Asthma diagnosis and treatment
Are phosphodiesterase 4 inhibitors just more theophylline?

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Theophylline has been relegated to a second- or even third-line therapy in the treatment of asthma and chronic obstructive pulmonary disease (COPD), behind glucocorticosteroids and β2-agonists, although recent findings have suggested that theophylline possesses anti-inflammatory and immunomodulatory effects in addition to its well-recognized effects as a bronchodilator. In part, theophylline has fallen out of favor because of its adverse side-effect profile, and this has led to the search for more effective and safer drugs based on the knowledge that theophylline is orally active and that it is a nonselective phosphodiesterase (PDE) inhibitor. This has led to the development of selective PDE4 inhibitors, originally designed for depression, for the treatment of both COPD and asthma. Such drugs have shown clinical efficacy in the treatment of respiratory disease while having a considerably safer side-effect profile in comparison with theophylline, particularly because there are no reported drug interactions with PDE4 inhibitors, a feature that complicates the use of theophylline. In addition, it is also becoming increasingly apparent that theophylline is not working solely through PDE inhibition, as formerly assumed, and that this drug has other relevant pharmacologic activities that are likely to contribute to its efficacy, such as adenosine receptor antagonism and induction of histone deacetylase. Thus, the introduction of PDE4 inhibitors represents an entirely new class of drugs for the treatment of respiratory disease.

Section snippets

Theophylline

Since the first prescription of theophylline for the treatment of asthma in 1937, it has been widely used as an inexpensive oral treatment of both asthma and COPD.1 Traditional dogma has attributed the therapeutic effect of theophylline primarily to bronchodilatation, but at lower concentrations, it also possesses both immunomodulatory and anti-inflammatory actions, which are likely to contribute to some of the efficacy of the drug in treating patients with pulmonary disease.2

However,

Classification of PDEs

Eleven PDE families have now been identified by a variety of criteria, including substrate specificity, inhibitor potency, genetic makeup, and enzyme kinetics.11, 12 They act by hydrolyzing the phosphodiester bond of the second messengers cyclic nucleotides—cyclic 3′,5′ adenosine monophosphate (cAMP) and cyclic 3′,5′ guanosine monophosphate (cGMP), converting them to the inactive 5′ mononucleotides AMP and guanosine monophosphate, respectively.13 cAMP and cGMP are key second messengers in

PDE4: A therapeutic target in COPD and asthma

The PDE4 isoenzyme was identified as a major therapeutic target in respiratory diseases because it is the predominant isoenzyme in the majority of inflammatory cells, including neutrophils, which are implicated in the pathogenesis of COPD,16 and eosinophils, which characterize inflammation in asthma.17 PDE4 is also present alongside the PDE3 isoenzyme in airway smooth muscle; the PDE3 isoenzyme is considered to predominate in airway smooth muscle, and inhibition of this enzyme, rather than

Conclusion

Therapeutically, PDE4 inhibitors represent a novel class of orally active drugs for the treatment of respiratory disease, with no need to monitor plasma levels, reliable efficacy (even in current smokers), and fewer concerns from drug interactions, although the gastrointestinal side effects do give rise to some concerns regarding their use. However, given the positive effects of roflumilast in comparison with those of inhaled beclomethasone diproprionate,62 such drugs might be oral alternatives

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    Disclosure of potential conflict of interest: C. Page has consultant arrangements with Johnson and Johnson, Glenmark Pharmaceuticals, and Altana; has stock in Rhinopharma; and is a speaker for Altana. V. Boswell-Smith has received grants from Altana. M. Cazzola has consultant arrangements with Altana; has received grants from Altana, AstraZeneca, and Chiesi Famaceutici; and is on the speakers' bureau for Altana, GlaxoSmithKline, Pfizer, Chiesi Famaceutici, Novartis, and Boehringer-Ingelheim.

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