Efficacy of tolvaptan in an infant with syndrome of inappropriate antidiuretic hormone secretion associated with holoprosencephaly:A case report

BACKGROUND Holoprosencephaly(HPE)is a congenital malformation with various degrees of incomplete separation of the cerebral hemispheres due to differentiation disorders of the forebrain.Although HPE with diabetes insipidus due to associated pituitary dysfunction has been reported,HPE with the syndrome of inappropriate antidiuretic hormone secretion(SIADH)is very rare.Tolvaptan,a vasopressin V2 receptor antagonist,is effective in adults with SIADH.However,there is no report of its efficacy in infants with SIADH.The purpose of this report is to demonstrate that tolvaptan is effective for SIADH in infants and that administration of tolvaptan eliminates the need for restriction of water intake and sodium administration.CASE SUMMARY A 2414-g female infant was born at 38 wk by normal vaginal delivery.Facial anomalies and head magnetic resonance imaging indicated semilobar HPE.After birth,she had hyponatremia due to SIADH and was treated using water and sodium restriction.However,she developed an exaggerated response to the fluid restrictions,resulting in large fluctuations in serum sodium levels.Subsequent administration of tolvaptan improved the fluctuations in serum sodium levels without the need for adjustment of water or sodium administration.Serum sodium was maintained within the normal range after discontinuation of tolvaptan at 80 d of life.There were no side effects,such as hypernatremia or liver dysfunction,during the administration of tolvaptan.CONCLUSION This is the first report on the safety and efficacy of tolvaptan in an infant with SIADH associated with HPE.

Clinical efficacy of tolvaptan for treatment of refractory ascites in liver cirrhosis patients

AIM: To evaluate the efficacy and safety of tolvaptan to treat refractory ascites in decompensated liver cirrhosis patients with or without further complications, such as hepatorenal syndrome and/or hepatocellular carcinoma.

Tolvaptan regulates aquaporin-2 and fecal water in cirrhotic rats with ascites

AIM: To investigate the role of tolvaptan in regulating aquaporin(AQP)-2 expression and fecal water content in cirrhotic rats with ascites.METHODS: Cirrhosis with ascites was induced in rats by repetitive dorsal injection of CCl4 for 14 wk. In total, 84 cirrhotic rats with ascites divided into three groups(vehicle, 3 mg/kg and 5 mg/kg tolvaptan), and then further divided into five subgroups(days 1, 2, 3, 4, and 5). Blood samples were obtained to measure vasopressin and sodium concentrations. Rats were killed and colonic mucosa was scraped for analysis of protein expression and AQP-2 transcriptional level. The whole layer was fixed for hematoxylin&eosin(HE) staining and feces were collected for determination of fecal water content. CONCLUSION: Compared with vehicle, vasopressin decreased significantly in the tolvaptan groups from day 2 to a similar level in each treatment group. AQP-2 showed significant upregulation in cirrhotic rats with ascites compared with an untreated control group(100% ± 22.9% vs 22.2% ± 10.23%, P < 0.01). After administration of tolvaptan, AQP-2 expression began to decrease significantly from day 2 in each treatment group, but no significant difference was finally found between the treatment groups. Fecal water content inthe distal colon was increased by 5 mg/kg tolvaptan on day 1(66.8% ± 9.3% vs 41.4% ± 6.3%, in the vehicle group, P < 0.05). Fecal water content returned to baseline at day 4 at the latest in both treatment groups, and did not correspond to the change in AQP-2 expression. HE staining of the colonic mucosa showed no mucosal damage related to tolvaptan.CONCLUSION: Upregulation of AQP-2 in the distal colon is found in cirrhotic rats with ascites. Tolvaptan inhibits its expression and may decrease water reabsorption and induce diarrhea.

Efficacy of tolvaptan in patients with refractory ascites in a clinical setting

AIM: To elucidate the efficacies of tolvaptan(TLV) as a treatment for refractory ascites compared with conventional treatment. METHODS: We retrospectively enrolled 120 refractory ascites patients between January 1, 2009 and September 31, 2014. Sixty patients were treated with oral TLV at a starting dose of 3.75 mg/d in addition to sodium restriction(> 7 g/d), albumin infusion(10-20 g/wk), and standard diuretic therapy(20-60 mg/d furosemide and 25-50 mg/d spironolactone) and 60 patients with large volume paracentesis in addition to sodium restriction(less than 7 g/d), albumin infusion(10-20 g/wk), and standard diuretic therapy(20-120 mg/d furosemide and 25-150 mg/d spironolactone). Patient demographics and laboratory data, including liver function, were not matched due to the small number of patients. Continuous variables were analyzed by unpaired t-test or paired t-test. Fisher's exact test was applied in cases comparing two nominal variables. We analyzed factors affecting clinical outcomes using receiver operating characteristic curves and multivariate regression analysis. We also used multivariate Cox's proportional hazard regression analysis to elucidate the risk factors that contributed to the increased incidence of ascites.RESULTS: TLV was effective in 38(63.3%) patients. The best cut-off values for urine output and reduced urine osmolality as measures of refractory ascites improvement were > 1800 mL within the first 24 h and > 30%, respectively. Multivariate regression analysis indicated that > 25% reduced urine osmolality [odds ratio(OR) = 20.7; P < 0.01] and positive hepatitis C viral antibodies(OR = 5.93; P = 0.05) were positively correlated with an improvement of refractory ascites, while the total bilirubin level per 1.0 mg/dL(OR = 0.57;P = 0.02) was negatively correlated with improvement. In comparing the TLV group and controls, only the serum sodium level was significantly lower in the TLV group(133 mE q/L vs 136 mE q/L; P = 0.02). However, there were no significant differences in the other parameters between the two groups. The cumulative incidence rate was significantly higher in the control group with a median incidence time of 30 d in the TLV group and 20 d in the control group(P = 0.01). Cox hazard proportional multivariate analysis indicated that the use of TLV(OR = 0.58; P < 0.01), uncontrolled liver neoplasms(OR = 1.92; P < 0.01), total bilirubin level per 1.0 mg/dL(OR = 1.10; P < 0.01), and higher sodium level per 1.0 m Eq/L(OR = 0.94; P < 0.01) were independent factors that contributed to incidence. CONCLUSION: Administration of TLV results in better control of refractory ascites and reduced the incidence of additional invasive procedures or hospitalization compared with conventional ascites treatments.

Usefulness of portal vein pressure for predicting the effects of tolvaptan in cirrhotic patients

AIM: To elucidate influencing factors of treatment response, then tolvaptan has been approved in Japan for liquid retention.METHODS: We herein conducted this study to clarify the influencing factors in 40 patients with decompensated liver cirrhosis complicated by liquid retention. Tolvaptan was administered at a dosage of 7.5 mg once a day for patients with conventional diuretic-resistant hepatic edema for 7 d. At the initiation of tolvaptan, the estimated hepatic venous pressure gradient (HVPG) value which was estimated portal vein pressure was measured using hepatic venous catheterization. We analyzed the effects of tolvaptan and influencing factors associated with treatment response.RESULTS: Subjects comprised patients with a median age of 65 (range, 40-82) years. According to the Child-Pugh classification, class A was 3 patients, class B was 19, and class C was 18. Changes from the baseline in body weight were -1.0 kg (P = 2.04 × 10-6) and -1.3 kg (P = 1.83 × 10-5), respectively. The median HVPG value was 240 (range, 105-580) mmH2O. HVPG was only significant influencing factor of the weight loss effect. When patients with body weight loss of 2 kg or greater from the baseline was defined as responders, receiver operating characteristic curve analysis showed that the optimal HVPG cutoff value was 190 mmH2O in predicting treatment response. The response rate was 87.5% (7/8) in patients with HVPG of 190 mmH2O or less, whereas it was only 12.5% (2/16) in those with HVPG of greater than 190 mmH2O (P = 7.46 × 10-4). We compared each characteristics factors between responders and non-responders. As a result, HVPG (P = 0.045) and serum hyaluronic acid (P = 0.017) were detected as useful factors.CONCLUSION: The present study suggests that tolvaptan in the treatment of liquid retention could be more effective for patients with lower portal vein pressure.

血管加压素拮抗剂Tolvaptan对院内心力衰竭患者的疗效：随机对照试验

背景：美国每年约有一百万人因慢性心力衰竭而入院，多数与充血性心力衰竭恶化有关。利尿剂是充血性心力衰竭的主要治疗手段，可导致电解质紊乱和肾功能恶化。与利尿剂不同，血管加压素拮抗剂tolvaptan在减少心力衰竭患者血容量的同时对电解质和肾功能无副作用。

Efficacy of tolvaptan for the patients with advanced hepatocellular carcinoma

To investigate the factors influenced the efficacy of tolvaptan (TLV) in liver cirrhosis. METHODSWe retrospectively enrolled 61 consecutive patients with refractory hepatic ascites. All of them had been treated with furosemide and spironolactone before admission, and treated with TLV for 7 d in our hospital. The effect of TLV was defined by the rate of body weight loss, and the factors that influenced TLV efficacy were analyzed using multiple regression. RESULTSCoexistent hepatocellular carcinoma (HCC) was the only significant predictive variable that attenuated the efficacy of TLV. In stratified analysis, high doses of furosemide decreased the efficacy of TLV in patients with HCC, and increased efficacy in those without HCC. In the latter, a high Child-Pugh-Turcotte score had a positive influence and a high concentration of lactate dehydrogenase had a negative influence on the effectiveness of TLV. CONCLUSIONDevelopment of ascites may differ between patients with liver failure and those with HCC progression. A sufficient preceding dose of furosemide decreases diuretic effect of TLV.

The Effect of Loop Diuretics on Sarcopenia and Long-Term Prognosis in Patients with Refractory Hepatic Ascites Treated with Tolvaptan

We investigated sarcopenia, focusing on the dose of loop diuretics used in 70 patients with refractory hepatic ascites treated with tolvaptan. Bloating improved in 68.5% of patients, as determined using the Japanese version of the Support Team Assessment Schedule. The psoas muscle index (PMI) was used to define sarcopenia. A statistically significant difference was observed in the PMI between patients receiving low-dose (3.6 ± 1.2 cm2/m2) and high-dose furosemide (3.1 ± 1.2 cm2/m2) before tolvaptan treatment (P = 0.048). The PMI increased from 3.2 ± 1.1 cm2/m2 to 3.5 ± 1.3 cm2/m2 (P = 0.002) in responders, but decreased from 3.4 ± 1.2 cm2/m2 to 3.0 ± 1.0 cm2/m2 (P = 0.106) in non-responders before and after tolvaptan treatment, respectively. The long-term prognosis improved in responders compared with non-responders (mean survival time: 646 days vs. 228 days, P < 0.001). Early introduction of tolvaptan treatment is necessary to prevent the progression of sarcopenia.

The Evaluation of Tolvaptan Therapy and Long-Term Prognosis in Hepatocellular Carcinoma with Refractory Ascites

We investigated Tolvaptan efficacy and long-term prognosis with focus on nutrition in 20 patients with refractory hepatic ascites in hepatocellular carcinoma (HCC). Bloating improved in 55% of patients, as determined using a Japanese version of the Support Team Assessment Schedule. Nutritional status improved with Tolvaptan treatment, based on the Controlling Nutritional Status score and Onodera’s prognostic nutritional index. Long-term prognosis was better in responders than in non-responders (mean survival time: 308 days vs. 97 days, p = 0.031). Tolvaptan was even effective in many patients with HCC, with additional improvement in long-term prognosis expected with improvement in the nutritional status.

Tolvaptan ameliorated kidney function for one elderly autosomal dominant polycystic kidney disease patient: A case report

BACKGROUND Polycystic kidney disease(PKD)is a genetic disorder characterized by the growth of numerous cysts within the kidneys.Disease progress of some patients often occurs at the early stage.Thus,managing and controlling disease progress is important to slow the kidney function decline especially for the patient with other disorders.CASE SUMMARY One 80-year-old male autosomal dominant polycystic kidney disease(ADPKD)patient with chronic kidney disease and other clinical disorders was treated with tolvaptan and edoxaban.Estimated glomerular filtration rate,creatinine and uric acid were monitored during the treatment.In addition,the whole exome sequencing was performed to screen ADPKD genetic variants.The kidney function decline was prevented after using tolvaptan and edoxaban treatment and in the meantime,a venous thromboembolism was removed and leg and pedal edema were alleviated.One mutation c.10102G>A/p.D3368N in the PKD1 gene was identified.CONCLUSION Tolvaptan combined with edoxaban administration could delay kidney function decline and eliminate the edema caused by the thromboembolism.

Tolvaptan在低钠血症研究中有效

日本大塜制药公司说，其开发的低钠血症治疗药tolvaptan（Ⅰ）的二项试验显示，（Ⅰ）在使该症患者血钠水平正常化的情况下是安全有效的。

Tolvaptan获美快通道审批地位

美国FDA已经授予马里兰大塚研究所用于治疗常染色体显性多囊肾的血管紧张素-2抑制剂tolvaptan（Ⅰ）快速审批地位。此药物正处于预防严重染色体显性多囊肾病、肾脏增大及合并症如高血压、蛋白尿、肾痛的Ⅲ期临床试验中。在2004年的一项研究中，（Ⅰ）提高了使用血管紧张素抑制剂治疗充血性心力衰竭病人出现系统性水肿的可能性。马里兰大士冢研究所是大探制药公司的一部分。

大塚的tolvaptan被FDA受理

美国FDA已经受理了大螺制药公司的选择性V2加压素受体拮抗剂tolvaptan的新药申请，用于两种适应症：治疗成人恶化性心力衰竭和低钠血症。公司也计划向欧洲申请该药。

Plasma copeptin concentration is a predictor of tolvaptan efficacy in patients with hepatic ascites

Aims:No solid evidence-based opinion was raised regarding predictors of the degree of ascites reduction with tolvaptan.This retrospective cohort study aimed to examine whether serum copeptin concentration is a useful predictor of this.Methods:The study population consisted of 80 patients with liver cirrhosis treated with tolvaptan for hepatic ascites effusions at Nara Medical University Hospital from May 2014 to December 2018.Forty-three patients who lost>1.5 kg of body weight in the first week after starting tolvaptan were classified as good responders and the remaining 37 as poor responders.Various laboratory parameters were measured immediately before the start of tolvaptan therapy to examine factors associated with predicting its efficacy.Results:In the univariate analysis,no significant differences with respect to age(67.6 vs.69.8 years,p>0.05),sex,body mass index(24.8 vs.23.7 kg/m^(2),p>0.05),Child-Pugh score(9.4 vs.9.7,p>0.05),and Model for End-stage Liver Disease score(11 vs.12,p>0.05)were found between the two groups.Conversely,aspartate transferase and alanine transaminase(ALT)levels were significantly lower in the good response group(52.9±56.3 vs.68.8±50.7 U/L,p<0.05;26.2±30.6 vs.40.5±33.5 U/L,p<0.01),whereas serum copeptin and serum sodium concentrations were significantly higher(57.1±15.0 vs.45.8±16.0 pg/mL,p<0.01;136.3±3.4 vs.133.8±5.8 mEq/L,p<0.05).In the multivariate analysis,serum copeptin concentration and ALT were statistically significant factors(p<0.01,p<0.05).Regression analysis of the association between the tolvaptan efficacy for refractory ascites and pretreatment serum copeptin concentration showed that a copeptin concentration cutoff of 45.9 pg/mL could predict treatment efficacy with a sensitivity,specificity,and area under the curve of 76.7%,59.5%,and 0.71%,respectively.Conclusion:Serum copeptin concentration may be a predictor of tolvaptan efficacy for refractory ascites effusion in Japanese patients with liver cirrhosis.

The Efficacy and Safety of Tolvaptan in Heart Failure Patients with Congestive Signs:A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Objective:The aim of this study was to investigate the efficacy and safety of tolvaptan,as well as the impact of its treatment dose and duration in heart failure patients with congestive signs.Methods:The PubMed,Embase,Cochrane Library,and ClinicalTrials.gov databases were searched to collect data from all randomized controlled trials(RCT)examining the efficacy and safety of tolvaptan in heart failure patients with congestive signs compared with placebo or blank control until March 4,2021.Urine volume,change in body weight,improvement in dyspnea,and reduction of edema were evaluated as efficacy indicators.All-cause mortality,worsening heart failure,and adverse events were considered safety indicators.The quality of eligible publications was assessed using the Cochrane risk of bias for RCTs.Results:Ten RCTs with 5,980 patients were included in this analysis.Compared with control,tolvaptan significantly reduced weight in the short term(day 1,7 RCTs,weighted mean difference(WMD):-1.09,95%confidence interval(CI):-1.27 to-0.91;day 2,2 RCTs,WMD:-1.67,95%CI:-3.00 to-0.33;day 7,4 RCTs,WMD:-0.95,95%CI:-1.25 to-0.66),increased urine volume(WMD:1,825.72,95%CI:1,438.38-2,213.07),and relieved dyspnea(risk ratio(RR):1.12,95%CI:1.05-1.19)without increasing the mortality rate(RR:0.96,95%CI:0.87-1.06).Furthermore,the weight loss and increase in urine volume were not dose-dependent effects,and prolonged medication did not lead to sustained weight loss.In addition,there seemed to be more adverse events(RR:1.17,95%CI:1.03-1.32)after treatment with tolvaptan.Further analysis revealed that patients treated with tolvaptan were more likely to report thirst(RR:6.09,95%CI:3.37-11.00)and dry mouth(RR:6.36,95%CI:4.09-9.90),as well as develop hypernatremia(RR:12.76,95%CI:3.52-46.32).Conclusions:The meta-analysis shows that tolvaptan can improve congestion with no increase in mortality rate,but should be used to guard against adverse events.Deserve to be mentioned,the number of RCTs included was limited,suggesting that the observed results should be interpreted with caution.Additional robust clinical studies are warranted to validate the present findings.

托伐普坦治疗射血分数保留型心力衰竭合并低钠血症的临床观察

目的探讨托伐普坦治疗射血分数保留型心力衰竭(HFpEF)合并低钠血症的疗效和安全性。方法选择2020年1月1日-2023年6月1日南阳医学高等专科学校第一附属医院心内科收治的HFpEF合并有低钠血症患者106例,根据随机数字表法分为常规治疗组(53例)和托伐普坦组(53例)。常规治疗组患者给予常规治疗;托伐普坦组患者在常规治疗组的基础上给予托伐普坦片15 mg,24 h后增至30 mg,然后根据血清钠水平增减剂量,最大剂量不超过60 mg/d,血清钠水平≥150 mmol/L时停药。两组患者均治疗6个月。比较两组患者治疗前后的心功能指标[左室射血分数(LVEF)、左心室收缩末期内径(LVESD)、左心室舒张末期内径(LVEDD)、氨基末端脑利钠肽前体(NT-proBNP)]、24 h尿量、血清钠、血肌酐、尿素氮水平及其变化幅度,并记录不良反应发生情况。结果治疗前,两组患者各指标组间比较,差异均无统计学意义(P>0.05)。治疗后,两组患者的LVEF、24 h尿量、血清钠水平均显著高于同组治疗前,且托伐普坦组显著高于常规治疗组;LVESD、LVEDD、NT-proBNP均显著低于同组治疗前,且托伐普坦组显著低于常规治疗组(P<0.05或P<0.01)。托伐普坦组患者的心功能指标、24 h尿量、血清钠水平的变化均较常规治疗组更明显(P<0.05)。两组患者治疗前后的血肌酐、尿素氮水平及变化幅度,以及恶心呕吐、头晕、高钠血症、尿频的发生率比较,差异均无统计学意义(P>0.05)。结论托伐普坦能够改善HFpEF合并低钠血症患者的心功能,增加血钠水平,且不影响其肾功能,不增加不良反应的发生风险。