Biology Reference
In-Depth Information
the result of changes in the affinity of sildenafil for PDE5 or in the conformational
state of PDE5 on inhibitor binding (Francis et al.
1998
; Mullershausen et al.
2003
;
Rybalkina et al.
2010
). The FDA has approved the use of 20 mg sildenafil three
times a day for PAH, although the dose can be increased to 40-80 mg or until side
effects such as headache or dyspepsia develop.
Subsequently, the PHIRST (Pulmonary Arterial Hypertension and Response to
Tadalafil) trial was undertaken, which demonstrated that vardenafil given 40 mg
once per day (a single dose PDE5 inhibitor is thought to improve patient compli-
ance) to PAH-patients for 16 weeks increased the 6-min walking distance by an
average of 33 m, decreased mPAP and PVR and improved the time to clinical
worsening, which led to FDA approval in June 2009 (Galie et al.
2009a
). Vardenafil
(5 mg once daily for the first 4 weeks, then 5 mg twice daily for 1 year) was tested in
a multicenter, open-label study in PAH patients; this study showed comparable
improvements in hemodynamic parameters and exercise capacity as was noted with
sildenafil and tadalafil (Jing et al.
2009
).
No clinical trials have directly compared the long-term therapeutic effects of all
three of these inhibitors; however, in patients with IPAH, the acute effects of
sildenafil, tadalafil, and vardenafil vary in terms of kinetics of pulmonary vasodila-
tion (most rapid effect was vardenafil), pulmonary vascular selectivity (vardenafil
also decreased systemic resistance), and ability to improve arterial oxygenation
(only sildenafil improved oxygenation), strongly suggesting that longer-term stud-
ies are needed to determine whether such acute effects translate into clinical
effectiveness (Ghofrani et al.
2004
). Experimentally, although all three drugs dose-
dependently relax isolated rat PAs, some data suggest that downstream signaling may
differ among the PDE5 inhibitors. For example, only vardenafil markedly reduces
CaCl
2
-induced contractions in phenylephrine-treated isolated PA, whereas only
vardenafil inhibits the hypoxia-induced upregulation of TNF-
a
and IL-1
b
in PA
(Toque et al.
2008
; Tsai et al.
2006
).
As has been the case for the treatment of systemic hypertension, it is likely that
combination therapy may be more efficacious in reducing mPAP and PA remodel-
ing in PAH. A number of experimental and clinical studies have demonstrated
that PDE5 inhibition additively or even synergistically improves pulmonary hemo-
dynamics when used with a number of approved or experimental drugs for PAH.
The combination of sildenafil with prostanoids, such as epoprostenol or inhaled
iloprost, has been shown to be effective both experimentally and clinically and to
decrease mPAP more than each agent alone (Ghofrani et al.
2003
; Wilkens et al.
2001
). In PAH patients, sildenafil reversed the decline in the 6-min walk test that
was observed after three months of inhaled iloprost and sustained this benefit for
over 1 year. Similarly, when the clinical benefits of an endothelin-A receptor
antagonist declined in PAH patients, sildenafil increased the 6-min walk test by
43% and, importantly, no dose adjustment of either agent was required upon
coadministration (Hoeper et al.
2004
; Stavros et al.
2010
). In the chronic-hypoxic
rat and when administered acutely to PAH patients, the decrease in mPAP and PVR
by sildenafil can be augmented by the addition of ANP, BNP, or inhibitors of
neutral endopeptidase; such data support the hypothesis that the beneficial effects
