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Ivacaftor

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https://www.readbyqxmd.com/read/28611235/improvement-in-exercise-duration-lung-function-and-well-being-in-g551d-cystic-fibrosis-patients-a-double-blind-placebo-controlled-randomised-cross-over-study-with-ivacaftor
#1
Dominic T Keating, Deirdre Edgeworth, Matthew Ellis, Brenda Button, Elyssa Williams, Denise Clark, Audrey Tierney, Stephane Heritier, Anastase Kotsimbos, John Wilson
G551D , a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, results in impaired chloride channel function in cystic fibrosis (CF) with multiple end-organ manifestations. The effect of ivacaftor, a CFTR-potentiator, on exercise capacity in cystic fibrosis (CF) is unknown. Twenty G551D-CF patients were recruited to a single-centre, double-blind, placebo-controlled, 28-day crossover study of ivacaftor. Variables measured included percentage change from baseline (%Δ) of VO2max (maximal oxygen consumption, primary outcome) during cardiopulmonary exercise testing (CPET), relevant other CPET physiological variables, lung function, BMI, sweat chloride, and disease specific health related quality of life (QOL) measures (CFQ-R and Alfred Wellness (AWEscore))...
June 13, 2017: Clinical Science (1979-)
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
#2
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®) and combination therapy with lumacaftor (Orkambi®). Each therapy targets specific patient populations: Kalydeco treats patients carrying one of nine gating mutations in the cystic fibrosis transmembrane conductance regulator protein (CFTR), while 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...
June 13, 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
#3
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)...
June 8, 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
#4
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.
June 8, 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/28592822/bacterial-sphingomyelinase-is-a-state-dependent-inhibitor-of-the-cystic-fibrosis-transmembrane-conductance-regulator-cftr
#5
B B Stauffer, G Cui, K A Cottrill, D T Infield, N A McCarty
Sphingomyelinase C (SMase) inhibits CFTR chloride channel activity in multiple cell systems, an effect that could exacerbate disease in CF and COPD patients. The mechanism by which sphingomyelin catalysis inhibits CFTR is not known but evidence suggests that it occurs independently of CFTR's regulatory "R" domain. In this study we utilized the Xenopus oocyte expression system to shed light on how CFTR channel activity is reduced by SMase. We found that the pathway leading to inhibition is not membrane delimited and that inhibited CFTR channels remain at the cell membrane, indicative of a novel silencing mechanism...
June 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28554721/current-and-emerging-comorbidities-in-cystic-fibrosis
#6
Nicola J Ronan, Joseph Stuart Elborn, Barry J Plant
Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed ubiquitously throughout the body. Thus, while respiratory manifestations dominate much of cystic fibrosis (CF) care, there are prominent multi-organ manifestations and comorbidities. In the general population, the number of comorbidities increases with aging. Few illnesses have experienced such a dramatic improvement in survival as CF, which has been transformed from an illness of childhood death to one of adult survival. Hence, as longevity increases in CF, it is paralleled by an increasing number of patients with multicomplex comorbidities availing of care from adult CF multi-disciplinary teams...
May 26, 2017: La Presse Médicale
https://www.readbyqxmd.com/read/28529073/real-life-acute-lung-function-changes-after-lumacaftor-ivacaftor-first-administration-in-pediatric-patients-with-cystic-fibrosis
#7
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/28477428/the-pharmacokinetic-interaction-between-ivacaftor-and-ritonavir-in-healthy-volunteers
#8
Anne Marie Liddy, Gavin McLaughlin, Susanne Schmitz, Deirdre M D'Arcy, Michael G Barry
AIM: The aim of this study was to determine the pharmacokinetic interaction between ivacaftor and ritonavir. METHODS: A liquid chromatography mass spectrometry (LC-MS) method was developed for the measurement of ivacaftor in plasma. An open-label, sequential, cross-over study was conducted with 12 healthy volunteers. Three pharmacokinetic profiles were assessed for each volunteer: ivacaftor 150 mg alone (study A) ivacaftor 150 mg plus ritonavir 50 mg daily (study B) and ivacaftor 150 mg plus ritonavir 50 mg daily after two weeks of ritonavir 50 mg daily (study C)...
May 6, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28445004/cftr-dependent-chloride-efflux-in-cystic-fibrosis-mononuclear-cells-is-increased-by-ivacaftor-therapy
#9
Lorenzo Guerra, Susanna D'Oria, Maria Favia, Stefano Castellani, Teresa Santostasi, Angela M Polizzi, Maria A Mariggiò, Crescenzio Gallo, Valeria Casavola, Pasqualina Montemurro, Giuseppina Leonetti, Antonio Manca, Massimo Conese
AIM: The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) potentiator ivacaftor (Kalydeco®) improves clinical outcome in G551D cystic fibrosis (CF) patients. Here, we have investigated whether ivacaftor has a clinical impact on non-G551D gating mutations and function of circulating leukocytes as well. METHODS: Seven patients were treated with ivacaftor and evaluated at baseline, and at 1-3 and 6 months. Besides clinical and systemic inflammatory parameters, circulating mononuclear cells (MNC) were evaluated for CFTR-dependent chloride efflux by spectrofluorimetry, neutrophils for oxidative burst by cytofluorimetry and HVCN1 mRNA expression by real time PCR...
April 26, 2017: Pediatric Pulmonology
https://www.readbyqxmd.com/read/28419121/the-magnitude-of-ivacaftor-effects-on-fluid-secretion-via-r117h-cftr-channels-human-in-vivo-measurements
#10
Jessica E Char, Colleen Dunn, Zoe Davies, Carlos Milla, Richard B Moss, Jeffrey J Wine
We optically measured effects of orally available ivacaftor (Kalydeco®) on sweat rates of identified glands in 3 R117H subjects, each having a unique set of additional mutations, and compared them with 5 healthy control subjects tested contemporaneously. We injected β-adrenergic agonists intradermally to stimulate CFTR-dependent 'C-sweat' and methacholine to stimulate 'M-sweat', which persists in CF subjects. We focused on an R117H-7T/F508del subject who produced quantifiable C-sweat off ivacaftor and was available for 1 blinded, 3 off ivacaftor, and 3 on ivacaftor tests, allowing us to estimate in vivo fold-increase in sweat rates produced by ivacaftor's effect on the open probability (PO) of R117H-CFTR...
2017: PloS One
https://www.readbyqxmd.com/read/28406713/an-observational-study-of-outcomes-and-tolerances-in-patients-with-cystic-fibrosis-initiated-on-lumacaftor-ivacaftor
#11
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 FDA approved lumacaftor/ivacaftor for use in patients with 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 CF population. METHODS: Retrospective cohort study of individuals followed at the Johns Hopkins CF Center, who initiated treatment with lumacaftor/ivacaftor...
April 13, 2017: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/28371569/pseudomonas-eradication-and-clinical-effectivness-of-ivacaftor-in-four-hispanic-patients-with-s549n
#12
Abigail Strang, Anthony J Fischer, Aaron Chidekel
Ivacaftor was approved for rarer class-III CFTR mutations including S549N in 2014. Since these mutations are uncommon, ongoing reports of patient experiences with Ivacaftor and these mutations are important. This case series describes the clinical effectiveness (including airway infection status, lung function, and growth) of Ivacaftor therapy in four pediatric Hispanic patients with S549N and F508del over 24 months. In these patients, Ivacaftor was highly efficacious with no further Pseudomonas-positive cultures despite prior chronic colonization in three patients as well as notable improvements in lung function and growth...
April 3, 2017: Pediatric Pulmonology
https://www.readbyqxmd.com/read/28366727/corrector-vx-809-promotes-interactions-between-cytoplasmic-loop-one-and-the-first-nucleotide-binding-domain-of-cftr
#13
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
#14
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
#15
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
https://www.readbyqxmd.com/read/28314539/immediate-effects-of-lumacaftor-ivacaftor-administration-on-lung-function-in-patients-with-severe-cystic-fibrosis-lung-disease
#16
Natalia Popowicz, Jamie Wood, Anna Tai, Sue Morey, Siobhain Mulrennan
Safety-data for lumacaftor/ivacaftor (LUM/IVA) combination therapy in patients with severe lung disease (percent predicted forced expiratory volume in 1s [ppFEV1] <40) remain limited. We report immediate post-dose respiratory-related adverse events in 12 patients with severe cystic fibrosis (CF) lung disease (median [IQR] ppFEV1: 34 [31-36]) prescribed LUM/IVA. All patients experienced a decline in ppFEV1 from baseline at 2-hours (median [IQR] relative change: -19 [-21 to -11]%, p<0.001) that persisted at 24-hours but recovered in most patients at 1-month...
May 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/28300821/impact-of-cftr-modulation-on-intestinal-ph-motility-and-clinical-outcomes-in-patients-with-cystic-fibrosis-and-the-g551d-mutation
#17
Daniel Gelfond, Sonya Heltshe, Changxing Ma, Steven M Rowe, Carla Frederick, Ahmet Uluer, Leonard Sicilian, Michael Konstan, Elizabeth Tullis, R N Christine Roach, Katherine Griffin, Elizabeth Joseloff, Drucy Borowitz
OBJECTIVES: A defect in bicarbonate secretion contributes to the pathophysiology of gastrointestinal complications in patients with cystic fibrosis (CF). We measured gastrointestinal pH, clinical outcomes, and intestinal transit profiles in patients with the G551D mutation before and after treatment with ivacaftor, a CF transmembrane regulator channel (CFTR) potentiator. METHODS: Observational studies of ivacaftor effectiveness were conducted in the United States and Canada...
March 16, 2017: Clinical and Translational Gastroenterology
https://www.readbyqxmd.com/read/28222269/restoring-cystic-fibrosis-transmembrane-conductance-regulator-function-reduces-airway-bacteria-and-inflammation-in-people-with-cystic-fibrosis-and-chronic-lung-infections
#18
Katherine B Hisert, Sonya L Heltshe, Christopher Pope, Peter Jorth, Xia Wu, Rachael M Edwards, Matthew Radey, Frank J Accurso, Daniel J Wolter, Gordon Cooke, Ryan J Adam, Suzanne Carter, Brenda Grogan, Janice L Launspach, Seamas C Donnelly, Charles G Gallagher, James E Bruce, David A Stoltz, Michael J Welsh, Lucas R Hoffman, Edward F McKone, Pradeep K Singh
RATIONALE: Previous work indicates that ivacaftor improves cystic fibrosis transmembrane conductance regulator (CFTR) activity and lung function in people with cystic fibrosis and G551D-CFTR mutations but does not reduce density of bacteria or markers of inflammation in the airway. These findings raise the possibility that infection and inflammation may progress independently of CFTR activity once cystic fibrosis lung disease is established. OBJECTIVES: To better understand the relationship between CFTR activity, airway microbiology and inflammation, and lung function in subjects with cystic fibrosis and chronic airway infections...
June 15, 2017: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/28190780/pregnancy-among-cystic-fibrosis-women-in-the-era-of-cftr-modulators
#19
Sonya L Heltshe, Emily M Godfrey, Tatiana Josephy, Moira L Aitken, Jennifer L Taylor-Cousar
BACKGROUND: Little is known about how new therapies that partially correct the basic cystic fibrosis (CF) defect (ivacaftor and lumacaftor) might alter hormonal contraceptive effectiveness, impact pregnancy outcomes, or affect pregnancy timing. Examination of pregnancy rates among CF women during periods of CFTR modulator therapy initiation will provide foundation for further research in this area. METHODS: The Cystic Fibrosis Foundation Patient Registry was used to examine pregnancy rates and outcomes by genotype class before, during, and after the introduction of CFTR modulator therapies between 2005 and 2014...
February 9, 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/28143919/growth-in-prepubertal-children-with-cystic-fibrosis-treated-with-ivacaftor
#20
Michael S Stalvey, Jesse Pace, Minoo Niknian, Mark N Higgins, Valerie Tarn, Joy Davis, Sonya L Heltshe, Steven M Rowe
BACKGROUND AND OBJECTIVES: Cystic fibrosis (CF) is known for its impact on the lung and pancreas of individuals; however, impaired growth is also a common complication. We hypothesized that targeting the biological defect in the CF transmembrane conductance regulator (CFTR) protein may affect growth outcomes. METHODS: In this post hoc analysis, we assessed linear growth and weight in 83 children (aged 6-11 years) enrolled in 2 clinical trials, the longitudinal-observation GOAL study and the placebo-controlled ENVISION study, to evaluate the effects of ivacaftor, a CFTR potentiator...
February 2017: Pediatrics
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