Frossard Nelly, Strolin-Benedetti Margherita, Purohit Ashok, Pauli Gabrielle
Faculty of Pharmacy, University Louis Pasteur-Strasbourg I, Strasbourg, France.
Br J Clin Pharmacol. 2008 Feb;65(2):172-9. doi: 10.1111/j.1365-2125.2007.03009.x. Epub 2007 Oct 29.
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.
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.
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.
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.
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.
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.
可重复且标准化的组胺诱导风团和潮红模型有助于确定抗组胺药在人体中的客观疗效，以及它们在起效时间和作用持续时间上的差异。一些最新的抗组胺药已经在这种模型下进行了直接比较。然而，它们抑制变应原诱导的风团和潮红反应的客观作用尚未见报道。
此处呈现的时间反应研究显示了新一代抗组胺药左西替利嗪和地氯雷他定在一项随机、交叉、安慰剂对照试验中抑制变应原诱导的风团和潮红反应的客观活性。由于招募了过敏受试者，并且对变应原的反应除了组胺外还涉及肥大细胞脱颗粒以及多种血管活性和促炎介质的释放，所以该模型在临床环境中具有重要意义。此外，本研究报告了两种抗组胺药在治疗剂量下的受体占有率，从而能够分析活性方面的潜在差异。本研究清楚地表明，当地氯雷他定和左西替利嗪在临床情况下以变应原作为激发剂时，它们在皮肤活性方面具有潜在的抗炎特性。
评估新一代抗组胺药左西替利嗪和地氯雷他定在治疗剂量下于给药后1.5小时、4小时、7小时、12小时和24小时对变应原诱导的风团和潮红反应的抑制活性，并测量它们的血浆和皮肤浓度。
对18名过敏受试者进行了一项双盲、随机、交叉、安慰剂对照研究。通过方差分析比较风团和潮红反应曲线下面积（AUC）的时间反应。
与安慰剂相比，两种抗组胺药均显著（P < 0.001）抑制了变应原诱导的风团和潮红反应。左西替利嗪的效力显著高于地氯雷他定。与安慰剂（(1318.5 +/- 361.0 mm(2) h)）相比，左西替利嗪的平均±标准误风团AUC(0 - 24 h)为506.4 +/- 81.0，地氯雷他定为995.5 +/- 81.0 mm(2) h。潮红AUC(0 - 24 h)分别为5927.3 +/- 1686.5和15838.2 +/- 1686.5 mm(2) h [与安慰剂((22508.2 +/- 7437.1 mm(2) h))相比两者均P < 0.001]。与安慰剂相比，左西替利嗪在给药后1.5小时就显著抑制了风团和潮红（P ≤ 0.001）；地氯雷他定仅在4小时后才产生显著效果。摄入后12小时和24小时，左西替利嗪的平均总血浆浓度较高（分别为58.1 +/- 13.4和20.0 +/- 8.1 ng ml(-1)），而地氯雷他定分别为(0.82 +/- 0.24和0.45 +/- 0.16 ng ml(-1))。同样，摄入后24小时左西替利嗪的平均未结合皮肤浓度（1.80 ng g(-1)）高于地氯雷他定（0.07 ng g(-1)）。这与24小时时左西替利嗪的受体占有率（%）高于地氯雷他定（34%）相关。
左西替利嗪比地氯雷他定更有效地抑制皮肤过敏反应，这与其高受体占有率相关。受体占有率而非药物亲和力或血浆半衰期更能代表抗组胺药的效力。
