Development and validation of an HPLC-MS/MS method to quantify clopidogrel acyl glucuronide, clopidogrel acid metabolite, and clopidogrel in plasma samples avoiding analyte back-conversion

A new sensitive and fast quantitative analytical method for the simultaneous determination of clopidogrel, its main metabolite clopidogrel carboxylic acid, and the newly described acyl glucuronide metabolite, in human plasma samples, is presented. The analytical procedures (plasma storage, handling, and extract storage in the autosampler) were optimized in order to avoid back-conversion; a known drawback in measurements of clopidogrel. Clopidogrel acyl glucuronide was confirmed as a major source of back-conversion to the parent drug in the presence of methanol, and thorough stability experiments were carried out to find the most appropriate conditions for an accurate analysis of clopidogrel and the two metabolites. The method was validated by assessing selectivity, sensitivity, linearity, accuracy, and precision for all three analytes, in accordance to Food and Drug Administration guidelines. Spiked quality controls in plasma as well as incurred samples were used to verify back-conversion in the selected conditions, with results meeting European Medicines Agency acceptance criteria (concentrations within 80–120% of the first reading). The method was then applied to a pharmacokinetic study, and for the first time, a pharmacokinetic curve of clopidogrel acyl glucuronide in human plasma is presented. The concentrations ranged up to 1,048.684 ng/mL, with a mean of 470.268 ng/mL, while clopidogrel had a mean C _max of 1.348 ng/mL; these orders of magnitude show how much the back-conversion of this metabolite may influence clopidogrel quantification if it is not properly controlled.     

A semi-Markov process with an inverse Gaussian distribution as sojourn time

Let X_n denote the state of a device after n repairs. We assume that the time between two repairs is the time τ taken by a Wiener process {W(t), t ? 0}, starting from w₀ and with drift μ < 0, to reach c ∈ [0, w₀). After the nth repair, the process takes on either the value X_n?1 + 1 or X_n?1 + 2. The probability that X_n = X_n?1 + j, for j = 1, 2, depends on whether τ ? t₀ (a fixed constant) or τ > t₀. The device is considered to be worn out when X_n ? k, where k ∈ {1, 2, …}. This model is based on the ones proposed by Rishel (1991) [1] and Tseng and Peng (2007) [2]. We obtain an explicit expression for the mean lifetime of the device. Numerical methods are used to illustrate the analytical findings.     

Nonlinear interaction between self- and parametrically excited wind-induced vibrations

Nonlinear Dynamics - The aeroelastic behavior of a planar prismatic visco-elastic structure, subject to a turbulent wind, flowing orthogonally to its plane, is studied in the nonlinear field. The...     

The radiation of polarized matter in a wave-guide of general cross-section with many dielectrics I

In this first part a straight general wave-guide with a perfectly conducting outer wall and several dielectrics, excited by an electrically generally polarized matter is considered and the electromagnetic field is determined.     

Enantioselective Alternating Olefin-Carbon Monoxide Copolymerization: A new concept for activity and stereoselectivity

Cationic Pd-complexes modified by dicyclohexyl{(R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyl}phosphine ( 1a ) give very active catalytic systems for the regioregular isotactic specific copolymerization of propene with CO. Other alk-1-enes also give stereoregular and regioregular copolymers, even if with lower productivity. The copolymers are isolated as poly(4-alkyl-tetrahydrofuran-2,2,5,5-tetrayl-2-oxy-2-methylenes) B in the solid state and give the isomeric poly(2-alkyl-1-oxopropane-1,3-diyls) A by dissolution in (CF₃)₂CHOH. Solid polymer A (R = Et) is formed back at least partially when the dissolved material is reprecipitated from MeOH. The use of the related (ferrocenyl)diphosphine ligands 1b ? e and 2 as the catalyst modifier shows that the presence of both elements of chirality and of large substituents on the P-atoms of the ligand is necessary to achieve good stereocontrol, and that the large difference in basicity between the two P-atoms is probably the reason for the good catalytic activity.     

Synthesis,structural analysis,and self-assembly of phenylene ethynylene oligomers and their ?F, ?CF3, and ?CH3 substituted derivatives

Oligomers consisting of aromatic building blocks separated by alkynyl units were synthesized by Sonogashira cross-coupling of aryl halides with terminal acetylenes. Strong electron acceptors such as  F and  CF₃ and weak electron donors like  CH₃ were placed as substituents on one of the benzene rings. Acetyl-protected sulfhydryl groups were attached to one end of these molecules to promote their self-organization on gold surfaces. The electron-transport properties of such self-assembled monolayers (SAMs) are highly sensitive to the local order of the molecules in the solid state. Single crystals were analyzed by X-ray diffraction experiments that revealed structural details that could lead to a better understanding of the electron-transport properties. The unsymmetrical substitution of the aromatic rings by electron-active groups in the ortho-, meta-, or para positions resulted in changes of such molecular parameters as bonding and torsion angles and planarity. These parameters, in turn, can affect the angle of the molecular attachment to a gold substrate and the density of the resulting SAMs. Patterned SAMs of some of these molecules and comparison alkane thiols were obtained on gold by microcontact printing or flooding. The SAM thickness was determined by spectroscopic ellipsometry. Surface potential differences between adjacent SAMs or between SAMs and the gold substrate were measured by scanning surface potential microscopy under ambient conditions. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 541–550, 2004     

Solid‐state 13C and 129Xe NMR study of poly(vinyl alcohol) and poly(vinyl alcohol)/lactosilated chitosan gels

Dry and hydrated poly(vinyl alcohol) (PVA) gels with 55% (a‐PVA) and 61% (s‐PVA) syndiotacticity and related PVA/lactyl chitosan (LC) blends have been investigated with ¹²⁹Xe and cross‐polarization/magic‐angle‐spinning ¹³C NMR techniques. Although the dry gels exhibit two broad ¹²⁹Xe resonances in the slow‐to‐intermediate exchange limit, both hydrated gels show three resonances. The corresponding dry blends exhibit two signals, the chemical shifts and line widths of which change with respect to those of pure PVA, whereas one (a‐PVA/LC) or two (s‐PVA/LC) signals appear in the spectra of the hydrated blends. A comparative analysis of the data demonstrates that LC rearranges the domains of the polymeric matrix in both the dry and hydrated blends according to the syndiotacticity of the PVA chains. Information on the molecular motions of the amorphous and swollen polymeric domains in the kilohertz range has been obtained from an analysis of the spin‐lattice relaxation times. These data indicate that the dynamics and arrangement of the PVA chains in the gels are strongly affected by their tacticity and the addition of the copolymer LC. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 3123–3131, 2003     

Spin-adapted wave functions of the serber type and time reversal

A procedure is proposed for generating Serber-type spin eigenfunctions withM _s = 0. The procedure uses the time-reversal invariance of these functions to increase the efficiency and to reduce the storage requirements. Simplifications in calculating the matrix elements of an observable operator which follow from the use of the time-reversal symmetry are briefly discussed.     

The decay of the 23min131Sb

The direct and the coincidence spectra of gamma-rays from the¹³¹Sb decay have been measured by means of different Ge(Li) detectors. The Sb sources have been prepared from mixture of²³⁵U thermal neutron fission products. The proposed level scheme of the¹³¹Te nuclei is based on the coincidence measurements, the analysis of the energy sums and the reaction data. The 49 of the total number of 64 gamma-rays observed have been placed in the present decay scheme. Properties of the some levels in¹³¹Te are compared with those observed in other oddmass Te isotopes. A probable structure of some of the excited states in¹³¹Te is discussed.     

Photoinduzierte umlagerung von isoxazolinen: Syntheseweg zu 2,4,5,8-Tetrahedron-1,3-dicx-5-azocinen

A high yield 2,4,5,8-tetrahydro-1,3-diox-5-azocine synthesis, which employs a sequence of cycloaddition and photoinduced rearrangement has been developed.