The CD45dim/CD123bright/HLADRneg BAT in the Anti-histamine Drug Allergy.

No Abstract.

Treatment of chronic spontaneous urticaria: Immunomodulatory approaches.

This paper summarizes and reviews the mechanisms of action and data concerning efficacy of recommended treatments as well as other treatments that have been tested, independently of the outcomes, in the management of chronic spontaneous urticaria. Due to the central role of mast cells, basophils and histamine in the pathophysiology of this disease, H1-antihistamines remain the first-line treatment. However, current knowledge about this complex disease, also recognizes an important role for T lymphocytes, B lymphocytes, and autoantibodies. Implications of these others mediators thus provide further targets for treatment. Indeed, agents previously used to treat other autoimmune and inflammatory diseases, have demonstrated efficacy in chronic spontaneous urticaria and are therefore potential therapeutic alternatives for antihistamine unresponsive patients.

Update on prescription and over-the-counter histamine inverse agonists in rhinitis therapy.

Allergic rhinitis (AR) is associated with histamine-mediated physiologic events. The currently used histamine antagonists are all inverse agonists that bind and inactivate histamine H1 receptors. Second-generation antihistamines are much more H1-receptor selective with less central nervous system penetration than first-generation agents. Antihistamines typically are more effective in seasonal than perennial AR and do not demonstrate significant relief of nasal congestion. The recent availability of some second-generation antihistamines as over-the-counter products clearly places them as the preferred first-line treatment for mild to moderate AR based on safety when compared with first-generation over-the-counter antihistamines. The remaining prescription-only second-generation antihistamines, fexofenadine, desloratadine, and levocetirizine, all have unique attributes. Antihistamines in oral, intranasal, or intraocular formulations will likely remain among the mainstays of allergy therapeutics.

Antiinflammatory effects of H1-antihistamines: clinical and immunological relevance.

Signs supporting antiinflammatory effects of H1-antihistamines were first reported long ago, but their clinical relevance remains controversial, especially with respect to their ability to inhibit the release of histamine and other preformed mediators. Experimental studies have documented that H1-antihistamines may affect several inflammatory events, including chemotaxis and the survival of eosinophils, the expression of adhesion molecules, and the release of chemokines and cytokines from different sources, thus highlighting the potential for a modulation of chronic inflammation and immune responses. Interestingly, a specific inhibitory effect on Th2-type cytokine secretion has been demonstrated for some new generation antihistamines. The mechanisms responsible for the antiinflammatory activity of H1-antihistamines are still unclear, but are presumed to be both receptor-dependent and receptor-independent. Recent findings have indicated the ability of these drugs to down-regulate intracellular signaling pathways, i.e., NF-kappaB. In this article, the current knowledge and novel findings about the antiinflammatory action and mechanisms of H1-antihistamines are briefly reviewed and critically analyzed, from the standpoint of possible clinical implications with special reference to skin disorders.

Clinical and immunologic effects of H1 antihistamine preventive medication during honeybee venom immunotherapy.

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.

Emerging treatment of atopic dermatitis.

Atopic dermatitis is a chronically relapsing eczematous disease of the skin. A wide range of therapeutic regimens has been used for atopic dermatitis. A better understanding of its pathogenesis will also lead to the development of novel approaches to treating this disease. This article reviews the recent advances in allergen-specific sublingual immunotherapy and therapy with antileukotriene drugs, probiotics, mycophenolate mofetil, leflunomide, and intermittent fluticasone propionate ointment, which the authors expect will be clinically useful therapies in the near future.

Practical approach to diagnosis and treatment of ocular allergy: a 1-year systematic review.

PURPOSE OF REVIEW: A 1-year systematic review in the field of ocular allergy was carried out to select new information which may be useful for a practical approach to allergic conjunctivitis. RECENT FINDINGS: Out of the 56 articles listed by PubMed, 27 papers were included in the review following a consensus achieved among the authors who had independently reviewed all abstracts. Selected articles were classified according to their main focus: antihistamines, omalizumab, new treatments for vernal keratoconjunctivitis and inflammatory ocular disorders, and sublingual immunotherapy. SUMMARY: The data reviewed are discussed with the aim of underlining unmet needs and making recommendations for future studies on diagnosis and treatment of ocular allergy which may better guide clinical practice in this important area of allergy and clinical immunology.

Montelukast treatment in children with moderately severe atopic dermatitis.

BACKGROUND: Moderately severe atopic dermatitis makes up nearly one-fifth of children with atopic dermatitis. OBJECTIVE: To determine the clinical and laboratory effects of montelukast in moderately severe atopic dermatitis. METHODS: Randomized, double-blind, placebo-controlled, crossover trial with washout period, conducted from May 2002 to February 2006. The study involved 25 patients, 2-16 years old with dermatitis. Patients received oral montelukast (9 patients, Group B) or placebo (16 patients, Group A) in phase 1, and were crossed over to placebo or montelukast, respectively, for phase 2. Patients included if > 10% of skin was involved and failed response to 2 week conventional treatment. Itching, sleep disturbance, frequency of use of oral antihistamines & topical steroids, severity scores were serially assessed. In addition, eosinophil and serum IgE were serially collected. RESULTS: Most of patients were 6-10 years of age. Both groups had comparable gender distribution. The patients in Group B were more likely to have a history of bronchial asthma (55.6%) or allergic rhinitis (33.3%) than patients in Group A, but were less likely to have a positive history of atopy. While on montelukast, there was a reduction of mean score for itching in phase 2, for sleep disturbance in phase 2, for antihistamines in phase 1, for extent-of-disease in phase 1 and 2, and for severity score in phase 2 and blood eosinophil & IgE in phase 2. CONCLUSION: Montelukast reduces itching, sleep disturbance, disease extent and severity, blood eosinophil count and serum IgE.

Use of antihistamines in pediatrics.

Drugs with antihistamine action are among the most commonly prescribed medicines in pediatrics. According to the International Medical Statistics (IMS), almost two million antihistamine units (in solution) for pediatric use were sold in Spain during 2006--at a cost of nearly 6 million euros. Of this amount, 34% corresponded to first-generation (or sedating) antihistamines. The difficulties inherent to research for drug development increase considerably when the pediatric age range is involved. The use of any medication in this age group must adhere to the strictest safety criteria, and must offer the maximum guarantees of efficacy. For this reason, detailed knowledge of the best scientific evidence available in relation to these aspects is essential for warranting drug use. The first-generation antihistamines have never been adequately studied for pediatric age groups, though they are still widely used in application to such patients. In contrast, studies in children have been made with the second-generation antihistamines, allowing us to know their safety profile, and such medicines are available at pediatric dosages that have been well documented from the pharmacological perspective. The present review affords an update to our most recent knowledge on antihistamine use in children, based on the best scientific evidence available.

Antihistamines in the treatment of chronic urticaria.

Chronic urticaria is highly prevalent in the general population, and while there are multiple treatments for the disorder, the results obtained are not completely satisfactory. The second-generation H1 antihistamines remain the symptomatic treatment option of choice. Depending on the different pharmacokinetics and H1 receptor affinity of each drug substance, different concentrations in skin can be expected, together with different efficacy in relation to the histamine-induced wheal inhibition test--though this does not necessarily have repercussions upon clinical response. The antiinflammatory properties of the H1 antihistamines could be of relevance in chronic urticaria, though it is not clear to what degree they influence the final therapeutic result. Before moving on to another therapeutic level, the advisability of antihistamine dose escalation should be considered, involving increments even above those approved in the Summary of Product Characteristics. Physical urticaria, when manifesting isolatedly, tends to respond well to H1 antihistamines, with the exception of genuine solar urticaria and delayed pressure urticaria. In some cases of chronic urticaria, the combination of H2 antihistamines may prove effective--though only with common liver metabolism (CYP3A4 isoenzyme-mediated) H1 antihistamines, due to the existence of mutual metabolic interferences. The role of leukotriene antagonists associated to antihistamines in application to chronic urticaria remains to be clearly defined.

Nasal allergic response mediated by histamine H3 receptors in murine allergic rhinitis.

BACKGROUND: Histamine is one of the most important chemical mediators causing nasal allergic symptoms, and H1 receptor antagonist have been used as the treatment first choice in nasal allergy. The presence of H3 receptors has also been determined in the human nasal mucosa, but few studies have investigated the involvement of H3 receptors in nasal allergy. OBJECTIVE: We used a murine allergic model to investigate the presence of nasal mucosa H3 receptor mRNA and any H3 receptor agonist or antagonist influences on clinical nasal allergic symptoms. METHODS: H3 receptor mRNA in nasal mucosa was investigated by reverse-transcription polymerase chain reaction. OVA-sensitized mice were given an intraperitoneal injection of H3 receptor agonist or antagonist, and clinical nasal allergic symptoms were scored over 10 minutes after nasal provocation of OVA. Inhibition of nasal allergic symptoms was also examined using an H1 receptor antagonist alone and using a both an H3 receptor agonist and an H1 receptor antagonist. RESULTS: H3 receptor mRNA was identified in the murine nasal mucosa. The H3 receptor agonist (R)-alpha-metylhistamine significantly inhibited clinical nasal allergic symptoms of OVA-sensitized mice. The H3 receptor agonist and H1 receptor antagonist inhibited clinical nasal allergic symptoms in the murine allergic model more strongly than the single drug. CONCLUSION: The foregoing results indicate that H3 receptors are involved in modulation of nasal allergy. H3 receptor agonists can also be useful as a novel therapeutic approach in nasal allergy. Both H3 receptor agonist and H1 receptor antagonist may be more effective than a single drug.

Desloratadine inhibits constitutive and histamine-stimulated nuclear factor-kappaB activity consistent with inverse agonism at the histamine H1 Receptor.

BACKGROUND: The human histamine H1 receptor is constitutively active and exhibits basal activation of nuclear factor-kappaB (NF-kappaB), an important modulator of allergic inflammation. Certain H1 antihistamines have recently been shown to inhibit basal NF-kappaB activity by stabilizing the H1 receptor in an inactive state, a phenomenon called 'inverse agonism'. METHODS: We evaluated the effect of the new H1 antihistamine, desloratadine, on basal and histamine-stimulated NF-kappaB activity and compared it with the activities of other H1 antihistamines. RESULTS: Transiently transfected COS-7 cells co-expressing NF-kappaB-luciferase and the H1 receptor exhibited constitutive NF-kappaB activity. H1 antihistamines reduced basal NF-kappaB activity (rank order of potency: desloratadine > pyrilamine > cetirizine > loratadine > fexofenadine). Histamine stimulated basal NF-kappaB activity 8-fold, which was blocked by H1 antihistamines (rank order of potency: desloratadine > cetirizine > pyrilamine > loratadine > fexofenadine). Neither histamine nor antihistamines had any effect on NF-kappaB activity in the absence of the H1 receptor. CONCLUSIONS: Desloratadine, acting through the histamine H1 receptor, inhibited basal NF-kappaB activity and can thus be classified as an inverse agonist. Inhibition of basal and histamine-stimulated NF-kappaB activity may help to explain previously reported inhibitory effects of desloratadine on allergic inflammatory mediators.

Histamine induces Toll-like receptor 2 and 4 expression in endothelial cells and enhances sensitivity to Gram-positive and Gram-negative bacterial cell wall components.

Histamine is a major inflammatory molecule released from the mast cell, and is known to activate endothelial cells. However, its ability to modulate endothelial responses to bacterial products has not been evaluated. In this study we determined the ability of histamine to modulate inflammatory responses of endothelial cells to Gram-negative and Gram-positive bacterial cell wall components and assessed the role of Toll-like receptors (TLR) 2 and 4 in the co-operation between histamine and bacterial pathogens. Human umbilical vein endothelial cells (HUVEC) were incubated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), or peptidoglycan (PGN) in the presence or absence of histamine, and the expression and release of interleukin-6 (IL-6), and NF-kappaB translocation were determined. The effect of histamine on the expression of mRNA and proteins for TLR2 and TLR4 was also evaluated. Incubation of HUVEC with LPS, LTA and PGN resulted in marked enhancement of IL-6 mRNA expression and IL-6 secretion. Histamine alone markedly enhanced IL-6 mRNA expression in HUVEC, but it did not stimulate proportional IL-6 release. When HUVEC were incubated with LPS, LTA, or PGN in the presence of histamine marked amplification of both IL-6 production and mRNA expression was noted. HUVEC constitutively expressed TLR2 and TLR4 mRNA and proteins, and these were further enhanced by histamine. The expression of mRNAs encoding MD-2 and MyD88, the accessory molecules associated with TLR signalling, were unchanged by histamine treatment. These results demonstrate that histamine up-regulates the expression of TLR2 and TLR4 and amplifies endothelial cell inflammatory responses to Gram-negative and Gram-positive bacterial components.

H1-receptors: localization and role in airway physiology and in immune functions.

Histamine H(1)-receptors are involved in the pathologic processes of allergy. Clinical trials of H(1)-receptor antagonists have demonstrated the efficacy of these agents in reducing the sneezing, pruritus, and rhinorrhea associated with allergic rhinitis. In the lung, H(1)-receptors mediate the bronchoconstrictive effects of histamine and increase vascular permeability, which lead to plasma exudation. H(1)-receptors are present on T cells, B cells, monocytes, and lymphocytes, and stimulation of these receptors induces pro-inflammatory effects. It has been suggested that a signal from the H(1)-receptor contributes to the antigen receptor-mediated signaling pathways that induce proliferative responses and lead to the production of cytokines and antibodies by T cells and B cells, respectively. It would appear, therefore, that the H(1)-receptor has a wider role in inflammatory processes than simply mediating the actions of histamine.

The histamine-cytokine network in allergic inflammation.

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.

Effects of fexofenadine and other antihistamines on components of the allergic response: adhesion molecules.

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.