Tailoring of Bilosomal Nanogel for Augmenting the Off-Label Use of Sildenafil Citrate in Pediatric Pulmonary Hypertension.

Pediatric pulmonary hypertension is a serious syndrome with significant morbidity and mortality. Sildenafil is widely used off-label in pediatric patients with pulmonary arterial hypertension. In this study, bile salt-stabilized nanovesicles (bilosomes) were screened for their efficacy to enhance the transdermal delivery of the phosphodiesterase type 5 inhibitor, sildenafil citrate, in an attempt to augment its therapeutic efficacy in pediatric pulmonary hypertension. A response surface methodology was implemented for fabricating and optimizing a bilosomal formulation of sildenafil (SDF-BS). The optimized SDF-BS formulation was characterized in terms of its entrapment efficiency (EE), zeta potential, vesicle size, and in vitro release profile. The optimized formula was then loaded onto hydroxypropyl methyl cellulose (HPMC) hydrogel and assessed for skin permeation, in vivo pharmacokinetics, and pharmacodynamic studies. The optimized SDF-BS showed the following characteristic features; EE of 88.7 ± 1.1%, vesicle size of 185.0 + 9.2 nm, zeta potential of -20.4 ± 1.1 mV, and efficiently sustained SDF release for 12 h. Skin permeation study revealed a remarkable improvement in SDF penetration from bilosomal gel compared to plain SDF gel. In addition, pharmacokinetic results revealed that encapsulating SDF within bilosomal vesicles significantly enhanced its systemic bioavailability (∼3 folds), compared to SDF oral suspension. In addition, pharmacodynamic investigation revealed that, compared to plain SDF gel or oral drug suspension, SDF-BS gel applied topically triggered a significant elevation (p < 0.05) in cGMP serum levels, underscoring the superior therapeutic efficacy of SDF-BS gel. Conclusively, bilosomes can be viewed as a promising nanocarrier for transdermal delivery of SDF that would grant higher therapeutic efficiency while alleviating the limitations encountered with SDF oral administration.

Piceatannol: a renaissance in antibacterial innovation unveiling synergistic potency and virulence disruption against serious pathogens.

In the relentless battle against multi-drug resistant Gram-negative bacteria, piceatannol emerges as a beacon of hope, showcasing unparalleled antibacterial efficacy and a unique ability to disrupt virulence factors. Our study illuminates the multifaceted prowess of piceatannol against prominent pathogens-Proteus mirabilis, Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. Notably, piceatannol demonstrated a remarkable ability to inhibit biofilm formation, reduce bacterial mobility, and diminish extracellular enzyme synthesis.Mechanistic insights into piceatannol's activity unraveled its impact on membrane potential, proton motive force, and ATP production. Furthermore, our study delved into piceatannol's anti-quorum sensing (QS) activity, showcasing its potential to downregulate QS-encoding genes and affirming its affinity to critical QS receptors through molecular docking. Crucially, piceatannol exhibited a low propensity for resistance development, positioning it as a promising candidate for combating antibiotic-resistant strains. Its mild effect on red blood cells (RBCs) suggests safety even at higher concentrations, reinforcing its potential translational value. In an in vivo setting, piceatannol demonstrated protective capabilities, significantly reducing pathogenesis in mice infected with P. aeruginosa and P. mirabilis. This comprehensive analysis positions piceatannol as a renaissance in antibacterial innovation, offering a versatile and effective strategy to confront the evolving challenges posed by resilient Gram-negative pathogens.

Assessing the antibacterial potential of 6-gingerol: Combined experimental and computational approaches.

The rise of antibiotic resistance in bacteria is becoming a global concern, particularly due to the dwindling supply of new antibiotics. This situation mandates the discovery of new antimicrobial candidates. Plant-derived natural compounds have historically played a crucial role in the development of antibiotics, serving as a rich source of substances possessing antimicrobial properties. Numerous studies have supported the reputation of 6-gingerol, a prominent compound found in the ginger family, for its antibacterial properties. In this study, the antibacterial activities of 6-gingerol were evaluated against Gram-negative bacteria, Acinetobacter baumannii and Klebsiella pneumoniae, with a particular focus on the clinically significant Gram-negative Pseudomonas aeruginosa and Gram-positive bacteria Staphylococcus aureus. Furthermore, the anti-virulence activities were assessed in vitro, in vivo, and in silico. The current findings showed that 6-gingerol's antibacterial activity is due to its significant effect on the disruption of the bacterial cell membrane and efflux pumps, as it significantly decreased the efflux and disrupted the cell membrane of S. aureus and P. aeruginosa. Furthermore, 6-gingerol significantly decreased the biofilm formation and production of virulence factors in S. aureus and P. aeruginosa in concentrations below MICs. The anti-virulence properties of 6-gingerol could be attributed to its capacity to disrupt bacterial virulence-regulating systems; quorum sensing (QS). 6-Gingerol was found to interact with QS receptors and downregulate the genes responsible for QS. In addition, molecular docking, and molecular dynamics (MD) simulation results indicated that 6-gingerol showed a comparable binding affinity to the co-crystalized ligands of different P. aeruginosa QS targets as well as stable interactions during 100 ns MD simulations. These findings suggest that 6-gingerol holds promise as an anti-virulence agent that can be combined with antibiotics for the treatment of severe infections.

Spanlastic-laden nanogel as a plausible platform for dermal delivery of bimatoprost with superior cutaneous deposition and hair regrowth efficiency in androgenic alopecia.

Bimatoprost (BIM) is a prostaglandin F2α analogs originally approved for the treatment of glaucoma and ocular hypertension. Recent studies have highlighted its potential to boost hair growth. The objective of this investigation is to challenge the potential of spanlastics (SLs) as a surfactant-based vesicular system for promoting the cutaneous delivery of BIM for the management of alopecia. BIM-loaded spanlastics (BIM-SLs), composed of Span as the main vesicle component and Tween as the edge activator, were fabricated by ethanol injection method. The formulated BIM-SLs were optimized by 23 full factorial design. The optimized formula (F1) was characterized for entrapment efficiency, surface charge, vesicle size, and drug release after 12 h (Q12h). The optimized formula (F1) exhibited high drug entrapment efficiency (83.1 ± 2.1%), appropriate zeta potential (-19.9 ± 2.1 mV), Q12h of 71.3 ± 5.3%, and a vesicle size of 364.2 ± 15.8 nm, which favored their cutaneous accumulation. In addition, ex-vivo skin deposition studies revealed that entrapping BIM within spanlastic-based nanogel (BIM-SLG) augmented the dermal deposition of BIM, compared to naïve BIM gel. Furthermore, in vivo studies verified the efficacy of spanlastic vesicles to boost the cutaneous accumulation of BIM compared to naive BIM gel; the AUC0-12h of BIM-SLG was 888.05 ± 72.31 µg/mL.h, which was twice as high as that of naïve BIM gel (AUC0-12h 382.86 ± 41.12 µg/mL.h). Intriguingly, BIM-SLG outperforms both naïve BIM gel and commercial minoxidil formulations in stimulating hair regrowth in an androgenetic alopecia mouse model. Collectively, spanlastic vesicles might be a potential platform for promoting the dermal delivery of BIM in managing alopecia.

Development of Carvedilol Nanoformulation-Loaded Poloxamer-Based In Situ Gel for the Management of Glaucoma.

The objective of the current study was to fabricate a thermosensitive in situ gelling system for the ocular delivery of carvedilol-loaded spanlastics (CRV-SPLs). In situ gel formulations were prepared using poloxamer analogs by a cold method and was further laden with carvedilol-loaded spanlastics to boost the precorneal retention of the drug. The gelation capacity, rheological characteristics, muco-adhesion force and in vitro release of various in situ gel formulations (CS-ISGs) were studied. The optimized formula (F2) obtained at 22% w/v poloxamer 407 and 5% w/v poloxamer 188 was found to have good gelation capacity at body temperature with acceptable muco-adhesion properties, appropriate viscosity at 25 °C that would ease its ocular application, and relatively higher viscosity at 37 °C that promoted prolonged ocular residence of the formulation post eye instillation and displayed a sustained in vitro drug release pattern. Ex vivo transcorneal penetration studies through excised rabbit cornea revealed that F2 elicited a remarkable (p ˂ 0.05) improvement in CRV apparent permeation coefficient (Papp = 6.39 × 10-6 cm/s) compared to plain carvedilol-loaded in situ gel (CRV-ISG; Papp = 2.67 × 10-6 cm/s). Most importantly, in normal rabbits, the optimized formula (F2) resulted in a sustained intraocular pressure reduction and a significant enhancement in the ocular bioavailability of carvedilol, as manifested by a 2-fold increase in the AUC0-6h of CRV in the aqueous humor, compared to plain CRV-ISG formulation. To sum up, the developed thermosensitive in situ gelling system might represent a plausible carrier for ophthalmic drug delivery for better management of glaucoma.

The Anti-Virulence Activities of the Antihypertensive Drug Propranolol in Light of Its Anti-Quorum Sensing Effects against Pseudomonas aeruginosa and Serratia marcescens.

The development of bacterial resistance is an increasing global concern that requires discovering new antibacterial agents and strategies. Bacterial quorum sensing (QS) systems play important roles in controlling bacterial virulence, and their targeting could lead to diminishing bacterial pathogenesis. In this context, targeting QS systems without significant influence on bacterial growth is assumed as a promising strategy to overcome resistance development. This study aimed at evaluating the anti-QS and anti-virulence activities of the ß-adrenoreceptor antagonist propranolol at sub-minimal inhibitory concentrations (sub-MIC) against two Gram-negative bacterial models Pseudomonas aeruginosa and Serratia marcescens. The effect of propranolol on the expression of QS-encoding genes was evaluated. Additionally, the affinity of propranolol to QS receptors was virtually attested. The influence of propranolol at sub-MIC on biofilm formation, motility, and production of virulent factors was conducted. The outcomes of the propranolol combination with different antibiotics were assessed. Finally, the in vivo protection assay in mice was performed to assess propranolol's effect on lessening the bacterial pathogenesis. The current findings emphasized the significant ability of propranolol at sub-MIC to reduce the formation of biofilms, motility, and production of virulence factors. In addition, propranolol at sub-MIC decreased the capacity of tested bacteria to induce pathogenesis in mice. Furthermore, propranolol significantly downregulated the QS-encoding genes and showed significant affinity to QS receptors. Finally, propranolol at sub-MIC synergistically decreased the MICs of different antibiotics against tested bacteria. In conclusion, propranolol might serve as a plausible adjuvant therapy with antibiotics for the treatment of serious bacterial infections after further pharmacological and pharmaceutical studies.

Ophthalmic Bimatoprost-Loaded Niosomal In Situ Gel: Preparation, Optimization, and In Vivo Pharmacodynamics Study.

This study aimed at formulating the antiglaucoma agent, Bimatoprost (BMT), into niosomal in situ gel (BMT-ISG) for ocular delivery. Niosomes containing cholesterol/span 60 entrapping BMT were fabricated using a thin-film hydration method. The fabricated niosomes were optimized and characterized for entrapment efficiency (%EE) and size. The optimized BMT-loaded niosomal formulation prepared at a cholesterol/span 60 ratio of 1:2 exhibited the highest entrapment (81.2 ± 1.2%) and a small particle size (167.3 ± 9.1 nm), and they were selected for incorporation into in situ gelling systems (BMT-ISGs) based on Pluronic F127/Pluronic F68. Finally, the in vivo efficiency of the BMT-ISG formulation, in terms of lowering the intraocular pressure (IOP) in normotensive male albino rabbits following ocular administration, was assessed and compared to that of BMT ophthalmic solution. All the formulated BMT-ISGs showed sol-gel transition temperatures ranging from 28.1 °C to 40.5 ± 1.6 °C. In addition, the BMT-ISG formulation sustained in vitro BMT release for up to 24 h. Interestingly, in vivo experiments depicted that topical ocular administration of optimized BMT-ISG formulation elicited a significant decline in IOP, with maximum mean decreases in IOP of 9.7 ± 0.6 mm Hg, compared to BMT aqueous solution (5.8 ± 0.6 mm Hg). Most importantly, no signs of irritation to the rabbit's eye were observed following topical ocular administration of the optimized BMT-ISG formulation. Collectively, our results suggested that niosomal in situ gels might be a feasible delivery vehicle for topical ocular administration of anti-glaucoma agents, particularly those with poor ocular bioavailability.

Dual targeting multiwalled carbon nanotubes for improved neratinib delivery in breast cancer.

The aim of this study was to develop biotinylated chitosan (Bio-Chi) decorated multi-walled carbon nanotubes (MWCNTs) for breast cancer therapy with the tyrosine kinase inhibitor, neratinib (NT). For achieving such a purpose, carboxylic acid functionalized multiwalled carbon nanotubes (c-MWCNTs) were initially decorated non-covalently with biotin-chitosan (Bio-Chi) coating for achieving a dual targeting mode; pH-dependent release with chitosan and biotin-receptor mediated active targeting with biotin. Afterwards, Bio-Chi decorated c-MWCNTs were loaded with the tyrosine kinase inhibitor, neratinib (NT). The formulation was then characterized by dynamic light scattering, FTIR and EDX. The drug loading efficiency was estimated to be 95.6 ± 1.2%. In vitro drug release studies revealed a pH-dependent release of NT from Bio-Chi decorated c-MWCNTs, with a higher drug release under acidic pH conditions. Sulforhodamine B (SRB) cytotoxicity assay of different NT formulations disclosed dose-dependent cytotoxicities against SkBr3 cell line, with a superior cytotoxicity observed with NT-loaded Bio-Chi-coated c-MWCNTs, compared to either free NT or NT-loaded naked c-MWCNTs. The IC50 values for free NT, NT-loaded c-MWCNTs and NT-loaded Bio-Chi-coated c-MWCNTs were 548.43 ± 23.1 µg mL-1, 319.55 ± 17.9 µg mL-1, and 257.75 ± 24.5 µg mL-1, respectively. Interestingly, competitive cellular uptake studies revealed that surface decoration of drug-loaded c-MWCNTs with Bio-Chi permitted an enhanced uptake of c-MWCNTs by breast cancer cells, presumably, via biotin receptors-mediated endocytosis. To sum up, Bio-Chi-decorated c-MWCNTs might be a promising delivery vehicle for mediating cell-specific drug delivery to breast cancer cells.

Anticancer potentials of metformin loaded coconut oil nanoemulsion on MCF-7, HepG2 and HCT-116 cell lines.

In order to load metformin in a nano formula and evaluate the produced nano form towards cancer cells, metformin was loaded on natural carrier coconut oil. The formed metformin-loaded coconut oil nanoemulsion was characterized by Zeta potential, particle size, drug content, drug release, and drug stability. The formed nanoemulsion was evaluated towards MCF-7, HepG2, and HCT-116 cell lines. Cell cycle analysis and apoptosis mechanism were studied. The nanoemulsion was created using deionized water, 1.5% Span 20, 1.5% Tween 80, 1.5% coconut oil, and 0.5% Metformin in an ultrasonicator to produce a homogenous solution. The anticancer activities of the metformin-loaded coconut nanoemulsion were highly improved compared to non-formulated metformin with IC50s of 8.3 ± 0.1 µg/ml, 12 ± 1.5 µg/ml, 2.685 ± 0.3 µg/ml for MCF-7, HepG2, and HCT-116 cell lines, respectively. There was a 76.5 ± 2.3 and 78.3 ± 3.2% increase in the number of apoptotic cells of MCF-7 and HepG2 cells after nanoemulsion treatment. This formula may be considered a new anticancer medication.

Formulation optimization, in vitro and in vivo evaluation of niosomal nanocarriers for enhanced topical delivery of cetirizine.

Cetirizine hydrochloride (CTZ), a second-generation anti-histaminic drug, has been recently explored for its effectiveness in the treatment of alopecia. Niosomes are surfactant-based nanovesicular systems that have promising applications in both topical and transdermal drug delivery. The aim of this study was to design topical CTZ niosomes for management of alopecia. Thin film hydration technique was implemented for the fabrication of CTZ niosomes. The niosomes were examined for vesicle size, surface charge, and entrapment efficiency. The optimized niosomal formulation was incorporated into a hydrogel base (HPMC) and explored for physical characteristics, ex vivo permeation, and in vivo dermato-kinetic study. The optimized CTZ-loaded niosomal formulation showed an average size of 403.4 ± 15.6 nm, zeta potential of - 12.9 ± 1.7 mV, and entrapment efficiency percentage of 52.8 ± 1.9%. Compared to plain drug solution, entrapment of CTZ within niosomes significantly prolonged in vitro drug release up to 12 h. Most importantly, ex-vivo skin deposition studies and in vivo dermato-kinetic studies verified superior skin deposition/retention of CTZ from CTZ-loaded niosomal gels, compared to plain CTZ gel. CTZ-loaded niosomal gel permitted higher drug deposition percentage (19.2 ± 1.9%) and skin retention (AUC0-10h 1124.5 ± 87.9 µg/mL.h) of CTZ, compared to 7.52 ± 0.7% and 646.2 ± 44.6 µg/mL.h for plain CTZ gel, respectively. Collectively, niosomes might represent a promising carrier for the cutaneous delivery of cetirizine for the topical management of alopecia.

Ocular Delivery of Bimatoprost-Loaded Solid Lipid Nanoparticles for Effective Management of Glaucoma.

Glaucoma is a progressive optic neuropathy characterized by a rise in the intraocular pressure (IOP) leading to optic nerve damage. Bimatoprost is a prostaglandin analogue used to reduce the elevated IOP in patients with glaucoma. The currently available dosage forms for Bimatoprost suffer from relatively low ocular bioavailability. The objective of this study was to fabricate and optimize solid lipid nanoparticles (SLNs) containing Bimatoprost for ocular administration for the management of glaucoma. Bimatoprost-loaded SLNs were fabricated by solvent evaporation/ultrasonication technique. Glyceryl Monostearate (GMS) was adopted as solid lipid and poloxamer 407 as surfactant. Optimization of SLNs was conducted by central composite design. The optimized formulation was assessed for average particle size, entrapment efficiency (%), zeta potential, surface morphology, drug release study, sterility test, isotonicity test, Hen's egg test-chorioallantoic membrane (HET-CAM) test and histopathology studies. The optimized Bimatoprost-loaded SLNs formulation had an average size of 183.3 ± 13.3 nm, zeta potential of -9.96 ± 1.2 mV, and encapsulation efficiency percentage of 71.8 ± 1.1%. Transmission electron microscopy (TEM) study revealed the nearly smooth surface of formulated particles with a nano-scale size range. In addition, SLNs significantly sustained Bimatoprost release for up to 12 h, compared to free drug (p < 005). Most importantly, HET-CAM test nullified the irritancy of the formulation was verified its tolerability upon ocular use, as manifested by a significant reduction in mean irritation score, compared to positive control (1% sodium dodecyl sulfate; p < 0.001). Histopathology study inferred the absence of any signs of cornea tissue damage upon treatment with Bimatoprost optimized formulation. Collectively, it was concluded that SLNs might represent a viable vehicle for enhancing the corneal permeation and ocular bioavailability of Bimatoprost for the management of glaucoma.

Piperine-Loaded In Situ Gel: Formulation, In Vitro Characterization, and Clinical Evaluation against Periodontitis.

Periodontitis is an inflammatory disorder associated with dysbiosis and characterized by microbiologically related, host-mediated inflammation that leads to the damage of periodontal tissues including gingiva, connective tissues, and alveolar bone. The aim of this study was to develop an in situ gel consisting of piperine. Eight in situ gel formulations were designed by varying the concentration of deacylated gellan gum cross-linked with sodium tripolyphosphate, and poloxamer-407. The prepared gels were evaluated for gelation temperature, gelation time, viscosity, piperine-loading efficiency, and piperine release. Finally, the optimized formula was evaluated for anti-inflammatory effectiveness among human patients during a 14-day follow-up. The optimized in situ gel formulation exhibited a gelation temperature of 35 ± 1 °C, gelling of 36 ± 1 s, excellent syringeability, and piperine loading of 95.3 ± 2.3%. This formulation efficiently sustained in vitro drug release for up to 72 h. In vivo studies revealed an efficient sol-to-gel transformation of optimized in situ gel formulation at physiological conditions, permitting an efficient residence time of the formulation within a periodontitis pocket. Most importantly, a clinical study revealed that treatment with the optimized formulation elicited a significant reduction in the mean plaque score (p = 0.001), gingival index (p = 0.003), and pocket depth (p = 0.002), and exerted a potent anti-inflammatory potential, compared to the control group. Collectively, piperine-loaded in situ gel might represent a viable therapeutic approach for the management of gingival and periodontal diseases.

Ganetespib with Methotrexate Acts Synergistically to Impede NF-κB/p65 Signaling in Human Lung Cancer A549 Cells.

Among the various types of cancer, lung cancer accounts for the highest number of fatalities across the globe. A combination of different cancer chemotherapeutics is regarded as an effective strategy for clinical management of different cancers. Ganetespib (GAN) is a well-established hsp90 inhibitor with enhanced pharmacological properties in comparison with its first-generation counterparts. Previous preclinical studies have shown that GAN exerts significant effects against cancer cells; however, its therapeutic effects against non-small cell lung cancer (NSCLC) A549 cells, achieved by modulating the expression of the NF-κB/p65 signaling pathway, remains unexplored. In this study, the combinatorial effect of GAN and methotrexate (MTX) against lung carcinomas was investigated through both in silico and in vitro studies. A combinatorial treatment regimen of GAN/MTX exerted more significant cytotoxic effects (p < 0.001) against A549 cells than individual treatments. The GAN/MTX combination also instigated nuclear fragmentation followed by augmentation in intracellular ROS levels (p < 0.001). The elevated ROS in A549 cells upon exposure to GAN/MTX combinatorial regimen was concomitantly accompanied with a remarkable reduction in mitochondrial viability. In addition, it was observed that the GAN/MTX combination succeeded in elevating caspase-3 activity and downregulating the expression levels of anti-apoptotic mediators Bcl2 and survivin in NSCLC A549 cells. Most importantly, the GAN/MTX combinatorial regimen impeded the activation of the NF-kB/p65 signaling pathway via repression of the expression of E-cadherin and N-cadherin, which was confirmed by molecular docking studies. Collectively, these findings demonstrated the synergistic effect of the GAN/MTX combinatorial regimen in suppressing the growth of A549 cells by modulating the NF-κB/p65 signaling pathway.

Analytical Methodologies for the Estimation of Oxazolidinone Antibiotics as Key Members of anti-MRSA Arsenal: A Decade in Review.

Gram-positive bacterial infections are among the most serious diseases related with high mortality rates and huge healthcare costs especially with the rise of antibiotic-resistant strains that limits treatment options. Thus, development of new antibiotics combating these multi-drug resistant bacteria is crucial. Oxazolidinone antibiotics are the only totally synthetic group of antibiotics that showed activity against multi-drug resistant Gram positive bacteria including MRSA because of their unique mechanism of action in targeting protein synthesis. This group include approved marketed members (tedizolid, linezolid and contezolid) or those under development (delpazlolid, radezolid and sutezolid). Due to the significant impact of this class, larger number of analytical methods were required to meet the needs of both clinical and industrial studies. Analyzing these drugs either alone or with other antimicrobial agents commonly used in ICU, in the presence of pharmaceutical or endogenous biological interferences, or in the presence of matrix impurities as metabolites and degradation products poses a big analytical challenge. This review highlights current analytical approaches published in the last decade (2012-2022) that dealt with the determination of these drugs in different matrices and discusses their advantages and disadvantages. Various techniques have been described for their determination including chromatographic, spectroscopic, capillary electrophoretic and electroanalytical methods. The review comprises six sections (one for each drug) with their related tables that depict critical figures of merit and some experimental conditions for the reviewed methods. Furthermore, future perspectives about the analytical methodologies that can be developed in the near future for determination of these drugs are suggested.

In Vitro Cytotoxicity and In Vivo Antitumor Activity of Lipid Nanocapsules Loaded with Novel Pyridine Derivatives.

This study demonstrates high drug-loading of novel pyridine derivatives (S1-S4) in lipid- and polymer-based core-shell nanocapsules (LPNCs) for boosting the anticancer efficiency and alleviating toxicity of these novel pyridine derivatives. The nanocapsules were fabricated using a nanoprecipitation technique and characterized for particle size, surface morphology, and entrapment efficiency. The prepared nanocapsules exhibited a particle size ranging from 185.0 ± 17.4 to 223.0 ± 15.3 nm and a drug entrapment of >90%. The microscopic evaluation demonstrated spherical-shaped nanocapsules with distinct core-shell structures. The in vitro release study depicted a biphasic and sustained release pattern of test compounds from the nanocapsules. In addition, it was obvious from the cytotoxicity studies that the nanocapsules showed superior cytotoxicity against both MCF-7 and A549 cancer cell lines, as manifested by a significant decrease in the IC50 value compared to free test compounds. The in vivo antitumor efficacy of the optimized nanocapsule formulation (S4-loaded LPNCs) was investigated in an Ehrlich ascites carcinoma (EAC) solid tumor-bearing mice model. Interestingly, the entrapment of the test compound (S4) within LPNCs remarkably triggered superior tumor growth inhibition when compared with either free S4 or the standard anticancer drug 5-fluorouracil. Such enhanced in vivo antitumor activity was accompanied by a remarkable increase in animal life span. Furthermore, the S4-loaded LPNC formulation was tolerated well by treated animals, as evidenced by the absence of any signs of acute toxicity or alterations in biochemical markers of liver and kidney functions. Collectively, our findings clearly underscore the therapeutic potential of S4-loaded LPNCs over free S4 in conquering EAC solid tumors, presumably via granting efficient delivery of adequate concentrations of the entrapped drug to the target site.

Atorvastatin-loaded pro-nanolipospheres with ameliorated oral bioavailability and antidyslipidemic activity.

Despite significant advances in oral drug delivery technologies, many drugs are prone to limited oral bioavailability due to biological barriers that hinder drug absorption. Pro-nanolipospheres (PNL) are a form of delivery system that can potentiate the oral bioavailability of poorly water-soluble drugs through a variety of processes, including increased drug solubility and protecting them from degradation by intestinal or hepatic first-pass metabolism. In this study, pro-nanolipospheres were employed as a delivery vehicle for improving the oral bioavailability of the lipophilic statin, atorvastatin (ATR). Various ATR-loaded PNL formulations, composed of various pharmaceutical ingredients, were prepared by the pre-concentrate method and characterized by determining particle size, surface charge, and encapsulation efficiency. An optimized formula (ATR-PT PNL) showing the smallest particle size, highest zeta potential, and highest encapsulation efficiency was selected for further in vivo investigations. The in vivo pharmacodynamic experiments demonstrated that the optimized ATR-PT PNL formulation exerted a potent hypolipidemic effect in a Poloxamer® 407-induced hyper-lipidaemia rat model by restoring normal cholesterol and triglyceride serum levels along with alleviating serum levels of LDL while elevating serum HDL levels, compared to pure drug suspensions and marketed ATR (Lipitor®). Most importantly, oral administration of the optimized ATR-PT PNL formulation showed a dramatic increase in ATR oral bioavailability, as evinced by a 1.7- and 3.6-fold rise in systemic bioavailability when compared with oral commercial ATR suspensions (Lipitor®) and pure drug suspension, respectively. Collectively, pro-nanolipospheres might represent a promising delivery vehicle for enhancing the oral bioavailability of poorly water-soluble drugs.

Drug repositioning: doxazosin attenuates the virulence factors and biofilm formation in Gram-negative bacteria.

The resistance development is an increasing global health risk that needs innovative solutions. Repurposing drugs to serve as anti-virulence agents is suggested as an advantageous strategy to diminish bacterial resistance development. Bacterial virulence is controlled by quorum sensing (QS) system that orchestrates the expression of biofilm formation, motility, and virulence factors production as enzymes and virulent pigments. Interfering with QS could lead to bacterial virulence mitigation without affecting bacterial growth that does not result in bacterial resistance development. This study investigated the probable anti-virulence and anti-QS activities of α-adrenoreceptor blocker doxazosin against Proteus mirabilis and Pseudomonas aeruginosa. Besides in silico study, in vitro and in vivo investigations were conducted to assess the doxazosin anti-virulence actions. Doxazosin significantly diminished the biofilm formation and release of QS-controlled Chromobacterium violaceum pigment and virulence factors in P. aeruginosa and P. mirabilis, and downregulated the QS encoding genes in P. aeruginosa. Virtually, doxazosin interfered with QS proteins, and in vivo protected mice against P. mirabilis and P. aeruginosa. The role of the membranal sensors as QseC and PmrA was recognized in enhancing the Gram-negative virulence. Doxazosin downregulated the membranal sensors PmR and QseC encoding genes and could in silico interfere with them. In conclusion, this study preliminary documents the probable anti-QS and anti-virulence activities of doxazosin, which indicate its possible application as an alternative or in addition to antibiotics. However, extended toxicological and pharmacological investigations are essential to approve the feasible clinical application of doxazosin as novel efficient anti-virulence agent. KEY POINTS: • Anti-hypertensive doxazosin acquires anti-quorum sensing activities • Doxazosin diminishes the virulence of Proteus mirabilis and Pseudomonas aeruginosa • Doxazosin could dimmish the bacterial espionage.

Diminishing the Pathogenesis of the Food-Borne Pathogen Serratia marcescens by Low Doses of Sodium Citrate.

Protecting food from bacterial contamination is crucial for ensuring its safety and avoiding foodborne illness. Serratia marcescens is one of the food bacterial contaminants that can form biofilms and pigments that spoil the food product and could cause infections and illness to the consumer. Food preservation is essential to diminish such bacterial contaminants or at least reduce their pathogenesis; however, it should not affect food odor, taste, and consistency and must be safe. Sodium citrate is a well-known safe food additive and the current study aims to evaluate its anti-virulence and anti-biofilm activity at low concentrations against S. marcescens. The anti-virulence and antibiofilm activities of sodium citrate were evaluated phenotypically and genotypically. The results showed the significant effect of sodium citrate on decreasing the biofilm formation and other virulence factors, such as motility and the production of prodigiosin, protease, and hemolysins. This could be owed to its downregulating effect on the virulence-encoding genes. An in vivo investigation was conducted on mice and the histopathological examination of isolated tissues from the liver and kidney of mice confirmed the anti-virulence activity of sodium citrate. In addition, an in silico docking study was conducted to evaluate the sodium citrate binding ability to S. marcescens quorum sensing (QS) receptors that regulates its virulence. Sodium citrate showed a marked virtual ability to compete on QS proteins, which could explain sodium citrate's anti-virulence effect. In conclusion, sodium citrate is a safe food additive and can be used at low concentrations to prevent contamination and biofilm formation by S. marcescens and other bacteria.

A Prospective Cohort Study of COVID-19: Evaluation of the Early Role of IL-1 and IL-6 Antagonists in Improving the Outcome of the Illness and Reduction in the Risk of Death.

The COVID-19 pandemic had a profound impact on global health, economies, and social systems. The crucial factor that determines the success of COVID-19 treatments is preventing the need for mechanical ventilation and intensive care admission. In the context of COVID-19, several treatments have been found to play a role in the disease's progression and severity. Interleukins (ILs) have been identified as key mediators of the cytokine storm that can occur in severe cases of COVID-19, leading to respiratory failure and other complications. For instance, IL-1 antagonist (anakinra) and IL-6 antagonist (tocilizumab) are supposed to be promising treatments as well as cortisones for COVID-19. This prospective study aims to evaluate the effectiveness of anakinra or tocilizumab in addition to cortisone in preventing the progression of mild to moderate COVID-19 cases to severe intensive care admission. Biochemical and hematological parameters, such as D-dimer, ferritin, LDH, CRP, and white blood cells (WBCs), were measured after treatment with either anakinra or tocilizumab in addition to cortisone or cortisone alone. The study also recorded the number of deaths and patients admitted to intensive care. The results indicate that anakinra significantly improved outcomes and decreased the number of intensive care admissions compared to tocilizumab or cortisone alone. Therefore, anakinra may play a vital role in controlling the progression of COVID-19, and its use in mild to moderate cases may prevent the worsening of the disease to severe stages.

Clinical Resistant Strains of Enterococci and Their Correlation to Reduced Susceptibility to Biocides: Phenotypic and Genotypic Analysis of Macrolides, Lincosamides, and Streptogramins.

Enterococci are troublesome nosocomial, opportunistic Gram-positive cocci bacteria showing enhanced resistance to many commonly used antibiotics. This study aims to investigate the prevalence and genetic basis of antibiotic resistance to macrolides, lincosamides, and streptogramins (MLS) in Enterococci, as well as the correlation between MLS resistance and biocide resistance. From 913 clinical isolates collected from King Khalid Hospital, Hail, Saudi Arabia, 131 isolates were identified as Enterococci spp. The susceptibility of the clinical enterococcal isolates to several MLS antibiotics was determined, and the resistance phenotype was detected by the triple disk method. The MLS-involved resistance genes were screened in the resistant isolates. The current results showed high resistance rates to MLS antibiotics, and the constitutive resistance to all MLS (cMLS) was the most prevalent phenotype, observed in 76.8% of resistant isolates. By screening the MLS resistance-encoding genes in the resistant isolates, the erythromycin ribosome methylase (erm) genes that are responsible for methylation of bacterial 23S rRNA were the most detected genes, in particular, ermB. The ereA esterase-encoding gene was the most detected MLS modifying-encoding genes, more than lnuA (adenylation) and mphC (phosphorylation). The minimum inhibitory concentrations (MICs) of commonly used biocides were detected in resistant isolates and correlated with the MICs of MLS antibiotics. The present findings showed a significant correlation between MLS resistance and reduced susceptibility to biocides. In compliance with the high incidence of the efflux-encoding genes, especially mefA and mefE genes in the tolerant isolates with higher MICs to both MLS antibiotics and biocides, the efflux of resistant isolates was quantified, and there was a significant increase in the efflux of resistant isolates with higher MICs as compared to those with lower MICs. This could explain the crucial role of efflux in developing cross-resistance to both MLS antibiotics and biocides.