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83.    Antihistamines and corticoids co-treatment rationale. Potentiation of                                   glucocorticoids anti-inflammatory effects.

Histamine H1 receptor (H1R) antagonists and glucocorticoid receptor (GR) agonists are used to treat many inflammatory conditions, such as allergic rhinitis and asthma, and their receptors are the targets with the greatest number of approved drugs. In many situations their ligands are co-administered, although this drug association
has no clear rationale and has arisen from clinical practice. We hypothesized that H1R signaling could affect GR-mediated activity, affecting its transcriptional outcome. To test our hypothesis we used HEK293T cells co-transfected with plasmids coding for GR, H1R and a GR-responsive luciferase reporter plasmid to study transactivation (TAT3-Luc) or transrepression (IL6-Luc) of responsive genes. Our results show a dual regulation of GR activity by the H1R: a potentiation mediated by G-protein βγ subunits and a parallel inhibitory effect mediated by Gαq- PLC pathway. Activation of the H1R by its full agonists resulted in a composite potentiating effect. Intriguingly, inactivation of the Gαq-PLC pathway by H1R inverse agonists resulted also in a potentiation of GR activity. To analyze the consequences of this modulation, we studied genes involved in inflammatory processes in pathophysiologically relevant cell lines. In lung A549 cells and in promonocytic U937 cells, clinically relevant antihistamines synergized with the GR agonist dexamethasone to induce gene transactivation (GILZ, MKP1) and transrepression (IL8, COX2 and GMCSF). Finally, we tested the clinical relevance by using Dexamethasone (Dex) and the H1 antihistamine Azelastine (Aze) on a murine model of asthma. Balb/c mice were ip sensitized and airway challenged with ovoalbumin, and then treated with Dex alone (1 mg/kg optimal dose or 0.1 mg/kg suboptimal dose) or in combination with 0.5 mg/kg Aze. Vehicle and Aze alonetreated mice were used as experimental controls. We found that levels of allergenspecific immunoglobulin IgE and bronchoalveolar lavage eosinophilia were reduced only in animals treated with 1 mg/kg Dex or co-treated with 0.1 mg/kg Dex + Aze compared to allergic control mice (p<0.05). From a therapeutic point of view, our results suggest that the potentiating effect of antihistamines on Dex response could result in the reduction of the Dex doses needed to reach anti-inflammatory effects, particularly in asthma.

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