Tigecycline Absorption Improved by Selected Excipients.

To investigate the effects of (2,6-di-O-methyl)-ß-cyclodextrin (DM-ß-CD), (2-hydroxypropyl)-ß-cyclodextrin (HP-ß-CD), tocopherol polyethylene glycol 1000 succinate (TPGS), sodium desoxycholate (SDOCH), trimethyl chitosan (TMC), and sodium caprate (C10) on the plasma concentration and the oral bioavailability of tigecycline in broiler chickens. To test the effects of the excipients on absorption of tigecycline, a tetracycline that is poorly absorbed from the gastrointestinal tract, broiler chickens were used as an animal model. Tigecycline (10 mg/kg body weight) was administered intravenously, orally, and orally with one of the excipients. Plasma samples were taken after administration. To measure tigecycline concentrations, high-performance liquid chromatography coupled with tandem mass spectrometry was used. Compartmental and non-compartmental analyses were used for pharmacokinetic analyses of mean plasma concentrations versus time. With the exception of sodium caprate, all the excipients significantly increased the area under the curve and bioavailability of tigecycline (p < 0.05). These parameters were approximately doubled by HP-ß-CD, TPGS, and SDOCH, with 95% confidence intervals (95% CIs) for the difference that included only increases of 1.5-fold or higher (bioavailability: control, 1.67%; HP-ß-CD, 3.24%; TPGS, 3.30%; and SDOCH, 3.24%). The increases in these parameters were smaller with DM-ß-CD and TMC (DM-ß-CD, 2.41%; TMC, 2.55%), and the 95% CIs ranged from close to no difference to nearly double the values in the control group. These results indicate that HP-ß-CD, TPGS, and SDOCH substantially increase the area under the curve and oral bioavailability of tigecycline. They suggest that DM-ß-CD and TMC may also substantially increase these parameters, but more research is needed for more precise estimates of their effects.

Alkaline-Earth Metal Mediated Benzene-to-Biphenyl Coupling.

Complex [(DIPeP BDI)Ca]2 (C6 H6 ), with a C6 H6 2- dianion bridging two Ca2+ ions, reacts with benzene to yield [(DIPeP BDI)Ca]2 (biphenyl) with a bridging biphenyl2- dianion (DIPeP BDI=HC[C(Me)N-DIPeP]2 ; DIPeP=2,6-CH(Et)2 -phenyl). The biphenyl complex was also prepared by reacting [(DIPeP BDI)Ca]2 (C6 H6 ) with biphenyl or by reduction of [(DIPeP BDI)CaI]2 with KC8 in presence of biphenyl. Benzene-benzene coupling was also observed when the deep purple product of ball-milling [(DIPP BDI)CaI(THF)]2 with K/KI was extracted with benzene (DIPP=2,6-CH(Me)2 -phenyl) giving crystalline [(DIPP BDI)Ca(THF)]2 (biphenyl) (52 % yield). Reduction of [(DIPeP BDI)SrI]2 with KC8 gave highly labile [(DIPeP BDI)Sr]2 (C6 H6 ) as a black powder (61 % yield) which reacts rapidly and selectively with benzene to [(DIPeP BDI)Sr]2 (biphenyl). DFT calculations show that the most likely route for biphenyl formation is a pathway in which the C6 H6 2- dianion attacks neutral benzene. This is facilitated by metal-benzene coordination.

Access to a Labile Monomeric Magnesium Radical by Ball-Milling.

In order to isolate a monometallic Mg radical, the precursor (Am)MgI⋅(CAAC) (1) was prepared (Am=tBuC(N-DIPP)2 , DIPP=2,6-diisopropylphenyl, CAAC=cyclic (alkyl)(amino)carbene). Reduction of a solution of 1 in toluene with the reducing agent K/KI led to formation of a deep purple complex that rapidly decomposed. Ball-milling of 1 with K/KI gave the low-valent MgI complex (Am)Mg⋅(CAAC) (2) which after rapid extraction with pentane and crystallization was isolated in 15 % yield. Although a benzene solution of 2 decomposes rapidly to give Mg(Am)2 (3) and unidentified products, the radical is stable in the solid state. Its crystal structure shows planar trigonal coordination at Mg. The extremely short Mg-C distance of 2.056(2) Šindicates strong Mg-CAAC bonding. Calculations and EPR measurements show that most of the spin density is in a π* orbital located at the C-N bond in CAAC, leading to significant C-N bond elongation. This is supported by calculated NPA charges in 2: Mg +1.73, CAAC -0.82. Similar metal-to-CAAC charge transfer was calculated for M0 (CAAC)2 and [MI (CAAC)2 + ] (M=Be, Mg, Ca) complexes in which the metal charges range from +1.50 to +1.70. Although the spin density of the radical is mainly located at the CAAC ligand, complex 2 reacts as a low-valent MgI complex: reaction with a I2 solution in toluene gave (Am)MgI⋅(CAAC) (1) as the major product.

N-Activated 1,3-Benzoxazine Monomer as a Key Agent in Polybenzoxazine Synthesis.

A novel and successful application of ring-closing reactions of aminophenols has been proposed for the formation of a new type of 1,3-benzoxazine ionic derivatives. The optimization of the reaction and detailed computational studies have been reported for the estimation of heterocyclic ring stability and its further transformation, which is crucial in the polymerization process. The molecular structure of the obtained compounds has been fully characterized by applying X-ray analysis and spectroscopic methods. The novel benzoxazines undergo an intriguing thermal reaction leading to classical benzoxazines and chloroalkanes, which is the first step of transformation before polymerization. To gain more insights into the transformation behavior of ionic benzoxazine derivatives, the Fourier transform infrared (FT-IR) spectra of gaseous products were recorded in experiments with near simultaneous FT-IR/TGA measurements. The combination of thermogravimetry with FT-IR spectroscopy enables the quantitative and qualitative characterization of thermal transformation products and clarification of the reaction mechanism. The experimental data have been verified by applying DFT(B3LYP) and DFT(M062x) theoretical studies.

Lastingly Colored Polylactide Synthesized by Dye-Initiated Polymerization.

An efficient synthesis strategy of a well-defined polylactide-dye conjugate in a controlled fashion is presented. The introduction of coloring species as end groups of polylactide (PLA) has been performed by using new homoleptic aminophenolate magnesium or zinc coordination compounds. The molecular structure of metal complexes has been determined in solution by NMR spectroscopy, and in the solid state by X-ray analysis. Lastingly colored polymers were obtained with 2-[4-(Nitrophenylazo)-N-ethylphenylamino]ethanol (Disperse Red 1) and 2-[4-(2-Chloro-4-nitrophenylazo)-N-ethylphenylamino]ethanol (Disperse Red 13) at very high lactide conversions, based on MALDI-ToF measurement, and the macromolecules were nearly fully chain end dye-functionalized. Based on 1H NMR, the DPn of conjugates was in the range of 10-300, which was consistent with the reaction setup. Various methods of gel-permeation chromatography (GPC) analysis were applied, and they demonstrated that the number-average molar mass (Mn) values (polystyrene (PS) standards) were a bit higher than calculated, the molar mass distribution index (ƉM) values were moderate to high, the TDA (triple detection array) system was inappropriate for analysis, measurements with PDA (photo diode array) detection at 470 nm gave nearly the same molar mass distributions such as the refractometer, and the relative absorbance of conjugates at 470 nm increased linearly versus (DPn)-1. The presented approach connects the gap between the current strategy of obtaining colored polymer fibers and the design of tailor-made initiators with eco polyesters designed for the targeted applications.

Scrabbling around in Synthetic Nuances Managing Sodium Compounds: Bisphenol/Bisnaphthol Synthesis by Hydroxyl Group Masking.

A unique method of bisphenol/bisnaphthol synthesis is being proposed, serendipitously discovered in the course of the careful analysis of an aminophenol methylation reaction. The insightful exploration of the synthesis of N- or O-methylated species, originating from functionalized phenols obtained by a conventional strategy, provided the opportunity to discover an unexpected reaction pathway yielding various bisphenols. Sodium complexes were found to be crucial intermediates in the synthetic scenario. Their formation, which is usually an imperceptive step, was substantial for the productive outcome of functional group protection. Thorough exploration revealed an essential structural motif of aminophenolate, necessary for the successful outcome of the reaction, and also enabled establishing the limitations of the new method. The work demonstrated that a slight change in the perspective and close inspection of the synthetic nuances can answer the important question concerning what a specific target-oriented synthesis strategy is lacking.

Preparation and Characterization of Self-Assembled Poly(l-Lactide) on the Surface of ß-Tricalcium Diphosphate(V) for Bone Tissue Theranostics.

This work was aimed to obtain and characterize the well-defined biocomposites based on ß-tricalcium diphosphate(V) (ß-TCP) co-doped with Ce3+ and Pr3+ ions modified by poly(l-lactide) (PLLA) with precise tailored chain length and different phosphate to polymer ratio. The composites as well as ß-tricalcium diphosphate(V) were spectroscopically characterized using emission spectroscopy and luminescence kinetics. Morphological and structural properties were studied using X-Ray Diffraction (XRD) and Scanning Electron Microscopy (SEM). The self-assembled poly(l-lactide) in a shape of rose flower has been successfully polymerized on the surface of the ß-tricalcium diphosphate(V) nanocrystals. The studied materials were evaluated in vitro including cytotoxicity (MTT assay) and hemolysis tests. The obtained results suggested that the studied materials may find potential application in tissue engineering.

Serendipitous Synthesis Found in the Nuances of Homoleptic Zinc Complex Formation.

A series of aminophenolate and aminonaphtholate homoleptic zinc complexes were obtained using a simple and unique synthetic strategy. A rigorous analysis of the byproduct supported modifications of the main course of the bis-chelation reaction. Controlled alcoholysis was followed by alternation and controlled anaerobic hydrolysis of ethyl-zinc aminophenolate or aminonaphtholate complexes. This new and intriguing reaction yielded a new class of zinc corona complexes. All the synthesized complexes were fully characterized in the solid state and in solution using X-ray and spectroscopic methods as well as density functional theory calculations.

Bio- and chemocatalysis cascades as a bridge between biology and chemistry for green polymer synthesis.

The development and integration of bio- and chemocatalytic processes to convert renewable or biomass feedstocks into polymers is a vibrant field of research with enormous potential for environmental protection and the mitigation of global warming. Here, we review the biotechnological and chemical synthetic strategies for producing platform monomers from bio-based sources and transforming them into eco-polymers. We also discuss their advanced bio-application using the example of polylactide (PLA), the most valuable green polymer on the market.

Lactide as the Playmaker of the ROP Game: Theoretical and Experimental Investigation of Ring-Opening Polymerization of Lactide Initiated by Aminonaphtholate Zinc Complexes.

A family of homo- and heteroleptic zinc complexes bearing aminonaphtholate ligands was synthesized and fully characterized. Using NMR spectroscopy and DFT calculation, bis-alkoxy-bridged complexes [LZn(µ-OR)]2 were confirmed to have dimeric structures in solution, analogous to those obtained via X-ray crystallography. Surprisingly, a detailed experimental and theoretical study of the catalytic activity of [LZn(µ-OR)]2 in the ring-opening polymerization (ROP) of lactides showed that although well-defined alkoxy dimers possess a single-site structural motif, the most active initiator is obtained during in situ alcoholysis of the alkylzinc precursor. These results indicate that rational ancillary and alkoxy ligand design that takes into account its mutual interaction on monomer coordination may be key to the synthesis of new high-performance ROP catalysts.

Effects of dexamethasone and meloxicam on bovine CD25+ CD8+ and CD25- CD8+ T cells--in vitro study.

The aim of undertaken research was an in vitro evaluation of the effects of dexamethasone and meloxicam on selected bovine CD8(+) T lymphocyte subpopulations. Dexamethasone induced a fast-occurring and lasting depletion of CD25(-)CD8(+) cells. This was primarily the result of the proapoptotic effect of dexamethasone, but the antiproliferative effect of the drug was clearly responsible for the deepening of this disturbance. Dexamethasone transiently increased the relative and absolute CD25(high)CD8(+) and CD25(low)CD8(+) cell numbers. This effect was not a consequence of increased proliferation, but at least partly resulted from the antiapoptotic effect of the drug on these cells. The obtained results indicate that induction of CD8(+) lymphocyte depletion and impairment of IFN-γ production by these cells participate in the production of the anti-inflammatory and immunosuppressive effect of dexamethasone in cattle. An increase in Foxp3, IL-10 and TGF-ß production by CD8(+) lymphocytes is not involved in the production of these effects because the drug did not affect the percentage of TGF-ß(+)CD8(+) cells, while paradoxically reducing the percentage of cells with the suppressive phenotype, i.e. IL-10(+)CD25(low)CD8(+) and Foxp3(+)CD25(low)CD8(+) cells. Meloxicam did not substantially affect CD8(+) lymphocytes as to their percentage, absolute number, apoptosis, proliferation, Foxp3 expression and IFN-γ, IL-10 and TGF-ß production. Thus, in the context of the parameters being estimated, meloxicam seems a relatively safe anti-inflammatory drug to be used in infectious diseases in cattle.