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In-Depth Information
muscle cells, endothelial cells, aside from neutrophils mitigating the overall burden
of oxidative stress (Nielson et al.
1990
; Schudt et al.
1991b
; Hatzelmann and Schudt
2001
; Muzaffar et al.
2008
; Milara et al.
2008b
; Diebold et al.
2009
).
The influence of PDE4 inhibitors on major disease mechanisms in COPD is
further corroborated in animal models. For example, PDE4 inhibitors were shown to
suppress (1) BAL neutrophil influx following short-term exposure of mice or guinea
pigs to tobacco smoke (Fitzgerald et al.
2003
; Leclerc et al.
2006
; Weidenbach et al.
2008a
,
b
), (2) the specific cellular pattern of lung adaptive and innate immunity
(dendritic cells, B, CD4+, CD8+ T cells) evolving after long-term (7 months)
exposure of mice to tobacco smoke (Martorana et al.
2008
), (3) airspace enlarge-
ment and lung peripheral destruction following tobacco smoke exposure in mice
over 7 months (Martorana et al.
2005
), (4) bleomycin-induced lung fibrotic remo-
delling (Cortijo et al.
2009
) and (5) pulmonary vascular remodelling and PHT
secondary to monocrotalin or hypoxia in rats (Izikki et al.
2009
).
The following additional aspects may further underpin the role of PDE4 inhibi-
tors in COPD. In situ PDE4 activity is subject to a network of dynamic regulations
at the transcriptional and post-translational (phosphorylation, protein-protein
interaction) levels, and there is evidence to assume an augmented PDE4 activity
in areas of inflammation or remodelling. In those areas, elevated levels of autocrine
factors such as PGE2 or adenosine may be present that potentially strengthen
cellular effects from a PDE4 inhibitor.
In summary, PDE4 inhibitors potentially restore normal physiology in inflam-
matory and structural cells that are imbalanced in COPD. In this respect, the
profile of a PDE4 inhibitor apparently overlaps with pathomechanisms in COPD.
Roflumilast, recently approved for severe COPD unfolds efficacy in all of the
COPD-related in vitro (Table
8
) and in vivo models. A summary of these preclinical
effects has recently been published (Hatzelmann et al.
2010
). The moderate but
pleiotropic effects of the PDE4 inhibitor on a broad spectrum of cell functions that
govern COPD may finally orchestrate the proven clinical efficacy of roflumilast to
improve lung function and reduce exacerbation rates in this ailment.
The recent publication of four large-scale clinical trials demonstrating that the
oral, once daily PDE4 inhibitor roflumilast improved lung function and the rate of
acute exacerbations in patients afflicted from moderate to severe COPD (Calverley
et al.
2009
; Fabbri et al.
2009
) may herald the age of PDE4 inhibitors as oral
remedies in COPD. This, for the first time after more than two decades, adds a new
and oral concept different from (inhaled) long-acting ß
2
-adrenoceptor agonists
(LABA), (inhaled) long-acting muscarinic receptor antagonists (LAMA), or inhaled
corticosteroids (ICS) to the therapeutic armamentarium of physicians. Meanwhile,
roflumilast received marketing authorization for severe COPD in several countries
including EU/USA (Giembycz and Field
2010
).
With roflumilast, a fully competitive PDE4 inhibitor for the PDE4 active site, has
been developed, and it is effective and well tolerated in COPD (Fabbri et al.
2009
;
Calverley et al.
2009
). The therapeutic potential of PDE4 inhibitors may have
targets far beyond COPD to ailments that are comorbid (Barnes and Celli
2008
)
or to other ailments as diverse as asthma, lung and liver fibrosis, Alzheimer's, IBD,
