Recent advances in preclinical in vitro approaches towards quantitative prediction of hepatic clearance and drug-drug interactions involving organic anion transporting polypeptide (OATP) 1B transporters

Hepatic uptake mediated by organic anion transporting polypeptide (OATP) 1B1 and 1B3 can serve as a major elimination pathway for various anionic drugs and as a site of drug-drug interactions (DDIs). This article provides an overview of the in vitro approaches used to predict human hepatic clearance (CL_h) and the risk of DDIs involving OATP1Bs. On the basis of the so-called extended clearance concept, in vitro–in vivo extrapolation methods using human hepatocytes as in vitro systems have been used to predict the CL_h involving OATP1B-mediated hepatic uptake. CL_h can be quantitatively predicted using human donor lots possessing adequate OATP1B activities. The contribution of OATP1Bs to hepatic uptake can be estimated by the relative activity factor, the relative expression factor, or selective inhibitor approaches, which offer generally consistent outcomes. In OATP1B1 inhibition assays, substantial substrate dependency was observed. The time-dependent inhibition of OATP1B1 was also noted and may be a mechanism underlying the in vitro–in vivo differences in the inhibition constant of cyclosporine A. Although it is still challenging to quantitatively predict CL_h and DDIs involving OATP1Bs from only preclinical data, understanding the utility and limitation of the current in vitro methods will pave the way for better prediction.     

普通变异型免疫缺陷病合并肝硬化1例并文献复习

目的:讨论普通变异型免疫缺陷病(common variable immunodeficiency disease,CVID)的发病机制、临床表现及治疗方法。方法:报道1例普通变异型免疫缺陷病合并肝硬化患者并复习相关文献。结果:普通变异型免疫缺陷病是临床少见病,易误诊,病因不清,临床表现复杂,部分患者病程中可出现肝功能异常,甚至并发肝硬化。结论:临床反复感染的患者应考虑CVID的可能,须进一步作血浆免疫球蛋白的检测确诊。对已经确诊患者定期补充静脉丙种球蛋白,同时还应定期检查肝功能。     

Measuring the appropriateness of carbamazepine and valproic acid prescribing and utilization using a newly implemented online system in the Tabuk Region of Saudi Arabia

Epilepsy is a common neurologic disorder, which is efficiently treated with carbamazepine and valproic acid. Moreover, Saudi Ministry of Health implemented a new E-system for Poison Control Centers called Awtar to enhance technology utilization in ensuring patients’ satisfaction and to improve treatment outcomes. Therefore, we conducted this study to assess appropriateness of indication of requests and therapeutic levels of carbamazepine and valproic acid in Tabuk area, North West Saudi Arabia. This is a retrospective observational study conducted in Poison Control & Forensic Chemistry Center, Tabuk, Saudi Arabia. Patients’ data were obtained for years 2018 and 2019. The blood levels of carbamazepine and valproic acid were measured by Therapeutic Drug Monitoring (TDM) Unit. We selected patients treated with either valproic acid or carbamazepine alone without any history of drug allergy. Data of 264 patients were extracted from Awtar E-system. Serum carbamazepine levels were within therapeutic range in 114 patients (75.50%), above-therapeutic range in 13 patients (8.61%) and sub-therapeutic levels in 24 patients (15.89%). Regarding serum valproic acid, it is within therapeutic range in 62 patients (54.87%), above-therapeutic range in 11 patients (9.73%) and sub-therapeutic levels in 40 patients (35.40%). In conclusion, this study gives information about partial appropriateness of usage of carbamazepine and low level of appropriateness of valproic acid. However, more efforts are needed to improve results of appropriateness of indication of antiepileptic drugs.     

Macroporous thin membranes for cell transplant in regenerative medicine

The aim of this paper is to present a method to produce macroporous thin membranes made of poly (ethyl acrylate-co-hydroxyethyl acrylate) copolymer network with varying cross-linking density for cell transplantation and prosthesis fabrication. The manufacture process is based on template techniques and anisotropic pore collapse. Pore collapse was produced by swelling the membrane in acetone and subsequently drying and changing the solvent by water to produce 100 microns thick porous membranes. These very thin membranes are porous enough to hold cells to be transplanted to the organism or to be colonized by ingrowth from neighboring tissues in the organism, and they present sufficient tearing stress to be sutured with surgical thread. The obtained pore morphology was observed by Scanning Electron Microscope, and confocal laser microscopy. Mechanical properties were characterized by stress–strain experiments in tension and tearing strength measurements. Morphology and mechanical properties were related to the different initial thickness of the scaffold and the cross-linking density of the polymer network. Seeding efficiency and proliferation of mesenchymal stem cells inside the pore structure were determined at 2 h, 1, 7, 14 and 21 days from seeding.     

Effects of probiotics on gastrointestinal complications and nutritional status of postoperative patients with esophageal cancer: A protocol of randomized controlled trial

Background:Gastrointestinal complications and malnutrition are common problems that affect postoperative rehabilitation and survival of patients with esophageal cancer. Evidence has shown that probiotics have a positive effect on improving gastrointestinal complications and nutritional status of patients with esophageal cancer after surgery, but there is a lack of prospective studies on this topic. We designed this prospective randomized controlled trial to evaluate the effects of probiotics on gastrointestinal complications and nutritional status in patients with postoperative esophageal cancer.Methods:This is a prospective, randomized, double-blind, placebo-controlled trial. It was approved by the Clinical Research Ethics Committee of our hospital. 192 patients will be randomly divided into probiotics group and the placebo group in a 1:1 ratio. After operation, probiotics and placebo will be given orally for 8 weeks. The indexes of nutritional status and incidence of digestive tract complications will be recorded and the data will be analyzed by SPSS 18.0 software.Discussion:This study will evaluate the effect of probiotics on gastrointestinal complications and nutritional status of postoperative patients with esophageal cancer. The results of this study will provide clinical basis for the use of probiotics in postoperative treatment of esophageal cancer.Trial registration:OSF Registration number: D DOI 10.17605/OSF.IO/QHW86     

Redox active or thiol reactive? Optimization of rapid screens to identify less evident nuisance compounds

Compounds that exhibit assay interference or undesirable mechanisms of bioactivity are routinely encountered in assays at various stages of drug discovery. We observed that assays for the investigation of thiol-reactive and redox-active compounds have not been collected in a comprehensive review. Here, we review these assays and subject them to experimental optimization to improve their reliability. We demonstrate the usefulness of our assay cascade by assaying a library of bioactive compounds, chemical probes, and a set of approved drugs. These high-throughput assays should complement the array of wet-lab and in silico assays during the initial stages of hit discovery campaigns to pursue only hit compounds with tractable mechanisms of action.