Unique Positive Cooperativity Between the ß-Arrestin-Biased ß-Blocker Carvedilol and a Small Molecule Positive Allosteric Modulator of the ß2-Adrenergic Receptor.

Among ß-blockers that are clinically prescribed for heart failure, carvedilol is a first-choice agent with unique pharmacological properties. Carvedilol is distinct from other ß-blockers in its ability to elicit ß-arrestin-biased agonism, which has been suggested to underlie its cardioprotective effects. Augmenting the pharmacologic properties of carvedilol thus holds the promise of developing more efficacious and/or biased ß-blockers. We recently identified compound-6 (cmpd-6), the first small molecule positive allosteric modulator of the ß2-adrenergic receptor (ß2AR). Cmpd-6 is positively cooperative with orthosteric agonists at the ß2AR and enhances agonist-mediated transducer (G-protein and ß-arrestin) signaling in an unbiased manner. Here, we report that cmpd-6, quite unexpectedly, displays strong positive cooperativity only with carvedilol among a panel of structurally diverse ß-blockers. Cmpd-6 enhances the binding affinity of carvedilol for the ß2AR and augments its ability to competitively antagonize agonist-induced cAMP generation. Cmpd-6 potentiates ß-arrestin1- but not Gs-protein-mediated high-affinity binding of carvedilol at the ß2AR and ß-arrestin-mediated cellular functions in response to carvedilol including extracellular signal-regulated kinase phosphorylation, receptor endocytosis, and trafficking into lysosomes. Importantly, an analog of cmpd-6 that selectively retains positive cooperativity with carvedilol acts as a negative modulator of agonist-stimulated ß2AR signaling. These unprecedented cooperative properties of carvedilol and cmpd-6 have implications for fundamental understanding of G-protein-coupled receptor (GPCR) allosteric modulation, as well as for the development of more effective biased beta blockers and other GPCR therapeutics. SIGNIFICANCE STATEMENT: This study reports on the small molecule-mediated allosteric modulation of the ß-arrestin-biased ß-blocker, carvedilol. The small molecule, compound-6 (cmpd-6), displays an exclusive positive cooperativity with carvedilol among other ß-blockers and enhances the binding affinity of carvedilol for the ß2-adrenergic receptor. Cooperative effects of cmpd-6 augment the ß-blockade property of carvedilol while potentiating its ß-arrestin-mediated signaling functions. These findings have potential implications in advancing G-protein-coupled receptor allostery, developing biased therapeutics and remedying cardiovascular ailments.

Molecular determinants of pro-arrhythmia proclivity of d- and l-sotalol via a multi-scale modeling pipeline.

Drug isomers may differ in their proarrhythmia risk. An interesting example is the drug sotalol, an antiarrhythmic drug comprising d- and l- enantiomers that both block the hERG cardiac potassium channel and confer differing degrees of proarrhythmic risk. We developed a multi-scale in silico pipeline focusing on hERG channel - drug interactions and used it to probe and predict the mechanisms of pro-arrhythmia risks of the two enantiomers of sotalol. Molecular dynamics (MD) simulations predicted comparable hERG channel binding affinities for d- and l-sotalol, which were validated with electrophysiology experiments. MD derived thermodynamic and kinetic parameters were used to build multi-scale functional computational models of cardiac electrophysiology at the cell and tissue scales. Functional models were used to predict inactivated state binding affinities to recapitulate electrocardiogram (ECG) QT interval prolongation observed in clinical data. Our study demonstrates how modeling and simulation can be applied to predict drug effects from the atom to the rhythm for dl-sotalol and also increased proarrhythmia proclivity of d- vs. l-sotalol when accounting for stereospecific beta-adrenergic receptor blocking.

In depth investigation of the retention behavior of structurally related ß-blockers on RP-HPLC column: Quality by design and quantitative structure-property relationship complementary approaches for optimization and validation.

The persistent introduction of new ß-blockers motivates the demand for optimizing RP-HPLC well-designed analytical procedures that could be applied to this structurally related and commonly prescribed pharmacological group in order to reduce time and chemicals consumption in quality control units. Betoxolol HCl (BEX) and Carvidolol (CAR) were selected as representative examples to conduct predictive studies based on two complementary approaches, Quality by design (QBD) and Quantitative structure property relationship (QSPR). In concern QBD, a Box-Behnken design was adopted at variable chromatographic parameters to achieve the most proper conditions that might be applied for efficient analysis of the majority of group members. On the other hand, the retention time was chosen as the target property in the QSPR study that was conducted onto seven ß. blockers (the two investigated drugs in addition to five other ß. blockers) to find the best correlated molecular descriptors to the retention behavior. Both external and internal validation studies have comparable quality with training levels. Hence a simple selection algorithm of conventional features provides robust confirmatory predictive QBD and QSPR models. Derringer's desirability function as as a multi-criteria approach was applied for getting the optimum chromatographic analysis conditions. Efficient analysis of BET and CAR was achieved at column temperatures of 26.00 and 27.50 °C, respectively using acetonitrile and phosphate buffer (pH 4.55) 70:30 v/v as a mobile phase with a flow rate of 1.00 mL/min, and UV detection at 220 nm. The method was validated in accordance to ICH guidelines, and had exhibited acceptable precision, accuracy, linearity, and robustness.

Imprinted ß-ketoenamine-linked covalent organic frameworks as dispersive sorbents for the fluorometric determination of timolol.

Timolol accompanied the formation of fluorescent ß-ketoenamine-linked covalent organic frameworks (COFs) via the Sc(Tof)3-catalyzed condensation of derivated carbaldehyde and hydrazide in a 1,4-dioxane/mesitylene porogen to construct timolol-imprinted COFs (TICOFs). With high imprinting factors, the synthesis-optimized TICOFs were characterized by fluorescence, UV-Vis spectrometry, X-ray diffraction, N2 adsorption/desorption analyses, scanning electron microscopy, and FTIR spectrometry. The TICOF fluorescence measured at 390 nm/510 nm is dynamically quenched by timolol and was thus utilized to quantify timolol in a linear range of 25-500 nM with a LOD of 8 nM. The TICOF recovered 99.4% of 0.5% timolol maleate in a commercial eye drop (RSD = 1.1%, n = 5). In addition, TICOF was used as a dispersive sorbent to recover 95% of 2.0 nM timolol from 20 mg of TICOF in 25 mL phosphate buffer. Dilution factors of 25 and 75 were the maximum tolerated proportions of the urine and serum matrix spiked with 2.0 nM timolol to reach recoveries of 92.4% and 90.3%, respectively.

Beta-Blockers and Berberine: A Possible Dual Approach to Contrast Neuroblastoma Growth and Progression.

The use of nutraceuticals during cancer treatment is a long-lasting debate. Berberine (BBR) is an isoquinoline quaternary alkaloid extracted from a variety of medicinal plants. BBR has been shown to have therapeutic effects in different pathologies, particularly in cancer, where it affects pathways involved in tumor progression. In neuroblastoma, the most common extracranial childhood solid tumor, BBR, reduces tumor growth by regulating both stemness and differentiation features and by inducing apoptosis. At the same time, the inhibition of ß-adrenergic signaling leads to a reduction in growth and increase of differentiation of neuroblastoma. In this review, we summarize the possible beneficial effects of BBR in counteracting tumor growth and progression in various types of cancer and, in particular, in neuroblastoma. However, BBR administration, besides its numerous beneficial effects, presents a few side effects due to inhibition of MAO A enzyme in neuroblastoma cells. Therefore, herein, we proposed a novel therapeutic strategy to overcome side effects of BBR administration consisting of concomitant administration of BBR together with ß-blockers in neuroblastoma.

Clinical Pharmacokinetics of Propranolol Hydrochloride: A Review.

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.

Gold nanoparticles coated with a tetramethylammonium lactobionate ionic liquid for enhanced chiral differentiation in open tubular capillary electrochromatography: application to enantioseparation of ß-blockers.

A new bilayer chiral stationary phase for use in open tubular capillary electrochromatography (OT-CEC) system is described. Gold nanoparticles were modified with L-cysteine, with a tetramethylammonium lactobionate ionic liquid that acts as the chiral selector. The gold nanoparticle-coated column provides good enantioseparation and favorable reproducibility. Compared with an uncoated separation system, the column developed displays improved separation of the racemic ß-blockers propranolol, esmolol, bisoprolol and sotalol (resolutions of enotiomers are 6.29, 6.11, 6.12 and 6.02, respectively). The materials and coatings were characterized by scanning electron microscopy and transmission electron microscopy. The main driving forces (CEC and electro-osmotic flow) were studied to evaluate the variation of the immobilized columns. The effects of buffer pH value, concentration of chiral selector, type of organic modifier and applied voltage were optimized. Satisfactory relative standard deviations were achieved in run-to-run, day-to-day and column-to-column experiments. Graphical abstractSchematic preparation of a capillary column with bilayer chiral selectors coated gold nanoparticles. This novel OT-CEC system was applied for separation of four basic racemic ß-blockers.

Blockade of adrenergic ß-receptor activation through local delivery of propranolol from a 3D collagen/polyvinyl alcohol/hydroxyapatite scaffold promotes bone repair in vivo.

OBJECTIVES: Activation of the sympathetic system and adrenergic ß-receptors following traumatic bone defects negatively impairs bone regeneration. Whether preventing ß-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 ß-receptor activation. CONCLUSIONS: This study demonstrates that local adrenergic ß-receptor blockade can effectively enhance the treatment of bone defects by stimulating osteogenic differentiation, inhibiting osteoclastogenesis and enhancing BMSCs migration.

Selective determination of some beta-blockers in urine and plasma samples using continuous flow membrane microextraction coupled with high performance liquid chromatography.

In this work, an efficient method termed as continuous flow membrane microextraction coupled with high performance liquid chromatography is introduced for a highly selective determination of metoprolol and propranolol in the biological samples. According to this method, an aqueous source phase of the analytes (donor phase, 10 mL) is circulated into an extraction cell, which is separated from an aqueous acceptor phase (100 µL) by a small piece of polypropylene membrane sheet whose pores are impregnated by an organic solvent (1-octanol, 15 µL). The analytes are extracted from the donor phase into the organic solvent. They are subsequently selectively back-extracted into the acceptor solution due to the pH gradient. The proposed method is very convenient and has the capability of being fully automated. It provides a good preconcentration and an excellent repeatability. The extractant is an aqueous phase, and by prevention of the extraction of macromolecules through the membrane, the developed method provides a high sample clean-up. In order to maximize the extraction efficiency, the influential parameters including the type of mediator solvent, pH values for the donor and acceptor solutions, extraction time, ionic strength, stirring rate, and volume of the acceptor solution are optimized. The calibration curves were obtained with a reasonable linearity (r2 = 0.999) in the range of 3-1000 ng mL-1. The limits of detection were 0.5 and 1.0 ng mL-1, and excellent relative standard deviations were obtained (between 3.2% and 4.0%). Finally, the reliability of the procedure is evaluated by determination of metoprolol and propranolol in the human urine and plasma samples, which indicates the suitability, sensitivity, and high sample clean-up of the proposed method.

A New Class of ß-Pyrrolidino-1,2,3-Triazole Derivatives as ß-Adrenergic Receptor Inhibitors: Synthesis, Pharmacological, and Docking Studies.

New 1,4-disubstituted ß-pyrrolidino-1,2,3-triazoles were synthesized using a reusable copper-iodide-doped neutral alumina catalyst. Synthesis of diversely substituted triazoles and recyclability of CuI catalyst explains the broad scope of this protocol. The synthesized compounds were screened for their antimicrobial and anticancer properties. Most of the compounds showed significant antimicrobial activities against all the tested microorganisms compared to standard drugs. Furthermore, compounds 5a, 5e, 5g, 5h, 5i, and 5j showed moderate to potent activities against A549 and HepG-2 cells. In addition, compounds 5g and 5h displayed potential cytotoxicity activity against A549 cells with IC50 values of 72 ± 3.21 and 58 ± 2.31 µM, respectively. The molecular docking study revealed that some of the synthesized compounds exhibited comparable binding as co-crystalized ligands with the DNA topoisomerase IV and anaplastic lymphoma kinase receptors.

Multi-residue method for enantioseparation of psychoactive substances and beta blockers by gas chromatography-mass spectrometry.

Currently, consumption of illicit drugs and pharmaceuticals has increased significantly. Many of these substances are chiral and can be available as racemates or enantiomerically pure. Determination of the enantiomeric fraction (EF) in wastewater is useful for: i) distinguishing between the consumption of prescribed and illicit drugs; ii) identification of possible local of illegal synthesis; iii) illegal discharge of sewage and estimation of illicit drugs and pharmaceuticals consumption by a community (wastewater-based epidemiology). This work describes the development of an indirect method by gas chromatography-mass spectrometry (GC-MS) for enantiomeric quantification of chiral substances namely psychoactive drugs and ß-blockers based on the formation of diastereomers using (R)-(-)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride ((R)-MTPA-Cl) as chiral derivatization reagent. The developed method presented linearity (R2 > 0.99) for 20 compounds, 9 diastereomer pairs and paroxetine (PAR) and sertraline (SER). Recovery ranged from 80.7 to 114.5% (RSD < 9.1%) and accuracy between 84.6 and 118% (RSD < 9.9%). The limits of detection (LOD) varied from 0.03 and 26.0 ngL-1 and limits of quantification (LOQ) from 0.15 and 104 ngL-1. Results showed the occurrence of amphetamine (AMP), illicit drugs as 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (MAMP), alprenolol (ALP), norfluoxetine (NFLX), (SER), metoprolol (MET) and propranolol (PHO) at concentrations ranging from 21.7 ngL-1 (MDMA) to 622 ngL-1 (PHO). Measured concentrations were used to estimate the drug loads of the target chiral substances in a specific population. The EF was determined providing valuable information about the consumption and origin of the target drugs.

Development and evaluation of performance characteristics of timolol-loaded composite ocular films as potential delivery platforms for treatment of glaucoma.

Thin and erodible polymeric films were developed as potential ocular drug delivery systems to increase drug retention on the eye with the aim of improving bioavailability and achieving controlled drug release. Two biocompatible film forming polymers, hyaluronic acid (HA) and hydroxypropyl methylcellulose (HPMC), which are currently used as thickening agents in eye drops were employed. Two different films were prepared (i) as single polymer and (ii) as composite formulations by solvent casting method, incorporating glycerol (GLY) as plasticizer and timolol maleate (TM) as model glaucoma drug. After preliminary optimization of transparency and ease of handling, the formulations were further characterized for their physicochemical properties. No indication of significant drug-polymer or polymer-polymer (in composite films) interaction was observed from FTIR results while evaluation by IR mapping revealed uniform distribution of drug throughout the films. Amorphization of TM in the film matrix was confirmed by both DSC and XRD. Swelling studies illustrated remarkable swelling capacity of HA in comparison with HPMC which directly affected the drug release profiles, making HA a suitable polymer for controlled ocular drug delivery. Tensile and mucoadhesion properties confirmed higher elasticity and adhesiveness of HA while HPMC produced stronger films. The effect of sterilization by UV radiation on mechanical properties was also evaluated and showed no significant difference between the sterilized and non-sterilized films. The SEM results confirmed smoothness and homogeneity of film surfaces for all the formulations studied. The in vitro drug dissolution studies showed more extended release profiles of formulations containing HA. Cytotoxicity study (cell viability) using MTT assay on HeLa cells, confirmed that the single polymer and composite films are generally safe for ocular administration. The present work shows excellent film forming ability of HA and HPMC which can be used as single polymer or combined in composite formulations as potential topical ocular drug delivery platform to enhance drug retention on the ocular surface and therefore potential improved bioavailability.

Development of Solid Dispersion by Hot Melt Extrusion Using Mixtures of Polyoxylglycerides With Polymers as Carriers for Increasing Dissolution Rate of a Poorly Soluble Drug Model.

Various polyoxylglycerides have been researched extensively in the development of solid dispersions (SDs) for bioavailability enhancement of poorly water-soluble drugs. However, because of their low melting points (40°C-60°C), SDs produced are usually soft and semisolid. The objective of present study was to prepare SDs of a Biopharmaceutical Classification System class II drug, carvedilol, in mixtures of stearoyl polyoxylglycerides (Acconon® C-50; m.p. ∼50°C) with polymers by hot melt extrusion to obtain free-flowing powder upon grinding. Miscibility of carvedilol with Kollidon® VA64, hydroxypropyl methylcellulose acetate succinate, and Klucel™ EXF was first evaluated by film casting, and Kollidon® VA64 was selected for further study. SDs containing 5%-20% carvedilol, 0%-20% Acconon® C-50, and the remaining Kollidon® VA64 were prepared for hot melt extrusion. SDs were characterized by differential scanning calorimetry and powder X-ray diffraction analysis, and dissolution tests were conducted in 250 mL of pH 6.8 phosphate buffer by filling powders in capsules. Carvedilol was miscible with all polymers tested up to 50% and remained amorphous in SDs. The drug release from formulations containing 20% carvedilol and 0, 5%, 10%, and 20% Acconon® C-50 were 30%, 30%, 70%, and 90%, respectively, in 60 min. SDs containing carvedilol and Acconon® C-50, up to 20% each, as well as Kollidon® VA64, were physically stable after 3 months of storage at 25°C/60% relative humidity.

Thin polymeric films for the topical delivery of propranolol.

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.

Development of Timolol Maleate Loaded Chitosan Nanoparticles For Improved Ocular Delivery.

BACKGROUND: The poor retention and penetration are the major issues in the bioavailability of drugs through ocular route. Recently, the natural polymers have been exploited for the development of nanoparticles to improve the ocular performance of various drugs. In the present investigation, nanoparticles of timolol maleate (TM) were developed by using chitosan polymer to improve its release through ocular delivery. METHOD: Ionic gelation method was used for the development of timolol loaded chitosan nanoparticles by using a cross linking agent, sodium tripolyphosphate (NaTPP). The Box- Behnken design was used for the optimization of various parameters for the development of nanoparticles. OBJECTIVE: The objective behind the study was to study the effect of three critical parameters; concentration of chitosan (X1), the concentration of NaTPP (X2), and the volume of NaTPP (X3) on the drug release from the prepared nanoparticles. RESULTS: The results obtained showed that high level of the chitosan concentration and low level of the NaTPP concentration and the mid levels of the NaTPP volume resulted in high levels of encapsulation efficiency. The loading capacity was found maximum at a low level of chitosan and mid level of volume of the NaTPP with a low level of NaTPP concentration. The optimized batch (NP-2) showed that the entrapment efficiency was 75.34±0.17%, the particle size of 190.9 nm and in vitro cumulative percentage of drug release was 49.11±0.49% in 12 h. CONCLUSION: The study concluded that chitosan nanoparticles loaded with timolol maleate resulted in improved drug release for ocular treatment.

Propranolol.

Propranolol is a noncardioselective ß-blocker. It is reported to have membrane-stabilizing properties, but it does not own intrinsic sympathomimetic activity. Propranolol hydrochloride is used to control hypertension, pheochromocytoma, myocardial infarction, cardiac arrhythmias, angina pectoris, and hypertrophic cardiomyopathy. It is also used to control symptoms of sympathetic overactivity in the management of hyperthyroidism, anxiety disorders, and tremor. Other indications cover the prophylaxis of migraine and of upper gastrointestinal bleeding in patients with portal hypertension. This study provides a detailed, comprehensive profile of propranolol, including formulas, elemental analysis, and the appearance of the drug. In addition, the synthesis of the drug is described. The chapter covers the physicochemical properties, including X-ray powder diffraction, pK, solubility, melting point, and procedures of analysis (spectroscopic, electrochemical, and chromatographic). In-depth pharmacology is also presented (pharmacological actions, therapeutic dosing, uses, Interactions, and adverse effects and precautions). More than 60 references are given as a proof of the abovementioned studies.

Influence of Peroxide Impurities in Povidone on the Stability of Selected ß-Blockers with the Help of HPLC.

A present study was conducted to investigate compatibility of ß-blocker drugs( like atenolol, labetalol hydrochloride, bisoprolol fumarate, metoprolol succinate, carvedilol and propranolol hydrochloride) with the pharmaceutical excipient povidone. To check the influence of peroxide impurity present in povidone on the stability of ß-blockers, a binary mixture technique has been adopted. The binary mixtures (1:1) of ß-blockers with povidone excipient were stored for the duration of 6 months at accelerated conditions (40°C and 75% RH) and analyzed with the technique of high-performance liquid chromatography (HPLC). On analysis, HPLC results shows that, the percentage of total impurity for atenolol-2.15%, bisoprolol fumarate-3.55%, carvedilol-2.19%, and labetalol hydrochloride-1.89%, with respect to povidone. To verify the interaction of H2O2 present in povidone as an impurity, oxidative degradation of selected active pharmaceutical ingredients were performed and degradation profile were compared with that of degradation impurities generated in drug-excipient mixture at accelerated conditions. The relative retention time (RRT) of impurities generated in accelerated stability study samples resembles the RRT of degradation products generated by oxidative degradation of pure drugs. Thus, it confirms that degradation of ß-blockers with povidone was mediated by organic peroxides present as an impurity in povidone.

Periocular Tissue Concentrations of Propranolol after Ocular Instillation of a Gel-Forming Solution.

BACKGROUND: The aim of this study was to determine the concentrations of propranolol in periocular tissues and plasma after ocular instillation of 0.5% propranolol gel-forming solution (GFS) as compared to 0.5% propranolol non-gelforming solution (non-GFS) for potential use in the treatment of periocular capillary hemangiomas. METHODS: A GFS prepared in 1% sodium alginate or a non-GFS in phosphatebuffered saline was instilled into the eyes of rabbits. At predetermined time intervals after dosing, blood was withdrawn, rabbits were euthanized, and periocular tissues were dissected. RESULTS: Ocular instillation of the GFS resulted in higher concentrations of propranolol in the outer layers of both the upper and lower eyelids (in the range of 9.9-36.9 µg/g) and maintained higher levels of propranolol in these tissues for 24 h after dosing, as compared to the ocular instillation of the non-GFS (in the range of 3.4-15.1 µg/g). While the concentrations of propranolol in the other periocular tissues were generally similar for GFS and non-GFS at 1 h after dosing, the concentrations of propranolol in the extraocular muscles and periocular fat were higher for GFS than those for non-GFS between 4-24 h after dosing. Lower level of propranolol in plasma was observed at 1 h with GFS as compared with non-GFS. CONCLUSION: The use of the propranolol gel-forming solution can prolong drug retention on the ocular surface and increase its distribution to the outer layers of the eyelids while decreasing systemic exposure to the drug.

Y-site Physical Compatibility of Beta-blocker Infusions with Intensive Care Unit Admixtures.

Parenteral beta-blocker therapy via continuous infusion has shown promising results for improved outcomes for patients with septic shock. As patients with septic shock may require multiple intravenous medications, compatibility is necessary to co-infuse these medications through a y-site connector. The purpose of this study was to examine the physical compatibility of select intravenous drugs used for patients with septic shock combined with various intravenous beta-blockers including esmolol, labetalol, and metoprolol through a simulated y-site infusion. The tested drugs included albumin, levothyroxine, acetaminophen, esomeprazole, doripenem, epinephrine, ibuprofen, norepinephrine, levofloxacin, cefepime, ciprofloxacin, meropenem, cisatracurium, and hydrocortisone. Equal volumes of normal saline, esmolol, labetalol, and metoprolol were combined with each test drug at maximum or commercially available concentrations as appropriate used clinically in intensive care units.The samples were examined visually against a white and black background andalso using turbidimetric measurements to determine physical compatibility.Beginning immediately after mixing, observations and analyses were taken over a one-hour period at 15-minute intervals. Each test was performed in triplicate. Many of the test drugs demonstrated visual and/or turbidimetric physical compatibility when combined with esmolol, labetalol, or metoprolol during a simulated y-site infusion. Albumin, cefepime, and hydrocortisone demonstrated physical incompatibility when combined with labetalol and should not be co-infused with labetalol. Esomeprazole and ibuprofen demonstrated physical incompatibility when combined with esmolol and labetalol and should not be co-infused with either beta-blocker. Esmolol and ciprofloxacin mixtures exhibited a statistically significant difference from control solutions and should not be co-infused.