Effect of tecastemizole on pulmonary and cutaneous allergic inflammatory responses.
BACKGROUND
Tecastemizole, a major metabolite of astemizole, is a potent and selective H1 receptor antagonist. Evidence suggests that this and certain other H1 receptor antagonists may possess anti-inflammatory effects that are, in some cases, independent of H1 receptor antagonism. Objective The aim of this study was to investigate the anti-inflammatory effects of tectastemizole in models of allergic inflammation.


METHODS
Effects of tecastemizole were assessed in a murine model of allergic lung inflammation, in passive cutaneous anaphylaxis (PCA) responses in guinea-pig skin and in in vitro assays measuring endothelial adhesion molecule expression and leucocyte-endothelial adhesion.


RESULTS
Tecastemizole inhibited antigen-induced eosinophil recruitment to the lungs of allergic mice in a dose-dependent manner. Furthermore, combination of a sub-effective dose of tecastemizole, combined with a sub-effective dose of dexamethasone inhibited eosinophil accumulation in this model. Plasma extravasation in PCA reactions was inhibited by tecastemizole, although by a mechanism that would appear to be H1 receptor-dependent. Cytokine-induced endothelial intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, as well as mononuclear cell adhesion to human umbilical vein endothelial cells was inhibited by tecastemazole in a manner independent of H1 receptor antagonism.


CONCLUSIONS
These data suggest that tecastemizole may have H1 receptor-independent effects in inhibiting late-phase inflammatory responses, while acute responses appear to be inhibited in a H1 receptor-dependent manner. Furthermore, our data suggest an important potential steroid-sparing role for such drugs in the treatment of allergic inflammatory conditions.
Lever
R
R
Department of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London, UK.
Hefni
A
A
Moffatt
J D
JD
Paul
W
W
Page
C P
CP
D000707:Anaphylaxis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016589:Astemizole / Q000494:pharmacology / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D015815:Cell Adhesion Molecules; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology; D004804:Eosinophils / Q000276:immunology / Q000473:pathology; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011969:Receptors, Histamine H1 / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D014471:Umbilical Veins / Q000276:immunology / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology
D000893:Anti-Inflammatory Agents; D001562:Benzimidazoles; D015815:Cell Adhesion Molecules; D006634:Histamine H1 Antagonists; D010880:Piperidines; D011969:Receptors, Histamine H1; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D016589:Astemizole; D003907:Dexamethasone; C106448:tecastemizole