Improved Cardiac Performance and Decreased Arrhythmia in Hypertrophic Cardiomyopathy With Non-ß-Blocking R-Enantiomer Carvedilol.

BACKGROUND: Hypercontractility and arrhythmia are key pathophysiologic features of hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. ß-Adrenergic receptor antagonists (ß-blockers) are the first-line therapy for HCM. However, ß-blockers commonly selected for this disease are often poorly tolerated in patients, where heart-rate reduction and noncardiac effects can lead to reduced cardiac output and fatigue. Mavacamten, myosin ATPase inhibitor recently approved by the US Food and Drug Administration, has demonstrated the ability to ameliorate hypercontractility without lowering heart rate, but its benefits are so far limited to patients with left ventricular (LV) outflow tract obstruction, and its effect on arrhythmia is unknown. METHODS: We screened 21 ß-blockers for their impact on myocyte contractility and evaluated the antiarrhythmic properties of the most promising drug in a ventricular myocyte arrhythmia model. We then examined its in vivo effect on LV function by hemodynamic pressure-volume loop analysis. The efficacy of the drug was tested in vitro and in vivo compared with current therapeutic options (metoprolol, verapamil, and mavacamten) for HCM in an established mouse model of HCM (Myh6R403Q/+ and induced pluripotent stem cell (iPSC)-derived cardiomyocytes from patients with HCM (MYH7R403Q/+). RESULTS: We identified that carvedilol, a ß-blocker not commonly used in HCM, suppresses contractile function and arrhythmia by inhibiting RyR2 (ryanodine receptor type 2). Unlike metoprolol (a ß1-blocker), carvedilol markedly reduced LV contractility through RyR2 inhibition, while maintaining stroke volume through α1-adrenergic receptor inhibition in vivo. Clinically available carvedilol is a racemic mixture, and the R-enantiomer, devoid of ß-blocking effect, retains the ability to inhibit both α1-receptor and RyR2, thereby suppressing contractile function and arrhythmias without lowering heart rate and cardiac output. In Myh6R403Q/+ mice, R-carvedilol normalized hyperdynamic contraction, suppressed arrhythmia, and increased cardiac output better than metoprolol, verapamil, and mavacamten. The ability of R-carvedilol to suppress contractile function was well retained in MYH7R403Q/+ iPSC-derived cardiomyocytes. CONCLUSIONS: R-enantiomer carvedilol attenuates hyperdynamic contraction, suppresses arrhythmia, and at the same time, improves cardiac output without lowering heart rate by dual blockade of α1-adrenergic receptor and RyR2 in mouse and human models of HCM. This combination of therapeutic effects is unique among current therapeutic options for HCM and may particularly benefit patients without LV outflow tract obstruction.

Exploring algorithms to select candidates for non-selective beta-blockers in cirrhosis: a post-hoc analysis of the PREDESCI trial.

BACKGROUND & AIMS: Whether non-invasive tests (NITs) can accurately select patients with cirrhosis requiring non-selective beta-blockers (NSBB) for clinically significant portal hypertension (CSPH) and prevention of decompensation is unclear. Our aim was to test the performance of NIT-based algorithms for CSPH diagnosis using the prospective PREDESCI cohort. We investigated a new algorithm combining NITs with endoscopy to improve performance. METHODS: We included patients with compensated cirrhosis and available liver elastography who were screened during the trial. The performance of models based on liver stiffness measurement (LSM) and platelet count was evaluated. An algorithm considering endoscopy for patients with inconclusive results (the "grey zone") was then developed and validated in an independent cohort of 195 patients in whom also spleen stiffness was available. RESULTS: We included 170 patients from the PREDESCI cohort. An LSM≥25 kPa alone (Baveno VII criteria) or an LSM>20 kPa plus thrombocytopenia (AASLD criteria) ruled-in CSPH with positive predictive value of 88 and 89%, respectively. However, 37%-47% patients fell into the grey zone while at high-risk of decompensation or death. Performing endoscopy in inconclusive cases identified patients with varices that, when re-classified as high-risk for CSPH, significantly reduced the grey zone to 22%. In this algorithm, 86% of CSPH patients were correctly classified as high-risk. The diagnostic performance was confirmed in the external validation cohort, where combining Baveno VII criteria with spleen stiffness showed similar accuracy to the model using endoscopy. CONCLUSIONS: Algorithms based only on LSM and platelet count are suboptimal to identify NSBB treatment candidates. Performing endoscopy in patients with indeterminate findings from NITs improved diagnostic performance and risk stratification. Endoscopy may be substituted by spleen stiffness for stratifying the risk in the grey zone. IMPACT AND IMPLICATIONS: The PREDESCI trial demonstrated that non-selective beta-blockers prevent decompensation in CSPH patients. Still it is unclear whether we can select treatment candidates using non-invasive tests to assess the presence of CSPH without measuring HVPG. In the prospective cohort of patients screened during the trial, we showed that algorithms based on liver stiffness and platelet count had suboptimal performance, mainly due to a high rate of indeterminate results. Performing endoscopy in the grey zone patients allowed to significantly increase the number of patients with CSPH and improved the risk stratification for decompensation or death on long-term follow-up. These findings were validated in an independent cohort. In addition, a model using spleen stiffness instead of endoscopy showed similar diagnostic performance in the external validation cohort, suggesting that adequate risk stratification to select treatment candidates can be achieved with a fully non-invasive algorithm.

Beta-Blockers Lower First Decompensation in Patients With Cirrhosis and Enduring Portal Hypertension After Etiological Treatment.

BACKGROUND AND AIMS: Non-selective beta-blockers (NSBBs) can lower the risk of first decompensation in patients with cirrhosis and clinically significant portal hypertension (CSPH) (identified by a hepatic venous pressure gradient ≥10 mm Hg) with active etiology. Our aim was to examine the effect of NSBBs on first decompensation occurrence in patients with cirrhosis and enduring CSPH after etiological treatment. METHODS: Patients with compensated cirrhosis and clinical evidence of CSPH (gastroesophageal varices [GEVs] and/or spontaneous portosystemic collaterals [SPSSs]) after 2 years from etiological treatment. The primary endpoint was first decompensation (occurrence of variceal bleeding, ascites, or hepatic encephalopathy) in patients on NSBBs vs off NSBBs. RESULTS: The final cohort included 406 patients. Baseline characteristics of patients on NSBBs (n = 187) and off NSBBs (n = 219) were comparable, except for signs of portal hypertension that were more pronounced in the on-NSBBs group. During a mean follow-up of 32 months, 127 (31%) patients decompensated, with ascites being the most common (77%) decompensating event. Decompensation rates were lower in patients on NSBBs (16% vs 44%; P < .0001). The benefit of NSBBs on decompensation was maintained in patients with small GEVs (17% vs 43%; P < .0001), in those with spontaneous portosystemic shunt only (8% vs 43%; P = .003), and in each different etiology, including hepatitis C virus-cured cirrhosis (9% vs 32%; P < .0001). At Cox regression analysis, hemoglobin, Child-Pugh, Model for End-Stage Liver Disease-Sodium, diabetes at baseline, and previous bacterial infections were independent predictors of decompensation, while NSBBs use had a protective effect (hazard ratio, 0.32; 95% confidence interval, 0.20-0.49; P < .0001). NSBBs use significantly reduced bacterial infection rates (hazard ratio, 0.36; 95% confidence interval, 0.22-0.58; P < .0001). CONCLUSION: NSBBs decrease the risk of first decompensation in patients with cirrhosis and enduring CSPH after etiological treatment.

Antidepressant effect of carvedilol on streptozotocin-induced diabetic peripheral neuropathy mice by altering gut microbiota.

RATIONALE: Although diabetic peripheral neuropathic pain (DPNP) and depression have been recognized for many years, their co-morbidity relationship and effective treatment choices remain uncertain. OBJECTIVES: To evaluate the antidepressant effect of carvedilol on streptozotocin-induced DPNP mice, and the relationship with gut microbiota. METHODS: The hyperalgesia and depressive behaviors of mice with comorbidity of DPNP and depression were confirmed by pain threshold of the mechanical sensitivity test (MST), immobility time of the tail suspension test (TST) and the forced swimming test (FST). The anti-depressive effect and fecal gut microbiota composition were studied in DPNP mice treated with carvedilol (10 mg/kg/day), and the relationships between them were analyzed by Spearman's correlation. RESULTS: Depression was successfully induced in DPNP mice. Carvedilol can reverse the decreased mechanical pain threshold and relieve the depressive behaviors of DPNP mice, while increasing the abundance of Prevotella, Ruminococcus, Helicobacter and Desulfovibrio, and decreasing the abundance of Akkermansia and Allobaculum. CONCLUSIONS: Carvedilol can alleviate the mechanical hyperalgesia and alter gut microbiota to ameliorate the depression-like behaviors which induced by DPNP.

Programmed death of cardiomyocytes in cardiovascular disease and new therapeutic approaches.

Cardiovascular diseases (CVDs) have a complex pathogenesis and pose a major threat to human health. Cardiomyocytes have a low regenerative capacity, and their death is a key factor in the morbidity and mortality of many CVDs. Cardiomyocyte death can be regulated by specific signaling pathways known as programmed cell death (PCD), including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, etc. Abnormalities in PCD can lead to the development of a variety of cardiovascular diseases, and there are also molecular-level interconnections between different PCD pathways under the same cardiovascular disease model. Currently, the link between programmed cell death in cardiomyocytes and cardiovascular disease is not fully understood. This review describes the molecular mechanisms of programmed death and the impact of cardiomyocyte death on cardiovascular disease development. Emphasis is placed on a summary of drugs and potential therapeutic approaches that can be used to treat cardiovascular disease by targeting and blocking programmed cell death in cardiomyocytes.

The potential for improved outcomes in the prevention and therapy of diabetic kidney disease through 'stacking' of drugs from different classes.

Aggressive therapy of diabetic kidney disease (DKD) can not only slow the progression of DKD to renal failure but, if utilized at an early enough stage of DKD, can also stabilize and/or reverse the decline in renal function. The currently recognized standard of therapy for DKD is blockade of the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). However, unless utilized at a very early stage, monotherapy with these drugs in DKD will only prevent or slow the progression of DKD and will neither stabilize nor reverse the progression of DKD to renal decompensation. Recently, the addition of a sodium-glucose cotransporter-2 inhibitor and/or a mineralocorticoid receptor blocker to ACE inhibitors or ARBs has been clearly shown to further decelerate the decline in renal function. The use of glucagon-like peptide-1 (GLP-1) agonists shown promise in decelerating the progression of DKD. Other drugs that may aid in the deceleration the progression of DKD are dipeptidyl peptidase-4 inhibitors, pentoxifylline, statins, and vasodilating beta blockers. Therefore, aggressive therapy with combinations of these drugs (stacking) should improve the preservation of renal function in DKD.

Rerouting cardiovascular management following gastric bypass surgery: Dose optimization of carvedilol using population-based analysis.

AIMS: A population-based pharmacokinetic (PK) modeling approach (PopPK) was used to investigate the impact of Roux-en-Y gastric bypass (RYGB) on the PK of (R)- and (S)-carvedilol. We aimed to optimize carvedilol dosing for these patients utilizing a pharmacokinetic/pharmacodynamic (PK/PD) link model. METHODS: PopPK models were developed utilizing data from 52 subjects, including nonobese, obese, and post- RYGB patients who received rac- carvedilol orally. Covariate analysis included anthropometric and laboratory data, history of RYGB surgery, CYP2D6 and CYP3A4 in vivo activity, and relative intestinal abundance of major drug- metabolizing enzymes and transporters. A direct effect inhibitory Emax pharmacodynamic model was linked to the PK model of (S)- carvedilol to simulate the changes in exercise- induced heart rate. RESULTS: A 2-compartmental model with linear elimination and parallel first-order absorptions best described (S)-carvedilol PK. RYGB led to a twofold reduction in relative oral bioavailability compared to nonoperated subjects, along with delayed absorption of both enantiomers. The intestinal ABCC2 mRNA expression increases the time to reach the maximum plasma concentration. The reduced exposure (AUC) of (S)-carvedilol post-RYGB corresponded to a 33% decrease in the predicted area under the effect curve (AUEC) for the 24-hour ß-blocker response. Simulation results suggested that a 50-mg daily dose in post-RYGB patients achieved comparable AUC and AUEC to 25-mg dose in nonoperated subjects. CONCLUSION: Integrated PK/PD modeling indicated that standard dosage regimens for nonoperated subjects do not provide equivalent ß-blocking activity in RYGB patients. This study highlights the importance of personalized dosing strategies to attain desired therapeutic outcomes in this patient cohort.

Carvedilol induces pyroptosis through NLRP3-caspase1-ASC inflammasome by nuclear migration of NF-κB in prostate cancer models.

BACKGROUND: Pyroptosis is an inflammatory type of programmed cell death, and could overcome the drug-resistance induced by anti-apoptotic effect of cancers. Carvedilol (CVL), a ß-adrenergic receptors antagonist, has shown anti-inflammatory response and anti-cancer effect. The aim of this study is to investigate whether pyroptosis can be activated by CVL in prostate cancer (PCa). METHODS AND RESULTS: Datasets were used to analyze the expressions of pyroptosis-related proteins. Intracellular morphological change, cell viability, LDH and Il-1ß release by cells,, and Hoechst/PI staining were used to detect the occurrence of pyroptosis. Realtime-PCR, western blot, immunofluorescence, and immunohistochemistry (IHC) were used to investigate the expressions of pyroptosis-related proteins. Datasets analyze showed the expressions of NLRP3, Caspase 1, ASC and GSDMD were all decreased in PCa comparing with normal tissues, but without prognostic significance. CVL treatment weakened the viabilities of PCa cells. Cell morphology changing, cytoplasmic vacuole formation, membrane integrity loss, LDH and IL-1ß release and PI positive cells increasing were observed. NLRP3, Caspase 1, ASC, GSDMD and N-GSDMD expressions were elevated after CVL treatment, accompanied by a tendency of NF-κB transferring into nucleus. In vivo, CVL inhibited the growth of subcutaneous transplanted tumor. IHC showed CVL increased the expressions of NLRP3, ASC, and GSDMD, and decreased the expression of Ki-67 in transplanted tumor tissues. CONCLUSION: This study demonstrated that CVL could induce pyroptosis in PCa cells through NLRP3-caspase1-ASC inflammasome by promoting nuclear translocation of NF-κB, which would lay a foundation for the application of adrenergic receptor antagonist in PCa.

Prognostic value of virtual portal pressure gradient response in compensated cirrhotic patients treated with carvedilol.

AIM: This study aimed to assess the prognostic significance of virtual portal pressure gradient (vPPG) response to carvedilol in patients with compensated cirrhosis (CC). METHODS: Compensated cirrhosis patients with high-risk varices were prospectively enrolled to receive carvedilol for prevention of first variceal hemorrhage (VH) and followed up for 1 year. The vPPG response was defined as a reduction of vPPG >10% from baseline after 1-month therapy. Logistic and Cox regression analyses were performed to identify independent predictors for vPPG response and first decompensation, respectively. Competitive risk models were constructed to predict disease progression, and validated using the C-index, Kaplan-Meier analysis, competitive risk analysis, and calibration curves. RESULTS: A total of 129 patients completed this study, of whom 56 (43.4%) achieved vPPG response and were referred as vPPG responders. Baseline vPPG, red color sign, Model for End-stage Liver Disease score, serum monocyte chemoattractant protein-1 (MCP-1), and laminin levels significantly correlated with vPPG response, which itself was further documented as an independent predictor of VH, ascites, and overall decompensation events in CC. Moreover, the red color sign or Child-Turcotte-Pugh score effectively predicted VH, while ascites correlated well with portal flow velocity or MCP-1. The predictive models for VH and ascites showed a good discrimination with C-index values of 0.747 and 0.689 respectively, and the high consistency on calibration curves. CONCLUSION: The vPPG response could be used as a noninvasive tool for prediction of disease progression in patients with CC.

Real world prescription of beta-blockers in patients with asthma.

PURPOSE: This study aimed to investigate the prescription of beta-blockers (ß-blockers) for patients with asthma. METHODS: In this retrospective cross-sectional study using the National Patient Sample (NPS) of the Health Insurance Review and Assessment Service (HIRA) of South Korea, ß-blockers and asthma medications were investigated using generic name codes provided by HIRA. Concomitant administration was identified when a ß-blocker and an asthma medication were co-prescribed in one billing statement or when separate ß-blocker and asthma prescriptions had overlapping dates of use. RESULTS: In the 1027 patients with asthma who were prescribed non-selective ß-blockers (non-SBs), 3087 non-SB prescriptions were identified, of which 62.3% and 37.3% were for carvedilol and propranolol, respectively. Of the 906 patients with asthma prescribed selective ß-blockers (SBs), 2942 SB prescriptions were identified, of which 48.5%, 28.3%, and 20.3% were for bisoprolol, atenolol, and nebivolol, respectively. Overall, 2149 non-SB and 2124 SB prescriptions with overlapping use dates with asthma medications were identified, which were prescribed to 726 and 657 patients, accounting for 70.7% and 72.5% of the patients receiving non-SBs and SBs, respectively. ß2-agonists accounted for 39.9% of the concomitant asthma medications with overlapping dates of use with non-SBs. Co-prescribing of bronchodilators occurred at a rate of 38.7% and 45.1% for the 3087 non-SB prescriptions and 2942 SB prescriptions, respectively. CONCLUSIONS: Carvedilol and propranolol accounted for half of all ß-blockers prescribed to asthma patients. Prescribing ß-blockers to patients with asthma requires caution to prevent exacerbation of asthma and drug interactions between ß-blockers and co-prescribed asthma medications.

The improvement of routine drug quality control analysis of some antihypertensive drugs using high-performance thin-layer chromatography densitometry method with greenness profile evaluation.

The common antihypertensive drugs are B-blockers and diuretics. For the determination of beta-blocker medicines (bisoprolol fumarate and carvedilol) and diuretic drug (Furosemide), new and accurate chromatographic method has been developed. The separation was achieved using a developing system that includes chloroform:methanol:ethyl acetate:ammonia (6:2:2:0.2 by volume) as a mobile phase and the bands were detected at 240 nm. The concentration ranges were 5-25, 1-7, and 1-3.5 µg/band for bisoprolol fumarate, carvedilol, and furosemide, respectively. This chromatographic approach is the first methodology for simultaneously determining bisoprolol fumarate, carvedilol, and furosemide in their pure forms and in their pharmaceutical dosage forms. The advantages of using known analytical procedures are their simplicity, speed, cost effectiveness, lack of laboriousness, and ability to save time as the three tablets are determined in one step and can be used for routine analysis of the investigated combinations in quality control laboratories. According to International Conference of Harmonization guidelines, the established procedures have been validated, and the results were statistically compared to those obtained by the reported reversed-phase-high-performance liquid chromatography methods using Student's t-test and F-test, with no significant difference between them, indicating that the proposed methods can be used for routine drug quality control analysis.

Roles of ß-adrenoceptor Subtypes and Therapeutics in Human Cardiovascular Disease: Heart Failure, Tachyarrhythmias and Other Cardiovascular Disorders.

ß-Adrenoceptors (ß-ARs) provide an important therapeutic target for the treatment of cardiovascular disease. Three ß-ARs, ß1-AR, ß2-AR, ß3-AR are localized to the human heart. Activation of ß1-AR and ß2-ARs increases heart rate, force of contraction (inotropy) and consequently cardiac output to meet physiological demand. However, in disease, chronic over-activation of ß1-AR is responsible for the progression of disease (e.g. heart failure) mediated by pathological hypertrophy, adverse remodelling and premature cell death. Furthermore, activation of ß1-AR is critical in the pathogenesis of cardiac arrhythmias while activation of ß2-AR directly influences blood pressure haemostasis. There is an increasing awareness of the contribution of ß2-AR in cardiovascular disease, particularly arrhythmia generation. All ß-blockers used therapeutically to treat cardiovascular disease block ß1-AR with variable blockade of ß2-AR depending on relative affinity for ß1-AR vs ß2-AR. Since the introduction of ß-blockers into clinical practice in 1965, ß-blockers with different properties have been trialled, used and evaluated, leading to better understanding of their therapeutic effects and tolerability in various cardiovascular conditions. ß-Blockers with the property of intrinsic sympathomimetic activity (ISA), i.e. ß-blockers that also activate the receptor, were used in the past for post-treatment of myocardial infarction and had limited use in heart failure. The ß-blocker carvedilol continues to intrigue due to numerous properties that differentiate it from other ß-blockers and is used successfully in the treatment of heart failure. The discovery of ß3-AR in human heart created interest in the role of ß3-AR in heart failure but has not resulted in therapeutics at this stage.

Evaluation of the effect of carvedilol orodispersible tablets on ischemia-reperfusion injury and flap viability in rats: An in vivo study.

Flap surgery is an integral part of plastic surgery, and ischemia-reperfusion (I/R) injury significantly affects the viability of the flap. Carvedilol (CRV), a nonselective beta-blocker with alpha-1 blocking and antioxidant properties, and known for its potential in reducing I/R damage, was chosen as the active substance for our study. The aim of this study was to investigate the vasodilator and antioxidant effects of CRV on rat inferior epigastric artery skin flap using orally disintegrating tablets (ODTs). The optimized ODT formulation was subjected to in vivo experiments using Sprague-Dawley female rats (n = 24) divided into three groups: Group I (control, I/R), Group II (treatment, I/R + CRV), and Group III (treatment, I/R), I/R + CRV ODT). Reperfusion was then observed following the release of the microclamp from the pedicle, and the flap was then re-adapted to its original position. Control rats were given oral isotonic solution via gavage and were subjected to 8 h of ischemia and 12 h of reperfusion. Group II was given 2 mg/kg CRV oral tablets for 7 days before and after surgery. Group III was given 2 mg/kg/day CRV ODT for the same period. Biopsies were taken from the flap and histopathological and biochemical analyses including superoxide dismutase, glutathionenitric oxide, malondialdehyde, paraoxonase 1, total oxidant, and total antioxidant capacities were performed. This study demonstrates that CRV ODTs significantly increased flap viability by approximately 25% compared to the control group, highlighting their promising therapeutic potential.

Assessment of the Impact of Carvedilol Administered Together with Dexrazoxan and Doxorubicin on Liver Structure and Function, Iron Metabolism, and Myocardial Redox System in Rats.

Late cardiotoxicity is a formidable challenge in anthracycline-based anticancer treatments. Previous research hypothesized that co-administration of carvedilol (CVD) and dexrazoxane (DEX) might provide superior protection against doxorubicin (DOX)-induced cardiotoxicity compared to DEX alone. However, the anticipated benefits were not substantiated by the findings. This study focuses on investigating the impact of CVD on myocardial redox system parameters in rats treated with DOX + DEX, examining its influence on overall toxicity and iron metabolism. Additionally, considering the previously observed DOX-induced ascites, a seldom-discussed condition, the study explores the potential involvement of the liver in ascites development. Compounds were administered weekly for ten weeks, with a specific emphasis on comparing parameter changes between DOX + DEX + CVD and DOX + DEX groups. Evaluation included alterations in body weight, feed and water consumption, and analysis of NADPH2, NADP+, NADPH2/NADP+, lipid peroxidation, oxidized DNA, and mRNA for superoxide dismutase 2 and catalase expressions in cardiac muscle. The iron management panel included markers for iron, transferrin, and ferritin. Liver abnormalities were assessed through histological examinations, aspartate transaminase, alanine transaminase, and serum albumin level measurements. During weeks 11 and 21, reduced NADPH2 levels were observed in almost all examined groups. Co-administration of DEX and CVD negatively affected transferrin levels in DOX-treated rats but did not influence body weight changes. Ascites predominantly resulted from cardiac muscle dysfunction rather than liver-related effects. The study's findings, exploring the impact of DEX and CVD on DOX-induced cardiotoxicity, indicate a lack of scientific justification for advocating the combined use of these drugs at histological, biochemical, and molecular levels.

Characterization and Crystal Structural Analysis of Novel Carvedilol Adipate and Succinate Ethanol-Solvated Salts.

Two ethanol-solvated adipate and succinate salts of carvedilol (CVD), a Biopharmaceutics Classification System class 2 drug, were synthesized by crystallizing ethanol with adipic acid (ADP) and succinic acid (SUA). Proton transfer from ADP and SUA to CVD and the presence of ethanol in the two novel compounds were confirmed using powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and single-crystal X-ray diffraction measurements. The two novel ethanol-solvated salts exhibited enhanced solubility and dissolution rates compared with pure carvedilol in phosphate buffer (pH 6.8). Additionally, the morphologies and attachment energies of the two novel compounds and pure CVD were calculated based on their single-crystal structures, revealing a correlation between attachment energy and dissolution rate.

Investigating Carvedilol's Repurposing for the Treatment of Non-Small Cell Lung Cancer via Aldehyde Dehydrogenase Activity Modulation in the Presence of ß-Adrenergic Agonists.

Repurposing existing drugs appears to be a potential solution for addressing the challenges in the treatment of non-small cell lung cancer (NSCLC). ß-adrenoceptor antagonist drugs (ß-blockers) have tumor-inhibiting effects, making them promising candidates for potential NSCLC treatment. This study investigates the anticancer potential of a subset of ß-blockers in NSCLC cell lines; A549 and H1299. Additionally, it investigates the underlying mechanism behind ß-blockers' anticancer effect by influencing a potential novel target named aldehyde dehydrogenase (ALDH). The MTT assay assessed ß-blockers' cytotoxicity on both cell lines, while Western blot and NADH fluorescence assays evaluated their influence on ALDH protein expression and activity. Carvedilol (CAR) was the most effective blocker in reducing cell survival of A549 and H1299 with IC50 of 18 µM and 13.7 µM, respectively. Significantly, CAR led to a 50% reduction in ALDH expression and 80% decrease in ALDH activity in A549 cells, especially when combined with ß-agonists, in comparison to the control. This effect might be attributed to ß-agonist blockade or an alternative pathway. This novel finding adds to our understanding of CAR's multifaceted anticancer properties, implying that combining CAR with ß-agonists could be a useful strategy for lung cancer treatment.

Beta-blockers in the era of precision medicine in patients with cirrhosis.

For decades, non-selective beta-blockers (NSBBs) have been the standard of care for the primary and secondary prevention of bleeding from oesophageal varices. However, several questions regarding the best clinical use of NSBBs remain unanswered and new data continue to emerge. Herein, we aim to delineate the therapeutic window of NSBBs in cirrhosis from a more individualised perspective. We address the current controversy of widening the therapeutic window and prescribing NSBBs to all patients with clinically significant portal hypertension. Although transient elastography is useful to rule-in clinically significant portal hypertension, we lack robust data supporting the use of NSBBs in patients without varices. While most data are based on propranolol, accumulating evidence suggests that carvedilol is superior and should be the first-line treatment until the decompensated stage. The clinical risk-to-benefit ratio appears to deteriorate in advanced decompensated stages and the risk of harm is high in patients with refractory ascites, low blood pressure and renal impairment, which clinically define closure of the therapeutic window. We also critically review non-invasive surrogates and biomarkers for predicting the haemodynamic response to NSBBs and confirm that the absence of reliable non-invasive methods is one of the main challenges facing the field.

Carvedilol exhibits anti-acute T lymphoblastic leukemia effect in vitro and in vivo via inhibiting ß-ARs signaling pathway.

An increasing number of studies have focus upon ß-adrenergic receptor blockers and their anti-tumor effects. However, the use of Carvedilol (CVD), the third generation ß-AR blocker, has not been explored for use against T-ALL. In this study, the level of ß-ARs was explored in pediatric T-ALL patients. Moreover, the antitumor effects of CVD against T-ALL were assessed in vitro and in vivo, and the underlying mechanisms were investigated. The viability of T-ALL cells following CVD treatment was detected using a CCK-8 assay, and the apoptotic and cell cycle effects were measured using flow cytometry. The protein levels of ß-ARs, cAMP, Epac, JAK2, STAT3, p-STAT3, PI3K, p-PI3K, AKT, p-AKT, mTOR, cyclin D1, PCNA, and cleaved caspase-3 were assessed by Western blotting. In vivo experiments were used to investigate the effect of CVD on T-ALL growth in mice. The results indicated that ß-ARs were highly expressed in the newly diagnosed T-ALL cells when compared to those in the control group (P < 0.05). In vitro, CVD significantly inhibited T-ALL cell viability, promoted apoptosis and blocked the G0/G1 phase of cell cycle. After CVD treatment, the protein levels of ß-ARs, cAMP, Epac, PI3K, p-PI3K, AKT, p-AKT, mTOR, JAK2, STAT3, p-STAT3, cyclin D1 and PCNA were significantly downregulated (P < 0.05); whereas cleaved caspase-3 was significantly upregulated (P < 0.05). In vivo, the volume and weight of the xenograft tumors were significantly decreased in the CVD group (P < 0.05). CVD promoted xenograft tumor apoptosis and reduced the proportion of CEM-C1 cells in murine peripheral blood and bone marrow (P < 0.05). Our results demonstrate that ß-ARs are expressed in T-ALL. CVD has a strong antitumor effect against T-ALL and inhibits ß-AR associated signaling pathways. Therefore, CVD may provide a potential therapy for T-ALL.

Carvedilol Reduces the Neuronal Apoptosis after Ischemic Stroke by Modulating Activator of Transcription 3 Expression in vitro.

Cerebral ischemia is divided into local cerebral ischemia and diffuse cerebral ischemia. The etiology of localized cerebral ischemia includes middle cerebral artery embolism; stenosis, occlusion, or thrombosis of extracranial internal carotid artery or vertebral artery; and cerebral artery spasm. The causes of diffuse cerebral ischemia include cardiac arrest, hypotension, anemia, and hypoglycemia. However, the underlying mechanism is still unclear. In this study, we demonstrated that activator of transcription 3 (ATF3) is a hubgene in IS by bioinformatics analysis. The expression of ATF3 was increased in PC12 cells with oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. ATF3 deficiency inhibited cell viability and induced cell apoptosis, whereas ATF3 overexpression showed the opposite role in cell viability and cell apoptosis. Moreover, Carvedilol as a compound targeting ATF3 also facilitated cell viability and reduced cell apoptosis. ATF3 deficiency retarded the increase in cell viability and inhibition of cell apoptosis in OGD/R-PC12 cells with Carvedilol treatment. Additionally, the decreased Bax and cleaved caspase-3 were released in OGD/R-PC12 cells with Carvedilol and siATF3 treatment, while Bcl-2 expression was inhibited in OGD/R-PC12 cells with Carvedilol and siATF3 treatment. In conclusion, Carvedilol may be a key compound targeting ATF3 in OGD/R-PC12 cells. Graphical Abstract: Carvedilol positively regulated cell viability and negatively regulated cell apoptosis in OGD/R-PC12 cells by inhibition of ATF3.

Potential cardioprotective and anticancer effects of carvedilol either free or as loaded nanoparticles with or without doxorubicin in solid Ehrlich carcinoma-bearing mice.

AIM: The aim of this study was to investigate the potential cardioprotective and anti-cancer effects of carvedilol (CAR) either free or as loaded nano-formulated with or without doxorubicin (DOX) in solid Ehrlich carcinoma (SEC)-bearing mice. It focused on assessment of cardiac damage, drug resistance, apoptosis, oxidative stress status, angiogenesis and proliferation. METHODS: CAR was loaded into poly-D,L lactic-co-glycolic acid)PLGA(or Niosomes. SEC was induced in female albino mice as an experimental model of breast cancer. Seventy-two mice were randomly divided into 9 equal groups (Normal control, Untreated-SEC, SEC + DOX, SEC + CAR-free, SEC + CAR-PLGA, SEC + CAR-Niosomes, SEC + DOX + CAR-free, SEC + DOX + CAR-PLGA and SEC + DOX + CAR-Niosomes). Tumor volume and survival rate were recorded. On day 28 from tumor inoculation, mice were sacrificed, and blood samples were collected for determination of serum lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB). One part from tumor tissues was prepared for assessment of multidrug resistance protein-1 (MDR-1), caspase-3, reduced glutathione (GSH) and malondialdehyde (MDA), while the other part was processed for histopathological examination and immunohistochemical expression of vascular endothelial growth factor (VEGF) and Ki-67. RESULTS: There was non-significant difference between CAR-free, CAR-PLGA and CAR-Niosomes as anticancer either alone or when combined with DOX. However, CAR-free demonstrated potential cardioprotective effects against cardiac damage mediated by cancer or DOX that have been enhanced using CAR-PLGA or CAR-Niosomes, but that of Niosomes outperformed them both. CONCLUSION: CAR could be used as an adjuvant therapy with DOX, especially when nanoformualted with PLGA and even better with Niosomes, without compromising its cytotoxicity against cancer cells and preventing its cardiotoxic impacts.