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https://www.readbyqxmd.com/read/28211169/a-first-in-human-study-of-ds-1040-an-inhibitor-of-the-activated-form-of-thrombin-activatable-fibrinolysis-inhibitor-in-healthy-subjects
#1
Jin Zhou, Jarema Kochan, Ophelia Yin, Vance Warren, Cynthia Zamora, George Atiee, Joseph Pav, Yasushi Orihashi, Vijay Vashi, Victor Dishy
BACKGROUND: Current treatments for acute ischemic stroke and venous thromboembolism, such as recombinant tissue plasminogen activator and thrombectomy, are limited by a narrow time window and the risk of bleeding. DS-1040 is a novel low-molecular weight compound inhibiting the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa), developed as a fibrinolysis enhancer for treatment of thromboembolic diseases. OBJECTIVES: This first-in-human, randomized, placebo-controlled, three-part, phase 1 study was conducted to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of DS-1040 in healthy subjects...
February 17, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28206702/statistical-issues-in-first-in-human-studies-on-bia-10-2474-neglected-comparison-of-protocol-against-practice
#2
Sheila M Bird, Rosemary A Bailey, Andrew P Grieve, Stephen Senn
By setting the regulatory-approved protocol for a suite of first-in-human studies on BIA 10-2474 against the subsequent French investigations, we highlight 6 key design and statistical issues, which reinforce recommendations by a Royal Statistical Society Working Party, which were made in the aftermath of cytokine release storm in 6 healthy volunteers in the United Kingdom in 2006. The 6 issues are dose determination, availability of pharmacokinetic results, dosing interval, stopping rules, appraisal by safety committee, and clear algorithm required if combining approvals for single and multiple ascending dose studies...
February 16, 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28202366/modulation-of-the-trpv4-ion-channel-as-a-therapeutic-target-for-disease
#3
REVIEW
Megan S Grace, Sara J Bonvini, Maria G Belvisi, Peter McIntyre
Transient Receptor Potential Vanilloid 4 (TRPV4) is a broadly expressed, polymodally gated ion channel that plays an important role in many physiological and pathophysiological processes. TRPV4 knockout mice and several synthetic pharmacological compounds that selectively target TRPV4 are now available, which has allowed detailed investigation in to the therapeutic potential of this ion channel. Results from animal studies suggest that TRPV4 antagonism has therapeutic potential in oedema, pain, gastrointestinal disorders, and lung diseases such as cough, bronchoconstriction, pulmonary hypertension, and acute lung injury...
February 12, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28196430/first-in-human-trial-of-a-type-i-positive-allosteric-modulator-of-alpha7-nicotinic-acetylcholine-receptors-pharmacokinetics-safety-and-evidence-for-neurocognitive-effect-of-avl-3288
#4
Kelvin W Gee, Ann Olincy, Richard Kanner, Lynn Johnson, Derk Hogenkamp, Josette Harris, Minhtam Tran, Stephen A Edmonds, William Sauer, Ryan Yoshimura, Timothy Johnstone, Robert Freedman
Type I positive allosteric modulators (PAMs) of the alpha7-nicotinic receptor enhance its cholinergic activation while preserving the spatiotemporal features of synaptic transmission and the receptor's characteristic rapid desensitization kinetics. Alpha7-nicotinic receptor agonists have shown promise for improving cognition in schizophrenia, but longer-term trials have been disappointing. Therefore, the type I PAM AVL-3288 was evaluated for safety and preliminary evidence of neurocognitive effect in healthy human subjects...
February 1, 2017: Journal of Psychopharmacology
https://www.readbyqxmd.com/read/28193657/preclinical-pharmacokinetics-and-first-in-human-pharmacokinetics-safety-and-tolerability-of-velpatasvir-a-pangenotypic-hcv-ns5a-inhibitor-in-healthy-subjects
#5
Erik Mogalian, Polina German, Brian P Kearney, Cheng Yong Yang, Diana Brainard, John Link, John McNally, LingLing Han, John Ling, Anita Mathias
Preclinical characterization of velpatasvir (VEL; GS-5816), an inhibitor of HCV NS5A protein, demonstrated favourable in vitro and in vivo properties, including potent antiviral activity against hepatitis C virus genotypes 1 to 6 replicon, good metabolic stability, low systemic clearance, and adequate bioavailability and physicochemical properties to warrant clinical evaluation. The Phase 1 (first-in-human) study evaluated the safety, tolerability, and pharmacokinetics of VEL in healthy human subjects following administration of single and multiple (7) once-daily ascending doses and of VEL in the presence and absence of food...
February 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28188907/safety-pharmacokinetic-and-pharmacodynamic-study-in-healthy-subjects-of-oral-neo6860-a-modality-selective-trpv1-antagonist
#6
William Brown, Richard L Leff, Andrew Griffin, Stuart Hossack, Roxane Aubray, Philippe Walker, Dan A Chiche
: Most previous TRPV1 antagonist programs have been put on hold, mainly due on-target adverse events: hyperthermia and impaired noxious heat sensation. NEO6860 is a TRPV1 antagonist, blocking capsaicin activation of the target, with little or no effect against pH or heat activation. The hypothesis is that this pharmacological profile will translate into analgesia without undesired effects on the body temperature or heat-pain threshold. This phase I, double blind, placebo controlled, ascending dose study, included 64 subjects...
February 7, 2017: Journal of Pain: Official Journal of the American Pain Society
https://www.readbyqxmd.com/read/28186682/repair-of-torn-avascular-meniscal-cartilage-using-undifferentiated-autologous-mesenchymal-stem-cells-from-in-vitro-optimization-to-a-first-in-human-study
#7
Michael R Whitehouse, Nicholas R Howells, Michael C Parry, Eric Austin, Wael Kafienah, Kyla Brady, Allen E Goodship, Jonathan D Eldridge, Ashley W Blom, Anthony P Hollander
Meniscal cartilage tears are common and predispose to osteoarthritis (OA). Most occur in the avascular portion of the meniscus where current repair techniques usually fail. We described previously the use of undifferentiated autologous mesenchymal stem cells (MSCs) seeded onto a collagen scaffold (MSC/collagen-scaffold) to integrate meniscal tissues in vitro. Our objective was to translate this method into a cell therapy for patients with torn meniscus, with the long-term goal of delaying or preventing the onset of OA...
December 15, 2016: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28186349/effect-of-gonadotropin-inhibitory-hormone-gnih-on-luteinizing-hormone-secretion-in-humans
#8
J T George, M Hendrikse, J D Veldhuis, I J Clarke, R A Anderson, R P Millar
: Gonadotropin inhibitory hormone (GnIH, human homologue of RFRP-3) suppresses gonadotropin secretion in animal models, but its effects have not been studied in the human. OBJECTIVE: We tested the hypotheses that exogenous GnIH inhibits LH secretion a) in postmenopausal women, and b) in men concurrently administered exogenous kisspeptin. DESIGN: Following in vitro and in vivo pre-clinical studies to functionally characterize the GnIH peptide, a dose-finding study (human GnIH 1...
February 10, 2017: Clinical Endocrinology
https://www.readbyqxmd.com/read/28161451/feasibility-of-laser-marking-in-barrett-s-esophagus-with-volumetric-laser-endomicroscopy-first-in-man-pilot-study
#9
A Swager, A J de Groof, S L Meijer, B L Weusten, W L Curvers, J J Bergman
BACKGROUND AND AIM: Volumetric laser endomicroscopy (VLE) provides a circumferential scan of the esophageal wall layers, and has potential to improve neoplasia detection in Barrett's esophagus (BE). The novel VLE laser marking system enables direct in vivo marking of suspicious areas as identified on VLE. These laser marked areas can subsequently be targeted for biopsies. The aim was to evaluate the visibility and positional accuracy of laser marks in different esophageal tissue types on white-light endoscopy (WLE) and VLE...
February 1, 2017: Gastrointestinal Endoscopy
https://www.readbyqxmd.com/read/28160012/first-in-human-studies-of-seletalisib-an-orally-bioavailable-small-molecule-pi3k%C3%AE-inhibitor-for-the-treatment-of-immune-and-inflammatory-diseases
#10
Eric Helmer, Mark Watling, Emma Jones, Dominique Tytgat, Mark Jones, Rodger Allen, Andrew Payne, Annelize Koch, Eugene Healy
PURPOSE: PI3Ks are potential therapeutic targets in immune-inflammatory diseases. These studies aimed to investigate the safety, tolerability and PK profile of seletalisib, a selective inhibitor of PI3Kδ in humans. METHODS: These phase I, randomised, double-blind, placebo-controlled, single-centre studies (NCT02303509, NCT02207595) evaluated single and multiple oral doses of seletalisib (5-90 mg QD and 30 mg BID) in healthy adults and subjects with mild-to-moderate psoriasis (Study-1)...
February 4, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28150789/consider-drug-efficacy-before-first-in-human-trials
#11
Jonathan Kimmelman, Carole Federico
No abstract text is available yet for this article.
30, 2017: Nature
https://www.readbyqxmd.com/read/28150073/first-in-human-phase-i-study-of-sor-c13-a-trpv6-calcium-channel-inhibitor-in-patients-with-advanced-solid-tumors
#12
S Fu, H Hirte, S Welch, T T Ilenchuk, T Lutes, C Rice, N Fields, A Nemet, D Dugourd, S Piha-Paul, V Subbiah, L Liu, J Gong, D Hong, J M Stewart
Introduction This was an open-label, dose escalation (3 + 3 design), Phase I study of SOR-C13 in patients with advanced tumors of epithelial origin. Primary objectives were to assess safety/tolerability and pharmacokinetics. Secondary goals were to assess pharmacodynamics and efficacy of SOR-C13. Methods SOR-C13 was administered IV QD on days 1-3 and 8-10 of a 21-day cycle. Doses were 2.75 and 5.5 mg/kg (20-min infusion) and 1.375, 2.75, 4.13 and 6.2 mg/kg (90-min infusion). Toxicity was assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4...
February 1, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28145041/first-in-human-experience-of-a-new-self-expandable-percutaneous-pulmonary-valve-implantation-using-knitted-nitinol-wire-and-tri-leaflet-porcine-pericardial-valve-in-the-native-right-ventricular-outflow-tract
#13
Gi Beom Kim, Bo Sang Kwon, Hong Gook Lim
Balloon-expandable percutaneous pulmonary valve systems using the Melody and Edwards SAPIEN transcatheter heart valves have been increasingly used instead of surgically implantable pulmonary valves. However, limited patients with right ventricular outflow tract (RVOT) lesions are suitable candidates for percutaneous pulmonary valve implantation (PPVI) using these systems after surgical correction of tetralogy of Fallot. Therefore, larger self-expandable valved-stents are being developed for native RVOT lesions...
February 1, 2017: Catheterization and Cardiovascular Interventions
https://www.readbyqxmd.com/read/28143428/bk-um-in-patients-with-recurrent-ovarian-cancer-or-peritoneal-cancer-a-first-in-human-phase-i-study
#14
Shingo Miyamoto, Fusanori Yotsumoto, Taeko Ueda, Tatsuya Fukami, Ayako Sanui, Kohei Miyata, Sung Ouk Nam, Satoshi Fukagawa, Takahiro Katsuta, Miyako Maehara, Haruhiko Kondo, Daisuke Miyahara, Kyoko Shirota, Toshiyuki Yoshizato, Masahide Kuroki, Hiroaki Nishikawa, Keijiro Saku, Yoshio Tsuboi, Kenji Ishitsuka, Yasushi Takamatsu, Kazuo Tamura, Akira Matsunaga, Toru Hachisuga, Shinsuke Nishino, Takashi Odawara, Kazuhiro Maeda, Sadao Manabe, Toyokazu Ishikawa, Yoshinobu Okuno, Minako Ohishi, Tomoya Hikita, Hiroto Mizushima, Ryo Iwamoto, Eisuke Mekada
BACKGROUND: BK-UM (CRM197) is a mutant form of diphtheria toxin and a specific inhibitor of heparin-binding epidermal growth factor-like growth factor (HB-EGF). We assessed the safety, pharmacokinetics, recommended dose, and efficacy of BK-UM in patients with recurrent ovarian cancer (OC) or peritoneal cancer (PC), and measured HB-EGF levels in serum and abdominal fluid after BK-UM administration. METHODS: Eleven patients with advanced or recurrent OC or PC were enrolled and treated with BK-UM via the intraperitoneal route...
January 31, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28139349/safety-and-efficacy-of-ozanezumab-in-patients-with-amyotrophic-lateral-sclerosis-a-randomised-double-blind-placebo-controlled-phase-2-trial
#15
Vincent Meininger, Angela Genge, Leonard H van den Berg, Wim Robberecht, Albert Ludolph, Adriano Chio, Seung H Kim, P Nigel Leigh, Matthew C Kiernan, Jeremy M Shefner, Claude Desnuelle, Karen E Morrison, Susanne Petri, Diane Boswell, Jane Temple, Rajat Mohindra, Matt Davies, Jonathan Bullman, Paul Rees, Arseniy Lavrov
BACKGROUND: Neurite outgrowth inhibitor A (Nogo-A) is thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). A monoclonal antibody against Nogo-A showed a positive effect in the SOD1(G93A) mouse model of ALS, and a humanised form of this antibody (ozanezumab) was well tolerated in a first-in-human trial. Therefore, we aimed to assess the safety and efficacy of ozanezumab in patients with ALS. METHODS: This randomised, double-blind, placebo-controlled, phase 2 trial was done in 34 centres in 11 countries...
January 27, 2017: Lancet Neurology
https://www.readbyqxmd.com/read/28135684/evaluation-of-the-immunogenicity-of-human-ips-cell-derived-neural-stem-progenitor-cells-in-vitro
#16
Masahiro Ozaki, Akio Iwanami, Narihito Nagoshi, Jun Kohyama, Go Itakura, Hiroki Iwai, Soraya Nishimura, Yuichiro Nishiyama, Soya Kawabata, Keiko Sugai, Tsuyoshi Iida, Kohei Matsubayashi, Miho Isoda, Rei Kashiwagi, Yoshiaki Toyama, Morio Matsumoto, Hideyuki Okano, Masaya Nakamura
To achieve the goal of a first-in-human trial for human induced pluripotent stem cell (hiPSC)-based transplantation for the treatment of various diseases, allogeneic human leukocyte antigen (HLA)-matched hiPSC cell banks represent a realistic tool from the perspective of quality control and cost performance. Furthermore, considering the limited therapeutic time-window for acute injuries, including neurotraumatic injuries, an iPS cell bank is of potential interest. However, due to the relatively immunoprivileged environment of the central nervous system, it is unclear whether HLA matching is required in hiPSC-derived neural stem/progenitor cell (hiPSC-NS/PC) transplantation for the treatment of neurodegenerative diseases and neurotraumatic injuries...
January 19, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28123075/ron-kinase-a-target-for-treatment-of-cancer-induced-bone-destruction-and-osteoporosis
#17
Kelsi Andrade, Jaime Fornetti, Ling Zhao, Scott C Miller, R Lor Randall, Neysi Anderson, Susan E Waltz, Mark McHale, Alana L Welm
Bone destruction occurs in aging and numerous diseases, including osteoporosis and cancer. Many cancer patients have bone osteolysis that is refractory to state-of-the-art treatments, which block osteoclast activity with bisphosphonates or by inhibiting the receptor activator of nuclear factor κB ligand (RANKL) pathway. We previously showed that macrophage-stimulating protein (MSP) signaling, which is elevated in about 40% of breast cancers, promotes osteolytic bone metastasis by activation of the MSP signaling pathway in tumor cells or in the bone microenvironment...
January 25, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28119295/first-in-human-phase-1-study-of-margetuximab-mgah22-an-fc-modified-chimeric-monoclonal-antibody-in-patients-with-her2-positive-advanced-solid-tumors
#18
Y J Bang, G Giaccone, S A Im, D Y Oh, T M Bauer, J L Nordstrom, H Li, G R Chichili, P A Moore, S Hong, S J Stewart, J E Baughman, R J Lechleider, H A Burris
BACKGROUND: Margetuximab is an anti-HER2 antibody that binds with elevated affinity to both the lower and higher affinity forms of CD16A, an Fc-receptor important for antibody dependent cell-mediated cytotoxicity (ADCC) against tumor cells. A Phase 1 study was initiated to evaluate the toxicity profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of margetuximab in patients with HER2-overexpressing carcinomas. PATIENTS AND METHODS: Patients with HER2-positive breast or gastric cancer, or other carcinomas that overexpress HER2, for whom no standard therapy was available, were treated with margetuximab by intravenous infusion at doses of 0...
January 24, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28109872/5-year-safety-and-efficacy-of-resolute%C3%A2-zotarolimus-eluting-stent-the-resolute-global-clinical-trial-program
#19
Robert W Yeh, Sigmund Silber, Lianglong Chen, Shaoliang Chen, Shirish Hiremath, Franz-Josef Neumann, Shubin Qiao, Shigeru Saito, Bo Xu, Yuejin Yang, Laura Mauri
OBJECTIVES: The authors evaluated the 5-year cumulative incidence of cardiovascular events following Resolute zotarolimus-eluting stent (R-ZES) implantation. BACKGROUND: Individual trials are often underpowered to show differences for low-frequency adverse events. The R-ZES was studied in 10 prospective clinical trials, designed with identical adverse event definitions, ascertainment, and adjudication. METHODS: The RESOLUTE Global Clinical Trial Program includes 7,618 patients treated with R-ZES: RESOLUTE first-in-human study (N = 139), RESOLUTE All Comers (N = 1,140), RESOLUTE International (N = 2,349), RESOLUTE US (N = 1,402), RESOLUTE US 38 mm (N = 114), RESOLUTE Japan (N = 100), RESOLUTE Japan Small Vessel Study (N = 65), RESOLUTE Asia (N = 311), RESOLUTE China Randomized Controlled Trial (N = 198), and RESOLUTE China Registry (N = 1,800)...
February 13, 2017: JACC. Cardiovascular Interventions
https://www.readbyqxmd.com/read/28105999/transcatheter-aortic-valve-replacement-with-the-portico-valve-one-year-results-of-the-early-canadian-experience
#20
Gidon Y Perlman, Anson Cheung, Eric Dumont, Dion Stub, Danny Dvir, Maria Del Trigo, Marc Pelletier, Sami Alnasser, Jian Ye, David Wood, Christopher Thompson, Philipp Blanke, Jonathon Leipsic, Michael A Seidman, Heather LeBlanc, Christopher E Buller, Josep Rodés-Cabau, John G Webb
AIMS: The aim of this study was to examine the short- and medium-term outcomes of transcatheter aortic valve replacement (TAVR) with the self-expanding and repositionable Portico valve (St. Jude Medical, St. Paul, MN, USA). METHODS AND RESULTS: A total of 57 patients underwent TAVR with the Portico valve between March 2012 and August 2014, representing the first-in-human experience and the entire early experience in Canada. Patients were followed up at 30 days and one year with repeat echocardiography and clinical review...
January 20, 2017: EuroIntervention
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