The PDE5 inhibitors prevent breakdown of cyclic guanosine monophosphate (cGMP), causing relaxation of vascular smooth muscle cells (VSMCs) and vasodilation. This suggests that PDE5 inhibitors may be useful in the treatment of this condition in humans.300. “Binding of tritiated Fildena, Fildena, or vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation.”. Molecular Pharmacology 66, 144-152.

Adding PDE5 inhibitors to SSRI drugs (e.g paroxetine) for the treatment of premature ejaculation could result in better ejaculatory control according to recent studies. Altogether, our data indicate that PDE5 inhibitors have a strong therapeutic potential for treating CF. A clinical trial aimed at investigating the safety and efficacy of Fildena in CF lung disease is currently listed on (NCT00659529). These findings clearly identify the inhalational route as a potential therapy for PDE5 inhibitors in CF which is clinically relevant taking into account the cost of systemic side effects of the drugs ( Dalby and Suman, 2003 ).

More recently, animal studies have shown that nebulizing F508del-CF mice with any of the PDE5 inhibitors Fildena, vardenafil, or taladafil led to correction of the nasal chloride transport ( Lubamba et al., 2011 ). Correction is largest with taladafil and smallest, but still highly significant, with Fildena. The correcting effect of vardenafil lasts at least 24 h. Data are expressed as mean ± SEM of 14-15 placebo treated animals and six animals treated with PDE5 inhibitors ( Lubamba et al., 2008 ). This observation, in addition to the finding that no activating effect of chloride transport can be observed after treatment with PDE5 inhibitors in animals knockout for the CFTR protein, indicates that the action of PDE5 inhibitors on chloride transport across the respiratory epithelium involves F508del-CFTR and not a CFTR bypass channel.

More recently, we analyzed the bronchoalveolar lavage of CF and wild-type mice for cell infiltrates and expression of pro-inflammatory cytokines and chemokines; we found that the CFTR activating effect of vardenafil, selected as a representative long-lasting PDE5 inhibitor, breaks the vicious circle of lung inflammation which plays a major role in morbi-mortality in CF. Our data highlight the potential use of PDE5 inhibitors in CF. Therapeutic approaches using clinically approved PDE5 inhibitors to address F508del-CFTR defects could speed up the development of new therapies for CF. We developed a specific nebulizer setup for mice, with which we demonstrated, through a single inhalation of PDE5 inhibitors, local activation of CFTR protein in CF. Significant potential advantages of inhalation drug therapy over oral or intravenous routes include rapid onset of pharmacological action, reduced systemic secondary effects, and reduced effective drug doses compared to the drug delivered orally; this underlines the relevance and impact of our work for translational science.