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Laura J Byrnes, Yingrong Xu, Xiayang Qiu, Justin D Hall, Graham M West
Cystic Fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Mutations associated with CF cause loss-of-function in CFTR leading to salt imbalance in epithelial tissues. Kalydeco (also called VX-770 or ivacaftor) was approved for CF treatment in 2012 but little is known regarding the compound's interactions with CFTR including the site of binding or mechanisms of action. In this study we use hydrogen/deuterium exchange (HDX) coupled with mass spectrometry to assess the conformational dynamics of a thermostabilized form of CFTR in apo and ligand-bound states...
March 16, 2018: Scientific Reports
Elizabeth B Burgener, Richard B Moss
PURPOSE OF REVIEW: The aim of this study was to describe the newest development in cystic fibrosis (CF) care, CF transmembrane conductance regulator (CFTR) modulator therapies. RECENT FINDINGS: Phase II results showing CFTR modulator triple therapies are more effective than current CFTR modulators. SUMMARY: CFTR modulator therapy targets the protein defective in CF and boosts its function, but the drug must match mutation pathobiology. Ivacaftor, a CFTR potentiator, was the first modulator approved in 2012, with impressive improvement in lung function and other measures of disease in patients with gating and other residual function mutations (∼10% of CF patients)...
March 13, 2018: Current Opinion in Pediatrics
Heather S Kirkham, Francis Staskon, Nishita Hira, Darren McLane, Karl M Kilgore, Alexis Parente, Seung Kim, Gregory S Sawicki
OBJECTIVE: To compare medication adherence, pulmonary exacerbations, healthcare utilization, and costs for patients with cystic fibrosis (CF) who utilized a pharmacy-based therapy management program to a matched control group. We hypothesized that patient management services would be associated with better medication adherence, and thus require fewer visits to the emergency room or hospitalizations. METHODS: This retrospective, observational cohort study used claims data from the MORE2 claims Registry®...
March 7, 2018: Pediatric Pulmonology
Iwona Pranke, Laure Bidou, Natacha Martin, Sandra Blanchet, Aurélie Hatton, Sabrina Karri, David Cornu, Bruno Costes, Benoit Chevalier, Danielle Tondelier, Emmanuelle Girodon, Matthieu Coupet, Aleksander Edelman, Pascale Fanen, Olivier Namy, Isabelle Sermet-Gaudelus, Alexandre Hinzpeter
Premature termination codons (PTCs) are generally associated with severe forms of genetic diseases. Readthrough of in-frame PTCs using small molecules is a promising therapeutic approach. Nonetheless, the outcome of preclinical studies has been low and variable. Treatment efficacy depends on: 1) the level of drug-induced readthrough, 2) the amount of target transcripts, and 3) the activity of the recoded protein. The aim of the present study was to identify, in the cystic fibrosis transmembrane conductance regulator (CFTR) model, recoded channels from readthrough therapy that may be enhanced using CFTR modulators...
January 2018: ERJ Open Research
Jennifer S Guimbellot, Edward P Acosta, Steven M Rowe
The CFTR potentiator ivacaftor is responsible for significant clinical improvements among a subset of patients with cystic fibrosis. Because it is a substrate of the cytochrome P450 system, specifically CYP3A4/5, ivacaftor is subject to significant drug-drug interactions, including due to commonly used antimicrobials such as rifampin. While the interaction of rifampin and ivacaftor has been examined in vitro, severe adverse events resulting from this interaction have not been reported in the literature. In this report, we describe the termination of steady, long-term improvement in a patient taking ivacaftor, resulting from the use of rifampin and precipitating a significant pulmonary exacerbation...
February 28, 2018: Pediatric Pulmonology
Benjamin T Kopp, Scott McCulloch, Chandra L Shrestha, Shuzhong Zhang, Lisa Sarzynski, Frederick W Woodley, Don Hayes
BACKGROUND: Cystic fibrosis (CF) is a life-limiting disease caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Lumacaftor/Ivacaftor is a novel CFTR modulator approved for patients that are homozygous for Phe508del CFTR, but its clinical effectiveness varies amongst patients, making it difficult to determine clinical responders. Therefore, identifying biochemical biomarkers associated with drug response are clinically important for follow-up studies...
February 20, 2018: Pediatric Pulmonology
Christian Murer, Lars Christian Huber, Thomas Kurowski, Astrid Hirt, Cécile A Robinson, Urs Bürgi, Christian Benden
AIMS OF THE STUDY: Cystic fibrosis is the most common genetic disorder in Caucasians. The combination of the cystic fibrosis transmembrane conductance regulator (CFTR) corrector lumacaftor / potentiator ivacaftor (LUM/IVA) has been shown to increase forced expiratory volume in 1 second (FEV1) moderately, but predominantly reduce acute exacerbation rate (AER) in Phe508del homozygous cystic fibrosis patients; however, patients with FEV1 <40% predicted were excluded from studies. We used LUM/IVA on a "compassionate use" basis in cystic fibrosis patients with end-stage pulmonary disease...
February 16, 2018: Swiss Medical Weekly
Do-Yeon Cho, Dong-Jin Lim, Calvin Mackey, Christopher G Weeks, Jaime A Peña Garcia, Daniel Skinner, Jessica W Grayson, Harrison S Hill, David K Alexander, Shaoyan Zhang, Bradford A Woodworth
BACKGROUND: Biofilms may contribute to refractory chronic rhinosinusitis (CRS), as they lead to antibiotic resistance and failure of effective clinical treatment. l-Methionine is an amino acid with reported biofilm-inhibiting properties. Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator with mild antimicrobial activity via inhibition of bacterial DNA gyrase and topoisomerase IV. The objective of this study was to evaluate whether co-treatment with ivacaftor and l-methionine can reduce the formation of Pseudomonas aeruginosa biofilms...
February 7, 2018: International Forum of Allergy & Rhinology
Misak Harutyunyan, Yunjie Huang, Kyu-Shik Mun, Fanmuyi Yang, Kavisha Arora, Anjaparavanda P Naren
Cystic fibrosis (CF) is the most common life-shortening genetic disease affecting approximately 1 in 3500 of the Caucasian population. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. To date, over 2000 CFTR mutations have been identified and produce a wide range of phenotypes. The CFTR protein, a chloride channel, is normally expressed on epithelial cells lining the lung, gut, and exocrine glands. Mutations in CFTR have led to pleiotropic effects in CF patients and have resulted in early morbidity and mortality...
December 14, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
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
RATIONALE: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators are a new class of medications targeting the underlying defect in CF. Ivacaftor (IVA) and IVA combined with lumacaftor (LUM; IVA/LUM) have been approved by the U.S. Food and Drug Administration (FDA) for use in patients with CF. 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...
March 2018: Annals of the American Thoracic Society
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
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
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
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
Tony Kirby
No abstract text is available yet for this article.
January 2018: Lancet Respiratory Medicine
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
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
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
Barbara Porsio, Emanuela Fabiola Craparo, Nicolò Mauro, Gaetano Giammona, Gennara Cavallaro
Here, mucus-penetrating nanoparticles (NPs) for pulmonary administration of ivacaftor in patients with cystic fibrosis (CF) were produced with the dual aim of enhancing ivacaftor delivery to the airway epithelial cells, by rapid diffusion through the mucus barrier, and at the same time, promoting ivacaftor lung cellular uptake. Pegylated and Tat-decorated fluorescent nanoparticles (FNPs) were produced by nanoprecipitation, starting from two synthetic copolymers, and showed nanometric sizes (∼70 nm), a slightly negative ζ potential, and high cytocompatibility toward human bronchial epithelium cells...
January 10, 2018: ACS Applied Materials & Interfaces
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
RATIONALE: 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 (cystic fibrosis transmembrane conductance regulator) and is upregulated by the CF genetic modifier TGF (transforming growth factor)-β. OBJECTIVES: To demonstrate that miR-145 mediates TGF-β inhibition of CFTR synthesis and function in airway epithelia...
March 1, 2018: American Journal of Respiratory and Critical Care Medicine
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