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https://www.readbyqxmd.com/read/28441238/diaphragm-activation-in-ventilated-patients-using-a-novel-transvenous-phrenic-nerve-pacing-catheter
#1
Steven Reynolds, Adrian Ebner, Tracy Meffen, Viral Thakkar, Matt Gani, Kaity Taylor, Linda Clark, Gautam Sadarangani, Ramasamy Meyyappan, Rodrigo Sandoval, Elizabeth Rohrs, Joaquín A Hoffer
OBJECTIVES: Over 30% of critically ill patients on positive-pressure mechanical ventilation have difficulty weaning from the ventilator, many of whom acquire ventilator-induced diaphragm dysfunction. Temporary transvenous phrenic nerve pacing using a novel electrode-bearing catheter may provide a means to prevent diaphragm atrophy, to strengthen an atrophied diaphragm, and mitigate the harms of mechanical ventilation. We tested the initial safety, feasibility, and impact on ventilation of this novel approach...
April 22, 2017: Critical Care Medicine
https://www.readbyqxmd.com/read/28427597/intentional-percutaneous-laceration-of%C3%A2-the%C3%A2-anterior-mitral-leaflet-to-prevent%C3%A2-outflow%C3%A2-obstruction-during-transcatheter-mitral-valve-replacement-first-in-human%C3%A2-experience
#2
Vasilis C Babaliaros, Adam B Greenbaum, Jaffar M Khan, Toby Rogers, Dee Dee Wang, Marvin H Eng, William W O'Neill, Gaetano Paone, Vinod H Thourani, Stamatios Lerakis, Dennis W Kim, Marcus Y Chen, Robert J Lederman
OBJECTIVES: This study sought to use a new catheter technique to split the anterior mitral valve leaflet (AML) and prevent iatrogenic left ventricular outflow tract (LVOT) obstruction immediately before transcatheter mitral valve replacement (TMVR). BACKGROUND: LVOT obstruction is a life-threatening complication of TMVR, caused by septal displacement of the AML. METHODS: The procedure was used in patients with severe mitral valve disease and prohibitive surgical risk...
April 24, 2017: JACC. Cardiovascular Interventions
https://www.readbyqxmd.com/read/28422758/first-in-human-trial-of-multikinase-vegf-inhibitor-regorafenib-and-anti-egfr-antibody-cetuximab-in-advanced-cancer-patients
#3
Vivek Subbiah, Muhammad Rizwan Khawaja, David S Hong, Behrang Amini, Jiang Yungfang, Hui Liu, Adrienne Johnson, Alexa B Schrock, Siraj M Ali, James X Sun, David Fabrizio, Sarina Piha-Paul, Siqing Fu, Apostolia M Tsimberidou, Aung Naing, Filip Janku, Daniel D Karp, Michael Overman, Cathy Eng, Scott Kopetz, Funda Meric-Bernstam, Gerald S Falchook
BACKGROUND: The combination of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab overcomes intrinsic and acquired resistance in both EGFR-sensitive and EGFR-resistant preclinical models of colorectal cancer (CRC). METHODS: Utilizing a standard 3+3 design, a phase I study was designed to determine safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) of the regorafenib plus cetuximab combination among patients with advanced cancer including CRC...
April 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28422499/development-of-a-18f-labeled-radiotracer-with-improved-brain-kinetics-for-positron-emission-tomography-imaging-of-translocator-protein-18-kda-in-ischemic-brain-and-glioma
#4
Masayuki Fujinaga, Rui Luo, Katsushi Kumata, Yiding Zhang, Akiko Hatori, Tomoteru Yamasaki, Lin Xie, Wakana Mori, Yusuke Kurihara, Masanao Ogawa, Nobuki Nengaki, Feng Wang, Ming-Rong Zhang
We designed four novel acetamidobenzoxazolone compounds 7a-d as candidates of positron emission tomography (PET) radiotracers for imaging translocator protein (18 kDa, TSPO) in ischemic brain and glioma. Among these compounds, 2-(5-(6-fluoropyridin-3-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)-N-methyl-N-phenylacetamide (7d) exhibited high binding affinity (Ki = 13.4 nM) with TSPO and moderate lipophilicity (LogD: 1.92). [18F]7d was radiosynthesized by [18F]fluorination of the bromopyridine precursor 7h with [18F]F- at 12 ± 3% radiochemical yield (n = 6, decay-corrected)...
April 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28420041/-18-f-nifene-test-retest-reproducibility-in-first-in-human-imaging-of-%C3%AE-4%C3%AE-2-nicotinic-acetylcholine-receptors
#5
Patrick J Lao, Tobey J Betthauser, Dana L Tudorascu, Todd E Barnhart, Ansel T Hillmer, Charles K Stone, Jogeshwar Mukherjee, Bradley T Christian
The aim of this study was to examine the suitability of [(18) F]nifene, a novel α4β2* nicotinic acetylcholine receptor (nAChR) radiotracer, for in vivo brain imaging in a first-in-human study. METHODS: Eight healthy subjects (4M,4F;21-69,44±21yrs) underwent a [(18) F]nifene PET scan (200±3.7MBq), and seven underwent a second scan within 58±31days. Regional estimates of DVR were measured using the multilinear reference tissue model (MRTM2) with the corpus callosum as reference region...
April 18, 2017: Synapse
https://www.readbyqxmd.com/read/28419590/cracking-the-neural-code-treating-paralysis-and-the-future-of-bioelectronic-medicine
#6
C Bouton
The human nervous system is a vast network carrying not only sensory and movement information, but also information to and from our organs, intimately linking it to our overall health. Scientists and engineers have been working for decades to tap into this network and 'crack the neural code' by decoding neural signals and learning how to 'speak' the language of the nervous system. Progress has been made in developing neural decoding methods to decipher brain activity and bioelectronic technologies to treat rheumatoid arthritis, paralysis, epilepsy and for diagnosing brain-related diseases such as Parkinson's and Alzheimer's disease...
April 16, 2017: Journal of Internal Medicine
https://www.readbyqxmd.com/read/28410303/personalized-therapy-tumor-antigen-discovery-for-adoptive-cellular-therapy
#7
Cassian Yee, Gregory A Lizee
Adoptive cell therapy using endogenous T cells involves the ex vivo isolation and expansion of antigen-specific T cells from the peripheral blood and is uniquely suited for validating and translating antigen discovery. Endogenous T-cell therapy does not require accessible tumor as a source of infiltrating T cells and is free of regulatory and logistical constraints associated with engineering T cells. Candidate epitope peptides identified through antigen discovery may be rapidly implemented as targets in clinical trials of endogenous T-cell therapy and even incorporated as an "ad hoc" approach to personalized treatment when autologous tumor is available...
March 2017: Cancer Journal
https://www.readbyqxmd.com/read/28403743/nonclinical-profile-of-blz-100-a-tumor-targeting-fluorescent-imaging-agent
#8
Julia Parrish-Novak, Kelly Byrnes-Blake, Narine Lalayeva, Stefanie Burleson, Janean Fidel, Rhonda Gilmore, Pamela Gayheart-Walsten, Gregory A Bricker, William J Crumb, K S Tarlo, Stacey Hansen, Valorie Wiss, Errol Malta, William S Dernell, James M Olson, Dennis M Miller
BLZ-100 is a single intravenous use, fluorescent imaging agent that labels tumor tissue to enable more complete and precise surgical resection. It is composed of a chlorotoxin peptide covalently bound to the near-infrared fluorophore indocyanine green. BLZ-100 is in clinical development for intraoperative visualization of human tumors. The nonclinical safety and pharmacokinetic (PK) profile of BLZ-100 was evaluated in mice, rats, canines, and nonhuman primates (NHP). Single bolus intravenous administration of BLZ-100 was well tolerated, and no adverse changes were observed in cardiovascular safety pharmacology, PK, and toxicology studies in rats and NHP...
March 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28398597/results-from-the-first-in-human-study-with-ozanimod-a-novel-selective-sphingosine-1-phosphate-receptor-modulator
#9
Jonathan Q Tran, Jeffrey P Hartung, Robert J Peach, Marcus F Boehm, Hugh Rosen, Heather Smith, Jennifer L Brooks, Gregg A Timony, Allan D Olson, Sheila Gujrathi, Paul A Frohna
The sphingosine-1-phosphate 1 receptor (S1P1R ) is expressed by lymphocytes, dendritic cells, and vascular endothelial cells and plays a role in the regulation of chronic inflammation and lymphocyte egress from peripheral lymphoid organs. Ozanimod is an oral selective modulator of S1P1R and S1P5R receptors in clinical development for the treatment of chronic immune-mediated, inflammatory diseases. This first-in-human study characterized the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy volunteers using a range of single and multiple doses (7 and 28 days) and a dose-escalation regimen...
April 11, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28393481/comparative-study-of-therapeutic-antibody-candidates-derived-from-mini-pool-and-clonal-cell-lines
#10
Lianchun Fan, Giovanni Rizzi, Kathleen Bierilo, Jun Tian, Joon Chong Yee, Reb Russel, Tapan Das
The long journey of developing a drug from initial discovery target identification to regulatory approval often leaves many patients with missed window of opportunities. Both regulatory agencies and biopharmaceutical industry continue to develop creative approaches to shorten the time of new drug development in order to deliver life-saving medicine to patients. Historically, drug substance materials to support the toxicology and early phase clinical study can only be manufactured after creating the final Master Cell Bank (MCB) of the clonally-derived cell line, which normally takes 1-2 years...
April 10, 2017: Biotechnology Progress
https://www.readbyqxmd.com/read/28391576/phase-i-trial-and-pharmacokinetic-study-of-tanibirumab-a-fully-human-monoclonal-antibody-to-vascular-endothelial-growth-factor-receptor-2-in-patients-with-refractory-solid-tumors
#11
Su Jin Lee, Seon Young Lee, Weon Sup Lee, Jin San Yoo, Jong-Mu Sun, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Myung-Ju Ahn, Ho Yeong Lim, Won Ki Kang, Young Suk Park
Background Tanibirumab is a fully human monoclonal antibody to vascular endothelial growth factor receptor 2 (VEGFR-2). We conducted a first-in-human phase I study of tanibirumab in patients with solid tumors refractory to standard chemotherapy. Primary endpoints were evaluating safety, pharmacokinetics (PKs), estimating maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Methods We designed our study to escalate tanibirumab at 9 different dose levels with a 3 + 3 method and tanibirumab (1-28 mg/kg) was administered intravenously on D1, 8, 15 in 28-day courses...
April 8, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28389981/erratum-to-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
No abstract text is available yet for this article.
April 7, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28389265/preclinical-pharmacokinetics-pharmacodynamics-tissue-distribution-and-interspecies-scaling-of-recombinant-human-coagulation-factor-xa-i16l
#13
Chuenlei Parng, Victoria Markiewicz, Jianqing Chen, Beth Leary, Nicole Duriga, Lisa Dyleski, Teresa Caiazzo, Michael Bolt, Alison Joyce, Boris Gorovits, Debra D Pittman, Robert Webster
FXa(I16L) is a recombinant human FXa variant which is currently being evaluated in the clinic for treating intracerebral hemorrhage. The aim of our studies was to investigate overall pharmacokinetics, pharmacodynamics and distribution of FXa(I16L) in preclinical species, and to understand its potential implication in human. Pharmacokinetics of FXa(I16L) was examined using active site probes and the results showed that FXa(I16L) displayed fast clearance, low volume of distribution and a very short plasma resident time in mice, rats and monkeys...
April 4, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28388548/safety-and-efficacy-of-p62-dna-vaccine-elenagen-in-a-first-in-human-trial-in-patients-with-advanced-solid-tumors
#14
Dmitry M Ponomarenko, Irina D Klimova, Yulia A Chapygina, Viktoria V Dvornichenko, Natalia V Zhukova, Rashida V Orlova, Georgy M Manikhas, Alexandr V Zyryanov, Lilya A Burkhanova, Irina I Badrtdinova, Basile N Oshchepkov, Elena V Filippova, Sergei V Orlov, Sergei I Kolesnikov, Albert A Sufianov, Svetlana R Baum, Olga Y Zaitzeva, Andrey B Komissarov, Mikhail P Grudinin, Oleg I Kiselev, Anatoly F Tsyb, Franco Venanzi, Vita Shcherbinina, Andrey Chursov, Vladimir L Gabai, Alexander M Shneider
Elenagen is a plasmid encoding p62/SQSTM1, the first DNA vaccine possessing two mutually complementing mechanisms of action: it elicits immune response against p62 and mitigates systemic chronic inflammation. Previously, Elenagen demonstrated anti-tumor efficacy and safety in rodent tumor models and spontaneous tumors in dogs. This multicenter I/IIa trial evaluated safety and clinical activity of Elenagen in patients with advanced solid tumors. Fifteen patients were treated with escalating doses of Elenagen (1- 5 mg per doses, 5 times weekly) and additional 12 patients received 1 mg dose...
March 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28387940/the-bial-10-2474-phase-1-study-a-drug-development-perspective-and-recommendations-for-future-first-in-human-trials
#15
REVIEW
Philip Chaikin
BIA 10-2474 (a fatty acid amide hydrolase inhibitor) was evaluated in a first-in-human phase 1 study in normal volunteers to assess safety/tolerability, pharmacokinetics, pharmacodynamics, and food effect. The dose-escalation process consisted of a single-ascending-dose phase (SAD) and multiple-ascending-dose phase (MAD). Prospective determination of the starting dose and maximal escalated dose was consistent with the usual clinical pharmacology principles for extrapolation of preclinical toxicology data to human equivalent doses...
April 7, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28374497/enabling-robust-assessment-of-qtc-prolongation-in-early-phase-clinical-trials
#16
Devan V Mehrotra, Li Fan, Fang Liu, Kuenhi Tsai
Since the implementation of the International Conference on Harmonization (ICH) E14 guideline in 2005, regulators have required a "thorough QTc" (TQT) study for evaluating the effects of investigational drugs on delayed cardiac repolarization as manifested by a prolonged QTc interval. However, TQT studies have increasingly been viewed unfavorably because of their low cost effectiveness. Several researchers have noted that a robust drug concentration-QTc (conc-QTc) modeling assessment in early phase development should, in most cases, obviate the need for a subsequent TQT study...
April 3, 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28363636/safety-tolerability-pharmacokinetics-and-activity-of-the-novel-long-acting-antimalarial-dsm265-a-two-part-first-in-human-phase-1a-1b-randomised-study
#17
James S McCarthy, Julie Lotharius, Thomas Rückle, Stephan Chalon, Margaret A Phillips, Suzanne Elliott, Silvana Sekuloski, Paul Griffin, Caroline L Ng, David A Fidock, Louise Marquart, Noelle S Williams, Nathalie Gobeau, Lidiya Bebrevska, Maria Rosario, Kennan Marsh, Jörg J Möhrle
BACKGROUND: DSM265 is a novel antimalarial that inhibits plasmodial dihydroorotate dehydrogenase, an enzyme essential for pyrimidine biosynthesis. We investigated the safety, tolerability, and pharmacokinetics of DSM265, and tested its antimalarial activity. METHODS: Healthy participants aged 18-55 years were enrolled in a two-part study: part 1, a single ascending dose (25-1200 mg), double-blind, randomised, placebo-controlled study, and part 2, an open-label, randomised, active-comparator controlled study, in which participants were inoculated with Plasmodium falciparum induced blood-stage malaria (IBSM) and treated with DSM265 (150 mg) or mefloquine (10 mg/kg)...
March 28, 2017: Lancet Infectious Diseases
https://www.readbyqxmd.com/read/28348152/pharmacokinetics-and-tolerance-of-the-phage-endolysin-based-candidate-drug-sal200-after-a-single-intravenous-administration-among-healthy-volunteers
#18
Soo Youn Jun, In Jin Jang, Seonghae Yoon, Kyungho Jang, Kyung-Sang Yu, Joo Youn Cho, Moon-Woo Seong, Gi Mo Jung, Seong Jun Yoon, Sang Hyeon Kang
This study is a phase 1, single-center, randomized, double-blind, placebo-controlled, single-dosing, and dose-escalating study of intravenous SAL200. It is a new candidate drug for antibiotic-resistant staphylococcal infections based on a recombinant form of the phage endolysin SAL-1. The study evaluated the pharmacokinetics, pharmacodynamics, and tolerance among healthy male volunteers after the intravenous infusion of single ascending doses of SAL200 (0.1, 0.3, 1, 3, and 10 mg/kg).SAL200 was well tolerated, and no serious adverse events (AEs) were observed in this clinical study...
March 27, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28335703/corrigendum
#19
(no author information available yet)
Holden A, Merrilees S, Buckley B, et al. First-in-human experience with the Gore balloon-expandable covered endoprosthesis in iliac artery occlusive disease. J Endovasc Ther. 2017;24:11-18. doi: 10.1177/1526602816680570 .
April 2017: Journal of Endovascular Therapy
https://www.readbyqxmd.com/read/28331534/ford-and-edison-in-a-modern-regulatory-environment-the-first-in-human-trial-of-night-work-and-artificial-light
#20
EDITORIAL
Thomas C Erren, David M Shaw, Ursula Wild, J Valérie Groß
A thought experiment places Henry Ford and Thomas Alva Edison in a modern regulatory environment. In a utopian occupational world devoid of night-shifts or artificial light, Ford wants to experiment with "working through the night". To support Ford's project, Edison offers his patented electric lamps to "turn nights into days". An ethics committee [EC] does not approve the night-work experiment and Utopia's Food and Drug Administration [FDA] does not approve the potential medical device as safe for use by humans...
2017: Journal of Occupational Medicine and Toxicology
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