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Ivacaftor

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https://www.readbyqxmd.com/read/27898234/lumacaftor-ivacaftor-treatment-of-patients-with-cystic-fibrosis-heterozygous-for-f508del-cftr
#1
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
#2
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
#3
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...
November 19, 2016: Journal of Obstetric, Gynecologic, and Neonatal Nursing: JOGNN
https://www.readbyqxmd.com/read/27812499/the-use-of-ivacaftor-in-cftr-mutations-resulting-in-residual-functioning-protein
#4
S Guigui, J Wang, R I Cohen
INTRODUCTION: Ivacaftor, a cystic fibrosis transmembrane regulator (CFTR) potentiator is currently approved for use in individuals with class III gating mutations and the R117H mutation, a non-gating mutation with residual functioning CFTR. Nevertheless, ivacaftor may also be effective in individuals who have CF mutations giving rise to a residual functioning protein. However, aside from case reports involving a single patient, little data exist on the use of ivacaftor in such individuals...
2016: Respiratory Medicine Case Reports
https://www.readbyqxmd.com/read/27805836/lumacaftor-ivacaftor-in-patients-aged-6-11-years-with-cystic-fibrosis-homozygous-for-f508del-cftr
#5
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-orkambi
#6
REVIEW
Elena K Schneider, Felisa Reyes-Ortega, Jian Li, Tony Velkov
Cystic fibrosis is a life limiting disease caused by defective or deficient cystic fibrosis trans-membrane conductance regulator (CFTR) activity. The recent 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 the vast majority of patients with CF? This review covers the contemporary clinical and scientific knowledge-base for Orkambi and highlights the emerging issues from recent conflicting literature reports...
November 2, 2016: 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
#7
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...
October 24, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/27773592/correlation-of-sweat-chloride-and-percent-predicted-fev1-in-cystic-fibrosis-patients-treated-with-ivacaftor
#8
Meredith C Fidler, Jack Beusmans, Paul Panorchan, Frederick Van Goor
Ivacaftor, a CFTR potentiator that enhances chloride transport by acting directly on CFTR to increase its channel gating activity, has been evaluated in patients with different CFTR mutations. Several previous analyses have reported no statistical correlation between change from baseline in ppFEV1 and reduction in sweat chloride levels for individuals treated with ivacaftor. The objective of the post hoc analysis described here was to expand upon previous analyses and evaluate the correlation between sweat chloride levels and absolute ppFEV1 changes across multiple cohorts of patients with different CF-causing mutations who were treated with ivacaftor...
October 20, 2016: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/27772929/breakthrough-treatment-in-cystic-fibrosis-ivacaftor-and-sweat-chloride
#9
John Massie
No abstract text is available yet for this article.
February 2016: Pathology
https://www.readbyqxmd.com/read/27768743/evaporimeter-and-bubble-imaging-measures-of-sweat-gland-secretion-rates
#10
Jeeyeon Kim, Miesha Farahmand, Colleen Dunn, Zoe Davies, Eric Frisbee, Carlos Milla, Jeffrey J Wine
Beta-adrenergically-stimulated sweat rates determined by evaporimetry or by sweat bubble imaging are useful for measuring CFTR function because they provide a near-linear readout across almost the full range of CFTR function. They differentiate cystic fibrosis (CF) subjects from CF carriers and carriers from controls. However, evaporimetry, unlike bubble imaging, appears to be unable to detect improved levels of CFTR function in G551D subjects taking the CFTR modulator ivacaftor. Here, we quantify the sensitivity of evaporimetry and bubble imaging methods for assessing low levels of CFTR-dependent sweat rates...
2016: PloS One
https://www.readbyqxmd.com/read/27745802/bone-demineralization-is-improved-by-ivacaftor-in-patients-with-cystic-fibrosis-carrying-the-p-gly551asp-mutation
#11
Isabelle Sermet-Gaudelus, Martial Delion, Isabelle Durieu, Jacky Jacquot, Dominique Hubert
Low bone mineral density (BMD) is a common problem in adults with cystic fibrosis (CF), the etiology of which is multifactorial. In this study, we provide the first evidence that ivacaftor improves BMD in CF patients carrying the p.Gly551Asp mutation. Consistently, in vitro experiments with TNF-α-stimulated primary F508del-CFTR osteoblasts demonstrated that correction of p.Phe508del-CFTR markedly decreased RANKL protein production, a major factor of bone resorption. These clinical and fundamental observations suggest that rescue of mutated CFTR protein improves bone remodeling and support the link between CFTR and bone cell physiology...
October 10, 2016: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/27707539/therapeutic-benefit-observed-with-the-cftr-potentiator-ivacaftor-in-a-cf-patient-homozygous-for-the-w1282x-cftr-nonsense-mutation
#12
Venkateshwar Mutyam, Emily Falk Libby, Ning Peng, Denis Hadjiliadis, Michael Bonk, George M Solomon, Steven M Rowe
Premature termination codons (PTCs) in cystic fibrosis transmembrane conductance regulator (CFTR) gene result in nonfunctional CFTR protein and are the proximate cause of ~11% of CF causing alleles. Aminoglycosides and other novel agents are known to induce translational readthrough of PTCs, a potential therapeutic approach. Among PTCs, W1282X CFTR is unique, as it is a C-terminal CFTR mutation that can exhibit partial activity, even in the truncated state. The potentiator ivacaftor (VX-770) is approved for treating CF patients with G551D and other gating mutations...
October 1, 2016: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
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/27659740/changes-of-cftr-functional-measurements-and-clinical-improvements-in-cystic-fibrosis-patients-with-non-p-gly551asp-gating-mutations-treated-with-ivacaftor
#15
Myriam Mesbahi, Michal Shteinberg, Michael Wilschanski, Aurelie Hatton, Thao Nguyen-Khoa, Hannah Friedman, Michael Cohen, Virginie Escabasse, Muriel Le Bourgeois, Vicenzina Lucidi, Isabelle Sermet-Gaudelus, Laurence Bassinet, Galit Livnat
Ivacaftor, a CFTR potentiator, has been found to improve CFTR function and clinical outcomes in patients with cystic fibrosis (CF) gating mutations. We investigated the effects of ivacaftor on CFTR functional measurement in CF patients carrying gating mutations other than p.Gly551Asp. Two siblings aged 13 and 12 carrying the p.Ser549Asn mutation, two sisters (45 and 43years old) compound heterozygotes for p.Asp1152His and p.Gly1244Glu, a 37year old man homozygous for the p.Gly1244Glu mutation, and a 7year old girl with p...
September 19, 2016: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/27636560/pharmgkb-summary-ivacaftor-pathway-pharmacokinetics-pharmacodynamics
#16
Alison E Fohner, Ellen M McDonagh, John P Clancy, Michelle Whirl Carrillo, Russ B Altman, Teri E Klein
No abstract text is available yet for this article.
January 2017: Pharmacogenetics and Genomics
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
#17
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
#18
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/27585394/the-cftr-potentiator-ivacaftor-augments-mucociliary-clearance-abrogating-cftr-inhibition-by-cigarette-smoke
#19
S Vamsee Raju, Vivian Y Lin, Limbo Liu, Carmel M McNicholas, Suman Karki, Peter A Sloane, Liping Tang, Patricia L Jackson, Wei Wang, Landon Wilson, Kevin J Macon, Marina Mazur, John Kappes, Lawrence J DeLucas, Stephen Barnes, Kevin Kirk, Guillermo T Tearney, Steven M Rowe
RATIONALE: Acquired CFTR dysfunction may contribute to COPD pathogenesis and is a potential therapeutic target. OBJECTIVES: To determine the acute effects of cigarette smoke on ion transport and the mucociliary transport apparatus, their mechanistic basis; and whether deleterious effects could be reversed with the CFTR potentiator ivacaftor (VX-770). METHODS: Primary human bronchial epithelial cells (HBE) and human bronchi were exposed to cigarette smoke extract (CSE) and/or ivacaftor...
September 1, 2016: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/27571897/cystic-fibrosis-gene-modifier-slc26a9-modulates-airway-response-to-cftr-directed-therapeutics
#20
Lisa J Strug, Tanja Gonska, Gengming He, Katherine Keenan, Wan Ip, Pierre-Yves Boëlle, Fan Lin, Naim Panjwani, Jiafen Gong, Weili Li, David Soave, Bowei Xiao, Elizabeth Tullis, Harvey Rabin, Michael D Parkins, April Price, Peter C Zuberbuhler, Harriet Corvol, Felix Ratjen, Lei Sun, Christine E Bear, Johanna M Rommens
Cystic fibrosis is realizing the promise of personalized medicine. Recent advances in drug development that target the causal CFTR directly result in lung function improvement, but variability in response is demanding better prediction of outcomes to improve management decisions. The genetic modifier SLC26A9 contributes to disease severity in the CF pancreas and intestine at birth and here we assess its relationship with disease severity and therapeutic response in the airways. SLC26A9 association with lung disease was assessed in individuals from the Canadian and French CF Gene Modifier consortia with CFTR-gating mutations and in those homozygous for the common Phe508del mutation...
August 29, 2016: Human Molecular Genetics
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