Biology Reference
In-Depth Information
Furthermore, there are examples of nonselective PDE4 inhibitors that have in vivo
anti-inflammatory activity but are not emetogenic (Aoki et al.
2000
,
2001
; Gale
et al.
2002
). Similarly, the emetic profile of various PDE4 inhibitors (PMNPQ
>
R-rolipram
CT-2450) could not be explained by a preferred selectivity for
PDE4D over PDE4A or PDE4B (Robichaud et al.
1999
,
2002b
). Some PDE4
inhibitors may preferentially partition within the area postrema in the CNS and
thereby enhancing the inhibition of PDE4D in area postrema neurons and explain-
ing the differences in the emetic potential of these drugs (Aoki et al.
2001
;
Robichaud et al.
2002a
). Indeed, brain penetration by PMNPQ was 46-fold greater
than CT-2450; however, the concentration of the “low emetic” PDE4 inhibitor,
CT-2450, within the CNS was still 475-fold greater than the PDE4D inhibitory
potency for CT-2450, and presumably still in sufficient concentrations to inhibit
this enzyme. Moreover, the area postrema is not completely behind the blood-brain
barrier and therefore accessible to free drug within the circulation (Gross et al.
1990
). Whether differential partitioning of these inhibitors within the area postrema
accounts for why some PDE4 inhibitors have a reduced emetic profile remains to be
established. Alternatively, partial inhibition of PDE4D within the emetic center of
the brain may not to be sufficient to promote an emetogenic signal, although this
degree of inhibition within inflammatory cells is sufficient enough to exert an
in vitro anti-inflammatory effect (Burgin et al.
2010
).
A number of preclinical studies have highlighted a number of other potential
disadvantages to targeting PDE4, and these include the development of mesenteric
vasculitis (Spina
2004
), immunosuppression (Spina
2004
), heart failure, and arrhy-
thmia (Lehnart et al.
2005
). However, none of these events appear to be realized in
phase II and phase III clinical trials undertaken to date, at least with cilomilast and
roflumilast. Similarly, slow release theophylline has been used for decades in the
treatment of asthma and COPD and has not been associated with a number of these
potentially adverse events despite being shown to cause mesenteric vasculitis
preclinically in some models (Nyska et al.
1998
; Ohta et al.
2004
). It has also
been suggested that PDE4 inhibitors may have pro-inflammatory properties, which
is based on the finding that at very high doses, roflumilast (100 mg/kg) promoted
the recruitment of neutrophils to the airways and this correlated with the release of
IL-8 from cultured endothelial cells in vitro (McCluskie et al.
2006
). This mecha-
nism might explain why animals that have been chronically treated with high doses
of PDE4 inhibitors document vasculitis. However, the concentrations required to
achieve these untoward effects are at least 1,000 times greater than the ED
50
and
EC
50
values reported for roflumilast against several in vivo biomarkers of inflam-
mation and cell function in vitro, respectively (Bundschuh et al.
2001
; Hatzelmann
and Schudt
2001
). It is unlikely that the plasma concentrations required to produce
this purported pro-inflammatory effect could be achieved even with chronic dosing.
Similarly, another study has shown that PDE4 inhibitors, at concentrations that are
pharmacologically relevant, delay apoptosis of neutrophils and eosinophils, an
effect that increased when combined with
b
2
-agonists (Parkkonen et al.
2007
).
However, the extent to which these findings translate into the clinic is unclear,
particularly as the beneficial effect of roflumilast in moderate-to-severe COPD
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