The present study demonstrates that a dual CCR3 and histamine H1-receptor antagonist (AZD3778) can exert anti-eosinophil and symptom-reducing effects in a condition in man characterised by allergic airway inflammation. Our data are of interest with regard to the pharmacology of CCR3-antagonism, the relative importance of eosinophil actions to the symptomatology of allergic rhinitis, and the potential use of AZD3778 in the treatment of allergic rhinitis.
Preceding in vitro studies performed by MDS Pharma Services indicted that AZD3778 had a whole blood A2 at the CCR3-receptor of 0.2 μmol/L. Furthermore, with regard to antagonism of the histamine H1-receptor, a whole blood exposure of 1.0 μmol/L was equivalent to A2. In the present study, plasma levels of AZD3778 were stable late into the treatment series. At trough, the plasma concentration of AZD3778 suggested that exposures were close to those required for 24-hour antagonism of the CCR3 and H1-receptors.
It is difficult to compare treatment-effects in allergic rhinitis during the pollen season, reflecting uncertainties regarding onset and intensity of natural allergen exposure. Accordingly, it is impossible to perform accurate studies of crossover design and when resorting to parallel group studies these are hampered by inter-individual differences in allergen sensitivity. In order to overcome these problems, we have introduced a model where nasal challenges with individualized doses of allergen are given for seven consecutive days to create a repeatable artificial pollen season characterized by development of rhinitis symptoms and allergic inflammation [24
]. In the present study, this model was used and around-the-clock rhinitis symptoms were produced by the allergen-challenges in the placebo-run. Notably, symptom scores reached at placebo treatment were very similar to those recorded previously in the model.
Using the mean over the last three days of the allergen challenge series, based on previous evaluations in the present model in which symptoms gradually increased over time [24
], AZD3778 reduced post-challenge TNSS compared with placebo. In contrast, no statistically significant effects were observed for morning and evening symptoms when focusing on this period. By these characteristics, which were of the same profile and magnitude as for anti-histamines: loratadine (this study) and cetirizine [28
], it might be suggested that AZD3778 acted through H1
-antagonism or that CCR3-antagonism resulted in the same effect-profile as that of anti-histamines. However, AZD3778 also reduced post-challenge nasal blockage and improved post-challenge nasal PIF. Moreover, when focusing on the last five days of the allergen challenge series (which was valid since an effect plateau was reached already at allergen challenge day three), AZD3778 exerted statistically significant reducing effects also on morning and evening symptoms. These latter effects, which were not observed for loratadine, also suggest that CCR3-antagonism per se
has specific anti-rhinitis effects. Accordingly, CCR3-antagonists may have a potential as a treatment for allergic rhinitis. From a therapeutic point of view, the possibility that AZD3778 exerts CCR3 as well as H1
-antagonistic effects is attractive. However, compared with previous observations in the present model [24
], the effect of AZD3778 will likely be inferior that of a topical corticosteroid. Further studies are warranted to evaluate AZD3778 and other CCR3-antagonists in allergic rhinitis.
In the present placebo run, nasal lavage fluid levels of ECP, tryptase, and α2
-macroglobulin increased during the allergen challenge series compared with baseline data. This was in agreement with previous observations in the present model and indicated a development of allergic airway inflammation [25
]. Whereas loratadine failed to affect these indices, AZD3778 reduced the levels of ECP compared with placebo. For the pre-bradykinin challenge lavage, the numerical 37% reduction in ECP failed to reach statistical significance, whereas the reduction was significant for the post-bradykinin observation. (Plasma exudation events acutely produced by histamine is known to improve the recovery of tryptase and ECP [25
]: bradykinin was employed in the present study to achieve this and its exudative effect was confirmed.) The effect of AZD3778 likely reflected CCR3-antagonism and not H1
-antagonism, since it was not observed for loratadine. In contrast to its effects on ECP, AZD3778 failed to affect the levels of tryptase, which disagreed with the observation by Nakamura et al
. on mast cell stabilizing effects of a CCR3-antagonist in a mouse model [20
]. Differences between test systems, species, and the employed antagonists might account for the discrepancy. AZD3778 as well as loratadine also failed to reduce the allergen challenge induced plasma exudation (α2
-macroglobulin). Taken together, our findings suggest that AZD3778 exerts a selective anti-eosinophil effect. The observation is in keeping with previous findings on such effects by CCR3 antagonism in experimental models [9
], and extends them to include allergic rhinitis. While reducing eosinophil activity in allergic rhinitis, the effect profile of AZD3778 is different from what is expected for a topical corticosteroid, which reduces all the employed lavage fluid indices in the present model [25
In the present study, AZD3778 exerted a moderate anti-eosinophilic and symptom-reducing effect in allergic rhinitis. We might not conclude that the effect on nasal symptoms was secondary to anti-eosinophilic actions associated with CCR3-antagonism. However, the findings suggest that part of the symptomathology of allergic rhinitis depends on eosinophil activity. Indirectly, this is in agreement with observations on seasonal allergic rhinitis as a condition featuring particularly intense eosinophil activity. For instance, eosinophil degranulation (assessed by transmission electron microscopy) is much greater in on-going allergic rhinitis than in asthma [29
]. Based on the present findings, and observations by Erjefält et al. [29
], it can be suggested that interventions aiming at reducing eosinophil activity in airway inflammation may better be evaluated in allergic rhinitis than in asthma. Such intervention may include IL-5 receptor antagonists, despite the fact that trials with IL-5 active drugs (in asthma) have been disappointing [30
]. A specific area in which it may be of interest to explore effects of anti-eosinophil active drugs, notably CCR3-antagonists, is the interaction between allergic/eosinophilic inflammation and the common cold. For example, a series of observations indicate the importance of rhinovirus infections to exacerbations of asthma [33
], and experimental inoculation studies suggest that CC-chemokines and eosinophils may be involved in this interaction [34