Synthesis, Docking, and DFT Studies on Novel Schiff Base Sulfonamide Analogues as Selective COX-1 Inhibitors with Anti-Platelet Aggregation Activity.

Selective COX-1 inhibitors are preferential therapeutic targets for platelet aggregation and clotting responses. In this study, we examined the selective COX-1-inhibitory activities of four newly synthesized compounds, 10-13, along with their abilities to inhibit platelet aggregation against ADP and collagen. The target compounds 10-13 were synthesized using the conventional method, sonication, and microwave-assisted methods. Microanalytical and spectral data were utilized to elucidate the structures of the new compounds 10-13. Additionally, a spectral NMR experiment [NOESY] was conducted to emphasize the configuration around the double bond of the imine group C=N. The obtained results revealed no observed correlation between any of the neighboring protons, suggesting that the configuration at the C=N double bond is E. Biological results revealed that all the screened compounds 10-13 might serve as selective COX-1 inhibitors. They showed IC50 values ranging from 0.71 µM to 4.82 µM against COX-1 and IC50 values ranging from 9.26 µM to 15.24 µM against COX-2. Their COX-1 selectivity indices ranged between 2.87 and 18.69. These compounds show promise as promising anti-platelet aggregation agents. They effectively prevented platelet aggregation induced by ADP with IC50 values ranging from 0.11 µM to 0.37 µM, surpassing the standard aspirin with an IC50 value of 0.49 µM. Additionally, they inhibited the platelet aggregation induced by collagen with IC50 values ranging from 0.12 µM to 1.03 µM, demonstrating superior efficacy compared to aspirin, which has an IC50 value of 0.51 µM. In silico molecular modeling was performed for all the target compounds within the active sites of COX-1 and COX-2 to rationalize their selective inhibitory activities towards COX-1. It was found that the binding interactions of the designed compounds within the COX-1 active site had remained unaffected by the presence of celecoxib. Molecular modeling and DFT calculations using the B3LYP/6-31+G (d,p) level were performed to study the stability of E-forms with respect to Z-forms for the investigated compounds. A strong correlation was observed between the experimental observations and the quantum chemical descriptors.

Enhancing Pharmacokinetics and Pharmacodynamics of Rosuvastatin Calcium through the Development and Optimization of Fast-Dissolving Films.

Rosuvastatin (RSV) is a widely used cholesterol-lowering medication, but its limited bioavailability due to its susceptibility to stomach pH and extensive first-pass metabolism poses a significant challenge. A fast-dissolving film (FDF) formulation of RSV was developed, characterized, and compared to the conventional marketed tablet to address this issue. The formulation process involved optimizing the thickness, disintegration time, and folding durability. All formulations were assessed for in vitro disintegration, thickness, folding endurance, in vitro dissolution, weight, and content uniformity. The study's results revealed that the optimized RSV-FDF displayed a significantly faster time to maximum plasma concentration (tmax) of 2 h, compared to 4 h for the marketed tablet. The maximum plasma concentration (Cmax) for the RSV-FDF (1.540 µg/mL ± 0.044) was notably higher than that of the marketed tablet (0.940 µg/mL ± 0.017). Additionally, the pharmacodynamic assessment in male Wistar rats demonstrated that the optimized RSV-FDF exhibited an improved lipid profile, including reduced levels of low-density lipoproteins (LDLs), elevated high-density lipoproteins (HDLs), decreased triglycerides (TGs), and lower very-low-density lipoproteins (VLDLs) compared to the conventional tablet. These findings underscore the potential of RSV-FDFs as a promising alternative to enhance the bioavailability and therapeutic efficacy of rosuvastatin in treating dyslipidemia. The faster onset of action and improved lipid-lowering effects make RSV-FDFs an attractive option for patients requiring efficient cholesterol management.

A novel role of Nano selenium and sildenafil on streptozotocin-induced diabetic nephropathy in rats by modulation of inflammatory, oxidative, and apoptotic pathways.

AIMS: The present study aimed to investigate the effect of nano selenium, sildenafil, and their combination on inflammation, oxidative stress, and apoptosis in streptozotocin-induced diabetic nephropathy in rats. Herein, a new anti-inflammatory pathway for sildenafil as a high-mobility group box (HMGB1) inhibitor was proposed using the molecular docking technique. MATERIALS AND METHODS: Rats were divided into 7 groups: normal control, control nano selenium, control sildenafil, control diabetic, diabetic+ nano selenium, diabetic+ sildenafil, diabetic+ nano selenium+ sildenafil. The effects of drugs were evaluated by measuring serum urea, creatinine, lactate dehydrogenase (LDH), levels of tumor necrosis factor-alpha (TNF-α), Interleukin 1 beta (IL-1ß), HMGB1, receptor advanced glycation end product (RAGE), malondialdehyde (MDA), thioredoxin reductase (TrxR) by biochemical assays, nuclear factor-kappa b (NF-κB), toll-like receptor (TLR4) by immunohistochemistry, gene expressions of caspase 3 and monocyte chemoattractant protein (MCP-1) besides histopathological investigations of renal cells. KEY FINDINGS: Results showed beneficial effects of 8 weeks of treatment by nano selenium and sildenafil supported by improvement in kidney function, histopathological changes, and reduction in all of these parameters. These results supported molecular docking that indicated sildenafil had a high binding score and interactions with the HMGB1 receptor. SIGNIFICANCE: The current study demonstrated a renoprotective effect of nano­selenium and sildenafil by interfering at multiple pathways, especially the HMGB1/NF-κB signaling pathway.

Nano selenium ameliorates oxidative stress and inflammatory response associated with cypermethrin-induced neurotoxicity in rats.

Cypermethrin (CYP), a class II synthetic pyrethroid, is used to control household insects. CYP can cross the blood-brain barrier to exert neurotoxicity through changes in sodium ion channels. Selenium is an essential component of glutathione peroxidise enzyme; in addition, it shows a potential anti-inflammatory property. The present study aimed to investigate the neuroprotective role of Nano-Se on CYP-induced neurotoxicity. Twenty-four adult male Wister rats were randomly divided into three groups: a) control, b) CYP (1mg/kg) administered orally for 21 days, c) CYP (1mg/kg) administered orally for 21 days and Nano-Se (2.5 mg/kg) given once a day three times a week for three weeks). Locomotor activity was assessed using open field test then rats were sacrificed under anaesthesia, and their brains were dissected out and processed for biochemical and histopathological studies. Histological examination of CYP-treated rats demonstrated some degenerative changes; besides, CYP affected rat locomotor activity. CYP-treated rats showed increased levels of malondialdehyde (MDA), TNF-α and IL-1ß in addition to the reduction of glutathione (GSH) levels and gamma-Aminobutyric acid (GABA). Nano-Se restored normal behavioural function and significantly attenuated CYP-evoked degenerative changes. Nano-Se increased levels of GABA and glutathione; on the other hand, it significantly prevented the rise in the levels of MDA, TNF-α and IL-1ß. Therefore, Nano-Se demonstrated both anti-oxidant and anti-inflammatory potential. Nano-Se may be suggested to be a prospective candidate to ameliorate CYP-induced neurotoxicity.

Development of Betamethasone Dipropionate-Loaded Nanostructured Lipid Carriers for Topical and Transdermal Delivery.

INTRODUCTION: Betamethasone dipropionate is a highly effective corticosteroid anti-inflammatory. However, the main drawback of its topical use is the limited skin penetration into deeper skin layers. Also, its systemic use has shown many side effects. OBJECTIVE: The goal of this research was to formulate betamethasone dipropionate in nanostructured lipid carriers (NLC) formulae that contain oleic acid to aid its penetration to deeper skin layers and to aid absorption to local regions upon topical application. METHODS: NLC formulae were prepared by high shear homogenization then sonication. Formulae were characterized for their particle size, size distribution, electric potential, occlusion factor, entrapment efficiency, drug loading, transmission electron microscopy, in vitro drug release, and ex vivo skin penetration. Compatibility of ingredients with drug was tested using differential scanning calorimetry. Formulae were shown to have appropriate characteristics. NLC formulae were superior to traditional topical formulation in drug release. RESULTS: Upon testing ex vivo skin penetration, betamethasone dipropionate prepared in NLC formulae was shown to penetrate more efficiently into skin layers than when formulated as a traditional cream. NLC formulation that contained higher percentage of oleic acid showed higher penetration and higher amount of drug to pass through skin. CONCLUSION: In general, NLC with lower oleic acid percentage was shown to deliver betamethasone dipropionate more efficiently into deeper skin layers while that of a higher oleic acid percentage was shown to deliver the drug more efficiently into deeper skin layers and through the skin, transdermally.

Antibiotic consumption in non-teaching Lebanese hospitals: A cross-sectional study.

The rising threat of antibiotic resistance is linked to patterns of antibiotic use in hospital settings where global efforts are undertaken to encourage reporting and benchmarking antibiotic consumption in an attempt to improve prescription regimens. In Lebanon, where data concerning the level of antibiotic consumption in hospitals is scarce, the aim of our paper is to track the intensity of antibiotic consumption in order to identify potential evidence of antibiotic misuse or abuse. The study is conducted in 2012 for a period of 12-month using data from pharmacy records in 27 non-teaching Lebanese hospitals according to the Anatomical, Therapeutic and chemical classification system and Defined Daily Dose (ATC/DDD) recommended by the World Health Organization and compiling data on ABC Calc software version 3.1. Results show that the average antibiotic consumption excluding pediatric cases is 72.56 Defined Daily Dose per 100 Bed-Days (DDD/100BD). Total broad spectrum antibiotic consumption is 12.14 DDD/100BD with no significant difference found between public and private hospitals (p>0.05 for all). The most commonly used antibiotics were Amoxycillin/Clavulanic acid, Ceftriaxone, Amoxycillin and Cefuroxime for parenteral use. Consumption of beta-lactams, Cephalosporins, Carbapenems, Monobactams and quinolones did not vary significantly by region, occupancy rate, number of beds including the number of intensive care unit beds. Our data findings provides baseline information on patterns of antibiotic consumption in Lebanon and the issue calls for concerted efforts to encourage data reporting on national basis and to correlate future findings with results of antibiotic susceptibility testing which can provide insights and tools needed to assess the public health consequences of antimicrobial misuse and to evaluate the impact of antibiotic resistance containment interventions.