The Effect of Aspirin during Aspirin "Desensitisation" on Compound 48/80 and Histamine-Induced Skin Responses in Aspirin-Sensitive Asthmatics

In a group of aspirin-sensitive asthmatics we studied skin weal and flare responses to intradermal injections of compound 48/80 and histamine during oral aspirin (ASA) provocation and after ASA "desensitisation". During provocation (bronchospasm accompanied by naso-ocular symptoms) the mean weal area after compound 48/80 increased to about 42.4% (P less than 0.05). Neither the threshold (provocative) doses of ASA nor 600 mg ASA, when given after ASA-desensitisation, significantly influenced the weal reactions to compound 48/80 (mean changes of area were -1.8% and -16.5% respectively). Aspirin did not change flare reactions to compound 48/80 and weal and flare reactions to histamine on any of the three study occasions. Initial (pre-aspirin) weal reactions to compound 48/80 after desensitisation to the threshold ASA doses were significantly reduced, but after desensitisation to 600 mg ASA were significantly increased as compared with the reactions before. These data suggest that ASA-"desensitisation" may influence the skin reactivity to non-specific mast cell degranulating stimulus in ASA-sensitive asthmatics.     

Blood flow in histamine- and allergen-induced weal and flare responses, effects of an H1 antagonist, α-adrenoceptor agonist and a topical glucocorticoid

Allergen has previously been shown to induce a continuous increase in local dermal blood flow after a prick test in allergic subjects, whereas histamine induced, initially, similar peak increases in blood flow of much shorter duration. Blood flow changes induced by histamine and allergen have now been evaluated (i) after pretreatment with a local corticosteroid cream, clobetasole-17-propionate; (ii) after oral administration of the H1-antihistamine loratadine; and (iii) after oral pretreatment with the alpha 1-adrenoceptor agonist pseudoephedrine. Blinded placebo-controlled designs were used in the substudies. Laser doppler flowmetry was used for non-invasive recording of changes in local blood flow intermittently for 24 h after the topical corticosteroid, 6 h for the substudies on loratadine and pseudoephedrine. The size of the immediate weal and flare reactions, as well as late phase reactions, were also determined. Pretreatment with clobetasole-17-propionate cream on the skin for 1 week prior to prick tests did not affect the blood flow response elicited by histamine or allergen, in either the initial part (up to 1 h) or the protracted 24 h determinations. The size of the weal and flare reactions decreased. Loratadine and pseudoephedrine did not reduce the initial allergen-induced increase in blood flow, while lower blood flow compared with placebo pretreatment was noted for the protracted (1-6 h) determinations. Blood flow changes after histamine were unaffected. The histamine-induced weal and flare was inhibited by loratadine more effectively than the corresponding allergen-induced reaction. The weal and flare reactions after histamine and allergen were not changed after pseudoephedrine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative vascular effects of histamine, prostaglandin (PG) D2 and its metabolite 9α, 11β-PGF2 in human skin

In this double-blind study we have investigated the vascular effects of prostaglandin, (PG) D₂, in normal skin and compared these effects with histamine and the initial PGD₂ metabolite 9α, 11β-PGF₂. In eight healthy subjects the vascular response to intradermal injections of histamine, PGD₂, a combination of histamine and PGD₂, and 9α, 11β-PGF₂, was assessed by measurement of the weal and flare area. Histamine caused dose-related increases in weal area ( P <0.01). The weal response due to PGD₂ was greater than saline control only at a dose of 71.0 and 710 nmol ( P <0.05). Because of the small size of the weal produced by PGD₂ when compared with histamine, it was not possible to determine their relative potencies. Histamine and PGD₂ caused dose-related increases in flare area ( P <0.05), and when compared at a response level of 10 cm² and 15 cm², histamine was 45 and 251 ( P <0.01) times more potent than PGD₂ in molar terms. Weal and flare responses due to 9α, 11β-PGF₂ were similar to those observed with the equimolar concentration of PGD₂. The weal and flare responses when PGD₂ and histamine when combined were not significantly different from that predicted by a purely additive effect. We conclude that histamine is likely to be an important mediator contributing towards increased vascular permeability and vasodilatation following immunological activation of skin mast cells in vivo , while PGD₂ and its metabolite 9α, 11β-PGF₂ play only a minor role.     

Mast cells, tissue histamine and eosinophils in early- and late-phase skin reactions: effects of a single dose of prednisolone

Skin prick tests with allergen and histamine were performed on the volar aspect of the forearms in a double-blind, cross-over study with 40 mg of prednisolone and placebo in 16 pollen-allergic subjects. Skin biopsies were taken before any treatment and 15 min (group 1; n = 8) and 6 h (group 2; n = 8) after local challenge with allergen, corresponding to the timing of an early- and late-phase reaction. The specimens were used for the histological evaluation of mast cell and eosinophil density as well as for the determination of the histamine and protein content. The size of the induced weal and flare area as well as of any late-phase reaction was determined using digitized planimetry. The single dose of prednisolone, given 2 h prior to challenge, did not affect the size of the weal and flare response. Only 4 of the individuals developed a visible late-phase response. Eosinophils were virtually absent before allergen exposure, but were already present 15 min after allergen challenge, largely associated with the blood vessels, and were numerous at 6 h. There was, however, no relationship between eosinophil density and the presence or extent of any visual late phase. The mast cells/basophils showed a tendency to increase at the 6-hour determination. The infiltration of eosinophils was blocked by the glucocorticoid. This treatment also induced a difference in the mast cell density at the 6-hour determinations, associated with a similar difference in the histamine content of the biopsy specimens.(ABSTRACT TRUNCATED AT 250 WORDS)     

Topical dermal anaesthesia inhibits the flare but not the weal response to allergen and histamine in the skin-prick test

The effect of topical dermal anaesthesia on the immediate allergic skin reaction was evaluated in a double-blind, randomized, placebo-controlled study. Twenty-one patients with strictly seasonal allergic rhinitis, confirmed by a positive skin test for the respective pollen allergen, were studied in the pollen-free winter months. Skin-prick tests for one pollen allergen and histamine were performed after pre-treatment of the skin for 1 hr with an emulsion of lidocaine and prilocaine (EMLA®) and the equivalent vehicle on different test sites. The skin-prick tests were made with a preloaded standardized test needle (Phazet®). The area of the induced weal-and-flare reaction was measured and subsequently calculated with the help of a digitizer served by a microcomputer. The topical dermal anaesthesia induced a reduction of the flare response to histamine by 49% (P < 0.01) and allergen by 21% (P < 0.05). No reduction of the histamine- and allergen-induced weal response were noted. Our findings indicate that the treatment did not affect the allergen-induced release of inflammatory mediators and the vascular leakage induced by these mediators. However, this study seems to confirm earlier suggestions that the flare response is partly mediated through neural reflex activity as it was ameliorated by topical anaesthesia. Furthermore, from a clinical point of view, this study shows that it is possible to perform a valid skin test, without any associated itching and pain, if only the weal response is taken into account n i the evaluation of the skin-prick test.     

Effect of Terbutaline, a β2-adrenergic Receptor Stimulating Compound, on Cutaneous Responses to Histamine, Allergen, Compound 48/80, and Trypsin

The beta-adrenoceptor stimulating agent terbutaline (2 ng-2 microgram) injected intradermally in eight atopic subjects produced a dose-dependent inhibition of the skin reactions induced by subsequently injected allergen. After injection of 0.5 microgram terbutaline inhibition of the flare and weal responses was demonstrable throughout the observation period of 90 min. The flare response induced by histamine, the histamine liberator compound 48/80 and the proteolytic enzyme trypsin was not inhibited by terbutaline in the doses used, suggesting a selective action of terbutaline on the allergen-induced response. The weal response elicited by histamine and compound 48/80 was slightly reduced by 2 microgram terbutaline. It is suggested that pretreatment of the skin with terbutaline interferes with the ability of the cutaneous mast cells to respond to challenge with allergen and that terbutaline produces this effect in doses lower than those needed to counteract the permeability increasing effect of released mediator substances.     

Effect of topical application with capsaicin on skin responses to bradykinin and histamine in man

Pre-treatment with topical capsaicin is known to induce neuropeptide depletion from sensory nerve endings and it is a useful pharmacological tool to evaluate the contribution of these nerves to skin injury and inflammation. To investigate the relative contribution of sensory neural stimulation to the action of bradykinin and histamine, a randomized, double-blind study has been undertaken evaluating the effect of topical capsaicin pre-treatment on the responses to intradermal injections of both agonists in 12 healthy volunteers. Capsaicin pre-treatment caused significant inhibition of the immediate mean flare responses (95% CI) to both bradykinin (from 51.5 [39.7-63.3] mm2 to 16.2 [8.0-24.5] mm2) (P < 0.01) and histamine (from 108.4 [80.4-136.4] mm2 to 52.3 [37.1-67.1] mm2) (P < 0.01). Topical capsaicin elicited a significant inhibition of the weal response induced by histamine, the mean weal area being reduced from 14.8 (12.6-17.0) mm2 to 12.1 (10.1-14.1) mm2 (P < 0.05). In addition, the effect of topical capsaicin was to completely inhibit the bradykinin induced weal response compared to control, the mean weal area (95% CI) being reduced from 13.4 (11.4-15.4) mm2 to 8.2 (5.3-11.0) mm2 (P < 0.01). Our findings show that repeated topical application with capsaicin led to a significant reduction of the skin responses to intradermal injections with both agonists, and particularly with bradykinin. The weal responsiveness to bradykinin may entirely follow neuropeptide release from sensory nerves within the skin and the same applies to the flare response, although this is not completely inhibited by topical application with capsaicin.     

The effect of cetirizine and loratadine on codeine-induced histamine release in human skin in vivo assessed by cutaneous microdialysis

Objective and Design To determine whether or not cetirizine and loratadine inhibit codeine- induced histamine release in human skin in vivo, we conducted a placebo-controlled double-blind trial in which histamine release was assessed by dermal microdiaysis.Subjects A group of ten normal volunteers were studied, each subject visiting the laboratory on three occasions with intervals of at least 2 weeks between visits.Treatment Cetirizine, loratadine (both 10 mg) or placebo was given orally 4h before provocation of weal and flare responses in the skin by intradermal injection of 25 l of 3 or 10 mg/ml codeine 1 mm from the centre of individual 216 m diameter microdialysis fibres inserted in the dermis.Methods Dialysate was collected at 2 min intervals for 4 min before and 20 min after codeine injection and histamine assayed spectrofluorometrically. Weal and flare responses to codeine were assessed in the opposite arm.Results Histamine concentrations in the microdialysis fibre outflow with 3 and 10 mg/ml codeine were maximal at 2–4 min when 910±156 and 1194±304 nM respectively were found in the placebo group. Cetirizine and loratadine did not modify either the kinetics or total histamine release while significantly (p<0.01) inhibiting weal and flare responses.Conclusions Neither cetirizine nor loratadine inhibited codeine-induced histamine release or modified the time course of its release in human skin in vivo when given in clinically used doses which are sufficient to significantly reduce weal and flare responses.accepted by M. J. Parnham     

Structural and secretory characteristics of bovine lung and skin mast cells: evidence for the existence of heterogeneity

We have examined cells dispersed enzymatically from three different sites in the bovine lung (tracheal mucosa, bronchial mucosa and parenchyma) and the skin, in order to ascertain whether the bovine model could be used to study mast cell heterogeneity. Histochemically there were two sub-populations of mast cells present in both lung and skin (on the basis of toluidine blue staining and the sensitivity to formalin fixation), but their proportions were similar in all sites studied. Skin mast cells contained approximately twice the amount of histamine than their counterparts in the lung (P less than 0.05). Functional heterogeneity was examined by in vitro release of histamine following secretagogue challenge. Calcium ionophore induced a substantial release of histamine; skin mast cells releasing significantly more histamine than any of the lung mast cells (at 10 microM ionophore, 37.1% and 20.7% net histamine release, respectively, P less than 0.05), although the time-course of release from the two tissues was similar. The neuropeptides vasoactive intestinal peptide and somatostatin induced a modest but statistically significant release of histamine from both skin and lung mast cells, whilst substance P only induced histamine secretion from skin mast cells. A range of other potential immunological and non-immunological secretagogues was unsuccessful in eliciting histamine release from mast cells in any of the tissues. We conclude that there were no convincing histochemical differences between mast cells from the sites examined in the lung or skin. Additionally, there was no discernable functional heterogeneity between mast cells within the lung, but functional differences were evident between mast cells of the bovine lung and skin. However, in the absence of a suitable immunological stimulus the bovine model cannot be regarded as a good model of mast cell heterogeneity.     

Investigation into the mechanisms by which nedocromil sodium, frusemide and bumetanide inhibit the histamine-induced itch and flare response in human skin in vivo

BACKGROUND: In a previous study, iontophoresis of nedocromil sodium into human skin in vivo was shown to reduce histamine-induced itch and flare. In asthma, the Na+/K+/2Cl- cotransporter inhibitors, frusemide and bumetanide, have been reported to have many similar actions to nedocromil sodium. OBJECTIVE: To compare the effects of these drugs in the histamine-induced itch, flare and weal response in human skin in vivo and elucidate their site of action. METHODS: Nedocromil sodium, frusemide bumetanide and reversed osmosis water (control), were introduced by iontophoresis into the forearm skin of 10 volunteers in each of two single-blind studies. In study 1, histamine (20 microL of 100 microM) or vehicle was injected into the area of iontophoresis 10 min later. In study 2, histamine or vehicle was injected 5 mm outside the area of iontophoresis so the flare developed over the area of iontophoresis. Itch was scored on a visual analogue scale every 20 s for 5 min, flare areas were assessed using scanning laser Doppler imaging up to 10 min and weal was assessed by planimetry at 10 min. RESULTS: In study 1, nedocromil sodium, frusemide and bumetanide reduced itch scores by 36%, 48% and 34%, respectively, and flare areas by 17%, 26% and 15% respectively (all P<0.05). Weal areas and blood flux in the flare were unaffected. In study 2, itch scores, flare areas and weal areas were not inhibited. Also, blood flux values in areas of drug and water iontophoresis were not different. CONCLUSION: This study has provided evidence to support the hypothesis that nedocromil sodium, frusemide and bumetanide inhibit sensory nerve activation to reduce the itch and flare responses induced by histamine in human skin in vivo. It is likely that inhibition of a Na+/K+/2Cl- cotransporter in the sensory nerve membrane is a possible mechanism of action.     

Cetirizine inhibits bradykinin-induced cutaneous wheal and flare in atopic and healthy subjects

BACKGROUND: Kinins are vasoactive mediators involved in allergic reactions. When applied on the skin or in the nose, bradykinin (BK) elicits inflammation that is poorly affected by previous H1-blockade. The aim of this study was to compare the possible effect of cetirizine (an H1-antagonist) on wheal and flare responses to BK, histamine, and compound 48/80 in atopic and healthy subjects. METHODS: In a randomized, double-blind, crossover study, eight atopic and eight healthy subjects received cetirizine (10 mg/day) or placebo for 3 days before cutaneous tests. Intradermal tests (IDT) and prick tests (PT) were performed with BK (20 nmol/ml for IDT and 20 micromol/ml for PT), histamine (100 microg/ml IDT and 100 mg/ml PT), and compound 48/80 (100 microg/ml IDT and 100 mg/ml PT) as positive controls and saline as negative control. The skin responses were monitored by measurement of wheal and flare areas. RESULTS: BK, histamine, and 48/80 induced wheal and flare reactions in all placebo-treated subjects. Histamine elicited larger wheal and flare reactions than BK and 48/80. IDT with BK induced four- to sixfold larger wheal and flare reaction than PT. No differences in BK-induced wheal and flare were observed between atopic and healthy subjects. In atopic subjects, cetirizine induced a significant reduction of flare reactions after the BK test (80% for IDT, and 94% for PT [P < 0.01]). Moreover, cetirizine reduced significantly BK-induced wheals by 70% for IDT (P < 0.01) and 65% for PT (P < 0.01). A similar inhibiting effect of cetirizine was also observed in healthy subjects. CONCLUSIONS: These findings showed that the wheal and flare reactions induced by BK challenge were markedly inhibited by previous intake of cetirizine. The mechanism by which this effect is mediated cannot be established at present.     

Duration of the antihistaminic effect after discontinuationof ebastine

BACKGROUND: The inhibitory effect of antihistamines on allergen-induced skin reactions can impair the results of allergen skin testing, which are necessary for the diagnosis of atopic diseases. This study was designed to determine the time period required for the inhibitory effect of ebastine on allergen-induced skin reactivity to disappear completely. METHODS: This was a double-blind, placebo-controlled, parallel-group study including 23 out of 27 randomized patients. They received either ebastine 20 mg or placebo once daily for 7 days. At the end of treatment, allergen challenge was performed daily for 7 days. Histamine challenge was performed on day 1 (6 and 24 h) and day 5 after treatment. The wheal and flare surface areas were measured and analyzed. RESULTS: Highly significant inhibition of the wheal and flare response induced by allergen was observed after ebastine treatment on days 1 and 2 as compared with placebo (P < 0.01 for both). The inhibition was reduced, although still significant, by day 3 (P < 0.05). No significant difference was observed by day 4 between the ebastine and the placebo groups. The effects of histamine challenge were significantly reduced in the ebastine compared with the placebo group at day 1 (6 and 24 h), and were similar at day 5 after treatment. CONCLUSION: Our results show that the wheal and flare response to allergen after ebastine discontinuation returns to placebo values after 4 days. Therefore, patients using ebastine need to be antihistamine-free for 4 days before the skin prick test. This is valuable information for the allergologist seeking to diagnose allergen sensitivity.     

Cetirizine inhibits skin reactions but not mediator release in immediate and developing late-phase allergic cutaneous reactions. A double-blind, placebo-controlled study

BACKGROUND: Recent reports have indicated cetirizine, a potent H(1)-receptor antagonist, to possess a number of anti-inflammatory effects, e.g. inhibition of mast cell degranulation and inhibition of leucocyte migration and activation. OBJECTIVE: The aim of this study was to compare the effects of cetirizine on skin responses and mediator release in intact skin in immediate and developing late-phase allergic reactions by microdialysis technique. METHODS: Cetirizine 10 mg once daily or matching placebo were administered to 10 atopic subjects for 6 days followed by a 2-week washout in a randomized, double-blind, placebo-controlled, cross-over trial. Immediate skin test responses to allergen, codeine, and histamine and late-phase reactions to allergen were assessed. The time course of extracellular levels of inflammatory mediators in intact skin were monitored by microdialysis techniques using 2 kDa and 3 MDa cut-off fibers, respectively. RESULTS: Cetirizine significantly reduced immediate weal and flare reactions to allergen, codeine, and histamine. Injection of allergen, but not buffer controls, induced a significant release of histamine, tryptase, prostaglandin D(2), total protein, and eosinophilic cationic protein. No significant increase of leukotriene B(4) and myeloperoxidase was observed. Cetirizine inhibited early total protein extravasation by 40%, but this did not reach a significant level. None of the inflammatory mediators were significantly inhibited by cetirizine. Cetirizine significantly reduced the late-phase skin induration to allergen by approximately 30%. CONCLUSION: Cetirizine potently reduced skin responses in immediate allergic reactions without inhibition of early mediators. These data indicate cetirizine to be a potent H1-receptor antagonist with no effect on mast cell activation. It did not inhibit any of the late-phase mediators, but it reduced the late skin reaction. These data suggest that mediators other than those actually measured may play a significant role in the clinical late-phase reaction.     

Dermal blood flow after local challenges with allergen, histamine, bradykinin and compound 48/80

Blood flow was determined in weal and flare reactions and in late dermal reactions after skin-prick tests with allergen, histamine, bradykinin and compound 48/80 in pollen-allergic subjects. Local blood flow was measured with laser Doppler flowmetry intermittently for up to 48 hr at three distances from the prick centre (2 mm; weal, 15 mm; flare and 30 mm). Continuous recordings were also made in the weal area after challenge with bradykinn and compound 48/80. The size of the induced weal and flare area of all the substances and the late phase after allergen was determined using digitized planimetry. Furthermore, simultaneous determinations of local dermal temperature and blood flow in the weal and flare site were performed intermittently for 6 hr after allergen and histamine challenges. There was a dose-dependent and distance-related increase in blood flow for all the substances tested. The blood flow in the 2-mm registrations had normalized 20 min after bradykinin, 1.5-2 hr after histamine and 3 hr after compound 48/80, while allergen induced a continuous increase in blood flow for more than 24 hr. The area of the weal and flare reaction was dose related for all substances, and a similar dose-dependent increase was noted for the observed dermal late-phase reactions present after allergen. The local temperature after challenge with allergen and histamine was also increased in a distance-dependent manner. These studies suggest that laser Doppler flowmetry is a sensitive and reproducible method to quantify blood flow changes occurring after skin-prick tests. Different putative mediators or mast cell stimulating substances produce various response profiles, all of which differ from those observed after allergen. Temperature measurements after skin-prick tests seem to follow the observed changes in blood flow as measured with laser Doppler flowmetry, which may be why both techniques might reflect changes in capillary blood flow.     

Histamine content and mast cell numbers in tissues of normal and athymic rats

Tissue histamine levels and mast cell numbers were determined in the skin, tongue and jejunum of female rnu/nu and rnu/+ rats aged between 5 and 29 weeks. The tongue and jejunal mucosa of rnu/nu rats had a larger mast cell density and histamine content than rnu/+. There was a marked increase in subepithelial mast cells in the skin of rnu/nu rats compared with their normal littermates, while mast cell numbers in the deep skin layer and the histamine content were similar in the two groups of rat. Subepithelial skin mast cells were smaller, of more variable shape and contained fewer granules than mast cells in the deep dermal layer, and, unlike the latter, did not emit a yellow fluorescence after treatment with o-phthaladehyde. The results indicate that the bulk of the skin histamine is contained in mast cells residing in deep skin layers. They also support the view that the thymus may have a suppressive effect on both mucosal and connective tissue mast cellsin vivo.     

Effect of topically applied local anaesthesia on histamine flare in man measured by laser Doppler velocimetry

The direct and indirect effects of histamine on the cutaneous microvasculature were measured by laser Doppler velocimetry. Histamine (6.51×10^–4 M) was injected intradermally into the forearms of eight healthy subjects following treatment with a topically applied local anaesthetic cream (EMLA) or equivalent placebo. The blood flow at the injection site (0 cm) and at 1 and 2 cm proximally was measured by laser Doppler velocimetry over 80 minutes. Analysis of the changes in magnitude of the hyperaemic responses with time showed no difference at the 0 and 1 cm sites, but a marked reduction was found at the 2 cm site following EMLA treatment (p<0.05). At all three sites the decay of the histamine-induced hyperaemia was faster following EMLA treatment than with placebo (p<0.04). The experiments showed that the indirect effect of histamine on the cutaneous microvasculature in the peripheral flare around the injection site was greatly diminished by prior application of EMLA cream and this supports the neurogenic hypothesis: pre-treatment with EMLA cream did not affect the development of hyperaemia and oedema at the site of histamine injection where the mediator acts directly on the cutaneous microvasculature.     

The substance P receptor on rat mast cells and in human skin

(D-Pro⁴ D-Trp^7,9,10)SP_4–11 (SPA) has been shown to be a competitive antagonist of the histamine releasing action of substance P in rat peritoneal mast cells. Antagonist activity of SPA is expressed in the concentration range 1 to 10 M, but at higher concentrations SPA releases histamine.SPA inhibits the flare response induced by substance P in human skin but is without effect on the wheal response. Up to 12.5 pmol SPA produces neither wheal nor flare response by itself.The structurally related peptide, kassinin, does not cause histamine release from rat mast cells at concentrations up to 10 M whereas the methyl ester of substance P was found to 1.6 times more active than substance P in this respect.The findings are discussed in terms of the classification of substance P receptors and the mechanism of wheal and flare in human skin.     

The effect of capsaicin application on mast cells in normal human skin

Peptides released from sensory nerves during an axon reflex are thought to cause mast cell degranulation, histamine (Hi) release and Hi-induced vasodilatation leading to the flare of the triple response. Capsaicin stimulates peptide release from sensory neurones and causes flarein vivo but does not cause Hi release from mast cellsin vitro. The effects of capsaicin on mast cell degranulation in human skinin vivo has been studied by histological examination of skin biopsies after topical capsaicin (1%) treatment of stratum corneum-denuded forearm in four volunteers. The results show a significant reduction in the visible numbers of mast cells and the appearance of degranulated mast cell ghosts in the skin six hours after capsaicin application. Since capsaicin itself does not release Hi from mast cells, these data suggest that capsaicin-induced release of peptides from neurones could cause mast cell degranulation.     

Immediate and late phase allergic cutaneous reactions are not inducers of unspecific or specific local hyperreactivity

The present study evaluates the possibility of allergen-induced unspecific and specific dermal hyperreactivity with special reference to the presence of late cutaneous reactions and allergen-induced nasal hyperreactivity. Twenty-six patients with strictly seasonal allergic rhinitis participated. All had a positive skin prick test for birch (Betula verrucosa) and/or timothy (Phleum pratense). Ten patients had previously displayed an allergen-induced nasal hyperreactivity and six patients a late cutaneous reaction. An initial skin prick test with a relevant pollen allergen was done in triplicate. The immediate skin reactions were recorded after 15 min and any late-phase reaction after 6 h. Twenty-four hours later the patients were retested. The same pollen allergen was sited in the first flare reaction from the previous day. A histamine prick test was sited in the weal as well as in the third reaction from day 1. A histamine control was also performed in a previously unaffected area. The allergen-induced weal reactions decreased significantly at rechallenge compared with the results from the previous day (P less than 0.05). The histamine tests resulted in similar skin reactions regardless of whether or not they were done on a previous allergen test site. This was true for both specific and unspecific reactions when the subgroups of patients with previously demonstrated allergen-induced nasal hyperreactivity or late-phase skin reactions were evaluated separately. These results indicate that allergen-induced hyperreactivity is not a general feature of allergic inflammation but is a phenomenon restricted to specific sites, such as the airway mucosa.     

Cetirizine inhibits bradykinin-induced cutaneous wheal and flare in atopic and healthy subjects

BACKGROUND: Kinins are vasoactive mediators involved in allergic reactions. When applied on the skin or in the nose, bradykinin (BK) elicits inflammation that is poorly affected by previous H1-blockade. The aim of this study was to compare the possible effect of cetirizine (an H1-antagonist) on wheal and flare responses to BK, histamine, and compound 48/80 in atopic and healthy subjects. METHODS: In a randomized, double-blind, crossover study, eight atopic and eight healthy subjects received cetirizine (10 mg/day) or placebo for 3 days before cutaneous tests. Intradermal tests (IDT) and prick tests (PT) were performed with BK (20 nmol/ml for IDT and 20 micromol/ml for PT), histamine (100 microg/ml IDT and 100 mg/ml PT), and compound 48/80 (100 microg/ml IDT and 100 mg/ml PT) as positive controls and saline as negative control. The skin responses were monitored by measurement of wheal and flare areas. RESULTS: BK, histamine, and 48/80 induced wheal and flare reactions in all placebo-treated subjects. Histamine elicited larger wheal and flare reactions than BK and 48/80. IDT with BK induced four- to six-fold larger wheal and flare reaction than PT. No differences in BK-induced wheal and flare were observed between atopic and healthy subjects. In atopic subjects, cetirizine induced a significant reduction of flare reactions after the BK test (80% for IDT, and 94% for PT [P<0.01]). Moreover, cetirizine reduced significantly BK-induced wheals by 70% for IDT (P<0.01) and 65% for PT (P<0.01). A similar inhibiting effect of cetirizine was also observed in healthy subjects. CONCLUSIONS: These findings showed that the wheal and flare reactions induced by BK challenge were markedly inhibited by previous intake of cetirizine. The mechanism by which this effect is mediated cannot be established at present.