Ex vivo CF diagnosis by intestinal current measurements (ICM) in small aperture, circulating Ussing chambers

Jonge, Hugo R. de; Ballmann, Manfred; Veeze, Henk J.; Bronsveld, Inez; Stanke, Frauke; Tümmler, Burkhard; Sinaasappel, M.

doi:10.1016/j.jcf.2004.05.034

Cited by 75 publications

(88 citation statements)

References 8 publications

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“…In shortcircuited colon of Cftr ϩ/ϩ mice (Fig. 9A), the application of 500 M amiloride inhibited the resting Na ϩ current set by the activity of the amiloride-sensitive ENaC channels (De Jonge et al, 2004). After the serosal application of 10 M fsk, ⌬I sc increased by 19 Ϯ 3.6 A ⅐ cm Ϫ2 (N ϭ 7), which corresponds to Cl Ϫ secretion.…”

Section: Activation Of a Linear CLmentioning

confidence: 92%

Discovery of Pyrrolo[2,3-b]pyrazines Derivatives as Submicromolar Affinity Activators of Wild Type, G551D, and F508del Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channels

Noël

Faveau²,

Norez³

et al. 2006

J Pharmacol Exp Ther

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The cystic fibrosis transmembrane conductance regulator (CFTR) represents the main Cl Ϫ channel in the apical membrane of epithelial cells for cAMP-dependent Cl Ϫ secretion. Here we report on the synthesis and screening of a small library of 6-phenylpyrrolo [2,3-b]pyrazines (named RP derivatives) evaluated as activators of wild-type CFTR, G551D-CFTR, and F508del-CFTR Cl These results show that RP107 stimulates wild-type CFTR and mutated CFTR, with submicromolar affinity by a cAMPindependent mechanism. Our preliminary structure-activity relationship study identified 4-hydroxyphenyl and 7-n-butyl as deter-

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Section: Activation Of a Linear CLmentioning

confidence: 92%

Discovery of Pyrrolo[2,3-b]pyrazines Derivatives as Submicromolar Affinity Activators of Wild Type, G551D, and F508del Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channels

Noël

Faveau²,

Norez³

et al. 2006

J Pharmacol Exp Ther

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“…In ICM of healthy individuals, the apical potassium efflux in reaction to carbachol and histamine is masked by the much larger chloride efflux. In cystic fibrosis, the response is reversed due to the apical potassium efflux in the absence of a chloride efflux, or biphasic due to residual CFTR-mediated chloride efflux in milder forms of cystic fibrosis [35][36][37].…”

Section: Scope and Purpose Of The Guidelinementioning

confidence: 99%

CFTR biomarkers: time for promotion to surrogate end-point

Boeck

Kent

Davies

et al. 2012

European Respiratory Journal

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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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“…Intestinal epithelia of CF subjects have been evaluated by two different laboratory methods (circulating vs. continuously perfused) (De Jonge et al, 2004;Mall et al, 2004). The common finding of both approaches demonstrates absent or diminished chloride secretion after stimulation with agonists that act via intracellular cAMP.…”

Section: Intestinal Ion Channel Measurementmentioning

confidence: 99%