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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, H 1 -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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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.

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.

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.

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.

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.

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.

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.

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.

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.

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., (2004 S. Karger AG, Basel.)

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.

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 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.

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.

Towards understanding how histamine, a vital neurotransmitter, can perform multiple physiological tasks, an analysis of the different proteins that bind histamine is reported here. Their structural comparison reveals conformational rigidity of histamine. Yet, flexibility in the modes of histamine binding has been observed, which appears to suit specific biological roles of the proteins. These results will be helpful in developing specific antihistamines and also in understanding the pharmacological and toxicological profiles of existing antihistamines.

Cumulative clinical and laboratory evidence on histamine and its actions suggests that it has a pathophysiologic role in asthma. These findings have renewed interest in the potential therapeutic role of H1 antihistamines in this disease. A murine model of allergen-induced airway inflammation and methacholine-induced airway hyperresponsiveness has been used to clarify mechanisms of airway function, to identify potential therapeutic targets, and to investigate the effects of the H1-receptor antagonist fexofenadine. Findings suggest that there may be a role for second-generation antihistamines in treating asthma, with patient selection as well as dosing both important therapeutic considerations. Because high-dose therapy may be required to achieve a clinical response, agents with the widest therapeutic window and the lowest potential for sedation would offer the greatest therapeutic potential.

Background: It was the aim of the authors to compare all of the latest second-generation antihistamines and to see if there were significant differences in their efficacy. It is important for ENT specialists to know if these differences exist, as it is for general practitioners trying to choose between these drugs., Methods: In 12 confirmed grass pollen allergic patients the authors performed nasal smears to asses eosinophilia, histamine/grass pollen skin tests, and grass pollen nasal provocation tests. All tests were performed before and after administration of one of five different antihistamines (cetirizine, loratadine, ebastine, fexofenadine, mizolastine) or placebo. The order of administration of antihistamines and placebo was randomised, and patients were not aware of which drug they were given. A decrease in nasal eosinophilia (nasal smear), or nasal or skin reactivity (provocation tests) was looked for., Results: A significant decrease in nasal eosinophilia was observed for all antihistamines but not for placebo. For the grass pollen nasal provocation tests, the decrease was significant for nasal blockage and sneezing; for rhinorrhea there was an insignificant decrease that was true for all antihistamines. A significant reduction in histamine/grass pollen skin test reactivity was also observed for all antihistamines, during an 8 h observation period. A significant difference in efficacy between the different antihistamines could not be found with any of the tests performed., Conclusions: For the newer nonsedating H1-antagonists there appears to be no clinically relevant differences in activities--at least not in our study. Preference of the patient may be the most important factor in making a choice between these drugs.

In recent years there has been a tremendous development in molecular biology and with that an improved understanding of the immunological and inflammatory background for rhinitis. However, this progress has not yet had any influence on diagnosis or choice of treatment. Today it is emphasized that allergic rhinitis is an inflammatory disease. However, the majority of allergic rhinitis symptoms are caused by histamine, which can be released from a non-inflamed mucous membrane. Thus, the role of inflammation may be overestimated as a cause of rhinitis symptoms. It is often claimed that the 2nd generation antihistamines have non-H1 mediated anti-inflammatory effects of clinical significance. However, the large majority of published clinical data speaks against this hypothesis. Corticosteroids do not, as often believed have a general anti-inflammatory effect in the nose. They are highly effective in a disease associated with eosinophil-dominated inflammation (e.g. allergic rhinitis), but not in a disease associated with neutrophil-dominated inflammation (e.g. the common cold). It is recommended that drugs are used merely based on a thorough cost-risk-benefit-patient-compliance analysis in the single patient and disease entity with little attention being paid to the assumed mode of action of the drug, which may or may not be of clinical relevance.

We studied, separately, the effects of the histamine antagonist, fexofenadine hydrochloride, and the leukotriene antagonist, montelukast sodium, and their placebos on airway sensitivity to and recovery from inhaled mannitol in subjects with asthma. Two 180-mg doses of fexofenadine were taken over 14 h, and three 10-mg doses of montelukast over 36 h, with the last dose 5 h before challenge. Fexofenadine reduced sensitivity to mannitol and the PD(15) was (mean [95% confidence interval] 138 [95, 201]) mg versus placebo (51 [25, 106] mg) (p < 0.001). The final percent reduction in FEV(1) with fexofenadine was 20.8 +/- 5.4% and not different from placebo (20.1 +/- 5.3%) (p = 0.7); however, recovery was slower with fexofenadine compared with placebo (p < 0.001). By contrast, montelukast had no effect on sensitivity to mannitol and the PD(15) was 71 [36, 144] mg versus placebo (87 [51, 148] mg (p = 0.35). The total dose of mannitol delivered and the final percent reduction in FEV(1) with montelukast were 171 +/- 142 mg and 21 +/- 4% and for placebo were 182 +/- 144 mg and 20 +/- 5% (p = 0.35, p = 0.59, respectively). However, recovery of FEV(1) to baseline was faster with montelukast, with the area under the percent reduction FEV(1)-versus-time curve reduced (220 +/- 121% change.min) compared with placebo (513 +/- 182% change.min) (p < 0.001). We conclude that whereas histamine is important for the initial airway response, leukotrienes are important in sustaining the airway response to inhaled mannitol.

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.

Urticaria is a common disorder that adversely affects quality of life; work-related and recreational activities are restricted, while rest, sleep, and emotions are seriously disturbed in a significant proportion of patients. The pathogenic mechanisms vary, but cutaneous mast-cell activation with release of histamine and other vasoactive or proinflammatory mediators is thought to be the final common pathway for lesion induction in most cases. A subsequent, but incompletely understood, late-phase allergic reaction seems to prolong the inflammatory process, particularly in certain chronic forms of the disorder. Although histamine is considered an important mediator of urticaria, additional substances, including the cysteinyl leukotrienes (LTs), are putative mediators of the immediate urticarial responses and the inflammatory events that follow in some types of urticaria. A second-generation antihistamine, mizolastine, which exhibits dual activity with selective H1-receptor antagonism and, as shown in animal studies, anti-5-lipoxygenase activity, represents an advance in the treatment of urticaria. It has rapid, potent and sustained action. At the recommended 10-mg dose, mizolastine suppresses the histamine-induced wheal reaction as early as 1 h after oral administration. Compared to placebo, mizolastine significantly reduces overall patient discomfort and pruritus in patients with chronic idiopathic urticaria. Double-blind, placebo-controlled studies have also shown mizolastine to be at least as effective as other second-generation antihistamines. Furthermore, with long-term use of mizolastine over 1 year, a reduction in pruritus and the number of urticarial episodes was maintained with no evidence of tachyphylaxis or tolerance. Mizolastine has also been shown to be an effective treatment for cold-induced urticaria, causing significant delay in the whealing response to the ice-cube test and also reducing the wheal diameter.

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.

IL-5 is known to be closely related to the infiltration, activation and proliferation of eosinophils. In this study, we evaluated the in vivo effects of anti-IL-5 monoclonal antibody (mAb) in the murine model of nasal allergy. The mAb treatment inhibited the antigen-induced late phase eosinophilia, but had no effects on the number of basophilic cells. It also inhibited early phase nasal symptoms, and tended to inhibit histamine hypersensitivity. These findings suggest that IL-5 plays an important role in the pathogenesis of allergic nasal disorders.

Effects of 11 histamine H1 receptor antagonists on IgE-mediated biphasic cutaneous reaction in mice were examined. The immediate phase reaction (IPR) assessed at 1 hour after antigen application was significantly inhibited by all antihistamines examined. The inhibition of IPR by cetirizine and mequitazine were potent, but those by cyproheptadine and diphenhydramine were weak. The later phase reaction (LPR) assessed at 24 hours after antigen application was inhibited by chlorpheniramine, oxatomide, ketotifen, mequitazine, emedastine, terfenadine and azelastine. The inhibition of LPR by emedastine was potent, but those by ketotifen and terfenadine were only partial. Emedastine inhibited both IPR and LPR comparably. Present results indicate that H1 receptor activation is involved in the IPR of the biphasic cutaneous reaction, and that the blockade of H1 receptors at IPR does not contribute to the attenuation of following LPR. Histamine H1 receptor antagonists inhibiting the LPR have a property distinct from H1 receptor antagonism, which may have an additional benefit for the treatment of allergic diseases.

Despite numerous studies, the cardiac actions of histamine are still obscure. Yet, histamine could probably be clinically relevant. It is stored in large amounts in human cardiac tissue, where it is contained in the cytoplasmatic granules of mast cells. Mast cells are present in normal human heart tissue; they are more abundant in diseased human heart tissue where they lie in close proximity to blood vessels and between myocytes. The histamine content of human heart mast cells is comparable to the histamine content of lung parenchymal and skin mast cells. Ultrastructural studies confirmed the presence of mast cells around vessels and between myocytes. Consequently, these cells are easily accessible to circulating antigens, drugs and stimuli that activate the cells to release vasoactive mediators which in turn can exert significant cardiovascular effects. Histamine possesses arrhythmogenic effects and once locally released, may enhance automaticity and induce triggering activity resulting in severe tachyarrhythmias. The major arrhythmogenic effects of histamine consist in increasing sinus rate and ventricular automaticity, and in slowing atrioventricular conduction. In addition, histamine may interfere with depolarization and repolarization through its effects on calcium and potassium currents. These effects are mediated by H2-receptor. Therefore direct activation of histamine receptor can induce cardiac arrhythmias. Consequently, the interference of these histaminergic effects may explain, at least in part, the arrhythmogenic effects described for some second-generation antihistamines, such as terfenadine and astemizole. In this brief review we will discuss the cardiac effects of histamine in experimental animal models and in man, and will review data on the safety of the new second-generation antihistamines, focusing on their cardiotoxic effects.

Contradictory immunohistochemical data have been reported on the localization of N-acetylaspartylglutamate in the rat forebrain, using different carbodiimide fixation protocols and antibody purification methods. In one case, N-acetylaspartylglutamate immunoreactivity was observed in apparent interneurons throughout all allocortical and isocortical regions, suggesting possible colocalization with GABA. In another case, strong immunoreactivity was observed in numerous pyramidal cells in neocortex and hippocampus, suggesting colocalization with glutamate or aspartate. Reconciling these disparate findings is crucial to understanding the role of N-acetylaspartylglutamate in nervous system function. Antibodies to N-acetylaspartylglutamate and a structurally related molecule, N-acetylaspartate, were purified in stages, and their cross-reactivities with protein conjugates of N-acetylaspartylglutamate and N-acetylaspartate were monitored at each stage by solid-phase immunoassay. Reduction of the cross-reactivity of the anti-N-acetylaspartylglutamate antibodies of N-acetylaspartate-protein conjugates to about 1% eliminated significant staining of most pyramidal neurons in the rat forebrain. Utilizing highly purified antibodies, the distributions of N-acetylaspartylglutamate and N-acetylaspartate were examined in several major telencephalic and diencephalic regions of the rat, and were found to be distinct. N-acetylaspartylglutamate-immunoreactivity was observed in specific neuronal populations, including many groups thought to use GABA as a neurotransmitter. Among these were the globus pallidus, ventral pallidum, entopeducular nucleus, thalamic reticular nucleus, and scattered non-pyramidal neurons in all layers of isocortex and allocortex. N-acetylaspartate-immunoreactivity was more broadly distributed than N-acetylaspartylglutamate-immunoreactivity in the rat forebrain, appearing strongest in many pyramidal neurons. Although N-acetylaspartate-immunoreactivity was found in most neurons, it exhibited a great range of intensities between different neuronal types.

N-acetylaspartylglutamate (NAAG) is an endogenous brain dipeptide that satisfies many of the criteria for a neurotransmitter. We have previously identified NAAG immunoreactivity in neurons of the lateral geniculate nucleus (LGN) of the cat and monkey. To determine whether all LGN neurons contain NAAG, we treated sections of cat LGN with affinity-purified antibodies to NAAG and counterstained them with thionin. The larger neurons contained NAAG, but the smaller neurons did not. We treated other sections with antiserum to glutamic acid decarboxylase (GAD), the rate-limiting enzyme in the synthesis of gamma-aminobutyric acid (GABA), in order to label interneurons of the LGN. In these sections, the smaller cells were labeled; the larger neurons were not. We hypothesized that NAAG was present in relay cells, but not interneurons. We used two double-labeling paradigms to test this hypothesis. We combined immunocytochemistry for NAAG using a fluorescent secondary antibody with either (1) fluorescent retrograde tracers (true blue, granular blue, rhodamine beads, or propidium iodide) injected into areas 17 and/or 18 or (2) immunocytochemistry for GAD using a second fluorescent secondary antibody. In the LGN, over 99% of retrogradely labeled cells contained NAAG, but few GAD-positive neurons did. In contrast, neurons of the perigeniculate nucleus contained both NAAG and GAD, demonstrating that staining by one set of antisera did not inhibit staining by the other and that perigeniculate neurons are chemically distinct from the interneurons of the LGN. We conclude that in LGN, the relay cells, which project to visual cortex, contain NAAG, whereas most of the interneurons, which contain GABA, do not.

We have studied the effect of cyclo-oxygenase inhibition and H1-receptor antagonism on the early and late bronchoconstrictor responses to inhaled allergen in mild atopic asthmatics. In the first phase of the study histamine inhalation challenge tests were performed in seven mild, atopic asthmatics 2 h after treatment with placebo or flurbiprofen (50, 100 or 150 mg). Flurbiprofen in these single doses had no effect on histamine reactivity. Ten atopic asthmatics participated in the second phase of the study in which the time course of the bronchoconstrictor response to inhalation of allergen was observed on four separate occasions after treatment with (a) placebo, (b) flurbiprofen, 150 mg, (c) terfenadine 180 mg, and (d) the combination of flurbiprofen and terfenadine. On each occasion subjects inhaled a concentration of allergen (Dermatagaphoides pteronyssinus, grass pollen) that had previously been shown to produce a 30% fall in FEV1 (PC30 allergen). The mean maximum fall in FEV1 during the early reaction was 33.2 +/- 3.3% from the post-saline baseline value following placebo and this was reduced to 27.5 +/- 5.3% after flurbiprofen (n.s.), 20.3 +/- 3.2% after terfenadine (P less than 0.05), and 23.1 +/- 2.3 after the treatment combination (P less than 0.05). Seven subjects developed late asthmatic reactions (LAR) after placebo and in these subjects the mean maximum fall in PEFR during the LAR was reduced from 22.6 +/- 3.1% after placebo to 16.7 +/- 3.2% after flurbiprofen (P less than 0.05), 15.2 +/- 2.3% after terfenadine (P less than 0.05) and 11.5 +/- 3.1% after the treatment combination (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Immediate and late cutaneous reactions were induced in healthy and atopic subjects by anti-IgE challenge and a skin-window technique was used in order to verify if the pattern of cells observed at 24 hr was similar in both groups. The study was first performed under basal conditions, and in a second double-blind cross-over step, it was performed again during treatment with cetirizine 10 mg b.i.d. and terfenadine 60 mg b.i.d. Anti-IgE challenge was followed by a significant eosinophil accumulation in atopic subjects only. Cetirizine significantly inhibited this phenomenon while terfenadine showed a mild non-significant inhibitory effect.

We have attempted to use a potent and selective histamine H1-receptor antagonist terfenadine to allow a larger dose of allergen to be administered to previous single early responders to investigate if an increased dose of allergen could induce a late asthmatic response. Pre-treatment with 180 mg of terfenadine enabled a geometric mean increase in allergen dose of 4.12-fold to be inhaled by eight atopic subjects with mild asthma, who initially were classified as single early responders, with maximal fall in FEV1 3-8 hr after allergen challenge (Lmax) of less than 15% from baseline value. The magnitude of early asthmatic response was similar to that obtained on the control day when allergen challenge was performed in the absence of terfenadine. Two subjects were converted to dual responders with Lmax of 23.1 and 24.3%, which occurred with a 32- and 65-fold increase in allergen dose respectively, and a 6- and 4.9-fold decrease in non-specific airways responsiveness measured as the cumulative provocative concentration of methacholine that caused a 20% fall in FEV1 from baseline. The remaining six subjects failed to achieve an Lmax of greater than 10% even with a 1.29-2.66-fold increase in allergen dose. For the group as a whole an increase in allergen dose was associated with an increase in overall bronchoconstrictor response 3-8 hr after challenge. These results indicate that it is possible to induce a late asthmatic response in a subject who previously demonstrated only an early response by increasing the dose of allergen inhaled.

A radioimmunoassay procedure was developed for the antihistamine terfenadine (alpha[4-(1,2-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1-piperidinebutanol). The keto analog of terfenadine was converted to its O-carboxymethyloxime derivative, which was conjugated to bovine thyroglobulin by a mixed anhydride technique. Rabbits were immunized with the resulting conjugate, and antiserums capable of binding radiolabeled terfenadine were obtained. Tritium-labeled terfenadine was prepared by a combination of exchange and reduction with platinum oxide in the presence of tritium gas, and the procedure yielded a specific activity of 48 Ci/mmole. Plasma containing terfenadine was diluted with sodium carbonate solution and extracted with hexane, and the hexane extracts were evaporated and analyzed. The between-assay coefficient of variation on control samples ranged from 8% at 10 ng/ml to 14% at 1 ng/ml. The lower practical sensitivity limit was at least as low as 0.25 ng/ml (25 pg measured). Two metabolites of terfenadine cross-reacted 16-30% with the antiserum used. However, extraction eliminated essentially all of these compounds. Analysis of plasma samples from human subjects given terfenadine showed marked intersubject variability and low plasma levels.

The effect of the H2-receptor antagonist cimetidine upon H1-receptor antagonist tolerant histamine induced weal and flare responses was studied in nine healthy male subjects taking clemastine 1 mg orally twice a day. After 21 days clemastine therapy, the weal response became tolerant to clemastine but the flare response did not. Cimetidine, 400 mg, did not produce a significantly greater decrease in the area of the H1-receptor antagonist tolerant weal response than in the non-tolerant weal response. The results suggest that histamine mediated skin reactions may develop a tolerance to H1-receptor antagonist therapy that cannot be overcome by the addition of the H2-receptor antagonist cimetidine.

The effect of antihistaminic drugs, histamine and their combinations on the development of anaphylactic shock and the period of repeated resolution doses was studied in rabbit experiments. It was established that administration of dimedrol during sensibilization aggravated while diazolin and histamine attenuated the course of anaphylactic shock and periods of repeated resolution injections. Simultaneous administration of antihistaminic agents and histamine enhanced the allergization of the body. Under conditions reported dimedrol prevented hypertrophy of the adrenals that occurred in response to sensibilization. Meanwhile diazolin did not interfere with the reaction development and histamine stimulated it. Combined administration of the antihistaminic agents and histamine provoked an inhibition of the above reaction of the adrenals to body sensibilization.

In ovalbumin-sensitized guinea pigs, the serum catecholamines were significantly increased 20 or 120 min after antigen injection. The highest serum cathecholamine values were obtained in animals which were selected during a severe state of protracted shock, and in those which died in protracted shock. Antihistamine pretreatment reduced the serum noradrenaline, but not the adrenaline values in anaphylaxis. In urethane anesthesia, the anaphylactic serum catecholamine levels (especially noradrenaline) were lower than in nonanesthetized animals. The adrenaline and noradrenaline content of the adrenals in protracted and in acute anaphylactic shock did not differ from control values.