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1.
Clin Exp Hypertens ; 43(8): 730-741, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34425059

RESUMO

Background: Hyperuricemia is a risk factor for the development of hypertension and is comorbid in many hypertensive patients. According to Japanese hypertension management guidelines published in 2019, a target serum uric acid level of ≤6.0 mg/dL is recommended in hypertensive patients with gout or asymptomatic hyperuricemia. Dotinurad is a novel uric acid-lowering drug classified as a selective urate reabsorption inhibitor. A pooled analysis was performed on the uric acid-lowering effect of dotinurad in 222 hypertensive patients with gout or asymptomatic hyperuricemia in four clinical trials (NCT02344862, NCT02416167, NCT03100318, NCT03372200). Moreover, we analyzed the long-term uric acid-lowering effect of dotinurad in 154 hypertensive patients with gout or asymptomatic hyperuricemia (NCT03006445).Results: In the pooled analysis, the percent change in the decrease of serum uric acid with the use of dotinurad was 42.17 ± 12.42% at a dose of 2 mg and 60.42 ± 8.03% at a dose of 4 mg; the percentage of patients who achieved a serum uric acid level of ≤6.0 mg/dL was 82.8% and 100.0%. The long-term uric acid-lowering effect of dotinurad showed almost the same results. In this study, the concomitant use of diuretics or angiotensin II receptor blockers affected the uric acid-lowering effect of dotinurad at only a dose of 2 mg in the pooled analysis.Conclusions: In the pooled analysis, dotinurad lowered serum uric acid levels. Dotinurad has an achievement rate of over 80% for serum uric acid level of ≤6.0 mg/dL in both analyses, and will be clinically useful for the management of hyperuricemic states in hypertensive patients.


Assuntos
Gota , Hipertensão , Hiperuricemia , Preparações Farmacêuticas , Benzotiazóis , Ensaios Clínicos Fase II como Assunto , Gota/complicações , Gota/tratamento farmacológico , Supressores da Gota/uso terapêutico , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hiperuricemia/complicações , Hiperuricemia/tratamento farmacológico , Ácido Úrico , Uricosúricos/uso terapêutico
2.
Clin Exp Nephrol ; 25(12): 1336-1345, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34328574

RESUMO

BACKGROUND: Dotinurad is a selective urate reabsorption inhibitor (SURI), which selectively inhibits URAT1 to lower serum uric acid levels in patients with hyperuricemia. Herein, the effects of dotinurad were compared among patient groups with different stages of renal dysfunction. METHODS: Patient data from four clinical trials were pooled and divided into four groups according to the stage of renal dysfunction to compare the effects of dotinurad at different stages. The grouping (stages G1-G3b) was based on the estimated glomerular filtration rate (eGFR) of the patients. In addition, patient data from a long-term study (34 or 58 weeks) were evaluated in the same manner. RESULTS: In the pooled analysis, the percentage of patients achieving a serum uric acid level of ≤ 6.0 mg/dL was 64.7-100.0% at a dose of 2 or 4 mg. In the long-term analysis, the percentage of patients achieving a serum uric acid level of ≤ 6.0 mg/dL was 60.0-100.0% at a dose of 2 or 4 mg. Although the outcomes in stage G3b were worse due to higher baseline serum uric acid levels, satisfactory outcomes were observed in all stages. Even in stages G3a and G3b, when renal function declined, the eGFR remained constant throughout the dose period. CONCLUSION: The efficacy of dotinurad was confirmed in hyperuricemic patients with normal renal function (stage G1) and mild to moderate renal dysfunction (stage G2-G3b). Dotinurad was found to be effective in the treatment of hyperuricemia in patients with mild to moderate renal dysfunction.


Assuntos
Benzotiazóis/uso terapêutico , Hiperuricemia/tratamento farmacológico , Nefropatias/fisiopatologia , Rim/efeitos dos fármacos , Reabsorção Renal/efeitos dos fármacos , Ácido Úrico/sangue , Uricosúricos/uso terapêutico , Adulto , Idoso , Benzotiazóis/efeitos adversos , Biomarcadores/sangue , Ensaios Clínicos como Assunto , Feminino , Taxa de Filtração Glomerular , Humanos , Hiperuricemia/sangue , Hiperuricemia/diagnóstico , Hiperuricemia/fisiopatologia , Rim/metabolismo , Rim/fisiopatologia , Nefropatias/diagnóstico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Uricosúricos/efeitos adversos
3.
Biochem J ; 363(Pt 3): 761-8, 2002 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-11964177

RESUMO

The mechanism of inhibition of cell growth by deoxyspergualin was studied using mouse mammary carcinoma FM3A cells. Results of studies using deoxyspergualin analogues showed that both the guanidinoheptanate amide and glyoxyspermidine moieties of deoxyspergualin were necessary to cause inhibition of cell growth. When deoxyspergualin was added to the medium, there was a strong inhibition of cell growth and formation of active eukaryotic translation initiation factor 5A (eIF5A) at the third day of culture. There was also a marked decrease in cellular putrescine content and a small decrease in spermidine content. Accumulation of decapped mRNA, which is typically associated with eIF5A deficiency in yeast, was also observed. The inhibition of cell growth and the formation of active eIF5A was not reversed by addition of spermidine. The activity of deoxyhypusine synthase, the first enzyme in the formation of active eIF5A, was inhibited by deoxyspergualin in a cell-free system. These results, taken together, indicate that inhibition of active eIF5A formation is strongly involved in the inhibition of cell growth by deoxyspergualin.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Guanidinas/farmacologia , Lisina/análogos & derivados , Fatores de Iniciação de Peptídeos/antagonistas & inibidores , Proteínas de Ligação a RNA , Animais , Feminino , Guanidinas/química , Lisina/metabolismo , Camundongos , Modelos Químicos , Putrescina/metabolismo , Capuzes de RNA/metabolismo , RNA Mensageiro/metabolismo , Espermidina/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Fator de Iniciação de Tradução Eucariótico 5A
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