36 mmoles/liter and being free of flares. This result was accomplished with significantly more therapy intensification. The small sample size plays a role in the significance of results.

Over the last 70 years, pharmacotherapy in gout with urate-lowering drugs has consisted of four drugs only: In 1952, a mild uricosuric probenecid became available, the xanthine oxidase inhibitor Allopurinol in 1964, and the latter became the most frequently used urate-lowering drug worldwide; in the Eurozone, the uricosuric benzbromarone was welcomed in 1977. Only in 2002, the potent non-purine xanthine oxidase inhibitor febuxostat was introduced. In many countries, uricosurics such as probenecid and benzbromarone have not been available up to now, and these days, the new uricosuric lesinurad is the first uricosuric that may be introduced in these countries, which is the reason for describing the position this novel uricosuric deserves in treating gout. Recent literature will be shortly reviewed, and the current proposed position for lesinurad will be given as an aid for clinicians.

Gout is an increasingly common chronic disorder of urate crystal deposition that manifests as flares of acute inflammatory arthritis. Hyperuricaemia is a prerequisite and a fifth of both men and woman are hyperuricaemic. The prevalence of gout is much lower than the prevalence of hyperuricaemia for reasons that are not currently clear. Gout is more common in men than women prior to menopause due to the uricosuric effects of oestrogen, but after menopause the incidence of gout rises substantially in women. Co-morbidities are an important issue in gout, with cardiovascular disease, diabetes mellitus, obesity and chronic kidney disease all common in patients with gout. Environmental factors like diet affect the incidence of gout but there is little evidence to support an emphasis on diet in treating established gout. The diagnosis of gout is often made without the use of joint aspiration and validated diagnostic rules are available for both primary and secondary care as well as classification criteria for research use. The overarching principle of the management of gout with pharmacotherapy is the need to reduce serum urate levels to below a target of 0.30 mmol/L or 0.36 mmol/L depending on whether it is tophaceous or non-tophaceous respectively. The use of allopurinol has been researched extensively and newer strategies for safer effective dosing are now recommended. Newer agents have been introduced for the treatment of gout, including febuxostat and lesinurad. A number of important questions in the field are under current investigation.

We have previously shown a strong relation between high serum uric acid and pulse wave velocity (PWV) as expression of arterial stiffness. This relation was even stronger than with blood pressure. In addition to its hypoglycemic effect, sodium-glucose transport protein 2 inhibitors (SGLT2i) may reduce serum uric acid (SUA) by a uricosuric effect. Aims: to evaluate in type 2 diabetic patients with hypertension and normal renal function the effect of canagliflozin on SUA and carotid femoral PWV. Methods: 20 patients with type 2 diabetes mellitus (DM) 10 females, 59±4y received metformin 2000mg, canagliflozin 100-300mg and amlodipine 10mg daily during 6 months. Laboratory parameters including HbA1C, fasting blood glucose level, glomerular filtration rate, SUA, 24h ambulatory blood pressure monitoring (ABPM) and PWV were determined at baseline and after a 6-month treatment course with canagliflozin 100-300mg. Results: After 6 months of treatment, PWV dropped from 12±3 to 8.5±4 m/sec, p Conclusions: Canagliflozin ameliorates arterial stiffness in patients with type 2 DM and hypertension. This effect seems to be related, among other mechanisms, such as blood pressure drop and plasma volume contraction to the reduction in serum uric acid level. Since SUA has been shown to predict the risk of cardiovascular morbidity and mortality in hypertension and DM, lowering serum uric acid by SGLT2i might be contributing to cardiovascular protection. Disclosure R.A. Sanchez: None. M.J. Sanchez: None. A.J. Ramirez: None.

Background Studies on renal solute carrier transporters have made the renal pathophysiology be in progress towards more mechanistic and the knowledge on renal drugs including drug-drug interaction be more evidentiary. Among the evidence, uricosuric phenomenon has been known that rodent experimental model is also useful for predicting human uricosuria. Objectives The aim of this study was to assess the substrate uptake at the overexpression of renal transporters, OAT1, OAT3 and URAT1 at kidney proximal tubular cell lines with or without a commercial herbal medicine, Keishibukuryogan (K-06) and to further measure serum and urinary uric acid concentrations in the setting of potassium oxonate (PO)-induced ICR mouse model with or without K-06. Methods The transporter-expressed HEK293-OAT1 and HEK293-OAT3 cells were seeded on BD poly-d-lysine microplates to uptake the [3H] estrone sulfate for 5 min in absence or presence of K-06. URAT1 was overexpressed using Xenopus oocytes being injected with in vitro-copied RNA of URAT1, and then to measure the uptake of [14C] uric acid with/without K-06. Total radioactivity was measured using a liquid scintillation counter. Serum and urinary uric acid was measured in PO ICR mice after three-day intake of K-06. They were assigned by 4 per each group; 1) control group, 2) PO-induced group, 3) PO-induced with allopurinol 50 mg/kg/day intake group and 4) PO-induced with allopurinol plus K-06 300 mg/kg/day intake group. Results To determine the kinetic parameters of concentration-dependent uptake of overexpressed OAT1 and OAT3 transporters in HEK293 cells, the K-06 inhibitory parameters on OAT1 and OAT3 were presented with the IC50 values of 49.3 and 31.5 µg/mL, respectively. The K-06 inhibited URAT1 with IC50 of 59.3 µg/mL. The K-06 (300 mg/kg) reduced serum levels of uric acid approximately 30% compared to that of PO-control group (p=0.039) and K-06 showed the slight elevation of urinary uric acid by 12% compared to that of PO-control group with no statistical significance. Conclusions The present findings demonstrated that the K-06 modulated basolateral and apical renal transporters and the K-06 showed the slight increased uric acid excretion and the uric acid lowering effect in experimental mouse setting. References [1] Becker GJ, Hewitson TD. Animal models of chronic kidney disease: useful but not perfect. Nephrol Dial Transplant2013;28:2432–8. doi: 10.1093/ndt/gft071 [2] Key difference between mouse and human kidney cells. Which isavailable at https://www.sciencedaily.com/releases/2016/03/160318181600.htm Acknowledgements This study was supported by the Traditional Korean Medicine R and D program funded by the Ministry of Health and Welfare through the Korea Health Industry Development Institute (KHIDI, Grant # HI16C0864). The commercial herbal products, Keishibukuryogan (K-06) were donated by the virtue of Kracie Pharma, Co., Ltd. Disclosure of Interest None declared

Background Gout is the most prevalent inflammatory arthritis, affecting 2.5% of adults in the UK. However, management is often inadequate in both primary and secondary care, with only 45% of patients achieving target serum urate (SUA) level Objectives To compare the management of gout in the rheumatology service against the 2007 British Society for Rheumatology (BSR) and 2006 European League Against Rheumatism (EULAR) gout guidelines, and the NICE febuxostat technology appraisal (TA164). Methods We retrospectively audited all new out-patient referrals with gout seen in our department over a 12 month period (January-December 2015). Data were collected by electronic review of case notes and completion of a structured proforma. Three mutually exclusive groups were compared: those seen once in rheumatology and discharged to GP (group1), followed-up in general rheumatology clinics (group2), or followed-up in a specialist gout clinic (group3). Follow-up SUA levels were specifically compared to EULAR ( Results 150 new consecutive gout referrals (50 per group) were included in the audit: 83% were male and mean age was 62 years. Gout was diagnosed by monosodium urate crystal identification in 16 (11%) and 25% had tophi. 43 (29%) patients were already on ULT, and 107 (71%) patients were newly commenced on ULT. Prophylactic medications were co-prescribed in 86% (130) cases. 44 patients were taking diuretics; diuretics were advised to be stopped or reduced in 12% cases. Nearly all patients starting allopurinol commenced a daily dose of ≤100 mg (99% cases). Of the patients started on a uricosuric/febuxostat, 92% had taken allopurinol previously. Of the 15 patients commenced on febuxostat, 3 (15%) had ischaemic heart disease (IHD) or cardiac failure. Chronic kidney disease (CKD) stage 3 (group1 28%, group2 22%, group3 34%), CKD stage 4/5 (2%, 2%, 10%), IHD/cardiac failure (30%, 30%, 40%), clinically evident tophi (16%, 18%, 42%) and previous allopurinol intolerance (10%, 14%, 24%) were more common in group 3 than groups 1 and 2. After 12 months, only 90 (60%) patients achieved target Conclusions Allopurinol starting dose, use of prophylaxis, and use of allopurinol first-line concorded well with national and international guidelines. We achieved target SUA levels more commonly than the UK national average in a recent national rheumatology audit. Patients discharged to the GP with a management plan prior to achieving a target SUA level achieved target less frequently suggesting that rheumatologists should follow patients in order to ensure treatment is escalated until the target SUA level is achieved. Disclosure of Interest None declared

To provide insight into pharmacological treatment of hyperuricemia we developed a semi‐mechanistic, dynamical model of uric acid (UA) disposition in human. Our model represents the hyperuricemic state in terms of production of UA (rate, PUA), its renal filtration (glomerular filtration rate, GFR) and proximal tubular reabsorption (fractional excretion coefficient, FE). Model parameters were estimated using data from 9 Phase I studies of xanthine oxidase inhibitors (XOI) allopurinol and febuxostat and a novel uricosuric, the selective UA reabsorption inhibitor lesinurad, approved for use in combination with a XOI. The model was qualified for prediction of the effect of patients' GFR and FE on concentration of UA in serum (sUA) and UA excretion in urine and their response to drug treatment, using data from 2 Phase I and 4 Phase III studies of lesinurad. Percent reduction in sUA from baseline by a XOI is predicted to be independent of GFR,FE or PUA. Uricosurics are more effective in underexcreters of UA or patients with normal GFR. Co‐administration of a XOI and an uricosuric agent should be considered for patients with high sUA first in the treatment algorithm of gout before uptitration of XOI. The XOI dose in combination with a uricosuric can be reduced compared to XOI alone for the same target sUA to the degree dependent on patient's GFR and FE. This exposure‐response model of UA can be used to rationally select the best drug treatment option to lower elevated sUA in gout patients under differing pathophysiological situations.

Background Transient receptor potential vanilloid 2 is a calcium channel activated by probenecid. Probenecid is a Food and Drug Administration–approved uricosuric drug that has recently been shown to induce positive lusitropic and inotropic effects in animal models through cardiomyocyte transient receptor potential vanilloid 2 activation. The aim of this study was to test the hypothesis that oral probenecid can improve cardiac function and symptomatology in patients with heart failure with reduced ejection fraction and to further elucidate its calcium‐dependent effects on myocyte contractility. Methods and Results The clinical trial recruited stable outpatients with heart failure with reduced ejection fraction randomized in a single‐center, double‐blind, crossover design. Clinical data were collected including a dyspnea assessment, physical examination, ECG, echocardiogram to assess systolic and diastolic function, a 6‐minute walk test, and laboratory studies. In vitro force generation studies were performed on cardiomyocytes isolated from murine tissue exposed to probenecid or control treatments. The clinical trial recruited 20 subjects (mean age 57 years, mean baseline fractional shortening of 13.6±1.0%). Probenecid therapy increased fractional shortening by 2.1±1.0% compared with placebo −1.7±1.0% ( P =0.007). Additionally, probenecid improved diastolic function compared with placebo by decreasing the E/E′ by −2.95±1.21 versus 1.32±1.21 in comparison to placebo ( P =0.03). In vitro probenecid increased myofilament force generation (92.36 versus 80.82 mN/mm 2 , P P Conclusions Probenecid improves cardiac function with minimal effects on symptomatology and no significant adverse effects after 1 week in patients with heart failure with reduced ejection fraction and increases force development and calcium sensitivity at the cardiomyocyte level. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 01814319.

Gout is the most common type of arthritis in developed countries that is often inadequately managed. Evidence regarding role of hyperuricaemia in poor outcomes in gout patients (e.g., disability, recurrent hospital admissions) with/without other chronic cardiometabolic comorbidities prompts the search of newer and more effective drugs. Current management of gout is limited to NSAIDS and intra-articular corticosteroids in acute gout and Allopurinol or Febuxostat with or without probenecid in chronic gout. Other drugs used as add-on therapy in refractory cases of gout who fail on monotherapy include benzbromarone and pegloticase but with limited role. Though these drugs have been available for several years, significant proportion of compliant patients fail to achieve consistent control of uric acid levels resulting in acute gout flares. Recent advances in the role of urate transporters in proximal tubules of kidney have resulted in the development of new generation uricosuric drugs including lesinurad. It is recently approved by US Food and Drug Administration (US FDA) and European Medicines Agency (EMA) in patients with uncontrolled gout along with Allopurinol or Febuxostat. Hopefully, it will contribute to fulfill the unmet goals in management of gout. This review aims at exploring the current therapeutic strategies for the management of chronic gout patients as well as their limitations and the role of Lesinurad in patients who have failed on monotherapy. The published studies and poster presentations were identified by conducting a literature search from electronic database from 1980 till January 2017, using various medical subject headings and terminologies. These studies were screened and publications considered relevant to the topic were included in the study.

Gout is common in the elderly, affecting an estimated 4.7 million people aged > 60 years in the USA alone. The incidence and prevalence of gout increases, and male predisposition to gout reduces, with increasing age. The elderly have more comorbidities, and gout manifests differently, with more frequent involvement of knees, ankles, and wrists at disease onset, systemic upset, and tophi. Comorbidities and polypharmacy make the management of gout flares challenging in this population. Intra-articular corticosteroid injection remains the treatment of choice for accessible joints, oral prednisolone is preferred over low-dose colchicine, and non-steroidal anti-inflammatory drugs (NSAIDs) are best avoided. Xanthine oxidase inhibitors (XOI) remain the first-line treatment for hyperuricemia in the elderly. Arhalofenate, an emerging uricosuric anti-inflammatory drug, prevents gout flares while reducing serum urate. It may be particularly relevant in the treatment of gout in the elderly as they are unable to tolerate long-term colchicine for flare prophylaxis and frequently have contraindications to corticosteroids and NSAIDs. However, given its modest urate-lowering effect, it can only be used in combination with an XOI, and the safety and efficacy of this drug has not been examined in the elderly or in those with chronic kidney disease. Diuretics and beta-blockers should be discontinued where feasible, whereas low-dose aspirin can be continued if otherwise indicated.

The aim of this review was to summarize the evidence for combination therapy to achieve serum urate (SUA) target levels in gout. Within this overarching aim, a second aim was to evaluate the evidence for a new uricosuric agent lesinurad, which inhibits urate transport in the kidney. In summary, this review indicates that there are a number of ways to approach patients who do not achieve a target serum urate with allopurinol (APL) monotherapy. These include higher doses of APL up to 600-800 mg/d, switching to febuxostat, or adding in a uricosuric. For the latter option, controlled supporting evidence is available for benzbromarone, probenecid, and lesinurad. All options appear similar in terms of success rates, so the choice of option comes down to physician and patient choice, cost, experience, and strength of the evidence base. Increasing the dose of APL is the cheapest option, while febuxostat is consistently superior to standard doses of APL. The strongest evidence for the uricosuric option is available for lesinurad as trials of other agents are either nonexistent or based on small single-centre trials. It is suggested that guidelines should be expanded to consider all of these evidence-based options in the not-uncommon occurrence of APL inadequate response.

A gout revolution is at hand as can be seen from the number of publications and our recent increase in a better understanding of gout regarding imaging, regarding pathogenetic involvement of crystals, cells and cytokines, as well as regarding new pharmacotherapeutic options. We should now focus on rational pharmacotherapy to significantly improve gout care. With modern combinations of xanthine oxidase inhibition PLUS uricosuric all serum urate concentrations can be targeted. The pharmacotherapeutic literature of synthetic urate lowering treatment is reviewed and a plea is given for rational pharmacotherapy combining different modes of action aiming at the rheumatologically predefined optimal serum urate concentrations instead of a more reluctant approach to just lower a serum urate to any lower level with a fixed dose allopurinol.

Muskuloskeletal ultrasound and dual-energy-CT (DECT) findings are increasingly relevant for the establishment of the diagnosis of gout, and are therefore incorporated into the novel ACR / EULAR classification criteria. Canakinumab, a monoclonal antibody directed against interleukin-1β (IL-1β) has been approved in 2013 for the treatment of acute gout and for prophylaxis of flares. In patients demonstrating an inadequate response upon treatment with allopurinol or febuxostat, combination therapy with lesinurad might reduce uric acid levels to the target of < 6 mg / dl (< 5 mg / dl in tophaceous gout). Rapid lowering of uric acid levels and effective tophi reduction can be achieved with pegloticase, which can be utilized in selected patients presenting contraindications to xanthine oxidase inhibitors and uricosuric drugs. This article summarizes current scientific aspects of diagnosis, treatment and comorbidities of gout in the context of clinical relevance.

Objectives\ud To assess the concordance of gout management by UK rheumatologists with evidence-based best-practice recommendations.\ud \ud Methods\ud Data were collected on patients newly referred to UK rheumatology out-patient departments over an 8-week period. Baseline data included demographics, method of diagnosis, clinical features, comorbidities, urate-lowering therapy (ULT), prophylaxis and blood tests. Twelve months later, the most recent serum uric acid level was collected. Management was compared with audit standards derived from the 2006 EULAR recommendations, 2007 British Society for Rheumatology/British Health Professionals in Rheumatology guideline and the National Institute for Health and Care Excellence febuxostat technology appraisal.\ud \ud Results\ud Data were collected for 434 patients from 91 rheumatology departments (mean age 59.8 years, 82% male). Diagnosis was crystal-proven in 13%. Of 106 taking a diuretic, this was reduced/stopped in 29%. ULT was continued/initiated in 76% of those with one or more indication for ULT. One hundred and fifty-eight patients started allopurinol: the starting dose was most commonly 100 mg daily (82%); in those with estimated glomerular filtration rate

The European League Against Rheumatism published updated recommendations for the management of gout in 2016, comprising 3 overarching principles and 11 key recommendations for clinical practice. Patient education about the pathophysiology of gout and its comorbidities, as well as the existence of effective treatments are important, and understanding the principles of managing acute attacks and eliminating urate crystals by lifelong lowering of the serum urate (SU) below a target level are essential. Advice about lifestyle, diet, weight, and other risk factors, as well as the need to screen for, and manage, comorbidities is emphasized. For the treatment of flares, colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), and oral or intraarticular steroids, or a combination thereof, are recommended. In patients with frequent flares and contraindications to colchicine, NSAIDs, and corticosteroids, an interleukin-1 blocker should be considered. Urate-lowering therapy (ULT) should be discussed from the first presentation of the disease, and SU levels should be maintained at less than 6 mg/dl (360 µmol/l), or less than 5 mg/dl (300 µmol/l) in patients with severe gout. Allopurinol is recommended as first-line ULT with dose adjustment according to renal function. If the SU target cannot be achieved with allopurinol, then febuxostat, a uricosuric, or combining a xanthine oxidase inhibitor with a uricosuric should be considered. All ULTs should be started at low dose and titrated upwards until the SU target is achieved. Unless contraindicated, flare prophylaxis with low-dose colchicine or with NSAIDs at low dosage is recommended during the first 6 months of ULT. In patients with refractory gout, pegloticase can be considered.

Gout is a potentially progressive and debilitating form of chronic inflammatory arthritis caused by the deposition of monosodium urate crystals in synovial fluid and other tissues, characterized by sudden & severe episode of pain, warmth and swelling in a joint. People suffering from recurrent attacks frequently experience pain and disability, reduced health-related quality of life and productivity and increased morbidity. NSAIDs, colchicines, glucocorticoids, uric acid lowering agent like uricostatic drugs (allopurinol, a xanthine oxidase inhibitor), Uricosuric drugs (Probenecid) are very effective but risky in patients having pre-existing renal, cardiovascular, gastrointestinal and metabolic disorders. Cupping (Al-Hijama) is a widely used therapeutic regimen of Unani system of medicine with high acceptance in Egypt and Arab countries. It is used for the treatment of various inflammatory and painful conditions like sciatica, gout, rheumatoid arthritis, pain of knee, removal of deep swelling, disease of liver and skin etc. It is a minor surgical excretory procedure related scientifically to the principles of renal glomerular filtration and abscess evacuation where a pressure-dependent excretion of causative pathological substances occurs. Cupping is thought to act mainly by increasing local blood circulation and relieving the painful muscle tension. It acts by improving microcirculation, promoting capillary endothelial cell repair, accelerating granulation, and angiogenesis in the regional tissues. It is the best deep tissue massage which normalizes the patient’s functional state and progressive muscle relaxation. In Unani system of Medicine, this is a simple and economic treatment, effectively treating diseases with different etiologies and pathogenesis.

Rhizoma Dioscoreae Nipponicae, from Discorea nipponica, is a widely used traditional Chinese herb. It is used to treat arthroncus, arthrodynia, and arthritis. Hyperuricemia is an important foundation of gouty arthritis. The current study was aimed at investigating whether the effects of total saponins from Rhizoma Dioscoreae Nipponicae on hyperuricemia were due to renal organic ion transporters in potassium oxonate-induced hyperuricemia mice. Hyperplasia of synovial cells prepared from Wistar rats was induced by IL-1β (1 × 104 µg/mL). MTT was used and to screen active components in the inhibition of hyperplasia by total saponins from Rhizoma Dioscoreae Nipponica, individual pure compounds, and different combinations of these compounds. Sixty Kun Ming mice were randomly divided into six groups: normal, model, allopurinol (40 mg/kg), and three total saponins groups receiving dose (600 mg/kg), middle (300 mg/kg), and low doses (60 mg/kg). Hyperuricemic mice were induced with potassium oxonate (300 mg/kg) intragastrically. The total saponins were given six days and the positive drug allopurinol was given one day before inducing hyperuricemia. The serum and urine levels of uric acid and creatinine and the fractional excretion of uric acid were measured in normal and hyperuricemic mice treated with Rhizoma Dioscoreae Nipponicae and allopurinol. The mRNA and protein levels of the mouse urate transporter 1, glucose transporter 9, organic anion transporter 1, and organic anion transporter 3 were analyzed by real-time-PCR and Western blotting methods, respectively. Total saponins from Rhizoma Dioscoreae Nipponicae could effectively reverse potassium oxonate-induced alterations in renal mouse urate transporter 1, glucose transporter 9, organic anion transporter 1, and organic anion transporter 3 mRNA and protein levels, resulting in enhancement of renal urate excretion in mice. These findings suggested that the total saponins from Rhizoma Dioscoreae Nipponicae had a uricosuric effect on the regulation of renal organic ion transporters in hyperuricemic animals.

The purpose of the present study was to determine whether a physiologic plasma concentration of α-ketoglutarate (αKG) influences the kinetic interaction of ligands with organic anion transporter 1 (OAT1). The effect of extracellular αKG on the kinetics of para-aminohippurate (PAH) and cidofovir transport was examined along with its effect on the potency of 10 drugs in five different classes (uricosuric, nonsteroidal anti-inflammatories, loop diuretics, angiotensin II receptor antagonists, and β-lactam antibiotics) to inhibit OAT1 expressed in Chinese hamster ovary cells. Extracellular αKG competitively inhibited PAH and cidofovir transport with Ki values (∼5 μM) approximating its unbound plasma concentration (determined by equilibrium dialysis). When PAH was the substrate, extracellular αKG (5 μM) significantly increased IC50 values for some inhibitors (up to 4-fold), such as probenecid, but not for others (an inhibitor-dependent effect). For some inhibitors, a significant increase in IC50 value was observed when cidofovir was the substrate, but not PAH (a substrate-dependent effect). A significant increase in IC50 value was also observed for inhibition of PAH transport by probenecid in renal basolateral membrane vesicles (5.2-fold). The substrate- and inhibitor-dependent effect of extracellular αKG on ligand interactions with OAT1 highlights the complexity of the OAT1 ligand-binding surface. The effect of extracellular αKG on the potency of OAT1 inhibition should be considered when assessing drug-drug interaction potential at the transporter.

Objective Studies in human volunteers have shown that vitamin C reduces serum urate (SU) levels. The aim of this study was to determine the effects of vitamin C on SU levels in patients with gout. Methods Patients with gout and an SU level >0.36 mmoles/liter (6 mg/dl) were recruited. Twenty patients already taking allopurinol were randomized to receive an increase in the dose of allopurinol or to commence taking vitamin C (500 mg/day). Twenty patients who had not been taking allopurinol were randomized to start receiving either allopurinol (up to 100 mg/day) or vitamin C (500 mg/day). Levels of plasma ascorbate, creatinine, and SU were measured on day 0 and week 8. Results There was no significant difference in the baseline SU level or estimated glomerular filtration rate (eGFR) between those who received vitamin C and those who did not (for SU, mean ± SEM 0.50 ± 0.11 mmoles/liter [8.4 ± 1.8 mg/dl] versus 0.50 ± 0.09 mmoles/liter [8.4 ± 1.5 mg/dl]; for eGFR, mean ± SEM 65.5 ± 3.5 ml/minute/1.73 m(2) versus 67.9 ± 4.6 ml/minute/1.73 m(2) ). Among the randomized patients, 30% in the vitamin C group and 25% in the no vitamin C control group were receiving diuretics. In the patients receiving vitamin C, there was a significant increase between day 0 and week 8 in the plasma ascorbate level. The reduction in SU level over 8 weeks was significantly less in those patients receiving vitamin C compared to those who started or increased the dose of allopurinol (mean reduction 0.014 mmoles/liter [0.23 mg/dl] versus 0.118 mmoles/liter [1.9 mg/dl]; P Conclusion A modest dosage of vitamin C (500 mg/day) for 8 weeks had no clinically significant urate-lowering effects in patients with gout, despite the fact that plasma ascorbate levels increased. These results differ from previous findings in healthy control subjects with hyperuricemia. The uricosuric effect of modest-dose vitamin C appears to be small in patients with gout, when administered as monotherapy or in combination with allopurinol.

Epidemiologic studies, animal models, and preliminary clinical trials in children implicate uric acid in the development of essential hypertension. Controversy remains as to whether the observations indicate a general mechanism or a surrogate phenomenon. We sought to determine whether uric acid is a causative mediator of increased blood pressure (BP) and impaired vascular compliance. We report a randomized, double-blinded, placebo-controlled trial comparing 2 mechanisms of urate reduction with placebo in prehypertensive, obese, adolescents, aged 11 to 17 years. Subjects were randomized to the xanthine oxidase inhibitor, allopurinol, uricosuric, probenecid, or placebo. Subjects treated with urate-lowering therapy experienced a highly significant reduction in BP. In clinic systolic BP fell 10.2 mm Hg and diastolic BP fell 9.0 mm Hg in treated patients compared with a rise of 1.7 mm Hg and 1.6 mm Hg systolic and diastolic BP, respectively in patients on placebo. Urate-lowering therapy also resulted in significant reduction in systemic vascular resistance. These data indicate that, at least in adolescents with prehypertension, uric acid causes increased BP that can be mitigated by urate lowering therapy.

The aim of the present study is to discover multidrug resistance-associated protein (MRP) inhibitors with neuroblastoma-selective cytotoxicity by means of fluorescence assay with a membrane-permeable fluorescent dye, Fluo-8 AM, based on our observation that gene expression of Mrp3 in neuroblastoma Neuro2a cells was remarkably higher than that in primary cultured cortical neurons, as determined by real-time PCR. Neuro2a cells showed minimal fluorescence upon incubation with Fluo-8 AM. However, blocking of Mrp3 efflux function by small interfering RNA (siRNA) transfection or inhibition with probenecid resulted in significant dye accumulation, observed as an increase of fluorescence. Interestingly, Mrp3 siRNA or probenecid treatment also resulted in increased cytotoxicity, as evidenced by decreased 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-reducing activity of Neuro2a, with a concomitant increase in release of lactate dehydrogenase. On the other hand, primary cultured neurons exhibited higher fluorescence intensity after incubation with Fluo-8 AM regardless of addition of probenecid. Also, probenecid only minimally affected MTT-reducing activity. Thus, probenecid showed selective cytotoxicity towards Neuro2a cells. Based on these findings, we screened a series of established therapeutic agents for ability to induce Fluo-8 accumulation in Neuro2a cells. Several uricosuric and nonsteroidal anti-inflammatory drugs were identified, and these drugs were confirmed to decrease MTT-reducing activity selectively in Neuro2a. There was a negative linear correlation between Fluo-8 accumulation and cytotoxicity of these agents. Although the compounds identified here are insufficiently potent for practical application, further screening to discover higher-affinity MRP3 inhibitors using larger chemical libraries may uncover drug candidates with potent neuroblastoma-selective cytotoxicity.