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Since 3D printing technology is an emerging field in pharmaceutical technology, the present study aimed at the development of a mixed-mode liquid chromatographic method for the separation and determination of hydrochlorothiazide, diltiazem, and propranolol to investigate their in-vitro release performance from 3D printed tablets. Due to the unique properties of the mixed-mode stationary phase, the three drugs were separated in less than 8 min under isocratic elution. Method development was accomplished following the Analytical Quality by Design principles and was evaluated using risk assessment and multivariate analysis. The influences of critical method parameters on critical method attributes (were screened using a 2-level fractional factorial design and subsequently optimized through a central composite design. The method operable design region was approved by the establishment of a robust zone using Monte Carlo simulation and capability analysis. The validation of the HPLC method was performed based on the total error concept. The relative bias was varied between ─ 11.6 % and 10.5 % and the RSD values for repeatability and intermediate precision were below 4.4 % in all cases. The limits of detection (LOD) ranged between 0.17 - 0.90 μg/mL and were adequate for the specific application. The developed method was successfully applied to the analysis of the studied drugs in in-vitro drug release samples obtained from 3D-printed tablets combining the above-mentioned active pharmaceutical ingredients (APIs)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Innovative chiral capillary silica monoliths (CSMs) were developed based on DNA nanoflowers (DNFs). Baseline separation of enantiomers such as atenolol, tyrosine, histidine, and nefopam was achieved by using DNF-modified CSMs, and the obtained resolution value was higher than 1.78. To further explore the effect of DNFs on enantioseparation, different types of chiral columns including DNA strand containing the complementary sequence of the template (DCT)-modified CSMs, DNF 2 -modified CSMs, and DNF 3 -modified CSMs were prepared as well. It was observed that DNF-modified CSMs displayed better chiral separation ability compared with DCT-based columns. The intra-day and inter-day repeatability of model analytes' retention time and resolution kept desirable relative standard deviation values of less than 8.28%. DNF 2 /DNF 3 -modified CSMs were able to achieve baseline separation of atenolol, propranolol, 2'-deoxyadenosine, and nefopam enantiomers. Molecular docking simulations were performed to investigate enantioselectivity mechanisms of DNA sequences for enantiomers. To indicate the successful construction of DNFs and DNF-modified CSMs, various charaterization approaches including scanning electron microscopy, agarose gel electrophoresis, dynamic light scattering analysis, electroosmotic flow, and Fourier-transform infrared spectroscopy were utilized. Moreover, the enantioseparation performance of DNF-modified CSMs was characterized in terms of sample volume, applied voltage, and buffer concentration. This work paves the way to applying DNF-based capillary electrochromatography microsystems for chiral separation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

This research investigated the adsorption of propranolol (PROP) by functionalized green carbon nanotubes (MWCNT-B), assessing the influence of pH, in addition to kinetic, equilibrium, and thermodynamic studies and reuse of the material. For this purpose, speciation of PROP and the point of zero charge (pH PZC ) of MWCNT-B were performed, indicating a pKa of 9.67 and pH PZC of 3.31. The adsorption tests at different pH values revealed that in the range of pH 3 to 9, there is no significant variation in PROP uptake, despite this, at pH 11, the removal decreases. Regarding PROP adsorption, the equilibrium time ranged from 30 to 90 min, and the PFO model best represented the kinetic data. The Langmuir model was more predictive in representing isotherms (R 2  > 0.95), and the adsorption process was spontaneous and favorable (ΔG <  - 20 kJ mol -1 ) and indicated exothermic behavior (ΔH =  - 33 kJ mol -1 ) for PROP removal. In addition, the material showed satisfactory thermal regeneration results and can be reused for four cycles. The results suggest that MWCNT-B is an attractive adsorbent and exhibits effective removal of propranolol from aqueous matrices., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The main issue with Hypertension therapy is quick commencement of effect. The creation of suitable dose forms may help address the issue of medications having a delayed beginning of effect. Oral Antihypertensive medication treatment is best suited for and has seen a rise in popularity with fast-disintegrating tablets. In terms of patient compliance, quick start of action, precise dosage, strong chemical stability, ease of self-administration, and compactness, they are superior to other traditional methods. As a popular hypertension medication, Propranolol HCl is a strong candidate for development into Fast Dissolving Tablets (FDTs). Because to first pass metabolism, it has a limited bioavailability. Therefore, the primary goal of the research was to create Propranolol HCl fast-dissolving tablets in order to increase the drug's bioavailability and dissolution rate. Microcrystalline cellulose used to make fast-dissolving Propranolol HCl tablets, together with varying concentrations of super disintegrates such as Chia Seed mucilage and sodium starch glycolate. Each batch was made by compressing it directly. Three formulation variables were combined, and the combined impact was examined using a 23 Full Factorial design. Here, the disintegration time is examined as a dependent parameter and the concentrations of chia seed mucilage, Sodium Starch Glycolate, and Microcrystalline Cellulose were considered as independent variables, X1, X2, and X3, respectively. The program Design Expert is used to depict the data.

This study introduces (S)-Opto-prop-2, a second-generation photoswitchable ligand designed for precise modulation of β 2 -adrenoceptor (β 2 AR). Synthesised by incorporating an azobenzene moiety with propranolol, (S)-Opto-prop-2 exhibited a high PSS cis (photostationary state for cis isomer) percentage (∼90 %) and a favourable half-life (>10 days), facilitating diverse bioassay measurements. In vitro, the cis-isomer displayed substantially higher β 2 AR binding affinity than the trans-isomer (1000-fold), making (S)-Opto-prop-2 one of the best photoswitchable GPCR (G protein-coupled receptor) ligands reported so far. Molecular docking of (S)-Opto-prop-2 in the X-ray structure of propranolol-bound β 2 AR followed by site-directed mutagenesis studies, identified D113 3.32 , N312 7.39 and F289 6.51 as crucial residues that contribute to ligand-receptor interactions at the molecular level. In vivo efficacy was assessed using a rabbit ocular hypertension model, revealing that the cis isomer mimicked propranolol's effects in reducing intraocular pressure, while the trans isomer was inactive. Dynamic optical modulation of β 2 AR by (S)-Opto-prop-2 was demonstrated in two different cAMP bioassays and using live-cell confocal imaging, indicating reversible and dynamic control of β 2 AR activity using the new photopharmacology tool. In conclusion, (S)-Opto-prop-2 emerges as a promising photoswitchable ligand for precise and reversible β 2 AR modulation with light. The new tool shows superior cis-on binding affinity, one of the largest reported differences in affinity (1000-fold) between its two configurations, in vivo efficacy, and dynamic modulation. This study contributes valuable insights into the evolving field of photopharmacology, offering a potential avenue for targeted therapy in β 2 AR-associated pathologies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Hepatic toxicity is a leading cause of the termination of clinical trials and the withdrawal of therapeutics following regulatory approval. The detection of drug-induced liver injury (DILI) is therefore of importance to ensure patient safety and the effectiveness of novel small molecules and drugs. DILI encompasses drug-induced steatosis (DIS) and drug-induced phospholipidosis (DIPL) which involve the accumulation of excess intracellular lipids. Here, we develop hyperspectral stimulated Raman scattering (SRS) microscopy as a label-free methodology for discriminating DIS and DIPL in mammalian cell culture. We demonstrate that hyperspectral SRS imaging in tandem with spectral phasor analysis is capable of discriminating DIS and DIPL based on the nature and distribution of intracellular lipids resulting from each process. To demonstrate the practical application of this methodology, we develop a panel of alkyne-tagged propranolol analogues that display varying DILI effects. Using hyperspectral SRS imaging together with spectral phasor analysis, our label-free methodology corroborated the standard fluorescence-based assay for DILI. As a label-free screening method, it offers a convenient and expedient methodology for visualizing hepatotoxicity in cell cultures which could be integrated into the early stages of the drug development process for screening new chemical entities for DILI.

Aim: Our investigation aims to estimate the antifungal effect of propranolol hydrochloride (PNL). Methods: Oleosomes (OLs) were fabricated by thin-film hydration and evaluated for entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and amount of drug released after 6 h Q6h (%). Results: The optimal OL showed a rounded shape with optimum characteristics. The ex-vivo permeation and confocal laser scanning microscopy verified the prolonged release and well deposition of PNL-loaded OLs-gel. The in-silico assessment demonstrated the good stability of PNL with OLs' ingredients. In vivo evaluations for PNL-loaded OLs-gel showed a good antifungal impact against Candida albicans with good safety. Conclusion: This work highlights the potential of PNL-loaded OLs-gel as a potential treatment for candida vaginal infection.

Atenolol (ATE) and propranolol (PRO) inclusion complexes with β-cyclodextrin have been investigated in aqueous solution. The aqueous solution was examined and characterized using UV-vis, fluorescence spectroscopy, and 1 H NMR. The physical mixture was characterized using FTIR. The existence of inclusion complexes is confirmed by observing changes in spectroscopic properties. The ATE complex with β-CD exhibited an interaction as host and (β-CD) as a guest in a 1:1 ratio, with an inclusion constant K of 2.09 × 10 -3 µM -1 , as determined by the typical double-reciprocal graphs. Similarly, the PRO complex with β-CD exhibited an interaction as host and (β-CD) guest in 1:1 and 1:2 stoichiometry at the same time; the inclusion constants were K1 = 5.80 × 10 -5 µM -1 and K2 = 4.67 × 10 -8 µM -1 , as determined by typical double-reciprocal graphs. The variables influencing the formation of the inclusion complexes were investigated and optimized. Based on the enhancement in fluorescence intensity due to the formation of inclusion complexes, spectrofluorometric methods were developed and validated for determination of each drug's pharmaceutical formulation. The quantification of the fluorescence intensity for ATE and PRO was conducted at λ ex /λ em 226/302 nm and λ ex /λ em 231/338 nm, respectively. Under the optimal reaction circumstances, linear relationships with good correlation coefficients of 0.9918 and 0.99 were found in the concentration ranges of 0.3-1.7 μM, and 0.1-1.1 μM for ATE and PRO, respectively. The limits of detection (LODs) were found to be 0.13 and 0.01 μM for ATE and PRO, respectively. The suggested approach was effectively applied to the analysis of both drugs' pharmaceutical formulations.

Carbonate radical (CO 3 •- ) has been proved to be an important secondary radical in advanced oxidation processes due to various radical reactions involved HCO 3 - /CO 3 2- . However, the roles and contributions of CO 3 •- in organic micropollutant degradation have not been explored systematically. Here, we quantified the impact of CO 3 •- on the degradation kinetics of propranolol, a representative pollutant in the UV/peroxymonosulfate (PMS) system, by constructing a steady-state radical model. Substantially, the measured values were coincident with the predictive values, and the contributions of CO 3 •- on propranolol degradation were the water matrix-dependent. Propranolol degradation increased by 130% in UV/PMS system containing 10 mM HCO 3 - , and the contribution of CO 3 •- was as high as 58%. Relatively high pH values are beneficial for propranolol degradation in pure water containing HCO 3 - , and the contributions of CO 3 •- also enhanced, while an inverse phenomenon was shown for the effects of propranolol concentrations. Dissolved organic matter exhibited significant scavenging effects on HO • , SO 4 •- , and CO 3 •- , substantially retarding the elimination process. The developed model successfully predicted oxidation degradation kinetics of propranolol in actual sewage, and CO 3 •- contribution was up to 93%, which in indicative of the important role of CO 3 •- in organic micropollutant removal via AOPs treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Numerous studies have shown that there are multiple neural activities involved in the process of bone resorption and bone regeneration, and promoting osteogenesis by promoting neural network reconstruction is an effective strategy for repairing critical size bone defects. However, traumatic bone defects often cause activation of the sympathetic nervous system (SNS) in the damaged area, releasing excess catecholamines (CAs), resulting in a decrease in the rate of bone formation. Herein, a 3D-printed scaffold loaded with propranolol (PRN) is proposed to reduce CA concentrations in bone defect areas and promote bone regeneration through drug release. For this purpose, PRN-loaded methacrylated gelatin (GelMA) microspheres were mixed with low-concentration GelMA and perfused into a 3D-printed porous hydroxyapatite (HAp) scaffold. By releasing PRN, which can block β-adrenergic receptors, it hinders the activation of sympathetic nerves and inhibits the release of excess CA by the SNS. At the same time, the composite scaffold recruits bone marrow mesenchymal stem cells (BMSCs) and promotes the differentiation of BMSCs in the direction of osteoblasts, which effectively promotes bone regeneration in the rabbit femoral condyle defect model. The results of the study showed that the release of PRN from the composite scaffold could effectively hinder the activation of sympathetic nerves and promote bone regeneration, providing a new strategy for the treatment of bone defects.

Interaction of neutral and charged lipophilic beta-blocker drug, propranolol (PPL) with biomimicking nanocavities formed by micelles bearing same and opposite charges namely, cationic cetyltrimethylammonium bromide (CTAB), a surface-active ionic liquid 1-hexadecyl-3-methylimidazolium chloride (HDMIC) and anionic sodium dodecyl sulphate (SDS) have been investigated using fluorescence and absorption spectroscopic techniques. Binding of PPL to SDS at pH < pKa is characterised by biphasic interactions with decrease in fluorescence intensity at lower concentrations and subsequent increase post micellization. All the surfactants show significant interactions with the neutral drug molecule at pH > pKa, which is evident from the strongest binding constant ( K b ) values at pH 10.4. Results of quenching studies indicate that the location of drug molecule is determined by its charge, which is influenced by both pH and charge on micelle surface. For PPL-CTAB and PPL-HDMIC systems, quenching was strongest at pH 10.4, moderate at pH 7.4 and was absent at pH 3.5. However, the PPL-SDS system displayed similar K SV values at all pH conditions, suggesting that the probe is at the same position regardless of pH. Non-covalent interactions, which play crucial role in biological systems, are similarly the primary driving force governing the interaction between PPL and surfactant micelles., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mucilage of C. pareira leaves was utilized, being manufactured for use in pharmaceutical products. Carrageenan and Eudragit® NE30D were used to combined. Glycerin was used as a plasticizer at a concentration of 20 % w/w based on the amount of polymer used. Computer software optimized its characteristics, including tensile properties, moisture uptake, and erosion; the optimal formulation was 1.4:1.2:2.8. The percentages of optimization error ranged from 8.48 to 13.80 %. Propranolol HCl was mixed to an optimal formulation. The film layer was tight, homogeneous, and smooth, with no holes. DSC thermogram showed no interaction peaks at 101.33 °C and 170.50 °C. Propranolol HCl concentration in the film ranged from 2.18 to 2.20 mg/cm 2 . Propranolol HCl was quickly released from the film. The kinetic model for the release profile was first-order kinetic. Although propranolol HCl had a high-release profile, its skin permeation was limited. The permeation lag time, J ss , and K p were 1.60-2.65 h, 0.0182-0.0338 μg/cm 2 /h, and 9.10-15.35 cm/h, respectively. A significant amount of propranolol HCl residue was found on the skin's surface. Glycerin appeared to influence propranolol HCl permeability. Therefore, the plant leaf mucilage/carrageenan/Eudragit® NE30D blended film can be utilized in pharmaceutical applications to control drug release from its film layer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The objective of this study was to investigate the effect of dispersion time interval (DTI) on physicochemical properties of drug following the incorporation of propranolol HCl (Pro) and carbamazepine (CBZ) within ethyl cellulose (EC) microparticle blends using solvent evaporation method. The first Pro emulsion and second CBZ oil phase were dispersed in an external aqueous phase, with DTI of 0 and 60 min. The morphology of microparticle blends were characterized by SEM. The particle size mean of the emulsion droplets/hardened microparticles were monitored by FBRM. Encapsulation efficiency (EE) and in vitro drug release were also investigated. The resulting microparticle blends were spherical and formed two populations. The particle size mean of microparticle blends ranged from 113.27 µm to 122.42 µm. The EE was 77.28% to 78.64% for Pro and 96.48% to 98.64% for CBZ. FBRM studies showed that the size of microparticle blend prepared as W/O/W (Pro) and O/W (CBZ) system with DTI of 60 min and stirring time 4 h were larger than those prepared with DTI of 0 min. In vitro drug release studies after 28 days that revealed the CBZ release (58.72%) was faster than Pro release (43.16%). Investigation on surface morphology by SEM showed that the second drug CBZ which added as the oil phase in the W/O/W emulsion system had blocked the pores on the surface Pro microparticles prepared from the first primary emulsion, therefore affecting the drug release. This blocking effects of second drug (CBZ) on first emulsion microparticles (Pro) depended on the DTI. This phenomenon is only applicable if the first primary emulsion is W/O/W system., (© 2022. The Author(s).)

Aim: The study was aimed to understand the underlying causes for the differences in propranolol pharmacokinetics (PK) between healthy and cirrhosis populations by using a systematic whole-body physiologically based pharmacokinetic (PBPK) model-building approach for suggesting model informed propranolol dosing in liver cirrhosis patients with different stages of disease severity., Methods: A whole-body PBPK model was developed by using population simulator PK-Sim ® by using reported physicochemical and clinical data for propranolol in healthy and liver cirrhosis populations. The model evaluation was done by visual verification and comparison of PK parameters using their observed/predicted ratios (R obs/pred )., Results: The developed model has effectively described the disposition of propranolol after intravenous and oral application in healthy and liver cirrhosis populations. All the model predictions were comparable to the observed clinical data and the R obs/pred for all the PK parameters were within a 2-fold range. A significant increase in plasma concentration of propranolol and decrease in drug clearance was observed in progressive stages of liver cirrhosis. The developed model after evaluation with the reported clinical PK data was used for suggesting model informed propranolol dosing in different stages of liver cirrhosis based on systemic unbound drug concentration., Conclusion: The developed PBPK model has successfully described propranolol PK in healthy and cirrhosis populations after IV and oral administration. The evaluated PBPK propranolol-cirrhosis model can have many implications in predicting propranolol dosing in liver cirrhosis patients with different stages of disease severity., Competing Interests: The authors indicate that they have no conflicts of interest in this work., (© 2021 Kalam et al.)

Capillary electrophoresis-frontal analysis (CE-FA) together with mobility shift affinity CE is the most frequently used mode of affinity CE for a study of plasma protein-drug interactions, which is a substantial part of the early stage of drug discovery. Whereas in the classic CE-FA setup the sample is prepared by off-line mixing of the interaction partners in the sample vial outside the CE instrument and after a short incubation period loaded into the capillary and analysed, in this work a new methodological approach has been developed that combines CE-FA with the mixing of interacting partners directly inside the capillary. This combination gives rise to a fully automated and versatile methodology for the characterization of these binding interactions besides a substantial reduction in the amounts of sample compounds used. The minimization of possible experimental errors due to the full involving of sophisticated CE instrument in the injection procedure, mixing and separation instead of manual manipulation is another fundamental benefit. The in-capillary mixing is based on the transverse diffusion of laminar flow profile methodology introduced by Krylov et al. using its multi-zone injection modification presented by Řemínek at al.. Actually, after the method optimization, the alternate introduction of six plugs of drug and six plugs of bovine serum protein in BGE, each injected for 3 s at a pressure of -10 mbar (-1 kPa) into the capillary filled by BGE, was found to be the best injection procedure. The method repeatability calculated as RSDs of plateau highs of bovine serum albumin and propranolol as model sample compounds were better than 3.44 %. Its applicability was finally demonstrated on the determination of apparent binding parameters of bovine serum albumin for basic drugs propranolol and lidocaine and acid drug phenylbutazone. The values obtained by a new on-line CE-FA methodology are in agreement with values estimated by classic off-line CE-FA, as well as with literature data obtained using different techniques., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Objects of the present study are improved fullerene C 60 drug carrier properties trough encapsulation by microbial polysaccharides, levan (LEV), pullulan (PUL), and their hydrophobized cholesterol-derivatives (CHL and CHP), that show better interaction with cancer cells. The zeta potential, polydispersity index, and the diameter of particles were determined, and their cytotoxicity against three cancer cell lines were tested. Biochemical changes in HeLa cells are analyzed by synchrotron radiation (SR) FTIR spectro-microscopy combined with the principal component analysis (PCA). The most significant changes occur in HeLa cells treated with LEV-C 60 and correspond to the changes in the protein region, i.e. Amide I band, and the changes in the structure of lipid bodies and membrane fluidity are evident. The highest cytotoxicity was also induced by LEV-C 60 . In HeLa cells, cytotoxicity could not be strictly associated with biochemical changes in lipids, proteins and nucleic acids, but these findings are significant contribution to the study of the mechanism of interaction of C 60 -based nanoparticles with cellular biomolecules. In conclusion, LEV, PUL, CHL, and CHP enhanced fullerene C 60 potential to be used as target drug delivery system with the ability to induce specific intracellular changes in HeLa cancer cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Water pollution arising from pharmaceuticals has raised great concerns about the potential risks for biosphere and human health. However, rapid and efficient removal of pharmaceutical contaminants from water remains challenging. Wood sawdust, a byproduct of the wood-processing industry, is an abundant, cost-effective, and sustainable material with a unique hierarchically porous microstructure. These features make wood sawdust quite interesting as a filtration material. Here, we report a novel cross-flow filtration composite based on β-cyclodextrin-polymer-functionalized wood sawdust (β-CD/WS) in which the pharmaceutical contaminant water flows through the sawn-off vessel channels and the micropores on the surface of the cell walls, generating the turbulence. Such water flow characteristics ensure full contact between pharmaceutical pollutants and β-CD grafted on the cellulose backbone of wood sawdust, thereby enhancing the water treatment efficiency. Consequently, the β-CD/WS filter device shows a high removal efficiency of over 97.5% within 90 s for various pharmaceutical contaminants including propranolol, amitriptyline, chlortetracycline, diclofenac, and levofloxacin, and a high saturation uptake capacity of 170, 156, 257, 159, and 185 mg g -1 , respectively. The high-performance wood-sawdust-based cross-flow filtration opens new avenues for solving the global water pollution issues, especially those caused by pharmaceutical contaminants.

This study reports on the propranolol (PRO) degradation performance and product toxicity of an ultraviolet light-emitting diode (UV-LED)/chlorine process. The effects of experimental parameters including solution pH, chlorine dosage, and water matrix constituents on PRO removal were evaluated. Up to 94.5% of PRO could be eliminated within 15 min at a PRO-to-chlorine molar ratio of 1:4. The overall removal efficiency of PRO was non-pH dependent in the range of 5-9, while the initial rate was accelerated under alkaline conditions. The presence of Cl - /HCO 3 - had little influence on the PRO degradation, whereas either humic acid or NO 3 - had an obvious inhibitory effect. Radical scavenger experiments showed that both HO and Cl primarily contributed to the PRO degradation, and electron paramagnetic resonance data demonstrated the generation of 1 O 2 . The transformation of PRO during this process led to five detected products, which exhibited a higher acute toxicity than the parent compound according to the bright luminescent bacillus T3 method. It is worth mentioning that under the same ultraviolet illumination intensity, the degradation of PRO under UV-LED/chlorine gave a better performance than UV 254 /chlorine, but the EEO of the former is obviously higher than the latter. So further research is required on improving the electric current to photon conversion efficiency for UV-LED. Additionally, the UV-LED/chlorine system was effective in the degradation of other drugs including sulfamethoxazole, oxytetracycline hydrochloride, and gatifloxacin, suggesting the possible application of the UV-LED/chlorine process for the removal of pharmaceuticals during wastewater treatment., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In this study a heart-cutting 2D-LC method was successfully developed and optimized in order to discriminate and quantitate (S)-propranolol, (R)-propranolol, and its hydroxy metabolites, namely the isomeric (S)-4'‑hydroxy propranolol, (R)-4'‑hydroxy propranolol, (S)-5'‑hydroxy propranolol, (R)-5'‑hydroxy propranolol, (S)-7'-hydroxy propranolol, and (R)-7'‑hydroxy propranolol in one chromatographic run. Thereby, experiments investigating chiral discrimination in ring hydroxylation of propranolol were made feasible. Analysis of human urine samples after administration of a single oral dose of 40 mg of propranolol clearly revealed considerable chiral shifts in propranolol and its 4'-, 5'-, and 7'-hydroxy metabolites. Furthermore, the excretion rates of the individual (S)- and (R)-enantiomers were continuously monitored over 24 h post administration. Studies were performed utilizing a 2D-LC system hyphenated to a triple quadrupole mass spectrometer. The chromatographic system was endued with a reversed phase column (phenyl-hexyl) in first dimension and a teicoplanin based chiral column in second dimension. The method was basically validated and successfully evaluated as robust. Calibration was performed achieving accuracy between 80% and 120%. Maximal excretion rates of (S)-propranolol, (R)-propranolol, (S)-4'‑hydroxy propranolol, (R)-4'‑hydroxy propranolol, (S)-5'‑hydroxy propranolol, (R)-5'‑hydroxy propranolol, and (R)-7'‑hydroxy propranolol were 237 ng/min, 281 ng/min, 4 ng/min, 4 ng/min, 1 ng/min, 9 ng/min, and 3 ng/min, respectively., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019. Published by Elsevier B.V.)

The clinical studies proved the adverse effect of Propranolol on sexual function. Regarding this issue, the key research question of this study was, whether the designed herbal nanohybrid formula EGCG-chitosan-alginate has an efficacy versus Propranolol, or not? The formula was optimized according to the coacervation method. Its molecular structure and characteristics were confirmed. The entrapment efficiency was determined, and the stability, as well in vitro release study was conducted. The in vivo study was conducted for 65 days. To answer the raised question, tissue weights of the testis, epididymis seminal vesicles, and prostate were determined. Oxidative stress markers as MDA and GSH were measured in testis and epididymis, while testosterone in blood serum. The semen analysis was performed. DNA damage was detected according to the comet assay procedures. Conventional pathological examination was done in special concern to testis and epididymis. The characterization results reflected the good preparation of the formula with an amorphous structure in a range of 200 nm, high stability with ZP + 57.3 mV. The calculated EE was 84.10 ± 1.19% and the release percent was 72.11 ± 0.77% for 24 hrs. All the rats increased in the weight with variations among the groups in the tissue organs. The finding exposed a significant decrease in the average of MDA in the rats' testes with a significant increase in GSH while a non-significant difference in the epididymis, in both. The testosterone, the seminal parameters, and the DNA integrity significantly increased in the nano-formula compared to propranolol. Likewise, normal pathological findings of the nano-formula in the testis and Epididymis compared to abnormal of propranolol. In total, the current research confirmed that EGCG had no toxic effects and able to promote fertility. The most important finding was the administration of EGCG either in normal or nano-form prior to propranolol alleviated the effects of propranolol. These findings reflected the protection evident of EGCG versus propranolol.

The aim of this work was to develop a mathematical model to estimate the drug release from a conventional single-compartment reservoir pellet and extend its applicability to multi-compartment reservoir pellets. Conventional pellets were prepared by layering the drug onto starter-core then applying various ethylcellulose/HPC coatings for drug release control. Multi-layered pellets comprised a first drug layer of propranolol HCl (D 1 ) followed by a first controlled release coating (C 1 ) and consecutively a second drug layer of carbamazepine or caffeine (D 2 ) and then a second controlled-release coating (C 2 ). Drug release from single- and multi-compartment pellets generally increased with an increase of the water-soluble HPC in the coatings. The response described a sigmoidal curve, which agreed with a cumulative normal distribution function. The developed mathematical model facilitated quantification of the drug release of pellets as a function of the porogen content and the coating level. Additionally, the model was applied successfully in multi-compartment pellets to calculate theses effects on the release of drugs with a broad range of aqueous solubility., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Polymeric film coatings based on quaternary polymethacrylates (QPMs, e.g. Eudragits®) are frequently used for controlled release applications. However, their considerable sticking tendency is a major drawback in practice. In this study, different amounts of magnesium aluminum silicate (MAS) were added to the film coatings in order to overcome this hurdle. MAS is negatively charged and can electrostatically interact with the positively charged QPM. Different types of tablet cores were coated with aqueous Eudragit® RL 30D dispersions, optionally containing varying amounts of MAS. Dynamic changes in the wet mass of the systems as well as drug release upon exposure to 0.1 M HCl and phosphate buffer pH 6.8 were monitored. Propranolol HCl, acetaminophen, and diclofenac sodium were used as cationic, nonionic and anionic model drugs. The tablets were optionally cured for 12 h at 45 or 60 °C. Importantly, the addition of MAS to aqueous Eudragit® RL 30D dispersion substantially reduced the films' stickiness and led to stable inner coating structures, even without curing. Desired drug release rates can be adjusted by varying the QPM:MAS ratio and coating level., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The purpose of this study was to develop a new solid paediatric formulation for propranolol hydrochloride (PR). This drug is used to treat various paediatric diseases, and recently received clearance to treat haemangioma. However, PR has a bitter salty taste that does not facilitate high rates of compliance among children, especially in liquid formulations. In addition, the solid formulations are designed for adults and often their dosage is not suitable for children that require a flexible dose based on their weight. Therefore, matrix microbeads of EUDRAGIT® E PO containing PR were manufactured to overcome these limitations. Nine different samples were prepared using the prilling-congealing technique with high yield. Using 2 nozzles, 300 and 450 μm (code n), the diameters obtained of microbeads (from 333 to 699 μm) were homogenous and appropriate to be swallowed by children. In this study, the ratio drug:matrix for the microbeads was also examined in detail: 1:25 (F 1 ), 1:15 (F 2 ) and 1:10 (F 3 ) in aqueous and tert-butyl alcohol/aqueous (code t) media. Most of the examined microbeads were characterized by high percentage of encapsulation efficiency (22-100%) and drug loading (22-77 mg of drug per g of matrix) effective for the administration of low and high doses of PR. SEM analysis revealed a matrix with a radial or a spongy structure, with numerous pores that generated soft floating microbeads in aqueous solution. Release studies confirmed a low release and dissolution of the drug in artificial saliva, mainly F 1n  > F 1  > F 2nt , and a prompt dissolution in simulated gastric media. Finally, electronic tongue measurements revealed the ability of these formulations to mask the bitter drug taste, especially for the sample with a ratio 1:25 (F 1n and F 1 ). These samples were chemically and physically stable for six months. In conclusion, the projected microbeads F 1 , and F 1n reached the goal of the study, and could be proposed as new solid oral formulations dedicated to use by children., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A kind of light-responsive vesicle was prepared by aqueous self-assembly of α-CD and an azobenzene-containing M-helical foldamer, which displayed dynamic disassembly-reassembly structural transformation when alternately irradiated by UV and visible light. Distinctively, this vesicle also exhibited enantioselective release abilities toward racemic propranolol (a β-blocker), owing to the M-helical building blocks.

Deoxyribonucleoside triphosphates (dNTPs) are building blocks for the biosynthesis of DNA. Various modified dNTPs' analogs have synthesized by structural changes of nucleoside's susgar and nucleobases and employed for synthesis of modified DNA. A very few modified dNTPs have prepared from non-sugar nucleoside analogs. This report describes the synthesis of acyclic nucleoside triphosphate (NTP) analog from amino acid L-Serine as aminopropanolyl-thymine triphosphate ( ap- TTP) and demonstrate its biochemical evaluation as enzymatic incorporation of ap- TTP into DNA with DNA polymerases with primer extension methods. Alanyl peptide nucleicacids (Ala-PNA) are the analogs of DNA which contains alanyl backbone. Aminopropanolyl - analogs are derivatives of alanyl back bone. Ap-TTP analog is nucleoside triphosphate analog derived from Ala-PNA. Importantly, this report also sheds light on the crystal packing arrangement of alaninyl thymine ester derivative in solid-state and reveals the formation of self-duplex assembly in anti -parallel fashion via reverse Watson-Crick hydrogen bonding and π-π interactions. Hence, ap- TTP is a useful analog which also generates the free amine functional group at the terminal of DNA oligonucleotide after incorporation.

Background: Nobel laureate Sir James Black's molecule, propranolol, still has broad potential in cardiovascular diseases, infantile haemangiomas and anxiety. A comprehensive and systematic review of the literature for the summarization of pharmacokinetic parameters would be effective to explore the new safe uses of propranolol in different scenarios, without exposing humans and using virtual-human modeling approaches., Objective: This review encompasses physicochemical properties, pharmacokinetics and drug-drug interaction data of propranolol collected from various studies., Methods: Clinical pharmacokinetic studies on propranolol were screened using Medline and Google Scholar databases. Eighty-three clinical trials, in which pharmacokinetic profiles and plasma time concentration were available after oral or IV administration, were included in the review., Results: The study depicts that propranolol is well absorbed after oral administration. It has dose-dependent bioavailability, and a 2-fold increase in dose results in a 2.5-fold increase in the area under the curve, a 1.3-fold increase in the time to reach maximum plasma concentration and finally, 2.2 and 1.8-fold increase in maximum plasma concentration in both immediate and long-acting formulations, respectively. Propranolol is a substrate of CYP2D6, CYP1A2 and CYP2C19, retaining potential pharmacokinetic interactions with co-administered drugs. Age, gender, race and ethnicity do not alter its pharmacokinetics. However, in renal and hepatic impairment, it needs a dose adjustment., Conclusion: Physiochemical and pooled pharmacokinetic parameters of propranolol are beneficial to establish physiologically based pharmacokinetic modeling among the diseased population., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: Activation of the sympathetic system and adrenergic β-receptors following traumatic bone defects negatively impairs bone regeneration. Whether preventing β-receptor activation could potentially improve bone defect repair is unknown. In this study, we investigated the effect of systematic administration and local delivery of propranolol through composite scaffolds on bone healing., Materials and Methods: Collagen/PVA/propranolol/hydroxyapatite（CPPH）composite scaffolds were fabricated with 3D printing technique and characterized by scanning electron microscope (SEM). Micro-CT analysis and bone formation histology were performed to detect new bone formation. Osteogenic differentiation of bone marrow stromal cells (BMSCs) and osteoclastogenesis of bone marrow monocytes cultured with scaffolds extract were performed for further verification., Results: Intraperitoneal injection of propranolol did not significantly improve bone repair, as indicated by micro-CT analysis and bone formation histology. However, CPPH scaffolds exhibited sustained release of propranolol in vitro and significantly enhanced bone regeneration compared with vehicle collagen/PVA/hydroxyapatite (CPH) scaffolds in vivo. Moreover, in vitro experiments indicated the scaffolds containing propranolol promoted the osteogenic differentiation and migration of rat BMSCs and inhibited osteoclastogenesis by preventing β-receptor activation., Conclusions: This study demonstrates that local adrenergic β-receptor blockade can effectively enhance the treatment of bone defects by stimulating osteogenic differentiation, inhibiting osteoclastogenesis and enhancing BMSCs migration., (© 2019 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.)

Ionic liquids (ILs) are organic salts of asymmetric organic cations and inorganic/organic anions and are considered green alternative to organic solvents. ILs have high thermal stability, low volatility, low toxicity and high biodegradability. ILs are frequently used for enhancing the solubility and stability of active pharmaceutical ingredients. This study describes an invention related to the preparation of amorphous melts of propranolol incorporated into transdermal patches for infantile hemangioma intervention. Reduction in skin irritation and a significant increase in transdermal permeability of propranolol from its amorphous melts was reported. However, toxicity and stability issues of the IL-based active pharmaceutical ingredients and their drug delivery systems are yet to be established from regulatory perspective before exploiting commercial viability of these forms.

Permeability ( P m ) across biological membranes is of fundamental importance and a key factor in drug absorption, distribution, and development. Although the majority of drugs will be charged at some point during oral delivery, our understanding of membrane permeation by charged species is limited. The canonical model assumes that only neutral molecules partition into and passively permeate across membranes, but there is mounting evidence that these processes are also facile for certain charged species. However, it is unknown whether such ionizable permeants dynamically neutralize at the membrane surface or permeate in their charged form. To probe protonation-coupled permeation in atomic detail, we herein apply continuous constant-pH molecular dynamics along with free energy sampling to study the permeation of a weak base propranolol (PPL), and evaluate the impact of including dynamic protonation on P m . The simulations reveal that PPL dynamically neutralizes at the lipid-tail interface, which dramatically influences the permeation free energy landscape and explains why the conventional model overestimates the assigned intrinsic permeability. We demonstrate how fixed-charge-state simulations can account for this effect, and propose a revised model that better describes pH-coupled partitioning and permeation. Our results demonstrate how dynamic changes in protonation state may play a critical role in the permeation of ionizable molecules, including pharmaceuticals and drug-like molecules, thus requiring a revision of the standard picture.

Two novel sorbents based on polydopamine (PDA)-coated magnetic graphite oxide-metal organic frameworks nanoparticles [Cu(L-mal)(bpy)]·H 2 O (MGO-CuLBH) and [Cu(D-mal)(bpy)]·H 2 O (MGO-CuDBH) possessing of both magnetic property and excellent enantioselective ability were prepared and characterized. Solutions of racemic propranolol hydrochloride (Rac-PRO) were chosen to investigate the enantioselective performance of MGO-CuLBH and MGO-CuDBH by dispersive magnetic nanoparticle solid phase extraction (d-MNSPE). The results showed that the nanocomposites have excellent enantioselectivity to PROs with enantiomeric excess (ee) values reaching up to 98%. The entire process with PROs by the d-MNSPE method was fast, convenient and the collected composites could be easily recycled. Multi-stage operations using MGO-CuLBH and MGO-CuDBH were scaled up to obtain milligram quantities of R-propranolol hydrochloride (R-PRO) and S-propranolol hydrochloride (S-PRO). Furthermore, on the basis of the successful preparations, the differences in the cytotoxicity of Rac-PRO, R-PRO and S-PRO on A549 cells in vitro were all evaluated., (Copyright © 2019. Published by Elsevier B.V.)

This work shows that the metal organic framework (MOF) HKUST-1 of type Cu 3 (BTC) 2 (also referred to as MOF-199; a face-centered-cubic MOF containing nanochannels) is a most viable coating for use in enantioseparation in capillary electrochromatography (CEC). A HKUST-1 modified capillary was prepared and characterized by scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectra, elemental analysis and thermogravimetric analysis. CEC-based enantioseparation of the basic drugs propranolol (PRO), esmolol (ESM), metoprolol (MET), amlodipine (AML) and sotalol (SOT) was performed by using carboxymethyl-β-cyclodextrin as the chiral selector. Compared with a fused-silica capillary, the resolutions are improved (ESM: 1.79; MET: 1.80; PRO: 4.35; SOT: 1.91; AML: 2.65). The concentration of chiral selector, buffer pH value, applied voltage and buffer concentration were optimized, and the reproducibilities of the migration times and R s values were evaluated. Graphical abstract Schematic presentation of the preparation of a HKUST-1@capillary for enantioseparation of racemic drugs. Cu(NO 3 ) 2 and 1,3,5-benzenetricarboxylic acid (BTC) were utilized to prepare the HKUST-1@capillary. Then the capillary was applied to construct capillary electrochromatography system with carboxymethyl-β-cyclodextrin (CM-β-CD) for separation of basic racemic drugs.

We previously developed propranolol-encapsulated liposomes-in-microspheres (PLIM) to realize the sustained propranolol release for the treatment of hemangiomas. However, the liposomes released from the microspheres still lacked specificity for CD133-positive hemangioma-derived stem cells (HemSCs) which are considered to be the seeds of hemangiomas. Therefore, we hereby encapsulated propranolol-loaded CD133 aptamers conjugated liposomes in poly(lactic-co-glycolic acid (PLGA) microspheres to develop propranolol-loaded CD133 aptamers conjugated liposomes-in-microspheres (PCLIM), to realize the aim of the sustained and targeted therapy of hemangiomas. The evaluation of the release of propranolol from PCLIM was carried out, and the cytotoxic effect and angiogenic growth factor expression inhibitory ability of PCLIM were performed in HemSCs. The in vivo hemangioma inhibitory ability of PCLIM was also investigated in nude mice with subcutaneous human hemangiomas. PCLIM possessed a desired size of 29.2 μm, drug encapsulation efficiency (25.3%), and a prolonged drug release for 40 days. Importantly, PCLIM could inhibit HemSCs proliferation and the protein expression of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor-A (VEGF) in HemSCs to a greater extent compared with PLIM. In nude mice bearing hemangioma xenograft, PCLIM showed the best therapeutic efficacy towards hemangiomas, as reflected by remarkably decreased hemangioma volume, weight and microvessel density (MVD). Thus, our results demonstrated that PCLIM realized the sustained and targeted treatment of hemangiomas, resulting in remarkable inhibition of hemangiomas., (Copyright © 2019. Published by Elsevier Masson SAS.)

A versatile, robust and efficient differential potential ratiometric sensing platform was developed for enantioselective recognition of dual chiral targets based on a composite membrane of molecularly imprinted polymers (MIPs) and reduced graphene oxide (rGO) modified glassy carbon electrode (GCE). The functional chitosan-based MIPs and rGO were compatibly immobilized on the GCE with high selectivity and efficient signal amplification. Moreover, via the systematic optimization of series conditions, a distinct potential difference (PD), reaching 135 mV, was obtained between the R-/S-prop based on the MIPs/rGO/GCE. In a controllable concentration range from 50 μM to 1000 μM, different ratios of R-/S-prop were linearly related to the peak potentials (Eps) in the racemic mixture. Using this low-cost reversible electrochemical platform, both Prop enantiomers were simultaneously identified with high repeatability and time-based stability. This novel semi-quantitative electrochemical sensing platform was established to rapidly quantify the ratio of S-/R-prop by Ep for the chiral drug recognition with great potential for practical applications in fields of pharmacological detection and clinical analysis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Infantile hemangioma (IH) is one of the most common neoplasm of infancy. Although with the potential to involute slowly after proliferation, IH has several subsets that could develop severe complications and lead to functional impairment or permanent disfigurement. In the present study, a novel propranolol (PRN) delivery system is developed that encapsulated in mesoporous silica nanoparticles (MSN). The primary nanoparticles are further treated with polyvinyl alcohol (PVA) to form PVA-MSN-PRN nanoparticles. The encapsulation efficiency is 58.8% ± 7.2%, and nanoparticles could release PRN in a controlled-release way. It is discovered that PVA-MSN-PRN could significantly suppress hemangioma stem cell (Hemsc) proliferation, promote Hemsc apoptosis in vitro, and inhibit the growth of hemangiomain xenografts in vivo. A conclusion could be made that this novel nanodrug delivery system has high therapeutic efficacy, low cytotoxicity, low administration frequency, and provides an attractive strategy for efficient IH therapy., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Molecularly imprinted polymers (MIPs) capable of selectively recognizing small organic analytes in complex biological samples hold great promise in many real-world bioanalytical and biomedical applications, but development of such advanced synthetic receptors remains a challenging task. Herein, a facile and highly efficient new approach to obtaining well-defined complex biological sample-compatible MIP microspheres is developed by combining RAFT polymerization and thiol-epoxy coupling chemistry. Its proof-of-principle has been demonstrated by the first synthesis of propranolol-imprinted polymer microspheres with surface epoxy groups (briefly MIP-EP) via the combined use of reversible addition-fragmentation chain transfer (RAFT) precipitation polymerization and surface-initiated RAFT polymerization and their subsequent coupling reaction with a hydrophilic macromolecular thiol (i.e., thiol-terminated poly(2-hydroxyethyl methacrylate) (PHEMA-SH)). MIP-EP proved to show good propranolol recognition ability in an organic solvent but not in aqueous solution. The coupling reaction between PHEMA-SH and MIP-EP readily led to MIP microspheres with densely grafted PHEMA brushes, which greatly enhanced the surface hydrophilicity of MIP particles and transformed water-incompatible MIP-EP particles into biological sample-compatible ones (i.e., the resulting hydrophilic MIP microspheres exhibited specific template binding almost as good as they showed in the organic solvent and high template selectivity in biological samples including undiluted pure milk and pure bovine serum). In sharp contrast, the simple ring-opening of the epoxy groups on MIP-EP particles by using perchloric acid (following a previously reported method for obtaining water-compatible MIPs) only provided MIPs with propranolol recognition ability in pure water instead of in the complex biological samples.

The objective of this study was to modify the release of two drugs having different solubility in a combined matrix tablet as a fixed-dose combination for extended release. Propranolol HCl (freely soluble) and carbamazepine (very slightly soluble) were used as model drugs, water-soluble hydroxypropyl methylcellulose (HPMC) and water-insoluble ethylcellulose (EC) were used as matrix-forming polymers. Tablets were prepared by direct compression of powder blends, or propranolol HCl was first granulated with one of the matrix-forming polymers (1:1) followed by compression with carbamazepine and matrix former. Propranolol HCl release from directly compressed tablets was faster than carbamazepine because of its higher solubility. The release of both drugs was fast when HPMC-propranolol HCl granules were compressed with carbamazepine into EC matrix tablet. Conversely, the release of both drugs was decreased when HPMC-propranolol HCl granules and carbamazepine were compressed into HPMC matrices. The desired release of both drugs was approached when EC-propranolol HCl granules were compressed with carbamazepine into HPMC matrix. Erosion of the HPMC matrix and, therefore, drug release were adjusted by varying the molecular weight of HPMC. A burst release of propranolol HCl decreased when it was granulated with EC in a fluidized bed coater followed by compression with carbamazepine into HPMC matrix.

Propranolol is a popular β adrenergic antagonists that, together with pindolol, binds also to serotoninergic receptors, namely 5-HT 1A/B . In this work the rigidification of the propranolol structure by locking its hydroxyl group within a 1,3-dioxolane ring was investigated. Constrained derivatives of propranolol were synthesized, fully characterized and tested for their affinity at β-adrenoreceptors and 5-HT 1A/B/C receptors using radioligand binding assay. The constrained derivatives were inactive, as expected, at β 1/2/3 adrenergic receptors. Although less expected, these derivatives failed to bind also to 5-HT 1A/B/C receptors. The rigidification of propranolol is detrimental for 5-HT 1A R activity.

In this work, the effect of supporting electrolytes on the simultaneous electrochemical oxidation of the pharmaceuticals sulfamethoxazole (SMX), propranolol (PRO), and carbamazepine (CBZ) in aqueous solutions has been studied. Based on the identified by-products, the degradation mechanisms were proposed and the acute toxicity was evaluated for each electrolyte. Assays were carried out in batch mode in a 2 L undivided reactor using a niobium coated with boron-doped diamond (Nb/BDD) mesh anode and Ti cathode at 2.5 A in presence of different supporting electrolytes (Na 2 SO 4 , NaCl, or NaBr) at the same concentration of 7 mM. The degradation rates were higher in the assays with NaCl and NaBr. Reaction by-products were identified by gas chromatography-mass spectrometry. Indirect oxidation by electrogenerated reactive halogen species (RHS) was the main mechanism when halide ions were used as electrolytes. Ten by-products were detected using Na 2 SO 4 as electrolyte, while 19 (12 non-halogenated and 7 halogenated) and 20 (10 non-halogenated and 10 halogenated) using NaCl and NaBr respectively. The proposed degradation pathways involve transformation (hydroxylation, deamination, desulfonation, and halogenation) and bond rupture to produce less molecular weight compounds and their further transformation until total degradation. Chlorinated and brominated by-products confirm halogenation reactions. The electrogenerated RHS presented a significant inhibition effect on Vibrio fischeri; nevertheless, acute toxicity was not presented using Na 2 SO 4 as electrolyte and a pharmaceutical concentration of 5 μg/L. In this view, the role of the supporting electrolyte in electrochemical oxidation process is crucial since it strongly influence degradation rate, by-products, and acute toxicity.

Background/aims: Infantile hemangioma (IH), the most common benign tumor of childhood, is currently treated with propranolol. The aim of this work was to study in vitro propranolol permeation and skin retention from an original polymeric film, composed of polyvinyl alcohol and an acrylic polymer., Methods: Propranolol polymeric films were applied in occlusive and non-occlusive conditions, on either full thickness skin or isolated epidermis. Experiments were performed also on stripped skin, to simulate the skin permeability of damaged skin., Results: The results obtained underline the importance of determining skin concentration when dealing with drugs that should act on the skin. Skin permeation data are a poor predictor of skin retention data, in particular in critical conditions, such as heavily damaged skin., Conclusion: The film proposed for the treatment of IH (and other vascular diseases) with propranolol seems to be a good alternative to semisolid formulations, in particular if used in non-occlusive conditions, because it guarantees high proportions of drug retained in the skin, compared to permeated across the skin, reducing the risks of systemic side effect., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Tapioca starch (TS) is produced from Cassaca roots and it is differentiated from other starches because it contains about 17-20% amylase and low amount of residual substances. Propranolol (POP) is a non-selective beta-adrenergic blocking agent and it is in the World Health Organization's List of Essential Medicines. The aim of this work was to investigate the potential of TS in the development of POP tablets by means of direct compression. Its evaluation was performed by X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), Nuclear Magnetic Resonance (NMR) relaxometry, scanning electron microscopy (SEM), uniformity of weight, drug content, disintegration, friability, hardness, dissolution test and drug release kinetics. The TS granules were spherical with mean diameter of 10.09 ± 1.85 µm. The XRD, FTIR and NMR suggested physical interaction between TS and POP. The tablets presented average diameter of 1.1 ± 0.0 cm, 0.24 ± 0.02 cm thickness and average weight of 0.544 ± 0.003 g. The hardness of tablets was 10.98 ± 0.31 N and the percentage of friability was 25.74 ± 0.08%. POP was released after 45 min and the release kinetics properly fitted the Hixson-Crowell equation.

Propranolol, a β-adrenergic receptor antagonist, is a chiral compound that is marketed as a racemate, but only the (S)-(-)-enantiomer is responsible for the β-adrenoceptor blocking activity. Different chromatographic methods have been applied for separation and determination of enantiomers of (RS)-propranolol. In this article a review is presented on different liquid chromatographic methods used for enantioseparation of (RS)-propranolol, using both HPLC and TLC. In addition, some aspects of enantioseparation under achiral phases of liquid chromatography have been briefly mentioned., (© 2018 John Wiley & Sons, Ltd.)

We present a simple approach to calculate the kinetic properties of lipid membrane crossing processes from biased molecular dynamics simulations. We demonstrate that by using biased simulations, one can obtain highly accurate kinetic information with significantly reduced computational time with respect to unbiased simulations. We describe how to conveniently calculate the transition rates to enter, cross, and exit the membrane in terms of the mean first passage times. To obtain free energy barriers and relaxation times from biased simulations only, we constructed Markov models using the dynamic histogram analysis method (DHAM). The permeability coefficients that are calculated from the relaxation times are found to correlate highly with experimentally evaluated values. We show that more generally, certain calculated kinetic properties linked to the crossing of the membrane layer (e.g., barrier height and barrier crossing rates) are good indicators of ordering drugs by permeability. Extending the analysis to a 2D Markov model provides a physical description of the membrane crossing mechanism.

This study investigated the degradation of propranolol (PRO), a beta (β)-blockers, by nano zero-valent iron (nZVI) activated persulfate (PS) under ultrasonic irradiation. Effects of several critical factors were evaluated, inclusive of PS concentration, nZVI dosage, ultrasound power, initial pH, common anions, and chelating agent on PRO degradation kinetics. Higher PS concentration, nZVI dosage and ultrasound power as well as acidic pH favored the PRO degradation. Conversely, anions and chelating agent took on the inhibitory effect towards PRO degradation to different extents. Furthermore, the variations of morphology and surface composition of nZVI before and after the reaction were characterized by TEM, XRD and XPS. Finally, on the basis of identified degradation intermediates by LC/MS/MS analysis, this work tentatively proposed the degradation pathways. These encouraging results suggest that US/nZVI/PS process is a promising strategy for the treatment of PRO-induced water pollutant., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Compounded liquid medication is frequently required in children to allow easy dose adjustment and overcome swallowing difficulties. The objective of this study was to evaluate the stability of oral suspensions compounded with SyrSpend SF PH4 and the commonly used active pharmaceutical ingredients baclofen 2.0 mg/mL, carvedilol 5.0 mg/mL, hydrochlorothiazide 2.0 mg/mL, mercaptopurine 10.0 mg/mL, methadone hydrochloride 10.0 mg/mL, oseltamivir phosphate 6.0 mg/mL, phenobarbital 9.0 mg/mL and 15.0 mg/mL, propranolol hydrochloride 0.5 mg/mL and 5.0 mg/mL, pyrazinamide 100.0 mg/mL, spironolactone 2.0 mg/mL and 2.5 mg/mL, sotalol hydrochloride 5.0 mg/mL, tacrolimus monohydrate 0.5 mg/mL, ursodeoxycholic acid 20.0 mg/mL, and vancomycin hydrochloride 25.0 mg/mL. Suspensions were compounded with raw powders, except for mercaptopurine, pyrazinamide, and sotalol hydrochloride, which were made from commercial tablets. Stability was assessed by measuring the percentage recovery at 0 (baseline), 60 days, and 90 days after compounding for suspensions made with raw powders, which were stored at 2ÅãC to 8ÅãC. The stability of tablets, which were stored at 2ÅãC to 8ÅãC and 20ÅãC to 25ÅãC, was assessed by measuring the percentage recovery at 0 (baseline), 7 days, 14 days, 30 days, 60 days, and 90 days. Active pharmaceutical ingredients quantification was performed by ultraviolet high-performance liquid chromatography via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredients + vehicle) was at least 90 days for all suspensions in the conditions tested. This suggests that SyrSpend SF PH4 is suitable for compounding active pharmaceutical ingredients from different pharmacological classes., (Copyright© by International Journal of Pharmaceutical Compounding, Inc.)

The aim of the present study was to evaluate the sorption and desorption of sulfamethoxazole (SMX), propranolol (PRP) and sertraline (SER) by polyethylene (PE) microplastics in water. After the 96 h mixture, the sorption percentages of pharmaceuticals on PE microplastics decreased according to the following order: SER (28.61%) > PRP (21.61%) > SMX (15.31%). The sorption kinetics were fitted well with the pseudo-second-order model. Both linear and Freundlich models were able to describe the sorption isotherm. The results suggest that the sorption process of the pharmaceuticals may be adequately described by their hydrophobicity and electrostatic interactions. The desorption results showed that 8% and 4% of PRP and SER, respectively, were released from the microplastics within 48 h, but the sorption of SMX was irreversible. The results indicate the potential risks of PRP and SER for bioaccumulation in aquatic organisms via ingestion of the microplastics in aquatic environments., (Copyright © 2018. Published by Elsevier Ltd.)

TAML activators enable unprecedented, rapid, ultradilute oxidation catalysis where substrate inhibitions might seem improbable. Nevertheless, while TAML/H 2 O 2 rapidly degrades the drug propranolol, a micropollutant (MP) of broad concern, propranolol is shown to inhibit its own destruction under concentration conditions amenable to kinetics studies ([propranolol] = 50 μM). Substrate inhibition manifests as a decrease in the second-order rate constant k I for H 2 O 2 oxidation of the resting Fe III -TAML (RC) to the activated catalyst (AC), while the second-order rate constant k II for attack of AC on propranolol is unaffected. This kinetics signature has been utilized to develop a general approach for quantifying substrate inhibitions. Fragile adducts [propranolol, TAML] have been isolated and subjected to ESI-MS, florescence, UV-vis, FTIR, 1 H NMR, and IC examination and DFT calculations. Propranolol binds to Fe III -TAMLs via combinations of noncovalent hydrophobic, coordinative, hydrogen bonding, and Coulombic interactions. Across four studied TAMLs under like conditions, propranolol reduced k I 4-32-fold (pH 7, 25 °C) indicating that substrate inhibition is controllable by TAML design. However, based on the measured k I and calculated equilibrium constant K for propranolol-TAML binding, it is possible to project the impact on k I of reducing [propranolol] from 50 μM to the ultradilute regime typical of MP contaminated waters (≤2 ppb, ≤7 nM for propranolol) where inhibition nearly vanishes. Projecting from 50 μM to higher concentrations, propranolol completely inhibits its own oxidation before reaching mM concentrations. This study is consistent with prior experimental findings that substrate inhibition does not impede TAML/H 2 O 2 destruction of propranolol in London wastewater while giving a substrate inhibition assessment tool for use in the new field of ultradilute oxidation catalysis.

Photolysis of the widely used beta-blocker propranolol (PRO) was investigated in the presence of fulvic acid (FA) and inorganic ions under simulated solar irradiation. PRO undergoes direct photolysis proceeding mainly via degradation of the triplet excited state, 3 PRO*. FA and inorganic ions inhibited photolysis of PRO in the order of FA > Fe 3+  > Cl -  > Ca 2+  > Mg 2+  > NO 3 -  > K + . An antagonistic effect between FA and inorganic ions toward the suppression of PRO photolysis was exhibited. The binding behaviors of PRO, FA, and inorganic ions were examined through fluorescence quenching experiments, which showed that inorganic ions affected the binding between FA and PRO through competing for the binding sites of FA or PRO. The correlation analysis demonstrated a positive correlation between the binding constant (K OC ) of FA-PRO and the inhibition rate of FA on PRO photolysis. The observed rate constants of photolysis (k obs ) have opposite correlations with the concentration of singlet oxygen ( 1 O 2 ). These findings strongly suggest that inorganic ions decrease the inhibition effect of FA on PRO photolysis via restraining the complexation of FA-PRO and production of 1 O 2 .

ß-Blockers are weak bases with acidity constants related to their secondary amine group. At environmental pH they are protonated with the tendency to shift to their neutral species at more alkaline pH. Here we studied the influence of pH from 5.5 to 8.6 on the toxicity of the four ß-blockers atenolol, metoprolol, labetalol and propranolol in zebrafish embryos, relating toxicity not only in a conventional way to external aqueous concentrations but also to measured internal concentrations. Besides lethality, we evaluated changes in swimming activity and heartbeat, using the Locomotor Response (LMR) method and the Vertebrate Automated Screening Technology (VAST) for high throughput imaging. Effects of metoprolol, labetalol and propranolol were detected on phenotype, heart rate and swimming activity. External effect concentrations decreased with increasing neutral fraction for all three pharmaceuticals, attributed by an enhanced uptake of the neutral species in comparison to the corresponding charged form. The LC 50 of metoprolol decreased by a factor of 35 from 1.91 mM with almost complete cationic state at pH 7.0 to 0.054 mM with 8% neutral fraction at pH 8.6. For propranolol the LC 50 of 2.42 mM at pH 5.5 was even 100 fold higher than the LC 50 at pH 8 with 0.023 mM where 3% were neutral fraction. No effects were detected in the zebrafish embryo exposed to atenolol. The internal concentrations for metoprolol and propranolol were quantified at non-toxic concentrations and at the LC 10 . Apparent bioconcentration factors (BCF) ranged from 1.96 at pH 7.0 to 32.0 at pH 8.6 for metoprolol and from 1.86 at pH 5.5 to 169 at pH 8.0 for propranolol. The BCFs served to predict the internal effect concentrations from the measured external effect concentrations. Internal effect concentrations of metoprolol and propranolol were in a similar range for all pH-values and for all endpoints. Interestingly, the internal effect concentrations were in the internal concentration range of baseline toxicity, which suggests that the effects of the ß-blockers are rather unspecific, even for sublethal effects on heart rate. In summary, our data confirm that the pH-dependent toxicity related to external concentrations can be explained by toxicokinetic effects and that the internal effect concentrations are pH-independent., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: The preparation of magnetic multi-walled carbon nanotube poly(styrene-co-divinylbenzene) for propranolol magnetic solid-phase extraction is described., Materials & Methods: A study comparing propranolol adsorption and desorption was performed with only magnetic multi-walled carbon nanotubes, and different poly(styrene-co-divinylbenzene) with and without magnetic multi-walled carbon nanotubes. Enantiomeric separation of propranolol took place by cyclodextrin-modified capillary electrophoresis and the method was validated in spiked human urine samples., Results: Recovery values raised when styrene/divinylbenzene millimoles ratio was 19.57:15.80. Enrichment factors increased up to approximately 100, detection limits were 13.8 and 10.5 ng ml -1 for R- and S-propranolol respectively, quantitation limits were 46.0 and 34.8 ng ml -1 for R- and S-propranolol respectively, recoveries from spiked samples ranged from 90.9 to 109.0%, and relative standard deviations were <6.3%., Conclusion: This methodology was proven to be more effective than classical solid-phase extraction strategies and may be applied to other kind of biological samples.

In the present study, the interaction of human serum albumin (HSA) with some cardiovascular drugs (CARs) under physiological conditions was investigated via the fluorescence spectroscopic and Fourier transform infrared spectroscopy. The CAR included Captopril, Timolol, Propranolol, Atenolol, and Amiodarone. Cardiovascular drugs can effectively quench the endogenous fluorescence of HSA by static quenching mechanism. The fluorescence quenching of HSA is mainly caused by complex formation of HSA with CAR. The binding reaction of CAR with HSA can be concluded that hydrophobic and electrostatic interactions are the main binding forces in the CAR-HSA system. The results showed that CAR strongly quenched the intrinsic fluorescence of HSA through a static quenching procedure, and nonradiation energy transfer happened within molecules. Fourier transform infrared spectroscopy absorption studies showed that the secondary structure was changed according to the interaction of HSA and CAR. The binding reaction of CAR with HSA can be concluded that hydrophobic and electrostatic interactions are the main binding forces in the CAR-HSA system. The results obtained herein will be of biological significance in pharmacology and clinical medicines., (Copyright © 2018 John Wiley & Sons, Ltd.)