Preparation, Optimization, and Evaluation of Hyaluronic Acid-Based Hydrogel Loaded with Miconazole Self-Nanoemulsion for the Treatment of Oral Thrush.

Miconazole nitrate (MZ) is a BCS class II antifungal poorly water-soluble drug with limited dissolution properties and gastrointestinal side effects. Self-nanoemulsifying delivery system-based gel of MZ can improve both solubility and oral mucosal absorption with enhanced antifungal activity. The study aims to formulate MZ self-nanoemulsion (MZ-NE) and combine it within hyaluronic acid-based gel. MZ solubility in various oils, surfactants, and cosurfactant used in NE formulations were evaluated. Mixture design was implemented to optimize the levels of NE components as a formulation variable to study their effects on the mean globule size and antifungal inhibition zones. Further, the optimized MZ-NE was loaded into a hyaluronic acid gel base. Rheological behavior of the prepared gel was assessed. Ex vivo permeability of optimized formulation across buccal mucous of sheep and inhibition against Candida albicans were examined. Mixture design was used to optimize the composition of MZ-NE formulation as 22, 67, and 10% for clove oil, Labrasol, and propylene glycol, respectively. The optimized formulation indicated globule size of 113 nm with 29 mm inhibition zone. Pseudoplastic flow with thixotropic behavior was observed, which is desirable for oral gels. The optimized formulation exhibited higher ex vivo skin permeability and enhanced antifungal activity by 1.85 and 2.179, respectively, compared to MZ-SNEDDS, and by 1.52 and 1.72 folds, respectively, compared to marketed gel. Optimized MZ-NE hyaluronic acid-based oral gel demonstrated better antifungal activity, indicating its potential in oral thrush pharmacotherapy.

Camel Milk Attenuates Rheumatoid Arthritis Via Inhibition of Mitogen Activated Protein Kinase Pathway.

BACKGROUND/AIMS: Camel milk (CM) has shown beneficial anti-inflammatory actions in several experimental and clinical settings. So far, its effect on rheumatoid arthritis (RA) has not been previously explored. Thus, the current work aimed to evaluate the effects of CM in Adjuvant-induced arthritis and air pouch edema models in rats, which mimic human RA. METHODS: CM was administered at 10 ml/kg orally for 3 weeks starting on the day of Freund's adjuvant paw inoculation. The levels of TNF-α and IL-10 were measured by ELISA while the protein expression of NF-κBp65, COX-2 and iNOS was detected by immunohistochemistry. The expression of MAPK target proteins was assessed by Western blotting. RESULTS: CM attenuated paw edema, arthritic index and gait score along with dorsal pouch inflammatory cell migration. CM lowered the TNF-α and augmented the anti-inflammatory IL-10 levels in sera and exudates of arthritic rats. It also attenuated the expression of activated NF-κBp65, COX-2 and iNOS in the lining of the dorsal pouch. Notably, CM inhibited the MAPK pathway signal transduction via lowering the phosphorylation of p38 MAPK, ERK1/2 and JNK1/2 in rat hind paws. Additionally, CM administration lowered the lipid peroxide and nitric oxide levels and boosted glutathione and total anti-oxidant capacity in sera and exudates of animals. CONCLUSION: The observed CM downregulation of the arthritic process may support the interest of CM consumption as an adjunct approach for the management of RA.

Correction to Pyramid-Shaped PEG-PCL-PEG Polymeric-Based Model Systems for Site-Specific Drug Delivery of Vancomycin with Enhance Antibacterial Efficacy.

[This corrects the article DOI: 10.1021/acsomega.9b04064.].

Anti-atherogenic effect of Nepitrin-7-O-glucoside: A flavonoid isolated from Nepeta hindostana via acting on PPAR - α receptor.

Atherogenic dyslipidemia is a condition and responsible for the induction of major cardiovascular diseases. Traditionally, Nepeta hindostana a medicinal plant commonly used as cardioprotective in Indo-Pak regions has gained importance because of its therapeutic active flavonoid Nepitrin-7-O-glucoside. Flavonoid-glycosides are steroids having the ability to exert specific, decisive action on the cardiac muscle. In the present research work flavonoid, Nepitrin-7-O-glucoside was isolated from methanolic extract via chromatographic techniques. The structure was elucidated and confirmed by different spectral techniques like Mass and 1H NMR spectrometry. Various preclinical atherosclerosis parameters such as lipid levels, SGOT/SGPT, body weight, histology of aorta and heart were estimated and beneficial effect of Nepitrin in high-fat diet (HFD) induced atherosclerosis for six weeks were observed. Outcomes of the preclinical results showed and proved that Nepitrin significantly improved dyslipidemia at an effective dose of 50 mg/kg as compared with HFD control and Simvastatin. Molecular docking showed significant binding affinity towards the target PPAR-α receptor (PDB: 2P54). Further the docked ligands with PDB: 2P54 were exposed to molecular dynamics studies to confirm the dynamic behaviour of PPAR-α receptor. Outcomes of the results of the in-vivo study and molecular dynamics study were in correlation with each-others. Further, it can be concluded that Nepitrin has a potent antiatherogenic agent and act by reducing the lipid levels via acting on PPAR-α receptor and regenerating the damaged cells.

Evaluation of the Potential of National Sharing of a Unified Progress Test Among Colleges of Pharmacy in the Kingdom of Saudi Arabia.

BACKGROUND: With the expansion in pharmacy education in Saudi Arabia, there is a pressing need to maintain quality assurance in pharmacy programs using several tools. The progress test is a formative assessment tool that can serve to provide information to all stakeholders. This study evaluated the results of a unified progress test that was shared among 15 colleges of pharmacy. METHODS: The progress test was composed of 100 MCQs where 30% of which cover basic pharmaceutical sciences and 70% cover pharmacy practice. The questions were collected from all the 15 colleges of pharmacy participated in the test. The test was administered online to all undergraduate students in the professional programs of these colleges. RESULTS: The overall attendance rate was 80% from the total number of students enrolled in the participating colleges. Mean scores of students in basic pharmaceutical sciences were relatively higher than in pharmacy practice. The assessment results of the students in the unified program learning outcomes among colleges were higher in the domains of knowledge and skills compared to competence domain. There was a significant increment in the mean scores of the students as they progress through the years of the professional program. No correlation was found between the mean scores in the test and the cumulative grade point average (cGPA) of all students regardless of their level. CONCLUSION: The results indicated growth and maintenance of the gained knowledge and skills by the students as they progress through the years of the professional program with consistency in the results among the participating colleges. Sharing a unified test was effective as a valuable tool for the colleges of pharmacy for the purposes of benchmarking and improving the curricula. In addition, it could serve to evaluate learning of students and harmonize knowledge and skills gained by students at different institutions.

Targeting oxidative stress, proinflammatory cytokines, apoptosis and toll like receptor 4 by empagliflozin to ameliorate bleomycin-induced lung fibrosis.

Lung fibrosis is one of the serious complications of bleomycin use in cancer therapy. The aim of this study was to investigate the effect of pre-treatment versus post-treatment with empagliflozin on pulmonary fibrosis induced by bleomycin. One hundred male C57BL/6 mice were divided into 5 equal groups as follows: control group; bleomycin group; bleomycin + carboxymethyl cellulose group; bleomycin group pretreated with empagliflozin and a group treated with empagliflozin after 15 days from starting bleomycin injection. The survival rate, lung weight/body weight ratio, lung tissue hydroxyproline, malondialdehyde, glutathione reductase, superoxide dismutase, nuclear factor (Erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO-1) and toll-like receptor 4 (TLR4) were assessed. Also, bronchoalveolar lavage fluid (BALF) was analyzed for total and differential leucocytic count, lactate dehydrogenase, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta 1 (TGF-ß1). The pulmonary tissues were subjected to histopathological, immunohistochemical and electron microscopic study. Empagliflozin induced significant decrease in lung weight/body weight ratio, BALF lactate dehydrogenase, total leucocytic count, IL-6, TNF-α, TLR4 and TGF-ß1 associated with significant decrease in lung tissue oxidative stress and hydroxyproline and significant increase in the survival rate and tissue Nrf2/HO-1 content compared to bleomycin group. This was accompanied with significant improvement of the histopathological, immunohistochemical and electron microscopic picture compared to bleomycin group. These effects were significant in mice pretreated with empagliflozin compared to the group that received empagliflozin 15 days after starting bleomycin injection. In conclusion, empagliflozin may be used prophylactically to prevent pulmonary fibrosis induced by bleomycin.

Pyramid-Shaped PEG-PCL-PEG Polymeric-Based Model Systems for Site-Specific Drug Delivery of Vancomycin with Enhance Antibacterial Efficacy.

Antibacterial resistance remains a major global problem due to frequent prescriptions, leading to significant toxicities. To overcome the limitations of antibiotic therapy, it is highly desirable to provide site-specific delivery of drugs with controlled release. Inspired by the biocompatible, biodegradable, and site-specific mimicking behavior of poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL), we developed vancomycin-PEG-PCL-PEG conjugates to maximize the pharmacological effects and minimize the side effects. Drug-loaded vancomycin-PEG-PCL-PEG conjugates are influenced by size, shape, surface area, encapsulation efficiency, in vitro drug release, hemolysis assay, cytotoxicity, and antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and bacterial kill kinetics. The results demonstrated that vancomycin (VCM) release from PEG-PCL-PEG triblock revealed a biphasic manner. Hemolysis assay showed the nonprescription nature of VCM-PEG-PCL-PEG. Cytotoxicity studies confirmed the biocompatibility of VCM-PEG-PCL-PEG. The in vitro antibacterial results showed enhance activity with minimum inhibitory concentration compared to bare VCM. Molecular dynamics simulation study revealed that binding between VCM and PEG-PCL-PEG by hydrophobic interactions offers molecular encapsulation and steric barrier to drug degradation. This newly developed therapeutic delivery system can offer to enhance activity and delivery VCM against MRSA.

Formulation and evaluation of gastro-retentive floating bilayer tablet for the treatment of hypertension.

The paper aimed to progress an ideal gastro retentive drug delivery system intended for directing Losartan and Hydrochlorothiazide as a fixed-dose combination for anti-hypertensive therapy. The bilayer tablets were primed through direct compression method. Losartan was formulated by means of a floating layer expending hydrophilic swellable polymer Hydroxy Propyl Methyl Cellulose K4M, ethyl cellulose (4cps) as a buoyancy enhancer, sodium bicarbonate as a gas spawning agent. The amount of polymer blends remains optimized using 23 full factorial designs. The clout of experimental factors such as swelling agent concentration, buoyancy enhancer and gas generating agent on floating lag time, total floating time, T50% and % drug release remain investigated to get optimized formulation. The responses remain analyzed using Analysis of variance, and polynomial equation stood created for every retort using Multiple linear regression analysis. Entirely preparations floated for more than 12 h. The release pattern of losartan stood fitted to diverse models based on the coefficient of correlation (r). All the formulations, except F2, showed the Korsemeyer-Peppas model as the best fit model. Formulation F2 showed the zero-order model. Diffusion exponents (n) remained indomitable designed for entirely formulations (0.45-0.89), accordingly the chief drug discharge mechanism was non-fickian (anamolous) transport. Formulation F4 containing 20% w/w Hydroxy Propyl Methyl Cellulose K4M, 15% Sodium bicarbonate and 5% ethyl cellulose (4cps) was the best formulation as per the range of drug release remain institute to be more than 95 % in 12h and floating lag time was 20.15 s. The immediate-release layer stood optimized using crospovidone and Indion 414 as a super disintegrant. Formulation A8 containing 2% Indion 414 was considered as optimized formulation as it released 99% drug within 35 min and possessed less disintegration time. Optimized formulation F4 from the controlled-release layer and A8 from immediate-release layer was used to formulate bilayer tablet. The optimized formulation was imperilled to stability reading for three months at 40○C/75% relative humidity. The stability revision exhibited no substantial alteration in the appearance of tablets, floating characteristics, drug content and in-vitro drug dissolution. Consequently, a biphasic drug release design was effectively accomplished over the formulation of floating bilayer tablets.

Investigation of six plasmid-mediated quinolone resistance genes among clinical isolates of pseudomonas: a genotypic study in Saudi Arabia.

Background: Quinolones are among the most effective antibiotics against Pseudomonas spp. Several chromosomal and/or plasmid-mediated quinolone-resistance mechanisms have been found in Pseudomonas.  Plasmid-mediated quinolone-resistance (PMQR) is mediated by quinolone-resistance (QNR) proteins, modifying enzymes or efflux pumps. Only a few previous studies examined the prevalence of quinolone-resistance in the Kingdom of Saudi Arabia (KSA) and showed it is increasing. Mechanisms of quinolone-resistance among Pseudomonas spp. in the KSA; examined herein; have not been extensively studied. Methods: Ninety-two Pseudomonas isolates were collected and their resistance to seven different types of quinolones was determined by the microbroth dilution method. PMQR mechanisms were examined using a PCR screen to identify six PMQR genes including qnrA, qnrB, qnrD, qnrS, aac(6´)-Ib-cr, and qepA. Clonal relatedness of the quinolone-resistant isolates was determined by ERIC-PCR. Results: Of the isolates, 42.4% (39/92) were resistant to 1-7 of the tested quinolones. Gemifloxacin resistance was the lowest (28.3%) while resistance to the other six quinolones were ≥ 35%. The most common biotype among the 39 quinolone-resistant isolates was resistance to the seven tested quinolones (26/39; 66.7%). qnrD, qnrS, and aac(6´)-Ib-cr were found in 31 (79.5%), 31 (79.5%) and 28 (71.8%) of the 39 isolates, respectively, and all three genes together were found in 22 of the 39 isolates (56.4%). qnrA, qnrB, and qepA were not detected in any of the isolates and two isolates did not harbor any of the six tested genes. The isolates showed 38 different ERIC profiles and only two isolates (Pa16 and Pa17) had an identical profile. Conclusion: This is the first description of PMQR mechanisms among clinical Pseudomonas isolates from the KSA, which appears to be mainly mediated by qnrD, qnrS, and aac(6´)-Ib-cr.

Linagliptin potentiates the effect of l-dopa on the behavioural, biochemical and immunohistochemical changes in experimentally-induced Parkinsonism: Role of toll-like receptor 4, TGF-ß1, NF-κB and glucagon-like peptide 1.

OBJECTIVE: Our aim was to assess the effect of different doses of linagliptin with or without l-dopa/Carbidopa on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in mice. METHODS: Eighty Balb/c mice were divided into 8 equal groups: Control; MPTP; MPTP + l-dopa/Carbidopa; MPTP + linagliptin 3 mg/kg/day; MPTP + linagliptin 10 mg/kg/day; MPTP + Carboxymethyl cellulose; MPTP + l-dopa/Carbidopa + linagliptin 3 mg/kg/day and MPTP + l-dopa/Carbidopa + linagliptin 10 mg/kg/day. Striatal dopamine, tumor necrosis factor alpha (TNF-α), interleukin 10 (IL-10), transforming growth factor beta 1 (TGF-ß1), toll-like receptor 4 (TLR4), antioxidant enzymes, adenosine triphosphate (ATP), glucagon-like peptide-1 (GLP-1), receptors of advanced glycation end products (RAGE), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO-1), mitochondrial complex I activity, catalepsy and total swim scores were measured. Also, the substantia nigra was subjected to immunohistochemical examination. RESULTS: The combination of l-dopa/Carbidopa and linagliptin in a dose-dependent manner resulted in significant improvement of the behavioural changes, striatal dopamine, antioxidant parameters, Nrf2/HO-1 content, GLP-1, ATP and mitochondrial complex I activity with significant decrease in striatal RAGE, TGF-ß1, TNF-α, IL-10, TLR4 and alleviated the immunohistochemical changes better than the groups that received either l-dopa/Carbidopa or linagliptin alone. CONCLUSION: The combination of l-dopa/Carbidopa and linagliptin might represent a promising therapeutic modality for management of parkinsonism.