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https://www.readbyqxmd.com/read/29146575/lumacaftor-vx-809-restores-the-ability-of-cf-macrophages-to-phagocytose-and-kill-pseudomonas-aeruginosa
#1
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
#2
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/29046368/enhancement-of-lung-gene-delivery-after-aerosol-a-new-strategy-using-non-viral-complexes-with-antibacterial-properties
#3
Angelique 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, 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 cystic fibrosis or chronic obstructive pulmonary disease, require the intake of many drugs. This simultaneous absorption may lead to undesired 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...
October 18, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/29040441/advancing-precision-medicine-for-the-treatment-of-long-qt-syndrome-type-2-shedding-light-on-lumacaftor
#4
Brian P Delisle, Craig T January
No abstract text is available yet for this article.
October 11, 2017: European Heart Journal
https://www.readbyqxmd.com/read/29032041/transformative-therapies-for-rare-cftr-missense-alleles
#5
REVIEW
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...
October 13, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29020304/identification-of-a-targeted-and-testable-antiarrhythmic-therapy-for-long-qt-syndrome-type-2-using-a-patient-specific-cellular-model
#6
Ashish Mehta, Chrishan J A Ramachandra, Pritpal Singh, Anuja Chitre, Chong Hui Lua, Manuela Mura, Lia Crotti, Philip Wong, Peter J Schwartz, Massimiliano Gnecchi, Winston Shim
Aims: Loss-of-function mutations in the hERG gene causes long-QT syndrome type 2 (LQT2), a condition associated with reduced IKr current. Four different mutation classes define the molecular mechanisms impairing hERG. Among them, Class 2 mutations determine hERG trafficking defects. Lumacaftor (LUM) is a drug acting on channel trafficking already successfully tested for cystic fibrosis and its safety profile is well known. We hypothesize that LUM might rescue also hERG trafficking defects in LQT2 and exert anti-arrhythmic effects...
July 21, 2017: European Heart Journal
https://www.readbyqxmd.com/read/28992608/where-are-we-with-transformational-therapies-for-patients-with-cystic-fibrosis
#7
REVIEW
Kris De Boeck, Jane C Davies
The disease cystic fibrosis (CF) is caused by a disturbance in the synthesis or function of the CFTR anion channel. Several types of small molecules geared to overcome the underlying defect in specific patient groups are in the clinical pipeline. Two drugs have obtained regulatory approval. The potentiator ivacaftor brings major clinical benefit in patients with CFTR protein expression at the cell membrane; the combination ivacaftor plus corrector lumacaftor brings a modest benefit for patients homozygous for the most common mutation F508del...
October 6, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28978522/cigarette-smoke-activates-cftr-through-ros-stimulated-camp-signaling-in-human-bronchial-epithelial-cells
#8
Francis H Wong, Asmahan AbuArish, Elizabeth Matthes, Mark J Turner, Lana E Greene, Alexandre Cloutier, Renaud Robert, David Y Thomas, Gonzalo Cosa, Andre M Cantin, John W Hanrahan
Air pollution stimulates airway epithelial secretion through a cholinergic reflex that is unaffected in cystic fibrosis (CF), yet a strong correlation is observed between passive smoke exposure in the home and impaired lung function in CF children. Our aim was to study the effects of low smoke concentrations on CFTR function in vitro. Cigarette smoke extract stimulated robust anion secretion that was transient, mediated by cystic fibrosis transmembrane conductance regulator (CFTR), and dependent on cAMP-dependent protein kinase activation...
October 4, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28891346/lumacaftor-ivacaftor-a-novel-agent-for-the-treatment-of-cystic-fibrosis-patients-who-are-homozygous-for-the-f580del-cftr-mutation
#9
REVIEW
Marilyn N Bulloch, Cameron Hanna, Richard Giovane
Cystic Fibrosis (CF) is an autosomal recessive disease affecting up to 90,000 people worldwide. Approximately 73% of patients are homozygous for the F508del cystic fibrosis transmembrane conductance regulator [CFTR] mutation. Traditionally treatment has only included supportive care. Therefore, there is a need for safe and effective novel therapies targeting the underlying molecular defects seen with CF. Areas covered: In 2016, the Food and Drug Administration and the European Commission approved LUM/IVA (Orkambi), a CFTR modulator that includes both a CFTR corrector and potentiator, for CF patients homozygous for the F508del CFTR mutation...
October 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28846049/the-safety-of-lumacaftor-and-ivacaftor-for-the-treatment-of-cystic-fibrosis
#10
REVIEW
Maria Talamo Guevara, Susanna A McColley
Lumacaftor-ivacaftor is indicated for treatment of cystic fibrosis (CF) in patients homozygous for the Phe-508del cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. In clinical trials, treated patients showed improved pulmonary function, reduced pulmonary exacerbations, and other benefits. This article reviews safety of this therapy. Areas covered: Safety findings in ivacaftor, lumacaftor and combined therapy trials, and reported subsequently through post-approval evaluation, were accessed by PubMed and Google searches using key words 'VX-770', 'ivacaftor', 'VX-809', and 'lumacaftor'...
November 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28769592/drug-induced-dyspnea-versus-cystic-fibrosis-exacerbation-a-diagnostic-dilemma
#11
Saqib Walayat, Nooreen Hussain, Jaymon Patel, Faiz Hussain, Preeti Patel, Sonu Dhillon, Bhagat Aulakh, Subramanyam Chittivelu
Cystic fibrosis (CF) is a disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator protein in the epithelial membrane, and affects at least 30,000 people in the USA. There are between 900 and 1000 new cases diagnosed every year. Traditionally, CF has been treated symptomatically with pancreatic enzymes, bronchodilators, hypertonic saline, and pulmozyme. In July 2015, the US Food and Drug Administration approved Orkambi (lumacaftor/ivacaftor), a combination drug that works on reversing the effects of the defective cystic fibrosis transmembrane conductance regulator protein...
2017: International Medical Case Reports Journal
https://www.readbyqxmd.com/read/28667089/orkambi%C3%A2-and-amplifier-co-therapy-improves-function-from-a-rare-cftr-mutation-in-gene-edited-cells-and-patient-tissue
#12
Steven V Molinski, Saumel Ahmadi, Wan Ip, Hong Ouyang, Adriana Villella, John P Miller, Po-Shun Lee, Kethika Kulleperuma, Kai Du, Michelle Di Paola, Paul Dw Eckford, Onofrio Laselva, Ling Jun Huan, Leigh Wellhauser, Ellen Li, Peter N Ray, Régis Pomès, Theo J Moraes, Tanja Gonska, Felix Ratjen, Christine E Bear
The combination therapy of lumacaftor and ivacaftor (Orkambi(®)) is approved for patients bearing the major cystic fibrosis (CF) mutation: ΔF508 It has been predicted that Orkambi(®) could treat patients with rarer mutations of similar "theratype"; however, a standardized approach confirming efficacy in these cohorts has not been reported. Here, we demonstrate that patients bearing the rare mutation: c.3700 A>G, causing protein misprocessing and altered channel function-similar to ΔF508-CFTR, are unlikely to yield a robust Orkambi(®) response...
September 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28611092/altering-metabolic-profiles-of-drugs-by-precision-deuteration-2-discovery-of-a-deuterated-analog-of-ivacaftor-with-differentiated-pharmacokinetics-for-clinical-development
#13
RANDOMIZED CONTROLLED TRIAL
Scott L Harbeson, Adam J Morgan, Julie F Liu, Ara M Aslanian, Sophia Nguyen, Gary W Bridson, Christopher L Brummel, Lijun Wu, Roger D Tung, Lana Pilja, Virginia Braman, Vinita Uttamsingh
Ivacaftor is currently used for the treatment of cystic fibrosis as both monotherapy (Kalydeco; Vertex Pharmaceuticals, Boston, MA) and combination therapy with lumacaftor (Orkambi; Vertex Pharmaceuticals). Each therapy targets specific patient populations: Kalydeco treats patients carrying one of nine gating mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, whereas Orkambi treats patients homozygous for the F508del CFTR mutation. In this study, we explored the pharmacological and metabolic effects of precision deuteration chemistry on ivacaftor by synthesizing two novel deuterated ivacaftor analogs, CTP-656 (d9-ivacaftor) and d18-ivacaftor...
August 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28606620/efficacy-and-safety-of-lumacaftor-and-ivacaftor-in-patients-aged-6-11-years-with-cystic-fibrosis-homozygous-for-f508del-cftr-a-randomised-placebo-controlled-phase-3-trial
#14
Felix Ratjen, Christopher Hug, Gautham Marigowda, Simon Tian, Xiaohong Huang, Sanja Stanojevic, Carlos E Milla, Paul D Robinson, David Waltz, Jane C Davies
BACKGROUND: Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR) in placebo-controlled studies and patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. We report efficacy and safety of lumacaftor and ivacaftor in patients with cystic fibrosis aged 6-11 years homozygous for F508del-CFTR. METHODS: In this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK)...
July 2017: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/28602538/worsening-anxiety-and-depression-after-initiation-of-lumacaftor-ivacaftor-combination-therapy-in-adolescent-females-with-cystic-fibrosis
#15
Cameron J McKinzie, Jennifer L Goralski, Terry L Noah, George Z Retsch-Bogart, Mary Beth Prieur
In both phase III studies of LUM/IVA, as well as an extension study, worsening of mental health was not reported as a common side effect. Here we describe five cases in adolescent female patients that suggest a worsening of anxiety or depression associated with its use. In these five patients, two experienced suicidal ideation and three made suicide attempts that resulted in psychiatric hospitalizations.
July 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/28529073/real-life-acute-lung-function-changes-after-lumacaftor-ivacaftor-first-administration-in-pediatric-patients-with-cystic-fibrosis
#16
Aurélie Labaste, Camille Ohlmann, Catherine Mainguy, Virginie Jubin, Marie Perceval, Laurianne Coutier, Philippe Reix
The combination of lumacaftor and ivacaftor (LUM/IVA) has been reported to induce a mean acute absolute drop of -4.1% predicted forced expiratory volume in 1s (FEV1) after a unique administration in healthy subjects. The aim of the present study was to assess acute FEV1 changes after the first dose of LUM/IVA in CF patients. A total of 32 pediatric patients were included. Respiratory manifestations occurred in only 3 patients (9.4%), but FEV1 consistently decreased (-10.4±4.6%, range: -1.5; -21.8%). FEV1 only partially resumed after salbutamol inhalation...
May 18, 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/28406713/an-observational-study-of-outcomes-and-tolerances-in-patients-with-cystic-fibrosis-initiated-on-lumacaftor-ivacaftor
#17
Mark T Jennings, Rebecca Dezube, Shruti Paranjape, Natalie E West, Gina Hong, Andrew Braun, Jonathan Grant, Christian A Merlo, Noah Lechtzin
RATIONALE: In July 2015, the U.S. Food and Drug Administration approved lumacaftor/ivacaftor for use in patients with cystic fibrosis (CF). This drug targets the primary defect in the CFTR protein that is conferred by the F508del CFTR mutation. OBJECTIVE: As there is limited experience with this therapy outside of clinical trials, this study aims to examine the clinical experience of this new drug in a population with CF. RESULTS: Retrospective cohort study of individuals followed at the Johns Hopkins CF Center who initiated treatment with lumacaftor/ivacaftor...
November 2017: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/28366727/corrector-vx-809-promotes-interactions-between-cytoplasmic-loop-one-and-the-first-nucleotide-binding-domain-of-cftr
#18
Tip W Loo, David M Clarke
A large number of correctors have been identified that can partially repair defects in folding, stability and trafficking of CFTR processing mutants that cause cystic fibrosis (CF). The best corrector, VX-809 (Lumacaftor), has shown some promise when used in combination with a potentiator (Ivacaftor). Understanding the mechanism of VX-809 is essential for development of better correctors. Here, we tested our prediction that VX-809 repairs folding and processing defects of CFTR by promoting interactions between the first cytoplasmic loop (CL1) of transmembrane domain 1 (TMD1) and the first nucleotide-binding domain (NBD1)...
July 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28362199/effects-of-lumacaftor-ivacaftor-in-a-pediatric-cohort-homozygous-for-f508del-cftr
#19
Marie E Egan
No abstract text is available yet for this article.
April 1, 2017: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/28325531/real-life-initiation-of-lumacaftor-ivacaftor-combination-in-adults-with-cystic-fibrosis-homozygous-for-the-phe508del-cftr-mutation-and-severe-lung-disease
#20
Dominique Hubert, Raphaël Chiron, Boubou Camara, Dominique Grenet, Anne Prévotat, Laurence Bassinet, Stéphane Dominique, Gilles Rault, Julie Macey, Isabelle Honoré, Reem Kanaan, Sylvie Leroy, Nadine Desmazes Dufeu, Pierre-Régis Burgel
OBJECTIVE: To investigate the short-term adverse events and effectiveness of lumacaftor/ivacaftor combination treatment in adults with cystic fibrosis (CF) and severe lung disease in a real life setting. METHODS: A multicentre observational study investigated adverse events, treatment discontinuation, FEV1 and body mass index (BMI) one month and three months after lumacaftor/ivacaftor initiation in adults with CF and FEV1 below 40% predicted. RESULTS: Respiratory adverse events (AEs) were reported by 27 of 53 subjects (51%) and 16 (30%) discontinued treatment...
May 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
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