Ethanol-assisted kneading of apigenin with arginine for enhanced dissolution rate of apigenin: development of rapidly disintegrating tablets.

Apigenin is a natural flavonoid which is claimed to have many pharmacological activities ranging from simple anti-inflammatory to anticancer action. However, poor dissolution slowed the advancement of this drug through the development pipelines. The objective of this work was to probe ethanol-aided kneading of apigenin with arginine as a new strategy for enhanced dissolution rate. The work was extended to develop rapidly disintegrating tablets of apigenin. Apigenin was mixed with increasing molar ratios of arginine before ethanol-aided kneading. The resulting products were examined using Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction in addition to probing the dissolution characteristics of apigenin. The analytical techniques highlighted the existence of new crystalline species with a possibility of salt formation. The recorded alterations in the crystalline properties were associated with a significant enhancement in the dissolution rate of apigenin. The presence of arginine did not have any negative effect of the cytotoxic power of apigenin. Optimum formulation was successfully prepared as rapidly disintegrating tablets which showed fast liberation of apigenin. The study introduced arginine as a potential excipient for enhanced dissolution of apigenin after ethanol-assisted kneading.

Development of Provesicular Nanodelivery System of Curcumin as a Safe and Effective Antiviral Agent: Statistical Optimization, In Vitro Characterization, and Antiviral Effectiveness.

Curcumin is a natural compound that has many medical applications. However, its low solubility and poor stability could impede its clinical applications. The present study aimed to formulate dry proniosomes to overcome these pitfalls and improve the therapeutic efficacy of Curcumin. Curcumin-loaded proniosomes were fabricated by the slurry method according to 32 factorial design using Design-Expert software to demonstrate the impact of different independent variables on entrapment efficiency (EE%) and % drug released after 12 h (Q12h). The optimized formula (F5) was selected according to the desirability criteria. F5 exhibited good flowability and appeared, after reconstitution, as spherical nanovesicles with EE% of 89.94 ± 2.31% and Q12h of 70.89 ± 1.62%. F5 demonstrated higher stability and a significant enhancement of Q12h than the corresponding niosomes. The docking study investigated the ability of Curcumin to bind effectively with the active site of DNA polymerase of Herpes simplex virus (HSV). The antiviral activity and the safety of F5 were significantly higher than Curcumin. F5 improved the safety of Acyclovir (ACV) and reduced its effective dose that produced a 100% reduction of viral plaques. Proniosomes could be promising stable carriers of Curcumin to be used as a safe and efficient antiviral agent.

Enhancing the Oral Bioavailability of Candesartan Cilexetil Loaded Nanostructured Lipid Carriers: In Vitro Characterization and Absorption in Rats after Oral Administration.

Candesartan Cilexetil (CC) is a prodrug widely used in the treatment of hypertension and heart failure, but it has some limitations, such as very poor aqueous solubility, high affinity to P-glycoprotein efflux mechanism, and hepatic first-pass metabolism. Therefore, it has very low oral bioavailability. In this study, glyceryl monostearate (GMS) and Capryol™ 90 were selected as solid and liquid lipids, respectively, to develop CC-NLC (nanostructured lipid carrier). CC was successfully encapsulated into NLP (CC-NLC) to enhance its oral bioavailability. CC-NLC was formulated using a hot homogenization-ultrasonication technique, and the physicochemical properties were characterized. The developed CC-NLC formulation was showed in nanometric size (121.6 ± 6.2 nm) with high encapsulation efficiency (96.23 ± 3.14%). Furthermore, it appeared almost spherical in morphology under a transmission electron microscope. The surgical experiment of the designed CC-NLC for absorption from the gastrointestinal tract revealed that CC-NLC absorption in the stomach was only 15.26% of that in the intestine. Otherwise, cellular uptake study exhibit that CC-NLCs should be internalized through the enterocytes after that transported through the systemic circulation. The pharmacokinetic results indicated that the oral bioavailability of CC was remarkably improved above 2-fold after encapsulation into nanostructured lipid carriers. These results ensured that nanostructured lipid carriers have a highly beneficial effect on improving the oral bioavailability of poorly water-soluble drugs, such as CC.

Endovascular repair of traumatic aortic isthmic rupture: Early and mid-term results.

INTRODUCTION: Conventional open repair of a traumatic aortic isthmic rupture is associated with a significantly high mortality and morbidity rates. Thoracic endovascular aortic repair (TEVAR) is currently often performed because it is a less invasive treatment than surgery. The aim of this study was to evaluate short and mid-term results of TEVAR in traumatic aortic isthmic rupture. METHODS: This is a retrospective study conducted between 2010 and 2018 including patients who underwent TEVAR for traumatic aortic isthmic rupture. RESULTS: Thirty-six consecutive patients were included. All patients had sustained a violent blunt chest trauma after a sudden deceleration with associated injuries. The injury severity score (ISS) was 40 (14-66). All patients were hemodynamically stable at admission. We deployed thoracic aorta stent grafts with a mean diameter of 26mm (18-36). The procedural success rate was 100%. We reported one intra-operative complication which was a distal migration of the graft, managed by an implantation of an aortic extension graft. On the first postoperative day, one patient presented an acute lower limb ischemia, probably due to the surgical femoral access, treated with an embolectomy with a Fogarty catheter with satisfactory results. The mean follow-up was 40.41 months (6.5-96). The mortality and paraplegia rates were 0% at one month and during the follow-up period. We reported a case of kinking of the graft that occurred at 6 months. No cases of endoleak neither re-intervention were reported. CONCLUSION: TEVAR is a safe and a reliable method for the treatment of sub-acute traumatic thoracic aortic injuries.

Effect of nanostructured lipid carriers on transdermal delivery of tenoxicam in irradiated rats.

Transdermal delivery of non-steroidal anti-inflammatory drugs (NSAIDs) is an effective route of drug administration, as it directs the drug to the inflamed site with reduced incidence of systemic adverse effects such as gastric hemorrhage and ulcers. Tenoxicam (TNX) is a member of NSAIDs that are marketed only as oral tablets due to very poor absorption through the skin. The current study intended to formulate and characterize a hydrogel loaded with nanostructured lipid carriers (NLCs) to enhance the transdermal delivery of TNX. Six formulations of TNX were formulated by slight modifications of high shear homogenization and ultrasonication method. The selected formula was characterized for their particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE), in-vitro drug release and ex-vivo skin permeation studies. Moreover, the effectiveness of the developed formula was studied in-vivo using carrageenan-induced paw edema and hyperalgesia model in irradiated rats. Formula F4 was chosen from six formulations, as the average diameter was 679.4 ± 51.3 nm, PDI value of about 0.02, zeta potential of -4.24 mV, EE of 92.36%, globules nanoparticles without aggregations and absence of interactions in the developed formula. Additionally, the in-vivo study showed the efficacy of formula F4 (TNX-NLCs hydrogel) equivalent to oral TNX in reducing the exaggerated inflammatory response induced by carrageenan after irradiation. In conclusion, the present findings suggest that TNX-NLCs hydrogel could be a potential transdermal drug delivery system alternative to the oral formulation for the treatment of various inflammatory conditions.

Fabrication of Transgelosomes for Enhancing the Ocular Delivery of Acetazolamide: Statistical Optimization, In Vitro Characterization, and In Vivo Study.

Acetazolamide (ACZ) is a potent carbonic anhydrase inhibitor that is used for the treatment of glaucoma. Its oral administration causes various undesirable side effects. This study aimed to formulate transgelosomes (TGS) for enhancing the ocular delivery of ACZ. ACZ-loaded transfersomes were formulated by the ethanol injection method, using phosphatidylcholine (PC) and different edge activators, including Tween 80, Span 60, and Cremophor RH 40. The effects of the ratio of lipid to surfactant and type of surfactant on % drug released after 8 h (Q8h) and entrapment efficiency (EE%) were investigated by using Design-Expert software. The optimized formula was formulated as TGS, using poloxamers as gelling agents. In vitro and in vivo characterization of ACZ-loaded TGS was performed. According to optimization study, F8 had the highest desirability value and was chosen as the optimized formula for preparing TGS. F8 appeared as spherical elastic nanovesicles with Q8h of 93.01 ± 3.76% and EE% of 84.44 ± 2.82. Compared to a free drug, TGS exhibited more prolonged drug release of 71.28 ± 0.46% after 8 h, higher ex vivo permeation of 66.82 ± 1.11% after 8 h and a significant lowering of intraocular pressure (IOP) for 24 h. Therefore, TGS provided a promising technique for improving the corneal delivery of ACZ.

Co-crystallization for enhanced dissolution rate of bicalutamide: preparation and evaluation of rapidly disintegrating tablets.

Objectives: Enhance the dissolution rate of bicalutamide via co-crystallization with sucralose (sweetener), with the aim to develop rapidly disintegrating tablets with subsequent prompt dissolution. Significance: Bicalutamide is antiandrogenic agent for the treatment of prostate cancer but has low and variable oral bioavailability, mainly attributed to poor dissolution. Co-crystallization with benign excipients is promising for dissolution enhancement with the additive serving dual functions. The benefit will become greater if dissolution enhancement is associated with the development of orodispersible tablets which is suitable for elderly patients who are the most vulnerable for prostate cancer. Methods: Bicalutamide was dissolved in acetone in the presence of increasing molar ratios of sucralose. The solvent was evaporated while mixing to deposit crystals that were subjected to wet co-grinding until drying. The developed solids were characterized using Fourier transform infrared spectroscopy, differential thermal analysis and X-ray diffraction in addition to monitoring bicalutamide dissolution. Results: Instrumental analysis provided evidences for co-crystallization which was initiated at 1:1 molar ratio of bicalutamide to sucralose with complete co-crystallization at 1:4 molar ratio. The co-crystals provided faster bicalutamide dissolution compared with the unprocessed drug and that recrystalized from acetone in the absence of sucralose. The formulation containing bicalutamide with sucralose at 1:4 molar ratio was selected for tablet formulation into which superdisintegrants were included. The developed tablets exhibited flash disintegration with subsequent fast dissolution of bicalutamide. Conclusions: The study introduced co-crystallization of bicalutamide with sucralose as an efficient tool to enhance the dissolution rate and to develop rapidly dissolving tablets for intraoral administration.

Evaluation of computational techniques for predicting non-synonymous single nucleotide variants pathogenicity.

The human genetic diseases associated with many factors, one of these factors is the non-synonymous Single Nucleotide Variants (nsSNVs) cause single amino acid change with another resulting in protein function change leading to disease. Many computational techniques have been released to expect the impacts of amino acid alteration on protein function and classify mutations as pathogenic or neutral. Here in this article, we assessed the performance of eight techniques; FATHMM, SIFT, Provean, iFish, Mutation Assessor, PANTHER, SNAP2, and PON- P2 using a VaribenchSelectedPure dataset of 2144 pathogenic variants and 3777 neutral variants extracted from the free standard database "Varibench." The first five techniques achieve (45.60-83.75) % specificity, (52.64-94.13) % sensitivity, (51.00-88.90) % AUC, and (49.76-88.24) % ACC on whole dataset, while all eight techniques achieve (36.54-77.88) % specificity, (50.00-75.00) % sensitivity, (51.00-76.40) % AUC, and (25.00-77.78) % ACC on random sample dataset. We also created a Meta classifier (CSTJ48) that combines FATHMM, iFish, and Mutation Assessor. It registers 96.33% specificity, 86.07% sensitivity, 91.20% AUC, and 91.89 ACC. By comparing the results, it's clear that FATHMM gives the highest performance over the seven individual techniques, where it achieves 83.75% and 77.88% specificity, 94.13%, and 75.00% sensitivity, 88.90% and 76.40% AUC, and 88.24% and 77.78% ACC on whole and random sample dataset, respectively. Also, the launched Meta classifier (CSTJ48) is outperforming over all the eight individual tools that compared here.

A review study: Computational techniques for expecting the impact of non-synonymous single nucleotide variants in human diseases.

Non-Synonymous Single-Nucleotide Variants (nsSNVs) and mutations can create a diversity effect on proteins as changing genotype and phenotype, which interrupts its stability. The alterations in the protein stability may cause diseases like cancer. Discovering of nsSNVs and mutations can be a useful tool for diagnosing the disease at a beginning stage. Many studies introduced the various predicting singular and consensus tools that based on different Machine Learning Techniques (MLTs) using diverse datasets. Therefore, we introduce the current comprehensive review of the most popular and recent unique tools that predict pathogenic variations and Meta-tool that merge some of them for enhancing their predictive power. Also, we scanned the several types computational techniques in the state-of-the-art and methods for predicting the effect both of coding and noncoding variants. We then displayed, the protein stability predictors. We offer the details of the most common benchmark database for variations including the main predictive features used by the different methods. Finally, we address the most common fundamental criteria for performance assessment of predictive tools. This review is targeted at bioinformaticians attentive in the characterization of regulatory variants, geneticists, molecular biologists attentive in understanding more about the nature and effective role of such variants from a functional point of views, and clinicians who may hope to learn about variants in human associated with a specific disease and find out what to do next to uncover how they impact on the underlying mechanisms.

One-step green approach for functional printing and finishing of textiles using silver and gold NPs.

In this study, we present a successful simple method for printing and finishing of polyester and cotton fabrics using gold and silver nanoparticles (Au-NPs and Ag-NPs, respectively) as stable, fast colorants and functional components. The surface plasmon resonance (SPR) bands of the colloidal gold and silver NPs were observed at λ max 520 nm and 450 nm, respectively, indicating the presence of spherical Au-NPs and Ag-NPs, which was further confirmed by TEM analysis. The printed samples were subjected to SEM, XRD and EDX analyses. The SEM images and EDX spectra unequivocally confirmed the existence of embedded NPs on the fabric surfaces. Both the cotton and polyester samples possessed excellent color fastness, as indicated from the color fastness test. The functional properties of the printed fabrics indicated that the incorporation of Au-NPs and Ag-NPs into the fabrics simultaneously imparted multifunctional properties such as stable brilliant colors, highly durable antimicrobial activity and very good UV-protection properties.

Generation of CRISPR/Cas9-mediated bicistronic knock-in ins1-cre driver mice.

In the present study, we generated novel cre driver mice for gene manipulation in pancreatic ß cells. Using the CRISPR/Cas9 system, stop codon sequences of Ins1 were targeted for insertion of cre, including 2A sequences. A founder of C57BL/6J-Ins1(em1 (cre) Utr) strain was produced from an oocyte injected with pX330 containing the sequences encoding gRNA and Cas9 and a DNA donor plasmid carrying 2A-cre. (R26GRR x C57BL/6J-Ins1(em1 (cre) Utr)) F1 mice were histologically characterized for cre-loxP recombination in the embryonic and adult stages; cre-loxP recombination was observed in all pancreatic islets examined in which almost all insulin-positive cells showed tdsRed fluorescence, suggesting ß cell-specific recombination. Furthermore, there were no significant differences in results of glucose tolerance test among genotypes (homo/hetero/wild). Taken together, these observations indicated that C57BL/6J-Ins1(em1 (cre) Utr) is useful for studies of glucose metabolism and the strategy of bicistronic cre knock-in using the CRISPR/Cas9 system could be useful for production of cre driver mice.

Germline recombination in a novel Cre transgenic line, Prl3b1-Cre mouse.

Spermatogenesis is a complex and highly regulated process by which spermatogonial stem cells differentiate into spermatozoa. To better understand the molecular mechanisms of the process, the Cre/loxP system has been widely utilized for conditional gene knockout in mice. In this study, we generated a transgenic mouse line that expresses Cre recombinase under the control of the 2.5 kbp of the Prolactin family 3, subfamily b, member 1 (Prl3b1) gene promoter (Prl3b1-cre). Prl3b1 was initially reported to code for placental lactogen 2 (PL-2) protein in placenta along with increased expression toward the end of pregnancy. PL-2 was found to be expressed in germ cells in the testis, especially in spermatocytes. To analyze the specificity and efficiency of Cre recombinase activity in Prl3b1-cre mice, the mice were mated with reporter R26GRR mice, which express GFP ubiquitously before and tdsRed exclusively after Cre recombination. The systemic examination of Prl3b1-cre;R26GRR mice revealed that tdsRed-positive cells were detected only in the testis and epididymis. Fluorescence imaging of Prl3b1-cre;R26GRR testes suggested that Cre-mediated recombination took place in the germ cells with approximately 74% efficiency determined by in vitro fertilization. In conclusion, our results suggest that the Prl3b1-cre mice line provides a unique resource to understand testicular germ-cell development. genesis 54:389-397, 2016. © 2016 Wiley Periodicals, Inc.

Enhancement of Bioavailability and Pharmacodynamic Effects of Thymoquinone Via Nanostructured Lipid Carrier (NLC) Formulation.

Thymoquinone (TQ), obtained from black cumin (Nigella sativa), is a natural product with anti-oxidant, anti-inflammatory, and hepatoprotective effects but unfortunately with poor bioavailability. Aiming to improve its poor oral bioavailability, TQ-loaded nanostructured lipid carriers (NLCs) were prepared by high-speed homogenization followed by ultrasonication and evaluated in vitro. Bioavailability and pharmacodynamic studies were also performed. The resultant NLCs showed poor physical homogeneity in Compritol 888 ATO Pluronic F127 system which consequently produced larger particle size and polydispersity index, smaller zeta potential values, and lower short-term (30 days) physical stability than other systems. Encapsulation efficiency percentage (EE%) lied between 84.6 ± 5% and 96.2 ± 1.6%. TQ AUC0-t values were higher in animals treated with NLCs, with a relative bioavailability of 2.03- and 3.97-fold (for F9 and F12, respectively) higher than TQ suspension, indicating bioavailability enhancement by NLC formulation. Hepatoprotective effects of F12 showed significant (P < 0.05) decrease in both serum alanine amino transferase and aspartate amino transferase to reach 305.0 ± 24.88 and 304.7 ± 23.55 U/ml, respectively, when compared with untreated toxic group. Anti-oxidant efficacy of F12 showed significant (P < 0.05) decline of malondialdehyde and elevation of reduced glutatione. This improvement was also confirmed histopathologically.

Modulating Effects of Spirulina platensis against Tilmicosin-Induced Cardiotoxicity in Mice.

OBJECTIVE: Tilmicosin (TIL) is a long-acting macrolide antibiotic used to treat cattle for pathogens that cause bovine respiratory disease. However, overdoses of this medication have been reported to induce cardiac damage. Our experimental objective was to evaluate the protective effects of Spirulina platensis (SP) administration against TIL-induced cardiotoxicity in mice. MATERIALS AND METHODS: Our experimental in vivo animal study used 40 male albino mice that were divided into five groups of eight mice per group. The first group served as a control group and was injected with saline. The second group received SP at dose of 1000 mg/kg body weight for five days. The third group received a single dose of TIL (75 mg/kg, subcutaneously). Groups 4 and 5 were given SP at doses of 500 and 1000 mg/kg body weight for five consecutive days just before administration of TIL at the same dose and regimen used for group 3. RESULTS: TIL treated animals showed a significant increase in serum cardiac injury biomarkers as well as cardiac lipid peroxidation, however they had evidence of an inhibition in antioxidant biomarkers. SP normalized elevated serum levels of lactate dehydrogenase (LDH), creatine kinase (CK), and CK-MB. Furthermore, SP reduced TIL-induced lipid peroxidation and oxidative stress in a dose-dependent manner. CONCLUSION: Administration of SP minimized the toxic effects of TIL by its free radicalscavenging and potent antioxidant activity.

Seroepidemiology of toxoplasma gondii infection in women with first trimester spontaneous miscarriage in qena governorate, egypt.

INTRODUCTION: To determine seroprevalence and risks factors for T. gondii in women with early miscarriage, Sera of 76 women were analyzed infection by indirect enzyme linked immunosorbent assay (ELISA). Seropositive cases were further examined histopathologically for evidence of Toxoplasma gondii organisms. MATERIAL AND METHODS: Demographic data were obtained from participants to gather information on risk factors. RESULT AND DISCUSSION: Of 76 women with spontaneous abortion screened for Toxoplasma-specific IgG and IgM antibodies with ELISA, 35 were IgG seropositive, of which, 14 samples were IgM seropositive. Therefore, seropositivity rates of 46.1% (95% CI: 35.1%, 57.3%), and 18.4% (95% CI: 10.89%, 28.32%) for IgG and IgM, respectively were found. These indicate that, 27.6 % (21 cases) of studied women (IgG+/IgM-) were immune to toxoplasmosis and 53.94 %(41 cases) were susceptible to primary infection (IgG-/IgM-). Mean while acute toxoplasmosis (IgG+/IgM+) was 18.4 %( 14 cases) with one case (1.3%) confirmed for recent infection as she had Tachyzoites on histopathology study. On the basis of multivariate logistic regression, living in a rural area was found to be the only independent predictor of toxoplasmosis (OR=3.800, CI= 1.100-10.813, p=0.034). CONCLUSION: The seroprevalence of T. gondii infection in women with first trimester abortion in Qena governorate of Egypt is high. Pregnant women living in rural area are at a higher risk for acquiring infection during pregnancy. Antenatal screening of pregnant women and educational program about risks for Toxoplasmosis in rural areas is needed.

Modified Lanz incision in appendicectomy - the surgical trainees best friend.

Appendicitis is one of the commonest acute surgical diseases and treatment by appendicectomy is the most frequently performed surgical procedure in the western world. After obtaining adequate basic surgical experience, an open appendicectomy is an ideal procedure for junior surgical trainees to develop their operative skills and despite a reduction in training hours, recent figures suggest that surgical SHOs still perform about 30% of these cases. Although they are clearly routine and suitable for junior staff to perform under supervision, as many as 20% of appendicectomies, are for a variety of reasons considered difficult. We aim to be the first to present a modified Lanz incision that we believe provides not only a cosmetic scar but also is placed more frequently over the base of the appendix. It gives adequate access in difficult cases and we feel this is the most appropriate incision for a trainee to use when performing an appendicectomy.