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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
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.
September 22, 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
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...
August 23, 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...
August 17, 2018: Clinical and Translational Science
Rianne de Ligt, Esther van Duijn, Dimitri Grossouw, Sieto Bosgra, Jacobus Burggraaf, Albert Windhorst, Pierre A M Peeters, Gerrit A van der Luijt, Camilla Alexander-White, Wouter H J Vaes
A clinical pharmacokinetic study was performed in 12 healthy women to evaluate systemic exposure to aluminum following topical application of a representative antiperspirant formulation under real-life use conditions. A simple roll-on formulation containing an extremely rare isotope of aluminum (26 Al) chlorohydrate (ACH) was prepared to commercial specifications. A 26 Al radio-microtracer was used to distinguish dosed aluminum from natural background, using accelerated mass spectroscopy. The 26 Al citrate was administered intravenously (i...
July 27, 2018: Clinical and Translational Science
Jie Shen, Brandon Swift, Richard Mamelok, Samuel Pine, John Sinclair, Mayssa Attar
A milestone step in translational science to transform basic scientific discoveries into therapeutic applications is the advancement of a drug candidate from preclinical studies to initial human testing. First-in-human (FIH) trials serve as the link to advance new promising drug candidates and are conducted primarily to determine the safe dose range for further clinical development. Cross-functional collaboration is essential to ensure efficient and successful FIH trials. The aim of this publication is to serve as a tutorial for conducting FIH trials for both small molecule and biological drug candidates with topics covering regulatory requirements, preclinical safety testing, study design considerations, safety monitoring, biomarker assessment, and global considerations...
July 26, 2018: Clinical and Translational Science
Jaime A Aponte Ortiz, Ewa Konik, Elizabeth C Eckert, Kay M Pepin, Alexandra Greenberg-Worisek
No abstract text is available yet for this article.
September 2018: Clinical and Translational Science
Jeffrey L Woodhead, Franziska Paech, Martina Maurer, Marc Engelhardt, Anne H Schmitt-Hoffmann, Jochen Spickermann, Simon Messner, Mathias Wind, Anne-Therese Witschi, Stephan Krähenbühl, Scott Q Siler, Paul B Watkins, Brett A Howell
Elevations of liver enzymes have been observed in clinical trials with BAL30072, a novel antibiotic. In vitro assays have identified potential mechanisms for the observed hepatotoxicity, including electron transport chain (ETC) inhibition and reactive oxygen species (ROS) generation. DILIsym, a quantitative systems pharmacology (QSP) model of drug-induced liver injury, has been used to predict the likelihood that each mechanism explains the observed toxicity. DILIsym was also used to predict the safety margin for a novel BAL30072 dosing scheme; it was predicted to be low...
September 2018: Clinical and Translational Science
Valérie Cosson, Franziska Schaedeli-Stark, Mona Arab-Alameddine, Clarisse Chavanne, Elena Guerini, Michael Derks, Navita L Mallalieu
Dizziness, the most frequently observed adverse event in patients with major depressive disorder, was observed with basimglurant, a selective, orally active metabotropic glutamate receptor subtype 5 negative allosteric modulator. The potential relationship between dizziness and basimglurant exposure was explored. The pharmacokinetics of basimglurant was characterized with nonlinear mixed effects modeling using data from 288 trial participants enrolled in five clinical trials. The pharmacokinetics of basimglurant after daily oral administration of a modified release formulation was best described by a two-compartment disposition model with a transit compartment, lag time for the absorption, and first-order elimination...
September 2018: Clinical and Translational Science
Jeremiah Hadwen, Faraz Farooq, Luke Witherspoon, Sarah Schock, Kevin Mongeon, Alex MacKenzie
Duchenne muscular dystrophy is a recessive X-linked disease characterized by progressive muscle wasting; cardiac or respiratory failure causes death in most patients by the third decade.  The disease is caused by mutations in the dystrophin gene that lead to a loss of functional dystrophin protein. Although there are currently few treatments for Duchenne muscular dystrophy, previous reports have shown that upregulating the dystrophin paralog utrophin in Duchenne muscular dystrophy mouse models is a promising therapeutic strategy...
September 2018: Clinical and Translational Science
Pearl A McElfish, Christopher R Long, James P Selig, Brett Rowland, Rachel S Purvis, Laura James, Angel Holland, Holly C Felix, Marie-Rachelle Narcisse
Prior research suggests that rural and minority communities participate in research at lower rates. While rural and minority populations are often cited as being underrepresented in research, population-based studies on health research participation have not been conducted. This study used questions added to the 2015 Behavioral Risk Factor Surveillance System to understand factors associated with i) health research participation, ii) opportunities to participate in health research, and iii) willingness to participate in health research from a representative sample (n = 5,256) of adults in Arkansas...
September 2018: Clinical and Translational Science
Yasuyuki Ishii, Yuko Ito, Shunji Matsuki, Kasumi Sanpei, Osamu Ogawa, Kenji Takeda, Edgar L Schuck, Naoto Uemura
BFE1224, prodrug of ravuconazole, is a novel, once-daily, oral, triazole antifungal drug, and currently in development for the treatment of onychomycosis. The clinical drug-drug interaction (DDI) potential of BFE1224 with cytochrome P450 (CYP) and transporter was assessed by using two types of cocktails in healthy subjects in separate clinical studies. The CYP and transporter cocktails consisted of caffeine/tolbutamide/omeprazole/dextromethorphan/midazolam used in study 1 and digoxin/rosuvastatin used in study 2...
September 2018: Clinical and Translational Science
Brandon Swift, Lokesh Jain, Craig White, Vasu Chandrasekaran, Aman Bhandari, Dyfrig A Hughes, Pravin R Jadhav
While efficacy and safety data collected from randomized clinical trials are the evidentiary standard for determining market authorization, this alone may no longer be sufficient to address the needs of key stakeholders (regulators, providers, and payers) and guarantee long-term success of pharmaceutical products. There is a heightened interest from stakeholders on understanding the use of real-world evidence (RWE) to substantiate benefit-risk assessment and support the value of a new drug. This review provides an overview of real-world data (RWD) and related advances in the regulatory framework, and discusses their impact on clinical research and development...
September 2018: Clinical and Translational Science
Gemma L Clayton, Asher D Schachter, Baldur Magnusson, Yue Li, Laurence Colin
Clinicians working on first-in-human clinical studies need to be able to judge whether safety signals observed on an investigational drug were more likely to have occurred by chance or to have been caused by the drug. We retrospectively reviewed 84 Novartis studies including 1,234 healthy volunteers receiving placebo to determine the expected incidence of changes in commonly measured laboratory parameters and vital signs, in the absence of any active agent. We calculated the frequency of random incidence of safety signals, focusing on the liver, cardiovascular system, kidney, and pancreas...
September 2018: Clinical and Translational Science
Hwa-Ping Feng, Zifang Guo, Luzelena Caro, William L Marshall, Fang Liu, Deborah Panebianco, Pavan Vaddady, Christina Reitmann, Patricia Jumes, Dennis Wolford, Iain Fraser, Robert Valesky, Monika Martinho, Joan R Butterton, Marian Iwamoto, Lynn Webster, Wendy W Yeh
We conducted two phase I trials to evaluate the pharmacokinetic interactions between elbasvir (EBR), grazoprevir (GZR), and methadone (MK-8742-P010 and MK-5172-P030) in non-hepatitis C virus (HCV)-infected participants on methadone maintenance therapy. Coadministration of EBR or GZR with methadone had no clinically meaningful effect on EBR, GZR, or methadone pharmacokinetics. The geometric mean ratios (GMRs) for R- and S-methadone AUC0-24 were 1.03 (90% confidence interval (CI), 0.92-1.15) and 1.09 (90% CI, 0...
July 24, 2018: Clinical and Translational Science
Hwa-Ping Feng, Zifang Guo, Luzelena Caro, William L Marshall, Fang Liu, Deborah Panebianco, Pavan Vaddady, April Barbour, Christina Reitmann, Patricia Jumes, Jocelyn Gilmartin, Dennis Wolford, Robert Valesky, Monika Martinho, Joan R Butterton, Marian Iwamoto, Iain Fraser, Lynn Webster, Wendy W Yeh
The aims of these phase I trials were to evaluate the pharmacokinetic interaction between elbasvir (EBR) or grazoprevir (GZR) and buprenorphine/naloxone (BUP/NAL). Trial 1 was a single-dose trial in healthy participants. Trial 2 was a multiple-dose trial in participants on BUP/NAL maintenance therapy. Coadministration of EBR or GZR with BUP/NAL had minimal effect on the pharmacokinetics of BUP/NAL, EBR, and GZR. The geometric mean ratios (GMRs (90% CI)) for BUP, norbuprenorphine, and NAL AUC0-∞ were 0.98 (0...
July 24, 2018: Clinical and Translational Science
Sarah Robertson
No abstract text is available yet for this article.
July 10, 2018: Clinical and Translational Science
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