Search

Your search keyword '"LOO, leave-one-out"' showing total 3 results
Start Over Descriptor "LOO, leave-one-out" Search Limiters Academic (Peer-Reviewed) Journals
3 results on '"LOO, leave-one-out"'

1. Combining an in silico proarrhythmic risk assay with a tPKPD model to predict QTc interval prolongation in the anesthetized guinea pig assay

Author

Jin Zhai, Mary Jo Wildey, Elisa Passini, John Imredy, Frederick Sannajust, Kevin Fitzgerald, Anne Chain, Sebastian Polak, Christopher P. Regan, Pierre Morissette, Patrick Fanelli, Jeffrey Travis, and Blanca Rodriguez

Subjects
0301 basic medicine, ICH, The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, TN, True Negative, PPV, Positive Predictive Value, Pharmacology, TdP, Torsade de Pointes, Toxicology, Membrane Potentials, 0302 clinical medicine, HTS, High Throughput Screening, QTcVdW, Van de Water's Heart Rate QT-corrected Interval, In Silico modeling, Medicine, Translational PKPD modeling, NCEs, New Chemical Entities, CTD90, Ca2+-Transient Duration at 90% repolarization, education.field_of_study, Anesthetized Cardiovascular Guinea Pig, HR, Heart Rate, PNV, Predictive Negative Value, Safety pharmacology, ECG, Electrocardiogram, FIH, First in Human, IKr, rapidly-activating delayed rectifier potassium current, AP, Action Potential, QTc, Heart Rate corrected QT Interval, PX, PatchXpress®, 030220 oncology & carcinogenesis, Electrophysiologic Techniques, Cardiac, FP, False Positive, LVP, Left Ventricular Pressure, Anti-Arrhythmia Agents, In silico, Population, Guinea Pigs, QT interval, Models, Biological, Article, Ventricular action potential, Cell Line, CVGP, Cardiovascular Anesthetized Guinea Pig, GP, Guinea Pig, 03 medical and health sciences, hERG, Human Ether-a-go-go Related Gene, Pharmacokinetics, In vivo, Animals, Humans, Computer Simulation, education, QT corrected interval, BP, Blood Pressure, business.industry, M5P, M5 trees automated pruning model, tPKPD, thranslational pharmacokinetic/pharmacodynamic, FLIPR, Fluorescent Imaging Plate Reader, Arrhythmias, Cardiac, ORd, O'Hara Rudy model, Electrophysiological Phenomena, 030104 developmental biology, HEK293 Cells, Models, Chemical, Pharmacodynamics, Torsade de Pointes, EMw, Electromechanical window, FN, False Negative, TP, True Positive, Calcium, Calcium Channels, LOO, Leave-One-Out, business, APD90, Action Potential Duration at 90% repolarization
Abstract

Human-based in silico models are emerging as important tools to study the effects of integrating inward and outward ion channel currents to predict clinical proarrhythmic risk. The aims of this study were 2-fold: 1) Evaluate the capacity of an in silico model to predict QTc interval prolongation in the in vivo anesthetized cardiovascular guinea pig (CVGP) assay for new chemical entities (NCEs) and; 2) Determine if a translational pharmacokinetic/pharmacodynamic (tPKPD) model can improve the predictive capacity. In silico simulations for NCEs were performed using a population of human ventricular action potential (AP) models. PatchXpress® (PX) or high throughput screening (HTS) ion channel data from respectively n = 73 and n = 51 NCEs were used as inputs for the in silico population. These NCEs were also tested in the CVGP (n = 73). An M5 pruned decision tree-based regression tPKPD model was used to evaluate the concentration at which an NCE is liable to prolong the QTc interval in the CVGP. In silico results successfully predicted the QTc interval prolongation outcome observed in the CVGP with an accuracy/specificity of 85%/73% and 75%/77%, when using PX and HTS ion channel data, respectively. Considering the tPKPD predicted concentration resulting in QTc prolongation (EC5%) increased accuracy/specificity to 97%/95% using PX and 88%/97% when using HTS. Our results support that human-based in silico simulations in combination with tPKPD modeling can provide correlative results with a commonly used early in vivo safety assay, suggesting a path toward more rapid NCE assessment with reduced resources, cycle time, and animal use., Highlights • Cardiac electrophysiological in silico model predicts QTc interval prolongation in the guinea pig. • PKPD model predicts relevant QTc interval prolongation concentration in guinea pig. • Combining the models improves the accuracy of predicting guinea pig QTc effects. • Combining models accelerates assessment of QTc with lower resources and animal use.

Published
2020

2. Conformationally constrained butyrophenones as new pharmacological tools to study 5-HT2A and 5-HT2C receptor behaviours

Author

Brea, José, Masaguer, Christian F., Villazón, María, Isabel Cadavid, M., Raviña, Enrique, Fontaine, Fabien, Dezi, Cristina, Pastor, Manuel, Sanz, Ferran, and Isabel Loza, M.

Subjects
*HYDROGEN bonding, *AMINO acids, *AFFINITY labeling
Abstract

This study presents new pharmacological and molecular modelling studies on a recently described series of conformationally constrained butyrophenones. Alignment-free three-dimensional quantitative structure-activity relationship models developed on the basis of GRid Independent descriptors and partial least squares regression analysis, allow feasible predictions of activity of new compounds and reveal structural requirements for optimal affinity, particularly in the case of the 5-HT2A receptor. The requirements for the 5-HT2A affinity consist in a precise distance between hydrogen bond donor (protonated amino group) and hydrogen bond acceptor groups, as well as an optimal distance between the protonated amino group and the farthest extreme of the compounds. Another significant result has been the characterisation of two structurally similar compounds as interesting pharmacological tools (1-[(4-Oxo-4,5,6,7-tetrahydrobenzo[b]furan-5-yl)ethyl]-4-(6-fluorobenzisoxazol-3-yl)piperidine and 1-[(4-Oxo-4,5,6,7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(6-fluorobenzisoxazol-3-yl)piperidine). In spite of their structural similarity, the first compound shows clearly higher affinity for the 5-HT2C receptor (about 100 fold) and higher Meltzer ratio (1.17 vs. 0.99) than the second. Moreover, the first compound inhibits arachidonic acid release in a biphasic concentration-dependent way in functional experiments at the 5-HT2A receptor and it acts as inverse agonist at the 5-HT2C receptor, behaviours that are not shown by the second compound. [Copyright &y& Elsevier]

Published
2003
Full Text
View/download PDF

3. Adolescent binge drinking disrupts normal trajectories of brain functional organization and personality maturation

Author

Zhaowen Liu, Herta Flor, Frauke Nees, Gabriel Robert, Christian Büchel, Juliane H. Fröhner, Tobias Banaschewski, Yunyi Zhou, Michael N. Smolka, Sylvane Desrivières, Fei Li, Qiang Luo, Robert Whelan, Andreas Heinz, Arun L.W. Bokde, Gunter Schumann, Luise Poustka, Erin Burke Quinlan, Marie-Laure Paillère Martinot, Henrik Walter, Penny A. Gowland, Vincent Frouin, Jianfeng Feng, Hongtao Ruan, Bernd Ittermann, Hugh Garavan, Jean-Luc Martinot, Dimitri Papadopoulos Orfanos, Uli Bromberg, Sarah Hohmann, Jonchère, Laurent, Santé Mentale et Addictions - Dépression à l'Adolescence: Structure cérébrale et myélinisation - - ADODEP2012 - ANR-12-SAMA-0004 - SAMENTA - VALID, Fudan University [Shanghai], Comportement et noyaux gris centraux = Behavior and Basal Ganglia [Rennes], Université de Rennes (UR)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes (INCR), Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, Xidian University, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim], Discipline of Psychiatry [Dublin], School of Medicine [Dublin], Trinity College Dublin-Trinity College Dublin, Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Vermont [Burlington], University of Nottingham, UK (UON), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Physikalisch-Technische Bundesanstalt [Braunschweig] (PTB), Neuroimagerie en psychiatrie (U1000), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Heidelberg University, University Medical Center Göttingen (UMG), Technische Universität Dresden = Dresden University of Technology (TU Dresden), MR/N000390/1, Medical Research Council Canada, 20152234, Shanghai Municipal Education Commission, AERIAL 01EE1406A, Bundesministeriumfür Bildung und Forschung, ANR-12-SAMA-0004, ANR, Shanghai AI Platform for Diagnosis and Treatment of Brain Diseases, Fondation pour la Recherche Médicale, Assistance-Publique-Hôpitaux-de-Paris, 16/ERCD/3797, National Institutes of Health, Science Foundation Ireland, IDEX 2012, Université Paris-Sud, RO1 MH085772-01A1, U.S.A., U54 EB020403, NIH, National Institute for Health Research, MR/N027558/1, BRIDGET, 81761128035, National Natural Science Foundation of China, Fondation de France, LSHM-CT- 2007-037286, European Commission, 2016-17, Project of Zhangjiang Hi-Tech District Management Committee, Shanghai, SFB 940/1, Deutsche Forschungsgemeinschaft, 695313, Horizon 2020 Framework Programme, Mission Interministérielle de Lutte Contre les Drogues et les Conduites Addictives, 17ZR1444400, Natural Science Foundation of Shanghai, Svenska Forskningsrådet Formas, 2018SHZDZX01, Shanghai Municipal Science and Technology, 602450, FP7, Zhangjiang Lab, 16JC1420402, Shanghai Science and Technology Innovation Plan, B18015, Higher Education Discipline Innovation Project, GDEK201709, Shanghai Municipal Commission of Health and Family Planning, 16CR2025B, Shanghai Shenkang Hospital Development Center, 17XD1403200, Shanghai Committee of Science and Technology, 2018YJRC03, Xinhua Hospital of Shanghai Jiao Tong University School of Medicine, PR-ST-0416-10004, ERANID, Institut National de la Santé et de la Recherche Médicale, 603016, MATRICS, 115300-2, Innovative Medicine Initiative Project EU-AIMS, Maudsley NHS Foundation Trust, 2018YFC0910503, National Basic Research Program of China (973 Program), King's College London, ANR-12-SAMA-0004,ADODEP,Dépression à l'Adolescence: Structure cérébrale et myélinisation(2012), Université de Rennes (UR)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes = Institute of Clinical Neurosciences of Rennes (INCR), University Hospital Mannheim | Universitätsmedizin Mannheim, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes (INCR), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11)

Subjects
Male, Support Vector Machine, Time Factors, Co-development, [SDV]Life Sciences [q-bio], iFC, increased rsFC, Binge drinking, Underage Drinking, Adolescent, Genome, Personality, Resting state, lcsh:RC346-429, 0302 clinical medicine, rsFC, resting-state functional connectivity, Longitudinal Studies, Cantab, Cambridge Neuropsychological Test Automated Battery, Age of Onset, Big Five personality traits, media_common, rsfMRI, resting-state fMRI, ANOVA, Analysis of Variance, NEO-PI-R, Revised NEO Personality Inventory, 05 social sciences, Brain, Regular Article, SNP, single nucleotide polymorphism, Magnetic Resonance Imaging, [SDV] Life Sciences [q-bio], ESPAD, European School Survey Project on Alcohol and Drugs, Neurology, lcsh:R858-859.7, Female, Functional organization, medicine.symptom, Psychology, Alcohol consumption, Clinical psychology, Adult, FDR, false discovery rate, Cognitive Neuroscience, media_common.quotation_subject, SVM, support-vector machine, AUC, area under curve, Impulsivity, lcsh:Computer applications to medicine. Medical informatics, 050105 experimental psychology, Young Adult, 03 medical and health sciences, Connectome, medicine, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, pSNP, protective SNP, ROC, receiver operational characteristic, lcsh:Neurology. Diseases of the nervous system, rSNP, risk SNP, dFC, decreased rsFC, Resting state fMRI, Adolescent Development, Mental health, LOO, leave-one-out, NRI, net reclassification improvement, Personality Development, Impulsive Behavior, Neurology (clinical), SURPS, Substance Use Risk Profile Scale, 030217 neurology & neurosurgery
Abstract

Adolescent binge drinking has been associated with higher risks for the development of many health problems throughout the lifespan. Adolescents undergo multiple changes that involve the co-development processes of brain, personality and behavior; therefore, certain behavior, such as alcohol consumption, can have disruptive effects on both brain development and personality maturation. However, these effects remain unclear due to the scarcity of longitudinal studies. In the current study, we used multivariate approaches to explore discriminative features in brain functional architecture, personality traits, and genetic variants in 19-year-old individuals (n = 212). Taking advantage of a longitudinal design, we selected features that were more drastically altered in drinkers with an earlier onset of binge drinking. With the selected features, we trained a hierarchical model of support vector machines using a training sample (n = 139). Using an independent sample (n = 73), we tested the model and achieved a classification accuracy of 71.2%. We demonstrated longitudinally that after the onset of binge drinking the developmental trajectory of improvement in impulsivity slowed down. This study identified the disrupting effects of adolescent binge drinking on the developmental trajectories of both brain and personality., Highlights • History of binge drinking could be identified by multivariate features at age 19. • Adolescent binge drinking disrupted frontal connectivity maturation in the brain. • Impulsivity improvement slowed down after the onset of adolescent binge drinking.

Published
2019

Catalog

Books, media, physical & digital resources
See catalog results