Influence of genetic and non-genetic factors on acenocoumarol maintenance dose requirement in a Tunisian population.

PURPOSE: We aimed to study potential variables involved in interindividual variability to acenocoumarol (AC) response in order to establish a pharmacogenetic algorithm (PA) that includes clinical and genetic factors to predict adequate AC dose to stabilize anticoagulation in a cohort of Tunisian patients. METHODS: Genotyping of the CYP2C9, VKORC1, CYP4F2, and CALU polymorphisms was conducted on 246 patients using PCR-RFLP technique. AC normalized maintenance dose (NMD): ((mean maintenance dose/international normalized ratio (INR)) equilibrium) was calculated. The statistical study was carried out with SPSS V20. RESULTS: A significant correlation was found between age, BMI, and daily AC dose (r = - 0.397; p < 0.001 and r = 0.215; p = 0.001, respectively). The carriers of mutated alleles CYP2C9*2 or CYP2C9*3 or VKORC1 haplotypes (H1 and H7) were associated with AC hyper-sensibility. After adjustment to potential covariates, these patients presented supra-therapeutic INR during treatment period and needed low AC dose (ORs* = 0.28 [0.06-0.60], p = 0.004; ORs* = 0.12 [0.04-0.05], p < 0.001; ORs* = 0.45 [0.24-0.84], p = 0.01; and ORs* = 0.28 [0.06-0.98], p = 0.049, respectively). However, carriers of VKORC1 haplotypes (H3 and H12) or mutated alleles CYP4F2 (rs2108622) or CALU (rs1043550) tend to resist to treatment, hence long period of therapy initiation, and must be treated with high AC dose (ORs* = 2.67 [81.12-5.91], p = 0.013; ORs* = 8.76 [1.07-76.26], p = 0.019; ORs* = 3.12 [1.01-9.63], p = 0.047; and ORs* = 3.96 [1.41-11.09], p = 0.009, respectively). A final multivariate regression model explained 48.1% of the global interindividual variability in AC dose requirement. CONCLUSION: The PA demonstrated that VKORC1 and CYP2C9 polymorphisms contribution was more important than clinical factors. Applying the PA would allow dose adjustment to treat patients in a personalized manner.

Preparation and evaluation of periodontal films based on polyelectrolyte complex formation.

Local intra-pocket drug delivery devices can provide an effective concentration of the antimicrobial agent at the site of action with avoidance of undesirable side effects. This study explored the application of chitosan-alginate and chitosan-pectin polyelectrolyte complex (PEC) films as drug release regulators for tetracycline HCl (Tc) to treat periodontal pockets. Periodontal films with 1:1 Tc:PEC ratio were prepared using 1:1 chitosan (Ch) to sodium alginate (A) or 1:3 Ch to pectin (P). The scanning electron microscope showed acceptable film appearance and differential scanning calorimetry analysis confirmed complex formation. The in vitro release studies for both films showed a burst drug release, followed by prolonged release for 70 h. A prolonged antibacterial activity of both films against Staphylococcus aureus ATCC 6538 was observed over a period of 21 days. Aging studies indicated that the five months storage period in freezer did not significantly influence the drug release profile or the antibacterial activity of both films. Clinical evaluation showed a significant reduction in pocket depth (p < 0.0001) to their normal values (≤3 mm). PEC films could be exploited as a prolonged drug release devices for treatment of periodontal pockets.

Comparative study to investigate the effect of meloxicam or minocycline HCl in situ gel system on local treatment of periodontal pockets.

In situ gelling formulations allow easy application to the target area. Gelation is induced by physiological stimuli at the site of application where the formula attains semisolid properties and exerts sustained drug release. In situ gelling formulations containing either 3% meloxicam (Mx) or 2% minocycline HCl (MH) were prepared for local application into the periodontal pockets. Gel formulations were based on the thermosensitive Pluronic(®) (Pl) and the pH-sensitive Carbopol(®) (C) polymers. C gels were prepared in combination with HPMC (H) to decrease its acidity. The total percent drug released from Pl formulae was 21.72% after 1 week for Mx and 85% after 3 days for MH. Their release kinetics data indicated anomalous non-Fickian behavior that could be controlled by both diffusion and chain relaxation. Addition of MH to C/H gels (1:2.5) resulted in liquefaction, followed by drug precipitation. Regarding C/H gel containing Mx, it showed a prolonged release rate up to 7 days with an initial burst effect; the kinetics data revealed Fickian-diffusion mechanism. The in vitro antibacterial activity studies for MH gel in Pl revealed that the drug released exceeded the minimum inhibitory concentration (MIC) of MH against Staphylococcus aureus ATCC 6538; placebo gel showed no effect on the microorganism. Clinical evaluation of Pl gels containing either Mx or MH showed significant improvement in chronic periodontitis patients, manifested by decrease in pocket depth and gingival index and increase in bone density.

Brain targeted lactoferrin coated lipid nanocapsules for the combined effects of apocynin and lavender essential oil in PTZ induced seizures.

Apocynin (APO) is a plant derived antioxidant exerting specific NADPH oxidase inhibitory action substantiating its neuroprotective effects in various CNS disorders, including epilepsy. Due to rapid elimination and poor bioavailability, treatment with APO is challenging. Correspondingly, novel APO-loaded lipid nanocapsules (APO-LNC) were formulated and coated with lactoferrin (LF-APO-LNC) to improve br ain targetability and prolong residence time. Lavender oil (LAV) was incorporated into LNC as a bioactive ingredient to act synergistically with APO in alleviating pentylenetetrazol (PTZ)-induced seizures. The optimized LF-APO-LAV/LNC showed a particle size 59.7 ± 4.5 nm with narrow distribution and 6.07 ± 1.6mV zeta potential) with high entrapment efficiency 92 ± 2.4% and sustained release (35% in 72 h). Following subcutaneous administration, LF-APO-LAV/LNC brought about ⁓twofold increase in plasma AUC and MRT compared to APO. A Log BB value of 0.2 ± 0.14 at 90 min reflects increased brain accumulation. In a PTZ-induced seizures rat model, LF-APO-LAV/LNC showed a Modified Racine score of 0.67 ± 0.47 with a significant increase in seizures latency and decrease in duration. Moreover, oxidant/antioxidant capacity and inflammatory markers levels in brain tissue were significantly improved. Histopathological and immunohistochemical assessment of brain tissue sections further supported these findings. The results suggest APO/LAV combination in LF-coated LNC as a promising approach to counteract seizures.

Impact of palladium/palladium hydride conversion on electrochemical CO2 reduction via in-situ transmission electron microscopy and diffraction.

Electrochemical conversion of CO2 offers a sustainable route for producing fuels and chemicals. Pd-based catalysts are effective for converting CO2 into formate at low overpotentials and CO/H2 at high overpotentials, while undergoing poorly understood morphology and phase structure transformations under reaction conditions that impact performance. Herein, in-situ liquid-phase transmission electron microscopy and select area diffraction measurements are applied to track the morphology and Pd/PdHx phase interconversion under reaction conditions as a function of electrode potential. These studies identify the degradation mechanisms, including poisoning and physical structure changes, occurring in PdHx/Pd electrodes. Constant potential density functional theory calculations are used to probe the reaction mechanisms occurring on the PdHx structures observed under reaction conditions. Microkinetic modeling reveals that the intercalation of *H into Pd is essential for formate production. However, the change in electrochemical CO2 conversion selectivity away from formate and towards CO/H2 at increasing overpotentials is due to electrode potential dependent changes in the reaction energetics and not a consequence of morphology or phase structure changes.

Correction: Youssef et al. Glibenclamide Nanocrystal-Loaded Bioactive Polymeric Scaffolds for Skin Regeneration: In Vitro Characterization and Preclinical Evaluation. Pharmaceutics 2021, 13, 1469.

Figure Correction [...].

Chemical Structure and Distribution in Nickel-Nitrogen-Carbon Catalysts for CO2 Electroreduction Identified by Scanning Transmission X-ray Microscopy.

Atomically dispersed metal-nitrogen-carbon (M-N-C) materials are a class of electrocatalysts for fuel cell and electrochemical CO2 reduction (CO2R) applications. However, it is challenging to characterize the identity and concentration of catalytically active species owing to the structural heterogeneity of M-N-C materials. We utilize scanning transmission X-ray microscopy (STXM) as a correlative spectromicroscopy approach for spatially resolved imaging, identification, and quantification of structures and chemical species in mesoscale regions of nickel-nitrogen-carbon (Ni-N-C) catalysts, thereby elucidating the relationship between Ni content/speciation and CO2R activity/selectivity. STXM results are correlated with conventional characterization approaches relying on either bulk average (X-ray absorption spectroscopy) or spatially localized (scanning transmission electron microscopy with electron energy loss spectroscopy) measurements. This comparison illustrates the advantages of soft X-ray STXM to provide spatially resolved identification and quantification of active structures in Ni-N-C catalysts. The active site structures in these catalysts are identified to be atomically dispersed NiN x /C sites distributed throughout entire catalyst particles. The NiN x /C sites were notably demonstrated by spectroscopy to possess a variety of chemical structures with a spectroscopic signature that most closely resembles nickel(II) tetraphenylporphyrin molecules. The quantification and spatial distribution mapping of atomically dispersed Ni active sites achieved by STXM address a target that was elusive to the scientific community despite its importance in guiding advanced material designs.

CoAID-DEEP: An Optimized Intelligent Framework for Automated Detecting COVID-19 Misleading Information on Twitter.

COVID-19 has affected all peoples' lives. Though COVID-19 is on the rising, the existence of misinformation about the virus also grows in parallel. Additionally, the spread of misinformation has created confusion among people, caused disturbances in society, and even led to deaths. Social media is central to our daily lives. The Internet has become a significant source of knowledge. Owing to the widespread damage caused by fake news, it is important to build computerized systems to detect fake news. The paper proposes an updated deep neural network for identification of false news. The deep learning techniques are The Modified-LSTM (one to three layers) and The Modified GRU (one to three layers). In particular, we carry out investigations of a large dataset of tweets passing on data with respect to COVID-19. In our study, we separate the dubious claims into two categories: true and false. We compare the performance of the various algorithms in terms of prediction accuracy. The six machine learning techniques are decision trees, logistic regression, k nearest neighbors, random forests, support vector machines, and naïve Bayes (NB). The parameters of deep learning techniques are optimized using Keras-tuner. Four Benchmark datasets were used. Two feature extraction methods were used (TF-ID with N-gram) to extract essential features from the four benchmark datasets for the baseline machine learning model and word embedding feature extraction method for the proposed deep neural network methods. The results obtained with the proposed framework reveal high accuracy in detecting Fake and non-Fake tweets containing COVID-19 information. These results demonstrate significant improvement as compared to the existing state of art results of baseline machine learning models. In our approach, we classify the data into two categories: fake or nonfake. We compare the execution of the proposed approaches with Six machine learning procedures. The six machine learning procedures are Decision Tree (DT), Logistic Regression (LR), K Nearest Neighbor (KNN), Random Forest (RF), Support Vector Machine (SVM), and Naive Bayes (NB). The parameters of deep learning techniques are optimized using Keras-tuner. Four Benchmark datasets were used. Two feature extraction methods were used (TF-ID with N-gram) to extract essential features from the four benchmark datasets for the baseline machine learning model and word embedding feature extraction method for the proposed deep neural network methods. The results obtained with the proposed framework reveal high accuracy in detecting Fake and non-Fake tweets containing COVID-19 information. These results demonstrate significant improvement as compared to the existing state of art results of baseline machine learning models.

Glibenclamide Nanocrystal-Loaded Bioactive Polymeric Scaffolds for Skin Regeneration: In Vitro Characterization and Preclinical Evaluation.

Skin restoration following full-thickness injury poses significant clinical challenges including inflammation and scarring. Medicated scaffolds formulated from natural bioactive polymers present an attractive platform for promoting wound healing. Glibenclamide was formulated in collagen/chitosan composite scaffolds to fulfill this aim. Glibenclamide was forged into nanocrystals with optimized colloidal properties (particle size of 352.2 nm, and polydispersity index of 0.29) using Kolliphor as a stabilizer to allow loading into the hydrophilic polymeric matrix. Scaffolds were prepared by the freeze drying method using different total polymer contents (3-6%) and collagen/chitosan ratios (0.25-2). A total polymer content of 3% at a collagen/chitosan ratio of 2:1 (SCGL3-2) was selected based on the results of in vitro characterization including the swelling index (1095.21), porosity (94.08%), mechanical strength, rate of degradation and in vitro drug release. SCGL3-2 was shown to be hemocompatible based on the results of protein binding, blood clotting and percentage hemolysis assays. In vitro cell culture studies on HSF cells demonstrated the biocompatibility of nanocrystals and SCGL3-2. In vivo studies on a rat model of a full-thickness wound presented rapid closure with enhanced histological and immunohistochemical parameters, revealing the success of the scaffold in reducing inflammation and promoting wound healing without scar formation. Hence, SCGL3-2 could be considered a potential dermal substitute for skin regeneration.

Galvanostatic entrapment of penicillinase into polytyramine films and its utilization for the potentiometric determination of penicillin.

A sensitive and reliable potentiometric biosensor for determination of penicillin has been developed by exploiting the self-limiting growth of the non-conducting polymer, polytyramine. Optimum polytyramine-penicillinase (PTy-PNCnase) films for potentiometric detection of penicillin were accomplished with monomer solutions which contained 0.03 M tyramine, 37 U/mL penicillinase, 0.01 M KNO3, and 3 mM penicillin with an applied current density of 0.8 mA/cm2 and an electropolymerisation time of 40 seconds. The potentiometric biosensor gave a linear concentration range of 3-283 µM for penicillin and achieved a minimum detectable concentration of 0.3 µM. The biosensor was successfully utilized for the detection of Amoxycillin and gave an average percentage recovery of 102±6%. Satisfactory recoveries of penicillin G were also achieved in milk samples with the potentiometric biosensor when concentrations are ≥20 ppm.

Saliva diagnostic utility in patients with type 2 diabetes: Future standard method.

BACKGROUND: The purpose of the present study was to assess saliva reliability in diagnosis and monitoring type 2 diabetes instead of blood. METHODS: Blood and unstimulated whole saliva were collected from 300 type 2 diabetic subjects and 300 healthy controls in fasting. Then, the salivary flow rate was calculated. All parameters including glucose, urea, amylase, total protein, albumin, C-reactive protein (CRP), immunoglobulin A (IgA), potassium, calcium and chloride were assessed in the supernatant, using an autoanalyzer. Oral exam was conducted by a single examiner on full mouth excluding third molars. Statistical analysis was performed by the SPSS 20.0 version. RESULTS: Saliva screening showed that glucose, urea, amylase, total protein, potassium, calcium and chloride were significantly higher in patients compared to controls (p < 0.05). Whereas, the IgA level and salivary flow rate were significantly reduced in patients (p < 0.05). No significant difference was found in albumin and CRP levels (p > 0.05). There was a significant positive correlation between salivary and plasma glucose levels (r = 0.887, and r = 0.900, p < 0.001), as well as, salivary and blood urea (r = 0.586, and r = 0.688, p < 0.001) in patients and controls, respectively. CONCLUSIONS: From this study, saliva could be suggested as a useful diagnostic tool for type 2 diabetes.

A novel nasal almotriptan loaded solid lipid nanoparticles in mucoadhesive in situ gel formulation for brain targeting: Preparation, characterization and in vivo evaluation.

This work aimed at designing efficient safe delivery system for intranasal (IN) brain targeting of the water soluble anti- migraine drug Almotriptan malate (ALM). Solid lipid nanoparticles (SLNs) were prepared by w/o/w double emulsion-solvent evaporation method. Selection of the optimized SLNs formula was based on evaluating particle size (PS), poly dispersity index (PDI) and entrapment efficiency (%EE). Optimized formula exhibited acceptable ranges; PS of 207.9 nm, PDI of 0.41 and %EE of 50.81%. Poloxamer 407 (Plx) at different concentrations (16%, 18%, 20% w/v), with different mucoadhesive polymers (Carbopol-974P, Na alginate, Na-CMC) were evaluated for gelling time and temperature, pH and mucoadhesion. The chosen mucoadhesive in-situ gel formula; 18% Plx 407 based-0.75%w/v Na-CMC, showed acceptable results, so that the optimized SLNs formula was further dispersed in it and evaluated for in vitro release, stability, in vivo and pharmacokinetics studies. Biomarkers' evaluation and histopathological examination were also investigated. Results revealed rapid ALM brain delivery of the optimized formula; Brain/blood ratios at 10 min. for NF (SLNs based IN in-situ gel), ND (Free ALM IN in situ gel) and ALM i.v. (ALM IV solution) were 0.89, 0.19 and 0.31, respectively. Toxicological results confirmed the safety of NF for nasal administration. The achieved out comings are encouraging for further clinical trials of the developed system in humans in future research.

A dual strategy to improve psychotic patients' compliance using sustained release quetiapine oral disintegrating tablets.

Quetiapine (QT) is a short acting atypical antipsychotic drug effective in schizophrenia and bipolar disorder. This study aims at designing a novel dosage form of sustained release taste-masked QT orally disintegrating tablets (ODTs) based on solid lipid micro-pellets (SLMPs). QT SLMPs were prepared using the hot melt extrusion technique and utilizing three lipid carriers: Compritol, Precirol and white beeswax either alone or in mixtures. They showed sustained QT release and a taste masking effect. The selected QT SLMP was further blended with an aqueous solution containing polyvinylpyrollidone (2.5 %), croscarmellose sodium (2 %) and mannitol (50 %); it was then lyophilized into ODT in a mass ratio of 1:2, respectively. ODTs containing QT SLMPs showed: average wetting time (40.92 s), average oral disintegration time (21.49 s), average hardness (16.85 N) and also imparted suitable viscosity to suspend pellets during the lyophilization process. In conclusion, lyophilization is a promising technique for the formulation of multiparticulate systems into ODTs.

Mucoadhesive buccal patches of miconazole nitrate: in vitro/in vivo performance and effect of ageing.

Mucoadhesive patches containing 10mg miconazole nitrate were evaluated. The patches were prepared with ionic polymers, sodium carboxymethyl cellulose (SCMC) and chitosan, or non-ionic polymers, polyvinyl alcohol (PVA), hydroxyethyl cellulose (HEC) and hydroxypropylmethyl cellulose (HPMC). Convenient bioadhesion, acceptable elasticity, swelling and surface pH were obtained. Patches exhibited sustained release over more than 5h and the addition of polyvinyl pyrrolidone (PVP) generally enhanced the release rate. Optimum release behaviour was shown with patches containing 10% w/v PVA and 5% w/v PVP. Study of the in vivo release from this formulation revealed uniform and effective salivary levels with adequate comfort and compliance during at least 6h. On the contrary, in vivo release of the commercial oral gel product resulted in a burst and transient release of miconazole, which diminished sharply after the first hour of application. Storage of these patches for 6 months did not affect the elastic properties, however, enhanced release rates were observed due to marked changes in the crystal habit of the drug.