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Clinical and Translational Science

Nathan P Coussens, G Sitta Sittampalam, Rajarshi Guha, Kyle Brimacombe, Abigail Grossman, Thomas D Y Chung, Jeffrey R Weidner, Terry Riss, O Joseph Trask, Douglas Auld, Jayme L Dahlin, Viswanath Devanaryan, Timothy L Foley, James McGee, Steven D Kahl, Stephen C Kales, Michelle Arkin, Jonathan Baell, Bruce Bejcek, Neely Gal-Edd, Marcie Glicksman, Joseph V Haas, Philip W Iversen, Marilu Hoeppner, Stacy Lathrop, Eric Sayers, Hanguan Liu, Bart Trawick, Julie McVey, Vance P Lemmon, Zhuyin Li, Owen McManus, Lisa Minor, Andrew Napper, Mary Jo Wildey, Robert Pacifici, William W Chin, Menghang Xia, Xin Xu, Madhu Lal-Nag, Matthew D Hall, Sam Michael, James Inglese, Anton Simeonov, Christopher P Austin
The Assay Guidance Manual (AGM) is an eBook of best-practices for the design, development, and implementation of robust assays for early drug discovery. Initiated by pharmaceutical company scientists, the manual provides guidance for designing a "testing funnel" of assays to identify genuine hits using high-throughput screening (HTS) and advancing them through pre-clinical development. Combined with a workshop/tutorial component, the overall goal of the AGM is to provide a valuable resource for training translational scientists...
June 7, 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...
June 7, 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 (MDD), 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. Pharmacokinetics (PK) of basimglurant was characterized with nonlinear mixed effects modeling using data from 288 trial participants enrolled in five clinical trials. The PK 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...
June 7, 2018: Clinical and Translational Science
Meric Ovacik, Kedan Lin
The tutorial introduces the readers to the fundamentals of antibody pharmacokinetics (PK) in the context of drug development. Topics covered include an overview of antibody development, PK characteristics and the application of antibody PK/Pharmacodynamics (PD) in research and development decision-making. We also discuss the general considerations for planning a nonclinical PK program and describe the types of PK studies that should be performed during early development of monoclonal antibodies (mAbs). This article is protected by copyright...
June 7, 2018: Clinical and Translational Science
Abdul Basit, John K Amory, Bhagwat Prasad
Development of an oral testosterone (T) therapy has proven extremely challenging because of extensive and variable first-pass metabolism. We investigated the in vivo metabolism of T with increasing oral doses of T, both alone and with the co-administration of dutasteride (5α-reductase inhibitor) by LC-MS/MS. In eugonadal men prior to dosing, the circulating concentration of T, androstenedione, etiocholanolone-glucuronide, and androsterone-glucuronide was 8.6, 20.9, 9.1 and 55.3%, respectively, of the total T-related species, whereas T-glucuronide was ∼1%...
June 7, 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...
June 7, 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...
May 17, 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...
May 16, 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...
May 16, 2018: Clinical and Translational Science
Tessa van der Kolk, Salma Assil, Rianne Rijneveld, Erica S Klaassen, Gary Feiss, Edwin Florencia, Errol P Prens, Jacobus Burggraaf, Matthijs Moerland, Robert Rissmann, Martijn B A van Doorn
Imiquimod (IMQ) is often used as topical challenge agent to provoke local skin inflammation. The objective of this study was to develop and refine a rapid, temporary and reversible human skin inflammation model with IMQ for application in clinical drug development. A randomized, vehicle-controlled, open-label, dose-ranging study was conducted in 16 healthy male subjects. IMQ (5 mg) was applied once daily for 72h under occlusion to intact skin (n = 8) or tape stripped (TS) skin (n = 8). Although IMQ alone induced limited effects, TS+IMQ treatment showed larger responses in several domains including erythema and perfusion (p<0...
May 16, 2018: Clinical and Translational Science
Tao Liu, Vijay Ivaturi, Philip Sabato, Jogarao V S Gobburu, Jacqueline M Greer, John J Wright, B Douglas Smith, Keith W Pratz, Michelle A Rudek
Sorafenib administered at the approved dose continuously is not tolerated long-term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure-response relationship in patients with AML. A one-compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS-like tyrosine kinase 3 (FLT3)-ITD and extracellular signal-regulated kinase (ERK)) were described by an inhibitory maximum effect (Emax ) model...
April 27, 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...
April 27, 2018: Clinical and Translational Science
Yang He, Dong-Hui Ao, Xiao-Qing Li, Shan-Shan Zhong, Rong A, Yang-Yang Wang, Ya-Juan Xiang, Bao-Lei Xu, Ting-Ting Yang, Xu-Guang Gao, Guang-Zhi Liu
As a proinflammatory cytokine, CD137 (4-1BB, TNFRSF9) is present in membrane-bound and soluble forms. Increased expression of CD137 was recently found in T cells in human atherosclerotic plaques. However, the exact role of CD137 in ischemic stroke is not clear. In this study we analyzed the protein levels of soluble CD137 (sCD137) and the expression of CD137 on CD4+ T cells in the peripheral blood of patients with acute atherothrombotic stroke by using the cytometry beads array (CBA) and flow cytometry. Within 24 hours of onset, the stroke patients showed elevated levels of sCD137 (2...
April 26, 2018: Clinical and Translational Science
Lynn D Hudson, Rebecca D Kush, Eileen Navarro Almario, Nathalie Seigneuret, Tammy Jackson, Barbara Jauregui, David Jordan, Ronald Fitzmartin, F Liz Zhou, James K Malone, Jose Galvez, Lauren B Becnel
No abstract text is available yet for this article.
April 26, 2018: Clinical and Translational Science
Jessica K Juarez, Joseph C Wenke, Jessica C Rivera
No abstract text is available yet for this article.
April 26, 2018: Clinical and Translational Science
Michael J Jelinek, Sang Mee Lee, Alicia Wyche Okpareke, Claudia Wing, Jay L Koyner, Patrick T Murray, Walter M Stadler, Peter H O' Donnell
Acute kidney injury (AKI) limits cisplatin use. We tested whether urine cystatin C (uCyC) and neutrophil gelatinase-associated lipocalin (uNGAL) can preidentify patients at risk for AKI. Patients initiating cisplatin-based chemotherapy were prospectively enrolled. uNGAL/uCyC were measured pre/post-cisplatin administration and compared with serum creatinine (sCr). AKI was defined as sCr increase ≥50% or ≥0.3 mg/dL above baseline. In all, 102 patients were enrolled; 95 provided evaluable data. Twenty-five patients developed AKI...
April 24, 2018: Clinical and Translational Science
Pascale Fisel, Elke Schaeffeler, Matthias Schwab
The solute carrier (SLC) SLC16 gene family comprises 14 members and encodes for monocarboxylate transporters (MCTs), which mediate the absorption and distribution of monocarboxylic compounds across plasma membranes. As the knowledge about their physiological function, activity, and regulation increases, their involvement and contribution to cancer and other diseases become increasingly evident. Moreover, promising opportunities for therapeutic interventions by directly targeting their endogenous functions or by exploiting their ability to deliver drugs to specific organ sites emerge...
April 16, 2018: Clinical and Translational Science
Marc Cantillon, Robert Ings, Laxminarayan Bhat
RP5063 is a multimodal dopamine (D)-serotonin (5-HT) stabilizer with a high affinity for D2/3/4 and 5-HT1A/2A/2B/7 receptors and moderate affinity for the serotonin transporter. Single-dose (10 and 15 mg fasting, 15 mg fed) safety in healthy volunteers and multiple-dose (10, 20, 50, and 100 mg fed, 10 days) safety and pharmacodynamics in patients with stable schizophrenia were defined in two phase I studies. In the single-dose study, 32 treatment-emergent adverse events (TEAEs) were observed. Orthostatic hypotension (n = 6), nausea (n = 5), and dizziness (n = 4) were the most common...
April 10, 2018: Clinical and Translational Science
Christopher Cabanski, Houston Gilbert, Sofia Mosesova
Visualizations are a powerful tool for telling a story about a data set or analysis. If done correctly, visualizations not only display data but also help the audience digest key information. However, if done haphazardly, visualization has the potential to confuse the audience and, in the most extreme circumstances, deceive. In this tutorial, we provide a set of general principles for creating informative visualizations that tell a complete and accurate story of the data.
March 30, 2018: Clinical and Translational Science
Shlomit Radom-Aizik, Frank P Zaldivar, Dwight M Nance, Fadia Haddad, Dan M Cooper, Gregory R Adams
Advances in therapies have led to prolonged survival from many previously lethal health threats in children, notably among prematurely born babies and those with congenital heart disease. Evidence for catch-up growth is common in these children, but in many cases the adult phenotype is never achieved. A translational animal model is required in which specific tissues can be studied over a reasonable time interval. We investigated the impact of postnatal hypoxia (HY) (12%O2 (HY12) or 10% O2 (HY10)) on growth in rats relative to animals raised in room air...
March 30, 2018: Clinical and Translational Science
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