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 418

2 Inhibition of Multiple Phosphodiesterases

Methods to target multiple PDEs include deploying inhibitors that have a pharma-
cophore that blocks the catalytic site of more single PDE isoenzyme family or by
combining two selective inhibitors in a single delivery device, such as an inhaler
(Giembycz 2005b ). Of the 11 PDE families that have been unequivocally identi-
fied, compounds that inhibit PDE4 as well as PDE1, PDE3, PDE5, and/or PDE7
could offer potential opportunities to enhance clinical efficacy. Indeed, additive
and/or synergistic effects are produced in a variety of model systems when multiple
PDEs are inhibited concurrently. In the context of treating inflammatory airway
diseases, these interactions are described below in Sects. 2.1 - 2.5 . For the purposes
of this chapter, no distinction is made between the effects of a compound that
inhibits two or more PDEs and two isoenzyme-selective inhibitors that are used in
combination.

2.1 Inhibition of PDE1 and PDE4

Airway remodeling is a characteristic feature of asthma and refers to several
distinct processes that together increase the volume of the respiratory tract wall.
In some individuals, airway remodeling leads to an irreversible or refractory form
of the disease where lung function and symptoms continue to decline despite
maximal therapy (Lazaar and Panettieri 2003 ; Wenzel 2003 ). On histological
examination, remodeling is manifest by mucous gland hyperplasia, subepithelial
deposition of collagens, an increase in smooth muscle mass, and revascularization
of the mucosa (Jeffery 2001 ). With respect to smooth muscle, recent investigations
have extended the original histopathological findings by demonstrating that both
hypertrophy (an increase in cell size) and hyperplasia (an increase in cell number)
may contribute to the increase in volume of the airway wall occupied by smooth
muscle in fatal and nonfatal asthma (Benayoun et al. 2003 ; Ebina et al. 1993 ; Heard
and Hossain 1973 ; Hirst et al. 2004 ; Woodruff et al. 2004 ). Airway hyperrespon-
siveness (AHR) is a phenomenon characterized by exaggerated narrowing of the
airways in response to a diverse range of (nonspecific) constrictor stimuli. Credible
evidence exists that thickening of the airway wall is a major determinant of AHR
(Hogg 1996 ; Martin et al. 2000 ; Stewart 2001 ; Wiggs et al. 1990 ).
Substantial airway remodeling and AHR are also characteristic features of
COPD (Aoshiba and Nagai 2004 ; Hogg 2004 ; Hogg et al. 2004 ; Hossain and
Heard 1970 ; Jeffery 2001 ). Indeed, like in asthma, the increase in the volume of
the walls of airways is thought to be a principal determinant of AHR (Postma
and Kerstjens 1998 ; Wiggs et al. 1990 ). To a large degree, remodeling in COPD
involves connective tissue deposition in the subepithelial and adventitial compart-
ments (Dunnill et al. 1969 ; Hogg et al. 2004 ), but there is also an increase in smooth