Design, synthesis, antitumor activity and molecular docking study of novel 5-deazaalloxazine analogs

open access articleProtein tyrosine kinases (PTKs) are the most potential therapeutic targets for cancer. Herein, we present a sound rationale for synthesis of a series of novel 2-(methylthio), 2-(substituted alkylamino), 2-(heterocyclic substituted), 2-amino, 2,4-dioxo and 2-deoxo-5-deazaalloxazine derivatives by applying structure-based drug design (SBDD) using AutoDock 4.2. Their antitumor activities against human CCRF-HSB-2, KB, MCF-7 and HeLa have been investigated in vitro. Many 5-deazaalloxazine analogs revealed high selective activities against MCF-7 tumor cell lines (IC50: 0.17–2.17 µM) over HeLa tumor cell lines (IC50 > 100 µM). Protein kinase profiling revealed that compound 3h induced multi- targets kinase inhibition including −43% against (FAK), −40% against (CDKI) and −36% against (SCR). Moreover, the Annexin-V/PI apoptotic assay elucidate that compound 3h showed 33% and potentially 140% increase in early and late apoptosis to MCF-7 cells respectively, compared to the control. The structure-activity relationship (SAR) and molecular docking study using PTK as a target enzyme for the synthesized 7-deazaalloaxazine derivatives were investigated as potential antitumor agents. The AutoDock binding affinities of the 5deazaalloxazine analogs into c-kit PTK (PDB code: 1t46) revealed reasonable correlations between their AutoDock binding free energy and IC50

Vardenafil Oral Dispersible Films (ODFs) with advanced dissolution, palatability, and bioavailability

Oral, quick response, and on demand, also known as a spontaneous oral treatment for erectile dysfunction, is highly needed by both patients and physicians. Vardenafil is selective (fewer side effects) and more effective in difficult-to-treat conditions than sildenafil. This study aims at fostering the dual objectives of using biomolecules such as artificial sweetening agents to solubilize and mask the bitterness of vardenafil loaded on biodegradable polymeric materials (PVA, MC, SA, and PVP K30) to fabricate oral, fast-dissolving films (vardenafil ODFs) in the mouth without the need for water to ingest the dosage form. Furthermore, coprecipitated-dispersed mixtures of vardenafil and three sweeteners (sorbitol, acesulfame K, and sucralose) were prepared and characterized using FTIR, DSC, and solubility studies. Moreover, eight different vardenafil ODFs were prepared using the solvent-casting method. Modified gustatory sensation test, in vitro disintegration, and release studies were performed. In addition, the optimized ODF (F8) was compared with the commercial film-coated tablets pharmacokinetically (relative bioavailability, onset, and duration of actions were estimated). The results indicated that the three sweetening agents had comparable solubilizing capacity. However, both sucralose- and acesulfame K-based ODFs have a more enhanced sweet and palatable taste than sorbitol-sweetened ODF. The SA- and PVP K30-based ODFs showed significantly faster disintegration times and release rates than MC. In conclusion, PVA has good film-forming properties, but a higher ratio of PVA adversely affected the disintegration and release characteristics. The % relative bioavailability for ODF was 126.5%, with a superior absorption rate constant (Ka) of 1.2-fold. The C(max) and estimated T(max) were compared to conventional film-coated tablets

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Formulation and evaluation of simvastatin polymeric nanoparticles loaded in hydrogel for optimum wound healing purpose

Usama Farghaly Aly,1 Heba A Abou-Taleb,2 Ahmed AH Abdellatif,3,4 Nahla Sameh Tolba21Department of Pharmaceutics, Faculty of Pharmacy, Minia University, EL-Minia, Egypt; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Nahda University (NUB), Beni-Suef, Egypt; 3Department of Pharmaceutics, College of Pharmacy, Qassim University, Al Qassim, Kingdom of Saudi Arabia; 4Department of Pharmaceutics and Industrial Pharmacy, Al-Azhar University, Assiut, Egypt Purpose: The aim of this study was to formulate a hydrogel loaded with polymeric nanoparticles (PoNPs) of simvastatin (SIM) for topical wound healing application. Materials and methods: The SIM PoNPs were prepared by using the nanoprecipitation method to improve the drug solubility and skin permeation. Furthermore, drug content, solubility, particle size, surface charge, and transmission electron microscopy of the prepared PoNPs were evaluated. Then, the PoNPs were loaded on hydrogel, and physical characteristics, in vitro release, and ex vivo permeation of the hydrogel were evaluated. Finally, the prepared gel was applied on rat wounds, and a histopathological study was performed. Results: The results showed that the drug content in the PoNPs was 86.4%. The PoNPs were spherical in shape with a smooth surface and a uniform size distribution. The particle size was 268.4±2.6, polydispersity index was ≤0.302, and zeta potential was -33±1.67 mV. The hydrogel loaded with SIM PoNPs was homogenous, and the pH was accepted and compatible with the skin. Moreover, the viscosity and spreadability assured its ease of application. The drug content was 97.25±0.02%. Furthermore, about 81% of SIM was released within 24 hours, while in the ex vivo permeation study 69.19% of SIM passed through the skin after 24 hours. Finally, the histopathological studies confirmed the efficacy of the SIM PoNPs-loaded hydrogel in wound healing due to the formation of the normal epithelial layer on day 11 after wound creation.Conclusion: The hydrogel loaded with SIM PoNPs showed a good efficacy in accelerating the healing of the rat wound with complete epithelialization and minimal inflammatory cell infiltration. Keywords: simvastatin, Carbopol® gel, ex vivo permeation, nanoprecipitaion method, wound healin

Chemistry of the Egyptian Mediterranean coastal waters

Investigation on the major ions of seawater; Na+, K+, Ca++, Mg++, SO4− and Br− is based on more than 660 samples collected at 21 sections distributed along the Egyptian Mediterranean coast starting from Salloum to Arish during summer (2008), in addition to some samples taken at certain sections during spring (2008) and the winters of 2008, 2009 and 2010. In respect of the analysed major ions, the total average content (mg/l) and their corresponding chlorinity ratios are as follows: Na+; 12,337, 0.586, K+; 381.2, 0.0180, Ca++; 403, 0.0183, Mg++; 1506.6, 0.0709, SO4−; 3068, 0.139 and Br−; 64.9, 0.00296. The ion content and their chlorinity ratios indicate interesting temporal and spatial fluctuations. The Mg/Ca ratio average fluctuated between 3.1 and 4.6. With respect to the total average of ion/chlorinity ratios, Na and Mg showed almost positive declinations above the normal oceanic ratios. K, Ca and Br/chlorinity ratios, on the other hand, deviated strongly below normal while SO4/Cl ratio mean is closely nearer to normal. Strong anomalies of chlorinity ratios could be detected at several locations that coincided with high dilution and drop of salinity affected with land based effluents; e.g. in front of Mex, Krir and Sahl El-Tina areas

Elimination of detached Listeria monocytogenes from the biofilm on stainless steel surfaces during milk and cheese processing using natural plant extracts

Abstract Bacterial cells can form biofilm on food contact surfaces, becoming a source of food contamination with profound health implications. The current study aimed to determine some Egyptian medicinal plants antibacterial and antibiofilm effects against foodborne bacterial strains in milk plants. Results indicated that four ethanolic plant extracts, Cinnamon (Cinnamomum verum), Chamomile (Matricaria chamomilla), Marigold (Calendula officinalis), and Sage (Salvia officinalis), had antibacterial (12.0–26.5 mm of inhibition zone diameter) and antibiofilm (10–99%) activities against Staphylococcus aureus, Bacillus cereus, Listeria monocytogenes and Salmonella Typhimurium. The tested extracts had minimum inhibitory concentration values between 0.14 and 2.50 mg/ml and minimum bactericidal concentration values between 0.14 and 12.50 mg/ml. L. monocytogenes was more sensitive for all tested ethanolic extracts; Sage and Cinnamon showed a bacteriocidal effect, while Chamomile and Marigold were bacteriostatic. The ethanolic extracts mixture from Chamomile, Sage, and Cinnamon was chosen for its antibiofilm activity against L. monocytogenes using L-optimal mixture design. Gas chromatography and mass spectrometry analysis showed that this mixture contained 12 chemical compounds, where 2-Propenal,3-phenyl- had the maximum area % (34.82%). At concentrations up to 500 µg/ml, it had no cytotoxicity in the normal Vero cell line, and the IC50 value was 671.76 ± 9.03 µg/ml. Also, this mixture showed the most significant antibacterial effect against detached L. monocytogenes cells from formed biofilm in stainless steel milk tanks. At the same time, white soft cheese fortified with this mixture was significantly accepted overall for the panelist (92.2 ± 2.7) than other cheese samples, including the control group