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Lumacaftor

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https://www.readbyqxmd.com/read/27898234/lumacaftor-ivacaftor-treatment-of-patients-with-cystic-fibrosis-heterozygous-for-f508del-cftr
#1
Steven M Rowe, Susanna A McColley, Ernst Rietschel, Xiaolei Li, Scott C Bell, Michael W Konstan, Gautham Marigowda, David Waltz, Michael P Boyle
RATIONALE: Lumacaftor/ivacaftor treatment (≤28 days) in patients with cystic fibrosis (CF) heterozygous for F508del-CFTR did not improve lung function. OBJECTIVES: To evaluate an optimized lumacaftor/ivacaftor dosing regimen with longer duration in a cohort of patients heterozygous for F508del-CFTR. METHODS: Patients age ≥18 years with a confirmed CF diagnosis and percent predicted forced expiratory volume in 1 second (ppFEV1) of 40 to 90 were randomized to lumacaftor/ivacaftor (400 mg/250 mg every 12 hours) or placebo daily for 56 days...
November 29, 2016: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/27894875/effect-of-bronchodilators-in-healthy-individuals-receiving-lumacaftor-ivacaftor-combination-therapy
#2
Gautham Marigowda, Fang Liu, David Waltz
In an open-label, single-center phase 1 pharmacokinetic study in healthy subjects who received lumacaftor (LUM) in combination with ivacaftor (IVA), review of spirometry data showed a transient decline in percent predicted forced expiratory volume in 1s (ppFEV1) within 4h of drug administration. An additional cohort of healthy subjects with normal baseline ppFEV1 values was studied to evaluate the ppFEV1 response to LUM/IVA administration and assess the effect of long-acting bronchodilators (LABDs) and short-acting bronchodilators (SABDs) on ppFEV1 response...
November 25, 2016: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/27875677/a-case-report-of-pregnancy-during-use%C3%A2-of-targeted-therapeutics-for-cystic%C3%A2-fibrosis
#3
Sigrid Ladores, Traci M Kazmerski, Steven M Rowe
New therapeutics, such as ivacaftor, and the combination drug lumacaftor/ivacaftor that target the underlying genetic cause of cystic fibrosis are being hailed as game-changers in this era of personalized medicine. Although these drugs improve lung function, their effects on female fertility have not been studied. In this case report we describe one woman's experience with ivacaftor and her unanticipated pregnancy. Implications related to comprehensive sexual and reproductive health care for women with cystic fibrosis are presented...
November 19, 2016: Journal of Obstetric, Gynecologic, and Neonatal Nursing: JOGNN
https://www.readbyqxmd.com/read/27821435/what-can-be-learned-from-recent-new-drug-applications-a-systematic-review-of-drug-interaction-data-for-drugs-approved-by-the-u-s-fda-in-2015
#4
Jingjing Yu, Zhu Zhou, Katie H Owens, Tasha K Ritchie, Isabelle Ragueneau-Majlessi
As a follow-up to previous reviews, the aim of the present analysis was to systematically examine all drug metabolism, transport, PK, and DDI data available in the 33 NDAs and 12 BLAs approved by the FDA in 2015, using the University of Washington Drug Interaction Database©, and to highlight the significant findings. All of the NDAs were well-characterized with regard to drug metabolism, transport, and/or organ impairment, and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one DME or transporter...
November 7, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27805836/lumacaftor-ivacaftor-in-patients-aged-6-11-years-with-cystic-fibrosis-homozygous-for-f508del-cftr
#5
Carlos E Milla, Felix Ratjen, Gautham Marigowda, Fang Liu, David Waltz, Margaret Rosenfeld
RATIONALE: Combination lumacaftor/ivacaftor has been shown to improve lung function and other endpoints in patients aged ≥12 years with cystic fibrosis homozygous for F508del-CFTR but has not been assessed in younger patients. OBJECTIVES: This open-label phase 3 trial evaluated the safety, tolerability, pharmacodynamics, and efficacy of lumacaftor/ivacaftor combination therapy in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR. METHODS: Patients (N = 58) received 200 mg lumacaftor/250 mg ivacaftor orally every 12 hours for 24 weeks in addition to their existing cystic fibrosis medications...
November 2, 2016: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/27804127/can-cystic-fibrosis-patients-finally-catch-a-breath-with-orkambi
#6
REVIEW
Elena K Schneider, Felisa Reyes-Ortega, Jian Li, Tony Velkov
Cystic fibrosis is a life limiting disease caused by defective or deficient cystic fibrosis trans-membrane conductance regulator (CFTR) activity. The recent FDA approval of lumacaftor combined with ivacaftor (Orkambi) targets patients with the F508del-CFTR. The question remains, is this breakthrough combination therapy the 'magic-bullet' cure the vast majority of patients with CF? This review covers the contemporary clinical and scientific knowledge-base for Orkambi and highlights the emerging issues from recent conflicting literature reports...
November 2, 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27792891/development-of-hplc-and-lc-ms-ms-methods-for-the-analysis-of-ivacaftor-its-major-metabolites-and-lumacaftor-in-plasma-and-sputum-of-cystic-fibrosis-patients-treated-with-orkambi-or-kalydeco
#7
Elena K Schneider, Felisa Reyes-Ortega, John W Wilson, Tom Kotsimbos, Dominic Keating, Jian Li, Tony Velkov
ORKAMBI (ivacaftor-lumacaftor [LUMA]) and KALYDECO (ivacaftor; IVA) are two new breakthrough cystic fibrosis (CF) drugs that directly modulate the activity and trafficking of the defective CFTR underlying the CF disease state. Currently, no therapeutic drug monitoring assays exist for these very expensive, albeit, important drugs. In this study, for the first time HPLC and LC-MS methods were developed and validated for rapid detection and quantification of IVA and its major metabolites hydroxymethyl-IVA M1 (active) and IVA-carboxylate M6 (inactive); and LUMA in the plasma and sputum of CF patients...
October 24, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/27662106/therapeutic-challenges-posed-by-critical-drug-drug-interactions-in-cystic-fibrosis
#8
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
https://www.readbyqxmd.com/read/27660821/analysis-of-cystic-fibrosis-associated-p67l-cftr-illustrates-barriers-to-personalized-therapeutics-for-orphan-diseases
#9
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
https://www.readbyqxmd.com/read/27626100/an-unlikely-pair-the-antimicrobial-synergy-of-polymyxin-b-in-combination-with-the-cystic-fibrosis-transmembrane-conductance-regulator-drugs-kalydeco-and-orkambi
#10
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
https://www.readbyqxmd.com/read/27614011/the-investigational-cystic-fibrosis-drug-trimethylangelicin-directly-modulates-cftr-by-stabilizing-the-first-membrane-spanning-domain
#11
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
https://www.readbyqxmd.com/read/27450143/brivaracetam-lumacaftor-ivacaftor-and-deoxycholic-acid
#12
Daniel A Hussar, Jerry Rachel George
No abstract text is available yet for this article.
July 2016: Journal of the American Pharmacists Association: JAPhA
https://www.readbyqxmd.com/read/27394157/lumacaftor-ivacaftor-a-review-in-cystic-fibrosis
#13
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
https://www.readbyqxmd.com/read/27393775/chronic-rhinosinusitis-in-patients-with-cystic-fibrosis
#14
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
https://www.readbyqxmd.com/read/27334259/characterizing-responses-to-cftr-modulating-drugs-using-rectal-organoids-derived-from-subjects-with-cystic-fibrosis
#15
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
https://www.readbyqxmd.com/read/27298017/efficacy-and-safety-of-lumacaftor-ivacaftor-combination-therapy-in-patients-with-cystic-fibrosis-homozygous-for-phe508del-cftr-by-pulmonary-function-subgroup-a-pooled-analysis
#16
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
https://www.readbyqxmd.com/read/27168400/ribosomal-stalk-protein-silencing-partially-corrects-the-%C3%AE-f508-cftr-functional-expression-defect
#17
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
https://www.readbyqxmd.com/read/27031658/cystic-fibrosis-a-model-system-for-precision-medicine
#18
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
https://www.readbyqxmd.com/read/27030675/new-and-emerging-targeted-therapies-for-cystic-fibrosis
#19
REVIEW
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...
March 30, 2016: BMJ: British Medical Journal
https://www.readbyqxmd.com/read/27027688/lumacaftor-ivacaftor-orkambi-for-cystic-fibrosis
#20
(no author information available yet)
No abstract text is available yet for this article.
March 28, 2016: Medical Letter on Drugs and Therapeutics
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