Pulmonary arterial hypertension (PAH) is characterized by abnormalities in 
endothelial and smooth muscle cell function. Prostacyclin released by 
endothelial cells is a potent vasodilator by increasing cyclic adenosine 
monophosphate. Sildenafil, an inhibitor of phosphodiesterase-5, increases cyclic 
guanosine monophosphate in the lungs, producing vasodilation. To test for a 
therapeutic benefit of the combination of a prostacyclin analogue, subcutaneous 
treprostinil, and sildenafil, a proof-of-concept, open-label investigational 
trial was initiated. Subjects with PAH in World Health Organization (WHO) 
functional classes II to IV receiving subcutaneous treprostinil for > or =6 
months were evaluated with an exercise treadmill test using the Naughton-Balke 
protocol at baseline and after 12 weeks. Sildenafil 50 mg 3 times daily was 
added to the treprostinil. Mean treadmill times in seconds were compared before 
and after 12 weeks of therapy. Nine subjects enrolled in the trial; 7 were women 
(mean age 35 years). At baseline, 3 subjects were in WHO functional class II and 
6 subjects were in WHO functional class III. The mean treadmill time at baseline 
was 465 +/- 167 seconds and at 12 weeks was 656 +/- 205 seconds (42% 
improvement, p = 0.049). All patients had symptomatic improvement. In 
conclusion, this pilot study of subcutaneous treprostinil with sildenafil for 
PAH suggests additive beneficial effects.