vx-770 and Rhinitis

Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that improves pulmonary function in cystic fibrosis (CF) patients with at least 1 copy of the G551D CFTR mutation. The purpose of this study is to evaluate the impact of ivacaftor on chronic rhinosinusitis (CRS) symptoms in this population.. The G551D Observational (GOAL) study was a multicenter prospective cohort study enrolling CF patients ≥6 years with at least 1 G551D mutation. Subjects were provided 20-item Sino-Nasal Outcome Test (SNOT-20) questionnaires prior to ivacaftor therapy and at 1, 3, and 6 months afterward. The impact on rhinologic (R), psychological (P), sleep (S), and ear/facial (E) quality of life (QOL) domains was evaluated separately.. Of 153 subjects, 129 (84%) completed all questionnaires. Typical baseline symptom burden was low (75% with scores <1) and degree of improvement (ie, reduced scores) was greater with higher baseline scores. SNOT-20 decreased, reflecting improvement, at all follow-up intervals (1 month: [mean change ± standard deviation] -0.25 ± 0.53, p < 0.01; 3 months; -0.29 ± 0.58, p < 0.01; 6 months: -0.21 ± 0.58, p = 0.02), but less than the prespecified minimal clinically important difference (0.8). Significant improvement was observed at 1, 3, and 6 months in the R domain (1 month: -0.24, p < 0.01; 3 months: -0.34, p < 0.01; 6 months: -0.25, p < 0.01) and P domain (1 month: -0.25, p < 0.01; 3 months: -0.32, p < 0.01; 6 months: -0.26, p < 0.01), and 1 and 3 months in the S domain (1 months: -0.35, p < 0.01; 3 months: -0.32, p < 0.01; 6 months: -0.18, p = 0.07). There was no improvement in the E domain at any time point.. Ivacaftor improves QOL in the R, P, and S domains in G551D CF patients, although QOL instruments validated for CRS may not translate well to CF CRS patients because symptom burden was surprisingly low.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aminophenols; Child; Chronic Disease; Cohort Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Mental Health; Middle Aged; Mutation; Prospective Studies; Quality of Life; Quinolones; Rhinitis; Sinusitis; Sleep; Surveys and Questionnaires; Young Adult

Biofilms may contribute to refractory chronic rhinosinusitis (CRS), as they lead to antibiotic resistance and failure of effective clinical treatment. l-Methionine is an amino acid with reported biofilm-inhibiting properties. Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator with mild antimicrobial activity via inhibition of bacterial DNA gyrase and topoisomerase IV. The objective of this study was to evaluate whether co-treatment with ivacaftor and l-methionine can reduce the formation of Pseudomonas aeruginosa biofilms.. P aeruginosa (PAO-1 strain) biofilms were studied in the presence of l-methionine and/or ivacaftor. For static biofilm assays, PAO-1 was cultured in a 48-well plate for 72 hours with stepwise combinations of these agents. Relative biofilm inhibitions were measured according to optical density of crystal violet stain at 590 nm. Live/dead assays (BacTiter-Glo™ assay, Promega) were imaged with laser scanning confocal microscopy. An agar diffusion test was used to confirm antibacterial effects of the drugs.. l-Methionine (0.5 μM) significantly reduced PAO-1 biofilm mass (32.4 ± 18.0%; n = 4; p < 0.001) compared with controls. Low doses of ivacaftor alone (4, 8, and 12 μg/mL) had no effect on biofilm formation. When combined with ivacaftor (4 μg/mL), a synergistic anti-biofilm effect was noted at 0.05 μM and 0.5 μM of l-methionine (two-way analysis of variane, p = 0.0415) compared with corresponding concentrations of l-methionine alone.. Ivacaftor enhanced the anti-biofilm activity of l-methionine against the PAO-1 strain of P aeruginosa. Further studies evaluating the efficacy of ivacaftor/l-methionine combinations for P aeruginosa sinusitis are planned.

Topics: Aminophenols; Anti-Bacterial Agents; Biofilms; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Progression; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Humans; Methionine; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones; Rhinitis; Sinusitis