Uricosuric Agents Research Articles

Cardiovascular Outcomes of Uric Acid Lowering Medications: A Meta-Analysis.

Although hyperuricemia is a recognized risk factor for cardiovascular diseases, mixed results have been reported regarding the associations between uric acid-lowering medications and cardiovascular events. This meta-analysis compared the cardiovascular outcomes of different uric acid-lowering medications and placebo. Following PRISMA guidelines, we searched OVID Medline, Embase, Web of Science, and Cochrane databases to identify potentially relevant articles until December 2023. Studies must be randomized or observational, report cardiovascular and mortality outcomes, and compare uric acid-lowering medications to placebo or each other. Data was analyzed using Revman (version 5.4) software. A total of 3,393 studies were searched, after which 47 studies were included, totaling 3,803,509 patients (28 studies comparing xanthine oxidase inhibitors (XOI) versus placebo, 17 studies comparing allopurinol and febuxostat, and 2 studies comparing XOI and uricosuric agents). Overall mean age was 57.3years, and females comprised 20.8% of all studies. There were no significant differences between XOI and placebo for cardiovascular outcomes (mortality, myocardial infarction, major adverse cardiovascular events, heart failure, or arrhythmia). There was significant heterogeneity in all these pooled analyses. Comparing Allopurinol to Febuxostat, there was a lower risk of heart failure in febuxostat than allopurinol in 3 RCTs (OR 0.66, 95% CI 0.50-0.89, p = 0.006). Other cardiovascular outcomes were not different. Lastly, when comparing XOI and uricosuric agents, no significant differences in MI rates were evident. XOI was not associated with reduced cardiovascular events compared to placebo. When comparing XOI agents, Febuxostat might reduce the risk of HF, but future studies are required to confirm the findings from the current study.

Drug-Induced Hypouricemia.

Hypouricemia is defined as a serum uric acid concentration of ≤ 2.0mg/dL or 119μmol/L. Hypouricemia may occur secondarily to a number of underlying conditions, including severe hepatocellular disease, neoplasia, defective renal tubular reabsorption of uric acid, inherited metabolic defect in purine metabolism, and drugs. Medications are an important cause of hypouricemia. They can cause hypouricemia by a variety of mechanisms. Drug-induced hypouricemia mostly occurs as overtreatment of hyperuricemia by urate-lowering therapies including xanthine oxidase inhibitors, uricosuric agents and uricases. Drugs not used in the treatment of gout may also lead to a decrease of uric acid levels. In this literature review, medications leading to hypouricemia are summarized with regard to their mechanism of action and clinical significance.

The Efficacy of Amruta Guggulu (Internal) and Madhuyashtyadi Taila (External) in the Management of Vatarakta w.s.r. to Gouty Arthritis

Ayurveda is the only medical science which has focused more on prevention of diseases and maintenance of health. The system advocates for a balance between lifestyle, diet, upright attitude. In the modern context of life, people and their dietary habits, lifestyle, social structure and environment have undergone a remarkable change leading to many avoidable diseases. Vatarakta is one among those diseases. The name Vatarakta indicates the unique pathology of morbid Vata dosha and Rakta dhatu. Based on aetiolgy, pathogenesis, signs and symptoms Vatarakta can be compared with Gouty Arthritis of contemporary medicine. It is a painful metabolic disorder caused due to hyperuricemia, which in turn is caused by genetic factors, dietary factors which are rich in purine, alcohol consumption, drugs, smoking and lack of physical activity. In moderns medicine Gouty Arthritis is treated by NSAIDS, steroids, uricosuric agents, allopurinol, febuxostat etc. But in due course all these drugs can lead to adverse effects when used for long duration. This causes additional trouble to the patients. Keeping this in view, there is a need for simple, safe and effective treatment. Hence this study has been initiated to evaluate the clinical efficacy of Amruta guggulu (internal) and Madhuyashtyadi taila (external) in the management of Vatarakta w.s.r to Gouty Arthritis.

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

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

Development of Benziodarone Analogues with Enhanced Potency for Selective Binding to Transthyretin in Human Plasma.

Transthyretin amyloidosis is a fatal disorder caused by transthyretin amyloid aggregation. Stabilizing the native structure of transthyretin is an effective approach to inhibit amyloid aggregation. To develop kinetic stabilizers of transthyretin, it is crucial to explore compounds that selectively bind to transthyretin in plasma. Our recent findings demonstrated that the uricosuric agent benziodarone selectively binds to transthyretin in plasma. Here, we report the development of benziodarone analogues with enhanced potency for selective binding to transthyretin in plasma compared to benziodarone. These analogues featured substituents of chlorine, bromine, iodine, a methyl group, or a trifluoromethyl group, at the 4-position of the benzofuran ring. X-ray crystal structure analysis revealed that CH···O hydrogen bonds and a halogen bond are important for the binding of the compounds to the thyroxine-binding sites. The bioavailability of benziodarone analogues with 4-Br, 4-Cl, or 4-CH3 was comparable to that of tafamidis, a current therapeutic agent for transthyretin amyloidosis.

Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability.

Gout and hyperuricemia are metabolic diseases characterized with high serum uric acid (SUA) levels that significantly impact human health. Lesinurad, a uricosuric agent, is limited to concurrent use with xanthine oxidase inhibitors (XOIs) in clinical practice due to its restricted efficacy and potential nephrotoxicity. Herein, extensive structural modifications of lesinurad were conducted through scaffold hopping and substituent modification strategies, affording 54 novel derivatives containing pyrimidine-fused cyclic structures. Notably, the thienopyrimidine compound 29 demonstrated a remarkable 2-fold increase in SUA-lowering in vivo activity compared to lesinurad, while exhibiting potent inhibitory activity against the urate transporter 1 (URAT1, IC50 = 2.01 μM) and glucose transporter 9 (GLUT9, IC50 = 18.21 μM). Furthermore, it possessed a lower effective dosage of 0.5 mg/kg, favorable safety profile without any apparent acute toxicity at doses of 1000 mg/kg, and improved pharmacokinetic properties. Overall, we have discovered an efficacious URAT1/GLUT9 dual inhibitor for inhibiting urate reabsorption with favorable pharmacokinetic profiles.

Assessment of the Therapeutic Potential of Nimbadi Churna and Kokilakshadi Kwath in Managing Vatarakta (Gout): A Randomized Comparative Clinical Study

The rise in hyperuricemia, often linked to changing dietary habits, has increased the global prevalence of gout, affecting 2.1 million people with a prevalence of 0.2-0.6%. Gout is indicative of underlying comorbidities such as obesity, diabetes, hypertension, and renal diseases. In contemporary medicine, Vatarakta is likened to gout due to shared causes and symptoms, involving the vitiation of Vata and Rakta by distinct etiological factors, and the restricted movement of vitiated Vata by vitiated Rakta leads to Vatarakta. While asymptomatic hyperuricemia may not necessitate intervention, clinically manifest gout requires long-term treatment to lower uric acid levels and acute pain relief. Current medications like allopurinol, uricosuric agents, NSAIDs, colchicine, and glucocorticosteroids carry mild to severe side effects. Recognising the need for an effective, affordable, and well-accepted treatment. The study assessed the efficacy of Nimbadi Churna and Kokilakshadi Kashay in managing Vatarakta through an open, randomized clinical trial with 60 patients. Both treatments were administered for 28 days. Dosages were 3gm B.I.D for Nimbadi Churna and 40ml B.I.D for Kokilakshadi Kashay. Four follow-ups were performed every 7th day, assessing subjective parameters via grade scores and serum uric acid levels. Results indicated both treatments were significantly effective (p<0.001), with no statistical difference between them (p>0.05). Nimbadi Churna and Kokilakshadi Kashay demonstrated notable efficacy in Vatarakta management, presenting promising alternatives with minimal complications. While further research is necessary for validation, these findings highlight the promise of Ayurvedic approaches in the comprehensive management of gout.

A nephrological perspective of herbal remedies on the progression of chronic kidney disease: A systematic review

Medicinal herbs are currently making a comeback as they appear to offer advantages over pharmaceuticals in combating chronic kidney disease progression. Conclusive evidence of their safety and efficacy is lacking. Therefore, this unfunded review was conducted to provide a more detailed picture of this issue, serving as a fruitful addition to the literature pool concerned with phytochemicals safety and efficacy in this disease. A systematic approach using specific search terms was used to find 49 articles meeting the study’s inclusion criteria after the study authors scrutinized the articles from different perspectives independently. Many plants were able to delay disease progression by lowering blood pressure via suppression of the renin-angiotensin system, antioxidant and anti-inflammatory effects, and increasing nitric oxide levels; lowering blood glucose levels; improving lipid profile via lipid resistance and oxidation induction; lowering proteinuria; and lowering serum uric acid levels as uricostatic or uricosuric agents, or both. In contrast, some herbal preparations increased blood pressure, induced insulin resistance, and promoted uric acid production through their adrenergic components or mineralocorticoid-like effects. In conclusion, based on the validity of the results obtained, recommendations were made for the proper use of herbal medicines in patients with vulnerable kidneys and for future research directions.

MODERN VIEW ON ANTI-INFLAMMATORY AND URAT-LOWERING THERAPY FOR GOUT

This article provides a thorough analysis of new and promising pharmaceuticals for the treatment of gout, encompassing anti-inflammatory and urate-lowering therapies. It covers drugs that have already received regulatory approval and are in active clinical use, as well as those in various stages of implementation and clinical research, showcasing their notable efficacy and safety. Additionally, the article discusses contemporary gout treatment approaches in alignment with international and domestic clinical guidelines. Emphasis is placed on the safety and efficacy of colchicine in gouty arthritis and its cardioprotective properties for patients with gout and comorbid cardiovascular disease. The article provides the information on the effectiveness of canakinumab, a new anti-inflammatory agent for the symptomatic therapy of gout. The effectiveness and safety of anakinra makes it possible to consider it as a promising alternative to the traditional approach to the anti-inflammatory therapy of gout. Rylonacept allows physicians to develop more effective treatment algorithms for those patients with gout who unsatisfactory respond to conventional therapy. The article provides a historical perspective on the use of adrenocorticotropic hormone as an anti-inflammatory agent for gout. It also highlights existing, new, and potential anti-inflammatory drugs, with a primary focus on the safety and effectiveness of febuxostat, supported by recent large randomized clinical trial results. Additionally, the article describes other medications aimed at reducing uric acid levels in the bloodstream, including uricosuric agents (such as probenecid, benzbromarone, sulfinpyrazone, lesinurad, verinurad, dotinurad, and archalofenate), xanthine oxidase inhibitors (allopurinol and topiroxostat), and pegylated uricase drugs, which may hold promise for future use in combination with primary urate-lowering therapies.

Hyperuricemia and Gout: The Role of Losartan.

Losartan is the only angiotensin II receptor blocker that has shown to significantly lower uric acid levels. The addition of or switch to losartan as an antihypertensive agent for patients with gout is recommended by clinical guidelines because of its benefit as a uricosuric agent.

Potentiation of the Uricosuric Effect of Dotinurad by Trans-Inhibition of the Uric Acid Reabsorptive Transporter URAT1.

URAT1 is a transporter responsible for uric acid (UA) reabsorption by renal proximal tubules and a pharmacological target of uricosuric agents. Probenecid and benzbromarone have been used as uricosuric agents, while dotinurad was recently approved in Japan. Notably, the in vitro inhibition potential (IC 50) of dotinurad on URAT1 is not strong enough to explain its in vivo uricosuric effect estimated based on clinical unbound plasma concentrations, suggesting the presence of mechanisms other than competition with UA uptake at the extracellular domain of URAT1 (cis-inhibition). In this study, trans-inhibition was hypothesized as the mechanism underlying URAT1 inhibition by dotinurad, wherein intracellularly accumulated dotinurad inactivates URAT1. In URAT1-expressing MDCK-II cells and Xenopus oocytes, pre-incubation with dotinurad potentiated the inhibitory effect more than co-incubation alone, but this effect was not observed with benzbromarone or probenecid. Under co-incubation, dotinurad inhibited UA uptake in a competitive manner (cis-inhibition). When we pre-injected dotinurad directly into oocytes and immediately measured [14C]UA uptake without co-incubation (only trans-inhibition), dotinurad noncompetitively inhibited UA uptake. URAT1 is an exchange transporter for UA and monocarboxylates such as nicotinic acid (NA). Pre-injected dotinurad and extracellular UA attenuated and facilitated efflux of [3H]NA, respectively, whereas pre-injection of benzbromarone or probenecid did not affect it, suggesting that dotinurad exhibits trans-inhibition by attenuating URAT1-mediated efflux of monocarboxylates, which is a driving force for UA uptake by URAT1. Accordingly, dotinurad ameliorates URAT1-mediated UA reabsorption by both cis- and trans-inhibition, explaining its clinically stronger uricosuric effect than that estimated by the in vitro IC 50 value. Significance Statement The uricosuric agent dotinurad inhibits uric acid reabsorptive transporter URAT1 with a clinical potency stronger than that estimated from IC 50 obtained by in vitro URAT1 inhibition. This in vivo-in vitro discrepancy was explained by the trans-inhibition effect of dotinurad on URAT1. Trans-inhibition was due to the attenuation of monocarboxylates efflux via URAT1, which is a driving force for URAT1-mediated exchange transport of uric acid. Overall, this is the first study to experimentally demonstrate trans-inhibition mechanism of URAT1.

Phytochemical Screening And Test For Reducing Uric Acid Levels In Male Rats After Administration Of Ethanol Extract Of The Herb Binara (Artemisia vulgaris L.)

Hyperuricemia is a metabolic disease generally characterized by high uric acid levels in the blood. The general treatment strategy for hyperuricemia is to decrease uric acid production using xanthine oxidation reductase inhibitors such as allopurinol and uricosuric agents. However, the drugs showed side effects, including skin rashes, diarrhoea and liver damage. To overcome the side effects of synthetic drugs, alternatives are used, namely by researching to find plants that have activity in reducing uric acid levels. The activity of reducing uric acid levels in plants is likely due to the presence of flavonoid compounds as antioxidants. Flavonoids active in reducing uric acid levels are kaempferol through xanthine oxidase inhibitors. Quercetin also has the potential to reduce uric acid levels through inhibition of the xanthine oxidase enzyme. Binara plant (Artemisia vulgaris L.) has flavonoids, tannins, alkaloids, glycosides and saponins which have potential as antioxidants and analgesics, anti-inflammatory, immunomodulating, and hepatoprotective, through secondary metabolites of flavonoids, terpenes, and phenolic acids. The Karo people have traditionally used Binara leaves to treat wounds, diarrhoea and heartburn by chewing some of the leaves and then placing them on the wounds outside the body, such as cuts and for diarrhoea and stomach ulcers and placing them around the sick stomach. This study was conducted to know the anti-hyperuricemia effect of the Ethanol Extract of Herba Binara (Artemisia vulgaris L.) on gout rats; phytochemical screening was carried out first to determine the content of Herba Binara (Artemisia vulgaris L.) compounds. The results showed that Herb Binara fulfilled the simplicia characterization requirements and contained secondary metabolites such as alkaloids, flavonoids, tannins, glycosides, saponins and steroids. Herb Binara Ethanol Extract has been shown to reduce uric acid levels in hyperuricemia rats, with the best concentrations being 400 and 800 mg/kg body weight. This was based on significantly different results p>0.05 compared to the positive control group.

Benziodarone and 6-hydroxybenziodarone are potent and selective inhibitors of transthyretin amyloidogenesis

Transthyretin amyloidosis is a progressive systemic disorder that is caused by the amyloid deposition of transthyretin in various organs. Stabilization of the native transthyretin is an effective strategy for the treatment of transthyretin amyloidosis. In this study we demonstrate that the clinically used uricosuric agent benziodarone is highly effective to stabilize the tetrameric structure of transthyretin. An acid-induced aggregation assay showed that benziodarone had strong inhibitory activity similar to that of tafamidis, which is currently used as a therapeutic agent for transthyretin amyloidosis. Moreover, a possible metabolite, 6-hydroxybenziodarone, retained the strong amyloid inhibitory activity of benziodarone. An ex vivo competitive binding assay using a fluorogenic probe showed that benziodarone and 6-hydroxybenziodarone were highly potent for selective binding to transthyretin in human plasma. An X-ray crystal structure analysis revealed that the halogenated hydroxyphenyl ring was located at the entrance of the thyroxine binding channel of transthyretin and that the benzofuran ring was located in the inner channel. These studies suggest that benziodarone and 6-hydroxybenziodarone would potentially be effective against transthyretin amyloidosis.

Probenecid, an Old Drug with Potential New Uses for Central Nervous System Disorders and Neuroinflammation.

Probenecid is an old uricosuric agent used in clinics to treat gout and reduce the renal excretion of antibiotics. In recent years, probenecid has gained attention due to its ability to interact with membrane proteins such as TRPV2 channels, organic anion transporters, and pannexin 1 hemichannels, which suggests new potential therapeutic utilities in medicine. Some current functions of probenecid include their use as an adjuvant to increase the bioavailability of several drugs in the Central Nervous System (CNS). Numerous studies also suggest that this drug has important neuroprotective, antiepileptic, and anti-inflammatory properties, as evidenced by their effect against neurological and neurodegenerative diseases. In these studies, the use of probenecid as a Panx1 hemichannel blocker to reduce neuroinflammation is highlighted since neuroinflammation is a major trigger for diverse CNS alterations. Although the clinical use of probenecid has declined over the years, advances in its use in preclinical research indicate that it may be useful to improve conventional therapies in the psychiatric field where the drugs used have a low bioavailability, either because of a deficient passage through the blood-brain barrier or a high efflux from the CNS or also a high urinary clearance. This review summarizes the history, pharmacological properties, and recent research uses of probenecid and discusses its future projections as a potential pharmacological strategy to intervene in neurodegeneration as an outcome of neuroinflammation.

Probenecid slows disease progression in a murine model of autosomal dominant polycystic kidney disease.

Development of autosomal dominant polycystic kidney disease (ADPKD) involves renal epithelial cell abnormalities. Cystic fluid contains a high level of ATP that, among other effects, leads to a reduced reabsorption of electrolytes in cyst-lining cells, and thus results in cystic fluid accumulation. Earlier, we demonstrated that Pkd1RC/RC mice, a hypomorphic model of ADPKD, exhibit increased expression of pannexin-1, a membrane channel capable of ATP release. In the current study, we found that human ADPKD cystic epithelia have higher pannexin-1 abundance than normal collecting ducts. We hypothesized that inhibition of pannexin-1 function with probenecid can be used to attenuate ADPKD development. Renal function in male and female Pkd1RC/RC and control mice was monitored between 9 and 20 months of age. To test the therapeutic effects of probenecid (a uricosuric agent and a pannexin-1 blocker), osmotic minipumps were implanted in male and female Pkd1RC/RC mice, and probenecid or vehicle was administered for 42 days until 1 year of age. Probenecid treatment improved glomerular filtration rates and slowed renal cyst formation in male mice (as shown in histopathology). The mechanistic effects of probenecid on sodium reabsorption and fluid transport were tested on polarized mpkCCDcl4 cells subjected to short-circuit current measurements, and in 3D cysts grown in Matrigel. In the mpkCCDcl4 epithelial cell line, probenecid elicited higher ENaC currents and attenuated in vitro cyst formation, indicating lower sodium and less fluid retention in the cysts. Our studies open new avenues of research into targeting pannexin-1 in ADPKD pathology.

Urate Transporter 1 Can Be a Therapeutic Target Molecule for Chronic Kidney Disease and Diabetic Kidney Disease: A Retrospective Longitudinal Study.

Chronic kidney disease (CKD) is a major global health problem for which there are no curative drug treatments. Hyperuricemia is one of risk factors for CKD. The evidence on effects of uric acid (UA)-lowering treatments on the progression of CKD was very limited and previous meta-analyses used only trials which primarily used xanthin oxidase (XO) inhibitors because the reports on fulminant hepatitis due to benzbromarone kept us from using uricosuric agents for hyperuricemia patients. Dotinurad, a novel selective urate reabsorption inhibitor for the treatment of hyperuricemia, reduces serum UA levels by selectively inhibiting urate transporter 1 (URAT1). We retrospectively picked up patients who had taken dotinurad from June 2018 to August 2021 and compared metabolic parameters at baseline with the data at 3 and 6 months after the start of dotinurad. We found 84 patients, and approximately 74% of patients were complicated with CKD. After the start of dotinurad, improvements in serum lipids, systolic blood pressure, body weight, and albuminuria, in addition to reduction in serum UA, were observed. Dotinurad increased urinary UA excretion, and was effective to reduce serum UA in patients with both UA underexcretion type and renal UA overload type. Furthermore, urinary UA excretion was significantly and negatively correlated with serum creatine levels at baseline and at 6 months after the start of dotinurad, and the change in urinary UA excretion after 3 months was significantly and negatively correlated with change in serum creatine levels. The property of dotinurad, which selectively inhibits URAT1, but not other UA transporters, such as ATP-binding cassette, subfamily G, and 2 (ABCG2), which ABCG2 is a UA and uremic toxin exporter, may be beneficially associated with pathology of CKD. URAT1 can be a therapeutic target molecule for CKD and DKD.

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

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

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

The uricosuric drug benzbromarone, widely used for treatment of gout, hyperpolarizes the membrane potential of airway smooth muscle cells, but how it works remains unknown. Here we show a novel role of benzbromarone in activation of large conductance calcium-activated K+ channels. Benzbromarone results in dose-dependent activation of macroscopic big potassium (BK) currents about 1.7- to 14.5-fold with an EC50 of 111 μM and shifts the voltage-dependent channel activation to a more hyperpolarizing direction about 10 to 54 mV in whole-cell patch clamp recordings. In single-channel recordings, benzbromarone decreases single BKα channel closed dwell time and increases the channel open probability. Coexpressing β1 subunit also enhances BK activation by benzbromarone with an EC50 of 67 μM and a leftward shift of conductance-voltage (G-V) curve about 44 to 138 mV. Site-directed mutagenesis reveals that a motif of three amino acids 329RKK331 in the cytoplasmic linker between S6 and C-terminal regulator of potassium conductance (RCK) gating ring mediates the pharmacological activation of BK channels by benzbromarone. Further ex vivo assay shows that benzbromarone causes reduction of tracheal strip contraction. Taken together, our findings demonstrate that uricosuric benzbromarone activates BK channels through molecular mechanism of action involving the channel RKK motif of S6-RCK linker. Pharmacological activation of BK channel by benzbromarone causes reduction of tracheal strip contraction, holding a repurposing potential for asthma and pulmonary arterial hypertension or BK channelopathies. SIGNIFICANCE STATEMENT: We describe a novel role of uricosuric agent benzbromarone in big potassium (BK) channel activation and relaxation of airway smooth muscle contraction. In this study, we find that benzbromarone is an activator of the large-conductance Ca2+- and voltage-activated K+ channel (BK channel), which serves numerous cellular functions, including control of smooth muscle contraction. Pharmacological activation of BK channel by the FDA-approved drug benzbromarone may hold repurposing potential for treatment of asthma and pulmonary arterial hypertension or BK channelopathies.

PIDA-mediated N-N bond formation to access pyrazolidine-3,5-diones: a novel process for uricosuric agents G-25671 and sulfinpyrazone.

Traditionally, toxic and expensive hydrazine building blocks are required to construct pharmaceutically important pyrazolidine-3,5-diones. Herein, we have described a novel method for their synthesis based on metal-free oxidative dehydrogenative N-N bond formation by PIDA-mediated reaction of easily accessible dianilide precursors. The developed mild reaction protocol features a good functional group tolerance and scalability. The application of this method is demonstrated by offering a unique route for the synthesis of uricosuric agents G-25671 and sulfinpyrazone from inexpensive starting material aniline via smooth functionalization of the well-designed diversity-oriented cyclopropyl key intermediate.

What is the Place for Uricosuric Agents in Gout Management?

What is the Place for Uricosuric Agents in Gout Management?