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https://www.readbyqxmd.com/read/28817613/diflunisal-inhibits-prestin-by-chloride-dependent-mechanism
#1
Guillaume Duret, Fred A Pereira, Robert M Raphael
The motor protein prestin is a member of the SLC26 family of anion antiporters and is essential to the electromotility of cochlear outer hair cells and for hearing. The only direct inhibitor of electromotility and the associated charge transfer is salicylate, possibly through direct interaction with an anion-binding site on prestin. In a screen to identify other inhibitors of prestin activity, we explored the effect of the non-steroid anti-inflammatory drug diflunisal, which is a derivative of salicylate. We recorded prestin activity by whole-cell patch clamping HEK cells transiently expressing prestin and mouse outer hair cells...
2017: PloS One
https://www.readbyqxmd.com/read/28817486/overcoming-clopidogrel-resistance-three-promising-novel-antiplatelet-drugs-developed-in-china
#2
Hong-Guang Xie, Yu-Meng Jia, Ting Tai, Jin-Zi Ji
Clopidogrel is one of the most frequently prescribed drugs worldwide; however, the presence of clopidogrel resistance and high susceptibility to genetic variations and drug interactions are facilitating the development of other antiplatelet drugs. To overcome clopidogrel resistance, several promising clopidogrel analogues have been developed in China, such as vicagrel (and its deuterated analogues), PLD-301, and W1. These novel chemical analogues are all characterized by much faster and more efficient bioconversion to clopidogrel thiolactone (or 2-oxo-clopidogrel, the precursor of clopidogrel active metabolite) in the intestine than clopidogrel through bypassing the first-step P450-mediated oxidation of clopidogrel in the liver...
August 4, 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28817479/comparison-of-instructional-methods-for-screening-brief-intervention-and-referral-to-treatment-for-substance-use-in-nursing-education
#3
Sarah Knopf-Amelung, Heather Gotham, Araba Kuofie, Pamela Young, Ronalda Manney Stinson, Jolene Lynn, Kendra Barker, Jessica Hildreth
Most nursing programs lack curriculum on substance use. This project evaluated 3 didactic instructional methods for teaching baccalaureate nursing students about screening, brief intervention, and referral to treatment for substance use. In-person, asynchronous narrated slides and interactive online instructional methods were all effective in developing students' competency; however, active learning methods (in-person and interactive online course) were more effective in changing students' attitudes about their role in screening and intervening for drug use...
August 16, 2017: Nurse Educator
https://www.readbyqxmd.com/read/28817468/longitudinal-associations-of-local-cigarette-prices-and-smoking-bans-with-smoking-behavior-in-the-multi-ethnic-study-of-atherosclerosis-mesa
#4
Stephanie L Mayne, Amy H Auchincloss, Mark F Stehr, David M Kern, Ana Navas-Acien, Joel D Kaufman, Yvonne L Michael, Ana V Diez Roux
BACKGROUND: Few studies have examined associations of geographically proximal cigarette prices with within-person changes in smoking outcomes, or assessed interactions between cigarette prices and smoking bans. METHODS: We linked neighborhood cigarette prices (inflation-adjusted) at chain supermarkets and drug stores and bar/restaurant smoking ban policies to cohort participants (632 smokers from the Multi-Ethnic Study of Atherosclerosis, 2001-2012, baseline mean aged 58) using geocoded retailer and participant addresses...
August 16, 2017: Epidemiology
https://www.readbyqxmd.com/read/28817206/loureirin-b-promotes-insulin-secretion-through-inhibition-of-katp-channel-and-influx-of-intracellular-calcium
#5
Yijie Sha, Yuelin Zhang, Jing Cao, Kai Qian, Bing Niu, Qin Chen
The development of new diabetes drugs continues to be explored. Loureirin B, a flavonoid, extracted from Dracaena cochinchinensis, has been confirmed to increase insulin secretion and decrease blood glucose levels. For searching the promotion of insulin secretion with the treatment of loureirin B, experiments were employed based on cell experiments and computational methods. Firstly, promotion of insulin secretion was dependent on extracellular glucose concentration. At the genetic level, loureirin B enhanced the relative mRNA level of Pdx-1 and MafA...
August 17, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28817204/new-insight-into-the-control-of-peptic-ulcer-by-targeting-the-histamine-h2-receptor
#6
Vijai Singh, Nisarg Gohil, Robert Ramírez-García
Peptic ulcer disease is one of the major challenges in public health globally and new evidence shows that it can be controlled by targeting the histamine H2 receptor (H2 R). Recently, a number of H2 R antagonists have been synthesized and used to block the action of histamine on the parietal cells in the stomach and decrease the acid production. In this study, we modeled the H2 R by homology modeling using the 3-D crystal structure and this model was validated based on free energy and amino acid residues present in the allowed regions of a Ramachandran plot...
August 17, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28816926/feasibility-and-relevance-of-antipsychotic-safety-monitoring-in-children-with-tourette-syndrome-a-prospective-longitudinal-study
#7
Tamara Pringsheim, Josephine Ho, Justyna R Sarna, Tracy Hammer, Scott Patten
PURPOSE/BACKGROUND: Antipsychotics are efficacious for tics and are increasingly prescribed to children with behavioral disorders. Antipsychotics have important adverse effects, and systematic monitoring of drug safety is infrequently performed. The objectives of this study were to determine the feasibility of antipsychotic safety monitoring in children with Tourette Syndrome using a defined protocol and to evaluate the risk of adverse effects with chronic use. METHODS/PROCEDURES: A prospective longitudinal study of children prescribed antipsychotics was performed...
August 14, 2017: Journal of Clinical Psychopharmacology
https://www.readbyqxmd.com/read/28816562/behcet-s-disease-and-pregnancy-what-to-expect
#8
Gokcen Orgul, Fatih Aktoz, Mehmet Sinan Beksac
The relationship between Behcet's disease (BD) and pregnancy is only reported in limited number of studies. We retrospectively collected data of 26 women with BD diagnosis and their 66 pregnancies. We analysed patients according to disease activity, age at BD diagnosis, age at first/last pregnancy, obstetric history, obstetric complications, neonatal birthweight, associated foetal abnormalities and pregnancy-related complications. Sixteen miscarriages (24.2%), two intrauterine deaths (3%) and 48 live births (72...
August 17, 2017: Journal of Obstetrics and Gynaecology: the Journal of the Institute of Obstetrics and Gynaecology
https://www.readbyqxmd.com/read/28816544/animal-inflammation-based-models-of-depression-and-their-application-to-drug-discovery
#9
Li Ma, Konstantin A Demin, Tatyana O Kolesnikova, Sergey L Kharsko, Xiaokang Zhu, Xiaodong Yuan, Cai Song, Darya A Meshalkina, Brian E Leonard, Li Tian, Allan V Kalueff
Depression, anxiety and other affective disorders are globally widespread and severely debilitating human brain diseases. Despite their high prevalence and mental health impact, affective pathogenesis is poorly understood, and often remains recurrent and resistant to treatment. The lack of efficient antidepressants and presently limited conceptual innovation necessitate novel approaches and new drug targets in the field of antidepressant therapy. Areas covered: Herein, the authors discuss the emerging role of neuro-immune interactions in affective pathogenesis, which can become useful targets for CNS drug discovery, including modulating neuroinflammatory pathways to alleviate affective pathogenesis...
August 17, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28816073/overactive-bladder-treatment-application-of-methylene-blue-to-improve-the-injection-technique-of-onabotulinum-toxin-a
#10
Michał Szczypior, Wojciech Połom, Marcin Markuszewski, Krzesimir Ciura, Magdalena Buszewska-Forajta, Julia Jacyna, Michał Markuszewski, Marcin Matuszewski
OBJECTIVE: The aim of this study was to test the addition of methylene blue (MB) to onabotulinum toxin A (BTX-A) solution in overactive bladder (OAB) treatment, as a means of facilitating observation of the injection site and assessing the distribution of the drug under the bladder mucosa during injection. Pharmacological interactions between BTX-A and MB were also evaluated. MATERIALS AND METHODS: The study was conducted between December 2014 and April 2016 on 30 patients: six males and 24 females (median age 57...
August 17, 2017: Scandinavian Journal of Urology
https://www.readbyqxmd.com/read/28816025/aromatic-interactions-at-the-ligand-protein-interface-implications-for-the-development-of-docking-scoring-functions
#11
Michal Brylinski
The ability to design and fine-tune non-covalent interactions between organic ligands and proteins is indispensable to rational drug development. Aromatic stacking has long been recognized as one of the key constituents of ligand-protein interfaces. In this communication, we employ a two-parameter geometric model to conduct a large-scale statistical analysis of aromatic contacts in the experimental and computer-generated structures of ligand-protein complexes, considering various combinations of aromatic amino acid residues and ligand rings...
August 17, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28815894/challenges-of-developing-and-conducting-clinical-trials-in-rare-disorders
#12
REVIEW
Lucas Kempf, Jonathan C Goldsmith, Robert Temple
Rare disease drug development is a rapidly expanding field. Clinical researchers in rare diseases face many challenges when conducting trials in small populations. Disease natural history is often poorly understood and the ability to detect clinically meaningful outcomes requires understanding of their rate of occurrence and variability, both of which contribute to difficulties in powering a study. Standard trial designs are not optimized to obtain adequate safety and efficacy data from small numbers of patients, so alternative designs (enrichment, crossover, adaptive, N-of 1) need to be considered...
August 16, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28815830/determinants-of-the-inhibition-of-dpre1-and-cyp2c9-by-antitubercular-thiophenes
#13
Renhe Liu, Xiaoxuan Lyu, Mei-Hui Hsu, Catherine Vilcheze, Scott G Franzblau, William R Jacobs, Gurdyal S Besra, Eric F Johnson, Klaus Fütterer, Feng Wang
Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9...
August 16, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28815754/pharmacokinetic-interactions-and-dosing-rationale-for-antiepileptic-drugs-in-adults-and-children
#14
S C van Dijkman, W M Rauwé, M Danhof, O Della Pasqua
AIM: Population pharmacokinetic modelling has been widely used across many therapeutic areas to identify sources of variability, which are incorporated into models as covariate factors. Despite numerous publications on pharmacokinetic (PK) drug-drug interactions (DDIs) between antiepileptic drugs (AEDs), such data are not used to support the dose rationale for polytherapy in the treatment of epileptic seizures. Here we assess the impact of DDIs on plasma concentrations and evaluate the need for AED dose adjustment...
August 16, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28815595/sigma-1-receptor-ligands-inhibit-catecholamine-secretion-from-adrenal-chromaffin-cells-due-to-block-of-nicotinic-acetylcholine-receptors
#15
Rebecca L Brindley, Mary Beth Bauer, Nolan D Hartley, Kyle J Horning, Kevin P M Currie
Adrenal chromaffin cells (ACCs) are the neuroendocrine arm of the sympathetic nervous system and key mediators of the physiological stress response. Acetylcholine (ACh) released from preganglionic splanchnic nerves activates nicotinic acetylcholine receptors (nAChRs) on chromaffin cells causing membrane depolarization, opening voltage-gated Ca(2+) channels (VGCC), and exocytosis of catecholamines and neuropeptides. The serotonin transporter (SERT) is expressed in ACCs and interacts with 5-HT1A receptors to control secretion...
August 16, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28815428/the-pharmacology-and-toxicology-of-third-generation-anticonvulsant-drugs
#16
REVIEW
Paul LaPenna, Laura M Tormoehlen
Epilepsy is a neurologic disorder affecting approximately 50 million people worldwide, or about 0.7% of the population [1]. Thus, the use of anticonvulsant drugs in the treatment of epilepsy is common and widespread. There are three generations of anticonvulsant drugs, categorized by the year in which they were developed and released. The aim of this review is to discuss the pharmacokinetics, drug-drug interactions, and adverse events of the third generation of anticonvulsant drugs. Where available, overdose data will be included...
August 16, 2017: Journal of Medical Toxicology: Official Journal of the American College of Medical Toxicology
https://www.readbyqxmd.com/read/28815392/strategy-for-cyp3a-induction-risk-assessment-from-preclinical-signal-to-human-a-case-example-of-a-late-stage-discovery-compound
#17
Jialin Mao, Peter Fan, Susan Wong, Jianshuang Wang, Moulay Hicham Alaoui Ismaili, Brian Dean, Cornelis E C A Hop, Matthew Wright, Yuan Chen
PURPOSE: The exposure of G2917 decreased by four-fold at oral doses of 100 mg/kg twice daily for seven days in cynomolgus monkeys. Additional investigative work was conducted to understand: (1) the causes for the significant reduction in G2917 exposure in monkeys; (2) the extrapolation of in vitro induction data to in vivo findings in monkeys, and (3) the relevance of this pre-clinical finding to humans at the projected human efficacious dose. METHODS: Pharmacokinetic and induction potency (in vitro and in vivo) of G2917 in monkeys, and the in vitro human induction potency were studied...
August 16, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28815216/epistatic-interactions-within-the-influenza-a-virus-polymerase-complex-mediate-mutagen-resistance-and-replication-fidelity
#18
Matthew D Pauly, Daniel M Lyons, William J Fitzsimmons, Adam S Lauring
Lethal mutagenesis is a broad-spectrum antiviral strategy that employs mutagenic nucleoside analogs to exploit the high mutation rate and low mutational tolerance of many RNA viruses. Studies of mutagen-resistant viruses have identified determinants of replicative fidelity and the importance of mutation rate to viral population dynamics. We have previously demonstrated the effective lethal mutagenesis of influenza A virus using three nucleoside analogs as well as the virus's high genetic barrier to mutagen resistance...
July 2017: MSphere
https://www.readbyqxmd.com/read/28815153/high-risk-drug-drug-interactions-between-clinical-practice-guidelines-for-management-of-chronic-conditions
#19
Geoffrey J Tso, Samson W Tu, Mark A Musen, Mary K Goldstein
Clinicians and clinical decision-support systems often follow pharmacotherapy recommendations for patients based on clinical practice guidelines (CPGs). In multimorbid patients, these recommendations can potentially have clinically significant drug-drug interactions (DDIs). In this study, we describe and validate a method for programmatically detecting DDIs among CPG recommendations. The system extracts pharmacotherapy intervention recommendations from narrative CPGs, normalizes the terms, creates a mapping of drugs and drug classes, and then identifies occurrences of DDIs between CPG pairs...
2017: AMIA Summits on Translational Science Proceedings
https://www.readbyqxmd.com/read/28815131/integrating-medication-alert-data-into-a-clinical-data-repository-to-enable-retrospective-study-of-drug-interaction-alerts-in-clinical-practice
#20
Mei Liu, Brittany L Melton, Gregory Ator, Lemuel R Waitman
Current clinical data repositories primarily extract data from multiple administrative and electronic medical record (EMR) data resources (e.g., hospital and physician billing records) containing specific patient-level data including demographics, medications, laboratory results, diagnoses, and procedure codes. It overlooks the importance of EMR system-level data (e.g., medication alerts that are routinely used by physicians, nurses, and pharmacists for decision support) for the surveillance of EMR decision support tools...
2017: AMIA Summits on Translational Science Proceedings
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