Search Results (112)

Melanoma, in advanced stages, is the most invasive type of skin cancer, with currently available treatments showing limited efficiency. The number of melanoma cancer cases is expected to increase in the coming years, emphasizing the need for more efficient therapeutic strategies. The present study aimed to evaluate the potential of β-blockers, commonly used to treat cardiac conditions, to be repurposed for the treatment of melanoma. The effects of non-selective β-blockers (carvedilol and propranolol), β1 selective blockers (atenolol and metoprolol) and antineoplastics drugs (cisplatin and 5-fluorouracil) on the A375 melanoma cell line were studied, individually and in combined exposures, by assessing cell viability over a 72 h period. The 72 h half-maximal inhibitory concentrations (IC₅₀s) determined for A375 cells allow the ranking of toxicity as: cisplatin (2.46 (1.87–3.38) μM) > 5-fluorouracil (4.77 (4.48–5.07) μM) > carvedilol (16.91 (15.47–18.99) μM) > propranolol (58.03 (57.08–59.11) μM) > atenolol and metoprolol (β1 selective blockers that exhibited no significant effect on the cell’s viability). The effects of combined exposures were also studied. Metoprolol and carvedilol exhibited synergistic interactions with cisplatin at specific concentrations. Overall, the data highlight the concentration-dependent nature of mixture effects and support the potential application of β-blockers melanoma treatment. Full article

Background/Objectives: This study investigated how selected functionality-related characteristics (FRCs) of hypromellose (HPMC)—namely viscosity, hydroxypropoxy substitution, particle size, and the ratio of water-soluble (FlowLac^® 100) to water-insoluble (Avicel^® PH-102) fillers— affect the release of carvedilol from matrix tablets. Methods: Using a Central Composite Design (CCD) Design of Experiments (DoE), mixtures of HPMC QbD samples were prepared to achieve target HPMC FRC levels. Within the CCD, levels of FlowLac^® 100 and Avicel^® PH-102 were also varied. The mean and standard deviation of carvedilol release at each analyzed time point of the release profile were used as target variables for individual multiple linear regression (MLR) models. Results: Lactose, the water-soluble filler, significantly accelerated carvedilol release, whereas the water-insoluble MCC slowed and stabilized release by improving gel integrity. Among the HPMC FRCs, particle size had the strongest influence during the early release phase, while HPMC viscosity and hydroxypropoxy substitution degree became more important in later phases. Analysis of the results using optimized multiple linear regression (MLR) models revealed key interaction effects, particularly between HPMC viscosity and lactose content, and between viscosity and particle size, demonstrating their combined role in modulating release kinetics. Conclusions: These findings provide valuable insight into how controlling HPMC’s FRCs and filler composition can reduce interbatch variability in drug release and support the rational design of robust controlled release formulations. Full article

Propranolol is a non-selective β-adrenergic receptor antagonist widely used in cardiovascular and neurological therapy. Its naphthalene-based structure contributes to its high lipophilicityand central nervous system penetration. Clinically, propranolol is indicated for hypertension, arrhythmias, anxiety, migraine, and other conditions. It undergoes extensive hepatic metabolism via cytochrome P450 enzymes, notably CYP2D6, with a significant first-pass effect limiting oral bioavailability. This review integrates pharmacological profiling with crystallographic analysis to explore propranolol’s molecular interactions and therapeutic versatility. High-resolution crystal structures of the human β₂-adrenergic receptor (hβ₂-AR), particularly PDB ID: 6PS5 obtained via serial femtosecond crystallography (SFX), reveal key binding determinants responsible for receptor affinity and antagonism. Comparative structural analysis with other β-blockers—alprenolol, timolol, and carvedilol—highlights how variations in aromatic and heterocyclic frameworks influence pharmacokinetics and receptor selectivity. Superimposition results (RMSD: 0.032 for propranolol–alprenolol, 0.078 for propranolol–carvedilol, and 1.078 for propranolol–timolol) quantitatively illustrate molecular similarity and divergence. The enantioselective behavior of propranolol is also discussed, with the S-enantiomer showing greater receptor affinity and pharmacological potency than the R-form. Beyond canonical β-adrenergic targets, propranolol interacts with non-canonical proteins such as the cellulase enzyme Cel7A and lactoferrin, suggesting off-target effects and novel therapeutic potential. These findings underscore the importance of propranolol’s amphiphilic character, stereochemistry, and electrostatic properties in shaping its pharmacological profile. Overall, the integration of crystallographic data with pharmacological insights supports the rational design of next-generation β-adrenergic ligands with enhanced selectivity, bioavailability, and clinical efficacy. Full article

Hypertrophic cardiomyopathy (HCM) is the most common cardiomyopathy in cats and is classified as obstructive (HOCM) or non-obstructive based on anatomical differences in the left ventricular outflow tract (LVOT). In severe obstructive cases, while beta-blockers are the recommended initial treatment in humans, some patients exhibit treatment resistance. For these cases, the addition of the antiarrhythmic agent disopyramide is common. However, its use in cats has only been documented in a case report. In this study, the use of disopyramide resulted in a significant reduction in the LVOT velocity and cardiac troponin I levels. Additionally, no significant adverse effects were observed. These findings suggest that disopyramide could be a potential therapeutic option for the treatment in cats with HOCM. Full article

Ischemic heart disease remains the leading cause of death despite substantial advances in diagnosis, revascularization therapies, and risk-factor control. Beta-adrenergic receptor blockers (Beta-Blockers, BBs), long used to control heart rate, blood pressure, and reduce arrhythmic risk, may also confer cardioprotection through mechanisms beyond hemodynamic unloading. This review integrates an extensive range of preclinical, translational, and clinical studies to present a comprehensive overview of the cardioprotective effects of BBs in the context of myocardial ischemia and reperfusion injury. Mechanistic domains include modulation of redox homeostasis, attenuation of inflammation and neutrophil activation, preservation of mitochondrial integrity and anti-apoptotic signaling, improvement of endothelial function, and stabilization of calcium handling. Third-generation compounds, carvedilol and nebivolol, demonstrate additional antioxidant and vasodilatory benefits compared with first- and second-generation agents; however, no consistent class-wide effect exists across most pathways. The evidence base remains fragmented, often derived from agent- or context-specific studies in heterogeneous populations, with uncertainty surrounding optimal timing of intervention. By bridging mechanistic understanding with clinical outcomes, this review highlights the importance of standardized assessment of BB effects, the development of personalized treatment approaches, and the pursuit of future research to address ongoing translational gaps. Full article

Breast cancer (BC) is associated with multiple molecular factors such as overexpression of the beta-2 adrenergic receptor (ADRB2) and the overproduction of its agonists (norepinephrine and epinephrine). The role of adrenergic signaling in BC highlights the therapeutic potential of non-selective beta-blockers (nsBBs) as inhibitors of well-established protumor signaling pathways related to ADRB2 and their possible affinity for other important protumoral receptors. Our aim was to identify how nsBBs currently prescribed may also interact with receptors other than ADRB2, which are related to the pathophysiology of BC, using bioinformatic intracellular pathway analysis (BIPA). Subsequently, the affinity of nsBBs for both ADRB2 and the targets identified by BIPA was evaluated. We found that, beyond ADRB2, both receptor tyrosine kinase 2 (ERBB2) and neuropeptide Y receptor (NPYR) are promising targets for nsBBs in the adjuvant treatment of BC, according to BIPA. Docking studies showed that the nsBB with the highest binding affinity (ΔG) was carvedilol (−10.5 kcal/mol), followed by propranolol (−8.5 kcal/mol). These in silico findings suggest previously unrecognized pharmacological mechanisms for nsBBs in the possible treatment for BC. Notably, differences in receptor affinity were observed among the nsBBs, with carvedilol exhibiting the strongest binding affinity values on ADRB2, ERBB2, and NPYR as biological targets against BC cells. These promising results require future experimental validation. Full article

Background/Objectives: Sarcoidosis is a systemic inflammatory disease that can cause cardiac autonomic dysfunction (SCAD), often underrecognized despite its clinical importance. While [¹⁸F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ([¹⁸F]FDG PET/CT) and cardiac magnetic resonance imaging (CMR) assess cardiac involvement, [¹²³I]-meta-iodinebenzylguanidine ([¹²³I]MIBG) scintigraphy evaluates cardiac sympathetic innervation, offering complementary insights to potentially improve SCAD detection and management. This retrospective study explores the role of [¹²³I] MIBG scintigraphy in detecting SCAD among patients with unexplained cardiac symptoms. It focuses on its potential to provide complementary diagnostic information in patients where established imaging techniques, such as [¹⁸F]FDG PET/CT and CMR, fail to detect cardiac sarcoidosis. Methods: Sarcoidosis patients referred to the St. Antonius Hospital (2017–2024) who underwent [¹²³I]MIBG scintigraphy were included. Collected data encompassed demographics, SCAD symptoms, cardiac imaging findings, and carvedilol treatment outcomes. [¹²³I] MIBG abnormalities were defined as a heart-to-mediastinal ratio ≤1.6 or a washout rate ≥20%. Results: Among the final cohort of 40 sarcoidosis patients with unexplained cardiac symptoms and normal [¹⁸F]FDG PET/CT and CMR findings, 19 patients (48%) showed abnormal [¹²³I] MIBG scintigraphy results suggestive of SCAD. No significant differences were observed in clinical characteristics between patients with normal and abnormal [¹²³I]MIBG findings. Of the 16 patients treated with carvedilol, 88% reported symptom improvement, although 50% experienced side effects. Conclusions: [¹²³I]MIBG scintigraphy revealed abnormalities in a substantial number of sarcoidosis patients with unexplained cardiac symptoms despite normal [¹⁸F]FDG PET/CT and CMR. These findings indicate a potential role for [¹²³I]MIBG in detecting SCAD, but prospective studies are needed to confirm their clinical significance. Full article

Objectives: A novel two-step flow-through in vitro lipolysis model was developed for the evaluation of drug release from a self-microemulsifying drug delivery system (SMEDDS). Methods: Firstly, the SMEDDS was dispersed in an acidic medium. Subsequently, the pH was increased, and a lipolytic reaction was immediately initiated, accompanied by medium flow onset. The latter enabled increase of the initial low pH of the medium, improving the physiological relevance of the method by simulating dosage form retainment in the stomach and transfer to the duodenum, which is very important for a weakly basic active pharmaceutical ingredient (API) incorporated in an SMEDDS. Results: Conversely to the traditional pH-stat in vitro lipolysis, the developed method is not established on titration, as the reaction vessel pH is regulated by a medium flow and buffer capacity. Individual parameters, such as pancreatin activity, buffer capacity, and medium shift, were researched using traditional pH-stat in vitro lipolysis prior to their implementation in the flow-through setup. Conclusions: The concentration of the solubilized model API, carvedilol, was increased as pancreatin activity decreased and as buffer capacity increased. The ratios between release profiles obtained under different conditions utilizing the pH-stat and novel two-step flow-through in vitro lipolysis were comparable; however, the differences were more pronounced in the flow-through method. Full article

Background: Compounding is performed to adjust dosages and support medication for children. In Japan, tablets are crushed, diluted with lactose, and stored in bottles or sachets until use, but the stability and impact on dissolution of the ingredients after crushing have not been evaluated. Methods: Using a database established by the National Center for Child Health and Development in collaboration with 11 medical facilities, the status of tablet crushing was investigated. Commonly compounded drugs were selected as the target drugs. The selected drugs were sieved through a 500 μm mesh after crushing and diluted with lactose hydrate. The stability at 25 ± 2 °C/60 ± 5% relative humidity and the dissolution of the ingredients were evaluated after storing them for up to 120 days under the following conditions: (I) stored in a closed polycarbonate bottle (closed), (II) bottle opened once a day (in-use), or (III) stored in a laminated cellophane and polyethylene sachet (laminated). The changes in the ingredient content and dissolution behavior were evaluated in accordance with the Japanese Pharmacopoeia. Results: Five cardiovascular drugs (amlodipine besylate, carvedilol, propranolol hydrochloride, hydrochlorothiazide, and tadalafil) were selected as target drugs. No more than 10% change in ingredient content was observed for all five formulations compared to day 0. In addition, no related substances (impurities) were detected at more than 0.01%. There was no change in the dissolution rate of the samples after 120 days of storage under each storage condition. Conclusions: The five cardiovascular drugs commonly compounded for children in Japan maintained their pharmaceutical quality after compounding, even after long-term storage. Full article

Carvedilol (CARV) is a nonselective beta and alpha-1 adrenoceptor antagonist commonly indicated for chronic heart failure and hypertension. Its clinical potential is limited by its low aqueous solubility, resulting in poor bioavailability. Encapsulation of CARV by cyclodextrins (CDs) was performed to exceed its solubility-related barriers. This study examines the impact of the CD type and ethanol, as a co-solvent used in the preparation step, on the complexation of CARV with two β-CD derivatives. The inclusion complexes (ICs) were prepared employing the kneading method and investigated using different analytical techniques, including thermoanalytical methods, powder X-ray diffractometry (PXRD), universal attenuated total reflectance Fourier transform infrared (UATR-FTIR) spectroscopy, UV spectroscopy and saturation solubility studies. The binary products of CARV with heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) and randomly methylated β-cyclodextrin (RM-β-CD) exhibit different thermal behavior, different FTIR spectral and diffractometric profiles from those of the parent compounds, emphasizing the interaction between the components and the IC formation. CARV solubility increased 1.78 to 3.32 times as a result of drug complexation with CDs. Analytical data indicate a significant influence of both solvent systems and CD type on the IC solubility, highlighting the CARV/DM-β-CD IC as a promising entity for further research to obtain new formulations containing CARV with improved bioavailability. Full article

This study developed a solid self-nanoemulsifying drug delivery system (S-SNEDDS) to improve the oral bioavailability of poorly soluble carvedilol using mesoporous silica nanoparticles (MSNs). The liquid self-nanoemulsifying drug delivery system (L-SNEDDS) consisted of carvedilol, Peceol, Tween 80, and Labrasol in a weight ratio of 10:25:50:25. The liquid SNEDDS was suspended in MSN at various ratios and spray-dried to produce S-SNEDDS. The emulsion size, PDI, solubility, and dissolution of various ratios of MSN were evaluated to make the optimal S-SNEDDS. The optimal S-SNEDDS, manufactured using a ratio of MSN to L-SNEDDS 1000 at 500, formed a nanoemulsion and achieved efficient supersaturation compared to carvedilol alone, which significantly improved drug solubility (approximately 400 times), dissolution (approximately 5.7 times at 60 min), area under the curve (AUC) (21.7 times), and maximum plasma concentration (Cmax) (15.7 times). In addition, the physicochemical properties of the optimal S-SNEDDS were evaluated by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), Fourier transform infrared (FT-IR), particle size, and scanning electron microscopy (SEM) images. S-SNEDDS showed a smaller particle size than MSN alone, and the crystalline drug was transformed into an amorphous substance, resulting in encapsulation in MSN. These results suggest that MSN can be a novel biocompatible carrier contributing to a safer and more effective delivery system. Full article

Hypoxia/reoxygenation (HR) often occurs under cardiac pathological conditions, and HR-induced oxidative stress usually leads to cardiomyocyte damage. Carvedilol, a non-selective β-blocker, is used clinically to treat cardiac ischemia diseases. Moreover, Carvedilol has also been reported to have an antioxidant ability by reducing lipid peroxidation. However, the mechanism of Carvedilol to inhibit lipid peroxidation is still elusive. To explore the protective mechanism of Carvedilol to resist lipid peroxidation on cardiomyocytes, HL-1 cells were cultured under normoxia, hypoxia, and HR and treated with Carvedilol to investigate the alteration on metabolism, protein expression, and mRNA level to explain its oxidative mechanism. The study found that Carvedilol upregulated glutathione peroxidase 4 (GPX4) protein expression to resist HR-induced lipid peroxidation by metabolic remodeling under HR. Also, Carvedilol promoted ferroptosis-related genes, ferritin heavy chain 1 (FTH1) and ferritin light chain 1 (FTL1) mRNA levels, to reduce lipid peroxidation under both hypoxia and HR. In conclusion, our study explores a mechanism by which Carvedilol inhibits ferroptosis by upregulating GPX4, FTH1, and FTL1 levels to downregulate lipid peroxidation under HR. The study provides a potential strategy for using Carvedilol in clinical applications, inspiring further research and development in the area of heart diseases. Full article

Background/Objectives: Selective laser sintering (SLS) is one of the most promising 3D printing techniques for pharmaceutical applications as it offers numerous advantages, such as suitability to work with already approved pharmaceutical excipients, the elimination of solvents, and the ability to produce fast-dissolving, porous dosage forms with high drug loading. When the powder mixture is exposed to elevated temperatures during SLS printing, the active ingredients can be converted from the crystalline to the amorphous state, which can be used as a strategy to improve the dissolution rate and bioavailability of poorly soluble drugs. This study investigates the potential application of SLS 3D printing for the fabrication of tablets containing the poorly soluble drug carvedilol with the aim of improving the dissolution rate of the drug by forming an amorphous form through the printing process. Methods: Using SLS 3D printing, eight tablet formulations were produced using two different powder mixtures and four combinations of experimental conditions, followed by physicochemical characterization and dissolution testing. Results: Physicochemical characterization revealed that at least partial amorphization of carvedilol occurred during the printing process. Although variations in process parameters were minimal, higher temperatures in combination with lower laser speeds appeared to facilitate a greater degree of amorphization. Ultimately, the partial conversion to the amorphous form significantly improved the dissolution of carvedilol compared to its pure crystalline form. Conclusions: Obtained results suggest that the SLS 3D printing technique can be effectively used to convert poorly water-soluble drugs to their amorphous state, thereby improving solubility and bioavailability. Full article

Background/Objectives: Some specific types of white blood cells (WBCs) and the neutrophil/lymphocyte ratio (NLR) are independent predictors of outcome for heart failure (HF) patients. WBC redistribution is induced by catecholamines, and therefore we evaluate how different types of beta-blockers (BBs) influence it. Methods: The HF patients were clinically evaluated, and blood was drawn to measure N-Terminal pro–B-type natriuretic peptide (NT-proBNP), WBC-differential formula, etc. Results: On admission, 61.16% of patients who used a BB had no significant difference in the number of lymphocytes (Lym) and neutrophils (Neu), but NLR and NT- proBNP were significantly lower compared with those without BB. NT-proBNP correlated with BB dose on admission and was significantly lower in patients treated with Metoprolol (Met) as compared with Carvedilol (Car). The type and dose of BB used was responsible for 6.1% and 5.9% of the variability in the number of Lym and Neu, respectively. Patients treated with ≥100 mg Met/day had a higher Lym number, but not of Neu, with reduced NLR, compared with lower doses. Patients treated with ≥25 mg Car/day had a lower Lym number and a greater Neu number, compared with lower doses, with increased NLR. Conclusions: However, both BBs had the same rehospitalization rate during the 12 month follow-up and had an improved outcome. Full article