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https://www.readbyqxmd.com/read/28444890/utilizing-pbpk-modeling-to-evaluate-the-potential-of-a-significant-drug-drug-interaction-between-clopidogrel-and-dasabuvir-a-scientific-perspective
#1
V Arya, P Zhao, K S Reynolds, P Mishra, I R Younis
Dasabuvir, a component of VIEKIRA PAK, is a substrate of CYP2C8 enzymes. Prescribing information for VIEKIRA PAK contraindicates gemfibrozil, a strong CYP2C8 inhibitor, because coadministration significantly increases dasabuvir exposures, which may increase the risk of QT prolongation. Clopidogrel may increase dasabuvir exposures primarily due to CYP2C8 inhibition by clopidogrel-acyl-β-D-glucuronide. This commentary outlines the US Food and Drug Administration (FDA) interdisciplinary review team's scientific perspective to address the potential for a significant drug-drug interaction (DDI) between clopidogrel and VIEKIRA PAK...
April 26, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28443594/diastolic-electrocardiographic-parameters-predict-implantable-device-detected-asymptomatic-atrial-fibrillation
#2
Ahmet İlker Tekkeşin, Yalçın Velibey, Ceyhan Türkkan, Ahmet Taha Alper, Yasin Çakıllı, Tolga Sinan Güvenç, Ozan Tanık, Adnan Kaya, Özlem Yıldırımtürk, Nazmiye Özbilgin, Özge Güzelburç, Ahmet Öz, Regayip Zehir, Kadir Gürkan
BACKGROUND: Atrial fibrillation (AF) is the most common clinically significant arrhythmia. It is now established that atrial high rate episodes (AHRE) correlate highly with AF. AIMS: Present study aimed to investigate the relation between diastolic electrocardiographic parameters and subclinical AF detected by cardiac implantable electronic devices. STUDY DESIGN: This study was cross-sectional study that included a total of 203 patients who had a DDDR pacemaker due to sinus node dysfunction...
April 6, 2017: Balkan Medical Journal
https://www.readbyqxmd.com/read/28443483/aneurysm-size-and-the-windkessel-effect-an-analysis-of-contrast-intensity-in-digital-subtraction-angiography
#3
Ahmed E Hussein, Darian R Esfahani, Andreas Linninger, Fady T Charbel, Chih-Yang Hsu, Fady T Charbel, Ali Alaraj
Large cerebral aneurysms are considered more dangerous than their smaller counterparts, with higher risk of subarachnoid hemorrhage. Understanding the hemodynamics of large aneurysms has potential to predict their response to treatment. Digital subtraction angiography images for patients with intracranial aneurysms over a seven-year period were reviewed. Unruptured solitary aneurysms of the internal carotid artery (ICA) proximal to the terminus and posterior communicating artery were included. Contrast intensity over time was analyzed at the center of the M1 segment of the middle cerebral artery distal to the aneurysm and compared to the contralateral side...
January 1, 2017: Interventional Neuroradiology
https://www.readbyqxmd.com/read/28438924/analysis-of-the-effects-on-the-qt-interval-of-a-gatifloxacin-containing-regimen-versus-standard-treatment-of-pulmonary-tuberculosis
#4
Piero L Olliaro, Corinne Merle, Thuli Mthiyane, Boubacar Bah, Ferdinand Kassa, Evans Amukoye, Alimatou N' Diaye, Christian Perronne, Christian Lienhardt, Helen Mcilleron, Katherine Fielding
Background: The effects on ventricular repolarisation - recorded on the ECG as lengthening of the QT interval - of acute tuberculosis and those of standard and alternative anti-tuberculosis regimens are under-documented. A correction factor (QTc) is introduced to make the QT independent of the heart rate, translating into the slope of the regression line between QT and heart rate being close to zero.Methods: ECGs were performed pre- and 1-5 hours post-dosing (month 1, 2, end of treatment) around drugs' peak concentration time in tuberculosis patients treated with either the standard 6-month treatment (rifampicin and isoniazid for 6 months, pyrazinamide and ethambutol for 2 months; "control") or a test regimen with gatifloxacin, rifampicin and isoniazid given for 4 months (pyrazinamide for the first 2 months) as part of the OFLOTUB study, a randomized controlled trial conducted in five African countries...
April 24, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28438721/clinical-profile-and-mutation-spectrum-of-long-qt-syndrome-in-saudi-arabia-the-impact-of-consanguinity
#5
Zuhair N Al-Hassnan, Majid Al-Fayyadh, Bander Al-Ghamdi, Azam Shafquat, Yaseen Mallawi, Faten Al-Hadeq, Sahar Tulbah, Zarghuna Ma Shinwari, Abdulrahman Almesned, Ali Alakhfash, Fadel Al Fadly, Ahmed S Hersi, Abdullah Alhayani, Amal Al-Hashem, Dia Arafah, Nduna Dzimiri, Brian Meyer, Monther Rababh, Waleed Al-Manea
BACKGROUND: Congenital long QT syndrome (LQTS) is an inherited potentially fatal arrhythmogenic disorder. At least 16 genes have been implicated in LQTS; the yield of genetic analysis of 3 genes (KCNQ1, KCNH2, and SCN5A) is about 70% with KCNQ1 mutations accounting for ∼50% of positive cases. LQTS is mostly inherited in an autosomal dominant pattern. Systemic analysis of LQTS has not been previously conducted in a population with a high degree of consanguinity. OBJECTIVES: We aim to describe the clinical and molecular profiles of LQTS in the highly consanguineous Saudi population...
April 21, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/28437484/ecg-view-ii-a-freely-accessible-electrocardiogram-database
#6
Young-Gun Kim, Dahye Shin, Man Young Park, Sukhoon Lee, Min Seok Jeon, Dukyong Yoon, Rae Woong Park
The Electrocardiogram Vigilance with Electronic data Warehouse II (ECG-ViEW II) is a large, single-center database comprising numeric parameter data of the surface electrocardiograms of all patients who underwent testing from 1 June 1994 to 31 July 2013. The electrocardiographic data include the test date, clinical department, RR interval, PR interval, QRS duration, QT interval, QTc interval, P axis, QRS axis, and T axis. These data are connected with patient age, sex, ethnicity, comorbidities, age-adjusted Charlson comorbidity index, prescribed drugs, and electrolyte levels...
2017: PloS One
https://www.readbyqxmd.com/read/28437058/psychotic-and-bipolar-disorders-antipsychotic-drugs
#7
Sarah D Holder, Alaina L Edmunds, Sherri Morgan
Antipsychotic drugs block dopamine receptors and are used to manage psychosis as well as other mental illnesses that may or may not have psychotic features, such as bipolar disorders and major depressive disorder. First-generation antipsychotic drugs are more likely to cause adverse effects such as extrapyramidal symptoms and tardive dyskinesia. Adverse effects of second-generation antipsychotic drugs typically are related to metabolic abnormalities such as weight gain, abnormal blood glucose levels, and elevated lipid levels...
April 2017: FP Essentials
https://www.readbyqxmd.com/read/28436171/sex-and-regional-differences-in-rabbit-right-ventricular-l-type-calcium-current-levels-and-mathematical-modeling-of-arrhythmia-vulnerability
#8
Zane M Kalik, Joshua L Mike, Cassandra Slipski, Moriah Wright, Jozsi Z Jalics, Mark D Womble
Previous studies have shown that adult rabbit left ventricular myocytes exhibit sex and regional differences in L-type calcium current (ICa-L ) levels that contribute to increased susceptibility to arrhythmogenic early afterdepolarizations (EADs). We used patch clamp recordings from isolated adult male and female rabbit right ventricular myocytes to determine apex-base differences in ICa-L density, and mathematical modeling to examine ICa-L contribution to EAD formation. Current density measured at 0 mV in female base myocytes was 67% higher than male base myocytes and 55% higher than female apex myocytes...
April 24, 2017: Experimental Physiology
https://www.readbyqxmd.com/read/28434969/translational-science-approach-for-assessment-of-cardiovascular-effects-and-proarrhythmogenic-potential-of-the-beta-3-adrenergic-agonist-mirabegron
#9
Cees Korstanje, Masanori Suzuki, Koichiro Yuno, Shuichi Sato, Masashi Ukai, Marlowe J Schneidkraut, Gan X Yan
INTRODUCTION: Translational assessment of cardiac safety parameters is a challenge in clinical development of beta-3 adrenoceptor agonists. The preclinical tools are presented that were used for assessing human safety for mirabegron. METHODS: Studies were performed on electrical conductance at ion channels responsible for cardiac repolarization (IKr, IKs, Ito, INa, and ICa,L), on QT-interval, subendocardial APD90, Tpeak-end interval, and arrhythmia's in ventricular dog wedge tissue in vitro and on cardiovascular function (BP, HR, and QTc) in conscious dogs...
April 20, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/28434968/cardiac-contractility-correction-strategies-applied-to-telemetry-data-from-a-hesi-sponsored-consortium
#10
Emmanuel Boulay, Michael K Pugsley, Vincent Jacquemet, Alain Vinet, Michael V Accardi, Maxim Soloviev, Eric Troncy, Jennifer M Doyle, Jennifer Beck Pierson, Simon Authier
INTRODUCTION: QT has a long history of heart rate (HR) correction but limited investigations have been undertaken to assess the impact of cardiovascular parameters on left ventricular (LV) contractility in drug safety testing. Cardiac contractility is affected by preload (Cyon-Frank-Starling law), afterload (Anrep effect) and HR (Bowditch effect). We evaluated multi-parameter correction methods to help with dP/dtmax interpretation. METHODOLOGY: Modeling was undertaken using data from dogs in single or double 4×4 Latin square studies...
April 20, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/28434730/the-effect-of-vitamin-concentrates-on-the-flavor-of-pasteurized-fluid-milk
#11
E B Yeh, A N Schiano, Y Jo, D M Barbano, M A Drake
Fluid milk consumption in the United States continues to decline. As a result, the level of dietary vitamin D provided by fluid milk in the United States diet has also declined. Undesirable flavor(s)/off flavor(s) in fluid milk can negatively affect milk consumption and consumer product acceptability. The objectives of this study were to identify aroma-active compounds in vitamin concentrates used to fortify fluid milk, and to determine the influence of vitamin A and D fortification on the flavor of milk. The aroma profiles of 14 commercial vitamin concentrates (vitamins A and D), in both oil-soluble and water-dispersible forms, were evaluated by sensory and instrumental volatile compound analyses...
April 20, 2017: Journal of Dairy Science
https://www.readbyqxmd.com/read/28433559/the-kcnh2-ivs9-28a-g-mutation-causes-aberrant-isoform-expression-and-herg-trafficking-defect-in-cardiomyocytes-derived-from-patients-affected-by-long-qt-syndrome-type-2
#12
Manuela Mura, Ashish Mehta, Chrishan J Ramachandra, Rita Zappatore, Federica Pisano, Maria Chiara Ciuffreda, Vincenzo Barbaccia, Lia Crotti, Peter J Schwartz, Winston Shim, Massimiliano Gnecchi
BACKGROUND: Long QT Syndrome type 2 (LQT2) is caused by mutations in the KCNH2 gene that encodes for the α-subunit (hERG) of the ion channel conducting the rapid delayed rectifier potassium current (IKr). We have previously identified a disease causing mutation (IVS9-28A/G) in the branch point of the splicing of KCNH2 intron 9. However, the mechanism through which this mutation causes the disease is unknown. METHODS AND RESULTS: We generated human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from fibroblasts of two IVS9-28A/G mutation carriers...
April 12, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/28431243/cryo-em-structure-of-the-open-human-ether-%C3%A3-go-go-related-k-channel-herg
#13
Weiwei Wang, Roderick MacKinnon
The human ether-à-go-go-related potassium channel (hERG, Kv11.1) is a voltage-dependent channel known for its role in repolarizing the cardiac action potential. hERG alteration by mutation or pharmacological inhibition produces Long QT syndrome and the lethal cardiac arrhythmia torsade de pointes. We have determined the molecular structure of hERG to 3.8 Å using cryo-electron microscopy. In this structure, the voltage sensors adopt a depolarized conformation, and the pore is open. The central cavity has an atypically small central volume surrounded by four deep hydrophobic pockets, which may explain hERG's unusual sensitivity to many drugs...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431069/-tpeak-tend-qrs-and-tpeak-tend-qt-%C3%A3-qrs-novel-markers-for-predicting-arrhythmic-risk-in-the-brugada-syndrome
#14
Gary Tse
No abstract text is available yet for this article.
April 1, 2017: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
https://www.readbyqxmd.com/read/28431056/long-term-outcome-of-transvenous-pacemaker-implantation-in-infants-a-retrospective-cohort-study
#15
Laura M Vos, Janneke A E Kammeraad, Matthias W Freund, Andreas C Blank, Johannes M P J Breur
Aim: Evaluation of long-term outcome of transvenous pacemaker (PM) implantation in infants. Methods and Results: A retrospective analysis of all transvenous PM implantations in infants <10 kg between September 1997 and October 2001 was made. Indications for PM implantation, age at implantation, and determinants of long-term outcome including cardiac function, PM function, and PM (system) complications were noted. Seven patients underwent transvenous VVI(R) PM implantation...
April 1, 2017: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
https://www.readbyqxmd.com/read/28429460/automated-t-wave-analysis-can-differentiate-acquired-qt-prolongation-from-congenital-long-qt-syndrome
#16
Alan Sugrue, Peter A Noseworthy, Vaclav Kremen, J Martijn Bos, Bo Qiang, Ram K Rohatgi, Yehu Sapir, Zachi I Attia, Peter Brady, Pedro J Caraballo, Samuel J Asirvatham, Paul A Friedman, Michael J Ackerman
BACKGROUND: Prolongation of the QT on the surface electrocardiogram can be due to either genetic or acquired causes. Distinguishing congenital long QT syndrome (LQTS) from acquired QT prolongation has important prognostic and management implications. We aimed to investigate if quantitative T-wave analysis could provide a tool for the physician to differentiate between congenital and acquired QT prolongation. METHODS: Patients were identified through an institution-wide computer-based QT screening system which alerts the physician if the QTc ≥ 500 ms...
April 21, 2017: Annals of Noninvasive Electrocardiology
https://www.readbyqxmd.com/read/28427417/novel-trigenic-cacna1c-des-mypn-mutations-in-a-family-of-hypertrophic-cardiomyopathy-with-early-repolarization-and-short-qt-syndrome
#17
Yanhong Chen, Hector Barajas-Martinez, Dongxiao Zhu, Xihui Wang, Chonghao Chen, Ruijuan Zhuang, Jingjing Shi, Xueming Wu, Yijia Tao, Weidong Jin, Xiaoyan Wang, Dan Hu
BACKGROUND: Hypertrophic cardiomyopathy (HCM) patients with early repolarization (ER) pattern are at higher risk of ventricular arrhythmia, yet the genetic background of this situation has not been well investigated. Here we report novel trigenic mutations detected in a Chinese family of obstructive HCM with ER and short QT syndrome (SQTS). METHODS: Proband and family members underwent detailed medical assessments. DNAs were extracted from peripheral blood leukocytes for genetic screening with next generation method...
April 20, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28421417/estimation-of-qt-interval-prolongation-through-model-averaging
#18
Peter L Bonate
The current method to analyze concentration-QT interval data, which is based on predictions conditional on a best model, fails to take into account the uncertainty of the model. Previous studies have suggested that failure to take into account model uncertainty using a best model approach can result in confidence intervals that are overly optimistic and may be too narrow. Theoretically, more realistic estimates are obtained using model-averaging where the overall point estimate and confidence interval are a weighted-average from a set of candidate models, the weights of which are equal to each model's Akaike weight...
April 18, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28419747/a-randomized-placebo-and-positive-controlled-single-dose-crossover-thorough-qt-qtc-study-assessing-the-effect-of-daprodustat-on-cardiac-repolarization-in-healthy-subjects
#19
Stephen Caltabiano, Jon Collins, Gul Serbest, Lisa Morgan, Deborah A Smith, Ramiya Ravindranath, Alexander R Cobitz
Daprodustat (GSK1278863) is a prolyl hydroxylase inhibitor in phase 3 clinical studies for the treatment of anemia associated with chronic kidney disease. This study was conducted to evaluate the effect of daprodustat on cardiac repolarization and enrolled 55 healthy adult male (29) and female (26) subjects who received single-dose 75 and 500 mg daprodustat, 400 mg moxifloxacin, and placebo. Mean placebo-corrected change from baseline QT interval for daprodustat showed no statistically significant increase...
April 17, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28419650/cardiovascular-safety-in-refractory-incontinent-patients-with-overactive-bladder-receiving-add-on-mirabegron-therapy-to-solifenacin-beside
#20
Marcus J Drake, Scott MacDiarmid, Christopher R Chapple, Adil Esen, Stavros Athanasiou, Javier Cambronero Santos, David Mitcheson, Sender Herschorn, Emad Siddiqui, Moses Huang, Matthias Stoelzel
AIMS/OBJECTIVES: In the BESIDE study, combination therapy (antimuscarinic [solifenacin] and β3 -adrenoceptor agonist [mirabegron]) improved efficacy over solifenacin monotherapy without exacerbating anticholinergic side effects in overactive bladder (OAB) patients; however, a potential synergistic effect on the cardiovascular (CV) system requires investigation. METHODS: OAB patients remaining incontinent despite daily solifenacin 5 mg during 4-week single-blind run-in, were randomised 1:1:1 to double-blind daily combination (solifenacin 5 mg/mirabegron 25 mg, increasing to 50 mg after week 4), solifenacin 5 or 10 mg for 12 weeks...
April 16, 2017: International Journal of Clinical Practice
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