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Three different alkyne-terminated aggregation-induced emission molecules based on a para-substituted di-thioether were attached to the surface of ultrasmall gold nanoparticles (2 nm) by copper-catalyzed azide–alkyne cycloaddition (click chemistry). They showed a strong fluorescence and were well water-dispersible, in contrast to the dissolved AIE molecules. The AIE-loaded nanoparticles were not cytotoxic and easily penetrated the membrane of HeLa cells, paving the way for an intracellular application of AIE molecules, e.g., for imaging. [ABSTRACT FROM AUTHOR]

LYS006 is a novel, highly potent and selective, new‐generation leukotriene A4 hydrolase (LTA4H) inhibitor in clinical development for the treatment of neutrophil‐driven inflammatory diseases. We describe the complex pharmacokinetic to pharmacodynamic (PD) relationship in blood, plasma, and skin of LYS006‐treated nonclinical species and healthy human participants. In a randomized first in human study, participants were exposed to single ascending doses up to 100 mg and multiple ascending doses up to 80 mg b.i.d.. LYS006 showed rapid absorption, overall dose proportional plasma exposure and nonlinear blood to plasma distribution caused by saturable target binding. The compound efficiently inhibited LTB4 production in human blood and skin blister cells, leading to greater than 90% predose target inhibition from day 1 after treatment initiation at doses of 20 mg b.i.d. and above. Slow re‐distribution from target expressing cells resulted in a long terminal half‐life and a long‐lasting PD effect in ex vivo stimulated blood and skin cells despite low plasma exposures. LYS006 was well‐tolerated and demonstrated a favorable safety profile up to highest doses tested, without any dose‐limiting toxicity. This supported further clinical development in phase II studies in predominantly neutrophil‐driven inflammatory conditions, such as hidradenitis suppurativa, inflammatory acne, and ulcerative colitis. [ABSTRACT FROM AUTHOR]

The re-development of abandoned industrial areas and city cores characterizes the transition from industrial to post-industrial societies in Western Europe. Shorter-term and project-based urban programs, like the re-developments of waterfronts and station areas, emerged as more sui in response to the consequences of economic, demographic, political and cultural change than long-term, top-down spatial planning. Notably, processes and outcomes of strategic spatial planning vary across European cities and may display unique characteristics. This study compares eleven urban transformations in Germany, Austria, and Switzerland to shed light on the degree to which these programmatic urban transformations have been successful in shifting the urban fabric from an industrial to a post-industrial state. We examine the combinations of factors that, over time, have contributed to a qualitative urban change. Using primary and secondary sources, we perform a Trajectory-Based Qualitative Comparative Analysis (TJ-QCA) to identify recipes for successful urban transitions. Results show that there are two main planning recipes associated with successful urban transformations: either a combination of a high strategic character of the project with a leading role of public actors, or a combination of a high strategic character with brownfield redevelopment. • Compares urban transformations in Germany, Austria and Switzerland to identify under what conditions transformations become successful. • Finds that either a combination of a high strategic character of the project with a leading role of public actors, or a combination of a high strategic character with brownfield redevelopment, are associated with success. • Uses Trajectory-based Qualitative Comparative Analysis, which is a methodological innovation in urban studies. [ABSTRACT FROM AUTHOR]

Abstract: Silymarin was assessed for drug–drug interaction by permeability studies with Caco-2 cells, for cytochrome P450 induction with human primary hepatocytes and for cytochrome P450 inhibition with human liver microsomes. Studies with Caco-2 cells revealed no interference of silymarin with the permeability of nifedipine. Silymarin did not induce cytochromes P450 2C9 and 3A4 at concentrations of 0.1; 1; and 100μM, measured as silibinin. The inhibitory effect was tested on the nine major cytochromes P450 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 at concentrations of 1 and 100μM silymarin. At 1μM concentration no or negligible inhibition of cytochromes P450 1A2, 2A6, 2B6, 2C8, 2C9, and 2E1, minor inhibition of 3A4 (<20%), and moderate inhibition of 2C19 and 2D6 (<40%) were observed. Inhibition constant K i of silymarin was determined for cytochromes P450 3A4 with 12μM, 2C19 with 2μM, and 2D6 with 12μM. Only at the high concentration of 100μM silymarin, inhibition at >50% of the cytochromes P450 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 was observed, and no or moderate inhibition was for the cytochromes P450 1A2, 2A6, and 2E1. However, in view of the clinically relevant plasma concentration of approx. 0.2μM measured as silibinin, it is evident that there is no drug–drug interaction problem with silymarin. [Copyright &y& Elsevier]

Multicompartment micelles (MCMs) have become attractive drug delivery systems as they allow the separate storage of two or more incompatible cargos in their core compartments (e.g., drugs and dyes for imaging). A recent hierarchical self‐assembly process for hydrophobic terpolymers in organic solvents showed the ability to form very homogeneous MCM populations, yet the transfer of this process into water requires a better understanding of the formation mechanism and influence of chain mobility during assembly. Here, the synthesis of a linear poly(oligo(ethylene glycol) methacrylate)‐block‐poly(benzyl acrylate)‐block‐poly(4‐vinylpyridine) (POEGMA‐b‐PBzA‐b‐P4VP) triblock terpolymer by reversible addition‐fragmentation chain transfer (RAFT) polymerization is reported as well as its step‐wise assembly into MCMs in water with POEGMA corona, PBzA patches, and P4VP core. Reversible assembly/disassembly of the MCMs is investigated through protonation/deprotonation of the P4VP core. Interestingly, the low glass transition temperature (Tg) of the hydrophobic PBzA middle block causes MCMs to directly disassemble into molecularly dissolved chains instead of patchy micelles due to mechanical stress from electrosteric repulsion of the protonated P4VP corona chains. In addition, pH resistant MCMs are created by core‐crosslinking and fluorescent properties are added by covalent anchoring of fluorescent dyes via straightforward click chemistry. [ABSTRACT FROM AUTHOR]

Abstract: The metabotropic glutamate receptor subtype 5 has evolved into a promising target for the treatment of various diseases of the central nervous system, such as Fragile X and l-DOPA induced dyskinesia. One of the most advanced clinical compound is Novartis’ AFQ-056 (Mavoglurant), which served us as a template for a scaffold hopping approach, generating a structurally diverse set of potent analogs. Both the limited aqueous solubility and the relatively poor metabolic stability of AFQ-056 were improved with hexahydrocyclopenta[c]pyrrole derivative 54a, which proved to be a valuable candidate for further development. [Copyright &y& Elsevier]

Abstract: Recently, it has been proposed that activation of either metabotropic glutamate receptors e.g. mGlu5 by positive allosteric modulators or stimulation of mGluR2/3 receptors by agonists may offer new strategy in schizophrenia treatment. The aim of the present study was to compare the effect of mGlu5 receptor positive allosteric modulator, ADX47273 (S-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol—5-yl]-piperidin-1-yl}-methanone), mGluR2/3 agonist, LY354740 ((1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate) and selected neuroleptics in animal models for positive schizophrenia symptoms. ADX47273 (3 and 10mg/kgi.p.), the typical antipsychotic haloperidol (0.1 and 0.2mg/kgi.p.), the atypical antipsychotics aripiprazole (1.25–5mg/kgi.p.) and olanzapine (2.5 and 5mg/kgi.p.) all reduced amphetamine-induced hyperlocomotion in Sprague–Dawley rats, unlike the mGlu2/3 receptor agonist LY354740 (1–10mg/kgi.p.). Interestingly, haloperidol (0.1 and 0.2mg/kgi.p.), aripiprazole (1.25–5mg/kgi.p.) and olanzapine (1.25–5mg/kgi.p.), but not ADX47273 (1–10mg/kgi.p.), all reduced spontaneous locomotion and rearings at doses effective against amphetamine-induced hyperlocomotion. This indicates that the effect of ADX47273 in combination with amphetamine may be specific, and also suggests a lack of sedative side effects. Moreover, ADX47273 (30mg/kgi.p.), haloperidol (0.1 and 0.2mg/kgi.p.) and aripiprazole (5 and 10mg/kgi.p.) reversed apomorphine (0.5mg/kgs.c.)-induced deficits of prepulse inhibition, whereas neither LY354740 (1–10mg/kgi.p.) nor olanzapine (1.25–5mg/kgi.p.) produced this effect. Lack of effect of olanzapine was unexpected and at present no convincing explanation can be provided. In conclusion, in selected rodent models for positive schizophrenia symptoms, ADX47273 showed better efficacy than LY354740. [Copyright &y& Elsevier]