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Fernando Alfonso, Marcos García-Guimaraes, Teresa Bastante, Esther González-Bartol, Javier Cuesta, Fernando Rivero
No abstract text is available yet for this article.
March 13, 2018: Coronary Artery Disease
Valeria Paradies, Ori Ben-Yehuda, Michael Jonas, Shmuel Banai, Andres Iñiguez, Gidon Y Perlman, David E Kandzari, Gregg W Stone, Pieter C Smits
AIMS: To evaluate the efficacy and safety of the BioNIR stent compared with the Resolute stent for the treatment of coronary artery disease. METHODS AND RESULTS: This first-in-human, multicenter, single-blind randomized non-inferiority trial was performed in Europe and Israel. Patients with stable coronary artery disease or acute coronary syndromes (ACS) were randomly assigned to treatment with BioNIR or Resolute stents in a 2:1 fashion. The primary endpoint was angiographic in-stent late lumen loss (LLL) at 6 months...
March 13, 2018: EuroIntervention
Jessica Wagner, C Leah Kline, Lanlan Zhou, Kerry S Campbell, Alexander W MacFarlane, Anthony J Olszanski, Kathy Q Cai, Harvey H Hensley, Eric A Ross, Marie D Ralff, Andrew Zloza, Charles B Chesson, Jenna H Newman, Howard Kaufman, Joseph R Bertino, Mark N Stein, Wafik El-Deiry
ONC201 is a first-in-class, orally active anti-tumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in the first-in-human trial where patients were dosed every 3 weeks. We hypothesized that dose-intensification of ONC201 may impact anti-tumor efficacy. We discovered that ONC201 exerts dose- and schedule-dependent effects on tumor progression and cell-death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion...
March 13, 2018: Journal of Clinical Investigation
Tomas Majtan, Erez M Bublil, Insun Park, Erland Arning, Teodoro Bottiglieri, Frank Glavin, Jan P Kraus
AIMS: PEGylated human truncated cystathionine beta-synthase, lacking the C-terminal regulatory domain (PEG-CBS), is a promising preclinical candidate for enzyme replacement therapy in homocystinuria (HCU). It was designed to function as a metabolic sink to decrease the severely elevated plasma and tissue homocysteine concentrations. Here we evaluated pharmacokinetics (PK), pharmacodynamics (PD) and sub-chronic toxicity of PEG-CBS in homocystinuric mice and wild type rats and monkeys to estimate the minimum human efficacious dose for clinical trials...
March 8, 2018: Life Sciences
Eric P Hoffman, Valerie Riddle, Maxime A Siegler, Daniel Dickerson, Miroslav Backonja, William G Kramer, Kanneboyina Nagaraju, Heather Gordish-Dressman, Jesse M Damsker, John M McCall
BACKGROUND: Glucocorticoid drugs are highly effective anti-inflammatory agents, but chronic use is associated with extensive pharmacodynamic safety concerns that have a considerable negative impact on patient quality of life. PURPOSE: Vamorolone (VBP15) is a first-in-class steroidal multi-functional drug that shows potent inhibition of pro-inflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor, high affinity antagonism for the mineralocorticoid receptor, and membrane stabilization properties...
March 7, 2018: Steroids
Dean F Wong, Hiroto Kuwabara, Andrew G Horti, Joshua M Roberts, Ayon Nandi, Nicola Casella, James Brasic, Elise M Weerts, Kelly Kitzmiller, Jenny A Phan, Lorena Gapasin, Akira Sawa, Heather Valentine, Gary Wand, Noble George, Michael McDonald, William Kem, Robert Freedman, Albert Gjedde
Background: The α7 nicotinic acetylcholine receptor (nAChR) increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The highly cortical distribution of α7-nAChR suggests a role in cognition. Methods: We expanded the first-in-human PET imaging of α7-nAChR with [18F]ASEM from five to 21 healthy non-smoking volunteers and added a feasibility study in six male patients with schizophrenia. Study aims included 1) confirmation of test-retest reproducibility of [18F]ASEM binding, 2) demonstration of specificity by competition with DMXB-A, an α7-nAChR partial agonist, 3) estimation of [18F]ASEM binding potentials and α7-nAChR density in vivo in humans, and 4) demonstrating the feasibility of studying α7-nAChR as a target for schizophrenia...
March 7, 2018: International Journal of Neuropsychopharmacology
Arvind Bhimaraj, Barry Trachtenberg, Miguel Valderrábano
No abstract text is available yet for this article.
March 2018: Circulation. Heart Failure
Hans Ericsson, Karin Nelander, Maria Lagerstrom-Fermer, Clare Balendran, Maria Bhat, Ligia Chialda, Li-Ming Gan, Maria Heijer, Magnus Kjaer, John Lambert, Eva-Lotte Lindstedt, Gun-Britt Forsberg, Carl Whatling, Stanko Skrtic
We evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD5718, a novel 5-lipooxygenase activating protein (FLAP) inhibitor, in a randomized, single-blind, placebo-controlled, first-in-human (FIH) study consisting of single and multiple ascending dosing (SAD and MAD) for 10 days in healthy subjects. Target engagement was measured by ex vivo calcium ionophore stimulated leukotriene B (LTB4 ) production in whole blood and endogenous leukotriene E (LTE4 ) in urine. No clinically relevant safety and tolerability findings were observed...
March 8, 2018: Clinical and Translational Science
Vikash Reebye, Kai-Wen Huang, Vivian Lin, Sheba Jarvis, Pedro Cutilas, Stephanie Dorman, Simona Ciriello, Pinelopi Andrikakou, Jon Voutila, Pal Saetrom, Paul J Mintz, Isabella Reccia, John J Rossi, Hans Huber, Robert Habib, Nikos Kostomitsopoulos, David C Blakey, Nagy A Habib
Liver diseases are a growing epidemic worldwide. If unresolved, liver fibrosis develops and can lead to cirrhosis and clinical decompensation. Around 5% of cirrhotic liver diseased patients develop hepatocellular carcinoma (HCC), which in its advanced stages has limited therapeutic options and negative survival outcomes. CEPBA is a master regulator of hepatic function where its expression is known to be suppressed in many forms of liver disease including HCC. Injection of MTL-CEBPA, a small activating RNA oligonucleotide therapy (CEBPA-51) formulated in liposomal nanoparticles (NOV340- SMARTICLES) upregulates hepatic CEBPA expression...
March 7, 2018: Oncogene
Anthony Tolcher, Keith Flaherty, Geoffrey I Shapiro, Jordan Berlin, Thomas Witzig, Thomas Habermann, Andrea Bullock, Edwin Rock, Agnes Elekes, Chester Lin, Dusan Kostic, Naoto Ohi, Drew Rasco, Kyriakos P Papadopoulos, Amita Patnaik, Lon Smith, Gregory M Cote
LESSONS LEARNED: OPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation that exhibited promising anticancer activity in preclinical models.In this first-in-human phase I study of OPB-111077 in unselected advanced cancers, treatment-emergent adverse events, most frequently nausea, fatigue, and vomiting, were generally mild to moderate in intensity and could be medically managed.Overall, only modest clinical activity was observed after OPB-111077 given as monotherapy...
March 6, 2018: Oncologist
D Kuah, S Sivell, T Longworth, K James, A Guermazi, F Cicuttini, Y Wang, S Craig, G Comin, D Robinson, J Wilson
BACKGROUND: Cell therapies are being investigated as potential disease modifying treatment options for osteoarthritis (OA). Progenza (PRG) comprises in vitro expanded mesenchymal stem cells derived from human donor adipose tissue combined with cell culture supernatant. The primary objective of this first-in-human study was to evaluate the safety and tolerability of PRG. METHODS: We conducted a single centre, randomized, double-blind, placebo-controlled, single ascending dose study...
March 6, 2018: Journal of Translational Medicine
Maarten Timmers, Vikash Sinha, Borje Darpo, Brian Smith, Randy Brown, Hongqi Xue, Georg Ferber, Johannes Streffer, Alberto Russu, Luc Tritsmans, Bhavna Solanki, Jennifer Bogert, Luc Van Nueten, Giacomo Salvadore, Partha Nandy
Nonclinical assays with JNJ-54861911, a β-secretase 1 inhibitor have indicated that at high concentrations, it may delay cardiac repolarization. A 4-way crossover thorough QT (TQT) study was performed in 64 healthy subjects with 50 and 150 mg JNJ-54861911 once daily for 7 days, placebo, and 400 mg moxifloxacin. Retrospective high-precision QT (HPQT) analysis was performed on serial elecrocardiograms extracted from first-in-human single-ascending dose (SAD) and multiple-ascending dose (MAD) studies to evaluate if early studies could detect and predict QT effect...
March 5, 2018: Journal of Clinical Pharmacology
Michael Creane, Mary Mc Elroy, Aoife Duffy, Chaansha Shaik Dawood, Timothy O'Brien
Critical limb ischemia (CLI) represents the severest manifestation of peripheral arterial disease and is a major unmet medical need. This disease occurs when the arterial blood supply within the limb fails to meet the metabolic demands of the resting muscle or tissue, resulting in chronic ischemic rest pain and/or tissue necrosis. Human mesenchymal stromal cells, termed hMSCs, represent an exciting therapeutic modality for the treatment of this disease due to their immunomodulatory and tissue reparative functions...
January 1, 2018: Toxicologic Pathology
Xavier Pivot, Jean Paul Deslypere, Lisa Soyeon Park, Michael Jinwoo Kim, Wonjae Lee, Jeonghyeon Lee
PURPOSE: This first-in-human study of HD201 was designed to evaluate the pharmacokinetic (PK) equivalence between this biosimilar candidate and trastuzumab sourced in the European Union (EU-trastuzumab)*. METHODS: In this randomized, blinded, single-dose comparative PK study, healthy male subjects were randomized to receive a single 6 mg/kg IV dose of HD201 or EU-trastuzumab. The primary PK end point was AUC0-∞ . Equivalence was determined by using the predefined margins of 0...
March 1, 2018: Clinical Therapeutics
Mun Peak Nyon, Lanying Du, Chien-Te Kent Tseng, Christopher A Seid, Jeroen Pollet, Kevin S Naceanceno, Anurodh Agrawal, Abdullah Algaissi, Bi-Hung Peng, Wanbo Tai, Shibo Jiang, Maria Elena Bottazzi, Ulrich Strych, Peter J Hotez
Middle East respiratory syndrome coronavirus (MERS-CoV) has infected at least 2040 patients and caused 712 deaths since its first appearance in 2012, yet neither pathogen-specific therapeutics nor approved vaccines are available. To address this need, we are developing a subunit recombinant protein vaccine comprising residues 377-588 of the MERS-CoV spike protein receptor-binding domain (RBD), which, when formulated with the AddaVax adjuvant, it induces a significant neutralizing antibody response and protection against MERS-CoV challenge in vaccinated animals...
February 26, 2018: Vaccine
Jörg Täubel, Ulrike Lorch, Simon Coates, Sara Fernandes, Paul Foley, Georg Ferber, Jean-Pierre Gotteland, Oliver Pohl
OBE022, a new orally active prostaglandin F2α  receptor antagonist (OBE022) with myometrial selectivity is being developed to reduce uterine contractions during preterm labor. This first-in-human study evaluated the effect of OBE022 following multiple doses on the QT interval in 23 healthy postmenopausal women, using the effect of a meal on QTc to demonstrate assay sensitivity. We report the cardiac safety outcome performed during the multiple ascending part of this trial. OBE022 was administered after a standardized breakfast on day 1 and in the fasted state from day 3 to day 9 wth a standardized lunch 4 hours after administration...
February 28, 2018: Clinical Pharmacology in Drug Development
Chad E Glasser, Michael R Gartner, Dawn Wilson, Barry Miller, Matthew L Sherman, Kenneth M Attie
INTRODUCTION: ACE-083 is a locally acting follistatin-based therapeutic that binds myostatin and other muscle regulators and has been shown to increase muscle mass and force in neuromuscular disease mouse models. This first-in-human study examined these effects. METHODS: In this phase 1, randomized, double-blind, placebo-controlled, dose-ranging study in healthy postmenopausal women, ACE-083 (50-200 mg) or placebo was administered unilaterally into rectus femoris (RF) or tibialis anterior (TA) muscles as 1 or 2 doses 3 weeks apart...
February 27, 2018: Muscle & Nerve
Corey T Walker, Jakub Godzik, U Kumar Kakarla, Jay D Turner, Alexander C Whiting, Peter Nakaji
BACKGROUND: Tethering after spinal surgery is caused by adhesions that arise from intradural tissue manipulation. Microsurgical detethering is the only treatment for symptomatic patients, but retethering occurs commonly and no treatment is widely available to prevent this complication. OBJECTIVE: To apply human amniotic membrane (HAM) grafts, which are immune-privileged and known to possess antifibrogenic properties, in patients requiring microsurgical detethering...
February 22, 2018: Neurosurgery
A Toumazi, E Comets, C Alberti, T Friede, F Lentz, N Stallard, S Zohar, M Ursino
BACKGROUND AND OBJECTIVE: Dose-finding, aiming at finding the maximum tolerated dose, and pharmacokinetics studies are the first in human studies in the development process of a new pharmacological treatment. In the literature, to date only few attempts have been made to combine pharmacokinetics and dose-finding and to our knowledge no software implementation is generally available. In previous papers, we proposed several Bayesian adaptive pharmacokinetics-based dose-finding designs in small populations...
April 2018: Computer Methods and Programs in Biomedicine
Howard A Burris, Ian W Flinn, Manish R Patel, Timothy S Fenske, Changchun Deng, Danielle M Brander, Martin Gutierrez, James H Essell, John G Kuhn, Hari P Miskin, Peter Sportelli, Michael S Weiss, Swaroop Vakkalanka, Michael R Savona, Owen A O'Connor
BACKGROUND: Umbralisib (TGR-1202) is a novel next-generation inhibitor of phosphatidylinositol 3-kinase (PI3K) isoform p110δ (PI3Kδ), which is structurally distinct from other PI3Kδ inhibitors and shows improved isoform selectivity. Umbralisib also uniquely inhibits casein kinase-1ε, a major regulator of protein translation. The aim of this first-in-human phase 1 study was to establish the safety and preliminary activity profile of umbralisib in patients with haematological malignancies...
February 20, 2018: Lancet Oncology
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