3D-QSAR pharmacophore modeling, virtual screening, molecular docking, MD simulations, in vitro and in vivo studies to identify potential anti-hyperplasia drugs.

Psoriasis is a common immune-mediated skin condition characterized by aberrant keratinocytes and cell proliferation. The purpose of this study was to explore the FDA-approved drugs by 3D-QSAR pharmacophore model and evaluate their efficiency by in-silico, in vitro, and in vivo psoriasis animal model. A 3D-QSAR pharmacophore model was developed by utilizing HypoGen algorithm using the structural features of 48 diaryl derivatives with diverse molecular patterns. The model was validated by a test set of 27 compounds, by cost analysis method, and Fischer's randomization test. The correlation coefficient of the best model (Hypo2) was 0.9601 for the training set while it was 0.805 for the test set. The selected model was taken as a 3D query for the virtual screening of over 3000 FDA-approved drugs. Compounds mapped with the pharmacophore model were further screened through molecular docking. The hits that showed the best docking results were screened through in silico skin toxicity approach. Top five hits were selected for the MD simulation studies. Based on MD simulations results, the best two hit molecules, that is, ebastine (Ebs) and mebeverine (Mbv) were selected for in vitro and in vivo antioxidant studies performed in mice. TNF-α and COX pro-inflammatory mediators, biochemical assays, histopathological analyses, and immunohistochemistry observations confirmed the anti-inflammatory response of the selected drugs. Based on these findings, it appeared that Ebs can effectively treat psoriasis-like skin lesions and down-regulate inflammatory responses which was consistent with docking predictions and could potentially be employed for further research on inflammation-related skin illnesses such as psoriasis.

An overview of viral mutagenesis and the impact on pathogenesis of SARS-CoV-2 variants.

Viruses are submicroscopic, obligate intracellular parasites that carry either DNA or RNA as their genome, protected by a capsid. Viruses are genetic entities that propagate by using the metabolic and biosynthetic machinery of their hosts and many of them cause sickness in the host. The ability of viruses to adapt to different hosts and settings mainly relies on their ability to create de novo variety in a short interval of time. The size and chemical composition of the viral genome have been recognized as important factors affecting the rate of mutations. Coronavirus disease 2019 (Covid-19) is a novel viral disease that has quickly become one of the world's leading causes of mortality, making it one of the most serious public health problems in recent decades. The discovery of new medications to cope with Covid-19 is a difficult and time-consuming procedure, as new mutations represent a serious threat to the efficacy of recently developed vaccines. The current article discusses viral mutations and their impact on the pathogenicity of newly developed variants with a special emphasis on Covid-19. The biology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), its mutations, pathogenesis, and treatment strategies are discussed in detail along with the statistical data.

Nanocrytals-Mediated Oral Drug Delivery: Enhanced Bioavailability of Amiodarone.

The aim of this study was to improve the saturation solubility, dissolution profile and oral bioavailability of amiodarone hydrochloride (AMH), a highly lipophilic drug. Stabilizer (Pluronic F-127)-coated AMH nanocrystals (AMH-NCs) were developed by a combination of antisolvent precipitation and homogenization techniques. The optimized formulation comprised pluronic F-127 and AMH at the concentration of 4% and 2% w/v, respectively. The particle size (PS), zeta potential (ZP) and polydispersity index (PDI) of the optimized formulation was found to be 221 ± 1.2 nm, 35.3 mV and 0.333, respectively. The optimized formulation exhibited a rough surface morphology with particles in colloidal dimensions and a significant reduction in crystallinity of the drug. AMH-NCs showed a marked increase in the saturation solubility as well as rapid dissolution rate when compared with the AMH and marketed product. The stability study displayed that the formulation was stable for 3 months, with no significant change in the PS, ZP and PDI. The in vivo pharmacokinetic study demonstrated the ability of AMH-NCs to significantly (p < 0.05) improve the oral bioavailability (2.1-fold) of AMH in comparison with AMH solution, indicating that the production of AMH-NCs using a combination of antisolvent precipitation and homogenization techniques could enhance the bioavailability of the drug.

Development and In Vitro/In Vivo Evaluation of pH-Sensitive Polymeric Nanoparticles Loaded Hydrogel for the Management of Psoriasis.

Methotrexate (MTX), the gold standard against psoriasis, poses severe problems when administered systemically viz increased toxicity, poor solubility and adverse reactions. Hence, a topical formulation of MTX for the management of psoriasis can be an effective approach. The present study aimed to develop an MTX based nanoparticle-loaded chitosan hydrogel for evaluating its potential efficacy in an imiquimod-induced psoriatic mice model. MTX-NPs loaded hydrogel was prepared and optimized using the o/w emulsion solvent evaporation method. Particle size, zeta potential, entrapment efficiency, in vitro drug release, ex vivo permeation, skin irritation and deposition studies were performed. Psoriatic Area and Severity Index (PASI) score/histopathological examinations were conducted to check the antipsoriatic potential of MTX-NPs loaded hydrogel using an imiquimod (IMQ)-induced psoriatic model. Optimized MTX-NPs showed a particle size of 256.4 ± 2.17 nm and encapsulation efficiency of 86 ± 0.03%. MTX-NPs loaded hydrogel displayed a 73 ± 1.21% sustained drug release in 48 h. Ex vivo permeation study showed only 19.95 ± 1.04 µg/cm2 of drug permeated though skin in 24 h, while epidermis retained 81.33% of the drug. A significant decrease in PASI score with improvement to normalcy of mice skin was observed. The developed MTX-NPs hydrogel displayed negligible signs of mild hyperkeratosis and parakeratosis, while histopathological studies showed healing signs of mice skin. So, the MTX-NPs loaded hydrogel can be a promising delivery system against psoriasis.

Development of an intelligent, stimuli-responsive transdermal system for efficient delivery of Ibuprofen against rheumatoid arthritis.

The present study aimed to fabricate and evaluate the therapeutic efficacy of pH-responsive Ibuprofen (IB) nanoparticles (NPs) loaded transdermal hydrogel against rheumatoid arthritis (RA). The IB loaded Eudragit® L 100 (EL 100) nanoparticles were formulated through a modified nanoprecipitation technique and optimized using central composite design software. The optimized NPs were loaded into Carbopol® 934-based hydrogel by solvent evaporation method and were analyzed for physicochemical characteristics. The mean particle size of the prepared NPs was 48 nm with an entrapment efficiency of 90%. The transdermal hydrogel showed a pH-responsive sustained drug release and high penetration through the skin. Moreover, the prepared nanocarrier system exhibited therapeutic efficacy at inflamed joints' sites both in acute and chronic RA mice model. The therapeutic efficacy of the prepared formulation was confirmed through the results of various behavioral, biochemical, and cytokines-based assays. Similarly, the assessment of histopathological and radiological images, as well as the skin irritation studies further strengthens the potential use of the prepared formulation through the transdermal route. The current findings suggested that IB loaded pH-responsive NPs based transdermal hydrogel can be used as an efficient agent to manage RA.

Surfactant-Free, Self-Assembled Nanomicelles-Based Transdermal Hydrogel for Safe and Targeted Delivery of Methotrexate against Rheumatoid Arthritis.

Methotrexate (MTX) is the first line agent for therapy against rheumatoid arthritis (RA); however, orally its efficacy is hampered by poor solubility, less permeability, short plasma half-life, and reduced bioavailability. Meanwhile, parenteral formulations are associated with severe adverse effects. In an attempt to improve the efficacy of MTX, we synthesized polycaprolactone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL) triblock copolymer by a ring-opening copolymerization reaction and used it as a carrier for the fabrication of MTX-loaded nanomicelles. Surfactant-free, self-assembled nanomicelles were prepared by nanoprecipitation technique and optimized through central composite design. The optimized nanomicelles exhibited a size distribution of 31 nm and an encapsulation efficiency of 91%. In vitro, the nanomicelles exhibited hemocompatibility, sustained release, and significantly high uptake in lipopolysaccharide activated macrophages. To facilitate application on the skin, optimized nanomicelles were loaded into a Carbopol 934-based hydrogel with eucalyptus oil as a penetration enhancer. Eucalyptus oil significantly improved the permeation of nanomicelles through the skin (p < 0.001). When the hydrogel was applied on the RA mice model, nanomicelles exhibited preferentially highest accumulation in the inflamed joints than other organs. As compared with the free MTX, MTX nanomicelles significantly improved the pharmacokinetic (4.34-fold greater half-life, 3.68-fold higher AUC0-t, and 3.15-fold higher mean residence time) and pharmacodynamic profile ascertained through low inflammatory cytokines expression, improved oxidation protection, recovered behavioral responses, and radiological analysis. MTX nanomicelles-based hydrogel also significantly reduced the hepatotoxicity and did not activate the immune system. These results suggest that the MTX-loaded nanomicelles-based transdermal hydrogel can prove to be a promising agent against RA.

Development of novel pH-sensitive nanoparticle-based transdermal patch for management of rheumatoid arthritis.

Aim: To formulate and evaluate a pH-responsive nanoparticle (NP)-based patch for efficient transdermal delivery of flurbiprofen against rheumatoid arthritis. Materials & methods: Nanoprecipitation technique was used for preparation of NPs and central composite design was employed for optimization purposes. Optimized NPs were loaded into the transdermal patch by the solvent evaporation method. Results: Prepared NPs exhibited an average size of 69 nm, while NPs loaded onto the transdermal patch showed sustained release and high permeation through the skin. In in vivo studies, the prepared carrier system elucidated high therapeutic potential in both acute and chronic inflammatory models as evident from the results of behavioral, radiological, histopathological and antioxidant analyses. Conclusion: The flurbiprofen-loaded pH-sensitive NP-based transdermal patch has the potential to manage rheumatoid arthritis effectively.

Comprehensive investigation on the synergistic antibacterial activities of Jatropha curcas pressed cake and seed oil in combination with antibiotics.

Synergistic combinations of various antimicrobial agents are considered ideal strategies in combating clinical and multidrug resistant (MDR) infections. In this study, antibacterial potential of Jatropha curcas crude seed extracts, seed oil, commercially available antibiotics, and their combinations were investigated for their synergistic effect against clinical, MDR and ATCC bacterial strains by agar well diffusion assay. Methanolic extracts remained more active against Staphylococcus aureus (ATCC), with zone of inhibition (ZOI) of 21 mm, than clinical and methicillin-resistant S. aureus (MRSA) strains (ZOI range ~ 15.0-17.0 mm). Molecular docking demonstrated that beta-monolaurin from methanolic extract exhibited greater affinity conformation for UDP-N-acetylmuramoyl-tripeptide-D-alanyl-D-alanine (MurF) ligase's active pocket with binding energy of -7.3 kcal/mol. Moxifloxacin exhibited greater activity against Escherichia coli (ATCC) (ZOI ~ 50.0 mm), followed by ofloxacin against Pseudomonas chlororaphis (47.3 mm), moxifloxacin against P. monteilii (47 mm), P. aeruginosa (46.3 mm) and MRSA2 (46 mm) and ofloxacin against S. aureus (ATCC) strains (45.7 mm). Methanolic extract in combination with rifampicin showed the highest synergism against MRSA strains, A. baumannii, E. coli, E. faecalis, S. aureus, and P. aeruginosa, A. baumannii (MDR strain), P. chlororaphis, E. coli ATCC25922 and S. aureus ATCC25923. In combinations, moxifloxacin exhibited the highest antagonism. The methanolic, n-hexane, aqueous extracts and seed oil in various combinations with antibiotics showed 44.71, 32.94, 9.41 and 25.88% synergism, respectively. The current study showed that potency of antibiotics was improved when screened in combination with J. curcas seed's components, supporting the drug combination strategy to combat antibacterial resistance.