Simultaneous Quantification of 25 Fentanyl Derivatives and Metabolites in Oral Fluid by Means of Microextraction on Packed Sorbent and LC–HRMS/MS Analysis

Fentanyl and fentalogs’ intake as drugs of abuse is experiencing a great increase in recent years. For this reason, there are more and more cases in which it is important to recognize and quantify these molecules and related metabolites in biological matrices. Oral fluid (OF) is often used to find out if a subject has recently used a psychoactive substance and if, therefore, the person is still under the effect of psychotropics. Given its difficulty in handling, good sample preparation and the development of instrumental methods for analysis are essential. In this work, an analytical method is proposed for the simultaneous determination of 25 analytes, including fentanyl, several derivatives and metabolites. OF was collected by means of passive drool; sample pretreatment was developed in order to be fast, simple and possibly semi-automated by exploiting microextraction on packed sorbent (MEPS). The analysis was performed by means of LC–HRMS/MS obtaining good identification and quantification of all the analytes in less than 10 min. The proposed method was fully validated according to the Scientific Working Group for Forensic Toxicology (SWGTOX) international guidelines. Good results were obtained in terms of recoveries, matrix effect and sensitivity, showing that this method could represent a useful tool in forensic toxicology. The presented method was successfully applied to the analysis of proficiency test samples.     

Anti-Multiple Myeloma Potential of Secondary Metabolites from Hibiscus sabdariffa—Part 2

Multiple Myeloma (MM) is an aggressive tumor causing millions of deaths every year and currently available therapies are often unsuccessful or correlated with severe side effects. In our previous work we demonstrated that the Hibiscus sabdariffa hydroalcoholic extract inhibits the growth of the MM cell line and we isolated two metabolites responsible for the activity: Hib-ester and Hib-carbaldehyde. Herein we report their interaction with proteasome, one of the main targets in the fight against MM. The molecular modelling study outlined a good interaction of both compounds with the target and these results prompted us to investigate their potential to inhibit proteasome. Metabolites were then isolated from the calyces and an extract with a high content of Hib-ester and Hib-carbaldehyde was prepared. An anticancer profile was drawn, evaluating apoptosis, autophagy and proteasome inhibition, with the anticancer properties being mainly attributed to the Hib-ester and Hib-carbaldehyde, while the proteasome inhibition of the extract could also be ascribed to the presence of anthocyanins, a class of secondary metabolites already known for their proteasome inhibitory activity.     

Mimicking Ziegler‐Natta Catalysts in Homogeneous Phase, 1. C2‐Symmetric Octahedral Zr(IV) Complexes with Tetradentate [ONNO]‐Type Ligands

Results of propene polymerization in the presence of two known octahedral C₂‐symmetric Zr complexes bearing tetradentate [ONNO]‐type ligands are reported for the first time. Depending on the steric hindrance at the active metal, isotactic site‐controlled or weakly syndiotactic chain‐end‐controlled polymers were obtained, in both cases via highly regioselective 1,2 (primary) monomer insertion. In this respect, the complexes mimic the behavior of the active Ti species on the surface of the heterogeneous Ziegler‐Natta catalysts of which they might represent good structural models.     

Molecular‐Dynamics and NMR Investigation of the Property Space of the Zwitterionic Antihistamine Cetirizine

The zwitterionic antihistamine cetirizine and its parent drug hydroxyzine as reference compound were examined for their 3D structures and dynamics. After attributing, by NMR spectroscopy, the two basic pK_a values, the most common conformations for each electrical species were determined by molecular‐dynamics simulations and confirmed by NMR measurements. For cetirizine, the results demonstrate that the zwitterion, which is the predominant species at physiological pH, exists as folded conformers able to partly mask polar groups. Extended and folded conformers of similar energy were also found for neutral hydroxyzine, whereas its monocationic species displayed folded conformers stabilized by intramolecular H‐bonds. These findings are in full agreement with previous results on the lipophilicity behavior of cetirizine in isotropic solvent systems and, taken together, could explain the favorable pharmacokinetic properties of the drug.     

Stick–slip oscillations in a multiphysics system

Nonlinear Dynamics - This work analyzes a multiphysics system with stick–slip oscillations. The system is composed of two subsystems that interact, a mechanical and an electromagnetic (a DC...     

On the existence of extremal functions for a weighted Sobolev embedding with critical exponent

We investigate the existence of ground state solutions to the Dirichlet problem in , u = 0 on , where , and is a domain in . In particular we prove that a non negative ground state solution exists when the domain is a cone, including the case . Moroever, we study the case of arbitrary domains, showing how the geometry of the domain near the origin and at infinity affects the existence or non existence of ground state solutions. Received April 16, 1998 / Accepted June 24, 1998     

Alk‐1‐ene Polymerization in the Presence of a Monocyclopentadienyl Zirconium(IV) Acetamidinate Catalyst: Microstructural and Mechanistic Insights

Suitably activated, (Cp*){N(^tBu)C(Me)N(Et)}ZrMe₂ is known to initiate the ‘living’ and isotactic‐selective polymerization of alk‐1‐enes, and it can be used to synthesize block copolymers and stereoblock polymers. We report a full molecular kinetic investigation of propene, but‐1‐ene, and hex‐1‐ene polymerization with a MAO‐activated catalyst system. By combining NMR microstructural polymer analysis with QM modeling of the active species, the complicated regio‐ and stereochemistry of the polyinsertion process, as well as the active chain‐transfer pathways, are investigated. The perspectives and limitations of this catalyst for application in (stereo)block polymerizations are discussed.