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Abstract Aims Few studies have focused on the effect of torsemide versus furosemide after discharge on prognosis in patients with heart failure with preserved ejection fraction (HFpEF). This single‐centre retrospective real‐world study was conducted to evaluate the effect of torsemide versus furosemide after discharge on all‐cause mortality and rehospitalization for heart failure in patients with HFpEF. Methods Consecutive patients who were diagnosis with HFpEF after discharge between January 2015 and April 2018 at the First Affiliated Hospital of Dalian Medical University and who had been treated with torsemide or furosemide were included in this study. The primary outcome was all‐cause mortality. The second outcome was rehospitalization for heart failure. Results A total of 445 patients (mean age 68.56 ± 8.07, female 55%) were divided into the torsemide group (N = 258) or furosemide group (N = 187) based on the treatment course at discharge from the hospital. During a mean follow‐up of 87.67 ± 11.15 months, death occurred in 68 of 258 patients (26.36%) in the torsemide group and 60 of 187 patients (30.09%) in the furosemide group [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.57–1.15, P = 0.239]. Rehospitalization for heart failure occurred in 111 of 258 patients (43.02%) in the torsemide groups and 110 of 187 patients (58.82%) in the furosemide group (HR 0.64, 95% CI 0.49–0.85, P = 0.002). Conclusions Compared with furosemide, torsemide did not significantly reduce all‐cause mortality, but there was association between torsemide and reduced rehospitalization for heart failure in patients with HFpEF.

Aims Methods and results Conclusion The TRANSFORM‐HF trial found no difference in clinical outcomes between torsemide versus furosemide after hospitalization for heart failure. This analysis aimed to assess the impact of diuretic dosing on the primary and secondary clinical outcomes.This post‐hoc analysis of TRANSFORM‐HF categorized patients into three groups by discharge diuretic dose: (1) ≤40 mg, (2) >40–80 mg, and (3) >80 mg of furosemide equivalents. The associations between discharge dose and 12‐month clinical events, and change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ‐CSS), were assessed. Overall, 2379 patients were included, aged 65 years (interquartile range 56–75), 883 (37.1%) women, and 812 (34.2%) Black. Furosemide had adjusted hazard ratios (aHR) for all‐cause mortality of 1.21 (95% confidence interval [CI] 0.91–1.59) for discharge dose group 2 and 1.40 (95% CI 1.04–1.88) for group 3, compared with group 1. For torsemide, aHRs were 1.74 (95% CI 1.32–2.30) for group 2 and 1.58 (95% CI 1.14–2.19) for group 3. No evidence of heterogeneity for the association between increased mortality and higher dose was found by loop diuretic type (pinteraction = 0.17). Higher doses of furosemide and torsemide were associated with increased risk of all‐cause hospitalization and the composite of all‐cause mortality and hospitalization, without evidence of heterogeneity by loop diuretic type (pinteraction > 0.2). Changes in KCCQ‐CSS from baseline at 12 months was similar across dose groups for both drugs.Following hospitalization for heart failure, higher loop diuretic dosing was independently associated with worse clinical and patient‐reported outcomes. The correlation between higher loop diuretic dose and outcomes was consistent, regardless of loop diuretic used. [ABSTRACT FROM AUTHOR]

BACKGROUND: UMOD (uromodulin) has been linked to hypertension through potential activation of Na+-K+-2Cl- cotransporter (NKCC2), a target of loop diuretics. We posited that hypertensive patients carrying the rs13333226-AA UMOD genotype would demonstrate greater blood pressure responses to loop diuretics, potentially mediated by this UMOD/NKCC2 interaction. METHODS: This prospective, multicenter, genotype-blinded trial evaluated torasemide (torsemide) efficacy on systolic blood pressure (SBP) reduction over 16 weeks in nondiabetic, hypertensive participants uncontrolled on ≥1 nondiuretic antihypertensive for >3 months. The primary end point was the change in 24-hour ambulatory SBP (ABPM SBP) and SBP response trajectories between baseline and 16 weeks by genotype (AA versus AG/GG) due to nonrandomized groups at baseline (ClinicalTrials.gov: NCT03354897). RESULTS: Of 251 enrolled participants, 222 received torasemide and 174 demonstrated satisfactory treatment adherence and had genotype data. The study participants were middle-aged (59±11 years), predominantly male (62%), obese (body mass index, 32±7 kg/m²), with normal eGFR (92±17 mL/min/1.73 m²) and an average baseline ABPM of 138/81 mm Hg. Significant reductions in mean ABPM SBP were observed in both groups after 16 weeks (AA, -6.57 mm Hg [95% CI, -8.44 to -4.69]; P<0.0001; AG/GG, -3.22 [95% CI, -5.93 to -0.51]; P=0.021). The change in mean ABPM SBP (baseline to 16 weeks) showed a difference of -3.35 mm Hg ([95% CI, -6.64 to -0.05]; P=0.048) AA versus AG/GG genotypes. The AG/GG group displayed a rebound in SBP from 8 weeks, differing from the consistent decrease in the AA group (P=0.004 for difference in trajectories). CONCLUSIONS: Our results confirm a plausible interaction between UMOD and NKCC2 and suggest a potential role for genotype-guided use of loop diuretics in hypertension management. [ABSTRACT FROM AUTHOR]

Torsemide is a long acting pyridine sulfonylurea diuretic. Torsemide hydrochloride is widely used now, there are only a few organic acid salts reported. Cocrystallization with organic acids is an effective way to improve its solubility. Here, we reported maleate and phthalate of torsemide, in which the organic acid lost a proton transferring to the pyridine of torsemide, and torsemide interacted with organic acid through N+ − H⋯O− hydrogen bond to form salts crystal. Surprisingly, maleate showed a clear "spring" pattern in apparent solubility, whereas phthalate had a "spring-parachute" effect. Both crystalline salts kept a higher solubility than torsemide without falling. The "spring-parachute" effect of crystalline salts promoted rapid dissolution of torsemide and kept a high concentration, thereby increasing its bioavailability. [ABSTRACT FROM AUTHOR]

A simple and facile microwave‐assisted method was developed for the synthesis of highly fluorescent nitrogen‐doped carbon quantum dots (N‐CQDs) using sucrose and urea. The produced quantum dots exhibited a strong emission band at 376 nm after excitation at 216 nm with quantum yield of 0.57. The as‐prepared N‐CQDs were characterized using Fourier‐transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM) images, and ultraviolet‐visible (UV‐visible) spectra. The average particle size was 7.7 nm. It was found that torsemide (TRS) caused an obvious quenching of the fluorescent N‐CQDs; so, they were used for its spectrofluorometric estimation. An excellent linear correlation was found between the fluorescence quenching of N‐CQDs and the concentration of the drug in the range of 0.10 to 1.0 μg/mL with limit of quantitation (LOQ) of 0.08 μg/mL and limit of detection (LOD) of 0.027 μg/mL. The method was successfully applied for the assay of the drug in its commercial tablets and spiked human plasma samples, and the results obtained were satisfactory. Complex GAPI was used for greenness assessment of the analytical procedures and the pre‐analysis steps. Interference likely to be introduced from co‐administered drugs was also studied. [ABSTRACT FROM AUTHOR]

Rationale & objectiveHeart failure treatment relies on loop diuretics to induce natriuresis and decongestion, but the therapy is often limited by diuretic resistance. We explored the association of renin-angiotensin-aldosterone system (RAAS) activation with diuretic response.Study designObservational cohort.Setting & populationEuvolemic ambulatory adults with chronic heart failure were administered torsemide in a monitored environment.PredictorsPlasma total renin, active renin, angiotensinogen, and aldosterone levels. Urine total renin and angiotensinogen levels.OutcomesSodium output per doubling of diuretic dose and fractional excretion of sodium per doubling of diuretic dose.Analytical approachRobust linear regression models estimated the associations of each RAAS intermediate with outcomes.ResultsThe analysis included 56 participants, and the median age was 65 years; 50% were women, and 41% were Black. The median home diuretic dose was 80-mg furosemide equivalents. In unadjusted and multivariable-adjusted models, higher levels of RAAS measures were generally associated with lower diuretic efficiency. Higher plasma total renin remained significantly associated with lower sodium output per doubling of diuretic dose (β = -0.41 [-0.76, -0.059] per SD change) with adjustment; higher plasma total and active renin were significantly associated with lower fractional excretion of sodium per doubling of diuretic dose (β = -0.48 [-0.83, -0.14] and β = -0.51 [-0.95, -0.08], respectively) in adjusted models. Stratification by RAAS inhibitor use did not substantially alter these associations.LimitationsSmall sample size; highly selected participants; associations may not be causal.ConclusionsAmong multiple measures of RAAS activation, higher plasma total and active renin levels were consistently associated with lower diuretic response. These findings highlight the potential drivers of diuretic resistance and underscore the need for high-quality trials of decongestive therapy enhanced by RAAS blockade.

Diuresis with loop diuretics is the mainstay treatment for volume optimization in patients with congestive heart failure, in which perfusion and volume expansion play a crucial role. There are robust guidelines with extensive evidence for the management of heart failure; however, clear guidance is needed for patients who do not respond to standard diuretic treatment. Diuretic resistance (DR) can be defined as an insufficient quantity of natriuresis with proper diuretic therapy. A combination of diuretic regimens is used to overcome DR and, more recently, SGLT2 inhibitors have been shown to improve diuresis. Despite DR being relatively common, it is challenging to treat and there remains a notable lack of substantial data guiding its management. Moreover, DR has been linked with poor prognosis. This review aims to expose the multiple approaches for treatment of patients with DR and the importance of intravascular volume expansion in the response to therapy.

Abstract Background Two loop diuretics, torsemide and frusemide, can affect the urinary system and consequently the cardiordiovascular haemodynamics in different ways. Objectives This study compared a number of echocardiographic parameters and systemic arterial blood pressure (ABP) changes following administration of furosemide or torsemide. Methods Five shelter dogs underwent transthoracic two‐dimensional M‐mode echocardiography to obtain the following measurements: left ventricular internal dimension at end‐systole (LVIDs), left ventricular internal dimension at end‐diastole (LVIDd), fractional shortening (FS), heart rate (HR) and the distance between the mitral valve socket and the ventricle wall (septal to E Point, SEP). Arterial blood pressure was measured using the oscillometric method. Measurements recorded before treatment (baseline data) were compared to those after the dogs received furosemide (5 mg/kg) or torsemide (0.5 mg/kg). Results Torsemide significantly reduced blood pressure 1 h after administration, but this was not seen with furosemide. Fractional shortening, LVIDd and SEP decreased following both treatments, but there were no significant differences between the treatment groups. Torsemide increased heart rate above that seen in the furosemide groups. Conclusions The results of this study indicate that 1 h after administration, torsemide increases heart rate and decreases blood pressure when compared to furosemide, but both drugs have similar effects on measured cardiovascular indices.

Background: Loop diuretics are a primary therapy for the symptomatic treatment of heart failure (HF), but whether torsemide improves patient symptoms and quality of life better than furosemide remains unknown. As prespecified secondary end points, the TRANSFORM-HF trial (Torsemide Comparison With Furosemide for Management of Heart Failure) compared the effect of torsemide versus furosemide on patient-reported outcomes among patients with HF. Methods: TRANSFORM-HF was an open-label, pragmatic, randomized trial of 2859 patients hospitalized for HF (regardless of ejection fraction) across 60 hospitals in the United States. Patients were randomly assigned in a 1:1 ratio to a loop diuretic strategy of torsemide or furosemide with investigator-selected dosage. This report examined effects on prespecified secondary end points, which included Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; assessed as adjusted mean difference in change from baseline; range, 0–100 with 100 indicating best health status; clinically important difference, ≥5 points) and Patient Health Questionnaire-2 (range, 0–6; score ≥3 supporting evaluation for depression) over 12 months. Results: Baseline data were available for 2787 (97.5%) patients for KCCQ-CSS and 2624 (91.8%) patients for Patient Health Questionnaire-2. Median (interquartile range) baseline KCCQ-CSS was 42 (27–60) in the torsemide group and 40 (24–59) in the furosemide group. At 12 months, there was no significant difference between torsemide and furosemide in change from baseline in KCCQ-CSS (adjusted mean difference, 0.06 [95% CI, –2.26 to 2.37]; P =0.96) or the proportion of patients with Patient Health Questionnaire-2 score ≥3 (15.1% versus 13.2%: P =0.34). Results for KCCQ-CSS were similar at 1 month (adjusted mean difference, 1.36 [95% CI, –0.64 to 3.36]; P =0.18) and 6-month follow-up (adjusted mean difference, –0.37 [95% CI, –2.52 to 1.78]; P =0.73), and across subgroups by ejection fraction phenotype, New York Heart Association class at randomization, and loop diuretic agent before hospitalization. Irrespective of baseline KCCQ-CSS tertile, there was no significant difference between torsemide and furosemide on change in KCCQ-CSS, all-cause mortality, or all-cause hospitalization. Conclusions: Among patients discharged after hospitalization for HF, a strategy of torsemide compared with furosemide did not improve symptoms or quality of life over 12 months. The effects of torsemide and furosemide on patient-reported outcomes were similar regardless of ejection fraction, previous loop diuretic use, and baseline health status. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03296813. [ABSTRACT FROM AUTHOR]

In a Quality by Design (QbD) approach, the impact and interaction of critical variables are understood and optimized using Design of Experiment (DoE). DoE includes statistical multivariate analysis and modeling of data for continuous improvement of the method. In the present research work, 24 full factorial designs were applied to optimize and select appropriate chromatographic conditions for the RP-HPLC method for the development of Torsemide (TOR) and Spironolactone (SPI) in synthetic mixtures. The drug was analyzed using a LiChrospher® C 18 (5μm, 250Ã--4 mm) and a mobile phase of acetonitrile: buffer (57.4:42.6 v/v) at a flow rate of 1 mL/min, with TOR showing considerable absorbance at 290 nm and SPI showing significant absorbance at 238 nm. For TOR and SPI, the technique was shown to be linear over the concentration range of 2-12 μg/mL and 10-60 μg/mL, respectively. LOD and LOQ values for TOR were 0.10 g/mL and 0.32 g/mL, respectively, whereas those for SPI were 0.75 μg/mL and 2.29 μg/mL. The correlation coefficient (R2) was found to be 0.9973 for TOR and 0.9976 for SPI. The recovery study for accuracy was found in the range of 97.55%-99.05% and 94.82%-100% for TOR and SPI, respectively. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the effects of Two drug combinations of Torsemide-Enalapril-Digoxin and Furosemide-Enalapril-Digoxin on the cardiovascular system in the treated dogs. For this purpose, five 1.5-year-old mixed breed dogs were selected to undergo echocardiography at three times (The first time as the control group, the second time as the first group and the third time as the second group). No drugs were used in the control group. In the first group, 2.5 mg/kg of furosemide, 0.5 mg/kg of enalapril and 3 µg/kg of digoxin and in the second group, 0.3 mg/kg of Torsemide, 0.5 mg/kg of enalapril and 3 µg/kg of digoxin were administered orally. Echocardiography of the dogs was done after one hour of drug administration. Measured echocardiographic parameters included: Left ventricular size during systole, left ventricular size during diastole, heart rate and fractional shortening. The results of each group were evaluated using chi square analysis method. The results of this study showed that changes in heart rate and left the ventricular size changes during diastole were not significant between the control and other groups. Although left ventricular size during systole was significantly lower in the torsemide-enalapril-digoxin group than the other groups, in this study, it was found that the fractional shortening changes in the group receiving torsemide-enalapril-digoxin were significantly higher than the other two groups. The results of this study indicate better effects of torsemide than furosemide in improving heart function and increasing short fractional shortening, but both drugs have similar effects on other cardiac parameters. [ABSTRACT FROM AUTHOR]

Background: Two loop diuretics, torsemide and frusemide, can affect the urinary system and consequently the cardiordiovascular haemodynamics in different ways. Objectives: This study compared a number of echocardiographic parameters and systemic arterial blood pressure (ABP) changes following administration of furosemide or torsemide. Methods: Five shelter dogs underwent transthoracic two‐dimensional M‐mode echocardiography to obtain the following measurements: left ventricular internal dimension at end‐systole (LVIDs), left ventricular internal dimension at end‐diastole (LVIDd), fractional shortening (FS), heart rate (HR) and the distance between the mitral valve socket and the ventricle wall (septal to E Point, SEP). Arterial blood pressure was measured using the oscillometric method. Measurements recorded before treatment (baseline data) were compared to those after the dogs received furosemide (5 mg/kg) or torsemide (0.5 mg/kg). Results: Torsemide significantly reduced blood pressure 1 h after administration, but this was not seen with furosemide. Fractional shortening, LVIDd and SEP decreased following both treatments, but there were no significant differences between the treatment groups. Torsemide increased heart rate above that seen in the furosemide groups. Conclusions: The results of this study indicate that 1 h after administration, torsemide increases heart rate and decreases blood pressure when compared to furosemide, but both drugs have similar effects on measured cardiovascular indices. [ABSTRACT FROM AUTHOR]

Abstract Aims Furosemide, a short‐acting loop diuretic (SD), is the dominant agent prescribed for heart failure (HF) in clinical practice. However, accumulating data suggests that long‐acting loop diuretics (LD), such as torsemide or azosemide, might have more favourable pharmacological profiles. This study aimed to investigate the relationship between the type of loop diuretics and long‐term outcomes among patients hospitalized for acute HF enrolled in a contemporary multicentre registry. Methods and results Within the West Tokyo Heart Failure Registry from 2006 to 2017, a total of 2680 patients (60.1% men with a median age of 77 years) were analysed. The patients were characterized by the type of diuretics used at the time of discharge; 2073 (77.4%) used SD, and 607 (22.6%) used LD. The primary endpoint was composite of all‐cause death or HF re‐admission after discharge, and the secondary endpoints were all‐cause death and HF re‐admission, respectively. During the median follow‐up period of 2.1 years, 639 patients died [n = 519 (25.0%) in the SD group; n = 120 (19.8%) in the LD group], and 868 patients were readmitted for HF [n = 697 (33.6%) in the SD group; n = 171 (28.2%) in the LD group]. After multivariable adjustment, the LD group had lower risk for the composite outcome [hazard ratio (HR), 0.80; 95% confidence interval (CI), 0.66–0.96; P = 0.017], including all‐cause death (HR; 0.73; 95% CI; 0.54–0.99; P = 0.044) and HF re‐admission (HR, 0.81; 95% CI, 0.66–0.99; P = 0.038), than the SD group. Propensity score matching yielded estimates that were consistent with those of the multivariable analyses, with sub‐group analyses demonstrating that use of LD was associated with favourable outcomes predominantly in younger patients with reduced ejection fraction. Conclusions LD was associated with lower risk of long‐term outcomes in patients with HF and a recent episode of acute decompensation.

Background: It is still debatable whether loop diuretics should be given intravenously as boluses or continuously by infusion while treating acute decompensated heart failure (ADHF). Objective: We aimed to evaluate the differences between the two administration routes on the thoracic fluid content (TFC), renal functions, urine output, electrolytes, haemodynamic parameters, echo cardiographic parameters, incidence of atrial fibrillation and NYHA class. Patients and Methods: Eight hundred thirty patients admitted to the Critical Care Medicine Department, Faculty of Medicine Helwan University, Egypt with acute decompensated heart failure (ADHF) were enrolled in the study; thirty patients were excluded due to EF>40%, myocardial infarction within 30 days and baseline creatinine level > 4 mg/dl. Torsemide 200 mg per day was given to the remaining 800 patients who continued in the study after 1:1 randomization to either continuous intravenous infusion (group I, 400 patients), or twice equal intermittently daily doses (group II, 400 patients). No subsequent dose titration done all over the first 4 days. Results: The delta TFC all through the four days were all statistically significant giving the superiority of the infusion route over the twice daily regimen. While urine output was increased all through the four days, with significant statistical difference in favor of the infusion group but creatinine level, urea level, creatinine clearance were all nonsignificant statistically when comparing the two groups. The NYHA class started to be significant statistically from the third and fourth days in favor of infusion group. Conclusions: We concluded that torsemide infusion when compared to the torsemide twice equal dose in ADHF, causes more decrease in TFC, symptomatic improvement with non-significant nephrotoxic effects. [ABSTRACT FROM AUTHOR]

This study focuses on developing and evaluating mucoadhesive buccal tablets containing Torsemide, utilizing HPMC K-100, Xanthan Gum, and chitosan polymers at varying concentrations. Physicochemical parameters were wellmaintained according to Indian Pharmacopeia standards. Swelling indices ranged from 201.75% to 241.85% over 8 hours, with suitable tablet pH (6.8-6.9) for buccal administration. Mucoadhesive strengths (18.00-27.33 g) varied with polymer concentration. Batch 6 displayed sustained Torsemide release (73.73% at 8 h), supported by optimized swelling index and mucoadhesive strength. Formulation F6, combining Xanthan Gum and Chitosan, emerged as optimal. Dissolution followed zero-order kinetics, fitting the Korsmeyer-Peppas model, indicating a diffusion-based, non-Fickian mechanism. No Torsemide-excipient interactions were observed through Fourier Transform Infrared Spectroscopy. This study successfully designed controlled-release mucoadhesive buccal tablets, influenced by polymer behavior and concentration, advancing drug delivery systems. [ABSTRACT FROM AUTHOR]

Torsemide is a widely used diuretic in clinical practice. In this study, pharmacokinetic (PK) and pharmacodynamic (PD) simulations of torsemide for various population groups and exposure scenarios were performed through human-scale physiologically-based PK-PD (PBPK-PD) modeling of torsemide. For PBPK-PD modeling of torsemide, invitro and clinical data of torsemide reported previously were used. After exposure to clinical doses of torsemide, observed plasma (or serum) concentration and urine torsemide excretion profiles were used as PK-data, and observed urinary sodium excretion rate was used as PD-data. The model was then extended to take into account physiological and biochemical factors according to different CYP2C9 phenotypes or patient populations. The established model captured various torsemide clinical results well. Differences in torsemide PKs and PDs between patient groups or CYP2C9 genetic polymorphisms were modelologically identified. It was confirmed that degrees of differences in torsemide PKs and PDs by disease groups were greater than those according to different CYP2C9 phenotypes. According to torsemide administration frequency or dose change, it was confirmed that although the difference in plasma PKs between groups (healthy adult and patient groups) could increase to 14.80 times, the difference in PDs was reduced to 1.01 times. Results of this study suggested that it is very important to consider disease groups in the setting of torsemide clinical therapy and that it is difficult to predict PD proportionally with only differences in PKs of torsemide between population groups. The PBPK-PD model established in this study is expected to be utilized for various clinical cases involving torsemide application in the future, enabling optimal drug therapy. [ABSTRACT FROM AUTHOR]

Background: Current guidelines suggest the use of loop diuretics as the preferred agent for decongestion in patients with heart failure. However, there is no clear evidence as to superiority of one loop diuretic over the other. The understanding of pharmacokinetic and pharmacodynamic superiority of torsemide over furosemide has generated the hypothesis that these features could result in better clinical outcomes., Objectives: To determine whether the use of torsemide is associated with reduced risk for mortality and rehospitalizations in comparison to furosemide among patients with heart failure., Methods: The study involves a comprehensive search of literature from PubMed, Cochrane CENTRAL, and ClinicalTrials.gov of clinical trials addressing the use of torsemide vs. furosemide in patients with heart failure. Pooled risk ratios (RR) were used to measure association for all outcomes with inverse-variance weighting and random effects model., Results: The literature search included 188 studies that were screened individually. A total of 24 studies were identified out of which 12 were excluded. The pooled risk ratio (RR) revealed all-cause mortality of 0.98 [0.87 to 1.10] with 0% heterogeneity, all cause rehospitalization of 0.95 [0.88 to 1.02] with 5% heterogeneity, and heart failure rehospitalization of 0.85 [0.52 to 1.38] with 55% heterogeneity., Conclusion: Considering the evidence from pooled randomised trials, the use of torsemide compared to furosemide did not result in statistically significant differences in all-cause mortality or rehospitalization rates.

Aims: Furosemide, a short‐acting loop diuretic (SD), is the dominant agent prescribed for heart failure (HF) in clinical practice. However, accumulating data suggests that long‐acting loop diuretics (LD), such as torsemide or azosemide, might have more favourable pharmacological profiles. This study aimed to investigate the relationship between the type of loop diuretics and long‐term outcomes among patients hospitalized for acute HF enrolled in a contemporary multicentre registry. Methods and results: Within the West Tokyo Heart Failure Registry from 2006 to 2017, a total of 2680 patients (60.1% men with a median age of 77 years) were analysed. The patients were characterized by the type of diuretics used at the time of discharge; 2073 (77.4%) used SD, and 607 (22.6%) used LD. The primary endpoint was composite of all‐cause death or HF re‐admission after discharge, and the secondary endpoints were all‐cause death and HF re‐admission, respectively. During the median follow‐up period of 2.1 years, 639 patients died [n = 519 (25.0%) in the SD group; n = 120 (19.8%) in the LD group], and 868 patients were readmitted for HF [n = 697 (33.6%) in the SD group; n = 171 (28.2%) in the LD group]. After multivariable adjustment, the LD group had lower risk for the composite outcome [hazard ratio (HR), 0.80; 95% confidence interval (CI), 0.66–0.96; P = 0.017], including all‐cause death (HR; 0.73; 95% CI; 0.54–0.99; P = 0.044) and HF re‐admission (HR, 0.81; 95% CI, 0.66–0.99; P = 0.038), than the SD group. Propensity score matching yielded estimates that were consistent with those of the multivariable analyses, with sub‐group analyses demonstrating that use of LD was associated with favourable outcomes predominantly in younger patients with reduced ejection fraction. Conclusions: LD was associated with lower risk of long‐term outcomes in patients with HF and a recent episode of acute decompensation. [ABSTRACT FROM AUTHOR]

Abstract A simple, precise, accurate and robust high performance liquid chromatographic method has been developed for simultaneous estimation of Torsemide and Eplerenone in tablet dosage form. Design of experiment was applied for multivariate optimization of the experimental conditions of RP-HPLC method. A Central composite design was used to study the response surface methodology and to analyse in detail the effects of these independent factors on responses. Total eleven experiments along with 3 center points were performed. Two factors were selected to design the matrix, one factor is variation in ratio of Acetonitrile and the second factor is flow rate (mL/min). Optimization in chromatographic conditions was achieved by applying Central composite design. The optimized and predicted data from contour diagram comprised mobile phase (acetonitrile, water and methanol in the ratio of 50: 30: 20 v/v/v respectively), at a flow rate of 1.0 ml/min and at ambient column temperature. Using these optimum conditions baseline separation of both drugs with good resolution and run time of less than 5 minutes were achieved. The optimized assay conditions were validated as per the ICH guidelines (2005). Hence, the results showed that the Quality by design approach could successfully optimize RP-HPLC method for simultaneous estimation of Torsemide and Eplerenone.

Torsemide is a diuretic drug used for several cardiovascular and chronic diseases. With regard to the clinical application of torsemide, studies on individualized pharmacotherapy and modeling that take variability in pharmacokinetics (PKs) within a population into account have been rarely reported. Thus, the objective of this study was to perform population pharmacokinetic (Pop-PK) modeling and to identify effective covariates that could explain the inter-individual variability (IIV) of torsemide PK. Pop-PK modeling for torsemide was performed based on serum concentration data obtained from 112 healthy Korean males and analysis of various genetic and physicochemical parameters. Modeling was performed with nonlinear mixed-effects (NLME) using Phoenix NLME. The finally developed model was fully verified. The model was also reconfirmed using NONMEM software. As a basic model, the PKs of torsemide within the population were well described by a two-compartment model reflecting the lag-time on oral absorption. According to the genetic polymorphisms of OATP1B1 and CYP2C9, significant associations were found in the V/F, CL/F, and CL2/F of torsemide. These were reflected as effective covariates in the final Pop-PK model of torsemide, resulting in an approximately 5–10% improvement in the model parameter IIV values. Considering that torsemide is a substrate for CYP2C9 and OATP1B1, it was important to search for genetic polymorphisms in CYP2C9 and OATP1B1 as covariates to explain the PK diversity of torsemide between individuals. The differences in CL/F and CL2/F between the phenotypes of CYP2C9 were approximately 36.5–51%. The difference in V/F between the phenotypes of OATP1B1 was approximately 41–64.6%. These results suggested that the phenotypes of CYP2C9 and OATP1B1 produced significant differences in torsemide PKs. Considering that CYP2C9 and OATP1B1 phenotypes as covariates affected different PK parameters of torsemide, it could be inferred that torsemide's cell membrane permeation process by OATP1B1 and the metabolic process by CYP2C9 could independently affect each other in vivo without interplay. There was no significant difference in the parameter estimates between modeling software (Phoenix NLME vs. NONMEM). In this study, the torsemide PK variability between individuals was largely explained. In the future, individualized effective drug therapy of torsemide taking individual patient's genotypes into account might become possible. [ABSTRACT FROM AUTHOR]