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In-Depth Information
emesis and nausea, as exemplified by the mixed PDE3/4 inhibitor zardaverine,
which although inducing bronchodilation clinically also induced nausea (Brunnee
et al.
1992
).
Another approach might be the use of antisense oligodeoxynucleotides targeting
PDE4, which could be delivered by the inhaled route. The positive results obtained
in the successful targeting of the adenosine A1 receptor in a rabbit model of allergic
inflammation (Nyce and Metzger
1997
) illustrates the potential of this approach.
A preclinical study has demonstrated that antisense oligonucleotides against mRNA
for PDE4B/4D and PDE7 delivered topically to the lung by the endotracheal route
of administration suppressed inflammation following 2 weeks of cigarette smoke
exposure in mice (Fortin et al.
2009
). The advantage of this technique is that side
effects such as nausea and emesis are likely to be avoided. Alternatively, the
recently identified allosteric modulators of PDE4 are proposed to confer lower
emetic potential because despite only partially inhibiting PDE4 activity, the effect
is nonetheless sufficient to inhibit inflammatory cell activity completely (Burgin
et al.
2010
). This is an important possibility that could be exploited in the discovery
of nonemetic PDE4 inhibitors for the treatment of inflammatory diseases.
Another reason that targeting PDE4 alone may not fully resolve airway inflam-
mation is the fact that there are other PDE types exist in structural and inflammatory
cells in the lung (Table
1
). Therefore, targeting multiple PDEs may be required for
optimal anti-inflammatory action. For example, the macrophage is viewed as a
critical cell type in the pathogenesis of COPD (Barnes
2008
); however, the ability
of these cells to release TNF
a
in response to endotoxin was only inhibited to a small
degree by PDE4 inhibitors (Hatzelmann and Schudt
2001
) and the potential func-
tional involvement of PDE3 and PDE7 in these cells cannot be completely ignored.
The inhibitory action of PDE4 inhibitors on the cellular activity of CD8
+
T-lymphocytes and macrophages was significantly increased in the presence of
PDE7 selective inhibitors (Smith et al.
2004
). Similarly, combined PDE3 and PDE4
inhibitor in a single molecule offers the advantage of delivering a bronchodilator
and anti-inflammatory substance. Moreover, it is likely that retention of the inhibi-
tor within the lung may be required in order to maintain anti-inflammatory activity
with the airways (Boswell-Smith et al.
2006a
).
8 Conclusion
A number of clinical trials assessing the efficacy of PDE4 inhibitors for the
treatment of inflammatory disease including asthma, COPD, atopic dermatitis,
and psoriasis have demonstrated moderate success. However, the dose-limiting
side effects such as nausea, emesis, and headache potentially limit the utility of
these drugs. Importantly, there are examples of PDE4 inhibitors that have low
emetogenic potential, although the molecular basis of this phenomenon remains to
be established. Other strategies include topical delivery (e.g., inhalation for admin-
istration to the lung; direct application to the skin), development of subtype
