The role of Hl receptor in Allergic Inflammation

The role of Hl receptor in Allergic Inflammation

Retno W. Soebaryo

Dept. Dermato-venereology, Fac. of Medicine, Univ.of Indonesia, Jakarta, Indonesia

Introduction: The last steps of allergic reactions are mediated through the histamine bound on histamine receptors (Hl - H4 receptors) on the cellular surfaces of almost every tissue. Hl-receptor is found on bronchus, GI tract, smooth muscle and brain; H2-receptor in gastric mucosal, uterus and brain; H3-receptor in brain, smooth muscle, and bronchus; H4-receptor is expressed on mast cells and eosinophils and important for accumulation and chemotaxis of these cells in inflamed allergic tissue. Acting on the same Hl receptor, histamine is also the mediator of skin itch, although other mediators are also involved, such as tryptase and substance P.

Antihistamines, classified in 3 groups: first generation antihistamine (hydroxycine, promethazine, chlorpheniramine), second generation antihistamine (cetirizine, loratadine, terfenadine), and newer-generation (3^rd generation) antihistamine (levocetirizine, desloratadine, fexofenadine), that block the Hl-receptors are important to the management of allergic disease. The second and newer-generation antihistamines have a highly selectivity for the Hl-receptors, with few or no central nervous system sedative effects, rapid onset of actions, and long half-lives. On going studies revealed a wide variability of pharmacological action of these drugs that implies the application on several variety of disease, especially diseases with allergic inflammation background.

Objective: to emphasize the clinical considerations of the use of antihistamine on diseases with allergic inflammation background.

Discussion: The properties of the newer generation Hl antihistamine to decrease the production and release of certain mediators of allergy, adhesion molecule, several cytokines The anti-allergy, anti-inflammatory and immune-regulatory properties are the considerations for the use in several inflammatory disease in general medicine and in skin diseases such as urticaria and atopic dermatitis. The anti-allergic properties of antihistamine refers to their ability to reduce the synthesis and release of arachidonic acid metabolites and down regulate adhesion molecule (ICAM-l) on epithelial cells at the inflammation sites. As consequences, the production and release of histamine by several cells including basophil is inhibited Antihistamine could interfere eosinophil function by inhibiting chemotaxis and survival of these cells. Release of other inflammatory mediators such as TNF-, IL-l, IL-6 could also be reduced. Other immune-regulatory cytokines, IL-4 and IL-l0 are decreased by H-l antihistamie. These properties of Hl antihistamine are demonstrated on therapeutic dose.

In current, the effect of treatment is not merely measured by the efficacy of the drug based on clinical parameters but also the impact on quality of live, especially concerning itch reduction.

The wide variety of antihistamine availability from different classification enables them to have a role in disease management and give the physician a broader opportunity treat a disease.

As the newer-generation antihistamine, Levocetirizine  is minimally metabolized and excreted unchanged (only 2.4% comprised of metabolite ) through urine and feces. Wheal and flare reaction is block after 1 hour, with the the peak on 6 hour and continued for 24 hours after administration of the drug. Almost no drug to drug interaction (not metabolite by CYP2D6) was observed, with the half-life of 7-8 hours and have a high plasma protein binding and minimal drug toxicity. The low volume of distribution is fundamental for the safety and efficacy of the drug.

Conclusion: The immune-regulatory properties of the newer-generation antihistamine are  potentially fundamental for the use of these drugs in many conditions than merely symptomatic relief. The high selectivity for the Hl receptor, few or no central nervous  system sedative effects, rapid onset of action, and long half-life are the considerations to achieve high level of patients conveinces and compliance and a better quality of  life.

A potent antihistamine : The key to succesful treatment or urticaria

Alexander Kapp, Bettina Wedi

Dept. of Dermatology and Allergology, Hannover Medical University, Germany.

Chronic urticaria involves release of histamine from mast cells and/or basophils, which in turn promotes the classic inflammatory cascade. The resultant symptoms can severely impact sufferers’ quality of life and in severe cases prevent them from leading a normal existence, with consequent burdens on family and society.

Rapid initiation of effective reliable therapy is important in combating chronic urticaria, together with avoidance of triggers or exacerbating factors, if known. Whilst newer immunologically-based therapies are beginning to be developed, antihistamines remain a cornerstone of effective therapy. Treatment should be tailored to individual patient circumstances, but in principle the choice of antihistamine component should be governed by the availability of evidence of rapid and prolonged efficacy specifically in chronic urticaria and evidence of good tolerability and safety. Increasingly, evidence of beneficial effects on patient quality of life is also required for rational selection of an antihistamine from amongst those available.

To assess the management of chronic skin diseases the formal assessment of patient health related quality of life (HRQL) has been included in recent studies. All studies performed so far demonstrate substantial overall impact of CU on HRQL. The Dermatology Life Quality Index (DLQI) has been used in most studies in CU and demonstrated high reliability. A minimal important difference (MID) in the DLQI under treatment exceeding 2.24 to 3.10 indicates that a therapy can be recommended in CU. Levocetirizine is a new single-isomer antihistamine with a proven efficacy on chronic urticaria as documented in two recent clinical studies, which have included effectiveness and quality of life assessments (1,2). Accordingly, it has been shown for levocetirizine 5 mg a MID of 3.3 and 4.9 in the DLQI compared to placebo (3). The main symptom of CU, pruritus, significantly decreased whereas HRQL and productivity significantly increased. Levocetirizine demonstrated favourable effects in histamine-induced wheal and flare reaction experiments in comparison to other non-sedating antihistamines (4). Moreover, Levocetirizine has been shown to be capable of influencing T-lymphocyte immune response in vitro (5).

Fast onset of action, clinical efficacy, improvement of HRQL, safety and cost- effectiveness of levocetirizine are important characteristics, particularly with respect to the current European management guidelines for CU.

1. Kapp A, Wedi B: Chronic urticaria: Clinical aspects, and focus on a new antihistamine, levocetirizine. J Drugs Dermatol 3:632-639 (2004)

2. Kapp A, Pichler WJ: Levocetirizine is an effective treatment in  patient suffering from chronic idiopathic urticaria: a randomize, double-blind, placebo-controlled, parallel, multicenter study. Int J Dermatol 45:469-474 (2006)

3. Kapp A, Demarteau N: Cost effectiveness of  Levocetirizine in chronic idiopathic urticaria: A pooled analysis of two randomized controlled trials. Clin Drug Invest 26:1-11 (2006)

4. Grant JA et al: A double-blind, randomized, single-dose, crossover comparison of levocetirizine with ebastine, fexofenadine, loratadine, mizolastine, and placebo: suppression of histamine-induced wheal-and-flare response during 24 hours in healthy male subjects. Ann Allergy Asthma Immunol 88:190-197 (2002)

5. Gutzmer R, et al. Direct immunomodulatory effects of Levocetirizine on 1ymphocytes. XXII Congress of the EAACI, Paris, 2003.