Scaffold Repurposing Reveals New Nanomolar Phosphodiesterase Type 5 (PDE5) Inhibitors Based on Pyridopyrazinone Scaffold: Investigation of In Vitro and In Silico Properties

Inhibition of PDE5 results in elevation of cGMP leading to vascular relaxation and reduction in the systemic blood pressure. Therefore, PDE5 inhibitors are used as antihypertensive and antianginal agents in addition to their major use as male erectile dysfunction treatments. Previously, we developed a novel series of 34 pyridopyrazinone derivatives as anticancer agents (series A–H). Herein, a multi-step in silico approach was preliminary conducted to evaluate the predicted PDE5 inhibitory activity, followed by an in vitro biological evaluation over the enzymatic level and a detailed SAR study. The designed 2D-QSAR model which was carried out to predict the IC50 of the tested compounds revealed series B, D, E and G with nanomolar range of IC50 values (6.00–81.56 nM). A further docking simulation model was performed to investigate the binding modes within the active site of PDE5. Interestingly, most of the tested compounds showed almost the same binding modes of that of reported PDE5 inhibitors. To validate the in silico results, an in vitro enzymatic assay over PDE5 enzyme was performed for a number of the promising candidates with different substitutions. Both series E and G exhibited a potent inhibitory activity (IC50 = 18.13–41.41 nM). Compound 11b (series G, oxadiazole-based derivatives with terminal 4-NO2 substituted phenyl ring and rigid linker) was the most potent analogue with IC50 value of 18.13 nM. Structure–activity relationship (SAR) data attained for various substitutions were rationalized. Furthermore, a molecular dynamic simulation gave insights into the inhibitory activity of the most active compound (11b). Accordingly, this report presents a successful scaffold repurposing approach that reveals compound 11b as a highly potent nanomolar PDE5 inhibitor worthy of further investigation

Dissolution Enhancement and Formulation of Rapid-Release Lornoxicam Mini-Tablets

The aim was to enhance the dissolution of lornoxicam (LOR) and to produce mini-tablets with an optimised system to provide a rapid-release multi-particulate formulation. LOR systems were prepared through co-evaporation with either polyethylene glycol 6000 or Pluronic® F-68 (PLU) and adsorption onto Neusilin® US2 alone or co-adsorption in the presence of different amounts of polysorbate 80. All systems were characterised by FT-IR, differential scanning calorimetry, X-ray diffraction, flowability and dissolution techniques. Mini-tablets were prepared using the system with the optimum dissolution profile and flowability. Tensile strengths, content uniformity and dissolution profiles of the mini-tablets were evaluated. The effects of different excipients and storage conditions on mini-tablet properties were also studied. The optimised rapid-release LOR mini-tablets were further evaluated for their in vivo pharmacokinetic profile. The co-evaporate of LOR with PLU showed significantly faster dissolution and superior flowability and was evaluated together with three directly compressible excipients (Cellactose® 80, StarLac® (STA) and Emcompress®) for mini-tablet formulation. The formulation with STA provided the optimum results in terms of tensile strength content uniformity and rapid drug release following a 3-month stability study and was selected for further in vivo evaluation. The pharmacokinetic profile indicated the potential of the mini-tablets achieving rapid release and increased absorption of LO

Ginger (Zingiber Officinale)-derived nanoparticles in Schistosoma mansoni infected mice: Hepatoprotective and enhancer of etiological treatment.

BackgroundNanotechnology has been manufactured from medicinal plants to develop safe, and effective antischistosmal alternatives to replace today's therapies. The aim of the study is to evaluate the prophylactic effect of ginger-derived nanoparticles (GNPs), and the therapeutic effect of ginger aqueous extract, and GNPs on Schistosoma mansoni (S. mansoni) infected mice compared to praziquantel (PZQ), and mefloquine (MFQ).Methodology/principal findingsEighty four mice, divided into nine different groups, were sacrificed at 6th, 8th, and 10th week post-infection (PI), with assessment of parasitological, histopathological, and oxidative stress parameters, and scanning the worms by electron microscope. As a prophylactic drug, GNPs showed slight reduction in worm burden, egg density, and granuloma size and number. As a therapeutic drug, GNPs significantly reduced worm burden (59.9%), tissue egg load (64.9%), granuloma size, and number at 10th week PI, and altered adult worm tegumental architecture, added to antioxidant effect. Interestingly, combination of GNPs with PZQ or MFQ gave almost similar or sometimes better curative effects as obtained with each drug separately. The highest therapeutic effect was obtained when ½ dose GNPs combined with ½ dose MFQ which achieved 100% reduction in both the total worm burden, and ova tissue density as early as the 6th week PI, with absence of detected eggs or tissue granuloma, and preservation of liver architecture.Conclusions/significanceGNPs have a schistosomicidal, antioxidant, and hepatoprotective role. GNPs have a strong synergistic effect when combined with etiological treatments (PZQ or MFQ), and significantly reduced therapeutic doses by 50%, which may mitigate side effects and resistance to etiological drugs, a hypothesis requiring further research. We recommend extending this study to humans

Multi-detector computed tomography (MDCT) and audiological criteria to diagnose large vestibular aqueduct syndrome

Objective: The purpose of this study was to compare between Valvassori and Cincinnati criteria and to correlate between vestibular aqueduct measurements made in axial plane with those made in 45° oblique reformats. Patients and methods: The study group included 61 children with LVAS. All participants were subjected to full Audiological evaluation and MDCT scanning in axial plane. The axial data were transferred to workstation for post-processing with multiplanar reformatting software in order to obtain the 45° oblique reformats. Vestibular aqueduct measurements were made at 4 points: midpoint and operculum in both the axial plane and 45° oblique reformats. Results: 100% (122 ears) were diagnosed according to Cincinnati criteria, while 81% (99 ears) of children with LVAS fit Valvassori criterion, and 19% were (23 ears) missed. There were statistically significant correlations among the diameters of the VA in the axial plane (midpoint and operculum) and their counterparts in the 45° oblique reformats. Values equal to or greater than 1.2 mm in the midpoint and 1.3 mm in the operculum are proposed to be the criteria to diagnose LVA in the 45° oblique reformats. Conclusion: Cincinnati criteria are more sensitive than Valvassori criteria in the diagnosis of LVAS

Solving 2D-Poisson equation using modified cubic B-spline differential quadrature method

In this study a modified cubic B-spline differential quadrature method (MCBDQM) is used to solve the two dimensional Poisson equation. Using the cubic B-spline functions, explicit expressions of weighting coefficients for approximation of derivatives are obtained. Examples of two dimensional Poisson equation under Dirichlet and mixed boundary conditions are studied using the method. Comparisons between the results of the method, the results of using Shu's general approach and results of other methods are presented. Good agreement with Shu's general approach and with the other methods is reached in case of Dirichlet boundary condition. The differential quadrature based on modified cubic B-splines is found to be an efficient method to solve the two dimensional Poisson equation. Keywords: Differential quadrature method, Modified cubic B-spline, Shu’s general approach, Two dimensional Poisson equatio

Effectiveness of Adding a Salt Tolerant Crop to the Egyptian Crop Pattern to Adapt with the Water Salinity and Shortage Conditions

The imbalance between the high water demand and the limited water supplies in Egypt makes water resources management a big challenge. The Mediterranean Sea water intrusion is predicted to increase, causing high water salinity at the Nile delta. A future reduction in the Nile’s water supply is also expected to occur leading to further water stress. Such water shortage will increase the re-use of drainage water which leads to further increase in the water’s salinity. This study aims at adding a salt-tolerant crop to the traditional Egyptian crop pattern. Using quinoa is suggested as an alternative for wheat crop in areas with high water salinity, where the wheat’s productivity is negatively affected. The effectiveness of the proposed crop is evaluated by using the agriculture sector model for Egypt (ASME) which estimates the water demand and the agricultural productivity for different cropping patterns. The results show that quinoa is a good substitution that produces a reliable yield in the case of Nile flow reduction. A base case considering the current water supply conditions is first studied. Then, a 10% reduction in the Nile water supply and the population projection in the year 2030 are presented in two scenarios, one of which considers financial incentives for supporting quinoa. The results show that the Nile flow reduction adversely affects most of crops’ yields, and accordingly, decreases the total crops’ water productivity, but quinoa is found to have a potential high yield in case of water shortage. The total yield of both quinoa and wheat together decrease from 8,643 million tons to 8.223 million tons for the scenario of 10% Nile water reduction without economic incentives, while it jumps to 11.474 million tons  under the same conditions but with  incentives that encourage the farmers to cultivate quinoa

Edge Detection of Noisy Medical Images Based Mixed Entropy

Edge detection of medical image has used as one of diagnostics techniques largely applied for the doctor's diagnosis determination. Although the edge detection of medical images is existing since years but it is still challenging and scope of research. It has been found that the previous used algorithms were not able to produce optimized or ideal results in different cases. In most applications, medical images contain object boundaries and object shadows and noise. Therefore, they may be difficult to distinguish the exact edge from noise or trivial geometric features. In this paper, we propose a new efficient algorithm for edge detection of noisy medical images based on mixed entropy. Mixed entropy  is defined in order to suppress noise and adapt to different edge in the image. Our target is to get the best edge representation under noise effect. The performance of our algorithm is compared against other methods using images corrupted with various levels of "salt and pepper". It is observed that the proposed algorithm displayed superior noise resilience and decrease the computation time. The results indicate the accuracy of the proposed edge-detection method is superior to that of conventional edge-detection methods for medical image. Keywords: Edge Detection; Medical Images ; Entropy; Noisy Image

Blastocystis SPP. infection prevalence and associated patient characteristics as predictors among a cohort of symptomatic and asymptomatic Egyptians

Blastocystis species (spp.) is a large unicellular intestinal protozoan parasite that has a worldwide distribution. It has unclear pathogenicity and is linked to many clinical disorders. The study purpose was to determine the prevalence of Blastocystis spp. molecularly in a cohort of symptomatic and asymptomatic individuals and to assess the association of Blastocystis spp. with the patient characteristics as possible predictors of the occurrence of Blastocystis spp. Fecal specimens were collected from 139 Egyptians of both sexes, aged from 5 months to 74 years. All fecal specimens were examined coproscopically for detection of gut parasites and cultured on Modified Jones’ medium for detection of Blastocystis spp. Molecular assay using nested PCR (nPCR) was performed for cultured Blastocystis. The association between detection of Blastocystis spp. and patient demographics and clinical data was determined. Prevalence of parasitic infections was 62 (44.6%) using coproscopy. Blastocystis spp. was the most prevalent parasite (21.6%) in both symptomatic and asymptomatic individuals, followed by E. histolytica complex (13.7%) and Giardia intestinalis (10.8%). Cryptosporidium spp. (2.2%) and E. coli (2.1%) were the least detected parasites. Among studied patient characteristics, only age showed statistical significance in association with detection of Blastocysitis spp.