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Pesquisa : D27.505.519.174 [Categoria DeCS]
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  1 / 1591 MEDLINE  
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[PMID]:29505505
[Au] Autor:Zhang ZG; Liu XM
[Ti] Título:A case report with shock induced by tolvaptan in an elderly patient with congestive heart failure.
[So] Source:Medicine (Baltimore);97(1):e8706, 2018 Jan.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Tolvaptan (TLV) is a new vasopressin type 2 receptor antagonist effective in patients with heart failure (HF). Accumulating evidences have revealed that treatment with TLV does not alter the blood pressure significantly. PATIENT CONCERNS: An 84-year-old man was diagnosed with acute exacerbation of chronic HF due to ischemic cardiomyopathy, arrhythmia, mitral and aortic regurgitation. Treatment with TLV increased the urine volume and improved the dyspnea. After 4 days use of TLV (3.75 mg QD, 7.5 mg QD, 7.5 mg QD, and 15 mg QD, respectively), decrease in blood pressure to less than 90/60 mmHg was observed continuously and the lowest blood pressure was 80/37 mmHg. He was apyretic and felt only thirsty. Central venous pressure was 12 cmH2O. DIAGNOSES: Because no other medications were changed and no signs of hypovolemic, septic, allergic, or cardiac shock were detected, we suspected an adverse reaction to TLV. INTERVENTION: Intravenous hydration was performed with 250 mL of normal saline. OUTCOMES: His blood pressure increased gradually and the statue of hypotention lasted for 14 hours. The dose of TLV was decreased to 7.5 mg/d from the next day to discharge. During this period, his blood pressure was stable at about 125/60 mmHg. LESSONS: TLV has side effect of severe hypotension that is consistent with its physiological activity. The dose should be increased gradually to achieve the desired effect, while attention should be paid to potential drug interactions.
[Mh] Termos MeSH primário: Antagonistas de Receptores de Hormônios Antidiuréticos/efeitos adversos
Benzazepinas/efeitos adversos
Insuficiência Cardíaca/tratamento farmacológico
Choque/induzido quimicamente
[Mh] Termos MeSH secundário: Idoso de 80 Anos ou mais
Seres Humanos
Masculino
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antidiuretic Hormone Receptor Antagonists); 0 (Benzazepines); 21G72T1950 (tolvaptan)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180306
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000008706


  2 / 1591 MEDLINE  
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[PMID]:29384972
[Au] Autor:Liu YH; Han XB; Fei YH; Xu HT
[Ti] Título:Long-term low-dose tolvaptan treatment in hospitalized male patients aged >90 years with hyponatremia: Report on safety and effectiveness.
[So] Source:Medicine (Baltimore);96(52):e9539, 2017 Dec.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The retrospective study aimed at investigating the safety and clinical efficacy of long-term application of tolvaptan in patients >90 years old with hyponatremia. Although tolvaptan has been used to treat hyponatremia, the effect of its long-term use in elderly patients was unknown.Seven patients over 90 with isovolumic or hypervolemic hyponatremia admitted to the PLA Navy General Hospital between October 2011 and October 2013 were enrolled. The patients' serum sodium levels <135 mmol/L persisted for more than 3 months, and oral treatment with tolvaptan lasted for more than 12 months. Tolvaptan dose started from 7.5 mg once daily, with maximum dose no more than 30 mg daily. Clinical and laboratory data of the patients before and after treatment were compared.Serum sodium and chlorine levels increased significantly in the 1st 3 days after treatment (P < .05). All patients' serum sodium levels were above 135 mmol/L 1 month after treatment, and sustained through 1 year after treatment, without extra sodium supplementation. No serious complications were observed.The result indicated a significant improvement in the serum sodium levels and no serious adverse effects after long-term use in very elderly patients.
[Mh] Termos MeSH primário: Antagonistas de Receptores de Hormônios Antidiuréticos/uso terapêutico
Benzazepinas/uso terapêutico
Hiponatremia/tratamento farmacológico
[Mh] Termos MeSH secundário: Idoso de 80 Anos ou mais
Antagonistas de Receptores de Hormônios Antidiuréticos/administração & dosagem
Antagonistas de Receptores de Hormônios Antidiuréticos/efeitos adversos
Benzazepinas/administração & dosagem
Benzazepinas/efeitos adversos
Peso Corporal
Cloro/sangue
Relação Dose-Resposta a Droga
Hospitalização
Seres Humanos
Masculino
Estudos Retrospectivos
Sódio/sangue
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antidiuretic Hormone Receptor Antagonists); 0 (Benzazepines); 21G72T1950 (tolvaptan); 4R7X1O2820 (Chlorine); 9NEZ333N27 (Sodium)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180201
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009539


  3 / 1591 MEDLINE  
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[PMID]:28470952
[Au] Autor:Ouyang J; Carroll KJ; Koch G; Li J
[Ad] Endereço:Department of Biostatistics, Otsuka Pharmaceutical Development and Commercialization Incorporated, Princeton, NJ, USA.
[Ti] Título:Coping with missing data in phase III pivotal registration trials: Tolvaptan in subjects with kidney disease, a case study.
[So] Source:Pharm Stat;16(4):250-266, 2017 Jul.
[Is] ISSN:1539-1612
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Missing data cause challenging issues, particularly in phase III registration trials, as highlighted by the European Medicines Agency (EMA) and the US National Research Council. We explore, as a case study, how the issues from missing data were tackled in a double-blind phase III trial in subjects with autosomal dominant polycystic kidney disease. A total of 1445 subjects were randomized in a 2:1 ratio to receive active treatment (tolvaptan), or placebo. The primary outcome, the rate of change in total kidney volume, favored tolvaptan (P < .0001). The key secondary efficacy endpoints of clinical progression of disease and rate of decline in kidney function also favored tolvaptan. However, as highlighted by Food and Drug Administration and EMA, the interpretation of results was hampered by a high number of unevenly distributed dropouts, particularly early dropouts. In this paper, we outline the analyses undertaken to address the issue of missing data thoroughly. "Tipping point analyses" were performed to explore how extreme and detrimental outcomes among subjects with missing data must be to overturn the positive treatment effect attained in those subjects who had complete data. Nonparametric rank-based analyses were also performed accounting for missing data. In conclusion, straightforward and transparent analyses directly taking into account missing data convincingly support the robustness of the preplanned analyses on the primary and secondary endpoints. Tolvaptan was confirmed to be effective in slowing total kidney volume growth, which is considered an efficacy endpoint by EMA, and in lessening the decline in renal function in patients with autosomal dominant polycystic kidney disease.
[Mh] Termos MeSH primário: Rim Policístico Autossômico Dominante
[Mh] Termos MeSH secundário: Antagonistas de Receptores de Hormônios Antidiuréticos
Benzazepinas
Método Duplo-Cego
Seres Humanos
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE III; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Antidiuretic Hormone Receptor Antagonists); 0 (Benzazepines); 21G72T1950 (tolvaptan)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1002/pst.1808


  4 / 1591 MEDLINE  
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[PMID]:29394475
[Au] Autor:Pazmiño PA
[Ad] Endereço:Nephrology, Internal Medicine, and Hypertension Center, El Paso, TX drppazmino@msn.com
[Ti] Título:Tolvaptan in Later-Stage Polycystic Kidney Disease.
[So] Source:N Engl J Med;378(5):488-9, 2018 02 01.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Antagonistas de Receptores de Hormônios Antidiuréticos
Benzazepinas
[Mh] Termos MeSH secundário: Seres Humanos
Rim
Doenças Renais Policísticas
Rim Policístico Autossômico Dominante
[Pt] Tipo de publicação:LETTER; COMMENT
[Nm] Nome de substância:
0 (Antidiuretic Hormone Receptor Antagonists); 0 (Benzazepines); 21G72T1950 (tolvaptan)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180203
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMc1716478


  5 / 1591 MEDLINE  
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[PMID]:29394474
[Au] Autor:De Tymowski C; Legrand M
[Ad] Endereço:Hôpital Saint-Louis, Paris, France
[Ti] Título:Tolvaptan in Later-Stage Polycystic Kidney Disease.
[So] Source:N Engl J Med;378(5):488, 2018 02 01.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Antagonistas de Receptores de Hormônios Antidiuréticos
Benzazepinas
[Mh] Termos MeSH secundário: Seres Humanos
Rim
Doenças Renais Policísticas
Rim Policístico Autossômico Dominante
[Pt] Tipo de publicação:LETTER; COMMENT
[Nm] Nome de substância:
0 (Antidiuretic Hormone Receptor Antagonists); 0 (Benzazepines); 21G72T1950 (tolvaptan)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180203
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMc1716478


  6 / 1591 MEDLINE  
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[PMID]:29385372
[Au] Autor:Torres VE; Gansevoort RT; Czerwiec FS
[Ad] Endereço:Mayo Clinic, Rochester, MN torres.vicente@mayo.edu
[Ti] Título:Tolvaptan in Later-Stage Polycystic Kidney Disease.
[So] Source:N Engl J Med;378(5):489-490, 2018 02 01.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Antagonistas de Receptores de Hormônios Antidiuréticos
Benzazepinas
[Mh] Termos MeSH secundário: Seres Humanos
Rim
Doenças Renais Policísticas
Rim Policístico Autossômico Dominante
[Pt] Tipo de publicação:LETTER; COMMENT
[Nm] Nome de substância:
0 (Antidiuretic Hormone Receptor Antagonists); 0 (Benzazepines); 21G72T1950 (tolvaptan)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180201
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMc1716478


  7 / 1591 MEDLINE  
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[PMID]:29332911
[Au] Autor:Nakano Y; Mizuno T; Niwa T; Mukai K; Wakabayashi H; Watanabe A; Ando H; Takashima H; Murotani K; Waseda K; Amano T
[Ad] Endereço:Department of Cardiology, Aichi Medical University.
[Ti] Título:Impact of Continuous Administration of Tolvaptan on Preventing Medium-Term Worsening Renal Function and Long-Term Adverse Events in Heart Failure Patients with Chronic Kidney Disease.
[So] Source:Int Heart J;59(1):105-111, 2018 Jan 27.
[Is] ISSN:1349-3299
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Tolvaptan (TLV) has an inhibiting effect for worsening renal function (WRF) in acute decompensated heart failure (HF) patients. However, there are limited data regarding the effect of continuous TLV administration on medium-term WRF.This was a retrospective observational study in hospitalized HF patients with chronic kidney disease (CKD). TLV was administered to those patients with fluid retention despite standard HF therapy. We compared 34 patients treated with TLV (TLV group) to 33 patients treated with conventional HF therapy with high-dose loop diuretics (furosemide ≥ 40 mg) (Loop group). Clinical outcomes, including the incidence of medium-term WRF, defined as increase of serum creatinine > 0.3 mg/dL, at 6 months after discharge and adverse events rate, were evaluated.Baseline patient characteristics were not different between the TLV and Loop group. The TLV group consisted of less frequent use of loop diuretics and carperitide compared with the Loop group. The incidence of medium-term WRF was significantly lower in the TLV group than in the Loop group (3.2% versus 31.0%, P = 0.002). Multivariate logistic analysis showed that the TLV non-user was an independent predictor of medium-term WRF. Kaplan-Meier analysis revealed that the long-term event-free survival was significantly higher in the TLV group (log-rank P = 0.01).Continuous administration of TLV may reduce the risk of medium-term WRF, resulting possibility in improvement of long-term adverse outcomes in HF patients with CKD.
[Mh] Termos MeSH primário: Benzazepinas/administração & dosagem
Taxa de Filtração Glomerular/efeitos dos fármacos
Insuficiência Cardíaca/tratamento farmacológico
Insuficiência Renal Crônica/prevenção & controle
[Mh] Termos MeSH secundário: Idoso
Antagonistas de Receptores de Hormônios Antidiuréticos/administração & dosagem
Creatinina/metabolismo
Relação Dose-Resposta a Droga
Feminino
Seguimentos
Insuficiência Cardíaca/complicações
Insuficiência Cardíaca/metabolismo
Seres Humanos
Testes de Função Renal
Masculino
Prognóstico
Insuficiência Renal Crônica/complicações
Insuficiência Renal Crônica/fisiopatologia
Estudos Retrospectivos
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (Antidiuretic Hormone Receptor Antagonists); 0 (Benzazepines); 21G72T1950 (tolvaptan); AYI8EX34EU (Creatinine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180206
[Lr] Data última revisão:
180206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180116
[St] Status:MEDLINE
[do] DOI:10.1536/ihj.16-625


  8 / 1591 MEDLINE  
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[PMID]:29375117
[Au] Autor:Nakamura M; Sunagawa O; Kinugawa K
[Ad] Endereço:Second Department of Internal Medicine, University of Toyama.
[Ti] Título:Tolvaptan Improves Prognosis in Responders with Acute Decompensated Heart Failure by Reducing the Dose of Loop Diuretics.
[So] Source:Int Heart J;59(1):87-93, 2018.
[Is] ISSN:1349-3299
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:It is unknown whether a response to tolvaptan (TLV) is related to prognosis in patients with acute decompensated heart failure (ADHF). We selected 25 patients as responders by their urinary response to TLV and by reduction of loop diuretics from 37 consecutive ADHF patients treated with TLV. As a control group, we selected 25 patients from 100 consecutive ADHF patients who were not treated with TLV by propensity score matching for age, serum sodium level, serum creatinine level, plasma B-type natriuretic peptide (BNP) level, systolic blood pressure, heart rate, and dose of loop diuretics. The primary outcome was defined as a composite endpoint of mortality and/or hemodialysis. The amount of loop diuretics administered to responders was reduced by TLV from 68.8 ± 26.2 mg to 30.4 ± 18.6 mg of furosemide equivalents per day, whereas the loop diuretic dose administered to non-responders was increased. The event-free survival of the TLV responders during 20 months was significantly better than that of the control group (95.8% versus 68.4%, P = 0.0406). The TLV responders, plasma BNP level, and estimated glomerular filtration rate were significantly related to the events in the Cox proportional hazard analysis. Patients with ADHF who respond to TLV may have a better prognosis than propensity-matched patients not receiving TLV treatment. In TLV responders, it may be possible to improve the patient's prognosis if the dose of loop diuretics can be reduced with TLV therapy.
[Mh] Termos MeSH primário: Benzazepinas/administração & dosagem
Insuficiência Cardíaca/tratamento farmacológico
Inibidores de Simportadores de Cloreto de Sódio e Potássio/administração & dosagem
[Mh] Termos MeSH secundário: Idoso
Antagonistas de Receptores de Hormônios Antidiuréticos/administração & dosagem
Intervalo Livre de Doença
Relação Dose-Resposta a Droga
Feminino
Seguimentos
Taxa de Filtração Glomerular/efeitos dos fármacos
Taxa de Filtração Glomerular/fisiologia
Insuficiência Cardíaca/mortalidade
Insuficiência Cardíaca/fisiopatologia
Seres Humanos
Hiponatremia
Japão/epidemiologia
Masculino
Prognóstico
Pontuação de Propensão
Estudos Retrospectivos
Taxa de Sobrevida/tendências
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antidiuretic Hormone Receptor Antagonists); 0 (Benzazepines); 0 (Sodium Potassium Chloride Symporter Inhibitors); 21G72T1950 (tolvaptan)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180205
[Lr] Data última revisão:
180205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180130
[St] Status:MEDLINE
[do] DOI:10.1536/ihj.17-099


  9 / 1591 MEDLINE  
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[PMID]:28905441
[Au] Autor:Clark WF; Devuyst O; Roussel R
[Ad] Endereço:Division of Nephrology, Department of Medicine, London Health Sciences Centre, London, ON, Canada.
[Ti] Título:The vasopressin system: new insights for patients with kidney diseases: Epidemiological evidence and therapeutic perspectives.
[So] Source:J Intern Med;282(4):310-321, 2017 Oct.
[Is] ISSN:1365-2796
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:People with chronic kidney disease (CKD) are at risk of severe outcomes, such as end-stage renal disease or cardiovascular disease, and CKD is a globally increasing health burden with a high personal and economic cost. Despite major progresses in prevention and therapeutics in last decades, research is still needed to reverse this epidemic trend. The regulation of water balance and the state of activation of the vasopressin system have emerged as factors tightly associated with kidney health, in the general population but also in specific conditions; among them, various stages of CKD, diabetes and autosomal dominant polycystic kidney disease (ADPKD). Basic science findings and also epidemiological evidence have justified important efforts towards interventional studies supporting causality, and opening therapeutic avenues. On the basis of recent clinical data, the blockade of V2 vasopressin receptors using tolvaptan in patients with rapidly progressing ADPKD has been granted in several countries, and a long-term randomized trial evaluating the effect of an increase in water intake in patients with CKD is on-going.
[Mh] Termos MeSH primário: Nefropatias/fisiopatologia
Vasopressinas/fisiologia
[Mh] Termos MeSH secundário: Antagonistas de Receptores de Hormônios Antidiuréticos/uso terapêutico
Biomarcadores/sangue
Nefropatias Diabéticas/sangue
Nefropatias Diabéticas/fisiopatologia
Hidratação
Glicopeptídeos/sangue
Glicopeptídeos/fisiologia
Seres Humanos
Rim/fisiopatologia
Nefropatias/epidemiologia
Nefropatias/terapia
Rim Policístico Autossômico Dominante/tratamento farmacológico
Insuficiência Renal Crônica/epidemiologia
Insuficiência Renal Crônica/fisiopatologia
Insuficiência Renal Crônica/terapia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antidiuretic Hormone Receptor Antagonists); 0 (Biomarkers); 0 (Glycopeptides); 0 (copeptins); 11000-17-2 (Vasopressins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170915
[St] Status:MEDLINE
[do] DOI:10.1111/joim.12654


  10 / 1591 MEDLINE  
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[PMID]:28898297
[Au] Autor:Wu MY; Chen TT; Chen YC; Tarng DC; Wu YC; Lin HH; Tu YK
[Ad] Endereço:Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
[Ti] Título:Effects and safety of oral tolvaptan in patients with congestive heart failure: A systematic review and network meta-analysis.
[So] Source:PLoS One;12(9):e0184380, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:AIMS: Several studies reported treatment benefits of tolvaptan in patients with congestive heart failure (CHF). However, the optimal dosage remains unclear. We aimed to compare different dosage of tolvaptan to determine the optimal dosage in terms of the efficacy and safety. METHODS: We searched MEDLINE, PubMed, EMBASE, Cochrane CENTRAL and ClinicalTrials.gov through Aug 31, 2016. Randomized controlled trials (RCTs) comparing tolvaptan of different dosages or to placebo in patients with CHF were included. We used network meta-analysis to look for the optimal dosage in terms of effectiveness and safety. Urine output, body weight change and change in serum sodium were the main outcomes of efficacy. Adverse effects were the secondary outcomes. Quality was assessed by Cochrane risk-of-bias tool. RESULTS: Twelve RCTs reporting 14 articles with 5793 patients (mean age, 65.7 ± 11.9 years; 73.7% man) were included. Compared with placebo, the tolvaptan 30 mg had similar effects to tolvaptan 45-90 mg in terms of urine output (mean difference [MD] 2.03 liter; 95% confidence interval [CI] 1.3 to 2.71), body weight change (MD -1.12 kg; 95% CI -1.37 to -0.88) and change in serum sodium (MD 3.06 meq/L; 95% CI 2.43 to 3.68). Compared with placebo, tolvaptan of different dosage showed a non-significant higher risk of adverse effects. CONCLUSIONS: These findings suggest that tolvaptan 30 mg and 45 mg may be the optimum dosage for CHF patients, because of its ability to provide favourable clinical results without greater adverse effects. However, tolvaptan is not beneficial for reducing all-cause mortality in CHF patients.
[Mh] Termos MeSH primário: Antagonistas de Receptores de Hormônios Antidiuréticos/efeitos adversos
Benzazepinas/efeitos adversos
Insuficiência Cardíaca/tratamento farmacológico
[Mh] Termos MeSH secundário: Administração Oral
Adulto
Idoso
Antagonistas de Receptores de Hormônios Antidiuréticos/administração & dosagem
Antagonistas de Receptores de Hormônios Antidiuréticos/uso terapêutico
Benzazepinas/administração & dosagem
Benzazepinas/uso terapêutico
Feminino
Seres Humanos
Masculino
Meia-Idade
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; REVIEW
[Nm] Nome de substância:
0 (Antidiuretic Hormone Receptor Antagonists); 0 (Benzazepines); 21G72T1950 (tolvaptan)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170913
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184380



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