Efficacy of Sakubatril Valsartan Combined with Tolvaptan in the Treatment of Heart Failure Patients with Reduced Ejection Fraction and the Effects on Cardiovas-cular Events / 医药导报

Objective To investigate the efficacy of sakubatril valsartan combined with tolvaptan in the treatment of heart failure patients with reduced ejection fraction(HFrEF)and the effects on echocardiography and cardiovascular events.Methods According to the random number table method,400 patients with HFrEF admitted to the First People's Hospital from September 2017 to January 2022 were divided into the control group and the combination group with 200 cases each.Both groups were given conventional treatment,based on which the control group was given sacubitril valsartan and the combination group was given sacubitril valsartan combined with tolvaptan.The efficacy,echocardiographic indexes[left ventricular ejection fraction(LVEF),left ventricular end-diastolic internal diameter(LVEDD),left ventricular end-systolic internal diameter(LVESD)],myocardial injury indexes[serum brain natriuretic peptide(BNP),high-sensitivity troponin T(hs-CTnT),growth transforming factor-15(GDF-15)],urine output,neuroendocrine factors[antidiuretic hormone(ADH),angiotensin(PRA),angiotensin Ⅱ(Ang Ⅱ)],cardiovascular events and adverse effects were compared between the two groups.Results The total effective rate was 94.50%(189/200)higher in the combined group than 86.00%(172/200)in the control group(P＜0.05);LVEF was high-er in the combined group than in the control group after treatment,and LVEDD and LVESD were lower than in the control group(P＜0.05);BNP,hs-CTnT,GDF-15,ADH PRA,and Ang II were lower in the combined group than in the control group,and urine volume was higher than in the control group(P＜0.05);at 6-month follow-up after treatment,there were no statistically significant differences in the rehospitalization rate of heart failure,the incidence of non-fatal infarction,post-discharge cardiovascular mortali-ty and all-cause mortality in the combined group compared with those of the control group(P＞0.05);there were no statistically significant differences in the incidence of adverse events in the combined group compared with that of the control group(P＞0.05).Conclusion Sacubitril valsartan combined with tolvaptan is effective in treating HFrEF,by reducing myocardial inju-ry,promoting urination,and improving patients'cardiac function without increasing the risk of cardiovascular events and adverse reactions.

Clinical and biochemical profile of hyponatremia and the role of vaptans in comparison to other standard modalities of therapy

Background: This study, conducted from August 2014 to August 2015, investigated hyponatremia in 228 in-hospital patients, aiming to discern its clinical and biochemical features and compare the efficacy of vaptans against standard treatments. The null hypothesis assumed no significant disparity in outcomes, while the alternate hypothesis posited otherwise. Methods: Using an open-label, non-blinded, observational, prospective comparative design, we assessed 228 hyponatremia patients. We scrutinized their clinical and biochemical profiles and made comparisons between moderate and profound hyponatremia cases, along with different treatment approaches. Results: Our findings revealed that patients aged 61-80, primarily females, dominated the cohort. Moderate hyponatremia occurred in 56.6% of cases, with severe hyponatremia in 43.4%. Common symptoms included drowsiness, nausea, and vomiting. Euvolemic hyponatremia was predominantly due to SIADH, while heart failure led to most hypervolemic cases. Various treatments were employed, with fluid restriction and normal saline being common. Tolvaptan and 1.6% hypertonic saline significantly increased serum sodium levels at 24 and 48 hours. Hospital stay duration didn’t significantly differ, and no osmotic demyelination cases emerged. Mortality stood at 10.5%, notably higher in profound hyponatremia cases. Conclusions: This study provides insights into hyponatremia’s clinical and biochemical aspects and compares vaptans to standard treatments. Tolvaptan and hypertonic saline displayed promise in raising serum sodium levels. Nevertheless, further research is warranted to validate these findings and explore additional factors impacting hyponatremia treatment outcomes.

Efficacy and safety of tolvaptan for hyponatremia：an overview of systematic reviews/meta-analysis / 中国药房

OBJECTIVE To reevaluate systematic reviews/meta-analysis of efficacy and safety of tolvaptan for hyponatremia. METHODS Retrieved from CNKI， Wanfang Data， VIP， CBM， PubMed， Embase and the Cochrane Library database， systematic reviews/meta-analysis about tolvaptan for the treatment of hyponatremia were included from the inception to June 15， 2022. After screening literature and extracting data， the PRISMA statement， AMSTAR 2 scale and GRADE method were used to evaluate the reporting quality， methodological quality and evidence quality of the included literature， respectively. RESULTS A total of 6 articles were included， of which 1 was systematic review and 5 were meta-analysis， including 56 outcome indicators. All of the 6 studies had PRISMA scores ranging from 15.0 to 20.5， and the quality of them was moderate. Results of the AMSTAR 2 scale showed that the methodological quality of 5 literatures were very low， and the quality of 1 literature was low. The quality of GRADE evidence showed that there were 6 moderate-quality indicators， 13 low-quality indicators， 35 very low-quality indicators， and 2 indicators that could not be assessed due to missing data. The main factors causing degradation were limitations， inconsistency， imprecision and publication bias. In terms of efficacy， tolvaptan could effectively increase the level of serum sodium， increase urine volume， reduce body weight， reduce abdominal circumference， relieve edema， and reduce alaninetransaminase level. In terms of safety， the incidence of total adverse drug reaction induced by tolvaptan was controversial； it may increase the risk of dry mouth， thirst， frequent urination or excessive correction of serum sodium. CONCLUSIONS Tolvaptan has great efficacy in the treatment of hyponatremia， but serum sodium overcorrection should be avoided in terms of safety. Relevant systematic reviews/meta-analysis have shortcomings of low reporting quality， methodological quality and evidence quality， which may reduce the reliability of the results， so the results should be treated with caution.

Identification of In Vivo Metabolites of Tolvaptan in Rats / 医药导报

Objective The metabolites of tolvaptan in rats were identified by ultra-performance liquid chromatography-quadrupole-exactive orbitrap high-resolution mass spectrometry(UFLC-Q-Exactive Orbitrap MS),and the possible metabolic pathways of tolvaptan in rats were discussed.Methods Plasma,urine and fecal samples from rats were collected after a single oral administration of 60 mg·kg-1 tolvaptan solid dispersion solution.The protein in the samples was precipitated with acetonitrile.UFLC-Q-exactive orbitrap MS technology was adopted for the sample analysis and the data were processed by Xcalibur 2.0 software.Results According to the retention time,precise relative molecular mass,characteristic fragment ions and related literature reports of each compound,35 metabolites were identified in rat biological samples.Moreover,23,26 and 30 metabolites in the plasma,urine and feces were identified,respectively.The major metabolic pathways of tolvaptan were identified as hydroxylation,carboxylation,hydrolysis,dehydrogenation,glucuronidation and acetylation.Conclusion Our study confirmed the major metabolites of tolvaptan in rats,enriched the metabolite spectrum of tolvaptan in vivo,and provided an experimental basis for the in-depth study of the pharmacodynamic substance basis of tolvaptan.

Poliquistosis renal autosómica dominante: ¿quiénes se benefician del tratamiento con tolvaptán?. Estado del arte / Autosomal dominant polycystic kidney disease. Who can benefit from tolvaptan therapy? State of the art / Doença renal policística autossômica dominante: quem se beneficia do tratamento com tolvaptano? Estado da arte

Resumen: La poliquistosis renal autosómica dominante es la enfermedad renal hereditaria más frecuente. Se caracteriza por la progresiva aparición de quistes renales que suelen conducir a la enfermedad renal crónica extrema en la edad adulta. La aprobación del uso de tolvaptán (antagonista del receptor V2 de la vasopresina) ha marcado un cambio significativo en el tratamiento de esta enfermedad. En los últimos años apareció evidencia que demuestra el beneficio en iniciar tratamiento con tolvaptán en pacientes que presentan una enfermedad con rápida evolución. Se realiza una revisión descriptiva de los principales estudios clínicos publicados en el periodo 2012-2022 y se sugiere un esquema de utilidad para seleccionar aquellos pacientes que pueden beneficiarse del inicio de tratamiento.

Abstract: Autosomal dominant polycystic kidney disease is the most common hereditary kidney disease. It is characterized by the progressive appearance of renal cysts that usually lead to extreme chronic kidney disease in adulthood. The approval of the use of tolvaptán (V2 vasopressin receptor antagonist) has meant a significant change in the treatment of this disease. In recent years, evidence has proved the benefits of initiating treatment with tolvaptán in patients with a rapidly evolving disease. A descriptive review of the main clinical studies published in 2012-2022 period is carried out and a useful scheme is suggested to select those patients who can benefit from the start of treatment.

Resumo: A doença renal policística autossômica dominante é a doença renal hereditária mais comum. Caracteriza-se pelo aparecimento progressivo de cistos renais que geralmente levam à doença renal crônica extrema na idade adulta. A aprovação do uso do tolvaptano (antagonista do receptor de vasopressina V2) marcou uma mudança significativa no tratamento dessa doença. Nos últimos anos, surgiram evidências que demonstram o benefício de iniciar o tratamento com tolvaptano em pacientes com doença de evolução rápida. Faz-se uma revisão descritiva dos principais estudos clínicos publicados no período 2012-2022 e sugere-se um esquema útil para selecionar aqueles pacientes que podem se beneficiar do início do tratamento.

Tolvaptan add-on therapy and its effects on efficacy parameters and outcomes in patients hospitalized with heart failure

Introduction: Even with the adequate use of diuretics and vasodilators, volume overload and congestion are the major causes of morbidity and mortality in patients hospitalized with acute heart failure (HF). We aim to evaluate the additive effect of tolvaptan on efficacy parameters as well as outcomes in hospitalized patients with HF. Methods: We searched PubMed, EMBASE, Cochrane library, and Web of Science databases for randomized controlled trials that studied the effects of tolvaptan versus placebo in hospitalized patients with HF. Studies were included if they had any of the following endpoints: mortality, re-hospitalization, and inhospital parameters like dyspnea relief, change in weight, sodium, and creatinine. Results: The meta-analysis analyzed data from 14 studies involving 5945 patients. The follow up duration ranged from 30 days to 2 years. Between tolvaptan and placebo groups, there was no difference in mortality and rehospitalization. HF patients had a better dyspnea relief score (Likert score) in tolvaptan group and mean reduction in weight in the first 48 h (short-term). However, at 7 days (medium-term) the mean difference in weight was not significant. Serum sodium increased significantly in tolvaptan group. There was no difference in creatinine among the two groups. Conclusions: Our meta-analysis shows that tolvaptan helps in short-term symptomatic dyspnea relief and weight reduction, but there are no long term benefits including reduction in mortality and rehospitalization.

Refractory hyponatremia caused by acute intermittent porphyria / 中华内分泌代谢杂志

Hyponatremia is common in the attack of acute intermittent porphyria(AIP), which can cause epilepsy, coma and other adverse events and endanger the life of patients. Carbohydrate loading therapy is applied to control the attack of AIP in the clinic. But the application of glucose can exacerbate hyponatremia. It is difficult for clinicians to effectively correct hyponatremia while treating AIP with glucose. We reported a case of AIP whose refractory hyponatremia was corrected with short-term low-dose tolvaptan to improve knowledge in management.

Signal mining and analysis of adverse drug events for tolvaptan based on FAERS database / 中国药房

OBJECTIVE To mine the signals of adverse dr ug events （ADE）for tolvaptan based on FAERS database ，and to provide reference for safe use of drugs in clinic. METHODS The data of tolvaptan-induced ADE were collected from FAERS database during the first quarter of 2004 to the third quarter of 2020；the reporting odds ratio （ROR）method and the proportional reporting ratio （PRR）method of disproportional method were used for data mining. RESULTS A total of 4 744 ADE reports of the target drug tolvaptan were extracted ，involving 1 279 ADEs. The reporting countries were mainly the United States and Japan ，etc. A total of 199 ADE signals were obtained ，involving 21 system organ classes （SOCs），which mainly focused on various examinations（n＝56），hepatobiliary disorders （n＝17），renal and urinary disorders （n＝14），etc. Among them ，80 signals were not mentioned in existing instructions for tolvaptan in China ，such as decreased glomerular filtration rate ，positional vertigo ， rupture of renal cyst ，renal cyst infection ，pulmonary malignant tumor. CONCLUSIONS Before using tolvaptan ，drug evaluation should be performed well ，especially the patients with basic diseases such as heart failure ，liver insufficiency and renal insufficiency. During treatment ，the indexes of liver function and renal function should be closely monitored ；timely intervention measures should be taken to avoid related injury and disease deterioration caused by ADE when ADE or disease progression occurs.

Experiencia clínica con el uso ambulatorio de tolvaptan. Costes y efectividad en nueve casos / Clinical experience with Tolvaptan outpatient use. Cost and effectiveness in 9 cases

Resumen Introducción: La introducción de tolvaptan ha supuesto la principal novedad en el tratamiento de la hiponatremia en los últimos años. Objetivo: Describir la experiencia con tolvaptan en el Complejo Asistencial Universitario de León, España. Método: Estudio observacional retrospectivo de utilización ambulatoria de tolvaptan en un hospital de tercer nivel, de marzo de 2014 a agosto de 2017. Resultados: Fueron tratados con tolvaptan de forma ambulatoria nueve pacientes, 23.1 % alcanzó eunatremia en 24 horas. Posterior a la administración de tolvaptan se registró reducción en días de hospitalización (361 versus 70, p = 0.007), especialmente por hiponatremia (306 versus 49, p = 0.009). Conclusiones: El uso a largo plazo de tolvaptan parece ser seguro y se relaciona con descenso en los días de hospitalización.

Abstract Introduction: Tolvaptan introduction has constituted the main therapeutic novelty in the management of hyponatremia in recent years. Objective: To describe the experience with this drug at Complejo Asistencial Universitario de León, Spain. Method: Retrospective, observational study of tolvaptan outpatient use in a tertiary care hospital from March 2014 to August 2017. Results: A total of 9 patients were treated with tolvaptan in the outpatient setting. Eunatremia was reached in 24 h by 23.1%. After tolvaptan administration, a reduction in days of hospitalization was recorded (361 vs. 70; p = 0.007), especially in those days of hospitalization that were attributable to hyponatremia (306 vs. 49; p = 0.009). Conclusions: Long-term use of tolvaptan appears to be safe and is associated with a decrease in days of hospitalization.

Data Mining and Analysis of Tolvaptan Related Adverse Events of Death based on FAERS / 中国药学杂志

OBJECTIVE: To detect and analyze signals of tolvaptan related adverse events of death through data mining methods based on FAERS data. METHODSE: Downloaded 60 quarters of FARES data from 2004Q1 to 2018Q4. After drug names standardized by MedEx and adverse events classified by MedDRA, searched tolvaptan related to death events reports, and detected the ADE signal using ROR and PRR methods. RESULTS: A total of 4 641 reports of tolvaptan were gathered, including 360 death reports, PRR=1.90, χ2=158.59, the signal of death wasn't detected. However, the lower limit of ROR 95%CL=1.72, the signal of death was detected. There were significant differences between the two methods. The signal of subgroup of death were detected by both methods, a=8, PRR=2.29, χ2=5.72, the lower limit of ROR 95%CI=2.28. In the death reports, 41.39% were old patients(>65 years old), there were cases suffering multiple comorbidities and using multiple drugs. CONCLUSION: The potential death risk of tolvaptan should be paid attention to, especially the old patients and drug-drug interactions should be strictly monitored.

Tolvaptan attenuates atrial remodeling in rats undergoing chronic intermittent hypoxia via miRNA-21 / 中华心血管病杂志

Objective@#To investigate the effects and potential mechanisms of tolvaptan on chronic intermittent hypoxia (CIH)-induced atrial remodeling in rats.@*Methods@#A total of 45 Sprague-Dawley rats were divided into 3 groups by the random number table: control group, CIH group (6 h/d for 30 days), CIH plus tolvaptan group (8 mg·kg-1·d-1 per gavage for 30 days). Echocardiography examination was performed after 30 days. Thereafter, 5 rats were randomly chosen for histology evaluation, 5 for molecular biological examinations and another 5 rats underwent isolated heart electrophysiology study in each group. Protein and mRNA expression levels of miRNA-21, Spry1, PTEN, ERK/p-ERK, MMP-9, PI3K, AKT/p-AKT were detected.@*Results@#Compared to the rats in control group, rats in the CIH group showed higher atrial interstitial collagen deposition (P<0.001), increased atrial fibrillation inducibility (P=0.022). The results of immunohistochemistry staining showed that the mean optical density (MOD) of ERK, p-ERK and MMP-9 were significantly increased (all P<0.05), the MOD of Spry1 and PTEN were significantly decreased (both P<0.05), above changes could be significantly reversed by cotreatment with tolvaptan. No significant differences were detected in PI3K and AKT among the three groups (P>0.05). In addition, compared with rats in control group, mRNA levels of miRNA-21, MMP-9, PI3K, AKT, and protein levels of ERK, p-ERK, MMP-9 were significantly increased in CIH group(all P<0.05), whereas protein levels of Spry1, PI3K, p-AKT were significantly decreased (all P<0.05). Above changes could be significantly attenuated.@*Conclusions@#CIH induces significant atrial remodeling in this rat model, which can be attenuated by tolvaptan possibly through modulating miRNA-21/Spry1/ERK/MMP-9 and miRNA-21/PTEN/PI3K/AKT signaling pathways.

Preventive Effect of Tolvaptan on Pleural Effusion after Cardiac Valvular Surgery / 日本心臓血管外科学会雑誌

Background : Post-operative fluid management after cardiac valvular surgery is very important. In our institute, carperitide 0.0125 γ was started during surgery and oral furosemide 20-40 mg/day and spironolactone 25 mg/day were started at post-operative day (POD) 1 as the standard therapy. Tolvaptan, vasopressin V2 receptor antagonist, was started when fluid retention such as pleural effusion occurred. With this strategy, the frequency of pleural drainage was more than 40%. Therefore we changed our standard therapy in February 2018. In this new standard therapy, carperitide (0.0125 γ) was started and maintained until oral intake became possible and tolvaptan 7.5 mg was started with furosemide 20 mg and spironolactone 25 mg as oral medicine usually at POD 1. In this study, whether tolvaptan prevents pleural effusion or not after cardiac surgery was examined. Subjects and Methods : Sixty-four patients were operated during February 2017 and December 2018 were included in this study. Thirty-two patients operated in the period until January 2018 served as control group and were compared with 32 patients for whom tolvaptan was started on POD 1 (tolvaptan group). Results : There was no significant difference between two groups for background, operative procedure, operation time, cardiopulmonary bypass time, aortic cross clamp time and fluid balance during procedure. Tolvaptan was given to all patients in the tolvaptan group and in 22% of patients in the control group. Oral furosemide dose (tolvaptan group 21±5 mg/day, control group 31±20 mg/day, p＝0.0112), and the frequency of patients with intravenous furosemide administration (tolvaptan group 9%, control group 44%, p＝0.0038) were significantly less in tolvaptan group. In the tolvaptan group, intravenous furosemide administrated only once in all patients, whereas the frequency of intravenous furosemide administration was 1-32 times, average 6.6 times in control group. Tolvaptan was stopped within 1 week because of too much urination in two patients and the elevation of liver enzyme in two patients without any adverse effects. Post-operative urination volume until POD 5 did not differ. In both groups, body weight increased at POD 1 and 2 and returned to pre-operative weight at POD 3. Pleural effusion was significantly less in the tolvaptan group at POD 3 (tolvaptan group : none 66%, small amount 22%, moderate amount 3%, drain tube inserted 9%, control group : none 16%, small amount 34%, moderate amount 13%, drain tube inserted 38%, p＝0.0003), at POD 7 (tolvaptan group : none 72%, small amount 28%, vs., control group : none 47%, small amount 19%, moderate amount 22%, drain tube inserted 13%, p＝0.0041) and at discharge (tolvaptan group : none 94%, small amount 6%, vs., control group : none 69%, small amount 22%, moderate amount 9%, p＝0.0301). The frequency of pleural drainage was also less in the tolvaptan group (tolvaptan group 9.4%, control group 44%, p＝0.0038). Conclusion : After cardiac valvular surgery, tolvaptan started at POD 1 is very effective to reduce the frequency of pleural effusion and pleural drainage, and careful checking for too much urination and the elevation of liver enzymes is mandatory.

Tolvaptán en un caso de síndrome cardiorrenal pediátrico: ¿Cuál es su papel? / Tolvaptan in a pediatric cardiorenal syndrome: What is its role?

El síndrome cardiorrenal se define como la asociación de insuficiencia renal y cardíaca de forma aguda o crónica. Se establece una resistencia a los diuréticos convencionales que hace difícil el manejo de estos niños. El tolvaptán, un antagonista de los receptores de vasopresina, ha sido empleado con éxito en adultos, aunque la experiencia en niños es muy limitada. Se presenta el caso de una paciente de 5 años en lista de trasplante cardíaco que padecía síndrome cardiorrenal. Había tenido una hospitalización prolongada con buena respuesta a dosis mínimas de tolvaptán (0,1 mg/kg/día). Se analizaron las curvas de urea, creatinina, sodio y volumen urinario, y se evidenció una mejoría llamativa en la función renal. Al cuarto día de haber iniciado el tratamiento, se le pudo dar el alta con seguimiento ambulatorio y buena evolución hasta el trasplante. El tolvaptán podría considerarse una opción de tratamiento en niños con resistencia a diuréticos convencionales e insuficiencia cardíaca, especialmente, cuando presentan insuficiencia renal.

The cardiorenal syndrome has been defined as a situation in which therapy to relieve congestive symptoms of heart failure is limited by a decreased renal function. The resistance to conventional diuretic treatment makes difficult managing these patients. Tolvaptan, a selective vasopressin-2 receptor antagonist, has been used successfully in adults with this pathology but the experience with children is very limited. A five-year-old girl with renal failure waiting for a heart transplant is presented. Tolvaptan (0.1 mg/kg/day) was started at very low dosage, resulting in an excellent response. We analyzed the creatinine, urea, urine volume and sodium evolution. Renal function also improved. She could be discharged after four days of treatment (156 days of hospitalization) with ambulatory favourable follow-up until heart transplant. Tolvaptan should be considered in pediatric cases of conventional diuretic-resistant congestive heart failure, especially when complicated by kidney disease.

Efficacy and Safety of Tolvaptan in the Treatment of Liver Cirrhosis Ascites with Hyponatremia:a Meta-analysis / 中国药房

OBJECTIVE:To evaluate the efficacy and safety of tolvaptan in the treatment of liver cirrhosis ascites with hyponatremia systematically,in order to provide reference for clinical drug use. METHODS:Retrieved from The Cochrane Library, PubMed,CNKI and Wanfang database,etc.,randomized controlled trials(RCTs)about tolvaptan combined with routine treatment plan(trial group)versus routine treatment plan with or without placebo(control group)in the treatment of liver cirrhosis ascites with hyponatremia were collected. The qualities of included studies were evaluated according to modified Jadad scale after extracting data. Meta-analysis was performed by using Rev Man 5.3 statistical software. RESULTS:A total of 16 RCTs were included, involving 1 271 patients.The results of Meta-analysis showed that serum sodium concentration[MD=6.51,95%CI(4.64,8.39),P<0.001],24 h urine volume [MD=1.36,95%CI(1.01,1.70),P<0.001],response rate of ascites and edema [RD=0.27,95%CI (0.20,0.35),P<0.001],body weight improvement[MD=-1.11,95%CI(-1.31,-0.91),P<0.001]and abdomen circumference improvement [MD=-2.13,95%CI(-2.96,-1.31),P<0.001] of trial group were significantly superior to those of control group, with statistical significance.There was no statistical significance in the levels of blood potassium,blood pressure,heart rate,TBiL,Scr or BUN between 2 groups before and after treatment(P>0.05). The level of ALT in trial group was significantly lower than control group,with statistical significance(P=0.003). Subgroup analysis showed that there was no statistical significance in 24 h urine volume when traditional diuretics were given only in control group or not used in two groups(P>0.05);the serum sodium concentration and 24 h urine volume of other subgroups were significantly higher than those of control group,with statistical significance(P<0.001). The incidence of ADR in trial group was higher than control group as dry mouth,thirst,frequent urination,insomnia,with statistical significance(P<0.05). Total incidence of ADR in trial group was slightly higher than control group,without statistical significance (P>0.05). CONCLUSIONS:Tolvaptan has good therapeutic efficacy for liver cirrhosis ascites with hyponatremia,can effectively improves serum sodium concentration,24 h urine volume,ascites and edema,body weight and abdomen circumference,but rarely affects blood potassium,heart rate,blood pressure,liver and renal function.However,ADR as thirst should be paid attention.

Two Cases of Severe Heart Failure in the Elderly Successfully Treated with Goreisan / 日本東洋医学雑誌

The number of elderly people with chronic heart failure is increasing ; they have acute exacerbations at a high rate due to mergers of infections and others. At that time, they received furosemide intravenous injection and tolvaptan oral medication as internal treatments. However, there are refractory patients (tolvaptan nonresponder) at a certain frequency. In these cases we experienced two cases in which goreisan were effective for untreatable congestive heart failure. Goreisan administration resulted in an increase in urine volume in both cases, marked improvements in symptoms, physiological findings and various laboratory findings. In addition, they continued taking these medicines after discharge. As a result, for about a year, they were never rehospitalized due to heart failure. It is conceivable that goreisan normalized the uneven distribution of water in organs and tissues, and reactivated the action of tolvaptan in the renal collecting duct. These results suggest that the combined use of goreisan will be useful for untreatable congestive heart failure.

Safety and Efficacy of Tolvaptan in Korean Patients with Hyponatremia Caused by the Syndrome of Inappropriate Antidiuretic Hormone

BACKGROUND: The aim of this multicenter study was to evaluate the safety and efficacy of tolvaptan (TLV) in Korean patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). METHODS: Of 51 enrolled patients with SIADH, 39 patients (16 female patients, aged 70.8 ± 11.3 years) were included in an intention to treat analysis. All patients received 15 mg/day as the initial dose, and the dose was then increased up to 60 mg/day (as needed) until day 4. RESULTS: Serum sodium increased significantly from baseline during the first 24 hours (126.8 ± 4.3 vs. 133.7 ± 3.8 mmol/L, P < 0.001), rose gradually between days 1 and 4 (133.7 ± 3.8 vs. 135.6 ± 3.6 mmol/L, P < 0.05), and then plateaued until day 11 (136.7 ± 4.5 mmol/L). The correlation between the change in serum sodium for the first 24 hours and initial serum sodium concentration was significant (r = −0.602, P < 0.001). In severe hyponatremia (< 125 mmol/L), the change was significantly higher (11.1 ± 4.8 mmol/L) than in moderate (6.4 ± 2.5 mmol/L, P < 0.05) or mild hyponatremia (4.3 ± 3.3 mmol/L, P < 0.01). In addition, logistic regression analysis showed that body weight (odds ratio [OR], 0.858; 95% confidence interval [CI], 0.775–0.976; P = 0.020) and body mass index (BMI) (OR, 0.692; 95% CI, 0.500–0.956; P = 0.026) were associated with rapid correction. No serious adverse events were reported, but in 13% of patients hyponatremia was overcorrected. CONCLUSION: TLV is effective in correcting hyponatremia and well-tolerated in Korean patients with SIADH. However, those with low body weight, low BMI or severe hyponatremia, could be vulnerable to overcorrection with the initial dose of 15 mg TLV.

Comparison of tolvaptan treatment between patients with the SIADH and congestive heart failure: a single-center experience

BACKGROUND/AIMS: Tolvaptan is a very effective treatment for hypervolemic or euvolemic hyponatremia. We compared the clinical efficacy of and response to tolvaptan in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and congestive heart failure (CHF). METHODS: We retrospectively reviewed the medical records of 50 patients (SIADH, n = 30; CHF, n = 20) who were prescribed tolvaptan between July 2013 and October 2015. Tolvaptan was prescribed when the serum sodium level was 135 mmol/L. RESULTS: After the initiation of tolvaptan therapy, there was an immediate response in the urine volume and serum sodium level in all patients. The improvements in the urine volume and serum sodium concentration were highest within the first 24 hours of treatment. In addition, the mean change in the serum sodium level during the first 24 hours was significantly higher in patients with SIADH than in those with CHF (∆Na, 9.9 ± 4.5 mmol/L vs. 6.9 ± 4.4 mmol/L, respectively; p = 0.025). Also, the mean maintenance dose was lower, and the total duration of tolvaptan use was slightly shorter in the SIADH group than CHF group (21.5 ± 14.9 days vs. 28.0 ± 20.1 days, p = 0.070). CONCLUSIONS: The early response to tolvaptan treatment was better in patients with SIADH than in those with CHF. Thus, the tolvaptan treatment strategy should be differed between patients with SIADH and those with CHF.

Efficacy and safety of toivaptan therapy for edema in patients with nephrotic syndrome / 中华肾脏病杂志

Objective To evaluate the efficacy and safety of tolvaptan therapy for edema in patients with nephrotic syndrome(NS).Methods Twelve patients with NS who had normal serum sodium and blood volume were enrolled.All of them were treated with oral tolvaptan of 15-30 mg per day for 7 days.The diuretic effects were observed and the adverse reactions including electrolyte disorders(especially hypernatremia),low blood volume,thromboembolic complications,and acute kidney injury were closely monitored.Results The average urine volume was significantly increased(F=5.792,P ＜ 0.001)and the body weight was significantly decreased(F=24.086,P ＜ 0.001)from the first day of tolvaptan therapy until the end of the treatment.The average serum sodium levels were significantly increased from the second day of tolvaptan therapy until the end of the treatment(F=2.790,P=0.012),but only 3 case-times(3.6％)among the total 84 case-times of serum sodium tests showed mild hypernatremia(the highest level 146.5 mmol/L)and all the hypernatremia returned back to normal after suspending tolvaptan for one day.There were no significant changes in the serum potassium levels(F=0.477,P=0.849)within the whole treatment course.There was also no significant difference of the blood volume between the level at the end of treatment and the baseline level[(74.3± 3.0)ml/kg vs(74.9±3.0)ml/kg,P=0.855].The thromboembolic complications and acute kidney injury both also did not take place.Conclusions As long as a rational and prudent treatment regimen is applied,tolvaptan has good diuretic effects and safety for treatment of edema in the NS patients with normal serum sodium and blood volume.

Long-term Tolvaptan Treatment of Autosomal Dominant Polycystic Kidney Disease in Korea

A 22-year-old male patient was diagnosed with autosomal dominant polycystic kidney disease (ADPKD). He received conservative treatment with an angiotensin-converting enzyme inhibitor. Two years later, oral therapy, consisting of 60 mg tolvaptan per day, was initiated. Compared with height-adjusted total kidney volume, the rate of kidney growth reduced significantly from 7.33% to 0.66% annually, since commencement of the tolvaptan therapy. The liver enzyme profile and serum sodium level and osmolality were constantly within normal ranges. In Korea, this is the first reported case of a patient with ADPKD who received tolvaptan treatment for more than 1 year. This case demonstrates that long-term tolvaptan treatment appears to be safe, well tolerated, and effective for ADPKD.

Osmotic Demyelination Syndrome Resulting from an Unexpected Response to Tolvaptan in a Patient with Heart Failure / 대한내과학회지

Hyponatremia is commonly encountered in patients with heart failure and has a poor prognosis. Tolvaptan, a novel selective vasopressin V2 receptor blocker, has received attention as an effective drug for treating the syndrome of inappropriate antidiuretic hormone secretion and hypervolemic hyponatremia. However, the safety of tolvaptan in the treatment of hyponatremia is not clear. We experienced a 78-year-old woman with a history of heart failure, atrial fibrillation, and hyponatremia who developed osmotic demyelination syndrome as an unexpected response to treatment with tolvaptan.