Abstract
BackgroundThe CC-chemokine receptor-3 (CCR3) has emerged as a target molecule for pharmacological intervention in allergic inflammation.ObjectiveTo examine whether a dual CCR3 and H1-receptor antagonist (AZD3778) affects allergic inflammation and symptoms in allergic rhinitis.MethodsPatients with seasonal allergic rhinitis were subjected to three seven days' allergen challenge series. Treatment with AZD3778 was given in a placebo and antihistamine-controlled design. Symptoms and nasal peak inspiratory flow (PIF) were monitored in the morning, ten minutes post challenge, and in the evening. Nasal lavages were carried out at the end of each challenge series and α2-macroglobulin, ECP, and tryptase were monitored as indices of allergic inflammation.ResultsPlasma levels of AZD3778 were stable throughout the treatment series. AZD3778 and the antihistamine (loratadine) reduced rhinitis symptoms recorded ten minutes post challenge during this period. AZD3778, but not the anti-histamine, also improved nasal PIF ten minutes post challenge. Furthermore, scores for morning and evening nasal symptoms from the last five days of the allergen challenge series showed statistically significant reductions for AZD3778, but not for loratadine. ECP was reduced by AZD3778, but not by loratadine.ConclusionsAZD3778 exerts anti-eosinophil and symptom-reducing effects in allergic rhinitis and part of this effect can likely be attributed to CCR3-antagonism. The present data are of interest with regard to the potential use of AZD3778 in allergic rhinitis and to the relative importance of eosinophil actions to the symptomatology of allergic rhinitis.Trial registrationEudraCT No: 2005-002805-21.
Highlights
The CC-chemokine receptor-3 (CCR3) has emerged as a target molecule for pharmacological intervention in allergic inflammation
AZD3778 exerts anti-eosinophil and symptom-reducing effects in allergic rhinitis and part of this effect can likely be attributed to CCR3-antagonism
The present data are of interest with regard to the potential use of AZD3778 in allergic rhinitis and to the relative importance of eosinophil actions to the symptomatology of allergic rhinitis
Summary
The CC-chemokine receptor-3 (CCR3) has emerged as a target molecule for pharmacological intervention in allergic inflammation. In a study involving ovalbumin-sensitized mice repeatedly challenged with ovalbumin to produce inflammation, showed that a CCR3-antagonist reduced BAL and tissue eosinophila and that this effect was associated with normalization of airway reactivity and prevention of goblet cell hyperplasia [18]. In a mouse model of allergic conjunctivitis, demonstrated that a highly selective CCR3-antagonist attenuated early and late phase symptoms [20], suggesting a symptomreducing potential in allergic conditions, and that the effect was associated with mast cell stabilization. Additional observations on effects of CCR3-antagonists comprise prevention of immediate and late-phase allergic skin reactions to allergen in a mouse allergy model [21], inhibition of eosinophil infiltration into the airways of monkeys following segmental bronchial provocation with eotaxin [22], and dose-dependent reduction of eosinophil recruitment into the lungs in an animal model of allergic airway inflammation [23]. Explorations of CCR3-inhibition in man are highly warranted
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