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https://www.readbyqxmd.com/read/29342367/cystic-fibrosis-pulmonary-guidelines-use-of-cftr-modulator-therapy-in-patients-with-cystic-fibrosis
#1
Clement L Ren, Rebecca L Morgan, Christopher Oermann, Helaine E Resnick, Cynthia Brady, Annette Campbell, Richard DeNagel, Margaret Guill, Jeffrey Hoag, Andrew Lipton, Thomas Newton, Stacy Peters, Donna Beth Willey-Courand, Edward T Naureckas
BACKGROUND: CFTR modulators are a new class of medications that target the underlying defect in in cystic fibrosis (CF). Ivacaftor (IVA) and IVA combined with lumacaftor (IVA/LUM) have been approved by the FDA for use in CF patients. However, the FDA label for these medications encompasses patient groups that were not studied as part of the drug approval process. CF clinicians, patients, and their families have recognized a need for recommendations to guide the use of these medications...
January 17, 2018: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/29327948/effects-of-lumacaftor-ivacaftor-therapy-on-cftr-function-in-phe508del-homozygous-patients-with-cystic-fibrosis
#2
Simon Y Graeber, Christian Dopfer, Lutz Naehrlich, Lena Gyulumyan, Heike Scheuermann, Stephanie Hirtz, Sabine Wege, Heimo Mairbäurl, Marie Dorda, Rebecca Hyde, Azadeh Bagheri-Hanson, Claudia Rueckes-Nilges, Sebastian Fischer, Marcus A Mall, Burkhard Tümmler
RATIONALE: The combination of the CFTR corrector lumacaftor with the potentiator ivacaftor has been approved for the treatment of patients with cystic fibrosis (CF) homozygous for the Phe508del CFTR mutation. The phase 3 trials examined clinical outcomes, but did not evaluate CFTR function in patients. OBJECTIVES: To examine the effect of lumacaftor-ivacaftor on biomarkers of CFTR function in Phe508del homozygous CF patients aged 12 years and older. METHODS: This prospective observational study assessed clinical outcomes including FEV1 % predicted and BMI, and CFTR biomarkers including sweat chloride concentration, nasal potential difference (NPD) and intestinal current measurement (ICM) before and 8-16 weeks after initiation of lumacaftor-ivacaftor...
January 12, 2018: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/29279204/ivacaftor-restores-cftr-dependent-sweat-gland-fluid-secretion-in-cystic-fibrosis-subjects-with-s945l-alleles
#3
Jeeyeon Kim, Zoe Davies, Colleen Dunn, Jeffrey J Wine, Carlos Milla
BACKGROUND: To determine in vivo effects of CFTR modulators on mutation S945L. METHODS: We measured effects of CFTR modulators on CFTR-dependent sweating ('C-sweat') in two pancreatic sufficient cystic fibrosis (CF) subjects. S1 (S945L/G542X) took ivacaftor and S2 (S945L/F508del) took ivacaftor+tezacaftor. Sweating was stimulated pharmacologically to produce sequentially both CFTR-independent (methacholine stimulated) M-sweat and C-sweat; and the ratio of these was compared...
December 23, 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/29262343/ptentiating-cftr-for-antimicrobial-immunity
#4
Kong Chen, Jay K Kolls
Ivacaftor is a potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) that reduces Pseudomonas aeruginosa culture positivity in CF patients with unclear mechanisms. Riquelme et al. (2017) propose that improved CFTR trafficking could enhance P. aeruginosa clearance through activating the tumor suppressor PTEN.
December 19, 2017: Immunity
https://www.readbyqxmd.com/read/29249670/effect-of-lumacaftor-ivacaftor-on-glucose-metabolism-and-insulin-secretion-in-phe508del-homozygous-cystic-fibrosis-patients
#5
Jan C Thomassen, Matthias I Mueller, Miguel A Alejandre Alcazar, Ernst Rietschel, Silke van Koningsbruggen-Rietschel
OBJECTIVE: To investigate the effect of Lumacaftor/Ivacaftor on glucose metabolism and insulin secretion in patients with cystic fibrosis (CF) (Phe508del/Phe508del). METHODS: A standard oral glucose tolerance test (OGTT) and an intravenous glucose tolerance test (IVGTT) were performed to investigate glucose metabolism and insulin secretion before and after 6-8weeks of treatment with Lumacaftor/Ivacaftor in 5 Phe508del-homozygous CF patients. The area under the curve (AUC) for glucose and insulin levels was calculated using the trapezoidal approximation...
December 15, 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/29248431/tezacaftor-ivacaftor-is-safe-and-efficacious-in-patients-with-cystic-fibrosis-with-phe508del-mutations
#6
Tony Kirby
No abstract text is available yet for this article.
December 13, 2017: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/29241892/forecasting-the-long-term-clinical-and-economic-outcomes-of-lumacaftor-ivacaftor-in-cystic-fibrosis-patients-with-homozygous-phe508del-mutation
#7
Piyameth Dilokthornsakul, Mausam Patidar, Jonathan D Campbell
OBJECTIVES: To forecast lifetime outcomes and cost of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis (CF) with homozygous phe508del mutation from the US payer perspective. METHODS: A lifetime Markov model was developed from a US payer perspective. The model included five health states: 1) mild lung disease (percent predicted forced expiratory volume in 1 second [FEV1] >70%), 2) moderate lung disease (40% ≤ FEV1 ≤ 70%), 3) severe lung disease (FEV1 < 40%), 4) lung transplantation, and 5) death...
December 2017: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
https://www.readbyqxmd.com/read/29241629/the-expression-of-mirc1-mir17-92-cluster-in-sputum-samples-correlates-with-pulmonary-exacerbations-in-cystic-fibrosis-patients
#8
Kathrin Krause, Benjamin T Kopp, Mia F Tazi, Kyle Caution, Kaitlin Hamilton, Asmaa Badr, Chandra Shrestha, Dmitry Tumin, Don Hayes, Frank Robledo, Luanne Hall-Stoodley, Brett G Klamer, Xiaoli Zhang, Santiago Partida-Sanchez, Narasimham L Parinandi, Stephen E Kirkby, Duaa Dakhlallah, Karen S McCoy, Estelle Cormet-Boyaka, Amal O Amer
INTRODUCTION: Cystic fibrosis (CF) is a multi-organ disorder characterized by chronic sino-pulmonary infections and inflammation. Many patients with CF suffer from repeated pulmonary exacerbations that are predictors of worsened long-term morbidity and mortality. There are no reliable markers that associate with the onset or progression of an exacerbation or pulmonary deterioration. Previously, we found that the Mirc1/Mir17-92a cluster which is comprised of 6 microRNAs (Mirs) is highly expressed in CF mice and negatively regulates autophagy which in turn improves CF transmembrane conductance regulator (CFTR) function...
December 11, 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/29235532/investigation-of-the-effects-of-the-cftr-potentiator-ivacaftor-on-human-p-glycoprotein-abcb1
#9
Swathi Lingam, Nopnithi Thonghin, Robert C Ford
Ivacaftor is a potentiator of the CFTR chloride channel and is in worldwide clinical use for the chronic treatment of cystic fibrosis in patients. There is evidence that the bioavailability of ivacaftor in the body may be influenced by the multi-drug exporter P-glycoprotein. Here we have employed purified and reconstituted P-glycoprotein to study its interaction with ivacaftor as well as the ability of the drug to compete with a known transported substrate of the protein. We find that ivacaftor stimulates the ATPase activity of the purified protein and can compete with the transport of the fluorescent substrate Hoechst 33342...
December 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29235345/mucus-and-cell-penetrating-nanoparticles-embedded-in-nano-into-micro-formulations-for-pulmonary-delivery-of-ivacaftor-in-cystic-fibrosis
#10
Barbara Porsio, Emanuela Fabiola Craparo, Nicolò Mauro, Gaetano Giammona, Gennara Cavallaro
Here, mucus-penetrating nanoparticles for pulmonary administration of Ivacaftor in patients with cystic fibrosis (CF) were produced with the dual aim to enhance Ivacaftor delivery to the airway epithelial cells, by a rapid diffusion through the mucus barrier and, at the same time, promote Ivacaftor lung cellular uptake. Pegylated and Tat-decorated Fluorescent Nanoparticles (FNPs) were produced by nanoprecipitation, starting by two synthetic copolymers and showed nanometric sizes (~70 nm), slightly negative ζ potential and high cytocompatibility towards human bronchial epithelium cells...
December 13, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/29232160/microrna-145-antagonism-reverses-tgf-%C3%AE-inhibition-of-f508del-cftr-correction-in-airway-epithelia
#11
Farruk Lutful Kabir, Namasivayam Ambalavanan, Gang Liu, Peng Li, George M Solomon, Charitharth V Lal, Marina Mazur, Brian Halloran, Tomasz Szul, William T Gerthoffer, Steven M Rowe, William T Harris
INTRODUCTION: microRNAs (miRNAs) destabilize mRNA transcripts and inhibit protein translation. miR-145 is of particular interest in cystic fibrosis (CF) as it has a direct binding site in the 3'-untranslated region of CFTR and is upregulated by the CF genetic modifier TGF-β. HYPOTHESIS: miR-145 mediates TGF-β inhibition of CFTR synthesis and function in airway epithelia. METHODS: Primary human CF (F508del homozygous) and non-CF airway epithelial cells (AECs) were grown to terminal differentiation at air-liquid interface on permeable supports...
December 12, 2017: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/29202459/nasospheroids-permit-measurements-of-cftr-dependent-fluid-transport
#12
Jennifer S Guimbellot, Justin M Leach, Imron G Chaudhry, Nancy L Quinney, Susan E Boyles, Michael Chua, Inmaculada Aban, Ilona Jaspers, Martina Gentzsch
Expansion of novel therapeutics to all patients with cystic fibrosis (CF) requires personalized CFTR modulator therapy. We have developed nasospheroids, a primary cell culture-based model derived from individual CF patients and healthy subjects by a minimally invasive nasal biopsy. Confocal microscopy was utilized to measure CFTR activity by analyzing changes in cross-sectional area over time that resulted from CFTR-mediated ion and fluid movement. Both the rate of change over time and AUC were calculated. Non-CF nasospheroids with active CFTR-mediated ion and fluid movement showed a reduction in cross-sectional area, whereas no changes were observed in CF spheroids...
November 16, 2017: JCI Insight
https://www.readbyqxmd.com/read/29169001/ivacaftor-for-cystic-fibrosis-an-evaluation-of-real-world-utilisation-and-expenditure-in-the-irish-healthcare-setting
#13
A Corcoran, N Hickey, M Barry, C Usher, L M McCullagh
In Ireland, Ivacaftor is reimbursed, on the High-Tech Drug Scheme, for the treatment of cystic fibrosis in patients age 6 years and older who have the G551D mutation. The aim of this study was to analyse the utilisation and expenditure of Ivacaftor on this scheme in the 12 month period post-reimbursement. All patients who had received Ivacaftor (regardless of General Medical Services Scheme eligibility/ineligibility) were included. A total of 140 individuals (male=74; 53%) received Ivacaftor over the defined 12 month study period (from January 2015 to December 2015 inclusive)...
August 12, 2017: Irish Medical Journal
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
RANDOMIZED CONTROLLED TRIAL
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 23, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29099333/tezacaftor-ivacaftor-in-residual-function-heterozygotes-with-cystic-fibrosis
#20
RANDOMIZED CONTROLLED TRIAL
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 23, 2017: New England Journal of Medicine
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