Electrocardiography of Atrioventricular Block.

Delayed atrioventricular (AV) conduction most commonly occurs in the AV node, resulting from AH prolongation on an intracardiac electrocardiogram and PR prolongation on a surface electrocardiogram. AV conduction may be blocked in a 2:1 manner, with a normal PR interval and wide QRS suggesting infranodal disease, whereas a prolonged PR interval and narrow QRS are more suggestive of AV nodal disease. Block within the His is suspected when there is 2:1 AV block with normal PR and QRS intervals. Complete heart block occurs when the atrial rhythm is totally independent of a junctional or lower escape rhythm.

Design and Preclinical Evaluation of Nicotine-Stearic Acid Conjugate-Loaded Solid Lipid Nanoparticles for Transdermal Delivery: A Technical Note.

This study aimed to develop and evaluate nicotine--stearic acid conjugate-loaded solid lipid nanoparticles (NSA-SLNs) for transdermal delivery in nicotine replacement therapy (NRT). Nicotine conjugation to stearic acid prior to SLN formulation greatly increased drug loading. SLNs loaded with a nicotine-stearic acid conjugate were characterized for size, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency, and morphology. Pilot in vivo testing was carried out in New Zealand Albino rabbits. The size, PDI, and ZP of nicotine-stearic acid conjugate-loaded SLNs were 113.5 ± 0.91 nm, 0.211 ± 0.01, and -48.1 ± 5.75 mV, respectively. The entrapment efficiency of nicotine-stearic acid conjugate in SLNs was 46.45 ± 1.53%. TEM images revealed that optimized nicotine-stearic acid conjugate-loaded SLNs were uniform and roughly spherical in shape. Nicotine-stearic acid conjugate-loaded SLNs showed enhanced and sustained drug levels for up to 96 h in rabbits when compared with the control nicotine formulation in 2% HPMC gel. To conclude, the reported NSA-SLNs could be further explored as an alternative for treating smoking cessation.

Ripple mapping in ventricular tachycardia substrate mapping and ablation of nonischemic ventricular tachycardia.

INTRODUCTION: Substrate-based ablation for ventricular tachycardia (VT) using Ripple map (RM) is an effective treatment strategy for patients with ischemic cardiomyopathy but has yet to be evaluated in patients with nonischemic cardiomyopathy (NICMO). The aim of this study is to determine the feasibility and effectiveness of an RM-based ablation for NICMO patients. METHODS AND RESULTS: This was a single-center, retrospective study including all NICMO patients undergoing VT ablation at St Vincent Hospital between January 1, 2018 and January 12, 2019. Retrospective RM analysis was performed on those that had a substrate-based ablation to identify the location and number of Ripple channels as well as their proximity to ablation lesions. Thirty-three patients met the inclusion criteria and had a median age of 65 (58, 73.5) with 15.2% of the population being female, and were followed for a median duration of 451 (217.5, 586.5) days. Of these patients, 23 (69.7%) had a substrate-based ablation with a median procedural duration of 196.4 (186.8, 339) min, 1946 (517, 2750) points collected per map, and 277 (141, 554) points were within the scar. Two (8.6%) procedural complications occurred, and 7 (30.4%) patients had VT recurrence during follow-up. RM analysis revealed an average of two Ripple channels and the patients without VT recurrence had ablation performed closer to the Ripple channels: 0 (0, 4.7) versus 14.3 (0, 23.5) cm; p = .02. CONCLUSION: An RM-based substrate ablation can be performed in NICMO patients and ablation within Ripple channels is a predictor of VT freedom.

Advances in in-vitro bioequivalence testing methods for complex ophthalmic generic products.

The United States Food and Drug Administration (USFDA) demands that the generic industry prove topical ocular products' pharmaceutical and bioequivalence (BE). In contrast to generic oral drugs, topical ocular product BE testing has proved difficult. New generic versions are compared to an authorized drug product known as a Reference Listed Drug (RLD) to demonstrate their bioequivalence. If the excellent in-vitro results may support the presumption of equivalence in-vivo performance and the only clinically significant difference between the generic and RLD is in its physicochemical qualities and drug release rate, then in-vivo BE studies may be waived. Proving BE through dissolution tests is a golden standard for most conventional dosage forms. However, due to the limited number of biorelevant in-vitro drug release testing (IVRT) approaches capable of differentiating their performance based on product quality and physicochemical properties, the development of generic ophthalmic products has been slow and time-consuming. Often, BE of topical ophthalmic formulations cannot be proved using a single in-vitro test; therefore, an elaborated discussion on various IVRT methods performed to demonstrate bioequivalence of complex generis like ophthalmic emulsions, suspensions, ointments, and gels is necessary. This manuscript aims to review the status of biowaiver criteria for complex ophthalmic products concerning the product-specific FDA guidance to the generic industry.

Electrocardiography of Atrioventricular Block.

Delayed atrioventricular (AV) conduction most commonly occurs in the AV node, resulting from AH prolongation on an intracardiac electrocardiogram and PR prolongation on a surface electrocardiogram. AV conduction may be blocked in a 2:1 manner, with a normal PR interval and wide QRS suggesting infranodal disease, whereas a prolonged PR interval and narrow QRS are more suggestive of AV nodal disease. Block within the His is suspected when there is 2:1 AV block with normal PR and QRS intervals. Complete heart block occurs when the atrial rhythm is totally independent of a junctional or lower escape rhythm.

Selection of Cryoprotectant in Lyophilization of Progesterone-Loaded Stearic Acid Solid Lipid Nanoparticles.

Cryoprotectants are often required in lyophilization to reduce or eliminate agglomeration of solute or suspended materials. The aim of this study was to select a cryoprotecting agent and optimize its concentration in a solid lipid nanoparticle formulation. Progesterone-loaded stearic acid solid lipid nanoparticles (SA-P SLNs) were prepared by hot homogenization with high speed mixing and sonication. The stearic acid content was 4.6% w/w and progesterone was 0.46% w/w of the initial formulation. Multiple surfactants were evaluated, and a lecithin and sodium taurocholate system was chosen. Three concentrations of surfactant were then evaluated, and a concentration of 2% w/w was chosen based on particle size, polydispersity, and zeta potential. Agglomeration of SA-P SLNs after lyophilization was observed as measured by increased particle size. Dextran, glycine, mannitol, polyvinylpyrrolidone (PVP), sorbitol, and trehalose were evaluated as cryoprotectants by both an initial freeze-thaw analysis and after lyophilization. Once selected as the cryoprotectant, trehalose was evaluated at 5%, 10%, 15%, and 20% for optimal concentration, with 20% trehalose being finally selected as the level of choice. Evaluation by DSC confirmed intimate interaction between stearic acid and progesterone in the SA-P SLNs, and polarized light microscopy shows successful lyophilization of the trehalose/SA-P SLN. A short term 28-day stability study suggests the need for refrigeration of the final lyophilized SA-P SLNs in moisture vapor impermeable packaging.

Lutein-Loaded, Biotin-Decorated Polymeric Nanoparticles Enhance Lutein Uptake in Retinal Cells.

Age related macular degeneration (AMD) is one of the leading causes of visual loss and is responsible for approximately 9% of global blindness. It is a progressive eye disorder seen in elderly people (>65 years) mainly affecting the macula. Lutein, a carotenoid, is an antioxidant, and has shown neuroprotective properties in the retina. However, lutein has poor bioavailability owing to poor aqueous solubility. Drug delivery to the posterior segment of the eye is challenging due to the blood-retina barrier. Retinal pigment epithelium (RPE) expresses the sodium-dependent multivitamin transporter (SMVT) transport system which selectively uptakes biotin by active transport. In this study, we aimed to enhance lutein uptake into retinal cells using PLGA-PEG-biotin nanoparticles. Lutein loaded polymeric nanoparticles were prepared using O/W solvent-evaporation method. Particle size and zeta potential (ZP) were determined using Malvern Zetasizer. Other characterizations included differential scanning calorimetry, FTIR, and in-vitro release studies. In-vitro uptake and cytotoxicity studies were conducted in ARPE-19 cells using flow cytometry and confocal microscopy. Lutein was successfully encapsulated into PLGA and PLGA-PEG-biotin nanoparticles (<250 nm) with uniform size distribution and high ZP. The entrapment efficiency of lutein was ≈56% and ≈75% for lutein-loaded PLGA and PLGA-PEG-biotin nanoparticles, respectively. FTIR and DSC confirmed encapsulation of lutein into nanoparticles. Cellular uptake studies in ARPE-19 cells confirmed a higher uptake of lutein with PLGA-PEG-biotin nanoparticles compared to PLGA nanoparticles and lutein alone. In vitro cytotoxicity results confirmed that the nanoparticles were safe, effective, and non-toxic. Findings from this study suggest that lutein-loaded PLGA-PEG-biotin nanoparticles can be potentially used for treatment of AMD for higher lutein uptake.

Evaluation of Formulation Parameters on Permeation of Ibuprofen from Topical Formulations Using Strat-M® Membrane.

Topical drug delivery is an attractive alternative to conventional methods because of advantages such as non-invasive delivery, by-pass of first pass metabolism, and improved patient compliance. However, several factors such as skin, physicochemical properties of the drug, and vehicle characteristics influence the permeation. Within a formulation, critical factors such as concentration of drug, physical state of drug in the formulation, and organoleptic properties affect the flux across the skin. The aim of the study was to develop and investigate topical semisolid preparations (creams and gels) with ibuprofen as the model drug and investigate the effect of various formulation parameters on the in-vitro performance across the Strat-M® membrane using flow-through cells. In addition, the physical stability of the developed formulations was investigated by studying viscosity, pH, and appearance. All the formulations developed in the study had appealing appearance with smooth texture and no signs of separation. Viscosity and pH of the formulations were acceptable. Cumulative amount of drug permeated at the end of 24 h was highest for clear gel (3% w/w ibuprofen; F6: 739.6 ± 36.1 µg/cm2) followed by cream with high concentration of ibuprofen in suspended form (5% w/w; F3: 320.8 ± 17.53 µg/cm2), emulgel (3% w/w ibuprofen; F5: 178.5 ± 34.5 µg/cm2), and cream with solubilized ibuprofen (3% w/w; F2A: 163.2 ± 9.36 µg/cm2). Results from this study showed that permeation of ibuprofen was significantly influenced by formulation parameters such as concentration of ibuprofen (3% vs. 5% w/w), physical state of ibuprofen (solubilized vs. suspended), formulation type (cream vs. gel), mucoadhesive agents, and viscosity (high vs. low). Thus, findings from this study indicate that pharmaceutical formulation scientists should explore these critical factors during the early development of any new topical drug product in order to meet pre-determined quality target product profile.

Effect of diet-induced obesity and metabolic syndrome on skeletal muscles of Ossabaw miniature swine.

Ossabaw swine fed excess kilocalorie diet develop metabolic syndrome (MS) characterized by obesity, hypertension, insulin resistance, and glucose intolerance with/without dyslipidemia. The purpose of this study was to test the hypothesis that MS would have a detrimental effect on skeletal muscle structure and cause changes in the expression of myosin heavy chains (MHCs). Adult male Ossabaw swine were fed for 24 wk high-fructose or high-fat/cholesterol/fructose diets to induce normolipidemic MS (MetS) or dyslipidemic MS (DMetS), respectively, and were compared with the lean swine on control diet. MetS swine showed mild MS, lacking increases in total and low density lipoprotein (LDL) cholesterol, both of which were highly upregulated in DMetS swine. There was an ∼1.2-fold increase in the cross-sectional areas of muscle fibers in MetS and DMetS groups compared with control for biceps femoris and plantaris muscles. In plantaris muscles, DMetS diet caused an ∼2-fold decrease in slow MHC mRNA and protein expression and an ∼1.2- to 1.8-fold increase in the number of intramyocellular lipid (IMCL) droplets without large changes in the size of the droplets. There was a trend to the decrease in slow MHC expression in muscles of swine on MetS diet. The number of IMCL droplets in muscle fibers of the MetS group was comparable to controls. These data correlate well with the data on total plasma cholesterol (control = 60, MetS = 70, and DMetS = 298 mg/dl) and LDL (control = 29, MetS = 30, and DMetS = 232 mg/dl). We conclude that structural changes observed in skeletal muscle of obese Ossabaw swine correlate with those previously reported for obese humans.