Phosphodiesterase Inhibitors in the Treatment of Inflammatory Diseases - Phosphodiesterases as Drug Targets - page 405

subjects was not compromised in patients taking long-acting b 2 -agonists (Fabbri
et al. 2009 ). The clinical evidence suggests that PDE4 inhibitors suppress rather
than exacerbate inflammation in the airways (Gamble et al. 2003 ; Grootendorst
et al. 2007 ). Furthermore, there was no evidence of an increased incidence of
pneumonia in patients with COPD clinically treated with roflumilast, which
might be anticipated if PDE4 inhibitors interfere with host defense (Fabbri et al.
2009 ; Calverley et al. 2009 ). Interestingly, weight loss was an unexpected effect in
subjects independent of any reports of gastrointestinal discomfort (Fabbri et al.
2009 ; Calverley et al. 2009 ) and could be a result of the well-recognized effect of
elevating cAMP in adipocytes in promoting lipolysis since it has been previously
reported that b 2 -agonists have a well-known lipolytic action. Mice deficient in
PDE4D but not PDE4B have abnormal growth development as demonstrated by
reduced fertility and litter size by female mice, reduced growth rates, and body
weight in both sexes, the latter a consequence of a significant reduction in the
weight of bone, muscle, and body organs (Jin et al. 1999 ; Jin and Conti 2002 ).
Although the effect of these gene deficiencies were not studied on lipolysis per se,
both PDE4B and PDE4D are present in rat adipocytes and inhibition of these
enzymes promotes basal lipolysis (Wang and Edens 2007 ).
7 PDE4 Inhibition and the Future
Strategies at improving the risk/benefit ratio for PDE4 inhibition will be important
if this drug class is to be widely used in the treatment of inflammatory diseases. The
therapeutic window between the anti-inflammatory action of these drugs and side
effects such as nausea and emesis is probably not wide enough for cilomilast, and
may limit the use of roflumilast. It is of interest that there are a number of PDE4
inhibitors currently in development that appear to lack significant emetic action;
these include oglemilast and IPL512602 (Boswell-Smith et al. 2006b ), apremilast
(Schafer et al. 2010 ), and the recently reported compounds produced by the Biotech
company Decode (Burgin et al. 2010 ), but the molecular basis for this lack of
emesis has not been published.
Most PDE4 inhibitors under development are designed for oral administration;
however, the inhaled route would deliver a PDE4 inhibitor directly to target cells
within the lung and thereby minimize systemic absorption and of course this
is a widely accepted route of administration in pulmonary medicine as a way of
minimizing systemic side effects with other drug classes. Both AWD 12-281
( N -(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic
acid amide) (Kuss et al. 2003 ) and UK-500,001 (Phillips et al. 2007 ; Vestbo et al.
2009 ) are examples of inhaled PDE4 inhibitors. Indeed, a 7-day treatment with the
inhaled PDE4 inhibitor GSK256066 produced modest attenuation of both the early
and the late asthmatic response to antigen challenge (Singh et al. 2010 ). It clearly
should be possible to obtain anti-inflammatory activity by direct delivery of this
drug class to the lung, although this does not always mean a complete loss of