NEW YORK (Reuters Health) - By correcting the mislocation of mutant cystic fibrosis transmembrane conductance regulator (CFTR), sildenafil may prove beneficial in the treatment of cystic fibrosis, according to a report in the January issue of Thorax.
“The most common mutant form of CFTR, deltaF508, is mislocalized within the cell, such that selective correction of both the location and function of [the mutation] will be needed for correction of cystic fibrosis disease manifestations in the majority of patients,” Dr. Robert L. Dormer from University of Wales College of Medicine, Cardiff, UK told Reuters Health. “We can correct the main problem with deltaF508-CFTR in cystic fibrosis cells by a relatively safe drug, sildenafil.”
Dr. Dormer and colleagues investigated the influence of sildenafil on the trafficking of deltaF508-CFTR from its mislocation near the nucleus to its correct location in the apical cell membrane.
In nasal cells from normal individuals, most CFTR was localized to the apical end of the cell, the authors report, but in nasal cells from cystic fibrosis patients deltaF508-CFTR was found near the nucleus, with only 10% present in the apical membrane.
Treatment with sildenafil resulted in a tripling of the percentage of cells having deltaF508-CFTR at the apical membrane, the report indicates. Similar results were seen in cells from an individual with the rare missense mutation R1283M.
This relocation came with sildenafil concentrations approximately 150 times higher than those achieved with a single oral dose (100 mg) of Viagra, the researchers note.
Sildenafil treatment was also able to restore the chloride channel activity of deltaF508-CFTR after its relocation to the apical membrane, the results indicate.
“The findings provide proof of principle for sildenafil (Viagra) as a deltaF508-CFTR trafficking drug and give encouragement for future testing of sildenafil and related PDE5 inhibitors in clinical trials in cystic fibrosis patients,” Dr. Dormer concluded.
“Because of the transient nature of sildenafil action in vivo, our proposed studies are aimed at investigating similar drugs in this family, including the longer acting PDE5 inhibitors, that can correct delF508-CFTR and which would be suitable for administering to cystic fibrosis patients in vivo in clinical trials,” Dr. Dormer added.
Source: Thorax 2005;60:55-59. [ Google search on this article ]
MeSH Headings:Ion Channels: Membrane Glycoproteins: Membrane Proteins: Chloride Channels: Cystic Fibrosis Transmembrane Conductance RegulatorCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
