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Clinical and Translational Science

David S Goldstein, Courtney Holmes, Jamie Cherup, Yehonatan Sharabi
Olives contain 3,4-dihydroxyphenyl compounds (catechols)-especially 3,4-dihydroxyphenylethanol (DOPET)-that have therapeutic potential as nutraceuticals. Whether olive ingestion affects plasma levels of free (unconjugated) catechols has been unknown. Arm venous blood was sampled before and 15, 30, 45, 60, 120, 180, and 240 min after six healthy volunteers ate 10 Kalamata olives. Catechols were assayed by alumina extraction followed by liquid chromatography with series electrochemical detection. Plasma DOPET increased to 18...
September 12, 2017: Clinical and Translational Science
Ferdinand C Breedveld, Heather E Jones, Kim Peifer, Joan Korth-Bradley
A randomized, parallel-dose study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of etanercept in 61 patients with rheumatoid arthritis (RA) who received doses from 10 mg once-weekly to 50 mg twice-weekly for 4 weeks. Empiric application of a maximal-effect (Emax ) model to pooled steady-state concentrations (Css ) and PD markers provided half-maximal-effect concentration estimates of 567, 573, 465, 87, and 159 ng/mL for change from baseline in number of swollen joints, number of painful joints, erythrocyte sedimentation rate, interleukin-6, and matrix metalloproteinase-3, respectively...
September 11, 2017: Clinical and Translational Science
Douglas A Luke, Cathy C Sarli, Amy M Suiter, Bobbi J Carothers, Todd B Combs, Jae L Allen, Courtney E Beers, Bradley A Evanoff
We report the development of the Translational Science Benefits Model (TSBM), a framework designed to support institutional assessment of clinical and translational research outcomes to measure clinical and community health impacts beyond bibliometric measures. The TSBM includes 30 specific and potentially measurable indicators that reflect benefits that accrue from clinical and translational science research such as products, system characteristics, or activities. Development of the TSBM was based on literature review, a modified Delphi method, and in-house expert panel feedback...
September 8, 2017: Clinical and Translational Science
Yan Jin, Claire Smith, Leijun Hu, David E Coutant, Kelly Whitehurst, Krista Phipps, Terry Ann McNearney, Xiao Yang, Bradley Ackermann, Thomas Pottanat, William Landschulz
Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator-blind, parallel-group, multiple-ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib. LY3127760 increased release of ex vivo tumor necrosis factor alpha after lipopolysaccharide/prostaglandin E2 stimulation when compared with placebo, suggesting a dose-dependent blockade of the EP4 receptor...
August 30, 2017: Clinical and Translational Science
Daniel Gonzalez, Gauri G Rao, Stacy C Bailey, Kim L R Brouwer, Yanguang Cao, Daniel J Crona, Angela D M Kashuba, Craig R Lee, Kathryn Morbitzer, J Herbert Patterson, Tim Wiltshire, Jon Easter, Scott W Savage, J Robert Powell
No abstract text is available yet for this article.
August 10, 2017: Clinical and Translational Science
Christopher P Austin, Christine M Cutillo, Lilian Pl Lau, Anneliene H Jonker, Ana Rath, Daria Julkowska, David Thomson, Sharon Terry, Beatrice de Montleau, Diego Ardigò, Virginie Hivert, Kym M Boycott, Gareth Baynam, Petra Kaufmann, Domenica Taruscio, Hanns Lochmüller, Makoto Suematsu, Carlo Incerti, Ruxandra Draghia-Akli, Irene Norstedt, Lu Wang, Hugh Js Dawkins
Due to the remarkable global surge in activity in rare diseases research over the last six years, including contributions by the International Rare Diseases Research Consortium (IRDiRC), the Consortium's 2020 goals have been largely achieved by 2017. Though these developments are gratifying, enormous challenges remain. With this paradox in mind, IRDiRC set new global rare disease goals for the coming decade with the ultimate aim of improved health for people living with rare diseases worldwide. This article is protected by copyright...
August 10, 2017: Clinical and Translational Science
L Caro, J de Hoon, M Depré, C Cilissen, J Miller, W Gao, D Panebianco, Z Guo, S L Troemel, M S Anderson, N Uemura, J Butterton, J Wagner, D H Wright
Vaniprevir is an inhibitor of the hepatitis C virus (HCV) NS3/4A protease. The aim of these double-blind, placebo-controlled phase I studies was to evaluate the safety and pharmacokinetics of vaniprevir in healthy male volunteers. The primary objective for both studies was the safety and tolerability of vaniprevir. Single-dose and steady-state pharmacokinetics were also assessed. In both studies, there was no apparent relationship between the frequency or intensity of adverse events and vaniprevir dose. At single doses >20 mg, the plasma area under the curve (AUC)0-∞ and maximum concentration (Cmax ) increased in a greater-than-dose-proportional manner...
August 10, 2017: Clinical and Translational Science
Hugh Js Dawkins, Ruxandra Draghia-Akli, Paul Lasko, Lilian Pl Lau, Anneliene H Jonker, Christine M Cutillo, Ana Rath, Kym M Boycott, Gareth Baynam, Hanns Lochmüller, Petra Kaufmann, Yann Le Cam, Virginie Hivert, Christopher P Austin
In 2011, the International Rare Diseases Research Consortium (IRDiRC) was formed to unite public and private sector funders of research, patient advocacy groups, and scientific researchers to advance rare diseases research worldwide. Six years after its official launch, IRDiRC is now reflecting on its progress and achievements toward its ambitious goals for the rare diseases research collective - to develop 200 new therapies and the means to diagnose most rare genetic diseases by the year 2020. This article is protected by copyright...
August 10, 2017: Clinical and Translational Science
Richard L Dunbar, Rajesh Movva, LeAnne T Bloedon, Danielle Duffy, Robert B Norris, Mohamad Navab, Alan M Fogelman, Daniel J Rader
A single dose of the apolipoprotein (apo)A-I mimetic peptide D-4F rendered high-density lipoprotein (HDL) less inflammatory, motivating the first multiple-dose study. We aimed to assess safety/tolerability, pharmacokinetics, and pharmacodynamics of daily, orally administered D-4F. High-risk coronary heart disease (CHD) subjects added double-blinded placebo or D-4F to statin for 13 days, randomly assigned 1:3 to ascending cohorts of 100, 300, then 500 mg (n = 62; 46 men/16 women). D-4F was safe and well-tolerated...
August 9, 2017: Clinical and Translational Science
Kimberly E Maxfield, ShaAvhrée Buckman-Garner, Ameeta Parekh
No abstract text is available yet for this article.
August 3, 2017: Clinical and Translational Science
Jeffrey Cummings
No abstract text is available yet for this article.
August 2, 2017: Clinical and Translational Science
Emily K Acton, Charles E Leonard, Warren B Bilker, Shobha Phansalkar, Sean Hennessy
We sought to assess whether a high-profile publication that demonstrated serious clinical consequences of specific drug-drug interactions (DDIs) reduced the concomitant use of those drugs. We conducted a quasi-experimental study using 2000-2008 prescription claims from a commercial health insurer to examine trends in the dispensing of the interacting drug pairs (angiotensin-converting enzyme inhibitors[ACEI] + potassium-sparing diuretic, digoxin + clarithromycin, and glyburide + cotrimoxazole) and control drug pairs previously reported in a top-tier general medicine journal...
July 28, 2017: Clinical and Translational Science
J Kevin Hicks, Amy Shealy, Allison Schreiber, Marissa Coleridge, Ryan Noss, Marvin Natowicz, Rocio Moran, Timothy Moss, Angelika Erwin, Charis Eng
Whole exome sequencing (WES) has the potential of identifying secondary findings that are predictive of poor pharmacotherapy outcomes. The purpose of this study was to investigate patients' wishes regarding the reporting of secondary pharmacogenomic findings. WES results (n = 106 patients) were retrospectively reviewed to determine the number of patients electing to receive secondary pharmacogenomic results. Phenotypes were assigned based on Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines...
July 27, 2017: Clinical and Translational Science
Maria M Posada, Ellen A Cannady, Christopher D Payne, Xin Zhang, James A Bacon, Y Anne Pak, J William Higgins, Nazila Shahri, Stephen D Hall, Kathleen M Hillgren
Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, undergoes active renal tubular secretion. Baricitinib was not predicted to inhibit hepatic and renal uptake and efflux drug transporters, based on the ratio of the unbound maximum eliminating-organ inlet concentration and the in vitro half-maximal inhibitory concentrations (IC50 ). In vitro, baricitinib was a substrate for organic anion transporter (OAT)3, multidrug and toxin extrusion protein (MATE)2-K, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP)...
July 27, 2017: Clinical and Translational Science
Daniela J Conrado, Timothy Nicholas, Kuenhi Tsai, Sreeraj Macha, Vikram Sinha, Julie Stone, Brian Corrigan, Massimo Bani, Pierandrea Muglia, Ian A Watson, Volker D Kern, Elena Sheveleva, Kenneth Marek, Diane T Stephenson, Klaus Romero
Given the recognition that disease-modifying therapies should focus on earlier Parkinson's disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinson's disease clinical trials. Patient-level longitudinal data of 672 subjects with early-stage Parkinson's disease in the Parkinson's Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed-effects model analysis...
July 27, 2017: Clinical and Translational Science
M D Joshi, J N O'Donnell, N Venkatesan, J Chang, H Nguyen, N J Rhodes, G Pais, R L Chapman, B Griffin, M H Scheetz
A translational need exists to understand and predict vancomycin-induced kidney toxicity. We describe: (i) a vancomycin high-performance liquid chromatography (HPLC) method for rat plasma and kidney tissue homogenate; (ii) a rat pharmacokinetic (PK) study to demonstrate utility; and (iii) a catheter retention study to enable future preclinical studies. Rat plasma and pup kidney tissue homogenate were analyzed via HPLC for vancomycin concentrations ranging from 3-75 and 15.1-75.5 μg/mL, respectively, using a Kinetex Biphenyl column and gradient elution of water with 0...
July 4, 2017: Clinical and Translational Science
Koichi Miyazaki, Yasunori Sato, Hideki Hanaoka, Yoshiaki Uyama
When global clinical trials are carried out, it is important to consider the influence of racial and ethnic differences on the outcome. From this viewpoint, global clinical trials in East Asia, where racial differences are estimated to be small, are now attracting close attention. Under such circumstances, we conducted a survey using the data registered with to investigate the status of participation of East Asian countries in global clinical trials and differences in the regions selected for drug development between Japanese enterprises and non-Japanese enterprises...
July 4, 2017: Clinical and Translational Science
T Burt, K S Button, Hhz Thom, R J Noveck, M R Munafò
The "false-negatives" of clinical development are the effective treatments wrongly determined ineffective. Statistical errors leading to "false-negatives" are larger than those leading to "false-positives," especially in typically underpowered early-phase trials. In addition, "false-negatives" are usually eliminated from further testing, thereby limiting the information available on them. We simulated the impact of early-phase power on economic productivity in three developmental scenarios. Scenario 1, representing the current status quo, assumed 50% statistical power at phase II and 90% at phase III...
July 4, 2017: Clinical and Translational Science
K Erb-Zohar, D Kropeit, J Scheuenpflug, H-P Stobernack, Egj Hulskotte, A van Schanke, H Zimmermann, H Rübsamen-Schaeff
Letermovir is a novel antiviral in clinical development for prophylaxis against human cytomegalovirus in immunocompromised transplant recipients. This two-part, single-center, randomized, double-blind, placebo-controlled trial evaluated the safety and pharmacokinetics of a hydroxypropyl β-cyclodextrin (HPβCD)-based intravenous formulation of letermovir in healthy women. Subjects received single, escalating doses (120, 240, 480, 720, and 960 mg; 6 letermovir, 2 placebo per cohort) or multiple, once-daily doses (240 mg; 8 letermovir, 4 placebo) of HPβCD-formulated letermovir and the associated pharmacokinetic profiles and adverse events were investigated...
July 4, 2017: Clinical and Translational Science
A W Krug, P Vaddady, R A Railkar, B J Musser, J Cote, Agh Ederveen, D G Krefetz, E DeNoia, A L Free, L Morrow, M V Chakravarthy, E Kauh, D A Tatosian, P A Kothare
GPR40 mediates free fatty acid-induced insulin secretion in beta cells. We investigated the safety, pharmacokinetics, and glucose response of MK-8666, a partial GPR40 agonist, after once-daily multiple dosing in type 2 diabetes patients. This double-blind, multisite, parallel-group study randomized 63 patients (placebo, n = 18; 50 mg, n = 9; 150 mg, n = 18; 500 mg, n = 18) for 14-day treatment. The results showed no serious adverse effects or treatment-related hypoglycemia. One patient (150-mg group) showed mild-to-moderate transaminitis at the end of dosing...
September 2017: Clinical and Translational Science
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