RESUMO
OBJECTIVE: Cystic fibrosis (CF) affects multiple organs, the most severe consequences being observed in the lungs. Despite significant progress in developing CF transmembrane conductance regulator-specific treatments for CF lung disease, exploring alternative CF-targeted medications seems reasonable. We sought to evaluate the potential beneficial effects of oral benzbromarone as an adjuvant therapy in CF patients with reduced lung function. METHODS: This was a prospective open-label pilot study of oral benzbromarone (100 mg/day) administered once daily for 90 days. Patients were followed at a tertiary referral center in southern Brazil. Safety was assessed by the number of reported adverse events. Secondary objectives included percent predicted FEV1 (FEV1%) and pulmonary exacerbations. RESULTS: Ten patients were enrolled. Benzbromarone was found to be safe, with no serious drug-related adverse events. Eight patients completed the study; the median relative change in FEV1% tended to increase during the treatment, showing an 8% increase from baseline at the final visit. However, a nonparametric test showed that the change was not significant (p = 0.06). Of a total of ten patients, only one experienced at least one pulmonary exacerbation during the study. CONCLUSIONS: Oral benzbromarone appears to be safe, and improved FEV1% has been observed in patients with CF. Further assessment in larger trials is warranted to elucidate whether oral benzbromarone can be a potential adjuvant therapy for CF.
Assuntos
Benzobromarona , Fibrose Cística , Humanos , Fibrose Cística/tratamento farmacológico , Fibrose Cística/fisiopatologia , Projetos Piloto , Masculino , Feminino , Benzobromarona/uso terapêutico , Benzobromarona/administração & dosagem , Estudos Prospectivos , Adulto , Resultado do Tratamento , Adulto Jovem , Adolescente , Volume Expiratório Forçado/efeitos dos fármacos , Uricosúricos/uso terapêutico , Estatísticas não Paramétricas , Quimioterapia Adjuvante , Fatores de TempoRESUMO
Abstract Background: The aims of this article were to assess the prevalence of nephrolithiasis and the factors associated with nephrolithiasis in Brazilian patients with primary gout. Methods: One hundred twenty-three patients with primary gout were recruited from a tertiary referral hospital in São Paulo, Brazil. All patients underwent ultrasonography and had their clinical and laboratory characteristics assessed. Results: One hundred fifteen (93.5%) patients were male, with a mean age of 62.9 ± 9.4 years. Twenty-three (18.7%) patients had asymptomatic nephrolithiasis (detected only by ultrasonography), 7 (6.0%) had symptomatic nephrolithiasis (detected by ultrasonography and a positive clinical history), and 13 (10.0%) had a history of kidney stones, but ultrasonography at evaluation did not show nephrolithiasis. Therefore, 35.0% of the patients had nephrolithiasis (detected either by ultrasonography and/or a positive clinical history). Nephrolithiasis was associated with male gender (43 [100%] vs 72 [90%], p = 0.049), the use of potassium citrate (13 [30.2%] vs 0, p < 0.001) and the use of medications for diabetes (10 [23.3%] vs 8 [10%], p = 0.047) and dyslipidemia (15 [34.9%] vs 10 [12.5%], p = 0.003); benzbromarone had an inverse association with nephrolithiasis (21 [48.8%] vs 55 [68.8%], p = 0.030). In patients with and without nephrolithiasis, no differences were found in the laboratory and ultrasonography characteristics, including serum uric acid levels, urinary uric acid excretion and urine pH. Conclusions: The prevalence of nephrolithiasis in primary gout was 35.0%, and 18.7% of the patients were asymptomatic. Nephrolithiasis was associated with male gender, diabetes and dyslipidemia. A positive history of nephrolithiasis probably biased the prescription of potassium citrate and benzbromarone.(AU)
Assuntos
Humanos , Síndrome Metabólica , Nefrolitíase/epidemiologia , Gota/fisiopatologia , Brasil/epidemiologia , Benzobromarona/efeitos adversos , Prevalência , Citrato de Potássio/efeitos adversos , Urolitíase/etiologiaRESUMO
BACKGROUND: Benzbromarone is a uricosuric drug that has been used in the treatment of gout over the last 30 years. Due to its potent inhibition of the dominant apical (luminal) urate exchanger in the human proximal tubule URAT1, it reduces the urate reabsorption, diminishing serum urate levels and therefore preventing gout flares. Through several clinical trials, Benzbromarone has been proved effective and safe, inclusive in patients with chronic kidney disease and as combination therapy with allopurinol. Due to hepatotoxicity reports, it was withdrawn from the European market by the manufacturer, however many authors have questioned the product's withdrawal due to a lack of clinical evidence in order to support its hepatotoxicity. Benzbromarone is still available in several European countries, New Zealand, Brazil and several other countries. Despite the product's marketing over more than 20 years after the first hepatotoxicity reports, we have found only five reports in our literature search, and no prospective or retrospective study correlating hepatotoxicity with benzbromarone use. SHORT CONCLUSION: Benzbromarone is a safe and effective molecule for the treatment of gout. However, due to in vitro and in vivo data related to hepatotoxicity, it is prudent to prescribe it with some caution, especially for patients with an already known liver condition.
Assuntos
Benzobromarona/uso terapêutico , Gota/tratamento farmacológico , Uricosúricos/uso terapêutico , Benzobromarona/efeitos adversos , Benzobromarona/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Humanos , Técnicas In Vitro , Fígado/efeitos dos fármacos , Fígado/metabolismo , Mitocôndrias Hepáticas/efeitos dos fármacos , Modelos Animais , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Retirada de Medicamento Baseada em Segurança , Exacerbação dos Sintomas , Uricosúricos/efeitos adversos , Uricosúricos/metabolismoRESUMO
BACKGROUND: The aims of this article were to assess the prevalence of nephrolithiasis and the factors associated with nephrolithiasis in Brazilian patients with primary gout. METHODS: One hundred twenty-three patients with primary gout were recruited from a tertiary referral hospital in São Paulo, Brazil. All patients underwent ultrasonography and had their clinical and laboratory characteristics assessed. RESULTS: One hundred fifteen (93.5%) patients were male, with a mean age of 62.9 ± 9.4 years. Twenty-three (18.7%) patients had asymptomatic nephrolithiasis (detected only by ultrasonography), 7 (6.0%) had symptomatic nephrolithiasis (detected by ultrasonography and a positive clinical history), and 13 (10.0%) had a history of kidney stones, but ultrasonography at evaluation did not show nephrolithiasis. Therefore, 35.0% of the patients had nephrolithiasis (detected either by ultrasonography and/or a positive clinical history). Nephrolithiasis was associated with male gender (43 [100%] vs 72 [90%], p = 0.049), the use of potassium citrate (13 [30.2%] vs 0, p < 0.001) and the use of medications for diabetes (10 [23.3%] vs 8 [10%], p = 0.047) and dyslipidemia (15 [34.9%] vs 10 [12.5%], p = 0.003); benzbromarone had an inverse association with nephrolithiasis (21 [48.8%] vs 55 [68.8%], p = 0.030). In patients with and without nephrolithiasis, no differences were found in the laboratory and ultrasonography characteristics, including serum uric acid levels, urinary uric acid excretion and urine pH. CONCLUSIONS: The prevalence of nephrolithiasis in primary gout was 35.0%, and 18.7% of the patients were asymptomatic. Nephrolithiasis was associated with male gender, diabetes and dyslipidemia. A positive history of nephrolithiasis probably biased the prescription of potassium citrate and benzbromarone.
Assuntos
Gota/complicações , Cálculos Renais/epidemiologia , Adulto , Doenças Assintomáticas/epidemiologia , Benzobromarona/uso terapêutico , Brasil/epidemiologia , Estudos Transversais , Diabetes Mellitus/tratamento farmacológico , Diuréticos/uso terapêutico , Dislipidemias/tratamento farmacológico , Feminino , Gota/tratamento farmacológico , Humanos , Hipoglicemiantes/uso terapêutico , Cálculos Renais/induzido quimicamente , Cálculos Renais/química , Cálculos Renais/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Citrato de Potássio/uso terapêutico , Prevalência , Fatores Sexuais , Ultrassonografia , Uricosúricos/uso terapêuticoRESUMO
Abstract Background Benzbromarone is a uricosuric drug that has been used in the treatment of gout over the last 30 years. Due to its potent inhibition of the dominant apical (luminal) urate exchanger in the human proximal tubule URAT1, it reduces the urate reabsorption, diminishing serum urate levels and therefore preventing gout flares. Main body of the abstract Through several clinical trials, Benzbromarone has been proved effective and safe, inclusive in patients with chronic kidney disease and as combination therapy with allopurinol. Due to hepatotoxicity reports, it was withdrawn from the European market by the manufacturer, however many authors have questioned the product's withdrawal due to a lack of clinical evidence in order to support its hepatotoxicity. Benzbromarone is still available in several European countries, New Zealand, Brazil and several other countries. Despite the product's marketing over more than 20 years after the first hepatotoxicity reports, we have found only five reports in our literature search, and no prospective or retrospective study correlating hepatotoxicity with benzbromarone use. Short conclusion Benzbromarone is a safe and effective molecule for the treatment of gout. However, due to in vitro and in vivo data related to hepatotoxicity, it is prudent to prescribe it with some caution, especially for patients with an already known liver condition.
Assuntos
Humanos , Benzobromarona/uso terapêutico , Gota/tratamento farmacológico , Alopurinol/administração & dosagem , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a MedicamentosRESUMO
BACKGROUND: Hyperuricemia frequently complicates cyclosporine (CsA) therapy. Previous studies have shown that hyperuricemia exacerbates interstitial and vascular lesions in the cyclosporine model. We tested the hypothesis that normalization of uric acid could prevent the development of cyclosporine toxicity. METHODS: CsA nephropathy was induced by administering CsA (15 mg/kg/day) for 7 weeks to rats on a low salt diet (CsA group). The effect of preventing hyperuricemia was determined by concomitant treatment with a xanthine oxidase inhibitor, allopurinol (CsAALP), or with a uricosuric, benzbromarone (CsABENZ), in drinking water. Control groups included vehicle-treated rats. RESULTS: CsA-treated rats developed mild hyperuricemia with arteriolar hyalinosis, tubular atrophy, striped interstitial fibrosis, increased cell proliferation and decreased VEGF expression. Treatment with allopurinol or benzbromarone limited renal disease, with reduced interstitial fibrosis, cell proliferation, macrophage infiltration, osteopontin expression and arteriolar hyalinosis, in association with restoration of VEGF expression. Both drugs provided comparable protection. CONCLUSIONS: An increase in uric acid exacerbates CsA nephropathy in the rat. Concomitant treatment with allopurinol or benzbromarone reduced the severity of renal disease. The similar protection observed with both drugs suggests that the effect is associated more with lowering uric acid levels than the antioxidant effect of allopurinol.
Assuntos
Alopurinol/farmacologia , Benzobromarona/farmacologia , Ciclosporina/toxicidade , Nefropatias/prevenção & controle , Animais , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Fibrose/prevenção & controle , Hiperuricemia/induzido quimicamente , Hiperuricemia/prevenção & controle , Imuno-Histoquímica , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Masculino , Osteopontina/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Ácido Úrico/sangue , Uricosúricos/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismoRESUMO
Gout continues to be a health problem around the world, and the treatment may turn into a real challenge when the patient presents a certain degree of chronic renal failure (CRF). We discuss a case of tophaceous gout in a 68-year-old male patient without urolithiasis and with uric acid (UA) underexcretion and CRF (creatinine clearance of 42 ml/min). Uricosuric treatment with benzbromarone and urinary alkalinization was administered, and acute gouty attacks improved substantially. Subsequently, allopurinol was added to the treatment to accelerate tophi reduction in the hands, feet, elbows and knees. After 30 months of treatment, serum UA declined from 10 to 3.2 mg/dl. Urinary UA excretion of 0.44 g/24 h in the baseline rose to 0.85 g/24 h, returning to the baseline value after 30 months. UA clearance tripled, rising from 3.05 ml/min before treatment to 9.48 ml/min, and remained at this level. It is worth stressing that even in cases of severe tophaceous gout, the response to clinical treatment may be satisfactory with substantial reduction of tophi and full acute gouty attack remission even in patients presenting a certain degree of CRF.
Assuntos
Benzobromarona/uso terapêutico , Gota/tratamento farmacológico , Ácido Úrico/urina , Uricosúricos/uso terapêutico , Idoso , Alopurinol/uso terapêutico , Taxa de Filtração Glomerular , Gota/complicações , Supressores da Gota/uso terapêutico , Humanos , Falência Renal Crônica/complicações , Masculino , Resultado do Tratamento , Ácido Úrico/sangue , Ácido Úrico/metabolismoRESUMO
The renal handling of urate was investigated in four children with hereditary renal hypouricemia and in their parents. The urate/creatinine clearance ratios in the four patients were 1.02 +/- 0.28, 0.93 +/- 0.11, 1.03 +/- 0.24, and 1.46 +/- 0.26, markedly higher than those in control subjects. Except for a partial response to pyrazinamide (change in clearance ratio from 1.46 to 1.07) in one patient, pyrazinamide and benzbromarone did not affect the clearance ratios in our patients. In the parents, the urate/creatinine clearance ratios were intermediate between those of the patients and control subjects, but responses to pyrazinamide and benzbromarone were normal. These data indicate that our patients have a combined defect in renal urate reabsorption, and that one of them might be subclassified as having the hypersecretion of defect. Results also show that heterozygotes can be identified by testing their urate/creatinine clearance ratio.
Assuntos
Nefropatias/genética , Túbulos Renais/fisiopatologia , Ácido Úrico/metabolismo , Benzobromarona , Criança , Pré-Escolar , Creatinina/sangue , Creatinina/urina , Humanos , Túbulos Renais/efeitos dos fármacos , Taxa de Depuração Metabólica , Pirazinamida , Ácido Úrico/sangue , Ácido Úrico/urinaRESUMO
A funçäo renal de 20 pacientes portadores de gota primária foi avaliada em estudo aberto, näo comparativo e unicêntrico, na vigência de tratamento com benzobromarona*. Foram incluídos no presente estudo somente pacientes normo ou hipoexcretores de ácido úrico. O fármaco foi administrado por via oral, na posologia de 100 mg diários, em uma única tomada, durante três semanas. Constatou-se um flagrante aumento da uricosúria em todos os casos avaliados, bem como uma acentuada reduçäo da uricemia. Os valores de calcemia, calciúria, fosfatemia, uréia, creatinina, sódio, potássio e a clearance de creatinina urinária näo mostraram alteraçöes importantes. Quanto à tolerabilidade ao medicamento, esta foi considerada boa, apesar de efeitos colaterais, facilmente controláveis, estarem presentes em 10 (50%) pacientes. Em nenhum dos casos foi necessário interromper-se a terapia