Viagra and PSC

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--- In , " Ivor.Sweigler " >

> P.S. For Dave - possibly useful info. Viagra prolongs the life of

cut plants by a week longer than usual - " Viagra makes flowers stand

up straight. " BMJ.199;274 (31 July). " ... 1mg of the drug ... in a

solution was enough to prevent 2 vases of cut flowers from wilting

for as much as a week longer than might be expected. "

Hi Ivor;

It is certainly intriguing that Viagra may affect the shelf life of

cut flowers. Thanks for sharing this info!

PSC has been proposed to be associated with an increased prevalence

of mutations in the cystic fibrosis gene, CFTR. According to

Freedman's group, PSCers often seem to be heterozygous for CFTR

mutations, and show intermediate nasal potential differences in

comparison to normal and CFTR homozygous patients (Sheth S, Shea JC,

Bishop MD, Chopra S, Regan MM, Malmberg E, C, Ricci R, Tsui

LC, Durie PR, Zielenski J, Freedman SD. Increased prevalence of CFTR

mutations and variants and decreased chloride secretion in primary

sclerosing cholangitis. Hum Genet. 2003 Aug;113(3):286-92. PMID:

12783301).

Therefore I was intrigued to read that Viagra seems to correct this

defect in chloride transport in nasal epithelial cells from cystic

fibrosis patients:

Thorax. 2005 Jan;60(1):55-9. Sildenafil (Viagra) corrects DeltaF508-

CFTR location in nasal epithelial cells from patients with cystic

fibrosis.

Dormer RL, CM, Z, Pereira MM, Doull IJ, Norez C, Becq F,

McPherson MA

Department of Medical Biochemistry and Immunology, University of

Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK.

dormer@...

BACKGROUND: Most patients with cystic fibrosis (CF) have a DeltaF508

mutation resulting in abnormal retention of mutant gene protein

(DeltaF508-CFTR) within the cell. This study was undertaken to

investigate DeltaF508-CFTR trafficking in native cells from patients

with CF with the aim of discovering pharmacological agents that can

move DeltaF508-CFTR to its correct location in the apical cell

membrane. METHOD: Nasal epithelial cells were obtained by brushing

from individuals with CF. CFTR location was determined using

immunofluorescence and confocal imaging in untreated cells and cells

treated with sildenafil. The effect of sildenafil treatment on CFTR

chloride transport function was measured in CF15 cells using an

iodide efflux assay. RESULTS: In most untreated CF cells DeltaF508-

CFTR was mislocalised within the cell at a site close to the nucleus.

Exposure of cells to sildenafil (2 hours at 37 degrees C) resulted in

recruitment of DeltaF508-CFTR to the apical membrane and the

appearance of chloride transport activity. Sildenafil also increased

DeltaF508-CFTR trafficking in cells from individuals with CF with a

single copy DeltaF508 (DeltaF508/4016ins) or with a newly described

CF trafficking mutation (R1283M). CONCLUSIONS: The findings provide

proof of principle for sildenafil as a DeltaF508-CFTR trafficking

drug and give encouragement for future testing of sildenafil and

related PDE5 inhibitors in patients with CF. PMID: 15618584.

http://thorax.bmj.com/cgi/content/full/60/1/55

If CFTR defects are involved in PSC, could Viagra be of potential

benefit in PSC treatment in the early stages?

Best regards,

Dave