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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 -
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 -
International Journal of Nephrology and... 2017Acute heart failure (AHF) is a leading cause of hospitalization and readmission in the US. The present study evaluated maximum diuresis while minimizing electrolyte...
INTRODUCTION
Acute heart failure (AHF) is a leading cause of hospitalization and readmission in the US. The present study evaluated maximum diuresis while minimizing electrolyte imbalances, hemodynamic instability, and kidney dysfunction, to achieve a euvolemic state safely in a shorter period of time.
METHODS AND RESULTS
A protocol of combined therapy with furosemide, metolazone, and spironolactone, with or without tolvaptan and acetazolamide, was used in 17 hospitalized patients with AHF. The mean number of days on combination diuretic protocol was 3.8 days. The mean daily fluid balance was 3.0±2.1 L negative. The mean daily urine output (UOP) was 4.1±2.0 L (range 1.8-10.5 L). There were minimal fluctuations in serum electrolyte levels and serum creatinine over the duration of diuretic therapy. There was no statistically significant change in patients' creatinine from immediately prior to therapy to the last day of therapy, with a mean increase in creatinine of 0.14 mg/dL (95% CI -0.03, +0.30, =0.10).
CONCLUSION
Our strategy of treating AHF by achieving high UOP, while maintaining stable electrolytes and creatinine in a short period to euvolemic state, is safe.
PubMed: 28652798
DOI: 10.2147/IJNRD.S135660 -
Scientia Pharmaceutica 2011A HPLC method has been described for simultaneous determination of Losartan potassium and Metolazone in formulation. This method is based on a HPLC separation of the two...
A HPLC method has been described for simultaneous determination of Losartan potassium and Metolazone in formulation. This method is based on a HPLC separation of the two drugs on the Thermo Hypersil BDS-C(18) (250 mm × 4.6 mm, 5.0 μm) with isocratic conditions and a simple mobile phase containing acetonitrile:water (60:40) at a flow rate of 0.8 mL/min using UV detection at 237 nm. This method has been applied to a marketed formulation without interference of excipients. The linear regression analysis data for the calibration plots showed a good linear relationship over the concentration range of 2-12 μg/mL for Losartan potassium and 0.2-1.2 μg/mL for Metolazone, respectively. The method was validated for precision, robustness and recovery. Statistical analysis showed that the method is repeatable and selective for the estimation of Losartan potassium and Metolazone.
PubMed: 21886902
DOI: 10.3797/scipharm.1105-13 -
The Western Journal of Emergency... Apr 2021The purpose of this study was to validate and assess the performance of the Emergency Heart Failure Mortality Risk Grade (EHMRG) to predict seven-day mortality in US...
INTRODUCTION
The purpose of this study was to validate and assess the performance of the Emergency Heart Failure Mortality Risk Grade (EHMRG) to predict seven-day mortality in US patients presenting to the emergency department (ED) with acute congestive heart failure (CHF) exacerbation.
METHODS
We performed a retrospective chart review on patients presenting to the ED with acute CHF exacerbation between January 2014-January 2016 across eight EDs in New York. We identified patients using codes from the International Classification of Diseases, 9th and 10 Revisions, or who were diagnosed with CHF in the ED. Inclusion criteria were patients ≥ 18 years of age who presented to the ED for acute CHF. Exclusion criteria included the following: end-stage renal disease related heart failure; < 18 years of age; pregnancy; palliative care; renal failure; and "do not resuscitate" directive. The primary outcome was seven-day mortality. We used mixed-effects logistic regression models to estimate C-statistics and continuous net reclassification index for events and nonevents.
RESULTS
We identified 3,320 ED visits associated with suspected CHF among 2,495 unique patients. Of the 3,320 ED visits, 94.7% patients were admitted to the hospital and 3.4% were discharged. The median age was 78.6 (interquartile range 68.01 - 86.76). There was an overall seven-day mortality of 2%, an inpatient mortality rate of 2.4%, and no mortality among the discharge group. Adding EHMRG to the risk prediction model improved the C-statistic (from 0.748 to 0.772) and led to a higher degree of reclassification for both events and nonevents.
CONCLUSION
The EHMRG can be used as a valuable and effective screening tool in the US while considering disposition decision for patients with acute CHF exacerbation. Emergency medical services transport and metolazone use is much higher in the US population as compared to the Canadian population. We observed minimal to no short-term mortality among discharged CHF patients from the ED.
Topics: Aged; Aged, 80 and over; Clinical Decision Rules; Emergency Medical Services; Emergency Service, Hospital; Heart Failure; Hospitalization; Humans; Logistic Models; Male; Middle Aged; New York; Retrospective Studies
PubMed: 34125045
DOI: 10.5811/westjem.2021.1.48978 -
American Journal of Physiology. Renal... Jun 2018Expression of Tamm-Horsfall protein (THP or uromodulin) is highly restricted to the kidney thick ascending limb (TAL) of loop of Henle. Despite the unique location and...
Expression of Tamm-Horsfall protein (THP or uromodulin) is highly restricted to the kidney thick ascending limb (TAL) of loop of Henle. Despite the unique location and recent association of THP gene mutations with hereditary uromodulin-associated kidney disease and THP single nucleotide polymorphisms with chronic kidney disease and hypertension, the physiological function(s) of THP and its pathological involvement remain incompletely understood. By studying age-dependent changes of THP knockout (KO) mice, we show here that young KO mice had significant salt and water wasting but were partially responsive to furosemide, due to decreased luminal translocation of Na-K-Cl cotransporter 2 (NKCC2) in the TAL. Aged THP KO mice were, however, markedly oliguric and unresponsive to furosemide, and their NKCC2 was localized primarily in the cytoplasm as evidenced by lipid raft floatation assay, cell fractionation, and confocal and immunoelectron microscopy. These aged KO mice responded to metolazone and acetazolamide, known to target distal and proximal tubules, respectively. They also had marked upregulation of renin in juxtaglomerular apparatus and serum, and they were hypertensive. Finally, the aged THP KO mice had significant upregulation of Na-coupled urate transporters Slc5a8 and Slc22a12 as well as sodium-hydrogen exchanger 3 (NHE3) in the proximal tubule and elevated serum uric acid and allantoin. Collectively, our results suggest that THP deficiency can cause progressive disturbances in renal functions via initially NKCC2 dysfunction and later compensatory responses, resulting in prolonged activation of the renin-angiotensin-aldosterone axis and hyperuricemia.
Topics: Age Factors; Animals; Blood Pressure; Cation Transport Proteins; Disease Models, Animal; Diuretics; Genetic Predisposition to Disease; Hypertension; Hyperuricemia; Kidney; Kidney Diseases; Male; Membrane Microdomains; Mice, 129 Strain; Mice, Knockout; Monocarboxylic Acid Transporters; Oliguria; Organic Anion Transporters; Phenotype; Renin-Angiotensin System; Sodium-Hydrogen Exchanger 3; Solute Carrier Family 12, Member 1; Urination; Uromodulin
PubMed: 29357410
DOI: 10.1152/ajprenal.00233.2017 -
Journal of the American Heart... Sep 2018Background In acute decompensated heart failure, guidelines recommend increasing loop diuretic dose or adding a thiazide diuretic when diuresis is inadequate. We set out...
Background In acute decompensated heart failure, guidelines recommend increasing loop diuretic dose or adding a thiazide diuretic when diuresis is inadequate. We set out to determine the adverse events associated with a diuretic strategy relying on metolazone or high-dose loop diuretics. Methods and Results Patients admitted to 3 hospitals using a common electronic medical record with a heart failure discharge diagnosis who received intravenous loop diuretics were studied in a propensity-adjusted analysis of all-cause mortality. Secondary outcomes included hyponatremia (sodium <135 mE q/L), hypokalemia (potassium <3.5 mE q/L) and worsening renal function (a ≥20% decrease in estimated glomerular filtration rate). Of 13 898 admissions, 1048 (7.5%) used adjuvant metolazone. Metolazone was strongly associated with hyponatremia, hypokalemia, and worsening renal function ( P<0.0001 for all) with minimal effect attenuation following covariate and propensity adjustment. Metolazone remained associated with increased mortality after multivariate and propensity adjustment (hazard ratio=1.20, 95% confidence interval 1.04-1.39, P=0.01). High-dose loop diuretics were associated with hypokalemia and hyponatremia ( P<0.002) but only worsening renal function retained significance ( P<0.001) after propensity adjustment. High-dose loop diuretics were not associated with reduced survival after multivariate and propensity adjustment (hazard ratio=0.97 per 100 mg of IV furosemide, 95% confidence interval 0.90-1.06, P=0.52). Conclusions During acute decompensated heart failure, metolazone was independently associated with hypokalemia, hyponatremia, worsening renal function and increased mortality after controlling for the propensity to receive metolazone and baseline characteristics. However, under the same experimental conditions, high-dose loop diuretics were not associated with hypokalemia, hyponatremia, or reduced survival. The current findings suggest that until randomized control trial data prove otherwise, uptitration of loop diuretics may be a preferred strategy over routine early addition of thiazide type diuretics when diuresis is inadequate.
Topics: Acute Disease; Aged; Cause of Death; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Guideline Adherence; Heart Failure; Humans; Injections, Intravenous; Male; Metolazone; Propensity Score; Retrospective Studies; Sodium Chloride Symporter Inhibitors; Sodium Potassium Chloride Symporter Inhibitors; Stroke Volume; Survival Rate; Treatment Outcome; United States
PubMed: 30371181
DOI: 10.1161/JAHA.118.009149 -
The Cochrane Database of Systematic... May 2014Hypertension is a modifiable cardiovascular risk factor. Although it is established that low-dose thiazides reduce mortality as well as cardiovascular morbidity, the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hypertension is a modifiable cardiovascular risk factor. Although it is established that low-dose thiazides reduce mortality as well as cardiovascular morbidity, the dose-related effect of thiazides in decreasing blood pressure has not been subject to a rigorous systematic review. It is not known whether individual drugs within the thiazide diuretic class differ in their blood pressure-lowering effects and adverse effects.
OBJECTIVES
To determine the dose-related decrease in systolic and/or diastolic blood pressure due to thiazide diuretics compared with placebo control in the treatment of patients with primary hypertension. Secondary outcomes included the dose-related adverse events leading to patient withdrawal and adverse biochemical effects on serum potassium, uric acid, creatinine, glucose and lipids.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 1), Ovid MEDLINE (1946 to February 2014), Ovid EMBASE (1974 to February 2014) and ClinicalTrials.gov.
SELECTION CRITERIA
We included double-blind, randomized controlled trials (RCTs) comparing fixed-dose thiazide diuretic monotherapy with placebo for a duration of 3 to 12 weeks in the treatment of adult patients with primary hypertension.
DATA COLLECTION AND ANALYSIS
Two authors independently screened articles, assessed trial eligibility, extracted data and determined risk of bias. We combined data for continuous variables using a mean difference (MD) and for dichotomous outcomes we calculated the relative risk ratio (RR) with 95% confidence interval (CI).
MAIN RESULTS
We included 60 randomized, double-blind trials that evaluated the dose-related trough blood pressure-lowering efficacy of six different thiazide diuretics in 11,282 participants treated for a mean duration of eight weeks. The mean age of the participants was 55 years and baseline blood pressure was 158/99 mmHg. Adequate blood pressure-lowering efficacy data were available for hydrochlorothiazide, chlorthalidone and indapamide. We judged 54 (90%) included trials to have unclear or high risk of bias, which impacted on our confidence in the results for some of our outcomes.In 33 trials with a baseline blood pressure of 155/100 mmHg, hydrochlorothiazide lowered blood pressure based on dose, with doses of 6.25 mg, 12.5 mg, 25 mg and 50 mg/day lowering blood pressure compared to placebo by 4 mmHg (95% CI 2 to 6, moderate-quality evidence)/2 mmHg (95% CI 1 to 4, moderate-quality evidence), 6 mmHg (95% CI 5 to 7, high-quality evidence)/3 mmHg (95% CI 3 to 4, high-quality evidence), 8 mmHg (95% CI 7 to 9, high-quality evidence)/3 mmHg (95% CI 3 to 4, high-quality evidence) and 11 mmHg (95% CI 6 to 15, low-quality evidence)/5 mmHg (95% CI 3 to 7, low-quality evidence), respectively.Direct comparison of doses did not show evidence of dose dependence for blood pressure-lowering for any of the other thiazides for which RCT data were available: bendrofluazide, chlorthalidone, cyclopenthiazide, metolazone or indapamide.In seven trials with a baseline blood pressure of 163/88 mmHg, chlorthalidone at doses of 12.5 mg to 75 mg/day reduced average blood pressure compared to placebo by 12.0 mmHg (95% CI 10 to 14, low-quality evidence)/4 mmHg (95% CI 3 to 5, low-quality evidence).In 10 trials with a baseline blood pressure of 161/98 mmHg, indapamide at doses of 1.0 mg to 5.0 mg/day reduced blood pressure compared to placebo by 9 mmHg (95% CI 7 to 10, low-quality evidence)/4 (95% CI 3 to 5, low-quality evidence).We judged the maximal blood pressure-lowering effect of the different thiazides to be similar. Overall, thiazides reduced average blood pressure compared to placebo by 9 mmHg (95% CI 9 to 10, high-quality evidence)/4 mmHg (95% CI 3 to 4, high-quality evidence).Thiazides as a class have a greater effect on systolic than on diastolic blood pressure, therefore thiazides lower pulse pressure by 4 mmHg to 6 mmHg, an amount that is greater than the 3 mmHg seen with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and renin inhibitors, and the 2 mmHg seen with non-selective beta-blockers. This is based on an informal indirect comparison of results observed in other Cochrane reviews on ACE inhibitors, ARBs and renin inhibitors compared with placebo, which used similar inclusion/exclusion criteria to the present review.Thiazides reduced potassium, increased uric acid and increased total cholesterol and triglycerides. These effects were dose-related and were least for hydrochlorothiazide. Chlorthalidone increased serum glucose but the evidence was unclear for other thiazides. There is a high risk of bias in the metabolic data. This review does not provide a good assessment of the adverse effects of these drugs because there was a high risk of bias in the reporting of withdrawals due to adverse effects.
AUTHORS' CONCLUSIONS
This systematic review shows that hydrochlorothiazide has a dose-related blood pressure-lowering effect. The mean blood pressure-lowering effect over the dose range 6.25 mg, 12.5 mg, 25 mg and 50 mg/day is 4/2 mmHg, 6/3 mmHg, 8/3 mmHg and 11/5 mmHg, respectively. For other thiazide drugs, the lowest doses studied lowered blood pressure maximally and higher doses did not lower it more. Due to the greater effect on systolic than on diastolic blood pressure, thiazides lower pulse pressure by 4 mmHg to 6 mmHg. This exceeds the mean 3 mmHg pulse pressure reduction achieved by ACE inhibitors, ARBs and renin inhibitors, and the 2 mmHg pulse pressure reduction with non-selective beta-blockers as shown in other Cochrane reviews, which compared these antihypertensive drug classes with placebo and used similar inclusion/exclusion criteria.Thiazides did not increase withdrawals due to adverse effects in these short-term trials but there is a high risk of bias for that outcome. Thiazides reduced potassium, increased uric acid and increased total cholesterol and triglycerides.
Topics: Adult; Antihypertensive Agents; Blood Pressure; Chlorthalidone; Essential Hypertension; Humans; Hydrochlorothiazide; Hypertension; Indapamide; Middle Aged; Randomized Controlled Trials as Topic; Sodium Chloride Symporter Inhibitors
PubMed: 24869750
DOI: 10.1002/14651858.CD003824.pub2 -
Journal of Clinical and Diagnostic... Mar 2016Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are severe mucocutaneous disease with high mortality rate. It is characterised by severe necrosis and...
Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are severe mucocutaneous disease with high mortality rate. It is characterised by severe necrosis and detachment of the epidermis. Drugs are the most common triggering agent for SJS/TEN. These are commonly reported with the use of aromatic antiepileptics, antiretrovirals, allopurinol, NSAID'S and sulfonamide antibiotics. Non antibiotic sulfonamides rarely cause SJS/TEN. Metolazone is a well known diuretic and is extensively used by clinicians. Although this drug is in market for last several decades, no case of SJS/TEN has been reported till date. We report a rare case of metolazone induced SJS/TEN overlap in a 55-year-old lady.
PubMed: 27134890
DOI: 10.7860/JCDR/2016/17768.7404 -
American Journal of Perinatology Jan 2015Diuretics are often prescribed off-label to premature infants, particularly to prevent or treat bronchopulmonary dysplasia. We examined their use and safety in this...
OBJECTIVE
Diuretics are often prescribed off-label to premature infants, particularly to prevent or treat bronchopulmonary dysplasia. We examined their use and safety in this group.
STUDY DESIGN
Retrospective cohort study of infants < 32 weeks gestation and < 1,500 g birth weight exposed to diuretics in 333 neonatal intensive care units from 1997 to 2011. We examined use of acetazolamide, amiloride, bumetanide, chlorothiazide, diazoxide, ethacrynic acid, furosemide, hydrochlorothiazide, mannitol, metolazone, or spironolactone combination. Respiratory support and fraction of inspired oxygen on the first day of each course of diuretic use were identified.
RESULTS
About 37% (39,357/107,542) infants were exposed to at least one diuretic; furosemide was the most commonly used (93% with ≥ 1 recorded dose), followed by spironolactone, chlorothiazide, hydrochlorothiazide, bumetanide, and acetazolamide. About 74% patients were exposed to one diuretic at a time, 19% to two diuretics simultaneously, and 6% to three diuretics simultaneously. The most common combination was furosemide/spironolactone, followed by furosemide/chlorothiazide and chlorothiazide/spironolactone. Many infants were not receiving mechanical ventilation on the first day of each new course of furosemide (47%), spironolactone (69%), chlorothiazide (61%), and hydrochlorothiazide (68%). Any adverse event occurred on 42 per 1,000 infant-days for any diuretic and 35 per 1,000 infant-days for furosemide. Any serious adverse event occurred in 3.8 for any diuretic and 3.2 per 1,000 infant-days for furosemide. The most common laboratory abnormality associated with diuretic exposure was thrombocytopenia.
CONCLUSION
Despite no Food and Drug Administration (FDA) indication and little safety data, over one-third of premature infants in our population were exposed to a diuretic, many with minimal respiratory support.
Topics: Acetazolamide; Amiloride; Bronchopulmonary Dysplasia; Chlorothiazide; Cohort Studies; Diazoxide; Diuretics; Drug Therapy, Combination; Ethacrynic Acid; Female; Furosemide; Humans; Hydrochlorothiazide; Infant, Extremely Premature; Infant, Newborn; Infant, Premature; Male; Mannitol; Metolazone; Off-Label Use; Respiration, Artificial; Retrospective Studies; Spironolactone; Thrombocytopenia
PubMed: 24801161
DOI: 10.1055/s-0034-1373845