Biology Reference
In-Depth Information
the inhaled route, development of nonemetic PDE4 inhibitors, mixed PDE inhibi-
tors, and/or antisense biologicals targeted toward PDE4.
Keywords Asthma
Cilomilast
COPD
Emesis
Inflammation
PDE4
Roflumilast
Abbreviations
COPD Chronic obstructive pulmonary disease
PDE
Phosphodiesterase
1
Introduction
Theophylline has been used in the treatment of asthma and chronic obstructive
pulmonary disease (COPD) since the 1930s, although its popularity has declined
due to the introduction of b 2 -adrenoceptor agonists and glucocorticosteroids.
Several mechanisms have been proposed to explain the potential beneficial action
of theophylline in respiratory disease. Theophylline has been shown to inhibit
the activity of a cyclic 3 0 ,5 0 nucleotide PDE with a K i of 100 m M (Butcher and
Sutherland 1962 ), which has been suggested to contribute to its ability to promote
suppressor cell activity in lymphocytes (Shore et al. 1978 ; Zocchi et al. 1985 ;
O'Shaughnessy et al. 2007 ) and its beneficial actions in patients with asthma
(Sullivan et al. 1994 ), COPD (Rennard 2004 ), or psoriasis (Papakostantinou et al.
2005 ). However, theophylline has been relegated to second- or third-line therapy
for the treatment of respiratory disease and is not routinely used in the treatment of
other inflammatory conditions such as rheumatoid arthritis, psoriasis, and inflam-
matory bowel disease, in part because it is not recognized as an anti-inflammatory
drug, but more importantly because of the very significant drug interactions
and narrow therapeutic window exhibited by theophylline; the side effect profile
of theophylline includes nausea, emesis, gastrointestinal disturbances, and arrhyth-
mias. These problems, in part, promoted an interest in understanding how the PDE
family of enzymes regulated cAMP levels within cells and the potential for
developing drugs inhibiting such enzymes, in a selective way as a way of improving
the therapeutic window of theophylline.
There are presently 11 known families of PDEs and at least 21 isoforms with
numerous splice variants that are characterized by differences in structure, substrate
specificity, inhibitor selectivity, tissue and cell distribution, regulation by kinases,
protein-protein interaction, and subcellular distribution (Conti and Beavo 2007 ;
McCahill et al. 2008 ). However, targeting PDE4, an enzyme family that exclusively
metabolizes cAMP (Houslay et al. 2005 , 2007 ), has been the focus for the deve-
lopment of drugs that could prove beneficial in the treatment of depression,
schizophrenia (Millar et al. 2007 ), respiratory diseases such as asthma and COPD
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