In vitro inhibition, by loratadine and descarboxyethoxyloratadine, of histamine release from human basophils, and of histamine release and intracellular calcium fluxes in rat basophilic leukemia cells (RBL-2H3)

Berthon, B; Taudou, G.; Combettes, Laurent; Czarlewski, W.; Carmi–Leroy, Annick; Marchand, Françoise; Weyer, A.

doi:10.1016/0006-2952(94)90478-2

Cited by 40 publications

(20 citation statements)

References 25 publications

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“…The mechanism by which desloratadine acts at the H 1 receptor is probably linked to alterations in intracellular calcium concentrations. Berthon et al [36]demonstrated that desloratadine (2.5–50 µ M ) decreased antigen-induced rises in intracellular calcium in basophil leukemic cells in vitro by both inhibiting the intracellular mobilization of calcium and the influx of extracellular calcium.…”

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

Int Arch Allergy Immunol

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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.

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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

Int Arch Allergy Immunol

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“…This decrease in colony histamine could also be interpreted as a relative maturing effect of DL on eosinophils in colonies. Precisely how DL may alter colony histamine content was not directly examined, although we can speculate that it may inhibit Eo/B CFU maturation potentially indirectly by modulating the release of colony-supporting cytokines from mast cells [37] or T cells [38], since it has been shown that DL can inhibit both IgE- and/or non-IgE-mediated mast cell [39] and basophil degranulation [40]. DL may interfere with Eo/B maturation by inhibiting the release of mast cell-derived hemopoietic cytokines, such as IL-3, IL-5, and GM-CSF.…”

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

Int Arch Allergy Immunol

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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.

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“…The importance of Ca2+-related effects in the inhibition of mediator release has been demonstrated for other, structurally unrelated, drugs e.g. loratadine (log P 5.2) in human basophils [28]. Oxatomide has been reported to inhibit voltage-dependent Ca2+-channels in bovine adrenal chromaffin cells [29].…”

Section: Discussionmentioning

confidence: 98%

Relation between effects of a set of anti-allergic drugs on calcium pathways and membrane structure in Fc∈RI activated signal transduction

et al. 1996

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The antigen induced stimulation of mast cells by aggregation of Fc epsilon RI receptors activates a signal transduction cascade leading to release of mediators of inflammation like histamine, arachidonic acid metabolites and cytokines. In this study we investigated a series of structurally related anti-allergic drugs, containing a common lipophilic diphenylmethyl piperazinyl tail and head groups that differ in lipophilicity. Effects of these drugs on various steps of the signal transduction cascade was investigated to gain insight into the mechanism of action of these drugs. It appeared that addition of the drugs to resting cells induced changes in the tyrosine phosphorylation of cellular proteins. The most active anti-allergics in inhibiting exocytosis, AL3264 and oxatomide, also induced the largest changes in phosphorylation. The effects of the drugs on tyrosine phosphorylation after cell activation was complex. Additionally, Ca2+ fluxes were investigated. Ca2+ efflux from the cells was negligibly influenced by the active drugs. However, the drugs inhibited influx from extracellular Ca2+, which was correlated with the effects of the drugs on inhibition of exocytosis and on membrane stabilization induced by the drugs, measured as haemolysis of erythrocytes. It is concluded that inhibition of Ca2+ influx is the major mechanism with which these drugs inhibit exocytosis and that for this effect drug-membrane interactions, possibly affecting the function of membrane embedded proteins, are of importance. Possible mechanisms including drug-membrane interactions, phosphorylation and inhibition of Ca2+ influx are discussed.

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In vitro inhibition, by loratadine and descarboxyethoxyloratadine, of histamine release from human basophils, and of histamine release and intracellular calcium fluxes in rat basophilic leukemia cells (RBL-2H3)

Cited by 40 publications

References 25 publications

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

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

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

Relation between effects of a set of anti-allergic drugs on calcium pathways and membrane structure in Fc∈RI activated signal transduction

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