Viagra a potentiator and corrector (in CF)

Viagra a potentiator and corrector (in CF)

JANUARY 22, 2013

The success of ivacaftor in targeting the CFTR defect in CF has re-focused attention on other agents that may potentiate or correct CFTR function. Among the candidates are the phosphodiesterase-5 (PDE-5) inhibitors such as sildenafil (Viagra), vardenafil (Levitra) and taladafil (Cialis).

An initial study reported that sildenafil increased CFTR trafficking to the apical membrane in nasal epithelial cells obtained from CF patients (Dormer et al. Thorax 2005;60:55-9; free full text atwww.ncbi.nlm.nih.gov/pmc/articles/PMC1747155/pdf/v060p00055.pdf). Two animal studies subsequently found that PDE-5 inhibitors administered either by intraperitoneal injection or nebulization were able to stimulate chloride transport as shown by changes in nasal potential difference (NPD) (Lubamba et al. Am J Respir Crit Care Med2008;177:506-515, free full text at http://ajrccm.atsjournals.org/content/177/5/506.full.pdf+html; Lubamba et al.Eur Respir J 2011;37:72-78).

A recent German study has also found that sildenafil acts as a potentiator and corrector of wild-type and F508del CFTR channel activity, however, the high doses required may not be suitable in the treatment of CF (Leier et al. Cell Physiol Biochem 2012;29:775-790).

A new review of PDE-5 inhibitors suggests that inhaled vardenafil may be more appropriate due to its potency and longer duration of action (Noel et al. Front Pharmacol 2012;3:167; free full text atwww.ncbi.nlm.nih.gov/pmc/articles/PMC3444771/pdf/fphar-03-00167.pdf). Inhalation had a more rapid onset of action, appeared well tolerated and was not associated with clinically significant changes in heart rate or blood pressure in phase I testing (Berry et al. J Sex Med 2009; epublished July 28, 2009). Preliminary data suggest that vardenafil also reduces the expression of inflammatory cytokines in bronchoalveolar fluid (Lubamba et al. J Cyst Fibros 2012;11:266-273), but further study is needed.

Comment
Dr. Pearce Wilcox: Advances in technology have made it feasible for many laboratories to test compounds that might facilitate CFTR function. These referenced studies in cell systems and animal models illustrate the potential in F508del for a class of medications with already established clinical roles – PDE-5 inhibitors. Given that cAMP-dependent chloride conductance in CF epithelial cells is impaired, there is reason to believe  that modulating intracellular levels of cAMP could have beneficial therapeutic effects for patients with CF.  While an understanding of the mechanisms are limited, there is work to show a partial correction of the basic transepithelial ion transport abnormalities, and mitigation of the exaggerated inflammatory responses related to the F508del-CFTR protein. A wide dose safety margin of these compounds, based especially on work in pulmonary hypertension, has been shown. However, the study of Leier et al suggests that supraphysiologic levels may be needed to potentiate CFTR function. Consequently, the work outlined utilizing a nebulized PDE -5 inhibitor with favourable pharmacokinetics is an important next step. This impressive body of CF-related PDE-5 inhibitor research (outlined in detail in the review by Noel et al.) is the basis to move this class of medications into clinical research, facilitated by the approval and experience in other disorders. Indeed clinicaltrials.gov shows that Phase 1 and 2 studies in CF are already underway.

Viagra Trial in Children and Young Adults With CF

Sildenafil Trial in Children and Young Adults With CF

This study is not yet open for participant recruitment.

Verified by Children's Hospital Medical Center, Cincinnati, September 2010

First Received: September 1, 2010   No Changes Posted

Sponsor:	Children's Hospital Medical Center, Cincinnati
Information provided by:	Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier:	NCT01194232

  Purpose

Cystic Fibrosis (CF), the most common inherited disease in Caucasians, is characterized by chronic pulmonary inflammation and progressive loss of gas exchange units that eventually results in respiratory failure. There is strong evidence that, in CF, abnormally low perfusion carries a high risk of death independent from the presence of pulmonary hypertension. However, the evolution of pulmonary vascular disease in CF and how it might contribute to the rate of decline in lung function is not known. Our knowledge remains limited to the results of old observational studies which concluded that the major causes of pulmonary vascular remodeling and hypertension in CF are hypoxic respiratory failure and destruction of lung tissue. Our recent data obtained by state-of-the-art Magnetic Resonance Imaging (MRI) of the pulmonary circulation, challenges the existing paradigm. We demonstrate that in the absence of hypoxia, significant changes in pulmonary perfusion and in surrogate measures of vascular resistance as well as in collateral blood flow begin early in the course of CF. Newly developed therapeutics have altered dramatically the course of patients suffering from pulmonary vascular disease. Through this 8 week trial, we will examine by Magnetic Resonance Imaging the effect of Sildenafil on pulmonary perfusion and systemic vascularization of the lungs in subjects with mild to moderate disease.

Condition	Intervention	Phase
Cystic Fibrosis With Mild to Moderate Lung Disease CMRI of Lung Perfusion Lung Perfusion Lung Vascularization	Drug: Sildenafil	Phase I Phase II

Study Type:	Interventional
Study Design:	Allocation: Randomized Control: Uncontrolled Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Randomized Controlled Study of Sildenafil in Children and Young Adults With Mild to Moderate Cystic Fibrosis Lung Disease

Resource links provided by NLM:

Genetics Home Reference related topics: cystic fibrosis

MedlinePlus related topics: Cystic Fibrosis

Drug Information available for: Sildenafil Sildenafil citrate

U.S. FDA Resources

Further study details as provided by Children's Hospital Medical Center, Cincinnati:

Primary Outcome Measures:

• Increase pulmonary perfusion [ Time Frame: 8 week visit ] [ Designated as safety issue: No ]
  • Increase of pulmonary perfusion by a minimum of 15% as measured by gadolinium contrast MRI with segmental perfusion and scored on a continuous scale;
  
  

Secondary Outcome Measures:

• Improved lung function [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  • Improved exercise performance as measured by the following variables:

  • Ventilatory equivalent of O2 and CO2 (VEO2 and VECO2)
  • Maximum oxygen consumption (VO2 max)
  
  

Estimated Enrollment:	36
Study Start Date:	October 2010
Estimated Study Completion Date:	September 2012
Estimated Primary Completion Date:	March 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Sildenafil: Experimental 24 subjects will receeive 8 week course of Sildenafil administered at a dose of 1 mg / Kg three times a day with a maximum dose of 20 mg per dose.	Drug: Sildenafil 8 week course of Sildenafil administered at a dose of 1 mg / Kg three times a day with a maximum dose of 20 mg per dose.

  Eligibility

Ages Eligible for Study:	8 Years to 21 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

• Age 8 years to age 21 years
• Diagnosis of cystic fibrosis confirmed by a prior sweat chloride evaluation of > 60 mmol/liter or by two identified CFTR mutations on genetic analysis
• Able to perform acceptable and repeatable spirometry per American Thoracic Society/European Respiratory Society (ATS/ERS) joint consensus criteria.
• Have valid spirometry data for at least 3 years
• Must have mild to moderate lung disease (Mild lung disease will be defined as an FEV1%p of 80-99% predicted. Moderate lung disease will be defined as an FEV1%p of 60-79% predicted.)
• If under the age of 18, the subject must assent to participation in the study, and the subject's parent or guardian must be able to give written informed consent and comply with the requirements of the study protocol
• If 18 years of age or older, the subject must be able to give written parental permission and comply with the requirements of the study protocol
• For female subjects: negative serum pregnancy test and must be willing to use contraception during study participation
• Able to tolerate MRI without sedation
• Subjects who are on alternating monthly on/off cycles of inhaled antibiotics must be willing to be off of inhaled antibiotic therapy for one "on" cycle.
• Must be currently enrolled in CCHMC IRB#: 2008-0926 5.2 Exclusion Criteria

Research subjects will be excluded from the study based on:

• History of CF-related liver disease with portal hypertension
• Currently smoking cigarettes or other tobacco products
• Use of daytime oxygen supplementation
• Previous organ transplantation
• Unstable or uncontrolled hypertension
• Ongoing use of oral corticosteroids
• For female subjects: pregnancy or lactation and unwillingness to use contraception during study participation
• Any hemodynamically significant congenital or acquired cardiac disease or significant cardiomyopathy, hematologic disease (i.e. hemoglobinopathies), or pulmonary disease associated with an increased risk of pulmonary perfusion defects or pulmonary hypertension other than as an outcome of CF
• History of renal and/or hepatic insufficiency, defined as cystatin-C level that exceeds normal range and a previous diagnosis of liver cirrhosis.
• History of uncontrolled asthma defined as oral steroid dependent
• History of hypersensitivity to gadolinium (Magnevist)
• Contraindications specific to MRI including a history of claustrophobia, cardiac pacemaker, or other non-MRI compatible surgical implants (This includes neuro-stimulators containing electrical circuitry, or which generate electrical signals and/or have moving metal parts, and metal orthopedic pins or plates. The research coordinator and/or the MRI technologist will screen all subjects using the standard checklist of medical history and safety questions used by the Radiology Department in routine clinical scans.)
• Daily use of montelukast and ibuprofen
• Use of nitrate medicines or other drugs known to have unsafe interactions with Sildenafil
• Known allergy to Sildenafil
• Inability to comply with study procedures

Laboratory Exclusion Criteria for research subjects (based on history or bloodwork before first MRI):

• Positive sputum, epiglottic, or brochoalveolar lavage culture for Mycobacterium abscessus during the 2 years prior to enrollment
• A positive serum pregnancy test
• Serum creatinine > two times the upper limit of normal for age
• A serum Cystatin C outside of normal range for age

  Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01194232

Contacts

Contact: Lorrie Duan, RN	513-636-7089	lorrie.duan@cchmc.org
Contact: Margo Moore, RN	60394	margo.moore@cchmc.org

Locations

United States, Ohio

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

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.