Assessment of pharmacokinetic interaction between piracetam and l‐carnitine in healthy subjects

A rapid, sensitive and specific method for quantifying piracetam in human plasma using Piracetam d‐8 as the internal standard (IS) is described. The analyte and the IS were extracted from plasma by one‐step precipitation of protein using an acetonitrile (100%). The extracts were analyzed by high‐performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC‐MS/MS). The method had a chromatographic run time of 3.8 min and a linear calibration curve over the range 0.5–50 µg/mL (r > 0.99). This LC‐MS‐MS procedure was used to assess the bioavailability of two piracetam formulations: piracetam + l‐carnitine (Piracar®; 270/330 mg tablet) and piracetam (Nootropil®; 800 mg tablet) in healthy volunteers of both sexes. The geometric means with corresponding 90% confidence interval (CI) for test/reference percentage ratios were 88.49% (90% CI = 81.19 – 96.46) for peak concentration/dose and 102.55% (90% CI = 100.62 – 104.51) for AUC_inf/dose. The limit of quantitation of 0.5 µg/mL is well suited for pharmacokinetic studies in healthy volunteers. It was concluded that piracetam (Piracar®; 270/330 mg tablet) has a bioavailability equivalent to the piracetam (Nootropil®; 800 mg tablet) formulation with regard to both the rate and the extent of absorption. Copyright © 2015 John Wiley & Sons, Ltd.     

Design of amino acid sulfonamides as transition-state analogue inhibitors of arginase

Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-arginine to form L-ornithine plus urea. Chiral L-amino acids bearing sulfonamide side chains have been synthesized in which the tetrahedral sulfonamide groups are designed to target bridging coordination interactions with the binuclear manganese cluster in the arginase active site. Syntheses of the amino acid sulfonamides have been accomplished by the amination of sulfonyl halide derivatives of (S)-(tert-butoxy)-[(tert-butoxycarbonyl)amino]oxoalkanoic acids. Amino acid sulfonamides with side chains comparable in length to that of L-arginine exhibit inhibition in the micromolar range, and the X-ray crystal structure of arginase I complexed with one of these inhibitors, S-(2-sulfonamidoethyl)-L-cysteine, has been determined at 2.8 A resolution. In the enzyme-inhibitor complex, the sulfonamide group displaces the metal-bridging hydroxide ion of the native enzyme and bridges the binuclear manganese cluster with an ionized NH(-) group. The binding mode of the sulfonamide inhibitor may mimic the binding of the tetrahedral intermediate and its flanking transition states in catalysis. It is notable that the ionized sulfonamide group is an excellent bridging ligand in this enzyme-inhibitor complex; accordingly, the sulfonamide functionality can be considered in the design of inhibitors targeting other binuclear metalloenzymes.     

Microseparation techniques for the study of the enantioselectivity of drug–plasma protein binding

Stereoselectivity in protein binding can have a significant effect on the pharmacokinetic and pharmacodynamic properties of chiral drugs. The investigation of enantioselectivity of drugs in their binding with human plasma proteins and the identification of the molecular mechanisms involved in the stereodiscrimination by the proteins represent a great challenge for clinical pharmacology. In this review, the separation techniques used for enantioselective protein binding experiments are described and compared. An overview of studies on enantiomer–protein interactions, enantiomer–enantiomer interactions as well as chiral drug–drug interactions, including allosteric effects, is presented. The contribution of individual plasma proteins to the overall enantioselective binding and the animal species variability in drug–plasma protein binding stereoselectivity are reviewed. Copyright © 2008 John Wiley & Sons, Ltd.     

Correction to: Finite Element Approximation of the Spectrum of the Curl Operator in a Multiply Connected Domain

Foundations of Computational Mathematics - In the published article, Figure 5 corresponds to an eigenfunction associated not with the first smallest positive eigenvalue.     

Synthetic carbapenem antibiotics III. 1-Methyl thienamycin

Total syntheses of 1α- and 1β-methyl thienamycin are reported. 1β-Methyl thienamycin retains the antibacterial activity of thienamycin and is highly resistant to hydrolysis by DHP-I enzyme.     

On the preparation of simple and universal buffers including polynuclear species

A simple generalized procedure for the calculation of electrolyte concentrations in pH-buffers is proposed. Mixtures of acid-base systems and formation of polynuclear species at high ionic strengths are considered, and a diagram useful for the study and preparation of the buffers is shown.     

Surface protonation data of kaolinite-reevaluation based on dissolution experiments

The aim of the present study is to compare available surface titration curves of kaolinite, to explain the differences between them, and to constrain their interpretation based on predictions of surface protonation that emerged from dissolution experiments. Comparison of six surface titration curves obtained at 25 degrees C reveals significant discrepancies, both in the shape of the curves and in the pH of the point of zero net proton charge (pH(PZNPC)). Based on an analysis of the different sites available for adsorption on kaolinite surfaces we conclude that different kaolinite samples are expected to have similar pH(PZNPC). Therefore, the major reason for the differences in the observed surface protonation is related to the different ways in which the pH(PZNPC) was determined. To compare the titration curves, some of the curves were recalculated so that the proton surface concentrations of all the titration curves would be zero around pH 5. As a result, we obtained a good agreement between the titration curves. A prediction of the molar fraction of protonated sites was retrieved from modeling of kaolinite dissolution reaction and was compared to the protonation data obtained from surface titration. The model successfully predicts the surface protonation data of most of the surface titrations.