title: Inhibitory activity of loratadine and descarboxyethoxyloratadine on histamine-induced activation of endothelial cells.
abstract: BACKGROUND
  The allergic inflammatory reaction is characterized by leucocyte adherence and infiltration processes which are controlled by the expression of adhesion molecules on the surface of vascular endothelium. One of the main mediators implicated in allergic reactions is represented by histamine. Histamine is a potent activator of endothelial cells (EC): it induces the expression of P-selectin on the surface of endothelium and the secretion of IL-6 and IL-8.
  
  
  OBJECTIVE
  Loratadine (L), a histamine H1-antagonist, and one of its active metabolites, descarboxyethoxyloratadine (DCL), were studied at different concentrations for their ability to reduce the histamine-induced activation of human umbilical vein EC (HUVEC).
  
  
  METHODS
  HUVEC were stimulated in the presence of histamine at 10(-6) M, 10(-5) M and 10(-4) M. We assessed by ELISA the expression of P-selectin on EC surface, as well as cytokine production in EC supernatants of 24 h culture.
  
  
  RESULTS
  Our results showed that for a 10(-4) M-histamine stimulation, L and DCL have a similar inhibitory effect on P-selectin expression (IC50 = 13 x 10[-9] M and 23 x 10[-9] M, respectively). L and DCL inhibited significantly IL-6 and IL-8 secretion induced by histamine with a more powerful efficiency of the active metabolite. For the dose of 10(-4) M histamine, a 50% inhibition of IL-6 secretion was obtained for a dose of DCL equal to 2.6 x 10(-12) M whereas the same magnitude of effects were only reached for a higher concentration of L (0.3 x 10[-6] M). Similar results were obtained for IL-8 (IC50 = 0.2 x 10[-6] M for L and 10[-9] M for DCL). Analysis of IL-8 mRNA expression by RT-PCR was in accordance with these data.
  
  
  CONCLUSIONS
  These results demonstrate that both L and DCL are active to reduce the histamine-induced activation of EC. Interestingly, DCL seems to be effective at lesser concentrations especially to inhibit cytokine secretion.
authors.affiliation: Unité INSERM U416, Institut Pasteur, Lille, France.
authors.forename: S
authors.initials: S
authors.lastname: Molet
authors.forename: P
authors.initials: P
authors.lastname: Gosset
authors.forename: P
authors.initials: P
authors.lastname: Lassalle
authors.forename: W
authors.initials: W
authors.lastname: Czarlewski
authors.forename: A B
authors.initials: AB
authors.lastname: Tonnel
mesh_terms: D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D006632:Histamine / Q000378:metabolism*; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D017336:Loratadine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019007:P-Selectin / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D006634:Histamine H1 Antagonists; D015850:Interleukin-6; D016209:Interleukin-8; D019007:P-Selectin; D012333:RNA, Messenger; C086094:des(ethoxycarbonyl)loratadine; D017336:Loratadine; D006632:Histamine; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases