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Sildenafil improves exercise capacity in patients with cystic fibrosis: a proof-of-concept clinical trial.

ABSTRACT: Background:Exercise intolerance is a common phenotype observed in patients with cystic fibrosis (CF). Treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, has previously been shown to improve exercise capacity (VO2 peak) in other patient populations. Thus, the present study sought to determine the acute and subacute effects of sildenafil on exercise capacity in patients with CF. Methods:The present investigation utilized a randomized, double-blind, placebo-controlled, crossover study with an acute dose of either sildenafil (50?mg) or placebo (n?=?13, age 25?±?10), followed by a 4?week open-label extension with sildenafil (20?mg, TID; n?=?15, age 23?±?11). A comprehensive evaluation of pulmonary function and a maximal exercise test were each performed at every visit. Results:A significant increase in VO2 peak was observed after the acute sildenafil dose with no changes following placebo (77?±?13 versus 72?±?13% predicted; p?=?0.033). In addition, after 4?weeks of treatment, patients showed a significant increase in exercise capacity (72?±?12 versus 75?±?12% predicted; p?=?0.028) and exercise duration (409?±?98 versus 427?±?101?s; p?=?0.014). A robust correlation (r?=?0.656; p?=?0.008) between baseline FEV1 (% predicted) and the change in exercise capacity following 4?weeks of treatment was identified. Conclusions:This proof-of-concept clinical trial demonstrates that sildenafil treatment can improve exercise capacity in patients with CF and that pulmonary function may play an important role in the effectiveness of treatment. Future investigations of sildenafil treatment in patients with CF are certainly warranted.

SUBMITTER: Rodriguez-Miguelez P

PROVIDER: S-EPMC6876159 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Sildenafil improves exercise capacity in patients with cystic fibrosis: a proof-of-concept clinical trial.

Rodriguez-Miguelez Paula P Ishii Haruki H Seigler Nichole N Crandall Reva R Thomas Jeffrey J Forseen Caralee C McKie Kathleen T KT Harris Ryan A RA

Therapeutic advances in chronic disease 20191121

<h4>Background</h4>Exercise intolerance is a common phenotype observed in patients with cystic fibrosis (CF). Treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, has previously been shown to improve exercise capacity (VO<sub>2</sub> peak) in other patient populations. Thus, the present study sought to determine the acute and subacute effects of sildenafil on exercise capacity in patients with CF.<h4>Methods</h4>The present investigation utilized a randomized, double-blind, pl ...[more]

PMID: 31803404

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Project description:Cystic fibrosis (CF), characterized by defective CFTR function, is associated with multiple systemic complications, including vascular dysfunction. Sildenafil, a phosphodiesterase type 5 inhibitor, not only enhances nitric oxide (NO) metabolism but has been shown to improve CFTR functionality as well. Thus, sildenafil has been proposed as a therapy to improve vascular health in CF; however, its potential therapeutic role has yet to be determined. We sought to investigate the effect of sildenafil on endothelial function in patients with CF. Patients with CF completed a randomized, double-blind, placebo-controlled, crossover study with an acute dose of sildenafil (50 mg) or placebo followed by a 4-wk open-label extension with sildenafil (20 mg/day). Flow-mediated dilation (FMD) was used to evaluate endothelial function before and after treatments. In addition, phosphorylated endothelial NO synthase (pNOS3) and total NOS3 protein expression was determined from endothelial cells that were exposed to plasma from the patients before and after 4 wk of sildenafil treatment. No changes ( P ≥ 0.110) in endothelial function were observed after the acute dose of sildenafil. However, FMD significantly ( P = 0.029) increased after 4 wk of treatment (∆FMD: 1.5 ± 2.2%). Moreover, pNOS3 protein expression significantly ( P = 0.013) increased after 4 wk of treatment (∆pNOS3: 0.31 ± 0.39 arbitrary units) and was associated ( r = 0.593, P = 0.033) with the change in FMD. These data suggest that 4 wk of sildenafil treatment can improve vascular endothelial function in patients with CF, likely through an increase in NOS3 phosphorylation. NEW & NOTEWORTHY Findings from the present study demonstrate, for the first time, significant improvement of endothelial function in patients with cystic fibrosis treated with sildenafil that is associated with greater phosphorylation of endothelial nitric oxide synthase. These results support the use of sildenafil as a potential novel therapy for this patient population.

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Sildenafil improves exercise capacity in patients with cystic fibrosis: a proof-of-concept clinical trial.

Publications

Sildenafil improves exercise capacity in patients with cystic fibrosis: a proof-of-concept clinical trial.

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