In Vitro and In Vivo Pharmaco-Toxicological Characterization of 1-Cyclohexyl-x-methoxybenzene Derivatives in Mice: Comparison with Tramadol and PCP

1-cyclohexyl-x-methoxybenzene is a novel psychoactive substance (NPS), first discovered in Europe in 2012 as unknown racemic mixture of its three stereoisomers: ortho, meta and para. Each of these has structural similarities with the analgesic tramadol and the dissociative anesthetic phencyclidine. In light of these structural analogies, and based on the fact that both tramadol and phencyclidine are substances that cause toxic effects in humans, the aim of this study was to investigate the in vitro and in vivo pharmacodynamic profile of these molecules, and to compare them with those caused by tramadol and phencyclidine. In vitro studies demonstrated that tramadol, ortho, meta and para were inactive at mu, kappa and delta opioid receptors. Systemic administration of the three stereoisomers impairs sensorimotor responses, modulates spontaneous motor activity, induces modest analgesia, and alters thermoregulation and cardiorespiratory responses in the mouse in some cases, with a similar profile to that of tramadol and phencyclidine. Naloxone partially prevents only the visual sensorimotor impairments caused by three stereoisomers, without preventing other effects. The present data show that 1-cyclohexyl-x-methoxybenzene derivatives cause pharmaco-toxicological effects by activating both opioid and non-opioid mechanisms and suggest that their use could potentially lead to abuse and bodily harm.     

Metric anticipation to manage mobility in mobile mesh and ad hoc wireless networks

In mobile ad hoc networks (MANETs), node mobility management is performed by the routing protocol. It may use metrics to reflect link state/quality. But, the delay between measures of the link quality and its integration in the route computation is very detrimental to the mobility management. Consequently, routing protocols may use lossy links for a few seconds leading to a significant performance deterioration. In this paper, we propose a new routing metric technique calculation which aims at anticipating link quality. Basically, the idea is to predict metric values a few seconds in advance, in order to compensate the delay involved by the link quality measurement and their dissemination by the routing protocol. Our technique is based on measurements of signal strength and is integrated in two classical routing metrics: ETX (expected transmission count) and ETT (expected transmission time). Validations are performed through both simulations and a testbed experimentation with OLSR as routing protocol. NS-3 simulations show that our metric may lead to a perfect mobility management with a packet delivery ratio of 100%. Experiments on a testbed prove the feasibility of our approach and show that this technique reduces the packet error rate by a factor of 3 in an indoor environment compared to the classical metrics calculation.     

The Genotoxicity of Acrylfentanyl,Ocfentanyl and Furanylfentanyl Raises the Concern of Long-Term Consequences

Three fentanyl analogues Acrylfentanyl, Ocfentanyl and Furanylfentanyl are potent, rapid-acting synthetic analgesics that recently appeared on the illicit market of new psychoactive substances (NPS) under the class of new synthetic opioids (NSO). Pharmacotoxicological data on these three non-pharmaceutical fentanyl analogues are limited and studies on their genotoxicity are not yet available. Therefore, the aim of the present study was to investigate this property. The ability to induce structural and numerical chromosomal aberrations in human lymphoblastoid TK6 cells was evaluated by employing the flow cytometric protocol of the in vitro mammalian cell micronucleus test. Our study demonstrated the non-genotoxicity of Fentanyl, i.e., the pharmaceutical progenitor of the class, while its illicit non-pharmaceutical analogues were found to be genotoxic. In particular, Acrylfentanyl led to a statistically significant increase in the MNi frequency at the highest concentration tested (75 μM), while Ocfentanyl and Furanylfentnyl each did so at both concentrations tested (150, 200 μM and 25, 50 μM, respectively). The study ended by investigating reactive oxygen species (ROS) induction as a possible mechanism linked to the proved genotoxic effect. The results showed a non-statistically significant increase in ROS levels in the cultures treated with all molecules under study. Overall, the proved genotoxicity raises concern about the possibility of serious long-term consequences.     

Study of C.I. Reactive Yellow 145, C.I. Reactive Red 238, and C.I. Reactive Blue 235 dyestuffs in order to use them in color formulation. Part 1: characterization and compatibility

Generally, textile dyeing is based on a mixture of several dyestuffs used in different proportions to achieve the desired-colors. The dyes used in a mixture should react with the fiber similarly; thus they must be compatible among themselves. So, to realize mixtures it is indispensable to study the compatibility of dyes, in order to ensure optimal dyeing formulation. This paper describes the characterization and studies the compatibility of three cold bifunctionnal reactive dyes (C.I. Reactive Yellow 145, C.I. Reactive Red 238, and C.I. Reactive Blue 235) in order to explore the possibility to use them in mixtures. The dye compatibility was studied based on several criteria such as dye extinction coefficients, exhaustion and fixation yield rates, adsorption kinetics, and adsorption isotherms. The exhaustion and fixation yield rates of all three dyes was compared between them and their adsorption kinetics and adsorption isotherms models were drawn and discussed. Between the different studied models, the Elovich model presents the best model describing the kinetics of different dyes, and Freundlich model presents the best model for analyzing the adsorption isotherms. The obtained results show that the analyzed dyes are perfectly compatible and have the same dyeing properties. They present close extinction coefficients as well as similar exhaustion and fixation yield rates.     

Application of genetic algorithm to color recipe formulation using reactive and direct dyestuffs mixtures

Color reproduction is a science in constant development. In this article, a new model to solve the color recipe prediction problem using a genetic algorithm is proposed. The objective is to optimize the color recipe prediction stage by determining the dyes to use in a mixture and their respective proportions to reproduce the target color. Two ranges of dyes were used for dyeing 100% cotton woven fabrics: three reactive dyes (CI Reactive Red 238, CI Reactive Yellow 145, and CI Reactive Blue 235) and four direct dyes (CI Direct Orange 34, CI Direct Red 227, CI Direct Blue 85, and CI Direct Black 22). The criterion of optimization, in reproducing the desired shades, is to minimize the CMC color difference between the desired reference color and the color resulting of the predicted recipe. The proposed algorithm revealed good results with small CMC color differences between target and reproduced colors. The effectiveness of the algorithm was also evaluated and proven by calculating errors between the predicted concentrations in the proposed recipes and the actual concentrations.     

In Vivo Bio-Activation of JWH-175 to JWH-018: Pharmacodynamic and Pharmacokinetic Studies in Mice

3-(1-Naphthalenylmethyl)-1-pentyl-1H-indole (JWH-175) is a synthetic cannabinoid illegally marketed for its psychoactive cannabis-like effects. This study aimed to investigate and compare in vitro and in vivo pharmacodynamic activity of JWH-175 with that of 1-naphthalenyl (1-pentyl-1H-indol-3-yl)-methanone (JWH-018), as well as evaluate the in vitro (human liver microsomes) and in vivo (urine and plasma of CD-1 male mice) metabolic profile of JWH-175. In vitro binding studies showed that JWH-175 is a cannabinoid receptor agonist less potent than JWH-018 on mouse and human CB1 and CB2 receptors. In agreement with in vitro data, JWH-175 reduced the fESPS in brain hippocampal slices of mice less effectively than JWH-018. Similarly, in vivo behavioral studies showed that JWH-175 impaired sensorimotor responses, reduced breath rate and motor activity, and increased pain threshold to mechanical stimuli less potently than JWH-018. Metabolic studies demonstrated that JWH-175 is rapidly bioactivated to JWH-018 in mice blood, suggesting that in vivo effects of JWH-175 are also due to JWH-018 formation. The pharmaco-toxicological profile of JWH-175 was characterized for the first time, proving its in vivo bio-activation to the more potent agonist JWH-018. Thus, it highlighted the great importance of investigating the in vivo metabolism of synthetic cannabinoids for both clinical toxicology and forensic purposes.