Insight into the mechanism of modulated syntheses: in situ synchrotron diffraction studies on the formation of Zr-fumarate MOF

In this work, the formation of a Zr-based metal-organic framework (MOF), Zr-fumarate MOF (Zr-fum MOF), is studied in situ by energy-dispersive diffraction. The Zr-fum MOF can be synthesised in DMF as well as in water-based synthesis systems. In both cases, its formation requires modulation, i.e. a monocarboxylic acid which is used as the modulator has to be added to the synthesis mixture. In general, different mechanisms of modulation are possible, for example, deprotonation of the linker molecule (deprotonation modulation) or coordination modulation (wherein the molecules of the modulator compete with the linker molecules for the coordination sites at the inorganic building units). Independently of the specific mechanism, modulation often improves the reproducibility of the MOF synthesis and the crystallinity of the product and may be used to control crystal size and morphology. This study is the first to investigate the kinetics of modulated MOF syntheses with regard to coordination modulation. According to this concept, the addition of a modulator usually decelerates the reaction. Our kinetic investigations show that this is the case for the formation of Zr-fum MOF in the water-based synthesis with formic acid used as a modulator. On the contrary, the addition of formic acid to the DMF-based synthesis results in an accelerating effect. This unexpected effect can be attributed to a small amount of water present in formic acid. Correspondingly, the addition of water to the synthesis mixture also showed an accelerating effect. These investigations emphasise the subtle interplay of the different ingredients in a MOF synthesis. In the case of the Zr-fum MOF, both the modulator formic acid and the water content strongly affect the kinetics of crystallisation. Quantitative evaluation of the kinetic data using the Gualtieri equation provides additional insight into the mechanisms of coordination-modulated MOF formation reactions and excludes the idea of deprotonation modulation.DFG/Porous Metal–Organic Frameworks/1362DESY/I-2011055

Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs

Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from a library of natural products, we combined target-based screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols were identified as hits, and a library of 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. brucei below 10 \u3bcM. Four X-ray crystal structures and docking studies explained the observed structure-activity relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies. Encapsulation of compound 2 in PLGA nanoparticles or cyclodextrins resulted in lower in vitro toxicity when compared to the free compound. Combination studies with methotrexate revealed that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration of 1.3 \u3bcM, 11.7-fold dose reduction index and no toxicity toward host cells. Our results provide the basis for further chemical modifications aimed at identifying novel antitrypanosomatidic agents showing higher potency toward PTR1 and increased metabolic stability

Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To Inhibit <i>Trypanosoma brucei </i>Pteridine Reductase in Support of Early-Stage Drug Discovery

Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated the potential of a previously identified class of thiadiazole inhibitors of Leishmania major PTR1 for activity against Trypanosoma brucei (Tb). We solved crystal structures of several TbPTR1-inhibitor complexes to guide the structure-based design of new thiadiazole derivatives. Subsequent synthesis and enzyme- and cell-based assays confirm new, mid-micromolar inhibitors of TbPTR1 with low toxicity. In particular, compound 4m, a biphenyl-thiadiazole-2,5-diamine with IC50 = 16 μM, was able to potentiate the antitrypanosomal activity of the dihydrofolate reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of the EC50 value. In addition, the antiparasitic activity of the combination of 4m and MTX was reversed by addition of folic acid. By adopting an efficient hit discovery platform, we demonstrate, using the 2-amino-1,3,4-thiadiazole scaffold, how a promising tool for the development of anti-T. brucei agents can be obtained

Appropriateness of treatment recommendations for PPI in hospital discharge letters

International audienc

Accelerating Drug Discovery Efforts for Trypanosomatidic Infections Using an Integrated Transnational Academic Drug Discovery Platform

According to the World Health Organization, more than 1 billion people are at risk of or are affected by neglected tropical diseases. Examples of such diseases include trypanosomiasis, which causes sleeping sickness; leishmaniasis; and Chagas disease, all of which are prevalent in Africa, South America, and India. Our aim within the New Medicines for Trypanosomatidic Infections project was to use (1) synthetic and natural product libraries, (2) screening, and (3) a preclinical absorption, distribution, metabolism, and excretion\u2013toxicity (ADME-Tox) profiling platform to identify compounds that can enter the trypanosomatidic drug discovery value chain. The synthetic compound libraries originated from multiple scaffolds with known antiparasitic activity and natural products from the Hypha Discovery MycoDiverse natural products library. Our focus was first to employ target-based screening to identify inhibitors of the protozoan Trypanosoma brucei pteridine reductase 1 (TbPTR1) and second to use a Trypanosoma brucei phenotypic assay that made use of the T. brucei brucei parasite to identify compounds that inhibited cell growth and caused death. Some of the compounds underwent structure-activity relationship expansion and, when appropriate, were evaluated in a preclinical ADME-Tox assay panel. This preclinical platform has led to the identification of lead-like compounds as well as validated hits in the trypanosomatidic drug discovery value chain

What happens to inappropiate recommendations of proton pump inhibitors after hospital discharge?

Einleitung: Die Verordnung von Protonenpumpeninhibitoren (PPI) ist in den letzten zehn Jahren um 613% angestiegen. Die Gründe dafür sind unklar. Aus internationalen Studien ist bekannt, dass PPI in erheblichem Maße ohne Indikation im Krankenhaus und in der ambulanten Versorgung eingesetzt werden.Ziel: Das Ziel der Studie war, die Indikation von PPI-Empfehlungen in Krankenhausentlassungsbriefen und deren Einfluss auf die hausärztliche Weiterverordnung zu untersuchen.Methode: Es handelt sich um eine retrospektive Beobachtungsstudie in 35 Hausarztpraxen in Mecklenburg-Vorpommern. In Kooperation mit einer Krankenkasse wurden alle Patienten der teilnehmenden Hausarztpraxen identifiziert, die in dem Zeitraum vom 1. Juli 2006 bis zum 30.Juni 2007 aus dem Krankenhaus mit einer PPI-Empfehlung entlassen wurden. PPI-Empfehlungen in Krankenhausentlassungsbriefen wurden von zwei Ratern als indiziert , nicht indiziert sowie unsicher indiziert klassifiziert. Des Weiteren wurde die Hausarztdokumentation sechs Monate vor bis sechs Monate nach Krankenhausentlassung auf PPI-Verordnungen und zugrundeliegende Indikationen untersucht.Ergebnisse: In den untersuchten Krankenhausentlassungsbriefen wurde in 52% ein PPI ohne erkennbare Indikation empfohlen. Diese nicht indizierte PPI-Therapie wurde von den weiterbehandelnden Hausärzten in 57% für mindestens einen Monat fortgeführt. Indizierte PPI-Therapie wurde in 33% nicht fortgeführt. Niedrigdosiertes Aspirin war der häufigste vermutete Auslöser für eine nicht indizierte Empfehlung des Krankenhauses, die häufigste Indikation bei Absetzen einer adäquaten Empfehlung war Ulkusprophylaxe bei Risikopatienten unter NSAR-Therapie. Als PPI-Präparat empfahlen die Kliniken in 72% explizit Pantoprazol, was von den Hausärzten in 57% befolgt wurde.Schlussfolgerung: Die in dieser Studie gefundene hohe Rate nicht indizierter PPI-Verordnungen in Krankenhäusern sowie deren Weiterverordnungen durch Hausärzte zeigt einen starken Einfluss der Krankenhausempfehlungen auf die Verordnungen der Hausärzte. Krankenhäuser sollten Verordnungen und Empfehlungen von PPI kritisch überprüfen und Indikationen in den Entlassungsbriefen klar dokumentieren. Hausärzte sollten Medikationsempfehlungen in Krankenhausentlassungsbriefen kritisch auf die Notwendigkeit einer Fortführung überprüfen, um das Weiterverordnen nicht indizierter PPI sowie das Absetzen indizierter PPI zu vermeiden

Supplier Development within Dyadic Relationships in the Swedish Furniture Retail Industry

Globalization and associated economic changes have led to a lot of opportunities and hazards that companies are facing. Especially the increased role of customer demands and the interconnected shift from seller markets to buyer markets were the driving factors and incentives for the research work of this Master Thesis. One quite new strategy that companies tend to apply in order to meet the occurring challenges is supplier development. By reason of the actuality of this topic, it was of high worth to investigate, especially when it comes to the lack of theoretical findings about challenges, difficulties and problems. Therefore, the main objective of this thesis was to find out which problems can occur in the process of supplier development, and how they can be solved. Hereby, the focus was laid on the furniture retail industry, as it is one of the fastest growing sectors in Sweden. For the empirical research the retailers Ikea and Mio were selected, because they play a very important role within the Swedish furniture retail industry due to the fact that they are the two biggest when it comes to market shares. Furthermore, the suppliers Bitc Möbel AB, Lundbergs Möbler and AB Wilo were chosen in order to examine their dyadic relationship with Mio. For the purpose of investigating the supplier development within the dyadic relationship of Ikea and its supplier, Bodilsen a/s was interviewed. Almost during the whole research of this thesis a lack of knowledge occurred. It was noticed that only few references exist regarding this topic, therefore the objective of this thesis was to attach importance to this issue, illustrate further problem areas and possible solutions. Hereby, a conceptual model was created that served as a basis for the empirical part. After collecting empirical data, a close analysis was accomplished. In the end, suggestions for companies to improve their supplier development were made and a final model was generated in order to illustrate the results of the study. The Swedish furniture retail industry is exposed to a strong price pressure and stress of competition, which makes it necessary to improve companies’ performance in order to withstand the competition and to succeed in the end. Its proximity to end customers makes a continuous product development necessary, which can only be successful when working closely together with manufacturers. Therefore, deploying supplier development is a recommendable strategy, but one should be aware of challenges that can occur. The results of this thesis provide support for the improvement of supplier development, especially when it comes to problem areas and correspondent solutions within dyadic relationships. Supplier development is an up-to-date topic and plays a crucial role within the fast changing business environment. It was chosen to raise the reader’s interest and to give an insight into current economic developments. The Swedish furniture retail industry turned out to be very interesting for the topic of this Master Thesis. Finally, there is nothing more to say than: ‘Enjoy the trip through the Swedish furniture industry!’Research questions: Which are the potential problem areas of Supplier Development within dyadic relationships in the Swedish furniture retail industry? Which possible solutions for these problem areas can be found in order to improve Supplier Development

The Phosphate Source Influences Gene Expression and Quality of Mineralization during In Vitro Osteogenic Differentiation of Human Mesenchymal Stem Cells.

For in vitro differentiation of bone marrow-derived mesenchymal stem cells/mesenchymal stromal cells into osteoblasts by 2-dimensional cell culture a variety of protocols have been used and evaluated in the past. Especially the external phosphate source used to induce mineralization varies considerably both in respect to chemical composition and concentration. In light of the recent findings that inorganic phosphate directs gene expression of genes crucial for bone development, the need for a standardized phosphate source in in vitro differentiation becomes apparent. We show that chemical composition (inorganic versus organic phosphate origin) and concentration of phosphate supplementation exert a severe impact on the results of gene expression for the genes commonly used as markers for osteoblast formation as well as on the composition of the mineral formed. Specifically, the intensity of gene expression does not necessarily correlate with a high quality mineralized matrix. Our study demonstrates advantages of using inorganic phosphate instead of β-glycerophosphate and propose colorimetric quantification methods for calcium and phosphate ions as cost- and time-effective alternatives to X-ray diffraction and Fourier-transform infrared spectroscopy for determination of the calcium phosphate ratio and concentration of mineral matrix formed under in vitro-conditions. We critically discuss the different assays used to assess in vitro bone formation in respect to specificity and provide a detailed in vitro protocol that could help to avoid contradictory results due to variances in experimental design

Evolution of the Morphologies of Zinc Oxide Mesocrystals Under the Influence of Natural Polysaccharides

In the present investigation, we have analyzed the influence of naturally occurring negatively charged polysaccharides on the morphology of zinc oxide obtained in low-temperature precipitation experiments. Performing detailed analyses of scanning electron microscopy (SEM) micrographs, we inferred the morphology of individual nanocrystals as well as the construction of their aggregates. X-ray and electron diffraction were used to identify directions of preferred growth. Whereas addition of hyaluronic acid (HYA) to the synthesis batch resulted in a rod-like morphology of the primary crystallites, addition of chondroitin-6-sulfate (C6S) leads to platelet-like crystallites. Despite their different shapes, the respective subunits aggregated in similar ways, with perfect orientation with regard to their <i>a</i>–<i>b</i> planes, thus leading to symmetrical superstructures. Further growth proceeded, via different mechanisms, that is, subunit growth or further aggregation of subunits, dependent on whether the precipitation was performed in the presence of HYA or C6S. These details were elucidated by testing different concentrations and reaction times. The formation of the morphological characteristics could be attributed to subtle differences in the nature of the two polysaccharides. Understanding how to direct the formation of mesocrystal morphologies is important for enhancing material properties, especially for highly demanding applications of zinc oxide, such as semiconducting films