Effect of pH on weakly acidic and basic model drugs and determination of their ex vivo transdermal permeation routes

The aim of the present study was to investigate the effect of donor pH on the transdermal permeability of the model drugs across rat skin and also to determine the major route of transport of the drugs. Weakly acidic drugs (partition coefficient) ibuprofen (3.6), aceclofenac (3.9), glipizide (1.9) and weakly basic drugs olanzapine (3.6), telmisartan (6.0), and sildenafil citrate (1.9) were selected for the study. The ex vivo permeation studies of these drugs at different donor pH (pH – 1.2, 4, 5, 6.8, 7.4, and 8) using Franz diffusion cell (area, 7.54 cm2 ) has shown a pH-dependent permeability. Among these drugs the weakly acidic drugs has shown higher permeation rates compared to the weakly basic drugs. The permeability coefficient and the distribution coefficient of the weakly basic drugs increased on increasing the pH whereas the weakly acidic drugs showed an inverse relation. The weakly basic drugs also showed an increase in permeation with increase in the fraction of unionized species indicating dominance of transcellular route of permeation. With an exception of sildenafil citrate, a weakly basic salt form of the drug which showed a high permeation value at pH 7.4 where 57% of the drug was unionized, indicating the involvement of both paracellular and transcellular route in its permeation

Towards a Correlation between Polar Surface Area of Drugs with Ex-vivo Transdermal Flux Variability

Abstract The aim of the present study was to investigate the relationship between the polar surface area and other molecular properties of the model drugs and their transdermal permeability across the rat skin. Few model drugs which are weakly acidic (ibuprofen, aceclofenac and glipizide) and weakly basic (olanzapine, telmisartan and sildenafil citrate) were selected for the study based on Polar surface area (PSA). Ex-vivo studies were carried out in franz diffusion cell. The skin permeation parameters of the model drugs were correlated to the physicochemical properties. The physicochemical properties considered for the study have shown to be synonymous with the pre-established ideal properties for the transdermal permeation. In acidic drugs, the order of correlation of the physicochemical properties to flux was mol. wt. > total no. of hydrogen bonds > M.P > PSA > Log P > Log D > solubility. In basic drugs, the order of correlation of the physicochemical properties to flux was mol. wt > PSA > solubility > log P > log D> total no. of hydrogen bonds> M.P. The property considered for the study PSA has acquired 4 th rank in acidic drugs with R 2 = 0.9465 and 2 nd in basic drugs with R 2 = 0.9477. The prime important factor for the study PSA, has shown a tortuous effect on the permeation of the selected drugs, whereas further study of PSA in relation to skin permeability parameters by considering larger drug data sets may impart a clearer image of its influence on transdermal permeation

Single-cell analysis of upper airway cells reveals host-viral dynamics in influenza infected adults [preprint]

Influenza virus infections are major causes of morbidity and mortality. Research using cultured cells, bulk tissue, and animal models cannot fully capture human disease dynamics. Many aspects of virus-host interactions in a natural setting remain unclear, including the specific cell types that are infected and how they and neighboring bystander cells contribute to the overall antiviral response. To address these questions, we performed single-cell RNA sequencing (scRNA-Seq) on cells from freshly collected nasal washes from healthy human donors and donors diagnosed with acute influenza during the 2017-18 season. We describe a previously uncharacterized goblet cell population, specific to infected individuals, with high expression of MHC class II genes. Furthermore, leveraging scRNA-Seq reads, we obtained deep viral genome coverage and developed a model to rigorously identify infected cells that detected influenza infection in all epithelial cell types and even some immune cells. Our data revealed that each donor was infected by a unique influenza variant and that each variant was separated by at least one unique non-synonymous difference. Our results demonstrate the power of massively-parallel scRNA-Seq to study viral variation, as well as host and viral transcriptional activity during human infection

Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis

Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. Here we demonstrate that the Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which has been implicated in inflammation, is abundantly expressed in ECs and in atherosclerotic plaques from mice and humans. On the basis of endothelial-specific MAP4K4 gene silencing and gene ablation experiments in Apoe(-/-) mice, we show that MAP4K4 in ECs markedly promotes Western diet-induced aortic macrophage accumulation and atherosclerotic plaque development. Treatment of Apoe(-/-) and Ldlr(-/-) mice with a selective small-molecule MAP4K4 inhibitor also markedly reduces atherosclerotic lesion area. MAP4K4 silencing in cultured ECs attenuates cell surface adhesion molecule expression while reducing nuclear localization and activity of NFkappaB, which is critical for promoting EC activation and atherosclerosis. Taken together, these results reveal that MAP4K4 is a key signalling node that promotes immune cell recruitment in atherosclerosis

Esthetic Rehabilitation with Direct Composite Veneering: A Report of 2 Cases

Esthetic or cosmetic dentistry is one of the main areas of dental practice. Increasing demand of patients for esthetics has resulted in the development of several techniques for restoring the anterior teeth. Composite resin restorations have become an integral part of contemporary restorative dentistry and can be called “star of minimal invasion” due to its conservative concepts. The direct composite veneering allows restoring the tooth in a natural way and preservation of sound tooth structure when compared to indirect restorations. This article presents two case reports of esthetic rehabilitation of anterior teeth using direct composite veneering with two-year follow-up with acceptable outcome

Evaluation of centralization ability and canal transportation of root canals prepared with three commercially available pediatric rotary files

Background: The complex root canal anatomy of primary root canals is considered to be most challenging. The quality of the root canal preparation plays a significant role in the success of endodontic treatment. Now, there are very few root canal instruments that are capable of cleaning the canal three dimensionally. To evaluate the efficacy of root canal instruments, various technologies have been used; one of the most reliable strategies was cone-beam computed tomography (CBCT). Aim: The aim of this study is to compare the centralization ability and canal transportation of three commercially available pediatric rotary file systems using CBCT analysis. Materials and Methods: Thirty-three extracted human primary teeth with a minimum 7 mm root length were randomly divided into three groups (group I – Kedo-SG Blue, group II – Kedo-S Square, and group III – Pro AF Baby Gold). Biomechanical preparation was done according to the manufacturers instructions. Pre- and postinstrumentation CBCT images were taken for each group to evaluate the remaining dentin thickness thereby assessing the centering ability and the canal transportation ability of different file systems. Results: Significant difference was noticed in canal transportation and centering ability between the three tested groups. Mesiodistal canal transportation was significant at all three levels, whereas buccolingual canal transportation was significant only at the apical third of the root. However, Kedo-SG Blue and Pro AF Baby Gold showed lesser canal transportation compared to Kedo-S Square rotary file system. Mesiodistal centering ability was significant at cervical and apical thirds of the root with Kedo-S Square rotary file system maintaining less canal centricity. Conclusions: All three file systems tested in the study were effective in removing the radicular dentin. However, Kedo-SG Blue and Pro AF Baby Gold rotary file systems showed comparatively less canal transportation and more centering ability than Kedo-S Square rotary file system

Evaluation of root dentin damage during retreatment procedure using various engine-driven retreatment file systems—A micro-CT study

Aim: The aim of this research was to assess the damage to root dentin that arises from retreatment with different engine-driven NiTi retreatment files employing micro-computed tomography. Materials and Methods: Sixty mandibular premolar teeth having a single root and root canal that were recently extracted were gathered and stored. The specimens were de-coronated at the cementoenamel junction under water irrigation to achieve a homogeneous root length of 16 millimeters. Gutta-percha cones were coated with sealants and placed within the radicular canal till the WL. All sixty premolars were randomly assigned to one of the following three groups, with every group comprising 20 sample teeth each. Group 1: MTwo Retreatment files, Group 2: ProTaper Universal Retreatment files, Group 3: Edge File XR Retreatment rotary files. The quantity of root dentinal injury was estimated by deducting the dentin volume (mm3) in the pre- and post-therapy micro-CT scans at apical, middle, and cervical 3rd points. Results: An intra-group comparative scrutiny showed that lower radicular dentinal injury was noted at apical 3rd (0.31 ± 0.16, 0.62 ± 0.02) in Edge File XR Retreatment file system and MTwo Retreatment file system in that order. The statistically significant disparity was seen amid the MTwo Retreatment file, Edge File XR Retreatment file system and ProTaper Universal Retreatment file, Edge File XR Retreatment file system with P value of 0.001on intergroup assessment. Conclusion: In spite of the limitations that this research had, it was inferred that each assessed file system proficiently eradicated the obturated material through the retreatment procedure performed. In addition, it was seen that the Edge File XR group showed lesser root dentin damage in contrast to MTwo and ProTaper Universal file systems

Assessing Vitamin E and Glutathione Peroxidase Levels in Salivary Samples of Children with and without Dental Caries

Introduction: Multiple factors influence the initiation and progression of caries. Recent research has revealed that free radicals can be a prime cause of several inflammatory oral pathologies, including dental caries by direct or indirect influence on the salivary constituents like disease mediated free radicals and antioxidants. Aim: The aim of the present study was comparative evaluation of Vitamin E and Glutathione Peroxidase levels with the prevalence of dental caries in a group of school-going children. Materials and Methods: The present cross-sectional clinical study was conducted in Department of Pedodontics and Preventive Dentistry, SIBAR Institute of Dental sciences, Guntur, Andhra Pradesh, India from November 2016 to November 2018. Hundred children aged between 6-12 years were selected and divided into two groups i.e., caries active group (n=50) and caries-free group (n=50). Children having at least five decayed teeth were considered as caries active and children with DMFT/deft score 0 were considered as caries-free group. A 2 mL of unstimulated saliva was collected from all the subjects and the levels of Glutathione Peroxidase (GPx) and Vitamin E were evaluated by spectrophotometric assay. Obtained imbibing values were subjected to statistical analysis using unpaired t-test and SPSS Version 21.0 software. The p-value <0.05 was considered statistically significant. Results: Of the 100 participants 52 were males and 48 were females. The mean age of the study participants was 10.21±1.4 years. Significant reduction in GPx (p<0.001**) and Vitamin E (p<0.05*) were noticed in caries active group when compared to the caries free group. Conclusion: GPx and Vitamin E levels showed an inverse relationship with the presence of dental caries. Thus these antioxidant levels can be used as biomarkers to assess the oral as well as general health. Caries activity can also be measured by these salivary factors which might be helpful in preventive dentistry