Synthesis of 3-hydroxy-2-naphthohydrazide-based hydrazones and their implications in diabetic management via in vitro and in silico approaches.

Diabetes mellitus (DM) has prevailed as a chronic health condition and has become a serious global health issue due to its numerous consequences and high prevalence. We have synthesized a series of hydrazone derivatives and tested their antidiabetic potential by inhibiting the essential carbohydrate catabolic enzyme, "α-glucosidase." Several approaches including fourier transform infrared, 1 H NMR, and 13 C NMR were utilized to confirm the structures of all the synthesized derivatives. In vitro analysis of compounds 3a-3p displayed more effective inhibitory activities against α-glucosidase with IC50 in a range of 2.80-29.66 µM as compared with the commercially available inhibitor, acarbose (IC50 = 873.34 ± 1.67 M). Compound 3h showed the highest inhibitory potential with an IC50 value of 2.80 ± 0.03 µM, followed by 3i (IC50 = 4.13 ± 0.06 µM), 3f (IC50 = 5.18 ± 0.10 µM), 3c (IC50 = 5.42 ± 0.11 µM), 3g (IC50 = 6.17 ± 0.15 µM), 3d (IC50 = 6.76 ± 0.20 µM), 3a (IC50 = 9.59 ± 0.14 µM), and 3n (IC50 = 10.01 ± 0.42 µM). Kinetics analysis of the most potent compound 3h revealed a concentration-dependent form of inhibition by 3h with Ki value = 4.76 ± 0.0068 µM. Additionally, an in silico docking approach was applied to predict the binding patterns of all the compounds, which indicates that the hydrazide and the naphthalene-ol groups play a vital role in the binding of the compounds with the essential residues (i.e., Glu277 and Gln279) of the α-glucosidase enzyme.

Development, characterization and evaluation of in vitro anti-inflammatory activity of Withania coagulans extract and extract loaded microemulsion.

Herbal medicines are gaining importance due to more advantages and less toxic effects. Withania coagulans is natural plant that possesses multiple activities. Its main constituents are withaferin and withanolide. The purpose of present study is to identify main constituent of Withania coagulans and preparation of extract loaded micro emulsions. Withania coagulans fruit extract in methanol/chloroform (1:1) was collected in semisolid form and LCMS was done to identify active compound, and then micro emulsions were prepared using Tween 80: Transcutol (1:1) Frankincense oil, and water to enhance its stability for topical application. Five formulations were prepared by Pseudo ternary phase diagram and evaluated for pH, conductivity, viscosity, drug contents, particle size analysis, and polydispersity. Withania coagulans extract was evaluated for anti-bacterial activity against (Staphylococcus aureus, E. coli, and S. typhi) and anti-fungal activity against (Candida albicans and Aspergillus niger). Anti-inflammatory activity was checked for both extract and Extract based micro emulsion. Among all five formulations F5 shows best physiochemical properties with small globule size, good stability and high anti-inflammatory activity. Based on these results it was concluded that Withania coagulans extract loaded micro emulsions can be used for topical application with promising anti-inflammatory activities. Data for in-vivo studies for checking the topical effect of Withania coagulans is provided elsewhere.

Stability indicating RP-HPLC method of dexibuprofen in nanocream formulation: Identification and quantification.

A stability indicating reverse phase-HPLC method was designed for determination of dexibuprofen in drug solution and in nanocream formulation. Chromatographic conditions were optimized simply by adjusting the content and different compositions of reverse phase associated with mobile phases. Different parameters like specificity, limit of quantification (LOQ), limit of detection, linearity, range, system suitability, precision and accuracy were determined. Stability studies of dexibuprofen in nanocream were taken under the stressed situations of alkali, acid, oxidation process, UV and heat degradation. Tailing factor and % RSD were found >2000 and <2% respectively. The method was identified linear over the range of 0.2-1.6mg/ml having co-efficient of correlation 0.9995. Intra-day and inter- day precision and accuracy values for dexibuprofen were < 0.6% and <1.1032 and < 0.3% and 1.10% respectively. Stability studies showed that dexibuprofen was stable in nanocream against alkali, acid, oxidation, UV light and heat. The developed validated method was precise and accurate for the evaluation of dexibuprofen in solution as well as in nanocream formulation.

Curcumin Encapsulation in Geranium Oil Microemulsion Elevates Its Antibacterial, Antioxidant, Anti-Inflammatory, and Anticancer Activities.

One of the major challenges with curcumin is its poor solubility in water, which limits its absorption and bioavailability in the body. This study aimed to develop and characterize stable microemulsions (MEs) as MEs increase the dispersibility of curcumin in water and aid its absorption in the body. Curcumin-loaded MEs were developed with the goal of enhancing topical delivery and its pharmacological activity (antioxidant, antibacterial, anticancer activity, and anti-inflammatory). The pseudoternary phase diagram was constructed to find out the desired microemulsion region. The prepared MEs (ME1-ME5) were evaluated for pH, viscosity, size of the particle, electrical conductivity, zeta potential, and ex vivo permeation of the drug. The optimized ME formulation was selected based on particle size and was further evaluated for biological activity (in vitro/vivo). In vitro cytotoxic effects of formulations were checked on the human liver cancer cell line, HEPG2 (a cell line exhibiting epithelial-like morphology that was isolated from a hepatocellular carcinoma). Geranium oil, Tween 80 (as a surfactant), and propylene glycol (as a cosurfactant) were screened out based on solubility to formulate MEs. The optimized ME formulation (ME5), with a composition of 20:50:30 (geranium oil:Tween 80:propylene glycol), exhibited pH 4.36 ± 0.057, conductivity of 40.06 ± 0.05 µS/cm, viscosity of 165 ± 0.37 mPa·s, and droplet diameter of 199.39 ± 0.017 nm. The ex vivo permeation study demonstrated a significant cumulative amount of curcumin permeated in 24 h and had a flux of 130.91 ± 0.02 µg/cm2/h. Antioxidant activity demonstrated that curcumin-loaded microemulsion (ME5) exhibited higher scavenging activity (99.27 ± 0.021%) than blank microemulsion (94.67 ± 0.001%). Optimized curcumin-loaded microemulsion (ME5) exhibited zones of inhibition of 25.18 and 28.37 mm against Escherichia coli and Staphylococcus aureus, respectively. Among the cell lines tested, a higher concentration of ME5 showed the greatest cytotoxicity with a % viability of 8.22 ± 1.09%. Evidently, it also revealed significant in vivo anti-inflammatory effects with 93.29 ± 0.030% inhibition by the carrageenan-induced paw edema model (6 h study) and 88.39 ± 0.002% inhibition by the formalin-induced paw edema model (14 day study). In conclusion, microemulsion was safe and effective for effective delivery of curcumin with the potential for antioxidant, antibacterial, cytotoxic, and in vivo anti-inflammatory activities.

Curcumin-loaded soluplus® based ternary solid dispersions with enhanced solubility, dissolution and antibacterial, antioxidant, anti-inflammatory activities.

Amorphous solid dispersion (ASD) has emerged to be an outstanding strategy among multiple options available for improving solubility and consequently biological activity. Interestingly several binary SD systems continue to exhibit insufficient solubility over time. Therefore, the goal of current research was to design ternary amorphous solid dispersions (ASDs) of hydrophobic model drug curcumin (CUR) to enhance the solubility and dissolution rate in turn, presenting enhanced anti-bacterial, antioxidant and anti-inflammatory activity. For this purpose several ternary solid dispersions (TSDs) consisting of Soluplus®, Syloid® XDP 3150, Syloid® 244 and Poloxamer® 188 in combination with HPMC E5 (binary carrier) were prepared using solvent evaporation method. Both solubility and dissolution testing of prepared solid dispersion were performed to determine the increase in solubility and dissolution. Solid state investigation was carried out utilizing infrared spectroscopy, also known as Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM),Differential scanning calorimetry (DSC) and X-ray diffraction (XRD).Optimized formulations were also tested for their biological effectiveness including anti-bacterial, anti-oxidant and anti-inflammatory activity. Amid all Ternary formulations F3 entailing 20 % soluplus® remarkably improved the solubility (186 µg/ml ± 3.95) and consequently dissolution (91 % ± 3.89 %) of curcumin by 3100 and 9 fold respectively. These finding were also supported by FTIR, SEM, XRD and DSC. In-vitro antibacterial investigation of F3 also demonstrated significant improvement in antibacterial activity against both gram positive (Staphylococcus aureus, Bacillus cereus) and gram negative (Pseudomonas aeruginosa, Escherichia coli) bacteria. Among all the tested strains Staphylococcus aureus was found to be most susceptible with a zone of inhibition of 24 mm ± 2.87. Antioxidant activity of F3 was also notably enhanced (93 % ± 5.30) in contrast to CUR (69 % ± 4.79). In vitro anti-inflammatory assessment also exhibited that F3 markedly protected BSA (bovine serum albumin) from denaturation with percent BSA inhibition of 80 % ± 3.16 in comparison to CUR (49 % ± 2.91). Hence, F3 could be an effective solid dispersion system for the delivery of model hydrophobic drug curcumin.

Making it internally persuasive: Analysis of the conspiratorial discourse on COVID-19.

This study attempts to generate new insights into the wide spread online and offline conspiratorial discourse on COVID-19. Twofold analytical lens consisted of narrative interrelations framework and content analysis showed how the linguistic resources and conversational such as popular socio-religious discourses, hypothetical narratives, personal narratives, personal mental archives, and interpolated arguments are integrated in the interpretation of intertextual Bases such as Bill Gates' TED talk 2015 (26%); Nematullah Wali's predictions (32%); 'End of Days' book by Sylvia Browne (14.9%); and 'The Eyes of Darkness' novel by Dean Koontz (22%) by which the conspiracists in Pakistan construct an internally persuasive discourse promoting conspiracy theories on COVID-19. Several linguistic resources such as mood, modality, topicalization, insinuation, and intertextuality emerged as the main tools of making the conspiracy theories internally persuasive.

Effect of hydrophilic polymers on the solubility and dissolution enhancement of rivaroxaban/beta-cyclodextrin inclusion complexes.

BCS class II drugs exhibit low aqueous solubility and high permeability. Such drugs often have an incomplete or erratic absorption profile. This study aimed to predict the effects of ß-cyclodextrin (ßCD) and different hydrophilic polymers (poloxamer 188 (PXM-188), polyvinyl pyrrolidone (PVP) and soluplus (SOLO)) on the saturated solubility and dissolution profile of hydrophobic model drug rivaroxaban (RIV). Binary inclusion complex with ßCD were prepared by kneading and solvent evaporation method, at drug to cyclodextrin weight molar ratios of 1:1, 1:2, and 1:4. Saturated solubility of the hydrophobic model moiety was evaluated with ßCD to explore the increment in saturated solubility. Dissolution test was carried out to assess the drug release from the produced binary inclusion complex in the aqueous medium. Solid state analysis was performed using Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Scanning electron microscopy (SEM) techniques. When compared to pure drug, the binary complex (Drug: ßCD at molar ratio of 1:2 w/w) demonstrated the best performance in terms of enhanced solubility and drug release. Furthermore, ternary inclusion complex was prepared with hydrophilic polymers SOLO, PVP K-30 and PXM-188 at 0.5%,1%,2.5%,5% and 10% w/w to optimized binary formulation RIV:ßCD (1:2) prepared by kneading (KN) and solvent evaporation (S.E) method. The findings demonstrated that among ternary formulations (1:2 Drug: ßCD: SOLO 10% S.E) manifested greatest improvement in saturated solubility and dissolution rate. Results of solubility enhancement and improvement in dissolution profile of model drug by ternary inclusion complexation were also supported by FTIR, DSC, XRD, and SEM analysis. So, it can be concluded that the ternary inclusion systems were more effective compared to the binary combinations in improving solubility as well as dissolution of hydrophobic model drug rivaroxaban.

Solubility and Dissolution Enhancement of Dexibuprofen with Hydroxypropylbetacyclodextrin (HPßCD) and Poloxamers (188/407) Inclusion Complexes: Preparation and In Vitro Characterization.

The objective of this study was to improve the dissolution and solubility of dexibuprofen (DEX) using hydroxypropyl beta cyclodextrin (HPßCD) inclusion complexes and also to evaluate the effect of presence of hydrophilic polymers on solubilization efficiency of HPßCD. Three different methods (physical trituration, kneading and solvent evaporation) were used to prepare binary inclusion complexes at various drug-to-cyclodextrin weight ratios. An increase in solubility and drug release was observed with the kneading (KN) method at a DEX/HPßCD (1:4) weight ratio. The addition of hydrophilic polymers poloxamer-188 (PXM-188) and poloxamer-407 (PXM-407) at 2.5, 5.0, 10.0 and 20% w/w enhanced the complexation efficiency and solubility of DEX/HPßCD significantly. Fourier-transform infrared (FTIR) analysis revealed that DEX was successfully incorporated into the cyclodextrin cavity. Differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) revealed less crystallinity of the drug and its entrapment in the cyclodextrin molecular cage. The addition of PXM-188 or PXM-407 reduced the strength of the DEX endothermic peak. With the addition of hydrophilic polymers, sharp and intense peaks of DEX disappeared. Finally, it was concluded that PXM-188 at a weight ratio of 10.0% w/w was the best candidate for improving solubility, stability and release rate of DEX.

On the Psychology of Argument: A Structural Analysis of Former Muslims' Postings Within Malaysian Social Media.

This research attempts to provide insights into the argumentation structures in the discussion of Islam on social media involving 14 Malaysian former Muslims. The social media accounts of the participants were observed for 12 months, from January to December 2019. A total of 368 postings put forth arguments related to Islamic authoritative discourse, the Quran and "Sunnah" of the Prophet Muhammad, to justify their renunciation of the Muslim religion. The analysis revealed that the Level 2 argument, which includes the claim, data to support the claim, and the warrant, was identified as the most common argument structure. Level 5, which has more than one rebuttal, was the least common argument structure. The analysis shows that most argument structures were at the lower levels (1-3) in that they offered no strong, clearly identifiable rebuttals. This study concludes that the arguments put forth by former Muslims, in the main, are loosely constructed rather than attempts to build a strong cumulative argumentation to support their reasons for abandoning the Muslim faith.

Poloxamer-188 and d-α-Tocopheryl Polyethylene Glycol Succinate (TPGS-1000) Mixed Micelles Integrated Orodispersible Sublingual Films to Improve Oral Bioavailability of Ebastine; In Vitro and In Vivo Characterization.

Orodispersible sublingual films (OSFs) composed of hydrophilic polymers were loaded with poloxamer-188 and d-α-tocopheryl polyethylene glycol succinate (TPGS-1000) mixed micelles to improve the oral bioavailability of a poorly soluble drug, ebastine (EBT). Mixed micelles formed by thin-film hydration method were incorporated into orodispersible sublingual film, consisting of HPMC and glycerol, using solvent casting technique. The mixed micelles and films were thoroughly evaluated for physicochemical characterization (size, polydispersity index, zeta potential, entrapment efficiency, thickness, weight, surface pH studies, disintegration time, swelling indices, mechanical properties, FTIR, PXRD, DSC, SEM, AFM, in vitro drug release, in vivo bioavailability, and toxicological studies). The results showed that the average particle size of mixed micelles was 73 nm. The mean zeta potential and PDI of the optimal mixed micelles formulation were -26 mV and 0.16, respectively. Furthermore, the maximum entrapment efficiency 82% was attained. The film's disintegration time was in the range of 28 to 102 s in aqueous media. The integrity of micelles was not affected upon incorporation in films. Importantly, the micelles-loaded films revealed rapid absorption, high permeability, and increased bioavailability of EBT as compared to the pure drug. The existence of ebastine loaded mixed micelles in the films enhanced the bioavailability about 2.18 folds as compared to pure drug. Further, the results evidently established in-vitro and in-vivo performance of bioavailability enhancement, biocompatibility, and good safety profile of micelles-loaded orodispersible EBT films. Finally, it was concluded that film loaded with poloxamer-188/TPGS-1000 mixed micelles could be an effective carrier system for enhancing the bioavailability of ebastine.