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1.
Lancet Haematol ; 7(2): e168-e176, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32004486

RESUMO

Tumour lysis syndrome is a complication of chemotherapy for haematological malignancies; in particular, aggressive leukaemias and lymphomas. For haematological malignancies, targeted therapies, such as small molecule inhibitors and monoclonal antibodies, have a high anti-tumour activity, are well tolerated, and have a low incidence of associated tumour lysis syndrome. The BCL-2 inhibitor venetoclax has a high anti-tumour activity in chronic lymphocytic leukaemia, achieving deep remissions by potently inducing apoptosis and increasing the risk for tumour lysis syndrome. In this Viewpoint, we discuss the pathophysiology, risk factors, monitoring, changes in laboratory parameters, and clinical manifestations of tumour lysis syndrome, and the prophylaxis and treatments available for this complication. Prophylaxis and treatment strategies have been implemented as standard of care in patients receiving venetoclax to minimise the risk of both laboratory and clinical manifestations of tumour lysis syndrome.


Assuntos
Antineoplásicos/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Terapia de Alvo Molecular/efeitos adversos , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Síndrome de Lise Tumoral/etiologia , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/terapia , Alopurinol/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/etiologia , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Sinergismo Farmacológico , Humanos , Hiperfosfatemia/etiologia , Hiperfosfatemia/terapia , Hiperuricemia/tratamento farmacológico , Hiperuricemia/etiologia , Leucemia Linfocítica Crônica de Células B/enzimologia , Diálise Renal , Fatores de Risco , Índice de Gravidade de Doença , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Síndrome de Lise Tumoral/diagnóstico , Síndrome de Lise Tumoral/tratamento farmacológico , Síndrome de Lise Tumoral/prevenção & controle , Urato Oxidase/uso terapêutico
2.
Int J Clin Pharmacol Ther ; 58(1): 21-28, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31657714

RESUMO

OBJECTIVE: Febuxostat, a novel non-purine selective xanthine oxidase inhibitor, is a recommended treatment option for patients with chronic kidney disease (CKD) and hyperuricemia. There are only a few trials on the long-term use of allopurinol and febuxostat for CKD. In this study, we compared the efficacy of allopurinol and febuxostat and their effects on renal function in patients with CKD and hyperuricemia. MATERIALS AND METHODS: This was a retrospective study of adult patients with hyperuricemia and CKD (estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73m2) treated with febuxostat or allopurinol. The proportion of patients who achieved the treatment goal and the difference in efficacy between different drug doses were evaluated. Further, the effects on cardiovascular and renal functions were assessed. Cardiovascular risk is defined as cardiovascular events occurring after treatment initiation. RESULTS: We enrolled 316 patients in the study, with 83 and 233 patients in the allopurinol and febuxostat groups, respectively. The application of linear mixed model for analysis revealed that febuxostat 40 mg was more effective than allopurinol 100 mg in reducing the serum uric acid level. The results indicated that the long-term eGFR slope of the febuxostat group was positive, whereas that of the allopurinol group was negative. CONCLUSION: The results showed that, in patients with CKD and hyperuricemia, febuxostat can be used to reduce the serum uric acid level. The long-term use of febuxostat may exert a protective effect on the kidneys. Moreover, there were no obvious adverse reactions and the patients tolerated the drug well.


Assuntos
Alopurinol/uso terapêutico , Febuxostat/uso terapêutico , Supressores da Gota/uso terapêutico , Hiperuricemia/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Adulto , Alopurinol/efeitos adversos , Febuxostat/efeitos adversos , Supressores da Gota/efeitos adversos , Humanos , Estudos Retrospectivos , Resultado do Tratamento , Ácido Úrico/sangue
3.
Eur J Med Chem ; 186: 111883, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761385

RESUMO

As part of a continuing study, we designed and synthesized four series of 1-phenylimidazole-4-carboxylic acid derivatives as xanthine oxidoreductase (XOR) inhibitors, evaluated their in vitro inhibitory potencies against XOR and hypouricemic effects in mice, and determined their structure-activity relationships (SARs). Most of the compounds exhibited in vitro XOR inhibition at the nanomolar level. In comparison to febuxostat (half-maximal inhibitory concentration [IC50] value of 7.0 nM), compounds Ie and IVa exhibited the most promising XOR inhibitory effects with IC50 values of 8.0 and 7.2 nM, respectively. In the potassium oxonate/hypoxanthine-induced acute and long-term hyperuricemia mouse models, compounds Ie and IVa displayed significant hypouricemic potencies (P < 0.05), that were slightly weaker than and similar to febuxostat, respectively. More interestingly, both compounds showed a capacity to improve kidney damage by decreasing creatinine and urea nitrogen levels compared to the long-term hyperuricemia mouse group (P < 0.05), while febuxostat showed no significant effect.


Assuntos
Ácidos Carboxílicos/farmacologia , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Xantina Desidrogenase/antagonistas & inibidores , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Imidazóis/síntese química , Imidazóis/química , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Xantina Desidrogenase/metabolismo
4.
Phytomedicine ; 66: 153111, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31790902

RESUMO

BACKGROUND: Hyperuricemia (HUA) is an important risk factor for renal diseases and contributes to renal fibrosis. It has been proved that phloretin has antioxidant and anti-inflammatory properties and could inhibit uric acid (UA) uptake in vitro. However, whether phloretin has a renal protective role in vivo remains unknown. PURPOSE: This study aims to evaluate the therapeutic effect of phloretin on HUA-induced renal injury in mice and to reveal its underlying mechanism. METHODS: Mice were induced hyperuricemic by oral gavage of adenine/potassium oxonate. The effects of phloretin on renal function, fibrosis, oxidative stress, inflammation, and UA metabolism in HUA mice were evaluated. The effect of phloretin on NLRP3 pathway was analyzed in human renal tubular cell lines (HK-2). RESULTS: HUA mice showed renal dysfunction with increased renal fibrosis, inflammation and mitochondrial stress. By contrast, phloretin reduced the level of serum blood urea nitrogen (BUN), urinary albumin to creatinine ratio (UACR), tubular necrosis, extracellular matrix (ECM) deposition and interstitial fibroblasts in HUA mice. The renal infiltration of inflammatory cells, cytokines such as NOD-like receptor family pyrin domain containing 3 (NLRP3) and interleukin-1ß (IL-1ß) release, mitochondrial reactive oxygen species (ROS) and morphological lesions in HUA mice also decreased. Furthermore, phloretin partly inhibited renal glucose transporter 9 (GLUT9) and promoted urinary UA excretion in HUA mice. In vitro, phloretin suppressed the NLPR3 pathway under LPS or UA stimulation in HK-2 cells. CONCLUSIONS: Phloretin could effectively attenuate UA-induced renal injury via co-inhibiting NLRP3 and UA reabsorption, and thus it might be a potential therapy to hyperuricemia-related renal diseases.


Assuntos
Fibrose/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Inflamação/tratamento farmacológico , Nefropatias/tratamento farmacológico , Floretina/farmacologia , Ácido Úrico/metabolismo , Animais , Linhagem Celular , Citocinas/metabolismo , Humanos , Inflamassomos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
Expert Opin Ther Pat ; 29(11): 871-879, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31593642

RESUMO

Introduction: Human urate transporter 1 (URAT1), which is an influx transporter protein, is located at the apical surface of renal tubular cells and presumed to be the major transporter responsible for the reabsorption of urate from blood. About 90% of patients develop hyperuricemia due to insufficient urate excretion; thus, it is important to develop URAT1 inhibitors that could enhance renal urate excretion by blocking the reabsorption of urate anion. Areas covered: In this review, the authors addressed the patent applications (2016-2019) about URAT1 inhibitors and some medicinal chemistry strategies employed in these patents. Expert opinion: Substituent decorating, bioisosterism, and scaffold hopping are three common medicinal chemistry strategies used in the discovery of URAT1 inhibitors. Meanwhile, the introduction of sulfonyl group into small molecules has become one of the important strategies for structural optimization of URAT1 inhibitors. Furthermore, developing drug candidates targeting both URAT1 and xanthine oxidase (XOD) has attracted lots of interest and attention.


Assuntos
Desenvolvimento de Medicamentos/métodos , Hiperuricemia/tratamento farmacológico , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Animais , Humanos , Hiperuricemia/fisiopatologia , Patentes como Assunto , Ácido Úrico/metabolismo , Xantina Oxidase/antagonistas & inibidores
6.
Int J Mol Sci ; 20(19)2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31546603

RESUMO

Hyperuricemia has been recognized as a risk factor for insulin resistance as well as one of the factors leading to diabetic kidney disease (DKD). Since DKD is the most common cause of end-stage renal disease, we investigated whether febuxostat, a xanthine oxidase (XO) inhibitor, exerts a protective effect against the development of DKD. We used KK-Ay mice, an established obese diabetic rodent model. Eight-week-old KK-Ay mice were provided drinking water with or without febuxostat (15 µg/mL) for 12 weeks and then subjected to experimentation. Urine albumin secretion and degrees of glomerular injury judged by microscopic observations were markedly higher in KK-Ay than in control lean mice. These elevations were significantly normalized by febuxostat treatment. On the other hand, body weights and high serum glucose concentrations and glycated albumin levels of KK-Ay mice were not affected by febuxostat treatment, despite glucose tolerance and insulin tolerance tests having revealed febuxostat significantly improved insulin sensitivity and glucose tolerance. Interestingly, the IL-1ß, IL-6, MCP-1, and ICAM-1 mRNA levels, which were increased in KK-Ay mouse kidneys as compared with normal controls, were suppressed by febuxostat administration. These data indicate a protective effect of XO inhibitors against the development of DKD, and the underlying mechanism likely involves inflammation suppression which is independent of hyperglycemia amelioration.


Assuntos
Anti-Inflamatórios/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Febuxostat/uso terapêutico , Xantina Oxidase/antagonistas & inibidores , Animais , Peso Corporal/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Colágeno/metabolismo , Nefropatias Diabéticas/imunologia , Intolerância à Glucose/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Glomérulos Renais/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Ácido Úrico/sangue
7.
Food Funct ; 10(9): 6000-6008, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31482168

RESUMO

Lemon is a healthy fruit with high medicinal value. This study found that lemon water soluble extract (LET) can reduce uric acid levels in mice with potassium oxonate induced hyperuricemia. Histopathological analysis suggested that LET caused little damage to the kidneys of mice. It affected mABCG2 and mGLUT9 mRNA expression only in hyperuricemic mice, but not in healthy mice. Our further results show that potassium citrate, rather than citric acid, is the main ingredient in LET with a hypouricemic effect. This study also indicates that lemon does have unique medicinal value for the treatment of hyperuricemia, and that potassium citrate has the potential to be developed as a drug for hyperuricemia. Lowering uric acid through LET and potassium citrate may directly promote the degradation of excessive uric acid in patients with hyperuricemia.


Assuntos
Citrus/química , Hiperuricemia/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Modelos Animais de Doenças , Frutas/química , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Humanos , Hiperuricemia/metabolismo , Masculino , Camundongos , Extratos Vegetais/análise , Citrato de Potássio/administração & dosagem , Citrato de Potássio/análise , Ácido Úrico/metabolismo
8.
Molecules ; 24(18)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31489932

RESUMO

Erding granule (EDG) is a traditional Chinese medicine that has recently been identified as having anti-hypouricemic effects. However, the active components and underlying mechanism for this new indication have not been elucidated. Therefore, we compared the effects of different EDG extracts (water, 50% ethanol and 95% ethanol) on serum uric acid concentrations in the hyperuricemia model mouse. We also analyzed the constituents of different extracts by ultra-high performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) to observe the variation between the active and inactive products. Extract activity and target site were evaluated by assessing uric acid- and inflammation-suppressing effects along with evaluating ability to regulate the uric acid transporter. The results showed that the 50% ethanol extract (EDG-50) had an obvious serum uric acid concentration lowering effect compared with water (EDG-S) and the 95% ethanol extract (EDG-95). UHPLC-Q-TOF-MS/MS analysis showed that EDG-50 was compositionally different to EDG-S and EDG-95. EDG-50 showed dose-dependent effects on reducing uric acid, suppressing inflammation and regulating uric acid transporters. Moreover, western blot analysis showed that EDG-50 down-regulated GLUT9 and URAT1 expression, and up-regulated OAT1 expression. Therefore, our findings enable the preliminarily conclusion that EDG-50 lowers serum uric acid concentrations, mainly by down-regulating the expression of GLUT9 and URAT1 proteins and up-regulating the expression of OAT1 proteins. This provides a research basis for clinical use of EDG as an anti-hyperuricemic agent.


Assuntos
Anti-Inflamatórios/administração & dosagem , Medicamentos de Ervas Chinesas/química , Etanol/administração & dosagem , Hiperuricemia/tratamento farmacológico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Etanol/química , Etanol/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Hiperuricemia/metabolismo , Masculino , Camundongos , Transportadores de Ânions Orgânicos/metabolismo , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray , Ácido Úrico/sangue
9.
Int J Clin Pharmacol Ther ; 57(11): 567-570, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31496508

RESUMO

OBJECTIVE: Hyperuricemia is an independent risk factor for renal dysfunction, cardiovascular events, and gouty arthritis. Xanthine oxidoreductase (XOR) inhibitors inhibit uric acid (UA) production and may be treatment options for hyperuricemia patients. I aimed to evaluate the effects of topiroxostat on circulating lipid concentrations in patients with hyperuricemia. MATERIALS AND METHODS: 83 hyperuricemic patients taking topiroxostat were enrolled into this retrospective study. RESULTS: Serum UA significantly decreased, total cholesterol (TC) decreased, and low-density lipoprotein cholesterol (LDL-c) decreased between baseline and 24 weeks. CONCLUSION: Topiroxostat may have the potential to lower serum UA, TC, and LDL-c concentrations in hyperuricemic patients.


Assuntos
Hiperuricemia/sangue , Lipídeos/sangue , Nitrilos/uso terapêutico , Piridinas/uso terapêutico , Colesterol/sangue , LDL-Colesterol/sangue , Humanos , Hiperuricemia/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento , Ácido Úrico/sangue
10.
Nutr Metab Cardiovasc Dis ; 29(10): 1011-1022, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31378626

RESUMO

BACKGROUND AND AIMS: Systemic reviews and meta-analyses suggest hyperuricemia is a cardiovascular risk factor. The effects of xanthine oxidase inhibitors on cardiac outcomes remain unclear. We assessed the effects of febuxostat and allopurinol on mortality and adverse reactions in adult patients with hyperuricemia. METHODS AND RESULTS: PubMed and EMBASE were searched to retrieve randomized controlled trials of febuxostat and allopurinol from January 2005 to July 2018. The meta-analysis consisted of 13 randomized controlled trials with a combined sample size of 13,539 patients. Febuxostat vs. allopurinol was not associated with an increased risk of cardiac-related mortality in the overall population (OR: 0.72, 95% CI: 0.24-2.13, P = 0.55). Regarding adverse skin reactions, the patients receiving febuxostat had significantly fewer adverse skin reactions than those receiving allopurinol treatment (OR: 0.50, 95% CI: 0.30-085, P = 0.01). Compared with allopurinol, febuxostat was associated with an improved safety outcome of cardiac-related mortality and adverse skin reactions (OR: 0.72, 95% CI: 0.55-0.96, P = 0.02). The net clinical outcome, composite of incident gout and the safety outcome, was not different significantly in the patients receiving febuxostat or allopurinol (OR: 1.04, 95% CI: 0.76-0.1.42, P = 0.79). In sensitivity analyses, a borderline significance was found in the patients randomized to febuxostat vs. allopurinol regarding cardiac-related mortality (OR: 1.29, 95% CI: 1.00-1.67, P = 0.05) after the CARES study was included. CONCLUSION: Febuxostat vs. allopurinol was associated with the improved safety outcome and have comparable mortality and net clinical outcome in patients with hyperuricemia. REGISTRATION NUMBER: PROSPERO(CRD42018091657).


Assuntos
Alopurinol/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Febuxostat/uso terapêutico , Supressores da Gota/uso terapêutico , Gota/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Ácido Úrico/sangue , Idoso , Alopurinol/efeitos adversos , Doenças Assintomáticas , Biomarcadores/sangue , Inibidores Enzimáticos/efeitos adversos , Febuxostat/efeitos adversos , Feminino , Gota/sangue , Gota/enzimologia , Gota/mortalidade , Supressores da Gota/efeitos adversos , Humanos , Hiperuricemia/sangue , Hiperuricemia/enzimologia , Hiperuricemia/mortalidade , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Xantina Oxidase/antagonistas & inibidores
11.
Eur J Med Chem ; 181: 111559, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31376568

RESUMO

Xanthine oxidase is an important target for the treatment of hyperuricemia, gout and other related diseases. Analysis of the high-resolution structure of xanthine oxidase with febuxostat identified the existence of a subpocket formed by the residues Leu648, Asn768, Lys771, Leu1014 and Pro1076. In this study, we designed and synthesized a series of 2-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid derivatives (8a-8z) with a tetrazole group targeting this subpocket of the xanthine oxidase active site, and they were further evaluated for their inhibitory potency against xanthine oxidase in vitro. The results showed that all the tested compounds (8a-8z) exhibited an apparent xanthine oxidase inhibitory potency, with IC50 values ranging from 0.0288 µM to 0.629 µM. Among them, compound 8u emerged as the most potent xanthine oxidase inhibitor, with an IC50 value of 0.0288 µM, which was comparable to febuxostat (IC50 = 0.0236 µM). The structure-activity relationship results revealed that the hydrophobic group at the 4'-position was indispensable for the inhibitory potency in vitro against xanthine oxidase. A Lineweaver-Burk plot revealed that the representative compound 8u acted as a mixed-type inhibitor for xanthine oxidase. Furthermore, molecular modeling studies were performed to gain insights into the binding mode of 8u with xanthine oxidase and suggested that the tetrazole group of the phenyl unit was accommodated in the subpocket, as expected. Moreover, a potassium oxonate-induced hyperuricemia model in rats was chosen to further confirm the hypouricemic effect of compound 8u, and the result demonstrated that compound 8u could effectively reduce serum uric acid levels at an oral dose of 5 mg/kg. In addition, acute oral toxicity study in mice indicated that compound 8u was nontoxic and tolerated at a dose up to 2000 mg/kg. Thus, compound 8u could be a potential and efficacious agent in treatment of hyperuricemia with low toxicity.


Assuntos
Ácidos Carboxílicos/farmacologia , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Pirimidinas/farmacologia , Xantina Oxidase/antagonistas & inibidores , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Hiperuricemia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Xantina Oxidase/metabolismo
12.
Cardiol Young ; 29(9): 1160-1164, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31451121

RESUMO

OBJECTIVES: Limited data exist for management of hyperuricemia in non-oncologic patients, particularly in paediatric cardiac patients. Hyperuricemia is a risk factor for acute kidney injury and may prompt treatment in critically ill patients. The primary objective was to determine if rasburicase use was associated with greater probability normalisation of serum uric acid compared to allopurinol. Secondary outcomes included percent reduction in uric acid, changes in serum creatinine, and cost of therapy. DESIGN: A single-centre retrospective chart review. SETTING: A 20-bed quaternary cardiovascular ICU in a university-based paediatric hospital in California. PATIENTS: Patients admitted to cardiovascular ICU who received rasburicase or intravenous allopurinol between 2015 and 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data from a cohort of 14 patients receiving rasburicase were compared to 7 patients receiving IV allopurinol. Patients who were administered rasburicase for hyperuricemia were more likely to have a post-treatment uric acid level less than 8 mg/dl as compared to IV allopurinol (100 versus 43%; p = 0.0058). Patients who received rasburicase had a greater absolute reduction in post-treatment day 1 uric acid (-9 mg/dl versus -1.9 mg/dl; p = 0.002). There were no differences in post-treatment day 3 or day 7 serum creatinine or time to normalisation of serum creatinine. The cost of therapy normalised to a 20 kg patient was greater in the allopurinol group ($18,720 versus $1928; p = 0.001). CONCLUSION: In a limited paediatric cardiac cohort, the use of rasburicase was associated with a greater reduction in uric acid levels and associated with a lower cost compared to IV allopurinol.


Assuntos
Alopurinol/administração & dosagem , Cardiopatias/complicações , Hiperuricemia/tratamento farmacológico , Urato Oxidase/administração & dosagem , Adolescente , Criança , Pré-Escolar , Creatinina/sangue , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Cardiopatias/sangue , Humanos , Hiperuricemia/sangue , Hiperuricemia/complicações , Injeções Intravenosas , Unidades de Terapia Intensiva , Masculino , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
13.
Ren Fail ; 41(1): 595-599, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31267805

RESUMO

The aim of this study was to evaluate the efficacy and tolerability of febuxostat in renal transplant recipients who were previously treated with allopurinol (the daily oral dose is 100 mg). A 6-month cohort study was conducted with 46 renal transplant recipients who had hyperuricemia. In 22 patients, treatment was changed from allopurinol to febuxostat (febuxostat was given at an oral dose of 20 mg once a day), and the other 24 patients continued the allopurinol treatment (the daily oral dose is 100 mg). The serum levels of uric acid (UA), creatinine, other biochemical parameters, estimated glomerular filtration rate (eGFR), and adverse events were measured at baseline as well as at 1, 3, and 6 months after the switch to febuxostat. Serum UA levels significantly decreased from 470.82 ± 34.37 to 378.77 ± 51.97 µmol/L in the febuxostat group, and decreased from 469.46 ± 33.47 to 428.21 ± 23.37 µmol/L in the allopurinol group. The eGFR increased from 75.55 to 85.23 mL/min in the febuxostat group, and decreased from 78.79 to 70.31 mL/min in the allopurinol group. In renal transplant recipients, febuxostat reduced the serum UA levels resulting in minor short-term improvement of renal function with no changes in the other biochemical parameters.


Assuntos
Alopurinol/administração & dosagem , Febuxostat/administração & dosagem , Supressores da Gota/administração & dosagem , Hiperuricemia/tratamento farmacológico , Transplante de Rim/efeitos adversos , Adulto , Aloenxertos/efeitos dos fármacos , Aloenxertos/fisiopatologia , Alopurinol/efeitos adversos , Substituição de Medicamentos , Febuxostat/efeitos adversos , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Supressores da Gota/efeitos adversos , Humanos , Hiperuricemia/sangue , Hiperuricemia/etiologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Transplantados , Resultado do Tratamento , Ácido Úrico/sangue
14.
Nat Rev Nephrol ; 15(12): 767-775, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31296965

RESUMO

Hyperuricaemia is common among patients with chronic kidney disease (CKD), and increases in severity with the deterioration of kidney function. Although existing guidelines for CKD management do not recommend testing for or treatment of hyperuricaemia in the absence of a diagnosis of gout or urate nephrolithiasis, an emerging body of evidence supports a direct causal relationship between serum urate levels and the development of CKD. Here, we review randomized clinical trials that have evaluated the effect of urate-lowering therapy (ULT) on the rate of CKD progression. Among trials in which individuals in the control arm experienced progressive deterioration of kidney function (which we define as ≥4 ml/min/1.73 m² over the course of the study - typically 6 months to 2 years), treatment with ULT conferred consistent clinical benefits. In contrast, among trials where clinical progression was not observed in the control arm, treatment with ULT was ineffective, but this finding should not be used as an argument against the use of uric acid-lowering therapy. Although additional studies are needed to identify threshold values of serum urate for treatment initiation and to confirm optimal target levels, we believe that sufficient evidence exists to recommend routine measurement of serum urate levels in patients with CKD and consider initiation of ULT among those who are hyperuricaemic with evidence of deteriorating renal function, unless specific contraindications exist.


Assuntos
Hiperuricemia/complicações , Insuficiência Renal Crônica/etiologia , Ácido Úrico/sangue , Humanos , Hiperuricemia/sangue , Hiperuricemia/tratamento farmacológico , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/tratamento farmacológico , Ácido Úrico/antagonistas & inibidores
15.
Am J Chin Med ; 47(5): 1133-1147, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31311296

RESUMO

Hyperuricemia is a metabolic disease of the kidney that results in decreased uric acid excretion. Here, we aimed to investigate the effects of ginsenosides and anserine on hyperuricemia and the expression of aquaporin (AQP) 1-4, which are indicators of renal excretion. Ginsenosides and anserine were administered separately or together after the establishment of hyperuricemia with adenine in BALB/c mice. Renal function indexes such as serum uric acid, creatinine, and urea nitrogen were measured in each group of mice, and the expression of AQP1-4 in renal tissues was detected. Serum uric acid and urea nitrogen were decreased in the ginsenoside and the anserine +UA groups. Meanwhile, the uric acid excretion and clearance rate were clearly increased in the co-treatment +UA group (p<0.05). Moreover, ginsenosides or anserine ginsenosides or anserine alone and treatment with both increased the expression of AQP1-4; however, the synergistic effects were more significantly enhanced (p<0.01). We provide the first reported evidence that ginsenosides and anserine have synergistic effects on uric acid excretion. The improvement in renal function in hyperuricemic mice after treatment with ginsenosides and anserine may result from up-regulation of AQP1-4 expressions.


Assuntos
Anserina/administração & dosagem , Aquaporinas/metabolismo , Ginsenosídeos/administração & dosagem , Hiperuricemia/tratamento farmacológico , Animais , Aquaporinas/genética , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Hiperuricemia/sangue , Hiperuricemia/genética , Hiperuricemia/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Regulação para Cima/efeitos dos fármacos , Ácido Úrico/sangue
16.
Int J Clin Pract ; 73(9): 1-11, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31250954

RESUMO

BACKGROUND: Urate Lowering Therapies (ULTs), mainly Xanthine Oxydase Inhibitors, are widely used by general practitioners (GPs) in asymptomatic hyperuricemia, although no guideline currently recommends to do so. The use of ULTs in asymptomatic hyperuricemia has been associated with an increased risk of ULTs-related adverse drug reactions. AIM: Our study aimed at exploring GPs' views and practices in relation to the prescription or non-prescription of ULT in asymptomatic hyperuricemia. METHODS: We conducted a qualitative study using individual semi-structured interviews with 14 French GPs. We built a purposeful sample searching for maximum variation on 8 GPs' personal and professional criteria such as age, years of installation, location of their practice. We conducted a thematic analysis of the transcripts, following Miles and Huberman three steps model: data reduction, data presentation, conclusion drawing and verifications. RESULTS: We identified two behaviors leading to inappropriate prescription of ULTs among interviewed GPs. Primary prescribers frequently used uric acid serum levels and had a positive representation of ULTs. Other GPs behaved in an ambivalent way: they did not initiate ULTs, but systematically renewed preexisting prescriptions. They had a negative perception of ULTs but considered them unimportant during drug reassessment. De-prescribing occurred mainly because of external input such as the need to lighten the prescription or the participation in an audit in general practice. CONCLUSIONS: Our results support several strategies of ULTs de-prescribing in asymptomatic hyperuricemia: the promotion of de-prescribing of serum acid uric lab test in daily practice (a), supporting the clinical reasoning in the case of asymptomatic hyperuricemia detection (b) but also during ULTs renewals (c) leading to a prioritization of the safest prescriptions (d) through shared medical decision (e). Additional studies are necessary to further develop and evaluate these de-prescribing strategies.


Assuntos
Medicina de Família e Comunidade/normas , Clínicos Gerais/normas , Hiperuricemia/tratamento farmacológico , Prescrição Inadequada/estatística & dados numéricos , Adulto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Hiperuricemia/sangue , Masculino , Pessoa de Meia-Idade , Padrões de Prática Médica/normas , Pesquisa Qualitativa , Ácido Úrico/sangue
17.
J Ethnopharmacol ; 242: 112040, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31252094

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Lychnophora pinaster, known as "Brazilian arnica" is used in folk medicine as alcoholic extract to treat inflammation, pain, rheumatism and bruises. AIM OF THE STUDY: Evaluate the effects of the Lychnophora pinaster's ethanolic extract and its chemical constituents on inflammation and hyperuricemia. MATERIALS AND METHODS: Ethanolic and hexanic extracts were obtained from the aerial parts of L. pinaster. Sesquiterpene E-lychnophoric acid was isolated from hexanic extract and identified by RMN, GC/MS and IR. In vivo anti-hyperuricemic and anti-inflammatory effects of the ethanolic extracts from L. pinaster (40, 125, 375 mg/kg), E-lychnophoric acid and other constituents previous isolated from L. pinaster and identified in the ethanolic extract by HPLC/UV/DAD (rutin, quercetin and vitexina flavonoids, caffeic, cinnamic and chlorogenic acids, lupeol and stigmasterol, at dose of 15 mg/kg) were assayed by experimental model of oxonate-induced hyperuricemia in Swiss mice, liver xanthine oxidase (XOD) inhibition and by MSU-induced paw edema in mice. RESULTS: Ethanolic extract and all its components presented anti-hyperuricemic activity by inhibiting the hepatic xanthine oxidase activity. Ethanolic extract and its chemical constituents, except quercetin and vitexin, were able to reduce paw edema size induced by urate crystals. Hypouricemic and anti-inflammatory results obtained for the ethanolic extract (40, 125, 375 mg/kg) and E-lychnophoric acid (15 mg/kg) were similar those obtained for standard drugs, allopurinol (10 mg/kg) and indomethacin (3 mg/kg). CONCLUSION: Ethanolic extract and E-lychnophoric, chlorogenic, cinnamic and caffeic acids, rutin, lupeol and stigmasterol presented anti-inflammatory and anti-hyperuricemic actvities. These compounds are responsible for the activities presented by the ethanolic extract of L. pinaster. Ethanolic extract and its chemical constituents can be considered promising agents in the therapeutic of inflammation, hyperuricemia and gout.


Assuntos
Anti-Inflamatórios/uso terapêutico , Asteraceae , Supressores da Gota/uso terapêutico , Hiperuricemia/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Etanol/química , Supressores da Gota/química , Supressores da Gota/farmacologia , Hexanos/química , Hiperuricemia/sangue , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Camundongos , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Componentes Aéreos da Planta , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Solventes/química , Ácido Úrico/sangue , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo
18.
Phytochemistry ; 164: 228-235, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31181354

RESUMO

Terminthia paniculata (Sanyeqi) is widely used for treating inflammation and rheumatic arthritis in the folk areas of Yunnan province, China. Its total extract was first revealed with xanthine oxidase (XO) inhibitory activity in vitro and anti-hyperuricemic effect in vivo. Bioassay-guided separation on Fr. A5 yielded six chalcone-flavonone heterodimers, termipaniculatones A-F. Their structures were elucidated based on extensive spectroscopic analyses involving HRESIMS, 1D and 2D NMR, UV, IR and [α]D, and the absolute configuration of termipaniculatone F was verified by ECD calculation. Termipaniculatones A and E showed obvious XO inhibitory activity with IC50 values of 55.6 and 89.5 µM, respectively, which took effects via a mix-type mode. A molecular modeling study revealed that termipaniculatone A was well located into the active site of XO by interacting with Glu802, Arg880, Thr1010 and Val1011 residues. Termipaniculatone A showed anti-hyperuricemic effects by decreasing serum uric acid levels and inhibiting XO activity in both serum and liver on potassium oxonate (PO)-induced hyperuricemia mice, and anti-inflammatory activity through alleviating paw swelling on monosodium urate (MSU)-induced mice, at the concentration of 20 mg/kg. This is the first time to reveal the anti-hyperuricemic and anti-acute gouty arthritis potency of T. paniculata and the characteristic biflavonoids as active constituents, which provides valuable information for searching new XO inhibitors from natural sources.


Assuntos
Anacardiaceae/química , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Gotosa/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Hiperuricemia/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/metabolismo , Chalcona/química , Chalcona/isolamento & purificação , Chalcona/farmacologia , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Flavanonas/química , Flavanonas/isolamento & purificação , Flavanonas/farmacologia , Hiperuricemia/induzido quimicamente , Hiperuricemia/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Ácido Oxônico/antagonistas & inibidores , Relação Estrutura-Atividade , Ácido Úrico/antagonistas & inibidores , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo
19.
Mar Drugs ; 17(6)2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185695

RESUMO

The purpose of this study was to investigate the preventive effects of fucoidan (Fc) and fucoxanthin (Fx) on hyperuricemic rats. Sprague Dawley (SD) rats were randomly assigned to seven groups: a control group, a hyperuricemia (HUA) group, low- and high-dose Fx groups, a Fc group, a combination Fc and Fx group, and a positive control group. Three weeks after the interventions, each group was given potassium oxonate (PO) and hypoxanthine (HX) to induce HUA in all groups except for the control group, and the rats were then sacrificed. Blood and urine were analyzed for biochemical properties, and differences in urine volume were determined. Livers and kidneys were collected to analyze xanthine oxidase (XO) activity and the expression of uric acid (UA) transporter-related proteins (GLUT9, ABCG2, OAT1, URAT1). The results show that HUA was successfully induced by PO/HX after 4 h of administration. The activity of XO was significantly reduced by a combination of Fc and Fx. In the combination group, both ABCG2 and OAT1 increased significantly, whereas GLUT9 and URAT1 decreased significantly. In summary, the combination of Fc and Fx can inhibit the activity of XO in the liver and regulate the expression of proteins related to UA transporter in the kidney to reduce the UA level in serum.


Assuntos
Hiperuricemia/induzido quimicamente , Ácido Oxônico , Polissacarídeos/farmacologia , Xantofilas/farmacologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperuricemia/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/enzimologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Polissacarídeos/uso terapêutico , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Xantina Oxidase/metabolismo , Xantofilas/uso terapêutico
20.
AAPS PharmSciTech ; 20(5): 218, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31187334

RESUMO

The aim of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) for enhancement of the oral bioavailability of isoliquiritigenin (ISL) as well as evaluate its in vivo anti-hyperuricemic effect in rats. The ISL-loaded self-microemulsifying drug delivery system (ISL-SMEDDS) was comprised of ethyl oleate (EO, oil phase), Tween 80 (surfactant), and PEG 400 (co-surfactant). The ISL-SMEDDS exhibited an acceptable narrow size distribution (44.78 ± 0.35 nm), negative zeta potential (- 10.67 ± 0.86 mV), and high encapsulation efficiency (98.17 ± 0.24%). The in vitro release study indicated that the release rates of the formulation were obviously higher in different release media (HCl, pH 1.2; PBS, pH 6.8; double-distilled water, pH 7.0) compared with the ISL solution. The oral bioavailability of the ISL-SMEDDS was enhanced by 4.71 times in comparison with the free ISL solution. More importantly, ISL-SMEDDS significantly reduced uric acid level by inhibiting xanthine oxidase (XOD) activity in the model rats. Collectively, the prepared ISL-SMEDDS proved to be potential carriers for enhancing the solubility and oral bioavailability of ISL, as well as ameliorating its anti-hyperuricemic effect.


Assuntos
Chalconas/administração & dosagem , Chalconas/sangue , Sistemas de Liberação de Medicamentos/métodos , Hiperuricemia/sangue , Hiperuricemia/tratamento farmacológico , Administração Oral , Animais , Disponibilidade Biológica , Emulsões , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/sangue , Masculino , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/metabolismo , Ratos , Ratos Sprague-Dawley , Solubilidade , Tensoativos/administração & dosagem , Tensoativos/metabolismo
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