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1.
PLoS One ; 19(6): e0305906, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38905201

RESUMO

Uric acid induces radical oxygen species formation, endothelial inflammation, and endothelial dysfunction which contributes to the progression of atherosclerosis. Febuxostat inhibits BCRP- and allopurinol stimulates MRP4-mediated uric acid efflux in human embryonic kidney cells. We hypothesized that endothelial cells express uric acid transporters that regulate intracellular uric acid concentration and that modulation of these transporters by febuxostat and allopurinol contributes to their different impact on cardiovascular mortality. The aim of this study was to explore a potential difference between the effect of febuxostat and allopurinol on uric acid uptake by human umbilical vein endothelial cells. Febuxostat increased intracellular uric acid concentrations compared with control. In contrast, allopurinol did not affect intracellular uric acid concentration. In line with this observation, febuxostat increased mRNA expression of GLUT9 and reduced MRP4 expression, while allopurinol did not affect mRNA expression of these uric acid transporters. These findings provide a possible pathophysiological pathway which could explain the higher cardiovascular mortality for febuxostat compared to allopurinol but should be explored further.


Assuntos
Alopurinol , Febuxostat , Proteínas Facilitadoras de Transporte de Glucose , Células Endoteliais da Veia Umbilical Humana , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Ácido Úrico , Humanos , Alopurinol/farmacologia , Febuxostat/farmacologia , Ácido Úrico/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética , Transporte Biológico/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos
2.
Med Sci Monit ; 30: e944314, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38865287

RESUMO

BACKGROUND Hyperuricemia, which is common in chronic kidney disease and diabetes mellitus patients, raises health concerns. Febuxostat, a first-line urate-lowering agent, prompts cardiovascular risk questions, especially in high-risk patients. This study compared the effects of febuxostat and allopurinol on cardiovascular risk in diabetes mellitus and chronic kidney disease patients. MATERIAL AND METHODS This retrospective observational cohort study, conducted using Taiwan's National Health Insurance Research Database, focused on patients diagnosed with chronic kidney disease and diabetes between January 2012 and December 2017. The study population was divided into 2 groups: allopurinol users (n=12 901) and febuxostat users (n=2997). We performed 1: 1 propensity score matching, resulting in subgroups of 2997 patients each. The primary outcomes were assessed using a competing risk model, estimating hazard ratios (HR) for long-term outcomes, including the risks of all-cause hospitalization, hospitalization for heart failure, and hospitalization for cardiovascular interventions. RESULTS Febuxostat users, compared to allopurinol users, had higher all-cause hospitalization (HR: 1.33; 95% confidence interval [CI]: 1.25 to 1.42; P<.001), hospitalization for heart failure (HR: 1.62; 95% CI: 1.43 to 1.83; P<.001), and hospitalization for cardiovascular interventions (HR: 1.51; 95% CI: 1.32 to 1.74; P<.001). Moreover, the adverse effects of febuxostat on cardiac health were consistent across most subgroups. CONCLUSIONS Use of febuxostat in patients with diabetes mellitus and chronic kidney disease is associated with higher cardiovascular risks compared to allopurinol. Prudent evaluation is essential when recommending febuxostat for this at-risk group.


Assuntos
Alopurinol , Doenças Cardiovasculares , Febuxostat , Supressores da Gota , Hiperuricemia , Insuficiência Renal Crônica , Humanos , Febuxostat/uso terapêutico , Febuxostat/efeitos adversos , Alopurinol/uso terapêutico , Alopurinol/efeitos adversos , Masculino , Feminino , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Taiwan/epidemiologia , Hiperuricemia/tratamento farmacológico , Hiperuricemia/complicações , Supressores da Gota/uso terapêutico , Supressores da Gota/efeitos adversos , Diabetes Mellitus/tratamento farmacológico , Fatores de Risco , Adulto , Hospitalização
3.
Sci Rep ; 14(1): 11167, 2024 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750091

RESUMO

Xanthine oxidoreductase (XOR) contributes to reactive oxygen species production. We investigated the cytoprotective mechanisms of XOR inhibition against high glucose (HG)-induced glomerular endothelial injury, which involves activation of the AMP-activated protein kinase (AMPK). Human glomerular endothelial cells (GECs) exposed to HG were subjected to febuxostat treatment for 48 h and the expressions of AMPK and its associated signaling pathways were evaluated. HG-treated GECs were increased xanthine oxidase/xanthine dehydrogenase levels and decreased intracellular AMP/ATP ratio, and these effects were reversed by febuxostat treatment. Febuxostat enhanced the phosphorylation of AMPK, the activation of peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC)-1α and PPAR-α and suppressed the phosphorylation of forkhead box O (FoxO)3a in HG-treated GECs. Febuxostat also decreased nicotinamide adenine dinucleotide phosphate oxidase (Nox)1, Nox2, and Nox4 expressions; enhanced superoxide dismutase activity; and decreased malondialdehyde levels in HG-treated GECs. The knockdown of AMPK inhibited PGC-1α-FoxO3a signaling and negated the antioxidant effects of febuxostat in HG-treated GECs. Despite febuxostat administration, the knockdown of hypoxanthine phosphoribosyl transferase 1 (HPRT1) also inhibited AMPK-PGC-1α-FoxO3a in HG-treated GECs. XOR inhibition alleviates oxidative stress by activating AMPK-PGC-1α-FoxO3a signaling through the HPRT1-dependent purine salvage pathway in GECs exposed to HG conditions.


Assuntos
Proteínas Quinases Ativadas por AMP , Células Endoteliais , Glucose , Xantina Desidrogenase , Humanos , Glucose/metabolismo , Xantina Desidrogenase/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Purinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Febuxostat/farmacologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Glomérulos Renais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
4.
Eur J Pharm Sci ; 198: 106788, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38705421

RESUMO

Physiologically based pharmacokinetic (PBPK) models can help to understand the effects of gastric emptying on pharmacokinetics and in particular also provide a platform for understanding mechanisms of food effects, as well as extrapolation between different postprandial conditions, whether standardized clinical or patient-oriented, non-clinical conditions. By integrating biorelevant dissolution data from the GastroDuo dissolution model into a previously described mechanistic model of fed-state gastric emptying, we simulated the effects of a high-calorie high-fat meal on the pharmacokinetics of sildenafil, febuxostat, acetylsalicylic acid, theobromine and caffeine. The model was able to simulate the variability in Cmax and tmax caused by the presence of the stomach road. The main influences investigated to affect the gastric emptying process were drug solubility (theobromine and caffeine), tablet dissolution rate (acetylsalicylic acid) and sensitivity to gastric motility (sildenafil and febuxostat). Finally, we showed how PBPK models can be used to extrapolate pharmacokinetics between different prandial states using theobromine as an example with results from a clinical study being presented.


Assuntos
Simulação por Computador , Esvaziamento Gástrico , Modelos Biológicos , Período Pós-Prandial , Solubilidade , Esvaziamento Gástrico/fisiologia , Período Pós-Prandial/fisiologia , Humanos , Febuxostat/farmacocinética , Febuxostat/química , Teobromina/farmacocinética , Teobromina/química , Cafeína/farmacocinética , Cafeína/química , Cafeína/administração & dosagem , Citrato de Sildenafila/farmacocinética , Citrato de Sildenafila/química , Liberação Controlada de Fármacos , Aspirina/farmacocinética , Aspirina/química , Aspirina/administração & dosagem
5.
Ann Med ; 56(1): 2332956, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38738384

RESUMO

PURPOSE: It is unknown whether febuxostat can delay the progression of kidney dysfunction and reduce kidney endpoint events. The aim was to evaluate the renoprotective effect of febuxostat in patients with hyperuricemia or gout by performing a meta-analysis of randomized controlled trials (RCTs). METHODS: MEDLINE, Web of science, EMBASE, ClinicalTrials.gov, and the Cochrane Central Register for Randomized Controlled Trials were searched. The main outcomes included kidney events (serum creatinine doubling or progression to end-stage kidney disease or dialysis). The secondary outcomes were the rate of change in the estimated glomerular filtration rate (eGFR) and changes in the urine protein or urine albumin to creatinine ratio from baseline to the end of follow-up. We used random-effects models to calculate the pooled risk estimates and 95% CIs. RESULTS: A total of 16 RCTs were included in the meta-analysis. In comparison with the control group, the patients who received febuxostat showed a reduced risk of kidney events (RR = 0.56, 95% CI 0.37-0.84, p = 0.006) and a slower decline in eGFR (WMD = 0.90 mL/min/1.73 m2, 95% CI 0.31-1.48, p = 0.003). The pooled results also revealed that febuxostat use reduced the urine albumin to creatinine ratio (SMD = -0.21, 95% CI -0.41 to -0.01, p = 0.042). CONCLUSION: Febuxostat use is associated with a reduced risk of kidney events and a slow decline in eGFR. In addition, the urine albumin to creatinine ratio decreased in febuxostat users. Accordingly, it is an effective drug for delaying the progression of kidney function deterioration in patients with gout.Systematic review registration: PROSPERO CRD42021272591.


Assuntos
Febuxostat , Taxa de Filtração Glomerular , Supressores da Gota , Gota , Hiperuricemia , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Creatinina/urina , Creatinina/sangue , Progressão da Doença , Febuxostat/uso terapêutico , Febuxostat/farmacologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Gota/tratamento farmacológico , Gota/complicações , Supressores da Gota/uso terapêutico , Hiperuricemia/tratamento farmacológico , Hiperuricemia/complicações , Rim/fisiopatologia , Rim/efeitos dos fármacos , Falência Renal Crônica/prevenção & controle , Falência Renal Crônica/complicações
6.
Cardiol J ; 31(3): 479-487, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38771265

RESUMO

Xanthine oxidase inhibitors, including allopurinol and febuxostat, are the first-line treatment of hyperuricemia. This meta-analysis investigated the association between urate-lowering therapy and all-cause mortality in different chronic diseases to match its users and non-users in a real-world setting. Overall, 11 studies were included, which reported adjusted hazard ratios for all-cause mortality over at least 12 months. Meta-analysis of all included studies showed no effect of the therapy on all-cause mortality. However, subgroup analyses showed its beneficial effect in patients with chronic kidney disease (14% risk reduction) and hyperuricemia (14% risk reduction), but not in patients with heart failure (28% risk increase). Urate-lowering therapy reduces all-cause mortality among patients with hyperuricemia and chronic kidney disease, but it seems to increase mortality in patients with heart failure and should be avoided in this subgroup.


Assuntos
Causas de Morte , Hiperuricemia , Xantina Oxidase , Humanos , Xantina Oxidase/antagonistas & inibidores , Hiperuricemia/tratamento farmacológico , Hiperuricemia/mortalidade , Hiperuricemia/sangue , Causas de Morte/tendências , Inibidores Enzimáticos/uso terapêutico , Fatores de Risco , Alopurinol/uso terapêutico , Supressores da Gota/uso terapêutico , Febuxostat/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/mortalidade , Ácido Úrico/sangue , Insuficiência Renal Crônica/mortalidade , Adulto
7.
Int J Rheum Dis ; 27(5): e15165, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38769820

RESUMO

OBJECTIVE: To compare the clinical efficacy of febuxostat combined with a low-purine diet versus allopurinol combined with a low-purine diet in the treatment of gout. METHODS: In this prospective controlled trial, 98 gout patients admitted to our hospital from February 2021 to December 2022 were enrolled as study subjects. Patients were randomly assigned to the study group (febuxostat combined with a low-purine diet) and the control group (allopurinol combined with a low-purine diet), with 49 patients in each group. The therapeutic effect was evaluated based on joint function and serum uric acid levels after treatment, and classified into three levels: markedly effective, effective, and ineffective. The levels of inflammatory factors, including tumor necrosis factor-a (TNF-a), cytokine interleukin-1beta (IL-1ß), and interleukin (IL)-18 (IL-18), were collected. The Numeric Rating Scale (NRS) was used to assess the degree of pain in patients. Clinical indicators before and 6 months after treatment were compared between the two groups. RESULTS: There was no statistically significant difference in age and gender between the two groups. After 6 months of treatment, the effective rate in the study group (48 cases, 97.96%) was higher than that in the control group (42 cases, 85.71%), with a statistically significant difference (p = .027). At the same time, the study group had significantly lower levels of serum uric acid (162.39 µmol/L ± 17.23 µmol/L vs. S198.32 µmol/L ± 18.34 µmol/L, p < .001), creatinine (87.39 mmol/L ± 9.76 mmol/L vs. 92.18 mmol/L ± 9.27 mmol/L, p = .014), total cholesterol (3.65 mmol/L ± 0.65 mmol/L vs. 4.76 mmol/L ± 0.73 mmol/L, p < .001), and triglycerides (1.76 mmol/L ± 0.32 mmol/L vs. 2.28 mmol/L ± 0.41 mmol/L, p < .001) compared to the control group, with statistically significant differences (p < .05). After treatment, the levels of inflammatory factors and degree of pain in the study group were significantly lower than those in the control group (all p < .05). During the treatment process, the incidence of adverse reactions in the study group (2 cases, 4.08%) was lower than that in the control group (9 cases, 18.37%), with a statistically significant difference (p = .025). CONCLUSION: Febuxostat combined with a low-purine diet can reduce inflammatory factors and alleviate the degree of pain in gout patients, significantly improving their clinical symptoms.


Assuntos
Alopurinol , Febuxostat , Supressores da Gota , Gota , Ácido Úrico , Humanos , Febuxostat/uso terapêutico , Febuxostat/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Alopurinol/uso terapêutico , Gota/tratamento farmacológico , Gota/sangue , Gota/diagnóstico , Supressores da Gota/uso terapêutico , Supressores da Gota/efeitos adversos , Estudos Prospectivos , Resultado do Tratamento , Ácido Úrico/sangue , Idoso , Purinas/uso terapêutico , Biomarcadores/sangue , Terapia Combinada , Fatores de Tempo , Adulto , Mediadores da Inflamação/sangue
8.
Photochem Photobiol Sci ; 23(6): 1067-1075, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38625651

RESUMO

Photodynamic Therapy (PDT) is an emerging method to treat colorectal cancers (CRC). Hypericin (HYP) is an effective mediator of PDT and the ABCG2 inhibitor, Febuxostat (FBX) could augment PDT. HT29 and HEK293 cells showed light dependant cytotoxic response to PDT in both 2D and 3D cell models. FBX co-treatment was not found to improve PDT cytotoxicity. Next, ABCG2 protein expression was observed in HT29 but not in HEK293 cells. However, ABCG2 gene expression analysis did not support protein expression results as ABCG2 gene expression results were found to be higher in HEK293 cells. Although HYP treatment was found to significantly reduce ABCG2 gene expression levels in both cell lines, FBX treatment partially restored ABCG2 gene expression. Our findings indicate that FBX co-treatment may not be suitable for augmenting HYP-mediated PDT in CRC but could potentially be useful for other applications.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Antracenos , Neoplasias Colorretais , Febuxostat , Proteínas de Neoplasias , Perileno , Fotoquimioterapia , Fármacos Fotossensibilizantes , Humanos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Antracenos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Perileno/análogos & derivados , Perileno/farmacologia , Febuxostat/farmacologia , Febuxostat/uso terapêutico , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Células HEK293 , Sobrevivência Celular/efeitos dos fármacos , Células HT29 , Antineoplásicos/farmacologia , Antineoplásicos/química
9.
Sci Total Environ ; 924: 171565, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38461984

RESUMO

Gout is a metabolic arthritis caused by hyperuricemia. In recent years, the prevalence of gout has been increased significantly in China due to the improvement of the living standards, and gout has become another common metabolic disease following diabetes mellitus. Gout severely affects the health status and life quality of human. In order to monitor the near real-time prevalence of gout, a wastewater-based epidemiology (WBE) approach was carried out in 257 Chinese cities using febuxostat as the biomarker. Febuxostat in wastewater was measured by a LC-MS/MS method with satisfactory results of method validation. The average concentration of febuxostat in wastewater was 53.05 ± 31.76 ng/L, with the estimated per capita consumption of 124.40 ± 73.37 mg/day/1000 inhabitant. The calculated prevalence of febuxostat was 0.41 % ± 0.24 %, and the prevalence of gout was finally estimated to be 1.30 % ± 0.77 % (0.60 % to 2.11 %), which was nearly consistent with value of 1.10 % obtained from the Guideline for the diagnosis and management of hyperuricemia and gout in China (2019). The results indicated that the febuxostat-based WBE approach might be reasonable to assess the near real-time gout prevalence in China.


Assuntos
Gota , Hiperuricemia , Humanos , Hiperuricemia/epidemiologia , Hiperuricemia/diagnóstico , Febuxostat/uso terapêutico , Vigilância Epidemiológica Baseada em Águas Residuárias , Prevalência , Cromatografia Líquida , Águas Residuárias , Espectrometria de Massas em Tandem , Gota/epidemiologia , Gota/diagnóstico , China/epidemiologia
10.
Clin Transl Sci ; 17(3): e13757, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38488426

RESUMO

The cardiovascular (CV) safety of febuxostat compared to allopurinol for the treatment of hyperuricemia among Asian patients is uncertain. In this study, we conducted a systematic review and meta-analysis to compare the CV safety profiles of febuxostat with allopurinol in Asian patients with hyperuricemia. A total of 13 studies were included. On the basis of the pooled results of cohort studies, febuxostat users were at a significantly higher risk for acute coronary syndrome (ACS; hazard ratio [HR]: 1.06, 95% confidence interval [CI]: 1.03-1.09, p < 0.01), atrial fibrillation (HR: 1.19, 95% CI: 1.05-1.35, p < 0.01) than allopurinol users, whereas no significant difference between febuxostat and allopurinol existed for urgent coronary revascularization (HR: 1.07, 95% CI: 0.98-1.16, p = 0.13), and stroke (HR: 0.96, 95% CI: 0.91-1.01, p = 0.13). Nevertheless, that difference in results of acute decompensated heart failure (ADHF; HR: 0.73, 95% CI: 0.35-1.53, p = 0.40) and all-cause death (HR = 0.86, 95% CI: 0.49-1.51, p = 0.60) was not significant based on randomized controlled trials. In the Chinese subgroup, febuxostat could increase the risk of ADHF (HR: 1.22, 95% CI: 1.01-1.48, p < 0.05), CV death (HR: 1.25, 95% CI: 1.03-1.50, p < 0.05), and all-cause mortality (HR: 1.07, 95% CI: 1.01-1.14, p < 0.05) compared to allopurinol. In conclusion, the use of febuxostat, compared with allopurinol among Asian patients, was associated with a significantly increased risk of adverse CV events.


Assuntos
Doenças Cardiovasculares , Gota , Hiperuricemia , Humanos , Alopurinol/efeitos adversos , Febuxostat/efeitos adversos , Hiperuricemia/complicações , Hiperuricemia/tratamento farmacológico , Supressores da Gota/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Gota/tratamento farmacológico , Resultado do Tratamento
11.
Clin Rheumatol ; 43(5): 1745-1754, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38492092

RESUMO

OBJECTIVE: Urate-lowering therapy (ULT) is widely recognized as the primary treatment for hyperuricemia and gout. Xanthine oxidase inhibitors (XOI), particularly febuxostat, have gained popularity as a frontline approach. However, the divergent efficacy and safety between febuxostat and the traditional ULT drug, benzbromarone, remain poorly understood. This knowledge gap necessitates a comprehensive analysis and evidence update to guide drug selection for physicians and patients. METHOD: We conducted a systematic analysis by extracting relevant clinical studies from four medical literature databases. Forest plots, funnel plots, sensitivity analysis, Egger's test, and subgroup analysis were utilized to compare relevant indicators. RESULTS: The advantages and disadvantages of the two drugs were evaluated based on various indicators such as serum uric acid (SUA), triglyceride (TG), urinary uric acid (UUA), white blood cell count (WBC), total cholesterol (TC), blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), estimated glomerular filtration rate (eGFR), and serum creatinine (SC). Benzbromarone demonstrated better efficacy in rapidly reducing SUA levels and inhibiting inflammation for hyperuricemia and gout patients. Febuxostat was slightly less effective in lowering SUA, but there was no significant difference in its impact on liver and kidney function after long-term use. CONCLUSION: This study highlights the superiority of benzbromarone in rapidly reducing SUA and inhibiting inflammation. Febuxostat shows comparable effects on liver and kidney function after long-term use. These findings provide valuable insights for clinicians and patients in drug selection. Key Points • Benzbromarone stands out as a highly effective treatment for hyperuricemia and gout, offering rapid reduction of serum uric acid levels and potent anti-inflammatory effects. • When it comes to long-term use, febuxostat demonstrates comparable effects on liver and kidney function. This provides reassurance for patients who require extended treatment duration. • Moreover, our study goes beyond previous research by presenting a more comprehensive and detailed analysis.


Assuntos
Gota , Hiperuricemia , Humanos , Febuxostat/uso terapêutico , Hiperuricemia/tratamento farmacológico , Benzobromarona/uso terapêutico , Ácido Úrico , Supressores da Gota/efeitos adversos , Gota/tratamento farmacológico , Resultado do Tratamento , Inflamação/tratamento farmacológico , Alopurinol/uso terapêutico
12.
Rheumatol Int ; 44(7): 1245-1253, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38538820

RESUMO

OBJECTIVE: The objective of this study was to analyze and compare the effects of different urate-lowering agents on testicular functions in men with gout in a clinical setting. METHODS: In this prospective cohort study (Clinical Trial Registration Number: NCT04213534), a total of 49 male patients aged 18-45 years with gout were enrolled. They were divided into three groups and received treatment with either allopurinol, febuxostat or benzbromarone for a duration of 3 months. Semen parameters, reproductive hormones and biochemical assessments were evaluated at baseline, month 1, and month 3. RESULTS: Overall, 40 individuals (81.6%) completed the follow-up visits. In allopurinol group, there were no significant differences in semen parameters from baseline to month 3. Most of sperm parameters in febuxostat group did not show notable changes, except for a decrease in sperm motility at month 3(33.6%, [22.9-54.3] vs 48.4%, [27.4-67.6], p = 0.033). However, the total motile sperm count did not differ significantly after febuxostat treatment. Surprisingly, administration of benzbromarone resulted in improved sperm concentration (37.19 M/mL, [29.6-69.92] vs 58.5 M/mL, [49.8-116.6], p = 0.001). There were no significant changes observed in sperm DNA integrity and reproductive hormones in the three groups from baseline to month 3. The incidence of adverse events did not differ significantly among the three groups as well. CONCLUSION: This study is the first to demonstrate that urate-lowering agents, allopurinol and febuxostat, do not have clinically relevant negative effects on sperm quality and reproductive hormones in men with gout, and benzbromarone presents improving sperm concentration. Results provide important preliminary guidance for the development of reproductive health management guidelines for patients RCID with gout.


Assuntos
Alopurinol , Benzobromarona , Febuxostat , Supressores da Gota , Gota , Espermatozoides , Humanos , Masculino , Gota/tratamento farmacológico , Gota/sangue , Adulto , Estudos Prospectivos , Supressores da Gota/uso terapêutico , Supressores da Gota/efeitos adversos , Pessoa de Meia-Idade , Febuxostat/uso terapêutico , Febuxostat/farmacologia , Benzobromarona/uso terapêutico , Adulto Jovem , Alopurinol/uso terapêutico , Espermatozoides/efeitos dos fármacos , Motilidade dos Espermatozoides/efeitos dos fármacos , Análise do Sêmen , Adolescente , Contagem de Espermatozoides , Ácido Úrico/sangue
13.
Artigo em Inglês | MEDLINE | ID: mdl-38359644

RESUMO

Adenine phosphoribosyltransferase (APRT) deficiency is a rare , hereditary disorder characterized by renal excretion of 2,8-dihydroxyadenine (DHA), leading to kidney stone formation and chronic kidney disease (CKD). Treatment with a xanthine oxidoreductase inhibitor, allopurinol or febuxostat, reduces urinary DHA excretion and slows the progression of CKD. The method currently used for therapeutic monitoring of APRT deficiency lacks specificity and thus, a more reliable measurement technique is needed. In this study, an ultra-performance liquid chromatography-tandem mass spectrometry method for simultaneous quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in human plasma was optimized and validated. Plasma samples were prepared with protein precipitation using acetonitrile followed by evaporation. The chemometric approach design of experiments was implemented to optimize gradient steepness, amount of organic solvent, flow rate, column temperature, cone voltage, desolvation temperature and desolvation flow rate. Experimental screening was conducted using fractional factorial design with addition of complementary experiments at the axial points for optimization of peak area, peak resolution and peak width. The assay was validated according to the US Food and Drug Administration guidelines for bioanalytical method validation over the concentration range of 50 to 5000 ng/mL for DHA, allopurinol and febuxostat, 100 to 5000 ng/mL for adenine and 50 to 12,000 ng/mL for oxypurinol, with r2 ≥ 0.99. The analytical assay achieved acceptable performance of accuracy (-10.8 to 8.3 %) and precision (CV < 15 %). DHA, adenine, allopurinol, oxypurinol and febuxostat were stable in plasma samples after five freeze-thaw cycles at -80 °C and after storage at -80 °C for 12 months. The assay was evaluated for quantification of the five analytes in clinical plasma samples from six APRT deficiency patients and proved to be both efficient and accurate. The proposed assay will be valuable for guiding pharmacotherapy and thereby contribute to improved and more personalized care for patients with APRT deficiency.


Assuntos
Adenina Fosforribosiltransferase/deficiência , Adenina/análogos & derivados , Alopurinol , Erros Inatos do Metabolismo , Insuficiência Renal Crônica , Urolitíase , Humanos , Alopurinol/uso terapêutico , Oxipurinol , Febuxostat , Cromatografia Líquida , Espectrometria de Massas em Tandem/métodos , Espectrometria de Massa com Cromatografia Líquida , Adenina/metabolismo , Adenina Fosforribosiltransferase/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico
14.
Medicine (Baltimore) ; 103(7): e36436, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38363901

RESUMO

This study aimed to analyze the distribution of gout patients and the utilization of healthcare services in South Korea to provide valuable recommendations to clinicians and policymakers. A cross-sectional study was conducted. Claims data from the Health Insurance Review and Assessment Service spanning 2010 to 2019 were utilized, and a sample of 69,680 patients was included in the study. The incidence of gout was observed to be high in male patients over the age of 40, with most patients receiving outpatient care for gout management. Nonsteroidal anti-inflammatory drugs and urate-lowering agents were the most frequently prescribed medications, with prescriptions for colchicine and febuxostat increasing among urate-lowering agents. Musculoskeletal disorders were found to be the most common comorbidities among gout patients. Although the total costs of gout management increased, there was no significant increase in cost per patient. This study provides insights into the current state of healthcare utilization for gout patients in South Korea and trends in the disease burden and use of medications. The findings have crucial implications for clinicians and policymakers involved in decision-making regarding the management and treatment of gout.


Assuntos
Supressores da Gota , Gota , Humanos , Masculino , Supressores da Gota/uso terapêutico , Estudos Transversais , Ácido Úrico , Gota/tratamento farmacológico , Gota/epidemiologia , Febuxostat/uso terapêutico , Seguro Saúde , Custos de Cuidados de Saúde , Aceitação pelo Paciente de Cuidados de Saúde
15.
Br J Clin Pharmacol ; 90(5): 1322-1332, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38382554

RESUMO

AIMS: The aim of this study was to estimate adherence to urate-lowering therapy (ULT), predominately allopurinol, from Australia's Pharmaceutical Benefits Scheme (PBS) claims database in association with (1) patient-reported doses and (2) World Health Organization's (WHO) defined daily doses (DDD), namely, allopurinol (400 mg/day) or febuxostat (80 mg/day). METHODS: Proportion of days covered (PDC) was calculated in 108 Gout App (Gout APP) trial participants with at least two recorded ULT dispensings in an approximately 12-month period before provision of intervention or control apps. Adherence was defined as PDC ≥80%. We measured the correlation between the two methods of calculating PDC using a Wilcoxon signed rank test. Agreement between ULT-taking status (self-reports) and ULT-dispensed status (PBS records) was tested with Cohen's kappa (κ), and positive and negative percent agreement. RESULTS: Allopurinol was prescribed in 93.5% of participants taking ULT. Their self-reported mean daily dose (SD) was 291 (167) mg/day. Mean PDC (SD) for allopurinol was 83% (21%) calculated using self-reported dose, and 63% (24%) using WHO's DDD. Sixty-three percent of allopurinol users were identified as adherent (PDC ≥80%) using self-reported dose. There was good agreement between self-reported ULT use and PBS dispensing claims (κ = 0.708, P < .001; positive percent agreement = 90%, negative percent agreement = 82%). CONCLUSIONS: Participant-reported allopurinol daily doses, in addition to PBS dispensing claims, may enhance confidence in estimating PDC and adherence compared to using DDD. This approach improves adherence estimations from pharmaceutical claims datasets for medications where daily doses vary between individuals or where there is a wide therapeutic dose range.


Assuntos
Alopurinol , Febuxostat , Supressores da Gota , Gota , Adesão à Medicação , Autorrelato , Ácido Úrico , Humanos , Gota/tratamento farmacológico , Gota/sangue , Alopurinol/administração & dosagem , Alopurinol/uso terapêutico , Supressores da Gota/administração & dosagem , Supressores da Gota/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Austrália , Masculino , Feminino , Pessoa de Meia-Idade , Febuxostat/administração & dosagem , Febuxostat/uso terapêutico , Autorrelato/estatística & dados numéricos , Ácido Úrico/sangue , Idoso , Adulto , Bases de Dados Factuais
16.
Clin Pharmacol Ther ; 115(6): 1358-1364, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38389505

RESUMO

A recent meta-analysis found no benefit of uric acid-lowering therapy including febuxostat on death, cardiovascular events, or renal impairment. However, there may be populations that benefit from febuxostat in reducing mortality and cerebral and cardiovascular events. The aim of the present study was to examine the clinical benefit of febuxostat in elderly patients stratified by age using Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED) data. FREED was a randomized study involving patients aged 65 years or older with hyperuricemia and risk factors for cerebral, cardiovascular, or renal diseases. A total of 1,070 patients were included in this post hoc analysis, divided into 2 age groups: 65-74 years and ≥ 75 years. Patients were randomized into febuxostat and non-febuxostat groups, with uric acid levels monitored for 36 months. The primary composite end point included cerebral, cardiovascular, and renal events. In patients aged between 65 and 74 years, febuxostat significantly reduced the risk of future cerebral and cardiorenovascular events. However, no effects of febuxostat were found in the older population aged ≥ 75 years. Heterogeneity in potential interactions between the age and febuxostat treatment was particularly observed in non-fatal cerebral and cardiovascular events and all-cause death. Patients aged ≥ 75 years exhibited more pre-existing factors associated with cerebral and cardiorenovascular events than those aged 65-74 years. The effectiveness of febuxostat varies by age group, with potential benefits for patients aged 65-74 years. The effects of febuxostat are complex and it is important to consider patient characteristics in its clinical use.


Assuntos
Doenças Cardiovasculares , Febuxostat , Supressores da Gota , Hiperuricemia , Ácido Úrico , Humanos , Febuxostat/uso terapêutico , Hiperuricemia/tratamento farmacológico , Hiperuricemia/sangue , Idoso , Masculino , Feminino , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/mortalidade , Supressores da Gota/uso terapêutico , Supressores da Gota/efeitos adversos , Ácido Úrico/sangue , Fatores Etários , Idoso de 80 Anos ou mais , Transtornos Cerebrovasculares/prevenção & controle , Fatores de Risco , Resultado do Tratamento
17.
Nephron ; 148(7): 448-456, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38342092

RESUMO

INTRODUCTION: The aim of the study was to explore the association between urate-lowering agents and reduced response to erythropoietin-stimulating agents in patients suffering from chronic kidney disease G5. METHODS: We conducted a cross-sectional, multicenter study in Japan between April and June 2013, enrolling patients aged 20 years or older with an estimated glomerular filtration rate of ≤15 mL/min/1.73 m2. Exclusion criteria encompassed patients with a history of hemodialysis, peritoneal dialysis, or organ transplantation. The patients were categorized into four groups based on the use of urate-lowering drugs: high-dose allopurinol (>50 mg/day), low-dose allopurinol (≤50 mg/day), febuxostat, and no-treatment groups. We used a multivariable logistic regression model, adjusted for covariates, to determine the odds ratio (OR) for erythropoietin hyporesponsiveness, defined by an erythropoietin resistance index (ERI) of ≥10, associated with urate-lowering drugs. RESULTS: A total of 542 patients were included in the analysis, with 105, 36, 165, and 236 patients in the high-dose allopurinol, low-dose allopurinol, febuxostat, and no-treatment groups, respectively. The median and quartiles of ERIs were 6.3 (0, 12.2), 3.8 (0, 11.2), 3.4 (0, 9.8), and 4.8 (0, 11.2) in the high-dose allopurinol, low-dose allopurinol, febuxostat, and no-treatment groups, respectively. The multivariate regression model showed a statistically significant association between the high-dose allopurinol group and erythropoietin hyporesponsiveness, compared to the no-treatment group (OR = 1.98, 95% confidence interval: 1.10-3.57). CONCLUSIONS: Our study suggests that the use of high-dose allopurinol exceeding the optimal dose may lead to hyporesponsiveness to erythropoiesis-stimulating agents.


Assuntos
Alopurinol , Eritropoetina , Insuficiência Renal Crônica , Humanos , Masculino , Feminino , Alopurinol/administração & dosagem , Alopurinol/uso terapêutico , Pessoa de Meia-Idade , Idoso , Estudos Transversais , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Eritropoetina/administração & dosagem , Supressores da Gota/administração & dosagem , Supressores da Gota/uso terapêutico , Adulto , Relação Dose-Resposta a Droga , Ácido Úrico/sangue , Hematínicos/administração & dosagem , Hematínicos/uso terapêutico , Japão , Febuxostat/administração & dosagem , Febuxostat/uso terapêutico
18.
Arthritis Care Res (Hoboken) ; 76(6): 871-881, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38303574

RESUMO

OBJECTIVE: We systematically examined comparative gout flare risk after initiation or escalation of different urate-lowering therapies (ULTs), comparative flare risk with and without concomitant flare prophylaxis, adverse event rates associated with flare prophylaxis, and optimal duration of flare prophylaxis. METHODS: We searched the Medline, Embase, Web of Science, and Cochrane databases and clinical trial registries from inception to November 2021 for trials investigating adults with gout initiating or escalating ULT. We performed random effects network meta-analyses and calculated risk ratios (RRs) between treatments. Bias was assessed using the revised Cochrane risk-of-bias tool. RESULTS: We identified 3,775 records, of which 29 publications (27 trials) were included. When compared to placebo plus prophylaxis, the RR of flares ranged from 1.08 (95% confidence interval [CI] 0.87-1.33) for febuxostat 40 mg plus prophylaxis to RR 2.65 [95% CI 1.58-4.45] for febuxostat 80 mg plus lesinurad 400 mg plus prophylaxis. Compared to ULT alone, the RR of flares was lower for ULT plus rilonacept 160 mg (RR 0.35 [95% CI 0.25-0.50]), ULT plus rilonacept 80 mg (RR 0.43 [95% CI 0.31-0.60]) and ULT plus colchicine (RR 0.50 [95% CI 0.35-0.72]). There was limited evidence for other flare prophylaxis and on prophylaxis harms and optimal duration. Primarily because of missing outcome data and bias in the selection of reported results, 71.4% and 63.4% of studies were assessed as high risk of bias for flares and adverse events, respectively. CONCLUSION: The RR of flares when introducing ULT varies depending on ULT drug and dosing strategies. There were limited data on ULT escalation. Flare prophylaxis with colchicine and rilonacept reduces flare incidence. More research is required on the harms and optimal duration of prophylaxis.


Assuntos
Supressores da Gota , Gota , Metanálise em Rede , Exacerbação dos Sintomas , Ácido Úrico , Humanos , Gota/tratamento farmacológico , Gota/sangue , Supressores da Gota/uso terapêutico , Supressores da Gota/efeitos adversos , Supressores da Gota/administração & dosagem , Ácido Úrico/sangue , Medição de Risco , Colchicina/uso terapêutico , Colchicina/efeitos adversos , Colchicina/administração & dosagem , Febuxostat/uso terapêutico , Febuxostat/administração & dosagem , Febuxostat/efeitos adversos , Resultado do Tratamento , Fatores de Risco , Quimioterapia Combinada , Proteínas Recombinantes de Fusão
19.
Medicine (Baltimore) ; 103(4): e37081, 2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38277524

RESUMO

Generic febuxostat tablets were listed in China's third-round centralized drug procurement program. However, there are no sufficient data available on the use of febuxostat in a real-world setting. This study aimed to compare the efficacy, safety, and cost of selected generic febuxostat with original febuxostat in primary gout and hyperuricemia. Medical records at 3 tertiary hospitals from January 2014 to February 2022 were retrospectively analyzed. Propensity score matching was used to balance the distribution of baseline characteristics. The proportion of patients achieving target serum uric acid (SUA) levels at 12 weeks, the percent changes from baseline in SUA, adverse drug reactions, and the cost of febuxostat therapy were assessed. A total of 221 patients were recruited and 57 pairs of patients were 1:1 matched in the 2 groups. There was no statistically significant difference in the proportion of patients achieving a target SUA levels below 300 µmol/L, the percent changes of SUA decreased from baseline, and the incidence of adverse drug reactions between the 2 groups (all P > .05). The daily febuxostat cost in the generic group were significantly lower than that in original group (P < .05). Based on the results of this study, the clinical efficacy of selected generic febuxostat is comparable to that of original febuxostat for gout with hyperuricemia. No serious adverse reactions were reported in the 2 groups, and generic febuxostat is more economical than the original febuxostat.


Assuntos
Febuxostat , Gota , Hiperuricemia , Humanos , China , Análise Custo-Benefício , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Febuxostat/uso terapêutico , Gota/tratamento farmacológico , Supressores da Gota/uso terapêutico , Hiperuricemia/complicações , Estudos Retrospectivos , Comprimidos , Resultado do Tratamento , Ácido Úrico
20.
Drug Deliv Transl Res ; 14(7): 1909-1922, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38185775

RESUMO

Febuxostat (FBX), a potent xanthine oxidase inhibitor, is widely used as a blood uric acid-reducing agent and has recently shown a promising repurposing outcome as an anti-cancer. FBX is known for its poor water solubility, which is the main cause of its weak oral bioavailability. In a previous study, we developed a binary system complex between FBX and sulfobutylether-ß-cyclodextrin (SBE7-ßCD) with improved dissolution behavior. The aim of the current study was to investigate the effect of incorporating a water-soluble polymer with a binary system forming a ternary one, on further enhancement of FBX solubility and dissolution rate. In vivo oral bioavailability was also studied using LC-MS/MS chromatography. The polymer screening study revealed a marked increment in the solubility of FBX with SBE7-ßCD in the presence of 5% w/v polyethylene glycol (PEG 6000). In vitro release profile showed a significant increase in the dissolution rate of FBX from FBX ternary complex (FTC). Oral in vivo bioavailability of prepared FTC showed more than threefold enhancement in Cmax value (17.05 ± 2.6 µg/mL) compared to pure FBX Cmax value (5.013 ± 0.417 µg/mL) with 257% rise in bioavailability. In conclusion, the association of water-soluble polymers with FBX and SBE7-ßCD system could significantly improve therapeutic applications of the drug.


Assuntos
Disponibilidade Biológica , Febuxostat , Polietilenoglicóis , Solubilidade , beta-Ciclodextrinas , Febuxostat/farmacocinética , Febuxostat/química , Febuxostat/administração & dosagem , Animais , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacocinética , beta-Ciclodextrinas/administração & dosagem , Masculino , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/administração & dosagem , Administração Oral , Água/química , Liberação Controlada de Fármacos , Ratos Sprague-Dawley , Ratos
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