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NeuroImmune Pharmacology and... Mar 2024Approximately 75 % of marketed drugs have the physicochemical property of being weak bases. Weak-base drugs with relatively high pK values enter acidic organelles...
OBJECTIVES
Approximately 75 % of marketed drugs have the physicochemical property of being weak bases. Weak-base drugs with relatively high pK values enter acidic organelles including endosomes and lysosomes (endolysosomes), reside in and de-acidify endolysosomes, and induce cytotoxicity. Divalent cations within endolysosomes, including iron, are released upon endolysosome de-acidification. Endolysosomes are "master regulators of iron homeostasis", and neurodegeneration is linked to ferrous iron (Fe)-induced reactive oxygen species (ROS) generation via Fenton chemistry. Because endolysosome de-acidification-induced lysosome-stress responses release endolysosome Fe, it was crucial to determine the mechanisms by which a functionally and structurally diverse group of weak base drugs including atropine, azithromycin, fluoxetine, metoprolol, and tamoxifen influence endolysosomes and cause cell death.
METHODS
Using U87MG astrocytoma and SH-SY5Y neuroblastoma cells, we conducted concentration-response relationships for 5 weak-base drugs to determine EC values. From these curves, we chose pharmacologically and therapeutically relevant concentrations to determine if weak-base drugs induced lysosome-stress responses by de-acidifying endolysosomes, releasing endolysosome Fe in sufficient levels to increase cytosolic and mitochondria Fe and ROS levels and cell death.
RESULTS
Atropine (anticholinergic), azithromycin (antibiotic), fluoxetine (antidepressant), metoprolol (beta-adrenergic), and tamoxifen (anti-estrogen) at pharmacologically and therapeutically relevant concentrations (1) de-acidified endolysosomes, (2) decreased Fe levels in endolysosomes, (3) increased Fe and ROS levels in cytosol and mitochondria, (4) induced mitochondrial membrane potential depolarization, and (5) increased cell death; effects prevented by the endocytosed iron-chelator deferoxamine.
CONCLUSIONS
Weak-base pharmaceuticals induce lysosome-stress responses that may affect their safety profiles; a better understanding of weak-base drugs on Fe interorganellar signaling may improve pharmacotherapeutics.
PubMed: 38532786
DOI: 10.1515/nipt-2023-0021 -
BioRxiv : the Preprint Server For... May 2024Propranolol reduces experimental murine cerebral cavernous malformations (CCMs) and prevents embryonic caudal venous plexus (CVP) lesions in zebrafish that follow mosaic...
Propranolol reduces experimental murine cerebral cavernous malformations (CCMs) and prevents embryonic caudal venous plexus (CVP) lesions in zebrafish that follow mosaic inactivation of . Because morpholino silencing of the β1 adrenergic receptor () prevents the embryonic CVP lesion, we proposed that plays a role in CCM pathogenesis. Here we report that zebrafish exhibited 86% fewer CVP lesions and 87% reduction of CCM lesion volume relative to wild type brood mates at 2dpf and 8-10 weeks stage, respectively. Treatment with metoprolol, a β1 selective antagonist, yielded a similar reduction in CCM lesion volume. zebrafish embryos exhibited reduced heart rate and contractility and reduced CVP blood flow. Similarly, slowing the heart and eliminating the blood flow in CVP by administration of 2,3-BDM suppressed the CVP lesion. In sum, our findings provide genetic and pharmacological evidence that the therapeutic effect of propranolol on CCM is achieved through β1 receptor antagonism.
PubMed: 38746306
DOI: 10.1101/2024.05.05.592554 -
Cardio-oncology (London, England) Mar 2024Cardiovascular (CV) disease is a leading cause of death in breast cancer (BC) patients due to the increased age and treatments. While individual β-blockers have been...
BACKGROUND
Cardiovascular (CV) disease is a leading cause of death in breast cancer (BC) patients due to the increased age and treatments. While individual β-blockers have been investigated to manage CV complications, various β-blockers have not been compared for their effects on CV death in this population. We aimed to compare CV mortality in older BC patients taking one of the commonly used β-blockers.
METHODS
This retrospective cohort study was conducted using the Surveillance, Epidemiology and End Results (SEER) - Medicare data (2010-2015). Patients of age 66 years or older at BC diagnosis receiving metoprolol, atenolol, or carvedilol monotherapy were included. The competing risk regression model was used to determine the risk of CV mortality in the three β-blocker groups. The multivariable model was adjusted for demographic and clinical covariates. The adjusted hazard ratio (HR) and 95% confidence intervals (CI) were reported for the risk of CV mortality.
RESULTS
The study cohort included 6,540 patients of which 55% were metoprolol users, 30% were atenolol users, and 15% were carvedilol users. Metoprolol was associated with a 37% reduced risk of CV mortality (P = 0.03) compared to carvedilol after adjusting for the covariates (HR = 0.63; 95% CI 0.41-0.96). No significant difference in the risk of CV mortality between atenolol and carvedilol users was observed (HR = 0.74; 95% CI 0.44-1.22).
CONCLUSIONS
Our findings suggest that metoprolol is associated with a reduced risk of CV mortality in BC patients. Future studies are needed to confirm these findings and understand the mechanism of action.
PubMed: 38532523
DOI: 10.1186/s40959-024-00217-1 -
Cureus Sep 2023A 31-year-old, primigravida, nullipara (G1P0) female with a past medical history of Ehlers-Danlos Syndrome (EDS), newly diagnosed Wolff-Parkinson-White Syndrome (WPW),...
A 31-year-old, primigravida, nullipara (G1P0) female with a past medical history of Ehlers-Danlos Syndrome (EDS), newly diagnosed Wolff-Parkinson-White Syndrome (WPW), and fetal breech presentation initially presented at 36+5 weeks gestation for an external cephalic version (ECV). The patient noted significant symptomatology related to her WPW which had worsened over the course of her pregnancy despite being started on oral metoprolol. Despite joint recommendations from the anesthesia and obstetric teams to combine the ECV with a same-day scheduled induction of labor or cesarean section, the patient declined. An epidural catheter was placed using ultrasound guidance and slowly titrated with 2% lidocaine; however, the ECV was unsuccessful. At 39 weeks gestation, the patient underwent an uncomplicated low transverse cesarean section under combined spinal-epidural anesthesia. The patient was discharged two days later in stable condition with a referral to an electrophysiologist. Here we describe the anesthetic preparation and management for an external cephalic version and subsequent cesarean section in a patient with these two rare conditions.
PubMed: 37859915
DOI: 10.7759/cureus.45486 -
European Journal of Pharmaceutical... Mar 2024Clinical practice guidelines advise against crushing modified-release dosage forms. Metoprolol succinate modified-release (MS-MR) tablets are commonly crushed in...
PURPOSE
Clinical practice guidelines advise against crushing modified-release dosage forms. Metoprolol succinate modified-release (MS-MR) tablets are commonly crushed in clinical practice to facilitate administration to patients with swallowing difficulties or using feeding tubes. To date, the effect of this practice remains unexplored. The in vitro effects of crushing commercially available MS-MR tablets were explored using a holistic approach.
METHODS
Dissolution profiles of crushed versus whole MS-MR tablets were compared. Tablets were crushed to powder state using pragmatic method mimicking hospital practices. For standardization purposes, the same operator, duration (60 seconds), hand, and mortar-pestle apparatus were used. Dissolution studies were conducted per U.S. Pharmacopeia at pH 1.2, pH 4.5, and pH 6.8 with USP apparatus 2 (paddle) at rotation speed of 50 rpm at 37±0.5 °C in 500 mL dissolution media. Samples were withdrawn at predetermined time points. Percent drug dissolved was measured by validated UV-vis Spectrophotometry. Comprehensive analysis of the dissolution data was conducted using model-independent, model-dependent, and ANOVA-based approaches (SPSS v.23 at α=0.05). Similarity (f) and difference (f) factors were calculated to compare the dissolution profiles between crushed (CT) and whole tablets (WT). Goodness of fit (GOF) analysis examined the compliance between in vitro dissolution behaviors and several drug release models. Model selection was based on GOF plots, Akaike criteria and adjusted coefficient of determination (R). Imaging and particle size distribution analysis were conducted to examine associated surface and morphologic changes.
RESULTS
The dissolution profiles were not similar at pH 4.5 (f=45.43, f=18.97) and pH 6.8 (f=31.47, f=32.94). CT best fitted with Higuchi (pH 1.2: R=0.9990), Weibull (pH 4.5: R=0.9884), and Korsmeyer-Peppas (pH 6.8: R=0.9719). Contrastingly, WT best fitted with Hopfenberg (pH 1.2: R=0.9986), logistic (pH 4.5: R=0.9839) and first-order (pH 6.8: R=0.9979) models. A significant difference in the dissolution profiles was found between CT and WT using multivariate analysis of variance per time points and between the tablet forms (p=0.004). This was confirmed by unparalleled dissolution profiles. Crushing resulted in variations in particle size and surface morphological changes to the micropellets.
CONCLUSION
Crushing practices change the dissolution profile of MS-MR tablets by deforming the surface morphology of embedded micropellets. Amounts of drug dissolved between CT and WT were not the same at the compared time points across gastrointestinal pH ranges. This suggests potential clinical impact on plasma-concentration profiles of critically ill patients using feeding tube.
Topics: Humans; Metoprolol; Drug Liberation; Tablets; Solubility; Delayed-Action Preparations
PubMed: 38191064
DOI: 10.1016/j.ejps.2024.106694 -
International Journal of Molecular... May 2024The impact of age on mesenchymal stromal cell (MSC) characteristics has been well researched. However, increased age is concomitant with increased prevalence of...
The impact of age on mesenchymal stromal cell (MSC) characteristics has been well researched. However, increased age is concomitant with increased prevalence of polypharmacy. This adjustable factor may have further implications for the functionality of MSCs and the effectiveness of autologous MSC procedures. We applied hyperspectral microscopy of cell autofluorescence-a non-invasive imaging technique used to characterise cytometabolic heterogeneity-to identify changes in the autofluorescence signals of MSCs from (1) young mice, (2) old mice, (3) young mice randomised to receive polypharmacy (9-10 weeks of oral therapeutic doses of simvastatin, metoprolol, oxycodone, oxybutynin and citalopram), and (4) old mice randomised to receive polypharmacy. Principal Component Analysis and Logistic Regression Analysis were used to assess alterations in spectral and associated metabolic characteristics. Modelling demonstrated that cells from young mice receiving polypharmacy had less NAD(P)H and increased porphyrin relative to cells from old control mice, allowing for effective separation of the two groups (AUC of ROC curve > 0.94). Similarly, cells from old polypharmacy mice were accurately separated from those from young controls due to lower levels of NAD(P)H ( < 0.001) and higher porphyrin ( < 0.001), allowing for an extremely accurate logistic regression (AUC of ROC curve = 0.99). This polypharmacy regimen may have a more profound impact on MSCs than ageing, and can simultaneously reduce optical redox ratio (ORR) and increase porphyrin levels. This has implications for the use of autologous MSCs for older patients with chronic disease.
Topics: Animals; Mesenchymal Stem Cells; Mice; Polypharmacy; Aging; Male; Optical Imaging; NADP
PubMed: 38892017
DOI: 10.3390/ijms25115830 -
Oxidative Medicine and Cellular... 2023[This retracts the article DOI: 10.1155/2022/5993459.].
[This retracts the article DOI: 10.1155/2022/5993459.].
PubMed: 37810553
DOI: 10.1155/2023/9897437 -
Journal of Chromatography. B,... Jun 2024Antiarrhythmic and antihypertensive drugs are frequently encountered in post mortem analysis, and the question may arise as to whether they were administered in...
Antiarrhythmic and antihypertensive drugs are frequently encountered in post mortem analysis, and the question may arise as to whether they were administered in therapeutic doses, and if they were taken in accidental, intentional, or suicidal overdose scenarios. Therefore, a novel analytical method was developed and validated for the quantification of 35 drugs with toxicological relevance, including antihypertensive and antiarrhythmic drugs (ajmaline, amlodipine, amiodarone, atenolol, bisoprolol, carvedilol, clonidine, desethylamiodarone, diltiazem, donepezil, doxazosin, dronedarone, esmolol, flecainide, lercanidipine, lidocaine, metoprolol, nebivolol, nimodipine, pindolol, prajmaline, propafenone, propranolol, sotalol, urapidil, and verapamil), as well as other medications commonly found in combination (sildenafil, tadalafil, atorvastatin, clopidogrel, dapoxetine, memantine, pentoxifylline, rivastigmine, and ivabradine). The method enables simultaneous identification and quantification in blood samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Validation exhibited excellent linearity across the concentration range for all analytes. Precision and accuracy were within acceptable limits, with bias and relative standard deviation (RSD) values consistently below 9 % and 10 %, respectively. Selectivity and specificity assessments confirmed the absence of any interference from contaminants or co-extracted drugs. The method demonstrated very high sensitivity, with limits of detection (LOD) as low as 0.01 ng/ml and limits of quantification (LOQ) as low as 0.04 ng/ml. Extraction recovery exceeded 57.5 % for all analytes except atenolol, and matrix effects were <17 % for all analytes except pindolol. Processed sample stability evaluations revealed consistent results with acceptable deviations for all analytes. In addition, the method was specifically tested for the use in post mortem analysis. The applicability of our method was demonstrated by the analysis of two authentic human autopsy blood samples.
PubMed: 38878710
DOI: 10.1016/j.jchromb.2024.124196 -
Membranes Nov 2023For the first time, a new composite voltammetric sensor based on yttria-stabilized zirconia doped with neodymium-carbon black-Nafion glassy carbon electrode...
For the first time, a new composite voltammetric sensor based on yttria-stabilized zirconia doped with neodymium-carbon black-Nafion glassy carbon electrode (YSZNd-CB-Nafion/GCE) for the determination of metoprolol (MET) has been developed. The instrumental parameters and supporting electrolyte were optimized. For 105 s accumulation time, linearity was achieved in the range of 0.01 to 0.2 µM. The limit of detection (for 105 s accumulation time) was equal to 2.9 nM (2 µg/L), and was the best result in comparison to other voltametric sensors. The reproducibility of the metoprolol signal presented as relative standard deviation (RSD) was equal to 1.9% ( = 7). Additionally, our electrode is characterized by high stability, is easy to use, and has a short preparation time. The proposed sensor was found useful for MET determination in plasma and urine, as well as for pharmaceutical samples, with a good recovery parameter (96-108%). Flow injection analysis (FIA) with amperometric detection was also performed for MET determination. The recovery was calculated and was in the range 101-103%, suggesting that the proposed material may be applied in flow injection analysis.
PubMed: 38132894
DOI: 10.3390/membranes13120890 -
Biological & Pharmaceutical Bulletin 2024This study aimed to validate the In vitro Dissolution Absorption System 2 (IDAS2) containing a biological barrier of Caco-2 or Madin-Darby canine kidney (MDCK) cell...
This study aimed to validate the In vitro Dissolution Absorption System 2 (IDAS2) containing a biological barrier of Caco-2 or Madin-Darby canine kidney (MDCK) cell monolayer through dose sensitivity studies. Metoprolol and propranolol were selected as Biopharmaceutics Classification System (BCS) Class I model drugs, and atenolol as a Class III model drug. The IDAS2 is comprised of a dissolution vessel (500 mL) and two permeation chambers (2 × 8.0 mL) mounted with Caco-2 or MDCK cell monolayer. One or two immediate-release tablet(s) of the model drug were added to the dissolution vessel, and the time profiles of dissolution and permeation were observed. Greater than 85% of metoprolol and propranolol (tested at two dosing concentrations) were dissolved by 15 min, and all drugs were fully dissolved by 30 min. All three drugs were more permeable across Caco-2 cells than MDCK cells with a linear increase in permeation across both cells at both dose concentrations. Thus, the dose sensitivity of the IDAS2 was demonstrated using both cell barriers. These results indicate a successful qualification of IDAS2 for the development/optimization of oral formulations and that MDCK cells can be utilized as a surrogate for Caco-2 cells.
Topics: Dogs; Caco-2 Cells; Humans; Animals; Madin Darby Canine Kidney Cells; Propranolol; Metoprolol; Atenolol; Solubility; Dose-Response Relationship, Drug; Biopharmaceutics; Permeability; Intestinal Absorption
PubMed: 38839364
DOI: 10.1248/bpb.b24-00150