title: Inhibition of allergen-induced wheal and flare reactions by levocetirizine and desloratadine.
abstract: BACKGROUND
  The reproducible and standardized histamine-induced wheal and flare model helps identify the objective effectiveness of antihistamines in humans, as well as their differences in onset and duration of action. Some of the newest antihistamines have already been compared in a head-to-head setting using this model. However, their objective action at inhibiting the allergen-induced wheal and flare response has not been reported yet.
  
  
  CONCLUSIONS
  The time-response study presented here shows the objective activity of two of the newest generation of antihistamines, levocetirizine and desloratadine, at inhibiting the allergen-induced wheal and flare response in a randomized, cross over, placebo-controlled trial. This model is interesting to the clinical setting since allergic subjects are recruited, and the response to allergen involves mast cell degranulation and release of numerous vasoactive and pro-inflammatory mediators additionally to histamine. In addition, this study reports receptor occupancy for both antihistamines at therapeutic dosage, leading to analysis of potential differences in activity. This study clearly shows the potential anti-inflammatory properties of desloratadine and levocetirizine in their skin activity when allergen is the challenging agent as occurs in the clinical situation.
  
  
  OBJECTIVE
  To evaluate the inhibitory activity of the new-generation antihistamines levocetirizine and desloratadine at their therapeutic doses on the allergen-induced wheal and flare reaction at 1.5 h, 4 h, 7 h, 12 h and 24 h postdose, and to measure their plasma and skin concentrations.
  
  
  METHODS
  A double-blind, randomized, cross-over, placebo-controlled study in 18 allergic subjects was carried out. The time-response of the wheal and flare reaction areas under the curve (AUC) were compared by anova.
  
  
  RESULTS
  Both antihistamines significantly (P < 0.001) inhibited the allergen-induced wheal and flare reactions compared with placebo. Levocetirizine was significantly more potent than desloratadine. Mean +/- SEM wheal AUC(0-24 h) was 506.4 +/- 81.0 with levocetirizine and 995.5 +/- 81.0 mm(2) h with desloratadine as compared with placebo (1318.5 +/- 361.0 mm(2) h). Flare AUC(0-24 h) was 5927.3 +/- 1686.5 and 15838.2 +/- 1686.5 mm(2) h, respectively [P < 0.001 for both compared with placebo (22508.2 +/- 7437.1 mm(2) h)]. Levocetirizine showed significant inhibition of wheal and flare already at 1.5 h postdose compared with placebo (P <or= 0.001); desloratadine achieved a significant effect only after 4 h. The mean total plasma concentration at 12 h and 24 h after intake was higher for levocetirizine (58.1 +/- 13.4 and 20.0 +/- 8.1 ng ml(-1), respectively) as compared with desloratadine (0.82 +/- 0.24 and 0.45 +/- 0.16 ng ml(-1)). Similarly, higher mean unbound skin concentrations were observed for levocetirizine 24 h after intake (1.80 ng g(-1)) than for desloratadine (0.07 ng g(-1)). This was associated with greater receptor occupancy for levocetirizine (54%) than desloratadine (34%) at 24 h.
  
  
  CONCLUSIONS
  Levocetirizine suppressed the cutaneous allergic reactions with a higher potency than desloratadine, which correlated with its high receptor occupancy. Receptor occupancy rather than drug affinity or plasma half-life is more representative of antihistamine potency.
authors.affiliation: Faculty of Pharmacy, University Louis Pasteur-Strasbourg I, Strasbourg, France. nelly.frossard@pharma.u-strasbg.fr
authors.forename: Nelly
authors.initials: N
authors.lastname: Frossard
authors.forename: Margherita
authors.initials: M
authors.lastname: Strolin-Benedetti
authors.forename: Ashok
authors.initials: A
authors.lastname: Purohit
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Pauli
mesh_terms: D000293:Adolescent; D000328:Adult; D000485:Allergens / Q000009:adverse effects*; D017332:Cetirizine / Q000627:therapeutic use*; D018680:Cholinergic Antagonists / Q000627:therapeutic use; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D039563:Histamine H1 Antagonists, Non-Sedating / Q000627:therapeutic use; D006801:Humans; D017336:Loratadine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use*; D011446:Prospective Studies; D014581:Urticaria / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000485:Allergens; D018680:Cholinergic Antagonists; D039563:Histamine H1 Antagonists, Non-Sedating; D010879:Piperazines; C472067:levocetirizine; D017336:Loratadine; C121345:desloratadine; D017332:Cetirizine