Biology Reference
In-Depth Information
Indeed, for many of these compounds, it is likely that the maximum tolerated dose
is either subtherapeutic or at the very bottom of the efficacy dose-response curve.
Thus, a significant ongoing challenge that faces the pharmaceutical industry is to
synthesize compounds with therapeutic ratios that are superior to roflumilast.
Several strategies are being considered, but clinically effective compounds with
an optimal pharmacophore have not, thus far, been reported. In this chapter,
alternative means of harnessing the clinical efficacy of PDE4 inhibitors are
described. These concepts are based on the assumption that additive or synergistic
anti-inflammatory effects can be produced with inhibitors that target either two or
more PDE families or with a PDE4 inhibitor in combination with other anti-
inflammatory drugs such as a glucocorticoid.
Keywords Airway inflammation
Asthma
cAMP
Chronic obstructive pulmonary
disease
Combination therapies
Gene transactivation
Glucocorticoids
Long-
acting
b
2
-adrenoceptor agonists
Nuclear hormone receptors
Phosphodiesterase 4
Abbreviations
AHR
Airway hyperresponsiveness
AP
Activator protein
AR
Androgen receptor
BP
Blood pressure
CNS
Central nervous system
COPD
Chronic obstructive pulmonary disease
FEV
1
Forced expiratory volume in 1 s
GILZ
Glucocorticoid-induced leucine zipper
GR
Glucocorticoid receptor
GRE
Glucocorticoid response element
HDAC
Histone deacetylase
HPV
Hypoxic pulmonary vasoconstriction
HR
Heart rate
ICS
Inhaled corticosteroid
IL
Interleukin
LABA
Long-acting
b
2
-adrenoceptor agonist
LVP
Left ventricular pressure
MKP
Mitogen-activated protein kinase phosphatase
MR
Mineralocorticoid receptor
NF
k
B
Nuclear factor-kappaB
PDE
Phosphodiesterase
PH
Pulmonary hypertension
PHA
Phytohemagglutinin
PKA
cAMP-dependent protein kinase
Ppa
Pulmonary artery pressure
