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1.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(4): 579-587, 2021 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-33963719

RESUMO

OBJECTIVE: To explore the mechanism of Simiao pills for treatment of hyperuricemia based on network pharmacology and molecular docking. OBJECTIVE: The active ingredients of Simiao pills and their targets of action were predicted using TCMSP, SEA, Swiss and PharmMapper databases. GeneCards and TCD databases were searched for the disease targets related to hyperuricemia. Cytoscape 3.6.1 was used to construct a protein-protein interaction network. GO enrichment analysis and KEGG pathway analysis were carried out on the STRING platform. The binding between the main compounds and the key targets were predicted using the SwissDock platform for molecular docking. OBJECTIVE: We identified 28 active ingredients and 429 potential targets in Simiao pills, 494 disease targets related to hyperuricemia, and 118 common targets between Simiao pills and hyperuricemia. Several key targets including AKT1, IL- 6, JUN, TNF and CASP3 were screened for molecular docking, which had good binding activities with berberrubine, epiberberine, stigmasterol and sitosterol. AKT1, IL-6, JUN, TNF and CASP3 were predicted to be the key targets for Simiao pills for treating hyperuricemia. KEGG pathway enrichment analysis showed that Simiao pills produced therapeutic effects on hyperuricemia through multiple signaling pathways including the TNF signaling pathway, apoptosis signaling pathway and IL-17 signaling pathway. OBJECTIVE: Simiao pills produces therapeutic effects on hyperuricemia through multiple components and targets and the synergy of several pathways. Our finding provides a theoretical basis for further study of the active ingredients and therapeutic mechanism of Simiao pills for treating hyperuricemia.


Assuntos
Medicamentos de Ervas Chinesas , Hiperuricemia , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Hiperuricemia/tratamento farmacológico , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Mapas de Interação de Proteínas
2.
Mediators Inflamm ; 2021: 6687412, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679237

RESUMO

Background: Novel coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly progressed to a global pandemic. Currently, there are limited effective medications approved for this deadly disease. Objective: To investigate the potential predictors of COVID-19 mortality and risk factors for hyperinflammation in COVID-19. Methods: Retrospective analysis was carried out in 1,149 patients diagnosed with COVID-19 in Tongji Hospital, Wuhan, China, from 1/13/2020 to 3/15/2020. Results: We found significant differences in the rates of hyperuricemia (OR: 3.17, 95% CI: 2.13-4.70; p < 0.001) and hypoalbuminemia (OR: 5.68, 95% CI: 3.97-8.32; p < 0.001) between deceased and recovered patients. The percentages of hyperuricemia in deceased patients and recovered patients were 23.6% and 8.9%, respectively, which were higher than the reported age-standardized prevalence of 6.2% in Chinese population. Of note, the percentages of both IL-6 and uric acid levels in survived COVID-19 patients were above 90%, suggesting that they might be good specificity for indicators of mortality in COVID-19 patients. The serum level of uric acid (UA) was positively associated with ferritin, TNF-α, and IL-6 but not with anti-inflammatory cytokine IL-10. In addition, the levels of these proinflammatory cytokines in COVID-19 patients showed a trend of reduction after uric acid lowering therapy. Conclusions: Our results suggest that uric acid, the end product of purine metabolism, was increased in deceased patients with COVID-19. In addition, the serum level of uric acid was positively associated with inflammatory markers. Uric acid lowering therapy in COVID-19 patients with hyperuricemia may be beneficial.


Assuntos
/sangue , Pandemias , Ácido Úrico/sangue , Adulto , Idoso , Biomarcadores/sangue , China/epidemiologia , Citocinas/sangue , Feminino , Humanos , Hiperuricemia/sangue , Hiperuricemia/complicações , Hiperuricemia/tratamento farmacológico , Mediadores da Inflamação/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
3.
Internist (Berl) ; 62(5): 513-525, 2021 May.
Artigo em Alemão | MEDLINE | ID: mdl-33721041

RESUMO

Gout is the most common inflammatory arthritis in men with a rising incidence worldwide. It is a metabolic disease caused by hyperuricemia. Common causes of hyperuricemia, in addition to hereditary reduced renal excretion of urate, include purine over-nutrition, aging, comorbidities and associated medications, some of which increase serum urate levels. The first gout flare represents the signal for deposited urate crystals. If hyperuricemia remains untreated, crystal deposition proceeds and can cause recurrent gout flares, joint destruction and tophi. There is evidence that silent inflammation is ongoing even during asymptomatic stages. Gout patients often exhibit other metabolic, renal and cardiovascular co-morbidities and have higher (cardiovascular) mortality. Therefore, guidelines call for consequent urate lowering strategies to bring serum urate levels to a target at least below 360 µmol/l. The following article summarizes the recent state of knowledge regarding the diagnosis and therapy of gout.


Assuntos
Gota , Hiperuricemia , Febuxostat/uso terapêutico , Gota/diagnóstico , Gota/tratamento farmacológico , Supressores da Gota/uso terapêutico , Humanos , Hiperuricemia/diagnóstico , Hiperuricemia/tratamento farmacológico , Masculino , Exacerbação dos Sintomas , Ácido Úrico/uso terapêutico
5.
Kardiologiia ; 60(12): 104-109, 2021 Jan 19.
Artigo em Russo | MEDLINE | ID: mdl-33522474

RESUMO

Asymptomatic hyperuricemia (HU) is widespread in the population. Results of multiple studies have demonstrated independent associations between increased levels of uric acid and risk of arterial hypertension, cardiovascular diseases, and chronic kidney disease. HU is considered as an independent predictor of cardiovascular and all-cause mortality. Despite the extensive study of this issue, there is still no unified answer to questions regarding the necessity of urate-lowering therapy in asymptomatic HU, whereas results of studies on the effect of this therapy on outcomes of cardiovascular and kidney diseases are controversial. This review summarized the basic, currently available information on this issue.


Assuntos
Doenças Cardiovasculares , Hiperuricemia , Insuficiência Renal Crônica , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Humanos , Hiperuricemia/complicações , Hiperuricemia/tratamento farmacológico , Rim , Insuficiência Renal Crônica/epidemiologia , Ácido Úrico
6.
Med Clin North Am ; 105(2): 297-310, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33589104

RESUMO

Gout is the most common inflammatory arthritis in the United States. Gouty arthritis is associated with significant morbidity and mortality and is caused by hyperuricemia. Gout is effectively managed and potentially cured by decreasing the overall urate burden with serum urate-lowering therapy. When serum urate is maintained at less than 6.0 mg/dL urate deposition is resolved and gout can be cured. Unfortunately, owing to a lack of physician monitoring and dose escalation the majority of patients do not achieve these urate levels.


Assuntos
Artrite Gotosa , Monitoramento de Medicamentos/métodos , Supressores da Gota/farmacologia , Gota , Artrite Gotosa/diagnóstico , Artrite Gotosa/prevenção & controle , Artrite Gotosa/terapia , Gota/sangue , Gota/fisiopatologia , Gota/terapia , Humanos , Hiperuricemia/tratamento farmacológico , Hiperuricemia/etiologia
7.
Artigo em Inglês | MEDLINE | ID: mdl-33419128

RESUMO

BACKGROUND: Our study analyzes the frequency and risk factors of hyperuricemia and the use of allopurinol in a representative cohort of the older Polish adult population. METHODS: The analysis was a part of a cross-sectional PolSenior study on aging in Poland. The complete medication data were available in 4873 out of 4979 community dwelling respondents aged 65 and over. Serum uric acid concentrations were evaluated in 4028 participants (80.9% of the cohort). RESULTS: Hyperuricemia was observed in 28.2% of women and 24.7% of men. Ten risk factors of hyperuricemia were selected based on multivariable LASSO logistic regression analysis. Nine factors showed significant odds ratios: eGFR < 60 mL/min/1.73 m2 (OR = 4.10), hypertriglyceridemia (OR = 1.88), obesity (OR = 1.75), heart failure (1.70), CRP > 3.0 mg/dL (OR = 1.64), coronary artery disease (OR = 1.30), use of loop-diuretics (OR = 4.20), hydrochlorothiazide (OR = 2.96), and thiazide-like diuretics (OR = 2.81). Allopurinol was used by 2.8% of men and 1.8% of women. The therapy was considered effective in 46.7% of men and 53.3% of women. CONCLUSIONS: Hyperuricemia was present in 23.1% (95% CI: 21.8-24.4) of the older Polish population. The frequency of hyperuricemia increases with age, reaching 30.5% in men and 33.7% in women aged 90 years or more. Chronic kidney disease, obesity, heart failure, hypertriglyceridemia, and the use of diuretics were the strongest risk factors for hyperuricemia in older adults. The treatment with allopurinol was ineffective in more than half of participants.


Assuntos
Alopurinol , Hiperuricemia , Idoso , Idoso de 80 Anos ou mais , Alopurinol/uso terapêutico , Estudos Transversais , Feminino , Humanos , Hiperuricemia/tratamento farmacológico , Hiperuricemia/epidemiologia , Masculino , Polônia , Prevalência , Fatores de Risco , Ácido Úrico
9.
Medicina (Kaunas) ; 57(1)2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33435164

RESUMO

This article aims to critically review the evidence on the available therapeutic strategies for the treatment of hyperuricemia. For this reason, several papers were reviewed. Xanthine oxidase inhibitors are the safest and most effective uric acid lowering drugs for the management of chronic hyperuricemia, while the efficacy of uricosuric agents is strongly modulated by pharmacogenetics. Emergent drugs (lesinurad, peglotidase) were found to be more effective for the acute management of refractory hyperuricemia, but their use is supported by a relatively small number of clinical trials so that further well-designed clinical research is needed to deepen their efficacy and safety profile.


Assuntos
Hiperuricemia/tratamento farmacológico , Uricosúricos/uso terapêutico , Xantina Oxidase/antagonistas & inibidores , Acetamidas/uso terapêutico , Alopurinol/uso terapêutico , Benzobromarona/uso terapêutico , Doença Crônica , Medicina Baseada em Evidências , Febuxostat/uso terapêutico , Supressores da Gota/uso terapêutico , Humanos , Naftalenos/uso terapêutico , Nitrilos/uso terapêutico , Fenilacetatos/uso terapêutico , Polietilenoglicóis/uso terapêutico , Probenecid/uso terapêutico , Propionatos/uso terapêutico , Piridinas/uso terapêutico , Tioglicolatos/uso terapêutico , Triazóis/uso terapêutico , Urato Oxidase/uso terapêutico
10.
J Ethnopharmacol ; 264: 113278, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32841699

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Liriodendron chinense (Hemsl.) Sarg, known as the Chinese tulip tree, has a long history of cultivation and utilization in many Asia countries, especially in China to use in traditional Chinese medicine for expelling "wind and dampness", a term corresponding to rheumatic fever and rheumatoid arthritis. Interestingly, the barks of Liriodendron chinense (Hemsl.) Sarg was also found in folk to treat gout. However, further experimental studies remained to confirm its uric acid-lowering effects. AIM OF THE STUDY: The aim of the study was to evaluate the protective effect of ethanol extract of the barks of Liriodendron chinense (Hemsl.) Sarg (EELC) in a mouse model of hyperuricemic nephropathy (HN) and the involved mechanisms. MATERIALS AND METHODS: EELC at a respective dose of 250 mg/kg/d or 500 mg/kg/d were orally administered to HN mice induced by a mixture of adenine (160 mg/kg/d)/potassium oxonate (2.4 g/kg/d) for 21 days. At the end of the treatment, serum uric acid, kidney functions (serum creatinine, blood urea nitrogen and urine microalbumin), 24-h urine uric acid excretion, as well as kidney pathological changes were investigated by biochemical assay, histopathological score, immunofluorescence and histochemistry, RT-qPCR, and western blotting analysis. RESULTS AND DISCUSSION: Oral administration of EELC significantly lowered serum uric acid level at 500 mg/kg (185.75 ± 15.49 µmol/L of EELC vs. 238.28 ± 20.97 µmol/L of HN model, p < 0.01) in HN mice. EELC at 500 mg/kg also remarkably reduced the levels of serum creatinine (82.92 ± 7.86 µmol/L of EELC vs. 92.08 ± 6.13 µmol/L of HN model, p < 0.0001), blood urea nitrogen (21.50 ± 1.87 mmol/L of EELC vs. 29.40 ± 3.95 mmol/L of HN model, p < 0.001) and urine microalbumin (4.25 ± 0.40 mg/L of EELC vs. 5.95 ± 0.33 mg/L of HN model, p < 0.001) to improve renal function. It also attenuated renal fibrosis, especially the high-dose of EELC. Furthermore, EELC could inhibit the activation of NF-κB, ASK1/JNK/c-Jun, JAK2/STAT3 signaling pathways and reduce the release of pro-inflammatory cytokine TNF-α in the kidneys of HN mice. Additionally, EELC remarkably increased urine uric acid excretion of HN mice, which may be achieved by the upregulation of organic anion transporter 1 (OAT1), OAT3 and ATP-binding cassette subfamily G member 2 (ABCG2) proteins. CONCLUSIONS: EELC alleviated the progression of HN by suppressing the activation of NF-κB, ASK1/JNK/c-Jun and JAK2/STAT3 signaling pathway, reducing the infiltration of inflammatory factors and uric acid accumulation in the kidney.


Assuntos
Etanol/uso terapêutico , Hiperuricemia/tratamento farmacológico , Nefropatias/tratamento farmacológico , Liriodendron , Casca de Planta , Extratos Vegetais/uso terapêutico , Animais , Etanol/isolamento & purificação , Fibrose , Hiperuricemia/patologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/isolamento & purificação
11.
Phytomedicine ; 80: 153374, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33075645

RESUMO

BACKGROUND: Insufficient renal urate excretion and/or overproduction of uric acid (UA) are the dominant causes of hyperuricemia. Baicalein (BAL) is widely distributed in dietary plants and has extensive biological activities, including antioxidative, anti-inflammatory and antihypertensive activities. PURPOSE: To investigate the anti-hyperuricemic effects of BAL and the underlying mechanisms in vitro and in vivo. METHODS: We investigated the inhibitory effects of BAL on GLUT9 and URAT1 in vitro through electrophysiological experiments and 14C-urate uptake assays. To evaluate the impact of BAL on serum and urine UA, the expression of GLUT9 and URAT1, and the activity of xanthine oxidase (XOD), we developed a mouse hyperuricemia model by potassium oxonate (PO) injection. Molecular docking analysis based on homology modeling was performed to explain the predominant efficacy of BAL compared with the other test compounds. RESULTS: BAL dose-dependently inhibited GLUT9 and URAT1 in a noncompetitive manner with IC50 values of 30.17 ± 8.68 µM and 31.56 ± 1.37 µM, respectively. BAL (200 mg/kg) significantly decreased serum UA and enhanced renal urate excretion in PO-induced hyperuricemic mice. Moreover, the expression of GLUT9 and URAT1 in the kidney was downregulated, and XOD activity in the serum and liver was suppressed. The docking analysis revealed that BAL potently interacted with Trp336, Asp462, Tyr71 and Gln328 of GLUT9 and Ser35 and Phe241 of URAT1. CONCLUSION: These results indicated that BAL exerts potent antihyperuricemic efects through renal UA excretal promotion and serum UA production. Thus, we propose that BAL may be a promising treatment for the prevention of hyperuricemia owing to its multitargeted inhibitory activity.


Assuntos
Flavanonas/farmacologia , Hiperuricemia/tratamento farmacológico , Ácido Úrico/urina , Xantina Oxidase/antagonistas & inibidores , Animais , Antioxidantes/farmacologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Flavanonas/química , Flavanonas/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/química , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Células HEK293 , Humanos , Hiperuricemia/induzido quimicamente , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Transportadores de Ânions Orgânicos/química , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/química , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Ácido Oxônico/toxicidade , Ácido Úrico/sangue
12.
Zhongguo Zhong Yao Za Zhi ; 45(21): 5248-5255, 2020 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-33350242

RESUMO

The aim of this paper was to study the specific mechanism of Fangji Huangqi Decoction(FHT) in decreasing uric acid and improving renal function in mice with hyperuricemia(HUA) induced by potassium oxonate, so as to provide theoretical basis for the research and development of drugs for clinical prevention and treatment of HUA and the modernization of traditional Chinese medicine. Sixty Kunming male mice were randomly divided into 6 groups, with 10 mice in each group, namely normal group, model group(250 mg·kg~(-1) potassium oxonate), FHT high, medium and low-dose groups(10 920, 5 460, and 2 730 mg·kg~(-1)) and positive drug allopurinol group(5 mg·kg~(-1)). Drug administration was given once a day for 7 days. On the 6 th day, mice of each group were kept in metabolic cages, and their urine was collected for 24 hours for determination of uric acid, creatinine, and ß2-microglobulin(ß2-MG) levels. After 7 days, the animals were sacrificed to determine serum uric acid, creatinine ß2-MG and interleukin-1ß(IL-1ß) levels, and their liver and kidney tissues were collected. The liver tissues were used for subsequent determination of xanthine oxidase(XOD) activity, and the kidney tissues were used for subsequent determination of IL-1ß levels, pathological tests and related Western blot experiments. In the cell transfection experiment, the cells were divided into blank group, model group(4.8 mmol·L~(-1) uric acid treatment), FHT administration group(4.8 mmol·L~(-1) uric acid+200 µg·mL~(-1) FHT), leucine-rich repeat kinase 1(LRRK1)-small interfering RNA(siRNA) group(4.8 mmol·L~(-1) uric acid+LRRK1-siRNA transfection) and LRRK1-siRNA+FHT group(4.8 mmol·L~(-1) uric acid+LRRK1-siRNA transfection+200 µg·mL~(-1) FHT). After 24 h incubation, the level of IL-1ß in the cell supernatant was detected, and the cellular proteins were extracted and used to determine LRRK1, epidermal growth factor receptor(EGFR), PDZ kinase 1(PDZK1) and nuclear factor-kappa B(NF-κB) protein expression levels. The results showed that, FHT could significantly reduce the uric acid, creatinine and ß2-MG levels in serum and ß2-MG levels in urine, increase the uric acid and creatinine levels in urine, and improve the renal pathological results of the HUA mice, but showed no effect on liver XOD activity; at the same time, we found that the expression level of IL-1ß in serum and kidney, NF-κB, LRRK1 and EGFR protein levels in kidney of HUA mice were significantly increased, and the expression level of PDZK1 protein was significantly decreased, while FHT could significantly improve the abnormal expression of these proteins, and FHT increased protein expression of renal organic anion transporter 1(OAT1), OAT3 and ATP bin-ding transporter G2(ABCG2) in HUA mice, but FHT had no effect on the expression of urate transporter 1(URAT1). In the cell transfection experiment, after transfection of LRRK1-siRNA, the levels of IL-1ß, EGFR and NF-κB in supernatant were significantly reduced, and the expression of PDZK1 protein was significantly increased. As compared with the LRRK1-siRNA group, the levels of IL-1ß, EGFR, PDZK1 and NF-κB did not change significantly with the additional FHT. This study showed that FHT may regulate the renal uric acid transport system through LRRK1 gene, improve the capacity of uric acid excretion, so as to reduce the level of serum uric acid. At the same time, FHT can not only protect the kidney directly, but also in an indirect manner by reducing the level of uric acid.


Assuntos
Medicamentos de Ervas Chinesas , Hiperuricemia , Animais , Hiperuricemia/tratamento farmacológico , Rim , Masculino , Camundongos , Ácido Úrico
13.
Ter Arkh ; 92(6): 60-68, 2020 Jul 09.
Artigo em Russo | MEDLINE | ID: mdl-33346494

RESUMO

AIM: To evaluate a 12-week course of combined alloturinol-lowering therapy with a prophylactic anti-inflammatory dose of movalis for the frequency of exacerbations and the quality of life of patients with gout. MATERIALS AND METHODS: Allopurinol was administered orally, 1 time per day. Every 3 weeks, the dosage of the drug was increased by 50 mg to 300 mg per day under the control of the level of serum uric acid (sUA). The total daily dose of the drug movalis, used in the form of different dosage forms, was 7.515 mg. The clinical effectiveness of the treatment was evaluated after 3, 6, 9 and 12 weeks according to physical examination, the dynamics of joint pain at rest, during movement and palpation, according to the visual analogue scale (VAS) in millimeters, Likert scale, EuroQol-5D-5L questionnaire, care for oneself, habitual daily activities, the presence of anxiety and depression, assessment of satisfaction with treatment (on a scale of 1 to 5, where 1 is the complete absence of improvement or worsening, and 5 is a very good result); took into account the period of remission, as well as the time before the onset of relapse of gouty arthritis. An adverse event (AE) was recorded. RESULTS AND DISCUSSION: On the background of treatment with movalis 7.5 mg per day more than two-thirds of patients showed no worsening of the articular syndrome with an increase in the dose of allopurinol to 300 mg per day. By the 12th week of observation, a significant difference was found between the severity of gouty arthritis characteristics in the direction of improving mobility, self-care, normal daily activities, reducing soreness, reducing anxiety and depression (p0.05). In addition, the ESR and sUA levels were significantly different initially and at the final observation point (p0.05), which indicates a positive effect on the inflammatory process. A 3-month course of combination therapy was not accompanied by significant increases in blood pressure, changes in creatinine clearance in blood serum. There were no adverse events from the gastrointestinal tract. 90.9% of patients rated the treatment result as very good. AE in the form of a skin allergic rash was observed in one patient; it did not require interruption of treatment and completely stopped without consequences after completion of the course. CONCLUSION: 12 a week-long combined therapy of the allopurinol-reducing drug with the anti-inflammatory dose movalis prevents the exacerbation of the articular syndrome and improves the quality of life of patients with gout.


Assuntos
Supressores da Gota/uso terapêutico , Gota , Hiperuricemia , Alopurinol/efeitos adversos , Alopurinol/uso terapêutico , Quimioterapia Combinada , Gota/tratamento farmacológico , Supressores da Gota/efeitos adversos , Humanos , Hiperuricemia/tratamento farmacológico , Meloxicam/uso terapêutico , Preparações Farmacêuticas , Qualidade de Vida , Ácido Úrico
14.
Nihon Yakurigaku Zasshi ; 155(6): 426-434, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33132262

RESUMO

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.


Assuntos
Hiperuricemia , Transportadores de Ânions Orgânicos , Uricosúricos , Humanos , Hiperuricemia/tratamento farmacológico , Japão , Filipinas , Comprimidos , Resultado do Tratamento
15.
Int Heart J ; 61(5): 984-992, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32921665

RESUMO

Uric acid is generated with reactive oxygen species via xanthine oxidase (XO), and hyperuricemia, which is identified as the excess of uric acid in the blood, has been associated with vascular endothelial dysfunction. However, the effects of urate-lowering medicines on endothelial function have not been fully elucidated. Thus this study determined and compared the effects of benzbromarone (urate transporter 1 inhibitor) and febuxostat (XO inhibitor) on endothelial function.This randomized, cross-over, open-label study initially recruited 30 patients with hyperuricemia. They were divided into two groups, treated initially with benzbromarone or febuxostat for three months and then were switched for the next three months. Endothelial function was defined as reactive hyperemia indexes (RHI) determined using Endo-PAT 2000 before and at three and six months after medication using the two agents. Blood levels of asymmetric dimethylarginine (ADMA) and high-molecular-weight (HMW) adiponectin were also compared. We finally analyzed data from 24 patients whose endothelial function was assessed as described above.Our findings show that levels of uric acid significantly decreased, whereas those of HMW adiponectin and the RHI have significantly increased after treatment with benzbromarone. Meanwhile, in patients administered with febuxostat, uric acid levels tended to decrease and RHI significantly decreased. Neither of the two agents altered ADMA levels. The changes in RHI (P = 0.026) and HMW adiponectin levels (P = 0.001) were found to be significantly greater in patients treated with benzbromarone than febuxostat. Changes in the levels of HMW adiponectin and of uric acid were significantly correlated (r = -0.424, P = 0.039).Benzbromarone has increased adiponectin besides reducing uric acid levels, and thus, this might confer more benefits on endothelial function than febuxostat.


Assuntos
Benzobromarona/uso terapêutico , Endotélio Vascular/fisiopatologia , Febuxostat/uso terapêutico , Hiperemia/fisiopatologia , Hiperuricemia/tratamento farmacológico , Uricosúricos/uso terapêutico , Adiponectina/sangue , Idoso , Arginina/análogos & derivados , Arginina/sangue , Estudos Cross-Over , Feminino , Supressores da Gota/uso terapêutico , Humanos , Hiperuricemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Resultado do Tratamento , Ácido Úrico/sangue , Xantina Oxidase/antagonistas & inibidores
16.
Cochrane Database Syst Rev ; 9: CD008652, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32877573

RESUMO

BACKGROUND: This is the second update of this systematic review. High blood pressure represents a major public health problem. Worldwide, approximately one-fourth of the adult population has hypertension. Epidemiological and experimental studies suggest a link between hyperuricaemia and hypertension. Hyperuricaemia affects 25% to 40% of those with untreated hypertension; a much lower prevalence has been reported in those with normotension or in the general population. However, whether lowering serum uric acid (UA) might lower blood pressure (BP), is an unanswered question. OBJECTIVES: To determine whether UA-lowering agents reduce BP in people with primary hypertension or prehypertension, compared with placebo. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to May 2020: the Cochrane Hypertension Specialised Register, CENTRAL 2018, Issue 12, MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also searched LILACS (1982 to May 2020), and contacted authors of relevant papers regarding further published and unpublished work. The searches had no language or date restrictions. SELECTION CRITERIA: To be included in this updated review, the studies had to meet the following criteria: 1) randomised or quasi-randomised, with a group assigned to receive a UA-lowering agent and another group assigned to receive placebo; 2) double-blind, single-blind, or open-label; 3) parallel or cross-over trial design; 4) cross-over trials had to have a washout period of at least two weeks; 5) minimum treatment duration of four weeks; 6) participants had to have a diagnosis of essential hypertension or prehypertension plus hyperuricaemia (serum UA greater than 6 mg/dL in women, 7 mg/dL in men, and 5.5 mg/dL in children or adolescents); 7) outcome measures included change in 24-hour ambulatory systolic or diastolic BP, or both; or clinic-measured systolic or diastolic BP, or both. DATA COLLECTION AND ANALYSIS: The two review authors independently collected the data using a data extraction form, and resolved any disagreements via discussion. We assessed risk of bias using the Cochrane 'Risk of bias' tool. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: In this review update, we screened 722 records, selected 26 full-text reports for evaluation. We identified no ongoing studies and did not add any new studies. We included three randomised controlled trials (RCTs), enrolling 211 people with hypertension or prehypertension, plus hyperuricaemia. Low-certainty evidence from three RCTs found inconclusive results between those who received UA-lowering drugs and placebo, in 24-hour ambulatory systolic (MD -6.2 mmHg, 95% CI -12.8 to 0.5) or diastolic BP (-3.9 mmHg, 95% CI -9.2 to 1.4). Low-certainty evidence from two RCTs found that UA-lowering drugs reduced clinic-measured systolic BP (-8.43 mmHg, 95% CI -15.24 to -1.62) but results for clinic-measured diastolic BP were inconclusive (-6.45 mmHg, 95% CI -13.60 to 0.70). High-certainty evidence from three RCTs found that serum UA levels were reduced by 3.1 mg/dL (95% CI 2.4 to 3.8) in the participants that received UA-lowering drugs. Low-certainty evidence from three RCTs found inconclusive results regarding the occurrence of adverse events between those who received UA-lowering drugs and placebo (RR 1.86, 95% CI 0.43 to 8.10). AUTHORS' CONCLUSIONS: In this updated Cochrane Review, the current RCT data are insufficient to know whether UA-lowering therapy lowers BP. More studies are needed.


Assuntos
Alopurinol/uso terapêutico , Hipertensão/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Uricosúricos/uso terapêutico , Adolescente , Adulto , Pressão Sanguínea/efeitos dos fármacos , Criança , Humanos , Hipertensão/complicações , Hiperuricemia/complicações , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Placebos/uso terapêutico , Pré-Hipertensão/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
Medicine (Baltimore) ; 99(33): e21610, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32872016

RESUMO

INTRODUCTION: Osteoarthritis (OA), a chronic and degenerative joint disease characterized by articular cartilage degeneration, sclerosis of subchondral bone, and osteophyte formation, is deemed a leading cause of activity limitation and disability among the elderly people. Serum uric acid (UA) is a terminal metabolite of purine compound, while hyperuricemia (HU) and UA crystals are recognized causes of gout. Several studies have investigated the correlations between HU, gout and OA, but the findings are inconclusive. We are also concerned whether the urate lowering therapy (ULT) can become a potential treatment for OA and intend to undertake this meta-analysis to clarify the related hypotheses. METHODS: Systematic literature search will be conducted on PubMed, Embase, and Web of Science to identify relevant studies up to February 2020 using appropriate search strategies. All citations and abstracts retrieved from literature search will be assessed by two reviewers independently. The Newcastle-Ottawa Scale or the Cochrane risk of bias assessment tool will be used as appropriate to assess the quality and the risk of bias of the included studies. The heterogeneity and the publication bias of the studies will be investigated accordingly. RESULTS: We propose to undertake this meta-analysis as a feasible approach to clarify the associations between HU, gout or ULT, and OA. DISCUSSIONS: This meta-analysis will help to strengthen our knowledge of the pathogenesis of OA and promote the development of preventive or treatment strategies. REGISTRATION: PROSPERO registration number CRD42020168769.


Assuntos
Gota/epidemiologia , Hiperuricemia/epidemiologia , Osteoartrite/epidemiologia , Ácido Úrico/sangue , Uricosúricos/administração & dosagem , Gota/tratamento farmacológico , Gota/prevenção & controle , Humanos , Hiperuricemia/tratamento farmacológico , Hiperuricemia/prevenção & controle , Estudos Observacionais como Assunto , Osteoartrite/tratamento farmacológico , Osteoartrite/prevenção & controle , Projetos de Pesquisa
18.
Medicine (Baltimore) ; 99(34): e21847, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846834

RESUMO

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.


Assuntos
Anestesia Geral/efeitos adversos , Hipoxantina Fosforribosiltransferase/genética , Síndrome de Lesch-Nyhan/psicologia , Propofol/administração & dosagem , Administração Intravenosa , Adolescente , Período de Recuperação da Anestesia , Anestesia Geral/métodos , Humanos , Hiperuricemia/tratamento farmacológico , Hiperuricemia/etiologia , Deficiência Intelectual/etiologia , Cálculos Renais/cirurgia , Síndrome de Lesch-Nyhan/sangue , Síndrome de Lesch-Nyhan/diagnóstico , Síndrome de Lesch-Nyhan/genética , Masculino , Nefrolitotomia Percutânea/métodos , Transtornos do Neurodesenvolvimento/etiologia , Comportamento Autodestrutivo/etiologia , Resultado do Tratamento , Ácido Úrico/sangue , Vômito/induzido quimicamente
19.
Clin Drug Investig ; 40(9): 847-859, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32621143

RESUMO

BACKGROUND AND OBJECTIVES: Topiroxostat, a selective xanthine oxidoreductase inhibitor, is used for the management of hyperuricemic patients with or without gout in Japan. Accumulating evidence has demonstrated the efficacy of topiroxostat for the treatment of hyperuricemia with or without gout. However, the safety and efficacy of topiroxostat in the clinical setting remain unclear, and there is little large-scale clinical evidence. We conducted a post-marketing observational study over 54 weeks. PATIENTS AND METHODS: Patients were centrally enrolled, and case report forms of 4491 patients were collected between April 2014 and March 2019 from 825 medical sites. RESULTS: Overall, 4329 patients were assessed for safety and 4253 patients for effectiveness. The overall incidence of adverse drug reactions was 6.95%, and the incidence rates of adverse drug reactions of gouty arthritis, hepatic dysfunction, and skin disorders, which are of special interest in this study, were 0.79%, 1.73%, and 0.95%, respectively. No case of serious gouty arthritis was observed. Serum urate levels decreased stably over time and showed a significant reduction rate at 54 weeks (21.19% ± 22.07%) and on the final visit (19.91% ± 23.35%) compared to the baseline. The rates for subjects who achieved serum uric acid levels ≤ 6.0 mg/dL at 18 and 54 weeks after administration were 43.80% and 48.28%, respectively. CONCLUSIONS: This study suggests that there is no particular concern about adverse drug reactions or the efficacy of topiroxostat for hyperuricemic patients with or without gout in a post-marketing setting in Japan.


Assuntos
Supressores da Gota/uso terapêutico , Gota/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Nitrilos/uso terapêutico , Vigilância de Produtos Comercializados , Piridinas/uso terapêutico , Xantina Desidrogenase/antagonistas & inibidores , Adulto , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/uso terapêutico , Feminino , Supressores da Gota/efeitos adversos , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Nitrilos/efeitos adversos , Piridinas/efeitos adversos , Resultado do Tratamento , Ácido Úrico/sangue
20.
Ann Hematol ; 99(9): 2193-2195, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32621180
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