Biology Reference
In-Depth Information
Harnessing the Clinical Efficacy
of Phosphodiesterase 4 Inhibitors
in Inflammatory Lung Diseases: Dual-Selective
Phosphodiesterase Inhibitors and Novel
Combination Therapies
Mark A. Giembycz and Robert Newton
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
2 Inhibition of Multiple Phosphodiesterases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418
2.1 Inhibition of PDE1 and PDE4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418
2.2 Inhibition of PDE3 and PDE4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
2.3 Inhibition of PDE4 and PDE5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
2.4 Inhibition of PDE4 and PDE7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
2.5 Nonselective PDE Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
3 Combination Therapies Involving Phosphodiesterase 4
Inhibitors: The Obvious and the Novel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
3.1 PDE4 Inhibitor/
b
2
-Adrenoceptor Agonist Combination Therapies . . . . . . . . . . . . . . . . . 427
3.2 PDE4 Inhibitor/Glucocorticoid Combination Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428
3.3 Other PDE4 Inhibitor/Nuclear Hormone Receptor Combinations . . . . . . . . . . . . . . . . . . 434
4 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
Abstract Phosphodiesterase (PDE) 4 inhibitors have been in development as a
novel anti-inflammatory therapy for more than 20 years, with asthma and chronic
obstructive pulmonary disease (COPD) being primary indications. Despite initial
optimism, only one selective PDE4 inhibitor, roflumilast (
Daxas
®
), has been
approved for use in humans and available in Canada and the European Union in
2011 for the treatment of a specific population of patients with severe COPD. In
many other cases, the development of PDE4 inhibitors of various structural classes
has been discontinued due to lack of efficacy and/or dose-limiting adverse events.
M.A. Giembycz (
*
)
Airways Inflammation Research Group, Departments of Physiology and Pharmacology, Institute
of Infection, Immunity and Inflammation, University of Calgary, 3280 Hospital Drive NW,
Calgary, AB T2N 4N1, Canada
e-mail: giembycz@ucalgary.ca
R. Newton
Cell Biology and Anatomy, Institute of Infection, Immunity and Inflammation, University of
Calgary, Calgary, AB, Canada
