Therapy Of Hyperuricemia Research Articles

Plantaginis Semen Ameliorates Hyperuricemia Induced by Potassium Oxonate.

Plantaginis semen is the dried ripe seed of Plantago asiatica L. or Plantago depressa Willd., which has a long history in alleviating hyperuricemia (HUA) and chronic kidney diseases. While the major chemical ingredients and mechanism remained to be illustrated. Therefore, this work aimed to elucidate the chemicals and working mechanisms of PS for HUA. UPLC-QE-Orbitrap-MS was applied to identify the main components of PS in vitro and in vivo. RNA sequencing (RNA-seq) was conducted to explore the gene expression profile, and the genes involved were further confirmed by real-time quantitative PCR (RT-qPCR). A total of 39 components were identified from PS, and 13 of them were detected in the rat serum after treating the rat with PS. The kidney tissue injury and serum uric acid (UA), xanthine oxidase (XOD), and cytokine levels were reversed by PS. Meanwhile, renal urate anion transporter 1 (Urat1) and glucose transporter 9 (Glut9) levels were reversed with PS treatment. RNA-seq analysis showed that the PPAR signaling pathway; glycine, serine, and threonine metabolism signaling pathway; and fatty acid metabolism signaling pathway were significantly modified by PS treatment. Further, the gene expression of Slc7a8, Pck1, Mgll, and Bhmt were significantly elevated, and Fkbp5 was downregulated, consistent with RNA-seq results. The PPAR signaling pathway involved Pparα, Pparγ, Lpl, Plin5, Atgl, and Hsl were elevated by PS treatment. URAT1 and PPARα proteins levels were confirmed by Western blotting. In conclusion, this study elucidates the chemical profile and working mechanisms of PS for prevention and therapy of HUA and provides a promising traditional Chinese medicine agency for HUA prophylaxis.

Atavistic strategy for the treatment of hyperuricemia via ionizable liposomal mRNA

Hyperuricemia is associated with an increased risk of gout, hypertension, diabetes, and cardiovascular diseases. Most mammals maintain normal serum uric acid (SUA) via urate oxidase (Uox), an enzyme that metabolizes poorly-soluble UA to highly-soluble allantoin. In contrast, Uox became a pseudogene in humans and apes over the long course of evolution. Here we demonstrate an atavistic strategy for treating hyperuricemia based on endogenous expression of Uox in hepatocytes mediated by mRNA (mUox) loaded with an ionizable lipid nanoparticle termed iLAND. mUox@iLAND allows effective transfection and protein expression in vitro. A single dose of mUox@iLAND lowers SUA levels for several weeks in two female murine models, including a novel long-lasting model, which is also confirmed by metabolomics analysis. Together with the excellent safety profiles observed in vivo, the proposed mRNA agent demonstrates substantial potential for hyperuricemia therapy and the prevention of associated conditions.

Targeting Liver Xor by GalNAc-siRNA Is an Effective Strategy for Hyperuricemia Therapy.

Hyperuricemia, i.e., increased plasma uric acid concentration, is a common problem in clinical practice, leading to gout or nephrolithiasis, and is associated with other disorders, such as metabolic syndrome, cardiovascular disease, and chronic renal disease. Xanthine oxidoreductase (XOR) is a critical rate-limiting enzyme involved in uric acid synthesis and a promising target for hyperuricemia therapy. However, XOR inhibitors currently face clinical problems such as a short half-life and side effects. Here, we found that specifically targeting liver Xor with GalNAc-siRNAs had a good therapeutic effect on hyperuricemia. First, siRNAs were designed to target various sites in the homologous region between Homo sapiens and Mus musculus Xor mRNA and were screened in primary mouse hepatocytes. Then, the siRNAs were modified to increase their stability in vivo and conjugated with GalNAc for liver-specific delivery. The effects of GalNAc-siRNAs were evaluated in three hyperuricemia mouse models, including potassium oxonate and hypoxanthine administration in WT and humanized XDH mice and Uox knockout mice. Febuxostat, a specific XOR inhibitor used for hyperuricemia treatment, was used as a positive control. Targeting liver Xor with GalNAc-siRNAs by subcutaneous administration reduced plasma uric acid levels, uric acid accumulation in the kidney, renal inflammation, and fibrosis, thereby alleviating kidney damage in hyperuricemia mouse models without hepatoxicity. The results demonstrated that targeting liver Xor with GalNAc-siRNAs was a promising strategy for hyperuricemia therapy.

Polyvinylpyrrolidone-Coated Cubic Hollow Nanocages of PdPt3 and PdIr3 as Highly Efficient Self-Cascade Uricase/Peroxidase Mimics.

Uricase-catalyzed uric acid (UA) degradation has been applied for hyperuricemia therapy, but this medication is limited by H2O2 accumulation, which can cause oxidative stress of cells, resulting in many other health issues. Herein, we report a robust cubic hollow nanocage (HNC) system based on polyvinylpyrrolidone-coated PdPt3 and PdIr3 to serve as highly efficient self-cascade uricase/peroxidase mimics to achieve the desired dual catalysis for both UA degradation and H2O2 elimination. These HNCs have hollow cubic shape with average wall thickness of 1.5 nm, providing desired synergy to enhance catalyst's activity and stability. Density functional theory calculations suggest the PdIr3 HNC surface tend to promote OH*/O* desorption for better peroxidase-like catalysis, while the PdPt3 HNC surface accelerates the UA oxidation by facilitating O2-to-H2O2 conversion. The dual catalysis power demonstrated by these HNCs in cell studies suggests their great potential as a new type of nanozyme for treating hyperuricemia.

Diet for gout and hyperuricaemia: some important questions

Diet has traditionally been viewed as playing a leading role in both the pathogenesis and treatment of gout. And although this thesis is controversial today, adherence to certain dietary rules for patients with gout and hyperuricemia (HU) is an integral part of therapy. The review examines the modern theoretical basis of dietary therapy for gout and HU, in particular the mechanisms of increasing serum uric acid levels and the risk of developing arthritis when certain foods are consumed and, conversely, reducing uric acid levels and the risk of gout when a diet containing a range of vitamins and foods in the supplements is followed.

Hesperitin-Copper(II) Complex Regulates the NLRP3 Pathway and Attenuates Hyperuricemia and Renal Inflammation.

Hyperuricaemia (HUA) is a disorder of purine metabolism in the body. We previously synthesized a hesperitin (Hsp)-Cu(II) complex and found that the complex possessed strong uric acid (UA)-reducing activity in vitro. In this study we further explored the complex's UA-lowering and nephroprotective effects in vivo. A mouse with HUA was used to investigate the complex's hypouricemic and nephroprotective effects via biochemical analysis, RT-PCR, and Western blot. Hsp-Cu(II) complex markedly decreased the serum UA level and restored kidney tissue damage to normal in HUA mice. Meanwhile, the complex inhibited liver adenosine deaminase (ADA) and xanthine oxidase (XO) activities to reduce UA synthesis and modulated the protein expression of urate transporters to promote UA excretion. Hsp-Cu(II) treatment significantly suppressed oxidative stress and inflammatory in the kidney, reduced the contents of cytokines and inhibited the activation of the nucleotide-binding oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3) inflammatory pathway. Hsp-Cu(II) complex reduced serum UA and protected kidneys from renal inflammatory damage and oxidative stress by modulating the NLRP3 pathway. Hsp-Cu(II) complex may be a promising dietary supplement or nutraceutical for the therapy of hyperuricemia.

Bacteroides xylanisolvens possesses a potent anti-hyperuricemia effect in goslings fed on a high-protein diet.

Hyperuricemia is widespread in humans and birds which is a necessary physiological factor leading to gout. Studies have shown an inextricable relationship between gut microbiota and hyperuricemia. This study explored the association between intestinal flora and hyperuricemia in Goslings. The hyperuricemia model was established in gosling by a high protein diet (HPD). 16S rDNA sequencing showed that the cecal microbiota differed significantly between the HPD and control groups (fed with the normal protein). The abundance of Firmicutes was higher in the HPD group, while the Bacteroidetes were lower than in controls. To investigate the role of intestinal flora in hyperuricemia, the cecum microbiotas from the HPD group and the control group were transplanted to the newly born goslings by gavage. The serum uric acid levels of the goslings that transplanted the cecal microbiota of the HPD group were significantly higher than the goslings that transplanted the cecal microbiota of the controls. Furthermore, the transplantation of cecal microbiota also affects the production and excretion of uric acid in goslings. Then we identify the gut bacterium Bacteroides xylanisolvens as an effective anti-hyperuricemia in the Goslings. B. xylanisolvens reduces serum uric acid concentrations in hyperuricemia in the Goslings' model, and it can up-regulation ABCG2 mRNA expression in the kidney and down-regulation XDH mRNA expression in the liver. The intestinal flora acts as a novel target for the therapeutic approach to hyperuricemia and gout, suggest Bacteroides xylanisolvens is a possible route to therapy for hyperuricemia and gout in goslings.

PS-P10-8: RELATIONSHIP BETWEEN BLOOD PRESSURE AND PRESENCE OF TREATMENT FOR HYPERURICEMIA

Background: Uric acid is strongly associated with hypertension. However, it is unclear whether drug treatment for hyperuricemia decreases blood pressure or not. Methods: This study is a cross-sectional study using the data from 13,087 participants (4,698 female) who had annual health check-up at the Health Management Center and Diagnostic Imaging Center, Toranomon Hospital, Tokyo in 2017. We compared systolic and diastolic blood pressure between participants with and without drug therapy for hyperuricemia. Moreover, we compared systolic and diastolic blood pressure between more than 7 mg/dL and 7 mg/dL and less of serum uric acid levels in participants with drug therapy for hyperuricemia. The presence or absence of drug therapy for hyperuricemia was confirmed by questionnaire methods. Results: The number of hyperuricemic participants was 18 in female and 642 in male. The number of hyperuricemic female was very small, and therefore, this study analyzed only hyperuricemic male. Of the 642 male, 153 participants were hyperuricemia without drug therapy and 489 participants were hyperuricemia with drug therapy. Serum uric acid levels and systolic and diastolic blood pressure in hyperuricemic participants with drug therapy is lower than those without drug therapy (serum uric acid levels 6.23 ± 1.01 mg/dL versus 7.25 ± 1.15 mg/dL; systolic blood pressure 124.2 ± 12.4 mmHg versus 125.1 ± 13.7 mmHg; diastolic blood pressure 79.13 ± 8.83 mmHg versus 79.69 ± 8.83 mmHg), even though the drug therapy group was significantly older than absence of drug therapy group (59.7 ± 9.7 years old versus 56.8 ± 11.2 years old, p = 0.002). In the drug therapy group, those with more than 7 mg/dL of serum uric acid (N = 79) had higher systolic and diastolic blood pressure than those with 7 mg/dL and less of serum uric acid (N = 410) (systolic blood pressure 125.2 ± 11.2 mmHg versus 124.0 ± 12.7 mmHg; diastolic blood pressure 80.52 ± 8.78 mmHg versus 78.86 ± 8.48 mmHg), even though those with more than 7 mg/dL of serum uric acid were significantly younger than those with 7 mg/dL and less of serum uric acid (57.3 ± 9.8 years old versus 60.2 ± 9.6 years old, p = 0.015). Conclusion: Drug therapy for hyperuricemia is associated with lower systolic and diastolic blood pressure compared with absence of drug therapy for hyperuricemia. Adequate hyperuricemia control could lead to good blood pressure control. Further randomized controlled trials are desired to reveal the relationship between blood pressure and presence of treatment for hyperuricemia.

ГИПЕРУРИКЕМИЯ: КЛИНИЧЕСКИЕ ПОСЛЕДСТВИЯ, СЕРДЕЧНО-СОСУДИСТЫЙ РИСК, СОВРЕМЕННЫЙ ПОДХОД К ТЕРАПИИ

Introduction. In recent decades, increased attention has been paid to hyperuricemia due to the widespread prevalence of this pathology in the population (16.8%), the presence of a connection with the risk of developing cardiovascular diseases, as well as the variety of its clinical consequences. Aim. A review of current data on the causes of hyperuricemia, clinical aspects, the effect of hyperuricemia on cardiovascular risk, and the current view of therapy, including asymptomatic hyperuricemia. Material and methods. The review carried out topical medical publications in foreign and domestic literature on this issue, accumulated at the present time. Results and discussion. An increase in uric acid level can occur as a result of inaccuracies in the diet, taking certain medications, impaired excretion of uric acid due to impaired renal function and other reasons. Hyperuricemia is the main cause of gout, which can manifest itself as acute gouty arthritis, chronic topical arthritis, urate nephropathy, and other diseases. Modern research shows that an increase in serum uric acid concentration is associated with an increased cardiovascular risk. Acting as an independent predictor of arterial hypertension, coronary heart disease, chronic heart failure, chronic kidney disease. Treatment with xanthine oxidase inhibitors (allopurinol, febuxostat) can affect hyperuricemia, gout, and various forms of ischemic and vascular damage. As evidence of the efficacy of urate-lowering therapy remains controversial, these drugs are not currently indicated for routine prophylactic treatment in patients without gout symptoms. In 2018, specialists in the field of hyperuricemia proposed an algorithm for the management of patients with asymptomatic hyperuricemia. However, the algorithm is not recommended for everyday practice due to further research's need to verify it. Conclusion. Classic manifestations of hyperuricemia such as gout and kidney damage remain the main indications for urate-lowering therapy. At the same time, the increased cardiovascular risk in hyperuricemia, proven by numerous studies, requires special attention in treating patients with comorbid pathology. Diet and lifestyle changes remain an integral part of therapy. The final decision on the need for pharmacological treatment of patients with asymptomatic hyperuricemia with xanthine oxidase inhibitors is made individually. The development of algorithms and indications for the appointment of urate-lowering therapy continues. Recommendations for drug therapy for hyperuricemia are only possible after large, double-blind, placebo-controlled, randomized trials.

Enzyme Mimics for Engineered Biomimetic Cascade Nanoreactors: Mechanism, Applications, and Prospects

AbstractMultiple enzyme‐driven biological catalytic cascades occur in living organisms, guiding highly efficient and selective transformations of substrates. Inspired by the merits of these biological catalytic cascade systems, enormous efforts have been devoted to developing novel cascade catalytic systems to mimic biological cascade catalytic reactions over the past few years. Nanozymes, a class of enzyme mimics, are nanomaterials with enzyme‐like catalytic activity. The emergence and development of nanozymes has significantly advanced the development of biomimetic cascade nanoreactors. Currently, biomimetic cascade nanoreactors driven by advanced nanozymes have been widely used and exhibit many advantages such as superior cascade catalytic efficiency and high stability, resulting in significant advancements in biosensing and biomedical applications. The latest advances in understanding the cascade catalytic mechanism of nanozyme‐engineered biomimetic cascade catalytic nanoreactors and their progressive applications for biosensing and biomedical applications are comprehensively covered here. First, nanozyme and enzyme/nanozyme‐engineered biomimetic cascade catalytic nanoreactors are categorized according to their catalytic mechanism and properties. Then, the biosensing and biomedical applications, including cancer therapy, antibacterial activity, antioxidation, and hyperuricemia therapy of the cascade catalytic systems are covered. The conclusion describes the most important challenges and opportunities remaining in this exciting area of research.

The use of hyperuricemia herbs at “Hortus Medicus” herbal medicine clinic Tawangmangu

Background: Hyperuricemia has become a health problems in Indonesia lately. The use of traditional medicine, especially herbs, has been used in the treatment of hyperuricemia. Hortus Medicus Herbal Medicine Clinic Tawangmangu has several herbal formulas that are applied in the care of hyperuricemia patients.Objective: This study aims to determine the description of the mostly used medicinal plants for hyperuricemia and the percentage of efficacy of hyperuricemia therapy using medicinal plant. Methods: This study was a retrospective cross-sectional study using purposive sampling. The total sample was 120 medical records and prescriptions for hyperuricemia patients at Hortus Medicus clinic for the period July-December 2020. Results: There were 3 hyperuricemia herbs formulas used in Hortus Medicus. Based on the calculation of the doctor's prescription for hyperuricemia, the first herbal formula consisting of secang (Caesalpinia sappan) bark, tempuyung (Sonchus arvensis) herb, kepel (Stelechocarpus burahol) leaf was prescribed as many as 72 prescriptions (60%). The second herbal formula consisting of cabe jawa (Piper retrofactum), daun sendok (Plantago mayor) leaves, celery (Apium graveolens) herbs with 36 prescriptions (30%), and the third herbal formula consisting of rumput bolong (Equisetum debille) herb, temulawak (Curcuma xanthorizza), turmeric (Curcuma domestica) with 12 prescriptions (10%). The therapeutic efficacy of herbal formula 1st, 2nd and 3rd were 80%; 60%; 50%. There was no significant relationship between sex and the outcome of hyperuricemia therapy (p= 0.804).Conclusion: Among three hyperuricemia herbal formulas used in Hortus Medicus, the 1st formula was mostly used. The percentage of therapeutic efficacy was also higher compared to the other two formulas.

Rice peptide and collagen peptide prevented potassium oxonate-induced hyperuricemia and renal damage

The study aimed to investigate the effects and mechanism of rice peptide (RP) and collagen peptide (CP) in reducing uric acid (UA) in hyperuricemia mice. RP and CP were prepared by enzymatic hydrolysis method. The two peptides determined by gel chromatography mothed were mainly distributed between 150 and 1000 Da indicating the small peptides composed of 2–7 amino acids were the main components. The functional evaluation was carried out by establishing hyperuricemia mouse model. The results showed that they suppressed the activities of xanthine oxidase (XOD) and adenosine deaminase (ADA), and showed significantly difference in reducing the activity of ADA. RP, CP and RCP could reduce the reabsorption of UA in renal though inhibit the expression of URAT1 and GLUT9 level and promote the expression of OAT1 level both in gene and protein level. Moreover, the three peptides play an important role in inhibiting renal function injury by reduce the content of BUN and CRE in serum. And, the combination of RP and CP has a better effect than the two peptides alone on preventing the occurrence of hyperuricemia and protecting kidney. These findings suggest that RP and CP have potential application prospects in prevention and therapy of hyperuricemia.

Arginine-rich peptide/platinum hybrid colloid nanoparticle cluster: A single nanozyme mimicking multi-enzymatic cascade systems in peroxisome

Recently, nanozymes have attracted sustained attention for facilitating next generation of artificial enzymatic cascade systems (ECSs). However, the fabrication of integrated multi-ECSs based on a single nanozyme remains a great challenge. Here, inspired by the biological function and self-assembling ability of arginine (R), we synthesized arginine-rich peptide-Pt nanoparticle cluster (ARP-PtNC) nanozymes that mimic two typical enzymatic cascade systems of uricase/catalase and superoxide dismutase/catalase in natural peroxisome. ARPs containing at least 10 arginine residues contribute to the cluster formation based on hydrogen bonding and coordination. The well-designed peptide-Pt hybrid nanozyme not only possesses excellent uricase-mimicking activity to degrade uric acid effectively, but also serves as a desired scavenger for reactive oxygen species (ROS) harnessing two efficient enzyme cascade catalysis of uricase/catalase and superoxide dismutase/catalase. The surface microenvironment of the hybrid nanozymes provided by arginine-rich peptides and the cluster structure contribute to the efficient multiply enzyme-like activities. Fascinatingly, the hybrid nanozyme can inhibit the formation of monosodium urate monohydrate effectively based on the architecture of ARP-PtNCs. Thus, ARP-PtNC nanozyme has the potential in gout and hyperuricemia therapy. Rational design of ingenious peptide-metal hybrid nanozyme with unique physicochemical surface properties provides a versatile and designed strategy to fabricate multi-enzymatic cascade systems, which opens new avenues to broaden the application of nanozymes in practice.

Clinical classification of hyperuricemia in patients with chronic kidney disease.

Clinical classification of hyperuricemia (HUA) could help to guide therapy of HUA. Studies on the classification of HUA with chronic kidney disease (CKD) are rare. Therefore, we aimed to investigate the classification of HUA with CKD. A cross-sectional study of 428 CKD patients was conducted, including 218 HUA patients. By correlation analysis, the association of 24-h urinary uric acid (24-h Uur), uric acid clearance rate (Cur), the urinary uric acid excretion per kilogram of weight per hour (Eur) and fractional excretion of uric acid (FEur) with estimated glomerular filtration rate (eGFR) was analyzed in the HUA and non-HUA groups. According to Eur combined with Cur and the 24-h Uur combined with FEur, HUA with CKD was classified into underexcretion, renal overload, combined and 'normal' types, which were also stratified by CKD stages. According to the Eur and Cur, in early CKD (eGFR ≥ 60mL/min/1.73m2), the underexcretion type accounted for 83.75%, and the renal overload type accounted for 2.5%. As the CKD stage increased, the proportion of the underexcretion type increased. According to the 24-h Uur and FEur, in early CKD, the underexcretion type accounted for 53.75%, and the renal overload type accounted for 15%. With increasing CKD stages, the proportion of the 'normal' type increased significantly. Different uses of Eur with Cur or 24-h Uur with FEur varied significantly in classifying HUA patients with CKD. Eur + Cur may be more applicable to the classification of HUA patients with CKD, and further research is needed.

Antihyperuricemic efficacy of Scopoletin-loaded Soluplus micelles in yeast extract/potassium oxonate-induced hyperuricemic mice

Scopoletin (Sco) has great potential for hyperuricemia therapy. However, the relatively low oral bioavailability of Sco limits its further applications. Soluplus-based Sco micelles (Sco-Ms) were successfully prepared in our previous work. The oral bioavailability of Sco-Ms was increased by 438% compared with free Sco. In this study, we aimed to compare the biodistribution and antihyperuricemic efficacy of Sco and Sco-Ms, and explore their therapeutic mechanisms as well. We studied the tissue biodistribution of Sco and Sco-Ms after they were orally administered to mice. The antihyperuricemic effect and the therapeutic mechanisms of Sco and Sco-Ms were evaluated using yeast extract/potassium oxonate-induced hyperuricemia model in mice. The Sco concentration in each tissue was significantly higher than that of Sco suspension after orally administrating Sco-Ms to mice. Oral delivery of Sco-Ms exhibited significantly stronger hypouricemic efficacy in hyperuricemic mice than Sco. Meanwhile, Sco-Ms showed a better protective effect on mice kidney injury. The hypouricemic efficacy of Sco was due to promoting the excretion of uric acid via modulating the alteration of gene expression levels of renal uric acid transporter (URAT1), glucose transporter (GLUT9), and organic anion transporter 1 (OAT1). Sco-Ms could not only restore the dysregulation of URAT1, GLUT9, and OAT1 more effectively, but also down-regulate the activity of hepatic xanthine oxidase (XOD) to inhibit the production of uric acid. In conclusion, taken together, Sco-Ms represents a potential oral strategy for the treatment of hyperuricemia.

Anti-hyperuricemic effects of three theaflavins isolated from black tea in hyperuricemic mice

• TF, TFDG and TF-3-G down-regulated the genes and proteins expression of GLUT9 and URAT1. • TF, TFDG and TF-3-G up-regulated the gene and protein expression of OAT1 and the genes expression of ABCG2, OCTN1, OCT1/2, and OAT2. • TF, TFDG and TF-3-G ameliorate the kidney damages of hyperuricemic mice. Theaflavins are characteristic ingredients of black tea which are correlated with their qualities and functions. The study aimed to evaluate the effects and mechanism of major theaflavin monomers reducing serum uric acid (SUA) in hyperuricemic mice. Three theaflavin monomers of TF, TFDG and TF-3-G were isolated and purified from black tea. The results showed that they have obvious SUA-lowering effect on hyperuricemic mice. They suppressed the activities of ADA and XOD, down-regulated the genes and proteins expression of GLUT9 and URAT1, up-regulated the gene and protein expression of OAT1 and the genes expression of ABCG2, OCTN1, OCT1/2, and OAT2. They could also decrease serum BUN and Cr values and improve renal damages of hyperuricemic mice. The mechanism might be correlation with reducing the amount of inflammatory cells and activating Nrf2/HO-1 pathway. These findings indicated that TF, TFDG and TF-3-G could have potential application prospects in prevention and therapy of hyperuricemia.

Pharmacological properties and clinical efficacy of dotinurad (URECE® tablets), a novel hypouricemic agent

In Jan 2020, dotinurad (URECE® tablets) was approved for gout and hyperuricemia therapy in Japan. We developed a novel hypouricemic agent because benzbromarone, a commercially available uricosuric agent, has several problems, such as drug-induced liver injury or drug-drug interaction caused by CYP2C9 inhibition. In transporter-overexpressing cells, dotinurad potently inhibited URAT1 which is localized in the renal proximal tubules and functions as a urate reabsorption. On the contrary, dotinurad hardly inhibited urate secretion transporters, ABCG2 or OAT1/3. In Cebus monkeys, dotinurad dose-dependently decreased plasma urate levels at low doses compared with benzbromarone. Inhibitory effect of dotinurad on mitochondria was weaker than that of benzbromarone and there was no observation suggesting a risk of drug-induced liver injury taking into consideration the clinical dose or exposure. Dotinurad weakly inhibited CYPs and further analysis indicated there was no drug-drug interaction risk in the clinical dose. In clinical pharmacology studies, there was no difference among sex and age. Furthermore, dosage and administration are equal even in hepatic impairment patients (mild to severe) and renal impairment patients (mild to moderate). In confirmatory phase II and long-term studies, dotinurad decreased serum urate levels at low doses and almost patients using maintenance dose (2 or 4 mg) achieved a serum urate level ≤ 6.0 mg/dL. Moreover, there was no finding to raise safety concern including liver injury. In conclusion, dotinurad, a selective urate reabsorption inhibitor (SURI) could be a therapeutic option because of its more effective hypouricemic action at low doses than those of commercially available uricosuric agents.

Effect of a Traditional Chinese Medicine Formula (CoTOL) on Serum Uric Acid and Intestinal Flora in Obese Hyperuricemic Mice Inoculated with Intestinal Bacteria.

CoTOL is a traditional Chinese medicine (TCM) formula in clinics for treating gout and hyperuricemia, especially in obese patients with recurrent attacks. However, fewer studies have investigated how CoTOL impacts the intestinal flora in reducing uric acid. In the present, we analyze the bacteria targeted by ingredients of CoTOL and evaluate the effects of CoTOL on uric acid and intestinal flora in a mice model of obese hyperuricemia inoculated with xanthine dehydrogenase- (XOD-) producing bacteria, Streptococcus faecalis. Firstly, ingredients of herbs in CoTOL and gene target by these ingredients were retrieved from TCMID 2.0, and these genes were screened by DAVID Bioinformatics Resources 6.8, deciphered to retrieve the bacteria. Then, 3-4-week-old male C57bl/6j mice were randomly divided into 6 groups and fed with high fat diet for 8 weeks up to obesity standard. The mice were inoculated intragastrically with 5 × 109 CFU Streptococcus faecalis 3 times at the 5th, 6th, and 7th week and intragastrically administrated with uricase inhibitor, potassium-oxonate (PO, 250 mg/kg), to induce hyperuricemia at the 8th week, once a day for 7 consecutive days, respectively (IB model). IB model plus CoTOL (0.4 ml/20g) and allopurinol (40 mg/kg) were administrated by gavage at the 5th week, once a day for 4 weeks. The feces and blood in each group were sampled at the 4th and 8th week. With no bacteria inoculation, CoTOL, allopurinol, and blank group were treated with CoTOL and allopurinol or water, respectively. 44 species of bacteria (i.e., Enterococcus faecalis, Streptococcus, etc.) genes were targeted by 6 ingredients of 6 herbs in CoTOL. Inoculation with Streptococcus faecalis significantly caused the elevation of uric acid and the change of intestinal flora structure, whereas treatment with CoTOL significantly increased the abundance of Akkermansia and those of Bacteroides and Alloprevotella decreased. Furthermore, CoTOL exhibited a unique effect on reducing weight unobserved in allopurinol intervention. The present study, for the first time, demonstrated that CoTOL has beneficial effects on hyperuricemia and overweight, which may be attributed to regulating material metabolism and improving the structure or function of intestinal flora. Thus, CoTOL may be a promising therapy for hyperuricemia and overweight in chronic gout management and can be integrated with conventional treatments.

Novel 3-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-1,2,4-oxadiazol-5(4H)-ones as promising xanthine oxidase inhibitors: Design, synthesis and biological evaluation.

Xanthine oxidase (XO) is a critical target for the therapy of hyperuricemia and gout. In this study, a number of 3-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-1,2,4-oxadiazol-5(4H)-ones (3a-3w) were newly designed by a bioisosteric replacement and hybrid strategy with the hope of obtaining novel and effective nonpurine XO inhibitors. Subsequently, these compounds were synthesized through a three-step procedure, with good yields. In addition, the in vitro bovine XO inhibitions were measured by spectrophotometric determination of uric acid formation at 295nm using allopurinol as a positive control. As a result, compound 3j was found to be the most potent XO inhibitor, with an IC50 value of 0.121µM, which was approximately 63-fold more potent than allopurinol, and the analysis of the structure-activity relationships indicated that the hydrophobic group at 4'-position was essential for inhibitory potency. Additionally, the molecular modeling results showed that the 1,2,4-oxadiazol-5(4H)-one moiety binds to XO active site via various hydrogen bonds with Arg880 and Thr1010. Moreover, the compound 3j was demonstrated to be a mixed-type nonpurine XO inhibitor. Furthermore, the hypouricemic studies on a rat model, induced by potassium oxonate, demonstrated that serum uric acid levels could be effectually reduced by compound 3j at an oral dose of 15mg/kg. Therefore, compound 3j could be a promising lead compound for the treatment of hyperuricemia and gout.

Simultaneous Monitoring of Febuxostat and Uric Acid in Human Serum Samples Using the Direct Square-Wave Voltammetric Method

Background: High uric acid serum level, hyperuricemia, is now associated with many diseases such as gout, chronic kidney disease, hypertension, coronary artery disease and diabetes. Febuxostat is a novel selective xanthine oxidase inhibitor approved for the treatment of hyperuricemia. Objective: The aim of this study was to develop a first analytical method for the simultaneous determination of febuxostat and uric acid. Methods: An unmodified boron-doped diamond electrode provided concurrent quantitation of drug at low levels and uric acid, which has clinical significance in the diagnosis and therapy of hyperuricemia, at relatively high concentrations. The direct square-wave voltammetric method was applied to the analysis of both analytes in human serum samples. Results: Under the optimized conditions, the linear response of peak current on febuxostat concentration was achieved in the range from 7.5 × 10-7 to 3 × 10-5 M, while uric acid showed two linear ranges of 5 × 10-6 - 5 × 10-5 M and 5 × 10-5 - 2 × 10-4 M. The method was successfully utilised for quantification of both analytes in human serum samples. Good recoveries were obtained without interference from common inorganic cations and anions as well as glucose, dopamine, ascorbic and folic acids at concentrations expected in physiological conditions. Conclusion: The great benefits of developed method are fast analysis (only 7.5 s for run), low cost and simplicity of performance.