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Ivacaftor

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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/28068001/in-vivo-and-in-vitro-ivacaftor-response-in-cystic-fibrosis-patients-with-residual-cftr-function-n-of-1-studies
#2
Meghan E McGarry, Beate Illek, Ngoc P Ly, Lorna Zlock, Sabrina Olshansky, Courtney Moreno, Walter E Finkbeiner, Dennis W Nielson
RATIONALE: Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, decreases sweat chloride concentration, and improves pulmonary function in 6% of cystic fibrosis (CF) patients with specific CFTR mutations. Ivacaftor increases chloride transport in many other CFTR mutations in non-human cells, if CFTR is in the epithelium. Some CF patients have CFTR in the epithelium with residual CFTR function. The effect of ivacaftor in these patients is unknown. METHODS: This was a series of randomized, crossover N-of-1 trials of ivacaftor and placebo in CF patients ≥8 years old with potential residual CFTR function (intermediate sweat chloride concentration, pancreatic sufficient, or mild bronchiectasis on chest CT)...
January 9, 2017: Pediatric Pulmonology
https://www.readbyqxmd.com/read/28042521/cftr-modulator-therapies-in-pediatric-cystic-fibrosis-focus-on-ivacaftor
#3
Elizabeth L Kramer, John P Clancy
INTRODUCTION: Mutations in the cystic fibrosis transmembrane conductance regulator protein (CFTR) cause cystic fibrosis (CF), a disease with life threatening pulmonary and gastrointestinal manifestations. Recent breakthrough therapies restore function to select disease-causing CFTR mutations. Ivacaftor is a small molecule that increases the open channel probability of certain CFTR mutations, producing clear evidence of bioactivity and efficacy in pediatric CF patients. CFTR modulators represent a significant advancement in CF treatment...
October 2016: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/28012258/functional-defect-of-variants-in-the-adenosine-triphosphate-binding-sites-of-abcb4-and-their-rescue-by-the-cystic-fibrosis-transmembrane-conductance-regulator-potentiator-ivacaftor-vx-770
#4
Jean-Louis Delaunay, Alix Bruneau, Brice Hoffmann, Anne-Marie Durand-Schneider, Véronique Barbu, Emmanuel Jacquemin, Michèle Maurice, Chantal Housset, Isabelle Callebaut, Tounsia Aït-Slimane
: ABCB4 (MDR3) is an adenosine triphosphate (ATP)-binding cassette (ABC) transporter expressed at the canalicular membrane of hepatocytes, where it mediates phosphatidylcholine (PC) secretion. Variations in the ABCB4 gene are responsible for several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), a rare disease that can be lethal in the absence of liver transplantation. In this study, we investigated the effect and potential rescue of ABCB4 missense variations that reside in the highly conserved motifs of ABC transporters, involved in ATP binding...
November 5, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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/27812499/the-use-of-ivacaftor-in-cftr-mutations-resulting-in-residual-functioning-protein
#12
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
#13
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
#14
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
#15
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/27773592/correlation-of-sweat-chloride-and-percent-predicted-fev1-in-cystic-fibrosis-patients-treated-with-ivacaftor
#16
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
#17
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
#18
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
#19
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...
November 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
#20
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
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