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Saturday, January 26, 2013

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.

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.