Psychotropic drugs and liver disease : a critical review of pharmacokinetics and liver toxicity

© 2017 Baishideng Publishing Group Inc. All rights reserved. This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license.The liver is the organ by which the majority of substances are metabolized, including psychotropic drugs. There are several pharmacokinetic changes in end-stage liver disease that can interfere with the metabolization of psychotropic drugs. This fact is particularly true in drugs with extensive first-pass metabolism, highly protein bound drugs and drugs depending on phase I hepatic metabolic reactions. Psychopharmacological agents are also associated with a risk of hepatotoxicity. The evidence is insufficient for definite conclusions regarding the prevalence and severity of psychiatric drug-induced liver injury. High-risk psychotropics are not advised when there is pre-existing liver disease, and after starting a psychotropic agent in a patient with hepatic impairment, frequent liver function/lesion monitoring is advised. The authors carefully review the pharmacokinetic disturbances induced by end-stage liver disease and the potential of psychopharmacological agents for liver toxicity.info:eu-repo/semantics/publishedVersio

Histone Methylation/Demethylation Inhibition Modulates Sleep

Histone methylation/demethylation plays an important modulatory role in chromatin restructuring, RNA transcription and is essential for controlling a plethora of biological processes. Due to many human diseases have been related to histone methylation/demethylation, several compounds such as 3-deazaneplanocin A (DZNep) or 3-((6-(4,5-Dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid; N-[2-(2-pyridinyl)-6-(1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-4-pyrimidinyl]-b-Alanine (GSK-J1), have been designed to inhibit histone methylase or suppress histone demethylase, respectively. In the present study, we investigated the effects on the sleep-wake cycle and sleep-related neurochemical levels after systemic injections of DZNep or GSK-J1 given during the light or dark phase in rats. DZNep dose-dependently (0.1, 1.0, or 10 mg/kg, i.p.) prolonged wakefulness (W) duration while decreased slow wave sleep (SWS) and rapid eye movement sleep (REMS) time spent during the lights-on period with no changes observed in dark phase. In opposite direction, GSK-J1 (0.1, 1.0, or 10 mg/kg, i.p.) injected at the beginning of the lights-on period induced no statistical changes in W, SWS, or REMS whereas if administered at darkness, we found a diminution in W and an enhancement in SWS and REMS. Finally, brain microdialysis experiments in freely moving animals were used to evaluate the effects of DZNep or GSK-J1 treatments on contents of sleep-related neurochemicals. The results showed that DZNep boosted extracellular levels of dopamine, norepinephrine, epinephrine, serotonin, adenosine, and acetylcholine if injected at the beginning of the lights-on period whereas GSK-J1 exerted similar outcomes but when administered at darkness. In summary, DZNep and GSK-J1 may control the sleep-wake cycle and sleep-related neurochemicals through histone methylation/demethylation activity

Immobilization of streptavidin on a plasmonic Au-TiO2 thin film towards an LSPR biosensing platform

Optical biosensors based on localized surface plasmon resonance (LSPR) are the future of label-free detection methods. This work reports the development of plasmonic thin films, containing Au nanoparticles dispersed in a TiO2 matrix, as platforms for LSPR biosensors. Post-deposition treatments were employed, namely annealing at 400 °C, to develop an LSPR band, and Ar plasma, to improve the sensitivity of the Au-TiO2 thin film. Streptavidin and biotin conjugated with horseradish peroxidase (HRP) were chosen as the model receptor–analyte, to prove the efficiency of the immobilization method and to demonstrate the potential of the LSPR-based biosensor. The Au-TiO2 thin films were activated with O2 plasma, to promote the streptavidin immobilization as a biorecognition element, by increasing the surface hydrophilicity (contact angle drop to 7°). The interaction between biotin and the immobilized streptavidin was confirmed by the detection of HRP activity (average absorbance 1.9 ± 0.6), following a protocol based on enzyme-linked immunosorbent assay (ELISA). Furthermore, an LSPR wavelength shift was detectable (0.8 ± 0.1 nm), resulting from a plasmonic thin-film platform with a refractive index sensitivity estimated to be 33 nm/RIU. The detection of the analyte using these two different methods proves that the functionalization protocol was successful and the Au-TiO2 thin films have the potential to be used as an LSPR platform for label-free biosensors.Portuguese Foundation for Science and Technology (FCT) in the framework of the Strategic Funding UIDB/04650/2020, UIDB/04050/2020, and UID/EMS/00285/2020, and by the projects NANO4BIO: POCI-01-0145-FEDER-032299, with FCT reference PTDC/FIS-MAC/32299/2017, and CO2Plasmon, with FCT reference EXPL/CTM-REF/0750/2021. Patrícia Pereira-Silva, Diana I. Meira, and Diogo Costa acknowledge FCT for their Ph.D. scholarships, 2020.08235.BD, SFRH/BD/143262/2019, and SFRH/BD/136279/2018, respectively. Augusto Costa-Barbosa also acknowledges FCT for his Ph.D. scholarships SFRH/BD/133513/2017 and COVID/BD/152169/2021. The authors would like to express their gratitude to Nuno P. Barradas (C2TN, University of Lisbon) and Eduardo Alves (IPFN, University of Lisbon) for RBS measurements and analysis

Development and In Vitro Validation of Antibacterial Paints Containing Chloroxylenol and Terpineol

This article belongs to the Section Toxicology.The establishment of self-disinfecting surfaces is an important method to avoid surface contamination. Recently, paints with antimicrobial properties have been developed to be applied on different surfaces, avoiding contamination with pathogens. In this work, self-disinfecting paints containing Chloroxylenol (CLX), Terpineol (TRP), and a mixture of both substances were developed. The goal was to evaluate and validate these paints using international standards for eventual commercialization and application in scenarios where surface contamination represents a problem. The paints were challenged with five different bacteria, Gram-positive and Gram- negative, before and after a scrub resistance test, where the long-term efficacy of the paints was evaluated. The antibacterial activity assessment was performed following ISO 22196 and JIS Z2801. In general, the paints showed very promising results, demonstrating their antibacterial activity, before and after scrub resistance test. The paint incorporating the mixture of CLX and TRP (CLX+TRP) stood out by revealing consistent results of antibacterial activity both before and after the scrub resistance test for most of the tested bacteria. The cytotoxicity of the developed paints was assessed in vitro by performing tests by direct contact with a human skin cell line, HaCaT, and testes on extracts with HaCaT and a pulmonary cell line, A549. The methodologies for cytotoxicity assessment were developed based in ISO 10993. For genotoxicity assessment, alkaline comet assay was conducted on both cell lines. The cytotoxicity assessment revealed promising results with the paints, demonstrating values of cellular viability above 70% and values of lactate dehydrogenase (LDH) leakage below 30%. The genotoxic assessment also revealed acceptable values of primary DNA damage for the developed antibacterial paints. In general, the selected methodologies presented good potential to be applied in the validation of both efficacy and safety of the antimicrobial paints, aiming to be applied in real scenarios.This research was funded by Programa Operacional Competitividade e Internacionaliza ção—COMPETE2020/FEDER, towards the project B-Safecoat (POCI-01-0247-FEDER-017875), and by FCT (Fundação para a Ciência e Tecnologia) through the PhD grant awarded to M.M.Q. (SFRH/BD/130203/2017)info:eu-repo/semantics/publishedVersio

Sleep and Neurochemical Modulation by DZNep and GSK-J1: Potential Link With Histone Methylation Status

Histone methylation/demethylation plays an important modulatory role in chromatin restructuring, RNA transcription and is essential for controlling a plethora of biological processes. Due to many human diseases have been related to histone methylation/demethylation, several compounds such as 3-deazaneplanocin A (DZNep) or 3-((6-(4,5-Dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid; N-[2-(2-pyridinyl)-6-(1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-4-pyrimidinyl]-β-Alanine (GSK-J1), have been designed to inhibit histone methylase or suppress histone demethylase, respectively. In the present study, we investigated the effects on the sleep-wake cycle and sleep-related neurochemical levels after systemic injections of DZNep or GSK-J1 given during the light or dark phase in rats. DZNep dose-dependently (0.1, 1.0, or 10 mg/kg, i.p.) prolonged wakefulness (W) duration while decreased slow wave sleep (SWS) and rapid eye movement sleep (REMS) time spent during the lights-on period with no changes observed in dark phase. In opposite direction, GSK-J1 (0.1, 1.0, or 10 mg/kg, i.p.) injected at the beginning of the lights-on period induced no statistical changes in W, SWS, or REMS whereas if administered at darkness, we found a diminution in W and an enhancement in SWS and REMS. Finally, brain microdialysis experiments in freely moving animals were used to evaluate the effects of DZNep or GSK-J1 treatments on contents of sleep-related neurochemicals. The results showed that DZNep boosted extracellular levels of dopamine, norepinephrine, epinephrine, serotonin, adenosine, and acetylcholine if injected at the beginning of the lights-on period whereas GSK-J1 exerted similar outcomes but when administered at darkness. In summary, DZNep and GSK-J1 may control the sleep-wake cycle and sleep-related neurochemicals through histone methylation/demethylation activity

iFloW: an integrated logistics software system for inbound supply chain traceability

Visibility plays an important role in supply chain management. Such visibility is not only important for better planning, but especially for real-time execution related with the traceability of goods. In inbound supply chain management, logistics planners need to trace raw materials from their requests in order to properly plan a plant’s production. The iFloW (Inbound Logistics Tracking System) integrates logistics providers IT applications and Global Positioning System (GPS) technology to track and trace incoming freights. The Estimated Time of Arrival (ETA) is updated in real-time allowing an improved materials planning process. This paper presents the iFloW project and describes how these issues are addressed and validated in a real pilot project.This research is sponsored by the Portugal Incentive System for Research and technological Development PEst-UID/CEC/00319/2013 and by project in co-promotion no 36265/2013 (Project HMIExcel—2013–2015)

Using scrum together with UML models: a collaborative university-industry R&D software project

Conducting research and development (R&D) software projects, in an environment where both industry and university collaborate, is challenging due to many factors. In fact, industrial companies and universities have generally different interests and objectives whenever they collaborate. For this reason, it is not easy to manage and negotiate the industrial companies’ interests, namely schedules and their expectations. Conducting such projects in an agile framework is expected to decrease these risks, since partners have the opportunity to frequently interact with the development team in short iterations and are constantly aware of the characteristics of the system under development. However, in this type of collaborative R&D projects, it is often advantageous to include some waterfall practices, like upfront requirements modeling using UML models, which are not commonly used in agile processes like Scrum, in order to better prepare the implementation phase of the project. This paper presents some lessons learned that result from experience of the authors in adopting some Scrum practices in a R&D project, like short iterations, backlogs, and product increments, and simultaneously using UML models, namely use cases and components.This research is sponsored by the Portugal Incentive System for Research and Technological Development PEst-UID/CEC/00319/2013 and by project in co–promotion nº 36265/2013 (Project HMIExcel - 2013-2015)

TREATMENT OF COGNITIVE DEFICITS IN ALZHEIMER\u27S DISEASE: A PSYCHOPHARMACOLOGICAL REVIEW

The growing and aging population has contributed to the increased prevalence of Alzheimer\u27s disease (AD) and other types of dementia in the world. AD is a progressive and degenerative brain disease with an onset characterized by episodic memory impairments, although progressive deficits can be observed in several domains including language, executive functions, attention and working memory. The relationship between cognitive impairments and the topography and progression of brain neuropathology is well established. The pathophysiologic mechanisms and processes that underline the course of cognitive and clinical decline have been the theoretical support for the development of pharmacological treatments for AD. Cholinesterase inhibitors (ChEIs) and Nmethyl- D-aspartate (NMDA) antagonists are the main drugs used in the management of global cognitive impairment and several studies also explore the effects of both in specific cognitive measures. Recent research trends also examine the effects of combination therapy using both compounds. This review aims to update practical recommendations for the treatment of global cognitive functioning and specific neurocognitive deficits in AD using ChEIs, NMDA antagonists and combination therapy with both drugs