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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
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
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
Hongde Liu, Kun Luo, Donghui Luo
Alzheimer's disease (AD) is a severe neurodegenerative disorder for which identification of differentially expressed genes is one way to find new therapeutic targets. Here, we conducted analysis to identify age-independent, AD-specific genes. We found that the MET, WIF1, and NPTX2 genes are downregulated in AD. WIF1 and MET are implicated in Wnt and MET signaling and regulate GSK3β activity and are thus linked with AD. Importantly, we found that the GMPR gene exhibited a gradual increase in AD progression...
February 9, 2018: Scientific Reports
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
Jia Liu, Hermann Bihler, Carlos M Farinha, Nikhil T Awatade, Ana M Romão, Dayna Mercadante, Yi Cheng, Isaac Musisi, Walailak Jantarajit, Yiting Wang, Zhiwei Cai, Margarida D Amaral, Martin Mense, David N Sheppard
BACKGROUND AND PURPOSE: Rescue of F508del-cystic fibrosis transmembrane conductance regulator (CFTR), the most common cystic fibrosis (CF) mutation, requires small molecules that overcome protein processing, stability and channel gating defects. Here, we investigate F508del-CFTR rescue by CFFT-004 (from WO2010/068863), a small molecule designed to independently correct protein processing and channel gating defects. EXPERIMENTAL APPROACH: Using CFTR-expressing recombinant cells and CF patient-derived bronchial epithelial cells, we studied CFTR expression by Western blotting and channel gating and stability with the patch-clamp and Ussing chamber techniques...
January 10, 2018: British Journal of Pharmacology
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
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
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
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
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
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
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
Angélique 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 (CF), 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 CF or chronic obstructive pulmonary disease (COPD), require the intake of many drugs. This simultaneous absorption may lead to undesirable 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...
December 22, 2017: Bioscience Reports
Brian P Delisle, Craig T January
No abstract text is available yet for this article.
October 11, 2017: European Heart Journal
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...
June 2017: Current Opinion in Pharmacology
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