Assay of free captopril in human plasma as monobromobimane derivative,using RPLC/(+)ESI/MS/MS: validation aspects and bioequivalence evaluation

A sensitive method for determination of free captopril as monobromobimane derivative in plasma samples is discussed. The internal standard (IS) was 5‐methoxy‐1H‐benzimidazole‐2‐thiol. Derivatization with monobromobimane immediately after blood collection and plasma preparation prevents oxidation of captopril to the corresponding disulfide compound and enhances the ionization yield. Consequently, derivatization enhances sample stability and detection sensitivity. Addition of the internal standard was made immediately after plasma preparation. The internal standard was also derivatized by monobromobimane, as it contains a thiol functional group. Preparation of plasma samples containing captopril and IS derivatives was based upon protein precipitation through addition of acetonitrile, in a volumetric ratio 1:2. The reversed‐phase liquid chromatographic separation was achieved on a rapid resolution cartridge Zorbax SB‐C₁₈, monitored through positive electrospray ionization and tandem MS detection using the multiple‐reaction monitoring mode. Transitions were 408–362 amu for the captopril derivative and 371–260 amu for the internal standard derivative. The kinetics of captopril oxidation to the corresponding disulfide compound in plasma matrix was also studied using the proposed method. A linear log–log calibration was obtained over the concentration interval 2.5–750 ng/mL. A low limit of quantitation in the 2.5 ng/mL range was obtained. The analytical method was fully validated and successfully applied in a three‐way, three‐period, single‐dose (50 mg), block‐randomized bioequivalence study for two pharmaceutical formulations (captopril LPH 25 and 50 mg) against the comparator Capoten 50 mg. Copyright © 2009 John Wiley & Sons, Ltd.     

Nonequilibrium phase transition in a periodically driven XY spin chain

We present a general formulation of Floquet states of periodically time-dependent open Markovian quasifree fermionic many-body systems in terms of a discrete Lyapunov equation. Illustrating the technique, we analyze periodically kicked XY spin-? chain which is coupled to a pair of Lindblad reservoirs at its ends. A complex phase diagram is reported with reentrant phases of long range and exponentially decaying spin-spin correlations as some of the system's parameters are varied. The structure of phase diagram is reproduced in terms of counting nontrivial stationary points of Floquet quasiparticle dispersion relation.     

Structural,optical and electrical properties of undoped and Si-doped AlxGa1−xN thin films on Si (1 1 1) substrate grown by PA-MBE

We have studied the structural properties of undoped and Si-doped Al_xGa_1?xN/GaN/AlN on Si (1 1 1) substrate prepared by plasma-assisted molecular beam epitaxy (PA-MBE) using high-resolution X-ray diffraction (HR-XRD) and atomic force microscopy (AFM). In comparison with undoped AlGaN, the roughness and dislocation density on the surface of the AlGaN layer decrease with Si doping. Full width half maximum (FWHM) of the undoped and Si-doped samples were equal to 0.69° and 0.52°, respectively. This indicates that the Si doping improves the crystalline quality of the Al_xGa_1?xN layer compared with the undoped one. Raman scattering measurement reveals that the optical phonon modes of A₁(LO) and E₂(H) of the AlGaN show a one-mode and two-modes behavior, respectively. The Fourier-transform infrared reflectance (FTIR) investigation confirms the one-mode (two-mode) behavior of the LO (TO) phonon in our samples. This is in good agreement with Raman measurement. Finally, the barrier height (Φ_B) of undoped and Si-doped Al_xGa_1?xN samples was found to be 0.86 and 0.74 eV, respectively.     

Effect of partial fluorination on the Lewis sites of microcrystalline γ-alumina studied by adsorption of pyridine as a probe molecule: A quantum chemical cluster model study

The influence of fluorination of microcrystalline γ-alumina on the acidity of Lewis sites was studied by quantum chemical cluster model approach. B3LYP and HF/6-31++G(d,p) levels of theory were employed, considering the standard and counterpoise-corrected potential energy surfaces (PESs). Explicit inclusion of dynamical electron correlation effects along with the elimination of the basis set superposition effects in geometry optimization and harmonic vibrational analysis were found to be crucial to reproduce the experimental trends in the shifts of the pyridine ν_19b and ν_8a modes upon fluorination. The acidity of surface-exposed Al-sites was found to increase upon fluorination, which is manifested as a ~ 10% increase of the interaction energies, and also in the characteristics of the electronic density and density Laplacian at the intermolecular bond critical point. Bader analysis of the electronic density has shown that pyridine adsorption on pure and fluorinated γ-alumina can be classified as non-covalent interaction.     

Robustness of dual divergence estimators for models satisfying linear constraints

We consider new classes of estimators and test statistics for models satisfying linear constraints with unknown parameter. These procedures are based on minimization of divergences through duality techniques. We prove that, for various divergences, the new approach provides robust estimation and test procedures, unlike the empirical likelihood method. We give general results using the influence function approach, which we exemplify in detail in the case of the Cressie–Read divergences. It is found that the Hellinger distance is one of the divergences that leads to robust procedures.     

Effect of microwave irradiation on the reactivity of chloroarenes in Suzuki—Miyaura reaction

Simple catalytic systems for the Suzuki—Miyaura reaction of aryl chlorides under microwave conditions were tested. Microwave irradiation facilitated the reaction course. The catalyst, base, and solvent effect were studied and two reaction systems offered reasonable to high yields within a short time.     

Metabolic Profiling of Murine Macrophages Exposed to Silver Nanoparticles at Dose and Time Dependencies

The macrophage time-dependent metabolic profile changing basal metabolism triggered by nanoparticles can be obtained and used to improve wound healing treatments. Herein this study demonstrates that metabolic status responds systematically to cytotoxicity manipulation, providing an interesting way of cellular control. Nuclear magnetic resonance (NMR) based metabolomics and cytotoxic assays are used to study RAW 264.7 cells exposed to AgNPs at different concentrations and incubation times. Cytotoxicity data show a slight decrease in cellular expansion rates accompanied by morphological changes in cells. Metabolomics show that despite the glycolytic activity of treated and non-treated cells remains unchanged; however, only the treated cells present a rich Citrate environment signaling up-regulation of Tricarboxylic-Acid-Cycle (TCA). Cells choose aerobic routes instead of anaerobic ones to produce energy and self-regulate their amino acid metabolism to balance TCA. Choline metabolism is down-regulated once its sub-products, Betaine and Glycine, are reduced, thus compromising Creatine synthesis. Phospholipid metabolism is down-regulated due to the decreasing of Phosphocholine and Sn-Glycerol-3-PC, in agreement with the cytotoxicity results. Pyroglutamate decreases in treated cells, signaling different levels of oxidative stress. These analytical tools can characterize AgNPs-treatments, even distinguishing dose and time dependencies. Therefore, the fine-tuning of exposition parameters can modulate cellular activity to achieve better wound healing.     

Amperometric Folic Acid Quantification Using a Supramolecular Tetraruthenated Nickel Porphyrin µ‐Peroxo‐Bridged Matrix Modified Electrode Associated to Batch Injection Analysis

A supramolecular Nickel (II) porphyrin complex containing four pyridyl‐bis(2,2′‐bipyridyl)chloro ruthenium meso substituents was submitted to successive voltammetric cycles in high alkaline media to produce a supramolecular matrix with Nickel centers linked by µ‐peroxo bridges, producing a highly stable thin film able to act as redox mediator for electrocatalytic oxidation of folic acid. The characterization of electrode surface material was performed by Scanning Electron Microscopy and Electrochemical Impedance Spectroscopy. The modified electrode was inserted into a batch injection electrochemical cell used for the rapid and precise quantification of folic acid in pharmaceutical products. The favorable hydrodynamic conditions provided by amperometry‐BIA association allowed a very high throughput with good linear range (1 to 200 µmol L^?1) and low detection limit (7.37×10^?7 mol L^?1). The electrochemical method was applied to the quantification of folic acid in different tablet samples. The results were comparable with values indicated by the manufacturer and those found using high HPLC according to the Brazilian Pharmacopoeia; commercial samples were submitted to a procedure in order to remove lactose of tablets, since carbohydrates act as interfering species. This procedure together with the electrochemical method showed to be simple, rapid, efficient and an appropriate alternative for quantifying this compound in real samples.     

Construction of a New Class of Tetracycline Lead Structures with Potent Antibacterial Activity through Biosynthetic Engineering

Antimicrobial resistance and the shortage of novel antibiotics have led to an urgent need for new antibacterial drug leads. Several existing natural product scaffolds (including chelocardins) have not been developed because their suboptimal pharmacological properties could not be addressed at the time. It is demonstrated here that reviving such compounds through the application of biosynthetic engineering can deliver novel drug candidates. Through a rational approach, the carboxamido moiety of tetracyclines (an important structural feature for their bioactivity) was introduced into the chelocardins, which are atypical tetracyclines with an unknown mode of action. A broad‐spectrum antibiotic lead was generated with significantly improved activity, including against all Gram‐negative pathogens of the ESKAPE panel. Since the lead structure is also amenable to further chemical modification, it is a platform for further development through medicinal chemistry and genetic engineering.     

Retention Behavior of Some Compounds Containing Polar Functional Groups on Perfluorophenyl Silica-Based Stationary Phase

A retention study on perfluorophenyl silica-based stationary phase was undertaken for some organic compounds containing different polar functionalities. The dependence of the retention factor on the content of organic modifier (acetonitrile, or methanol) in mobile phase was fitted by polynomial equations. The only exception was observed for adenine, which showed a sigmoidal dependence for the retention factor versus organic modifier content. The extrapolated values of retention factor for water as mobile phase (log k _w) from these dependences were well correlated with octanol–water partition constants (log K _ow), excepting the values for hexachlorocyclohexane isomers and adenine. Temperature dependences of the retention factor obeyed the van’t Hoff equation with thermodynamic parameters similar to those obtained in reversed phase on C8 or C18 stationary phases, excepting two statines whose dependences of ln k on the reciprocal value of absolute column temperature were nonlinear. Again, adenine had an atypical behavior with decrease in the retention factor with the increase in column temperature, due to possible tautomeric equilibria of this compound in presence of water, in accordance with theoretical models reported by literature. Charge modeling with MarvinSketch package program revealed charged centers from analyte molecule that could interact differently with charge centers from stationary phase.