Quantification of asenapine and three metabolites in human plasma using liquid chromatography-tandem mass spectrometry with automated solid-phase extraction: application to a phase I clinical trial with asenapine in healthy male subjects

The development and validation of methods for determining concentrations of the antipsychotic drug asenapine (ASE) and three of its metabolites [N-desmethylasenapine (DMA), asenapine-N(+) -glucuronide (ASG) and 11-O-sulfate-asenapine (OSA)] in human plasma using LC-MS/MS with automated solid-phase extraction is described. The three assessment methods in human plasma were found to be acceptable for quantification in the ranges 0.0250-20.0 ng/mL (ASE), 0.0500-20.0 ng/mL (DMA and OSA) and 0.250-50.0 ng/mL (ASG).     

Complexation of divalent metal ions with diols in the presence of anion auxiliary ligands: zinc-induced oxidation of ethylene glycol to glycolaldehyde by consecutive hydride ion and proton shifts

Ternary complexes of the type AH???M(2+)???L(-) (AH?=?diol, including diethylene and triethylene glycol, M?=?Ca, Mn, Fe, Co, Ni, Cu and Zn and auxiliary anion ligand L(-) =?CH(3)COO(-), HCOO(-) and Cl(-)) have been generated in the gas phase by MALDI and ESI, and their dissociation characteristics have been obtained. Use of the auxiliary ligands enables the complexation of AH with the divalent metal ion without AH becoming deprotonated, although A(-)???M(2+) is often also generated in the ion source or after MS/MS. For M?=?Ca, dissociation occurs to AH?+?M(2+)???L(-) and/or to A(-)???M(2+) + LH, the latter being produced from the H-shifted isomer A(-) ???M(2+)???LH. For a given ligand L(-), the intensity ratio of these processes can be interpreted (barring reverse energy barriers) in terms of the quantity PA(A(-)) - Ca(aff) (A(-)), where PA is the proton affinity and Ca(aff) is the calcium ion affinity. Deuterium labeling shows that the complex ion HOCH(2)CH(2) OH???Zn(2+)???(-)OOCCH(3), in addition to losing acetic acid (60 Da), also eliminates glycolaldehyde (HOCH(2)CH=O, also 60 Da); it is proposed that these reactions commence with a hydride ion shift to produce the ion-dipole complex HOCH(2)CHOH(+)??? HZnOOCCH(3), which then undergoes proton transfer and dissociation to HOCH(2)CH=O?+?HZn(+)???O?=?C(OH)CH(3). In this reaction, ethylene glycol is oxidized by consecutive hydride ion and proton shifts. A minor process leads to loss of the isomeric species HOCH=CHOH.     

Fragmentation trees for the structural characterisation of metabolites

Metabolite identification plays a crucial role in the interpretation of metabolomics research results. Due to its sensitivity and widespread implementation, a favourite analytical method used in metabolomics is electrospray mass spectrometry. In this paper, we demonstrate our results in attempting to incorporate the potentials of multistage mass spectrometry into the metabolite identification routine. New software tools were developed and implemented which facilitate the analysis of multistage mass spectra and allow for efficient removal of spectral artefacts. The pre-processed fragmentation patterns are saved as fragmentation trees. Fragmentation trees are characteristic of molecular structure. We demonstrate the reproducibility and robustness of the acquisition of such trees on a model compound. The specificity of fragmentation trees allows for distinguishing structural isomers, as shown on a pair of isomeric prostaglandins. This approach to the analysis of the multistage mass spectral characterisation of compounds is an important step towards formulating a generic metabolite identification method. Copyright ? 2012 John Wiley & Sons, Ltd.     

Structural rearrangements and magic numbers in reactions between pyridine-containing water clusters and ammonia

Molecular cluster ions H(+)(H(2)O)(n), H(+)(pyridine)(H(2)O)(n), H(+)(pyridine)(2)(H(2)O)(n), and H(+)(NH(3))(pyridine)(H(2)O)(n) (n = 16-27) and their reactions with ammonia have been studied experimentally using a quadrupole-time-of-flight mass spectrometer. Abundance spectra, evaporation spectra, and reaction branching ratios display magic numbers for H(+)(NH(3))(pyridine)(H(2)O)(n) and H(+)(NH(3))(pyridine)(2)(H(2)O)(n) at n = 18, 20, and 27. The reactions between H(+)(pyridine)(m)(H(2)O)(n) and ammonia all seem to involve intracluster proton transfer to ammonia, thus giving clusters of high stability as evident from the loss of several water molecules from the reacting cluster. The pattern of the observed magic numbers suggest that H(+)(NH(3))(pyridine)(H(2)O)(n) have structures consisting of a NH(4)(+)(H(2)O)(n) core with the pyridine molecule hydrogen-bonded to the surface of the core. This is consistent with the results of high-level ab initio calculations of small protonated pyridine/ammonia/water clusters.     

Complexation of divalent metal ions with diols in the presence of anion auxiliary ligands: zinc‐induced oxidation of ethylene glycol to glycolaldehyde by consecutive hydride ion and proton shifts

Ternary complexes of the type AH???M²⁺???L^– (AH = diol, including diethylene and triethylene glycol, M = Ca, Mn, Fe, Co, Ni, Cu and Zn and auxiliary anion ligand L^– = CH₃COO^–, HCOO^– and Cl^–) have been generated in the gas phase by MALDI and ESI, and their dissociation characteristics have been obtained. Use of the auxiliary ligands enables the complexation of AH with the divalent metal ion without AH becoming deprotonated, although A^–???M²⁺ is often also generated in the ion source or after MS/MS. For M = Ca, dissociation occurs to AH + M²⁺???L^– and/or to A^–???M²⁺ + LH, the latter being produced from the H‐shifted isomer A^–???M²⁺???LH. For a given ligand L^–, the intensity ratio of these processes can be interpreted (barring reverse energy barriers) in terms of the quantity PA(A^–) – Ca_aff(A^–), where PA is the proton affinity and Ca_aff is the calcium ion affinity. Deuterium labeling shows that the complex ion HOCH₂CH₂OH???Zn²⁺???^–OOCCH₃, in addition to losing acetic acid (60 Da), also eliminates glycolaldehyde (HOCH₂CH=O, also 60 Da); it is proposed that these reactions commence with a hydride ion shift to produce the ion–dipole complex HOCH₂CHOH⁺??? HZnOOCCH₃, which then undergoes proton transfer and dissociation to HOCH₂CH=O + HZn⁺???O = C(OH)CH₃. In this reaction, ethylene glycol is oxidized by consecutive hydride ion and proton shifts. A minor process leads to loss of the isomeric species HOCH=CHOH. Copyright © 2012 John Wiley & Sons, Ltd.     

Kinetic (T = 201-298 K) and equilibrium (T = 320-420 K) measurements of the C3H5 + O2 ⇆ C3H5O2 reaction

The kinetics and equilibrium of the allyl radical reaction with molecular oxygen have been studied in direct measurements using temperature-controlled tubular flow reactor coupled to a laser photolysis/photoionization mass spectrometer. In low-temperature experiments (T = 201-298 K), association kinetics were observed, and the measured time-resolved C(3)H(5) radical signals decayed exponentially to the signal background. In this range, the determined rate coefficients exhibited a negative temperature dependence and were observed to depend on the carrier-gas (He) pressure {p = 0.4-36 Torr, [He] = (1.7-118.0) × 10(16) cm(-3)}. The bimolecular rate coefficients obtained vary in the range (0.88-11.6) × 10(-13) cm(3) s(-1). In higher-temperature experiments (T = 320-420 K), the C(3)H(5) radical signal did not decay to the signal background, indicating equilibration of the reaction. By measuring the radical decay rate under these conditions as a function of temperature and following typical second- and third-law procedures, plotting the resulting ln K(p) values versus 1/T in a modified van't Hoff plot, the thermochemical parameters of the reaction were extracted. The second-law treatment resulted in values of ΔH(298)° = -78.3 ± 1.1 kJ mol(-1) and ΔS(298)° = -129.9 ± 3.1 J mol(-1) K(-1), with the uncertainties given as one standard error. When results from a previous investigation were taken into account and the third-law method was applied, the reaction enthalpy was determined as ΔH(298)° = -75.6 ± 2.3 kJ mol(-1).     

Osmotic pressure of a nematic solution of polydisperse rod-like macromolecules

For a nematic solution of polydisperse rigid rods the osmotic pressure is proved to be independent of the length distribution and proportional simply to the total number density. This rule holds in the gaussian approximation to the Onsager theory. Its accuracy is demonstrated for bidisperse systems.     

Harmonisation of proficiency testing schemes

The harmonisation of proficiency testing (PT) schemes has been under debate for a long time. There are obvious reasons why harmonisation of the practices in PT would be beneficial. In many areas, there is still a belief that further harmonisation of practices in PT would improve the comparability of measurement data. In particular when two laboratories are to be compared that have not participated in a single PT, problems arise which allegedly can be overcome by further harmonisation of PT schemes. In practice, however, parties involved in PT are not always embracing the idea of harmonisation. With the results of two European projects in mind, a discussion is given on harmonisation aspects, and some considerations are given that may help to decide in practice whether harmonisation is likely to solve particular problems. The first project, the European Proficiency Testing Network (EPTN), is concerned with further harmonisation. The second European project (COEPT) aims at providing a basis to assess equivalence across proficiency tests, and explores the conditions under which such an assessment is feasible.

     

Die affinen Projektivitätengruppen der lokalkompakten zusammenhängenden Translationsebenen

Ohne ZusammenfassungHerrn Professor Hans Freudenthal zum 80. Geburtstag gewidmet     

Convergence of linear multistep and one-leg methods for stiff nonlinear initial value problems

To prove convergence of numerical methods for stiff initial value problems, stability is needed but also estimates for the local errors which are not affected by stiffness. In this paper global error bounds are derived for one-leg and linear multistep methods applied to classes of arbitrarily stiff, nonlinear initial value problems. It will be shown that under suitable stability assumptions the multistep methods are convergent for stiff problems with the same order of convergence as for nonstiff problems, provided that the stepsize variation is sufficiently regular.