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Clinical and Translational Science

Matthew J McLaughlin, Jonathan Wagner, Valentina Shahknovich, Bruce Carleton, J Steven Leeder
Improving the utilization of pharmacologic agents in the pediatric population yields significant, perhaps life-long, benefits. Genetic factors related to the disposition of a medication or an alteration at the target receptor site contribute to the observed variability of exposure and response between individuals. An additional source of this variability specific to the pediatric population is ontogeny, where age-specific changes during development may require dose adjustments to obtain the same levels of drug exposure and response...
December 5, 2018: Clinical and Translational Science
Anuradha Ramamoorthy, Sook Wah Yee, Jason Karnes
No abstract text is available yet for this article.
November 26, 2018: Clinical and Translational Science
Asad E Patanwala, Charles Norwood, Heidi Steiner, Daniel Morrison, May Li, Keith Walsh, Marina Martinez, Sarah E Baker, Eric M Snyder, Jason H Karnes
Previous studies have shown associations between genetic polymorphisms and pain tolerance, but psychological evaluations are seldom measured. The objective of this study was to determine the independent effects of demographic, psychological and genetic predictors of cold noxious pain tolerance. Healthy subjects (n=89) completed the Pain Catastrophizing Scale (PCS) and Fear of Pain Questionnaire (FPQ-III), underwent genotyping for candidate single nucleotide polymorphisms (SNPs), and completed a cold-pressor test in a 1-2 degrees Celsius water bath for a maximum of three minutes...
November 23, 2018: Clinical and Translational Science
Jim J Xiao, Dorota Nowak, Rodryg Ramlau, Monika Tomaszewska-Kiecana, Piotr J Wysocki, Jeff Isaacson, Jeri Beltman, Eileen Nash, Robert Kaczanowski, Gerhard Arold, Simon Watkins
This phase 1 study (CO-338-044; NCT02740712), conducted in patients with an advanced solid tumor, evaluated the effect of the poly(ADP-ribose) polymerase inhibitor rucaparib on the pharmacokinetics of caffeine 200 mg, warfarin 10 mg, omeprazole 40 mg, and midazolam 2 mg (cytochrome P450 [CYP] 1A2, CYP2C9, CYP2C19, and CYP3A substrates; dosed as a cocktail) and digoxin 0.25 mg (P-glycoprotein substrate; dosed separately) without rucaparib and following oral rucaparib 600 mg twice daily (BID). Geometric mean (GM) ratios (90% CI) of AUC from time zero to last quantifiable measurement with and without rucaparib were: caffeine, 2...
November 14, 2018: Clinical and Translational Science
Douglas Leipold, Saileta Prabhu
The design and development of therapeutic monoclonal antibodies through optimizing their pharmacokinetic (PK) and pharmacodynamic (PD) properties is crucial to improve efficacy while minimizing adverse events. Many of these properties are interdependent, which highlights the inherent challenges in therapeutic antibody design, where improving one antibody property can sometimes lead to changes in others. Here, we discuss optimization approaches for PK/PD properties of therapeutic mAbs. This article is protected by copyright...
November 10, 2018: Clinical and Translational Science
Marina Brockway, Jay W Mason, Brian P Brockway
Since introduction of the ICH proarrhythmia guidelines in 2005, no new marketed drugs have been associated with unacceptable risk of TdP. Although cardiac safety improved, these guidelines had the unintended consequence of eliminating potentially beneficial drugs from pipelines early in development. More recently, it has been shown that a QTc prolonging drug may be safe if it impacts multiple ion channels vs. only hERG and that this effect can be discriminated using QT subintervals. We compared the predictive power of four ECG repolarization metrics to discriminate single vs...
November 10, 2018: Clinical and Translational Science
Christopher P Austin, Christine M Colvis, Noel T Southall
No abstract text is available yet for this article.
November 9, 2018: Clinical and Translational Science
Paul A Clemons
No abstract text is available yet for this article.
November 9, 2018: Clinical and Translational Science
(no author information available yet)
No abstract text is available yet for this article.
November 9, 2018: Clinical and Translational Science
Dan-Dan Tian, Senthil Natesan, John R White, Mary F Paine
The caffeine metabolic ratio is an established marker for cytochrome P450 (CYP) 1A2 activity. Optimal sample size calculation for clinical pharmacokinetic xenobiotic-caffeine interaction studies requires robust estimates of inter- and intraindividual variation in this ratio. Compared to interindividual variation, factors contributing to intraindividual variation are less defined. An exploratory analysis involving healthy nonsmoking non-naïve caffeine drinkers (1-3 cups/day; 12 men, 12 women) administered caffeine (160 mg) on five occasions evaluated the effects of CYP1A2 induction status (based on genotype) and other factors on intraindividual variation in CYP1A2 activity...
November 2, 2018: Clinical and Translational Science
Jay W Mason, Rakesh Chugh, Anasuya Patel, Ranjeet Gutte, Ashima Bhatia
The purpose of this study was to measure the electrocardiographic effects of WCK 2349 (L-alanine ester prodrug of levonadifloxacin) at a supratherapeutic oral dose of 2600 mg. A total of 48 healthy volunteers were randomized to treatment with placebo, WCK 2349 or oral moxifloxacin 400 mg in a crossover designed thorough QT study. A supratherapeutic mean maximum levonadifloxacin concentration (Cmax ) of 43.3 μg/ml was achieved at 3.1 hours. A therapeutic dose of 1000 mg BID in a previous study in patients resulted in a Cmax of 17...
October 28, 2018: Clinical and Translational Science
Molly E McCarthy, Scott P Oltman, Rebecca J Baer, Kelli K Ryckman, Elizabeth E Rogers, Martina A Steurer-Muller, John S Witte, Laura L Jelliffe-Pawlowski
Our objective was to assess the relationship between hyperbilirubinemia with and without kernicterus and metabolic profile at newborn screening. Included were 1,693,658 infants divided into a training or testing subset in a ratio of 3:1. Forty-two metabolites were analyzed using logistic regression (odds ratios (ORs), area under the receiver operating characteristic curve (AUC), 95% confidence intervals (CIs)). Several metabolite patterns remained consistent across gestational age groups for hyperbilirubinemia without kernicterus...
October 28, 2018: Clinical and Translational Science
Emily J Cicali, Kathryn Blake, Yan Gong, Edward B Mougey, Hadeel Al-Atrash, Nancy Chambers, Jolanda Denham, Jonathan Evans, Donald E George, Roberto Gomez, Pablo Palomo, Salik Taufiq, Julie A Johnson, John J Lima, James P Franciosi
The efficacy of proton pump inhibitor (PPI) medications is highly dependent on plasma concentrations, which varies considerably due to cytochrome P450 (CYP2C19) genetic variation. We conducted a pragmatic, pilot study of CYP2C19 genotype-guided pediatric dosing of PPI medications. Children aged 5-17 years old with gastric-acid-related conditions were randomized to receive either conventional dosing of a PPI or genotype-guided dosing for a total of 12 weeks. Sixty children (30 in each arm) were enrolled and had comparable baseline characteristics...
October 20, 2018: Clinical and Translational Science
David R Houck, Laurel Sindelar, Carlos R Sanabria, Stephanie H Stanworth, Maggie Krueger, Mary Suh, Torsten M Madsen
NYX-2925, a new chemical entity, acts as a co-agonist to glutamate at the N-methyl-D-aspartate receptor (NMDAR). At low concentrations of endogenous agonists (glycine/D-serine), NYX-2925 partially activates NMDARs, modulating neural pathways relevant for chronic pain. NYX-2925 is being developed for the treatment of chronic pain conditions, including painful diabetic peripheral neuropathy and fibromyalgia. In this first-in-human, Phase 1, single- (50-1200 mg) and multiple-ascending dose (150-900 mg) study, the safety, tolerability, and pharmacokinetics of NYX-2925 were evaluated in 84 healthy adult volunteers...
September 22, 2018: Clinical and Translational Science
Kazuya Narushima, Hiroshi Maeda, Masanari Shiramoto, Yuichi Endo, Satoko Ohtsuka, Hiroaki Nakamura, Yoshinori Nagata, Tatsuo Uchimura, Ayako Kannami, Ryutaro Shimazaki, Masafumi Fukagawa, Tadao Akizawa
Evocalcet is a novel calcimimetic agent for the treatment of secondary hyperparathyroidism (SHPT). This study evaluated the effects of evocalcet on inhibition and induction of cytochrome P450 (CYP) isozymes. Although drug interactions arising from reversible inhibition of CYP isozymes by evocalcet were considered unlikely based on the results of in vitro studies and static model analyses, the potential for evocalcet to cause time-dependent inhibition of CYP3A or induction of several CYP isozymes could not be ruled out...
September 20, 2018: Clinical and Translational Science
Jianguo Li, Mark Lovern, Michelle L Green, Joannellyn Chiu, Diansong Zhou, Craig Comisar, Yuan Xiong, Jeremy Hing, Merran MacPherson, James G Wright, Todd Riccobene, Timothy J Carrothers, Shampa Das
Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination for the treatment of serious infections caused by resistant gram-negative pathogens. Population pharmacokinetic (PopPK) models were built to incorporate pharmacokinetic (PK) data from five phase III trials in patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), or nosocomial (including ventilator-associated) pneumonia. Ceftazidime and avibactam pharmacokinetics were well-described by two-compartment disposition models, with creatinine clearance (CrCL) the key covariate determining clearance variability...
September 17, 2018: Clinical and Translational Science
(no author information available yet)
No abstract text is available yet for this article.
November 2018: Clinical and Translational Science
Luis G Rodriguez-Cartagena, Bradley S Bowles, Shaheen S Kurani, Anthony J Windebank, Saad S Kenderian, Alexandra J Greenberg-Worisek
No abstract text is available yet for this article.
November 2018: Clinical and Translational Science
Holger Rosenbrock, Michael Desch, Oliver Kleiner, Cornelia Dorner-Ciossek, Bernhard Schmid, Sascha Keller, Christina Schlecker, Viktoria Moschetti, Sophia Goetz, Karl-Heinz Liesenfeld, Gwenaelle Fillon, Riccardo Giovannini, Steven Ramael, Glen Wunderlich, Sven Wind
BI 425809 is a potent and selective glycine transporter 1 (GlyT1) inhibitor being developed for the treatment of cognitive impairment in Alzheimer disease and schizophrenia. Translational studies evaluated the effects of BI 425809 on glycine levels in rat and human cerebrospinal fluid (CSF). Oral administration of BI 425809 in rats induced a dose-dependent increase of glycine CSF levels from 30% (0.2 mg/kg, not significant) to 78% (2 mg/kg, P < 0.01), relative to vehicle. Similarly, oral administration of BI 425809 in healthy volunteers resulted in a dose-dependent increase in glycine CSF levels at steady state, with a mean 50% increase at doses as low as 10 mg...
November 2018: Clinical and Translational Science
Sally A Kinrade, Jay W Mason, Carlos R Sanabria, Craig R Rayner, Julie M Bullock, Stephanie H Stanworth, Mark T Sullivan
Potential effects on cardiac repolarization of single doses of moxidectin, a potent long-acting macrocyclic lactone endectocide, were assessed in a concentration-QT (c-QT; exposure-response) study. This double-blind, placebo-controlled, parallel-group study in healthy male volunteers (n = 60) randomized subjects to a single oral dose of moxidectin (4 mg, 8 mg, 16 mg, 24 mg, or 36 mg) or matching placebo. Serial plasma samples for pharmacokinetic (PK) analysis and concurrent triplicate electrocardiogram measurements were taken at baseline and 14 prespecified time points over 72 hours, yielding 900 QT interval-plasma concentration time-matched pairs...
November 2018: Clinical and Translational Science
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