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https://www.readbyqxmd.com/read/28624695/first-in-human-phase-i-study-of-oral-s49076-a-unique-met-axl-fgfr-inhibitor-in-advanced-solid-tumours
#1
Jordi Rodon, Sophie Postel-Vinay, Antoine Hollebecque, Paolo Nuciforo, Analia Azaro, Valérie Cattan, Lucie Marfai, Isabelle Sudey, Karl Brendel, Audrey Delmas, Stéphanie Malasse, Jean-Charles Soria
BACKGROUND AND OBJECTIVES: S49076 is a novel ATP-competitive tyrosine kinase inhibitor of MET, AXL and FGFR with a unique selectivity profile. A phase I open-label study was undertaken to establish the tolerability profile and determine the recommended dose (RD) and administration schedule. MATERIALS AND METHODS: Patients with advanced solid tumours received S49076 orally once-daily (qd) or twice-daily (bid) in continuous 21-day cycles at escalating doses guided by a 3 + 3 design and followed by an expansion phase at the RD...
June 15, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28612912/temporal-healing-patterns-and-coverage-dynamics-after-new-polish-transcatheter-pfo-occluder-implantation-in-a-swine
#2
Krzysztof Milewski, Roland Fiszer, Piotr Paweł Buszman, Przemysław Węglarz, Adam Janas, Agata Krauze, Michał Jelonek, Piotr Hirnle, Grzegorz Smolka, Robert Gil, Jacek Białkowski, Paweł Eugeniusz Buszman
BACKGROUND: Although currently used devices for interventional closure of patent foramen ovale (PFO) are widely used due to minimally invasive nature of this technique and high success rate, there is still a need to look for new materials and designs in order to improve the treatment outcomes. AIM: To evaluate safety, biocompatibility, temporal healing patterns and coverage dynamics of the new Polish PFO occluder (Balton, Warsaw, Poland) in a swine model - an observation that may assist decision with regard to its first-in-human use and duration of anticoagulation therapy...
June 14, 2017: Kardiologia Polska
https://www.readbyqxmd.com/read/28608618/bench-to-bedside-bridge-enhanced-anterior-cruciate-ligament-repair
#3
REVIEW
Gabriel S Perrone, Benedikt L Proffen, Ata M Kiapour, Jakob T Sieker, Braden C Fleming, Martha M Murray
Anterior cruciate ligament (ACL) injuries are one of the most well-known orthopaedic injuries and are treated with one of the most common orthopaedic procedures performed in the United States. This surgical procedure, ACL reconstruction, is successful at restoring the gross stability of the knee. However, the outcomes of ACL reconstruction can be limited by short and long term complications, including muscle weakness, graft rupture and premature osteoarthritis. Thus, new methods of treating this injury are being explored...
June 13, 2017: Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society
https://www.readbyqxmd.com/read/28605468/attenuation-of-insulin-action-by-an-allosteric-insulin-receptor-antibody-in-healthy-volunteers
#4
Kirk W Johnson, Ann Neale, Allan Gordon, Julie Roessig, Padma Bezwada, Sabine Vukelich, Ira Goldfine, Paul Rubin
Background: X358 (X358) is a fully human monoclonal antibody to the insulin receptor (InsR) that acts as a negative allosteric modulator of insulin signaling. It is being developed as a novel treatment for hyperinsulinemic hypoglycemia. This report describes pharmacokinetic (PK), and pharmacodynamic (PD) data from a first-in-human clinical trial. Methods: A double-blind, placebo-controlled, single ascending dose study was performed with 29 healthy adult males randomized to intravenous infusion of placebo or X358 at 0...
June 9, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28594750/blockade-of-hla-antibody-triggered-classical-complement-activation-in-sera-from-subjects-dosed-with-the-anti-c1s-monoclonal-antibody-tnt009-results-from-a-randomized-first-in-human-phase-1-trial
#5
Jakob Mühlbacher, Bernd Jilma, Markus Wahrmann, Johann Bartko, Farsad Eskandary, Christian Schörgenhofer, Michael Schwameis, Graham C Parry, James C Gilbert, Sandip Panicker, Georg A Böhmig
BACKGROUND: Complement may play a key role in antibody-mediated rejection (ABMR). A promising therapeutic approach may be classical pathway (CP) inhibition at the level of early component C1. METHODS: In this first-in-human, double-blind, randomized placebo-controlled phase 1 trial, we evaluated the safety and complement inhibitory effect of TNT009, a humanized monoclonal anti-C1s antibody. Sixty-four adult healthy volunteers received either single (n=48; 7 consecutive cohorts: 0...
June 7, 2017: Transplantation
https://www.readbyqxmd.com/read/28591833/a-new-fully-human-recombinant-fsh-follitropin-epsilon-two-phase-i-randomized-placebo-and-comparator-controlled-pharmacokinetic-and-pharmacodynamic-trials
#6
Khalid Abd-Elaziz, Ingrid Duijkers, Lars Stöckl, Bruno Dietrich, Christine Klipping, Kelvin Eckert, Steffen Goletz
STUDY QUESTION: What are the differences and similarities of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the novel recombinant human FSH follitropin epsilon expressed in the human cell line GlycoExpress compared with a Chinese hamster ovary (CHO) derived compound and a urinary derived product? SUMMARY ANSWER: Overall follitropin epsilon, with a fully human glycosylation, shows a comparable PK profile at single-dose as well as multiple-dose administration compared to recombinant CHO-derived FSH as well as urinary derived FSH, whereas the PD properties differ from product to product with follitropin epsilon being most active in PD parameters...
June 7, 2017: Human Reproduction
https://www.readbyqxmd.com/read/28588020/enasidenib-in-mutant-idh2-relapsed-or-refractory-acute-myeloid-leukemia
#7
Eytan M Stein, Courtney D DiNardo, Daniel A Pollyea, Amir T Fathi, Gail J Roboz, Jessica K Altman, Richard M Stone, Daniel J DeAngelo, Ross L Levine, Ian W Flinn, Hagop M Kantarjian, Robert Collins, Manish R Patel, Arthur E Frankel, Anthony Stein, Mikkael A Sekeres, Ronan T Swords, Bruno C Medeiros, Christophe Willekens, Paresh Vyas, Alessandra Tosolini, Qiang Xu, Robert D Knight, Katharine E Yen, Sam Agresta, Stéphane de Botton, Martin S Tallman
Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ~12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, leading to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human, phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies...
June 6, 2017: Blood
https://www.readbyqxmd.com/read/28584140/safety-tolerability-systemic-exposure-and-metabolism-of-crs3123-a-methionyl-trna-synthetase-inhibitor-developed-for-treatment-of-clostridium-difficile-infections-in-a-phase-i-study
#8
Seema U Nayak, J McLeod Griffiss, Jeffrey Blumer, Mary Ann O'Riordan, Wesley Gray, Robin McKenzie, Robert A Jurao, Amanda T An, Melissa Le, Stacie J Bell, Urs A Ochsner, Thale C Jarvis, Nebojsa Janjic, Jonathan M Zenilman
Clostridium difficile causes antibiotic associated diarrhea and is a major public health concern. Current therapies disrupt the protective intestinal flora, do not reliably prevent recurrent infections and will be decreasingly effective should less susceptible strains emerge. CRS3123 is an oral agent that inhibits bacterial methionyl-tRNA synthetase, has potent activity against C. difficile and aerobic Gram positive bacteria, but little activity against Gram negative bacteria, including anaerobes. This first-in-human, double-blind, placebo-controlled, dose-escalation study evaluated the safety and systemic exposure of CRS3123 after a single oral dose in healthy adults...
June 5, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28583788/thyroid-hormone-receptor-alpha-tra-tissue-expression-in-ductal-invasive-breast-cancer-a-study-combining-quantitative-immunohistochemistry-with-digital-slide-image-analysis
#9
P Charalampoudis, G Agrogiannis, K Kontzoglou, G Kouraklis, G C Sotiropoulos
BACKGROUND: In breast cancer, hormonal receptors hold promise for developing novel targeted therapies. The thyroid exerts its actions via the thyroid hormone receptors alpha and beta. The clinical significance of the expression of thyroid hormone receptors in breast cancer is unclear. MATERIAL AND METHODS: We studied thyroid hormone receptor alpha (TRa) expression in 82 samples from 41 women with ductal invasive breast cancer and no thyroid disease. We performed quantitative immunohistochemistry with digital image analysis and correlated TRa expression with clinicopathological parameters...
May 25, 2017: European Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28578312/a-next-generation-trk-kinase-inhibitor-overcomes-acquired-resistance-to-prior-trk-kinase-inhibition-in-patients-with-trk-fusion-positive-solid-tumors
#10
Alexander Drilon, Ramamoorthy Nagasubramanian, James F Blake, Nora Ku, Brian B Tuch, Kevin Ebata, Steve Smith, Veronique Lauriault, Gabrielle R Kolakowski, Barbara J Brandhuber, Paul D Larsen, Karyn S Bouhana, Shannon L Winski, Robyn Hamor, Wen-I Wu, Andrew Parker, Tony H Morales, Francis X Sullivan, Walter E Dewolf, Lance A Wollenberg, Paul R Gordon, Dorothea N Douglas-Lindsay, Maurizio Scaltriti, Ryma Benayed, Sandeep Raj, Bethany Hanusch, Alison M Schram, Philip Jonsson, Michael F Berger, Jaclyn F Hechtman, Barry S Taylor, Steve Andrews, S Michael Rothenberg, David M Hyman
Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. While responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a novel, selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs...
June 3, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28572487/biodistribution-and-radiation-dosimetry-of-18-f-ftc-146-in-humans
#11
Trine Hjørnevik, Peter W Cipriano, Bin Shen, Jun Hyung Park, Praveen Gulaka, Dawn Holley, Harsh Gandhi, Daehyun Yoon, Erik S Mittra, Greg Zaharchuk, Sanjiv S Gambhir, Christopher R McCurdy, Frederick T Chin, Sandip Biswal
The purpose of this study is to assess safety, biodistribution and radiation dosimetry in humans for the highly selective sigma-1 receptor (S1R) positron emission tomography (PET) agent (18)F-6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one ((18)F-FTC-146). Methods: Ten healthy volunteers (HV; five female, five male; age: 34.3 ± 6.5 years) were recruited, and written informed consent was obtained from all participants. Series of whole-body PET/magnetic resonance imaging (PET/MRI) examinations were acquired for up to three hours after injection (357...
June 1, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28571531/c-abl-inhibition-a-novel-therapeutic-target-for-parkinson-s-disease
#12
Abdelrahman Ibrahim Abushouk, Ahmed Negida, Rasha Abdelsalam Elshenawy, Hossam Zein, Ali M Hammad, Ahmed Menshawy, Wael M Y Mohamed
Parkinson's disease (PD) is the most prevalent movement disorder in the world. The major pathological hallmarks of PD are death of dopaminergic neurons and the formation of Lewy bodies. To the moment, there is no cure for PD; current treatments are symptomatic. Investigators are searching for neuroprotective agents and disease modifying strategies to slow the progress of PD. However, due to ignorance of the main pathological sequence of PD, many drug targets failed recently to provide neuroprotective effects in human trials...
June 1, 2017: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/28571486/repositionable-self-expanding-aortic-bioprosthesis
#13
Bruna Gomes, Hugo A Katus, Raffi Bekeredjian
Transcatheter aortic valve implantation/replacement (TAVI or TAVR) has been established as a first line therapy in patients with symptomatic severe aortic stenosis (AS) at high or prohibitive surgical risk and as an alternative in elderly patients with intermediate surgical risk. Since its first-in-human procedure in 2002, the past 15-years have shown rapid developments in TAVI technology with the introduction and further improvement of new transcatheter heart valves (THV). Areas covered: There are currently several THV systems available, based on balloon-expandable, self-expandable or other technologies...
June 14, 2017: Expert Review of Medical Devices
https://www.readbyqxmd.com/read/28558147/safety-and-efficacy-of-a-bioabsorbable-fluticasone-propionate-eluting-sinus-dressing-in-postoperative-management-of-endoscopic-sinus-surgery-a-randomized-clinical-trial
#14
Gwijde F J P M Adriaensen, Keng-Hua Lim, Wytske J Fokkens
BACKGROUND: Postoperative wound healing after endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis (CRS) is an important factor in procedural success. Local steroids and separation of opposing mucosa are commonly implemented to optimize healing. A bioabsorbable, fluticasone propionate (FP)-eluting implant, SinuBand FP, was assessed for its safety and efficacy when used in patients with CRS and nasal polyps, who were indicated for ESS including bilateral anterior and posterior ethmoidectomy...
May 30, 2017: International Forum of Allergy & Rhinology
https://www.readbyqxmd.com/read/28556418/phase-i-randomized-study-of-khk4083-an-anti-ox40-monoclonal-antibody-in-patients-with-mild-to-moderate-plaque-psoriasis
#15
K A Papp, M J Gooderham, G Girard, M Raman, V Strout
BACKGROUND: OX40 (CD134) is expressed in lesional but not healthy skin of patients with psoriasis. KHK4083 is a fully human monoclonal antibody against OX40. OBJECTIVE: The primary aim of this first-in-human phase 1 study was to determine the safety and tolerability of ascending single doses of KHK4083 in patients with mild to moderate plaque psoriasis. Secondary aims were to determine the pharmacokinetics and immunogenicity of KHK4083, and an exploratory objective was to assess clinical activity...
May 27, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28537452/safety-and-effectiveness-of-longer-focal-beam-and-burst-duration-in-ultrasonic-propulsion-for-repositioning-urinary-stones-and-fragments
#16
Karmon Janssen, Timothy C Brand, Bryan W Cunitz, Yak-Nam Wang, Julianna Simon, Frank Starr, H Denny Liggitt, Jeff Thiel, Mathew D Sorensen, Jonathan D Harper, Michael R Bailey, Barbrina Dunmire
PURPOSE: In the first-in-human trial of ultrasonic propulsion, subjects passed collections of residual stone fragments repositioned with a C5-2 probe. Here, effectiveness and safety in moving multiple fragments is compared between the C5-2 and a custom (SC-50) probe that produces a longer focal beam and burst duration. MATERIAL AND METHODS: Effectiveness was quantified by the number of stones expelled from a calyx phantom consisting of a 30-mm deep, water-filled well in a block of tissue mimicking material...
May 24, 2017: Journal of Endourology
https://www.readbyqxmd.com/read/28531827/safety-and-performance-of-the-second-generation-enlightn%C3%A2-renal-denervation-system-in-patients-with-drug-resistant-uncontrolled-hypertension
#17
Stephen G Worthley, Gerard T Wilkins, Mark W Webster, Joseph K Montarello, Sinny Delacroix, Robert J Whitbourn, Roderic J Warren
BACKGROUND AND AIMS: Catheter-based renal denervation for the treatment of drug-resistant hypertension has been intensively investigated in recent years. To date, only limited data have been published using multi-electrode radiofrequency ablation systems that can deliver lesions with a pre-determined pattern. This study was designed to evaluate the safety and performance of the second generation EnligHTN™ Renal Denervation System. METHODS: This first-in-human, prospective, multi-center, non-randomized study included 39 patients (62% male, mean age 63 years, and mean baseline office blood pressure 174/93 mmHg) with drug-resistant hypertension...
May 3, 2017: Atherosclerosis
https://www.readbyqxmd.com/read/28523582/first-in-human-radiation-dosimetry-of-68-ga-nodaga-rgdyk
#18
Silvano Gnesin, Periklis Mitsakis, Francesco Cicone, Emmanuel Deshayes, Vincent Dunet, Augusto F Gallino, Marek Kosinski, Sébastien Baechler, Franz Buchegger, David Viertl, John O Prior
BACKGROUND: Integrin-targeting radiopharmaceuticals have potential broad applications, spanning from cancer theranostics to cardiovascular diseases. We have previously reported preclinical dosimetry results of (68)Ga-NODAGA-RGDyK in mice. This study presents the first human dosimetry of (68)Ga-NODAGA-RGDyK in the five consecutive patients included in a clinical imaging protocol of carotid atherosclerotic plaques. Five male patients underwent whole-body time-of-flight (TOF) PET/CT scans 10, 60 and 120 min after tracer injection (200 MBq)...
December 2017: EJNMMI Research
https://www.readbyqxmd.com/read/28516358/mechanistic-modeling-of-the-pharmacodynamic-and-pharmacokinetic-relationship-of-tissue-factor-pathway-inhibitor-neutralizing-antibody-bay-1093884-in-cynomolgus-monkeys
#19
Jian-Ming Gu, Xiao-Yan Zhao, Thomas Schwarz, Joachim Schuhmacher, Andreas Baumann, Elena Ho, Babu Subramanyan, Kathy Tran, Timothy Myles, Chandra Patel, Maria Koellnberger
BAY 1093884 is a fully human monoclonal antibody against the tissue factor pathway inhibitor (TFPI) in development as prophylaxis in patients with hemophilia with or without inhibitors. In vitro, BAY 1093884 binds to human, mouse, and monkey TFPI. The objective of this study was to find a pharmacodynamic (PD) biomarker after administration of BAY 1093884 to normal monkeys. In monkey plasma, BAY 1093884 exhibited an IC50 (concentration that inhibits 50%) of 4.65 and 6.19 nM for free TFPI and diluted prothrombin time (dPT), respectively...
May 17, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28514206/first-in-human-pet-ct-imaging-of-metastatic-neuroendocrine-neoplasms-with-cyclotron-produced-44-sc-dotatoc-a-proof-of-concept-study
#20
Aviral Singh, Nicholas P van der Meulen, Cristina Müller, Ingo Klette, Harshad R Kulkarni, Andreas Türler, Roger Schibli, Richard P Baum
(44)Sc is a promising positron emission tomography (PET) radionuclide (T1/2 = 4.04 hours, Eβ+average = 632 keV) and can be made available, using a cyclotron production route, in substantial quantities as a highly pure product. Herein, the authors report on a first-in-human PET/CT study using (44)Sc-DOTATOC prepared with cyclotron-produced (44)Sc. The production of (44)Sc was carried out through the (44)Ca(p,n)(44)Sc nuclear reaction at Paul Scherrer Institut, Switzerland. After separation, (44)Sc was shipped to Zentralklinik Bad Berka, Germany, where radiolabeling was performed, yielding radiochemically pure (44)Sc-DOTATOC...
May 2017: Cancer Biotherapy & Radiopharmaceuticals
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