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We read with great interest the elegant paper by Luijk et al. (1). They described the effect of a topical treatment with potent A2A adenosine receptor agonist and competitive A3 antagonist activities (GW328267X). No protection against allergen-induced LAR or the accompanying increase in airway inflammation in asthma was observed in this study. There are several possible reasons for these negative findings.

An obvious explanation is that, as stated by the authors, the dose of the drug used in this study (25 μg twice daily) was sub-therapeutic. That this might be the case is also suggested by the complete lack of adverse effects at a cardiovascular level. Phase I studies have shown that higher doses of GW328267X are associated with decrease in blood pressure and increase in heart rate. These effects are related to the peripheral vasodilation due to the A2A agonistic activity (vasodilating) of the drug. Moreover, in relation to the putative anti-inflammatory effect of A2A stimulation, it should be noted that any positive effect of these class of drugs in term of improved lung function may be neutralized by the A2A mediated pulmonary vascular response with the resulting airway wall oedema and plasma leakage contributing to reduced airway calibre.

The authors also speculated that the observed negative findings could have been the net result of the differential actions of GW328267X on both A2A and A3 adenosine receptors. However, our understanding of the pharmacology of this compound (2) suggests that the therapeutic effect of this agent is probably largely mediated by its A2A agonist activity with only negligible effect being mediated by A3 receptors. Besides, it is not clear what actions are mediated by A3 receptors in human. A3 antagonists have been claimed for cancer, cerebral ischemia and asthma with several compounds being biologically tested (3). Most failed to show any efficacy and none has entered the clinical arena. The role of A3 adenosine receptors in the pathogenesis of asthma remains controversial and differences in the pharmacology of the A3 subtype from different species make it difficult to anticipate whether a strategy aimed at stimulating or inhibiting the A3 receptor would be a rationale option in asthma management.

A recent patent search on this compound (3), has shown that the only activities of GW328267X are reported for A1, A2A and A3 receptors. No mention of A2B at all. Therefore, an additional explanation for the observed negative findings is that the therapeutic target is wrong. Whilst all four adenosine receptors have been found in association with lung tissues and appear to be finely modulated during chronic inflammatory responses, a critical role of A2B antagonists in pulmonary inflammation, fibrosis and airway remodelling have been confirmed in several animal models (4). The notion that adenosine receptors are widely distributed in different organs and that elevated levels of adenosine are present in chronically inflamed airways, emphasize the importance of adenosine as a central therapeutic target. Recognition of the potential role of adenosine receptor signalling in the pathogenesis of chronic airway inflammatory diseases advocates the principle that modulating adenosine receptor signalling could translate into clinical benefit for patients with chronic airway diseases.

References

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  2. References
  • 1
    Luijk B, Van Den Berge M, Kerstjens HA, Postma DS, Cass L, Sabin A et al. Effect of an inhaled adenosine A2A agonist on the allergen-induced late asthmatic response. Allergy 2008;63:7580.
  • 2
    Bevan N, Butchers PR, Cousins R, Coates J, Edgar EV, Morrison V et al. Pharmacological characterisation and inhibitory effects of (2R,3R,4S,5R)-2-(6-amino-2-{[(1S)-2-hydroxy-1-(phenylmethyl)ethyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3,4-furandiol, a novel ligand that demonstrates both adenosine A(2A) receptor agonist and adenosine A(3) receptor antagonist activity. Eur J Pharmacol 2007;564:219225.
  • 3
    Press NJ, Gessi S, Borea PA, Polosa R. Therapeutic potential of adenosine receptor antagonists and agonists. Expert Opin Ther Patents 2007;17:979991.
  • 4
    Caruso M, Tringali G, Polosa R. Evidence for a functional contribution of adenosine signalling in inflammatory airway diseases. Immun Endoc & Metab Agents in Med Chem 2007;7:286297.