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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 -
Journal of Palliative Medicine Feb 2023
Topics: Humans; Metolazone; Furosemide; Conservative Treatment; Heart Failure; Kidney Failure, Chronic
PubMed: 36724315
DOI: 10.1089/jpm.2022.0532 -
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 -
Current Diabetes Reviews 2023Type 2 diabetes mellitus (T2DM) is a set of metabolic disorders specified by hyperglycemia as a result of abnormalities in insulin secretion or sensitivity. Chronic... (Review)
Review
Type 2 diabetes mellitus (T2DM) is a set of metabolic disorders specified by hyperglycemia as a result of abnormalities in insulin secretion or sensitivity. Chronic kidney disease (CKD) and cardiovascular disease (CVD) are the widespread co-morbidities of T2DM and share risk factors for onset and progression. Despite numerous mono- and combination therapies exist, the progression of diabetes complications remains a global health concern. Treatment options for diabetic- CKD and CVD include drugs targeting hyperglycemia, hypertension, albuminuria, hyperlipidemia and the renin-angiotensin aldosterone system (RAAS). The sodium-glucose co-transporter 2 channel (SGLT2) is abundantly present in proximal tubules of the kidney and its capacity to recover glucose and sodium from the glomerular filtrate limits urinary glucose and sodium excretion. SGLT2 inhibitors (SGLT2i) reduce sodium and glucose reabsorption in the proximal and thus increase urinary glucose excretion in T2DM. SGLT2i monotherapy can improve but dual SGLT2/RAAS inhibition or SGLT2i along with other classes of drugs are more effective in protecting the kidneys and the cardiovascular system in patients with and without diabetes. Combinations such as empagliflozin and linagliptin, ertugliflozin and metolazone, dapagliflozin and sacubitril- valsartan and many more show promising results. Here, we have reviewed the ongoing and completed clinical trials, addressed current theories, and discussed necessary future research to explain the possible risks and benefits of using an SGLT2i alone and in combination with existing antidiabetic drugs and drugs acting on the cardiovascular system.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Sodium-Glucose Transporter 2; Hypoglycemic Agents; Diabetic Nephropathies; Glucose; Hyperglycemia; Renal Insufficiency, Chronic; Cardiovascular Diseases; Sodium
PubMed: 35975848
DOI: 10.2174/1573399819666220816145907 -
Journal of Cardiac Failure Aug 2022Metolazone and intravenous (IV) chlorothiazide are commonly used diuretics for sequential nephron blockade (SNB) in patients with acute decompensated heart failure...
BACKGROUND
Metolazone and intravenous (IV) chlorothiazide are commonly used diuretics for sequential nephron blockade (SNB) in patients with acute decompensated heart failure (ADHF). Previous studies suggest metolazone may be comparable with chlorothiazide in terms of efficacy and safety. The objective of this study was to determine whether IV chlorothiazide is superior to metolazone in increasing net urine output (UOP) of hospitalized patients with ADHF.
METHODS AND RESULTS
This retrospective cohort study included hospitalized patients with ADHF and evidence of loop diuretic resistance in a tertiary academic medical center. The primary end point was the change in net 24-hour UOP in patients treated with IV chlorothiazide compared with metolazone. The relative cost of chlorothiazide doses and metolazone doses administered during SNB was a notable secondary end point. The median change in net 24-hour UOP in the IV chlorothiazide group was -1481.9 mL (interquartile range -2696.0 to -641.0 mL) and -1780.0 mL (interquartile range -3084.5 to -853.5 mL) in the metolazone group (P = .05) across 220 hospital encounters. The median cost of chlorothiazide and metolazone doses used during SNB was $360 and $4, respectively (P < .01).
CONCLUSIONS
Chlorothiazide was not superior to metolazone in changing the net 24-hour UOP of patients with ADHF and loop resistance. Preferential metolazone use in SNB is a potential cost-saving measure.
Topics: Chlorothiazide; Diuretics; Furosemide; Heart Failure; Humans; Metolazone; Nephrons; Retrospective Studies
PubMed: 35688407
DOI: 10.1016/j.cardfail.2022.05.011 -
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 -
Drug Research Jul 2022Acute decompensated heart failure is often treated with a combination of loop and thiazide-like diuretics. Of these thiazide-like diuretics, two common choices are...
OBJECTIVE
Acute decompensated heart failure is often treated with a combination of loop and thiazide-like diuretics. Of these thiazide-like diuretics, two common choices are intravenous chlorothiazide or oral metolazone. Metolazone is more potent and has a longer duration of action, but since it is an oral formulation, it has a longer on-set time as compared to chlorothiazide. In addition, metolazone is poorly water-soluble, thereby rendering intravenous formulation more challenging. To address these issues, we proposed the formulation of a solvent-free metolazone emulsion for intravenous administration.
METHODS
An oil-in-water emulsion containing 1 mg/mL of metolazone was formulated by homogenizing soybean oil and -lecithin in water in the presence of optimized concentrations of glycerin with tween 80 or poloxamer 188 as surfactant. The emulsion was characterized on the basis of particle size, zeta potential, morphology and metolazone release kinetics. The diuretic effect of the metolazone emulsion was evaluated in rats.
RESULTS
The 1 mg/mL metolazone emulsion prepared with 5% tween 80 displayed the best physical stability. The emulsion exhibited a hydrodynamic diameter of 157.13±1.52 nm. About 93% of metolazone was released from the formulation within 2 h. The 2 mg/kg and 4 mg/kg dose of the metolazone emulsion increased urine output in the rats by 68.9 and 134%, respectively, as compared to control rats. Furthermore, the 4 mg/kg dose exhibited a 168.8%, 25.8%, and 150.9% increase in sodium, potassium, and chloride, respectively.
CONCLUSION
This metolazone emulsion was capable of increasing urine volume output and demonstrated both natriuretic and kaliuretic properties.
Topics: Administration, Intravenous; Animals; Chlorothiazide; Diuretics; Emulsions; Heart Failure; Metolazone; Polysorbates; Rats; Water
PubMed: 35537450
DOI: 10.1055/a-1813-9489 -
Spectrochimica Acta. Part A, Molecular... Feb 2022In this study, a facile, rapid, and sensitive spectrofluorimetric method was evolved to analyse two antihypertensive drugs, namely, metolazone (MTZ) and valsartan (VST),...
In this study, a facile, rapid, and sensitive spectrofluorimetric method was evolved to analyse two antihypertensive drugs, namely, metolazone (MTZ) and valsartan (VST), in pharmaceutical and biological matrices. Both analytes exhibited intrinsic fluorescence activities which were significantly affected by environmental factors such as pH and solvent systems. However, simultaneous determination of MTZ and VST by conventional spectrofluorometry cannot be achieved simply because of the strong overlap between their fluorescence spectra. Thus, a combination of derivative and synchronous spectrofluorometry was conducted to overcome this dilemma. The proposed method relies on measurement of the first-order derivative of synchronous fluorescence intensity of the studied drugs at Δλ = 160 nm using 0.1 M acetic acid as the optimum solvent. The amplitudes of the first derivative synchronous fluorescence spectra of MTZ and VST were recorded at 236.0 nm (zero-crossing point of VST) and at 262.8 nm (zero-crossing point of MTZ) for simultaneous analysis of MTZ and VST, respectively. The fluorescent method was optimized efficiently to get the maximum selectivity and sensitivity by investigating different solvents, different buffer pHs, and different surfactants. The highest sensitivity and selectivity were achieved when 0.1 M acetic acid was used as a solvent. The method showed a linear concentration range of 10.0-100.0 ng mL and a limit of detection of <3.0 ng mL for each analyte. Statistical data analysis confirmed that no significant difference between the proposed spectrofluorometric method and the reference methods. The validity of the proposed spectrofluorometric method approved its suitability for quality control work. The proposed spectrofluorometric method was applied to assay the studied drugs in pharmaceutical dosage and in biological matrices with acceptable %recoveries and small RSD values.
Topics: Antihypertensive Agents; Metolazone; Pharmaceutical Preparations; Spectrometry, Fluorescence; Valsartan
PubMed: 34789407
DOI: 10.1016/j.saa.2021.120591 -
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