Viagra / Cialis / Levitra and restoration of chloride channels in CF

Eur Respir J. 2010 Jun 18.

Inhaled PDE5 inhibitors restore chloride transport in cystic fibrosis mice.

Lubamba B, Lebacq J, Reychler G, Marbaix E, Wallemacq P, Lebecque P, Leal T.
Université Catholique de Louvain Ave Hippocrate 10, Brussels, Belgium.

Abstract

Sildenafil and vardenafil, two selective inhibitors of phosphodiesterase type 5 (PDE5) are able, when applied by intraperitoneal injection, to activate chloride transport in cystic fibrosis (CF) mice homozygous for the F508del mutation.

Oral treatment with the drugs may be associated with adverse hemodynamic effects. We hypothesized that inhaled PDE5 inhibitors are able to restore ion transport in F508del-CF airway epithelium. We developed a restraint-free mouse chamber for inhalation studies. PDE5 inhibitors were nebulized for 15 minutes at concentrations adjusted from recommended therapeutic oral doses for male erectile dysfunction.

We measured in vivo nasal transepithelial potential difference 1 hour after a single inhalation of sildenafil, vardenafil or tadalafil in F508del-CF and in normal homozygous mice. After nebulization with the drugs in F508del mice, chloride transport, evaluated by perfusing the nasal mucosa with chloride-free buffer containing amiloride followed by forskolin, was normalized; the forskolin response was increased with the largest values being observed with tadalafil and intermediate values with vardenafil.

No detectable effect was observed on sodium conductance. Our results confirm the role of PDE5 inhibitors for restoring chloride transport function of F508del-CFTR protein and highlight the potential of inhaled sildenafil, vardenafil and tadalafil as a therapy for CF.

Does Levitra Normalize the Nasal Potential Difference in Cystic Fibrosis Patients?

Does a Nasal Instillation of Vardenafil Normalize the Nasal Potential Difference in Cystic Fibrosis Patients?

This study is not yet open for participant recruitment.

Verified by Cliniques universitaires Saint-Luc- Université Catholique de Louvain, October 2009

First Received: October 26, 2009 No Changes Posted

Sponsored by:	Cliniques universitaires Saint-Luc- Université Catholique de Louvain
Information provided by:	Cliniques universitaires Saint-Luc- Université Catholique de Louvain
ClinicalTrials.gov Identifier:	NCT01002534

Purpose

The purpose of this study is to investigate the effect of a nasal instillation of Vardenafil on nasal potential difference in cystic fibrosis patients homozygous for the F508del mutation

Condition	Intervention	Phase
Cystic Fibrosis	Drug: Vardenafil Drug: Placebo	Phase II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator), Placebo Control, Crossover Assignment, Efficacy Study
Official Title:	Does a Nasal Instillation of Vardenafil Normalize the Nasal Potential Difference in Cystic Fibrosis Patients Homozygous for the F508del Mutation? A Randomized, Double Blind, Placebo-controlled Study.

Resource links provided by NLM:

Genetics Home Reference related topics: cystic fibrosis

MedlinePlus related topics: Cystic Fibrosis

Drug Information available for: Vardenafil

U.S. FDA Resources

Further study details as provided by Cliniques universitaires Saint-Luc- Université Catholique de Louvain:

Primary Outcome Measures:

• Cumulated changes in response to Chloride-free solution and isoproterenol (reflecting chloride transport) [ Time Frame: Change from baseline (visit 1) and placebo to Vardenafil instillation ] [ Designated as safety issue: No ]
  

Secondary Outcome Measures:

• Change in basal voltage value and in amiloride response (reflecting sodium transport) [ Time Frame: Change from baseline (visit1) and placebo to Vardenafil instillation ] [ Designated as safety issue: No ]
  

Estimated Enrollment:	10
Study Start Date:	December 2009
Estimated Study Completion Date:	March 2010
Estimated Primary Completion Date:	March 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
baseline: No Intervention visit 1
Vardenafil: Active Comparator nasal instillation of Vardenafil ( visit 2 or 3)	Drug: Vardenafil Nasal instillation of Vardenafil
Placebo: Placebo Comparator Nasal instillation of placebo (visit 3 or 2)	Drug: Placebo Nasal instillation of placebo matching in appearance with the Vardenafil instillation

Detailed Description:

CFTR protein has been shown to be an ohmic, small conductance channel regulated by cAMP intracellular levels that are balanced by degradation through cyclic nucleotide phosphodiesterases (PDE). Several families of PDEs with varying selectivities for cAMP and/or cGMP have been identified. PDE5 is highly specific for cGMP and is involved in the regulation of the intracellular concentration of cGMP in various tissues. Recently, it has been shown , in a preclinical model of transgenic mice , that pharmacological doses of sildenafil and vardenafil, two clinically approved PDE5 inhibitors, stimulate chloride transport activity of the mutant F508del-protein (Lubamba et al, 2008); this parameter has been assessed by means of the nasal potential difference (NPD).An increasing effect od sildenafil on the expression of F508del-CFTR protein (Dormer et al, 2005) was originally reported in nasal epithelial cells harvested from patients with cystic fibrosis and cultured on impermeable supports, a configuration that allows interaction of drugs with the apical side of epithelia.

This study aims to investigate the effect of a single local administration of vardenafil on NPD measurements in CF patients homozygous for the F508del mutation.

Eligibility

Ages Eligible for Study:	14 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Cystic fibrosis patients homozygous for the F508del mutation as confirmed by a genetic test
• Aged 14 years and older
• Male and female
• FEV1 >50% of predicted normal

Exclusion Criteria:

• Acute respiratory tract infection or pulmonary exacerbation requiring antibiotic intervention within 2 weeks of visit 1
• Any condition prohibiting the correct measurement of the NPD
• Active or passive smoking
• Planned treatment or treatment with another investigational drug or therapy within 1 month prior to randomisation

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01002534

Contacts

Contact: Patrick LEBECQUE, MD, PhD	+32 2 764 1111 ext 1939	patrick.lebecque@uclouvain.be
Contact: Teresinha LEAL, MD, PhD	+32 2 764 6724	teresinha.leal@uclouvain.be

Locations

Belgium

Cliniques universitaires St. Luc

Brussels, Belgium, 1200

Sponsors and Collaborators

Cliniques universitaires Saint-Luc- Université Catholique de Louvain

Investigators

Principal Investigator:	Patrick LEBECQUE, MD, PhD	Cliniques universitaires St.Luc (Université catholique de Louvain)
Principal Investigator:	Teresinha LEAL, MD, PhD	Cliniques universitaires St.Luc ( Université Catholique de Louvain)

More Information
Publications:

Dormer RL, Harris CM, Clark Z, Pereira MM, Doull IJ, Norez C, Becq F, McPherson MA. Sildenafil (Viagra) corrects DeltaF508-CFTR location in nasal epithelial cells from patients with cystic fibrosis. Thorax. 2005 Jan;60(1):55-9.

Lubamba B, Lecourt H, Lebacq J, Lebecque P, De Jonge H, Wallemacq P, Leal T. Preclinical evidence that sildenafil and vardenafil activate chloride transport in cystic fibrosis. Am J Respir Crit Care Med. 2008 Mar 1;177(5):506-15. Epub 2007 Nov 15.

Responsible Party:	Cliniques universitaires Saint-Luc (Université Catholique de Louvain) ( Patrick Lebecque, MD, PhD )
Study ID Numbers:	VARD-99
Study First Received:	October 26, 2009
Last Updated:	October 26, 2009
ClinicalTrials.gov Identifier:	NCT01002534 History of Changes
Health Authority:	Belgium: Federal Agency for Medicinal Products and Health Products

Keywords provided by Cliniques universitaires Saint-Luc- Université Catholique de Louvain:

Cystic Fibrosis Vardenafil Nasal instillation Nasal Potential difference

Additional relevant MeSH terms:

Cystic Fibrosis Fibrosis Molecular Mechanisms of Pharmacological Action Enzyme Inhibitors Pharmacologic Actions Digestive System Diseases Pathologic Processes

Vardenafil Phosphodiesterase Inhibitors Respiratory Tract Diseases Genetic Diseases, Inborn Lung Diseases Pancreatic Diseases Infant, Newborn, Diseases

ClinicalTrials.gov processed this record on October 27, 2009


http://www.clinicaltrials.gov/ct2/show/NCT01002534?term=cystic+fibrosis&recr=Open&rcv_d=14