Search Results (119)

Clinically significant portal hypertension (CSPH) is a key driver of decompensation events and complications in patients with liver cirrhosis. The manifestation of hepatic decompensation is, in turn, associated with a drastic deterioration in prognosis in this vulnerable population. Therefore, a timely identification of patients at risk as well as an optimal drug treatment are key elements in the therapeutic management of patients with cirrhosis to improve survival. While invasive measurements represent the gold standard for assessing portal hypertension, significant progress has been made in recent years in developing non-invasive methods for evaluating CSPH, including the NICER and the ANTICIPATE model. These models, combining variables such as liver and spleen stiffness in combination with biomarkers such as platelet count for risk prediction, reliably identify patients with CSPH who are at risk for hepatic decompensation. In addition to advances in diagnostics, new evidence has emerged regarding optimal drug management strategies. Non-selective beta blockers are an important treatment option, even though a certain proportion of patients respond inadequately. Therefore, updated strategies are needed to identify these non-responders and improve treatment effectiveness. This review article provides a comprehensive overview of modern diagnostic approaches for CSPH, describes current management strategies including updated approaches, and provides an outlook on emerging potential treatment options. Full article

Background: Corylin (3-(2,2-dimethylchromen-6-yl)-7-hydroxychromen-4-one), a bioactive flavonoid, has been reported to exercise anti-inflammatory, antineoplastic, and antioxidant effects, and may also possess lifespan-extending properties. Objectives: Any modifications of transmembrane ionic currents produced by corylin remain largely unknown. Methods: The patch-clamp technique and docking prediction were used in this study. Results: In pituitary GH₃ somatolactotrophs, corylin concentration-dependently increased the magnitude of the M-type K⁺ current (I_K(M)), with an EC₅₀ of 3.8 μM. Concurrently, the activation time constant of I_K(M) was shortened. The addition of linopirdine (10 μM), an I_K(M) inhibitor, suppressed the current amplitude. Corylin also induced a leftward shift in the steady-state activation curve and enhanced I_K(M) during pulse-train stimulation. Moreover, corylin increases the hysteretic strength of I_K(M) evoked by a long-lasting triangular ramp pulse; this effect was attenuated by linopirdine. The stimulatory effect of corylin on I_K(M) was not altered by carvedilol or iberiotoxin but was reduced by dapagliflozin. In contrast, depolarization-activated I_K(M) was not affected by 17β-estradiol alone. In cell-attached recordings, corylin increased M-type K⁺ (K_M)-channel activity with minimal change in single-channel amplitude, while prolonging the mean open time. This stimulatory effect was reversed by linopirdine or dapagliflozin. Additionally, corylin slightly inhibited the erg-mediated current. Docking analysis further suggested that corylin potentially interacts with residues in KCNQ2 or KCNH2 channels via hydrogen bonding and hydrophobic interactions. Conclusions: These findings suggest that corylin modulates ionic currents, primarily through K_M (KCNQ/K_V7) channels, which may underlie its in vivo actions and those of related flavonoids. These effects may contribute to the regulation of functional activities of neuronal, neuroendocrine, and endocrine cells. Full article

(1) Background: Carvedilol is a poorly water-soluble drug, which limits its therapeutic performance. Deep eutectic solvents (DES) and cyclodextrins (CD) are emerging solubilizing agents that can improve drug bioavailability. (2) Methods: Twenty-one DES were prepared using choline chloride and polyols or sugars (xylitol, sorbitol, glucose, and fructose) at different molar ratios with water. α and β cyclodextrins (CD) were added (0.5–2 mM) using two incorporation strategies: (Method 1) addition to the aqueous phase before DES formation; (Method 2) direct addition to the preformed DES. (3) Results: Carvedilol solubility markedly increased with DES–CD combinations. In Method 1, xylitol-based DES provided up to a 16-fold enhancement, especially with β-CD at low concentrations, while glucose and sorbitol systems showed modest effects. Fructose-based mixtures improved mainly at a 2:1:35 ratio without CDs. In Method 2, α-CD with xylitol or sorbitol yielded the highest increases (up to 38.9-fold). (4) Conclusions: The solubilization efficiency depends on DES composition, CD type, and concentration. α-CD combined with xylitol-based DES showed the best results, highlighting this approach as a promising strategy to enhance carvedilol solubility for pharmaceutical applications. Full article

Background: Evidence regarding potential agent-specific differences among β-blockers in heart failure with mildly reduced ejection fraction (HFmrEF) remains limited. Objective: The present study sought to investigate the association of metoprolol versus carvedilol prescribed at hospital discharge with 30-month all-cause mortality and HF-related rehospitalization, and to explore potential effect modification by atrial fibrillation (AF). Methods: Consecutive patients hospitalized with HFmrEF between 2016 and 2022 were included. Exposure was β-blocker therapy at discharge (metoprolol succinate or carvedilol). Outcomes were analyzed using Kaplan–Meier estimates, multivariable Cox regression and propensity score matching. Results: Among 2109 patients discharged alive, 1625 (77.5%) received β-blockers (metoprolol n = 1033; carvedilol n = 283). Carvedilol recipients were younger (median 72 vs. 76 years) and more frequently had prior heart failure (44.2% vs. 33.2%). Thirty-month mortality occurred in 25.5% of metoprolol-treated and 31.8% of carvedilol-treated patients (unadjusted hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.61–0.98; p = 0.031). This association was observed in patients without AF, but not in those with AF. After multivariable adjustments, the association remained directionally similar (adjusted HR 0.76, 95% CI 0.58–1.00). In the matched cohort (n = 246 per group), metoprolol was still associated with lower mortality (HR 0.65, 95% CI 0.46–0.93; p = 0.017). By contrast, HF-related rehospitalization did not differ significantly between the two groups. Conclusions: In this observational HFmrEF cohort, treatment with metoprolol at index hospital discharge was associated with lower 30-month mortality compared with carvedilol. Given the observational study design in line with the higher burden of comorbidities in patients discharged on carvedilol, further prospective studies are needed to clarify the impact of different β-blocker types in heart failure patients. Full article

Background: Atrial fibrillation (AF) is a common arrythmia in post-myocardial infarction (MI) cardiac rehabilitation (CR) cohorts, and beta-adrenergic signaling remodeling and rate-control pharmacotherapy may influence functional capacity. Methods: We retrospectively studied 117 consecutive male post-MI patients referred to outpatient CR. Functional capacity was assessed with a 6 min walk test (6MWT). AF was identified from clinical records, and beta-blocker exposure was unified as carvedilol-equivalent daily dose. Results: Beta-blockers were used in 94.1% of patients and AF was present in 10.3%. Patients with AF were older (72.7 ± 6.6 vs 58.1 ± 9.3 years) and walked shorter distances (430.0 [375.0–497.5] vs. 540.0 [480.0–570.0] m). In the prespecified interaction model, age remained independently associated with lower 6MWT (−4.29 m/year; p < 0.001), AF was associated with lower 6MWT (−137.21 m; p = 0.01), and the beta-blocker dose × AF interaction was positive (+6.78; p = 0.02; R² = 0.44). Importantly, the beta-blocker dose was not associated with 6MWT in patients without AF, whereas a positive association was observed in AF (B = 7.55, p = 0.04). Conclusions: In this exploratory analysis, AF identified a subgroup with markedly reduced functional capacity in early post-MI CR, supporting the potential of phenotype-informed assessment. Additionally, the association between beta-blocker dose and 6MWT distance differed by rhythm status. These preliminary findings require confirmation in larger prospective cohorts. Full article

Background: The role of nonselective beta blockers (NSBB) in patients with cirrhosis and spontaneous bacterial peritonitis (SBP) has been a subject of debate. Conflicting studies exist regarding their impact on mortality in this population. This study aims to evaluate the effect of NSBB on mortality in patients with cirrhotic ascites and a history of SBP. Methods: Data were obtained from the TRNETX database, identifying patients aged 18 to 80 years with cirrhosis, ascites, and SBP using ICD-9 and ICD-10 codes. The study period spanned from September 2001 to January 2024. Patients were divided into two groups: those with SBP receiving NSBB (SBP + NSBB), such as carvedilol, nadolol, and propranolol, and those with SBP not receiving NSBB (SBP − NSBB). The primary outcome was all-cause mortality, and the secondary outcome was the development of acute kidney injury (AKI). Outcomes were assessed over a two-year follow-up period. Additionally, we evaluated the association of NSBB use and mortality in cirrhotic ascites by creating two separate cohorts: patients with cirrhotic ascites on NSBB (Ascites + NSBB) and those not on NSBB (Ascites − NSBB). A 1:1 propensity score matching was conducted based on baseline demographics, comorbidities, and laboratory parameters, including creatinine, INR, sodium, albumin, and bilirubin. Results: Before propensity matching, 18,160 patients were identified in the SBP-NSBB cohort, and 14,198 patients were in the SBP + NSBB cohort. After matching, each group comprised 11,801 patients. Patients with SBP who did not receive NSBB therapy exhibited higher mortality than those on NSBB therapy [OR 1.12, 95% CI 1.05–1.21]. Conversely, the incidence of AKI was higher in the SBP + NSBB group [OR 0.91, 95% CI 0.87–0.95]. In the cirrhotic ascites cohort, patients not receiving NSBB (Ascites − NSBB) demonstrated higher mortality compared to those on NSBB (Ascites + NSBB) [OR 1.17, 95% CI 1.13–1.20]. Conclusions: In a propensity-matched analysis of large patient cohorts, NSBB therapy was associated with reduced mortality in both patients with cirrhotic ascites and those with SBP. Despite a higher incidence of AKI in the SBP + NSBB group, NSBB treatment appears beneficial in reducing overall mortality in these populations. Full article

Background: Carvedilol, a non-selective β- and α1-blocker, is available in immediate-release (IR) and slow-release (SR) formulations. While carvedilol IR requires twice-daily dosing, SR was developed to improve adherence by allowing once-daily administration. This study aimed to compare long-term clinical outcomes between SR and IR carvedilol. Methods: A total of 38,563 patients taking either SR (n = 6223) or IR carvedilol (n = 32,340) were retrospectively analyzed using national claims data. Baseline characteristics, medication adherence, and cardiovascular outcomes were evaluated over a median follow-up period of 730 days. Multivariable Cox regression analyses were performed to adjust for potential confounders. Results: Despite a higher burden of comorbidities in the SR group, patients taking SR carvedilol had significantly lower risks of major adverse cardiovascular events (MACE), non-fatal myocardial infarction, and heart failure hospitalization compared to those on IR carvedilol. The adjusted hazard ratio for MACE with SR compared to IR was 0.61 (95% CI, 0.556–0.670; p < 0.001). No significant difference in non-fatal stroke was observed between the groups. Conclusions: In this claims-based observational cohort, SR carvedilol was associated with more favorable long-term cardiovascular outcomes than IR carvedilol. However, this association does not establish causal superiority, and prospective randomized studies are needed to confirm these findings. Full article

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