Harnessing adrenergic blockade in stress-promoted TNBC in vitro and solid tumor in vivo: disrupting HIF-1α and GSK-3ß/ß-catenin driven resistance to doxorubicin.

Sympathetic activation triggered by chronic stress afflicting cancer survivors is an emerging modulator of tumorigenesis. Adrenergic blockade was previously associated with improving response to doxorubicin (DOX) in triple-negative breast cancer (TNBC), yet the precise underlying mechanisms remain obscure. The resilience of cancer stem cells (CSCs) during chemotherapy fosters resistance and relapse. Hypoxia-inducible factor-1α (HIF-1α) and ß-catenin are intertwined transcriptional factors that enrich CSCs and evidence suggests that their expression could be modulated by systemic adrenergic signals. Herein, we aimed to explore the impact of adrenoreceptor blockade using carvedilol (CAR) on DOX and its potential to modulate CSCs overcoming chemoresistance. To achieve this aim, in vitro studies were conducted using adrenaline-preincubated MDA-MB-231 cells and in vivo studies using a chronic restraint stress-promoted solid tumor mouse model. Results revealed that adrenaline increased TNBC proliferation and induced a phenotypic switch reminiscent of CSCs, as evidenced by enhanced mammosphere formation. These results paralleled an increase in aldehyde dehydrogenase-1 (ALDH-1) and Nanog expression levels as well as HIF-1α and ß-catenin upsurge. In vivo, larger tumor volumes were observed in mice under chronic stress compared to their unstressed counterparts. Adrenergic blockade using CAR, however, enhanced the impact DOX had on halting TNBC cell proliferation and tumor growth via enhanced apoptosis. CAR also curbed HIF-1α and ß-catenin tumor levels subsequently suppressing ALDH-1 and SOX2. Our study unveils a central role for HIF-1α linking stress-induced sympathetic activation fueling CSC enrichment via the ß-catenin pathway. It also highlights novel insights into CAR's capacity in reversing DOX chemoresistance in TNBC.

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.

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.

The Incorporated Drug Affects the Properties of Hydrophilic Nanofibers.

Hydrophilic nanofibers offer promising potential for the delivery of drugs with diverse characteristics. Yet, the effects of different drugs incorporated into these nanofibers on their properties remain poorly understood. In this study, we systematically explored how model drugs, namely ibuprofen, carvedilol, paracetamol, and metformin (hydrochloride), affect hydrophilic nanofibers composed of polyethylene oxide and poloxamer 188 in a 1:1 weight ratio. Our findings reveal that the drug affects the conductivity and viscosity of the polymer solution for electrospinning, leading to distinct changes in the morphology of electrospun products. Specifically, drugs with low solubility in ethanol, the chosen solvent for polymer solution preparation, led to the formation of continuous nanofibers with uniform diameters. Additionally, the lower solubility of metformin in ethanol resulted in particle appearance on the nanofiber surface. Furthermore, the incorporation of more hydrophilic drugs increased the surface hydrophilicity of nanofiber mats. However, variations in the physicochemical properties of the drugs did not affect the drug loading and drug entrapment efficiency. Our research also shows that drug properties do not notably affect the immediate release of drugs from nanofibers, highlighting the dominant role of the hydrophilic polymers used. This study emphasizes the importance of considering specific drug properties, such as solubility, hydrophilicity, and compatibility with the solvent used for electrospinning, when designing hydrophilic nanofibers for drug delivery. Such considerations are crucial for optimizing the properties of the drug delivery system, which is essential for achieving therapeutic efficacy and safety.

Carvedilol increases seizure resistance in a mouse model of SCN8A-derived epilepsy.

Patients with mutations that alter the function of the sodium channel SCN8A present with a range of clinical features, including mild to severe seizures, developmental delay, intellectual disability, autism, feeding dysfunction, motor impairment, and hypotonia. In an effort to identify compounds that could be potentially beneficial in SCN8A-associated epilepsy, Atkin et al. conducted an in vitro screen which resulted in the identification of 90 compounds that effectively reduced sodium influx into the cells expressing the human SCN8A R1872Q mutation. The top compounds that emerged from this screen included amitriptyline, carvedilol, and nilvadipine. In the current study, we evaluated the ability of these three compounds to increase resistance to 6 Hz or pentylenetetrazole (PTZ)-induced seizures in wild-type CF1 mice and in a mouse line expressing the human SCN8A R1620L mutation. We also evaluated the effects of fenfluramine administration, which was recently associated with a 60%-90% decrease in seizure frequency in three patients with SCN8A-associated epilepsy. While amitriptyline, carvedilol, and fenfluramine provided robust protection against induced seizures in CF1 mice, only carvedilol was able to significantly increase resistance to 6 Hz- and PTZ-induced seizures in RL/+ mutants. These results provide support for further evaluation of carvedilol as a potential treatment for patients with SCN8A mutations.

The influence of drug-induced metabolic enzyme activity inhibition and CYP3A4 gene polymorphism on aumolertinib metabolism.

The purpose of this study is to clarify the drug interaction profile of aumolertinib, and the influence of CYP3A4 genetic polymorphism on aumolertinib metabolic characteristics. Through microsomal enzyme reactions, we screened 153 drugs and identified 15 that significantly inhibited the metabolism of aumolertinib. Among them, telmisartan and carvedilol exhibited potent inhibitory activities in rat liver microsomes (RLM) and human liver microsomes (HLM). In vivo, the pharmacokinetic parameters of aumolertinib, including AUC and Cmax, were significantly altered when co-administered with carvedilol, with a notable decrease in the clearance rate CLz/F. Interestingly, the pharmacokinetic parameters of the metabolite HAS-719 exhibited a similar trend as aumolertinib when co-administered. Mechanistically, both telmisartan and carvedilol exhibited a mixed-type inhibition on the metabolism of aumolertinib. Additionally, we used a baculovirus-insect cell expression system to prepare 24 recombinant CYP3A4 microsomes and obtained enzymatic kinetic parameters using aumolertinib as a substrate. Enzyme kinetic studies obtained the kinetic parameters of various CYP3A4 variant-mediated metabolism of aumolertinib. Based on the relative clearance rates, CYP3A4.4, 5, 7, 8, 9, 12, 13, 14, 17, 18, 19, 23, 24, 33, and 34 showed significantly lower clearance rates compared to the wild-type. Among the different CYP3A4 variants, the inhibitory potency of telmisartan and carvedilol on the metabolism of aumolertinib also varied. The IC50 values of telmisartan and carvedilol in CYP3A4.1 were 6.68 ± 1.76 µM and 0.60 ± 0.25 µM, respectively, whereas in CYP3A4.12, the IC50 exceeded 100 µM. Finally, we utilized adeno-associated virus to achieve liver-specific high expression of CYP3A4*1 and CYP3A4*12. In the group with high expression of the less active CYP3A4*12, the magnitude of the drug-drug interaction was significantly attenuated. In conclusion, CYP3A4 genetic polymorphism not only influences the pharmacokinetic characteristics of aumolertinib, but also the inhibitory potency of telmisartan and carvedilol on it.

Effects of carvedilol on human prostate tissue contractility and stromal cell growth pointing to potential clinical implications.

BACKGROUND: Apart from antagonizing ß-adrenoceptors, carvedilol antagonizes vascular α1-adrenoceptors and activates G protein-independent signaling. Even though it is a commonly used antihypertensive and α1-adrenoceptors are essential for the treatment of voiding symptoms in benign prostatic hyperplasia, its actions in the human prostate are still unknown. Here, we examined carvedilol effects on contractions of human prostate tissues, and on stromal cell growth. METHODS: Contractions of prostate tissues from radical prostatectomy were induced by electric field stimulation (EFS) or α1-agonists. Growth-related functions were examined in cultured stromal cells. RESULTS: Concentration-response curves for phenylephrine, methoxamine and noradrenaline were right shifted by carvedilol (0.1-10 µM), around half a magnitude with 100 nM, half to one magnitude with 1 µM, and two magnitudes with 10 µM. Right shifts were reflected by increased EC50 values for agonists, with unchanged Emax values. EFS-induced contractions were reduced by 21-54% with 0.01-1 µM carvedilol, and by 94% by 10 µM. Colony numbers of stromal cells were increased by 500 nM, but reduced by 1-10 µM carvedilol, while all concentrations reduced colony size. Decreases in viability were time-dependent with 0.1-0.3 µM, but complete with 10 µM. Proliferation was slightly increased by 0.1-0.5 µM, but reduced with 1-10 µM. CONCLUSIONS: Carvedilol antagonizes α1-adrenoceptors in the human prostate, starting with concentrations in ranges of known plasma levels. In vitro, effect sizes resemble those of α1-blockers used for the treatment of voiding symptoms, which requires concentrations beyond plasma levels. Bidirectional and dynamic effects on the growth of stromal cells may be attributed to "biased agonism".

Effect of carvedilol on pharmacokinetics of sofosbuvir and its metabolite GS-331007: role of P-glycoprotein.

Sofosbuvir (SOF) is a P-glycoprotein (P-gp) substrate, and carvedilol (CAR) is an inhibitor of P-gp, suggesting that it may affect the oral pharmacokinetics and safety of SOF. The current study investigated the pharmacokinetic interaction of CAR with SOF and its metabolite, GS-331007, and the possible consequent toxicities in rats. To assess the pharmacokinetics of SOF and GS-331007, rats were divided into three groups; all received a single oral dose of SOF preceded with saline (SAL), verapamil (VER) as a standard P-gp inhibitor, or CAR, respectively. The serosal, plasma, and hepatic tissue contents of SOF and GS-331007 were assessed using LC-MS/MS. Renal and hepatic toxicities were assessed using biochemical and histopathological tests. Serosal and plasma concentrations of SOF and GS-331007 were increased in the presence of CAR, suggesting a significant inhibitory effect of CAR on intestinal P-gp. Simultaneously, the pharmacokinetic profile of SOF showed a significant increase in the Cmax, AUC(0-t), AUC (0-∞), t1/2, and a reduction in its apparent oral clearance. While the pharmacokinetic profile of GS-331007 was not significantly affected. However, this notable elevation in drug oral bioavailability was corroborated by a significant alteration in renal functions. Hence, further clinical investigations are recommended to ensure the safety and dosing of CAR/SOF combination.

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.

Cardioprotective Diet to Prevent Anthracycline-Induced Cardiotoxicity in Patients with Breast Cancer: A Randomized Open-Label Controlled Trial.

Objectives: Several studies have indicated that dietary interventions may offer protection against the development of cardiac damage in the case of anthracycline-induced cardiomyopathy (AIC). The goal of this study was to assess whether an evidence-based cardioprotective diet can be effective in preventing AIC in patients with breast cancer. Design: Randomized, open-label, controlled trial. The study period was set for 18 weeks, and the data were analyzed by generalized estimating equation modeling and one-way repeated measures analysis of variance. Setting/Location: Shahid Rajaie Hospital affiliated (Tehran, Iran). Subjects: Fifty anthracycline-treated patients with breast cancer. Interventions: Patients were randomized to receive either a 2-hour training in evidence-based cardio-protective diet or Carvedilol 6.25 mg bid. Outcome Measures: The primary outcome was the number of patients with abnormal left ventricular ejection fraction (LVEF) after 18 weeks. Results: At week 18, 12 (48%) out of 25 participants in the cardioprotective diet group had abnormal LVEF in comparison with 21 (84%) out of 25 in the carvedilol group (p = 0.007). Also, 2 (8%) out of 25 in the cardioprotective diet group compared with 7 (28%) out of 25 participants in the carvedilol group had abnormal global longitudinal strain (p = 0.066). The diet group showed significant improvements in the quality-of-life dimensions named "health change" and "general health" compared with the carvedilol group using the Short Form-36 Health Survey questionnaire. Conclusions: This study suggests that an evidence-based cardioprotective diet can contribute to the prevention of AIC. Although current treatments for AIC can be effective, further research is mandatory for more options.

The effect of sustained-release CARvedilol in patients with hypErtension and heart failure with preserved ejection fraction: a study protocol for a pilot randomized controlled trial (CARE-preserved HF).

Background: Although beta-blockers improve clinical outcomes in heart failure with reduced ejection fraction, the benefit of beta-blockers in heart failure with preserved ejection fraction (HFpEF) is uncertain. Global longitudinal strain (GLS) is a robust predictor of heart failure outcomes, and recent studies have shown that beta-blockers are associated with improved survival in those with low GLS (GLS <14%) but not in those with GLS ≥14% among patients with LVEF ≥40%. Therefore, the objective of this trial is to evaluate the effect of sustained-release carvedilol (carvedilol-SR) on the outcome [N-terminal pro-B-natriuretic peptide (NT-proBNP) concentration] in patients with hypertension and HFpEF and will assess the differential effects of these drugs on the outcome, according to the GLS categories. Methods: This prospective randomized double-blind multicenter trial (CARE-preserved HF) will include 100 patients with HFpEF from three tertiary hospitals in South Korea. Patients with HFpEF and hypertension aged ≥20 years who have evidence of functional and structural heart disease on echocardiography and elevated natriuretic peptide will be enrolled. Eligible participants will be randomized 1:1 to either the carvedilol-SR group (n = 50) or the placebo group (n = 50). Patients in the carvedilol-SR group will receive 8, 16, 32, or 64 mg carvedilol-SR once daily for 6 months, and the dose of carvedilol will be up-titrated at the discretion of the treating physicians. The primary efficacy outcome was the time-averaged proportional change in N-terminal pro-B-natriuretic peptide concentration from baseline to months 3 and 6. We will also evaluate the differential effects of carvedilol-SR on primary outcomes according to GLS, using a cut-off of 14% or the median value. Discussion: This randomized controlled trial will investigate the efficacy and safety of carvedilol-SR in patients with HFpEF and hypertension. Clinical Trial Registration: ClinicalTrial.gov, identifier NCT05553314.

Intranasal Delivery of Carvedilol- and Quercetin-Encapsulated Cationic Nanoliposomes for Cardiovascular Targeting: Formulation and In Vitro and Ex Vivo Studies.

Carvedilol (CVD), an adrenoreceptor blocker, is a hydrophobic Biopharmaceutics Classification System class II drug with poor oral bioavailability due to which frequent dosing is essential to attain pharmacological effects. Quercetin (QC), a polyphenolic compound, is a potent natural antioxidant, but its oral dosing is restricted due to poor aqueous solubility and low oral bioavailability. To overcome the common limitations of both drugs and to attain synergistic cardioprotective effects, we formulated CVD- and QC-encapsulated cationic nanoliposomes (NLPs) in situ gel (CVD/QC-L.O.F.) for intranasal administration. We designed CVD- and QC-loaded cationic nanoliposomal (NLPs) in situ gel (CVD/QC-L.O.F.) for intranasal administration. In vitro drug release studies of CVD/QC-L.O.F. (16.25%) exhibited 18.78 ± 0.57% of QC release and 91.38 ± 0.93% of CVD release for 120 h. Ex vivo nasal permeation studies of CVD/QC-L.O.F. demonstrated better permeation of QC (within 96 h), i.e., 75.09% compared to in vitro drug release, whereas CVD permeates within 48 h, indicating the better interaction between cationic NLPs and the negatively charged biological membrane. The developed nasal gel showed a sufficient mucoadhesive property, good spreadability, higher firmness, consistency, and cohesiveness, indicating suitability for membrane application and intranasal administration. CVD-NLPs, QC-NLPs, and CVD/QC-NLPs were evaluated for in vitro cytotoxicity, in vitro ROS-induced cell viability assessment, and a cellular uptake study using H9c2 rat cardiomyocytes. The highest in vitro cellular uptake of CVD/QC-cationic NLPs by H9c2 cells implies the benefit of QC loading within the CVD nanoliposomal carrier system and gives evidence for better interaction of NLPs carrying positive charges with the negatively charged biological cells. The in vitro H2O2-induced oxidative stress cell viability assessment of H9c2 cells established the intracellular antioxidant activity and cardioprotective effect of CVD/QC-cationic NLPs with low cytotoxicity. These findings suggest the potential of cationic NLPs as a suitable drug delivery carrier for CVD and QC combination for the intranasal route in the treatment of various cardiovascular diseases like hypertension, angina pectoris, etc. and for treating neurodegenerative disorders.

A simple and robust parametric shared frailty model for recurrent events with the competing risk of death: An application to the Carvedilol Prospective Randomized Cumulative Survival trial.

Many non-fatal events can be considered recurrent in that they can occur repeatedly over time, and some researchers may be interested in the trajectory and relative risk of non-fatal events. With the competing risk of death, the treatment effect on the mean number of recurrent events is non-identifiable since the observed mean is a function of both the recurrent event and terminal event processes. In this paper, we assume independence between the non-fatal and the terminal event process, conditional on the shared frailty, to fit a parametric model that recovers the trajectory of, and identifies the effect of treatment on, the non-fatal event process in the presence of the competing risk of death. Simulation studies are conducted to verify the reliability of our estimators. We illustrate the method and perform model diagnostics using the Carvedilol Prospective Randomized Cumulative Survival trial which involves heart-failure events.

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.

Comparing the effects of various ß-blockers on cardiovascular mortality in breast cancer patients.

BACKGROUND: Cardiovascular (CV) disease is a leading cause of death in breast cancer (BC) patients due to the increased age and treatments. While individual ß-blockers have been investigated to manage CV complications, various ß-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 ß-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 ß-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.

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.

Optimized mucoadhesive niosomal carriers for intranasal delivery of carvedilol: A quality by design approach.

Carvedilol (CV), a ß-blocker essential for treating cardiovascular diseases, faces bioavailability challenges due to poor water solubility and first-pass metabolism. This study developed and optimized chitosan (CS)-coated niosomes loaded with CV (CS/CV-NS) for intranasal (IN) delivery, aiming to enhance systemic bioavailability. Utilizing a Quality-by-Design (QbD) approach, the study investigated the effects of formulation variables, such as surfactant type, surfactant-to-cholesterol (CHOL) ratio, and CS concentration, on CS/CV-NS properties. The focus was to optimize specific characteristics including particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%), and mucin binding efficiency (MBE%). The optimal formulation (Opt CS/CV-NS), achieved with a surfactant: CHOL ratio of 0.918 and a CS concentration of 0.062 g/100 mL, using Span 60 as the surfactant, exhibited a PS of 305 nm, PDI of 0.36, ZP of + 33 mV, EE% of 63 %, and MBE% of 57 %. Opt CS/CV-NS was characterized for its morphological and physicochemical properties, evaluated for stability under different storage conditions, and assessed for in vitro drug release profile. Opt CS/CV-NS demonstrated a 1.7-fold and 4.8-fold increase in in vitro CV release after 24 h, compared to uncoated CV-loaded niosomes (Opt CV-NS) and free CV, respectively. In vivo pharmacokinetic (PK) study, using a rat model, demonstrated that Opt CS/CV-NS achieved faster Tmax and higher Cmax compared to free CV suspension indicating enhanced absorption rate. Additionally, Opt CV-NS showed a 1.68-fold higher bioavailability compared to the control. These results underscore the potential of niosomal formulations in enhancing IN delivery of CV, offering an effective strategy for improving drug bioavailability and therapeutic efficacy.