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Lumacaftor

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https://www.readbyqxmd.com/read/28087700/two-small-molecules-restore-stability-to-a-sub-population-of-the-cystic-fibrosis-transmembrane-conductance-regulator-with-the-predominant-disease-causing-mutation
#1
Xin Meng, Yiting Wang, Xiaomeng Wang, Joe A Wrennall, Tracy L Rimington, Hongyu Li, Zhiwei Cai, Robert C Ford, David N Sheppard
Cystic fibrosis (CF) is caused by mutations that disrupt the plasma membrane expression, stability, and function of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. Two small molecules, the CFTR corrector lumacaftor and the potentiator ivacaftor, are now used clinically to treat CF, although some studies suggest that they have counteracting effects on CFTR stability. Here, we investigated the impact of these compounds on the instability of F508del-CFTR, the most common CF mutation...
January 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28011037/assessment-of-safety-and-efficacy-of-long-term-treatment-with-combination-lumacaftor-and-ivacaftor-therapy-in-patients-with-cystic-fibrosis-homozygous-for-the-f508del-cftr-mutation-progress-a-phase-3-extension-study
#2
Michael W Konstan, Edward F McKone, Richard B Moss, Gautham Marigowda, Simon Tian, David Waltz, Xiaohong Huang, Barry Lubarsky, Jaime Rubin, Stefanie J Millar, David J Pasta, Nicole Mayer-Hamblett, Christopher H Goss, Wayne Morgan, Gregory S Sawicki
BACKGROUND: The 24-week safety and efficacy of lumacaftor/ivacaftor combination therapy was shown in two randomised controlled trials (RCTs)-TRAFFIC and TRANSPORT-in patients with cystic fibrosis who were aged 12 years or older and homozygous for the F508del-CFTR mutation. We aimed to assess the long-term safety and efficacy of extended lumacaftor/ivacaftor therapy in this group of patients in PROGRESS, the long-term extension of TRAFFIC and TRANSPORT. METHODS: PROGRESS was a phase 3, parallel-group, multicentre, 96-week study of patients who completed TRAFFIC or TRANSPORT in 191 sites in 15 countries...
December 20, 2016: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/27990075/pharmaceutical-approval-update
#3
Michele B Kaufman
Lisinopril oral solution (Qbrelis) for the treatment of hypertension, heart failure, and acute myocardial infarction; etanercept-szzs (Erelzi) for multiple autoimmune disorders; and lumacaftor/ivacaftor (Orkambi) for cystic fibrosis.
December 2016: P & T: a Peer-reviewed Journal for Formulary Management
https://www.readbyqxmd.com/read/27976892/fatty-acid-cysteamine-conjugates-as-novel-and-potent-autophagy-activators-that-enhance-the-correction-of-misfolded-f508del-cystic-fibrosis-transmembrane-conductance-regulator-cftr
#4
Chi B Vu, Robert J Bridges, Cecilia Pena-Rasgado, Antonio E Lacerda, Curtis Bordwell, Abby Sewell, Andrew J Nichols, Sachin Chandran, Pallavi Lonkar, Dominic Picarella, Amal Ting, Allison Wensley, Maisy Yeager, Feng Liu
A depressed autophagy has previously been reported in cystic fibrosis patients with the common F508del-CFTR mutation. This report describes the synthesis and preliminary biological characterization of a novel series of autophagy activators involving fatty acid cysteamine conjugates. These molecular entities were synthesized by first covalently linking cysteamine to docosahexaenoic acid. The resulting conjugate 1 synergistically activated autophagy in primary homozygous F508del-CFTR human bronchial epithelial (hBE) cells at submicromolar concentrations...
December 23, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27970879/cost-effectiveness-of-ivacaftor-and-lumacaftor-combination-for-the-treatment-of-patients-with-cystic-fibrosis-in-the-united-states
#5
D Sharma, S Xing, Y Hung, R N Caskey, M L Dowell, D R Touchette
No abstract text is available yet for this article.
November 2016: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
https://www.readbyqxmd.com/read/27898234/lumacaftor-ivacaftor-treatment-of-patients-with-cystic-fibrosis-heterozygous-for-f508del-cftr
#6
Steven M Rowe, Susanna A McColley, Ernst Rietschel, Xiaolei Li, Scott C Bell, Michael W Konstan, Gautham Marigowda, David Waltz, Michael P Boyle
RATIONALE: Lumacaftor/ivacaftor treatment (≤28 days) in patients with cystic fibrosis (CF) heterozygous for F508del-CFTR did not improve lung function. OBJECTIVES: To evaluate an optimized lumacaftor/ivacaftor dosing regimen with longer duration in a cohort of patients heterozygous for F508del-CFTR. METHODS: Patients age ≥18 years with a confirmed CF diagnosis and percent predicted forced expiratory volume in 1 second (ppFEV1) of 40 to 90 were randomized to lumacaftor/ivacaftor (400 mg/250 mg every 12 hours) or placebo daily for 56 days...
November 29, 2016: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/27894875/effect-of-bronchodilators-in-healthy-individuals-receiving-lumacaftor-ivacaftor-combination-therapy
#7
Gautham Marigowda, Fang Liu, David Waltz
In an open-label, single-center phase 1 pharmacokinetic study in healthy subjects who received lumacaftor (LUM) in combination with ivacaftor (IVA), review of spirometry data showed a transient decline in percent predicted forced expiratory volume in 1s (ppFEV1) within 4h of drug administration. An additional cohort of healthy subjects with normal baseline ppFEV1 values was studied to evaluate the ppFEV1 response to LUM/IVA administration and assess the effect of long-acting bronchodilators (LABDs) and short-acting bronchodilators (SABDs) on ppFEV1 response...
November 25, 2016: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/27875677/a-case-report-of-pregnancy-during-use%C3%A2-of-targeted-therapeutics-for-cystic%C3%A2-fibrosis
#8
Sigrid Ladores, Traci M Kazmerski, Steven M Rowe
New therapeutics, such as ivacaftor, and the combination drug lumacaftor/ivacaftor that target the underlying genetic cause of cystic fibrosis are being hailed as game-changers in this era of personalized medicine. Although these drugs improve lung function, their effects on female fertility have not been studied. In this case report we describe one woman's experience with ivacaftor and her unanticipated pregnancy. Implications related to comprehensive sexual and reproductive health care for women with cystic fibrosis are presented...
January 2017: Journal of Obstetric, Gynecologic, and Neonatal Nursing: JOGNN
https://www.readbyqxmd.com/read/27821435/what-can-be-learned-from-recent-new-drug-applications-a-systematic-review-of-drug-interaction-data-for-drugs-approved-by-the-us-fda-in-2015
#9
Jingjing Yu, Zhu Zhou, Katie H Owens, Tasha K Ritchie, Isabelle Ragueneau-Majlessi
As a follow up to previous reviews, the aim of the present analysis was to systematically examine all drug metabolism, transport, pharmacokinetics (PK), and drug-drug interaction (DDI) data available in the 33 new drug applications (NDAs) approved by the Food and Drug Administration (FDA) in 2015, using the University of Washington Drug Interaction Database, and to highlight the significant findings. In vitro, a majority of the new molecular entities (NMEs) were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter...
January 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27805836/lumacaftor-ivacaftor-in-patients-aged-6-11-years-with-cystic-fibrosis-homozygous-for-f508del-cftr
#10
Carlos E Milla, Felix Ratjen, Gautham Marigowda, Fang Liu, David Waltz, Margaret Rosenfeld
RATIONALE: Combination lumacaftor/ivacaftor has been shown to improve lung function and other endpoints in patients aged ≥12 years with cystic fibrosis homozygous for F508del-CFTR but has not been assessed in younger patients. OBJECTIVES: This open-label phase 3 trial evaluated the safety, tolerability, pharmacodynamics, and efficacy of lumacaftor/ivacaftor combination therapy in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR. METHODS: Patients (N = 58) received 200 mg lumacaftor/250 mg ivacaftor orally every 12 hours for 24 weeks in addition to their existing cystic fibrosis medications...
November 2, 2016: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/27804127/can-cystic-fibrosis-patients-finally-catch-a-breath-with-lumacaftor-ivacaftor
#11
REVIEW
E K Schneider, F Reyes-Ortega, J Li, T Velkov
Cystic fibrosis (CF) is a life-limiting disease caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) activity. The recent US Food and Drug Administration (FDA) approval of lumacaftor combined with ivacaftor (Orkambi) targets patients with the F508del-CFTR. The question remains: Is this breakthrough combination therapy the "magic-bullet" cure for the vast majority of patients with CF? This review covers the contemporary clinical and scientific knowledge-base for lumacaftor/ivacaftor and highlights the emerging issues from recent conflicting literature reports...
January 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27792891/development-of-hplc-and-lc-ms-ms-methods-for-the-analysis-of-ivacaftor-its-major-metabolites-and-lumacaftor-in-plasma-and-sputum-of-cystic-fibrosis-patients-treated-with-orkambi-or-kalydeco
#12
Elena K Schneider, Felisa Reyes-Ortega, John W Wilson, Tom Kotsimbos, Dominic Keating, Jian Li, Tony Velkov
ORKAMBI (ivacaftor-lumacaftor [LUMA]) and KALYDECO (ivacaftor; IVA) are two new breakthrough cystic fibrosis (CF) drugs that directly modulate the activity and trafficking of the defective CFTR underlying the CF disease state. Currently, no therapeutic drug monitoring assays exist for these very expensive, albeit, important drugs. In this study, for the first time HPLC and LC-MS methods were developed and validated for rapid detection and quantification of IVA and its major metabolites hydroxymethyl-IVA M1 (active) and IVA-carboxylate M6 (inactive); and LUMA in the plasma and sputum of CF patients...
December 1, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/27662106/therapeutic-challenges-posed-by-critical-drug-drug-interactions-in-cystic-fibrosis
#13
Cameron L Jordan, Terry L Noah, Marianna M Henry
This review seeks to re-introduce cystic fibrosis (CF) clinicians to the pharmacology of drug-drug interactions among medications commonly used in CF and provide a framework for understanding these interactions among medications outside the scope of this discussion. We here focus on drugs impacted by the cytochrome P-450 (CYP450) enzyme system and on interactions involving antimicrobials, psychotropic medications, and cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Particular attention is needed when prescribing rifampin, azole antifungals and the CFTR modulators, ivacaftor, and lumacaftor/ivacaftor, in combination with other medications...
October 2016: Pediatric Pulmonology
https://www.readbyqxmd.com/read/27660821/analysis-of-cystic-fibrosis-associated-p67l-cftr-illustrates-barriers-to-personalized-therapeutics-for-orphan-diseases
#14
Carleen M Sabusap, Wei Wang, Carmel M McNicholas, W Joon Chung, Lianwu Fu, Hui Wen, Marina Mazur, Kevin L Kirk, James F Collawn, Jeong S Hong, Eric J Sorscher
Emerging knowledge indicates the difficulty in categorizing unusual cystic fibrosis (CF) mutations, with regard to both pathogenic mechanism and theratype. As case in point, we present data concerning P67L mutation of the cystic fibrosis transmembrane conductance regulator (CFTR), a defect carried by a small number of individuals with CF and sometimes attributed to a channel conductance abnormality. Findings from our laboratory and others establish that P67L causes protein misfolding, disrupts maturation, confers gating defects, is thermally stable, and exhibits near normal conductance...
September 8, 2016: JCI Insight
https://www.readbyqxmd.com/read/27626100/an-unlikely-pair-the-antimicrobial-synergy-of-polymyxin-b-in-combination-with-the-cystic-fibrosis-transmembrane-conductance-regulator-drugs-kalydeco-and-orkambi
#15
Elena K Schneider, Mohammad A K Azad, Mei-Ling Han, Qi Tony Zhou, Jiping Wang, Johnny X Huang, Matthew A Cooper, Yohei Doi, Mark A Baker, Phillip J Bergen, Mark T Muller, Jian Li, Tony Velkov
Novel combination therapies are desperately needed for combating lung infections caused by bacterial "superbugs". This study aimed to investigate the synergistic antibacterial activity of polymyxin B in combination with the cystic fibrosis (CF) drugs KALYDECO (ivacaftor) and ORKAMBI (ivacaftor + lumacaftor) against Gram-negative pathogens that commonly colonize the CF lung, in particular, the problematic Pseudomonas aeruginosa. The in vitro synergistic activity of polymyxin B combined with ivacaftor or lumacaftor was assessed using checkerboard and static time-kill assays against a panel of polymyxin-susceptible and polymyxin-resistant P...
July 8, 2016: ACS Infectious Diseases
https://www.readbyqxmd.com/read/27614011/the-investigational-cystic-fibrosis-drug-trimethylangelicin-directly-modulates-cftr-by-stabilizing-the-first-membrane-spanning-domain
#16
Onofrio Laselva, Steven Molinski, Valeria Casavola, Christine E Bear
Cystic Fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The most common mutation, deletion of phenylalanine 508 (F508del), disrupts tertiary assembly, causing protein misprocessing and loss of CFTR function in epithelial tissues. Lumacaftor (VX-809) is a Class 1 corrector molecule shown to partially rescue misprocessing of F508del and together with the potentiator of channel activity: ivacaftor (VX-770) has been approved for treatment of CF patients homozygous for the F508del mutation...
November 1, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27450143/brivaracetam-lumacaftor-ivacaftor-and-deoxycholic-acid
#17
Daniel A Hussar, Jerry Rachel George
No abstract text is available yet for this article.
July 2016: Journal of the American Pharmacists Association: JAPhA
https://www.readbyqxmd.com/read/27394157/lumacaftor-ivacaftor-a-review-in-cystic-fibrosis
#18
Emma D Deeks
Lumacaftor/ivacaftor (Orkambi™) is a fixed-dose tablet containing a corrector (lumacaftor) and potentiator (ivacaftor) of the cystic fibrosis transmembrane conductance regulator (CFTR) and is the first therapy approved to treat the underlying cause of cystic fibrosis in patients (aged ≥12 years) homozygous for the most common CFTR mutation, F508del. Lumacaftor improves the processing of F508del CFTR and its transport to the cell surface, while ivacaftor increases the channel's open probability and transport of chloride...
August 2016: Drugs
https://www.readbyqxmd.com/read/27393775/chronic-rhinosinusitis-in-patients-with-cystic-fibrosis
#19
Daniel L Hamilos
Chronic rhinosinusitis (CRS) is highly prevalent in patients with cystic fibrosis (CF) and accounts for significant morbidity and contribution to CF lung disease. Mutations of the cystic fibrosis transmembrane regulator gene occur with increased prevalence in patients with CRS without CF, suggesting some contribution to CRS pathophysiology. Nasal polyps (NPs) occur with increased prevalence in patients with CF of all ages and have a more neutrophilic appearance with fewer eosinophils and increased submucosal glandular elements in comparison to NPs from patients without CF...
July 2016: Journal of Allergy and Clinical Immunology in Practice
https://www.readbyqxmd.com/read/27334259/characterizing-responses-to-cftr-modulating-drugs-using-rectal-organoids-derived-from-subjects-with-cystic-fibrosis
#20
Johanna F Dekkers, Gitte Berkers, Evelien Kruisselbrink, Annelotte Vonk, Hugo R de Jonge, Hettie M Janssens, Inez Bronsveld, Eduard A van de Graaf, Edward E S Nieuwenhuis, Roderick H J Houwen, Frank P Vleggaar, Johanna C Escher, Yolanda B de Rijke, Christof J Majoor, Harry G M Heijerman, Karin M de Winter-de Groot, Hans Clevers, Cornelis K van der Ent, Jeffrey M Beekman
Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations...
June 22, 2016: Science Translational Medicine
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