Therapeutic Implications and Future Developments - Chronic Obstructive Pulmonary Disease - page 501

drugs such as PDE inhibitors, NF- k B, and p38 mitogen-activated protein
(MAP) kinase inhibitors also potently inhibit TNF- a expression.
VI. OTHER ANTI-INFLAMMATORY DRUGS
A. Phosphodiesterase-4 Inhibitors
Phosphodiesterase-4 (PDE4) is the predominant PDE expressed in neutro-
phils, CD8 þ cells, and macrophages, suggesting that PDE4 inhibitors would
be effective in controlling inflammation in COPD (60). Selective PDE4 inhibi-
tors, such as cilomilast and roflumilast, are active in animal models of neutro-
phil inflammation. Cilomilast had promising beneficial clinical effects in a
6-week study in patients with moderate to severe COPD (61) and has some
anti-inflammatory effects measurable in airway biopsies (62). Roflumilast
appears to be better tolerated than cilomilast at doses that significantly inhibit
TNF- a release from peripheral blood monocytes. Phosphodiesterase-4 inhibi-
tors have been limited by side effects, particularly nausea and other gastroin-
testinal effects, but it might be possible to develop more selective inhibitors in
the future, which are less likely to be dose-limited by adverse effects.
Several steps may be possible to overcome the limitation of side
effects. It now seems likely that vomiting is due to inhibition of a particular
subtype of PDE4. At least four human PDE4 genes have been identified and
each has several splice variants (63). This raises the possibility that subtype-
selective inhibitors may be developed that may preserve the anti-inflamma-
tory effect, while having less propensity to side effects. PDE4D appears to
be of particular importance in nausea and vomiting and is expressed in
the chemosensitive trigger zone in the brain stem (64), and in mice, deletion
of the gene for PDE4D prevents a behavioral equivalent of emesis (65). This
isoenzyme appears to be less important in anti-inflammatory effects, and
targeted gene disruption studies in mice indicate that PDE4B is more impor-
tant than PDE4D in inflammatory cells (66). PDE4B-selective inhibitors may
therefore have a greater therapeutic ratio and theoretically might be effective
anti-inflammatory drugs. Cilomilast is selective for PDE4D and therefore has
a propensity to cause emesis, whereas roflumilast, which is nonselective for
PDE4 isoenzymes, has a more favorable therapeutic ratio. Several potent
PDE4 inhibitors with a more favorable therapeutic ratio are now in clinical
development for COPD. Another approach is to give the PDE4 inhibitor by
inhalation and some PDE4 inhibitors have a low oral bioavailability and
are retained in the lung, so appear to be suitable for inhaled delivery (67),
but no clinical studies of inhaled PDE4 inhibitors have yet been reported.
B. Nuclear Factor- k B Inhibitors
Nuclear factor- k B regulates the expression of IL-8 and other chemokines,
TNF- a and other inflammatory cytokines, and some MMPs including the