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.

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.

The additive value of copeptin for early diagnosis and prognosis of acute coronary syndromes.

BACKGROUND: One promising biomarker that has received substantial interest for the evaluation of suspected acute coronary syndromes (ACS) is copeptin. Therefore, our goal was to assess the additive value of copeptin for early diagnosis and prognosis of Non-ST segment acute coronary syndromes (NSTE-ACS). METHODS: The study included ninety patients with suspected ACS. Patients with typical ischemic chest pain within six hours of symptom onset and without ST-segment elevation on electrocardiograph (ECG) were included. In addition to cardiac troponin I (cTnI), copeptin was assayed from venous blood samples obtained on admission, followed by serial troponin measurements six and twelve hours later. One year follow-up was performed for any major adverse cardiac events (MACEs) including cardiac death, re-infarction, re- hospitalization for ischemic events, heart failure, stroke and target lesion revascularization (TLR). RESULTS: Of seventy nine patients included in the final analysis, Forty (50.6%) were diagnosed as unstable angina (UA), while thirty nine (49.4%) had a non-ST elevation myocardial infarction (NSTEMI). Copeptin level on admission was significantly higher among NSTEMI patients than those with UA. With regard to the correlation analyses, copeptin was positively correlated with each of, Global Registry of Acute Coronary Events (GRACE), Thrombolysis In Myocardial Infarction (TIMI) and synergy between percutaneous coronary intervention with taxus and cardiac surgery (SYNTAX) scores. The sensitivity and negative predictive value (NPV) of the combination of admission copeptin and cTn-I were 100% and 100%, respectively, versus 57% and 70%, respectively, with admission of cTn-I alone. The area under curve (AUC) of the combination of copeptin and cTn-I was (0.975, p < 0.001) and was significantly higher than the AUC of cTn-I alone (0.888, p < 0.001). Admission copeptin was an independent predictor for MACEs by multiple regression analysis (OR: 0.01, 95% CI: 0.0-0.8, P = 0.04). High values of copeptin had the highest rate of MACEs and coronary revascularization during one year of follow up. CONCLUSION: The combination of copeptin and conventional troponin I aids in early rule out of NSTEMI virtually independent of chest pain onset (CPO) with high NPV in patients presenting within three hours from chest pain onset with excellent prognostic value for risk stratification and prediction of MACEs.

Enhancing the Hypolipidemic Effect of Simvastatin in Poloxamer-Induced Hyperlipidemic Rats via Liquisolid Approach: Pharmacokinetic and Pharmacodynamic Evaluation.

This study aimed to enhance the dissolution of simvastatin (SMV) through its formulation in liquisolid tablets (LSTs) to improve its bioavailability and hypolipidemic activity after oral administration. SMV-LSTs were optimized using Box-Behnken design to maximize the rate and extent of SMV dissolution. The optimized SMV-LST was evaluated for pharmacokinetic parameters and potential hypolipidemic activity on induced hyperlipidemic rats. The dissolution parameters revealed a shortening of mean dissolution time from 10.99 to 6.82 min, increasing of dissolution rate during the first 10 min from 1253.15 to 1667.31 µg/min, and enhancing of dissolution efficiency after 60 min from 71.92 to 86.93% for SMV-LSTs versus the commercial SMV tablets. The obtained data reflected an improvement in the relative bioavailability of SMV with 148.232% which was confirmed by the significant reduction of the levels of circulating total cholesterol, triglycerides that reached the normal level after 12 h. In particular, the optimized SMV-LSTs reduced serum low-density lipoproteins (LDL) by 44.6% which was significantly different from the commercial SMV tablets. In contrast, the level of serum high-density lipoprotein (HDL) was significantly augmented after 4 h in rats treated with the optimized SMV-LSTs by 47.6%. Finally, the optimized SMV-LSTs showed a significant lower atherosclerotic index value which could maximize its potential in decreasing the risk of coronary disease and atherosclerosis. Overall enhancement in pharmacokinetics and pharmacodynamics in comparison with the commercial tablets confers the potential of the liquisolid approach as a promising alternative for improved oral bioavailability, hypolipidemic, and cardioprotective effects of SMV. Graphical abstract.

Does low-density lipoprotein cholesterol induce inflammation? If so, does it matter? Current insights and future perspectives for novel therapies.

BACKGROUND: Dyslipidemia and inflammation are closely interrelated contributors in the pathogenesis of atherosclerosis. Disorders of lipid metabolism initiate an inflammatory and immune-mediated response in atherosclerosis, while low-density lipoprotein cholesterol (LDL-C) lowering has possible pleiotropic anti-inflammatory effects that extend beyond lipid lowering. MAIN TEXT: Activation of the immune system/inflammasome destabilizes the plaque, which makes it vulnerable to rupture, resulting in major adverse cardiac events (MACE). The activated immune system potentially accelerates atherosclerosis, and atherosclerosis activates the immune system, creating a vicious circle. LDL-C enhances inflammation, which can be measured through multiple parameters like high-sensitivity C-reactive protein (hsCRP). However, multiple studies have shown that CRP is a marker of residual risk and not, itself, a causal factor. Recently, anti-inflammatory therapy has been shown to decelerate atherosclerosis, resulting in fewer MACE. Nevertheless, an important side effect of anti-inflammatory therapy is the potential for increased infection risk, stressing the importance of only targeting patients with high residual inflammatory risk. Multiple (auto-)inflammatory diseases are potentially related to/influenced by LDL-C through inflammasome activation. CONCLUSIONS: Research suggests that LDL-C induces inflammation; inflammation is of proven importance in atherosclerotic disease progression; anti-inflammatory therapies yield promise in lowering (cardiovascular) disease risk, especially in selected patients with high (remaining) inflammatory risk; and intriguing new anti-inflammatory developments, for example, in nucleotide-binding leucine-rich repeat-containing pyrine receptor inflammasome targeting, are currently underway, including novel pathway interventions such as immune cell targeting and epigenetic interference. Long-term safety should be carefully monitored for these new strategies and cost-effectiveness carefully evaluated.

Electrocardiographic measures of ventricular repolarization dispersion and arrhythmic outcomes among ST elevation myocardial infarction patients with pre-infarction angina undergoing primary percutaneous coronary intervention.

BACKGROUND: Arrhythmias are considered one of the major causes of death in ST elevation myocardial infarction (STEMI), particularly in the early in-hospital phase. Pre-infarction angina (PIA) has been suggested to have a protective role. OBJECTIVES: To study the difference in acute electrocardiographic findings between STEMI patients with and without PIA and to assess the in-hospital arrhythmias in both groups. MATERIAL AND METHODS: We prospectively enrolled 238 consecutive patients with STEMI. Patients were divided into two groups: those with or without PIA. ECG data recorded and analyzed included ST-segment resolution (STR) at 90 min, corrected QT interval (QTc) and dispersion (QTD), T-peak-to-T-end interval (Tp-Te), and dispersion and Tp-Te/QT ratio. In-hospital ventricular arrhythmias encountered in both groups were recorded. Predictors of in-hospital arrhythmias were assessed among different clinical and electrocardiographic parameters. RESULTS: Of the 238 patients included, 42 (17%) had PIA and 196 (83%) had no PIA. Patients with PIA had higher rates of STR (p < 0.0001), while patients with no PIA had higher values of QTc (p = 0.006), QTD (p = 0.001), Tp-Te interval (p = 0.001), Tp-Te dispersion (p < 0.0001), and Tp-Te/QT ratio (p = 0.01) compared to those with angina preceding their incident infarction (PIA). This was reflected into significantly higher rates of in-hospital arrhythmias among patients with no PIA (20% vs. 7%, p = 0.04). Furthermore, longer Tp-Te interval and higher Tp-Te/QT ratio independently predicted in-hospital ventricular arrhythmias. CONCLUSION: Pre-infarction angina patients had better electrocardiographic measures of repolarization dispersion and encountered significantly less arrhythmic events compared to patients who did not experience PIA.

Development of optimized self-nanoemulsifying lyophilized tablets (SNELTs) to improve finasteride clinical pharmacokinetic behavior.

OBJECTIVE: Preparation of an optimized finasteride (FSD) lyophilized tablets loaded with self-nanoemulsifying drug delivery system (SNEDDS). SIGNIFICANCE: Enhance FSD bioavailability in male pattern baldness and benign prostatic hyperplasia. METHODS: Two-step optimization was implemented to achieve the study goals. First; the mixture design was used to develop an optimized SNEDDS through which the effect of cosurfactant number of carbon atoms on SNEDDS particle size and thermodynamic stability has been tested. Second; the different tablet excipients have been used to develop an optimized self-nanoemulsifying lyophilized tablets (SNELTs). The prepared tablets have been fully characterized. Interaction among tablet components has been studied. Finally, FSD clinical pharmacokinetic has been investigated on human volunteers. RESULTS: Anise oil and tween 80 were selected as oily phase and surfactant, respectively while different aliphatic alcohols were studied as cosurfactants. Percentages of oil, surfactant, and cosurfactants were significantly affecting SNEDDS particle size. Increasing cosurfactant number of carbon atoms achieved smaller particle size and higher stability. The optimized SNEDDS was found to contain 10.3455, 45.8972, and 43.7573% of anise oil, tween 80, and butanol, respectively. Variations in FSD cumulative release and disintegration time, from the prepared tablets, were attributed to change in the percent of plasdone XL, Avicel and silica. No interaction among components was noticed. Clinical pharmacokinetics illustrated significant enhancement in the studied parameters from the optimized lyophilized tablets loaded with drug SNEDDS when compared to marketed FSD product. CONCLUSION: Lyophilized tablets could be considered as a good alternative for conventional solid dosage forms especially when loaded with drug nanosystems.

Clinical pharmacokinetic study for the effect of glimepiride matrix tablets developed by quality by design concept.

OBJECTIVE: Implementation of a new pharmaceutical technique to improve aqueous solubility and thus dissolution, enhancement of drug permeation, and finally formulation of a controlled release tablet loaded with glimepiride (GLMP). SIGNIFICANCE: Improve GLMP bioavailability and pharmacokinetics in type II diabetic patients. METHODS: Different polymers were used to enhance aqueous GLMP solubility of which a saturated polymeric drug solution was prepared and physically adsorbed onto silica. An experimental design was employed to optimize the formulation parameters affecting the preparation of GLMP matrix tablets. A compatibility study was conducted to study components interactions. Scanning electron microscope (SEM) was performed before and after the tablets were placed in the dissolution medium. An in vivo study in human volunteers was performed with the optimized GLMP tablets, which were compared to pure and marketed drug products. RESULTS: Enhancement of GLMP aqueous solubility, using the polymeric drug solution technique, by more than 6-7 times when compared with the binary system. All the studied formulation factors significantly affected the studied variables. No significant interaction was detected among components. SEM illustrated the surface and inner tablet structure, and confirmed the drug release which was attributed to diffusion mechanism. The volunteer group administered the optimized GLMP tablet exhibited higher drug plasma concentration (147.4 ng/mL), longer time to reach maximum plasma concentration (4 h) and longer t1/2 (7.236 h) compared to other groups. CONCLUSIONS: Matrix tablet loaded with a physically modified drug form could represent a key solution for drugs with inconsistent dissolution and absorption profiles.

Solid lipid nanoparticles for transdermal delivery of avanafil: optimization, formulation, in-vitro and ex-vivo studies.

CONTEXT: Avanafil (AVA) is used in the treatment of erectile dysfunction, but is reported for its poor aqueous solubility. Solid lipid nanoparticles (SLNs) are lipid carriers that can greatly enhance drug solubility and bioavailability. OBJECTIVE: This work was aimed to formulate and optimize AVA SLNs with subsequent loading into hydrogel films for AVA transdermal delivery. MATERIALS AND METHODS: AVA SLNs were prepared utilizing homogenization followed by ultra-sonication technique. The prepared SLNs were characterized for particle size, charge, surface morphology and drug content. The optimized SLNs formulation was incorporated into transdermal films prepared using HPMC and chitosan. Hydrogel films were evaluated for ex-vivo rat skin permeation using automated Franz diffusion cells. The permeation parameters and the release mechanism were evaluated. The transdermal permeation of the prepared AVA SLNs through the skin layers was studied using confocal laser scanning microscope. RESULTS: Lipid concentration and % of oil in lipid had a pronounced effect on particle size while, entrapment efficiency was significantly affected by lipid concentration and % of cholesterol. The optimized AVA SLNs showed particle size and entrapment efficiency of 86 nm and 85.01%, respectively. TEM images revealed spherecity of the particles. High permeation parameters were observed from HPMC films loaded with AVA SLNs. The release data were in favor of Higuchi diffusion model. The prepared AVA SLNs were able to penetrate deeper in skin layers. CONCLUSION: HPMC transdermal film-loaded AVA SLNs is an effective and alternative to per-oral drug administration.

Preparation of transfersomes encapsulating sildenafil aimed for transdermal drug delivery: Plackett-Burman design and characterization.

The aim of this work was to study the effect of different processing and formulation parameters on the preparation of sildenafil (SD) transfersomes utilizing the Plackett-Burman design. The drug to phospholipid molar ratio (X1), phospholipid to surfactant ratio (X2), hydrophilic-lipophilic balance of the surfactant (X3), hydration medium pH (X4), hydration time (X5) and the temperature of hydration (X6) were investigated to study their effect on the vesicle size (Y1) and entrapment efficiency (EE) of the drug (Y2). The preparation conditions were optimized to minimize the vesicle size and maximize the EE. The prepared transfersomes were also subjected to zeta potential measurements, morphological and physicochemical characterization. The combinations of factors that achieve the optimum desirability were identified. An optimized formulation was prepared and characterized once more for its vesicle size, EE, in vitro permeation and deformability index. The results revealed that both X3 and X6 had a pronounced effect on Y1, while X1 and X4 showed a significant effect on Y2. Morphological and physicochemical study confirmed the transfersomes spherical shape and compatibility of the formulation ingredients. The formulation with optimum desirability showed EE and vesicle size of 97.21% and 610 nm, respectively. In vitro permeation of the drug-loaded transfersome showed more than 5-fold higher permeation rate compared with drug suspension. Deformability index verified elasticity of the preparation. The significant variables could be optimized again to produce smaller vesicle size that could increase SD permeation from transdermal delivery systems loaded drug optimized transfersomes.

Enhanced permeation parameters of optimized nanostructured simvastatin transdermal films: ex vivo and in vivo evaluation.

OBJECTIVE: Detailed optimization process was carried out to enhance permeation parameters, and hence bioavailability, of simvastatin (SMV) transdermal films. METHODS: SMV solubility was investigated in various oils, surfactants and co-surfactants/co-solvents. Mixtures of the selected components were prepared to identify zone of nanoemulsion formation that was utilized in Extreme Vertices mixture design to develop SMV self-nanoemulsifying drug delivery systems (SNEDDS) with minimum globule size. Optimized SMV-SNEDDS were included in the preparation of transdermal films. A fractional factorial design was implemented to evaluate effects of the factors on the amount of SMV permeated. The optimized film was investigated for ex vivo skin permeation and in vivo pharmacokinetic parameters. RESULTS: The optimum SNEDDS formula was 0.09, 0.8 and 0.11 for Sefsol 218, tween 80 and PEG 200, respectively. Fractional factorial design depicted the optimized SMV transdermal film with 2% HPMC and 2% DMSO as permeation enhancer that showed 1.82-fold improvements in skin flux. The pharmacokinetic data showed higher Cmax and almost doubled AUC compared with raw SMV-loaded films. CONCLUSION: The two-step optimization implemented to optimize and control the experimental conditions for the preparation of SMV-SNEDDS-transdermal film with improved ex vivo skin permeation and enhanced in vivo parameters.

Statistical optimization of controlled release microspheres containing cetirizine hydrochloride as a model for water soluble drugs.

The purpose was to improve the encapsulation efficiency of cetirizine hydrochloride (CTZ) microspheres as a model for water soluble drugs and control its release by applying response surface methodology. A 3(3) Box-Behnken design was used to determine the effect of drug/polymer ratio (X1), surfactant concentration (X2) and stirring speed (X3), on the mean particle size (Y1), percentage encapsulation efficiency (Y2) and cumulative percent drug released for 12 h (Y3). Emulsion solvent evaporation (ESE) technique was applied utilizing Eudragit RS100 as coating polymer and span 80 as surfactant. All formulations were evaluated for micromeritic properties and morphologically characterized by scanning electron microscopy (SEM). The relative bioavailability of the optimized microspheres was compared with CTZ marketed product after oral administration on healthy human volunteers using a double blind, randomized, cross-over design. The results revealed that the mean particle sizes of the microspheres ranged from 62 to 348 µm and the efficiency of entrapment ranged from 36.3% to 70.1%. The optimized CTZ microspheres exhibited a slow and controlled release over 12 h. The pharmacokinetic data of optimized CTZ microspheres showed prolonged tmax, decreased Cmax and AUC0-∞ value of 3309 ± 211 ng h/ml indicating improved relative bioavailability by 169.4% compared with marketed tablets.

Development of meloxicam in situ implant formulation by quality by design principle.

OBJECTIVE: The focus of this study was to develop and optimize in situ implant formulation of meloxicam by quality by design (QbD) principle for long-term management of musculoskeletal inflammatory disorders. METHODS: The formulation was optimized by Box-Behnken design with polylactide-co-glycolide (PLGA) level (X1), N-methyl pyrrolidone level (X2) and PLGA intrinsic viscosity (X3) as the independent variables and initial burst release of drug (Y1), cumulative release (Y2), and dissolution efficiency (Y3) as the dependent variables. The formulation was physicochemically characterized by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy and powder X-ray diffraction (PXRD). Pharmacokinetic studies of the optimized formulation were performed on Sprague-Dawley rats. RESULTS: Y1 was significantly affected by X2 and X3. Y2 was affected by X1 and X3 while Y3 was affected by all three independent variables employed in the formulations. Responses for the optimized formulation were in close agreement with the values predicted by the model. SEM photomicrographs indicated uniform gel formulation. No chemical interaction between the components of formulation was observed by FT-IR and meloxicam was found to be present in the amorphous form in the gel matrix as revealed by PXRD. The maximum plasma concentration (Cmax), time to achieve Cmax and area under plasma concentration curve were significantly different from those of the solution formulation used as the control. Plasma concentration of meloxicam was maintained above its IC50 concentration required for COX-2 inhibition for 23 days. CONCLUSION: Meloxicam in situ implant may provide long-term management of inflammatory conditions with improved patient compliance and better therapeutic index.

Biodegradable injectable in situ implants and microparticles for sustained release of montelukast: in vitro release, pharmacokinetics, and stability.

The objective of this study was to investigate the sustained release of a hydrophilic drug, montelukast (MK), from two biodegradable polymeric drug delivery systems, in situ implant (ISI) and in situ microparticles (ISM). N-Methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), triacetin, and ethyl acetate were selected as solvents. The release of 10% (w/v) MK from both systems containing poly-lactic-co-glycolic acid (PLGA) as the biodegradable polymer was compared. Upon contact with the aqueous medium, the PLGA in ISI and ISM systems solidified resulting in implants and microparticles, respectively. The in vitro drug release from the ISI system showed marked difference from miscible solvents (NMP and DMSO) than the partially miscible ones (triacetin and ethyl acetate), and the drug release decreased with increased PLGA concentration. In the ISM system, the initial in vitro drug release decreased with decreased ratio of polymer phase to external oil phase. In vivo studies in rats showed that ISM had slower drug release than the drug release from ISI. Also, the ISM system when compared to ISI system had significantly reduced initial burst effect. In vitro as well as the in vivo studies for both ISI and ISM systems showed sustained release of MK. The ISM system is suitable for sustained release of MK over 4-week period with a lower initial burst compared to the ISI system. Stability studies of the ISI and ISM formulations showed that MK is stable in the formulations stored at 4°C for more than 2 years.

Vitamin-K antagonist versus dual antiplatelet therapy in management of isolated and non-obstructive atherosclerotic coronary artery ectasia.

BACKGROUND: Treatment of isolated and non-obstructive atherosclerotic coronary artery ectasia (CAE) is still controversial. AIM: To assess the efficacy and safety of vitamin-K antagonist (VKA) versus dual antiplatelet (DAPT) therapy in management of patients with isolated and non-obstructive atherosclerotic CAE. METHODS: We prospectively enrolled 79 patients diagnosed on elective coronary angiography to have either isolated CAE or non-obstructive atherosclerotic CAE. Patients were assigned in 1:1 pattern to receive either VKA (warfarin) or DAPT (aspirin plus clopidogrel). Patients were followed-up for nine-months. The primary endpoint was the cumulative events rate including acute coronary event, target vessel intervention, or cardiac death. Analysis of cumulative events at different time intervals, its individual components, and bleeding were considered secondary endpoints. RESULTS: Cumulative events rate was 33%, with mortality rate of 2.5%. Both treatment groups showed comparable cumulative events during the nine-months follow-up duration. Nevertheless, Kaplan-Meier analysis beyond the first 3-months of follow-up showed significantly higher event-free survival among the VKA-group. Recurrent events (≥2) were significantly higher among the DAPT-group. Both groups showed no major bleeding events. Multivariable cox-regression analysis showed that presence of significant coronary tortuosity, use of DAPT in reference to VKA, and lower percent time in therapeutic range (%TTR) among those receiving VKA were significant independent predictors of clinical adverse events beyond the first 3-months of follow-up. CONCLUSION: Cumulative adverse events were comparable among both treatment groups for isolated non-obstructive CAE. However, adverse events were significantly more frequent in the DAPT-group beyond the first three months.

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.

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 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.

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.