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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: 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., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: 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., Methods and Results: 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 (p interaction  = 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 (p interaction > 0.2). Changes in KCCQ-CSS from baseline at 12 months was similar across dose groups for both drugs., Conclusion: 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., (© 2024 European Society of Cardiology.)

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/m 2 ), 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., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354897., Competing Interests: I.S. Mackenzie is a member of the British Heart Foundation Clinical Studies Committee. The other authors report no conflicts.

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., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Heart failure (HF) is the fastest-growing disease with a higher fatality rate. The most differentiating feature of HF is pulmonary or peripheral edema, which is characterized by a gradient between intravascular and extravascular pressure. Loop diuretics were chosen as the primary treatment for edema associated with HF due to their efficacy and early onset of action. If an oral dose had not been provided, intravenous (IV) administration of torsemide, or equal doses of furosemide and bumetanide, was preferred. However, the key variables for selecting and administering loop diuretics are their pharmacological qualities as well as their clinical efficacy. Torsemide has greater bioavailability, a higher rate of absorption, a longer duration of action, and lesser ototoxicity, making it the primary choice in the management of edematous HF., (© Journal of the Association of Physicians of India 2024.)

Loop diuretics are regarded as essential for the treatment of edematous conditions in heart failure, cirrhosis, and renal disease. The principal mechanism of action involves inhibiting the reabsorption of ions (Na+, 2Cl-, and K+) from the ascending loop of Henle. The pharmacokinetic (PK) and pharmacodynamic (PD) features of the commonly used diuretics (torsemide, furosemide, and bumetanide) influence the selection of diuretics in various disease states and dosing regimens. However, torsemide demonstrates superior PK and PD qualities, making it the preferred choice. Genetic polymorphisms must be explored to better understand the diversity of PK and PD parameters of loop diuretics between individuals., (© Journal of the Association of Physicians of India 2024.)

Free radical formation in two diuretics: indapamide and torasemide was examined during UV irradiation and storage at higher temperatures using X-band (9.3 GHz) electron paramagnetic resonance spectroscopy (EPR). The aim of this study was to investigate the possibility of storing indapamide and torasemide under UV irradiation and at higher temperatures, which may occur during exposure to light. The diuretic samples were exposed to UVA irradiation for 15, 30 and 45 minutes, and stored at temperatures of 40 ° C and 50 ° C by 30 minutes. The EPR spectra were analyzed to determine the amplitudes (A), linewidths (ΔB pp ), and integral intensities (I) and g factors. The concentrations of free radical (N) in the diuretic samples were also determined. The influence of microwave power on amplitudes, linewidths and the asymmetry parameter were evaluated. The result showed that the tested indapamide and torasemide samples exhibited high free radical concentrations in the range of 10 18 -10 19 spin/g after UV irradiation and heat treatment. Therefore, due to the significant free radical formation indapamide and torasemide should not be stored under UV light and at temperatures of 40 ° C and 50 ° C. The complex character of free radical systems in the diuretic samples was proved as evidenced by the changes of the asymmetry parameters of the EPR lines with increasing microwave power. Fast spin-lattice relaxation processes were observed in all tested diuretic samples, regardless of the storage conditions. Electron paramagnetic resonance spectroscopy is proposed as a useful method in pharmacy to determine the appropriate storage conditions for diuretics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

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., (© 2024 John Wiley & Sons Ltd.)

The Nitrosogenesis of skin cancer is a modern newly introduced concept in medicine, mainly concerning melanoma, but also keratinocytic cancers such as basal cell carcinoma. The nitroso-contamination of more than 300 drugs worldwide and the permanent (relatively short-term) intake of mutagen-contaminated drugs could create serious prerequisites for the development of skin cancer. Retrospective but also prospective analyses following potentially contaminated polymedication with a heterogeneous type of nitrosamines in real patients are indicative of a causal connection rather than a sporadic association between 1) intake of a possibly nitrosamine-contaminated drug and 2) generation of keratinocytic skin cancer. The pathogenesis of high-risk periocular localized basal cell carcinomas was until recently shrouded in mystery as it was mainly and until now associated with 1) intake of phototoxic drugs and 2) intense exposure to UV radiation (without intake of drugs), 3) congenital or acquired immunodeficiencies, and 4) Goltz Gorlin syndrome or 5) Xeroderma pigmentosum. Nitrosamines/ NDSRIs within the framework of polycotaminated drug intake appear to be one reasonable additional explanation for the association between carcinogen intake and subsequent skin cancer development and progression, and a relatively short-term one at that. Recently published scientific data provide information on a new ability of some of the nitrosamines - namely that some of them are photocarcinogenic or genotoxic after activation with UVA radiation. We present 4 patients who developed high-risk periocular localized basal cell carcinomas of the skin after/within the intake of potentially nitrosamine-contaminated drugs. The presented data are confirmatory with respect to previously published scientific observations on the carcinogenic effects of valsartan, candesartan, bisoprolol, metoprolol, perindopril, lisinopril and amlodipine. The contribution of newly validated data concerning potential/actual carcinogenic/genotoxic activity in the article is also due to the following newly announced nitroso preparations: torasemide, moxonidine and mirabegron. The expansion of the ˝bases of the pyramid˝ determining the stability of drug related (Photo) Nitrosogenesis/ Carcinogenesis (in terms of skin cancer generation) is growing daily. Exogenously/drug-induced Nitrosogenesis and the subsequently triggered carcinogenesis are a completely new explanatory concepts concerning the pathogenesis of skin tumors that remained unanalyzed and hidden for decades. Until now. The official lack of 1) availability, and of 2) precise concentrations regarding nitrosamines in medicinal preparations, are some of the most unexplained acts of irresponsibility to end-users and remain for the moment without a definitive answer from either regulators and manufacturers respectively. Polycontamination of polymedication in polymorbid patients remains highly problematic, at least as a cofactor in the development and progression of keratinocytic cancers, and this in the short term. Recently published data but also data from the past are suggestive that nitrosamines in tobacco are pivotal in the development of acquired mutations in p53 and RAS oncogenes in humans and rodents. The same genes are also affected by mutations in keratinocytic cancer patients. The overlapping mutation patterns of UV radiation-induced mutations in target genes such as p53 and RAS with those caused by some nitrosamines is indicative of a synergism available in terms of gene toxicity or possibly photocarcinogenicity of the latter. What leads the scientific community to believe that the nitrosamines in drugs, similar in composition and carcinogenic potency, act differently, is unclear. The link between drug intake, nitrosamine contamination, generation of some acquired mutations and subsequent cancer development becomes more than obvious and logically conditioned. The thesis of the controlled spread of cancer sounds more than logical today because: whoever controls and regulates the spread of carcinogens/mutagens/nitrosamines is also able to control the occurrence and spread of skin cancer. The Pharmaco-oncogenesis of skin cancer is determined by exogenously mediated Nitrosogenesis or the permissive availability for certain nitrosamines in drugs worldwide.

In this case report, a high dose of torsemide (6mg/kg, every 12 hours for 3 days followed by 12mg/kg, every 12 hours for 4 days) was administered orally to a horse with congestive heart failure (CHF) and atrial fibrillation. Blood samples for measurement of plasma torsemide concentrations were obtained one hour after each drug administration. Pharmacodynamic effects of oral torsemide were evaluated by daily physical examination, electrocardiography, and serum biochemistry. The horse tolerated administration of torsemide. A decrease in ventral oedema and venous congestion was subjectively noted at day 7. Torsemide plasma concentration markedly increased at day 5 (peak concentration of 15.41 µg/mL). Evidence of an increase in renal markers was observed throughout the study period. Electrolyte measurements revealed mild hyponatremia and hypochloremia, and moderate hypokalaemia. No electrocardiographic changes related to torsemide administration were observed. After seven days of treatment, the horse was euthanised due to his disease stage and poor prognosis. Results indicate that torsemide was absorbed after oral administration and was well tolerated in this horse. Furthermore, clinical improvement in this single case indicates that torsemide might be utilized as an oral alternative to furosemide in the management of equine patients in CHF. The high doses of torsemide used in this case report should be reserved for cases without clinical response to lower doses and with close monitoring of electrolytes and renal function parameters. Further investigation of torsemide clinical efficacy and safety in horses with CHF with a larger cohort and prolonged administration is warranted., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Torasemide is a new loop diuretic agent added illegally to health foods for weight loss, which can result in serious health risks for consumers. A rapid and sensitive immunochromatographic assay for detection of torasemide (ICA) based on a new monoclonal antibody (mAb) was developed. The mAb IC 50 for torasemide was 0.93 ng/mL, and the mAb did not cross-react with other analogues. In PBS, the cut-off value and limit of detection were 1 ng/mL and 0.11 ng/mL, respectively, with a linear range between 0.61 and 6.13 ng/mL. In slimming tablet and capsule samples, the cut-off value was 5 ng/g. Recoveries were 101.1% ± 1.7%-106.1% ± 1.3% in tablet samples and 101.2% ± 2.2%-109.1% ± 3.9% in capsule samples, with coefficients of variation 2.1%-3.1% and 1.8%-3.6%, respectively, consistent with existing LC-MS/MS methods. Therefore, the ICA is suitable for use in slimming tablet and capsule samples., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Loop diuretics are a standard pharmacologic therapy in heart failure (HF) management. Although furosemide is most frequently used, torsemide and bumetanide are increasingly prescribed in clinical practice, possibly because of superior bioavailability. Few real-world comparative effectiveness studies have examined outcomes across all 3 loop diuretics. The study goal was to compare the effects of loop diuretic prescribing at HF hospitalization discharge on mortality and HF readmission. We identified patients in Medicare claims data initiating furosemide, torsemide, or bumetanide after an index HF hospitalization from 2007 to 2017. We estimated 6-month risks of all-cause mortality and a composite outcome (HF readmission or all-cause mortality) using inverse probability of treatment weighting to adjust for relevant confounders. We identified 62,632 furosemide, 1,720 torsemide, and 2,389 bumetanide initiators. The 6-month adjusted all-cause mortality risk was lowest for torsemide (13.2%), followed by furosemide (14.5%) and bumetanide (15.6%). The 6-month composite outcome risk was 21.4% for torsemide, 24.7% for furosemide, and 24.9% for bumetanide. Compared with furosemide, the 6-month all-cause mortality risk was 1.3% (95% confidence interval [CI]: -3.7, 1.0) lower for torsemide and 1.0% (95% CI: -1.2, 3.2) higher for bumetanide, and the 6-month composite outcome risk was 3.3% (95% CI: -6.3, -0.3) lower for torsemide and 0.2% (95% CI: -2.5, 2.9) higher for bumetanide. In conclusion, the findings suggested that the first prescribed loop diuretic following HF hospitalization is associated with clinically important differences in morbidity in older patients receiving torsemide, bumetanide, or furosemide. These differences were consistent for the effect of all-cause mortality alone, but were not statistically significant., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., Competing Interests: Disclosure and potential conflicts of interest: The authors declare that they have no conflicts of interest relevant to this manuscript. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2023/12/dic.2023-6-5-COI.pdf, (Copyright © 2023 Fernandez Hazim C, Duarte G, Urena AP, Jain S, Mishra R, Vittorio TJ, Rodriguez-Guerra M.)

Loop diuretics are essential in the treatment of patients with heart failure (HF) who develop congestion. Furosemide is the most commonly used diuretic; however, some randomized controlled trials (RCTs) have shown varying results associated with torsemide and furosemide in terms of hospitalizations and mortality. We performed an updated meta-analysis of currently available RCTs comparing furosemide and torsemide to see if there is any difference in clinical outcomes in patients treated with these loop diuretics. PubMed, MEDLINE, Cochrane, and Embase databases were searched for RCTs comparing the outcomes in patients with HF treated with furosemide versus torsemide. The primary end points included all-cause mortality, all-cause hospitalizations, cardiovascular-related hospitalizations, and HF-related hospitalizations. A random-effects meta-analysis was performed to estimate the risk ratio (RR) with a 95% confidence interval (CI). A total of 10 RCTs with 4,127 patients (2,088 in the furosemide group and 2,039 in the torsemide group) were included in this analysis. A total of 56% of the patients were men and the mean age was 68 years. No significant difference was noted in all-cause mortality between the furosemide and torsemide groups (RR 1.02, 95% CI 0.91 to 1.15, p = 0.70); however, patients treated with furosemide compared with torsemide had higher risks of cardiovascular hospitalizations (RR 1.36, 95% CI 1.13 to 1.65, p = 0.001), HF-related hospitalizations (RR 1.65, 95% CI 1.21 to 2.24, p = 0.001), and all-cause hospitalizations (RR 1.06, 95% CI 1.01 to 1.11, p = 0.02). In conclusion, patients with HF treated with torsemide have a reduced risk of hospitalizations compared with those treated with furosemide, without any difference in mortality. These data indicate that torsemide may be a better choice to treat patients with HF., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Heart failure is associated with an increased frequency of hospitalization, reduced life span, and greater risk to public health, thus posing a challenge. In India, torsemide is one of the commonly used loop diuretics for decongestion in heart failure. However, this use of torsemide, including its dosing, and up/down titration, is based on practical experience. Loop diuretic therapy for heart failure patients poses several dilemmas due to the lack of robust evidence based on which treatment decisions can be made. To guide physicians on the optimal use of torsemide in heart failure patients with or without renal impairment, a panel of expert cardiologists and nephrologists from India convened to develop this expert opinion document for the use of torsemide. This expert opinion on torsemide will pave the way for optimal management with loop diuretic therapy in real-world heart failure patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Chopra et al.)

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., Competing Interests: Disclosures Dr Greene has received research support from the Duke University Department of Medicine Chair’s Research Award, American Heart Association (No. 929502), National Heart Lung and Blood Institute, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim/Lilly, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, and Sanofi; serves as a consultant for Amgen, Bayer, Bristol Myers Squibb, Boehringer Ingelheim/Lilly, CSL Vifor, Merck, PharmaIN, Roche Diagnostics, Sanofi, Tricog Health, Urovant Pharmaceuticals; and has received speaker fees from Boehringer Ingelheim, Cytokinetics, and Roche Diagnostics. Dr Anstrom has received research support from Merck, Bayer, Pfizer, National Institutes of Health, and PCORI. Dr DeWald reports consulting for Bodyport. Dr Mentz receives research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Pharmacosmos, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics and Zoll. All other authors report no disclosures.

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 (MMA V ) and dimethyarsinic acid (DMA V ) 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 DMA V (P < 0.05) in APL 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 MMA V (P < 0.05), decreased the urinary excretion rates and the urine concentrations of iAs (P < 0.05) and DMA V (P < 0.05), and enhanced iAs (P < 0.05) and MMA V (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, MMA V and DMA V 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., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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., (© 2023 The Authors. Veterinary Medicine and Science published by John Wiley & Sons Ltd.)

Loop diuretics such as furosemide and bumetanide, which act by inhibiting the Na-K-2Cl cotransporter NKCC2 at the thick ascending limb of the loop of Henle, have been shown to exert anti-seizure effects. However, the exact mechanism of this effect is not known. For bumetanide, it has been suggested that inhibition of the NKCC isoform NKCC1 in the membrane of brain neurons may be involved; however, NKCC1 is expressed by virtually all cell types in the brain, which makes any specific targeting of neuronal NKCC1 by bumetanide impossible. In addition, bumetanide only poorly penetrates the brain. We have previously shown that loop diuretics azosemide and torasemide also potently inhibit NKCC1. In contrast to bumetanide and furosemide, azosemide and torasemide lack a carboxylic group, which should allow them to better penetrate through biomembranes by passive diffusion. Because of the urgent medical need to develop new treatments for neonatal seizures and their adverse outcome, we evaluated the effects of azosemide and torasemide, administered alone or in combination with phenobarbital or midazolam, in a rat model of birth asphyxia and neonatal seizures. Neither diuretic suppressed the seizures when administered alone but torasemide potentiated the anti-seizure effect of midazolam. Brain levels of torasemide were below those needed to inhibit NKCC1. In addition to suppressing seizures, the combination of torasemide and midazolam, but not midazolam alone, prevented the cognitive impairment of the post-asphyxial rats at 3 months after asphyxia. Furthermore, aberrant mossy fiber sprouting in the hippocampus was more effectively prevented by the combination. We assume that either an effect on NKCC1 at the blood-brain barrier and/or cells in the periphery or the NKCC2-mediated diuretic effect of torasemide are involved in the present findings. Our data suggest that torasemide may be a useful option for improving the treatment of neonatal seizures and their adverse outcome., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of interest: None declared.

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.

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., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: In people and dogs, torasemide has higher bioavailability, longer half-life, and longer duration of action than equivalent doses of furosemide but data regarding pharmacological properties of torasemide in cats are limited., Objective: To assess pharmacokinetic and pharmacodynamic parameters of torasemide in healthy cats, and to investigate the effects of a single administration of torasemide on indicators of diuresis, plasma creatinine concentration, blood pressure, electrolyte concentrations and markers of the renin-angiotensin-aldosterone system (RAAS)., Animals: Six clinically healthy adult European shorthair cats., Methods: Randomized 4-period crossover design with 3 groups and 4 treatments. Pharmacokinetic parameters were obtained using a noncompartmental analysis, and the clinically effective dose was assessed using a Hill model., Results: Mean absolute bioavailability was estimated at 88.1%. Mean total body clearance was 3.64 mL/h/kg and mean terminal half-life was 12.9 hours. Urine output significantly increased after torasemide administration (P < .001). The urine sodium : potassium ratio (uNa : uK) paralleled and was statistically correlated to urine output (P < .001). Administration of a single torasemide dose led to a significant dose-dependent increase in urine aldosterone : creatinine ratio (uAldo : C; P < .001) and a transient decrease in plasma potassium concentration (P < .001) but did not affect blood pressure or plasma creatinine concentration., Conclusions and Clinical Importance: A single torasemide dose leads to a significant increase in diuresis and renin-angiotensin-aldosterone system (RAAS) activation in healthy cats, with high absolute bioavailability, and without clinically relevant adverse effects. Pharmacokinetic parameters indicate that once daily dosing of 0.27 mg/kg may be appropriate in a clinical setting., (© 2022 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Competing Interests: None disclosed

Rationale & Objective: Heart 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 Design: Observational cohort., Setting & Population: Euvolemic ambulatory adults with chronic heart failure were administered torsemide in a monitored environment., Predictors: Plasma total renin, active renin, angiotensinogen, and aldosterone levels. Urine total renin and angiotensinogen levels., Outcomes: Sodium output per doubling of diuretic dose and fractional excretion of sodium per doubling of diuretic dose., Analytical Approach: Robust linear regression models estimated the associations of each RAAS intermediate with outcomes., Results: The 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., Limitations: Small sample size; highly selected participants; associations may not be causal., Conclusions: Among 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.

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 CL 2 /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 CL 2 /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.

Toxic Epidermal Necrolysis (TEN), along with Stevens-Johnson Syndrome (SJS), are rare, life-threatening delayed type IV hypersensitivity mucocutaneous skin disorders that can often be precipitated by medications. The most common culprits are sulfonamide antibiotics and various antiseizure medications. We report a case of a 41-year-old Black female that initially presented with SJS, which then rapidly progressed to TEN, confirmed by hematoxylin and eosin stain skin biopsies. Approximately 80% of her body surface area had necrosis and epidermal detachment lesions. It was concluded that TEN was caused by the use of torsemide for treatment of her underlying diffuse anasarca attributable to alcoholic cirrhosis. During her one-month hospital stay, a multi-disciplinary team consisting of dermatology, gynecology, rheumatology, nephrology, and infectious disease evaluated and treated the patient. Interventions included various supportive care measures as well as intravenous steroids, cyclosporine, plasma exchange, and intravenous immunoglobulin. Given that the mortality rate for TEN is over 30%, and this patient had end-stage cirrhosis, her prognosis was extremely poor. Even though her TEN eventually healed slowly, the patient experienced complications. This case demonstrates the importance of cautiously using sulfonamide medications in patients with known hypersensitivity to sulfa drugs., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Reddy et al.)

Background: Loop diuretics are commonly used for patients with heart failure (HF) but it remains unknown if one loop diuretic is clinically superior., Hypothesis: Biomarkers and proteomics provide insight to how different loop diuretics may differentially affect outcomes., Methods: Blood and urine were collected from outpatients with HF who were taking torsemide or furosemide for >30 days. Differences were assessed in cardiac, renal, and inflammatory biomarkers and soluble protein panels using the Olink Cardiovascular III and inflammation panels., Results: Of 78 subjects, 55 (71%) were treated with furosemide and 23 (29%) with torsemide, and 25 provided a urine sample (15 treated with furosemide, 10 with torsemide). Patients taking torsemide were older (68 vs 64 years) with a lower mean eGFR (46 vs 54 ml/min/1.73 m 2 ), a higher proportion were women (39% vs 24%) and Black (43% vs 27%). In plasma, levels of hs-cTnT, NT-proBNP, and hsCRP were not significantly different between groups. In urine, there were significant differences in urinary albumin, β-2M, and NGAL, with higher levels in the torsemide-treated patients. Of 184 proteins testing in Olink panels, in plasma, 156 (85%) were higher in patients taking torsemide but none were significantly different after correcting for false discovery., Conclusions: We show differences in urinary biomarkers but few differences in plasma biomarkers among HF patients on different loop diuretics. Olink technology can detect differences in plasma protein levels from multiple biologic domains. These findings raise the importance of defining differences in mechanisms of action of each diuretic in an appropriately powered study., (© 2021 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Thirty-two (16 males and 16 females) healthy young beagles were randomly divided into four groups of eight. The control group remained untreated. Torasemide (ISEMID ® , Ceva Santé Animale) was orally administered, once daily, at 0.5 mg/kg from Days 1-5 then 0.25 mg/kg to Day 182, and at three times and five times this dosing regimen in two additional groups. Treated animals (predominantly at the higher dose levels) showed dryness of the oral mucosa, evidence of diuresis, decreased diet consumption, decreased bodyweight gain over the first 3 weeks, increased water consumption, increases in erythrocytes count, haemoglobin, calcium and magnesium, decrease in chloride, phosphorus, potassium and sodium, increases in urine pH, decreases in urine specific gravity and increases in serum aldosterone concentrations. Plasma concentrations of torasemide increased in a dose-dependent manner and showed no evidence of accumulation. There were also changes to electrocardiogram patterns and the macroscopic and microscopic appearance of the kidney and adrenal glands, but these changes were almost exclusively confined to the over-dosed groups. In conclusion, torasemide was found to be safe when administered to dogs at 0.25 mg/kg once daily for 26 weeks, and any changes were consistent with its known diuretic effects., (© 2021 CEVA. Journal of Veterinary Pharmacology and Therapeutics published by John Wiley & Sons Ltd.)

Background: Loop diuretics help to manage the patients with edema associated with congestive heart failure, liver cirrhosis, and renal disease and hypertension. The patients taking loop diuretics may receive other medications to treat comorbidities leading to drug interactions., Methods: The literature was searched in databases such as Medline/PMC/PubMed, Google Scholar, Cochrane Library, Science Direct, EMBASE, Web of science, Ebsco, Directory of open access journals (DOAJ) and reference lists were used to spot relevant articles using keywords Drug interactions, Pharmacodynamic interactions, Loop diuretics, Bumetanide, Ethacrynic acid, Furosemide, and Torsemide., Results: Loop diuretics are associated with hypokalemia, ototoxicity and other adverse effects. The drugs affected by hypokalemia and having the potential of inducing ototoxicity could interact with loop diuretics pharmacodynamically. Loop diuretics can interact with drugs such as amphotericin B, digoxin, angiotensin-converting enzyme inhibitors (ACE inhibitors), antidiabetic drugs, antifungal agents, dobutamine, gossypoland sotalol due to diuretic associated hypokalemia. In addition, the risk of ototoxicity could be enhanced by the concomitant use of loop diuretics and cisplatin, aminoglycoside antibiotics or phosphodiesterase 5 (PDE 5) inhibitors. Loop diuretics may also interact pharmacodynamically with drugs like cephalosporins, ceritinib, levothyroxine, pixantrone, probenecid, lithium, nonsteroidal anti-inflammatory drugs (NSAIDs), sulfonylureas and herbal drugs., Conclusion: Clinicians, pharmacists and other health care providers should take responsibility for the safe use of medications. In addition, they are required to be aware of the drugs interacting with loop diuretics to prevent adverse drug interactions., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Torsemide is a loop diuretic that inhibits the Na+/K+/2Cl- cotransporter type 2 in the thick ascending loop of Henle, leading to increased excretion of urinary sodium and chloride and associated diuresis. While furosemide remains the dominant diuretic utilized in current practice, increasing evidence supports potential advantages of torsemide in heart failure (HF) and/or renal disease., Areas Covered: This narrative review covers the evidence for use of torsemide in HF and renal disease. Comparative effectiveness with regards to clinical outcomes is reviewed, as well as the ongoing multicenter trial, TRANSFORM-HF, comparing the effect of torsemide versus furosemide among patients with HF., Expert Opinion: Compared with furosemide, torsemide has favorable pharmacodynamics/pharmacokinetics including higher bioavailability, longer duration of effect, minor renal excretion, decreased kaliuresis, and enhanced natriuresis/diuresis. These properties may be further supported by differential effects on RAAS regulation and fibrosis modulation as compared with other diuretics. The limited current body of evidence indicates that torsemide may be superior to furosemide with respect to improving HF functional status and reducing HF hospitalization, and there are mixed data regarding effect on reducing overall cardiovascular hospitalizations/mortality. Further, randomized data are necessary to definitively determine if torsemide can reduce risk of mortality and hospitalization among patients with HF.

Randomized clinical trials are the foundation of evidence-based medicine and central to practice guidelines and patient care decisions. Nonetheless, randomized trials in heart failure (HF) populations have become increasingly difficult to conduct and are frequently associated with slow patient enrollment, highly selected populations, extensive data collection, and high costs. The traditional model for HF trials has become particularly difficult to execute in the United States, where challenges to site-based research have frequently led to modest U.S. representation in global trials. In this context, the TRANSFORM-HF (Torsemide Comparison with Furosemide for Management of Heart Failure) trial aims to overcome traditional trial challenges and compare the effects of torsemide versus furosemide among patients with HF in the United States. Loop diuretic agents are regularly used by most patients with HF and practice guidelines recommend optimal use of diuretic agents as key to a successful treatment strategy. Long-time clinical experience has contributed to dominant use of furosemide for loop diuretic therapy, although preclinical and small clinical studies suggest potential advantages of torsemide. However, due to the lack of appropriately powered clinical outcome studies, there is insufficient evidence to conclude that torsemide should be routinely recommended over furosemide. Given this gap in knowledge and the fundamental role of loop diuretic agents in HF care, the TRANSFORM-HF trial was designed as a prospective, randomized, event-driven, pragmatic, comparative-effectiveness study to definitively compare the effect of a treatment strategy of torsemide versus furosemide on long-term mortality, hospitalization, and patient-reported outcomes among patients with HF. (TRANSFORM-HF: ToRsemide compArisoN With furoSemide FORManagement of Heart Failure [TRANSFORM-HF]; NCT03296813)., Competing Interests: Funding Support and Author Disclosures TRANSFORM-HF is supported through cooperative agreements from the National Heart, Lung, and Blood Institute: U01-HL125478 and U01-HL125511. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. Dr. Greene has received research support from the American Heart Association, Amgen, AstraZeneca, Bristol-Myers Squibb, Merck, and Novartis; has served on advisory boards for Amgen and Cytokinetics; and has served as a consultant for Amgen and Merck. Dr. Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, and Windtree Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. All rights reserved.)

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Diuretics have an essential role in the management of heart failure (HF). However, each drug has its own benefit and side effect. Side effects include fluid, electrolyte abnormalities, and acid-base disturbance. These adverse effects of diuretics predispose patients to serious cardiac arrhythmias and may increase the risk of arrhythmic mortality. Herein, we aim to summarize the relative efficacy and safety of all available diuretics used in the treatment of patients with HF. In June 2017, a systematic electronic database search was conducted in nine databases. All randomized controlled trials (RCTs) comparing the different diuretics used in HF were included for meta-analysis. The protocol was registered in Prospero with CRD42018084819. Among the included 54 studies (10,740 patients), 34 RCTs were eligible for quantitative network meta-analysis (NMA) and traditional meta-analysis while the other 20 studies were qualitatively analyzed. Our results showed that azosemide and torasemide caused a significant reduction in brain natriuretic peptide (BNP) level. Torasemide also caused a significant decrease in collagen volume fraction (CVF) and edema. No significant difference between the agents concerning glomerular filtration rate (GFR), water extraction, and sodium excretion was demonstrated. Regarding side effects, no significant difference among diuretics was observed in terms of hospital readmission and mortality rates. Diuretics are the main treatment of hypervolemia in HF patients. The choice of appropriate diuretic is essential for successful management and is mainly guided by patient clinical situations and the presence of other co-morbidities.

Objective: The aim: Of the article is to conduct a comparative evaluation of the effectiveness of torasemide and furosemide in patients with heart failure., Patients and Methods: Materials and methods: Analysis of the existing clinical trials and meta-analyzes that combine the results of the completed studies aimed at the investigation of comparative efficacy of furosemide and torasemide in patients with heart failure (НF)., Conclusion: Conclusions: There is enough convincing evidence to speak about the advantages of torasemide over furosemide both in terms of its pharmacological properties and taking into account the reduction of hospitalizations, functional progress and improvement in the quality of life of patients with НF. The safety profile of torasemide is more favorable, as it is associated with a reduced risk of hypokalemia compared to furosemide. The abovementioned facts favor the use of torasemide in patients with symptomatic НF, as well as the transition from furosemide to torasemide in patients with edema caused by НF, which remain uncontrolled despite receiving optimal doses of furosemide.

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., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In heart failure (HF) patients, current European Society of Cardiology (ESC) guidelines recommend the use of three loop diuretics (furosemide, torasemide, bumetanide) in order to not only reduce HF hospitalizations but also improve symptoms and exercise capacity in patients with signs and/or symptoms of congestion. In addition, for the first time in hypertensive patients, European Society of Hypertension (ESH) guidelines recommend the use of torasemide. This review aimed to summarize the mode of action of loop diuretics, to present their pharmacokinetic characteristics, and to discuss their place in the management of arterial hypertension and heart failure, with special emphasis however on torasemide., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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., Competing Interests: The author reported no actual or potential conflict of interest in relation to this continuing nursing education activity., (Copyright© by the American Nephrology Nurses Association.)

Diuretic resistance implies a failure to increase fluid and sodium (Na + ) output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of a loop diuretic to a ceiling level (80 mg of furosemide once or twice daily or greater in those with reduced glomerular filtration rate or heart failure). It is a major cause of recurrent hospitalizations in patients with chronic heart failure and predicts death but is difficult to diagnose unequivocally. Pharmacokinetic mechanisms include the low and variable bioavailability of furosemide and the short duration of all loop diuretics that provides time for the kidneys to restore diuretic-induced Na + losses between doses. Pathophysiological mechanisms of diuretic resistance include an inappropriately high daily salt intake that exceeds the acute diuretic-induced salt loss, hyponatremia or hypokalemic, hypochloremic metabolic alkalosis, and reflex activation of the renal nerves. Nephron mechanisms include tubular tolerance that can develop even during the time that the renal tubules are exposed to a single dose of diuretic, or enhanced reabsorption in the proximal tubule that limits delivery to the loop, or an adaptive increase in reabsorption in the downstream distal tubule and collecting ducts that offsets ongoing blockade of Na + reabsorption in the loop of Henle. These provide rationales for novel strategies including the concurrent use of diuretics that block these nephron segments and even sequential nephron blockade with multiple diuretics and aquaretics combined in severely diuretic-resistant patients with heart failure.

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., (© 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC. on behalf of the American College of Veterinary Internal Medicine.)

The pharmaceutical torasemide is an important loop diuretic and was 2017 one of the ten most prescribed drugs in Germany. Despite its detection in different compartments of the urban water cycle including drinking water, no studies were so far performed to elucidate its fate in the environment and the occurrence of transformation products (TPs). Therefore, we investigated the phototransformation, microbial degradation, transformation with human liver microsomes and anodic oxidation of torasemide to obtain good coverage of environmentally relevant degradation products. Overall sixteen products were identified, covering the following reaction mechanisms: aromatic and aliphatic hydroxylation, including further oxidation to carboxylic acids and quinone imines, amide cleavage, N-dealkylation, N-dearylation, and sulfonamide hydrolysis to sulfonic acids. Especially the formation of quinone imines could be of concern as they are highly reactive electrophiles. Torasemide itself was observed in all investigated wastewater treatment plant (WWTP) samples and wastewater-impacted surface waters. The maximum detected concentration was about 350 ng L -1 . Only three of the sixteen transformation products were generally observed in at least one of the samples and the most frequently detected TPs were the human metabolites hydroxytorasemide (TP 364a) and carboxytorasemide (TP 378a). The complete removal of TP 364a during wastewater treatment was in agreement with the results of microbial degradation experiments. TP 364a was most likely transformed into TP 378a, which was microbially less degraded in lab experiments. Based on estimated concentrations, TP 378a could reach about 1 μg L -1 in the investigated wastewater matrices., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)