Cutaneous drug eruption with two antihistaminic drugs of a same chemical family: cetirizine and hydroxyzine

BACKGROUND: H1-antihistamines are widely used to relieve symptoms of allergic disorders. A few skins reactions to H1-antihistamines have been described in the literature. We report the first case of cutaneous drug eruption as fixed drug eruption with 2 antihistamines of the same chemical family: cetirizine and hydroxyzine. CASE REPORT: A 73 year-old man was admitted because of a third cutaneous eruption with the same morphologic features of the same sites as before. The first and second eruption appeared after 4 hours of cetirizine intake, the third eruption appeared after 4 hours of hydroxyzine intake. Healing was obtained after stopping the medication. Histology showed induced drug reaction. Patch tests with cetirizine and hydroxyzine were negative, except false positivity with dimethylsulfoxide vehicles. DISCUSSION: The diagnosis of cutaneous drug eruption as non pigmenting fixed drug eruption related to cetirizine and hydroxyzine was retained. Allergy to both H1 antihistamines can be explained by the fact that they've got the same chemical node that is piperazine, and by the fact that cetirizine is the main metabolite of hydroxyzine. Oral test provocation was omitted because the patient had already reexposed himself to the drugs. To identify the drug responsible for fixed drug eruption, peroral provocation tests are the most valuable method, but carry the risk of a strong reaction. Some authors use patch tests, but their positivity is inconstant. Their interest in fixed drug eruption is undergoing assessment.     

Fixed drug eruption to cetirizine with positive lesional patch tests to the three piperazine derivatives

BACKGROUND: The H1-antihistamine cetirizine, a piperazine derivative widely used in daily practice, is rarely the cause of cutaneous drug reaction. Nevertheless, four cases of fixed drug eruption (FDE) as a result of this drug have been described recently. We present the case of a 45-year-old woman with a multilocalized FDE following oral intake of cetirizine for allergic rhinitis. METHODS: Patch testing with hydroxyzine 1% and 10% in petrolatum (Chemotechnique), and with powdered Zyrtec (cetirizine) and Xyzal (levocetirizine) pills, prepared at 20% in water and at 20% in petrolatum, was performed in both residual lesions and healthy skin. RESULTS: Positive results (++) to these drugs (24 h occlusion and readings at days 2 and 3) were obtained in residual lesions only. These results allowed us to confirm the drug responsible for this FDE and to study cross-reactions between antihistamines of the same chemical family. CONCLUSIONS: To the best of our knowledge, this is the first report of FDE to cetirizine with positive patch testing to hydroxyzine, cetirizine, and levocetirizine. This case highlights the importance of patch testing in the study of cutaneous drug reactions, namely FDE.     

Skin reactions to hydroxyzine

Sensitivity to histamine H1-antagonists has mainly been observed with phenothiazine and ethylenediamine, and is very rare with hydroxyzine. We report 3 cases of sensitization to hydroxyzine, which was prescribed to treat urticaria and atopic dermatitis. A generalized maculopapular eruption appeared shortly after taking the drug. Patch tests with Atarax® tablet were positive +++, and ++ or +++ with different dilutions of hydroxyzine. Patch tests with ethylenediamine, piperazrne and other antihistamines were negative: therefore, there is no cross-allergy. We believe these rapid systemic reactions to hydroxyzine after the initial dose may have been due to prior systemic sensitivity to this drug, which cannot be used topically. Allergy to antihistamines must be considered when cutaneous lesions worsen on such therapy.     

Cutaneous drug eruption induced by antihistamines

Topical application of antihistamines commonly leads to sensitization for patients, but systemic administration of antihistamines rarely induces allergic hypersensitivity, which is mainly linked to phenothiazine‐derived and piperazine‐derived compounds. We report a 70‐year‐old woman whose medical history included lichen planus, and who was referred by the dermatology department of our hospital for suspected allergy to corticosteroids. The reason for referral was that on the fourth day of treatment with prednisone and hydroxyzine, the patient presented a bilateral highly pruritic palmar erythema that evolved to a generalized morbilliform rash with subsequent complete desquamation. At a later time, she took cetirizine for a cold, and developed palmar erythema and desquamation. Skin tests (prick and intradermal tests) were performed with steroids, and patch tests (read after 48 and 96 h) with corticosteroids and antihistamines. Controlled oral challenge tests were performed with prednisone and with an alternative antihistamine. Skin tests were negative for all corticosteroids. Patch tests were negative for all corticosteroids, but the antihistamine test was positive for hydroxyzine. Oral challenge with prednisone and dexchlorpheniramine was negative. The patient was diagnosed with cutaneous drug eruption from hydroxyzine and cetirizine. We consider it is important to assess every patient whose skin condition worsens after treatment with antihistamines, especially hydroxyzine, because it is known that antihistamines are often not recognised as the culprit in cases of cutaneous eruption.     

Multiple H1-antihistamine-induced urticaria

H₁‐antihistamines are widely used in the treatment of various allergic diseases. Particularly, a cornerstone of the management of chronic idiopathic urticaria is treatment with H₁‐antihistamines. However, a few cases of H₁‐antihistamine‐induced urticaria have been reported. A 34‐year‐old woman presented with a 4‐month history of recurrent urticaria, which was prominently exacerbated by the administration of H₁‐antihistamines. The patient consented to a provocation test of fexofenadine among drugs including cetirizine and hydroxyzine, which were suspected of inducing severe symptoms in episodes. One hour after challenge with 12 mg fexofenadine (one‐fifth of the therapeutic dose), a urticarial reaction rapidly developed on nearly the entire body with remarkably increased levels of plasma histamine (190 nmol/L) and plasma leukotriene B4 (150 pg/mL). In challenge tests with other antihistamines, generalized urticaria occurred 5 and 1 h after intake of 10 mg loratadine and 10 mg bepotastine, respectively, whereas challenges with chlorpheniramine, mequitazine and azelastine were all negative. Skin prick tests with H₁‐antihistamines used in the challenges were all negative, indicating that the urticarial reactions after challenges with the causative drugs might not be immunoglobulin E‐mediated. Among the causative drugs in our case, cetirizine and hydroxyzine are the piperazine derivatives, whereas fexofenadine, bepotastine, ebastine and loratadine are the piperidine derivatives. The chemical structures of both derivatives are very similar. Therefore, in this case, H₁‐antihistamine‐induced urticaria may have been due to cross‐reactivity between metabolites of these drugs, but not to drugs before metabolization. Hypersensitivity to H₁‐antihistamines should be considered when urticarial lesions worsen after H₁‐antihistamine treatment.     

Suppression of wheal and flare in histamine test by the main H1 antihistamines commercialized in Brazil

Background:Several dermatoses are mediated by histamine, such as urticaria, angioedema, and papular urticaria. There are no Brazilian studies comparing the potency of antihistamines.Objectives:To evaluate the tolerability and efficacy of the main commercial brand and generic H1 antihistamines, regarding the suppression of the wheal and flare to the histamine test.Methods:A quasi-experimental, open study with 10 healthy adults submitted to the histamine test on the ventral aspect of the forearms. After 20 minutes, wheal and flares were measured. The tests were performed after two hours of intake of dexchlorpheniramine, hydroxyzine, levocetirizine, fexofenadine, cetirizine, loratadine, ebastine, desloratadine, epinastine and rupatadine, as well as generics of loratadine, cetirizine and fexofenadine.Results:All antihistamines presented a reduction in the wheal compared to the control (p <0.02), as well as in the flare, except for rupatadine (p = 0.70). In the internal comparison, cetirizine, fexofenadine, epinastine, levocetirizine, dexchlorpheniramine and hydroxyzine were the most potent, with no difference between them (p > 0.1). As for halo, cetirizine, epinastine, hydroxyzine and fexofenadine were the most potent, with no difference between them (p > 0.1). The most common adverse effect was drowsiness, which was more prevalent among first-generation drugs (p < 0.01). Generic loratadine, fexofenadine and cetirizine halos were higher than their controls (p >0.03)..Study limitations:A single-center study evaluating only aspects related to histamine.Conclusions:Brazilian commercial antihistamines presented different profiles of inhibition of wheal and flares in the histamine test, as well as adverse effects. Generic loratadine, fexofenadine and cetirizine presented larger flares than brand drugs.     

Treatment of Urticaria

Urticaria is a cutaneous syndrome characterized by dermal edema (wheal) and erythema (flare) that blanches with pressure. The lesions typically last less than 24 hours and are usually pruritic. In 1983, Christensen and Maibach summarized the theory behind the use of histamine H₁ receptor antagonists (antihistamines) in clinical dermatology. These agents remain the mainstay of treatment for urticaria. This article reviews the medical literature on the effectiveness of antihistamines in urticarial syndromes, including acute, chronic idiopathic and the physical urticarias. Older antihistamines, such as chlorpheniramine and hydroxyzine, are effective in the treatment of urticarias, but they also have marked sedative and anticholinergic effects. Newer nonsedating antihistamines (second-generation antihistamines) have been developed that have reduced adverse effects because they do not cross the blood-brain barrier; these agents (acrivastine, cetirizine, loratadine, mizolastine, fexofenadine, ebastine, azelastine and epinastine) cause significantly less sedation and psychomotor impairment than their older counterparts. A review of the literature reveals that there are few studies which document the efficacy of second-generation antihistamines in the treatment of acute urticaria, a biologic entity that usually resolves within 3 weeks. We did not identify controlled studies that suggested superiority of any antihistamine in the treatment of acute urticaria. Loratadine or cetirizine, and possibly mizolastine, appear to be treatments of choice for chronic idiopathic urticaria. For symptomatic dermatographism, the combination of an antihistamine and an H₂ antagonist, e.g. chlorpheniramine and cimetidine, appears to be effective. Very few studies have been conducted on the use of antihistamines in the treatment of cold, cholinergic, and pressure urticaria. Antihistamines are the mainstay of urticarial therapy. This evidence-based review suggests that there are efficacy differences between newer, nonsedating antihistamines and older agents in some forms of the disorder. Clearly, further well-controlled clinical trials in larger numbers of patients are needed to clarify the role of these agents in the treatment of urticaria.     

High dose cetirizine: a case report

We report the case of a 46-year-old man who tolerated 50 mg per day of cetirizine for the treatment of chronic idiopathic urticaria. The patient denied any sedation or somnolence and had no difficulty performing routine daily functions including driving. He had tried other antihistamines, including fexofenadine, loratadine, and hydroxyzine without improvement.     

Second- and third-generation antihistamines in the treatment of urticaria

ABSTRACT: Chronic urticaria is mainly idiopathic in nature and can be difficult to treat. While less responsive to antihistamine therapy than acute urticaria, antihistamines still play a key role in the management of symptomatology. While many of the antihistamines still commonly used to treat urticaria are first generation H₁ antagonists (e.g., diphenhydramine, hydroxyzine), the more recently developed second-generation agents (e.g., loratadine, cetirizine) and their metabolites—the third-generation antihistamines (e.g., fexofenadine, norastemizole, descarboxyloratadine)—possess many of the desirable clinical effects of the first-generation agents with a more tolerable side effect profile. This review discusses the advantages and disadvantages of each of the various second- and third-generation agents available, and presents some of the data showing the differences among these agents in the treatment of chronic urticaria.     

Quantitative time course study of the skin response to histamine and the effect of H1 blockers. A 3-week crossover double-blind comparative trial of cetirizine and terfenadine

A controlled, randomized, double-blind, crossover study was performed in 10 healthy volunteers to compare changes of cutaneous blood flow values (CBFV) determined by laser Doppler flowmetry before and after intake of a capsule containing either 10 mg cetirizine or 60 mg terfenadine. After the determination of the initial response to the anti-H1 agents, drugs were taken daily (cetirizine 10 mg, terfenadine 120 mg) over a 3-week period and the cutaneous response to histamine and saline was evaluated weekly, exactly 4 h after the last drug intake. The following significant variations were observed (analysis of variance for repeated measurements, p less than 0.05): (1) there is a decrease of histamine-induced wheal and flare under antihistamines (anti-H1), cetirizine being more potent than terfenadine; (2) CBFV, measured on the usual flare area, i.e. at 1 cm of the site of agonist injection, decreased after drug intake. There was a gradual increase of the CBFV inhibition over the 3-week follow-up, cetirizine being more effective than terfenadine, and (3) at the site of agonist injection, reduction of the edematous wheal was associated with significant increases of CBFV after drug intake. This quantitative pharmacologic in vivo assay on the agonist action indicates that at lower doses, cetirizine has a significantly higher anti-H1 activity than terfenadine and that this effect is maintained over a 3-week period. There was no tachyphylaxis.     

Therapy of acute and chronic urticaria

Background The drug management of chronic urticaria can be divided into three approaches: (i) blockade of released histamine at the receptor sites; (ii) blockade of histamine release from mast cells; and (iii) blockade of other mediators and possible inflammatory and cellular components. The first approach is the most successful and widely used. It primarily involves the use of H₁-antihistamines, although tricyclic antidepressants and H₂-antihistamines also have a place. Treatments The usefulness of classic H₁-antihistamines, such as hydroxyzine, may be limited by side-effects (most notably, sedation). The four most widely used of the newer antihistamines are loratadine, terfenadine, astemizole and cetirizine. These antihistamines are significantly superior to placebo and have similar efficacies comparable with hydroxyzine. Novel agents and methods, including nifedipine, sulphasalazine and plasmapheresis have been tried with some success in refractory patients. Guidelines If acute cases are inadequately controlled, short-term oral corticosteroids may be added. Systemic corticosteroids are occasionally indicated for the management of severe acute urticaria, severe serum sickness, pressure urticaria or urticarial vasculitis, or to break the cycle of a resistant case, but have no place in regular therapy for chronic urticaria. For those with severe acute urticaria with signs of respiratory distress, possible treatments include subcutaneous epinephrine, systemic corticosteroids and intramuscular H₁-antihistamines. Patients with chronic urticaria inadequately controlled on H₁-antihistamines alone may benefit from the addition of a classic antihistamine, a tricyclic antidepressant or an H₂-antihistamine. A short course of systemic corticosteroids may help those with severe chronic refractory disease.     

Treatment of acquired cold urticaria with cetirizine and zafirlukast in combination

Acquired cold urticaria is an infrequent physical urticaria that can provoke severe systemic reactions. Histamine is the primary mediator, but leukotrienes are also involved in the pathogenesis. H(1) antihistamines are recommended as first-choice treatment, but their efficacy is sometimes unsatisfactory. On the basis of pathogenic knowledge, it can be hypothesized that a combination therapy with antihistamines and leukotriene receptor antagonists is more effective than each drug given alone. We tested this hypothesis in 2 patients with severe systemic cold urticaria poorly responsive to conventional therapy. The patients underwent 3 consecutive treatment regimens (each of 2 weeks): cetirizine (10 mg once a day); zafirlukast (20 mg twice a day); and their combination. They were clinically evaluated, after each regimen, by means of a visual analog scale and ice-cube test. The combination therapy was superior to the 2 drugs given alone, as testified by subjective and objective evaluations.     

Evaluation of the efficacy of antihistamines using human monocyte-derived dendritic cells stimulated with histamine

BACKGROUND: It has been reported that histamine induces CD86 expression and chemokine production in human immature monocyte-derived dendritic cells (MoDCs), which can be blocked by both H(1)- and H(2)-receptor antagonists. OBJECTIVE: We sought to examine whether the efficacy of H(1)-type antihistamines can be assessed by using MoDCs. METHODS: We examined the suppressive effects of 1 H(2)-type antihistamine (cimetidine) and 5 different H(1)-type antihistamines (cetirizine, diphenhydramine, ketotifen, olopatadine, and emedastine) on the induction of CD86 and IL-8 production by MoDCs from 23 healthy individuals stimulated with histamine. We also examined the responses of MoDCs from 13 patients with chronic urticaria to these antihistamines, and compared the in vitro efficacy with the actual clinical response to antihistamines evaluated by patient and physician assessments. RESULTS: All the antihistamines we examined suppressed the increase of CD86(+) cells after histamine stimulation in a dose-dependent fashion, and all H(1)-type antihistamines were more efficacious than cimetidine. IL-8 production stimulated with histamine was also suppressed by cetirizine, ketotifen, and olopatadine. Unexpectedly, the suppressive effect of these antihistamines on the CD86 augmentation was highly variable among different healthy control participants. Interestingly, in 10 of 13 cases of chronic urticaria, this in vitro analysis of antihistamines correlated with the clinical response to antihistamines. CONCLUSION: This study suggests that the evaluation of antihistamines using MoDCs can be a useful method for the screening of effective antihistamines, for the comparison of the efficacy of antihistamines, and for predicting the efficacy of antihistamines on an individual basis.     

Chronic urticaria: a role for newer immunomodulatory drugs?

Chronic urticaria is now recognized as an autoreactive disorder in a substantial fraction of patients. A serologic mediator of whealing has been demonstrated in 50-60% of patients with chronic urticaria, and autoantibodies against the high affinity IgE receptor or IgE have been detected in about half of these patients. The demonstration that chronic urticaria is frequently autoimmune has encouraged a more aggressive therapeutic approach, with the use of immunomodulatory drugs.A step-by-step approach to the management of chronic urticaria is proposed, based on our personal experience and review of current medical literature, identified through Medline research and hand searching in medical journals. The non- or low-sedating H(1) receptor antagonists (antihistamines), such as cetirizine, fexofenadine, loratadine, mizolastine and, more recently, levocetirizine, desloratadine and ebastine, represent the basic therapy for all chronic urticaria patients. Older sedating antihistamines, such as hydroxyzine and diphenhydramine, may be indicated if symptoms are severe, are associated with angioedema, and if the patient is anxious and disturbed at night.Corticosteroid therapy with prednisone or methylprednisolone can be administered for a few days (7-14) if urticarial symptoms are not controlled by antihistamines and a rapid clinical response is needed. In cases of relapse after corticosteroid suspension, leukotriene receptor antagonists, such as montelukast and zafirlukast, should be tried. In our experience, remission of urticarial symptoms can be achieved in 20-50% of chronic urticaria patients unresponsive to antihistamines alone. When urticaria is unremitting and is not controlled by combined therapy with antihistamines and leukotriene receptor antagonists, prolonged corticosteroid therapy may be needed. Long-term corticosteroid therapy should be administered at the lowest dose able to control urticarial symptoms, in order to minimize adverse effects. In a few patients, however, high-dose corticosteroid therapy may have to be administered for long periods. In these patients, immunosuppressive treatment with low-dose cyclosporine can be started. This type of treatment has a corticosteroid-sparing effect and is also generally effective in patients with severe, unremitting urticaria, but requires careful monitoring of cyclosporine plasma concentration and possible adverse effects. Other immunomodulating drugs that have been tried in chronic urticaria patients include hydroxychloroquine, dapsone, sulfasalazine and methotrexate, but their efficacy has not been proven in large controlled studies. Warfarin therapy may also be considered in some patients with chronic urticaria and angioedema unresponsive to antihistamines.     

The effects of astemizole, cetirizine and loratadine on the time course of weal and flare reactions to histamine, codeine and antigen

An open cross-over study was performed to assess the effects of astemizole, cetirizine and loratadine on weal and flare reactions to intradermal histamine, codeine and house dust mite antigen. Percentage inhibition of weal area, flare area and weal volume was greatest for cetirizine, then astemizole and smallest for loratadine. Wealing due to mast-cell degranulation with either codeine or antigen was less inhibited by all three antihistamines than that due to histamine itself. Time-course studies revealed similarities between wealing provoked by codeine and histamine but different characteristics to that induced by antigen.     

Effects of acrivastine, loratadine and cetirizine on histamine-induced wheal and flare responses

It is accepted that studies evaluating histamine-induced wheal and flare reactions in the skin represent a simple and reliable method for demonstrating pharmacodynamic activity and pharmacokinetics of the H1-receptor antagonists. In this study, the effects of single oral doses of acrivastine (8 mg), loratadine (10 mg) and cetirizine (10 mg) on the histamine-induced wheal and flare reactions were compared in 60 healthy volunteers. The wheal and flare responses were produced by prick test using 1% histamine solution. Measurements were performed before the ingestion of antihistamines (baseline values) and afterwards at 15, 30, 90, 240, 360 min and 24 h. The values obtained for each antihistamine were compared with each other and with baseline values. Cetirizine was found to be superior to acrivastine and loratadine for the suppression of wheal and flare responses at 240, 360 min and 24 h (P < 0.05) and acrivastine was superior to the other two antihistamines for the suppression of flare response at 30 min (P < 0.05). Our results indicate that a single dose of cetirizine provides a more effective and long acting suppression on wheal and flare reactions in urticaria when compared to acrivastine and loratadine.     

Solar urticaria: pre-PUVA UVA desensitization

BACKGROUND: Solar urticaria is an uncommon disorder sometimes difficult to treat. It is characterized by the occurrence of typical whealing reactions on exposed skin a few minutes after sun exposure. The reactions resolve 1 to 5 hours after sun exposure ceases. We report a case evolving over several years, unresponsive to antihistamines and successfully treated by PUVAtherapy performed after UVA desensitization. CASE REPORT: For 3 years, a 22-year-old man developed erythema and itchy wheals at each solar exposure. The lesions appeared on all exposed areas including those usually exposed (face and hand) even in winter. An antihistamine regimen given for several weeks (cetirizine, loratadine) was ineffective. One trial of PUVA therapy led to an urticarial reaction of the entire body. Phototesting showed the minimal whealing dose for UVA was 0.4 J/cm(2). Phototherapy was therefore started by segmentary UVA irradiation at an initial dose of 0.1 J/cm(2). Exposure was then progressively increased allowing initiation of the PUVAtherapy on the 9(th) day with a dose of 0.5 J/cm(2) without whealing reaction. Slow increment PUVA therapy was able to induce good tolerance to sun exposure. DISCUSSION: Solar urticaria may sometimes have a deleterious effect on normal daily life. Severe cases are characterized by a whealing reaction after minimal sun exposure, even on regularly exposed skin. Antihistamines can provide some symptom relief in many patients, but high doses are required. If antihistamines are ineffective, PUVA therapy is indicated. Pre-PUVA UVA desensitization is often necessary. However, exposure to UVA alone has to be repeated every 24 to 48 hours to maintain the refractory state. The advantage of PUVA therapy is a more long lasting protection allowing weekly maintenance sessions.     

Combined H1 and H2 antihistamine therapy in chronic urticaria

Chronic urticaria is a frustrating problem for the patient and the physician. The cause is usually undetermined, and the therapy is directed toward controlling symptoms. Recent evidence that human skin blood vessels possess H2 receptors, as well as the commonly recognized H1 receptors, suggests a possible reason for the frequent failure of H1 antihistamines in controlling this disorder. Eighteen patients with refractory chronic idiopathic urticaria participated in a double-blind, cross-over study to evaluate the efficacy of combined H1 (hydroxyzine hydrochloride) and H2 (cimetidine) antihistamines vs H1 antihistamines alone. This study indicates that combined H1 and H2 antihistamine therapy is statistically more effective than H1 antihistamines alone in controlling the symptoms of chronic urticaria.     

Effects of loratadine and cetirizine on serum levels of neuropeptides in patients with chronic urticaria

H1‐receptor inhibiting drugs, namely loratadine and cetirizine, were frequently used in treatment of chronic urticaria. Urticarial weal and flare reactions, a neurogenic reflex due to neuropeptides, were reported to be more effectively inhibited by cetirizine than loratadine. The aim of this study was to determine and compare the effects of systemic loratadine and cetirizine treatments on serum levels of selected neuropeptides in chronic urticaria. Treatment groups of either systemic loratadine or cetirizine (10 mg/d), consisting of 16 and 22 patients, respectively, were included. Serum levels of stem cell factor (SCF), neuropeptide Y (NPY), calcitonin gene‐related peptide (CGRP), nerve growth factor (NGF), vasoactive intestinal peptide (VIP), and substance P (SP) were detected before and after one week of treatment with antihistamines. Serum NPY and VIP levels were significantly decreased when compared before and after treatment with antihistamines (P < 0.001 and P < 0.01, respectively). SCF and NGF values were also decreased after antihistamine treatment (P < 0.05). Post‐treatment levels of CGRP were significantly higher compared with pretreatment values, while no significant difference was detected between pre and post treatment levels of SP. Cetirizine was significantly more effective than loratadine on lowering serum levels of SCF among the other neuropeptides. Systemic loratadine and cetirizine treatments in patients with chronic urticaria precisely caused variations in serum levels of neuropeptides. The predominant effect of cetirizine compared to loratadine on reducing serum SCF levels might be explained with anti‐inflammatory properties of cetirizine.     

Effects of antihistamines on cutaneous reactions and influx of eosinophils after local injection of PAF, kallikrein, compound 48/80 and histamine in patients with chronic urticaria and healthy subjects.

The effects of one week's daily treatment with dexchlorpheniramine (3 + 3 mg x 2) and loratadine (10 mg x 2) on the cutaneous reactions to putative mediators of urticarial reactions were studied in healthy subjects and in patients with chronic urticaria. Biopsy specimens were taken from skin with delayed reactions and studied immunohistochemically for the presence of eosinophilic cationic protein (ECP). In healthy subjects both antihistamines significantly decreased the weal and flare induced by histamine and the histamine releaser compound 48/80. They also reduced the flare seen after injection of PAF (platelet activating factor) and kallikrein. In patients with chronic urticaria the delayed reactions to PAF and kallikrein were larger than in healthy subjects. The immediate flare seen after injection of histamine, 48/80 and PAF, and the delayed reaction to 48/80, were significantly decreased by treatment with loratadine. No correlation was found between the clinical response and test reactions. In the group of healthy subjects, eosinophils were increased in the skin of all subjects after intradermal injection of 100 micrograms of PAF and in 50% after 1 microgram of PAF, but no eosinophils were seen after injection of 1 ng of PAF. In patients with chronic urticaria the eosinophils were increased at all sites where 1 ng of PAF had been injected and also at a limited number of sites of injection of histamine, 48/80, kallikrein and saline. Treatment with the antihistamines had no effect on the influx of eosinophils in the skin.