Analysis of LK-157 in Plasma by LC–MS–MS: Application to Studies of Pharmacokinetics and Degradation Pathways in Rats and Dogs

Multiple-species plasma-stability testing and pharmacokinetic studies in rats and dogs were performed on LK-157, a novel 10-ethylidene tricyclic carbapenem and potent inactivator of β-lactamases of classes A, C, and D. An LC–MS–MS method was developed and validated for analysis of LK-157 in rat and dog plasma. Separation was achieved on a C₁₈ column by gradient elution. The lower limit of quantification for LK-157 in plasma was 50 ng mL^?1. Intra-day and inter-day precision were <12.5 and <11.8%, respectively. When degradation of LK-157 was assessed in buffer solutions and in rat, dog, and human plasma, the compound was found to be stable in pH 7.0–9.0 phosphate buffer for 24 h at room temperature, and in human plasma for 60 min at 37 °C. The stability of LK-157 was species-dependent. Results from study of in vitro metabolism showed that the enzymes liver cytochrome P450 and uridine diphosphate glycosyltransferase do not metabolize LK-157. LC–MS–MS was also successfully applied to a pharmacokinetic study. The pharmacokinetics of LK-157 after bolus intravenous administration (10 mg kg^?1) to Wistar rats and Beagle dogs was described by a two-compartment pharmacokinetic model. Human pharmacokinetic data were extrapolated from dog pharmacokinetic data. The extrapolated human terminal-phase half-life of LK-157 was 2.3 h. Stability and pharmacokinetic data for LK-157 are in agreement with results for other inactivators of β-lactamases.     

Phase equilibrium and charge fractionation in polyelectrolyte solutions

A new type of phase separation in the polyelectrolyte solutions consisting of several types of charged macromolecules differing in their degree of ionization is presented. Via a general thermodynamic consideration we show that even a small difference in the degree of ionization of otherwise equivalent high‐molecular components results in their spatial separation occurring upon decreasing the temperature much earlier than precipitation of any of the pure components from the solution. Some implications of charge fractionation are discussed, including the separation of DNA (or RNA) strands interacting with different proteins and the appearance of heterogeneities in polyelectrolyte solutions of partially charged hydrophobic chains with polydispersed charge distributions such as sodium polystyrene sulfonate. © 2007 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 45: 3003–3009, 2007     

Photoconductive organic materials based on N-vinylcarbazole copolymers with higher alkenes as recording media in photonics

With the purpose to obtain novel photoconductive organic materials with improved complex of physical–mechanical properties and high sensitivity value, the possibility of N-vinylcarbazole copolymerization with higher alkenes was studied.The deposited films were 1.0–2.0 pm thin after drying in vacuum. The photosensitivity of the copolymer films is one order of magnitude greater than other carbazole containing copolymers. The investigation of spectral sensitivity was realized. Photosensitivity reaches its maximal value in 400–800 nm wave band.A photothermoplastic information registration medium was developed using synthesized copolymers. On the prepared photothermoplastic film, were recorded diffraction gratings with diffractional efficiency of 8–10% and resolution of 1000 mm⁻¹, using electrophotographic method. Photographical sensitivity of obtained films allows real time (1–3 s) photographical and holographic image recording.     

An effective heuristic for large-scale capacitated facility location problems

The Capacitated Facility Location Problem (CFLP) consists of locating a set of facilities with capacity constraints to satisfy the demands of a set of clients at the minimum cost. In this paper we propose a simple and effective heuristic for large-scale instances of CFLP. The heuristic is based on a Lagrangean relaxation which is used to select a subset of “promising” variables forming the core problem and on a Branch-and-Cut algorithm that solves the core problem. Computational results on very large scale instances (up to 4 million variables) are reported.     

N,N,N′,N′,N″‐Pentamethyl‐N″‐[(trifluorosilyl)methyl] phosphoric triamide. First example of the existence of intramolecular PO→Si coordination bond in the Si‐containing phosphoric triamides

The N,N,N′,N′,N″‐pentamethyl‐N″‐(trifluorosilylmethyl)phosphoric triamide O?P(NMe₂)₂N(Me) CH₂SiF₃ with intramolecular P?O→Si coordination was formed by the reaction of N,N,N′,N′,N″‐pentamethyl‐N″[(triethoxysilyl)methyl]phosphoric triamide with BF₃·Et₂O. Copyright © 2007 John Wiley & Sons, Ltd.     

Topological origin of inertia

The purpose of the present article, following “Mach’s principle” (the main elements of which have contributed to the foundations of general relativity) is to propose a new (non-local) interpretation of the inertial interaction. We then suggest that the inertial interaction can be correctly described by the topological field theory proposed by Witten in 1988. In such a context, the instantaneous propagation and the infinite range of the inertial interaction might be explained in terms of the topological amplitude connected with the singular zero size gravitational instanton corresponding to the Initial Singularity of space-time.