E. W. Monroe, MD
Department of Dermatology, Milwaukee Medical Clinic, Milwaukee, Wisconsin, USA
Chronic urticaria is a common dermatologic condition that is idiopathic in most cases. Antihistamines are the mainstays of treatment for this condition. The newer, second and third generation antihistamines are the preferred agents because of their improved safety profile and comparable efficacy to the first generation antihistamines. Desloratadine is a new non-sedating H1-receptor antagonist. Based on clinical studies, desloratadine is a valuable new addition to the available treatment options and should be considered as a first-line therapy for patients with chronic urticaria.
desloratadine, chronic urticaria
Desloratadine is a new selective H1-receptor antagonist and is the primary active metabolite of loratadine (Claritin®, Schering-Plough). It has been approved for use in many countries throughout the world and is sold as Clarinex® in the US, and as Aerius® in Canada. In Europe it is being marketed as Neoclarityn™ and Aerius™. During the first quarter of 2002, it received US FDA approval for the relief of both nasal and non-nasal symptoms of allergic rhinitis (seasonal and perennial) in patients ≥12 years of age. Additionally, it is indicated for the symptomatic relief of pruritus and the reduction in the number and size of hives in patients ≥12 years of age with chronic idiopathic urticaria.
Urticaria is a cutaneous reaction pattern characterized by pruritic, transient, erythematous papules and wheals often with central clearing. It results from the transudation of fluid from the cutaneous vasculature. Numerous factors both immunologic and non-immunologic, including autoantibodies, can cause mast cell activation and the release of mediators capable of causing vascular permeability, and thus, hives. Histamine is the best documented of these mediators. Numerous etiologies exist for urticaria including: drugs, foods, infections, contactants, internal diseases, psychogenic factors, genetic factors and physical factors (pressure, cold, heat, etc.). Urticaria is classified as acute or chronic depending on whether its duration is > 6 weeks. The cause of acute urticaria is usually detectable. In chronic urticaria, most cases (90-95%) are idiopathic.
Mechanism of Action and Pharmacology
Desloratadine, is a selective H1-receptor antagonist. It is approximately 10-20 times more potent in H1-receptor binding than loratadine in vitro, and has 2.5-4 times more antihistaminic potency in animals,1,2 and has no significant cholinergic or H2-receptor affinity. Furthermore, desloratadine does not penetrate the blood-brain barrier in animal studies, a fact that has been confirmed by the lack of sedation or cognitive impairment in clinical trials.
In vitro studies have shown that desloratadine also possesses anti-allergic and anti-inflammatory activity. This product inhibits the release by mast cells and basophils of histamine and other inflammatory mediators.3,4 In addition, it inhibits cytokines, and the induction of cell adhesion molecules, as well as reducing eosinophil chemotaxis and activation.5,6,7 Although these in vitro effects do not necessarily translate into in vivo effects, these added properties may result in improved clinical responses.
Pharmacokinetics and Drug Interactions
Desloratadine is rapidly absorbed, has dose-proportional pharmacokinetics, and a half-life of 27 hours. The absorption of desloratadine is not affected by food, and the metabolism and elimination are not significantly affected by the subject’s age or sex. Metabolism of desloratadine does not involve the cytochrome P450 system or the pglycoprotein transport system. Results of electrocardiographic studies have revealed no clinically relevant interactions between desloratadine and erythromycin, ketoconazole or grapefruit juice.8
The efficacy and safety of desloratadine 5mg, once daily was studied in two randomized, double-blind, placebo-controlled, clinical trials of six weeks’ duration involving 416 patients, 12-84 years of age with chronic idiopathic urticaria.9,10 The primary efficacy variable, i.e., the mean improvement from baseline in pruritus over the first week of treatment, was significantly greater in the desloratadine group (47.9%) than in the placebo group (21.9%; p<.001). All secondary efficacy parameters, i.e., total symptom scores (pruritus, number and size of hives), quality of life measures (interference with sleep and daily activities), showed that desloratadine was significantly better than placebo at all time points from day 2 of treatment until the end of the study at 6 weeks.
The study showed statistically significant improvement after dosing that lasted for the entire 24-hour period after each dose (see Table 1). The safety profile of desloratadine was excellent with the overall adverse event profile, including somnolence, similar to placebo (see Table 2).
|Treatment Group||% Reduction in Itch at 24 Hours after First Dose||% Reduction in Itch from Baseline at Week 1||% Reduction in Total Symptom Score (Itch, #, Size of Hives at Week 1||% Reduction in Interference with Sleep at Week 1|
|Desloratadine 5 mg (n=116)9||40.3||47.9||43.3||44.0|
|Desloratadine 5 mg (n= 95)10||44.6||56.1||51.6||53.0|
Table 1: Dosage, adverse events, and clinical trials data
(Statistically significant: >= better than; = equal to)
|10 mg q.d.||L > Placebo|
L = Hydroxyzine
|10 mg q.d.||C > Placebo|
C = Hydroxyzine
|60 mg b.i.d. or 180 mg q.d.||F > Placebo||None|
|Desloratadine (D) (Clarinex®, Aerius™, Neoclarityn™, Schering-Plough)||5 mg q.d.||D > Placebo||None|
Clinical trials have demonstrated that desloratadine has a superior efficacy and similar safety profile to placebo in the treatment of patients with chronic idiopathic urticaria. Once-daily dosing provided rapid, prolonged benefits in objective and subjective disease and quality of life measures. Desloratadine’s effectiveness was maintained for the full 24 hours after each dosing, as well as throughout the 6 week study. Further active comparator studies will determine whether desloratadine’s potent H1- antihistaminic properties combined with potential anti-allergic and anti-inflammatory effects make it superior to other current treatment options. At this time, desloratadine should be considered one of the preferred first-line treatments for patients with chronic idiopathic urticaria.
- Kreutner W, Hey JA, Anthes J, Barnett A, Young S, Tozzi S. Preclinical pharmacology of desloratadine, a selective and nonsedating histamine H1 receptor antagonist. 1st communication: receptor selectivity, antihistaminic activity, and antiallergenic effects. Arzneimittelforschung 50(4):345-52 (2000 Apr).
- Anthes JC, Richard C, West RE, et al. Functional characterization of desloratadine and other antihistamines in human histamine H1 receptors. Allergy 55:277 (2000).
- Kleine-Tebbe J, Josties C, Frank G, et al. Inhibition of IgE and non-IgEmediated histamine release from human basophil leukocytes in vitro by a histamine H1-antagnoist, desethoxycarbonyl-loratadine. J Allergy Clin Immunol 93(2):494-500 (1994 Feb).
- Genovese A, Patella V, DeCrescenzo G, De Paulis A, Spadaro G, Marone G. Loratadine and desethoxylcarbonyl-loratadine inhibit the immunological release of mediators from human Fc epsilon RI+ cells. Clin Exp Allergy 27(5):559-67 (1997 May).
- Schroder JT, Schleimer RP, Lichtenstein LM, Kreutner W. Inhibition of cytokine generation and mediator release by human basophils treated with desloratadine. Clin Exp Allergy 31(9):1369-77 (2001 Sep).
- Vignola AM, Crampette L, Mondain M, et al. Inhibitory activity of loratadine and descarboethoxyloratadine on expression of ICAM-1 and HLA-DR by nasal epithelial cells. Allergy 50(3):200-3 (1995 Mar).
- Agrawal DK, Berro A, Townley RG. Desloratadine attenuation of eosinophil chemotaxis, adhesion, and superoxide generation. Allergy 55:276 (2000).
- Geha, RS, Meltzer EO. Desloratadine: A new, nonsedating, oral antihistamine. J Allergy Clin Immunol 107(4):752-62 (2001 Apr).
- Ring J, Hein R, Gauger A. Desloratadine in the treatment of chronic idiopathic urticaria. Allergy 56(Suppl 65):28-32 (2001).
- Monroe EW, Finn A, Patel P, et al. Efficacy and safety of desloratadine 5 mg once daily in the treatment of chronic idiopathic urticaria: a double-blind, randomized, placebo-controlled trial. 2002 Submitted for publication.