Inhibitory activity of loratadine and descarboethoxyloratadine on expression of ICAM‐1 and HLA‐DR by nasal epithelial cells

Background: Mizolastine is a potent, peripherally acting, selective H1-receptor antagonist with potential anti-inflammatory properties. The aim of the study was to evaluate the in vitro effects of mizolastine on the expression of adhesion molecules by primary human airway epithelial and stromal cultures; moreover, the activity of mizolastine on parameters which reflect the immune response efficacy was investigated. Methods: Airway epithelial and stromal cells were collected from hypereosinophilic subjects by enzymatic digestion of polyps or turbinates. Cells were stimulated with interferon (IFN)-γ (500 IU/ml) in the presence of various mizolastine concentrations (6 × 10^–8–6 × 10^–6 M) for 24 h and the expression of CD106, CD54, CD58 and HLA class I was evaluated. Peripheral blood mononuclear cells from healthy volunteers were incubated with 1% phytohemagglutinin or anti-CD3 monoclonal antibody (20 ng/ml) in the presence of mizolastine, then T lymphocyte proliferation, HLA-DR expression and T cell subpopulations were evaluated. Results: Both in epithelial and stromal cultures, IFN-γ significantly upregulated all of the tested surface molecules (p < 0.05). The highest dose of mizolastine (6 × 10^–6 M), corresponding to 10-fold the peak plasma level after a single oral administration of 10 mg, was able to act on fibroblasts, significantly downregulating the expression of CD54 (p < 0.05). Regarding T lymphocyte proliferation, the addition of mizolastine did not induce any significant change; furthermore, mizolastine was ineffective at all of the tested concentrations on both HLA-DR expression and CD4+/CD8+ ratio. Conclusions: This study demonstrated that mizolastine is able to selectively downregulate CD54 expression on stimulated stromal but not epithelial cells without impairing the immune system effectors. The possible clinical significance of these results are an antiallergic property and CD54 modulation on fibroblasts with a good safety profile as far as the lymphocyte response is concerned.

“…Additionally, the same results have been demonstrated on epithelial cells from different origins, such as conjunctiva, nose and intestine [7, 15]. …”

Section: Discussionsupporting

confidence: 60%

Effects of Mizolastine in vitro on Human Immunocompetent and Airway Cells: Evidence for Safety and Additional Property

Oddera

Cagnoni

Dellacasa

et al. 2000

“…DL has been shown to downregulate the adhesion molecule ICAM-1 [28, 29], which binds to its natural ligand LFA-1 present on eosinophils [30] and CD34+ progenitors [25, 26]. Histamine has been shown to increase VCAM-1 expression on endothelial cells and this effect can be blocked with the addition of antihistamine [31].…”

Section: Discussionmentioning

confidence: 99%

The Effect of Desloratadine on Eosinophil/Basophil Progenitors and Other Inflammatory Markers in Seasonal Allergic Rhinitis: A Placebo-Controlled Randomized Study

Cyr¹,

Hayes²,

Crawford³

et al. 2005

Background: Eosinophil/basophil (Eo/B) progenitors fluctuate in the peripheral circulation during seasonal allergen exposure in atopic subjects. Several drugs have been shown to modulate Eo/B progenitor levels in the peripheral blood but, to date, the possible effect of antihistamines on Eo/B progenitors has not been explored. Our objective was to evaluate whether the antihistamine desloratadine (DL) can modulate peripheral blood Eo/B progenitors or other markers of allergic inflammation. Methods: We performed a randomized double-blind placebo-controlled study on the effects of DL on peripheral blood Eo/B progenitors in subjects with symptomatic, seasonal allergic rhinitis during a ragweed pollen season. Forty-five subjects were randomized to treatment for 4 weeks with DL 20 mg daily or placebo. Results: The expected fall in the number of Eo/B progenitors from baseline to 2 weeks of treatment was seen in the placebo group [median drop of 1.0 colony-forming unit (CFU)/10⁶ cells], and was greater than in the DL group (median drop of 0.0 CFU/10⁶ cells) (p = 0.013). The change in histamine concentration per colony from baseline to 2 weeks of treatment was lower in the DL group (median decrease of 6.1 pg/colony) compared to placebo (median increase of 1.8 pg/colony) (p = 0.01). An increase in the nasal lavage eotaxin concentration from baseline to 4 weeks of treatment was statistically significant in the placebo group but not in the DL group. Eo/B CFU were not affected by varyingin vitro concentrations of DL. Conclusion: These results suggest that DL can modulate aspects of allergic inflammation in vivo through mechanisms other than simple blockade of H₁ histamine receptors.

“…Desloratadine reduces the generation of the cytokines IL-4/IL-13 [34], IL-6, IL-8 [38]and the adhesion molecules P-selectin [39]and ICAM-1 [40]from human basophils, mast cells and endothelium in vitro. Some of these effects were demonstrated at nanomolar or subnanomolar concentrations, which indicates that they may be clinically relevant.…”

Section: Discussionmentioning

confidence: 99%

Desloratadine Inhibits Constitutive and Histamine-Stimulated Nuclear Factor-κB Activity Consistent with Inverse Agonism at the Histamine H<sub>1</sub> Receptor

Wu¹,

Anthes²,

Kreutner³

et al. 2004

Background: The human histamine H₁ receptor is constitutively active and exhibits basal activation of nuclear factor-ĸB (NF-ĸB), an important modulator of allergic inflammation. Certain H₁ antihistamines have recently been shown to inhibit basal NF-ĸB activity by stabilizing the H₁ receptor in an inactive state, a phenomenon called ‘inverse agonism’. Methods: We evaluated the effect of the new H₁ antihistamine, desloratadine, on basal and histamine-stimulated NF-ĸB activity and compared it with the activities of other H₁ antihistamines. Results: Transiently transfected COS-7 cells co-expressing NF-ĸB-luciferase and the H₁ receptor exhibited constitutive NF-ĸB activity. H₁ antihistamines reduced basal NF-ĸB activity (rank order of potency: desloratadine > pyrilamine > cetirizine > loratadine > fexofenadine). Histamine stimulated basal NF-ĸB activity 8-fold, which was blocked by H₁ antihistamines (rank order of potency: desloratadine > cetirizine > pyrilamine > loratadine > fexofenadine). Neither histamine nor antihistamines had any effect on NF-ĸB activity in the absence of the H₁ receptor. Conclusions: Desloratadine, acting through the histamine H₁ receptor, inhibited basal NF-ĸB activity and can thus be classified as an inverse agonist. Inhibition of basal and histamine-stimulated NF-ĸB activity may help to explain previously reported inhibitory effects of desloratadine on allergic inflammatory mediators.