Biology Reference
In-Depth Information
was unaffected by the removal of PDE4D (Hansen et al.
2000
). This highlights the
potential complementary role of PDE4 isoforms in regulating allergic airway
inflammation, and the need to target more than one PDE4 isoform since the
inflammatory response, bronchial hyperresponsiveness, and airway remodeling in
allergic wild-type mice could be inhibited by nonselective PDE4 inhibitors such as
rolipram or roflumilast (Kung et al.
2000
; Kanehiro et al.
2001
; Kumar et al.
2003
).
Whilst the use of gene knockout studies can offer insights into the function of
proteins, it is likely that compensatory mechanisms at birth and the mixed back-
ground of the generated knockouts could confound attempts to define the biological
role of a particular protein. The use of conditional PDE4 knockouts or a biological
approach (e.g., siRNA) may be required to understand the biological role(s) of
PDE4 subtypes completely (Huston et al.
2008
).
The numerous preclinical studies reporting the anti-inflammatory potential of
PDE4 inhibitors in models of allergic inflammation and in human cells in vitro have
to some degree been corroborated in clinical trials in asthmatic subjects. Twice-daily
treatment for 9.5 days with the PDE4 inhibitor CDP840 inhibited the development
of the late phase response in asthmatic subjects by 30% (Harbinson et al.
1997
).
A similar degree of inhibition of the late phase response was observed following once
daily treatment for 7- to 10-day with roflumilast (van Schalkwyk et al.
2005
), while
2-week treatment with MK-0359 improved baseline FEV1 and reduced symptom
scores in chronic asthmatic subjects (Lu et al.
2009
). This late phase response is used
by clinicians to model the inflammatory component following an allergic insult to the
airways. In both allergen challenge studies, the effect of drug treatment on the acute
allergen bronchoconstriction was modest and consistent with the lack of demonstrable
action of PDE4 inhibition on both mast cell and airway smooth muscle function. This
highlights the role of other PDE enzymes, namely PDE3 in the regulation of the
function of these cell types in the airway (Table
1
). Bronchial hyperresponsiveness
was not reduced by these drugs, with only one study purporting to show modest
protection against allergen-induced bronchial hyperresponsiveness (Louw et al.
2007
). This suggests that PDE4 may not be a suitable target for this particular
phenomenon, or that higher doses are required to provide complementary and persis-
tent inhibition of the enzyme and hence attenuation of bronchial hyperresponsiveness.
It is of interest that roflumilast has a plasma half-life of 16 h following a single oral
administration and is metabolized by CYP3A4 to the active N-oxide metabolite,
which has considerably greater bioavailability with a half-life of 20 h that would
favor prolonged enzyme exposure (David et al.
2004
). This favorable pharmacoki-
netic profile would be anticipated to produce longer periods of PDE4 inhibition.
However, whilst there was a significant reduction in the activity of circulating
monocytes in subjects maintained on roflumilast for 4 weeks, the magnitude of this
change was small, resulting in only an approximately 1.3-fold reduction in TNFalpha
production by monocytes in response to endotoxin challenge in vitro (Timmer et al.
2002
). One could argue that only a partial inhibition of PDE4 activity was achieved at
the dose employed in clinical studies and consequently suppression of inflammatory
cell function within the airway tissue compartment is not maximal, a hypothesis borne
out in several clinical studies (Gamble et al.
2003
; Grootendorst et al.
2007
).
