Dual approach utilizing self microemulsifying technique and novel P-gp inhibitor for effective delivery of taxanes

In the present work, concomitant use of self-microemulsifying drug delivery systems (SMEDDS) and a novel third-generation P-gp inhibitor, GF120918 (elacridar), for the effective transport of taxanes (paclitaxel and docetaxel) across an in?vitro model of the intestinal epithelium and uptake into tumor cells were investigated. On the basis of solubility studies and ternary phase diagrams, different SMEDDS formulations of taxanes were prepared and characterized. In caco-2 cell permeation study, paclitaxel-loaded SMEDDS along with GF120918 showed a four-fold increase in apparent permeability, while docetaxel-loaded SMEDDS in combination with GF120918 showed a nine-fold increase in permeability, as compared to plain drug solution. Cell uptake studies on A549 cells were performed with microemulsions formed from both SMEDDS formulations loaded with rhodamine 123 dye and showed good uptake than plain dye solution. Confocal laser scanning microscopic images further confirmed the higher uptake of both SMEDDS formulations in the presence of GF120918.     

Simultaneous identification of prednisolone and its ten metabolites in human urine by high performance liquid chromatography-tandem mass spectrometry

The use of prednisolone and prednisone is prohibited by the World Anti‐Doping Agency (WADA) due to their performance‐enhancing effect. The purpose of the present work was to explore the possibility of identification and detection of various metabolites of prednisolone by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) in excretion study samples. Ten metabolites of prednisolone could be identified namely prednisone (11‐oxo metabolite) [M‐1], 6‐β‐OH‐prednisolone [M‐2], 20‐β‐OH‐prednisolone [M‐3], 20‐α‐OH‐prednisolone [M‐4], 20‐α‐OH‐prednisone [M‐5], 20‐β‐OH‐prednisone [M‐6], 2 tetrahydro epimers of 20‐β‐OH‐prednisolone [M‐7], 2 tetrahydro epimers of 20‐α‐OH‐prednisolone [M‐8], 2 tetrahydro epimers of 20‐β‐OH‐prednisone [M‐9], and 2 tetrahydro epimers of 20‐α–OH‐prednisone [M‐10]. Prednisolone was administered in 10‐, 20‐, and 40‐mg dosage to healthy volunteers to study detection of various metabolites. The parent, M‐1, M‐2, and M‐3 could be detected up to 72 h while rest of the metabolites were detectable up to 24 h after drug administration. The detection of newer metabolites of the drug can further be used for confirmatory purposes. Copyright © 2012 John Wiley & Sons, Ltd.     

The tug-of-war between dendritic cells and human chronic viruses

The human immune system is under constant challenge from many viruses, some of which the body is successfully able to clear. Other viruses have evolved to escape the host immune responses and thus persist, leading to the development of chronic diseases. Dendritic cells are professional antigen-presenting cells that play a major role in both innate and adaptive immunity against different pathogens. This review focuses on the interaction of different chronic viruses with dendritic cells and the viruses' ability to exploit this critical cell type to their advantage so as to establish persistence within the host.     

Weak or absent evidence for the association of HLA-DR antigens with risk of thyroid carcinoma: a meta-analysis of observational studies

Inconsistent reports of associations between human leukocyte antigen (HLA)-DR and thyroid cancers exist. We conducted a comprehensive search of the PubMed, Scopus and Web of Science databases. Using random-effects modeling, subgroup analyses, meta-regression and prediction interval (PI) estimation, we combined the existing evidence from 13 studies (977 cases of thyroid cancer and 3735 controls). Only HLA-DR1 and HLA-DR11 were significantly associated; however, the evidence for HLA-DR11 came from only three studies while that for HLA-DR1 had large between-study heterogeneity. All the PIs estimated in the study straddled unity. Therefore, current evidence for the studied association is incomplete as well as uncertain. Attempts to include HLA-DR typing as a prognostic or therapeutic marker may be premature at this time.     

Modulation of NO Bioavailability by Temporal Variation of the Cell-Free Layer Width in Small Arterioles

The cell-free layer exhibits dynamic characteristics in the time domain that may be capable of altering nitric oxide (NO) bioavailability in small arterioles. However, this effect has not been fully elucidated. This study utilized a computational model on NO transport to predict how temporal variations in the layer width could modulate NO bioavailability in the arterioles. Data on the layer width was acquired from high-speed video recordings in arterioles (ID = 48.4 ± 1.8 μm) of the rat cremaster muscle. We found that when wall shear stress response was not considered, the layer variability could lead to a slight decrease (1.6–6.6%) in NO bioavailability that was independent of transient changes in NO scavenging rate. Conversely, the transient response in wall shear stress and NO production rate played a dominant role in reversing this decline such that a significant augmentation (5.3–21.0%) in NO bioavailability was found with increasing layer variability from 24.6 to 63.8%. This study highlighted the importance of the temporal changes in wall shear stress and NO production rate caused by the layer width variations in prediction of NO bioavailability in arterioles.