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Background: H1 antihistamines increase safety during allergen-specific immunotherapy and might influence the outcome because of immunoregulatory effects., Objective: We sought to analyze the influence of 5 mg of levocetirizine (LC) on the safety, efficacy, and immunologic effects of ultrarush honeybee venom immunotherapy (BVIT)., Method: In a double-blind, placebo-controlled study 54 patients with honeybee venom allergy received LC or placebo from 2 days before BVIT to day 21. Side effects during dose increase and systemic allergic reactions (SARs) to a sting challenge after 120 days were analyzed. Allergen-specific immune response was investigated in skin, serum, and allergen-stimulated T-cell cultures., Results: Side effects were significantly more frequent in patients receiving placebo. Four patients receiving placebo dropped out because of side effects. SARs to the sting challenge occurred in 8 patients (6 in the LC group and 2 in the placebo group). Seven SARs were only cutaneous, and 1 in the placebo group was also respiratory. Difference of SARs caused by the sting challenge was insignificant. Specific IgG levels increased significantly in both groups. Major allergen phospholipase A(2)-stimulated T cells from both groups showed a slightly decreased proliferation. The decrease in IFN-gamma and IL-13 levels with placebo was not prominent with LC, whereas IL-10 levels showed a significant increase in the LC group only. Decreased histamine receptor (HR)1/HR2 ratio in allergen-specific T cells on day 21 in the placebo group was prevented by LC., Conclusions: LC reduces side effects during dose increase without influencing the efficacy of BVIT. LC modulates the natural course of allergen-specific immune response and affects the expression of HRs and cytokine production by allergen-specific T cells.

Intercellular adhesion molecules (ICAMs), in particular ICAM-1, appear to play a crucial role in the recruitment and migration of inflammatory cells to the site of an allergic reaction. Glucocorticoids and allergen-specific immunotherapy have been shown to exert effects on selected components of this system, both in vitro and in vivo, but further research is required to better understand the effects of these therapies. Nasal and conjunctival challenge models (including natural and experimental allergen exposure) represent useful and safe tools for studying the activity of antiallergy drugs in vivo. These tests allow the investigation of a wide variety of parameters including inflammatory infiltrate, ICAM-1 expression, and changes in the concentration of soluble inflammatory mediators. With these tools, anti-inflammatory activity related to the modulation of epithelial cell adhesion molecules has been demonstrated in vivo for several H(1)-receptor antagonists (azelastine, cetirizine, loratadine, levocabastine, oxatomide, and terfenadine). Fexofenadine is a nonsedating, long-acting antihistamine with highly selective H(1)-receptor antagonist activity and a particularly favorable safety profile. In addition, fexofenadine has proven anti-inflammatory activity and has been shown to inhibit a number of mediators at clinically relevant concentrations, including in vitro inhibition of ICAM-1 expression on conjunctival and nasal epithelial cells.

Histamine is synthesized and released by human basophils, mast cells, and neurons. Its pleiotropic effects are mediated by the activation of 4 receptors: H(1), H(2), H(3), and H(4). With the advent of selective antagonists (the antihistamines widely used to treat allergic disorders), the H(1)-receptor was the first member of the receptor family to be pharmacologically defined. Increasing evidence indicates that, in addition to exerting immediate vascular and bronchial responses, histamine might modulate the immune reaction by interacting with T cells, macrophages, basophils, eosinophils, and monocytes. We have shown that, in vitro, histamine induces a concentration-dependent release of IL-6 and beta-glucuronidase from macrophages isolated from the human lung parenchyma. These effects are inhibited by fexofenadine, an H(1)-receptor antagonist, but not by ranitidine, an H(2)-receptor antagonist. This observation raises the possibility that long-term treatment with fexofenadine might have beneficial effects on immune dysregulation and tissue damage/remodeling associated with histamine-mediated macrophage activation.

The primary mechanism of antihistamine action in the treatment of allergic diseases is believed to be competitive antagonism of histamine binding to cellular receptors (specifically, the H1-receptors), which are present on nerve endings, smooth muscles, and glandular cells. This notion is supported by the fact that structurally unrelated drugs antagonize the H1-receptor and provide clinical benefit. However, H1-receptor antagonism may not be their sole mechanism of action in treating allergic rhinitis. On the basis of in vitro and animal experiments, drugs classified as H1-receptor antagonists have long been recognized to have additional pharmacological properties. Most first-generation H1-antihistamines have anticholinergic, sedative, local anaesthetic, and anti-5-HT effects, which might favourably affect the symptoms of the allergic response but also contribute to side-effects. These additional properties are not uniformly distributed among drugs classified as H1-receptor antagonists. Azatadine, for example, inhibits in vitro IgE-mediated histamine and leukotriene (LT) release from mast cells and basophils. In human challenge models, terfenadine, azatadine, and loratadine reduce IgE-mediated histamine release. Cetirizine reduces eosinophilic infiltration at the site of antigen challenge in the skin, but not the nose. In a nasal antigen challenge model, cetirizine pretreatment did not affect the levels of histamine and prostaglandin D2 recovered in postchallenge lavages, whereas the levels of albumin, N-tosyl-L-arginine methyl ester (TAME) esterase activity, and LTs were reduced. Terfenadine, cetirizine, and loratadine blocked allergen-induced hyperresponsiveness to methacholine. In view of the complexity of the pathophysiology of allergy, a number of H1 antagonists with additional properties are currently under development for allergic diseases. Mizolastine, a new H1-receptor antagonist, has been shown to have additional actions that should help reduce the allergic response. In animal models, mizolastine inhibits antigen-induced eosinophil infiltration into mouse skin and into the nasal cavity of guinea-pigs. Mizolastine also significantly inhibits antigen-induced neutrophil infiltration into the bronchoalveolar lavage fluids of guinea-pigs. In addition, it inhibits arachidonic acid-induced paw oedema in rats without affecting carrageenin-induced rat paw oedema, suggesting an effect on LT generation. In man, mizolastine inhibits early and late antigen-induced soluble intercellular adhesion molecule 1 (ICAM-1) levels in skin blisters. It also inhibits anaphylactic release of histamine from rodent mast cells, LTC4 and LTB4 release from mouse bone-marrow-derived mast cells, LTC4 release from rat intestinal mast cells, and 5-lipoxygenase activity of polymorphonuclear neutrophils of guinea-pig intestines and rat basophilic leukaemia cells. It is clear that a number of H1-antihistamines have multiple effects on the allergic inflammatory response. It is equally clear that these antiallergic effects are not uniformly shared among all drugs of this class. The assessment of the clinical significance of these results and research regarding the parts of the molecules responsible for these activities are underway.

Symptoms of allergic rhinitis include sneezing; itching of the eyes, nose, and throat; nasal obstruction; and rhinorrhoea; they may be seasonal or perennial, depending on the causative allergen. The major symptom of perennial allergic rhinitis is nasal obstruction. Sneezing and rhinorrhoea are often present, but are less troublesome than in seasonal allergic rhinitis. Symptom relief is a priority in allergic rhinitis because patients have a severely impaired quality of life. The nasal vascular system is complex. Histamine acts on postcapillary venules during both the immediate and late phase of reactivity and causes plasma extravasation. Other inflammatory mediators can also induce this reaction. Thus, histamine antagonists that also have some additional antiallergic properties have advantages in the treatment of allergic rhinitis. Mizolastine is a second-generation antihistamine that has been shown, in experimental studies, to possess 5-lipoxygenase inhibitory properties in addition to its H1-receptor antagonistic activity. In the treatment of seasonal allergic rhinitis, mizolastine 10 mg/day has been shown to be effective in reducing nasal and ocular symptoms. It has been shown to be significantly more effective than placebo with a greater percentage of responders. Another study has shown that symptoms of seasonal allergic rhinitis in mizolastine-treated patients were reduced more significantly than in cetirizine-treated patients on the second and third days of treatment. In perennial allergic rhinitis, mizolastine significantly improved symptoms of nasal obstruction compared with placebo and also significantly reduced nasal membrane colour, nasal secretions, and mucosal swelling as shown by rhinoscopy. These effects were maintained over a 5-month treatment period. Mizolastine has also been shown to be at least as effective as loratadine, and in one trial even superior in the treatment of perennial allergic rhinitis.