vx-770 and Lung-Diseases

Topics: Aminophenols; Benzodioxoles; Humans; Indoles; Lung Diseases; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Topics: Aminophenols; Benzodioxoles; Humans; Indoles; Lung Diseases; Pyrazoles; Pyridines; Pyrrolidines; Quinolones

Topics: Adult; Aminophenols; Bronchiectasis; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Delivery, Obstetric; Drug Dosage Calculations; Exocrine Pancreatic Insufficiency; Female; Gestational Age; Humans; Infant, Newborn; Lung Diseases; Monitoring, Physiologic; Mutation; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pseudomonas; Quinolones

Ivacaftor is an innovative treatment for CF. Ivacaftor monotherapy in a phase III trial for patients with F508del and a residual function (RF) mutation showed improvement in lung function. We evaluated the effectiveness and safety of ivacaftor in patients with severe CF carrying RF mutations.. Data were collected from Italian CF centers with patients enrolled in an ivacaftor compassionate use program. Data were collected 1 year before and 1 year after commencement of ivacaftor.. In patients with CFTR mutations that confer RF with severe lung disease, treatment with Ivacaftor is safe and results in a clinically significant improvement that was evident at 1 month and maintained at 12 months.

Topics: Adult; Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Lung; Lung Diseases; Male; Middle Aged; Mutation; Quinolones; Respiratory Function Tests; Retrospective Studies; Treatment Outcome; Young Adult

The development of ivacaftor represents a significant advance in therapeutics for patients with cystic fibrosis (CF) who carry the G551D mutation. Patients with an FEV1 < 40% predicted represent a considerable proportion of eligible patients but were excluded from phase 3 clinical trials, and the effectiveness of the drug in this population is, therefore, unknown.. Data were collected from adult CF centers in the United Kingdom and Ireland with patients enrolled in an ivacaftor compassionate use program (FEV1 < 40% or on lung transplant waiting list). Clinically recorded data were collated from patient records for 1 year prior and for a period of 90 to 270 days following ivacaftor commencement. Each patient was matched to two control subjects who would have met the requirements for the compassionate use program with the exception of genotype.. Twenty-one patients received ivacaftor for a median of 237 days. Mean FEV1 improved from 26.5% to 30.7% predicted (P = .01), representing a 16.7% relative improvement. Median weight improved from 49.8 to 51.6 kg (P = .006). Median inpatient IV antibiotic days declined from 23 to 0 d/y (P = .001) and median total IV treatment days decreased from 74 to 38 d/y (P = .002) following ivacaftor. Changes in pulmonary function and IV antibiotic requirements were significant compared with control subjects.. Ivacaftor was clinically effective in patients with CF who carry the G551D mutation and have severe pulmonary disease. The reductions in treatment requirements were clinically and statistically significant and have not been described in less severe populations.

Topics: Administration, Oral; Adult; Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA; DNA Mutational Analysis; Female; Follow-Up Studies; Forced Expiratory Volume; Genotype; Humans; Lung Diseases; Male; Mutation; Quinolones; Retrospective Studies; Severity of Illness Index; Young Adult

We report on an adult with cystic fibrosis (ΔF508/G551D) with severe lung disease (forced expiratory volume (FEV1) in one second 24% predicted) who was admitted for a pulmonary exacerbation. He was managed with maximal medical therapy, but did not have significant improvement until after he was started on ivacaftor on hospital day 15. He subsequently had significant improvement in lung function with normalization of hypercarbia, oxygen saturation on room air, and increase in FEV1 to 36% predicted. Prior to use of ivacaftor he was being assessed for a lung transplant. However, after ivacaftor therapy for 6 months, he is no longer considering this treatment modality due to his improvement of lung function and functional status.

Topics: Adult; Aminophenols; Cystic Fibrosis; Forced Expiratory Volume; Humans; Lung Diseases; Male; Quinolones; Severity of Illness Index

Mucus stasis in chronic obstructive pulmonary disease (COPD) is a significant contributor to morbidity and mortality. Potentiators of cystic fibrosis transmembrane conductance regulator (CFTR) activity pharmacologically enhance CFTR function; ivacaftor is one such agent approved to treat CF patients with the G551D-CFTR gating mutation. CFTR potentiators may also be useful for other diseases of mucus stasis, including COPD.. In primary human bronchial epithelial cells, exposure to cigarette smoke extract diminished CFTR-mediated anion transport (65.8±0.2% of control, P<0.005) and mucociliary transport (0.17±0.05 µm/sec vs. 2.4±0.47 µm/sec control, P<0.05) by reducing airway surface liquid depth (7.3±0.6 µm vs. 13.0±0.6 µm control, P<0.005) and augmenting mucus expression (by 64%, P<0.05) without altering transepithelial resistance. Smokers with or without COPD had reduced CFTR activity measured by nasal potential difference compared to age-matched non-smokers (-6.3±1.4 and -8.0±2.0 mV, respectively vs. -15.2±2.7 mV control, each P<0.005, n = 12-14/group); this CFTR decrement was associated with symptoms of chronic bronchitis as measured by the Breathlessness Cough and Sputum Score (r = 0.30, P<0.05) despite controlling for smoking (r = 0.31, P<0.05). Ivacaftor activated CFTR-dependent chloride transport in non-CF epithelia and ameliorated the functional CFTR defect induced by smoke to 185±36% of non-CF control (P<0.05), thereby increasing airway surface liquid (from 7.3±0.6 µm to 10.1±0.4 µm, P<0.005) and mucociliary transport (from 0.27±0.11 µm/s to 2.7±0.28 µm/s, P<0.005).. Cigarette smoking reduces CFTR activity and is causally related to reduced mucus transport in smokers due to inhibition of CFTR dependent fluid transport. These effects are reversible by the CFTR potentiator ivacaftor, representing a potential therapeutic strategy to augment mucociliary clearance in patients with smoking related lung disease.

Topics: Adult; Aged; Aged, 80 and over; Aminophenols; Cystic Fibrosis Transmembrane Conductance Regulator; Demography; Epithelial Cells; Female; Humans; Ion Transport; Lung Diseases; Male; Membrane Potentials; Middle Aged; Mucus; Quinolones; Smoking