Biology Reference
In-Depth Information
Unfortunately, the doses that can be administered clinically with most orally
active PDE4 inhibitors are limited by side effects, the most commonly reported
being headache, nausea, and diarrhea of a mild-to-moderate severity (van Schalkwyk
et al.
2005
; Lu et al.
2009
). The availability of other nonemetic drugs such as
CDP840 (Harbinson et al.
1997
) might provide hope that such PDE4 inhibitors can
be developed for the treatment of asthma, a worthy goal to pursue in light of at least
one clinical study reporting comparable clinical efficacy between roflumilast and
the inhaled glucocorticosteroids beclomethasone diproprionate in persistent asthma
(Bousquet et al.
2006
). Such systemic side effects may also be eliminated by
using the inhaled route such that relatively higher doses of PDE4 inhibitor can
be delivered to the intrapulmonary compartment whilst reducing systemic bioavail-
ability as recently reported with GSK256066 (Singh et al.
2010
). However,
another inhaled PDE inhibitor, UK 50,000 failed to show any clinical benefit
(Phillips et al.
2007
) and an early mixed PDE 3/4 inhibitor zardaverine actively
elicited frank emesis at inhaled doses that induced bronchodilation (Brunnee et al.
1992
). Mesenteric arteritis, characterized by inflammation of the arterioles is
observed in rodents and primates following doses of some PDE4 inhibitors far
exceeding those that would be used clinically; however, this condition has not been
observed in subjects in clinical trials with roflumilast and therefore is unlikely to be
a major issue and even less so if inhaled formulations of this drug class are
developed (Spina
2008
).
4 COPD and PDE4
Unlike asthma, COPD is primarily caused by cigarette smoking, although in
developing countries smoke derived from burning biomass fuels is also a predis-
posing factor (Salvi and Barnes
2009
). COPD is also an inflammatory disease but
the nature of the inflammatory response is distinct from asthma. The inflammatory
response in COPD is characterized by the activation of macrophages and airway
epithelial cells, which in turn, secrete a range of chemokines and lipid mediators
resulting in the recruitment of neutrophils and CD8+ T-lymphocytes to the lung.
The secretion of a range of proteases from neutrophils (elastase, MMP9, cathepsins)
and macrophages (MMP12) is thought to contribute toward fibrosis of the small
airways and increased mucus secretion and destruction of the alveolar wall (Barnes
2008
) These pathological changes give rise to the symptoms of cough, mucus
secretion, dyspnea, and emphysema. Many of the cell types implicated in the
COPD inflammatory response express PDE4 (Table
1
).
The expression of PDE4A-D mRNA transcripts in peripheral blood neutrophils
and CD8 T cells is not altered in subjects with mild COPD (Jones et al.
2007
).
However, the expression of PDE4A4 mRNA transcript was significantly increased
in macrophages purified from bronchoalveolar lavage fluid from subjects with
mild-to-moderate COPD compared with healthy subjects or smokers who did not
present with COPD (Barber et al.
2004
). Of the 12 PDE4 variants analyzed, only the
