Biology Reference
In-Depth Information
inhibitors are anti-inflammatory in patients with COPD. Both roflumilast
(Grootendorst et al.
2007
) and cilomilast (Gamble et al.
2003
) reduced both the
number of inflammatory cells, such as, neutrophils and lymphocytes recruited to the
airways and the levels of two biochemical markers of this disease, namely IL-8 and
neutrophil elastase. The magnitude of the change in the number of these inflamma-
tory cells and concentration of mediators was between 30 and 50%, which might
contribute to the beneficial action of these two PDE4 selective in the clinic trials.
However, to date the substantial inhibition of PDE4 with an orally active inhibitor
has not been achieved because of dose-limiting side effects, which may also explain
the modest clinical benefit shown with these drugs. As discussed for asthma, it is
plausible that other PDE species (e.g., PDE3, 7; see Table
1
) may require targeting
for a full anti-inflammatory therapeutic action to be attained in treating this disease
(Banner and Press
2009
).
The most common side effect reported with roflumilast included diarrhea
(9%), headache (5%), and nausea (5%) (Rabe et al.
2005
; Calverley et al.
2007
,
2009
;Fabbrietal.
2009
). This was of the same order of magnitude as reported
with cilomilast, although abdominal pain and vomiting were also reported for
this drug (Rennard et al.
2006
). The adverse effects seemed to disappear with
continued use; nonetheless, these side effects were a major reason why patients
did not continue with the study during the first 3-4 weeks of treatment. No
cardiovascular liabilities were noted. One unanticipated side effect that was
noted following prolonged treatment with roflumilast was a significant reduction
in body weight in subjects. This might be attributed to gastrointestinal dis-
comfort in susceptible patients, although it was interesting to note that weight
loss was also reported in patients not complaining of gastrointestinal side effects
and might be an effect worthy of further study (Fabbri et al.
2009
; Calverley
et al.
2009
).
One might anticipate that the risk/benefit ratio would be improved by inhaled
delivery of a PDE4 inhibitor directly to the lung. Unfortunately, to date only one
study has evaluated the effect of an inhaled PDE4 nonselective subtype inhibi-
tor. This was used to treat moderate-to-severeCOPDandnosignificant
improvement in baseline FEV1 was observed after 6 weeks of treatment (Vestbo
et al.
2009
). As no inflammatory biomarker was measured in this study, it is
unclear whether a sufficient level of sustained PDE4 inhibition was achieved.
This seems likely because adverse events such as headache and improvements in
lung function that were noted at 2 weeks were absent after 6 weeks of treatment
with the high dose. Whether inhaled PDE4 inhibitors will be of utility in COPD
remains to be determined but there may be a cause for optimism in view of the
amelioration of the allergen-induced late phase response in asthma with the
inhaled PDE4 inhibitor GSK256066 (Singh et al.
2010
). This demonstrates that
in principle one can achieve inhibition of PDE4 following topical delivery to the
lung that could lead to clinical benefit, but the relevant clinical trials need to be
undertaken with GSK250666 to ascertain whether this drug will be of any clinical
benefit to patients with COPD.
