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Nicholas W Russo, Giovanna Petrucci, Bianca Rocca
Low-dose aspirin, alone or in combination, is recommended for the secondary prevention of acute non-cardioembolic ischemic stroke and transient ischemic attack, starting soon after the acute event. Clinically-relevant drug-drug interactions (DDIs) are a major concern of regulatory agencies and practicing physicians. Drug's pharmacodynamics and/or pharmacokinetics account for clinically-relevant DDIs that modify efficacy and/or safety of one or more of the co-administered drugs. Some non-steroidal anti-inflammatory drugs interact with aspirin pharmacodynamics by competing on the drug target, i...
October 17, 2016: Vascular Pharmacology
A Kenneth MacLeod, Lesley A McLaughlin, Colin J Henderson, C Roland Wolf
Tamoxifen is an oestrogen-receptor (ER) antagonist used in the treatment of breast cancer. It is a pro-drug, converted by several P450 enzymes to a primary metabolite, N-desmethyltamoxifen (NDT), which is then further modified by CYP2D6 to a pharmacologically potent secondary metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen). Anti-depressants (ADs), which are often co-prescribed to patients receiving tamoxifen, are also metabolised by CYP2D6 and evidence suggests that a drug-drug interaction (DDI) between these agents adversely affects the outcome of tamoxifen therapy by inhibiting endoxifen formation...
October 18, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Ping-Ping Lin, Xue-Ning Li, Fei Yuan, Wei-Li Chen, Meng-Jie Yang, Hong-Rong Xu
Huperzine A (HupA), one of the reversible and selective acetylcholinesterase inhibitors derived from Chinese herb Huperzia Serrata, possesses affirmative action of ameliorating cognitive dysfunction of Alzheimer's disease. Up to now, the effects of HupA on human cytochrome P450s (CYPs) have not been fully elucidated. The purpose of the present study was to clarify the metabolic pathway of HupA in vitro and in vivo, and to evaluate the CYPs inhibition/induction profile of HupA in vitro. The catalytic activity of CYP enzymes (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4) was measured by the quantification of specific enzyme substrates using validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods...
October 14, 2016: Biochemical and Biophysical Research Communications
Marta Johnson, Dipal R Patel, Christopher J Matheny, May Y K Ho, Liangfu Chen, Harma Ellens
Rosuvastatin is a widely prescribed anti-hyperlipidemic which undergoes limited metabolism, but is an in vitro substrate of multiple transporters (OATP1B1, OATP1B3, OATP1A2, OATP2B1, NTCP, BCRP, MRP2, MRP4, OAT3). It is therefore frequently used as probe substrate in clinical drug-drug interaction (DDI) studies to investigate transporter inhibition. While each of these transporters is believed to play a role in rosuvastatin disposition, multiple pharmacogenetic studies confirm that OATP1B1 and BCRP play an important role in vivo...
October 13, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Tal Lorberbaum, Kevin J Sampson, Jeremy B Chang, Vivek Iyer, Raymond L Woosley, Robert S Kass, Nicholas P Tatonetti
BACKGROUND: QT interval-prolonging drug-drug interactions (QT-DDIs) may increase the risk of life-threatening arrhythmia. Despite guidelines for testing from regulatory agencies, these interactions are usually discovered after drugs are marketed and may go undiscovered for years. OBJECTIVES: Using a combination of adverse event reports, electronic health records (EHR), and laboratory experiments, the goal of this study was to develop a data-driven pipeline for discovering QT-DDIs...
October 18, 2016: Journal of the American College of Cardiology
Kai Wu, Jianfeng Xu, Regan Fong, Xiaozhou Yao, Yanmei Xu, William Guiney, Frank Gray, Andrew Lockhart
OBJECTIVE: To evaluate in healthy volunteers the safety, pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interaction (DDI) potential of GSK2647544, (a selective lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor). METHODS: Study 1 was a single-blind, randomized, placebo-controlled, crossover study with healthy male volunteers randomized to receive single escalating oral doses (0.5 - 750 mg) of GSK2647544. Study 2 was a single-blind, randomized, placebo-controlled study with healthy volunteers randomized to receive repeat doses (80 mg) of GSK2647544...
October 10, 2016: International Journal of Clinical Pharmacology and Therapeutics
C S Moore, T J Wood, G Avery, S Balcam, L Needler, H Joshi, J R Saunderson, A W Beavis
The use of three physical image quality metrics, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and mean effective noise equivalent quanta (eNEQm) have recently been examined by our group for their appropriateness in the calibration of an automatic exposure control (AEC) device for chest radiography with an Agfa computed radiography (CR) imaging system. This study uses the same methodology but investigates AEC calibration for abdomen, pelvis and spine CR imaging. AEC calibration curves were derived using a simple uniform phantom (equivalent to 20 cm water) to ensure each metric was held constant across the tube voltage range...
October 7, 2016: Physics in Medicine and Biology
Amandine Cournil, Arsène Hema, Sabrina Eymard-Duvernay, Laura Ciaffi, Stéphanie Badiou, Firmin N Kabore, Assane Diouf, Liliane Ayangma, Vincent Le Moing, Jacques Reynes, Sinata Koulla-Shiro, Eric Delaporte
BACKGROUND: To investigate change in renal function in African patients initiating second line ART including ritonavir-boosted protease inhibitor (PI/r) with or without tenofovir disoproxil fumarate (TDF). METHODS: HIV-1 positive adults, failing standard first line ART were randomized to either TDF/FTC+LPV/r; ABC+ddI+LPV/r or TDF/FTC+DRV/r and followed until 18 months. Patients with an estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1,73m(2) at baseline were included in this analysis...
October 5, 2016: Antiviral Therapy
Jee Sun Min, Doyun Kim, Jung Bae Park, Hyunjin Heo, Soo Hyeon Bae, Jae Hong Seo, Euichaul Oh, Soo Kyung Bae
BACKGROUND: Evaluating the potential risk of metabolic drug-drug interactions (DDIs) is clinically important. OBJECTIVE: To develop a physiologically based pharmacokinetic (PBPK) model for sarpogrelate hydrochloride and its active metabolite, (R,S)-1-{2-[2-(3-methoxyphenyl)ethyl]-phenoxy}-3-(dimethylamino)-2-propanol (M-1), in order to predict DDIs between sarpogrelate and the clinically relevant cytochrome P450 (CYP) 2D6 substrates, metoprolol, desipramine, dextromethorphan, imipramine, and tolterodine...
2016: Drug Design, Development and Therapy
Behrouz Bokharaeian, Alberto Diaz, Hamidreza Chitsaz
MOTIVATION: Supervised biomedical relation extraction plays an important role in biomedical natural language processing, endeavoring to obtain the relations between biomedical entities. Drug-drug interactions, which are investigated in the present paper, are notably among the critical biomedical relations. Thus far many methods have been developed with the aim of extracting DDI relations. However, unfortunately there has been a scarcity of comprehensive studies on the effects of negation, complex sentences, clause dependency, and neutral candidates in the course of DDI extraction from biomedical articles...
2016: PloS One
Wei Cai, Xiao-Ya Shen, Bao-Ping Zhu, Shi-Lei Pan
OBJECTIVE: To explore the relationship between vitamin D receptor (VDR) gene pol-ymorphisms at Fok I site and the risk of preterm birth for potential intervention of of preterm birth or threatened premature delivery. METHODS: Fifty-seven women with preterm birth and 84 with full-term birth were included in this analysis. Polymerase chain reaction-restriction frag-ment length polymorphism (PCR-RFLP) was performed to identify VDR gene Fok I geno-types. RESULTS: No significant difference was found in age, D-dimer (DDI), fibrinogen (Fg), serum calcium (Ca(2+)), leukocyte count or glycosylated hemoglobin (HbA1c) level between the women in the preterm and full-term birth groups (P>0...
August 20, 2016: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
Francesco Maneschi, Desiree Biccirè, Giusi Santangelo, Seila Perrone, Alberto Scaini, Carmine Cosentino
PURPOSE: This study is aimed at investigating the clinical efficacy of the 4-category classification of urgent cesarean section. METHODS: Women giving birth from September 2012 to December 2014 were prospectively investigated. Urgency C-section categories were color-coded: red - maternal/fetal life threat; yellow - maternal/fetal compromise, not life-threatening; and green - early delivery necessary. Results were audited. RESULTS: A total of 4,754 women gave birth in the period considered, 1,313 (27...
September 30, 2016: Gynecologic and Obstetric Investigation
R Pushkin, Maria Iglesias-Ussel, Keedy Kara, C MacLauchlin, D R Mould, R Berkowitz, S Kreuzer, R Darouiche, D Oldach, P Fernandes
BACKGROUND:  Fusidic acid (FA) has been used for decades for bone infection, including prosthetic joint infection (PJI), often in combination with rifampin (RIF). An FA/RIF pharmacokinetic interaction has not previously been described. METHODS:  In a phase 2 open-label randomized study, we evaluated oral FA/RIF versus standard of care (SOC) IV antibiotics for treatment of hip or knee PJI. Outcome assessment occurred at re-implantation (week 12) for subjects with 2-stage exchange; and after 3 or 6 months of treatment for subjects with hip or knee debride and retain strategies, respectively...
September 28, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Fu Xiong, Zhisong Ji, Yanhui Liu, Yu Zhang, Lingling Hu, Qi Yang, Qinwei Qiu, Lingfeng Zhao, Dong Chen, Zhihui Tian, Xuan Shang, Leitao Zhang, Xiaofeng Wei, Cuixian Liu, Qiuxia Yu, Meichao Zhang, Jing Cheng, Jun Xiong, Dongri Li, Xiuhua Wu, Huijun Yuan, Wenqing Zhang, Xiangmin Xu
Dentin dysplasia type I (DDI) is an autosomal-dominant genetic disorder resulting from dentin defects. The molecular basis of DDI remains unclear. DDI exhibits unique characteristics with phenotypes featuring obliteration of pulp chambers and diminutive root, thus providing a useful model for understanding the genetics of tooth formation. Using a large Chinese family with 14 DDI patients, we mapped the gene locus responsible for DDI to 3p26.1-3p24.3 and further identified a missense mutation, c.353C>A (p...
September 29, 2016: Human Mutation
Tushar Garimella, Xiaoli You, Reena Wang, Shu-Pang Huang, Hamza Kandoussi, Marc Bifano, Richard Bertz, Timothy Eley
: The treatment of hepatitis C virus (HCV) infection has been revolutionized in recent years by the development of direct-acting antiviral regimens that do not contain peginterferon (pegIFN) and/or ribavirin (RBV). While direct-acting antiviral-based regimens have been shown to be greatly superior to pegIFN/RBV-based regimens in terms of efficacy and safety, they have a greater susceptibility to drug-drug interactions (DDIs). Daclatasvir (DCV)-the benchmark pangenotypic nonstructural protein 5A inhibitor-has been shown to be efficacious and generally well tolerated in partnership with other HCV direct-acting antivirals, including sofosbuvir, asunaprevir (ASV), and ASV plus beclabuvir...
September 23, 2016: Advances in Therapy
Jean-François Trempe, Klára Grantz Šašková, Monika Sivá, Colin D H Ratcliffe, Václav Veverka, Annabelle Hoegl, Marie Ménade, Xin Feng, Solomon Shenker, Michal Svoboda, Milan Kožíšek, Jan Konvalinka, Kalle Gehring
The eukaryotic Ddi1 family is defined by a conserved retroviral aspartyl protease-like (RVP) domain found in association with a ubiquitin-like (UBL) domain. Ddi1 from Saccharomyces cerevisiae additionally contains a ubiquitin-associated (UBA) domain. The substrate specificity and role of the protease domain in the biological functions of the Ddi family remain unclear. Yeast Ddi1 has been implicated in the regulation of cell cycle progression, DNA-damage repair, and exocytosis. Here, we investigated the multi-domain structure of yeast Ddi1 using X-ray crystallography, nuclear magnetic resonance, and small-angle X-ray scattering...
2016: Scientific Reports
Lindsey H M Te Brake, Jeroen J M W van den Heuvel, Aaron Ohene Buaben, Reinout van Crevel, Albert Bilos, Frans G Russel, Rob E Aarnoutse, Jan B Koenderink
INTRODUCTION: It is largely unknown if simultaneous administration of tuberculosis (TB) drugs and metformin leads to drug-drug interactions (DDIs). Disposition of metformin is determined by organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs). Thus any DDIs would primarily be mediated via these transporters. This study aimed to assess the in vitro inhibitory effects of TB drugs (rifampicin, isoniazid, pyrazinamide, ethambutol, amikacin, moxifloxacin and linezolid) on metformin transport, and whether TB drugs are also substrates themselves of OCTs and MATEs...
September 19, 2016: Antimicrobial Agents and Chemotherapy
Xi Chen, Bei Xu, Jian Yang, Juan Liu, Dailong Fang, Yongjun Gu, Zhifei Jian, Minghai Tang, Chunmei Fu, Zhi Zhang, Chunling Jiang, Xiangrong Song
To investigate the pharmacokinetic (PK) interaction between telmisartan (Tel) and pitavastatin (Pit), a rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometric assay method had been successfully established and fully validated for the simultaneous quantification of Tel and Pit in rat plasma. A simple protein precipitation procedure was adopted for the sample preparation with satisfactory extraction recovery for both analytes and the internal standard. The samples were chromatographed on an Inertsil ODS-3 C18 column (100mm×2...
November 30, 2016: Journal of Pharmaceutical and Biomedical Analysis
Barbara Wiśniowska, Sebastian Polak
A Quantitative Systems Pharmacology approach was utilized to predict the cardiac consequences of drug-drug interaction (DDI) at the population level. The Simcyp in vitro-in vivo correlation and physiologically based pharmacokinetic platform was used to predict the pharmacokinetic profile of terfenadine following co-administration of the drug. Electrophysiological effects were simulated using the Cardiac Safety Simulator. The modulation of ion channel activity was dependent on the inhibitory potential of drugs on the main cardiac ion channels and a simulated free heart tissue concentration...
November 2016: Journal of Pharmaceutical Sciences
Ayman F El-Kattan, Manthena V Varma, Stefan J Steyn, Dennis O Scott, Tristan S Maurer, Arthur Bergman
PURPOSE: To assess the utility of Extended Clearance Classification System (ECCS) in understanding absorption, distribution, metabolism, and elimination (ADME) attributes and enabling victim drug-drug interaction (DDI) predictions. METHODS: A database of 368 drugs with relevant ADME parameters, main metabolizing enzymes, uptake transporters, efflux transporters, and highest change in exposure (%AUC) in presence of inhibitors was developed using published literature...
September 12, 2016: Pharmaceutical Research
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