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Drugs in Context 2023Diuresis with loop diuretics is the mainstay treatment for volume optimization in patients with congestive heart failure, in which perfusion and volume expansion play a... (Review)
Review
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.
PubMed: 38188263
DOI: 10.7573/dic.2023-6-5 -
The American Journal of Cardiology Feb 2016Furosemide is the most commonly used loop diuretic in patients with heart failure (HF) despite data suggesting potential pharmacologic and antifibrotic benefits with... (Randomized Controlled Trial)
Randomized Controlled Trial
Furosemide is the most commonly used loop diuretic in patients with heart failure (HF) despite data suggesting potential pharmacologic and antifibrotic benefits with torsemide. We investigated patients with HF in Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure who were discharged on either torsemide or furosemide. Using inverse probability weighting to account for the nonrandom selection of diuretic, we assessed the relation between choice of diuretic at discharge with 30-day mortality or HF hospitalization and 180-day mortality. Of 7,141 patients in the trial, 4,177 patients were included in this analysis, of which 87% (n = 3,620) received furosemide and 13% (n = 557) received torsemide. Torsemide-treated patients had lower ejection fraction and blood pressure and higher creatinine and natriuretic peptide level compared with furosemide. Torsemide was associated with similar outcomes on unadjusted analysis and nominally lower events on adjusted analysis (30-day mortality/HF hospitalization odds ratio 0.89, 95% CI 0.62 to 1.29, p = 0.55 and 180-day mortality hazard ratio 0.86, 95% CI 0.63 to 1.19, p = 0.37). In conclusion, these data are hypothesis-generating and randomized comparative effectiveness trials are needed to investigate the optimal diuretic choice.
Topics: Acute Disease; Aged; Cause of Death; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Furosemide; Global Health; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Retrospective Studies; Sodium Potassium Chloride Symporter Inhibitors; Stroke Volume; Sulfonamides; Survival Rate; Torsemide; Treatment Outcome
PubMed: 26704029
DOI: 10.1016/j.amjcard.2015.10.059 -
Journal of Veterinary Internal Medicine Sep 2022In people and dogs, torasemide has higher bioavailability, longer half-life, and longer duration of action than equivalent doses of furosemide but data regarding...
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.
Topics: Aldosterone; Animals; Cats; Creatinine; Diuretics; Dogs; Electrolytes; Furosemide; Humans; Potassium; Sodium; Sulfonamides; Torsemide
PubMed: 35906901
DOI: 10.1111/jvim.16500 -
Cancer Medicine Dec 2022Transforming growth factor β-induced factor homeobox 1 (TGIF1) reportedly promotes the pathological processes of various malignant tumors. However, few studies have...
Transforming growth factor β-induced factor homeobox 1 (TGIF1) reportedly promotes the pathological processes of various malignant tumors. However, few studies have investigated the role of TGIF1 in gliomas. We aimed to explore the relationship between TGIF1 expression and the clinical characteristics of patients with glioma, including their overall survival. A total of thousands transcriptome datapoints were downloaded from public databases to determine the correlations between TGIF1 and various clinicopathological features using the Wilcoxon or Kruskal-Wallis tests. The Kaplan-Meier and Cox statistical methods were used to explore the prognostic significance of TGIF1. Gene set enrichment analysis (GSEA) was used to indirectly identify the pathological mechanisms modulated by TGIF1, and compounds that inhibit its expression were determined using a connectivity map (CMap). TGIF1 was significantly overexpressed in gliomas and was correlated with unfavorable prognostic factors and shorter overall survival. Cox analysis confirmed that TGIF1 expression was a significant predictor of poor prognosis in patients with glioma. GSEA revealed that the signaling pathways associated with TGIF1 expression in glioma included extracellular matrix receptor- and cell cycle-modulating proteins. CMap analysis showed that the small molecules scriptaid, torasemide, dexpropranolol, ipratropium bromide, and harmine were potential negative regulators of TGIF1. Finally, in vitro experiments demonstrated that knockdown of TGIF1 significantly inhibited the proliferation and invasion of glioma cell. Taken together, our study, which is the first to comprehensively analyze TGIF1 in gliomas, revealed it to be a novel oncogene in terms of its association with this disease. As such, TGIF1 may be a potential therapeutic target for individualized treatment of patients with glioma.
Topics: Humans; Brain Neoplasms; Genes, Homeobox; Glioma; Prognosis; Signal Transduction; Repressor Proteins; Homeodomain Proteins
PubMed: 35569122
DOI: 10.1002/cam4.4822 -
Drug Design, Development and Therapy 2021With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers,...
INTRODUCTION
With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers, five molecules, highlighted from a published theoretical screening, were selected to experimentally validate their affinity toward Mcl-1.
RESULTS
A detailed NMR study revealed that only two of the five tested drugs, Torsemide and Deferasirox, interacted with Mcl-1. NMR data analysis allowed the complete characterization of the binding mode of both drugs to Mcl-1, including the estimation of their affinity for Mcl-1. Biological assays evidenced that the biological activity of Torsemide was lower as compared to the Deferasirox, which was able to efficiently and selectively inhibit the anti-apoptotic activity of Mcl-1. Finally, docking and molecular dynamics led to a 3D model for the Deferasirox:Mcl-1 complex and revealed the positioning of the drug in the Mcl-1 P2/P3 pockets as well as almost all synthetic Mcl-1 inhibitors. Interestingly, contrary to known synthetic Mcl-1 inhibitors which interact through Arg263, Deferasirox, establishes a salt bridge with Lys234.
CONCLUSION
Deferasirox could be a potential candidate for drug repositioning as Mcl-1 inhibitor.
Topics: Apoptosis Regulatory Proteins; Deferasirox; Drug Repositioning; Lenalidomide; Magnetic Resonance Spectroscopy; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Myeloid Cell Leukemia Sequence 1 Protein; Oxcarbazepine; Risperidone; Torsemide
PubMed: 34949914
DOI: 10.2147/DDDT.S323077 -
Kidney Medicine Jun 2022Heart failure treatment relies on loop diuretics to induce natriuresis and decongestion, but the therapy is often limited by diuretic resistance. We explored the...
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.
PubMed: 35620081
DOI: 10.1016/j.xkme.2022.100465 -
Current Emergency and Hospital Medicine... Jun 2013Dyspnea is the predominant symptom for patients with acute heart failure and initial treatment is largely directed towards the alleviation of this. Contrary to...
Dyspnea is the predominant symptom for patients with acute heart failure and initial treatment is largely directed towards the alleviation of this. Contrary to conventional belief, not all patients present with fluid overload and the approach to management is rapidly evolving from a solitary focus on diuresis to one that more accurately reflects the complex interplay of underlying cardiac dysfunction and acute precipitant. Effective treatment thus requires an understanding of divergent patient profiles and an appreciation of various therapeutic options for targeted patient stabilization. The key principle within this paradigm is directed management that aims to diminish the work of breathing through situation appropriate ventillatory support, volume reduction and hemodynamic improvement. With such an approach, clinicians can more efficiently address respiratory discomfort while reducing the likelihood of avoidable harm.
PubMed: 24223323
DOI: 10.1007/s40138-013-0012-8 -
Nutrients Jun 2021Due to multifactorial reasons, such as decreased thirst and decreased total body water, elderly patients are vulnerable to dehydration. Mild cognitive impairment (MCI)...
Due to multifactorial reasons, such as decreased thirst and decreased total body water, elderly patients are vulnerable to dehydration. Mild cognitive impairment (MCI) or dementia increase the risk of dehydration and, in turn, dehydration decreases cognitive performance. The study aims to identify and assess differences in hydration status, taking into account patients' drug treatment and diseases, using bioelectrical impedance vector analysis (BIVA), thereby revealing unfavorable aspects of prognosis. 447 geriatric patients (241 women, 206 men) including information on medication and bioelectrical impedance analysis (BIA) were investigated, which allowed studying the association between 40 drugs and the hydration status. First, patients were divided into disease groups. Renal disease and diuretic treatment were significantly different in both sexes, whereas cardiovascular patients differed exclusively for females. Next, drug enrichment was examined in either hyperhydrated or dehydrated patients. Simvastatin, candesartan, bisoprolol, amlodipine, olmesartan, furosemide, torasemide, allopurinol, mirtazapine, pantoprazole, cholecalciferol, and resveratrol showed enrichment depending on hydration status. This study demonstrated that patients can be differentiated and stratified by BIVA, taking into account medication and disease associated with hydration status. Although patients diagnosed with MCI and therefore treated with resveratrol, BIVA still showed evaluated dehydration. This is unfavorable in terms of prognosis and requires special attention.
Topics: Aged; Aged, 80 and over; Body Composition; Cognitive Dysfunction; Dehydration; Female; Geriatrics; Humans; Male; Nutrition Assessment; Nutritional Status; Organism Hydration Status; Pharmaceutical Preparations
PubMed: 34199738
DOI: 10.3390/nu13061929 -
Congestive Heart Failure (Greenwich,... 2003Congestive heart failure is a disease state distinguished by the regular presence of both renal and hepatic abnormalities in drug handling. One such abnormality involves... (Review)
Review
Congestive heart failure is a disease state distinguished by the regular presence of both renal and hepatic abnormalities in drug handling. One such abnormality involves flaws in the process of drug absorption. In most instances, congestive heart failure-related abnormalities in drug absorption are of inconsequential significance. However, this is not the case with loop diuretics. Loop diuretic action ordinarily tracks the rate and extent of absorption if a sufficient amount of diuretic has been given to exceed the threshold for diuretic effect. In congestive heart failure, both the rate and absolute amount of loop diuretic absorbed can be reduced as a function of the heart failure state itself. In this setting, drug dissolution characteristics can assume added significance. Furosemide is the loop diuretic with the widest intra- and interpatient variability of absorption. Alternatively, the loop diuretic torsemide is rapidly and fairly completely absorbed independent of the heart failure state. This pattern of absorption establishes it as the preferred loop diuretic in the otherwise diuretic-resistant heart failure patient. However, the exact role of torsemide in the outpatient management of congestive heart failure remains to be determined.
Topics: Diuretics; Furosemide; Heart Failure; Humans; Intestinal Mucosa; Liver; Sulfonamides; Torsemide
PubMed: 14564148
DOI: 10.1111/j.1527-5299.2003.02399.x -
Journal of Veterinary Pharmacology and... Mar 2022Thirty-two (16 males and 16 females) healthy young beagles were randomly divided into four groups of eight. The control group remained untreated. Torasemide (ISEMID ,...
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.
Topics: Animals; Diuresis; Diuretics; Dogs; Female; Kidney; Male; Sulfonamides; Torsemide
PubMed: 34791658
DOI: 10.1111/jvp.13030