Alkylxanthines and Phosphodiesterase 4 Inhibitors for Allergic Diseases

Despite significant advances in our understanding of the pathogenesis of many allergic disorders, the etiology of allergy is still incompletely understood. However, both the World Allergy and World Health Organization [1] have identified and recognized the participation of immunoglobulin (Ig) E-driven mechanisms in many allergic diseases (Table 1). Since the incidence of allergy has reached epidemic proportions, it is very clear that drugs, which can prevent the overt and covert manifestations of allergic reactions and, ideally, suppress or even prevent the process of host sensitiza-tion can have a profound clinical and economic impact. While corticosteroids are considered the most effective antiallergic/anti-inflammatory drugs currently available, they are nonselective in action and not without adverse effects. Moreover, in diseases such as asthma, a significant proportion of patients who are treated with corticosteroids remain symptomatic [2]. Thus, new drugs with enhanced selectivity and improved side-effect profiles are clearly required. One group of drugs, which from a theoretical perspective, may exhibit powerful anti-inflammatory and immunomodulatory activity are inhibitors of certain of the cyclic nucleotide phospho-diesterase (PDE) isoenzymes that selectively degrade cyclic adenosine-3 ′,5′-monophosphate (cAMP) and/or cyclic guanosine-3 ′,5′-monophosphate (cGMP) [3– 9]. The prototype PDE inhibitors that have been used in the treatment of asthma for many years are the alkylxanthines of which theophylline is the most widely prescribed. The main beneficial activity of theophylline was originally attributed to its weak bronchodilator action. However, evidence accumulated in the 1990s suggested that this molecule might have anti-inflammatory activity at subbronchodilator doses [10– 12]. These, somewhat surprising data fuelled the idea that theophylline and, so-called, “second generation” PDE inhibitors could act as bronchodilators and potential antiallergic and/or anti-inflammatory agents [7, 13–18].