Nasal application of the cationic liposome DC-Chol:DOPE does not alter ion transport, lung function or bacterial growth

Middleton, Peter G.; Caplen, Natasha J.; Gao, Xiang; Huang, Leaf; Gaya, H.; Geddes, Duncan M.; Alton, Eric W.F.W.

doi:10.1183/09031936.94.07030442

Cited by 107 publications

(34 citation statements)

References 10 publications

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“…Consequently, the possibility of such an increase in inflammatory markers or an immunogenic response occurring in CF subjects as a result of administration of the lipid-DNA complex cannot be However, up to half of CF subjects exhibit airway hyperresponsiveness [15][16][17] and nebulisation of a hypotonic prepNo statistically significant changes were seen.…”

Section: Discussionmentioning

confidence: 99%

Safety of a single aerosol administration of escalating doses of the cationic lipid GL-67/DOPE/DMPE-PEG5000 formulation to the lungs of normal volunteers

Chadwick¹,

Kingston

Stern³

et al. 1997

Gene Ther

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Several groups are assessing the use of cationic lipids for administration and at intervals up to 21 days thereafter. respiratory gene therapy. To date no human data are availNo adverse clinical events were seen or any statistically able regarding the safety of intra-pulmonary cationic lipid significant changes in spirometry or gas transfer. There delivery. In preparation for a trial of pulmonary delivery of were no clinically significant changes in any of the blood the CFTR gene, we have assessed the safety of nebulised parameters and no CT changes were seen. Comparisons lipid GL-67/DOPE/DMPE-PEG 5000 (GL-67A), the cationic of the cellular subpopulations (neutrophils, eosinophils, lipid formulation to be used in this study. Fifteen healthy lymphocytes and macrophages) in induced sputum volunteers were given incremental doses of GL-67A via a showed no significant alterations following administration Pari LC Jet nebuliser; three volunteers in each of five dosof the GL-67A. This study suggests that a single appliing cohorts with a week interval between cohorts. Markers cation of aerosol formulation of GL-67A does not result in of safety included clinical assessment, measurement of clinically detectable changes when given by nebulisation lung function, chest CT scan, serological testing and analyinto the lungs of normal volunteers and provides an indisis of induced sputum. Measurements were taken before cation of a lipid dose tolerated in man.

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Section: Discussionmentioning

confidence: 99%

Safety of a single aerosol administration of escalating doses of the cationic lipid GL-67/DOPE/DMPE-PEG5000 formulation to the lungs of normal volunteers

Chadwick¹,

Kingston

Stern³

et al. 1997

Gene Ther

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“…Nasal PD was measured using previously described methods [5,7,8]. Briefly, the exploring electrode consisted of a double lumen silicone rubber tube with the openings of both lumens at the same site, 3 mm from the tip.…”

Section: Methodsmentioning

confidence: 99%

Hypertonic saline alters ion transport across the human airway epithelium

2001

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Aerosolized hypertonic saline is currently being investigated as a new agent for the treatment of impaired mucociliary clearance which occurs in many respiratory diseases. Mannitol aerosols, in particular dry powder inhalers, have been proposed as an alternative treatment to saline, offering the same osmotic load with other benefits. However, the effects of these hypertonic aerosols on airway epithelial ion transport processes have not been tested in human subjects in vivo. This report examines the effect of these solutions on airway ion transport using the nasal potential difference (PD) technique.Seven healthy nonsmoking adult volunteers were studied. On different days, a doseresponse curve was constructed for the saline added to Krebs N-[2-hydroxyethyl] piperazine-N9-[2-ethanesulphonic acid] (HEPES) diluent. The reversibility of this saline effect was measured, and the response to additional saline (500 mM) and mannitol (1 M) compared.Hypertonic saline decreased nasal PD in a dose-related manner, with mean (SEM) decreases in PD (less negative) of 6.6 (1.5), 7.6 (1.6), 10.0 (2.0), 13.1 (2.9) and 14.8 (3.2) mV (n~4) for addition of 150 mM, 250 mM, 500 mM, 1,200 mM and 2,000 mM NaCl to the Krebs HEPES diluent, respectively. The effect of hypertonic saline was fully reversible with washout for 3 min (presaline 15.9 (0.5) mV, postwashout 15.8 (1.1) mV, (n~4)). The hypertonic saline response was rapid in onset, sustained for at least 4 min, and decreased PD from 13.7 (1.7) mV to 5.1 (1.3) mV (n~7, pv0.001). In contrast, addition of mannitol to the perfusate did not significantly alter nasal PD, with a nonsignificant trend towards an increase (more negative) in the PD, (premannitol 13.9 (1.6) mV, postmannitol 15.3 (2.0) mV, n~7).As the osmotic stimulus of the 1 M mannitol is similar to that of the 500 mM sodium chloride, the divergent nasal potential difference responses suggest that the response to the saline was specific to the sodium chloride itself and not the simultaneous change in osmolarity. This demonstrates that the human airway epithelium in vivo can respond to topical hypertonic saline independent of the altered osmolarity.

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“…NPD and ICM measure the voltage potential or electrical current, respectively, resulting from epithelial ion fluxes at the mucosal surface in vivo and ex vivo, respectively. The NPD measurement is thought to provide information on both sodium absorption and chloride secretion [28,29]. In normal airway epithelia, sodium absorption is the primary ion transport activity so that the resulting airway surface potential difference is negative with reference to the interstitium.…”

Section: Scope and Purpose Of The Guidelinementioning

confidence: 99%

CFTR biomarkers: time for promotion to surrogate end-point

et al. 2012

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In patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points of efficacy in phase-III clinical trials with the disease modifying drugs ivacaftor (VX-770), VX809 and ataluren. The aim of this project was to review the literature on reliability, validity and responsiveness of nasal potential difference, sweat chloride and intestinal current measurement in patients with cystic fibrosis.Data on clinimetric properties were collected for each biomarker and reviewed by an international team of experts. Data on reliability, validity and responsiveness were tabulated. In addition, narrative answers to four key questions were discussed and agreed by the team of experts.The data collected demonstrated the reliability, validity and responsiveness of nasal potential difference. Fewer data were found on reliability of sweat chloride concentration; however, validity and responsiveness were demonstrated. Validity was demonstrated for intestinal current measurement, but further information is required on reliability and responsiveness. For all three end-points, normal values were collected and further research requirements were proposed.This body of work adds useful information to support the promotion of CFTR biomarkers to surrogate end-points and to guide further research in the area.

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Nasal application of the cationic liposome DC-Chol:DOPE does not alter ion transport, lung function or bacterial growth

Cited by 107 publications

References 10 publications

Safety of a single aerosol administration of escalating doses of the cationic lipid GL-67/DOPE/DMPE-PEG5000 formulation to the lungs of normal volunteers

Safety of a single aerosol administration of escalating doses of the cationic lipid GL-67/DOPE/DMPE-PEG5000 formulation to the lungs of normal volunteers

Hypertonic saline alters ion transport across the human airway epithelium

CFTR biomarkers: time for promotion to surrogate end-point

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