P-gp inhibition and enhanced oral bioavailability of amikacin Sulfate: A novel approach using Thiolated Chito-PEGylated Lipidic Hybrids.

This study aimed to develop oral lipidic hybrids of amikacin sulfate (AMK), incorporating thiolated chitosan as a P-glycoprotein (P-gp) inhibitor to enhance intestinal absorptivity and bioavailability. Three formulations were designed: PEGylated Liposomes, Chitosan-functionalized PEGylated (Chito-PEGylated) Lipidic Hybrids, and Thiolated Chito-PEGylated Lipidic Hybrids. The physical characteristics of nanovesicles were assessed. Ex-vivo permeation and confocal laser scanning microscopy (CLSM) studies were conducted to evaluate the formulations' potential to enhance AMK intestinal permeability. In-vivo pharmacokinetic studies in rats and histological/biochemical investigations assessed the safety profile and oral bioavailability. The AMK-loaded Thiolated Chito-PEGylated Lipidic Hybrids exhibited favorable physical characteristics, higher ex-vivo permeation parameters, and verified P-gp inhibition via CLSM. They demonstrated heightened oral bioavailability (68.62% absolute bioavailability) and a sufficient safety profile. Relative bioavailability was significantly higher (1556.3% and 448.79%) compared to PEGylated Liposomes and Chito-PEGylated Lipidic Hybrids, respectively, indicating remarkable oral AMK delivery with fewer doses, reduced side effects, and enhanced patient compliance.

Correction: Jamal et al. Preparation of 6-Mercaptopurine Loaded Liposomal Formulation for Enhanced Cytotoxic Response in Cancer Cells. Nanomaterials 2022, 12, 4029.

In the original publication [...].

Enhancing the Antiproliferative Activity of Perillyl Alcohol against Glioblastoma Cell Lines through Synergistic Formulation with Natural Oils.

BACKGROUND: Due to its volatility, photostability, and gastrointestinal toxicity, Perillyl Alcohol (POH), a monoterpenoid component of various plant species, is a chemotherapeutic drug with insufficient efficacy. Many naturally occurring bioactive compounds have well-known antiproliferative properties, including sefsol, jojoba, tea tree, and moringa oils. OBJECTIVE: This study sought to develop an oil-based Self Nanoemulsifying Drug Delivery System (SNEDDS) using tween 80 as the surfactant and Dimethyl Sulfoxide (DMSO) or Polyethylene Glycol (PEG) 400 as the cosurfactant; the oils were used in a range of 10-20% to boost POH's anticancer efficacy. METHODS: The formulations' size, charge, and impact on the viability of glioma cell lines, ANGM-CSS and A172, were evaluated. RESULTS: The developed SNEDDS formulations ranged from 3 nm to 362 nm in size, with electronegative surface charges between 5.05 and 17.0 mV and polydispersity indices between 0.3 and 1.0. CONCLUSION: The findings indicated that the antiproliferative effect of POH-loaded Nanoemulsion (NE) could be used as a possible anticancer therapy for glioblastoma in vitro, particularly when paired with the tested natural oils. Before asserting that this delivery technique is appropriate for glioblastoma therapy, additional in vitro and in vivo investigations are required.

Impact of residual coronary lesions on outcomes of myocardial infarction patients with multi-vessel disease.

BACKGROUND: The residual burden of coronary artery disease (CAD) after percutaneous coronary intervention (PCI) drew a growing interest. The residual SYNTAX Score (rSS) was a strong prognostic factor of adverse events and all-cause mortality in patients who underwent PCI. In addition, the SYNTAX Revascularization Index (SRI), a derivative of rSS, was used to figure out the treated proportion of CAD and could be used as a prognostic utility in PCI for patients with multi-vessel disease (MVD). PURPOSE: We aimed at the assessment of the use of rSS and the SRI as predictors of in-hospital outcomes and up to two-year cumulative follow-up outcomes in patients with MVD who had PCI for the treatment of ST-Elevation Myocardial Infarction (STEMI) or Non-STEMI (NSTEMI). METHODS: We recruited 149 patients who had either STEMI or NSTEMI while having MVD and received treatment with PCI. We divided them into tertiles based on their rSS and SRI values. We calculated baseline SYNTAX Score (bSS) and rSS using the latest version of the calculator on the internet, and we used both scores to calculate SRI. The study end-points were In-hospital composite Major Adverse Cardiovascular Events (MACE) and its components, in-hospital death, and follow-up cumulative MACE up to 2 years. RESULTS: Neither rSS nor SRI were significant predictors of in-hospital adverse events, while female sex, hypertension, and left ventricular ejection fraction were independent predictors of in-hospital MACE. At the two-year follow-up, Kaplan-Meyer analysis showed a significantly increased incidence of MACE within the third rSS tertile (rSS > 12) compared to other tertiles (log rank p = 0.03). At the same time, there was no significant difference between the three SRI tertiles. Unlike SRI, rSS was a significant predictor of cumulative MACE on univariate Cox regression (HR = 1.037, p < 0.001). On multivariate Cox regression, rSS was a significant independent predictor of two-year cumulative MACE (HR = 1.038, p = 0.0025) along with female sex, hypertension, and left ventricular ejection fraction. We also noted that all patients with complete revascularization survived well throughout the entire follow-up period. CONCLUSIONS: Neither rSS nor SRI could be good predictors of in-hospital MACE, while the rSS was a good predictor of MACE at two-year follow-up. Patients with rSS values > 12 had a significantly higher incidence of cumulative MACE after 2 years. The best prognosis was achieved with complete revascularization.

Design, Synthesis, and Antisickling Investigation of a Thiazolidine Prodrug of TD-7 That Prolongs the Duration of Action of Antisickling Aromatic Aldehyde.

The synthetic allosteric effector of hemoglobin, TD-7 has been investigated as a potential therapeutic agent for the treatment of sickle cell disease. The pharmacologic activity of TD-7 is due to formation of a Schiff-base interaction between its aldehyde group and the two N-terminal αVal1 amines of hemoglobin, effectively inhibiting sickling of red blood cells. However, TD-7 faces a challenge in terms of poor oral bioavailability due to rapid in-vivo oxidative metabolism of its aldehyde functional group. To address this shortcoming, researches have explored the use of a L-cysteine ethyl ester group to cap the aldehyde group to form a thiazolidine aromatic aldehyde prodrug complex, resulting in the improvement of the metabolic stability of this class of compounds. This report details the synthesis of a thiazolidine prodrug of TD-7, referred to as Pro-7, along with a comprehensive investigation of Pro-7 functional and biological properties. In an in-vitro Hb modification and Hb oxygen affinity studies using normal whole blood, as well as erythrocyte sickling inhibition using sickle whole blood, Pro-7 exhibited a gradual onset but progressive increase in all activities. Additionally, in-vivo pharmacokinetic studies conducted with Sprague Dawley rats demonstrated that Pro-7 can undergo hydrolysis to release TD-7. However, the blood concentration of TD-7 did not reach the desired therapeutic level. These findings suggest that the incorporation of the L-cysteine ethyl ester group to TD-7 represents a promising strategy to enhance the metabolic stability of aromatic aldehydes that could lead to the development of a more effective drug for the treatment of sickle cell disease.

Enhancing Ezetimibe Anticancer Activity Through Development of Drug Nano-Micelles Formulations: A Promising Strategy Supported by Molecular Docking.

Background: Ezetimibe, initially recognized as a cholesterol-lowering agent, has recently attracted attention due to its potential anticancer properties. We aimed to explore an innovative approach of enhancing the drug anticancer activity through the development of drug nano-formulations. Materials and Methods: Fifteen different nano-micelles formulations were prepared utilizing D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and pluronic F127. The prepared formulations were characterized for size, polydispersity index (PDI), zeta potential, and entrapment efficiency (EE). The formulations were morphologically characterized using light and transmission electron microscopies and the drug-binding mode with the active site was investigated using the molecular docking. Cell viability against MCF-7 and T47D was studied. Apoptosis and cell cycle were assessed. Results: The prepared formulations were in the nano-size range (34.01 ± 2.00-278.34 ± 9.11 nm), zeta potential values were very close to zero, and the TPGS-based micelles formulations showed the highest ezetimibe EE (94.03 ± 1.71%). Morphological study illustrated a well-defined, spherical nanoparticles with a uniform size distribution. Molecular docking demonstrated good interaction of ezetimibe with Interleukin-1 Beta Convertase through multiple hydrogen bonding, covalent bond, and hydrophobic interaction. TPGS-based nano-micelle formulation (F5) demonstrated the lowest IC50 against MCF-7 (4.51 µg/mL) and T47D (8.22 µg/mL) cancer cells. When T47D cells were treated with IC50 concentrations of F5, it exhibited significant inhibition with late apoptosis (43.9%), a response comparable to T47D cells treated with an IC50 dose of ezetimibe. Cell cycle analysis revealed that both ezetimibe and F5-treated T47D cells exhibited an increase in the subG1 phase, indicating reduced DNA content and cell death. Conclusion: These findings suggest that F5 could serve as a proficient drug delivery system in augmenting the cytotoxic activity of ezetimibe against breast cancer.

Incorporation of Perillyl Alcohol into Lipid-Based Nanocarriers Enhances the Antiproliferative Activity in Malignant Glioma Cells.

Perillyl alcohol (PA), a naturally existing monocyclic terpene related to limonene, is characterized by its poor aqueous solubility and very limited bioavailability. Its potential anti-cancer activity against malignant glioma has been reported. The aim was to develop PA-loaded lipid-based nanocarriers (LNCs), and to investigate their anti-cancer activity against two different brain cell lines. Non-medicated and PA-loaded LNCs were prepared and characterized. The mechanism of cytotoxic activity of PA was conducted using a molecular docking technique. The cell viabilities against A172 and ANGM-CSS cells were evaluated. The results revealed that the average particle size of the prepared LNCs ranged from 248.67 ± 12.42 to 1124.21 ± 12.77 nm, the polydispersity index was 0.418 ± 0.043-0.509 ± 0.064, while the zeta potential ranged from -36.91 ± 1.31 to -15.20 ± 0.96 mV. The molecular docking studies demonstrated that the drug had binding activity to human farnesyltransferase. Following exposure of the two glioblastoma cell lines to the PA-loaded nanoformulations, MTS assays were carried out, and the data showed a far lower half-maximal inhibitory concentration in both cell lines when compared to pure drug and non-medicated nanocarriers. These results indicate the potential in vitro antiproliferative activity of PA-loaded LNCs. Therefore, the prepared PA-loaded nanocarriers could be used to enhance drug delivery across the blood-brain barrier (BBB) in order to treat brain cancer, especially when formulated in a suitable dosage form. The size, surface charge, and lipid composition of the LNCs make them promising for drug delivery across the BBB. Detailed pharmacokinetic and pharmacodynamic assessments, including the evaluation of BBB penetration, are necessary to better understand the compound's distribution and effects within the brain.

Exploring the Enhanced Antiproliferative Activity of Turmeric Oil and 6-Mercaptopurine in a Combined Nano-Particulate System Formulation.

6-Mercaptopurine (6-MP) is a chemotherapeutic agent with inadequate efficacy due to its poor aqueous solubility and limited bioavailability. Turmeric oil is a naturally occurring bioactive substance obtained from the rhizomes of Curcuma longa Linn that has well-known antiproliferative activities. The aim of this study was to develop a 6-MP-loaded turmeric oil-based self-nanoemulsifying drug delivery system (SNEDDS) to improve the anticancer activity of 6-MP. Turmeric oil was extracted and used in a range of 15-25% to develop SNEDDS formulations utilizing tween 80 and dimethyl sulfoxide as the surfactant and cosurfactant, respectively. The size, charge, and effect of the formulations on the viability against HepG2 and MCF-7 cell models, as well as the apoptosis and cell cycle, were analyzed. The prepared SNEDDS formulations were in the size range of 425.7 ± 7.4-303.6 ± 19.3 nm, using a polydispersity index of 0.429-0.692 and electronegative surface charges. Moreover, 6-MP-loaded SNEDDS with 15% turmeric oil content (F1) showed smaller particle sizes and a noticeable antiproliferative activity against both cell line models. Also, F1 showed a higher rate of late apoptosis than the pure drug and the corresponding non-medicated formulation. A morphological study revealed significant changes in the HepG2 cells compared to untreated cells. More cells halted in the S phase, and a marked decrease in the proportions of cells in the G1/G0 phase was observed when using SNEDDS formulation compared to pure drug. Thus, SNEDDS formulation is a promising drug delivery system for improving the antiproliferative activity of 6-MP, especially when turmeric oil is incorporated.

Incorporating valsartan in sesame oil enriched self-nanoemulsifying system-loaded liquisolid tablets to improve its bioavailability.

Valsartan (VST) is a poorly soluble antihypertensive drug characterized by its limited dissolution rate and low bioavailability. This study aims to improve VST solubility and dissolution rate via developing liquisolid tablets (LSTs) containing a self-nanoemulsifying drug delivery system (SNEDDS), which is expected to enhance VST bioavailability. This aim was achieved via two designs of experiment. The first was the simplex-lattice design to optimize VST-loaded-SNEDDS using sesame oil, Tween 80, and polyethylene glycol 400. The second was the 32-3-level factorial design to optimize the liquisolid system using the SNEDDS-loaded VST and Neusilin®US2 as a carrier and fumed silica as a coating material. Different excipient ratios (X1) and varioussuper-disintegrants (X2) were also used in developing the optimized VST-LSTs. Thein vitrodissolution of VST from LSTs was compared with the marketed product (Diovan®). Non-compartmental analysis of plasma data after extravascular input with the linear trapezoidal method was used to calculate thepharmacokinetic parameters of the optimized VST-LSTs compared with the marketed tablet in male Wistar rats. The optimized SNEDDS compromised 24.9% sesame oil, 33.3% surfactant, and 41.8% cosurfactant, giving 173.9 nm size and 63.9 mg/ml loading capacity. Also, the SNEDDS-loaded VST tablet revealed good quality attributes with the release of 75% of its content in 5 min and 100% within 15 min. On the other hand, the marketed product took 1 h for the entire drug to be released.Moreover, the maximum plasma concentration (Cmax) of the optimizedVST-LSTwas6585.33 ng/ml within 1 h (Tmax), compared to 2884.67 ng/ml within 2 h of the marketed tablet.The relative bioavailability of the SNEDDS-loaded VST tablet was 213.7% compared to that of the marketed tablet, indicating that this formulation approach could be applied for increasing solubility, dissolution behavior in GIT, and bioavailability of poorly water-soluble drugs.

Incorporating sodium deoxycholate endorsed the buccal administration of avanafil to heighten the bioavailability and duration of action.

The highly effective phosphodiesterase type 5 inhibitor (avanafil; AVA) is routinely prescribed to treat erectile dysfunction. The drug has poor oral bioavailability and undergoes a significant first-pass metabolism. Therefore, altering AVA's solubility and choosing a different delivery method may boost its effectiveness. Nine different solid dispersion formulations utilizing polyvinylpyrrolidone (PVP) at three different ratios were prepared and characterized. The Box-Behnken design was employed to optimize AVA-buccal tablets. The pre-compression and post-compression characteristics of the tablets were assessed. The mucoadhesion strength of the optimized tablet was investigated using cow buccal mucosal tissue. In vivo performance of the optimized tablets was examined on human volunteers compared to the commercial tablets. PVP K90 at 2:1 drug to polymer ratio showed the highest solubilization capacity. The mucoadhesive polymer type and percentage and the mucopenetration enhancer percentage were significantly affect the mucoadhesion strength, tablet hardness, and the initial and cumulative AVA released from the prepared tablets. The optimized AVA-buccal tablet showed 4.96 folds increase in the mean residence time, higher plasma exposure, and an improvement in the relative bioavailability of AVA by 1076.27% compared with the commercial tablet. Therefore, a successful approach to deal with AVA first-pass metabolism and low bioavailability could be to employ buccal tablets containing a solubility-enhanced form of AVA.

Three-dimensional echocardiographic assessment of left ventricular geometric changes following acute myocardial infarction.

Acute ST-segment elevation myocardial infarction (STEMI) is associated with left ventricular (LV) structural and functional consequences. We aimed to elucidate LV geometric changes following STEMI using three-dimensional (3D) echocardiography (3DE) and to assess their functional implications using two-dimensional (2D) speckle tracking echocardiography (STE). The study included 71 patients with STEMI who underwent baseline and 6-month follow-up 2D- and 3DE. Measured parameters included LV dimensions, biplane volumes, wall motion assessment, 2D LV global longitudinal strain (GLS), and 3D LV volumes, sphericity index and systolic dyssynchrony index. According to 3DE, LV geometric changes were classified as, adverse remodeling, reverse remodeling, and minimal LV volumetric changes. The occurrence of in-hospital and follow-up major adverse cardiovascular events (MACE) was assessed among the study population. The incidence of developing adverse remodeling was 25.4% while that of reverse remodeling was 36.6%. Adverse remodeling patients had significantly higher in-hospital MACE. Reverse remodeling was associated with significantly improved GLS, that was less evident in those with minimal LV geometric changes, and non-significant improvement for adverse remodeling group. LV baseline 2D GLS significantly correlated with follow-up 3D volumes among both reverse and adverse remodeling groups. Female gender and higher absolute GLS change upon follow-up were significantly associated with reverse remodeling. ROC-derived cutoff for adverse remodeling reallocated a substantial number of patients from the minimal change group to the adverse remodeling. Following acute STEMI, two-dimensional GLS was associated with and potentially predictive of changes in LV volumes as detected by three-dimensional echocardiography.

Influences of Glimepiride Self-Nanoemulsifying Drug Delivery System Loaded Liquisolid Tablets on the Hypoglycemic Activity and Pancreatic Histopathological Changes in Streptozotocin-Induced Hyperglycemic Rats.

The development of an oral anti-diabetic medication characterized by enhanced hypoglycemic activity is in high demand. The goal was to study the hypoglycemic activity and pancreatic histopathology after the black-seed-based self-nanoemulsifying drug delivery system (SNEDDS) loaded with glimepiride liquisolid tablets to diabetic rats. The solubility of glimepiride in various vehicles was investigated. An optimization SNEDDS formulation was developed using a mixture of the experimental design approach. Box-Behnken design (BBD) was used to develop glimepiride liquisolid tablets utilizing Avicel PH 101 and Neusilin as a carrier mixture and FujiSil as a coating material. The quality attributes of the prepared tablets were assessed. Following the administration of the optimized tablets to diabetic rats, the pharmacodynamics and histopathological changes were investigated and compared to a commercial drug product. Results revealed that the optimized SNEDDS formulation that contains 15.43% w/w black seed oil, 40% w/w Tween 80, and 44.57% w/w Polyethylene glycol 400 showed an average droplet size of 34.64 ± 2.01 nm and a drug load of 36.67 ± 3.13 mg/mL. The optimized tablet formulation contained 0.31% Avicel in the carrier mixture, a 14.99 excipient ratio, and 8% superdisintegrant. Pre- and post-compression properties were satisfactory, and the optimized glimepiride liquisolid tablet showed a two-fold increase in dissolution. The optimized tablet demonstrated superior pharmacodynamics. The pancreatic tissues of the group treated with the optimized tablet displayed normal histological structure. The obtained data offered a commercially viable alternative for manufacturing solid dosage forms containing water-insoluble drugs, but additional clinical research is required.

Preparation of 6-Mercaptopurine Loaded Liposomal Formulation for Enhanced Cytotoxic Response in Cancer Cells.

6-Mercaptopurine (6-MP) is a well-known immunosuppressive medication with proven anti-proliferative activities. 6-MP possesses incomplete and highly variable oral absorption due to its poor water solubility, which might reduce its anti-cancer properties. To overcome these negative effects, we developed neutral and positively charged drug-loaded liposomal formulations utilizing the thin-film hydration technique. The prepared liposomal formulations were characterized for their size, polydispersity index (PDI), zeta potential, and entrapment efficiency. The average size of the prepared liposomes was between 574.67 ± 37.29 and 660.47 ± 44.32 nm. Positively charged liposomes (F1 and F3) exhibited a lower PDI than the corresponding neutrally charged ones (F2 and F4). Entrapment efficiency was higher in the neutral liposomes when compared to the charged formulation. F1 showed the lowest IC50 against HepG2, HCT116, and MCF-7 cancer cells. HepG2 cells treated with F1 showed the highest level of inhibition of cell proliferation with no evidence of apoptosis. Cell cycle analysis showed an increase in the G1/G0 and S phases, along with a decrease in the G2/M phases in the cell lines treated with drug loaded positively charged liposomes when compared to free positive liposomes, indicating arrest of cells in the S phase due to the stoppage of priming and DNA synthesis outside the mitotic phase. As a result, liposomes could be considered as an effective drug delivery system for treatment of a variety of cancers; they provide a chance that a nanoformulation of 6-MP will boost the cytotoxicity of the drug in a small pharmacological dose which provides a dosage advantage.

Prevention of radial artery occlusion by simultaneous ulnar and radial compression (PRO-SURC). A randomized duplex ultrasound follow-up study.

BACKGROUND: There might be a beneficial effect of transient ulnar artery compression in prevention of radial artery occlusion (RAO) after trans-radial catheterization. OBJECTIVE: The objective of this study was to assess, by Duplex ultrasound, the efficacy of simultaneous ulnar and radial artery compression (SURC), in prevention of RAO, compared to conventional and patent hemostasis techniques. PATIENTS AND METHODS: Four hundred and fifty consecutive patients undergoing elective trans-radial catheterization were enrolled. Patients were randomized in 1:1:1 fashion into 3 groups; conventional hemostasis (Group A, n = 150 patients), patent hemostasis (Group B, n = 150 patients), and SURC technique (Group C, n = 150 patients). RAO was assessed by duplex ultrasound at 1-h post TR band removal (primary endpoint), and at 1-month. RESULTS: The primary endpoint, RAO 1-h post TR-band removal, was significantly lower among patients of group C as compared to those of group A and B (1.3%, 6.7%, and 7.3%, respectively -p = 0.03). This was still consistent at 1-month (0.7%, 8%, and 6%, respectively -p = 0.03). Multiple regression analyses revealed that lower radial artery diameter (RAD) after flow-mediated dilatation (FMD) independently predicted RAO at 1-h, while RAD at 1-h post-TR band removal was the only independent predictor of RAO at 1-month. Receiver operator characteristic (ROC) analysis showed that RAD at 1-h post-TR band removal at cut-off ≤1.75 mm could predict RAO at 1-month with high accuracy (AUC = 0.9, CI = 0.8-1.0, p < 0.001-86% sensitivity, and 95% specificity). CONCLUSION: A technique of SURC is associated with less incidence of early and late RAO compared to conventional hemostasis techniques.

Pairing 3D-Printing with Nanotechnology to Manage Metabolic Syndrome.

Introduction: This work was aimed to develop a Curcuma oil-based self-nanoemulsifying drug delivery system (SNEDDS) 3D-printed polypills containing glimepiride (GMD) and rosuvastatin (RSV) for treatment of dyslipidemia in patients with diabetes as a model for metabolic syndrome (MS). Methods: Compartmentalized 3D printed polypills were prepared and studied in streptozotocin/poloxamer induced diabetic/dyslipidemic rats. The pharmacokinetic parameters of GMD and RSV in the prepared polypills were evaluated. Blood glucose level, lipid profile, antioxidant, and biochemical markers activities were investigated. Also, histopathological examination of the liver and pancreas was carried out. The atherosclerotic index, the area of islets of Langerhans, and liver steatosis lesion scores were calculated. Results: The developed SNEDDS-loaded GMD/RSV polypills showed acceptable quality control characteristics with a high relative bioavailability of 217.16% and 224.28% for GMD and RSV, respectively, when compared with the corresponding non-SNEDDS pills. The prepared polypills showed dramatic lowering in blood glucose levels and substantial improvement in lipid profile and hepatic serum biomarkers as well as remarkable decrease in serum antioxidants in response to Poloxamer 407 intoxication. The prepared polypills decreased the risk of atherosclerosis and coronary disease by boosting the level of high-density lipoprotein and lowering both triglyceride and low-density lipoprotein. Microscopic examination showed normal hepatic sinusoids and high protection level with less detectable steatosis in the examined hepatocytes. Normal size pancreatic islets with apparently normal exocrine acini and pancreatic duct were also noticed. Conclusion: This formulation strategy clearly shows the potential of the developed polypills in personalized medicine for treatment of patients with MS.

The role of preoperative venography in predicting the difficulty of a transvenous lead extraction procedure.

INTRODUCTION: We hypothesized that an accurate assessment of preoperative venography could be useful in predicting transvenous lead extraction (TLE) difficulty. METHODS AND RESULTS: A dedicated preoperative venogram was performed in consecutive patients with cardiac implantable electronic device who underwent TLE. The level of stenosis was classified as without significant stenosis, moderate, severe, and occlusion. The presence of extensive lead-venous wall adherence (≥50 mm) was also assessed. A total of 105 patients (median age: 71 years; 72% male) with a median of 2 (1-2) leads to extract were enrolled. Preoperative venography showed moderate to severe stenosis in 31 (30%), complete occlusion in 15 (14%), and extensive lead-venous wall adherence in 50 (48%) patients. Complete TLE success was achieved in 103 (98%) patients. A total of 55 (52%) were advanced extractions as they required a powered mechanical and/or laser sheath. They were more prevalent in the group with extensive lead-venous wall adherence (72% vs. 34%, p < .001), while no differences were found between patients with and without venous occlusion. In multivariate analysis, the presence of adherence was a predictor of advanced extraction (odds ratio: 2.89 [1.14-7.32], p = .025). The fluoroscopy time was also significantly longer (14.0 [8.2-18.7] vs. 5.1 [2.1-10.0] min, p < .001). The rate of complications did not differ based on the presence of venous lesions. CONCLUSION: Although procedural success and complication rates were similar, patients with extensive lead-venous wall adherence required a longer fluoroscopy time and were three times more likely to need advanced extraction tools. Conversely, the presence of total venous occlusion had no impact on the procedure complexity.

Development of 3D-Printed, Liquisolid and Directly Compressed Glimepiride Tablets, Loaded with Black Seed Oil Self-Nanoemulsifying Drug Delivery System: In Vitro and In Vivo Characterization.

Glimepiride is characterized by an inconsistent dissolution and absorption profile due to its limited aqueous solubility. The aim of this study was to develop glimepiride tablets using three different manufacturing techniques, as well as to study their quality attributes and pharmacokinetics behavior. Black seed oil based self-nanoemulsifying drug delivery system (SNEDDS) formulation was developed and characterized. Glimepiride liquisolid and directly compressed tablets were prepared and their pre-compression and post-compression characteristics were evaluated. Semi-solid pastes loaded with SNEDDS were prepared and used to develop three-dimensional printing tablets utilizing the extrusion technique. In vivo comparative pharmacokinetics study was conducted on Male Wistar rats using a single dose one-period parallel design. The developed SNEDDS formulation showed a particle size of 45.607 ± 4.404 nm, and a glimepiride solubility of 25.002 ± 0.273 mg/mL. All the studied tablet formulations showed acceptable pre-compression and post-compression characteristics and a difference in their in vitro drug release behavior. The surface of the liquisolid and directly compressed tablets was smooth and non-porous, while the three-dimensional printing tablets showed a few porous surfaces. The inner structure of the liquisolid tablets showed some cracks and voids between the incorporated tablet ingredients while that of the three-dimensional printing tablets displayed some tortuosity and a gel porous-like structure. Most of the computed pharmacokinetic parameters improved with the liquisolid and three-dimensional printed tablets. The relative bioavailabilities of the three-dimensional printed and liquisolid tablets compared to commercial product were 121.68% and 113.86%, respectively. Therefore, the liquisolid and three-dimensional printed tablets are promising techniques for modifying glimepiride release and improving in vivo performance but more clinical investigations are required.

Enhancing the Antifungal Activity and Ophthalmic Transport of Fluconazole from PEGylated Polycaprolactone Loaded Nanoparticles.

Fungal eye infections are caused mainly by an eye injury and can result in serious eye damage. Fluconazole (FLZ), a broad-spectrum antifungal agent, is a poorly soluble drug with a risk of hepatotoxicity. This work aimed to investigate the antifungal activity, ocular irritation, and transport of FLZ-loaded poly (ε-caprolactone) nanoparticles using a rabbit eye model. Three formulation factors affecting the nanoparticle's size, zeta potential, and entrapment efficiency were optimized utilizing the Box-Behnken design. Morphological characteristics and antifungal activity of the optimized nanoparticles were studied. The optimized nanoparticles were loaded into thermosensitive in situ hydrogel and hydroxypropylmethylcellulose (HPMC) hydrogel ophthalmic formulations. The rheological behavior, in vitro release and in vivo corneal transport were investigated. Results revealed that the percentage of poly (ε-caprolactone) in the nanoparticle matrix, polymer addition rate, and mixing speed significantly affected the particle size, zeta potential, and entrapment efficiency. The optimized nanoparticles were spherical in shape and show an average size of 145 nm, a zeta potential of -28.23 mV, and a FLZ entrapment efficiency of 98.2%. The antifungal activity of FLZ-loaded nanoparticles was significantly higher than the pure drug. The developed ophthalmic formulations exhibited a pseudoplastic flow, prolonged the drug release and were found to be non-irritating to the cornea. The prepared FLZ pegylated nanoparticles were able to reach the posterior eye segment without eye irritation. As a result, the developed thermosensitive in situ hydrogel formulation loaded with FLZ polymeric nanoparticles is a promising drug delivery strategy for treating deep fungal eye infections.