The development of efficient and environmentally compatible sample preparation strategies for the determination of pharmaceuticals in complex biological matrices remains an important challenge in bioanalytical chemistry. Herein, a deep eutectic solvent (DES)-impregnated electrospun nanofiber microextraction (DES-ENF-ME) approach was developed for the simultaneous extraction of carvedilol and verapamil from human plasma prior to HPLC-fluorescence detection. A hydrophobic fatty-acid-based DES composed of nonanoic acid and dodecanoic acid (3:1, molar ratio) was selected and impregnated onto electrospun polyacrylonitrile nanofibers. In this configuration, the DES acts as the primary extraction phase, while the nanofibrous matrix provides a porous support for retaining and handling the liquid extraction phase. Sample pH, nanofiber amount, salt concentration, and extraction time were simultaneously optimized using central composite design and a desirability function. The method exhibited a linear response over the range of 1-1000 ng/mL for both analytes, with coefficients of determination of 0.9988 and 0.9942 for carvedilol and verapamil, respectively. The corresponding limits of detection were 0.396 and 0.342 ng/mL. The method showed satisfactory precision and relative recoveries for spiked plasma samples. Moreover, the DES-impregnated nanofibrous material was reusable for at least four consecutive extraction cycles. Overall, the proposed configuration combines the extraction capability of a hydrophobic DES with the practical handling advantages of an electrospun nanofibrous support, providing a simple, miniaturized, and solvent-efficient platform for plasma bioanalysis.

Herein, a novel supramolecular solvent based cationic surfactant and monoterpene is developed as a green alterative for the microextraction of beta-blockers (propranolol, carvedilol) from human urine and serum. In an aqueous medium, the cationic surfactant (amylamine) produced an isotropic solution as a result of amphiphilic supramolecular self-assembly. Coacervation facilitated phase separation, while the monoterpenoid alcohol (terpineol) functioned as the coacervation agent, triggering the spontaneous in situ formation of nanosized supramolecular solvent droplets. The determination of the drugs was carried out using a HPLC-fluorescence detector (FLD). Various supramolecular solvents (SUPRAs) were examined composed of cationic surfactants and natural-occurring terpenoid analogs. A proposed mechanism of the extraction of the analytes and the formation of SUPRAs is provided. mechanism was attributed to the formation of mixed aggregates capable of effectively capturing the target analytes. For microextraction optimization, the volumes of amylamine and terpineol, sample pH and sample volume were investigated. Under optimized conditions, extraction recoveries higher than 80% for both drugs were obtained while the analytical method exhibited excellent predictive performance, with coefficients of determination exceeding 0.9909. Method validation demonstrated satisfactory precision (coefficient of variation, CV <13.7%) and accuracy, with relative recoveries ranging from 87.8% to 116.1% (for urine) and 83.4% to 114.7% (for serum). The limit of detection was estimated at 0.1 and 0.2 ng/mL for propranolol and carvedilol, respectively. The method greenness was evaluation using the MA-multicolor tool providing a reasonable balance between environmental sustainability, analytical performance, operational practicality, and safety. Finally, the method was successfully applied to the analysis of authentic human urine and serum samples, validating its effectiveness for real-world biological monitoring.

A boy with heart failure and mechanical pulsus alternans was treated with enalapril malate and carvedilol; however, left ventricular contraction did not improve. After treatment with ivabradine, the pulsus alternans disappeared, and left ventricle contraction improved. Thorough evaluation revealed an abdominal paraganglioma producing noradrenaline, and excision of the tumor normalised the left ventricle contraction. Catecholamine-induced cardiomyopathy caused by paragangliomas is an extremely rare but important differential diagnosis of dilated cardiomyopathy. Thus, ivabradine is a good candidate for the treatment of heart failure, even in the presence of catecholamine-producing tumours.

Objective: In this study, the solid-state properties of two amorphous forms of rosuvastatin calcium (ROS) and co-amorphous systems of rosuvastatin with carvedilol (CAR) were investigated. Methods: The studied systems were investigated using TGA, DSC, TMDSC, PXRD, SAXS, SSNMR, and DVS. Results: DSC, TMDSC and SAXS revealed subtle differences between as-received ROS (ROS AR) and freshly prepared amorphous ROS (ROS AM), providing evidence of relaxation polyamorphism. Analysis of the scanning-rate dependence of the glass transition temperature classified ROS as a fragile glass former. Water sorption studies of ROS AR using Brunauer-Emmett-Teller analysis, the Guggenheim-Anderson-de Boer equation, and Young-Nelson models indicated a moderate specific surface area and multilayer adsorption, with water binding both at the surface and within the bulk. Co-amorphous CAR-ROS systems in various molar ratios exhibited single glass transitions, confirming the formation of homogenous amorphous phases. Negative deviations from the Couchman-Karasz equation indicated non-ideal mixing behaviour. Physical ageing studies showed high stability of the ROS AM and CAR-ROS 1:1 co-amorphous system, which remained amorphous after three years of storage. Conclusions: Overall, ROS forms stable amorphous and co-amorphous systems with CAR, exhibiting favourable miscibility, structural stability, and potential for application in fixed-dose combination formulations.

Currently, many researchers strive to create eco-conscious methods for drug separation to avoid hazardous solvents. In line with this objective, this study focuses on developing two green chromatographic methods, TLC and UPLC, to determine the mixture of carvedilol (CAR) and ivabradine (IVA) used for controlling stable angina symptoms, along with their oxidative degradates. The TLC method employed toluene: methanol: ammonia (8:2:0.2, by volume) as a mobile phase and silica gel plates as the stationary phase, with detection at 270.0 nm using concentration ranges of 0.5-8.0 μg/band for each drug. The optimized UPLC method utilized a mobile phase of ethanol: 0.1% triethylamine adjusted by acetic acid to pH 6.4 (40:60 v/v) on an Agilent Poroshell C18 (150 mm × 3 mm) column, with a 0.3 mL/min flow rate at 30°C and fluorimetric detection at 285.0 nm excitation and 330.0 nm emission, with linearity of 0.2-12.0 μg/mL for both drugs. Green assessment of the proposed methods with 82 and 78 green Eco-scores, AGREE score values of 0.77 and 0.72 for UPLC and TLC methods, respectively were performed. Moreover, statistical comparison of the proposed methods with reported and official methods was conducted. Additionally, structure elucidation, molecular docking and ADMET assessment of the degradates were successfully performed.

The TREK subfamily of 2-pore domain potassium channels act as polymodal sensors of multiple physical and chemical stimuli, coupling electrical excitability to the cellular environment. A nuanced understanding of TREK channel pharmacology is necessary for the development of novel experimental tools, for potential pharmacotherapies, and for understanding potential beneficial or adverse effects of clinically used drugs. Here, we sought to determine the mechanism of action of 2 TREK channel inhibitors: the β-blocker carvedilol and the antipsychotic fluphenazine. Using patch and 2-electrode voltage-clamp electrophysiology, we show that both carvedilol and fluphenazine exhibit an activation-mode dependence, with mechanical- and temperature-activation of TREK channels reducing drug sensitivity approximately 10-fold. Mutagenesis at a key intramembrane fenestration site leucine, modulator competition experiments, and in silico docking studies are all consistent with carvedilol and fluphenazine binding at a shared, overlapping binding site. These findings establish a conserved conformation-dependent mechanism of action for structurally diverse TREK inhibitors and identify the fenestration as a promiscuous binding site for a range of clinically used drugs. SIGNIFICANCE STATEMENT: TREK potassium channels play key roles in regulating membrane excitability in a wide range of cells. Modulation of these channels has been proposed for potential antiarrhythmic and antidepressant effects. This study defined the off-target molecular mechanism of action of the clinically used drugs carvedilol and fluphenazine on TREK channels and identify the TREK channel fenestration as a promiscuous binding site for inhibitory drugs.

Beta-blockers are among the most widely prescribed drugs in the management of both supraventricular and ventricular arrhythmias, and they are frequently regarded as a homogeneous pharmacological class. They are not. The agents in current use differ substantially in beta1-receptor selectivity, lipophilicity, half-life, route of administration, intrinsic sympathomimetic activity, and ancillary properties, and arrhythmias themselves differ in mechanism, adrenergic dependence, anatomical origin, and structural substrate. This narrative review examines whether these pharmacological differences translate into clinically meaningful differences in efficacy and utility, asking not only whether a beta-blocker should be used but which one should be used. Evidence was drawn from a targeted search of PubMed, Web of Science, Scopus, Ovid, Embase, and the Cochrane Library, with priority given to randomized controlled trials, meta-analyses, large registries, and contemporary society guidelines, and was synthesized qualitatively by arrhythmia type. A class effect is apparent for many indications, particularly rate control in atrial fibrillation and atrial flutter, where metoprolol, bisoprolol, and carvedilol perform broadly similarly and the choice is driven mainly by comorbidity and tolerability. Drug-specific differences emerge in three settings. In adrenergically mediated inherited syndromes, namely catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, nonselective agents and especially nadolol are clearly superior to beta1-selective agents, and the same principle appears to extend to ventricular electrical storm, in which propranolol has outperformed metoprolol in a randomized comparison. In acute care, pharmacokinetics dominate, and the ultra-short-acting agents esmolol and landiolol permit a degree of titration that longer-acting drugs cannot match. In patients with heart failure and reduced ejection fraction, carvedilol, metoprolol succinate, and bisoprolol should be preferred irrespective of arrhythmia subtype because of their established mortality benefit. Conversely, beta1-selective agents, including the highly selective agent nebivolol, improve tolerability in bronchospastic disease, although this reflects respiratory tolerability rather than any demonstrated antiarrhythmic advantage, and beta-blockers have little role in Brugada syndrome or in bradycardia-dependent acquired torsades de pointes. Beta-blockers should therefore not be treated as interchangeable. Selection should integrate arrhythmic mechanism, structural substrate, and patient characteristics, and head-to-head trials remain conspicuously scarce.

The clinical efficacy of many antihypertensive medications is constrained by their poor water solubility, low membrane permeability, significant first-pass metabolism, and uncertain oral bioavailability, even though hypertension is still a major worldwide health concern. For BCS Class II and IV medications like telmisartan, amlodipine, nifedipine, and carvedilol, these restrictions are especially important and call for creative delivery methods. Because of their unique dual hydrophilic-hydrophobic structure, amphiphilic chitosan derivatives have emerged as adaptable nanocarriers that may overcome these limitations. Chitosan can self-assemble into micelles, nanoparticles, nanoemulsions, and hybrid systems, with high encapsulation efficiency for lipophilic drugs when chemically modified with alkyl chains, fatty acids, bile acids, sterols, or synthetic polymer segments. By keeping medications in an amorphous, molecularly dispersed state and providing protection against gastrointestinal degradation, these nanostructures improve solubility. In addition to increasing solubility, amphiphilic chitosan improves drug permeation and systemic absorption by providing strong mucoadhesion, extended intestinal residence, and temporary modulation of tight junctions. Combined oral delivery with these carriers often results in a 2- to 3- fold increase in bioavailability and extended antihypertensive action in preclinical studies. Moreover, amphiphilic chitosan systems can provide sustained and extended release, with reduced peak-trough fluctuations and enhanced therapeutic stability. Their natural origin, biodegradability, acceptable safety profile, and regulatory acceptability strengthen their translation potential. This review carefully scrutinizes the chemistry and self-assembly processes, formulation strategies, pharmacokinetic advantages, safety-related issues, and potential uses of amphiphilic chitosan-based nanocarriers. All things considered, these technologies represent an interesting emerging delivery approach that may improve the oral bioavailability and therapeutic efficacy of poorly soluble antihypertensive drugs.

Ectopic variceal hemorrhage accounts for approximately 5% of all variceal bleeding episodes and represents an uncommon manifestation of portal hypertension. This report describes recurrent parastomal variceal bleeding in a 43-year-old woman with rectal adenocarcinoma who underwent abdominoperineal resection followed by five cycles of oxaliplatin-containing chemotherapy. During chemotherapy, severe hepatocellular injury developed. A liver biopsy performed in June 2020 demonstrated severe interface hepatitis with lymphoplasmacytic portal inflammation, findings that supported a diagnosis of autoimmune hepatitis (AIH). No histopathological features diagnostic of portosinusoidal vascular disease (PSVD) were identified. Subsequently, progressive splenomegaly, gastroesophageal and parastomal varices, and a directly measured portal pressure of 35 cm H2O developed in the absence of established cirrhosis. Inferior mesenteric vein embolization and ultrasound-guided foam sclerotherapy reduced the frequency of recurrent parastomal variceal bleeding but did not achieve complete hemostatic control. Treatment with carvedilol and prednisone was subsequently initiated. The overall clinical presentation was most consistent with multifactorial non-cirrhotic portal hypertension associated with AIH and prior oxaliplatin exposure, with a potential contribution from oxaliplatin-associated sinusoidal or vascular liver injury rather than histologically confirmed PSVD. This case highlights the diagnostic complexity and the need for individualized management in individuals with coexisting autoimmune liver disease, chemotherapy-associated hepatic injury, and refractory ectopic variceal hemorrhage.

Severe low back pain from spinal epidural and paraspinal venous engorgement secondary to hepatosplenic schistosomiasis is rare. MRI revealed dilated epidural veins and neural foraminal narrowing. The patient was managed conservatively with analgesia and carvedilol for portal hypertension and subsequently experienced complete resolution of back pain.

The poor water solubility of many drugs and drug candidates is a limiting factor to their bioavailability after oral administration. Although dissolution enhancing approaches, e.g. amorphous solid dispersions, are often used to make enabling formulations, these are usually associated with high development and manufacturing costs. This study focuses on the potential of using pharmaceutical excipients (binders) in simple tablet formulations to improve drug release and thus bioavailability. Loperamide hydrochloride, fenofibrate, compound c0 (a drug candidate) and carvedilol were chosen for this study as poorly water-soluble model compounds. Their solubility in the absence and presence of three polymeric binders, polyvinylpyrrolidone (PVP) K90, hydroxypropyl methylcellulose (HPMC) E4M and E15, and methylcellulose (MC) was tested in FaSSIF-V1 buffer and biorelevant media. Additionally, after wet granulation using PVP K90 or HPMC E15 as binders and tablet compression, the dissolution of the model compounds was tested in FaSSIF-V1 buffer and biorelevant media. Although solubilities and dissolution profiles of the model compounds were mostly improved by the binders, correlation between solubility in buffers and dissolution from the tablets in biorelevant FaSSIF-V1 was poor, indicating that dissolution experiments may be a better screening tool than solubility experiments. An important conclusion of these studies is that it is possible to increase the rate, and in some cases, the extent of dissolution of four poorly soluble drugs using wet granulation with polymeric binders, followed by tablet compression - a simple and cost-effective approach to improving drug performance.