A Systematic Study of the In Vitro Pharmacokinetics and Estimated Human In Vivo Clearance of Indole and Indazole-3-Carboxamide Synthetic Cannabinoid Receptor Agonists Detected on the Illicit Drug Market

In vitro pharmacokinetic studies were conducted on enantiomer pairs of twelve valinate or tert-leucinate indole and indazole-3-carboxamide synthetic cannabinoid receptor agonists (SCRAs) detected on the illicit drug market to investigate their physicochemical parameters and structure-metabolism relationships (SMRs). Experimentally derived Log D7.4 ranged from 2.81 (AB-FUBINACA) to 4.95 (MDMB-4en-PINACA) and all SCRAs tested were highly protein bound, ranging from 88.9 ± 0.49% ((R)-4F-MDMB-BINACA) to 99.5 ± 0.08% ((S)-MDMB-FUBINACA). Most tested SCRAs were cleared rapidly in vitro in pooled human liver microsomes (pHLM) and pooled cryopreserved human hepatocytes (pHHeps). Intrinsic clearance (CLint) ranged from 13.7 ± 4.06 ((R)-AB-FUBINACA) to 2944 ± 95.9 mL min−1 kg−1 ((S)-AMB-FUBINACA) in pHLM, and from 110 ± 34.5 ((S)-AB-FUBINACA) to 3216 ± 607 mL min−1 kg−1 ((S)-AMB-FUBINACA) in pHHeps. Predicted Human in vivo hepatic clearance (CLH) ranged from 0.34 ± 0.09 ((S)-AB-FUBINACA) to 17.79 ± 0.20 mL min−1 kg−1 ((S)-5F-AMB-PINACA) in pHLM and 1.39 ± 0.27 ((S)-MDMB-FUBINACA) to 18.25 ± 0.12 mL min−1 kg−1 ((S)-5F-AMB-PINACA) in pHHeps. Valinate and tert-leucinate indole and indazole-3-carboxamide SCRAs are often rapidly metabolised in vitro but are highly protein bound in vivo and therefore predicted in vivo CLH is much slower than CLint. This is likely to give rise to longer detection windows of these substances and their metabolites in urine, possibly as a result of accumulation of parent drug in lipid-rich tissues, with redistribution into the circulatory system and subsequent metabolism

Resonant Auger spectroscopy at the L2,3 shake-up thresholds as a probe of electron correlation effects in nickel

The excitation energy dependence of the three-hole satellites in the L3-M4,5M4,5 and L2-M4,5M4,5 Auger spectra of nickel metal has been measured using synchrotron radiation. The satellite behavior in the non-radiative emission spectra at the L3 and L2 thresholds is compared and the influence of the Coster-Kronig channel explored. The three-hole satellite intensity at the L3 Auger emission line reveals a peak structure at 5 eV above the L3 threshold attributed to resonant processes at the 2p53d9 shake-up threshold. This is discussed in connection with the 6-eV feature in the x-ray absorption spectrum.Comment: 8 pages, 4 figures; http://prb.aps.org/abstract/PRB/v58/i7/p3677_

Electronic Structure of Transition Metals Fe, Ni and Cu in the GW Approximation

The quasiparticle band structures of 3d transition metals, ferromagnetic Fe, Ni and paramagnetic Cu, are calculated by the GW approximation. The width of occupied 3d valence band, which is overestimated in the LSDA, is in good agreement with experimental observation. However the exchange splitting and satellite in spectra are not reproduced and it is required to go beyond the GW approximation. The effects of static screening and dynamical correlation are discussed in detail in comparison with the results of the static COHSEX approximation. The dynamical screening effects are important for band width narrowing.Comment: 4 pages, 3 figure

Bus Frequency Optimization: When Waiting Time Matters in User Satisfaction

Reorganizing bus frequency to cater for the actual travel demand can save the cost of the public transport system significantly. Many, if not all, existing studies formulate this as a bus frequency optimization problem which tries to minimize passengers' average waiting time. However, many investigations have confirmed that the user satisfaction drops faster as the waiting time increases. Consequently, this paper studies the bus frequency optimization problem considering the user satisfaction. Specifically, for the first time to our best knowledge, we study how to schedule the buses such that the total number of passengers who could receive their bus services within the waiting time threshold is maximized. We prove that this problem is NP-hard, and present an index-based algorithm with $(1-1/e)$ approximation ratio. By exploiting the locality property of routes in a bus network, we propose a partition-based greedy method which achieves a $(1-\rho)(1-1/e)$ approximation ratio. Then we propose a progressive partition-based greedy method to further improve the efficiency while achieving a $(1-\rho)(1-1/e-\varepsilon)$ approximation ratio. Experiments on a real city-wide bus dataset in Singapore verify the efficiency, effectiveness, and scalability of our methods

Consumer price indexes: an analysis of heterogeneity across sub-populations

La rilevanza dell'Indece dei Prezzi al Consumo quale misura dell'inflazione è stata a lungo dibattuta in particolare esminando le differenti cause di distorsione dovute all'utilizzo di un paniere fisso di beni e servizi. Di conseguenza la letteratura ha proposto indici dei prezzi sperimentali per particolari sottogruppi di popolazioni. tali indici hanno rilevanza ai fini della politica economica e sociale, poiché è probabile che differenti gruppi di popolazione abbiano comportamenti nei consumi differenti dalla media, ad esempio i consumatori poveri (Garner, Johnson & Kokoski, 1996) e quelli anziani (Stewart, 2008). Lo scopo di questo lavoro è quello di esaminare le possibilità offerte da metodi di costruzione alternativi degli Indici dei Prezzi al Consumo ai fini di cogliere la variabilità dei tassi di inflazione relativi a differenti categorie di consumatori.The soundeness of Consumer Price Indexes (CPI) as a measure of inflation has long been debeate, focusing on the different sources of bias inherent to use of a constant basket of goods and services. Thus experimental consumer price indexes have been proposed for targeted sub-populations specifically relevant for social and economic policy, that are likely to have consumption patterns different from yhe average, i.e poor (Garner, Johnson & Kokoski, 1996) and elderly (Stewart, 2008)houseolds. Aim of this work is to investigate the possibilities offered by alternative methods of construction of consumer price indices in order to capture the variability of inflation rates facing different houseolds' types

Hitting the Jackpot – development of gas chromatography–mass spectrometry (GC–MS) and other rapid screening methods for the analysis of 18 fentanyl-derived synthetic opioids

© 2020 John Wiley & Sons, Ltd. In recent years, the occurrence of synthetic opioid fentanyl and its derivatives has grown significantly in forensic casework. This study presents the synthesis and analysis of 18 fentalogs, selected based on information received from local law enforcement. This study provides colorimetric tests, thin-layer chromatography (TLC) which can potentially be utilized for presumptive screening of the target compounds, as bulk powders or as trace-level adulterants. The fully validated confirmatory GC–MS method (employing SIM mode) allows the identification of the 18 derivatives, five commonly encountered controlled substances and four adulterants, within 20 minutes. The cross-validated method described herein provides a sensitive screening and quantitation method for the illicit (and potentially harmful) components at trace levels (LOD = 0.007–0.822 μg/mL and LOQ = 0.023–2.742 μg/mL respectively). Spectral data [1H-NMR, 13C-NMR, 19F-NMR, FT-IR, and HRMS] and assignments for the synthesized reference materials are also provided in the Supplementary Information for laboratories engaged in the routine analysis of fentanyl and its derivatives

Examining the Moderating Role of Rational-Versus Emotional-Focused Websites: The Case of Boutique Hotels

This article examines whether emotional or rational advertising appeals are more effective for website hospitality services. Specifically, it considers how attitudes towards websites, service expectations and attitudes towards boutique hotels may influence the two different types of advertising appeals and purchase intention. Results show that websites using emotional appeals tend to show a positive relationship between attitude towards hotels and attitude towards websites and purchase intention. It also indicates that emotional advertisements are better at gaining and retaining interest and attention, and as such can be highly beneficial for small boutique hotels. This article provides several marketing and business policy implications to aid practitioners and strategists in making better decisions