Elsevier

The Lancet

Volume 365, Issue 9454, 8–14 January 2005, Pages 167-175
The Lancet

New Drug Classes
Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease

https://doi.org/10.1016/S0140-6736(05)17708-3Get rights and content

Summary

Inhibitors of phosphodiesterase type 4 (PDE4) act by increasing intracellular concentrations of cyclic AMP, which has a broad range of anti-inflammatory effects on various key effector cells involved in asthma and chronic obstructive pulmonary disease (COPD). The therapeutic ratio for PDE4 inhibitors is thought to be determined by selectivity on receptor subtypes for relative effects on PDE4B (anti-inflammatory) and PDE4D (emesis). The two main orally active PDE4 inhibitors in the late phase III of clinical development are cilomilast and roflumilast; the latter (and its active metabolite N-oxide) is more selective and potent with a superior therapeutic ratio. Studies on cilomilast in COPD based on bronchial biopsy material have shown a broad range of anti-inflammatory activity, and the available evidence on clinical outcomes for up to 6 months with cilomilast 15 mg twice daily and roflumilast 500 μg once daily have shown variable but significant effects on exacerbations and quality of life, with small improvements in measures of pulmonary function. Roflumilast has a better safety and tolerability profile than cilomilast, with the main adverse effects being nausea, diarrhoea, and abdominal pain. Roflumilast also has activity in asthma as assessed by its attenuation of allergen and exercise challenges, and it shows clinical efficacy equivalent to that of beclomethasone dipropionate 400 μg daily. The emerging results of clinical trials on PDE4 inhibitors in asthma and COPD should be interpreted with cautious optimism since much of the evidence has been published only in abstract form to date. The next few years should resolve important issues about the potential role of these drugs as oral non-steroidal anti-inflammatory therapy for asthma and COPD and their place in management guidelines. Ultimately, clinicians will want to know whether PDE4 inhibitors are anything more than expensive “designer” theophylline, the archetypal non-selective phosphodiesterase inhibitor.

Section snippets

Inhibitors of phosphodiesterase type 4

The breakdown of the cyclic nucleotides cAMP and cGMP to their respective 5′-nucleotide monophosphates is catalysed by phosphodiesterase enzymes. 11 families of phosphodiesterases have been categorised so far, differing in their sequence, substrate specificity, cofactor requirements, and sensitivity to inhibitors.10 This review focuses on the inhibitors of type-4 phosphodiesterase (PDE4), a group of pharmacologically distinct enzymes encoded by at least four distinct genes (PDEA, PDEB, PDEC,

Pharmacology

Understanding of some of the basic pharmacology of PDE4 inhibitors is important for appreciation of how their therapeutic ratio can be refined and the pharmacologically predictable adverse effects of the class as a whole can be avoided. Initial attention focused on the possible role of the rolipram binding site. PDE4 is thought to have two conformations, PDE4H and PDE4L,14 for which the specific inhibitor rolipram has high and low affinity. PDEH is generally expressed in the central nervous

Preclinical anti-inflammatory profile of roflumilast and cilomilast

The anti-inflammatory and immunomodulatory activity of PDE4 inhibitors has been investigated in vitro and in animals in vivo. In terms of selective PDE4 inhibition of human neutrophil function, roflumilast was found to be roughly equipotent to its major metabolite, roflumilast N-oxide, and to piclamilast, but it showed potency more than 100 times greater than cilomilast or rolipram (table 2).17 The rank order of potency for PDE4 inhibitors was similar in human eosinophils. Compared with effects

Pharmacokinetics

The pharmacokinetics of cilomilast have been extensively investigated.21, 22 The drug is rapidly absorbed after oral administration with a tmax of about 1 h, 96% oral bioavailability, and a plasma elimination half-life of 7 h; it is subject to negligible first-pass hepatic metabolism. Moreover, cilomilast shows dose-related linear pharmacokinetics which are unaffected by age or by food. The metabolism of cilomilast is extensive, with less than 1% of the administered dose appearing as unchanged

The way forward

In patients with mild to moderate persistent asthma at step 2 of the guidelines, further placebo-controlled, multicentre studies will be needed to assess the effects of PDE4 inhibitors on important clinical outcome measures, such as exacerbations, that may be closer to the underlying inflammatory process than measures of airway calibre such as FEV1 and peak flow. Similar long-term studies powered on exacerbations in mild to moderate persistent asthma would also be indicated for direct

Search strategy and selection criteria

The search methods for this article included use of PubMed and EMBASE from 1990 to the present with no restrictions on language, with the keywords “phosphodiesterase type 4 inhibitors”, “roflumilast”, and “cilomilast”, as well as searches of relevant abstract books from conference proceedings such as: European Respiratory Society; American Thoracic Society; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; and European Academy of

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