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Ivacaftor

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https://www.readbyqxmd.com/read/29155707/optimized-lc-ms-ms-method-for-the-high-throughput-analysis-of-clinical-samples-of-ivacaftor-its-major-metabolites-and-lumacaftor-in-biological-fluids-of-cystic-fibrosis-patients
#1
Elena K Schneider, Felisa Reyes-Ortega, Jian Li, Tony Velkov
Defects in the cystic fibrosis trans-membrane conductance regulator (CFTR) are the cause of cystic fibrosis (CF), a disease with life-threatening pulmonary manifestations. Ivacaftor (IVA) and ivacaftor-lumacaftor (LUMA) combination are two new breakthrough CF drugs that directly modulate the activity and trafficking of the defective CFTR-protein. However, there is still a dearth of understanding on pharmacokinetic/pharmacodynamic parameters and the pharmacology of ivacaftor and lumacaftor. The HPLC-MS technique for the simultaneous analysis of the concentrations of ivacaftor, hydroxymethyl-ivacaftor, ivacaftor-carboxylate, and lumacaftor in biological fluids in patients receiving standard ivacaftor or ivacaftor-lumacaftor combination therapy has previously been developed by our group and partially validated to FDA standards...
October 15, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29148763/discovery-of-n-3-carbamoyl-5-5-7-7-tetramethyl-5-7-dihydro-4h-thieno-2-3-c-pyran-2-yl-lh-pyrazole-5-carboxamide-glpg1837-a-novel-potentiator-which-can-open-class-iii-mutant-cystic-fibrosis-transmembrane-conductance-regulator-cftr-channels-to-a-high-extent
#2
Steven Emiel Van der Plas, Hans Kelgtermans, Tom De Munck, Sébastien Laurent Xavier Martina, Sébastien Dropsit, Evelyne Quinton, Ann De Blieck, Caroline Joannesse, Linda Tomaskovic, Mia Jans, Thierry Christophe, Ellen Van der Aar, Monica Borgonovi, Luc Nelles, Maarten Gees, Pieter Fw Stouten, Jan Van Der Schueren, Oscar Mammoliti, Katja Conrath, Martin J Andrews
Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Orkambi, it has been shown that CFTR function can be partially restored by administering one or more small molecules. These molecules aim at either enhancing the amount of CFTR on the cell surface (correctors) or at improving the gating function of the CFTR channel (potentiators). Here we describe the discovery of a novel potentiator GLPG1837 which shows enhanced efficacy on CFTR mutants harboring Class III mutations compared to Ivacaftor, the first marketed potentiator...
November 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29146575/lumacaftor-vx-809-restores-the-ability-of-cf-macrophages-to-phagocytose-and-kill-pseudomonas-aeruginosa
#3
Roxanna Barnaby, Katja Koeppen, Amanda Nymon, Thomas H Hampton, Brent Berwin, Alix Ashare, Bruce Stanton
Cystic Fibrosis (CF), the most common lethal genetic disease in Caucasians, is characterized by chronic bacterial lung infection and excessive inflammation, which leads to progressive loss of lung function, and premature death. Although ivacaftor (VX-770) and the combination of ivacaftor and lumacaftor (VX-809) improve lung function in CF patients with the Gly551Asp and del508Phe mutation, respectively, the effects of these drugs on the function of human CF macrophages are unknown. Thus, studies were conducted to examine the effects of lumacaftor alone and in combination with ivacaftor (i...
November 16, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/29126871/lumacaftor-ivacaftor-in-patients-with-cystic-fibrosis-and-advanced-lung-disease-homozygous-for-f508del-cftr
#4
Jennifer L Taylor-Cousar, Manu Jain, Tara Lynn Barto, Tarik Haddad, Jeffrey Atkinson, Simon Tian, Rui Tang, Gautham Marigowda, David Waltz, Joseph Pilewski
OBJECTIVE: Evaluation of the safety, tolerability, and efficacy of lumacaftor/ivacaftor in patients with cystic fibrosis (CF) with severe lung disease. METHODS: Patients with CF 12 years of age and older, homozygous for F508del-CFTR, with percent predicted forced expiratory volume in 1 second (ppFEV1) <40 received lumacaftor 400 mg/ivacaftor 250mg every 12h (full dose) for 24weeks in an open-label, prospective study (NCT02390219). Dose modification to half dose for 1-2weeks (including at initiation) was permitted...
November 7, 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/29103672/effects-of-ivacaftor-in-three-pediatric-siblings-with-cystic-fibrosis-carrying-the-mutations-g551d-and-f508del
#5
Jochen G Mainz, Christin Arnold, Julia Hentschel, Harold Tabori
No abstract text is available yet for this article.
November 2, 2017: Archivos de Bronconeumología
https://www.readbyqxmd.com/read/29099344/tezacaftor-ivacaftor-in-patients-with-cystic-fibrosis-homozygous-for-phe508del
#6
Jennifer L Taylor-Cousar, Anne Munck, Edward F McKone, Cornelis K van der Ent, Alexander Moeller, Christopher Simard, Linda T Wang, Edward P Ingenito, Charlotte McKee, Yimeng Lu, Julie Lekstrom-Himes, J Stuart Elborn
Background Combination treatment with the cystic fibrosis transmembrane conductance regulator (CFTR) modulators tezacaftor (VX-661) and ivacaftor (VX-770) was designed to target the underlying cause of disease in patients with cystic fibrosis. Methods In this phase 3, randomized, double-blind, multicenter, placebo-controlled, parallel-group trial, we evaluated combination therapy with tezacaftor and ivacaftor in patients 12 years of age or older who had cystic fibrosis and were homozygous for the CFTR Phe508del mutation...
November 3, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29099333/tezacaftor-ivacaftor-in-residual-function-heterozygotes-with-cystic-fibrosis
#7
Steven M Rowe, Cori Daines, Felix C Ringshausen, Eitan Kerem, John Wilson, Elizabeth Tullis, Nitin Nair, Christopher Simard, Linda Han, Edward P Ingenito, Charlotte McKee, Julie Lekstrom-Himes, Jane C Davies
Background Cystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene that lead to progressive respiratory decline. Some mutant CFTR proteins show residual function and respond to the CFTR potentiator ivacaftor in vitro, whereas ivacaftor alone does not restore activity to Phe508del mutant CFTR. Methods We conducted a randomized, double-blind, placebo-controlled, phase 3, crossover trial to evaluate the efficacy and safety of ivacaftor alone or in combination with tezacaftor, a CFTR corrector, in 248 patients 12 years of age or older who had cystic fibrosis and were heterozygous for the Phe508del mutation and a CFTR mutation associated with residual CFTR function...
November 3, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29079713/a-common-mechanism-for-cftr-potentiators
#8
Han-I Yeh, Yoshiro Sohma, Katja Conrath, Tzyh-Chang Hwang
Cystic fibrosis (CF) is a channelopathy caused by loss-of-function mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a phosphorylation-activated and adenosine triphosphate (ATP)-gated chloride channel. In the past few years, high-throughput drug screening has successfully realized the first US Food and Drug Administration-approved therapy for CF, called ivacaftor (or VX-770). A more recent CFTR potentiator, GLPG1837 (N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide), has been shown to exhibit a higher efficacy than ivacaftor for the G551D mutation, yet the underlying mechanism of GLPG1837 remains unclear...
October 27, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/29079142/ivacaftor-withdrawal-syndrome-in-cystic-fibrosis-patients-with-the-g551d-mutation
#9
Aaron T Trimble, Scott H Donaldson
Ivacaftor use can lead to dramatic health improvements in cystic fibrosis (CF) patients with gating mutations. Here, we report five instances of dramatic clinical decline following withdrawal of ivacaftor in three individuals with the G551D-CFTR mutation. In each case, the patient's lung function and symptoms rapidly deteriorated after cessation of treatment. Awareness of this phenomenon should inform both clinical practices as well as the design of future clinical trials of highly active CFTR modulators.
October 24, 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/29073476/cftr-potentiators-from-bench-to-bedside
#10
REVIEW
Kang-Yang Jih, Wen-Ying Lin, Yoshiro Sohma, Tzyh-Chang Hwang
One major breakthrough in cystic fibrosis research in the past decade is the development of drugs that target the root cause of the disease-dysfunctional CFTR protein. One of the compounds, Ivacaftor or Kalydeco, which has been approved for clinical use since 2012, acts by promoting the gating function of CFTR. Our recent studies have led to a gating model that features energetic coupling between nucleotide-binding domain (NBD) dimerization and gate opening/closing in CFTR's transmembrane domains (TMDs). Based on this model, we showed that ATP analogs can enhance CFTR gating by facilitating NBD dimerization, whereas Ivacaftor works by stabilizing the open channel conformation of the TMDs...
November 5, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29046368/enhancement-of-lung-gene-delivery-after-aerosol-a-new-strategy-using-non-viral-complexes-with-antibacterial-properties
#11
Angelique Mottais, Tony Le Gall, Yann Sibiril, Julian Ravel, Véronique Laurent, Frédérique d'Arbonneau, Tristan Montier
The pathophysiology of obstructive pulmonary diseases, such as cystic fibrosis, leads to the development of chronic infections in the respiratory tract. Thus, the symptomatic management of the disease requires, in particular, repetitive antibiotherapy. Besides these antibacterial treatments, certain pathologies, such as cystic fibrosis or chronic obstructive pulmonary disease, require the intake of many drugs. This simultaneous absorption may lead to undesired drug interactions. For example, Orkambi® (lumacaftor/Ivacaftor, Vertex), a pharmacological drug employed to treat F508del patients, cannot be used with antibiotics such as rifampicin or rifabutin (rifamycin family) which are necessary to treat Mycobacteriaceae...
October 18, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/29045347/reduction-of-recurrence-risk-of-pancreatitis-in-cystic-fibrosis-with-ivacaftor-case-series
#12
Andres Carrion, Drucy S Borowitz, Steven D Freedman, Christopher M Siracusa, Jennifer L Goralski, Denis Hadjiladis, Saumini Srinivasan, Dennis C Stokes
The effect of ivacaftor in cystic fibrosis (CF) patients with recurrent pancreatitis is unknown. We conducted a multicenter retrospective study of CF patients taking ivacaftor who had a history of recurrent pancreatitis. During the first three months of therapy, only one of the six patients had an episode of pancreatitis, which was managed on an outpatient basis. Between three and twelve months on ivacaftor therapy, none of the patients had recurrence of pancreatitis or required hospitalization. The use of ivacaftor was associated with a reduced frequency and recurrence rate of pancreatitis in CF patients...
October 17, 2017: Journal of Pediatric Gastroenterology and Nutrition
https://www.readbyqxmd.com/read/29042177/antibiotic-exposure-and-interpersonal-variance-mask-the-effect-of-ivacaftor-on-respiratory-microbiota-composition
#13
Anton Y Peleg, Jocelyn M Choo, Katherine M Langan, Deirdre Edgeworth, Dominic Keating, John Wilson, Geraint B Rogers, Tom Kotsimbos
BACKGROUND: G551D is a class III mutation of the cystic fibrosis transmembrane regulator (CFTR) that results in impaired chloride channel function in cystic fibrosis (CF). Ivacaftor, a CFTR-potentiating agent improves sweat chloride, weight, lung function, and pulmonary exacerbation rate in CF patients with G551D mutations, but its effect on the airway microbiome remains poorly characterised. METHODS: Twenty CF patients with at least one G551D mutation from a single centre were recruited to a 4month double-blind, placebo-controlled, crossover study of ivacaftor with 28days of active treatment...
October 15, 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/29037527/cork-study-in-cystic-fibrosis-sustained-improvements-in-ultra-low-dose-chest-ct-scores-after-cftr-modulation-with-ivacaftor
#14
Nicola J Ronan, Gisli G Einarsson, Maria Twomey, Denver Mooney, David Mullane, Muireann NiChroinin, Grace O'Callaghan, Fergus Shanahan, Desmond M Murphy, Owen J O'Connor, Cathy A Shortt, Michael M Tunney, Joseph A Eustace, Michael M Maher, J Stuart Elborn, Barry J Plant
BACKGROUND: Ivacaftor produces significant clinical benefit in patients with cystic fibrosis (CF) with the G551D mutation. Prevalence of this mutation at the Cork CF Centre is 23%. This study assessed the impact of CFTR modulation on multiple modalities of patient assessment. METHODS: Thirty-three patients with the G551D mutation were assessed at baseline and prospectively every 3 months for 1 year after initiation of ivacaftor. Change in ultra-low-dose chest CT scans, blood inflammatory mediators, and the sputum microbiome were assessed...
October 14, 2017: Chest
https://www.readbyqxmd.com/read/29035122/homogeneity-of-aerosol-deposition-and-mucociliary-clearance-are-improved-following-ivacaftor-treatment-in-cystic-fibrosis
#15
William D Bennett, Kirby L Zeman, Beth L Laube, Jihong Wu, Gail Sharpless, Peter J Mogayzel, Scott H Donaldson
BACKGROUND: Using planar gamma scintigraphy of inhaled radioaerosols, we have developed new analytical methods for assessing homogeneity of aerosol deposition and time-dependent particle clearance on a pixel-by-pixel basis, and applied them to a therapeutic cystic fibrosis (CF) study. METHODS: At baseline and 1 month after beginning treatment with ivacaftor, a cystic fibrosis transmembrane regulator modulator for CF patients with at least one copy of the G551D mutation (n = 13), initial deposition and subsequent mucociliary clearance (MCC) of radiolabeled particles ((99m)Technetium-sulfur colloid, 5 μm mass median aerodynamic diameter) inhaled under controlled breathing conditions were measured...
October 16, 2017: Journal of Aerosol Medicine and Pulmonary Drug Delivery
https://www.readbyqxmd.com/read/29032041/transformative-therapies-for-rare-cftr-missense-alleles
#16
REVIEW
Kathryn E Oliver, Sangwoo T Han, Eric J Sorscher, Garry R Cutting
With over 1900 variants reported in the cystic fibrosis transmembrane conductance regulator (CFTR), enhanced understanding of cystic fibrosis (CF) genotype-phenotype correlation represents an important and expanding area of research. The potentiator Ivacaftor has proven an effective treatment for a subset of individuals carrying missense variants, particularly those that impact CFTR gating. Therapeutic efforts have recently focused on correcting the basic defect resulting from the common F508del variant, as well as many less frequent missense alleles...
October 13, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29020455/the-fda-s-experience-with-ivacaftor-in-cystic-fibrosis-establishing-efficacy-using-in-vitro-data-in-lieu-of-a-clinical-trial
#17
Anthony G Durmowicz, Robert Lim, Hobart Rogers, Curtis J Rosebraugh, Badrul A Chowdhury
No abstract text is available yet for this article.
October 11, 2017: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/28992608/where-are-we-with-transformational-therapies-for-patients-with-cystic-fibrosis
#18
REVIEW
Kris De Boeck, Jane C Davies
The disease cystic fibrosis (CF) is caused by a disturbance in the synthesis or function of the CFTR anion channel. Several types of small molecules geared to overcome the underlying defect in specific patient groups are in the clinical pipeline. Two drugs have obtained regulatory approval. The potentiator ivacaftor brings major clinical benefit in patients with CFTR protein expression at the cell membrane; the combination ivacaftor plus corrector lumacaftor brings a modest benefit for patients homozygous for the most common mutation F508del...
October 6, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28978522/cigarette-smoke-activates-cftr-through-ros-stimulated-camp-signaling-in-human-bronchial-epithelial-cells
#19
Francis H Wong, Asmahan AbuArish, Elizabeth Matthes, Mark J Turner, Lana E Greene, Alexandre Cloutier, Renaud Robert, David Y Thomas, Gonzalo Cosa, Andre M Cantin, John W Hanrahan
Air pollution stimulates airway epithelial secretion through a cholinergic reflex that is unaffected in cystic fibrosis (CF), yet a strong correlation is observed between passive smoke exposure in the home and impaired lung function in CF children. Our aim was to study the effects of low smoke concentrations on CFTR function in vitro. Cigarette smoke extract stimulated robust anion secretion that was transient, mediated by cystic fibrosis transmembrane conductance regulator (CFTR), and dependent on cAMP-dependent protein kinase activation...
October 4, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28953499/cystic-fibrosis-transmembrane-conductance-regulator-potentiation-as-a-therapeutic-strategy-for-pulmonary-edema-a-proof-of-concept-study-in-pigs
#20
Xiaopeng Li, Luis G Vargas Buonfiglio, Ryan J Adam, David A Stoltz, Joseph Zabner, Alejandro P Comellas
OBJECTIVES: To determine the feasibility of using a cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX-770/Kalydeco, Vertex Pharmaceuticals, Boston, MA), as a therapeutic strategy for treating pulmonary edema. DESIGN: Prospective laboratory animal investigation. SETTING: Animal research laboratory. SUBJECTS: Newborn and 3 days to 1 week old pigs. INTERVENTIONS: Hydrostatic pulmonary edema was induced in pigs by acute volume overload...
December 2017: Critical Care Medicine
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