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Cameron L Jordan, Terry L Noah, Marianna M Henry
This review seeks to re-introduce cystic fibrosis (CF) clinicians to the pharmacology of drug-drug interactions among medications commonly used in CF and provide a framework for understanding these interactions among medications outside the scope of this discussion. We here focus on drugs impacted by the cytochrome P-450 (CYP450) enzyme system and on interactions involving antimicrobials, psychotropic medications, and cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Particular attention is needed when prescribing rifampin, azole antifungals and the CFTR modulators, ivacaftor, and lumacaftor/ivacaftor, in combination with other medications...
October 2016: Pediatric Pulmonology
Carleen M Sabusap, Wei Wang, Carmel M McNicholas, W Joon Chung, Lianwu Fu, Hui Wen, Marina Mazur, Kevin L Kirk, James F Collawn, Jeong S Hong, Eric J Sorscher
Emerging knowledge indicates the difficulty in categorizing unusual cystic fibrosis (CF) mutations, with regard to both pathogenic mechanism and theratype. As case in point, we present data concerning P67L mutation of the cystic fibrosis transmembrane conductance regulator (CFTR), a defect carried by a small number of individuals with CF and sometimes attributed to a channel conductance abnormality. Findings from our laboratory and others establish that P67L causes protein misfolding, disrupts maturation, confers gating defects, is thermally stable, and exhibits near normal conductance...
September 8, 2016: JCI Insight
Elena K Schneider, Mohammad A K Azad, Mei-Ling Han, Qi Tony Zhou, Jiping Wang, Johnny X Huang, Matthew A Cooper, Yohei Doi, Mark A Baker, Phillip J Bergen, Mark T Muller, Jian Li, Tony Velkov
Novel combination therapies are desperately needed for combating lung infections caused by bacterial "superbugs". This study aimed to investigate the synergistic antibacterial activity of polymyxin B in combination with the cystic fibrosis (CF) drugs KALYDECO (ivacaftor) and ORKAMBI (ivacaftor + lumacaftor) against Gram-negative pathogens that commonly colonize the CF lung, in particular, the problematic Pseudomonas aeruginosa. The in vitro synergistic activity of polymyxin B combined with ivacaftor or lumacaftor was assessed using checkerboard and static time-kill assays against a panel of polymyxin-susceptible and polymyxin-resistant P...
July 8, 2016: ACS Infectious Diseases
Onofrio Laselva, Steven Molinski, Valeria Casavola, Christine E Bear
Cystic Fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The most common mutation, deletion of phenylalanine 508 (F508del), disrupts tertiary assembly, causing protein misprocessing and loss of CFTR function in epithelial tissues. Lumacaftor (VX-809) is a Class 1 corrector molecule shown to partially rescue misprocessing of F508del and together with the potentiator of channel activity: ivacaftor (VX-770) has been approved for treatment of CF patients homozygous for the F508del mutation...
November 1, 2016: Biochemical Pharmacology
Daniel A Hussar, Jerry Rachel George
No abstract text is available yet for this article.
July 2016: Journal of the American Pharmacists Association: JAPhA
Emma D Deeks
Lumacaftor/ivacaftor (Orkambi™) is a fixed-dose tablet containing a corrector (lumacaftor) and potentiator (ivacaftor) of the cystic fibrosis transmembrane conductance regulator (CFTR) and is the first therapy approved to treat the underlying cause of cystic fibrosis in patients (aged ≥12 years) homozygous for the most common CFTR mutation, F508del. Lumacaftor improves the processing of F508del CFTR and its transport to the cell surface, while ivacaftor increases the channel's open probability and transport of chloride...
August 2016: Drugs
Daniel L Hamilos
Chronic rhinosinusitis (CRS) is highly prevalent in patients with cystic fibrosis (CF) and accounts for significant morbidity and contribution to CF lung disease. Mutations of the cystic fibrosis transmembrane regulator gene occur with increased prevalence in patients with CRS without CF, suggesting some contribution to CRS pathophysiology. Nasal polyps (NPs) occur with increased prevalence in patients with CF of all ages and have a more neutrophilic appearance with fewer eosinophils and increased submucosal glandular elements in comparison to NPs from patients without CF...
July 2016: Journal of Allergy and Clinical Immunology in Practice
Johanna F Dekkers, Gitte Berkers, Evelien Kruisselbrink, Annelotte Vonk, Hugo R de Jonge, Hettie M Janssens, Inez Bronsveld, Eduard A van de Graaf, Edward E S Nieuwenhuis, Roderick H J Houwen, Frank P Vleggaar, Johanna C Escher, Yolanda B de Rijke, Christof J Majoor, Harry G M Heijerman, Karin M de Winter-de Groot, Hans Clevers, Cornelis K van der Ent, Jeffrey M Beekman
Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations...
June 22, 2016: Science Translational Medicine
J Stuart Elborn, Bonnie W Ramsey, Michael P Boyle, Michael W Konstan, Xiaohong Huang, Gautham Marigowda, David Waltz, Claire E Wainwright
BACKGROUND: Lumacaftor/ivacaftor combination therapy has shown clinical benefits in patients with cystic fibrosis homozygous for the Phe508del CFTR mutation; however, pretreatment lung function is a confounding factor that potentially affects the efficacy and safety of this therapy. We aimed to assess the efficacy and safety of lumacaftor/ivacaftor therapy in these patients, defined by specific categories of lung function. METHODS: Both trials (TRAFFIC and TRANSPORT) included in this pooled analysis were multinational, randomised, double-blind, placebo-controlled, parallel-group, phase 3 studies...
August 2016: Lancet Respiratory Medicine
Guido Veit, Kathryn Oliver, Pirjo M Apaja, Doranda Perdomo, Aurélien Bidaud-Meynard, Sheng-Ting Lin, Jingyu Guo, Mert Icyuz, Eric J Sorscher, John L Hartman Iv, Gergely L Lukacs
The most common cystic fibrosis (CF) causing mutation, deletion of phenylalanine 508 (ΔF508 or Phe508del), results in functional expression defect of the CF transmembrane conductance regulator (CFTR) at the apical plasma membrane (PM) of secretory epithelia, which is attributed to the degradation of the misfolded channel at the endoplasmic reticulum (ER). Deletion of phenylalanine 670 (ΔF670) in the yeast oligomycin resistance 1 gene (YOR1, an ABC transporter) of Saccharomyces cerevisiae phenocopies the ΔF508-CFTR folding and trafficking defects...
May 2016: PLoS Biology
Stacey L Martiniano, Scott D Sagel, Edith T Zemanick
PURPOSE OF REVIEW: Development of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, small molecule therapies that target the basic defect in cystic fibrosis (CF), represents a new era in CF treatment. This review highlights recent progress in CF therapeutics as an example of precision medicine and personalized approaches to test CFTR modulators using preclinical model systems. RECENT FINDINGS: CFTR modulators are now clinically available for approximately 50% of the United States CF population...
June 2016: Current Opinion in Pediatrics
Bradley S Quon, Steven M Rowe
Cystic fibrosis (CF) is a monogenic autosomal recessive disorder that affects about 70,000 people worldwide. The clinical manifestations of the disease are caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The discovery of the CFTR gene in 1989 has led to a sophisticated understanding of how thousands of mutations in the CFTR gene affect the structure and function of the CFTR protein. Much progress has been made over the past decade with the development of orally bioavailable small molecule drugs that target defective CFTR proteins caused by specific mutations...
2016: BMJ: British Medical Journal
(no author information available yet)
No abstract text is available yet for this article.
March 28, 2016: Medical Letter on Drugs and Therapeutics
Susanna A McColley
INTRODUCTION: Ivacaftor is indicated for treatment of cystic fibrosis (CF) mediated by 10 mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene that causes gating or partial function abnormalities. In placebo-controlled and open-label studies, ivacaftor-treated subjects showed improved pulmonary function, nutrition and quality of life measures. This article reviews ivacaftor safety. AREAS COVERED: Safety findings in ivacaftor clinical trials, and reported subsequently, were accessed by a PubMed search using key words "VX-770" or "ivacaftor"...
May 2016: Expert Opinion on Drug Safety
B Tümmler
Personalized medicine promises that medical decisions, practices and products are tailored to the individual patient. Cystic fibrosis, an inherited disorder of chloride and bicarbonate transport in exocrine glands, is the first successful example of customized drug development for mutation-specific therapy. There are two classes of CFTR modulators: potentiators that increase the activity of CFTR at the cell surface, and correctors that either promote the read-through of nonsense mutations or facilitate the translation, folding, maturation and trafficking of mutant CFTR to the cell surface...
May 2016: Pneumologie
Barbara Dhooghe, Jérémy Boris Haaf, Sabrina Noel, Teresinha Leal
INTRODUCTION: Twenty-six years after the identification of the gene responsible for cystic fibrosis (CF), controversies still surround the pathogenesis of the disease that continues to burden and shorten lives. Therefore, finding effective therapeutic strategies that target the basic defect of CF is crucially needed. AREAS COVERED: This review offers a comprehensive survey of fundamental therapies in early stages of development for the treatment of CF. The first part describes recent strategies targeting the basic defect either at the gene or at the transcript level...
2016: Expert Opinion on Investigational Drugs
Dennis J Cada, Danial E Baker, Shannon G Panther, Kyle Ingram PharmD
Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line...
September 2015: Hospital Pharmacy
Gudio Veit, Radu G Avramescu, Annette N Chiang, Scott A Houck, Zhiwei Cai, Kathryn W Peters, Jeong S Hong, Harvey B Pollard, William B Guggino, William E Balch, William R Skach, Garry R Cutting, Raymond A Frizzell, David N Sheppard, Douglas M Cyr, Eric J Sorscher, Jeffrey L Brodsky, Gergely L Lukacs
More than 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described that confer a range of molecular cell biological and functional phenotypes. Most of these mutations lead to compromised anion conductance at the apical plasma membrane of secretory epithelia and cause cystic fibrosis (CF) with variable disease severity. Based on the molecular phenotypic complexity of CFTR mutants and their susceptibility to pharmacotherapy, it has been recognized that mutations may impose combinatorial defects in CFTR channel biology...
February 1, 2016: Molecular Biology of the Cell
D Hubert, S Bui, C Marguet, V Colomb-Jung, M Murris-Espin, H Corvol, A Munck
BACKGROUND: The treatment of cystic fibrosis has been symptom-based for a number of years. New therapies that aim to improve CFTR protein function are now emerging. CURRENT SCIENTIFIC KNOWLEDGE: The results of gene therapy has been modest but a recent clinical trial shows a positive effect on FEV1. Recent research has focused primarily on CFTR protein function. Significant respiratory improvement (an average 10% FEV1 increase and a decrease in the frequency of exacerbations) has been achieved with ivacaftor, a CFTR potentiator, in patients with gating mutations, resulting in its marketing authorization (in 2012 for the G551D mutation and in 2015 for rarer mutations)...
January 21, 2016: Revue des Maladies Respiratoires
Martin Mayer
No abstract text is available yet for this article.
June 2016: Evidence-based Medicine
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