Harnessing the Clinical Efficacy of Phosphodiesterase 4 Inhibitors in Inflammatory Lung Diseases: Dual-Selective Phosphodiesterase Inhibitors and Novel Combination Therapies - Phosphodiesterases as Drug Targets - page 424

COPD with all layers of pulmonary vessels (intima, media, and adventitia) being
affected (Timms et al. 1985 ).
There is persuasive clinical evidence that PDE5 inhibition could arrest, or even
reverse, these pathological effects of alveolar hypoxia. Thus, both short- and long-
term dosing trials have clearly shown that inhibitors of PDE5 decrease pulmonary
vascular resistance (PVR) and/or Ppa in humans with PH (Bharani et al. 2003 ;
Chockalingam et al. 2005 ; Galie et al. 2005 ; Ghofrani et al. 2004 ; Lepore et al.
2005 ; Michelakis et al. 2002 , 2003 ; Prasad et al. 2000 ; Sastry et al. 2002 , 2004 ;
Steiner et al. 2005 ; Wilkens et al. 2001 ). Therefore, it is not unreasonable to suspect
that this class of drug could also be useful in those patients that have COPD-
associated PH. In a small study involving five patients with COPD with coexisting
PH at rest, oral sildenafil (50 mg) attenuated the increase in mean Ppa during
submaximal exercise in the absence of any change in stroke volume or cardiac
output (Holverda et al. 2008 ). In a similar study involving six patients with severe
COPD and elevated Ppa at rest, oral sildenafil (50 mg b.i.d. for 3 months) signifi-
cantly reduced PVR and mean Ppa. An improvement in exercise tolerance using
the 6 min walk test was also reported (Alp et al. 2006 ). Similar data have been
described in another small study involving seven patients with severe COPD
(GOLD Stage 4) (Madden et al. 2006 ). While these data are encouraging, the
obvious limitation is the low sample size. Accordingly, these results need to be
confirmed in much larger populations of patients with COPD-related PH.
In addition to relaxing pulmonary vascular smooth muscle, Charan ( 2001 ) has
published case reports describing beneficial effects of sildenafil on lung function. In
two patients with erectile dysfunction who had concurrent COPD, oral sildenafil
produced a rapid (within1hofadministration) and long-lasting improvement in
FEV 1 and forced vital capacity (24 and 12%, respectively) indicative of direct
bronchodilation. Finally, there is in vitro evidence that PDE5 inhibitors prevent
human platelet aggregation (Yu et al. 1996 ), which is prevalent in COPD (Cordova
et al. 1985 ) and also block the proliferation of myocytes derived from the human
pulmonary artery (Wharton et al. 2005 ). Thus, PDE5 inhibitors can, in theory, exact
multiple therapeutically beneficial effects on COPD-associated pulmonary vascular
pathologies. Clearly, the combination of such a drug with a PDE4 inhibitor, which
may also be antiproliferative in human pulmonary vascular myocytes (Growcott
et al. 2006 ), could offer a superior medicine to either drug alone since both the
inflammatory and vascular components of COPD would be targeted.

2.4 Inhibition of PDE4 and PDE7

All human immune and proinflammatory cells that have been studied express
mRNA and protein for PDE7A (Smith et al. 2003 ). The expression of this enzyme
family is, therefore, very similar to the distribution of PDE4. CD4 + and CD8 +
T-lymphocytes express relatively high levels of PDE7A1 that are readily detected
by western blotting. Human airway smooth muscle cells, blood monocytes, and