Biology Reference
In-Depth Information
In this context, one may consider that in mice that were deficient for PDE4D,
a
2
-
adrenoceptor-induced anesthesia was shortened, which is conceived as a correlate
to emesis in these non-emetic rodents (Robichaud et al.
2002
). It was striking then
that, contrary to expectations, the recently discovered highly PDE4D-selective,
allosteric PDE4 inhibitors (Burgin et al.
2010
) have almost no emetic potential in
several animal species and did not show reduced duration of
a
2
-adrenoceptor-
induced anesthesia at doses associated with desired pharmacological effects
(cognition enhancement) (Burgin et al.
2010
). These findings were in contrast to
rolipram that, however, suppresses catalytic activity of the different PDE4 subtypes
with comparable potency.
In any case, PDE4D inhibition adds to the overall anti-inflammatory effects of a
“balanced” PDE4 inhibitor, as this was exemplified in T-lymphocytes (Peter et al.
2007
) or neutrophils (Ariga et al.
2004
). “Balanced” PDE4 inhibitors are defined as
those suppressing all PDE4 subtypes and splice variants with comparable potency.
As the cyclohexanecarboxylic acid substituent of cilomilast is deprotonated to
the corresponding carboxylate anion at physiologic
pH
, drug penetration to the
brain should be limited and the risk of CNS-related adverse events may be reduced.
Cilomilast showed anti-inflammatory effects in patients afflicted with COPD. In
a 3-month trial in which patients received cilomilast at 15 mg BID versus placebo,
the PDE4 inhibitor substantially reduced CD8+ T-cells and CD68+ macrophages in
bronchial biopsies (Gamble et al.
2003
). On the other hand, sputum neutrophil
counts remained unaffected. No consistent anti-inflammatory effects could be
determined in two additional studies of comparable design (Rennard et al.
2008
).
In the phase III program involving patients with COPD treated with cilomilast
(15 mg BID), improvements in FEV
1
ranged from 24 to 44 ml, but apparently this
was not accompanied by consistent improvements in other clinical parameters.
In one study, the PDE4 inhibitor significantly reduced functional residual capa-
city (FRC), a measure of hyperinflation by 290 ml; however, in another study this
improvement (120 ml) remained below the level of significance (Rennard et al.
2008
). Finally, the rate of acute exacerbations was reduced in two 24-week trials,
but this was not confirmed in a later 1-year study that was designed to detect
a reduction in exacerbations (Rennard et al.
2008
).
2.5 Oglemilast
Oglemilast (GRC-3886, Glenmark) (5) is another potent (IC
50
PDE4B 0.3 nM,
nonselective among PDE4 subtypes) and selective PDE4 inhibitor that has been
undergoing clinical evaluation for COPD as an oral, once-daily remedy. While ogle-
milast was reported being non-emetic in ferrets (100 mg kg
1
) or dogs (12 mg kg
1
)
at doses resulting in plasma levels (Vakkalanka et al.
2005
) corresponding to
almost maximum suppression of cellular effects related to PDE4 inhibition (LPS-
induced TNF-
a
release in human whole blood and fMLP-induced superoxide
formation in human PMN in the presence of 80% plasma), the compound failed
