Efficacy of mizolastine, a new antihistamine, compared with placebo in the treatment of chronic idiopathic urticaria

A two-centre, double-blind, randomized, placebo (P)-controlled, parallel-group study was conducted in the UK to examine the efficacy and safety of mizolastine (M), a new H₁-receptor antagonist, as a once-daily 10-mg dose in chronic idiopathic urticaria. Fifty-six outpatients (M: n = 28; P: n = 28) with a mean age of 38 ± 15 years, a duration of disease of more than 3 years, and symptoms of urticaria at least twice a week in the absence of treatment were recruited. After a single-blind placebo run-in period, patients were allocated to one of two treatment groups and were evaluated after 7 and 28 days. The main characteristics (age, duration of disease, number of urticarial episodes, and total score) of the two groups were comparable at inclusion. Mizolastine was shown to improve the urticaria symptoms: at the end of the study, mizolastine produced a significantly greater decrease in the global symptom score comprising itch, wheals, and erythema (M: 2.1 ± 2.1 vs P: 0.4 ± 2.0; P = 0.002). The patient-rated global discomfort from symptoms measured by visual analog scale was significantly improved with mizolastine (M: 31.4 ± 36.7) compared to placebo (P: 5.4 ± 27.6; P = 0.003), with respectively more M responders (74.1%) than P responders (28.6%, P = 0.001), a responder being a patient with a ≥50% decrease in VAS. Premature dropouts due to lack of efficacy and loss to follow-up mainly occurred at the first evaluation (day 7) and were more often observed in patients in the placebo group ( n = 17) than in the mizolastine group ( n = 8) ( P = 0.031). No serious adverse events were recorded. Somnolence was reported in two mizolastine patients, one of whom discontinued the study. Thus, mizolastine may be considered a new treatment option for the symptoms of chronic urticaria.     

Anti-FcepsilonRIalpha serum autoantibodies in different subtypes of urticaria

BACKGROUND: In recent years, a histamine-releasing anti-FcepsilonRIalpha autoantibody has been demonstrated in about one-third of patients with chronic urticaria. However, its clinical significance is still unclear. The objective was to detect a possible correlation between the occurrence of the anti-FcepsilonRIalpha autoantibody and the clinical type or cause of urticaria. METHODS: Sera from 66 consecutively seen in- and outpatients with various types of urticaria and five healthy controls were examined for the presence of anti-FcepsilonRIalpha autoantibodies with a sandwich ELISA technique. In addition, basophil histamine release was studied in 13 autoantibody-positive sera. RESULTS: Anti-FcepsilonRIalpha autoantibodies were found in 17/48 patients with chronic urticaria, in 2/4 with angioedema, in 1/2 with urticarial vasculitis, and in 2/11 with dermographic urticaria. However, no anti-FcepsilonRIalpha autoantibodies were detected in acute, cold, or delayed-pressure urticaria; in urticaria pigmentosa; or in normal controls. Of all chronic urticaria patients, 22 were classified as idiopathic since no underlying cause could be found. Of this group, seven were seropositive for anti-FcepsilonRIalpha. However, anti-FcepsilonRIalpha was also found in patients who went into remission after treatment of identified causes; namely, in one with type I allergy, one with drug intolerance, one with Helicobacter infection, and six with food intolerance. The autoantibody was also detected in 2/4 patients with associated autoimmune diseases. Functional activity was shown in basophil histamine release in 3/4 autoantibody-positive sera of patients with chronic idiopathic urticaria and in 4/6 autoantibody-positive sera of patients who went into remission after the treatment of underlying causes. CONCLUSIONS: These data confirm that anti-FcepsilonRIalpha autoantibodies in urticaria are mostly found in chronic urticaria. Furthermore, their detection independently of the apparent cause of the urticaria suggests that as yet unidentified mechanisms must be operative, possibly related to the chronic inflammatory process and/or individual predispositions that favor their induction.     

Effects of a pseudoallergen-free diet on chronic spontaneous urticaria: a prospective trial

Background:  Chronic spontaneous urticaria is a skin disorder that is difficult to manage and can last for years. 'Pseudoallergens' are substances that induce hypersensitive/intolerance reactions that are similar to true allergic reactions. They include food additives, vasoactive substances such as histamine, and some natural substances in fruits, vegetables and spices. Eliminating pseudoallergens from the diet can reduce symptom severity and improve patient quality of life.
Aim:  To assess the effects of a pseudoallergen-free diet on disease activity and quality of life in patient's chronic spontaneous urticaria.
Methods:  Study subjects had moderate or severe chronic spontaneous urticaria that had not responded adequately to treatment in primary care. For 3 weeks, subjects followed a pseudoallergen-free diet. They kept a clinical diary, which recorded their wheal and pruritus severity each day, to yield a clinical rating of chronic spontaneous urticaria severity (the UAS4 score). The subjects also completed the DLQI, a validated quality-of-life instrument. Use of antihistamines and glucocorticoids was minimized, recorded, and analysed. Subjects were classified into nine response categories, according to the changes in symptom severity (UAS4), quality of life (DLQI) and medication usage.
Results:  From the 140 subjects, there were 20 (14%) strong responders and 19 (14%) partial responders. Additionally, there were nine (6%) subjects who made a substantial reduction in their medication without experiencing worse symptoms or quality of life.
Conclusions:  Altogether the pseudoallergen-free diet is beneficial for one in three patients. The pseudoallergen-free diet is a safe, healthy and cost-free measure to identify patients with chronic spontaneous urticaria that will benefit from avoiding pseudoallergens.     

Appraisal of the validity of histamine-induced wheal and flare to predict the clinical efficacy of antihistamines

Antihistaminic drugs have been used successfully for many years in the treatment of allergic diseases. Second-generation antihistamines have fewer sedating side effects than first-generation agents, and the number of newer drugs available for clinical use is growing. Various methods have been used to assess antihistaminic activity, the most popular of which is the epicutaneous histamine-induced wheal and flare. This test relies on the ability of epicutaneously injected histamine to bring about the wheal and flare, a neurovascular response that involves reflex vasodilation (flare) and local swelling caused by plasma extravasation (wheal). Antihistamines have been compared on the basis of their ability to block the histamine-induced wheal and flare in the skin. Results of these trials have been applied to predict the global antiallergic efficacy of various antihistamines. This review has examined the reliability of suppression of the histamine wheal and flare reaction in the skin to predict an antihistamine's clinical efficacy in two common allergic diseases, seasonal allergic rhinitis and chronic idiopathic urticaria. Although histamine is one mediator in the allergic response in the skin and nasal mucosa, many other agents are important modulators of the allergic response. In addition, the major structural and functional differences that exist between the nasal mucosa and the skin affect the type of local response. These manifest themselves as differences between the responses to antigen and histamine challenge in the skin and the nose. The allergic responses in these tissues are not simply the consequence of one chemical but are the result of a cascade of interactions among various cells and mediators. The clinical manifestations of these complex interactions obviously cannot be fully replicated by injection of one chemical mediator, histamine, into the outer layer of the skin. Studies with antihistamines have shown that certain drugs, such as cetirizine, are more suppressive than others (loratadine, terfenadine) in controlling the histamine-induced wheal and flare reaction in the skin. When the clinical efficacy of these medications is compared in clinical trials in seasonal allergic rhinitis and chronic idiopathic urticaria, all are equally efficacious in controlling symptoms. Although the histamine-induced wheal and flare reaction can serve as a useful clinical pharmacologic test to assess dose-response relations for an antihistamine, its lack of correlation with clinical responses among antihistamines indicates that this model should not be used to predict or compare clinical efficacies of antihistamines in seasonal allergic rhinitis and chronic idiopathic urticaria. (J Allergy Clin Immunol 1997;99:S798-806.)     

Skin responses to intradermal histamine and leukotrienes C4, D4, and E4 in patients with chronic idiopathic urticaria and in normal subjects

Mast cell inflammatory mediators, such as histamine, and newly formed compounds, such as the leukotrienes, cause wheal and flare when they are injected intradermally into normal subjects and may therefore play a role in the formation of urticaria. The effects of intradermal injections (50 microliters) of six different concentrations of histamine (range, 3.3 x 10(-4) to 3.3 x 10(-9) mol/L) and the leukotrienes C4, D4, and E4 (range, 2 x 10(-4) to 2 x 10(-9) mol/L) have been compared in 10 normal subjects and in 10 patients with chronic idiopathic urticaria. Wheal-and-flare sizes were measured at timed intervals up to 4 hours, and area under the curve for each response over time was calculated. There were no significant differences in leukotriene-induced responses between groups. Maximum sizes of histamine-induced wheal and flare were similar in each group of subjects. There were, however, significant increases in mean areas under the response curve of histamine wheal and flare in the patients with urticaria (wheal, p less than 0.001; flare, p less than 0.001; analysis of variance). These findings demonstrate a prolongation of skin responses to histamine in patients with urticaria and suggest an impaired clearance of histamine (or other vasoactive agents released by histamine) from the skin of these patients.     

Use of cetirizine to investigate non-H1 effects of second-generation antihistamines.

In addition to their increased potency as H1 blockers and their nonsedating effects, the second-generation antihistamines have other unusual and potentially beneficial properties. Evidence is accumulating from several laboratories that at least one of these agents under investigation, cetirizine, may be effective in inhibiting the late reaction. The Johns Hopkins group showed that during the cutaneous late phase response (LPR), histamine release was not altered by cetirizine, 20 mg, pretreatment. The most dramatic effect of cetirizine was attenuation of inflammatory cell migration into the chamber. Eosinophils, neutrophils, and basophils were reduced by about 75% during hours 6 to 8. It can be concluded that cetirizine influences the LPR by causing a reduction in the inflammatory cell infiltrate. Cetirizine, 10 mg, orally once a day also induced a significant decrease in the wheal and flare skin reactions caused by pollen, histamine, and compound 48/80. Cetirizine inhibited eosinophil recruitment and platelet-activating factor (PAF) in skin chambers 24 hours after pollen challenge. We and others have studied the mechanisms of this effect. The release of eosinophil peroxidase induced by PAF and formyl-methionyleucyl/phenylalanine was not attenuated by cetirizine. At therapeutic concentrations, however, cetirizine has a potent inhibitory action in vitro on eosinophil chemotaxis induced either by formyl-methionyleucyl/phenylalanine or PAF and also on IgE-dependent stimulation of platelets. In a separate study in patients with chronic urticaria, cetirizine markedly reduced both the immediate wheal and flare induced by PAF and the delayed reaction at six hours. These results suggest that cetirizine acts on eosinophil migration to inhibit the late reaction.     

Mizolastine

Mizolastine is a second generation antihistamine agent with high affinity and specificity for histamine H(1) receptors. Mizolastine has demonstrated antiallergic effects in animals and healthy volunteers and anti-inflammatory activity in animal models. Double-blind trials have shown mizolastine to be significantly more effective than placebo and as effective as other second generation antihistamine agents, such as loratadine or cetirizine, in the management of patients with perennial or seasonal allergic rhinitis and in patients with chronic idiopathic urticaria. Available data also suggest that prophylactic administration of mizolastine is significantly more effective than placebo and as effective as prophylactic terfenadine in delaying the onset of symptoms of seasonal allergic rhinitis. Mizolastine 10 mg/day is generally well tolerated, with the most common adverse events being drowsiness (7%), fatigue (2%), increased appetite (2%) and dry mouth (2%). In volunteers and patients the incidence of prolonged QT(c) interval was similar in mizolastine and placebo recipients, although mizolastine is contraindicated in those with cardiac disease or hepatic impairment or in those receiving erythromycin, ketoconazole or class I or III antiarrhythmic agents. Tests of psychomotor function in volunteers revealed no impairment after single doses of mizolastine 相似文献   

Mizolastine: antihistaminic activity from preclinical data to clinical evaluation

Mizolastine, a new H₁-receptor antagonist, is highly selective for histamine H₁ receptors and has no anticholinergic, antiadrenergic, or antiserotonin activity. It is rapidly absorbed after oral ingestion, with peak plasma concentrations occurring at 1.5 h. The distribution and terminal elimination half-life values are 2 and 13 h, respectively, in healthy young adult volunteers. Half-life values are longer in the elderly and in subjects with chronic renal insufficiency; however, the differences are not large enough to be clinically relevant or to necessitate a dose adjustment in these populations.
  Mizolastine produces prompt, sustained, peripheral blockade of histamine H₁ receptors in the skin. Suppression of the histamine-induced wheal and flare begins 40–60 min after ingestion of a 10-mg dose, peaks at 3–4 h, lasts for at least 24 h, and does not decrease during regular once-daily dosing. The amount of wheal suppression is comparable to that produced by other leading new H₁-receptor antagonists.
  These pharmacokinetic and pharmacodynamic studies of mizolastine provide its clinical pharmacology 'signature'. They also provide the scientific rationale for recommending a once-daily 10-mg dose and suggest that the efficacy and effectiveness of mizolastine will be widely confirmed in allergic disorders, especially rhinitis and urticaria.     

How not to miss autoinflammatory diseases masquerading as urticaria

Urticarial skin reactions are one of the most frequent problems seen by allergists and clinical immunologists in daily practice. The most common reason for recurrent wheals is spontaneous urticaria. There are, however, several less common diseases that present with urticarial rash, such as urticarial vasculitis and autoinflammatory disorders. The latter include cryopyrin‐associated periodic syndrome and Schnitzler's syndrome, both rare and disabling conditions mediated by increased interleukin‐1 secretion. Apart from the urticarial rash, patients are suffering from a variety of systemic symptoms including recurrent fever attacks, arthralgia or arthritis and fatigue. Autoinflammatory diseases are often associated with a diagnostic delay of many years and do not respond to antihistamines and other treatments of urticaria. Also, the chronic inflammation may lead to long‐term complications such as amyloidosis. It is therefore important not to miss these diseases when diagnosing and treating patients with chronic recurrent urticarial rash. Here, we present clinical clues and tips that can help to identify autoinflammatory disorders in patients presenting with chronic urticarial rash and discuss their clinical picture and management.     

Serological evidence that activation of ubiquitous human herpesvirus‐6 (HHV‐6) plays a role in chronic idiopathic/spontaneous urticaria (CIU)

Acute infection with viral pathogens in the herpesviridae family can trigger acute urticaria, and reactivation of herpesviridae is associated with cutaneous urticarial‐like syndromes such as drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DRESS). Reactivation of latent herpesviridae has not been studied systematically in chronic idiopathic/spontaneous urticaria (CIU). This review proposes that CIU is an inflammatory disorder with autoimmune features (termed ‘CVU’ for chronic viral urticaria), based on serology consistent with the hypothesis that reactivation of a latent herpesvirus or ‐viruses may play a role in CIU. Serology obtained from a cohort of omalizumab (Xolair)‐dependent patients with severe CIU was consistent with previous HHV‐6 infection, persistent viral gene expression and replication. CIU patients also exhibited serological evidence of increased immune response to HHV‐4 (Epstein–Barr virus, or EBV) but not all CIU patients were infected with EBV. These observations, combined with case reports of CIU response to anti‐viral therapy, suggest that HHV‐6, possibly interacting with HHV‐4 in cutaneous tissues, is a candidate for further prospective study as a co‐factor in CIU.     

Serum and cell bound IgE in chronic urticaria

Basophil leucocyte-bound IgE has been investigated in patients with chronic urticaria by the method of reversed anaphylaxis. In this reaction basophil-bound IgE behaves as an antigen, the amount present being inversely proportional to the concentration of anti-IgE producing maximum histamine release. Dose-response curves in which histamine release was plotted against the concentration of anti-IgE failed to reveal any substantial difference in the optimum concentration of anti-IgE for maximum release from basophils of urticarial subjects compared with control subjects, thus suggesting there is no quantitative abnormality of basophil bound IgE in chronic urticaria. However, the magnitude of maximum histamine release by anti-IgE from basophils of urticarial subjects was reduced compared with controls and this was not related to serum IgE concentrations since the mean serum IgE concentration was slightly higher in the urticaria group. Studies of spontaneous and compound 48/80-evoked histamine release in the two groups did not reveal any differences in stability of histamine stores or in the biochemical histamine release mechanism over a wide range of concentrations of 48/80. These results raise the possibility of a qualitative abnormality of basophil bound IgE in chronic urticaria.     

Cutaneous responses to histamine, compound 48/80, and codeine in patients with chronic renal failure

Pruritus is a common symptom associated with chronic renal failure (CRF). But increased plasma histamine levels and skin mast cell proliferation previously reported in these patients did not correlate with the intensity of the pruritus. Since increased mast cell releasability was described in chronic idiopathic urticaria, we attempted to examine whether this mechanism could explain pruritus in patients with CRF. Twenty-five patients with end stage renal failure were skin tested with histamine, codeine, and compound 48/80. There were nine patients on continuous ambulatory peritoneal dialysis, eight patients on hemodialysis, (tested both before and after dialysis) and eight patients with advanced CRF. Wheal area after intradermal injection of three concentrations of the above substances was measured. In general, the wheal areas in all patients with CRF were either similar to or smaller than those of the control group who were without renal impairment. In conclusion, patients with CRF with or without dialysis therapy demonstrated unchanged or decreased skin test responses to histamine, codeine, and compound 48/80. Increased mast cell releasability cannot explain the pruritus in patients with CRF.     

Dermal and bronchial hyperreactivity in urticarial dermographism and urticaria factitia

For investigation of a possible relationship between cutaneous and bronchial hyperreactivity, 74 subjects were grouped according to the presence ( n = 33) or absence ( n = 41) of urticarial dermographism after application of a standardized shearing pressure with a dermographometer (12.7 × 10⁵ Pa). The two groups did not differ in age, sex, smoking habits, presence of urticaria and atopy, or serum IgE levels. Erythema of the dermographic test sites was always significantly greater ( P <0.001) in the group with urticarial dermographism at 2, 4, and 8 min, and cutaneous reactivity with titrated prick tests was significantly increased in this group with low concentrations of histamine, 0.01% and substance P (0.25mM) ( P <0.05). After bronchial provocation with acetylcholine, 51 of the 74 subjects, 25 with and 26 without urticarial dermographism, exhibited bronchial hyperreactivity. However, significantly more subjects with urticarial dermographism had an increase in airway resistance and a decrease in specific airway conductance ( P <0.05). In the subgroup ( n = 9) of subjects with symptomatic urticarial dermographism (urticaria factitia), these differences were even more significant ( P < 0.001). These subjects also had larger skin test reactions and significantly higher IgE levels ( P <0.01). Thus, the present data show an association, which may be based on common mechanisms of allergic inflammation, between cutaneous and bronchial hyperreactivity.     

Histopathology of chronic urticaria

Urticaria of undetermined cause persisting longer than 6 wk is known as chronic idiopathic urticaria (CIU). The differential diagnosis of CIU is lengthy and a skin biopsy may be of value in making a more precise diagnosis. The histopathologic feature that differentiates chronic urticarial lesions from acute urticarial lesions is the presence of a mixed cellular perivascular infiltration, composed mostly of mononuclear cells, surrounding the dermal postcapillary venules. Mast cell numbers in CIU lesions may be increased compared to normal dermis. Various patterns of histopathologic findings have been described in CIU. An understanding of these patterns of infiltrating cells, mediators, cytokines, chemokines and adhesion molecules may provide insight into the mechanism of the cutaneous disease and provide valuable information that will help in the selection of a more effective therapeutic intervention.     

Effect in Man of Oral Terbutaline on Cutaneous Reactions Induced by Allergen and Gold Stimulation

In eight atopic subjects wheal and flare responses to intradermally injected horse dander and histamine were determined alter pretreatment with 5 mg oral terbutaline or placebo in a double-blind cross-over study. In each individual a dose of allergen was used that produced a flare reaction approximately the size of the ED50 for histamine. Pretreatment with terbutaline was found to attenuate both the wheal and the flare reactions to allergen throughout the observation period of 150 min but only the effect on the wheal response reached Statistical significance ( P < 0.01). The responses to histamine were not influenced. In five subjects with cold urticaria, treatment with 2.5 mg terbutaline t.i.d. for a week had no effect on the time period of cold provocation needed to evoke an urticarial lesion.
It is concluded that oral treatment with terbutaline may produce an inhibitory action on allergen induced reactions but that this effect is not strong enough to interfere with clinical skin testing and hence the drug need not to be withdrawn prior to such testing.     

Lack of subsensitivity to mizolastine over 8-week treatment

Mizolastine is a new, nonsedating antihistamine providing satisfactory symptom relief in allergic rhinitis and urticaria. The purpose of this study was to use the wheal and flare skin reactions model to assess the maintenance of the pharmacodynamic effect of mizolastine, administered for 2 months. This double-blind, parallel-group study involved 60 atopic patients randomly allocated, after a J-week placebo run-in, to once-daily 10 mg mizolastine ( n =29) or placebo ( n =31) groups. Treatment continued for 8 weeks. Pricks tests were performed in duplicate with histamine chlorhydrate (10 mg/ml), codeine phosphate (9%), and five increasing concentrations (1–500 reactivity index/ml) of standardized allergen extracts (grass pollen or mites) at days 0,7,28,42, and 56. After 7 days of treatment, inhibition of histamine-induced wheal was -76% and +20%, respectively, with mizolastine and placebo ( P =0.0001), in comparison with baseline; inhibition of flare was -86% and +5%, respectively, with mizolastine and placebo ( P =0.0001). Suppression was maintained to a similar extent throughout the study. Results were consistent between histamine-, codeine-, and allergen-induced tests. Safety was satisfactory in both groups. This study confirms mizolastine as a potent antihistamine which does not induce subsensitivity when taken for 81 weeks, and which can be safely recommended in allergic conditions.     

IL3 effect on basophils histamine release upon stimulation with chronic urticaria sera

BACKGROUND: Chronic urticaria is thought to be an autoimmune disorder in 35-40% of patients because of the presence of an immunoglobulin G (IgG) antibody reactive with the IgE receptor. Patients possessing this antibody are identified by the ability of serum to degranulate donor basophils to release histamine. We questioned whether priming of basophils with interleukin 3 (IL3) would facilitate identification of patients and/or alter the percentage of patients who have a positive assay. METHODS: We incubated 37 chronic urticaria sera with basophils from donors with no urticaria with and without priming with IL3 and compared histamine release in each instance. We also preincubated basophils from a 'non-releaser' with IL3, used these cells to assay chronic urticaria sera, and assessed the contribution of complement. RESULTS: Interleukin 3 increases the amount of histamine release by the sera which is able to activate basophils, but it does not convert negative sera into positive releasers. Interleukin 3 is able to partially reverse 'non-releaser' basophils into cells that respond to chronic urticaria sera, and complement cannot account for the augmentation seen. CONCLUSIONS: Preincubating basophils with IL3 facilitates the identification of sera with anti-IgE receptor antibody but does not affect the percentage of sera designated as positive.     

H2 Antihistamines (Cimetidine) and Allergic-Inflammatory Reactions

Experiments in the skin and synovialis have thrown new light on the allergic-inflammatory reactions. The inflammatory effect of histamine is thus due to stimulation of two different types of receptors in the vessels, i.e. histaminergic H1 and H2 receptors. Both types of receptors are of importance for the immediate cutaneous response to allergens and histamine. Treatment with a combination of H1 antagonists (classical antihistamines) and the H2 antagonist cimetidine will thus cause a much stronger inhibition of the urticarial reactions than treatment with the H1 and H2 antagonist alone. It is therefore probable that a combination therapy could have an advantage over the traditional treatment with classical antihistamines in urticaria and other histamine-mediated skin diseases. Histamine might also be of importance for the swelling of the joints in inflammatory diseases such as rheumatoid arthritis, and clinical trials with H1 and H2 antagonists are in progress.     

慢性荨麻疹非抗组胺药物治疗进展

慢性荨麻疹的一线治疗药物为第二代组胺H1受体拮抗剂,然而部分慢性难治性荨麻疹患者使用常规剂量组胺H1受体拮抗剂没有明显效果.因此,常联合非抗组胺药治疗慢性难治性荨麻疹.根据临床观察,联合治疗慢性荨麻疹的疗效明显优于单独使用组胺H1受体拮抗剂.常用的非抗组胺药物有白三烯受体拮抗剂、糖皮质激素、三环类抗抑郁药、免疫抑制剂、生物制剂等,但是非抗组胺药物的不良反应较多,建议在使用前权衡利弊,使用过程中还应注意监测不良反应的发生.     

Effects of calcineurin inhibitors on an in vitro assay for chronic urticaria

BACKGROUND: Chronic urticaria is a common skin disorder, which causes considerable morbidity. In approximately 40% of cases, patients have an autoimmune disorder in which functional antibodies cause degranulation of mast cells and basophils, and C5a complement augments this in varying amounts from patient to patient. Since the calcineurin inhibitor ciclosporin has been used in chronic autoimmune urticaria, we examined the effect of ciclosporin and other drugs on the release of histamine from basophils when stimulated by sera from patients with chronic autoimmune urticaria. METHODS: Leucocytes from healthy donors were isolated and incubated in varying concentrations of ciclosporin, ascomycin, methotrexate, diphenhydramine or hydroxyzine for 30 min prior to stimulation with serum from urticaria patients known to have functional immunoglobulin (Ig)G antibodies directed against the alpha subunit of the IgE receptor. Histamine release was then measured. RESULTS: Pre-incubating cells with ciclosporin and ascomycin produced dose-dependent inhibition of histamine release when cells were stimulated by sera of urticaria patients, by purified IgG from these sera, but not by C5a. Inhibition was not prevented by C5a receptor blocking antibodies. No inhibition was seen with methotrexate, diphenhydramine or hydroxyzine. CONCLUSIONS: This is the first demonstration of inhibition of histamine release by calcineurin inhibitors employing sera of patients with chronic autoimmune urticaria. These drugs may work by interfering with intracellular signalling in cells following cross-linking of the IgE receptor, but not following stimulation of the C5a receptor.