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Cureus Sep 2023Heart failure (HF) is a notable public health issue, and intravenous loop diuretics are frequently employed to address acute decompensated heart failure (ADHF) and... (Review)
Review
Heart failure (HF) is a notable public health issue, and intravenous loop diuretics are frequently employed to address acute decompensated heart failure (ADHF) and alleviate symptoms of congestion. However, prolonged use of loop diuretics can lead to drug resistance, and some patients experience refractory volume overload that does not respond to treatment. Sequential nephron blockade, which involves combining loop and thiazide diuretics, has been proposed as a strategy to overcome diuretic resistance and improve fluid overload management. This systematic review aims to critically evaluate the effectiveness and safety of this combination diuretic therapy. Following the directives detailed in the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive search was conducted. Eligibility criteria were established to select relevant studies, including the requirement for studies to be conducted on human subjects and published as free full-text papers in English within the last 10 years. Several databases were searched using a combination of Medical Subject Heading (MeSH) phrases and keywords related to heart failure, loop diuretics, and thiazide diuretics. The search yielded 948 references, and after screening titles, abstracts, and full-text papers, eight final studies (five observational studies and three randomized control trials) were included in the review. Based on the findings of this systematic review, there is substantial evidence to endorse the efficacy of combination diuretic therapy of loop and thiazide diuretics in augmenting diuresis and enhancing outcomes for patients who exhibit insufficient responses to single-agent diuretics. Additionally, the review provides valuable insights about the timing and type of diuretics to use, helping clinicians make informed therapeutic decisions. However, to ensure patient safety and well-being, it is imperative to take into account the potential for electrolyte disturbances and impacts on renal function, necessitating diligent and vigilant monitoring as well as effective management strategies. In light of these findings, further research is warranted to optimize the dosing regimens and to delve deeper into the long-term safety and efficacy of combination therapy. Such research endeavors will undoubtedly contribute to refining treatment approaches and advancing patient care in the field of HF management.
PubMed: 37720125
DOI: 10.7759/cureus.44624 -
European Heart Journal Aug 2023To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide.
METHODS AND RESULTS
A multi-centre, open-label, randomized, and active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 h). The primary endpoint was a diuretic effect, assessed by change in weight (kg). Secondary endpoints included a change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 h was 977 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 h was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; P = 0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) vs. 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; P = 0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments.
CONCLUSION
In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04860011.
Topics: Humans; Metolazone; Sodium Potassium Chloride Symporter Inhibitors; Furosemide; Heart Failure; Diuretics; Sodium
PubMed: 37210742
DOI: 10.1093/eurheartj/ehad341 -
Molecules (Basel, Switzerland) Jan 2023Sodium (S)-2-(dithiocarboxylato((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)-4(methylthio)butanoate (GMDTC) is the first compound to use cadmium repellent as an...
Sodium (S)-2-(dithiocarboxylato((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)-4(methylthio)butanoate (GMDTC) is the first compound to use cadmium repellent as an indication. In this paper, we established and validated a bioanalytical method for the determination of GMDTC in rat plasma, and used it to determine the drug concentrations in the plasma of rats after intravenous dosing in different genders and dosages. After pretreating the plasma samples with an acetonitrile-water-ammonia solution (70:30:1.25, //), liquid chromatographic separations were efficiently achieved with a XBridge C18 column using a 5 min gradient system of aqueous ammonium bicarbonate and 95% acetonitrile-water solution (95:5, /) as the eluent. The GMDTC and metolazone (internal standard, IS) detection were carried out using high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (LC-MS/MS), monitored at / 390.06-324.1 (for the GMDTC, tR: 2.03 min) and / 366.0-259.2 (for IS, tR: 3.88 min). The GMDTC was stable under various testing conditions, and this analytical method conforms to the verification standard of biological analysis methods. The half-life (t) was determined to be 0.54-0.65 h for the intravenous, mean distribution volume and clearances were 1.08-2.08 L/kg and 1-3 L/h/kg, respectively. The AUC and AUC found after increasing the dosage exhibited a linear relationship with the administered dose. There were no statistically significant differences in the values obtained for the different genders at dosages of 50, 100 and 250 mg/kg, respectively ( > 0.05). This is the first report of a bioanalytical method to quantify GMDTC in rat plasma using LC-MS/MS, which provides useful information for the study of its pharmacological effects and clinical applications.
Topics: Rats; Female; Male; Animals; Chromatography, Liquid; Tandem Mass Spectrometry; Chromatography, High Pressure Liquid; Indicators and Reagents; Cadmium; Reproducibility of Results
PubMed: 36770860
DOI: 10.3390/molecules28031191 -
Cureus Sep 2022Cardiac resynchronization therapy-defibrillator (CRT-D) and/or cardiac resynchronization therapy-pacemaker (CRT-P) play an important role in improving cardiac...
Cardiac resynchronization therapy-defibrillator (CRT-D) and/or cardiac resynchronization therapy-pacemaker (CRT-P) play an important role in improving cardiac synchronization and reducing the risk of ventricular fibrillation arrest (VFA) in patients with severe left ventricular systolic dysfunction (LVSD). Patients with LVSD may notice worsening symptoms when CRT-D or CRT-P is in dyssynchrony. We present a case of 59-year-old patient who presented with worsening shortness of breath (SOB) and progressive exertional dyspnea for the past few weeks accompanied by pink, frothy sputum, occasional urinary incontinence and urge. He was known to have severe LVSD with an ejection fraction of 10% and had CRT-D in situ. Clinical examination revealed bilateral crepitation and normal heart sounds. A chest radiograph showed pulmonary oedema. An electrocardiogram (ECG) showed atrial fibrillation (AF)/flutter with wide QRS complexes. The patient was treated for acute pulmonary oedema and had CRT-D reprogrammed to achieve biventricular synchrony. He was treated with intravenous furosemide and alternate day metolazone initially. He showed significant subjective and objective improvement and was planned for outpatient synchronized intra-device cardioversion. This case is important because patients with severe LVSD with malfunctioning cardiac resynchronization therapy can result in worsening heart failure (HF) leading to higher morbidity and mortality.
PubMed: 36258951
DOI: 10.7759/cureus.29096 -
Frontiers in Pharmacology 2022A network meta-analysis (NMA) of the current recommended drugs for the treatment of acute heart failure (AHF), was performed to compare the relative efficacy. We used... (Review)
Review
A network meta-analysis (NMA) of the current recommended drugs for the treatment of acute heart failure (AHF), was performed to compare the relative efficacy. We used PubMed, EMBASE, Cochrane Clinical Trials Register, and Web of Science systems to search studies of randomized controlled trials (RCT) for the treatment of AHF recommended by the guidelines and expert consensus until 1 December 2020. The primary outcome was all-cause mortality within 30 days. The secondary outcomes included 30-days all-cause rehospitalization, rates of HF-related rehospitalization, rates of adverse events, and rates of serious adverse events. A Bayesian NMA based on random effects model was performed. After screening 14,888 citations, 23 RCTs (17,097 patients) were included, focusing on nesiritide, placebo, serelaxin, rhANP, omecamtiv mecarbil, tezosentan, KW-3902, conivaptan, tolvaptan, TRV027, chlorothiazide, metolazone, ularitide, relaxin, and rolofylline. Omecamtiv mecarbil had significantly lower all-cause mortality rates than the placebo (odds ratio 0.04, 0.01-0.22), rhANP (odds ratio 0.03, 0-0.40), serelaxin (odds ratio 0.05, 0.01-0.38), tezosentan (odds ratio 0.04, 0-0.22), tolvaptan (odds ratio 0.04, 0.01-0.30), and TRV027 (odds ratio 0.03, 0-0.36). No drug was superior to the other drugs for the secondary outcomes and safety outcomes. No drug was superior to the other drugs for the secondary outcomes and safety outcomes. Current drugs for AHF show similar efficacy and safety.
PubMed: 36210851
DOI: 10.3389/fphar.2022.677589 -
Bioinformatics (Oxford, England) May 2022Drug repositioning is an attractive alternative to de novo drug discovery due to reduced time and costs to bring drugs to market. Computational repositioning methods,...
MOTIVATION
Drug repositioning is an attractive alternative to de novo drug discovery due to reduced time and costs to bring drugs to market. Computational repositioning methods, particularly non-black-box methods that can account for and predict a drug's mechanism, may provide great benefit for directing future development. By tuning both data and algorithm to utilize relationships important to drug mechanisms, a computational repositioning algorithm can be trained to both predict and explain mechanistically novel indications.
RESULTS
In this work, we examined the 123 curated drug mechanism paths found in the drug mechanism database (DrugMechDB) and after identifying the most important relationships, we integrated 18 data sources to produce a heterogeneous knowledge graph, MechRepoNet, capable of capturing the information in these paths. We applied the Rephetio repurposing algorithm to MechRepoNet using only a subset of relationships known to be mechanistic in nature and found adequate predictive ability on an evaluation set with AUROC value of 0.83. The resulting repurposing model allowed us to prioritize paths in our knowledge graph to produce a predicted treatment mechanism. We found that DrugMechDB paths, when present in the network were rated highly among predicted mechanisms. We then demonstrated MechRepoNet's ability to use mechanistic insight to identify a drug's mechanistic target, with a mean reciprocal rank of 0.525 on a test set of known drug-target interactions. Finally, we walked through repurposing examples of the anti-cancer drug imatinib for use in the treatment of asthma, and metolazone for use in the treatment of osteoporosis, to demonstrate this method's utility in providing mechanistic insight into repurposing predictions it provides.
AVAILABILITY AND IMPLEMENTATION
The Python code to reproduce the entirety of this analysis is available at: https://github.com/SuLab/MechRepoNet (archived at https://doi.org/10.5281/zenodo.6456335).
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Algorithms; Databases, Pharmaceutical; Drug Repositioning
PubMed: 35561182
DOI: 10.1093/bioinformatics/btac205 -
Critical Care Research and Practice 2021One of the strategies for overcoming diuretic resistance among heart failure (HF) patients is adding thiazide-type diuretics. The main aim of this article is to compare...
BACKGROUND
One of the strategies for overcoming diuretic resistance among heart failure (HF) patients is adding thiazide-type diuretics. The main aim of this article is to compare the adverse clinical outcomes, including death and re-hospitalization, among individuals suffering from severe acute decompensated HF (ADHF) that consumed furosemide or furosemide plus metolazone.
METHODS
This retrospective cohort study was done in the context of the Persian registry of cardiovascular disease (PROVE) from September 2017 to September 2018. One thousand and four hundred thirty-eight individuals (furosemide: 972 and furosemide plus metolazone: 466) with the final diagnosis of severe ADHF (left ventricular ejection fraction < 30%) were selected and followed for 10.3 ± 7.8 months. The association between two groups, as mentioned above, with the incidence of death and re-admission, was evaluated with different models.
RESULTS
The mean age of the study population was 68.19 ± 12.98 years. There was no significant relation in terms of death or re-hospitalization between patients with different diuretic regimens. After adjustment of potential confounders, we found that adding metolazone as an adjuvant HF therapy was not independently associated with death or re-hospitalization (hazard ratio (HR): 0.78,95% confidence interval (CI) = 0.59-1.03, = 0.085, and odds ratio (OR): 0.80, 95% CI: 0.60-1.07, = 0.135, respectively).
CONCLUSION
Our findings revealed that adding metolazone in patients with furosemide resistance is not associated with higher morbidity and mortality. Therefore, usage of these two therapeutic agents could be a helpful strategy for severe HF patients.
PubMed: 34721901
DOI: 10.1155/2021/3820292 -
Journal of Clinical Medicine Sep 2021Advanced heart failure (HF) is a condition often requiring elevated doses of loop diuretics. Therefore, these patients often experience poor diuretic response. Both...
BACKGROUND
Advanced heart failure (HF) is a condition often requiring elevated doses of loop diuretics. Therefore, these patients often experience poor diuretic response. Both conditions have a detrimental impact on prognosis and hospitalization.
AIMS
This retrospective, multicenter study evaluates the effect of the addition of oral metolazone on diuretic response (DR), clinical congestion, NTproBNP values, and renal function over hospitalization phase. Follow-up analysis for a 6-month follow-up period was performed.
METHODS
We enrolled 132 patients with acute decompensated heart failure (ADHF) in advanced NYHA class with reduced ejection fraction (EF < 40%) taking a mean furosemide amount of 250 ± 120 mg/day. Sixty-five patients received traditional loop diuretic treatment plus metolazone (Group M). The mean dose ranged from 7.5 to 15 mg for one week. Sixty-seven patients continued the furosemide (Group F). Congestion score was evaluated according to the ESC recommendations. DR was assessed by the formula diuresis/40 mg of furosemide.
RESULTS
Patients in Group M and patients in Group F showed a similar prevalence of baseline clinical congestion (3.1 ± 0.7 in Group F vs. 3 ± 0.8 in Group M) and chronic kidney disease (CKD) (51% in Group M vs. 57% in Group F; = 0.38). Patients in Group M experienced a better congestion score at discharge compared to patients in Group F (C score: 1 ± 1 in Group M vs. 3 ± 1 in Group F > 0.05). Clinical congestion resolution was also associated with weight reduction (-6 ± 2 in Group M vs. -3 ± 1 kg in Group F, < 0.05). Better DR response was observed in Group M compared to F (940 ± 149 mL/40 mgFUROSEMIDE/die vs. 541 ± 314 mL/40 mgFUROSEMIDE/die; < 0.01), whereas median ΔNTproBNP remained similar between the two groups (-4819 ± 8718 in Group M vs. -3954 ± 5560 pg/mL in Group F NS). These data were associated with better daily diuresis during hospitalization in Group M (2820 ± 900 vs. 2050 ± 1120 mL < 0.05). No differences were found in terms of WRF development and electrolyte unbalance at discharge, although Group M had a significant saline solution administration during hospitalization. Follow-up analysis did not differ between the group but a reduced trend for recurrent hospitalization was observed in the M group (26% vs. 38%).
CONCLUSIONS
Metolazone administration could be helpful in patients taking an elevated loop diuretics dose. Use of thiazide therapy is associated with better decongestion and DR. Current findings could suggest positive insights due to the reduced amount of loop diuretics in patients with advanced HF.
PubMed: 34575318
DOI: 10.3390/jcm10184207