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https://www.readbyqxmd.com/read/29679478/randomized-controlled-study-of-bleselumab-askp1240-pharmacokinetics-and-safety-in-patients-with-moderate-to-severe-plaque-psoriasis
#1
Mysore S Anil Kumar, Kim Papp, Ryo Tainaka, Udaya Valluri, Xuegong Wang, Tong Zhu, Christian Schwabe
This study evaluated pharmacokinetics (PK), efficacy, safety, and tolerability of bleselumab - a fully-human anti-CD40 monoclonal recombinant IgG4. Patients with moderate-to-severe psoriasis were randomized on Day 1 to receive bleselumab or placebo on Days 1, 15, and 29 in a dose-escalation of bleselumab 0.1, 0.3, 1.0, or 3.0mg/kg. The safety-analysis set (SAF) and full-analysis set (FAS) included all patients who received bleselumab or placebo, and the PK-analysis set (PKAS) included patients in the SAF with ≥1 quantifiable serum bleselumab concentration...
April 21, 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29678476/cabazitaxel-plus-lapatinib-as-therapy-for-her2-metastatic-breast-cancer-with-intracranial-metastases-results-of-a-dose-finding-study
#2
Denise A Yardley, Lowell L Hart, Patrick J Ward, Gail L Wright, Mythili Shastry, Lindsey Finney, Laura M DeBusk, John D Hainsworth
BACKGROUND: Lapatinib is an oral small molecule tyrosine kinase epidermal growth factor receptor-1/HER2 inhibitor that crosses the blood-brain barrier and is active against central nervous system (CNS) metastases. Cabazitaxel is a taxoid that is effective against taxane-resistant metastatic breast cancer (MBC) and has distinguished itself by its ability to cross the blood-brain barrier. The present phase II study (ClinicalTrials.gov identifier, NCT01934894) evaluated the combination of these agents to treat HER2+ MBC patients with CNS metastases...
March 8, 2018: Clinical Breast Cancer
https://www.readbyqxmd.com/read/29676189/association-between-clinical-factors-and-dose-modification-strategies-in-the-treatment-with-ustekinumab-for-moderate-to-severe-plaque-psoriasis
#3
Rosa M Romero-Jimenez, Vicente Escudero-Vilaplana, Ofelia Baniandres Rodriguez, Estela García Martín, Ana Mateos Mayo, Maria Sanjurjo Saez
PURPOSE: The aim of this study was to identify clinical factors associated with dose reduction and dose escalation in the treatment with ustekinumab in patients with moderate to severe plaque psoriasis. MATERIALS AND METHODS: An observational, longitudinal and retrospective study was conducted using patients with moderate to severe plaque psoriasis. We reviewed clinical histories and variables were recorded on a database (patients' characteristics, pharmacotherapeutics, effectiveness and safety)...
April 20, 2018: Journal of Dermatological Treatment
https://www.readbyqxmd.com/read/29674508/combined-braf-and-hsp90-inhibition-in-patients-with-unresectable-braf-v600e-mutant-melanoma
#4
Zeynep Eroglu, Yian Ann Chen, Geoffrey T Gibney, Jeffrey S Weber, Ragini R Kudchadkar, Nikhil I Khushalani, Joseph Markowitz, Andrew S Brohl, Leticia F Tetteh, Howida Ramadan, Gina Arnone, Jiannong Li, Xiuhua Zhao, Ritin Sharma, Lancia N F Darville, Bin Fang, Inna Smalley, Jane L Messina, John M Koomen, Vernon K Sondak, Keiran S M Smalley
PURPOSE: BRAF inhibitors are clinically active in patients with advanced BRAFV600 -mutant melanoma, although acquired resistance remains common. Preclinical studies demonstrated that resistance could be overcome using concurrent treatment with the HSP90 inhibitor XL888. METHODS: Vemurafenib (960 mg PO BID) combined with escalating doses of XL888 (30, 45, 90 or 135 mg PO twice weekly) was investigated in 21 patients with advanced BRAFV600 -mutant melanoma. Primary endpoints were safety and determination of a maximum tolerated dose...
April 19, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29674494/safety-and-efficacy-of-vorinostat-bortezomib-doxorubicin-and-dexamethasone-in-a-phase-i-ii-study-for-relapsed-or-refractory-multiple-myeloma-verumm-study-vorinostat-in-elderly-relapsed-and-unfit-multiple-myeloma
#5
Johannes M Waldschmidt, Alexander Keller, Gabriele Ihorst, Olga Grishina, Stefan Müller, Dagmar Wider, Anna V Frey, Kristina King, Roman Simon, Annette May, Pierfrancesco Tassone, Justus Duyster, Manfred Jung, Noopur Raje, Ralph Wäsch, Monika Engelhardt
This phase I/II trial was conducted to investigate the safety, efficacy, and pharmacodynamics of the pan-HDAC-inhibitor (HDACi) vorinostat combined with bortezomib, doxorubicin, and dexamethasone (VBDD) in patients suffering from relapsed/refractory multiple myeloma (RRMM). In the phase I part of this study, 9/33 patients received dose-escalated vorinostat (100, 200, 300mg), using a 4-day-on and 4-day-off schedule, and a standard 3+3 design. In the phase II part of the study, 24/33 patients were included to further assess VBDD's safety and efficacy...
April 19, 2018: Haematologica
https://www.readbyqxmd.com/read/29672897/evaluation-of-a-janus-kinase-1-inhibitor-pf-04965842-in-healthy-subjects-a-phase-1-randomized-placebo-controlled-dose-escalation-study
#6
Elena Peeva, Martin R Hodge, Elizabeth Kieras, Michael L Vazquez, Kosalaram Goteti, Sanela G Tarabar, Christine W Alvey, Christopher Banfield
AIMS: To determine the safety, tolerability, pharmacokinetics and pharmacodynamics of the Janus Kinase (JAK) 1-selective inhibitor, PF-04965842. METHODS: This was a phase 1, first-in-human, randomized, double-blind, placebo-controlled, combination single- and multiple-dose escalation, parallel design study in healthy subjects (ClinicalTrials.gov, NCT01835197). Subjects received a single dose of placebo or 3, 10, 30, 100, 200, 400 or 800 mg PF-04965842 (single ascending dose phase) and placebo or 30 mg once daily (QD), 100 mg QD, 200 mg QD, 400 mg QD, 100 mg twice daily (BID) or 200 mg BID PF-04965842 for 10 consecutive days (multiple ascending dose phase)...
April 19, 2018: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29669851/systemic-administration-of-the-antisense-oligonucleotide-ns-065-ncnp-01-for-skipping-of-exon-53-in-patients-with-duchenne-muscular-dystrophy
#7
Hirofumi Komaki, Tetsuya Nagata, Takashi Saito, Satoru Masuda, Eri Takeshita, Masayuki Sasaki, Hisateru Tachimori, Harumasa Nakamura, Yoshitsugu Aoki, Shin'ichi Takeda
Duchenne muscular dystrophy (DMD) is a lethal hereditary muscle disease caused by mutations in the gene encoding the muscle protein dystrophin. These mutations result in a shift in the open reading frame leading to loss of the dystrophin protein. Antisense oligonucleotides (ASOs) that induce exon skipping correct this frame shift during pre-mRNA splicing and partially restore dystrophin expression in mouse and dog models. We conducted a phase 1, open-label, dose-escalation clinical trial to determine the safety, pharmacokinetics, and activity of NS-065/NCNP-01, a morpholino ASO that enables skipping of exon 53...
April 18, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29668947/incidence-and-predictors-of-success-of-adalimumab-dose-escalation-and-de-escalation-in-ulcerative-colitis-a-real-world-belgian-cohort-study
#8
Saartje Van de Vondel, Filip Baert, Christine Reenaers, Stijn Vanden Branden, Leila Amininejad, Pieter Dewint, Wouter Van Moerkercke, Jean-François Rahier, Pieter Hindryckx, Peter Bossuyt, Marc Ferrante
Background: Adalimumab (ADM) has been shown efficacious in ulcerative colitis (UC). In randomized controlled trials, dose escalation from 40 mg ADM every other week to 40 mg every week was required in 20%-25% of patients within 1 year. Real-life data suggest higher escalation rates. Attempts for dose de-escalation have not been studied yet. We assessed the need for, outcome of, and predictors of dose escalation and de-escalation in a large retrospective cohort of UC patients treated with ADM...
April 13, 2018: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/29668893/therapeutic-drug-monitoring-guides-the-management-of-crohn-s-patients-with-secondary-loss-of-response-to-adalimumab
#9
Sophie Restellini, Che-Yung Chao, Peter L Lakatos, Achuthan Aruljothy, Haya Aziz, Omar Kherad, Alain Bitton, Gary Wild, Waqqas Afif, Talat Bessissow
Background: Managing loss of response (LOR) in Crohn's disase (CD) patients remains challenging. Compelling evidence supports therapeutic drug monitoring (TDM) to guide management in patients on infliximab, but data for other biologics are less robust. We aimed to asses if empiric dose escalation led to improved clinical outcome in addition to TDM-guided optimization in CD patients with LOR to adalimumab (ADA). Methods: Retrospective chart review of patients followed between 2014 and 2016 at McGill IBD Center with index TDM for LOR to ADA was performed...
April 13, 2018: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/29667921/glycemic-control-of-type-2-diabetes-mellitus-across-stages-of-renal-impairment-information-for-primary-care-providers
#10
Lili Tong, Sharon Adler
Chronic kidney disease (CKD) is a frequent complication of type 2 diabetes mellitus (T2DM) and elevates individuals' risk for cardiovascular disease, the leading cause of morbidity and mortality in T2DM. Achieving and maintaining tight glycemic control is key to preventing development or progression of CKD; however, improving glycemic control may be limited by effects of renal impairment on the efficacy and safety of T2DM treatments, necessitating dosing adjustments and careful evaluation of contraindications...
April 18, 2018: Postgraduate Medicine
https://www.readbyqxmd.com/read/29667116/intraoperative-pancreatic-cancer-detection-using-tumor-specific-multimodality-molecular-imaging
#11
Willemieke S Tummers, Sarah E Miller, Nutte T Teraphongphom, Adam Gomez, Idan Steinberg, David M Huland, Steve Hong, Sri-Rajasekhar Kothapalli, Alifia Hasan, Robert Ertsey, Bert A Bonsing, Alexander L Vahrmeijer, Rutger-Jan Swijnenburg, Teri A Longacre, George A Fisher, Sanjiv S Gambhir, George A Poultsides, Eben L Rosenthal
BACKGROUND: Operative management of pancreatic ductal adenocarcinoma (PDAC) is complicated by several key decisions during the procedure. Identification of metastatic disease at the outset and, when none is found, complete (R0) resection of primary tumor are key to optimizing clinical outcomes. The use of tumor-targeted molecular imaging, based on photoacoustic and fluorescence optical imaging, can provide crucial information to the surgeon. The first-in-human use of multimodality molecular imaging for intraoperative detection of pancreatic cancer is reported using cetuximab-IRDye800, a near-infrared fluorescent agent that binds to epidermal growth factor receptor...
April 17, 2018: Annals of Surgical Oncology
https://www.readbyqxmd.com/read/29666917/measurement-of-iron-status-in-chronic-kidney-disease
#12
Wesley Hayes
Anemia is a common complication of chronic kidney disease (CKD) in children, and dysregulation of iron homeostasis plays a central role in its pathogenesis. Optimizing iron status is a prerequisite for effective treatment of anemia. Insufficient iron can lead to inappropriate escalation of the erythropoiesis-stimulating agent (ESA) dose, which is associated with adverse outcomes. Excess iron supplementation also has negative sequelae including free radical tissue damage and increased risk of systemic infection...
April 17, 2018: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
https://www.readbyqxmd.com/read/29666122/iontophoretic-delivery-of-dexamethasone-phosphate-for-non-infectious-non-necrotising-anterior-scleritis-dose-finding-clinical-trial
#13
Erin C O'Neil, Jiayan Huang, Eric B Suhler, James P Dunn, Victor L Perez, David C Gritz, Kathy McWilliams, Ellen Peskin, Gui-Shuang Ying, Vatinee Y Bunya, Maureen G Maguire, John H Kempen
Currently available treatment options for non-infectious scleritis, including non-steroidal anti-inflammatory drugs, systemic corticosteroids and immunosuppressive therapies, have both efficacy and side effect limitations. Iontophoretic delivery of corticosteroids has been demonstrated to be effective for anterior uveitis and represents a potential new approach to scleritis therapy. We hypothesised that iontophoretic delivery would provide effective and precise medication delivery to the sclera, while limiting systemic exposure and side effects...
April 17, 2018: British Journal of Ophthalmology
https://www.readbyqxmd.com/read/29665437/multiplex-serology-of-helicobacter-pylori-antigens-in-detection-of-current-infection-and-atrophic-gastritis-a-simple-and-cost-efficient-method
#14
Ebrahim Shafaie, Samaneh Saberi, Maryam Esmaeili, Zeynab Karimi, Saeed Najafi, Mohammad Tashakoripoor, Afshin Abdirad, Mahmoud Eshagh Hosseini, Mohammad Ali Mohagheghi, Vahid Khalaj, Marjan Mohammadi
INTRODUCTION: Helicobacter pylori express a large array of antigens, each of which is duly responsible for successful colonization and pathogenesis. Here, we have studied host serum antibody responses to four of its immunodominant antigens in association with the infection status and the resulting clinical outcomes. METHODS: For this purpose, four individual H. pylori proteins (UreB, CagA, Tip-α and HP0175) were produced in recombinant forms. Serum antibody responses of 246 (75 GC and 171 NUD) patients, against the above antigens, were evaluated by multiplex immunoblotting...
April 14, 2018: Microbial Pathogenesis
https://www.readbyqxmd.com/read/29665045/high-body-mass-index-is-associated-with-increased-risk-of-treatment-failure-and-surgery-in-biologic-treated-patients-with-ulcerative-colitis
#15
S Kurnool, N H Nguyen, J Proudfoot, P S Dulai, B S Boland, N Vande Casteele, E Evans, E L Grunvald, A Zarrinpar, W J Sandborn, S Singh
BACKGROUND: Though pharmacokinetic studies suggest accelerated biologic drug clearance with increasing body weight, evidence of obesity's impact on clinical outcomes in biologic-treated patients with ulcerative colitis (UC) is inconsistent. AIMS: To evaluate the impact of obesity on real world response to biological therapy in patients with UC. METHODS: In a single-centre retrospective cohort study between 2011-2016 of biologic-treated patients with UC, we evaluated treatment response by baseline body mass index (BMI)...
April 17, 2018: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29663815/canakinumab-as-monotherapy-for-treatment-of-familial-mediterranean-fever-first-report-in-central-and-eastern-europe-region
#16
M Jesenak, K Hrubiskova, L Kapustova, M Kostkova, P Banovcin
Autoinflammatory disorders (AID) are characterized by spontaneous attacks of acute inflammation with a broad spectrum of clinical symptoms. Ongoing inflammation and reoccurrence of acute flares can lead to the development of amyloidosis. One group of AID is represented by monogenic periodic fever syndromes while familial Mediterranean fever (FMF) is the most common form of AID from this group. Its prevalence in Central and Eastern Europe was reported to be very low. We report a case of FMF patient with a very severe clinical course of FMF and intolerance to colchicine, which is a gold standard for FMF treatment...
2018: Bratislavské Lekárske Listy
https://www.readbyqxmd.com/read/29661774/accuracy-safety-and-reliability-of-novel-phase-i-trial-designs
#17
Heng Zhou, Ying Yuan, Lei Nie
A number of novel model-based and model-assisted designs have been proposed to find the maximum tolerated dose (MTD) in phase I clinical trials, but their differences and relative pros and cons are not clear to many practitioners. We review three model-based designs, including the continual reassessment method (CRM), dose escalation with overdose control (EWOC), and Bayesian logistic regression model (BLRM), and three model-assisted designs, including the modified toxicity probability interval (mTPI), Bayesian optimal interval (BOIN), and keyboard designs...
April 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29661389/esketamine-counters-opioid-induced-respiratory-depression
#18
K Jonkman, E van Rijnsoever, E Olofsen, L Aarts, E Sarton, M van Velzen, M Niesters, A Dahan
BACKGROUND: Opioids can produce life-threatening respiratory depression. This study tested whether subanaesthetic doses of esketamine stimulate breathing in an established human model of opioid-induced respiratory depression. METHODS: In a study with a randomised, double blind, placebo controlled, crossover design, 12 healthy, young volunteers of either sex received a dose escalating infusion of esketamine (cumulative dose 40 mg infused in 1 h) on top of remifentanil-induced respiratory depression...
May 2018: British Journal of Anaesthesia
https://www.readbyqxmd.com/read/29661378/differential-role-of-nitric-oxide-in-the-psychedelic-symptoms-induced-by-racemic-ketamine-and-esketamine-in-human-volunteers
#19
K Jonkman, R van der Schrier, M van Velzen, L Aarts, E Olofsen, E Sarton, M Niesters, A Dahan
BACKGROUND: Animal studies suggest that N-methyl-d-aspartate receptor (NMDAR) hypofunction and subsequent decline in intracellular nitric oxide (NO) are responsible for development of ketamine-induced psychedelic symptoms. To examine this mechanism in humans, we administered the NO donor sodium nitroprusside during infusion of racemic ketamine (RS-ketamine), containing equal amounts of S(+)- and R(-)-ketamine isomers, or esketamine, containing just the S(+)-isomer. METHODS: In this randomised, double blind, placebo-controlled crossover study, healthy volunteers were treated with sodium nitroprusside 0...
May 2018: British Journal of Anaesthesia
https://www.readbyqxmd.com/read/29660598/first-in-human-phase-1-dose-escalation-pharmacokinetic-and-pharmacodynamic-study-of-the-oral-dual-pi3k-and-mtorc1-2-inhibitor-pqr309-in-patients-with-advanced-solid-tumors-sakk-67-13
#20
Andreas Wicki, Nicholas Brown, Alexandros Xyrafas, Vincent Bize, Hanne Hawle, Simona Berardi, Nataša Cmiljanović, Vladimir Cmiljanović, Michael Stumm, Saša Dimitrijević, Richard Herrmann, Vincent Prêtre, Reto Ritschard, Alexandar Tzankov, Viviane Hess, Alexa Childs, Cinta Hierro, Jordi Rodon, Dagmar Hess, Markus Joerger, Roger von Moos, Cristiana Sessa, Rebecca Kristeleit
BACKGROUND: PQR309 is an orally bioavailable, balanced pan-phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR) C1 and mTORC2 inhibitor. PATIENTS AND METHODS: This is an accelerated titration, 3 + 3 dose-escalation, open-label phase I trial of continuous once-daily (OD) PQR309 administration to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics in patients with advanced solid tumours. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D)...
April 13, 2018: European Journal of Cancer
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