Biology Reference
In-Depth Information
reduce symptoms (Barnes
2006
). In addition, large multicenter clinical trials
have clearly demonstrated that the clinical efficacy of an ICS can be enhanced
by a LABA (Shrewsbury et al.
2000
). Given the lack of a clinically significant
anti-inflammatory effect of LABAs in asthma when given as a monotherapy, it
seems likely that some form of synergy must occur between these two classes of
drug to account for their superior efficacy when they are used in combination
(Giembycz et al.
2008
). Similarly, the balance of evidence suggests that
Advair
®
,
a LABA/ICS combination therapy, may produce similar, albeit less pronounced,
beneficial effects in patients with COPD (Celli et al.
2008
; Jenkins et al.
2009
).
While the detailed biochemical mechanisms that lead to these clinical observa-
tions remain unclear (but see Sect.
3.2.2
), it is reasonable to believe that other
drugs that raise intracellular cAMP, such as PDE4 inhibitors, may also enhance
the clinical efficacy of glucocorticoids (Newton et al.
2010
)inadditiontoexerting
anti-inflammatory activity in their own right. Support for this assumption comes
from clinical studies with the nonselective PDE inhibitor, theophylline. For
example,
in subjects with moderate asthma,
low-dose,
inhaled budesonide
together with theophylline (mean plasma concentration
8.7
m
g/ml) and high-
dose inhaled budesonide as a monotherapy produced similar clinical benefits in
lung function, severity of disease, and variability in peak expiratory flow, which is
a correlate of AHR (Evans et al.
1997
). This general finding has been indepen-
dently confirmed in several other trials in which the interaction of glucocorticoids
and theophylline in the control of asthma has been studied (Lim et al.
2000
; Ukena
et al.
1997
).
Clinical reports from the arthritis literature also support the general idea that
PDE inhibitors may augment glucocorticoid action. One of these described the
results of a phase IIa trial in which low-dose prednisolone in combination with
dipyridamole, a nonselective PDE inhibitor and adenosine uptake inhibitor, was
compared against placebo in subjects with hand osteoarthritis (Kvien et al.
2008
).
The primary efficacy end point measure was change in the Australian/Canadian
visual analog pain scale, and this combination therapy, named
Synavive
®
(CRx-102), significantly reduced pain relative to placebo (Kvien et al.
2008
).
Whether this benefit is due to a synergistic interaction between the glucocorticoid
and the ability of dipyridamole to nonselectively inhibit PDEs was not unex-
plored. Nevertheless, this is an intriguing possibility and similar investigations
have now been conducted in COPD and rhinitis with selective PDE4 inhibitors.
Thus, in a COPD study, Calverley et al. (
2007
) reported that roflumilast produced
a sustained, albeit modest, improvement in postbronchodilator FEV
1
in subjects
with severe disease (GOLD stages III and IV) in whom the use of ICS was
permitted (Calverley et al.
2007
). Thus, there was an enhanced clinical benefit
in lung function over that produced by the ICS alone. Moreover, in May 2008,
GlaxoSmithKline completed a phase II study in which the effect of intranasal
fluticasone, alone and in combination with an extraordinary potent PDE4 inhibi-
tor, GSK 256066 (Woodrow et al.
2009
), was examined in a cohort of subjects
with seasonal allergic rhinitis (
http://clinicaltrials.gov/ct2/show/NCT00612820
).
The results of that study are awaited with interest.
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