Microparticles based on hydrophobically modified chitosan as drug carriers

In this work, a hydrophobically modified (HM) chitosan derivative was prepared by covalent linkage of C₁₂ groups to the chitosan backbone. HM‐chitosan microparticles were prepared according to an emulsification‐solvent evaporation method and naltrexone (NTX) was used as a model drug. For comparison, unmodified chitosan and poly lactic‐co‐glycolic acid (PLGA) microparticles were also tested as carriers for NTX. HM‐chitosan formed viscous semi‐dilute solutions, suggesting a high level of chain entanglements and hydrophobic associations. HM‐chitosan microparticles generally showed higher production yield and encapsulation efficiency, as compared with chitosan and PLGA. The burst release shown by chitosan microparticles was significantly reduced when using the HM‐chitosan derivative. An enhanced control of drug release was observed over at least 50 days. PLGA particles demonstrated inferior controlled release properties as compared to HM‐chitosan subsequent to the initial release stage. These results revealed the potential of hydrophobic modification of chitosan as a means to improve the stability and sustained delivery properties of the polymer. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40055.     

Stabilization of pluronic gels in the presence of different polysaccharides

Several different polysaccharides have been added to pluronic F127 (poloxamer 407) gels to test their ability to stabilize the gels against dissolution in aqueous media over time. The studied polysaccharides include κ‐carrageenan, chitosan, hyaluronic acid, pectin, alginate, hydroxyethylcellulose, and ethyl(hydroxyethyl)cellulose. Although all the considered polysaccharides slowed down the dissolution time of the pluronic gels, unmodified polysaccharides only had a modest stabilization effect. However, hydrophobic modification of polysaccharides with a sufficiently long hydrocarbon chain (C₁₆) was found to partly prevent the gels from dissolving for more than 6 months. Shorter hydrocarbon chains did not have the same effect, even at high degrees of hydrophobicity. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40465.     

Design of a General‐Purpose European Compound Screening Library for EU‐OPENSCREEN

This work describes a collaborative effort to define and apply a protocol for the rational selection of a general‐purpose screening library, to be used by the screening platforms affiliated with the EU‐OPENSCREEN initiative. It is designed as a standard source of compounds for primary screening against novel biological targets, at the request of research partners. Given the general nature of the potential applications of this compound collection, the focus of the selection strategy lies on ensuring chemical stability, absence of reactive compounds, screening‐compliant physicochemical properties, loose compliance to drug‐likeness criteria (as drug design is a major, but not exclusive application), and maximal diversity/coverage of chemical space, aimed at providing hits for a wide spectrum of drugable targets. Finally, practical availability/cost issues cannot be avoided. The main goal of this publication is to inform potential future users of this library about its conception, sources, and characteristics. The outline of the selection procedure, notably of the filtering rules designed by a large committee of European medicinal chemists and chemoinformaticians, may be of general methodological interest for the screening/medicinal chemistry community. The selection task of 200K molecules out of a pre‐filtered set of 1.4M candidates was shared by five independent European research groups, each picking a subset of 40K compounds according to their own in‐house methodology and expertise. An in‐depth analysis of chemical space coverage of the library serves not only to characterize the collection, but also to compare the various chemoinformatics‐driven selection procedures of maximal diversity sets. Compound selections contributed by various participating groups were mapped onto general‐purpose self‐organizing maps (SOMs) built on the basis of marketed drugs and bioactive reference molecules. In this way, the occupancy of chemical space by the EU‐OPENSCREEN library could be directly compared with distributions of known bioactives of various classes. This mapping highlights the relevance of the selection and shows how the consensus reached by merging the five different 40K selections contributes to achieve this relevance. The approach also allows one to readily identify subsets of target‐ or target‐class‐oriented compounds from the EU‐OPENSCREEN library to suit the needs of the diverse range of potential users. The final EU‐OPENSCREEN library, assembled by merging five independent selections of 40K compounds from various expert groups, represents an excellent example of a Europe‐wide collaborative effort toward the common objective of building best‐in‐class European open screening platforms.     

AstPT Catalyses both Reverse N1‐ and Regular C2 Prenylation of a Methylated Bisindolyl Benzoquinone

Prenylated bisindolyl benzoquinones exhibit interesting biological activities, such as antidiabetic or anti‐HIV activities. A number of these compounds, including asterriquinones, have been isolated from Aspergillus terreus. In this study, we identified two putative genes by genome mining, ATEG_09980 and ATEG_00702, which share high sequence similarity with the known bisindolyl benzoquinone prenyltransferase TdiB from Aspergillus nidulans. The coding sequences were cloned and overexpressed in E. coli. The overproduced recombinant proteins were purified to near homogeneity and used for enzyme assays with asterriquinone D in the presence of dimethylallyl diphosphate. HPLC analysis showed that product formation was only detected in enzyme assays with EAU29429 encoded by ATEG_09980, not in those with EAU39348 encoded by ATEG_00702. Product isolation and structure elucidation by NMR and MS analyses led to identification of N1‐reversely and C2‐regularly monoprenylated derivatives, as well as N1′,N1′′reversely, N1′‐reversely, C2′′‐regularly diprenylated derivatives. This proved that EAU29429 functions as an asterriquinone prenyltransferase (AstPT) and indicated the involvement of EAU29429 rather than EAU39348 in the biosynthesis of methylated asterriquinones. Furthermore, incubation of monoprenylated enzyme products with AstPT resulted in the formation of the diprenylated derivatives.     

Non-positive autoimmune responses against CYP2E1 in refrigeration mechanics exposed to halogenated hydrocarbons

The aim of the study was to determine if occupational exposure to hydrofluorocarbons (HFC) and hydrochlorofluorocarbons (HCFC) generates autoimmune responses against CYP2E1. HFCs and HCFCs have replaced the chlorofluorocarbons (CFC) in e.g. refrigeration installations and air-conditioning systems. During the substitution period, refrigeration mechanics reported symptoms like asthma, influenza-like reactions, and joint troubles. These symptoms resemble those of chronic inflammatory diseases with an autoimmune component. Since exposure to structurally similar chemicals, e.g. halothane, has previously been associated with autoimmune responses and diseases, autoimmunity among the refrigeration mechanics might hypothetically explain the reported inflammatory symptoms. Serum from 44 Swedish men, occupationally exposed to halogenated hydrocarbons, was screened for antibodies against CYP2E1 with enzyme-linked immunosorbent assay. Thirty of the workers had asthma, joint problems or influenza-like symptoms whereas 14 of them had no such symptoms. They were all selected from a cohort of 280 refrigeration mechanics. Unexposed, healthy, Swedish men (n=35) constituted control group. The study was approved by the Ethics Committee at Karolinska Institutet. No increase in autoantibodies against CYP2E1 was detected among the occupationally exposed workers as compared to the unexposed controls. Further, there was no difference in antibody titer between the exposed workers with symptoms and the exposed, asymtomatic workers or the unexposed controls. The present study does not completely exclude a connection between exposure and effect but makes the relation less likely at these exposure levels.     

How Do People with Disabilities Consider Fire Safety and Evacuation Possibilities in Historical Buildings?—A Swedish Case Study

An exploratory focus group study of people with different types of disabilities, e.g. mobility, visual and auditory, was carried out to explore how evacuation safety in historical buildings can be improved for people with various disabilities. Accounts of real life experiences on how well evacuation routes in historical buildings are adapted to people with different types of disabilities, as well as suggestions for safety enhancing measures, were collected. Some examples of reported problems were level differences on the way to and in evacuation routes for people with mobility impairments. Other examples were problems with orientation for people with visual disabilities and problems with detecting the evacuation alarm signal for people with auditory disabilities. In general the participants expressed different problems and needs depending on their type of disability. A common view amongst all the participants were that organizational parameters concerning evacuation of people with disabilities have to be improved. One conclusion from the study was that there are shortcomings in the physical environment as well as in the organization of evacuation in historical buildings today. This means that emergency evacuation safety must be properly focused on when improving accessibility in historical buildings. Measures must be taken to address the different needs of people with various types of disabilities as well as to make improvements for all user groups.     

Nachgiebiger Elektrodenträger für Cochlea-Implantate mit fluidischer Aktuierung

The cochlear implant, consisting of a compliant electrode carrier (ET) and embedded electrodes with contact wires, is an auditory neuroprosthesis, which is surgically inserted into the inner ear (cochlea) in order to create an auditory impression in the hearing-impaired patients. For simplification of the insertion, a fluidically actuated electrode carrier with a changeable curvature is presented. The deformation of the ET is specifically manipulated by applying pressure to its interior and also by a non-stretchable thin fibre or stripe embedded in its wall. An analytical examination of scaling properties allows to use scaled structures for models and measurements. In order to determine the geometry of the ET, a model-based synthesis – FE method combined with analytical modelling – is carried out. The synthesis resulted in a conical shape of the ET with a cylindrical cavity closed at one end and a fiber running parallel to the cavity. Experimental studies on a measuring geometry show a maximum deviation of 0,6 bar at a maximum internal pressure of 6 bar. The investigations show that the proposed synthesis method is suitable for the development of surgical instruments with adjustable curvature.     

A monolithic computational approach to thermo‐structure interaction

In the present work, a monolithic solution approach for thermo‐structure interaction problems motivated by the challenging application of the behaviour of rocket nozzles is proposed. Structural and thermal fields are independently discretised via finite elements. The resulting system of equations is solved via a monolithic thermo‐structure interaction scheme, which is constructed by a block Gauss–Seidel preconditioner in combination with algebraic multigrid methods. The proposed method is tested for four numerical examples, the second Danilovskaya problem, a simplified rocket nozzle configuration, an internally loaded hollow sphere, and a fully three‐dimensional nozzle configuration of a subscale thrust chamber. Good agreement of the numerical results with results from the literature is observed. Furthermore, it is shown that the monolithic solution algorithm can handle the complete range of the parameter spectrum, whereas partitioned algorithms are limited to a certain parameter range only. Moreover, the monolithic algorithm exhibits improved efficiency and robustness compared to partitioned algorithms. Copyright © 2013 John Wiley & Sons, Ltd.