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https://www.readbyqxmd.com/read/28916704/delayed-neutrophil-apoptosis-enhances-net-formation-in-cystic-fibrosis
#1
Robert D Gray, Gareth Hardisty, Kate H Regan, Maeve Smith, Calum T Robb, Rodger Duffin, Annie Mackellar, Jennifer M Felton, Lily Paemka, Brian N McCullagh, Christopher D Lucas, David A Dorward, Edward F McKone, Gordon Cooke, Seamas C Donnelly, Pradeep K Singh, David A Stoltz, Christopher Haslett, Paul B McCray, Moira K B Whyte, Adriano G Rossi, Donald J Davidson
BACKGROUND: Cystic fibrosis (CF) lung disease is defined by large numbers of neutrophils and associated damaging products in the airway. Delayed neutrophil apoptosis is described in CF although it is unclear whether this is a primary neutrophil defect or a response to chronic inflammation. Increased levels of neutrophil extracellular traps (NETs) have been measured in CF and we aimed to investigate the causal relationship between these phenomena and their potential to serve as a driver of inflammation...
September 15, 2017: Thorax
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
#2
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...
September 11, 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28846049/the-safety-of-lumacaftor-and-ivacaftor-for-the-treatment-of-cystic-fibrosis
#3
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"...
August 28, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28835336/neutrophil-membrane-cholesterol-content-is-a-key-factor-in-cystic-fibrosis-lung-disease
#4
Michelle M White, Patrick Geraghty, Elaine Hayes, Stephen Cox, William Leitch, Bader Alfawaz, Gillian M Lavelle, Oliver J McElvaney, Ryan Flannery, Joanne Keenan, Paula Meleady, Michael Henry, Martin Clynes, Cedric Gunaratnam, Noel G McElvaney, Emer P Reeves
BACKGROUND: Identification of mechanisms promoting neutrophil trafficking to the lungs of patients with cystic fibrosis (CF) is a challenge for next generation therapeutics. Cholesterol, a structural component of neutrophil plasma membranes influences cell adhesion, a key step in transmigration. The effect of chronic inflammation on neutrophil membrane cholesterol content in patients with CF (PWCF) remains unclear. To address this we examined neutrophils of PWCF to evaluate the cause and consequence of altered membrane cholesterol and identified the effects of lung transplantation and ion channel potentiator therapy on the cellular mechanisms responsible for perturbed membrane cholesterol and increased cell adhesion...
August 16, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28769592/drug-induced-dyspnea-versus-cystic-fibrosis-exacerbation-a-diagnostic-dilemma
#5
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/28711222/retrospective-observational-study-of-french-patients-with-cystic-fibrosis-and-a-gly551asp-cftr-mutation-after-1-and-2years-of-treatment-with-ivacaftor-in-a-real-world-setting
#6
Dominique Hubert, Clémence Dehillotte, Anne Munck, Valérie David, Jinmi Baek, Laurent Mely, Stéphane Dominique, Sophie Ramel, Isabelle Danner Boucher, Sylvaine Lefeuvre, Quitterie Reynaud, Virginie Colomb-Jung, Prissile Bakouboula, Lydie Lemonnier
BACKGROUND: Ivacaftor has been shown to improve lung function and body weight in patients with CF and a gating mutation. Real-world evaluation is warranted to examine its safety and effectiveness over the long term. METHODS: A retrospective observational multicentre study collected clinical data in the year before and the 2years after ivacaftor initiation in patients with CF and a Gly551Asp-CFTR mutation. RESULTS: Fifty-seven patients were included...
July 12, 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/28694231/repurposing-ivacaftor-for-treatment-of-staphylococcus-aureus-infections
#7
Ritesh Thakare, Alok Kumar Singh, Swetarka Das, N Vasudevan, Gorakhnath R Jachak, D Srinivasa Reddy, Arunava Dasgupta, Sidharth Chopra
Drug repurposing of non-antimicrobials is a novel method to augment a seriously depleted drug pipeline for targeting drug-resistant pathogens. This article highlights the potent antimicrobial activity of Ivacaftor against Staphylococcus aureus, including vancomycin- and other multidrug-resistant strains. The potent activity of Ivacaftor in vivo is also demonstrated in a murine neutropenic thigh infection model. Taken together, these results support the potential of Ivacaftor as an antimicrobial agent for the treatment of staphylococcal infections...
July 8, 2017: International Journal of Antimicrobial Agents
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
#8
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/28666755/activity-of-innate-antimicrobial-peptides-and-ivacaftor-against-clinical-cystic-fibrosis-respiratory-pathogens
#9
Joanna E Payne, Alice V Dubois, Rebecca J Ingram, Sinead Weldon, Clifford C Taggart, J Stuart Elborn, Michael M Tunney
There is a clear need for new antimicrobials to improve current treatment of chronic lung infection in people with cystic fibrosis (CF). This study determined the activities of antimicrobial peptides (AMPs) and ivacaftor, a novel CF transmembrane conductance regulator potentiator, for CF treatment. Antimicrobial activities of AMPs [LL37, human β-defensins (HβD) 1-4 and SLPI] and ivacaftor against clinical respiratory isolates (Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus spp., Achromobacter spp...
June 27, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28651844/recovery-of-lung-function-following-a-pulmonary-exacerbation-in-patients-with-cystic-fibrosis-and-the-g551d-cftr-mutation-treated-with-ivacaftor
#10
Patrick A Flume, Claire E Wainwright, D Elizabeth Tullis, Sally Rodriguez, Minoo Niknian, Mark Higgins, Jane C Davies, Jeffrey S Wagener
BACKGROUND: Pulmonary exacerbations (PEx) are associated with acute loss of lung function that is often not recovered after treatment. We investigated lung function recovery following PEx for ivacaftor- and placebo-treated subjects. METHODS: Short- and long-term pulmonary function recovery data after PEx were summarized from a placebo-controlled trial in 161 cystic fibrosis patients≥12years old with the G551D-CFTR mutation (NCT00909532). Short-term recovery was measured 2 to 8weeks after treatment, and long-term recovery was determined at the end-of-study, both compared with baseline measured just prior to the PEx...
June 24, 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
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-randomized-cross-over-study-with-ivacaftor-treatment
#11
Deirdre Edgeworth, Dominic Keating, Matthew Ellis, Brenda Button, Elyssa Williams, Denise Clark, Audrey Tierney, Stephane Heritier, Tom 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 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, body mass index (BMI), sweat chloride and disease-specific health related quality of life (QOL) measures (CFQ-R and Alfred Wellness (AWEscore))...
August 1, 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
#12
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
#13
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
#14
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/28592822/bacterial-sphingomyelinase-is-a-state-dependent-inhibitor-of-the-cystic-fibrosis-transmembrane-conductance-regulator-cftr
#15
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
#16
REVIEW
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...
June 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
#17
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
#18
Anne Marie Liddy, Gavin McLaughlin, Susanne Schmitz, Deirdre M D'Arcy, Michael G Barry
AIMS: 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)...
October 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
#19
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
#20
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
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