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Nonsense (premature stop codon) mutations in mRNA for the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) in approximately 10% of patients. Ataluren (PTC124) is an oral drug that permits ribosomes to readthrough premature stop codons in mRNA to produce functional protein. To evaluate ataluren activity, safety, and pharmacokinetics in children with nonsense mutation CF. Patients were assessed in two 28-day cycles, comprising 14 days on and 14 days off ataluren. Patients took ataluren three times per day (morning, midday, and evening) with randomization to the order of receiving a lower dose (4, 4, and 8 mg/kg) and a higher dose (10, 10, and 20 mg/kg) in the two cycles. The study enrolled 30 patients (16 male and 14 female, ages 6 through 18 yr) with a nonsense mutation in at least one allele of the CFTR gene, a classical CF phenotype, and abnormal baseline nasal epithelial chloride transport. Ataluren induced a nasal chloride transport response (at least a -5-mV improvement) or hyperpolarization (value more electrically negative than -5 mV) in 50% and 47% of patients, respectively, with more hyperpolarizations at the higher dose. Improvements were seen in seven of nine nonsense mutation genotypes represented. Ataluren significantly increased the proportion of nasal epithelial cells expressing apical full-length CFTR protein. Adverse events and laboratory abnormalities were infrequent and usually mild. Ataluren pharmacokinetics were similar to those in adults. In children with nonsense mutation CF, ataluren can induce functional CFTR production and is well tolerated.

A small fraction of patients with cystic fibrosis have a genetic defect that introduces a premature stop codon into the CFTR gene; this results in a truncated protein that does not fulfill its normal biologic function. Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene that lead to dysfunction of the CFTR protein, which is an apical membrane protein regulating the transport of chloride and sodium in secretory epithelial cells. 1 Since the discovery of the CFTR gene, more than 1000 mutations have been identified, including missense, deletion or insertion, frame shift, splice site, and nonsense mutations. 2 Nonsense or stop mutations contain signals that cause a truncated or unstable protein, should result in a deficiency or absence of CFTR chloride channels, and are associated with a severe cystic fibrosis . . .

Most individuals with cystic fibrosis (CF) carry one or two mutations that result in a maturation defect of the full-length protein. One such mutation, ΔF508, results in a mutant membrane glycoprotein that fails to progress to the apical membrane, where the wild-type protein normally functions as a cyclic AMP-regulated chloride channel. 4-Phenylbutyrate (Buphenyl), an orally bioavailable short chain fatty acid, modulates heat shock protein expression and restores maturation of the ΔF508 protein in vitro and in vivo. We performed a randomized, double-blind, placebo-controlled, dose-escalation and safety study of Buphenyl in 19 adults with CF (homozygous ΔF508) to test the hypothesis that Buphenyl would be safe, well-tolerated, and associated with an increase in chloride transport in nasal epithelia. Three dose levels (20, 30, or 40 g divided t.i.d.) of drug or placebo were given for 1 week. Serial measurements of chloride transport by nasal potential difference (NPD) testing and metabolic safety testing were performed. A maximum tolerated dose of 20 g was defined based on minimal adverse reactions, the safety profile, and a statistically significant induction of chloride transport that was maximal by day 3. This short-term phase I/II study demonstrates proof of principle that modulation of ΔF508 CFTR biosynthesis and trafficking is a viable therapeutic approach for cystic fibrosis.

The mechanism by which pancreas divisum may lead to recurrent episodes of acute pancreatitis in a subset of individuals is unknown. Abnormalities of the cystic fibrosis gene product (CFTR) have been implicated in the genesis of idiopathic chronic pancreatitis. The aim of this study was to determine if CFTR function is abnormal in patients with pancreas divisum and recurrent acute pancreatitis (PD/RAP). A total of 69 healthy control subjects, 12 patients with PD/RAP, 16 obligate heterozygotes with a single CFTR mutation, and 95 patients with cystic fibrosis were enrolled. CFTR function was analyzed by nasal transepithelial potential difference testing in vivo. The outcomes of the PD/RAP patients following endoscopic and surgical treatments were concomitantly analyzed. Direct measurement of CFTR function in nasal epithelium in response to isoproterenol demonstrated that the values for PD/RAP were intermediate between those observed for healthy controls and cystic fibrosis patients. The median value was 13 mV for PD/RAP subjects, which was statistically different from healthy controls (22 mV, p= 0.001) and cystic fibrosis pancreatic sufficient (-1 mV, p < 0.0001) and pancreatic insufficient (-3 mV, p < 0.0001) patients. These results suggest a link between CFTR dysfunction and recurrent acute pancreatitis in patients with pancreas divisum and may explain why a subset of patients with pancreas divisum develops recurrent acute pancreatitis.

Purpose Continuous positive airway pressure (CPAP) is the gold standard in the treatment of obstructive sleep apnea (OSA), but its impact on ciliary function is unclear to date. Furthermore, CPAP is associated with numerous side effects related to the nose and upper airway. Humidified CPAP is used to relieve these symptoms, but again, little is known regarding its effect on ciliary function of the nasal respiratory epithelium. Methods In this prospective, randomized, crossover trial, 31 patients with OSA (AHI >15/h) were randomized to two treatment arms: nasal continuous positive airway pressure (nCPAP) with humidification or nCPAP without humidification for one night in each modality to assess short-term effects of ciliary beat frequency (CBF) and mucus transport time (MTT) and consecutively for 8 weeks in each modality to assess long-term effects in a crossover fashion. Results The baseline CBF was 4.8 ± 0.6 Hz, and baseline MTT was 540 ± 221 s. After one night of CPAP with and without humidification, ciliary function increased moderately yet with statistical significance ( p <0.05). The short-term groups with and without humidification did not differ statistically significant. Regarding long-term effects of CPAP, a statistically significant increase in ciliary function above the baseline level and above the short-term level was shown without humidification (7.2 ± 0.4 Hz; 402 ± 176 s; p <0.01). The increase above baseline level was even more pronounced with humidification (9.3 ± 0.7 Hz; 313 ± 95 s; p <0.01). There was a statistically significant difference between both groups at long-term assessment with regard to CBF ( p <0.01). Conclusions Independent of airway humidification, nCPAP has moderate effects on short-term ciliary function of the nasal respiratory epithelium. However, a significant increase in ciliary function—both in terms of an increased CBF and a decreased MTT—was detected after long-term use. The effect was more pronounced when humidification was used during nCPAP.

Solitary chemosensory cells (SCCs) of the nasal cavity are specialized epithelial chemosensors that respond to irritants through the canonical taste transduction cascade involving Gα-gustducin and transient receptor potential melastatin 5. When stimulated, SCCs trigger peptidergic nociceptive (or pain) nerve fibers, causing an alteration of the respiratory rate indicative of trigeminal activation. Direct chemical excitation of trigeminal pain fibers by capsaicin evokes neurogenic inflammation in the surrounding epithelium. In the current study, we test whether activation of nasal SCCs can trigger similar local inflammatory responses, specifically mast cell degranulation and plasma leakage. The prototypical bitter compound, denatonium, a well-established activator of SCCs, caused significant inflammatory responses in WT mice but not mice with a genetic deletion of elements of the canonical taste transduction cascade, showing that activation of taste signaling components is sufficient to trigger local inflammation. Chemical ablation of peptidergic trigeminal fibers prevented the SCC-induced nasal inflammation, indicating that SCCs evoke inflammation only by neural activity and not by release of local inflammatory mediators. Additionally, blocking nicotinic, but not muscarinic, acetylcholine receptors prevents SCC-mediated neurogenic inflammation for both denatonium and the bacterial signaling molecule 3-oxo-C12-homoserine lactone, showing the necessity for cholinergic transmission. Finally, we show that the neurokinin 1 receptor for substance P is required for SCC-mediated inflammation, suggesting that release of substance P from nerve fibers triggers the inflammatory events. Taken together, these results show that SCCs use cholinergic neurotransmission to trigger peptidergic trigeminal nociceptors, which link SCCs to the neurogenic inflammatory pathway.

Cystic fibrosis (CF) is a common, serious, inherited disease. The major cause of mortality in CF is lung disease, due to the failure of airway epithelial cells to express a functional product of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A potential treatment for CF lung disease is the expression of CFTR in the airways following gene transfer. We have undertaken a double-blinded, placebo-controlled, clinical study of the transfer of the CFTR cDNA to the nasal epithelium of 12 CF patients. Cationic liposomes complexed with plasmid containing the human CFTR cDNA were administered to eight patients, whilst four patients received placebo. Biopsies of the nasal epithelium taken 7 days after dosing were normal. No significant changes in clinical parameters were observed. Functional expression of CFTR assessed by in vivo nasal potential difference measurements showed transient correction of the CF chloride transport abnormality in two patients (15 days after dosing in one patient). Fluorescence microscopy demonstrated CFTR function ex vivo. In cells from nasal brushings. In total, evidence of functional CFTR gene transfer was obtained in six out of the eight treated patients. These results provide proof of concept for liposome-mediated CF gene transfer.

In cystic fibrosis (CF), mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene results in defective transepithelial ion transport, leading to life shortening inflammatory lung disease. Before lung studies, we tested the safety and efficacy of gene delivery to the nasal epithelium of CF patients using pCMV-CFTR-DOTAP cationic liposome complex. A single dose of 400 micrograms pCMV-CFTR:2.4 mg DOTAP was administered in a randomised, double-blinded fashion to the nasal epithelium of eight CF patients, with a further eight receiving buffer only. Patients were monitored for signs and symptoms for 2 weeks before treatment and 4 weeks after treatment. Inflammatory cells were quantified in a nasal biopsy taken 3 days after treatment. There was no evidence for excess nasal inflammation, circulating inflammatory markers or other adverse events ascribable to active treatment. Gene transfer and expression were assayed by the polymerase chain reaction. Transgene DNA was detected in seven of the eight treated patients up to 28 days after treatment and vector derived CFTR mRNA in two of the seven patients at +3 and +7 days. Transepithelial ion transport was assayed before and after treatment by nasal potential difference during drug perfusion and by SPQ fluorescence halide ion conductance. Partial, sustained correction of CFTR-related functional changes toward normal values were detected in two treated patients. The level of gene transfer and functional correction were comparable to those reported previously using adenoviral vectors or another DNA-liposome complex, but here were sustained and uncompromised by false positives. These results justify further studies with pCMV-CFTR-DOTAP aimed at treating CF lung disease.

Postoperative observations in patients undergoing radical endoscopic resection surgery for sinonasal tumors have frequently noted the occurrence of mucosal crusts or bleeding on the nasal epithelial surface. This study employs computational fluid dynamics (CFD) techniques to elucidate the critical fluidic factors associated with these postoperative morbidities. Three-dimensional models of the postoperative nasal cavities were constructed using thin-section computed tomography data from nine patients who underwent radical resection surgery for sinonasal tumors, encompassing endoscopic medial maxillectomy (N = 3), endoscopic craniofacial resection (N = 3), and endoscopic resection with septectomy (N = 3). Simulations of inspiratory airflow, assuming turbulent flow, were conducted to analyze airflow and air conditioning characteristics at sites where crust formation occurred. Frequent sites of crusting or bleeding were associated with the maxillary or sphenoidal sinuses (five out of nine subjects), where the ostia were substantially enlarged due to the surgery. Two distinct fluid dynamic features contributing to crust formation were identified. In five cases, crusts formed where local wall shear stress was elevated, while in four cases, crusts were observed in regions characterized by stagnant flow. Additionally, the relative humidity in the nasopharynx decreased to an unsatisfactory range (83.8‒85.7%). This study demonstrated that two distinct fluid dynamic environments conducive to postoperative crust formation are possible, indicating that the wall shear stress level alone is insufficient for crust formation. Additionally, impaired humidification function observed following the surgery underscores the necessity of providing adequate moisturization for post-surgical care.

ABSTRACT Background: This study was designed to evaluate the efficacy and safety of fluticasone furoate nasal spray (FFNS), a novel enhanced-affinity intranasal corticosteroid, in Japanese patients with perennial allergic rhinitis (PAR), and to determine the optimal dose. Methods: In this phase II, multicenter, double-blind, randomized, placebo-controlled, parallel-group, dose-ranging study, 240 patients (aged ≥ 16 years) received once-daily (od) treatment for 2 weeks with either FFNS 110 μg (n = 80), 220 μg (n = 81) or placebo (n = 79). Patients evaluated 3 nasal symptoms using a 4-point scale. Efficacy was assessed as the mean change from baseline in total nasal symptom score (TNSS). Results: Treatment with FFNS resulted in a significantly greater decrease over the treatment period in the mean 3TNSS (sneezing, rhinorrhea, and nasal congestion; p < 0.001 each dose vs. placebo), compared with placebo. More patients receiving FFNS had a markedly or moderately improved impression of treatment than placebo recipients (48% and 49% for FFNS 110 μg and 220 μg, respectively, vs. 18% for placebo; p < 0.001). Nasal rhinoscopy findings revealed significant improvements in mucosal swelling of the inferior turbinate (110 μg: p = 0.004; 220 μg: p = 0.011) and amount of watery rhinorrhea (110 μg: p = 0.003; 220 μg: p < 0.001), compared with placebo. Both doses of FFNS were well tolerated. Conclusions: Both FFNS 110 µg and 220 µg od were effective in alleviating nasal symptoms in Japanese patients with PAR over the 2-week duration of this study. FFNS 110 µg od was selected as the optimal dose for further evaluation in phase III clinical trials.