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BMC Pharmacology & Toxicology Nov 2017Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other thiazide diuretic drugs. However, the pharmacokinetics of metolazone in the Chinese population has rarely been studied. This study aimed to examine the pharmacokinetic characteristics, safety characteristic, and tolerability of metolazone in healthy Chinese subjects after single and multiple doses taken orally as well as the effects that food and gender have on oral metolazone pharmacokinetic parameters.
METHODS
An open-label, randomized, and single- and multiple-dosing investigation was performed in healthy Chinese subjects. The investigation included 3 study groups: the 0.5 mg, 1 mg and 2 mg dose groups were the single-dose study groups in the first stage. Eligible volunteers were randomly and orally administered a single 0.5 mg, 1 mg, or 2 mg metolazone tablet. The 0.5 mg dose group was also part of the multiple-dose study group, and the 1 mg dose group was the food-effect study group in the second stage. Human plasma samples were gathered pre-dosing and up to 48 h after dosing. The human plasma sample concentration of metolazone was quantified using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic data were calculated by a noncompartmental analysis method using WinNonlin version 6.4. Tolerability was evaluated based on adverse events, medical examination, 12-lead ECG, and other clinical laboratory exams.
RESULTS
Thirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and C showed dose proportionality after a single dose based on the linear-regression analysis. A comparison of the pharmacokinetic data revealed that the differences between the male and female groups were not statistically significant. The t of metolazone was increased by approximately 100% in the fed condition. Metolazone was well tolerated at the tested dose, and no adverse effects were observed.
CONCLUSIONS
Single dosing with 0.5 mg, 1 mg, or 2 mg metolazone yielded linear plasma pharmacokinetic properties in healthy Chinese subjects. Multiple oral doses of metolazone did not display significantly different distributions or elimination characteristics from those observed for a single dose. Gender factors did not appear to influence the pharmacokinetic parameter variation of metolazone. The t of metolazone increased in the fed condition. Metolazone was well tolerated at the tested dose in this study.
TRIAL REGISTRATION
This investigation is retrospectively registered at chictr.org.cn (ChiCTR-IIR-17012929, October 09 2017).
Topics: Administration, Oral; Adolescent; Adult; Antihypertensive Agents; Area Under Curve; Asian People; Diuretics; Drug Administration Schedule; Female; Food-Drug Interactions; Half-Life; Healthy Volunteers; Humans; Male; Metolazone; Tablets; Young Adult
PubMed: 29145890
DOI: 10.1186/s40360-017-0178-x -
Cardiovascular Therapeutics Apr 2015Sequential nephron blockade with thiazide-like diuretics is a strategy used to overcome diuretic resistance in acute decompensated heart failure (ADHF), but head-to-head... (Comparative Study)
Comparative Study
AIMS
Sequential nephron blockade with thiazide-like diuretics is a strategy used to overcome diuretic resistance in acute decompensated heart failure (ADHF), but head-to-head studies are lacking and equipoise exists regarding the preferred thiazide-like diuretic in this setting. We thus compared the effectiveness of oral metolazone versus intravenous (IV) chlorothiazide as add-on therapy to loop diuretics in hospitalized patients with ADHF and renal dysfunction.
METHODS
This retrospective cohort study evaluated the efficacy and safety of oral metolazone versus IV chlorothiazide as add-on therapy to loop diuretics in patients hospitalized with ADHF and renal dysfunction. The primary endpoint was net urine output (UOP) at 72 h after initiation of thiazide-like diuretics. Safety endpoints included worsening renal function, hypotension, and electrolyte abnormalities.
RESULTS
Fifty-five patients were enrolled with 33 patients receiving metolazone and 22 patients receiving chlorothiazide. There was no difference in median net UOP at 72 h in those receiving metolazone (4828 mL, interquartile range [IQR] 2800-7209 mL) compared to chlorothiazide (3779 mL, IQR 1885-6535 mL) (P = 0.16). There was no difference in hypotension, worsening renal function, hyponatremia, or hypokalemia (P = NS for all comparisons). Hospital length of stay was shorter in the metolazone cohort (median 7 days) compared to chlorothiazide (median 15 days), suggesting the chlorothiazide cohort was likely sicker.
CONCLUSION
Sequential nephron blockade with either metolazone or chlorothiazide appears to be efficacious and safe in ADHF, renal dysfunction, and diuretic resistance. Given the considerable cost difference favoring oral metolazone, larger randomized studies are warranted to confirm our findings and to exclude the possibility of confounding by indication.
Topics: Acute Disease; Administration, Intravenous; Administration, Oral; Aged; Chicago; Chlorothiazide; Drug Resistance; Drug Therapy, Combination; Female; Heart Failure; Hospitalization; Humans; Length of Stay; Male; Metolazone; Middle Aged; Nephrons; Retrospective Studies; Sodium Chloride Symporter Inhibitors; Sodium Potassium Chloride Symporter Inhibitors; Time Factors; Treatment Outcome; Urination
PubMed: 25712736
DOI: 10.1111/1755-5922.12109 -
Molecules (Basel, Switzerland) Jul 2019This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical...
This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical ingredients (APIs). Spray-dried, fully amorphous indapamide, metolazone, glibenclamide, hydrocortisone, hydrochlorothiazide, ketoconazole, and sulfathiazole were used as model APIs. The parameters used to assess the supersaturation potential and crystallization kinetics were the maximum supersaturation concentration (C), the area under the curve (AUC), and the crystallization rate constant (k). These were compared for freshly spray-dried and aged/crystallized samples. Aged samples were stored at 75% relative humidity for 168 days (6 months) or until they were completely crystallized, whichever came first. The solid-state changes were monitored with differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. Supersaturation potential and crystallization kinetics were investigated using a tenfold supersaturation ratio compared to the thermodynamic solubility using the µDISS Profiler. The physically aged indapamide and metolazone and the minimally crystallized glibenclamide and hydrocortisone did not show significant differences in their C and AUC when compared to the freshly spray-dried samples. Ketoconazole, with a crystalline content of 23%, reduced its C and AUC by 50%, with C being the same as the crystalline solubility. The AUC of aged metolazone, one of the two compounds that remained completely amorphous after storage, significantly improved as the crystallization kinetics significantly decreased. Glibenclamide improved the most in its supersaturation potential from amorphization. The study also revealed that, besides solid-state crystallization during storage, crystallization during dissolution and its corresponding pathway may significantly compromise the supersaturation potential of fully amorphous APIs.
Topics: Calorimetry, Differential Scanning; Chemical Phenomena; Crystallization; Drug Stability; Kinetics; Pharmaceutical Preparations; Preservation, Biological; Solubility; Spectrum Analysis, Raman; Time Factors
PubMed: 31357587
DOI: 10.3390/molecules24152731 -
PloS One 2021Twelve carbonic anhydrase (CA) isoforms catalyze carbon dioxide hydration to bicarbonate and acid protons and are responsible for many biological functions in human...
Twelve carbonic anhydrase (CA) isoforms catalyze carbon dioxide hydration to bicarbonate and acid protons and are responsible for many biological functions in human body. Despite their vital functions, they are also responsible for, or implicated in, numerous ailments and diseases such as glaucoma, high altitude sickness, and cancer. Because CA isoforms are highly homologous, clinical drugs designed to inhibit enzymatic activity of a particular isoform, can also bind to others with similar affinity causing toxic side effects. In this study, the affinities of twelve CA isoforms have been determined for nineteen clinically used drugs used to treat hypertension related diseases, i.e. thiazides, indapamide, and metolazone. Their affinities were determined using a fluorescent thermal shift assay. Stopped flow assay and isothermal titration calorimetry were also employed on a subset of compounds and proteins to confirm inhibition of CA enzymatic activity and verify the quantitative agreement between different assays. The findings of this study showed that pharmaceuticals could bind to human CA isoforms with variable affinities and inhibit their catalytic activity, even though the drug was intended to interact with a different (non-CA) protein target. Relatively minor structural changes of the compounds may cause significant changes in affinity and selectivity for a particular CA isoform.
Topics: Carbonic Anhydrases; Catalytic Domain; Humans; Isoenzymes; Protein Binding; Structure-Activity Relationship; Sulfonamides; Thiazides; Benzenesulfonamides
PubMed: 34166457
DOI: 10.1371/journal.pone.0253608 -
Journal of Controlled Release :... Jun 2017We developed a step-by-step experimental protocol using differential scanning calorimetry (DSC), dynamic vapour sorption (DVS), polarized light microscopy (PLM) and a...
We developed a step-by-step experimental protocol using differential scanning calorimetry (DSC), dynamic vapour sorption (DVS), polarized light microscopy (PLM) and a small-scale dissolution apparatus (μDISS Profiler) to investigate the mechanism (solid-to-solid or solution-mediated) by which crystallization of amorphous drugs occurs upon dissolution. This protocol then guided how to stabilize the amorphous formulation. Indapamide, metolazone, glibenclamide and glipizide were selected as model drugs and HPMC (Pharmacoat 606) and PVP (K30) as stabilizing polymers. Spray-dried amorphous indapamide, metolazone and glibenclamide crystallized via solution-mediated nucleation while glipizide suffered from solid-to-solid crystallization. The addition of 0.001%-0.01% (w/v) HPMC into the dissolution medium successfully prevented the crystallization of supersaturated solutions of indapamide and metolazone whereas it only reduced the crystallization rate for glibenclamide. Amorphous solid dispersion (ASD) formulation of glipizide and PVP K30, at a ratio of 50:50% (w/w) reduced but did not completely eliminate the solid-to-solid crystallization of glipizide even though the overall dissolution rate was enhanced both in the absence and presence of HPMC. Raman spectroscopy indicated the formation of a glipizide polymorph in the dissolution medium with higher solubility than the stable polymorph. As a complementary technique, molecular dynamics (MD) simulations of indapamide and glibenclamide with HPMC was performed. It was revealed that hydrogen bonding patterns of the two drugs with HPMC differed significantly, suggesting that hydrogen bonding may play a role in the greater stabilizing effect on supersaturation of indapamide, compared to glibenclamide.
Topics: Calorimetry, Differential Scanning; Crystallization; Drug Compounding; Drug Liberation; Drug Stability; Glipizide; Glyburide; Hydrogen Bonding; Hypromellose Derivatives; Indapamide; Metolazone; Molecular Dynamics Simulation; Povidone; Spectrum Analysis, Raman
PubMed: 28412224
DOI: 10.1016/j.jconrel.2017.04.015 -
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 -
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 -
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 -
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 -
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