Biology Reference
In-Depth Information
This could be particularly useful in COPD where ICSs, which are the gold standard
for treating the inflammation in asthma, are relatively ineffective (cf. asthma). In
this respect, patients with mild disease are often treated with LABAs and short-
acting b 2 -adenoceptor agonists (SABAs) on an as-needed basis (O'Donnell et al.
2008 ). Given that these drugs act principally via the cAMP/cAMP-dependent
protein kinase (PKA) signaling pathway (Giembycz and Newton 2006 ), it is not
unreasonable to suggest that the presence of a PDE4 inhibitor may enhance b 2 -
adrenoceptor-mediated responses. However, it is generally believed that pde4d
inhibitors do not effect bronchodilation in humans (Grootendorst et al. 2003 )so
improvements in lung function due to increased smooth muscle relaxation are
unlikely. Nevertheless, although SABAs and LABAs do not suppress inflammation
in human subjects with asthma or COPD when administered as monotherapies
(Howarth et al. 2000 ; Roberts et al. 1999 ; Sindi et al. 2009 ), it is entirely possible
that by enhancing cAMP synthesis in target cells they may boost the anti-inflam-
matory actions of a PDE4 inhibitor. In fibroblasts from pde4d -deficient mice,
cAMP accumulation and cAMP-response element-binding protein phosphorylation
were markedly enhanced following the addition of a b 2 -adrenoceptor agonist when
compared to fibroblasts from wild-type animals (Bruss et al. 2008 ). Moreover, in
monocytes, the SABAs, salbutamol, and procaterol, interact synergistically with
rolipram on cAMP accumulation and in the activation of PKA (Seldon et al. 1995 ).
Similar data have also been reported for human neutrophils (Meliton et al. 2006 )
and human eosinophils (Ezeamuzie 2001 ; Meliton et al. 2003 ). However, in proin-
flammatory and immune cells the balance of evidence indicates, paradoxically, that
despite synergy at the level of cAMP accumulation and downstream signal ampli-
fication, PDE4 inhibitors and b 2 -adrenoceptor agonists in combination usually act
additively in the suppression of a variety of proinflammatory mediators such as
TNF- a (Seldon et al. 1995 ). Thus, given that the first PDE4 inhibitor, roflumilast,
has now been approved for the treatment of severe COPD, it is not unreasonable to
predict that in certain patient populations this class of drugs will provide additional
benefit as an add-on therapy when symptoms are not adequately controlled by a
LABA alone (Gross et al. 2010 ). Indeed, this suggestion is supported by the results
of a recent 12-month phase III clinical trial in patients with severe COPD where
postbronchodilator FEV 1 at the end of the study was 60 ml greater in patients
treated with the combination of roflumilast and the LABA, salmeterol, when
compared to patients treated with salmeterol alone (Calverley et al. 2009 ).
3.2 PDE4 Inhibitor/Glucocorticoid Combination Therapies
3.2.1 Clinical Observations
Another attractive option to optimize anti-inflammatory activity is to combine a
PDE4 inhibitor with an ICS. In asthma, glucocorticoids downregulate the expres-
sion of proinflammatory genes and, thereby, dampen down inflammation and
Search WWH ::




Custom Search