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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: 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]

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]

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]

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]

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]

Loop diuretic medications work by inhibiting sodium reabsorption in the renal tubules. The net effect is increasing in urinary sodium and water excretion. Loop diuretics are routinely used for many clinical indications, and nephrology practitioners are well informed in the management of their use in daily practice. This article highlights key information on the most commonly used loop diuretics (e.g., furosemide and torsemide) and provides important clinical features related to pharmacokinetics properties, dosing consideration, route of administration, side effects, and other considerations for practitioners. [ABSTRACT FROM AUTHOR]

Background: Torasemide is a potent loop diuretic with potential to treat congestive heart failure (CHF) in dogs. Objective: Evaluate the efficacy and safety of torasemide compared to furosemide in dogs with first occurrence of CHF caused by degenerative mitral valve disease (DMVD). Animals Three hundred and nineteen dogs with new onset CHF attributable to DMVD. Methods: Double‐blinded randomized noninferiority study of PO torasemide vs furosemide in addition to standard CHF treatment. The primary efficacy criterion was decreased pulmonary edema and cough and no worsening of dyspnea or exercise tolerance at day 14. Secondary endpoints included clinical response at day 84 and time to death, euthanasia, or premature study withdrawal for cardiac reasons. Results: Torasemide q24h (n = 161) was noninferior to furosemide q12h (n = 158); percentage of dogs meeting primary efficacy criterion at day 14 was similar between groups (torasemide, 74.4% [95% confidence interval (CI), 66.8%‐81.0%] vs. furosemide, 73.5% [95% CI, 65.7%‐80.4%]; risk ratio [RR], 1.01; 95% CI, 0.89‐1.15; P =.87). Efficacy at day 84 showed similar results (RR, 1.05; 95% CI, 0.88‐1.25; P =.6). Dogs receiving torasemide had a longer time to endpoint and were less than half as likely to experience death, euthanasia, or premature study withdrawal (hazard ratio, 0.36; 95% CI, 0.19‐0.65; P =.001) than dogs receiving furosemide at any time during the study. Conclusion and Clinical importance: Torasemide was noninferior to furosemide as first line PO treatment for new onset CHF caused by DMVD. Torasemide significantly decreased risk of cardiac‐related death or premature study withdrawal for cardiac reasons compared to furosemide. [ABSTRACT FROM AUTHOR]

Abstract The inhibition of water permeation through aquaporins by ligands of pharmaceutical compounds is considered as a method to control the cell lifetime. The inhibition of aquaporin 1 (AQP1) by bacopaside-I and torsemide, was explored and its atomistic nature was elucidated by molecular docking and molecular dynamics (MD) simulation collectively along with Poisson-Boltzmann surface area (PBSA) method. Docking results revealed that torsemide has a lower level of docking energy in comparison with bacopaside-I at the cytoplasmic side. Furthermore, the effect of steric constraints on water permeation was accentuated. Bacopaside-I inhibits the channel properly due to the strong interaction with the channel and larger spatial volume, whereas torsemide blocks the cytoplasmic side of the channel imperfectly. The most probable active sites of AQP1 for the formation of hydrogen bonds between the inhibitor and the channel were identified by numerical analysis of the bonds. Eventually, free energy assessments indicate that binding of both inhibitors is favorable in complex with AQP1, and van der Waals interaction has an important contribution in stabilizing the complexes. Highlights • Aquaporins are special types of membrane proteins that are responsible for water molecules transport across the membrane. • Despite experimental and theoretical literature about inhibition of aquaporins, some biophysical aspects remain ambiguous. • This work utilizes docking along with MD simulation to provide an atomic image for key agents in the inhibition process. • The present work elucidates conformational changes of a membrane protein during the inhibition by a paradigmatic method. • Moreover, the approach takes into account both of the chemical and energetic aspects of the inhibition process. [ABSTRACT FROM AUTHOR]

Background: Diuretic treatment is the mainstay for management of congestive heart failure in horses, and its use has been restricted to injectable medications because no currently data supports the use of PO administered loop diuretics. Objectives: To determine the pharmacokinetic and pharmacodynamic properties of PO administered torsemide and, determine if PO administered torsemide, could be used as an alternative to injectable diuretics in the horse. Animals: Six healthy adult mares. Methods: A 2‐phase, prospective study, that consisted of pharmacokinetic profiling of a single dose (6 mg/kg PO) and pharmacodynamic effects of long‐term torsemide administration (2 mg/kg PO q12h) for 6 days in healthy horses. Results: Pharmacokinetic analysis identified a peak concentration (Cmax) of 10.14 µg/mL (range, 6.79–14.69 µg/mL) and elimination half‐life (T1/2) 9.2 hours (range, 8.4–10.4 hours). The area under the plasma drug concentration over time curve (AUC) was 80.7 µg × h/mL (range, 56.5–117.2 µg × h/mL). A statistically significant increase in urine volume and decrease in urine specific gravity were found from day 0 (baseline) to day 6 (P < .0001). Significant alterations in biochemical variables included hyponatremia, hypokalemia, hypochloremia, and increased serum creatinine concentration. Mean arterial blood pressure significantly decreased on day 6 (57.7 ± 8.8 mm Hg, P = .001) as compared with baseline (78 ± 6.1 mm Hg). Serum aldosterone concentrations significantly increased after 6 days of torsemide administration (P = .0006). Conclusions and Clinical Importance: PO administered torsemide (4 mg/kg/day) successfully reached therapeutic concentrations in blood, induced clinically relevant diuresis, and resulted in moderate pre‐renal azotemia and electrolyte disturbances. [ABSTRACT FROM AUTHOR]

• A TRS:β-CD-ICs are successfully prepared by different analytical methods. • TRS:β-CD-ICs are characterized by FT-IR,1H NMR, XRD, and SEM analysis. • Dissolution rate of ICs is enhanced about 30 times than pure TRS. • Antibacterial and antibiofilm performances of the ICs are reported. • Inhibition mechanism is firstly proposed by CLSM. The drug torsemide (TRS), which is partially water-soluble, forms inclusion complexes with the sugar β-cyclodextrin (β-CD). To facilitate Phase Solubility (PS) studies, UV spectroscopy is used to measure TRS's solubility and interaction with β-CD. A 1:1 stoichiometry is confirmed for ICs formed by the PS profile, which is AL. In addition to the physical method, solvent evaporation, kneading, and physical methods are also used to prepare the 1:1 molar ratio of ICs in solid form. Various analytical techniques are used for examining the ICs. As compared to TRS alone, TRS in the ICs dissolves more than 30 times faster. As a result of the ICs, research into TRS-sensitive microorganism antibacterial and antibiofilm has greatly improved. Due to their improved water solubility and ability to inhibit bacteria, ICs are promising drug carriers. [Display omitted] [ABSTRACT FROM AUTHOR]

Torsemide is commonly used to relieve edema during the treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO). We explored the effect of torsemide on the plasma concentrations of inorganic arsenic (iAs), monomethylarsonic acid (MMAV) and dimethyarsinic acid (DMAV) in APL patients treated with ATO and clarified its molecular mechanism in rats and cells. The study included 146 APL patients treated with ATO. 60（41.1 %) of these 146 patients were co-administered with torsemide. The treatment of torsemide increased plasma concentrations of iAs (P < 0.05) and DMAV (P < 0.05) in A P L patients. The single co-administration of ATO and torsemide in rats significantly increased the plasma concentrations and AUC (0−t) of iAs (P < 0.05) and MMAV (P < 0.05), decreased the urinary excretion rates and the urine concentrations of iAs (P < 0.05) and DMAV (P < 0.05), and enhanced iAs (P < 0.05) and MMAV (P < 0.05) concentrations in the kidneys of rats. In addition, torsemide decreased the expression of multidrug resistance protein 4 (MRP4) in rat kidneys after 7 days of continuous co-administration (P < 0.05). We also treated MRP4-overexpressing HEK293T cells with ATO and different concentrations of torsemide. Torsemide markedly increased the concentrations of iAs, MMAV and DMAV by inhibiting MRP4 compared with ATO alone (P < 0.05). In conclusion, torsemide increased the plasma concentrations of arsenic metabolites in APL patients treated with ATO by inhibiting the transporter MRP4 in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

Four sensitive and precise methods for determination of torsemide in presence of its degradation product and in pharmaceutical formulation were developed and validated. Method A is the second derivative spectrophotometry at 262.4 nm with mean percentage recoveries 100.06±0.75. Method B is first derivative of the ratio spectra spectrophotometry, at 232.4, 244.6 nm and at the total peak amplitude from the maximum at 232.4 nm to the minimum at 244.6 nm (1DD232.4+244.6nm). Method C is a TLC-densitometric one, for torsemide separation using acetone : chloroform : ethyl acetate (4:4:2 v/v) as a developing system. Method D is HPLC one, it provides complete separation of torsemide from its degradation product on C8 column with UV detection at 287 nm and recovery 99.98±0.76. The proposed methods have been successfully applied to the analysis of torsemide in pharmaceutical formulations without interference from other additives and the results were statistically compared with the official method. [ABSTRACT FROM AUTHOR]

Comparative study of cardio protective effect of aliskiren, telmisartan, and torsemide was carried out on l -nitro arginine methyl ester ( l -NAME) induced hypertension in rats. The three drugs were given daily for 8 weeks simultaneously with l -NAME, with a control group for each drug and l -NAME. The degree of protection was assessed by measurement of systolic blood pressure and heart rate of animals every two weeks. At the end of the experimental period blood sampling was carried out for estimation of the level of NO 2 − /NO 3 − . After which animals were sacrificed for heart dissection to detect collagen types I and III gene expression. Histopathological study was done to evaluate the extension of collagen deposits. The study revealed that the three drugs decreased blood pressure significantly compared to l -NAME. There was no significant difference between aliskiren and telmisartan in all measurements, but there was significant decrease in measurements of both aliskiren and telmisartan treated groups compared to torsemide starting from 4th week. There were insignificant changes in pulse rate values between the three l -NAME treated groups through the experiment. The three drugs significantly increased NO compared to l -NAME. Collagen I and III gene expression was significantly decreased by the three drugs but the highest percentage of inhibition was with telmisartan compared to l -NAME. Comparing the percentage inhibition of cardiac fibrosis, there was insignificant difference between telmisartan and torsemide treated groups while both were superior to aliskiren. In conclusion, further experimental studies are required to elucidate the potential cardioprotective mechanisms of aliskiren, telmisartan and torsemide, and assess their efficacy in treatment of heart failure. [ABSTRACT FROM AUTHOR]

An 11-year-old castrated male Maltese weighing 3.6 kg and a 12-year-old intact female Shih-tzu weighing 6.5 kg were admitted to the Veterinary Medical Teaching Hospital of Chungnam National University with decompensatory congestive heart failure. Diuretic resistance was suspected due to long term diuretic therapy with furosemide. However, the patients improved after the furosemide treatment was changed to torsemide, demonstrating the benefits of application of torsemide to treat diuretic resistance caused by long term use of furosemide. These findings suggest that torsemide should be applied for treatment of diuretic resistance caused by long term use of furosemide. [ABSTRACT FROM AUTHOR]

Objective: The objective of the present work was to prepare Torsemide loaded nanoparticulate suspension to enhance ocular residence time with increased absorption from the eye & produce sustained pharmacological activity along with reduced dosing frequency. Method: In the present study, torsemide nanoparticles were prepared by single emulsion solvent evaporation method using ethyl cellulose as non-biodegradable polymer which was used to formulate a novel (1%) ophthalmic suspension for better contactability of the drug at the site of action. Result: The results showed that the method was reproducible, easy and efficient (regarding the entrapment of drug). The in vitro release studies indicated that the torsemide loaded ethyl cellulose nanoparticles provided sustained drug release (49.62%) in simulated tear fluid over a period of 12 h. Conclusion: The present work led to the conclusion that nanoparticulate suspension, thus prepared, could be an alternative to conventional ophthalmic preparations pertaining to its ability to sustain the drug release by reducing the dosing frequency resulting in better patient compliance. [ABSTRACT FROM AUTHOR]

Objectives This study aimed to evaluate the effects of torsemide on warfarin therapy in humans and rats. Methods For the animal study, rats were orally dosed with warfarin (0.13 mg/kg, control group) or warfarin (0.13 mg/kg) with torsemide (2 mg/kg, low dose group and 10 mg/kg, high dose group). The pharmacodynamic response of warfarin was assessed by measuring the international normalized ratio ( INR) for 5 consecutive days following drug administration. For the human study, 191 patients on warfarin with mechanical heart valves were followed up retrospectively. The stable dose was calculated as the mean dose in INR levels of 2-3 for 3 consecutive times. Key findings In the animal study, the INR, maximum plasma concentration ( Cmax) and area under the plasma drug concentration-time curve ( AUC0-∞) of ( S)-warfarin in the high dose group were significantly higher than in other groups ( P < 0.05). Compared with the control group, Cmax and AUC0-∞ of ( R)-warfarin in the high and low dose groups were higher, whereas the volume of distribution/bioavailability and clearance/bioavailability were significantly lower ( P < 0.05). In the univariate analysis of the clinical study, diuretics significantly lowered stable warfarin doses ( P = 0.016) (5.07 ± 1.78 mg/day vs 5.77 ± 1.81 mg/day). After controlling confounding variables, the effects of diuretics were found to lower the warfarin dose by 0.464 mg. Conclusions It was concluded that warfarin dose needs to be lowered when it is used concomitantly with diuretics. [ABSTRACT FROM AUTHOR]

A simple, rapid and selective method was developed. The method was validated and found to be linear in the range of 100-4000 ng/ml. Chromatographic peaks were separated by means of a 5 µm, C18 silica column using acetonitrile and phosphate buffer (0.05 M) in proportion of 40:60 (pH 4.0) as a mobile phase. The retention time of torsemide was 5.00±0.20 min. The chromatograms showed good resolution and no interference from plasma. The mean recovery from human plasma was found to be above 82%. Both inter-day and intra-day accuracy and precision data showed good reproducibility. This method was applied to a single dose bioequivalence study. Log transformed values were compared by ANOVA followed by classical 90% confidence interval. Confidence limits for Cmax, AUC0-t and AUC0-inf ranged from 98.6 to 102.8, 101.8 to 105.3 and 102.4 to 105.5 respectively. These results suggested that the analytical method was linear, precise and accurate. Test and reference product were found to be bioequivalent. [ABSTRACT FROM AUTHOR]

In 97 unselected volunteers and two additional homozygous carriers of CYP2C9*3, we investigated the oral clearance of torsemide in relation to 37 polymorphisms at the CYP2C gene locus. Torsemide total oral clearance was linearly associated with the number of CYP2C9*3 alleles (geometric mean: 59, 40 and 20 ml/min in carriers of no, one and two alleles) and so were the methyl- and ring-hydroxylation but not the carboxylation clearance. Haplotypes including the CYP2C9*3 allele were similarly associated with the clearances but no other variant and no haplotype not including the CYP2C9*3 variant. The extended haplotype length (EHL) of the CYP2C9 haplotypes was positively associated with higher activity of the gene product. Torsemide total oral clearance was predictable with r2=82.1% using plasma concentrations at 0.5, 1, 2 and 24 h. In conclusion, torsemide's biotransformation strongly depended on the CYP2C9*3 variant but no other. Higher clearance CYP2C9 haplotypes appear to be evolutionarily selected.The Pharmacogenomics Journal (2007) 7, 200–211. doi:10.1038/sj.tpj.6500410; published online 12 September 2006 [ABSTRACT FROM AUTHOR]

Aims To investigate the association between torsemide renal clearance and genetic variation in the basolaterally expressed renal organic anion transporters OAT1 and OAT3 and in the luminally situated OAT4. Methods We analysed 22 polymorphisms in the OAT coding genes SLC22A6, SLC22A8 and SLC22A11 and their haplotypes and measured torsemide renal clearance in 95 healthy men. In addition, the effect of torsemide on the OAT-mediated transport was studied in vitro. Results In stably transfected HEK293 cells torsemide (100 µm) inhibited the uptake by human OAT1, OAT3 and OAT4 by 63.1, 58.1 and 68.0%, respectively. Torsemide renal clearance ranged from 6.5 to 43.1 ml min−1 with a log-normal distribution and a geometric mean of 15.6 ml min−1 (15.0–16.1 ± SEM). No clear outlier group was observed. AA carriers of the polymorphism rs11231809 in SLC22A11 had a torsemide renal clearance of 13.3 ml min−1 (12.7–13.9) compared with 15.1 ml min−1 (14.5–15.8) in AT and 18.0 ml min−1 (16.7–19.5) in TT carriers ( P = 0.002). The two most frequent haplotypes at SLC22A11 showed an association with torsemide renal clearance. Homozygous carriage of these two haplotypes resulted in renal clearances of 21.2 ml min−1 (19.0–23.7) and 11.8 ml min−1 (10.5–13.5), respectively. No association between reanl clearance and genetic variation in SLC22A6 or SLC22A8 was observed. Conclusions Genetic variation in the gene encoding the luminally expressed OAT4 rather than in the basolaterally expressed OATs may affect the renal clearance of torsemide. [ABSTRACT FROM AUTHOR]

Diuretic therapy in ARF (acute renal failure) is mainly done with loop diuretics, first of all furosemide. Torsemide has a longer duration of action and does not accumulate in renal failure. In chronic and acute renal failure, both diuretics have been effectively applied, with a more pronounced diuretic effect for torsemide. In this study, the effects of torsemide versus furosemide on renal function in cardiac surgery patients recovering from ARF after continuous renal replacement therapy (CRRT) were studied. Twenty-nine critically ill patients admitted to an intensive care unit at a university teaching hospital after cardiac surgery recovering from ARF after CRRT were included in this prospective, controlled, single-center, open-labeled, randomized clinical trial. Inclusion criteria were urine output > 0.5 mL/kg/h over 6 h under CRRT. Torsemide and furosemide dosages were adjusted with the target urine output being 0.8–1.5 mL/kg/h. Hemodynamic data, urine output, volume balance, serum creatinine clearance, electrolytes, blood urea nitrogen, serum creatinine, renin, and aldosterone concentrations were measured. Fourteen patients were included in the furosemide group and 15 patients in the torsemide group. Dosages of 29 (0–160) mg torsemide and a dosage of 60 (0–240) mg furosemide were given every 6 h in each group, respectively. The dosage given at the end of the study decreased significantly in furosemide and torsemide treated patients. Urine output, 24 h balance, and serum creatinine clearance did not differ significantly between groups. Urine output decreased in both groups, mostly dose-dependent in the torsemide group. The intragroup comparison of the first time-interval after inclusion with the last time-interval showed a significant increase in serum creatinine and blood urea nitrogen in the furosemide group. Renin and aldosterone concentrations did not show significant differences. In conclusion, torsemide and furosemide were effective in increasing urine output. Torsemide might show a better dose-dependent diuretic effect in ARF patients after CRRT treatment. Serum creatinine and blood urea nitrogen elimination were less pronounced in the furosemide group. [ABSTRACT FROM AUTHOR]

Food significantly affects the pharmacokinetics of oral loop diuretics in healthy individuals, but studies have not been performed in patients with edema. Because of this omission, foods effect on pharmacokinetics has been overlooked and may decrease the pharmacodynamic response in patients who rely on diuretics. Despite this potential interaction, reference manuals do not provide warnings about the effects on food on loop diuretic absorption. We reviewed the published human studies investigating the effects of food on loop diuretics. Peak plasma concentrations and urinary recovery were significantly decreased when taken with food, but only one study showed a corresponding decrease in total urine output, which is likely related to the diuretic threshold effect. These healthy subjects probably were always above the diuretic threshold under both fed and fasting conditions and thus could not augment their urine output. Based on these data in healthy subjects, the special implications for patients who routinely take diuretics are discussed. Therefore, food is more likely to have a clinical effect on the diuretic threshold given its effect in healthy subjects and the special considerations for patients with edema. Additional studies are needed to help answer these questions. Until such data are available, the most conservative, effective clinical approach is to administer oral loop diuretics without food. [ABSTRACT FROM AUTHOR]

Background: Torsemide has predictable absorption compared to furosemide. Thereby, torsemide results in more constant exposure to active drug. Our hypothesis was that this pharmacokinetic difference between these commonly used loop diuretics may translate into disparate antihypertensive responses in patients with chronic kidney disease (CKD).Methods: We conducted a randomized, double-blind, two-period, crossover trial to compare the pharmacodynamics of torsemide and furosemide, in 14 subjects with stage 2 or 3 CKD. We first performed an inpatient study, where after the subjects were brought into sodium balance on a 200 mEq per day diet, a single bioequivalent dose of oral loop diuretic was administered with an intervening washout period. Measurements of urinary electrolytes were made. Subjects then participated in an outpatient study, wherein they received daily therapy for 3 weeks with the loop diuretics in random order. Twenty four-hour ambulatory blood pressure monitoring was performed before and after each drug to assess the antihypertensive response.Results: In the inpatient phase, furosemide increased urinary sodium excretion from average (+/-SD) 199 +/- 49 mEq/day to 357 +/- 96 mEq/day and torsemide increased urinary sodium excretion from 213 +/- 79 mEq/day to 398 +/- 142 mEq/day. These differences between the diuretics were not significant, confirming bioequivalence. In the outpatient phase, furosemide reduced 24-hour ambulatory blood pressure from 147 +/- 17/78 +/- 11 mm Hg to 138 +/- 21/74 +/- 12 mm Hg (P = 0.021) and torsemide reduced it from 143 +/- 18/75 +/- 10 mm Hg to 133 +/- 19/71 +/- 10 mm Hg (P = 0.007). Although each diuretic was effective in reducing ambulatory blood pressure, the differences between diuretics were not statistically significant.Conclusion: Bioequivalent doses of torsemide and furosemide given in a randomized, double-blind design fail to demonstrate superiority of torsemide with respect to natriuresis or 24-hour ambulatory blood pressure control in subjects with stages 2 and 3 CKD. [ABSTRACT FROM AUTHOR]

Background: Torsemide is a new loop diuretic that has shown, in short-term studies, to induce a longer and higher diuretic and natriuretic action than frusemide. However, torsemide long-term effects and complications have not been sufficiently investigated. The aim was to compare the efficacy and safety of torsemide versus frusemide in cirrhotic patients with uncomplicated ascites. Methods: Forty-six patients were randomized in two groups to receive torsemide 20 mg/day (n = 22) or frusemide 40 mg/day (n = 24). Both drugs were administered in association with spironolactone 200 mg/day. The initial doses of diuretics were increased every 3 days up to 60, 120 and 400 mg/day, respectively, if the body weight loss was less than 300 g/day or natriuresis was below 50 mEq/day. Results: Torsemide induced a significantly greater diuretic response than frusemide at 24 h and the maximum diuresis while mean diuresis was similar in both groups. Natriuresis was also higher with torsemide but the difference was not significant. The body weight loss, the treatment period, the ascites resolution and complications were similar in both groups. Diuretic doses were increased in two patients treated with torsemide and in nine patients treated with frusemide (P < 0.05). Conclusions: These results show that torsemide is as effective and safe as frusemide for long-term treatment of cirrhotic patients with ascites. [ABSTRACT FROM AUTHOR]

Pseudoporphyria (PP) is used to describe a photodistributed bullous disorder with clinical and histologic features of porphyria cutanea tarda (PCT) but without accompanying biochemical porphyrin abnormalities. Medications, excessive sun and ultraviolet radiation exposure, have all been reported to develop PP. We report a case of PP in a 49-year-old man with CKD stage 3a, caused due to torsemide intake. This is probably the first reported case of PP developing in a dialysis naive patient CKD due to torsemide intake from India. [ABSTRACT FROM AUTHOR]

The sodium-potassium-chloride (Na–K–Cl) cotransporter NKCC1 is found in the plasma membrane of a wide variety of cell types, including neurons, glia and endothelial cells in the brain. Increased expression of neuronal NKCC1 has been implicated in several brain disorders, including neonatal seizures and epilepsy. The loop diuretic and NKCC inhibitor bumetanide has been evaluated as an antiseizure agent alone or together with approved antiseizure drugs such as phenobarbital (PB) in pre-clinical and clinical studies with varying results. The equivocal efficacy of bumetanide may be a result of its poor brain penetration. We recently reported that the loop diuretic azosemide is more potent to inhibit NKCC1 than bumetanide. In contrast to bumetanide, azosemide is not acidic, which should favor its brain penetration. Thus, azosemide may be a promising alternative to bumetanide for treatment of brain disorders such as epilepsy. In the present study, we determined the effect of azosemide and bumetanide on seizure threshold in adult epileptic mice. A structurally related non-acidic loop diuretic, torasemide, which also blocks NKCC1, was included in the experiments. The drug effects were assessed by determing the maximal electroshock seizure threshold (MEST) in epileptic vs. nonepileptic mice. Epilepsy was induced by pilocarpine, which was shown to produce long-lasting increases in NKCC1 in the hippocampus, whereas MEST did not alter NKCC1 mRNA in this region. None of the three loop diuretics increased MEST or the effect of PB on MEST in nonepileptic mice. In epileptic mice, all three diuretics significantly increased PB's seizure threshold increasing efficacy, but the effect was variable upon repeated MEST determinations and not correlated with the drugs' diuretic potency. These data may indicate that inhibition of NKCC1 by loop diuretics is not an effective means of increasing seizure threshold in adult epilepsy. • Alterations in the chloride cotransporter NKCC1 have been implicated in epilepsy. • The antiseizure efficacy of the NKCC1 inhibitor bumetanide is restricted by its poor brain penetration. • Here we examined whether the NKCC1 inhibitors azosemide or torasemide are more effective. • Drug effects on seizure threshold or the activity of phenobarbital were determined. • All 3 diuretics increased phenobarbital's effect in epileptic mice but the effect was variable. [ABSTRACT FROM AUTHOR]

• Abnormal expression of the Na+-K+-2Cl- symporter isotype 1 (NKCC1) has been involved in seizures and epilepsy. • The NKCC1 inhibitor bumetanide was proposed to be beneficial but only poorly penetrates into the brain. • Here we examined brain kinetics of the loop diuretics azosemide and torasemide in comparison to bumetanide. • All drugs hardly distributed into the brain, possibly as a result of probenecid-sensitive efflux transport. • At the doses used, NKCC1-inhibitory brain drug levels were reached for bumetanide and torasemide. Because of its potent inhibitory effect on the Na+-K+-2Cl- symporter isotype 1 (NKCC1) in brain neurons, bumetanide has been tested with varying results for treatment of seizures that potentially evolve as a consequence of abnormal NKCC1 activity. However, because of its physicochemical properties, bumetanide only poorly penetrates into the brain. We previously demonstrated that NKCC1 can be also inhibited by azosemide and torasemide, which lack the carboxyl group of bumetanide and thus should be better brain-permeable. Here we studied the brain distribution kinetics of azosemide and torasemide in comparison with bumetanide in mice and used pharmacokinetic-pharmacodynamic modelling to determine whether the drugs reach NKCC1-inhibitory brain concentrations. All three drugs hardly distributed into the brain, which seemed to be the result of probenecid-sensitive efflux transport at the blood–brain barrier. When fractions unbound in plasma and brain were determined by equilibrium dialysis, only about 6–17% of the brain drug concentration were freely available. With the systemic doses (10 mg/kg i.v.) used, free brain concentrations of bumetanide and torasemide were in the NKCC1-inhibitory concentration range, while levels of azosemide were slightly below this range. However, all three drugs exhibited free plasma levels that would be sufficient to block NKCC1 at the apical membrane of brain capillary endothelial cells. These data suggest that azosemide and torasemide are interesting alternatives to bumetanide for treatment of seizures involving abnormal NKCC1 functionality, particularly because of their longer duration of action and their lower diuretic potency, which is an advantage in patients with seizures. [ABSTRACT FROM AUTHOR]

• For the first time, HPTLC method was developed for the simultaneous quantification of this combination. • Additional spectrophotometric methods were established as more rapid and more economic alternatives, especially in the developing countries. • All methods were successfully applied to the analysis of combined tablets containing both drugs. • Privileges of the proposed methods over the few reported methods were discussed. Sudden death is common in patients with Congestive heart failure, occurring at a rate of six to nine times that of the general population. Day by Day, new combined therapies of more advanced drug generations are involved in treatment. Recently, the Eplerenone/ Torsemide binary therapy is displacing the older Spironolactone/ Frusemide treatment trend of heart disease because it proved better tolerability and potency. This necessitates fast development of analytical methods that are capable of simultaneous determination of such important drug mixture. In this study, validated analytical methods have been established for simultaneous quantitation of eplerenone (EPL) and torsemide (TOR). One of the methods represents the first high-performance thin-layer chromatographic (HPTLC) attempt for EPL-TOR simultaneous estimation. A mixture of ethyl acetate -methanol- chloroform (8:2:1, v/v/v) was applied as mobile phase. EPL and TOR were well resolved and scanned at 242 nm (at hR F 77) and 288 nm (at hR F 36), respectively. Other proposed methods include solvent-induced difference, derivative ratio and ratio subtraction (complemented with isosbetstic point) spectrophotometric methods that were adopted as faster, simpler and more economic alternatives for the routine analysis of the increasingly used binary EPL-TOR medication, especially in the developing countries. Both HPTLC and spectrophotometric methods successfully determined both drugs without interference from one another. All methods were validated as per ICH guidelines. In the HPTLC method, calibration plots were linear between 50–600 and 35–800 ng/band for EPL and TOR, respectively. The spectrophotometric methods proved excellent linearity in the range of 3–25 and 3–30 μg/mL for EPL and TOR, respectively. Within all the proposed methods, ratio subtraction spectrophotometric method was the most sensitive one for EPL (LOD = 0.75 μg/mL). Regarding TOR, direct spectrophotometry achieved the lowest LOD (0.71 μg/mL). The high accuracy, simplicity and low cost of the proposed methods recommend their application in the industrial analysis of EPL and TOR combined dosage forms. A full comparison with the reported techniques shows the privileges of the suggested analytical procedures. [ABSTRACT FROM AUTHOR]

The data of diuretics are still controversial. The ability to induce negative fluid balance has made diuretics useful in the treatment of a variety of conditions, particularly edematous states as heart failure (HF). At the beginning of 1940, only three drugs were accepted as effective agents to increase urine flow: caffeine (a mild diuretic), digitalis (a potent agent but useful only in HF), and mercury (despite its improvement as an organomercurial remained potentially a toxic one). In the late 1950s and 1960s, a significant breakthrough was achieved with the discovery of chlorothiazide and furosemide.1,2 Since them, diuretics have been the cornerstone for treatment of both acute and chronic HF, with signs and symptoms of congestion (NYHA II-IV), irrespective of ejection fraction (EF). They clearly improve hemodynamics and symptoms, although many studies have not been able to demonstrate a mortality benefit. A recent meta-analysis of a few small trials found that diuretics were associated with a reduction in mortality as well as reduced admission for worsening HF. In Croatia, we routinely used all four groups of diuretics diminishing sodium reabsorption at different sites in the nephron, thereby increasing urinary sodium and water losses. Examples of loop diuretics include: furosemide, torsemide. Examples of thiazide diuretics include: chlorthalidone, hydrochlorothiazide, indapamide. Examples of potassiumsparing diuretics include: spironolactone, eplerenone. Loop diuretics act in the thick ascending limb of the loop of Henle. The bioavailability of furosemide is extremely variable (10-90%). The bioavailability can be improved if it is taken before meals because food can disrupt its absorption. Furosemide is absorbed from the gastrointestinal tract, and its peak diuretic effect occurs between 1 and 1.5 hours after oral administration, and between 10 and 30 minutes after intravenous (iv.) administration. The half-life of the various loop diuretics are not the same: 1-1.5 hours for furosemide and 3-4 hours for torsemide. The half-life of furosemide is prolonged in advanced renal dysfunction, and the half-life of torsemide is doubled in hepatic dysfunction. Because diuretics acutely decrease left ventricular preload (Figure 1), they can lead to a reflex neurohormonal stimula- tion of the sympathetic nervous system and renin-angiotensin-aldosterone axis. Numerous studies have determined that activation of these pathways contributes to the pathophysiology of HF, thus potentially undermining the benefits of diuretic use. That is the reason why furosemide occasionally needs to be administered two or three times a day or in 24-hour infusion.1 Concurrent treatment with neurohormonal blockade (i.e., vasodilators, beta blockers, renin-angiotensin-aldosterone system antagonists) may improve outcomes. In patients with severe edema, the effect of furosemide may be altered due to inadequate gastrointestinal absorption. Patients unresponsive to oral furosemide should be switched to iv. therapy or oral torsemide. The bioavailability of torsemide is predictable. It is extremely well absorbed (80-90%), regardless of the presence of edema, because it undergoes substantial hepatic elimination. Torsemide can be administered once daily 5-20mg. The dosage of iv. administered furosemide is usually half of the oral dose. Furosemide is started with 20mg and can be incremented up to 40mg according to the diuretic response. Maximum single oral doses of furosemide for patients with normal glomerular filtration range from 40 to 80mg and the maximum daily dose is 600mg. If the maximum dose has already been given, it is recommended to increase the frequency of the dose to 2 or 3 times a day. Thiazide diuretics are most commonly used to treat hypertension, although they can be adjuncts in the management of HF. Adjunctive use of thiazides can overcome the resistance to loop diuretics associated with reactive hypertrophy of the distal convoluted tubule of the nephron. They inhibit the Na-Cl symporter in the distal convoluted tubule, leading to decreased sodium and water reabsorption. Spironolactone inhibits the aldosterone receptor in the cortical collecting duct, also limiting sodium and water reabsorption. Its diuretic effect is relatively weak, and its onset of action is slow. To conclude, diuretics are well established as the first-line therapy for HF patients with congestion. Since every patient represents a single entity and may have different responses to the same treatment, the best clinical approach should take into account physical examination, neuro-hormonal overdrive and kidney functional status. [ABSTRACT FROM AUTHOR]