Vichem Chemie (Hungary)

Background/Objectives: Fluvoxamine (FLU) is a selective serotonin reuptake inhibitor and one of the most potent agonists of the sigma-1 receptor. Emerging evidence shows that FLU exerts protective effects in multiple organs, making it a promising candidate for topical ocular therapy. Developing an FLU eyedrop for glaucoma can address a significant treatment gap with potentially fewer side effects compared with conventional therapies. To optimise formulation development, precise quantification of FLU in ocular compartments such as aqueous humour, as well as systemic circulation, is essential to characterise drug absorption, ocular bioavailability, and safety. Methods: We developed and validated a UHPLC-MS method for FLU detection in aqueous humour and serum using simple sample preparation steps. Results: The 11-min-long reverse phase chromatography followed by SRM-based mass spectrometry detection provides a highly selective and sensitive FLU detection method. Our method was proved to be linear in the 0.0625-1.5 µg/mL range and was validated according to the EMA guidelines. Conclusions: The simplicity of sample preparation, the tolerable matrix effects, and the favourable detection parameters provide a robust tool for preclinical pharmacokinetic and pharmacodynamic studies of FLU's ocular protective effects.

In this work, α-tocopherol and trolox were studied as compounds that have high biological activity. α-Tocopherol is considered a food additive because the refining process of vegetable oils causes the depletion of this vitamin, and thus, its inclusion is required to keep them from oxidizing. Computational tools have determined the antioxidant activity of these additives. The geometries of the studied molecules were optimized using two density functional methods, including M05-2X and M06-2X, in combination with the 6-311++G(2d,2p) basis set. The results indicated that when comparing the antioxidant activity of α-tocopherol and trolox, they were very similar to each other, but α-tocopherol had an antioxidant activity slightly higher, around 1.2 kJ/mol, than trolox. Thus, these additives can be used as polymer additives to protect materials from free-radical-induced stress. To test their applicability in polymeric formulations, flexible polyurethane foams were prepared with varying α-tocopherol ratios and NCO indices (1.0 and 1.1). Increasing the α-tocopherol content reduced the compressive force and altered the mechanical properties, likely due to its presence in the foam structure. This additive not only fine-tuned the mechanical properties but also provided antioxidant effects, enabling multiple enhancements in polymeric products with a single additive.

2 Es handelt sich um eine Sammlung von ca.hundert Rezepten: "Wie mann Zinober machen sol", "Wie mann Lasur machen sol", "Wie mann Spongrn machen sol" lauten die ersten Eintrge des Registers (f.A 2r). Die Rezepte sind handwerklichtechnischer Natur und frei von jeder Spekulation.Wenn sich unter den Rezepten auch eines findet "Golt au Kupffer zemachen" (f.A 2v), dann geht es dort schlicht darum, "Wie das Kupffer recht goldt varb gewint

Treatment-naïve small cell lung cancer (SCLC) is typically susceptible to standard-of-care chemotherapy consisting of cisplatin and etoposide recently combined with PD-L1 inhibitors. Yet, in most cases, SCLC patients develop resistance to first-line therapy and alternative therapies are urgently required to overcome this resistance. In this study, we tested the efficacy of dinaciclib, an FDA-orphan drug and inhibitor of the cyclin-dependent kinase (CDK) 9, among other CDKs, in SCLC. Furthermore, we report on a newly developed, highly specific CDK9 inhibitor, VC-1, with tumour-killing activity in SCLC. CDK9 inhibition displayed high killing potential in a panel of mouse and human SCLC cell lines. Mechanistically, CDK9 inhibition led to a reduction in MCL-1 and cFLIP anti-apoptotic proteins and killed cells, almost exclusively, by intrinsic apoptosis. While CDK9 inhibition did not synergise with chemotherapy, it displayed high efficacy in chemotherapy-resistant cells. In vivo, CDK9 inhibition effectively reduced tumour growth and improved survival in both autochthonous and syngeneic SCLC models. Together, this study shows that CDK9 inhibition is a promising therapeutic agent against SCLC and could be applied to chemo-refractory or resistant SCLC.

In the polyurethane industry, the undesirable dimerization and oligomerization of methylene diphenyl diisocyanate (MDI) are unwanted and problematic phenomena. The relative ratios of these dimers and oligomers have a strong temperature dependence, and they can be formed below and above the melting point of MDI (316.15 K). All possible structures of the isomers and their dimers were optimized, and then their thermodynamic functions were calculated at the M06-2X/6-31(d,p) level of theory. The dimerization of isocyanate groups can result in four-, five-, and six-membered rings. The four-membered ring is the most stable one due to the aromatic electrons in π orbitals of the uretidione ring. The relative stability of the dimers is therefore influenced by the steric effects and the relative positions of isocyanate groups. The most stable dimer is the one which is formed from the reaction of the p,o- and o,p-MDI isomers due to their intrinsic interactions, which were classified, and their impact on dimer stability was discussed.

A robust version of the off-resonance ROESY pulse scheme is suggested for the measurement of proton-proton distances or slow chemical exchange in small to medium-sized molecules. The method implements adiabatic ramps to establish a pair of opposite frequency off-resonance spin lock fields - with optionally randomized duration - and adiabatic inversion pulses with simultaneous gradients for efficient zero-quantum suppression. The amended pulse sequence yields pure absorption cross-peaks and works safely for small to medium-sized molecules. The applicability of the method has been demonstrated using small, rigid molecules (strychnine and codeine) and was also applied for a cyclic peptide and a small protein. We found that the pure phase cross-peaks of the new ROESY version are beneficial for distance measurements. The one-dimensional (selective) version of the new method is also powerful for measuring selected pair-wise interactions and distance determination. Copyright © 2016 John Wiley & Sons, Ltd.