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.     

Thermal behaviour of some new complexes with bismacrocyclic ligands as potential biological active species

Novel complexes of type [M₂LCl₄]·nH₂O ((1) M:Ni, n = 5; (2) M:Cu, n = 0 and (3) M:Zn, n = 2; L: ligand resulted from 1,2-phenylenediamine, 3,6-diazaoctane-1,8-diamine and formaldehyde template condensation) were synthesised and characterised. The features of complexes have been assigned from microanalytical, IR and UV–Vis data. The thermal analyses have evidenced the thermal intervals of stability and also the thermodynamic effects that accompany them. Processes as water or hydrochloric acid elimination as well as oxidative degradation of the organic ligand were observed. Complexes display a different thermal behaviour as result of dissimilar chemical interaction of metal ions with chloride anions. The final product of decomposition was metal(II) oxide as powder X-ray diffraction indicated.     

Thermal behavior of some vanadyl complexes with flavone derivatives as potential insulin-mimetic agents

Two new complexes having general formula VOL₂·nH₂O [(1) L: 5-hydroxyflavone, n = 1; (2) L: chrysin, n = 4] were synthesized and characterized. Based on IR and electronic data we concluded that studied flavones act as bidentate ligands in complexes with metallic ion coordinated in a square-pyramidal stereochemistry. The thermal analysis (TG, DTA) elucidated the composition and also the number and nature of the water molecules. The thermal behavior also indicated strong interactions between oxovanadium (IV) and these oxygen donor ligands.     

Activation/Inhibition Effects during the Coelectrodeposition of PtAg Nanoparticles: Application for ORR in Alkaline Media

PtAg bimetallic nanoparticles for oxygen reduction reaction (ORR) in alkaline media were prepared by pulse electrodeposition (PED). During PED the reduction of Ag⁺ ions predominates, thus an increased Ag content in the co‐deposit is accomplished. The mechanism for this anomalous co‐deposition was elucidated by potential pulse experiments, which revealed that nuclei formation mainly occurs via the reduction of Pt²⁺ ions. The growth of the particles is diffusion controlled leading to the formation of a Ag shell covering a PtAg alloyed region. However, the shell is not growing homogeneously on the PtAg alloy. Hence, regions of the PtAg alloy are exposed, which exhibit an enhanced ORR activity compared to a pure Ag surface.     

SL2-modules of small homological dimension

Let V _n be the SL₂-module of binary forms of degree n and let V = V_n1 ???V_np V = {V_{{n_1}}} \oplus \cdots \oplus {V_{{n_p}}} . We consider the algebra R = O(V)^{\textS\textL₂} R = \mathcal{O}{(V)^{{\text{S}}{{\text{L}}_2}}} of polynomial functions on V invariant under the action of SL₂. The measure of the intricacy of these algebras is the length of their chains of syzygies, called homological dimension hd R. Popov gave in 1983 a classification of the cases in which hd R ≤ 10 for a single binary form (p = 1) or hd R ≤ 3 for a system of two or more binary forms (p > 1). We extend Popov’s result and determine for p = 1 the cases with hd R ≤ 100, and for p > 1 those with hd R ≤ 15. In these cases we give a set of homogeneous parameters and a set of generators for the algebra R.     

Neutron-neutron correlation approach for 11Li halo structure investigation

The preemission of neutrons from ¹¹Li halo nuclei is considered. The present problems of investigation of ¹¹Li halo nucleus structure by means of the C _nn correlation function are briefly presented. The influence of the target screening on the halo neutron preemission is described. It is shown that, owing to the diminishing of the screening effect, the yield of preemission neutron pairs is expected to be much larger in the case of ¹²C than in the case of Si target. It is shown that a new experiment on a ¹²C target will allow one to solve the standing problems of C _nn and to test experimentally a recent new theory of C _nn. The text was submitted by the authors in English.     

Synthesis of trifunctional somatostatin based derivatives for improved cellular and subcellular uptake

It is now well established that the biological effects of Auger-emitting radionuclides are critically dependent on their subcellular location. Therefore, for their use in molecular imaging and targeted radionuclide therapy, attempts should be made to increase the nuclear specificity of the carriers. In the present paper the synthesis of novel trifunctional somatostatin derivatives containing a nuclear localization motif is described. These derivatives of [DOTA⁰, Tyr³]-octreotide (DOTATOC, DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) were obtained in high yields using Fmoc peptide synthesis in solid and in solution phase.     

Series of moderate deviation probabilities for martingales

We study Davis-type theorems on the moderate deviation probabilities of martingale differences with finite pth moments (1?p<∞). We prove that Davis' first result holds if p>4 and fails if 1?p<4, and Davis' second result holds if p>2 and fails if 1?p<2.     

<Emphasis Type="Italic">L</Emphasis><Superscript><Emphasis Type="Italic">p</Emphasis></Superscript> estimates for the uniform norm of solutions of quasilinear SPDE's

In this paper we prove L^p estimates (p≥2) for the uniform norm of the paths of solutions of quasilinear stochastic partial differential equations (SPDE) of parabolic type. Our method is based on a version of Moser's iteration scheme developed by Aronson and Serrin in the context of non-linear parabolic PDE.     

Electronic spectroscopy of the A1A' <-- X1A' system of CDF

To further investigate the Renner-Teller (RT) effect and barriers to linearity and dissociation in the simplest singlet carbene, we recorded fluorescence excitation spectra of bands involving the pure bending levels 2(n)(0) with n = 0-9 and the combination states 1(1)(0)2(n)(0) with n = 1-8 and 2(n)(0)3(1)(0) with n = 0-5 in the A(1)A'<-- X(1)A' system of CDF, in addition to some weak hot bands. The spectra were measured under jet-cooled conditions using a pulsed discharge source, and rotationally analyzed to yield precise values for the band origins and rotational constants; fluorescence lifetimes were also measured to probe for lifetime lengthening effects due to the RT interaction. The derived A state parameters are compared with previous results for CHF and with predictions of ab initio electronic structure theory. The approach to linearity in the A state is evidenced in a sharp increase in the A rotational constant with bending excitation, and a minimum in the vibrational intervals near 2(9). A fit of the vibrational intervals for the pure bending levels yields an A state barrier to linearity in good agreement both with that previously derived for CHF and ab initio predictions. From the spectra and lifetime measurements, the onset of extensive RT perturbations is found to occur at a higher energy than in CHF, consistent with the smaller A constant.